CA2557848A1 - Ion binding compositions - Google Patents
Ion binding compositions Download PDFInfo
- Publication number
- CA2557848A1 CA2557848A1 CA002557848A CA2557848A CA2557848A1 CA 2557848 A1 CA2557848 A1 CA 2557848A1 CA 002557848 A CA002557848 A CA 002557848A CA 2557848 A CA2557848 A CA 2557848A CA 2557848 A1 CA2557848 A1 CA 2557848A1
- Authority
- CA
- Canada
- Prior art keywords
- shell
- pharmaceutical composition
- core
- shell component
- solute
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000027455 binding Effects 0.000 title claims description 115
- 239000000203 mixture Substances 0.000 title abstract description 115
- 239000011258 core-shell material Substances 0.000 claims abstract description 107
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 66
- 238000000034 method Methods 0.000 claims abstract description 65
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 47
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 38
- 239000010452 phosphate Substances 0.000 claims abstract description 38
- 150000002500 ions Chemical class 0.000 claims abstract description 28
- 239000011734 sodium Substances 0.000 claims abstract description 20
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 16
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 16
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 230000000069 prophylactic effect Effects 0.000 claims abstract description 11
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- 201000000523 end stage renal failure Diseases 0.000 claims abstract description 5
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- 206010007558 Cardiac failure chronic Diseases 0.000 claims abstract description 3
- 206010016803 Fluid overload Diseases 0.000 claims abstract description 3
- 208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 3
- 208000028208 end stage renal disease Diseases 0.000 claims abstract description 3
- 229920000642 polymer Polymers 0.000 claims description 103
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- -1 iron ion Chemical class 0.000 claims description 30
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- 230000002209 hydrophobic effect Effects 0.000 claims description 22
- 238000000576 coating method Methods 0.000 claims description 21
- 229910001410 inorganic ion Inorganic materials 0.000 claims description 21
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 21
- 241001465754 Metazoa Species 0.000 claims description 20
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- 239000000463 material Substances 0.000 claims description 19
- 201000005991 hyperphosphatemia Diseases 0.000 claims description 18
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 14
- 229910001415 sodium ion Inorganic materials 0.000 claims description 14
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 13
- 238000003786 synthesis reaction Methods 0.000 claims description 13
- 229920001400 block copolymer Polymers 0.000 claims description 12
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 11
- 229910052742 iron Inorganic materials 0.000 claims description 11
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- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 9
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 claims description 9
- 229910001425 magnesium ion Inorganic materials 0.000 claims description 9
- 229920000083 poly(allylamine) Polymers 0.000 claims description 9
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
- 208000013038 Hypocalcemia Diseases 0.000 claims description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 7
- 230000000705 hypocalcaemia Effects 0.000 claims description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000004971 Cross linker Substances 0.000 claims description 6
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- 231100000765 toxin Toxicity 0.000 claims description 6
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- 208000002682 Hyperkalemia Diseases 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 238000009505 enteric coating Methods 0.000 claims description 5
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003131 biological toxin Substances 0.000 claims description 4
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- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 claims description 3
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- 239000011612 calcitriol Substances 0.000 claims description 3
- 229940109239 creatinine Drugs 0.000 claims description 3
- 230000000994 depressogenic effect Effects 0.000 claims description 3
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- 206010027417 Metabolic acidosis Diseases 0.000 claims description 2
- 230000001195 anabolic effect Effects 0.000 claims description 2
- FPIGOBKNDYAZTP-UHFFFAOYSA-N 1,2-epoxy-3-(4-nitrophenoxy)propane Chemical compound C1=CC([N+](=O)[O-])=CC=C1OCC1OC1 FPIGOBKNDYAZTP-UHFFFAOYSA-N 0.000 claims 2
- YZUMRMCHAJVDRT-UHFFFAOYSA-N 2-(hexadecoxymethyl)oxirane Chemical compound CCCCCCCCCCCCCCCCOCC1CO1 YZUMRMCHAJVDRT-UHFFFAOYSA-N 0.000 claims 2
- LWIOWIKKGKNURV-UHFFFAOYSA-N 2-[[5-nonyl-2-[4-nonyl-2-(oxiran-2-ylmethyl)phenoxy]phenyl]methyl]oxirane Chemical compound C1OC1CC1=CC(CCCCCCCCC)=CC=C1OC1=CC=C(CCCCCCCCC)C=C1CC1CO1 LWIOWIKKGKNURV-UHFFFAOYSA-N 0.000 claims 2
- 229920006037 cross link polymer Polymers 0.000 claims 2
- 125000003055 glycidyl group Chemical group C(C1CO1)* 0.000 claims 2
- 229920000559 poly(Bisphenol A-co-epichlorohydrin) Polymers 0.000 claims 2
- YHRUOJUYPBUZOS-UHFFFAOYSA-N 1,3-dichloropropane Chemical compound ClCCCCl YHRUOJUYPBUZOS-UHFFFAOYSA-N 0.000 claims 1
- BUSYHRRDAMGPJN-UHFFFAOYSA-N 2-(2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoroheptoxymethyl)oxirane Chemical compound FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)COCC1CO1 BUSYHRRDAMGPJN-UHFFFAOYSA-N 0.000 claims 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims 1
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- 239000011575 calcium Substances 0.000 description 14
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- 230000000694 effects Effects 0.000 description 13
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 12
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 12
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- 229910052791 calcium Inorganic materials 0.000 description 11
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- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 10
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F120/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
- C08F120/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F120/04—Acids; Metal salts or ammonium salts thereof
- C08F120/06—Acrylic acid; Methacrylic acid; Metal salts or ammonium salts thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F128/00—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a bond to sulfur or by a heterocyclic ring containing sulfur
- C08F128/02—Homopolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a bond to sulfur or by a heterocyclic ring containing sulfur by a bond to sulfur
Abstract
The present invention provides methods and compositions for the treatment of ion imbalances. In particular, the invention provides core-shell compositions and pharmaceutical compositions thereof. Methods of use of the core-shell compositions for therapeutic and/or prophylactic benefits are disclosed herein. Examples of these methods include the treatment of phosphate imbalance disorders, hypertension, chronic heart failure, end stage renal disease, liver cirrhosis, chronic renal insufficiency, fluid overload, or sodium overload.
Description
ION BINDING COMPOSITIONS
CROSS-REFERENCE
[0001] This application is a continuation-in-part of U.S. Application Serial No.
10/965,274, filed October 13, 2004 which is a continuation-in-part application of U.S.
Application Serial No. 10/814,527, filed March 30, 2004; U.S. Application Serial No.
10/814,749, filed March 30, 2004; and U.S. Application Serial No. 10/813,872, filed March 30, 2004 which are incorporated herein by reference in their entirety.
INTRODUCTION
[0002] Ion selective sorbents have been used in human therapy to correct disorders in electrolyte balance, in conditions such as hyperphosphatemia, hyperoxaluria, hypercalcemia, and hyperkalemia. Hyperphosphatemia occurs in patients with renal failure, whose kidneys no longer excrete enough phosphate ions to compensate exogenous phosphate uptake in the diet. This condition leads to high serum phosphate concentration and high calcium x phosphate product. Although the etiology is not fully demonstrated, high calcium x phosphate product has been held responsible for soft tissue calcification and cardiovascular disease. Cardiovascular disease is the cause of death in almost half of all dialysis patients.
CROSS-REFERENCE
[0001] This application is a continuation-in-part of U.S. Application Serial No.
10/965,274, filed October 13, 2004 which is a continuation-in-part application of U.S.
Application Serial No. 10/814,527, filed March 30, 2004; U.S. Application Serial No.
10/814,749, filed March 30, 2004; and U.S. Application Serial No. 10/813,872, filed March 30, 2004 which are incorporated herein by reference in their entirety.
INTRODUCTION
[0002] Ion selective sorbents have been used in human therapy to correct disorders in electrolyte balance, in conditions such as hyperphosphatemia, hyperoxaluria, hypercalcemia, and hyperkalemia. Hyperphosphatemia occurs in patients with renal failure, whose kidneys no longer excrete enough phosphate ions to compensate exogenous phosphate uptake in the diet. This condition leads to high serum phosphate concentration and high calcium x phosphate product. Although the etiology is not fully demonstrated, high calcium x phosphate product has been held responsible for soft tissue calcification and cardiovascular disease. Cardiovascular disease is the cause of death in almost half of all dialysis patients.
[0003] Aluminum, calcium, and, more recently, lanthanum salts have been prescribed to control phosphate ion absorption in the gastrointestinal (GI) tract and restore systemic phosphate levels back to normal. However these salts liberate soluble aluminum and calcium canons in the GI tract, which are then partially absorbed into the blood stream.
Aluminum absorption can cause serious side effects such as aluminum bone disease and dementia; high calcium uptake leads to hypercalcemia and puts patients at risk for coronary calcification.
Aluminum absorption can cause serious side effects such as aluminum bone disease and dementia; high calcium uptake leads to hypercalcemia and puts patients at risk for coronary calcification.
[0004] Metal-free phosphate binders such as strong base ion-exchanger materials, Dowex and Cholestyramine resins, have been suggested for use as phosphate binders.
However, their low capacity of binding requires high dosage that is not well tolerated by patients.
However, their low capacity of binding requires high dosage that is not well tolerated by patients.
[0005] Amine functional polymers have been described as phosphate or oxalate binders.
For example, see 5,985,938; 5,980,881; 6,180,094; 6,423,754; and PCT
publication WO
95/05184. Renagel, a crosslinked polyallylamine resin, is a phosphate sequestering material introduced in the market as a metal-free phosphate binder. Ih vitro phosphate binding of Renagel is approximately 6 mmol/gm in water and 2.5 mmol/gm when measured in 100mM sodium chloride solution. The recommended dosage for the targeted patient population is typically between 5 gms/day to 15 gms/day to keep the phosphate concentration below 6 mg/dL. Published phase I clinical trials on Renagel, performed on healthy volunteers, indicate that 15 gms of Renagel decrease the phosphate urinary excretion from a baseline of 25 mmole to 17 mmole, the difference being excreted in the feces as free and polymer-bound phosphate. From these data, the iii vivo capacity range can be established at 0.5-1 mmol/gm, which is much less than the ifa vitro capacity of 2.5 mmol/gr measured in saline. Considering only the ih vitro binding capacity of Renagel measured in saline, a dosage of 15 gm of the 2.5 mmol/gm phosphate binder would bind the entire phosphorous content of the average American diet, i.e. 37 mmol/day. The discrepancy between the ih vitro binding capacity and the documented low in vivo binding capacity has a negative impact on the therapeutic benefit of the drug since more resin is needed to bring the serum phosphate to a safe range.
For example, see 5,985,938; 5,980,881; 6,180,094; 6,423,754; and PCT
publication WO
95/05184. Renagel, a crosslinked polyallylamine resin, is a phosphate sequestering material introduced in the market as a metal-free phosphate binder. Ih vitro phosphate binding of Renagel is approximately 6 mmol/gm in water and 2.5 mmol/gm when measured in 100mM sodium chloride solution. The recommended dosage for the targeted patient population is typically between 5 gms/day to 15 gms/day to keep the phosphate concentration below 6 mg/dL. Published phase I clinical trials on Renagel, performed on healthy volunteers, indicate that 15 gms of Renagel decrease the phosphate urinary excretion from a baseline of 25 mmole to 17 mmole, the difference being excreted in the feces as free and polymer-bound phosphate. From these data, the iii vivo capacity range can be established at 0.5-1 mmol/gm, which is much less than the ifa vitro capacity of 2.5 mmol/gr measured in saline. Considering only the ih vitro binding capacity of Renagel measured in saline, a dosage of 15 gm of the 2.5 mmol/gm phosphate binder would bind the entire phosphorous content of the average American diet, i.e. 37 mmol/day. The discrepancy between the ih vitro binding capacity and the documented low in vivo binding capacity has a negative impact on the therapeutic benefit of the drug since more resin is needed to bring the serum phosphate to a safe range.
[0006] This loss of capacity of ion-exchange resins is not limited to Renagel when used in the complex environment of the GI tract environment. For example, cation exchange resins in the sodium or ammonium form have been administered to patients with hyperkalemia. The exchange capacity of these resins were measured from isolated feces and found to be about 20% of the ifa vitro capacity (Agarwal, R., Gastroenterology, 1994, 107, 548-571).
[0007] Although generally safe from a toxicological perspective, the large dose and inconvenience associated with taking multigram amounts of resin (e.g., up to 15 gms/day for Renagel and considerably higher in the cases of sodium-binding resins) argues for the need to improve resin capacity. As an example, even in reported safety studies of the Renagel binder, patients have noted gastrointestinal discomfort at doses as low as 1.2-2.0 gm/day for an 8 week treatment period. Patients receiving 5.4 gm of Renagellday were discontinued from treatment due to adverse events such as GI discomfort in 8.9% of the cases (Slatapolsky, et al Kidney Int. 55:299-307, 1999; Chertow, et al Nephrol Dial Transplant 14:2907-2914, 1999). Thus, an improvement in in vivo binding capacity that _2_ translates to lower, better tolerated dosing would be a welcome improvement in resin-based therapies.
[0008] As a result of these considerations there is still a great need for safe, high-capacity binders that selectively remove ions from the body with a lower drug dosage and a better patient compliance profile.
SUMMARY OF THE INVENTION
[0008] As a result of these considerations there is still a great need for safe, high-capacity binders that selectively remove ions from the body with a lower drug dosage and a better patient compliance profile.
SUMMARY OF THE INVENTION
[0009] In one aspect, the present invention provides core-shell compositions and pharmaceutical compositions thereof. The core-shell compositions of the present invention comprise of a core component and a shell component. In a preferred embodiment, the core of the core-shell composition is a polymer and can preferentially bind one or more target solutes, e.g., in the gastrointestinal (GI) tract of an animal. In another preferred embodiment, the permeability of the shell component is modified based on the extenial environment.
(0010] Another aspect of the invention provides methods for treatment of patients using the core-shell compositions described herein. In a preferred embodiment, the core-shell compositions are used to remove target solutes from the GI tract. Examples of target solutes that can be removed from the GI tract include, but are not limited to, phosphate, oxalate, sodium, chloride, protons, potassium, iron, calcium, ammonium, magnesium, urea, and creatinine. In another preferred embodiment, the compositions described herein are used in the treatment of hyperphosphatemia, hypocalcemia, hyperparathyroidism, depressed renal synthesis of calcitriol, tetany due to hypocalcemia, renal insufficiency, ecotopic calcification in soft tissues, hypertension, chronic heart failure, end stage renal disease, liver cirrhosis, fluid overload, sodium overload, hyperkalemia, metabolic acidosis, renal insufficiency, and anabolic metabolism.
BRIEF DESCRIPTION OF THE FIGURES
BRIEF DESCRIPTION OF THE FIGURES
[0011] FIG. 1 is a schematic representation of one embodiment of a core-shell composition.
[0012] FIG. 2 depicts the solute binding profile as a function of time for some embodiments of the invention.
[0013] Figure 3 depicts the membrane preparation for determination of ion permeability.
(0014] Figure 4 depicts the binding data of different polyethyleneimine coated beads for different cations.
[0015] Figure 5 depicts the effect of a Eudragit RL 100 shell on magnesium and potassium binding.
[0016] Figure 6 depicts binding of magnesium on benzylated polyethyleneimine coated Dowex (K) beads.
[0017] Figure 7 depicts the stability of Ben(84)-PEI coated Dowex (K) beads under acid conditions representative of the acidic conditions in the stomach.
[0018] Figure 8 depicts potassium and magnesium binding by Dowex beads coated with benzylated polyethyleneimine.
[0019] Figure 9 depicts magnesium binding by fluoroacrylic acid beads with benzylated polyethylene imine shell.
[0020] Figure 10 depicts a setup for determining membrane permeability.
[0021] Figure 11 depicts the permeability of benzylated polyethyleneimine membrane.
[0022] Figure 12 depicts the permeability and permselectivity of membranes comprising of mixtures of Eudragit RL100 and Eudragit RS 100.
[0023] Figure 13 depicts the effects of bile acids on potassium binding by Dowex(Li) coated with polyethyleneimine.
DETAILED DESCRIPTION OF THE INVENTION
DETAILED DESCRIPTION OF THE INVENTION
[0024] The present invention provides core-shell polymeric compositions. Also, methods and kits for using these compositions are described herein.
CORE SHELL COMPOSITIONS
CORE SHELL COMPOSITIONS
[0025] One aspect of the invention is a core-shell composition comprising a core component and a shell component. In a preferred embodiment, the core-shell composition is a polymeric composition and the core component can preferentially bind one or more target solutes, e.g., in the gastrointestinal (GI) tract of an animal. The term "animal" and "animal subject" as used herein includes humans as well as other mammals.
[0026] As shown in Fig. 1, in one embodiment, the core-shell composition comprises core-shell particles with a core component 2 and a shell component 4. The core component is capable of preferentially binding one or more target solutes and the shell component has a higher permeability for the target solutes compared to the permeability for one or more competing solutes. The size of the arrows in Fig. 1 corresponds to the magnitude of the permeability of the solutes. In preferred embodiments, the shell of the core-shell composition is essentially not disintegrated during the period of residence and passage through the gastro-intestinal tract.
[0027] The term "target solute" as used herein means a solute that is preferentially bound and/or retained by the core component of the core-shell composition. It is preferred that the target solute has a higher permeability across the shell compared to one or more competing solutes. In preferred embodiments, the shell preferentially allows contact of the target solute with the core. Target solutes include both ions and non-ionic molecules.
The ions include both organic and inorganic ions. The ions also include hydrophilic ions, hydrophobic ions, hydrophilic neutral molecules, and hydrophobic neutral molecules.
Examples of anionic target solutes include phosphate, chloride, bicarbonate, and oxalate ions. Examples of cationic target solutes include protons, sodium, potassium, magnesium, calcium, ammonium, and other heavy metal ions. Target solutes also include toxins such as uremic toxins. Examples of uremic toxins include urea, creatinine, and classes of compounds such as ribonucleosides, guanidines, polyols, peptides, purines, pyrimidines. See Vanholder et al., Kidney International, vo1.63, (2003), 1934-1943.
The ions include both organic and inorganic ions. The ions also include hydrophilic ions, hydrophobic ions, hydrophilic neutral molecules, and hydrophobic neutral molecules.
Examples of anionic target solutes include phosphate, chloride, bicarbonate, and oxalate ions. Examples of cationic target solutes include protons, sodium, potassium, magnesium, calcium, ammonium, and other heavy metal ions. Target solutes also include toxins such as uremic toxins. Examples of uremic toxins include urea, creatinine, and classes of compounds such as ribonucleosides, guanidines, polyols, peptides, purines, pyrimidines. See Vanholder et al., Kidney International, vo1.63, (2003), 1934-1943.
[0028] In one embodiment, the target solutes excludes high molecular weight molecules like proteins, polysaccharides, and cell debris whose molecular weight are greater than about 50,000 daltons, preferably greater than 5000 daltons. Taxget solutes also include non-ionic molecules such as organic and inorganic neutral molecules, as well as hydrophilic and hydrophobic neutral molecules. For example, the non-ionic molecules include biological toxins, enzymes, metabolites, drugs, bodily secretions, hormones, etc.
Typically, the toxins bound by the compositions disclosed herein axe less than about 10,000 daltons, preferably less than 5000 daltons, and even more preferably less than 2000 daltons. The compositions disclosed herein with suitable properties could be used to treat toxicities caused by uremia, drug overdoses or exposure to toxins such as biological toxins or chemical contaminants.
Typically, the toxins bound by the compositions disclosed herein axe less than about 10,000 daltons, preferably less than 5000 daltons, and even more preferably less than 2000 daltons. The compositions disclosed herein with suitable properties could be used to treat toxicities caused by uremia, drug overdoses or exposure to toxins such as biological toxins or chemical contaminants.
[0029] In one embodiment, the core-shell particle preferably binds target solutes, excluding bile acids. In another embodiment, the core-shell particle preferably binds a bile acid and one additional target solute which is not a bile acid.
[0030] The term "competing solute" as used herein means solutes that compete with the target solute for binding to a core component, but that are not desired to be contacted and/or bound to the core component. Typically, the competing solute for a core-shell composition depends on the binding characteristics of the core and/or the permeability characteristics of the shell component. A competing solute can be prevented from contacting and/or binding to a core-shell particle due to the preferential binding characteristics of the core component and/or the decreased permeability of the shell component for the competing solute from the external environment. Typically, the competing solute has a lower permeability from the external environment across the shell compared to that of the target solute. For example, for a core-shell composition with a core component that preferably binds phosphate ions, an example of a competing solute is bile acids and fatty acids. The bile acids and fatty acids can be kept away from the core and not be allowed to bind to the core due to the permeability barrier created by the shell component that is more permeable to phosphate ions than bile acids.
[0031] In one embodiment, the target solute is hydrophilic ions. The core-shell polymeric compositions which have hydrophilic ions as target solutes are preferably used to remove hydrophilic ions from physiological fluids. More preferably, such core-shell compositions have utility in selectively removing phosphate, oxalate and/or chloride anions. In another embodiment, the hydrophilic ions removed are sodium and/or potassium ions.
[0032] It is preferred that the core component of the core-shell particles preferentially binds at least one target solute. The term "preferential binding" and its grammatical equivalents are used herein to describe the favored binding of the target solute to the core component and/or core-shell particles compared to the binding of competing solutes. The preferential binding of target solute can be due to a higher binding affinity for target solutes compared to competing solutes. Preferential binding also encompasses an increased amount of binding of target solutes by the core component, compared to the binding of competing solutes. In some of the preferred embodiments, the core-shell particles bind a greater amount of target solute compared to the core by itself in the absence of the shell. The increased amount of binding can be from about 5% to 100%. It is preferred that the increase in binding of target solute in the presence of the shell compared to the amount bound in the absence of the shell is about 10% or greater, more preferred is about 25% or greater, even more preferred is about 50% or greater, and most preferred is about 95% or greater.
[0033] It is also preferred that the core-shell particles retain a significant amount of the bound target solute. The term "significant amount" as used herein is not intended to mean that the entire amount of the bound target solute is retained. It is preferred that at least some of the bound solute is retained, such that a therapeutic and/or prophylactic benefit is obtained. Preferred amounts of bound target solutes that are retained range from about 5% to about 100%. It is preferred that the core-shell compositions retain about 50% of the bound target solute, more preferred is about 75%, and even more preferred is greater than 95%. The period of retention of the bound sodium is preferred to be during the time that the core-shell composition is being used therapeutically and/or prophylactically. In the embodiment in which the core-shell composition is used to bind and remove target solutes from the gastro-intestinal tract, the retention period is preferred to be during the time of residence of the composition in the gastro-intestinal tract. For a topical preparation or a core-shell composition used for a local effect, the retention time is typically the period the composition is present on the topical location or the location that the local effect is desired.
[0034] In one embodiment, the core component is composed of polymers containing functional groups with specific binding properties for a given solute, i.e.
the target solute.
The fiuictional groups with the desired binding properties can be incorporated in the polymer backbone or pendant to the backbone. The binding interactions between the target solutes and the functional groups of the binding core can be of various kinds including, but not limited to, acid-base, coulombic, dipolar, hydrogen bonding, covalent binding, P; interaction, and combinations thereof.
the target solute.
The fiuictional groups with the desired binding properties can be incorporated in the polymer backbone or pendant to the backbone. The binding interactions between the target solutes and the functional groups of the binding core can be of various kinds including, but not limited to, acid-base, coulombic, dipolar, hydrogen bonding, covalent binding, P; interaction, and combinations thereof.
[0035] In different embodiments of the invention, the preferential binding between the target solute and the competing solutes can be controlled by the rate of sorption of solutes within the core material or by the rate of permeation of the solutes across the shell _7_ component. That is, it is possible to modify the affinity of a target solute for the core component by modifying the overall permeation rate across the particle while keeping the binding core characteristics constant. Also, it is possible to reverse the selectivity for a set of solutes for a given binding core, by creating a permeability coefficient difference in the shell.
[0036] Some of the characteristics of the shell membrane and the solutes that influence the permeation of solutes across the core-shell particles are:
size and shape of the hydrated solute;
degree of association/aggregation of the solute (e.g., when micelles are formed);
charge of the solutes;
hydration ratio of the shell;
mesh size of the shell; and interaction between shell and solutes.
size and shape of the hydrated solute;
degree of association/aggregation of the solute (e.g., when micelles are formed);
charge of the solutes;
hydration ratio of the shell;
mesh size of the shell; and interaction between shell and solutes.
