CA2129991A1 - Improved peritoneal dialysis solutions with polypeptides - Google Patents
Improved peritoneal dialysis solutions with polypeptidesInfo
- Publication number
- CA2129991A1 CA2129991A1 CA002129991A CA2129991A CA2129991A1 CA 2129991 A1 CA2129991 A1 CA 2129991A1 CA 002129991 A CA002129991 A CA 002129991A CA 2129991 A CA2129991 A CA 2129991A CA 2129991 A1 CA2129991 A1 CA 2129991A1
- Authority
- CA
- Canada
- Prior art keywords
- approximately
- polypeptides
- peritoneal dialysis
- solution
- dialysis solution
- 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.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/01—Hydrolysed proteins; Derivatives thereof
- A61K38/012—Hydrolysed proteins; Derivatives thereof from animals
- A61K38/018—Hydrolysed proteins; Derivatives thereof from animals from milk
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/02—Peptides of undefined number of amino acids; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
- A61M1/28—Peritoneal dialysis ; Other peritoneal treatment, e.g. oxygenation
- A61M1/287—Dialysates therefor
-
- 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
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
Abstract
The present invention provides an improved dialysis solution. The improved dialysis solution provides for the use of specific polypeptides as an osmotic agent with an additional osmotic agent such as dextrose. To this end, the present invention provides, in an embodiment, a peritoneal dialysis solution comprising as osmotic agents approximately 0.25 to about 4.0 % (w/v) polypeptides and approximately 0.5 % to about 4.0 % (w/v) dextrose. The polypeptides have well defined characteristics.
Description
. W094/1~821 2 9 9 9 t PCT/U593/12075 P ~ e I F I Ci~ T ~ O_N
TITL~
'~IHPROV~D P~RI~ON~AL DIALY8I8 80L~ION8 ~I~ POL~P~PTID~"
5BACKG~OUND OP THE INVENTION
The present invention relates generally to peritoneal dialysis. More specifically, the pr~sent invention relates ~o improved peritoneal dialysis ~olutions including polypeptide~. -It is known to use dialysis to suppor~ 21 patient whose renal function has decreased to the point where the kidneys no longer ~ufficiently function. Two principal dialysis methods are utilized: hemodialysi~; and p~ritoneal dialysis.
In hemodialysis, the patient'~ blood is passed through an artificial kidney dialysis machine. A
membrane in the machine acts as an artificial kidney for cleansing the blood. B~cause it is an extracorporeal traatment that requîres special machinery, there are certain inherent disadvantages with hem~dialysis.
To overcome the disadvantages as oci~ted with hemodialysis, peritoneal dialysis was developed.
Peritoneal dialysis utilizes the p~tient's own peritoneum as a ~emipermeable me~brane. The peritoneum is a membranous lining of the body cavity that due to the large number of blood ~essels and capillaries is c~pable of acting as a natural semipermeable mem~rane.
In peritoneal dialysis, a dialysis solution is introduced into the peritoneal cavity utilizing a catheter. After a sufficient period of time, an exchange of solutes between the dialysate and the ~lood is achieved. Fluid removal is achieved by providing a suitable osmotic gradient from the blood to the dialysate 21?~99l to permit water outflow from the blood~ This allows the proper acid-base, electrolyte and fluid balance to be returned to the blood and the dialysis 501ution is simply drained from the body cavity through the catheter.
Although there are many advantages to peritoneal dialysis, one of the difficulties that has been encountered is providing a dialysate that includes a suitable osmotic agent. What is re~uired is that a sufficient osmotic gradient is achieved. The osmotic agent is used in the dialysis solution to maintain the osmotic gradient reguired to cause transport of water and toxic substances across the peritoneum into the dialysis solution.
The appropriate osmotic agent needs to achieve at least a eouple criteria. First, it needs to be non-toxic and substantially biologically inert. However, the agent should be metabolizable~ Additionally, the agent should not rapidly cross the peritoneal membrane into the blood.
By achieving both these criteria, this would allow mainte~ance of the maximum ultrafiltration gradient, and also would pre~ent toxicity or accumulatiQn-~f unwanted substances in the blood.
No currently used substance completely sati fies the criteria for an osmotic agent in a dialysis solutionO
Presently, the osmotic agent that is most widely used is dextrose. Dextrose is fairly safe and is readily metaboli~ed if it enters the blood. However, one of the problems with dextrose is that it is readily taken up by the blood from the dialysate. Because dextrose crosses the peritoneum so rapidly, the osmotic gradient is dissipated within two to three hours of infusion. This can cause reversal of the direction of ultrafiltration, . W094/1~8 PCT~S93/12075 2:1~'Y9~1 causing water to be reabsorbed from the dialysate toward the end of the time allowed for the exchange.
Another concern with respect to dextrose i5 that because it i8 taken up so rapidly by the blood, it can represent a large proportion of the patient's energy ~ntake. While this may not significantly eff~ct a non-diabetic patient, it can represent a severe metabolic burden to a patient whos~ glucose tolerance is already impaired. Dextrose can also caus~ problems with respect to hyperglycemia and obesity.
Still further, a problem with dextrose is with respect to the prepar~tion of a dialysis solution.
Typically, dialysis solutions, similar to oth2r medical products, are sterilized by heating. Unfortunately, heat sterilization of dextro~e at physiological pH's will cause dextrose to caramelize. To compensate for this problem, it is known to adjuæt the pH of the dialysate to within the range of S to 5.5; at this low pH dextrose will not carameliæe when heated. However, it is believed that this low pH may be responsible for the pain experienced by some patients on in flow of dialysis solution and may cause other problems, e.g., may effect peritoneal host defense.
To address some of the above concerns, a number of substances have been proposed as alternatives to dextrose. However, none of the proposed materials has proven to be an adequate substitute for dextrose.
For example, dextrans, polyanions, and ~lucose polymers have been suggested as replacements for dextrose. Because of their high molecular weight, it is belie~ed that their diffusion across the peritoneum and into the blood should bP minimized. But, the low osmotic activity per unit mass of these materials dictates the WO94/14~8 PCT/US93/12075 need for larger concentrations (w/v) of these materials in the dialysis fluids in order for them to be effective.
Additionally, systemic absorption of these concentrations, mainly through the lymphatics, along with slow metabolism, raise~ serious concern about the long term safety of these agents.
Small molecular weight substances have also been explored. These substances include glycerol, sorbitol, xylitol, and fructose. However, these substances are believed to raise a number of safety concerns while offering no substantial advantages over dextrose.
Amino acids appear to be an attractive ~ubstitute for dex~rose in peritoneal dialysis solution. Short term studies have indicated that they are well tolerat~d.
Howe~er, because of their low molecular weights, they are transported quite rapidly through the peritoneum, resulting in rapid lo~s of the osmotic gradient. In addition, rapid uptake of amino acids leads to a considerable nitrogen burden and limits the use of amino acids to one to two exchanges per day.
Recently, polypeptides have been explored as a potential class of o motic agents. It is b21 ieved that polypeptides will have a low transport across the peritoneum, and therefore, maintain a prolonged osmo~ic gradient between dialysate and blood, U.S. Patent No. 4,906,616 to Gilchrist et al and European Patent No. 0218900 to Klein set forth polypeptides as the osmotic agent in a peritoneal dialysis solution. Each of these patents discusses the substitution of polypeptides for dextrose; polypeptides are the only osmotic agent utilized in the formulations disclosed.
. WO94il4~8 PCT~S93/12075 212~3g~31 In Gilchrist et al, the bulk of the polypeptides have a molecular weight of 1100 or greater. Indeed, approximately 50% of the peptides have in exce~s of 18 amino acid residue~. The polypeptides are the only 5osmotic agent used (s~e, e.g., col. 4, lines 33-35).
In Klein, the polypeptides are a mixture of relatively low molecular weight, including an alleged substantial portion between 300 to 2,000 daltons, peptides derived from the enzymatic hydrolysis of a high 10quality protein. The polypeptides are t~e only osmotic agents used. Further, as long as the mixture of polypeptide falls within an equivalent weight of 150 to 1,500 an~ the molecular weight of the polypeptides is between 300 to 2,000 daltons, the polypeptide mixture is 15sufficient for the needs of Kle~.