[0037] Other parameters also influence the overall mass transfer of solutes to the interior of the core-shell particles:
specific surface area (i.e. particle diameter);
thickness of the shell; and convection current at the outside of the particles.
specific surface area (i.e. particle diameter);
thickness of the shell; and convection current at the outside of the particles.
[0038] When there are no chemical interactions between the polymeric composition and the solute, the diffusion can be described by Fick's first law:
JS = P U~ - ~~ J
o where JS is the solute flux in g/cm2/s;
o L is the membrane thickness (cm);
o P is the permeability coefficient in cm2/s; and o Co-C; is the concentration gradient across the membrane.
The permeability coefficient is expressed as:
o where I~ is a dimension-less parameter (assimilated to the solute partition coefficient between the membrane and the solution) and o D is the solute coefficient in the aqueous solution.
Several models are known to express the permeability coefficient P, such as the capillary pore model (Renkin equation) and the free volume model, among others.
JS = P U~ - ~~ J
o where JS is the solute flux in g/cm2/s;
o L is the membrane thickness (cm);
o P is the permeability coefficient in cm2/s; and o Co-C; is the concentration gradient across the membrane.
The permeability coefficient is expressed as:
o where I~ is a dimension-less parameter (assimilated to the solute partition coefficient between the membrane and the solution) and o D is the solute coefficient in the aqueous solution.
Several models are known to express the permeability coefficient P, such as the capillary pore model (Renkin equation) and the free volume model, among others.
[0039] In the free volume model, the polymeric composition that makes up the core and/or shell component is considered to be a homogenously hydrated network.
The _g_ diffusion transport of solutes is considered to occur through fluctuating water-filled spaces within the polymeric network. The free volume diffusion model predicts that D
scales with the fraction of polymer in the membrane, cp, and the radius of the hydrated solute, f~s. A refinement has been proposed (Peppas et al., J. Appl. Polym.
Sci., 36,735-747, 1988) as the hydrodynamic model:
= k1 exp - k' s2 1 ~ diffusion model D = exp k~ys~3i41 hydrodynamic model D ,o ~ where D and Do are the diffusion coefficients in the membrane and the aqueous solution, respectively and ~ k1 is related to the sieving factor, when the geometry of the solute is the critical parameter that dictates the solute progression in the core-shell composition and k' and k~ are undefined structural factors.
The _g_ diffusion transport of solutes is considered to occur through fluctuating water-filled spaces within the polymeric network. The free volume diffusion model predicts that D
scales with the fraction of polymer in the membrane, cp, and the radius of the hydrated solute, f~s. A refinement has been proposed (Peppas et al., J. Appl. Polym.
Sci., 36,735-747, 1988) as the hydrodynamic model:
= k1 exp - k' s2 1 ~ diffusion model D = exp k~ys~3i41 hydrodynamic model D ,o ~ where D and Do are the diffusion coefficients in the membrane and the aqueous solution, respectively and ~ k1 is related to the sieving factor, when the geometry of the solute is the critical parameter that dictates the solute progression in the core-shell composition and k' and k~ are undefined structural factors.
[0040] For a target solute such as phosphate ions, a typical value of self diffusion coefficient is 10-5 cm2/s. Based on certain diffusion models, the permeation rate across a micron thick shell membrane is estimated to be extremely fast with respect to the time of use of the resin, typically hours.
[0041] If bile acid or fatty acid molecules, as the competing solutes, compete for the same core binding sites as phosphate ions, their self diffusion coefficient is inversely proportional to their size in solution, which is not so different from one of small ions.
Thus, this self diffusion coefficient may not be enough to create a permeability barrier, if the diffusion is unhindered. Accordingly, in some embodiments, several characteristics of the shell component are tuned so that a permeation difference is established. For example, when the mesh size of the shell material is in the same size range as the solute dimensions, the random walk of the bulkier solute through the shell component is significantly slowed down. For example, experimental studies (Krajewska, B., Reactive and Functional polyners 47, 2001, 37-47) report permeation coefficients in cellulose ester or crosslinked chitosan gel membranes for both ionic and non-ionic solutes shows slowing down of bulkier solutes when mesh size nears solute dimensions.
Accordingly, D values can decrease several orders of magnitude depending on the molecular size of the solutes and the polymer volume fraction in the core-shell compositions, the polymer volume fraction in the swollen resin being a good indicator of the mesh size within the composition. Theoretical studies have shown, for example, that mesh size usually scales with ~-3~4, ~ being the polymer volume fraction in the shell component when swollen in a solution.
Thus, this self diffusion coefficient may not be enough to create a permeability barrier, if the diffusion is unhindered. Accordingly, in some embodiments, several characteristics of the shell component are tuned so that a permeation difference is established. For example, when the mesh size of the shell material is in the same size range as the solute dimensions, the random walk of the bulkier solute through the shell component is significantly slowed down. For example, experimental studies (Krajewska, B., Reactive and Functional polyners 47, 2001, 37-47) report permeation coefficients in cellulose ester or crosslinked chitosan gel membranes for both ionic and non-ionic solutes shows slowing down of bulkier solutes when mesh size nears solute dimensions.
Accordingly, D values can decrease several orders of magnitude depending on the molecular size of the solutes and the polymer volume fraction in the core-shell compositions, the polymer volume fraction in the swollen resin being a good indicator of the mesh size within the composition. Theoretical studies have shown, for example, that mesh size usually scales with ~-3~4, ~ being the polymer volume fraction in the shell component when swollen in a solution.
[0042] In some embodiments, the permeability of the solute is modulated by the degree of interaction between the solute and the shell material. A strong interaction can trap the solute inside the shell component, almost shutting down the migration across the shell.
Examples of types of interaction include ionic, covalent, polar, hydrogen bonding, van der Waals, and hydrophobic interactions.
Examples of types of interaction include ionic, covalent, polar, hydrogen bonding, van der Waals, and hydrophobic interactions.
[0043] In some embodiments, depending upon the conditions of use and the type of solutes, the ratio between the diffusion coefficient of the target solute and the competing solutes through the shell, is between about 1.1:1 to about 109: l, preferably between about 2:1 to about 106:1.
[0044] When the core-shell particles of the invention are used, the solute binding profile as a function of time, of some embodiments, can be schematically represented as depicted in FIG. 2. In a preferred embodiment, the target solute migrates quickly through the shell to be bound to the core material quickly attaining its binding value corresponding to a non-competing mode. In contrast, the competing solute slowly progresses through the shell as a result of its lower permeation rate; it eventually reaches its binding equilibrium value later in time and then displaces the target solute, causing a drop in the target solute binding curve. Preferably the ratio of diffusion coefficients is adjusted so that, at the end of the time of use of the binder (which may correspond to mean residence time of the resin in the GI) is less than about 10% to about 100% of the competing solutes have reached their binding equilibrium value. Preferably less than about 10%, more preferably less than about 50%, and even more preferably less than about 75% of the competing solutes have reached their binding equilibrium value. For the target solutes more than about 10% to about 100% has reached its binding equilibrium value in a non-competing mode. Preferably more than about 25%, more preferably more than about SO%, even more preferably more than about 75% of the target solute has reached its binding equilibrium.
[0045] Methods for determining diffusion coefficients are known. For example, see, W.
Jost, D~usion ih Solids, Liquids ahd Gases, Acad. Press, New-York, 1960). For example, the diffusion coefficient of a shell polymer can be measured by casting it as a membrane over a solid porous material, which is then contacted with a physiological solution containing the solutes of interest, and measuring steady state permeation rates of said solutes. Membrane characteristics can then be optimized to achieve the best cooperation in terms of selectivity and permeation rate kinetics. Structural characteristics of the membrane can be varied by modifying, for example, the polymer volume fraction (in the swollen membrane), the chemical nature of the polymer(s), the polymer blend composition (if more than one polymer is used), the formulation with additives such as wetting agents, plasticizers, and the manufacturing process.
Jost, D~usion ih Solids, Liquids ahd Gases, Acad. Press, New-York, 1960). For example, the diffusion coefficient of a shell polymer can be measured by casting it as a membrane over a solid porous material, which is then contacted with a physiological solution containing the solutes of interest, and measuring steady state permeation rates of said solutes. Membrane characteristics can then be optimized to achieve the best cooperation in terms of selectivity and permeation rate kinetics. Structural characteristics of the membrane can be varied by modifying, for example, the polymer volume fraction (in the swollen membrane), the chemical nature of the polymer(s), the polymer blend composition (if more than one polymer is used), the formulation with additives such as wetting agents, plasticizers, and the manufacturing process.
[0046] Alternatively, if the shell membrane is applied to the core material in a separate coating process, then the selectivity effect provided by the shell can be obtained by measuring the binding capacity for the target solute using the core particles with and without the shell. The increase in selectivity, SI, can be simply expressed as the ratio of those two values, i.e. SI=CB~ore-sneu I CB~ore~ where CB represent the capacity of binding (i.e mole of solute per unit weight of particle). Preferably, SI is between about 1.05 to about 104, even more preferably from about 1.1 to about 102.
[0047] In some embodiments, the shell is a film-forming polymer. In another embodiment, the shell polymer forms a crosslinked gel with a three-dimensional network structure where chains are crosslinked through covalent bonds, ionic or other bonds. In yet another embodiment, the shell material is chemically identical to the binding core material, but the crosslink density increases outward from core to shell. In another embodiment, the shell material adopts a "brush" configuration, wherein individual polymer strands are covalently attached to the core material at their termini.
In this embodiment, the mesh size can be dictated by the density of chains anchored onto the surface and by the chain molecular weight. The polymer brush design variables that control the permeability of polymer brushes to solutes of various sizes and/or weights are known in the art. For example, see WO 0102452 (and references therein).
In this embodiment, the mesh size can be dictated by the density of chains anchored onto the surface and by the chain molecular weight. The polymer brush design variables that control the permeability of polymer brushes to solutes of various sizes and/or weights are known in the art. For example, see WO 0102452 (and references therein).
[0048] Permeability is also controlled by the interaction of the solute with the shell. A
strong and, preferably, irreversible interaction of the shell with the competing solutes can trap the competing solutes within the encapsulating shell, slowing down their progression inward. One means of quantifying the degree of interaction between a solute and the shell is the free energy of mixing, particularly the free enthalpy of mixing, which can be predicted by solubility parameters. Solubility parameters provide a numerical method of predicting the extent of interaction between materials, particularly liquids and polymers.
This model predicts that compounds with dissimilar solubility parameters will not co-dissolve and consequently can go through the membrane unhindered in the absence of size sieving effect. Conversely, compounds with similar solubility parameters may form a molecular solution and can be retained. Further, while solubility parameters poorly describe ionic interactions, charged solutes generally are retained by shell material of opposite charge. Also, the combination of hydrophobic and ionic interactions can be used to provide strong, often irreversible, interactions with competing solutes, resulting in higher sorption selectivity for the target solutes which display neither a hydrophobic or am ionic character.
strong and, preferably, irreversible interaction of the shell with the competing solutes can trap the competing solutes within the encapsulating shell, slowing down their progression inward. One means of quantifying the degree of interaction between a solute and the shell is the free energy of mixing, particularly the free enthalpy of mixing, which can be predicted by solubility parameters. Solubility parameters provide a numerical method of predicting the extent of interaction between materials, particularly liquids and polymers.
This model predicts that compounds with dissimilar solubility parameters will not co-dissolve and consequently can go through the membrane unhindered in the absence of size sieving effect. Conversely, compounds with similar solubility parameters may form a molecular solution and can be retained. Further, while solubility parameters poorly describe ionic interactions, charged solutes generally are retained by shell material of opposite charge. Also, the combination of hydrophobic and ionic interactions can be used to provide strong, often irreversible, interactions with competing solutes, resulting in higher sorption selectivity for the target solutes which display neither a hydrophobic or am ionic character.
[0049] The shell material can be chosen from natural or synthetic polymers, optionally crosslinked, alone or in combination with small molecules functional additives such as wetting agents, plasticizers, permeability enhancers, solvents, moisturizing agents, pigment, and/or dyes.
[0050] Naturally-occuring or semi-synthetic polymers include: cellulose ethers (ethyl cellulose, methyl cellulose and their copolymers), cellulose esters (cellulose acetate, cellulose propionate, cellulose phthalate, and their copolymers), hydroxypropyl cellulose, hydroxyl ethyl cellulose, chitosan, deacetylated chitosan, and the like. Other examples of possible shell materials are listed in the table below:
crylics Gums, vegetable olyvinyl acetate quacoat aqueous dispersionsalocarbon olyvinyl pyrrolidone qitateric enteric coatingsydrocarbon resins olyvinyl alcohol Cellulose Acetate ydroxy Propyl Celluloseolyvinyl chloride Cellulose Acetate ButyrateY~'oxy Propyl Methylolyvinylacetate Cellulose phthalate Cellullose Acetate Ydroxy Propyl Methylolyvinylidene chloride Phthalate Cellulose Phthalate Caseinates ynar fluoroplastics roteins Chlorinated rubber altodextrins ubber, synthetic Coateric coatings ethyl Cellulose Shellac Coating butters icrocrystalline wax Silicone aran latex ilk solids Starches extrins olasses Stearines thyl Cellulose ylon Sucrose Enterics Opadry coating systemsSurfactants Eudragits polymethacrylatesaraffin wax Surelease coating systems Ethylene Vinyl Acetatehenolics Teflon fluorocarbons ats olylactides Waxes atty Acids olyamino acids ein Gelatin olyethylene Glycerides olyethylene glycol Gums, vegetable [0051] Examples of suitable synthetic polymers that can be used in the shell component include polymers produced by free radical polymerization of ethylenic monomers (acrylic and methacrylic, styrenic, dienic, vinylic), polycondensates (polyester, polyamides, polycarbonate, polysulfone), polyisocyanate, polyurea, epoxy resins, and the like.
crylics Gums, vegetable olyvinyl acetate quacoat aqueous dispersionsalocarbon olyvinyl pyrrolidone qitateric enteric coatingsydrocarbon resins olyvinyl alcohol Cellulose Acetate ydroxy Propyl Celluloseolyvinyl chloride Cellulose Acetate ButyrateY~'oxy Propyl Methylolyvinylacetate Cellulose phthalate Cellullose Acetate Ydroxy Propyl Methylolyvinylidene chloride Phthalate Cellulose Phthalate Caseinates ynar fluoroplastics roteins Chlorinated rubber altodextrins ubber, synthetic Coateric coatings ethyl Cellulose Shellac Coating butters icrocrystalline wax Silicone aran latex ilk solids Starches extrins olasses Stearines thyl Cellulose ylon Sucrose Enterics Opadry coating systemsSurfactants Eudragits polymethacrylatesaraffin wax Surelease coating systems Ethylene Vinyl Acetatehenolics Teflon fluorocarbons ats olylactides Waxes atty Acids olyamino acids ein Gelatin olyethylene Glycerides olyethylene glycol Gums, vegetable [0051] Examples of suitable synthetic polymers that can be used in the shell component include polymers produced by free radical polymerization of ethylenic monomers (acrylic and methacrylic, styrenic, dienic, vinylic), polycondensates (polyester, polyamides, polycarbonate, polysulfone), polyisocyanate, polyurea, epoxy resins, and the like.
[0052] Shell deposition over the core material can be carried out using coating techniques such as spraying, pan coating, fluidized bed (Wurster coating units), dipping, solvent coacervation, polyelectrolyte inter-complex layers, and the "layer by layer"
encapsulation process. Other encapsulation processes are also applicable. For example, see Encapsulation and Controlled Release by R.A. Stephenson (Editor), David R.
Karsa (Editor), 1993.
encapsulation process. Other encapsulation processes are also applicable. For example, see Encapsulation and Controlled Release by R.A. Stephenson (Editor), David R.
Karsa (Editor), 1993.
[0053] The shell can comprise several layers of distinct composition, of which one can be an enteric coating (e.g. Eudragit acrylic polymers) that disintegrates and/or solubilizes at a specific location of the GI tract. Examples of suitable enteric coatings are known in the art, for example see Remington: The Science and Practice of Pharmacy by A.R.
Gennaro (Editor), 20th Edition, 2000.
Gennaro (Editor), 20th Edition, 2000.
[0054] The shell can also be grown on the core component through chemical means, for example by:
~ chemical grafting of shell polymer to the core using living polymerization from active sites anchored onto the core polymer;
~ interfacial reaction, i.e., a chemical reaction located at the core particle surface, such as interfacial polycondensation; and ~ using block copolymers as suspending agents during the core particle synthesis.
~ chemical grafting of shell polymer to the core using living polymerization from active sites anchored onto the core polymer;
~ interfacial reaction, i.e., a chemical reaction located at the core particle surface, such as interfacial polycondensation; and ~ using block copolymers as suspending agents during the core particle synthesis.
[0055] The interfacial reaction and use of block polymers are preferred techniques when chemical methods are used. In the interfacial reaction pathway, typically, the periphery of the core particle is chemically modified by reacting small molecules or macromolecules on the core interface. For example, an amine containing ion-binding core particle is reacted with a polymer containing amine reactive groups such as epoxy, isocyanate, activated esters, halide groups to form a crosslinked shell around the core.
[0056] In another embodiment, the shell is first prepared using interfacial polycondensation or solvent coacervation to produce capsules. The interior of the capsule is then filled up with core-forming precursors to build the core within the shell capsule.
[0057] Solvent coacervation is described in the art. For example, see Leach, I~. et al., J.
Microencapsulation, 1999, 16(2), 153-167. In this process, typically two polymers, core polymer and shell polymer are dissolved in a solvent which is further emulsified as droplets in an aqueous phase. The droplet interior is typically a homogeneous binary polymer solution. The solvent is then slowly driven off by careful distillation. The polymer solution in each droplet undergoes a phase separation as the volume fraction of polymer increases. One of the polymer migrates to the water/droplet interface and forms a more-or less perfect core-shell particle (or double-walled microsphere).
Microencapsulation, 1999, 16(2), 153-167. In this process, typically two polymers, core polymer and shell polymer are dissolved in a solvent which is further emulsified as droplets in an aqueous phase. The droplet interior is typically a homogeneous binary polymer solution. The solvent is then slowly driven off by careful distillation. The polymer solution in each droplet undergoes a phase separation as the volume fraction of polymer increases. One of the polymer migrates to the water/droplet interface and forms a more-or less perfect core-shell particle (or double-walled microsphere).
[0058] Solvent coacervation is one of the preferred methods to deposit a controlled film of shell polymer onto the core. In one embodiment, the coacervation technique consists in dispersing the core beads in a continuous liquid phase containing the shell material in a soluble form. The coacervation process then consists of gradually changing the solvency of the continuous phase so that the shell material becomes increasingly insoluble. At the onset of precipitation some of the shell material ends up as a fine precipitate or film at the bead surface. The change in solvency can be triggered by a variety of physical chemistry means such as , but not limited to, changes in pH, ionic strength (i.e.
osmolality), solvent composition (through addition of solvent or distillation), temperature (e.g when a shell polymer with a LCST ( lower critical solution temperature) is used), pressure particularly when supercritical fluids are used). More preferred are solvent coacervation processes when the trigger is either pH or solvent composition. Typically when a pH
trigger event is used and when the polymer is selected from an amine type material, the shell polymer is first solubilized at low pH. In a second step the pH is gradually increased to reach the insolubility limit and induce shell deposition; the pH
change is often produced by adding a base under strong agitation. Another alternative is to generate a base by thermal hydrolysis of a precursor (e.g. thermal treatment of urea to generate ammonia). The most preferred coacervation process is when a ternary system is used comprising the shell material and a solvent/non-solvent mixture of the shell material. The core beads are dispersed in that homogeneous solution and the solvent is gradually driven off by distillation. The extent of shell coating can be controlled by on-line or off line monitoring of the shell polymer concentration in the continuous phase. In the most common case where some shell material precipitates out of the core surface either in a colloidal form or as discrete particle, the core-shell particles are conveniently isolated by simple filtration and sieving. The shell thickness is typically controlled by the initial core to shell weight ratio as well as the extent of shell polymer coacervation described earlier. The core-shell beads can then be annealed to improve the integrity of the outer membrane as measured by competitive binding.
osmolality), solvent composition (through addition of solvent or distillation), temperature (e.g when a shell polymer with a LCST ( lower critical solution temperature) is used), pressure particularly when supercritical fluids are used). More preferred are solvent coacervation processes when the trigger is either pH or solvent composition. Typically when a pH
trigger event is used and when the polymer is selected from an amine type material, the shell polymer is first solubilized at low pH. In a second step the pH is gradually increased to reach the insolubility limit and induce shell deposition; the pH
change is often produced by adding a base under strong agitation. Another alternative is to generate a base by thermal hydrolysis of a precursor (e.g. thermal treatment of urea to generate ammonia). The most preferred coacervation process is when a ternary system is used comprising the shell material and a solvent/non-solvent mixture of the shell material. The core beads are dispersed in that homogeneous solution and the solvent is gradually driven off by distillation. The extent of shell coating can be controlled by on-line or off line monitoring of the shell polymer concentration in the continuous phase. In the most common case where some shell material precipitates out of the core surface either in a colloidal form or as discrete particle, the core-shell particles are conveniently isolated by simple filtration and sieving. The shell thickness is typically controlled by the initial core to shell weight ratio as well as the extent of shell polymer coacervation described earlier. The core-shell beads can then be annealed to improve the integrity of the outer membrane as measured by competitive binding.
[0059] In some embodiments, using the block copolymer approach, an amphiphilic block copolymer can be used as a suspending agent to form the core particle in an inverse or direct suspension particle forming process. When an inverse water-in-oil suspension process is used, then the block copolymer comprises a first block soluble in the continuous oil phase and another hydrophilic block contains functional groups that can react with the core polymer. When added to the aqueous phase, along with core-forming precursor, and the oil phase, the block copolymer locates to the water-in-oil interface and acts as a suspending agent. The hydrophilic block reacts with the core material, or co-reacts with the core-forming precursors. After the particles are isolated from the oil phase, the block copolymers form a thin shell covalently attached to the core surface.
The chemical nature and length of the blocks can be varied to vary the permeation characteristics of the shell towards solutes of interest.
The chemical nature and length of the blocks can be varied to vary the permeation characteristics of the shell towards solutes of interest.
[0060] In systems which combine positive charges and hydrophobicity, preferred shell polymers include amine functional polymers, such as those disclosed above, which are optionally alkylated with hydrophobic agents.
[0061] Alkylation involves reaction between the nitrogen atoms of the polymer and the alkylating agent (usually an alkyl, alkylaryl group carrying an amine-reactive electrophile). In addition, the nitrogen atoms which do react with the alkylating agents) resist multiple alkylation to form quaternary ammonium ions such that less than 10 mol of the nitrogen atoms form quaternary ammonium ions at the conclusion of alkylation.
[0062] Preferred alkylating agents are electrophiles such as compounds bearing functional groups such as halides, epoxides, esters, anhydrides, isocyanate, or a~i-unsaturated carbonyls. They have the fornlula RX where R is a C 1 -C20 alkyl (preferably C4 -C20), C1-C20 hydroxy-alkyl (preferably C4 -C20 hydroxyalkyl), C6 -C20 aralkyl, C1-C20 alkylammonium (preferably C4 -C20 alkyl ammonium), or C1 -C20 alkylamido (preferably C4 -C20 alkyl amido) group and X includes one or more electrophilic groups.
By "electrophilic group" it is meant a group which is displaced or reacted by a nitrogen atom in the polymer during the alkylation reaction. Examples of preferred electrophilic groups, X, include halide, epoxy, tosylate, and mesylate group. In the case of, e.g., epoxy groups, the alkylation reaction causes opening of the three-membered epoxy ring.
By "electrophilic group" it is meant a group which is displaced or reacted by a nitrogen atom in the polymer during the alkylation reaction. Examples of preferred electrophilic groups, X, include halide, epoxy, tosylate, and mesylate group. In the case of, e.g., epoxy groups, the alkylation reaction causes opening of the three-membered epoxy ring.