As ~et forth in detail in the examples hereinafter in this application, the polypeptide ~olutions proposed by Klein and Gilchrist et_al have very limited clinical utility. Although larger in size, like amino acids, 20these polypep~ide compositions are absorb2d from the peritoneum quite rapidly. This leads to uremic ~ymptoms.
In addition, these materials contain polypeptides that have the potential of producing allergic reactions. This is due to the size of the polypeptides that are used.
25There is therefore a need for an improved peritoneal dialysis solution~
SUMMARY OF THE INVENTIO~
The present inventio~ provides an improv~d dialysis solution. The improved dialysis solution provides for 30the use of specific polypeptides as an osmotic ~gent with an additional osmotic agent such as dextrose.
To this end, the present invention provides, in an embodiment, a peritoneal dialysis solution comprising as wos4/1~8 PCT~S93/12075~
2 ~
osmotic agents approximately 0.25 to about 4.0% (w/v) polypeptides and approximately 0.5% to about 4.0% (w/v) dextrose.
In an ~mbodiment, the peritoneal dialysis solution includes: approximately 120.00 to about 150.00 (mEq/L~
of sodium; approximately 80.0 to about llO.00 (mEqJL) of chloride; 0 to about 45.00 (mEqJL) of lactate; 0 to about 45.00 (m~q/L) of bicarbonate, 0 to about 4.00 (~Eq/L) of calcium; and 0 to about 4O00 (mEqJL) of magnesium.
Preferably, the pH of the solution is approximately 6.0 to about 7.4. ::
In an embodiment, the polypeptides are synthetic -~
peptides.
In an embodiment, the present invention provides a peritoneal dialysis solution comprising a polypeptide ~ixture as an osmotically active agent in an csmotically effective amount. The polypeptide mixture consists of not more than approximately 0.~0% of polypeptides having a molecular weight of greater than 1200, not more than approximately 25% of polypeptides having a molecular weight of les~ than 400, and the weight ave~age of the polypeptide mixture being within the range of approximately 400 to about 900 daltons.
In an embodiment, the periton2al dialysis solution provides: less than approximately 5 ppm of total heavy metals; and less than approximately 500 ppb aluminum.
Additionally, the peptides should have: less than approximately 50 mg/gm sodium; less than approximately 10 mg/gm chloride; less than approximately 0.2 mg/gm potassium; less than approximately l mg/gm magnesium;
less than approximately l mg/gm calcium; less than approximately l mg/gm phosphorus; and less than approximately 5 mg/gm lactose.
. W094/14~8 212 9 9 .9 I PCT~S93/12075 In an embodiment, a two part peritoneal dialysis solution designed to be mixed prior to infusion into a patient is provided. The two part solution comprises:
a first part housed in a first ~tructure including approximately l.0% to about 8% (w/v~ dextrose and a pH
of approximately 4.0 to ~bout 5.5; a second part housed in a second structure including approximately 0.5 to about 8.~ (w/v) polypeptides and a pH of approximately 6.0 to about 7.5; and including in either the first or 10the second structure: 0 to about 300 (mEq/L) ~odium; 0.0 to about 250.00 (mEq~L) chloride; 0.0 to about lO0.0 (mEq/L) lactate; 0.0 to about lO0.0 (mEq/L) bic~rbonate;
O.O to about lO.0 (mEq/L) calcium; and 0.0 to about lO.0 (mEq/L) magnesium.
15The present in~ention also provides for the use of polypeptides that have an amino acid composition that provides a nutritionally effe~tive solution.
In an embodimentl the present invention also provides a solution for delivering drugs to the 2~ peritoneum~
An advantage of the present invention -is that it provides an improved periton~al dialysis solutiun.
Stil~ further, an advantage of the present invention is that it provides an improved osmotic agent for use in a peritoneal dialysis solution.
A further advantage of the present invention is that it provides for the use of synthetic polypeptides for making an improved peritoneal dialy~is solution.
Furthermore, an advantage of the present inventi~n is that it provides for the ability to create peritoneal dialysis solutions ~hat are at a physiological pH to help reduce the pain of infusion.
WOs4/14K8 PCT~S93/12075 !