[0063] Examples of preferred alkylating agents include a C3 -C20 alkyl halide (e.g., an n-butyl halide, n-hexyl halide, n-octyl halide, n-decyl halide, n-dodecyl halide, n-tetradecyl halide, n-octadecyl halide, and combinations thereof); a C 1 -C20 hydroxyalkyl halide (e.g., an 11-halo-1-undecanol); a C1 -C20 aralkyl halide (e.g., a benzyl halide); a C1 -C20 alkyl halide ammonium salt (e.g., a (4-halobutyl) trimethylammonium salt, (6-halohexyl)trimethyl-ammonium salt, (8-halooctyl)trimethylammonium salt, (10-halodecyl)trimethylammonium salt, (12-halododecyl)-trimethylammonium salts and combinations thereof); a C1 -C20 alkyl epoxy ammoniumn salt (e.g., a (glycidylpropyl)-trimethylammonium salt); and a C1 -C20 epoxy alkylamide (e.g., an N-(2,3-eoxypropane)butyramnide, N-(2,3-epoxypropane) hexanamide, and combinations thereof). Benzyle halide and dodecyl halide are more preferred.
[0064] The alkylation step on the polyamine shell precursor can be carried out in a separate reaction, prior to the application of the shell onto the core beads.
Alternatively the alkylation can be done once the polyamine shell precursor is deposited onto the core beads. In the latter case, the alkylation is preferably performed with an alkylating agent that includes at least two electrophilic groups X so that the alkylation also induces crosslinking within the shell layer. Preferred polyfunctional alkylation agents include di-halo alkane, dihalo polyethylene glycol, and epichlorohydrine. Other crosslinkers containing acyl chlorides, isocyanate ,thiocyanate, chlorosulfonyl, activated esters (N-hydroxysuccinimide) , carbodiimide intermediates, are also suitable.
Alternatively the alkylation can be done once the polyamine shell precursor is deposited onto the core beads. In the latter case, the alkylation is preferably performed with an alkylating agent that includes at least two electrophilic groups X so that the alkylation also induces crosslinking within the shell layer. Preferred polyfunctional alkylation agents include di-halo alkane, dihalo polyethylene glycol, and epichlorohydrine. Other crosslinkers containing acyl chlorides, isocyanate ,thiocyanate, chlorosulfonyl, activated esters (N-hydroxysuccinimide) , carbodiimide intermediates, are also suitable.
[0065] Typically, the level of alkylation is adjusted depending upon the nature of the polyamine precursor and the size of the alkyl groups used on alkylation. Some factors that play a role in the level of alkylation include:
(a) Insolubility of the shell polymer under conditions of the GI tract. In particular, the low pH's prevailing in the stomach tend to solubilize alkylated polyamine polymers whose pH of ionization is 5 and above. For that purpose higher rate of alkylation and higher chain length alkyl are preferred. As an alternative, one may use an enteric coating to protect the shell material against acidic pH's, said enteric coating is released when the core-shell beads are progressing in the lower intestine.
(b) The permselectivity profile: When the alkylation ratio is low the persistence of the permselectivity for competing ions (e.g. Mg2+, Ca2+) can be shorter than the typical residence time in the colon. Conversely when the alkylation ratio (or the weight fraction of hydrophobes) is high then the material becomes almost impermeable to most inorganic cations, and thus, the rate of equilibration for K+ becomes long.
Preferably, the degree of alkylation is selected by an iterative approach monitoring the two variables mentioned above.
(a) Insolubility of the shell polymer under conditions of the GI tract. In particular, the low pH's prevailing in the stomach tend to solubilize alkylated polyamine polymers whose pH of ionization is 5 and above. For that purpose higher rate of alkylation and higher chain length alkyl are preferred. As an alternative, one may use an enteric coating to protect the shell material against acidic pH's, said enteric coating is released when the core-shell beads are progressing in the lower intestine.
(b) The permselectivity profile: When the alkylation ratio is low the persistence of the permselectivity for competing ions (e.g. Mg2+, Ca2+) can be shorter than the typical residence time in the colon. Conversely when the alkylation ratio (or the weight fraction of hydrophobes) is high then the material becomes almost impermeable to most inorganic cations, and thus, the rate of equilibration for K+ becomes long.
Preferably, the degree of alkylation is selected by an iterative approach monitoring the two variables mentioned above.
[0066] In a preferred embodiment, the shell is formed with Eudragit, for example Eudragit RL 100 or RS 100 or a combination thereof, or with polyethyleneimine (PEI).
These shells maybe applied by solvent coacervation technique. The PEI may be optionally benzylated and also optionally cross-linked. Examples of suitable cross-linkers include, but are not limited to, _ O
CI \ ~
OCN NCO ~ ~ CI ~O~O~
O
These shells maybe applied by solvent coacervation technique. The PEI may be optionally benzylated and also optionally cross-linked. Examples of suitable cross-linkers include, but are not limited to, _ O
CI \ ~
OCN NCO ~ ~ CI ~O~O~
O
[0067] lil some embodiments, the shell thickness can be between about 0.002 micron to about 50 micron, preferably about 0.005 micron to about 20 microns. Preferably the shell thickness is more than about 1 micron, more preferred is more than about 10 micron, even more preferred is more than about 20 micron, and most preferred is more than about 40 micron. Preferably the shell thickness is less than about 50 micron, more preferred is less than about 40 micron, even more preferred is less than about 20 micron, and most preferred is less than about 10 micron.
[0068] In another embodiment, the shell to core weight ratio comprises between about 0.01 % to about 50%, preferably between about 0.2% to about 10%. The size of the core-shell particles typically range from about 200 nm to about 2 mm, preferably being about 500 Vim. Preferably the size of the core-shell particles are more than about 1 Vim, more preferred is more than about 100 ~.m, even more preferred is more than about 200 Vim, and most preferred is more than about 400 p,m. Preferably the size of the core-shell particles are less than about 500 ~.m, more preferred is less than about 400 ~.m, even more preferred is less than about 200 yn, and most preferred is less than about 100 ~,m.
[0069] The binding selectivity of the core can be assessed by standard methods. One method consists of measuring the binding capacity of the target solute in a simple model solution with non interfering species, Cm, and in a simulant medium (Cs), and calculating a selectivity index as SI=Cs/Cm. The core-shell particles of the invention are expected to have selectivity indexes SI significantly higher than those reported for known prior-art sorbent resins.
[0070] In one embodiment, the permeability of the shell changes as a function of time.
In particular, the permeability of the shell may change over time when used ifz vivo. For example, in certain applications it is preferable to either diminish or conversely increase the permeability to target solutes over time during residence in a GI tract.
For example, the resin could bind a hydrophilic ionic solute at a certain location of the GI tract at a rate controlled by the solute concentration in equilibrium with the resin at that location. As the resin travels down the GI tract, the local target solute concentration may vary as a result of dilution or solute transport across the gut membrane. In this embodiment, the shell material is engineered to respond to such concentration or other physiological changes in the GI, so that its permeability is altered; more specifically, the permeability of the shell maybe decreasedduring its journey through the GI so that hydrophilic ions are no longer able to cross the shell membrane, during the later period of the core-shell composition's residence in the GI tract. This embodiment also applies to more hydrophobic solutes such as bile acids. In the case of bile acid sequesterants, studies have shown that the poor binding rate in vivo is caused by the release of bile acids past the ileum segment of the gut. At that point, bile acids are almost quantitatively reabsorbed by the mucosa, so that the binding equilibrium is shifted and the sequestering capacity is lowered. In this embodiment, the shell component has a permeability trigger that decreases the permeability of the shell to bile acids, when the core-shell resin passes the ileum so that the overall capacity is conserved.
In particular, the permeability of the shell may change over time when used ifz vivo. For example, in certain applications it is preferable to either diminish or conversely increase the permeability to target solutes over time during residence in a GI tract.
For example, the resin could bind a hydrophilic ionic solute at a certain location of the GI tract at a rate controlled by the solute concentration in equilibrium with the resin at that location. As the resin travels down the GI tract, the local target solute concentration may vary as a result of dilution or solute transport across the gut membrane. In this embodiment, the shell material is engineered to respond to such concentration or other physiological changes in the GI, so that its permeability is altered; more specifically, the permeability of the shell maybe decreasedduring its journey through the GI so that hydrophilic ions are no longer able to cross the shell membrane, during the later period of the core-shell composition's residence in the GI tract. This embodiment also applies to more hydrophobic solutes such as bile acids. In the case of bile acid sequesterants, studies have shown that the poor binding rate in vivo is caused by the release of bile acids past the ileum segment of the gut. At that point, bile acids are almost quantitatively reabsorbed by the mucosa, so that the binding equilibrium is shifted and the sequestering capacity is lowered. In this embodiment, the shell component has a permeability trigger that decreases the permeability of the shell to bile acids, when the core-shell resin passes the ileum so that the overall capacity is conserved.
[0071] One manner of achieving this loss of permeability to hydrophilic ions involves decreasing or even eliminating the free volume of permeation of the shell membrane.
The free volume of permeation of the membrane can be modified by controlling the hydration rate of the shell. hl this manner, it is possible to almost shut down the rate of permeation by inducing a shell collapse. While there are many ways to induce such a phase change, the preferred approach consists of rendering the membrane material increasingly hydrophobic so that the hydration rate decreases almost to zero.
This can be accomplished through several ways depending upon the type of triggering mechanism.
For example the triggering mechanism can be by pH change. The pH profile of the gastrointestinal tract presents several domains which may change as a function of time, but show some invariants indicated below (Fallinborg et al. Alimefzt. Plaarm.
Therap.
(199),3,605-613):
The free volume of permeation of the membrane can be modified by controlling the hydration rate of the shell. hl this manner, it is possible to almost shut down the rate of permeation by inducing a shell collapse. While there are many ways to induce such a phase change, the preferred approach consists of rendering the membrane material increasingly hydrophobic so that the hydration rate decreases almost to zero.
This can be accomplished through several ways depending upon the type of triggering mechanism.
For example the triggering mechanism can be by pH change. The pH profile of the gastrointestinal tract presents several domains which may change as a function of time, but show some invariants indicated below (Fallinborg et al. Alimefzt. Plaarm.
Therap.
(199),3,605-613):
_ GI tract segment Ph ran a _ 1-2 Stomach Duodenum - distal small intestine 6-7 Ceacum-ascending colon 7-5.5 Transverse-descending colon 5.5-6 Feces 6.5 [0072] Shell polymers exhibiting a chain collapse in any of these pH regions would be prone to permeability changes. For instance, core-shell particles suitable for binding a solute selectively in the stomach and keeping it in the particle core while the particles are moving down the small and large intestine, would display high permeability to solutes at low pH and very low permeability at neutral pH. This can be done by having a shell polymer with hydrophobic groups and groups that ionize subject to pH change.
For example, polymers built from hydrophobic monomers (e.g. long chain alcohol (meth)arylates, Nalkyl (meth)acrylamide), and basic monomers that ionize at low pH and remain neutral beyond their pKa (e.g. vinyl-pyridine, dialkylaminoethyl (meth)acrylamide) can be used. The relationship between pH and shell swelling ratio, and hence permeability, can be controlled by the balance of hydrophobic monomers and ionizable monomers. Examples of such systems are reported in the literature.
For example, see Batich et al, Macromolecules, 26, 4675-460.
For example, polymers built from hydrophobic monomers (e.g. long chain alcohol (meth)arylates, Nalkyl (meth)acrylamide), and basic monomers that ionize at low pH and remain neutral beyond their pKa (e.g. vinyl-pyridine, dialkylaminoethyl (meth)acrylamide) can be used. The relationship between pH and shell swelling ratio, and hence permeability, can be controlled by the balance of hydrophobic monomers and ionizable monomers. Examples of such systems are reported in the literature.
For example, see Batich et al, Macromolecules, 26, 4675-460.
[0073] A further drop in permeability may be desirable when pH increases (e.g.
from ileum to colon) to prevent bound electrolytes being released as the resin environment changes. This can be achieved where the shell material switches from a hydrated state to a collapsed, impermeable state as the pH gets slightly basic. In such embodiments, shell polymers typically contain a balanced amount of hydrophobic and acidic monomers.
Such systems are extensively described in the literature. For example, see Kraft et al.
Langmuir, 2003, 19, 910-915; Ito et al, Macromolecule,(1992), 25,7313-7316.
from ileum to colon) to prevent bound electrolytes being released as the resin environment changes. This can be achieved where the shell material switches from a hydrated state to a collapsed, impermeable state as the pH gets slightly basic. In such embodiments, shell polymers typically contain a balanced amount of hydrophobic and acidic monomers.
Such systems are extensively described in the literature. For example, see Kraft et al.
Langmuir, 2003, 19, 910-915; Ito et al, Macromolecule,(1992), 25,7313-7316.
[0074] Another means of changing shell permeability is by passive absorption.
As described above, components present in the GI tract, whether coming from the diet, produced as diet digest metabolites, from secretion, etc. are susceptible to adsorption on and within the shell in a quasi-irreversible manner and this adsorption may modify the permeability pattern by inducing membrane collapse. The vast majority of these GI tract components is negatively charged and shows various levels of hydrophobicity.
Some of these species have an amphiphilic character, such as fatty acids, bile acids, phospholipids, and biliary salts and behave as surfactants. Surfactants can adsorb non-specifically to surfaces through hydrophobic interactions, ionic interaction and combinations thereof. In the context of the present invention, this phenomenon can be used to change the permeability of the resin upon the course of binding to these surfactants during the resin's residence in the GI tract.
As described above, components present in the GI tract, whether coming from the diet, produced as diet digest metabolites, from secretion, etc. are susceptible to adsorption on and within the shell in a quasi-irreversible manner and this adsorption may modify the permeability pattern by inducing membrane collapse. The vast majority of these GI tract components is negatively charged and shows various levels of hydrophobicity.
Some of these species have an amphiphilic character, such as fatty acids, bile acids, phospholipids, and biliary salts and behave as surfactants. Surfactants can adsorb non-specifically to surfaces through hydrophobic interactions, ionic interaction and combinations thereof. In the context of the present invention, this phenomenon can be used to change the permeability of the resin upon the course of binding to these surfactants during the resin's residence in the GI tract.
[0075] For example, fatty acids and bile acids both form insoluble complexes when mixed with positively charged polymers. For example, see I~aneko et al, Mac~omolecula~ Rapid Commmucations, 2003, 24(13), 789-792). Both types of molecules present similarities with synthetic anionic surfactants, and numerous studies report the formation of insoluble complexes between anionic surfactants and cationically charged polymers. For example, see Chen, L. et al, Macromolecules (1998), 31(3), 787-794. Iii this embodiment, the shell material is selected from copolymers containing both hydrophobic and cationic groups, so that the shell forms a complex, preferably a tight complex, with anionically charged hydrophobs typically found in the GI tract, such as bile acids, fatty acids, bilirubin and related compounds. Suitable compositions also include polymeric materials described as bile acids sequestering agents, such as those reported in US 5607669, US 6294163, US 5374422, Figuly et al, Macrom~lecules, 1997, 30, 6174-6184. The formation of this complex induces a shell membrane collapse which in turn lowers or shuts down the permeation rate across the said membrane.
[0076] The shell permeability may also be modulated by enzymatic transformation. In one embodiment the shell comprises a hydrophobic backbone with pendant hydrophilic entities that are cleaved off via an enzymatic reaction in the gut. As the enzymatic reaction proceeds, the polymer membrane becomes more and more hydrophobic, and turns from a high swollen, high permeability material to a fully collapsed low hydration membrane with minimal permeability. Hydrophilic entities can be chosen amongst natural substrates of enzymes commonly secreted in the GI tract. Such entities include amino acids, peptides, carbohydrates, esters, phosphate esters, oxyphosphate monoesters, O- and S-phosphorothioates, phosphoramidates, thiophosphate, azo groups and other similar entities. Examples of enteric enzymes which can be used to chemically alter the shell polymer include, but are not limited to, lipases, phospholipases, carboxylesterase, glycosidases, azoreductases, phosphatases, amidases and proteases.
[0077] In some embodiments, the core material is chosen from polymer compositions with the desired ion binding properties. Examples of suitable polymers material include, but are not limited to:
1) anion binding materials such as amine functional polymers such as those described in U.S. patents 5,985,938; 5,980,881; 6,180,094; 6,423,754;
and PCT publication WO 95/05184 and 2) ration exchange polymers, such as those with acid functional groups such as carboxylate, phosphonate, sulfate, sulfonate, sulfamate functional polymers and combinations thereof.
1) anion binding materials such as amine functional polymers such as those described in U.S. patents 5,985,938; 5,980,881; 6,180,094; 6,423,754;
and PCT publication WO 95/05184 and 2) ration exchange polymers, such as those with acid functional groups such as carboxylate, phosphonate, sulfate, sulfonate, sulfamate functional polymers and combinations thereof.
[0078] Core-shell compositions that include anion binding materials are useful for the binding and removal from GI tract of phosphate, chloride, bicarbonate, and oxalate ions.
The ration exchange polymers have utility in binding and removal of physiologically important rations such as protons, sodium, potassium, magnesium, calcium, ammonium, and the like or heavy metals which cause poisoning.
The ration exchange polymers have utility in binding and removal of physiologically important rations such as protons, sodium, potassium, magnesium, calcium, ammonium, and the like or heavy metals which cause poisoning.
[0079] Examples of other suitable polymers for the core component are described in the following co-pending patent applications: 1) Polyamine Polymers, Attorney Docket Number: 29329-703, filed on November 3, 2003, Application No.: 10/701,385 and 2) Crosslinked Amine Polymers, Attorney Docket Number: 29329-749.201, filed on 22 March 2004, Application No.: 10/806,495.
[0080] Further examples of compositions that can be used in the core component include the phosphate binders in PCT publications WO 94/19379, WO 96/25440, WO
01/28527, WO 02/85378, WO 96/39156, WO 98/42355, WO 99/22743, WO 95/05184, WO
96/21454, and WO 98/17707; U.S. patents 5,698,190; 5,851,518; 5,496,545;
5,667,775;
6,083,495; and 6,509,013; and European Patent Application 01200604.5.
01/28527, WO 02/85378, WO 96/39156, WO 98/42355, WO 99/22743, WO 95/05184, WO
96/21454, and WO 98/17707; U.S. patents 5,698,190; 5,851,518; 5,496,545;
5,667,775;
6,083,495; and 6,509,013; and European Patent Application 01200604.5.
[0081] Aluminum, calcium, and lanthanum salts are used as phosphate binders.
Examples of inorganic metal salts used as phosphate binders include aluminum carbonate, aluminum hydroxide gel (Amphojel~), calcium carbonate, calcium acetate (PhosLo), and lanthanum carbonate (Fosrenol). In one embodiment, the core-shell particle comprises of a core component comprising of a metal phosphate binder, such as aluminum carbonate, aluminum hydroxide gel, calcium carbonate, calcium acetate, and lanthanum carbonate.
Examples of inorganic metal salts used as phosphate binders include aluminum carbonate, aluminum hydroxide gel (Amphojel~), calcium carbonate, calcium acetate (PhosLo), and lanthanum carbonate (Fosrenol). In one embodiment, the core-shell particle comprises of a core component comprising of a metal phosphate binder, such as aluminum carbonate, aluminum hydroxide gel, calcium carbonate, calcium acetate, and lanthanum carbonate.
[0082] In one embodiment, the core component has sodium ion binding properties.
Suitable polymers that can be used in the core so as to impart the core sodium-binding properties include crown ethers. Crown ethers exhibit selectivity for certain alkali metals over others, based mainly on the hole-size of the crown ether size and the size of the metal. Crown ethers of the type 15-18 are preferred for use in sodium ion binding core components. Also, other suitable compositions for sodium binding properties are described in co-pending patent application entitled "Methods and Compositions for Treatment of Ion Imbalances," Attorney Docket Number 29329-714.201, filed on March 2004, Application Serial Number: 10/514,527.
USES OF THE CORE-SHELL COMPOSITIONS
Suitable polymers that can be used in the core so as to impart the core sodium-binding properties include crown ethers. Crown ethers exhibit selectivity for certain alkali metals over others, based mainly on the hole-size of the crown ether size and the size of the metal. Crown ethers of the type 15-18 are preferred for use in sodium ion binding core components. Also, other suitable compositions for sodium binding properties are described in co-pending patent application entitled "Methods and Compositions for Treatment of Ion Imbalances," Attorney Docket Number 29329-714.201, filed on March 2004, Application Serial Number: 10/514,527.
USES OF THE CORE-SHELL COMPOSITIONS
[0083] In one aspect, the invention provides methods of preferentially binding solutes in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of core-shell compositions. Core shell compositions that bind hydorphillic cations and/or anions can be used to control ion homeostasis and treat electrolyte balance disorders in phosphate (hyperphosphatemia), oxalate (calcium oxalate kidney stones, oxaluria), sodium (hypertension), potassium (hyperkalemia), chloride (acidosis), or to remove toxic metals or oxidative anions in cases of poisoning.
[0084] The core-shell compositions with anion exchange resins are particularly useful in the binding and excretion of negatively charged ions from the body. Core-shell compositions can also be used to bind metallic ions. These compositions can be administered orally to bind and remove from an animal various negatively charged entities and metallic species from the gastro-intestinal tract. In one embodiment, the core-shell compositions of the present invention are used to remove phosphate, oxalate, bile acids, small molecules, proteins, metallic ions such as those comprised within the 6th and the 1 lth groups and 4th and 6th periods of the Periodic Table, also including the Lanthanoids and the Actanoids.
[0085] In some embodiments, the core-shell compositions with polyvicinalamines, such as those described in co-pending U.S. Patent application No. 10/701,35;
entitled Polyamine Polymers, Attorney Docket Number: 29329-703, filed on November 3, are useful in the treatment of renal diseases, hyperphosphatemia, and the removal of bile acids, oxalates and iron from the gastrointestinal tract.
entitled Polyamine Polymers, Attorney Docket Number: 29329-703, filed on November 3, are useful in the treatment of renal diseases, hyperphosphatemia, and the removal of bile acids, oxalates and iron from the gastrointestinal tract.
[0086] In some embodiments, the core-shell compositions are used in the treatment of phosphate imbalance disorders. The term "phosphate imbalance disorder" as used herein refers to conditions in which the level of phosphorus present in the body is abnormal.
One example of a phosphate imbalance disorder includes hyperphosphatemia. The term "hyperphosphatemia" as used herein refers to a condition in which the element phosphorus is present in the body at an elevated level. Typically, a patient is often diagnosed with hyperphosphatemia if the blood phosphate level is, for example, above 4.5 milligrams per deciliter of blood and/or glomerular filtration rate is reduced to, for example, more than about 20%
One example of a phosphate imbalance disorder includes hyperphosphatemia. The term "hyperphosphatemia" as used herein refers to a condition in which the element phosphorus is present in the body at an elevated level. Typically, a patient is often diagnosed with hyperphosphatemia if the blood phosphate level is, for example, above 4.5 milligrams per deciliter of blood and/or glomerular filtration rate is reduced to, for example, more than about 20%
[0087] Other diseases that can be treated with the methods and compositions of the present invention include hypocalcemia, hyperparathyroidism, depressed renal synthesis of calcitriol, tetany due to hypocalcemia, renal insufficiency, and ecotopic calcification in soft tissues including calcifications in joints, lungs, kidney, conjuctiva, and myocardial tissues. Also, the present invention can be used to treat ESRD and dialysis patients. In one embodiment, the core-shell compositions are used for prophylactic treatment of diseases.
[0088] The core-shell compositions described herein can also be used to treat diseases wherein a reduction in physiological levels of salt is desired. The core-shell compositions, depending on the ion binding properties of the core component, can be used to remove cations such as soditun and/or anions such as chloride.
[0089] In one embodiment, the core-shell compositions of the present invention are used to treat metallic poisoning, like iron poisoning. Iron poisoning typically is a result of children inadvertently taking iron supplement tablets. In iron overdose, binding of iron to oral charcoal, bicarbonate, deferoxarnine, or magnesium hydroxide are typical treatments.
Gastric lavage and profuse oral fluids are used to try to flush out the iron tablets. Non-absorbable core-shell compositions with iron chelating properties can be used for removal of metallic iron.
Gastric lavage and profuse oral fluids are used to try to flush out the iron tablets. Non-absorbable core-shell compositions with iron chelating properties can be used for removal of metallic iron.
[0090] Depending on the properties of the core andlor shell components, the core-shell compositions of the present invention also show utility in binding dietary oxalate in patients who suffer from hyperoxaluria, i.e. abnormally high levels of oxalate in the urine. Elevated urine oxalate levels are one of the causes of calcium-stone formation (i.e., kidney stones). Most calcium stones are composed of calcium oxalate, either alone or in combination with calcium phosphate or calcium orate. Elevated urinary oxalate levels can result from excessive dietary intake of oxalate (dietary oxaluria), gastrointestinal disorders that lead to malabsorption of oxalate (enteric oxaluria), or an inherited enzyme deficiency that results in excessive metabolism of oxalate (primary hyperoxaluria or PH). Dietary and enteric oxaluria can be treated with diet restriction or modifications to restrict intake of foods with high oxalate content. However patient compliance is often difficult owing to the wide distribution of oxalate and purine derivatives in many foods. Calcium carbonate tablets (500-650 mg/tablet; 3 tablets per meal) can also be taken to bind and remove intestinal oxalate, but again patient compliance is difficult owing to the amount of calcium carbonate needed. Core components made of polyvicinalamines, such as those described co-pending U.S.
Patent application No. 10/701,385; entitled Polyamine Polymers, Attorney Docket Number:
29329-703, filed on November 3, 2003, have high binding constants for oxalate and can be used to remove oxalate from the gastro-intestinal tract and subsequently lower the risk of kidney stone formation.
Patent application No. 10/701,385; entitled Polyamine Polymers, Attorney Docket Number:
29329-703, filed on November 3, 2003, have high binding constants for oxalate and can be used to remove oxalate from the gastro-intestinal tract and subsequently lower the risk of kidney stone formation.
[0091] In the present invention, the core-shell compositions can be co-administered with other active pharmaceutical agents depending on the condition being treated.
This co-administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. For example, for the treatment of hyperphosphatemia, the core-shell compositions can be co-administered with calcium salts which are used to treat hypocalcemia resulting from hyperphosphatemia. The calcium salt and core-shell composition can be formulated together in the same dosage form and administered simultaneously. Alternatively, the calcium salt and core-shell composition can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, the calcium salt can be administered just followed by the core-shell composition, or vice versa. In the separate administration protocol, the core-shell composition and calcium salt may be administered a few minutes apart, or a few hours apart, or a few days apart.
This co-administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. For example, for the treatment of hyperphosphatemia, the core-shell compositions can be co-administered with calcium salts which are used to treat hypocalcemia resulting from hyperphosphatemia. The calcium salt and core-shell composition can be formulated together in the same dosage form and administered simultaneously. Alternatively, the calcium salt and core-shell composition can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, the calcium salt can be administered just followed by the core-shell composition, or vice versa. In the separate administration protocol, the core-shell composition and calcium salt may be administered a few minutes apart, or a few hours apart, or a few days apart.
[0092] The term "treating" as used herein includes achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication, amelioration, or prevention of the underlying disorder being treated. For example, in a hyperphosphatemia patient, therapeutic benefit includes eradication or amelioration of the underlying hyperphosphatemia. Also, a therapeutic benefit is achieved with the eradication, amelioration, or prevention of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For example, administration of core-shell compositions to a patient suffering from renal insufficiency and/or hyperphosphatemia provides therapeutic benefit not only when the patient's serum phosphate level is decreased, but also when an improvement is observed in the patient with respect to other disorders that accompany renal failure and/or hyperphosphatemia like ectopic calcification and renal osteodistrophy. For prophylactic benefit, the core-shell compositions may be administered to a patient at risk of developing hyperphosphatemia or to a patient reporting one or more of the physiological symptoms of hyperphosphatemia, even though a diagnosis of hyperphosphatemia may not have been made.
[0093] The pharmaceutical compositions of the present invention include compositions wherein the core-shell compositions are present in an effective amount, i.e., in an amount effective to achieve therapeutic or prophylactic benefit. The actual amount effective for a particular application will depend on the patient (e.g., age, weight, etc.), the condition being treated, and the route of administration. Determination of an effective amount is well within the capabilities of those skilled in the art, especially in light of the disclosure herein.
[0094] The effective amount for use in humans can be determined from animal models.
For example, a dose for humans can be formulated to achieve circulating and/or gastrointestinal concentrations that have been found to be effective in animals.
For example, a dose for humans can be formulated to achieve circulating and/or gastrointestinal concentrations that have been found to be effective in animals.
[0095] The dosages of the core-shell compositions in animals will depend on the disease being, treated, the route of administration, the physical characteristics of the patient being treated, and the composition of the core and shell components. Dosage levels of the core-shell compositions for therapeutic and/or prophylactic uses can be from about about 0.5 gm/day to about 30 gm/day. It is preferred that these polymers are administered along with meals. The compositions may be administered one time a day, two times a day, or three times a day. Most preferred dose is about 15 gm/day or less. A preferred dose range is about 5 gmlday to about 20 gm/day, more preferred is about 5 gmlday to about gm/day, even more preferred is about 10 gm/day to about 20 gm/day, and most preferred is about 10 gm/day to about 15 gm/day.
[0096] liz some embodiments, the amount of target solute bound and/or retained by the 10 core-shell particles is greater than the amount if the core component is used in the absence of the shell. Hence, the dosage of the core component in some embodiments is lower when used in combination with a shell compared to when the core is used without the shell. Hence, in some embodiments of the core-shell pharmaceutical compositions, the amount of core component present in the core-shell pharmaceutical composition is 15 less than the amount that is administered to an animal in the absence of the shell component.
(0097] Preferably, the core-shell compositions used for therapeutic and/or prophylactic benefits can be administered alone or in the form of a pharmaceutical composition. The pharmaceutical compositions comprise of the core-shell compositions, one or more pharmaceutically acceptable carriers, diluents or excipients, and optionally additional therapeutic agents. The compositions can be administered by injection, topically, orally, transdermally, or rectally. Preferably, the core-shell composition or the pharmaceutical composition comprising the core-shell composition is administered orally. The oral form in wluch the core-shell composition is administered can include powder, tablet, capsule, solution, or emulsion. The therapeutically effective amount can be administered in a single dose or in a series of doses separated by appropriate time intervals, such as hours.
[0098] Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable Garners comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is _27_ dependent upon the route of administration chosen. Suitable techniques for preparing pharmaceutical compositions of the core-shell compositions are well known in the art.
[0099] In addition to the uses of the core-shell compositions described herein in the gastro-intestinal tract, these compositions can also be used for producing local effects in other parts of the body, for example in topical formulations for local effects on the skin or in systemic formulations for producing local effects in particular organs, like the liver or the heart.
[00100] hl some embodiments the polymers of the invention are provided as pharmaceutical compositions in the form of chewable tablets. In addition to the active ingredient, the following types of excipients are commonly used: a sweetening agent to provide the necessary palatability, plus a binder where the former is inadequate in providing sufficient tablet hardness; a lubricant to minimize frictional effects at the die wall and facilitate tablet ej ection; and, in some formulations a small amount of a disintegrant is added to facilitate mastication. In general excipient levels in currently-available chewable tablets are on the order of 3-5 fold of active ingredients) whereas sweetening agents make up the bulk of the inactive ingredients.
[00101] The present invention provides chewable tablets that contain a polymer or polymers of the invention and one or more pharmaceutical excipients suitable for formulation of a chewable tablet. The polymer used in chewable tablets of the invention preferably has a swelling ratio while transiting the oral cavity and in the esophagus of less than about 5, preferably less than about 4, more preferably less than about 3, more preferably less than 2.5, and most preferably less than about 2. The tablet comprising the polymer, combined with suitable excipients, provides acceptable organoleptic properties such as mouthfeel, taste, and tooth packing, and at the same time does not pose a risk to obstruct the esophagus after chewing and contact with saliva.
[00102] In some aspects of the invention, the polymers) provide mechanical and thermal properties that are usually performed by excipients, thus decreasing the amount of such excipients required for the formulation. In some embodiments the active ingredient (e.g., polymer) constitutes over about 30%, more preferably over about 40%, even more preferably over about 50%, and most preferably more than about 60%
by weight of the chewable tablet, the remainder comprising suitable excipient(s).
In some _28_ embodiments the polymer comprises about 0.6 gm to about 2.0 gm of the total weight of the tablet, preferably about 0.8 gm to about 1.6 gm. In some embodiments the polymer comprises more than about 0.8 gm of the tablet, preferably more than about 1.2 gm of the tablet, and most preferably more than about 1.6 gm of the tablet. The polymer is produced to have appropriate strength/friability and particle size to provide the same qualities for which excipients are often used, e.g., proper hardness, good mouth feel, compressibility, and the like. Unswelled particle size for polymers used in chewable tablets of the invention is less than about 80, 70, 60, 50, 40, 30, or 20 microns mean diameter. In preferred embodiments, the unswelled particle size is less than about 80, more preferably less than about 60, and most preferably less than about 40 microns.
by weight of the chewable tablet, the remainder comprising suitable excipient(s).
In some _28_ embodiments the polymer comprises about 0.6 gm to about 2.0 gm of the total weight of the tablet, preferably about 0.8 gm to about 1.6 gm. In some embodiments the polymer comprises more than about 0.8 gm of the tablet, preferably more than about 1.2 gm of the tablet, and most preferably more than about 1.6 gm of the tablet. The polymer is produced to have appropriate strength/friability and particle size to provide the same qualities for which excipients are often used, e.g., proper hardness, good mouth feel, compressibility, and the like. Unswelled particle size for polymers used in chewable tablets of the invention is less than about 80, 70, 60, 50, 40, 30, or 20 microns mean diameter. In preferred embodiments, the unswelled particle size is less than about 80, more preferably less than about 60, and most preferably less than about 40 microns.
[00103] Pharmaceutical excipients useful in the chewable tablets of the invention include a binder, such as microcrystalline cellulose, colloidal silica and combinations thereof (Prosolv 90), carbopol, providone and xanthan gum; a flavoring agent, such as sucrose, mannitol, xylitol, maltodextrin, fructose, or sorbitol; a lubricant, such as magnesium stearate, stearic acid, sodium stearyl fumurate and vegetable based fatty acids; and, optionally, a disintegrant, such as croscarmellose sodium, gellan gum, low-substituted hydroxypropyl ether of cellulose, sodium starch glycolate.
~ther additives may include plasticizers, pigments, talc, and the like. Such additives and other suitable ingredients are well-known in the art; see, e.g., Germaro AR (ed), Remington's Pha~maeeutical Sciences, 20th Edition.
~ther additives may include plasticizers, pigments, talc, and the like. Such additives and other suitable ingredients are well-known in the art; see, e.g., Germaro AR (ed), Remington's Pha~maeeutical Sciences, 20th Edition.
[00104] In some embodiments the invention provides a pharmaceutical composition formulated as a chewable tablet, comprising a polymer described herein and a suitable excipient. In some embodiments the invention provides a pharmaceutical composition formulated as a chewable tablet, comprising a polymer described herein, a filler, and a lubricant. In some embodiments the invention provides a pharmaceutical composition formulated as a chewable tablet, comprising a polymer described herein, a filler, and a lubricant, wherein the filler is chosen from the group consisting of sucrose, mannitol, xylitol, maltodextrin, fructose, and sorbitol, and wherein the lubricant is a magnesium fatty acid salt, such as magnesium stearate.
[00105] The tablet may be of any size and shape compatible with chewability and mouth disintegration, preferably of a cylindrical shape, with a diameter of about 10 mm to about 40 mm and a height of about 2 mm to about 10 mm, most preferably a diameter of about 22 mm and a height of about 6 mm.
[00106] In one embodiment, the polymer is pre-formulated with a high Tg / high melting point low molecular weight excipient such as mannitol, sorbose, sucrose in order to form a solid solution wherein the polymer and the excipient are intimately mixed.
Method of mixing such as extrusion, spray-drying, chill drying, lyophilization, or wet granulation are useful. Indication of the level of mixing is given by known physical methods such as differential scanning calorimetry or dynamic mechanical analysis.
Method of mixing such as extrusion, spray-drying, chill drying, lyophilization, or wet granulation are useful. Indication of the level of mixing is given by known physical methods such as differential scanning calorimetry or dynamic mechanical analysis.
[00107] Methods of making chewable tablets containing pharmaceutical ingredients, including polymers, are known in the art. See, e.g., European Patent Application No. EP373852A2 and U.S. Patent No. 6,475,510, and Remington's Pharmaceutical Sciences, which are hereby incorporated by reference in their entirety.
[00108] In some embodiments the polymers of the invention are provided as pharmaceutical compositions in the form of liquid formulations. In some embodiments the pharmaceutical composition contains an ion-binding polymer dispersed in a suitable liquid excipient. Suitable liquid excipients are known in the art; see, e.g., Remington's Plzarfnaceutical Sciences.
EXAMPLES
Synthesis of core-shell crosslinked polyallylamine particles [00109] In this process, spherical particles were formed by an inverse suspension procedure wherein a prepolymer (polyallylamine) is crosslinked with epichlorohydrine.
A block copolymer was used to impart mechanical stability to the droplets during the crosslinking reaction and provide a shell membrane chemically anchored to the core particle.
General procedure for block copolymers synthesis [00110] The block copolymers were prepared by RAFT living free radical polymerization method, using a dithiocarbazide compound as a reversible chain transfer agent (CTA) and a diazonitrile free radical initiator (AMVN) indicated below:
~ ~N o N~S ~ ~
OEt ANN~
RCN CN
CTA
Synthesis of Poly(n-butyl acrylate-co-t-butyl acrylate) first block [00111] n-Butyl acrylate (25g, 195 mmol) and t-butyl acrylate (25g, 195 mmol) were combined with the CTA (173:1 Monomer:CTA, 616 mg, 2.26 mmol)) and AIBN
(18.6 mg, 0.113 mmol). The monomer to CTA ratio is fixed so that the theoretical number average molecular weight (Mn) is 20,000 g.mol at 90% conversion. The solution was stirred while purging with Ar for 20 minutes at room temperature. After this time, it was heated to 65°C under Ar while stirnng for 3 hours and then cooled to room temperature. 1H NMR in CDC13 showed 87% conversion based on disappearance of monomer. The crude polymer was dissolved in 50 ml of acetone and precipitated into 900 ml of a 9:1(v/v) methanol: water solution. After several hours, the polymeric oil had separated to the bottom and the top layer was discarded. The polymeric oil was dried in vacuum to yield 44 g (88% yield) of extremely thick yellow oil. 1H NMR (300 MHz, CDC13): 8 = 4.15-3.95 (2H, bm), 2.45-2.05 (2H, bm). 1.95-1.75 (1H, bm), 1.60-1.5 (5H, bm), 1.5-1.3 (11H, bm), 0.93 (3H, t). GPC (THF, polystyrene standards): Mn =
25900;
PDI =1.13. GPC (DMF, polyethyleneglycol standards): Mn = 6600; PDI =1.58.
EXAMPLES
Synthesis of core-shell crosslinked polyallylamine particles [00109] In this process, spherical particles were formed by an inverse suspension procedure wherein a prepolymer (polyallylamine) is crosslinked with epichlorohydrine.
A block copolymer was used to impart mechanical stability to the droplets during the crosslinking reaction and provide a shell membrane chemically anchored to the core particle.
General procedure for block copolymers synthesis [00110] The block copolymers were prepared by RAFT living free radical polymerization method, using a dithiocarbazide compound as a reversible chain transfer agent (CTA) and a diazonitrile free radical initiator (AMVN) indicated below:
~ ~N o N~S ~ ~
OEt ANN~
RCN CN
CTA
Synthesis of Poly(n-butyl acrylate-co-t-butyl acrylate) first block [00111] n-Butyl acrylate (25g, 195 mmol) and t-butyl acrylate (25g, 195 mmol) were combined with the CTA (173:1 Monomer:CTA, 616 mg, 2.26 mmol)) and AIBN
(18.6 mg, 0.113 mmol). The monomer to CTA ratio is fixed so that the theoretical number average molecular weight (Mn) is 20,000 g.mol at 90% conversion. The solution was stirred while purging with Ar for 20 minutes at room temperature. After this time, it was heated to 65°C under Ar while stirnng for 3 hours and then cooled to room temperature. 1H NMR in CDC13 showed 87% conversion based on disappearance of monomer. The crude polymer was dissolved in 50 ml of acetone and precipitated into 900 ml of a 9:1(v/v) methanol: water solution. After several hours, the polymeric oil had separated to the bottom and the top layer was discarded. The polymeric oil was dried in vacuum to yield 44 g (88% yield) of extremely thick yellow oil. 1H NMR (300 MHz, CDC13): 8 = 4.15-3.95 (2H, bm), 2.45-2.05 (2H, bm). 1.95-1.75 (1H, bm), 1.60-1.5 (5H, bm), 1.5-1.3 (11H, bm), 0.93 (3H, t). GPC (THF, polystyrene standards): Mn =
25900;
PDI =1.13. GPC (DMF, polyethyleneglycol standards): Mn = 6600; PDI =1.58.
[00112] Following this procedure, 4 different first blocks were prepared, which are listed in TABLE 3 as Example 1-1 to 1-4.
Molecular ExampleIdentificationComposition weight /mol 1-1 nBAItBAl n-butyl acrylate-co-t-butyl20 000 20k - acrylate 50/50 ' mol-%
N,N-di-n-butyl acrylamide-1-2 nDiBAltBAl co-t-butyl acrylate20,000 20k 50/50 mol-1-3 nBAItBAI n-butyl acrylate-co-t-butyl50 000 SOk - acrylate 50/50 ' mol-%
N,N-di-n-butyl acrylamide-1-4 nDiBAltBAl co-t-butyl acrylate50,000 SOk 50/50 mol-Synthesis of Poly[(n-butyl acrylate-co-t-butyl acrylate)-b-(N,N-dimethylacrylamide-co-glycidyl methacrylate)]
Molecular ExampleIdentificationComposition weight /mol 1-1 nBAItBAl n-butyl acrylate-co-t-butyl20 000 20k - acrylate 50/50 ' mol-%
N,N-di-n-butyl acrylamide-1-2 nDiBAltBAl co-t-butyl acrylate20,000 20k 50/50 mol-1-3 nBAItBAI n-butyl acrylate-co-t-butyl50 000 SOk - acrylate 50/50 ' mol-%
N,N-di-n-butyl acrylamide-1-4 nDiBAltBAl co-t-butyl acrylate50,000 SOk 50/50 mol-Synthesis of Poly[(n-butyl acrylate-co-t-butyl acrylate)-b-(N,N-dimethylacrylamide-co-glycidyl methacrylate)]
[00113] Theoretical Mn=20,000 1St block and Mn=5000 2"d block at SO% con. A
solution of poly(n-butyl acrylate-co-t-butyl acrylate) terminated with the CTA
(2.53 ml, 40 wt% in DMF) and a solution of AMVN (4~.1 ~.1, 0.00736 mmol, 4 wt% in DMF) were combined manually. The mixture was then purged with Ar for 20 minutes. While stirring at room temperature, N,N-dimethylacrylamide (27.5 ~,1, 0.267 mmol) and a solution of glycidyl methacrylate (14.3 ~.1, 0.0296 mmol, 30 wt% in DMF) were added.
The solution temperature was then raised to 55°C over 30 minutes while stirring. At this time, N,N-dimethylacrylamide (10.3 ~,1, 0.100 mmol) and a solution of glycidyl methacrylate (5.4 ~,1, 0.0111 mmol, 30 wt% in DMF) were added via a robot.
Every 10 minutes for the next 4 hours N,N-dimethylacrylamide (10.3 ~,1, 0.100 mmol) and a solution of glycidyl methacrylate (5.4 ~1, 0.0111 mmol, 30 wt% in DMF) were added while the solution stirred under Ar at 55°C. After all additions had been completed, the solution was stirred for an additional 2 hours under Ar at 55°C and then cooled to room temperature. The crude polymer was dissolved in 2 ml acetone and precipitated into 30 ml water. The resulting mixture was centrifuged at 1000 rpm for 60 minutes and the upper water layer then removed. The polymeric powder was washed with an additional 10 ml of water, centrifuged, and the water layer removed. The resulting wet powder was dried under vacuiun at 30°C to give a viscous liquid. Subsequent lyophilization provided 1.19g (92% yield) of a sticky solid. GPC (DMF, polyethyleneglycol standards):
Mn =
X500; PDI = 2.10.
solution of poly(n-butyl acrylate-co-t-butyl acrylate) terminated with the CTA
(2.53 ml, 40 wt% in DMF) and a solution of AMVN (4~.1 ~.1, 0.00736 mmol, 4 wt% in DMF) were combined manually. The mixture was then purged with Ar for 20 minutes. While stirring at room temperature, N,N-dimethylacrylamide (27.5 ~,1, 0.267 mmol) and a solution of glycidyl methacrylate (14.3 ~.1, 0.0296 mmol, 30 wt% in DMF) were added.
The solution temperature was then raised to 55°C over 30 minutes while stirring. At this time, N,N-dimethylacrylamide (10.3 ~,1, 0.100 mmol) and a solution of glycidyl methacrylate (5.4 ~,1, 0.0111 mmol, 30 wt% in DMF) were added via a robot.
Every 10 minutes for the next 4 hours N,N-dimethylacrylamide (10.3 ~,1, 0.100 mmol) and a solution of glycidyl methacrylate (5.4 ~1, 0.0111 mmol, 30 wt% in DMF) were added while the solution stirred under Ar at 55°C. After all additions had been completed, the solution was stirred for an additional 2 hours under Ar at 55°C and then cooled to room temperature. The crude polymer was dissolved in 2 ml acetone and precipitated into 30 ml water. The resulting mixture was centrifuged at 1000 rpm for 60 minutes and the upper water layer then removed. The polymeric powder was washed with an additional 10 ml of water, centrifuged, and the water layer removed. The resulting wet powder was dried under vacuiun at 30°C to give a viscous liquid. Subsequent lyophilization provided 1.19g (92% yield) of a sticky solid. GPC (DMF, polyethyleneglycol standards):
Mn =
X500; PDI = 2.10.
[00114] Similar procedures were used to make block copolymers of various length and chemical compositions which are reported in the following tables, TABLES 4 and 5.