2~ 9 ~
Moreover, an advantage of the present invention is that it has reducad osmolalities along with physiologic pH to restore pha~ocytic function of macrophages.
Additionally, an advantage of the present invention is that it allows the use of dextrose in the solution and sterilization of same at a pH 4.0 to 5.5 to reduce the degradation products of dextrose.
Still further, an advantage of the present invention is that it provides higher weight average ~ol~cular weight of osmotic agents to improve ultrafiltration profile.
Another advantage of the present invention is that it provides balanced sup~lementation of polypeptides (protei~ source~ and dextrose (energy source) through a dialysis solution to improve the nutritional status of the renal patient.
Noreover, an advantage of the present invention is that it provides for the a~ility to increase infusion volumes and herlce small ~olute clearances as a result of decrease in molar concentrations of 05motic: agents.
Further, an advantage of th2 present ~nvention is that it provides a solution for intraperitoneal drug delivery .
Additional features and advantages of the present invention are described in, and will be apparent from, the detailed description of the presently preferred embodiments and from the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1-3 illustrate, graphically, molerular weight distributions for the peptide mixtures tested in Example No. l.
Figure 4 illustrates, graphically, volume profiles for Example No. 1.
WO94/1~8 212 9 9 9 I PCT~S93/1207~
Figure 5 illustrates, graphically, absorption of dextrose and peptides for Example No. l.
DETAILED DESCRIPTION
OF THE PRESENTLY PREFERR~D ~MBOPIMENT~
5The present inv~ntion provides improved peritoneal dialysis solutions containing polypeptides having well defined characteristics (e.g., molecular weight, distribution, amino acid composition, purity, etc.) ~or use in peritoneal dialysis solutions and intraperitoneal lOdrug delivery. The polypeptides are pre~erably used with another osmotic agent such as dextrose, polyglucose, amino acids, and ~lycerol.
As set forth in detail below, by selecting well defined polypeptides and utilizing same with an 15additional osmotic agent, the disadvantages of polypeptides alone and dextrose alone can be overcome.
To this end, prefer~bly, approximately 0.25% to a~out 4%
(w/v) polypeptides and approximately 0.5% to about 4%
(w/v) dextrose are used as the osmotic agent pursuant to 20the present invention.
In an embodiment, the polypeptides are obtained from enzymatic or acid hydroly~is of high biological value proteins. These proteins can be derived from milk, egg, potato, or soy. The polypeptides are prepared using 25enzymatic or chemical hydrolysis, dialysis, ultrafiltration, ion exchange, solvent fractionation, chromatography, or other related separation techniques.
For example5 whey can be ~ydroly2ed with a pro~eolytic enzyme, such as trypsin. The desired 30molecular weight fraction of the pre~ent invention, set forth below, is then separated using ultrafiltration and dialysis. By using ion exchange absorption, ions and heavy metals can be removed. A variety of methods can Wo94/14K8 PCT~S93/12075 2~,99~ 10-be used, as known in the art, for preparing such polypeptides.
The polypeptides can, in an embodiment, be synthetic polypeptides. The use of synthetic polypeptides allows one to provide peptides that have better defined characteristics and contain less impurities as compared with polypeptides that are obtained by hydrolysis proteins.
In order to determine the solutions of the present invention, the Klein solutions were tested.
Specifically, immunogenicity and ultrafiltration and absorption were evaluated. Accordingly, the following experiments were perfor~ed.
EXAMP~ N0. 1 ~he purpose of this study wa~ to evaluate peptides/
as disclosed in Klein, diff ering in weight average and number average molecular weights, as alternative osmotic agents t~ dextrose in dialysate solutions. These experiments were conducted in a nephric unanesthetized rat model.
The following peptide powders were received from E.
Klein (University of LouisYille)O
Run #123 & 132 Mw=695, Mn=640 Run ~138 Mw--2985, Mn=885 Run #140 Mw=6647, Mn=1020 Due to the presence of high levels of endo~oxin (>500 EU/ml) in each of the above preparations, a "clean up" procedure was performed as follows: 7% solutions of each peptide preparation was centrifuged to remove black particulate. Each solution was then passed through a 0.2 filter directly into a pre-washed Fresenius F-~0 dialyzer to remove endotoxin. The dialyzer was rinsed with sterile water following a single pass of peptide . W094/14~8 21~ 9 9 9 ~ PCT~S93/12075 solution. The peptide solutions were transferred into depyrogenated pans and lyophilized. All three peptide preparations were reanalyzed for endotoxin. Results indicated levPls below the pyrogenic response level of 0.5 EU/ml.