Library: Plate1 (ID: 100436) Unit: mg Row Col j nDiBAItBA1DiBAItBA1 DMF THF AMVN MA DMA
20k n 0k G
A 1 1065.7 0.0 754.2707.3 2.0 45.8 287.3 A 2 915.9 0.0 709.1665.0 1.7 78.7 493.8 A 3 714.9 0.0 648.6608.2 1.3 122.8 770.8 A 4 1065.7 0.0 754.2707.3 2.0 45.8 287.3 A 5 915.9 0.0 709.1665.0 1.7 78.7 493.8 A 6 714.9 0.0 648.6608.2 1.3 122.8 770.8 B 1 982.0 0.0 810.5760.1 1.8 116.8 190.1 B 2 798.9 0.0 806.5756.3 1.5 190.1 309.2 B 3 581.8 0.0 801.7751.8 1.1 276.8 450.4 B 4 982.0 0.0 810.5760.1 1.8 116.8 190.1 B 5 798.9 0.0 806.5756.3 1.5 190.1 309.2 B 6 581.8 0.0 801.7751.8 1.1 276.8 450.4 C 1 0.0 897.8 622.9584.1 0.7 38.6 242.0 C 2 0.0 770.4 585.8549.3 0.6 66.2 415.3 C 3 0.0 600.1 536.1502.7 0.4 103.1 647.0 C 4 0.0 897.8 622.9584.1 0.7 38.6 242.0 C 5 0.0 770.4 585.8549.3 0.6 66.2 415.3 C 6 0.0 600.1 536.1502.7 0.4 103.1 647.0 D 1 0.0 826.5 670.8629.0 0.6 98.3 160.0 D 2 0.0 671.1 668.2626.7 0.5 159.7 259.8 D 3 0.0 487.7 665.3623.9 0.4 232.1 377.6 D 4 0.0 826.5 670.8629.0 0.6 98.3 160.0 D 5 0.0 671.1 668.2626.7 0.5 159.7 259.8 D 6 0.0 487.7 665.3623.9 0.4 232.1 377.6 General Design and Variations from Example(mol:mol ratios) Starting Block (45.5wt%
solns): Rows A,B = 20k 1:1 N,N-di-n-Butyl Acrylamidea-Butyl Acylate Rows C,D = 50k 1:1 N,N-di-n-Butyl Acrylamidea-Butyl Acylate Initiator: AMVN
Temperature: 60C
2nd Block Compostion: Rows A,C = 1:9 GMA:DMA
Rows B,D = 3:7 GMA:DMA
Block Target Mn: A1,B1,A4,B4 = 5k A2,B2,A5,B5 = 10k A3,B3,A6,B6 = 20k C1,D1,C4,D4 = 12.5k C2,D2,C5,D5 = 25k C3,D3,C6,D6 = 50k 2nd Block Method: Columns 1,2,3 = Batch Addition Columns 4,5,6 = Spot Addition I ihrarw PIatP1 IIDv 1f1l1RRql l lnit~ mn Row Col GMA DMF nBA1tBA1 DMA AIBN
20k A 1 39.8 1566.0 963.2 249.2 1.2 A 2 72.5 1458.0 842.7 454.2 1.0 A 3 116.8 1311.6 679.3 732.2 0.8 A 4 39.8 1566.0 963.2 249.2 1.2 A 5 72.5 1458.0 842.7 454.2 1.0 A 6 116.8 1311.6 679.3 732.2 0.8 B 1 74.2 1604.6 935.9 206.6 1.2 B 2 132.1 1532.2 800.2 368.0 1.0 B 3 206.6 1439.1 625.7 575.5 0.8 B 4 74.2 1604.6 935.9 206.6 1.2 B 5 132.1 1532.2 800.2 368.0 1.0 B 6 206.6 1439.1 625.7 575.5 0.8 I
General Design (mol:mol ratios) Starting Block:20k 1:1 n-Butyl Acrylatea-Butyl Acylate I nitiator: AI BN
Temperature: 65C
2nd Block Compostion:Row A = 1:9 GMA:DMA
Row B = 2:8 GMA:DMA
2nd Block TargetColumns 1,4 = 5k Mn:
Columns 2,5 = 10k Columns 3,6 = 20k 2nd Block Method:Columns 1,2,3 = Batch Addition Columns 4,5,6 = Spot Addition General procedure for the synthesis of core/shell crosslinked polyallylamine particles:
Library: Plate1 (ID: 100436) Unit: mg Row Col j nDiBAItBA1DiBAItBA1 DMF THF AMVN MA DMA
20k n 0k G
A 1 1065.7 0.0 754.2707.3 2.0 45.8 287.3 A 2 915.9 0.0 709.1665.0 1.7 78.7 493.8 A 3 714.9 0.0 648.6608.2 1.3 122.8 770.8 A 4 1065.7 0.0 754.2707.3 2.0 45.8 287.3 A 5 915.9 0.0 709.1665.0 1.7 78.7 493.8 A 6 714.9 0.0 648.6608.2 1.3 122.8 770.8 B 1 982.0 0.0 810.5760.1 1.8 116.8 190.1 B 2 798.9 0.0 806.5756.3 1.5 190.1 309.2 B 3 581.8 0.0 801.7751.8 1.1 276.8 450.4 B 4 982.0 0.0 810.5760.1 1.8 116.8 190.1 B 5 798.9 0.0 806.5756.3 1.5 190.1 309.2 B 6 581.8 0.0 801.7751.8 1.1 276.8 450.4 C 1 0.0 897.8 622.9584.1 0.7 38.6 242.0 C 2 0.0 770.4 585.8549.3 0.6 66.2 415.3 C 3 0.0 600.1 536.1502.7 0.4 103.1 647.0 C 4 0.0 897.8 622.9584.1 0.7 38.6 242.0 C 5 0.0 770.4 585.8549.3 0.6 66.2 415.3 C 6 0.0 600.1 536.1502.7 0.4 103.1 647.0 D 1 0.0 826.5 670.8629.0 0.6 98.3 160.0 D 2 0.0 671.1 668.2626.7 0.5 159.7 259.8 D 3 0.0 487.7 665.3623.9 0.4 232.1 377.6 D 4 0.0 826.5 670.8629.0 0.6 98.3 160.0 D 5 0.0 671.1 668.2626.7 0.5 159.7 259.8 D 6 0.0 487.7 665.3623.9 0.4 232.1 377.6 General Design and Variations from Example(mol:mol ratios) Starting Block (45.5wt%
solns): Rows A,B = 20k 1:1 N,N-di-n-Butyl Acrylamidea-Butyl Acylate Rows C,D = 50k 1:1 N,N-di-n-Butyl Acrylamidea-Butyl Acylate Initiator: AMVN
Temperature: 60C
2nd Block Compostion: Rows A,C = 1:9 GMA:DMA
Rows B,D = 3:7 GMA:DMA
Block Target Mn: A1,B1,A4,B4 = 5k A2,B2,A5,B5 = 10k A3,B3,A6,B6 = 20k C1,D1,C4,D4 = 12.5k C2,D2,C5,D5 = 25k C3,D3,C6,D6 = 50k 2nd Block Method: Columns 1,2,3 = Batch Addition Columns 4,5,6 = Spot Addition I ihrarw PIatP1 IIDv 1f1l1RRql l lnit~ mn Row Col GMA DMF nBA1tBA1 DMA AIBN
20k A 1 39.8 1566.0 963.2 249.2 1.2 A 2 72.5 1458.0 842.7 454.2 1.0 A 3 116.8 1311.6 679.3 732.2 0.8 A 4 39.8 1566.0 963.2 249.2 1.2 A 5 72.5 1458.0 842.7 454.2 1.0 A 6 116.8 1311.6 679.3 732.2 0.8 B 1 74.2 1604.6 935.9 206.6 1.2 B 2 132.1 1532.2 800.2 368.0 1.0 B 3 206.6 1439.1 625.7 575.5 0.8 B 4 74.2 1604.6 935.9 206.6 1.2 B 5 132.1 1532.2 800.2 368.0 1.0 B 6 206.6 1439.1 625.7 575.5 0.8 I
General Design (mol:mol ratios) Starting Block:20k 1:1 n-Butyl Acrylatea-Butyl Acylate I nitiator: AI BN
Temperature: 65C
2nd Block Compostion:Row A = 1:9 GMA:DMA
Row B = 2:8 GMA:DMA
2nd Block TargetColumns 1,4 = 5k Mn:
Columns 2,5 = 10k Columns 3,6 = 20k 2nd Block Method:Columns 1,2,3 = Batch Addition Columns 4,5,6 = Spot Addition General procedure for the synthesis of core/shell crosslinked polyallylamine particles:
[00115] Preparation of polyallylamine (PAA) solution: Polyallylamine hydrochloride (Mw 15,000) was dissolved in water, and NaOH was added to neutralize 25 mol% of hydrochloride. The concentration of polyallyamine hydrochloride in solution was 33 wt.%.
[00116] Preparation of diblock copolymer solution: diblock copolymer was dissolved in toluene at 5 wt.%.
[00117] Preparation of core/shell particles: To 15 ml glass reactor was charged PAA solution, diblock copolymer solution, and toluene, and some typical solution compositions as shown in Tables 4-9. The mixture was emulsified with an Ultra-Turrax for 30 seconds and a magnetic stir bar was put into the suspension. The suspension was stirred and heated at 60°C for 30 minutes and epichlorohydrin (10 mol%
based on amine groups) was added. The suspension was further stirred at 60°C for ~
hours and then cooled to room temperature.
based on amine groups) was added. The suspension was further stirred at 60°C for ~
hours and then cooled to room temperature.
[00118] Purification of core/shell particles: To the reaction mixture above, methanol (10 mL) was added and white particles precipitated out. The mixture was shaken for 30 minutes and centrifuged. The white particles separated from supernatant solution and collected. The white particles were further washed with methanol (10 mL x 2) and water (10 mL x 3) by repeating the same shake/centrifuge procedure.
Finally the particles were freeze-dried for three days.
Synthesis of 1,3-Diaminopropane/epichlorohydrin crosslinked beads (Referred to herein as: Bead-Pi-4-s) [00119] The reaction vessel used was a 3-liter, three necked round bottom flask with four side baffles, equipped with an oil heating bath, cold-water reflux condenser, and mechanical stirrer with a 3 inch propeller. To this reaction vessel is introduced a solution of 1,3-diaminopropane (90.2 g, 1.21 mole) dissolved in 90.2 g of water, surfactant (branched dodecylbenzene sulfonic acid sodium salt, 6.4 g dissolved in 100 g of water), and 1 Kg of toluene. This initial charge is agitated to 600 rpm for 2 minutes and then lowered to 300 rpm for 10 minutes before the first addition of epichlorohydrin.
This speed is maintained through out the experiment. The solution was heated to 80°C
and maintained at this temperature throughout the experiment.
Finally the particles were freeze-dried for three days.
Synthesis of 1,3-Diaminopropane/epichlorohydrin crosslinked beads (Referred to herein as: Bead-Pi-4-s) [00119] The reaction vessel used was a 3-liter, three necked round bottom flask with four side baffles, equipped with an oil heating bath, cold-water reflux condenser, and mechanical stirrer with a 3 inch propeller. To this reaction vessel is introduced a solution of 1,3-diaminopropane (90.2 g, 1.21 mole) dissolved in 90.2 g of water, surfactant (branched dodecylbenzene sulfonic acid sodium salt, 6.4 g dissolved in 100 g of water), and 1 Kg of toluene. This initial charge is agitated to 600 rpm for 2 minutes and then lowered to 300 rpm for 10 minutes before the first addition of epichlorohydrin.
This speed is maintained through out the experiment. The solution was heated to 80°C
and maintained at this temperature throughout the experiment.
[00120] Into a separate vessel, a 40 mass% solution of epichlorohydrin in toluene was prepared. Using a syringe pump, 1.2 equivalents of epichlorohydrin (134.7 g, (1.45 mole)) was added over a 3 hour period. The reaction was continued for an additional 2 hours before adding 0.75 equivalents of sodium hydroxide (36.5 g (0.91 mole)) in a 40 weight % solution. The sodium hydroxide solution was added to the reaction via a syringe pump over a 2.5-hour period. The reaction was maintained at 80°C for a further 8 hours. The beads were purified by removing the toluene, washing with 1000 ml of acetone, followed by methanol, and then a 20% solution of NaOH (to remove the surfactant), and twice more with deionized water. The beads were freeze dried for 3 days to give a fme white powder weighing at 160 g (92 % yield), and having a mean diameter of 93 Vim.
Synthesis of 1 3-Diaminopropane /~ichlorohydrin crosslinked beads (Referred to herein as: Bead-Pi-3-s) [00121] The procedure described above was used with 1 equivalent of epichlorohydrin.
SSmthesis of water swollen crosslinked beads prepared with 1,3-Diaminopropane/epichlorohydrin in the presence of surfactant (Referred to herein as:
Bead-Pi-5-s) [00122] The procedure described above for the preparation of beads from 1,3-diaminopropane/epichlorohydrin was reproduced exactly up to stage 2. After the reaction flask had cooled to room temperature, the stirring was stopped. The beads settle to the bottom of the flask. The clear toluene layer was decanted from the reaction and replaced by fresh toluene to remove unreacted epichlorohydrin. This procedure was repeated 4 times and washing with a total of 3000 ml of toluene. Through out this process the beads were not allowed to dry out. The total weight of the solution was made to 756 g by adding toluene to give a 21 wt-% solution of bead suspended in toluene.
Preparation of ethyl cellulose shell/1 3 di-amino propane epichlorohydrine crosslinked core particle [00123] The beads obtained from Example 2 are spray-coated with an ethyl cellulose polymer shell using a Wurster fluid bed coater 2"- 4"/6" Portable Unit. The fluidized bed unit is operated so that an average 5 microns thick coating is deposited on the core particles, using a 30wt-% solid aqueous emulsion (Aquacoat~ ECD, FMC
core.).
Bindin capacity in a digestion mimic [00124] This procedure was used to mimic the conditions of use of a phosphate binder drug and measure the binding characteristics of the polymer for phosphate (target solute) in the presence of other metabolites (competing solutes). A liquid meal was prepared and the meal was artificially digested in the presence of pepsin and pancreatic juice. The sequence of addition of enzymes and the pH profile were controlled so that the digestion process was simulated down to the jejunum level. An aliquot of the digested meal mimic is centrifuged and the supernatant assayed for phosphate.
Synthesis of 1 3-Diaminopropane /~ichlorohydrin crosslinked beads (Referred to herein as: Bead-Pi-3-s) [00121] The procedure described above was used with 1 equivalent of epichlorohydrin.
SSmthesis of water swollen crosslinked beads prepared with 1,3-Diaminopropane/epichlorohydrin in the presence of surfactant (Referred to herein as:
Bead-Pi-5-s) [00122] The procedure described above for the preparation of beads from 1,3-diaminopropane/epichlorohydrin was reproduced exactly up to stage 2. After the reaction flask had cooled to room temperature, the stirring was stopped. The beads settle to the bottom of the flask. The clear toluene layer was decanted from the reaction and replaced by fresh toluene to remove unreacted epichlorohydrin. This procedure was repeated 4 times and washing with a total of 3000 ml of toluene. Through out this process the beads were not allowed to dry out. The total weight of the solution was made to 756 g by adding toluene to give a 21 wt-% solution of bead suspended in toluene.
Preparation of ethyl cellulose shell/1 3 di-amino propane epichlorohydrine crosslinked core particle [00123] The beads obtained from Example 2 are spray-coated with an ethyl cellulose polymer shell using a Wurster fluid bed coater 2"- 4"/6" Portable Unit. The fluidized bed unit is operated so that an average 5 microns thick coating is deposited on the core particles, using a 30wt-% solid aqueous emulsion (Aquacoat~ ECD, FMC
core.).
Bindin capacity in a digestion mimic [00124] This procedure was used to mimic the conditions of use of a phosphate binder drug and measure the binding characteristics of the polymer for phosphate (target solute) in the presence of other metabolites (competing solutes). A liquid meal was prepared and the meal was artificially digested in the presence of pepsin and pancreatic juice. The sequence of addition of enzymes and the pH profile were controlled so that the digestion process was simulated down to the jejunum level. An aliquot of the digested meal mimic is centrifuged and the supernatant assayed for phosphate.
[00125] An aliquot of dried resin of weight P(gr), was mixed under gentle agitation with a fixed volume ,V(ml), of a meal digest solution with a phosphate ion concentration of Cstart(~). After resin equilibration, the solution was decanted by centrifugation and the supernatant analyzed for residual phosphate concentration by ionic chromatography, Cea(mM). The binding capacity was calculated as BC (mmol/gr)=V. (CscarrCeq)~.
A. CorelShell Crosslin.ked Pol a~llylamine Particles [00126] Procedures described in Example 1 were implemented in a library format of 4x6 reactors, where the nature of the block copolymer was varied from well to well, as indicated in Tables 6-9. Entries correspond to the weight of chemicals used in each reaction well and to the phosphate binding capacity measured in the meal digest fluid. A
Selectivity Index (SI) was computed to measure the phosphate binding relative to the core material (i.e. crosslinked polyallylamine, Renagel). When SI was greater than 1, the core-shell material bound more phosphate than the corresponding core polymer on a weight basis. The SI values for the polymers are included in Tables 6-9.
A. CorelShell Crosslin.ked Pol a~llylamine Particles [00126] Procedures described in Example 1 were implemented in a library format of 4x6 reactors, where the nature of the block copolymer was varied from well to well, as indicated in Tables 6-9. Entries correspond to the weight of chemicals used in each reaction well and to the phosphate binding capacity measured in the meal digest fluid. A
Selectivity Index (SI) was computed to measure the phosphate binding relative to the core material (i.e. crosslinked polyallylamine, Renagel). When SI was greater than 1, the core-shell material bound more phosphate than the corresponding core polymer on a weight basis. The SI values for the polymers are included in Tables 6-9.
[00127] Results are shown in Tables 6-9. Results collated in this series of examples show that the core-shell particles of the invention display higher binding for phosphate over bare, non-encapsulated particles in simulated fluid representative of the real conditions of use. Some of the best performing core-shell materials are then assessed in binding phosphate in the ex-vivo aspirates from human intestinal content.
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_ O
m t N
~ CO ~ tn O a0 M W M N o CO 07 N = ~ N
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= o r .
r uy .
m .o w o V O c0 u7 c0 N O cr ao N N N f~ = ~ w co ~t V N ~ ~ N N N O M
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O O O o 0 0 47 O O O O O O o O O O O O O O O O
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r r r r r r r r r r r r r r r r O - ~=
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r~ rm. i. r~ ~ ~ ~ r. ~ rm. i. ~ ~ ~ o r~ N r~ rm. r r~ ~ ~ E ~
In l~ l~ LO l0 tf~ lf7 u7 Ln u7 _ r In l0 l0 N l0 u] t~ t~ Ll~ In C O
In In ~ N
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~ z ro 0 rrrrrrrrrrrrrrrrrrrr ~ r a U c n B. CorelShell Crosslizzked 1 3-dianzizzoproz~ane%pichlo~ohydz~iyze Particles [00128] Procedures described in Example 2 were implemented in a library format of 4x6 reactors, where the nature of the polymer was varied from well to well, as indicated in Tables 11-18. Entries in the Tables correspond to the weight of chemicals used in each reaction well, and to the phosphate binding capacity measured in the meal digest fluid. A Selectivity Index (S1) was computed as described above. The SI
values for the polymers are included in Tables 11-18.
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n u u n i n n O r a m re u r u v o 0 0 o O O O O O O o o O o O O V N
O O O o 0 0 47 O O O O O O o O O O O O O O O O
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r~ rm. i. r~ ~ ~ ~ r. ~ rm. i. ~ ~ ~ o r~ N r~ rm. r r~ ~ ~ E ~
In l~ l~ LO l0 tf~ lf7 u7 Ln u7 _ r In l0 l0 N l0 u] t~ t~ Ll~ In C O
In In ~ N
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~ z ro 0 rrrrrrrrrrrrrrrrrrrr ~ r a U c n B. CorelShell Crosslizzked 1 3-dianzizzoproz~ane%pichlo~ohydz~iyze Particles [00128] Procedures described in Example 2 were implemented in a library format of 4x6 reactors, where the nature of the polymer was varied from well to well, as indicated in Tables 11-18. Entries in the Tables correspond to the weight of chemicals used in each reaction well, and to the phosphate binding capacity measured in the meal digest fluid. A Selectivity Index (S1) was computed as described above. The SI
values for the polymers are included in Tables 11-18.
[00129] Each example comprised a library of 22 core-shell materials and one core material taken as a reference. The core materials are beads prepared from crosslinked 1,3-diaminopropane/epichlorohydrine as shown in Example 2 (bead 4-s, bead 3-s, and bead 5-s). They were used either as a dry powder (bead 4-s, bead 3-s) or as a slurry in toluene (bead 5-s). The core-shell particles were prepared in semi-continuous reactors arranged in a 4x6 library format. Each reactor had a 3 ml volume, was magnetically stirred, and temperature-controlled. In a typical procedure, the beads were first dispensed, followed by the addition of the selected solvent under magnetic agitation. The reaction temperature was set to 60°C. The shell materials were then robotically dispensed for 4 hours and the 24 reactions kept another 12 hours at the set temperature.
The library was then cooled down to ambient temperature and the content of the reactors transferred to 15 ml vials. The core-shell beads were then washed repeatedly with a fresh volume of the same solvent used during the shell coupling reaction, then with isopropanol, and finally with de-ionized water. The particles were finally lyophilized.
The library was then cooled down to ambient temperature and the content of the reactors transferred to 15 ml vials. The core-shell beads were then washed repeatedly with a fresh volume of the same solvent used during the shell coupling reaction, then with isopropanol, and finally with de-ionized water. The particles were finally lyophilized.
[00130] The chemical structures of the shell materials used are shown in Table 10.
Labet Name CAS ~tructare ' MW {glmol) # '.
Shell-AH-1POLY(METHYLVINYL
ETHER-ALT
MALEICANHYDRIDE) * ' MW -20,000 .-O *
p O O
Shell-AH-2POLY(METHYLVINYL
ETHER-ALT
MALEICANHYDRIDE) * MW ~-50,000 ~O *
O " O
Shell-AH-3PpLY(METHYLVINYL8011-16-9 Mn. -ETHER-ALT 80,000 MALEICANHYDRIDE) MW. ~
* -~O n * 216,000 Shell-AH-4POLYSTYRENE-MALEIC
ANHYDRIDE) MW=1600 50:50 (molar) Shell-AH-5POLYSTYRENE-MALEIC
ANHYDRIDE) MW=1900 75:25 (molar) POLYSTYRENE-co-MALEIC
Shell-AH-6ANHYDRIDE), 26762-29-8 Mn=1600 CUMENE
TERMINATED
POLYSTYRENE-co-MALEIC
Shell-AH-7ANHYDRIDE), 26762-29-8 Mn=1700 CUMENE
TERMINATED
POLYSTYRENE-co-MALEIC
Shell-AH-8ANHYDRIDE), 160611-46-1 Mn=2300 PARTIAL ISOCTYL
ESTER, CUMENE FW=658.8 TERMINATED
POLYSTYRENE-co-MALEIC
Shell-AH-9ANHYDRIDE), 160611-50-7 BUTOXYETHYLESTER,CUMENE AV. Mn=2500 TERMINATED
TABLE 10 (continued) l,abetName GAS Structure MW (gtmat~
~ #
POLYETHYLENE-co-ETHYL
Shell-AH-1ACRYLATE-co-MALEIC41171-14-6 ANHYDRIDE) POLYSTYRENE-co-MALEIC
Mn-1900 Shell-AH-1ANHYDRIDE), 160611-48-3 PARTIAL PROPYL
ESTER, CUMENE
TERMINATED
Shell-AH-1POLYETHYLENE-graft-MALEIC106343-08-2 FW-154.2 ANHYDRIDE
POLYISOPRENE-graft-MALEIC139948-75-7 FW=234.3 Shell-AH-1ANHYDRIDE Mf1-25000 POLYETHYLENE-co-BUTYL
FW=268 Shell-AH-1ACRYLATE-co-MALEIC64652-60-4 .
ANHYDRIDE) Shell-CI-1 15484-44-3O ~~ _ 166.56 ACID SODIUM O Na+
SALT
I
S
Shell-CI-2HYDROXYPROPANESULFONIC126-83-0O -~ 196.59 0 ' ACID SODIUM Na SALT
DIETHYLENE GLYCOL
Shell-Mc-1 4074-88-8 .
DIACRYLATE O O
Shell-Mc-2POLYETHYLENE 26570-49-8 Mn. -GLYCOL) 700 DIACRYLATE
o POLYETHYLENE-co-FW=256 Shell-Mc-3METHACRYLATE-co-GLYCIDYL51541-08-3 .
METHACRYLATE) EtO~ pEt ) I 288.5 Shell-EP-1ETHYLTRXETHOXYSILANE OEt p \~\\~
Shell-EP-2POLY(ETHYL GLYCOL)26403-72-5 526.6 DIGLYCIDYL ETHER
Shell-EP-3POLY(ETHYL GLYCOL)26403-72-5 2O0 (200) DIGLYCIDYL ETHER
O
Shell-EP-4POLY(ETHYL GLYCOL)26403-72-5~ 400 (400) DIGLYCIDYL ETHER
O
POLY(ETHYL GLYCOL)26403-72-5 600 SheII-EP-(600) DIGLYCIDYL ETHER
Shell-EP-6 POLY(ETHYL 26403-72-5 1 OOO
GLYCOL) (1000) DIGLYCIDYL ETHER
TABLE 10 (continued) ' t~abetName CAS St~uafiurs MW (glmai3 #
Shell-EP-71,3-BUTADIENE 1464-53-5 86.09 DIEPOXIDE O
FF F FF
3-(1 H,1 H,7H- O
~~ F
Shell-EP-8DODECAFLUOROHEPTYLOXY)-1,2799-34-8 388.15 EPOXYPROPANE F F F F F
o Shell-EP-9 6178-32-1I ~ 276.42 ETHER ~
OPYLENE GL
Y
L) Shell-EP-10(PR 26142-30-30 640 YCO
PCL
DIGLYCIDYL ETHER
Shell-EP-11GLYCIDYL HEXADECYL15965-99-8 ETHER O~ 298.51 O
O
Shell-EP-2-[(a-NITROPHENOXY)METHYL]OXIRAN5255-75-4O2N \ / O 195.18 12bIS E
POLY(BISPHENOL FW=487.0 A-co-Shell-EP-12EPICHLOROHYDRIN),25036-25-3 Mn -355 GLVCICYL
END-CAPPED
POLY(BISPHENOL FW=487.0 A-co-Shell-EP-13EPICHLOROHYDRIN), GLYCICYL Mn 1075 END-CAPPED
POLY(BISPHENOL
A-co-Shell-EP-14EPICHLOROHYDRIN), Mn-1750 GLYCICYL
END-CAPPED
POLY(BISPHENOL
A-co-Shell-EP-15EPICHLOROHYDRIN), I
GLYCICYL
END-CAPPED
Shell-EP-16POLY(o-CRESYL 28690-82-2 FW=194.2 GLYCIDYL
ETHER)-co-FORMALDEHYDE) Mn~540 Shell-EP-17POLY(o-CRESYL 28690-82-3 FW=194.2 GLYCIDYL
ETHER)-co-FORMALDEHYDE) Mn~1270 Shell-EP-18POLYETHYLENE-co-GLYCIDYL26061-90-5 FW=170.2 METHACRYLATE) Shell-EP-19BISPHENOL DIGLYCIDYL1675-54-3 ETHER
Shell-EP-20PoLY(DIMETHYLSILOxANE)130167-23-6 FW=282.5 DIGLYCIDYL TERMINATED EW~490 POLY[(PHENYL FW=180.2 Shell-EP-21GLYCIDYL ETHER)~
~a-FORMALDEHYDE] Mn-345 Shell-EP-22POLY[(PHENYL 28064-14-4 FW=180.2 GLYCIDYL ETHER) co-FORMALDEHYDE] Mn--570 Shell-EP-23POLY[(PHENYL 118345-05-0 FW=286.4 GLYCIDYL ETHER) co-DICYCLOPENTADIENE] Mn-490 POLY(EPICHLOROHYDRIN-co-Shell-EP-24ETHYLENE OXIDE-co-ALLY26587-37-1 GLYCIDYL ETHER
TABLE 10 (continued) l.abat' Name CAS Straatore MW jglmalj #
Shall-EP-25CASTOR OIL 74398-71-3 GLYCIDYL ETHER
Sh211-EP-26TETRAPHENYLOLETHANE/
GLYCIDYL ETHER
Sh211-EP-27EPONRESINS-828/
Labet Name CAS ~tructare ' MW {glmol) # '.
Shell-AH-1POLY(METHYLVINYL
ETHER-ALT
MALEICANHYDRIDE) * ' MW -20,000 .-O *
p O O
Shell-AH-2POLY(METHYLVINYL
ETHER-ALT
MALEICANHYDRIDE) * MW ~-50,000 ~O *
O " O
Shell-AH-3PpLY(METHYLVINYL8011-16-9 Mn. -ETHER-ALT 80,000 MALEICANHYDRIDE) MW. ~
* -~O n * 216,000 Shell-AH-4POLYSTYRENE-MALEIC
ANHYDRIDE) MW=1600 50:50 (molar) Shell-AH-5POLYSTYRENE-MALEIC
ANHYDRIDE) MW=1900 75:25 (molar) POLYSTYRENE-co-MALEIC
Shell-AH-6ANHYDRIDE), 26762-29-8 Mn=1600 CUMENE
TERMINATED
POLYSTYRENE-co-MALEIC
Shell-AH-7ANHYDRIDE), 26762-29-8 Mn=1700 CUMENE
TERMINATED
POLYSTYRENE-co-MALEIC
Shell-AH-8ANHYDRIDE), 160611-46-1 Mn=2300 PARTIAL ISOCTYL
ESTER, CUMENE FW=658.8 TERMINATED
POLYSTYRENE-co-MALEIC
Shell-AH-9ANHYDRIDE), 160611-50-7 BUTOXYETHYLESTER,CUMENE AV. Mn=2500 TERMINATED
TABLE 10 (continued) l,abetName GAS Structure MW (gtmat~
~ #
POLYETHYLENE-co-ETHYL
Shell-AH-1ACRYLATE-co-MALEIC41171-14-6 ANHYDRIDE) POLYSTYRENE-co-MALEIC
Mn-1900 Shell-AH-1ANHYDRIDE), 160611-48-3 PARTIAL PROPYL
ESTER, CUMENE
TERMINATED
Shell-AH-1POLYETHYLENE-graft-MALEIC106343-08-2 FW-154.2 ANHYDRIDE
POLYISOPRENE-graft-MALEIC139948-75-7 FW=234.3 Shell-AH-1ANHYDRIDE Mf1-25000 POLYETHYLENE-co-BUTYL
FW=268 Shell-AH-1ACRYLATE-co-MALEIC64652-60-4 .
ANHYDRIDE) Shell-CI-1 15484-44-3O ~~ _ 166.56 ACID SODIUM O Na+
SALT
I
S
Shell-CI-2HYDROXYPROPANESULFONIC126-83-0O -~ 196.59 0 ' ACID SODIUM Na SALT
DIETHYLENE GLYCOL
Shell-Mc-1 4074-88-8 .
DIACRYLATE O O
Shell-Mc-2POLYETHYLENE 26570-49-8 Mn. -GLYCOL) 700 DIACRYLATE
o POLYETHYLENE-co-FW=256 Shell-Mc-3METHACRYLATE-co-GLYCIDYL51541-08-3 .
METHACRYLATE) EtO~ pEt ) I 288.5 Shell-EP-1ETHYLTRXETHOXYSILANE OEt p \~\\~
Shell-EP-2POLY(ETHYL GLYCOL)26403-72-5 526.6 DIGLYCIDYL ETHER
Shell-EP-3POLY(ETHYL GLYCOL)26403-72-5 2O0 (200) DIGLYCIDYL ETHER
O
Shell-EP-4POLY(ETHYL GLYCOL)26403-72-5~ 400 (400) DIGLYCIDYL ETHER
O
POLY(ETHYL GLYCOL)26403-72-5 600 SheII-EP-(600) DIGLYCIDYL ETHER
Shell-EP-6 POLY(ETHYL 26403-72-5 1 OOO
GLYCOL) (1000) DIGLYCIDYL ETHER
TABLE 10 (continued) ' t~abetName CAS St~uafiurs MW (glmai3 #
Shell-EP-71,3-BUTADIENE 1464-53-5 86.09 DIEPOXIDE O
FF F FF
3-(1 H,1 H,7H- O
~~ F
Shell-EP-8DODECAFLUOROHEPTYLOXY)-1,2799-34-8 388.15 EPOXYPROPANE F F F F F
o Shell-EP-9 6178-32-1I ~ 276.42 ETHER ~
OPYLENE GL
Y
L) Shell-EP-10(PR 26142-30-30 640 YCO
PCL
DIGLYCIDYL ETHER
Shell-EP-11GLYCIDYL HEXADECYL15965-99-8 ETHER O~ 298.51 O
O
Shell-EP-2-[(a-NITROPHENOXY)METHYL]OXIRAN5255-75-4O2N \ / O 195.18 12bIS E
POLY(BISPHENOL FW=487.0 A-co-Shell-EP-12EPICHLOROHYDRIN),25036-25-3 Mn -355 GLVCICYL
END-CAPPED
POLY(BISPHENOL FW=487.0 A-co-Shell-EP-13EPICHLOROHYDRIN), GLYCICYL Mn 1075 END-CAPPED
POLY(BISPHENOL
A-co-Shell-EP-14EPICHLOROHYDRIN), Mn-1750 GLYCICYL
END-CAPPED
POLY(BISPHENOL
A-co-Shell-EP-15EPICHLOROHYDRIN), I
GLYCICYL
END-CAPPED
Shell-EP-16POLY(o-CRESYL 28690-82-2 FW=194.2 GLYCIDYL
ETHER)-co-FORMALDEHYDE) Mn~540 Shell-EP-17POLY(o-CRESYL 28690-82-3 FW=194.2 GLYCIDYL
ETHER)-co-FORMALDEHYDE) Mn~1270 Shell-EP-18POLYETHYLENE-co-GLYCIDYL26061-90-5 FW=170.2 METHACRYLATE) Shell-EP-19BISPHENOL DIGLYCIDYL1675-54-3 ETHER
Shell-EP-20PoLY(DIMETHYLSILOxANE)130167-23-6 FW=282.5 DIGLYCIDYL TERMINATED EW~490 POLY[(PHENYL FW=180.2 Shell-EP-21GLYCIDYL ETHER)~
~a-FORMALDEHYDE] Mn-345 Shell-EP-22POLY[(PHENYL 28064-14-4 FW=180.2 GLYCIDYL ETHER) co-FORMALDEHYDE] Mn--570 Shell-EP-23POLY[(PHENYL 118345-05-0 FW=286.4 GLYCIDYL ETHER) co-DICYCLOPENTADIENE] Mn-490 POLY(EPICHLOROHYDRIN-co-Shell-EP-24ETHYLENE OXIDE-co-ALLY26587-37-1 GLYCIDYL ETHER
TABLE 10 (continued) l.abat' Name CAS Straatore MW jglmalj #
Shall-EP-25CASTOR OIL 74398-71-3 GLYCIDYL ETHER
Sh211-EP-26TETRAPHENYLOLETHANE/
GLYCIDYL ETHER
Sh211-EP-27EPONRESINS-828/
[00131] Results are shown in Tables 11-18. Results collated in this series of example show that the core-shell particles of the invention display higher rate of binding for phosphate over bare, non-encapsulated particles in simulated fluid representative of the real conditions of use.
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Bifzdin~ capacity measuremefats in a noh inter e~in buffer [00132] An aliquot of dried resin of weight P(gr), is mixed under gentle agitation with a fixed volume ,V(ml), of a phosphate ion solution of concentration Csta,.t(mM) buffered at pH 6.5. After resin equilibration, the solution is decanted by centrifugation and the supernatant analyzed for residual phosphate concentration by ionic chromatography, Ceq(mM). The binding capacity is calculated as BC (mmol/gr)=V.
(Cstart-Ceq)~.
Bin.din~ capacity in a ex-vivo aspirates [00133] In this example healthy patients are given a meal of the same composition as the one prepared for the digestion mimic and aliquots of chyme are then sampled using a tube placed in the lumen of the small intestine.
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r-'N N NN N NN N N NN N NN N N N Nr r ~ O NCON rI~O f0d'O)t-d'N r t(7~ lf)NV O
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N M ~ t(7tn~tX17~ COt(7M~f7~ ~c7(O~ c0LntI7lO~ u7 r r rr r rr r r rr r rr r rr r rr r C .fl c V
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o UIo 0 00 0 00 0 0 00 0 00 0 00 0 00 0 '- e-CVC~<Y~C1rCVM d'u7r CVMd'~ CO~-CVMd'~
a v a a o- 0 0 00 0 00 0 0 00 0 00 0 00 0 00 0 M ' '' ' r r rr r NCVN N NM M MM Md V dd d P
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Bifzdin~ capacity measuremefats in a noh inter e~in buffer [00132] An aliquot of dried resin of weight P(gr), is mixed under gentle agitation with a fixed volume ,V(ml), of a phosphate ion solution of concentration Csta,.t(mM) buffered at pH 6.5. After resin equilibration, the solution is decanted by centrifugation and the supernatant analyzed for residual phosphate concentration by ionic chromatography, Ceq(mM). The binding capacity is calculated as BC (mmol/gr)=V.
(Cstart-Ceq)~.
Bin.din~ capacity in a ex-vivo aspirates [00133] In this example healthy patients are given a meal of the same composition as the one prepared for the digestion mimic and aliquots of chyme are then sampled using a tube placed in the lumen of the small intestine.
[00134] Normal subjects are intubated with a double lumen polyvinyl tube, with a mercury weighted bag attached to the end of the tube to facilitate movement of the tube into the small intestine. One aspiration aperture of the double lumen tube is located in the stomach and the other aperture is at the Ligament of Treitz (in the upper jejunum).
Placement takes place with the use of fluoroscopy.
Placement takes place with the use of fluoroscopy.
[00135] After correct tube is placed, 550 mL of a liquid standard test meal (supplemented with a marker, polyethylene glycol (PEG) - 2 g/SSOmL) is infused into the stomach through the gastric aperture at a rate of 22 mL per minute. It requires approximately 25 minutes for the entire meal to reach the stomach. This rate of ingestion simulates the duration of time required to eat normal meals.
[00136] Jejunal chyme is aspirated from the tube whose lumen is located at the Ligament of Treitz. This fluid is collected continuously during 30-minute intervals for a two and a half hour period. This results in 5 specimens that are mixed, measured for volume, and lyophilized.
[00137] The phosphate binding procedure is identical to the one described earlier with the non-interfering buffer experiment, except that the ex-vivo aspirate liquid is used (after reconstitution of the freeze-dried material in the proper amount of de-ionized water). The binding capacity in the ex-vivo aspirate (VA) is calculated in the same way.
Core-shell compositions bind more phosphate than the corresponding core component.
Examule 6: Method of selection of semi-permeable membrane with high potassium binding selectivity over magnesium and calcium [00138] This protocol describes a method to optimize polymeric materials with regards to their ion pennselectivity characteristics, which then can be used as the shell component for the making of potassium selective core-shell ion-exchange particles.
Polymer synthesis afzd membrane preparation:
Core-shell compositions bind more phosphate than the corresponding core component.
Examule 6: Method of selection of semi-permeable membrane with high potassium binding selectivity over magnesium and calcium [00138] This protocol describes a method to optimize polymeric materials with regards to their ion pennselectivity characteristics, which then can be used as the shell component for the making of potassium selective core-shell ion-exchange particles.
Polymer synthesis afzd membrane preparation:
[00139] Polymeric membrane materials with different compositions were prepared by radical copolymerization of DBA (N, N'-dibutyl acrylamide) and DEAEMA (N,N'-diethylaminoethylinethacrylate) in a glove box using miniaturized reactors in a library format. AIBN was used as the initiator and ethanol as the solvent. Polymers were isolated by precipitation into water, freeze-dried, and characterized by GPC
and H-NMR.
The composition of the polymer (DBA mol%) ranges from 30% to 70% and molecular weight ranges from 200K to 300K as shown below:
Table 19 Polymer ID D1 D2 D3 D4 DS D6 Mn (x10') 327 326 322 285 240 217 Mw (x10 ) 584 563 520 467 411 340 PDI 1.78 1.73 1.61 1.64 1.71 1.56 Composition 31.2: 37:1. 48.5 56:1 64.4 , ;68.5 (DBA, molf) a ~ -;;
and H-NMR.
The composition of the polymer (DBA mol%) ranges from 30% to 70% and molecular weight ranges from 200K to 300K as shown below:
Table 19 Polymer ID D1 D2 D3 D4 DS D6 Mn (x10') 327 326 322 285 240 217 Mw (x10 ) 584 563 520 467 411 340 PDI 1.78 1.73 1.61 1.64 1.71 1.56 Composition 31.2: 37:1. 48.5 56:1 64.4 , ;68.5 (DBA, molf) a ~ -;;
[00140] Polymer membranes were prepared by casting a 2-wt% toluene solution of DBA-co-DEAEMA onto a regenerated cellulose dialysis membrane (RC membrane with MWCO of 14 K). After toluene was evaporated, a polymer membrane was formed on the top of dialysis membrane. A composite membrane of polymer membrane and RC
membrane was thus prepared.
Perszzeability study oh catio~zs [00141] The composite membrane was first clamped onto a glass tube with diameter of 13 mm, and then immersed into a 2 L of donor solution of cations.
The tube was filled with 10 ml of acceptor solution (lactose solution with the same osmolality as the donor solution (240mM)). The acceptor solution was sampled at a specified time interval and analyzed by ion chromatography. See Figure 3.
membrane was thus prepared.
Perszzeability study oh catio~zs [00141] The composite membrane was first clamped onto a glass tube with diameter of 13 mm, and then immersed into a 2 L of donor solution of cations.
The tube was filled with 10 ml of acceptor solution (lactose solution with the same osmolality as the donor solution (240mM)). The acceptor solution was sampled at a specified time interval and analyzed by ion chromatography. See Figure 3.
[00142] Donor solution was prepared by mixing the aqueous solution of NaCI, KCl, CaC12.2Ha0, and MgS04.7H20. The solution was buffered to pH 6 by using 14 mM of MES (2-[N-morpholine]ethanesulfonic acid] solution. The concentrations of different rations determined by IC were as follows: [Na ], 40.46 mM; [K+], 31.44 mM;
[Mg2+], 33.25 mM; [Ca2+], 22.324 mM.
[Mg2+], 33.25 mM; [Ca2+], 22.324 mM.
[00143] Determination of the permeability coefficient (P) of different rations: As mentioned in the measurement set-up, the acceptor solution was sampled at a specific time interval and analyzed by IC. Assuming a Fick's first law of diffusion, P
is readily obtained by linearization of the data, following a method of calculation reported in equation 1 in G. Van den Mooter, C. Samyn, and R. Kinget, International Journal of Pharmaceutics, 111, 127-136(1994). The permeability coefficients of different rations were thus calculated from the slope from this linear relationship.
_1n ~ C~ Ca _ ..........
Va t ..Equation 1 Co Where C° is the initial concentration of the solute in the donor compartment and Ca the concentration in the acceptor compartment at time t, Va is the volume of the acceptor compartment, and S the surface of the membrane.
is readily obtained by linearization of the data, following a method of calculation reported in equation 1 in G. Van den Mooter, C. Samyn, and R. Kinget, International Journal of Pharmaceutics, 111, 127-136(1994). The permeability coefficients of different rations were thus calculated from the slope from this linear relationship.
_1n ~ C~ Ca _ ..........
Va t ..Equation 1 Co Where C° is the initial concentration of the solute in the donor compartment and Ca the concentration in the acceptor compartment at time t, Va is the volume of the acceptor compartment, and S the surface of the membrane.
[00144] Permselectivity: As described above, the permeability coefficient was calculated for each canon. By normalizing the permeability coefficient of Na as 1, the permselectivity for rations M1 and M2 can be calculated as follows: PM1M2 -P(M2)/P(M1) Permeability coefficients of different rations through different membranes:
[00145] Table 14 shows the permeability coefficients of different rations at different membranes. When polymers are more hydrophilic (Polymer D3 and D4 with DBA% 48.5 and 56.1%, respectively), all rations, such as Na ,K+, Mg2+, and Caz+, are more permeable and their permeability coefficients are comparable to those through a blank dialysis membrane (RC membrane) and reflect the self diffusivity of the rations.
However, with the increasing DBA content in polymer membrane (See Table 20 for DS
and D6), the permeability coefficients of different rations decreased as compared with blank membrane, which means that the hydrophobic nature of polymer membrane could make rations less permeable through the hydrophobic barrier.
Table 20: Permeability coefficients of canons at different membranes olymer DBA Na+ (cm/sec)K+ (cm/sec)Mgz+ Caz+
ID (mol%) (cm/sec) (cm/sec) 3 8.5 2.41(~0.26)E-43.11(~0.34)E-46.50(~0.08)E-S6.0(~0.07)E-5 4 56.1 .28(~0.44)E-56.11(~0.61)E-41.13(~0.11)E-51.04(~0.05)E-5 64.4 .32(~0.20)E-65.79(~3.59)E-65.42(~4.11)E-73.32(~3.33)E-7 6 68.5 1.50(~0.05)E-7 [00146] Another characteristic for the permeability of different rations is their permselectivity. By normalizing the value of PNa+ as 1, the permselectivity for other rations can be calculated and the results are shown in Table 21. The permselectivity of PMg~Na ~d Pca~rra decreases with the increasing DBA content in polymer membranes, which implies that more hydrophobic polymer membranes may have better selectivity for different rations. For a better selectivity for different rations, two factors should be considered - the charge density and the membrane hydrophobicity.
Polymer ID DBA % ~K+)/P(Na+) P(Ca~+)/P(Na+) P(Ma~+)/P Na+) P(K+)/P(M
D3 48.5 1.29 0.27 0.25 5.16 D4 56.1 1.43 0.26 0.24 5.96 D5 64.4 1.34 0.13 0.08 16.75 Example 7: Synthesis of poly-2-fluoroacrylic acid beads [00147] Beads are prepared by a direct suspension process where a mixture of 2-fluoroacrylic methyl ester/divinylbenzene/benzoyl peroxide in a weight ratio 90/9/1 are dispersed in water under high shear with polyvinylalcohol as a suspending agent. The suspension is stirred and heated at 80°C for l Ohours. The residual monomer is eliminated by steam stripping. The beads are then filtered and treated with aqueous 3M
NaOH to hydrolyze the polymer, then washed, treated with HCL, water-washed, and finally dried to form the desired polya,-fluoroacrylic acid particles. The average bead diameter is 250 microns as measured by Master Sizer (Malvern UK).
Example 8~ Preparation of poly-2-fluoroacrylic acid / core- (DSA-DEAEMA) /
shell particles [00148] The core-shell particles are prepared by forming a coating of polymer on the poly-2-fluoroacrylic acid beads prepared in example 5 using a Wurster coater.
The shell polymer prepared in example 4 is first dissolved at 20 wt-% in toluene, and the thus obtained solution then dispersed in water in a 1: 4 weight ratio with 2 wt-% based on the organic phase of CTAB (Hexadecyltrimethyl-Ammonium Bromide) as a surfactant, using a Ultra-Turrax high-shear homogeneizer. The toluene is then driven off by evaporation under reduced pressure. The average diameter of the dispersion particles is 0.3 micrometer, as measured by Dynamic Light Scattering. The poly-2-fluoroacrylic acid beads are spray-coated with the shell polymer dispersion using a Wurster fluid bed coater 2"- 4"/6" Portable Unit. The fluidized bed unit is operated so that an average 5 microns thick coating is deposited on the core particles.
Example 9~ Preparation of polystyrene sulfonate/core- polyethyleneimine shell particles with Na+ and K+ selective-binding propertie P~ocedure~ot~ coatih~ PEI oh Dowex beads [00149] PEI (poly(ethyleneimine), Mw10,000) and Dowex beads (H-form, X4-200) were purchased from commercial sources. PEI aqueous solutions with different concentrations were prepared by dissolving PEI directly into nanopure water.
However, with the increasing DBA content in polymer membrane (See Table 20 for DS
and D6), the permeability coefficients of different rations decreased as compared with blank membrane, which means that the hydrophobic nature of polymer membrane could make rations less permeable through the hydrophobic barrier.
Table 20: Permeability coefficients of canons at different membranes olymer DBA Na+ (cm/sec)K+ (cm/sec)Mgz+ Caz+
ID (mol%) (cm/sec) (cm/sec) 3 8.5 2.41(~0.26)E-43.11(~0.34)E-46.50(~0.08)E-S6.0(~0.07)E-5 4 56.1 .28(~0.44)E-56.11(~0.61)E-41.13(~0.11)E-51.04(~0.05)E-5 64.4 .32(~0.20)E-65.79(~3.59)E-65.42(~4.11)E-73.32(~3.33)E-7 6 68.5 1.50(~0.05)E-7 [00146] Another characteristic for the permeability of different rations is their permselectivity. By normalizing the value of PNa+ as 1, the permselectivity for other rations can be calculated and the results are shown in Table 21. The permselectivity of PMg~Na ~d Pca~rra decreases with the increasing DBA content in polymer membranes, which implies that more hydrophobic polymer membranes may have better selectivity for different rations. For a better selectivity for different rations, two factors should be considered - the charge density and the membrane hydrophobicity.
Polymer ID DBA % ~K+)/P(Na+) P(Ca~+)/P(Na+) P(Ma~+)/P Na+) P(K+)/P(M
D3 48.5 1.29 0.27 0.25 5.16 D4 56.1 1.43 0.26 0.24 5.96 D5 64.4 1.34 0.13 0.08 16.75 Example 7: Synthesis of poly-2-fluoroacrylic acid beads [00147] Beads are prepared by a direct suspension process where a mixture of 2-fluoroacrylic methyl ester/divinylbenzene/benzoyl peroxide in a weight ratio 90/9/1 are dispersed in water under high shear with polyvinylalcohol as a suspending agent. The suspension is stirred and heated at 80°C for l Ohours. The residual monomer is eliminated by steam stripping. The beads are then filtered and treated with aqueous 3M
NaOH to hydrolyze the polymer, then washed, treated with HCL, water-washed, and finally dried to form the desired polya,-fluoroacrylic acid particles. The average bead diameter is 250 microns as measured by Master Sizer (Malvern UK).
Example 8~ Preparation of poly-2-fluoroacrylic acid / core- (DSA-DEAEMA) /
shell particles [00148] The core-shell particles are prepared by forming a coating of polymer on the poly-2-fluoroacrylic acid beads prepared in example 5 using a Wurster coater.
The shell polymer prepared in example 4 is first dissolved at 20 wt-% in toluene, and the thus obtained solution then dispersed in water in a 1: 4 weight ratio with 2 wt-% based on the organic phase of CTAB (Hexadecyltrimethyl-Ammonium Bromide) as a surfactant, using a Ultra-Turrax high-shear homogeneizer. The toluene is then driven off by evaporation under reduced pressure. The average diameter of the dispersion particles is 0.3 micrometer, as measured by Dynamic Light Scattering. The poly-2-fluoroacrylic acid beads are spray-coated with the shell polymer dispersion using a Wurster fluid bed coater 2"- 4"/6" Portable Unit. The fluidized bed unit is operated so that an average 5 microns thick coating is deposited on the core particles.
Example 9~ Preparation of polystyrene sulfonate/core- polyethyleneimine shell particles with Na+ and K+ selective-binding propertie P~ocedure~ot~ coatih~ PEI oh Dowex beads [00149] PEI (poly(ethyleneimine), Mw10,000) and Dowex beads (H-form, X4-200) were purchased from commercial sources. PEI aqueous solutions with different concentrations were prepared by dissolving PEI directly into nanopure water.
[00150] Weighed dried Dowex beads were mixed with PEI aqueous solution in library format glass tubes. After a specified reaction time, the tubes were sealed and centrifuged at 1000 rpm for 15 minutes, the supernatant solutions were then decanted off.
To the beads in each tube was added nanopure water to a total volume of 10 ml and all tubes were sealed and tumbled for 30 minutes. The same tumbling-centrifuging was repeated 3 times. The beads were freeze-dried and weighted until a constant weight was obtained.
To the beads in each tube was added nanopure water to a total volume of 10 ml and all tubes were sealed and tumbled for 30 minutes. The same tumbling-centrifuging was repeated 3 times. The beads were freeze-dried and weighted until a constant weight was obtained.
[00151] The reaction solution composition and gel weight increase are displayed in Table 22.
Table 22: Conditions for coating PEI on Dowex beads Dowex Bead PEI Conc.PEI Reaction Coated bead ID Weight Weight (gm)(wt%) volume time increase (ml) (hours) (cwt%) 0.1274 2.5 10 1 DOWEX(2.5wt-lh) 0.2223 2.5 10 6 DOWEX(2.5wt-6h) 3.1 0.1609 1.5 10 1 DOWEX(2.5wt-lh) *
0.2407 1.5 10 6 DOWEX(2.5wt-6h) 0.9 0.2016 0.5 10 1 DOWEX(2.5wt-lh) 0.2347 0.5 10 6 DOWEX(2.5wt-6h) * No weight increase was observed.
Method, or bifzdi~g study [00152] A mixture of NaCl, KCI, MgCl2, and CaCl2 was dissolved in a MES buffer (pH6.0) (MES, 2-[N-morpholine]ethanesulfonic acid]. The concentration for each canon was determined by IC. The concentrations for Na , K+, Mg2+, and Ca2+ are 26.4 mM, 9.75 mM, 4.75 mM and 4.16 mM respectively.
Table 22: Conditions for coating PEI on Dowex beads Dowex Bead PEI Conc.PEI Reaction Coated bead ID Weight Weight (gm)(wt%) volume time increase (ml) (hours) (cwt%) 0.1274 2.5 10 1 DOWEX(2.5wt-lh) 0.2223 2.5 10 6 DOWEX(2.5wt-6h) 3.1 0.1609 1.5 10 1 DOWEX(2.5wt-lh) *
0.2407 1.5 10 6 DOWEX(2.5wt-6h) 0.9 0.2016 0.5 10 1 DOWEX(2.5wt-lh) 0.2347 0.5 10 6 DOWEX(2.5wt-6h) * No weight increase was observed.
Method, or bifzdi~g study [00152] A mixture of NaCl, KCI, MgCl2, and CaCl2 was dissolved in a MES buffer (pH6.0) (MES, 2-[N-morpholine]ethanesulfonic acid]. The concentration for each canon was determined by IC. The concentrations for Na , K+, Mg2+, and Ca2+ are 26.4 mM, 9.75 mM, 4.75 mM and 4.16 mM respectively.
[00153] Weighed dried PEI-coated bead was put into a tube which contains 5-ml of MES buffer solution of NaCl, KCI, MgCl2, and CaCl2. The tube was sealed and tumbled. After a certain period of time as indicated in figure 4, the tube was centrifuged.
100 microliter of solution was then taken out from the supernatant for IC
analysis. The binding amount of PEI coated beads for different cations were calculated from the concentration change in the solution.
The calculation is as follows:
Ion bound in beads (mmol/g) _ [V x (CD - Ct) l{[weight of beads] x 1000]
Co: initial concentration of metal ion (in mM) Ct: concentration of metal ion after bead binding at a certain time (t hrs) (in mM) V: solution volume (5 ml) Weight of beads (gm) [00154] The binding data of different PEI coated beads for different cations are shown in Figure 4. PEI coated Dowex beads show higher Na+ and K+ binding than the uncoated beads (bare beads). The coated beads show much more selective binding than bare beads. The thicker the PEI coating (e.g. Dowex (2.5wt-6h), coated from 2.5 wt%
PEI solution for 6 hours), the more selective for the different cations. The binding kinetic study shows that the binding of cations equilibrates faster for the thinner coated beads and bare beads.
Example 10: Polystyrene sulfonate beads with Eudra~it shell [00155] Shell material: Eudragit RL100 (Rohm), a copolymer of acrylic and methacrylic acid esters with 8.85-11.96% cationic ammonio methacrylate units, 10 wt%
in ethanol and l Owt% triacetin. Core: Lewatit (cross-linked polystyrene sulfonate in sodium form), size - 300 Vim.
I It - CHI - ~f~ CHI -C -I
~H OR. I I
z ~.CN3 H C-N'"..~, CH3 R = H CEi.
CI' ~H~ Ra=~Hs.CzH~
The shell was applied using a FluidAir Wurster coater.
100 microliter of solution was then taken out from the supernatant for IC
analysis. The binding amount of PEI coated beads for different cations were calculated from the concentration change in the solution.
The calculation is as follows:
Ion bound in beads (mmol/g) _ [V x (CD - Ct) l{[weight of beads] x 1000]
Co: initial concentration of metal ion (in mM) Ct: concentration of metal ion after bead binding at a certain time (t hrs) (in mM) V: solution volume (5 ml) Weight of beads (gm) [00154] The binding data of different PEI coated beads for different cations are shown in Figure 4. PEI coated Dowex beads show higher Na+ and K+ binding than the uncoated beads (bare beads). The coated beads show much more selective binding than bare beads. The thicker the PEI coating (e.g. Dowex (2.5wt-6h), coated from 2.5 wt%
PEI solution for 6 hours), the more selective for the different cations. The binding kinetic study shows that the binding of cations equilibrates faster for the thinner coated beads and bare beads.
Example 10: Polystyrene sulfonate beads with Eudra~it shell [00155] Shell material: Eudragit RL100 (Rohm), a copolymer of acrylic and methacrylic acid esters with 8.85-11.96% cationic ammonio methacrylate units, 10 wt%
in ethanol and l Owt% triacetin. Core: Lewatit (cross-linked polystyrene sulfonate in sodium form), size - 300 Vim.
I It - CHI - ~f~ CHI -C -I
~H OR. I I
z ~.CN3 H C-N'"..~, CH3 R = H CEi.
CI' ~H~ Ra=~Hs.CzH~
The shell was applied using a FluidAir Wurster coater.
[00156] Binding was measured under following conditions:
Donor solution: 50 mM KCl and 50 mM MgCl2 Bead concentration: 4 mg/ml Duration: 6 hours [00157] Figure 5 shows the effect of the shell on Mg2+ and K+ binding. With increasing ratio of shell to core, Mg2+ binding decreased and K+ binding increased. 20 wt% shell coating gave a K+ binding capacity of 1.65 meq/gm, which is about 3 times higher than for uncoated Dowex.
Example 11: Polystyrene sulfonate beads with benzylated polyethylene imine shell Syntlzesis of benzylated molyetlzyleneimine fPEl) [00158] To a 250 ml of round bottom flask were charged 15.6 g of PEI (363 mmol of NH2) and 125 ml of ethanol, this mixture was magnetically stirred until PEI
was completely dissolved, then 30 g of NaFIC03 (FW, 84; 256 nnnol) and 40 ml of benzyl chloride (363 mmol) were subsequently added. The above mixture was reacted at 55°C
under nitrogen atmosphere overnight. Dichloromomethane was added to the slurry reaction mixture, followed by filtration to remove inorganic salt. The solvent in filtrate was removed by vacuum. Dicholromethane was used again to re-dissolve the reaction product; inorganic salt was further removed by filtration. The solvent in the filtrate was removed again under vacuum. Finally, the product was triturated in hexane, filtered and washed with hexane, and dried under vacuum. The benzylation degree was 84% as determined by 1HNMR. Similar materials with various degree of benzylation (respectively 20% and 40% for Ben(20) and Ben(40)) were prepared by adjusting the benzyl chloride to PEI ratio.
Donor solution: 50 mM KCl and 50 mM MgCl2 Bead concentration: 4 mg/ml Duration: 6 hours [00157] Figure 5 shows the effect of the shell on Mg2+ and K+ binding. With increasing ratio of shell to core, Mg2+ binding decreased and K+ binding increased. 20 wt% shell coating gave a K+ binding capacity of 1.65 meq/gm, which is about 3 times higher than for uncoated Dowex.
Example 11: Polystyrene sulfonate beads with benzylated polyethylene imine shell Syntlzesis of benzylated molyetlzyleneimine fPEl) [00158] To a 250 ml of round bottom flask were charged 15.6 g of PEI (363 mmol of NH2) and 125 ml of ethanol, this mixture was magnetically stirred until PEI
was completely dissolved, then 30 g of NaFIC03 (FW, 84; 256 nnnol) and 40 ml of benzyl chloride (363 mmol) were subsequently added. The above mixture was reacted at 55°C
under nitrogen atmosphere overnight. Dichloromomethane was added to the slurry reaction mixture, followed by filtration to remove inorganic salt. The solvent in filtrate was removed by vacuum. Dicholromethane was used again to re-dissolve the reaction product; inorganic salt was further removed by filtration. The solvent in the filtrate was removed again under vacuum. Finally, the product was triturated in hexane, filtered and washed with hexane, and dried under vacuum. The benzylation degree was 84% as determined by 1HNMR. Similar materials with various degree of benzylation (respectively 20% and 40% for Ben(20) and Ben(40)) were prepared by adjusting the benzyl chloride to PEI ratio.
[00159] Benzylated polyethylene imine (Ben-PEI) was coated onto Dowex beads.
~ ~ ~
t~l ..-,~,N x _ ,~h~H ~r~ ~ .~
9:0 E. ~'~i (Cc~c~~erc~a! avai~a6fe~
~ ~ ~
t~l ..-,~,N x _ ,~h~H ~r~ ~ .~
9:0 E. ~'~i (Cc~c~~erc~a! avai~a6fe~
[00160] The shell was coated using solvent coacervation. The shell Ben(84)-PEI
was dissolved in methanol and water mixture (3:1) at pH of 3. Shell and core were mixed for 5 minutes and methanol was removed by rotovap (40 minutes), isolated, washed, and dried.
was dissolved in methanol and water mixture (3:1) at pH of 3. Shell and core were mixed for 5 minutes and methanol was removed by rotovap (40 minutes), isolated, washed, and dried.
[00161] Binding was measured under following conditions:
Donor solutions: 50 mM KCl and 50 mM MgCl2 Bead concentration: 4 mg/ml Duration: 6 and 24 hours [00162] Results of the binding measurements are shown in Figure 6. Ben(84)-PEI
showed selective binding for potassium after 6 and 24 hours as revealed by lower Mg2+
binding compared to naked beads.
Donor solutions: 50 mM KCl and 50 mM MgCl2 Bead concentration: 4 mg/ml Duration: 6 and 24 hours [00162] Results of the binding measurements are shown in Figure 6. Ben(84)-PEI
showed selective binding for potassium after 6 and 24 hours as revealed by lower Mg2+
binding compared to naked beads.
[00163] Figure 7 depicts the stability of Ben(84)-PEI coated Dowex (K) beads order acid conditions representative of the acidic conditions in the stomach.
The beads were exposed to pH 2 HCl for 6 hours, isolated, and dried. Binding selectivity was tested for the post-treated beads. Binding conditions were as follows:
Donor solutions: 50 mM KCl and 50 mM MgCl2 Bead concentration: 4 mg/ml Duration: 6 and 24 hours The coating was stable and binding selectivity was maintained at 6 and 24 hours.
Example 12: FAA beads with benzylated polyethylene imine shell [00164] The shell was applied on the FAA core by the process of solvent coacervation. The shell, Ben(84)-PEI, was dissolved in methanol and water mixture (3:1) at pH of 4.5. The shell and core were mixed for 5 minutes and methanol was removed by rotovap (40 minutes), isolated, washed, and dried.
The beads were exposed to pH 2 HCl for 6 hours, isolated, and dried. Binding selectivity was tested for the post-treated beads. Binding conditions were as follows:
Donor solutions: 50 mM KCl and 50 mM MgCl2 Bead concentration: 4 mg/ml Duration: 6 and 24 hours The coating was stable and binding selectivity was maintained at 6 and 24 hours.
Example 12: FAA beads with benzylated polyethylene imine shell [00164] The shell was applied on the FAA core by the process of solvent coacervation. The shell, Ben(84)-PEI, was dissolved in methanol and water mixture (3:1) at pH of 4.5. The shell and core were mixed for 5 minutes and methanol was removed by rotovap (40 minutes), isolated, washed, and dried.
[00165] Binding was measured under following conditions:
Donor solutions: 50 mM KCl and 50 mM MgCl2 Bead concentration: 4 mg/ml Duration: 6 hours [00166] The potassium binding was calculated from actual magnesium uptake and overall binding capacity of polymer which was 5.74 meqlgm. The results are shown in Figure 8. Increasing the ratio of shell/core caused a decrease in magnesium binding which indicates an increase in potassium binding.
Example 13: Coating by controlled precipitation induced by nH change [00167] The shell comprised of Benzylated PEI, Ben (~20%); and Ben (~40%) on a Dowex(K) core. Binding was measured in SO mM KCl and 50 mM MgCl2.
Donor solutions: 50 mM KCl and 50 mM MgCl2 Bead concentration: 4 mg/ml Duration: 6 hours [00166] The potassium binding was calculated from actual magnesium uptake and overall binding capacity of polymer which was 5.74 meqlgm. The results are shown in Figure 8. Increasing the ratio of shell/core caused a decrease in magnesium binding which indicates an increase in potassium binding.
Example 13: Coating by controlled precipitation induced by nH change [00167] The shell comprised of Benzylated PEI, Ben (~20%); and Ben (~40%) on a Dowex(K) core. Binding was measured in SO mM KCl and 50 mM MgCl2.
[00168] Figure 9 shows the results of the binding experiments. Controlled precipitation method for 40% benzylated PEI shows better coating and this combination of coating method and materials gives higher binding selectivity.
Example 14: Membrane screening of Shell Polymers [00169] Shell polymers were screened by coating a flat membrane via solvent casting and using the coated membrane as the barrier in a diffusion cell, as depicted in Figure 10. Donor solution was SOmM 2-[N-morpholino] ethane sulfonic acid (MES) buffer at pH6.5 with SOmM K+ and Mg2+. Permeability coefficient was calculated as described in Example 4 above. Cross-linked B-PEI was tested using this method.
B-PEI
(35mo1%) was cross-linked with 1, 4-butanediol diacrylate. The cross-linker was reacted on the top of dried B-PEI for 4 hours. The screening was performed in 50 mM
KCl and 50 mM MgCl2 in 50 mM MES buffer. Cross-linker (diacrylate) reacted with B-PEI
(35 mol%) membrane. As shown in Figuxe 11, addition of the cross-linker reduced permeability coefficient and also showed good selectivity.
Example 14: Membrane screening of Shell Polymers [00169] Shell polymers were screened by coating a flat membrane via solvent casting and using the coated membrane as the barrier in a diffusion cell, as depicted in Figure 10. Donor solution was SOmM 2-[N-morpholino] ethane sulfonic acid (MES) buffer at pH6.5 with SOmM K+ and Mg2+. Permeability coefficient was calculated as described in Example 4 above. Cross-linked B-PEI was tested using this method.
B-PEI
(35mo1%) was cross-linked with 1, 4-butanediol diacrylate. The cross-linker was reacted on the top of dried B-PEI for 4 hours. The screening was performed in 50 mM
KCl and 50 mM MgCl2 in 50 mM MES buffer. Cross-linker (diacrylate) reacted with B-PEI
(35 mol%) membrane. As shown in Figuxe 11, addition of the cross-linker reduced permeability coefficient and also showed good selectivity.
[00170] Blends of Eudragit RL 100 and RS 100 were also evaluated using the method of Figure 10. The results are shown in Figure 12. Adding RS 100 into can reduce the permeability and the permselectivity stays in the same range.
Membranes with more than SOwt% of RS 100 lost selectivity ([K+] in the same scale, but [Mgz+] much higher than other composites).
Example 15: Effects of bile acids on I~ binding [00171] Dowex(Li) 0100 ~,m) was first coated with PEI aqueous solution. The supernatant was removed and the coat was further crosslinked with 1,2-Bis-(2-iodoethoxy)-ethane (BIEE). Binding was measured in 50 mM KCl and 50 mM of MgCl2, MES buffer, pH 6.5. Bile acids extract used was 2 mg/ml (bile extract porcine with 60% bile acids and 40% unknowns, i.e., free fatty acids, phospholipids, etc.). Time:
6 and 24 hrs and Bead content: 4 mg/ml. Results are shown in Figure 13.
Enhanced performance of the shell was observed in the presence of bile acids, fatty acids, and lipids.
Membranes with more than SOwt% of RS 100 lost selectivity ([K+] in the same scale, but [Mgz+] much higher than other composites).
Example 15: Effects of bile acids on I~ binding [00171] Dowex(Li) 0100 ~,m) was first coated with PEI aqueous solution. The supernatant was removed and the coat was further crosslinked with 1,2-Bis-(2-iodoethoxy)-ethane (BIEE). Binding was measured in 50 mM KCl and 50 mM of MgCl2, MES buffer, pH 6.5. Bile acids extract used was 2 mg/ml (bile extract porcine with 60% bile acids and 40% unknowns, i.e., free fatty acids, phospholipids, etc.). Time:
6 and 24 hrs and Bead content: 4 mg/ml. Results are shown in Figure 13.
Enhanced performance of the shell was observed in the presence of bile acids, fatty acids, and lipids.
[00172] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
[00173] It will be apparent to one of ordinary skill in the art that many changes and modifications can be made thereto without departing from the spirit or scope of the appended claims.
Claims (53)
1. A pharmaceutical composition comprising core-shell particles wherein said core-shell particles comprise a core component and a shell component, said particles binding in an animal subject a greater amount of an inorganic ion in the presence of said shell component compared to the amount of inorganic ion bound in the absence of said shell component, wherein said inorganic ion is an anion.
2. The pharmaceutical composition of claim 1 wherein said core component retains a significant amount of said bound inorganic ion during a period of therapeutic and/or prophylactic use.
3. A pharmaceutical composition comprising core-shell particles wherein said core-shell particles comprise a core component and a shell component, said particles binding in an animal subject a greater amount of an inorganic ion in the presence of said shell component compared to the amount of inorganic ion bound in the absence of said shell component and retaining a significant amount of said bound inorganic ion during a period of therapeutic and/or prophylactic use, wherein said inorganic ion is an ration.
4. The pharmaceutical composition of claim 1 or 3 wherein said core component binds a greater amount of an inorganic ion in the presence of said shell component compared to the amount of inorganic ion bound in the absence of said shell component.
5. The pharmaceutical composition of claim 1 or 3 wherein the shell component modulates the movement of said inorganic ion and/or of a competing solute into and/or out of the core-shell particle.
6. The pharmaceutical composition of claim 1 wherein said inorganic ion is a phosphate ion.
7. The pharmaceutical composition of claim 1 wherein said inorganic ion is a chloride ion.
8. The pharmaceutical composition of claim 3 wherein said inorganic ion is a sodium ion.
9. The pharmaceutical composition of claim 3 wherein said inorganic ion is a H+, potassium ion, calcium ion, iron ion, ammonium ion, or magnesium ion.
10. The pharmaceutical composition of claim 1 or 3 wherein said shell component has a higher permeability for said iorganic ion compared to the permeability for one or more competing solutes.
11. The pharmaceutical composition of claim 10 wherein said permeability of said shell component is modulated by an environment of the gastrointestinal tract.
12. The pharmaceutical composition of claim 10 wherein said permeability of said shell component to said inorganic ion is modified in different environments.
13. The pharmaceutical composition of claim 12 wherein said shell component has increased permeability to said inorganic ion in a first environment and a decreased permeability to said inorganic ion in a second environment.
14. The pharmaceutical composition of claim 10 wherein said permeability of said shell component to said inorganic ion is independent of said permeability of said shell component to said competing solute.
15. The pharmaceutical composition of claim 1 or 3 wherein said shell component is hydrophobic.
16. The pharmaceutical composition of claim 1 or 3 wherein said shell component exhibits greater interaction with said competing solute compared to said inorganic ion.
17. The pharmaceutical composition of claim 1 or 3 wherein said shell component repels said competing solute.
18. The pharmaceutical composition of claim 1 or 3 wherein said core component comprises an optionally crosslinked polymer, said polymer comprising a repeat unit selected from the group consisting of
19. The pharmaceutical composition of claim 28 wherein said polymer is crosslinked with a crosslinker selected from the group consisting of
20. The pharmaceutical composition of claim 1 or 3 wherein said shell component is synthesized using a material selected from the group consisting of 3-(1H, 1H, dodecafluoroheptyloxy)-1,2-epoxypropane; glycidyl 4-nonylphenyl ether;
glycidyl hexadecyl ether; 2-[(4-nitrophenoxy)methyl]oxirane; poly(bisphenol A-co-epichlorohydrin), glycidyl end-capped; and poly(o-cresyl glycidyl ether)-co-formaldehyde).
glycidyl hexadecyl ether; 2-[(4-nitrophenoxy)methyl]oxirane; poly(bisphenol A-co-epichlorohydrin), glycidyl end-capped; and poly(o-cresyl glycidyl ether)-co-formaldehyde).
21. The pharmaceutical composition of claim 7 wherein said core component comprises an amine containing polymer and said material used to synthesize said shell chemically reacts with said amine in said core component.
22. The pharmaceutical composition of claim 1 or 3 wherein said shell component is deposited with a coating process.
23. The pharmaceutical composition of claim 1 or 3 wherein said shell component comprises an enteric coating.
24. The pharmaceutical composition of claim 1 or 3 wherein said core component comprises a 1,3-diaminopropane/1,3-dichloropropane crosslinked polymer and said shell component is synthesized using a material selected from the group consisting of 3-(1H, 1H, 7H-dodecafluoroheptyloxy)-1,2-epoxypropane; glycidyl 4-nonylphenyl ether;
glycidyl hexadecyl ether; 2-[(4-nitrophenoxy)methyl]oxirane; poly(bisphenol A-co-epichlorohydrin), glycidyl end-capped; and poly(o-cresyl glycidyl ether)-co-formaldehyde).
glycidyl hexadecyl ether; 2-[(4-nitrophenoxy)methyl]oxirane; poly(bisphenol A-co-epichlorohydrin), glycidyl end-capped; and poly(o-cresyl glycidyl ether)-co-formaldehyde).
25. The pharmaceutical composition of claim 1 or 3 wherein said core component comprises an epichlorohydrine crosslinked polyallylamine polymer and said shell component comprises a block copolymer, said block copolymer comprising a hydrophobic block and an amine reactive hydrophilic block.
26. The pharmaceutical composition of claim 32 wherein said hydrophobic block comprises at least one of poly(n-butyl acrylate-co-t-butyl acrylate) or poly(N,N-di-n-butyl acrylamide-co-t-butyl acrylate) and said amine reactive block comprises poly-(N,N-dimethylacrylamide-co-glycidyl methacrylate).
27. A method of treating an animal subject, comprising administering to an animal subject in need thereof an effective amount of the pharmaceutical composition of claim 1 or 3.
28. The method of claim 27 wherein said pharmaceutical composition removes phosphate from a gastrointestinal tract.
29. The method of claim 28 wherein said animal subject is suffering from a disease selected from the group consisting of hyperphosphatemia, hypocalcemia, hyperparathyroidism, depressed renal synthesis of calcitriol, tetany due to hypocalcemia, renal insufficiency, ecotopic calcification in soft tissues, and ESRD.
30. The method of claim 27 wherein said pharmaceutical composition removes sodium ions from a gastrointestinal tract.
31. The method of claim 30 wherein said animal subject is suffering from hypertension, chronic heart failure, end stage renal disease, liver cirrhosis, chronic renal insufficiency, fluid overload, or sodium overload.
32. The method of claim 27 wherein said pharmaceutical composition removes potassium ions from a gastrointestinal tract.
33. The method of claim 32 wherein said animal subject is suffering from at least one of hyperkalemia, metabolic acidosis, renal insufficiency, or anabolic metabolism.
34. A pharmaceutical composition comprising core-shell particles wherein said core-shell particles comprise a core component and a shell component, said particles binding in an animal subject a greater amount of a target solute in the presence of said shell component compared to the amount of target solute bound in the absence of said shell component and retailing a significant amount of said bound target solute during a period of therapeutic and/or prophylactic use.
35. The pharmaceutical composition of claim 34 wherein said core component binds a greater amount of said target solute in the presence of said shell component compared to the amount of target solute bound in the absence of said shell component.
36. The pharmaceutical composition of claim 34 wherein said target solute is not a bile acid or a sodium ion.
37. The pharmaceutical composition of claim 34 wherein said shell component preferentially excludes a bile acid or a sodium ion.
38. A pharmaceutical composition comprising core-shell particles wherein said core-shell particles comprise a core component and a shell component, said particles binding in an animal subject a greater amount of a target solute in the presence of said shell component compared to the amount of target solute bound in the absence of said shell component, wherein said target solute is not a bile acid or a sodium ion.
39. A pharmaceutical composition comprising core-shell particles wherein said core-shell particles comprise a core component and a shell component, said particles binding in an animal subject a greater amount of a target solute in the presence of said shell component compared to the amount of target solute bound in the absence of said shell component; wherein if said target solute is a bile acid, the core component binds an additional target solute, said additional target solute not being a bile acid.
40. The pharmaceutical composition of claim 34, 38, or 39 wherein said target solute is a hydrophilic ion.
41. The pharmaceutical composition of claim 34, 38, or 39 wherein said target solute is a biological toxin.
42. The pharmaceutical composition of claim 41 wherein said biological toxin is urea or creatinine.
43. The pharmaceutical composition of claim 34, 38, or 39 wherein said shell component is capable of modulating a movement of said target solute and/or of a competing solute into and/or out of said core-shell particle.
44. The pharmaceutical composition of claim 34, 38, or 39 wherein said core component retains a significant amount of said bound target solute during a period of therapeutic and/or prophylactic use.
45. The pharmaceutical composition of claim 34, 38, or 39 wherein said shell component is characterized by a higher permeability for said target solute compared to a permeability for one or more competing solutes.
46. The pharmaceutical composition of claim 45 wherein said permeability properties of said shell component are modulated by an environment of the gastrointestinal tract.
47. The pharmaceutical composition of claim 45 wherein said permeability of said shell component to said target solute is modified in different environments.
48. The pharmaceutical composition of claim 47 wherein said shell component has increased permeability to said target solute in a first environment and a decreased permeability to said target solute in a second environment.
49. The pharmaceutical composition of claim 45 wherein said permeability of said shell component to said target solute is independent of said permeability of said shell component to said competing solute.
50. The pharmaceutical composition of claim 34, 38, or 39 wherein said shell component is hydrophobic.
51. The pharmaceutical composition of claim 34, 38, or 39 wherein said shell component exhibits a greater interaction with said competing solute compared to said target solute.
52. The pharmaceutical composition of claim 34, 38, or 39 wherein said shell component repels said competing solute.
53. A method of treating an animal subject comprising administering to an animal subject in need thereof an effective amount of said pharmaceutical composition of claim 34, 38, or 39.
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US10/814,527 US7854924B2 (en) | 2004-03-30 | 2004-03-30 | Methods and compositions for treatment of ion imbalances |
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PCT/US2005/010747 WO2005097072A1 (en) | 2004-03-30 | 2005-03-30 | Ion binding compositions |
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Families Citing this family (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7381428B2 (en) | 2003-08-26 | 2008-06-03 | Shire International Licensing B.V. | Stabilized lanthanum carbonate compositions |
EA200970709A1 (en) | 2003-08-26 | 2010-04-30 | Шир Холдингз Аг | PHARMACEUTICAL COMPOSITION CONTAINING LANTHANE COMPOUNDS |
GB2456253B (en) * | 2004-03-30 | 2009-08-26 | Relypsa Inc | Ion binding polymers and uses thereof |
WO2005094384A2 (en) * | 2004-03-30 | 2005-10-13 | Ilypsa, Inc. | Methods and compositions for treatment of ion imbalances |
WO2007038801A2 (en) * | 2005-09-30 | 2007-04-05 | Ilypsa, Inc. | Monovalent cation-binding compositions comprising core-shell particles having crosslinked poly-vinylic shells, and methods of use thereof |
AU2006299449B2 (en) | 2005-09-30 | 2013-07-04 | Relypsa, Inc. | Methods and compositions for selectively removing potassium ion from the gastrointestinal tract of a mammal |
CA2624112A1 (en) * | 2005-09-30 | 2007-04-05 | Ilypsa, Inc. | Methods for preparing core-shell composites having cross-linked shells and core-shell composites resulting therefrom |
CN100398112C (en) * | 2006-03-24 | 2008-07-02 | 辽宁诺康生物制药有限责任公司 | Medicine for treating hyperphosphatemia and its preparing method |
TWI455731B (en) * | 2006-10-06 | 2014-10-11 | Scil Technology Gmbh | Dried reconstituted vesicle formation for pharmaceutical application |
TW200846071A (en) * | 2006-12-26 | 2008-12-01 | Chisso Corp | Metal salt of crosslinking cellulose derivative |
JP5277965B2 (en) * | 2006-12-26 | 2013-08-28 | Jnc株式会社 | Sodium absorption inhibitor, potassium absorption inhibitor and phosphorus absorption inhibitor, and prophylactic, therapeutic and food containing the same |
MX2009011898A (en) * | 2007-05-04 | 2009-11-18 | Ironwood Pharmaceuticals Inc | Compositions and methods for treating disorders associated with salt or fluid retention. |
WO2009029829A1 (en) * | 2007-08-29 | 2009-03-05 | Sorbent Therapeutics, Inc. | Polymeric compositions with enhanced saline holding capacity and their method of preparation and use |
JP5294681B2 (en) * | 2008-04-28 | 2013-09-18 | 東京エレクトロン株式会社 | Substrate processing apparatus and substrate transport method |
US20100104527A1 (en) * | 2008-08-22 | 2010-04-29 | Relypsa, Inc. | Treating hyperkalemia with crosslinked cation exchange polymers of improved physical properties |
US8337824B2 (en) * | 2008-08-22 | 2012-12-25 | Relypsa, Inc. | Linear polyol stabilized polyfluoroacrylate compositions |
KR102178208B1 (en) | 2008-08-22 | 2020-11-12 | 리립사, 인크. | Crosslinked cation exchange polymers, compositions and use in treating hyperkalemia |
AU2013204877B2 (en) * | 2008-08-22 | 2015-10-29 | Vifor (International) Ltd. | Crosslinked cation exchange polymers, compositions and use in treating hyperkalemia |
WO2010022382A2 (en) * | 2008-08-22 | 2010-02-25 | Relypsa, Inc. | Crosslinked polyfluoroacrylic acid and processes for the preparation thereof |
WO2010132662A1 (en) * | 2009-05-13 | 2010-11-18 | Relypsa, Inc. | Powder formulations of potassium-binding active agents |
ES2670580T3 (en) | 2010-03-20 | 2018-05-31 | Relypsa, Inc. | Continuous procedure to prepare polyfluoroacrylate particles |
US9314523B2 (en) | 2010-09-21 | 2016-04-19 | Elwha Llc | Ingestible salt grabber |
EP3246287A1 (en) | 2011-02-11 | 2017-11-22 | ZS Pharma, Inc | Microporous zirconium silicate for the treatment of hyperkalemia |
CN110028603A (en) | 2011-06-27 | 2019-07-19 | 瑞立普萨公司 | Method for converting polymeric acid for polyester |
WO2013003495A2 (en) | 2011-06-27 | 2013-01-03 | Relypsa, Inc. | Fluorination of acrylate esters and derivatives |
US9943637B2 (en) | 2012-06-11 | 2018-04-17 | ZS Pharma, Inc. | Microporous zirconium silicate and its method of production |
CA2878832A1 (en) * | 2012-07-11 | 2014-01-16 | ZS Pharma, Inc. | Microporous zirconium silicate for the treatment of hyperkalemia in hypercalcemic patients and improved calcium-containing compositions for the treatment of hyperkalemia |
WO2014015240A1 (en) * | 2012-07-19 | 2014-01-23 | Sorbent Therapeutics, Inc. | Compositions comprising crosslinked cation-binding polymers |
US9982940B2 (en) | 2012-08-09 | 2018-05-29 | Patheon Austria Gmbh & Co Kg | Process for drying polymeric materials |
CN104822383A (en) | 2012-10-08 | 2015-08-05 | 瑞立普萨公司 | Potassium-binding agents for treating hypertension and hyperkalemia |
AU2013334776B2 (en) | 2012-10-22 | 2017-08-31 | ZS Pharma, Inc. | Microporous zirconium silicate for treating hyperkalemia |
US10695365B2 (en) | 2012-10-22 | 2020-06-30 | ZS Pharma, Inc. | Microporous zirconium silicate for the treatment of hyperkalemia |
CA2912911C (en) | 2013-06-05 | 2023-10-03 | Tricida, Inc. | Proton-binding polymers for oral administration |
JP5740523B1 (en) * | 2013-12-11 | 2015-06-24 | 株式会社 資生堂 | Early diagnosis marker of renal failure |
US9675636B2 (en) * | 2014-01-31 | 2017-06-13 | University Of Kansas | Micelle sequestering polymers |
JP6468780B2 (en) * | 2014-09-30 | 2019-02-13 | 積水化成品工業株式会社 | Hollow resin particles and method for producing the same |
EP3229816B1 (en) | 2014-12-10 | 2020-02-05 | Tricida Inc. | Proton-binding polymers for oral administration |
US9592253B1 (en) | 2015-10-14 | 2017-03-14 | ZS Pharma, Inc. | Extended use zirconium silicate compositions and methods of use thereof |
ITUB20159278A1 (en) | 2015-12-23 | 2017-06-23 | Rjw Pharma Llc | PROCEDURE FOR THE SYNTHESIS OF PATIROMER |
US20200054669A1 (en) | 2016-05-06 | 2020-02-20 | Tricida, Inc. | Compositions for and methods of treating acid-base disorders |
JP2018125951A (en) * | 2017-01-31 | 2018-08-09 | 日本電産株式会社 | Motor and air blowing device with the same |
AU2018360867A1 (en) | 2017-11-03 | 2020-04-30 | Tricida, Inc. | Compositions for and method of treating acid-base disorders |
JP7365631B2 (en) * | 2019-09-02 | 2023-10-20 | 国立大学法人福井大学 | Core-shell type polymer fine particles having phosphonic acid or phosphonic acid ester structure, particle dispersion, molded body, and method for producing the fine particles |
CN113244339B (en) * | 2021-06-04 | 2021-09-24 | 南京厚生药业有限公司 | Cholestyramine powder for hyperlipidemia and preparation method thereof |
WO2023088111A1 (en) * | 2021-11-17 | 2023-05-25 | Waterstone Pharmaceuticals (Wuhan) Co., Ltd. | Pharmaceutical polymer for treating hyperkalemia and preparation method thereof |
WO2024035944A1 (en) * | 2022-08-12 | 2024-02-15 | University Of Kansas | Extraction of critical minerals using polyanions |
Family Cites Families (81)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2340111A (en) | 1942-07-03 | 1944-01-25 | Gen Electric | Process for removing cations from liquid media |
US2611730A (en) * | 1950-09-02 | 1952-09-23 | Simth Kline & French Lab | Medical preparation for reducing the body level of sodium |
US2798053A (en) * | 1952-09-03 | 1957-07-02 | Goodrich Co B F | Carboxylic polymers |
US2909462A (en) * | 1955-12-08 | 1959-10-20 | Bristol Myers Co | Acrylic acid polymer laxative compositions |
US3499960A (en) * | 1965-01-25 | 1970-03-10 | Merck & Co Inc | Palatable coated particles of an anion exchange resin |
FR2171934B1 (en) * | 1972-02-16 | 1974-09-13 | Rhone Poulenc Sa | |
US3974272A (en) * | 1972-09-01 | 1976-08-10 | Merck & Co., Inc. | Palatable cholestyramine coacervate compositions |
US4143130A (en) * | 1977-08-29 | 1979-03-06 | Warren-Teed Laboratories, Inc. | Method for treating kidney stones |
US4470975A (en) * | 1977-10-21 | 1984-09-11 | The Johns Hopkins University | Method and composition for the elimination of water from an animal body |
US4191812A (en) * | 1978-09-19 | 1980-03-04 | Rohm And Haas Company | Ion exchange process involving emulsion ion exchange resins |
US4380590A (en) * | 1978-09-19 | 1983-04-19 | Rohm And Haas Company | Emulsion copolymer cation exchange resins |
SE8003805L (en) | 1980-05-21 | 1981-11-22 | Haessle Ab | A PHARMACEUTICAL PREPARATION WITH IMPROVED EMISSION PROPERTY |
US4362711A (en) | 1980-07-11 | 1982-12-07 | Evreka Inc. | Blood cholesterol level reducing agent and method |
DE3031737A1 (en) | 1980-08-22 | 1982-04-01 | Bayer Ag, 5090 Leverkusen | METHOD FOR PRODUCING PEARL POLYMERISATS OF UNIFORM PARTICLE SIZE |
DE3149136A1 (en) | 1981-12-11 | 1983-06-23 | Robert Bosch Gmbh, 7000 Stuttgart | DEVICE FOR REGULATING THE FUEL-AIR RATIO IN INTERNAL COMBUSTION ENGINES |
JPS6090243A (en) * | 1983-10-25 | 1985-05-21 | Nitto Boseki Co Ltd | Small spherical crosslinked monoallylamine polymer and its preparation |
US5238924A (en) | 1984-05-03 | 1993-08-24 | Merck & Co., Inc. | Treatment of renal diseases with ace inhibitors |
KR920006865B1 (en) | 1984-05-18 | 1992-08-21 | 워싱톤 유니버시티 테크놀러지 어소우시에이츠 인코오퍼레이티드 | Method and apparatus for coating particles or liquid droplets |
US4747881A (en) * | 1985-02-05 | 1988-05-31 | Warner-Lambert Company | Ingestible aggregate and delivery system prepared therefrom |
US5186937A (en) * | 1985-06-07 | 1993-02-16 | A.E.C. Societe De Chimie Organique Et Biologique | Composition for feeding ruminants |
IT1190349B (en) * | 1986-06-16 | 1988-02-16 | Prodotti Formenti Srl | PHARMACEUTICAL COMPOSITIONS WITH SEQUESTRANT ACTIVITY OF BILE ACIDS CONTAINING COLESTYRAMINE AS THE ACTIVE INGREDIENT, AND PROCEDURE TO PREPARE THEM |
JPS63218713A (en) * | 1987-02-17 | 1988-09-12 | Daikin Ind Ltd | Alpha-fluoroacrylic acid polymer and use thereof |
US4837015A (en) * | 1987-03-05 | 1989-06-06 | Carolina Medical Products Company, Inc. | Alkali metal ion-charged, cation exchanger and use thereof to adjust sodium, potassium and calcium body fluid levels |
US5210079A (en) | 1988-01-07 | 1993-05-11 | E. I. Du Pont De Nemours And Company | Treatment of chronic renal failure with imidazole angiotensin-II receptor antagonists |
FR2634377B1 (en) * | 1988-06-30 | 1991-09-27 | Cortial | NOVEL EXTENDED RELEASE PHARMACEUTICAL FORM BASED ON AN ACTIVE RESIN-PRINCIPLE COMPLEX |
GB8817015D0 (en) * | 1988-07-16 | 1988-08-17 | Reckitt & Colmann Prod Ltd | Method of treatment |
GB8829088D0 (en) | 1988-12-13 | 1989-01-25 | Smith Kline French Lab | Compounds |
US5236701A (en) | 1989-07-19 | 1993-08-17 | Lowchol Scientific Inc. | Ingestible hydrophilic polymeric amines useful for lowering blood cholesterol |
DE3928990A1 (en) | 1989-09-01 | 1991-03-07 | Bayer Ag | METHOD FOR PRODUCING (ALPHA) -FLUOROACRYLIC ACID DERIVATIVES |
US5112993A (en) | 1989-11-14 | 1992-05-12 | E. I. Du Pont De Nemours And Company | Process for the preparation of difluoromaleic anhydride |
US5091175A (en) * | 1990-05-14 | 1992-02-25 | Erbamont Inc. | Pharmaceutical composition containing bile acid sequestrant enclosed in a size-exclusion membrane |
ATE116859T1 (en) * | 1990-07-04 | 1995-01-15 | Marcin Krotkiewski | BLOOD PRESSURE-LOWERING PREPARATION. |
IE914179A1 (en) | 1990-12-07 | 1992-06-17 | Ici Plc | Nitrogen derivatives |
US5162110A (en) | 1990-12-19 | 1992-11-10 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Binding theophylline to ion exchange resins |
US5281631A (en) * | 1991-12-20 | 1994-01-25 | Arch Development Corp. | Phosphonic acid based ion exchange resins |
EP0563731B1 (en) * | 1992-03-28 | 1995-11-15 | Hoechst Aktiengesellschaft | Medicaments containing polyhydroxymethylene-derivatives, process for their manufacture and use thereof |
NZ255758A (en) * | 1992-08-20 | 1997-10-24 | Du Pont | Crosslinked polymeric ammonium salts useful as bile sequestrants |
US5487888A (en) * | 1993-05-20 | 1996-01-30 | Geltex, Inc. | Iron-binding polymers for oral administration |
AU6818894A (en) | 1993-05-20 | 1994-12-20 | Geltex Pharmaceuticals, Inc. | Process for adjusting ion concentration in a patient and compositions therefor |
US5607669A (en) | 1994-06-10 | 1997-03-04 | Geltex Pharmaceuticals, Inc. | Amine polymer sequestrant and method of cholesterol depletion |
US5618530A (en) * | 1994-06-10 | 1997-04-08 | Geltex Pharmaceuticals, Inc. | Hydrophobic amine polymer sequestrant and method of cholesterol depletion |
US5667775A (en) * | 1993-08-11 | 1997-09-16 | Geltex Pharmaceuticals, Inc. | Phosphate-binding polymers for oral administration |
WO1995014531A1 (en) | 1993-11-25 | 1995-06-01 | Salternate B.V. | Particles for binding monovalent cations, use of such particles as well as methods for scavenging and removing sodium and/or potassium ions |
TW474813B (en) * | 1994-06-10 | 2002-02-01 | Geltex Pharma Inc | Alkylated composition for removing bile salts from a patient |
US5846990A (en) * | 1995-07-24 | 1998-12-08 | Bristol-Myers Squibb Co. | Substituted biphenyl isoxazole sulfonamides |
US5824339A (en) * | 1995-09-08 | 1998-10-20 | Takeda Chemical Industries, Ltd | Effervescent composition and its production |
US6498142B1 (en) | 1996-05-06 | 2002-12-24 | Curis, Inc. | Morphogen treatment for chronic renal failure |
JP3885130B2 (en) | 1996-06-11 | 2007-02-21 | 株式会社大塚製薬工場 | Guanidino compound reducing agent and moisture and potassium ion adsorbent |
EP2272536B1 (en) | 1996-06-26 | 2016-05-04 | Board of Regents, The University of Texas System | Hot-melt extrudable Pharmaceutical formulation |
WO1997049387A1 (en) * | 1996-06-27 | 1997-12-31 | G.D. Searle And Co. | Particles comprising amphiphilic copolymers, having a cross-linked shell domain and an interior core domain, useful for pharmaceutical and other applications |
US6623759B2 (en) * | 1996-06-28 | 2003-09-23 | Astrazeneca Ab | Stable drug form for oral administration with benzimidazole derivatives as active ingredient and process for the preparation thereof |
US5935599A (en) * | 1996-10-28 | 1999-08-10 | The Board Of Trustees Of The University Of Illinois | Polymer-associated liposomes for drug delivery and method of manufacturing the same |
JPH10130154A (en) | 1996-10-29 | 1998-05-19 | Otsuka Pharmaceut Factory Inc | Life prolongation ratio improver for nephritis patient |
KR100775154B1 (en) | 1997-12-19 | 2007-11-12 | 스미스클라인 비참 코포레이션 | Process for Manufacturing Bite-Dispersion Tablets |
US6280717B1 (en) * | 1998-07-31 | 2001-08-28 | Nikken Chemicals Co., Ltd. | Cation exchange resin preparation |
US6294163B1 (en) | 1998-10-02 | 2001-09-25 | Geltex Pharmaceuticals, Inc. | Polymers containing guanidinium groups as bile acid sequestrants |
JP2002529405A (en) * | 1998-11-06 | 2002-09-10 | ジー・ディー・サール・アンド・カンパニー | Combination therapy of angiotensin-converting enzyme inhibitor and aldosterone antagonist to reduce morbidity and mortality from cardiovascular disease |
AU1998200A (en) | 1999-01-07 | 2000-07-24 | Elan Corporation, Plc | Multiparticulate oral dosage forms |
US6558665B1 (en) * | 1999-05-18 | 2003-05-06 | Arch Development Corporation | Encapsulating particles with coatings that conform to size and shape of the particles |
US6733780B1 (en) * | 1999-10-19 | 2004-05-11 | Genzyme Corporation | Direct compression polymer tablet core |
US20020054903A1 (en) * | 1999-10-19 | 2002-05-09 | Joseph Tyler | Direct compression polymer tablet core |
EP1249240A4 (en) * | 2000-01-14 | 2003-03-19 | Otsuka Pharma Co Ltd | Inhibitors against sodium ion absorption, and preventive or therapeutic agents and foods containing the same |
FR2812632B1 (en) | 2000-08-07 | 2003-03-07 | Solvay | PROCESS FOR THE SYNTHESIS OF FLUOROORGANIC COMPOUNDS |
WO2002040039A2 (en) | 2000-11-20 | 2002-05-23 | Dow Global Technologies Inc. | In vivo use of water absorbent polymers |
WO2002062356A2 (en) | 2001-02-06 | 2002-08-15 | Ash Medical Systems, Inc. | Monovalent-selective cation exchangers as oral sorbent therapy |
US7033639B2 (en) * | 2001-05-16 | 2006-04-25 | Rohm And Haas Company | Polyaniline coating composition |
US6881484B2 (en) * | 2001-05-30 | 2005-04-19 | Mitsubishi Kagaku Iatron, Inc. | Core-shell particle including signal-generating substance enclosed therein and process for producing the same |
JP2004149525A (en) | 2002-10-09 | 2004-05-27 | Sekisui Chem Co Ltd | Potassium ion adsorbent, method for producing the same, and therapeutic agent for hyperkalemia |
JP5826445B2 (en) * | 2003-02-25 | 2015-12-02 | フィンフィーズ フィンランド オイ | Simulated moving floor system and method |
WO2005065291A2 (en) | 2003-12-31 | 2005-07-21 | Genzyme Corporation | Enteric coated aliphatic amine polymer bile acid sequestrants |
US7429394B2 (en) * | 2004-03-30 | 2008-09-30 | Relypsa, Inc. | Ion binding compositions |
WO2005094384A2 (en) | 2004-03-30 | 2005-10-13 | Ilypsa, Inc. | Methods and compositions for treatment of ion imbalances |
US7556799B2 (en) * | 2004-03-30 | 2009-07-07 | Relypsa, Inc. | Ion binding polymers and uses thereof |
US8192758B2 (en) * | 2004-03-30 | 2012-06-05 | Relypsa, Inc. | Ion binding compositions |
US8282960B2 (en) * | 2004-03-30 | 2012-10-09 | Relypsa, Inc. | Ion binding compositions |
US7854924B2 (en) * | 2004-03-30 | 2010-12-21 | Relypsa, Inc. | Methods and compositions for treatment of ion imbalances |
CA2624112A1 (en) | 2005-09-30 | 2007-04-05 | Ilypsa, Inc. | Methods for preparing core-shell composites having cross-linked shells and core-shell composites resulting therefrom |
AU2006299449B2 (en) | 2005-09-30 | 2013-07-04 | Relypsa, Inc. | Methods and compositions for selectively removing potassium ion from the gastrointestinal tract of a mammal |
US20100104527A1 (en) | 2008-08-22 | 2010-04-29 | Relypsa, Inc. | Treating hyperkalemia with crosslinked cation exchange polymers of improved physical properties |
WO2010022382A2 (en) | 2008-08-22 | 2010-02-25 | Relypsa, Inc. | Crosslinked polyfluoroacrylic acid and processes for the preparation thereof |
US8337824B2 (en) | 2008-08-22 | 2012-12-25 | Relypsa, Inc. | Linear polyol stabilized polyfluoroacrylate compositions |
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