After removal of endotoxin from the peptides, molecular weight and mean profile changed due to a loss of high molecular weight peptides after passing through the F-60 dialyzer. The final results are shown below:
Run #123 & 132 ~w=1128, Mn=734 Run #138 ~w=2004, MnzlO08 Run #140 Mw=2388, Mn-1016 Molecular distributions for each pe~tide mixture are shown in ~igures 1-3.
Peptide powders were formulated to match the electrolyte composition of Dianeal PD-2 as summarized in Table 1.
Table 1 Compo~itio~ of Perito~e~l Dialy~i~ 801utio~s 2.5% DQxtros~ Ru~
Co~po~t Di~al~ ~32 138 ~40 ~ . -- - --e --_ _ _ Peptide (g~dl) ___ 3.5 5.5 4.3 _ . _ . _ _ Dextrose (g/L) 25 ___ ___ __ _ _ , _ Sodium bound (mEq/L) ___ 25 31 31 . _ . .. _ _, Sodium (mEqJL) 132 148 153 15S
~ _ I
Chloride (mEq/L) 96 86 85 84 _ _ I
Lactate (mEq/L) 40 40 40 40 Calcium (mg/dl) 3.5 3.S 3.5 3.5 Magnesium (mEq/L) O.5 0.5 O~5 0.5 W094/1~8 PCT~S93/12075 c~
¦~loctrolyt~ total 272 278 2B2 283 I _ _ _ I
Osmolality (mOsm/kg) ~ 383 338 355 335 _ __ _._ _ _ ~ _ pH 5.1 7.7 7.3 7.3 _ - . ._ ~ = _ _ Rats were anesthetized by Metafane inhalation. The abdominal area of the rats was shaved. Dialysate solution (90 ml/kg) was injected intraperitoneally using a 23G needle. The dialysis solution contain~id approximately l ~ Ci 94C Dextran as a dilution marker.
Rats were allowed to rPcover and penmitted free access to water.
Dialysate samples (0.2 ml) were collected at 0.5, l, 2, and 4 hours during the dwell period.
~t the end of a 4 hour dwell period, a 1 ml blood sample was collected via the tail art~iry, plasma separated and frozen. Rats were euthanized by tail vein injection of solution.
The abdominal cavity was opened by midline incision, dialysate collected~ and vol~me recorded.
The experimental procedure was performed as described below.
Rats, n=6 peir group were randomly dosed with one of the following dialysate solutions: 1.5% Dextrose DIANEAL, 2.5% Dextrose DIANEAL~, Peptide run 132, Pep~ide run 138, or Peptide run 140~
Analyses: ~4C Dextran, all dialysate samples.
Osmolality in all dialysate samples and in all t=4 hr plasma samples.
Amino acids in all dialysate samples containing peptide runs Pre and 4 hr.
O.5, 1, and 2 hr samples run for some rats in Peptide groups.
Glucose, all Pre and 4 hr dialysate samples in DIANEAL group~.
Volume profiles for the experim~nt are s~own in Figure 4. Volumes between t=0 and the end of the dwell are based on 14C Dextran concentra~ions assuming a constant rate for disappearance of l~C Dextran.
Dialysate ~ampl~s were analyzed for ami.no acids following acid hydrolysis to generate free amino acids.
These analyses were used to calculate the percent of pep~ides absorbed during an exchange as co~1pared to dextrose. The results are sho~n in Figur~ 5.
The experiments demonstrate that a dialy5is solution containin~ peptides can produce ultrafiltration pro~iles similar to that seen with dextrose but with a lower initial osmolality.
Additionally, the experiments demonstra~e that peritoneal absorption of peptides at 4 hours is approximately 50-60%.
EXAMPLE NO. 2 An irritation screening was conducted using 2.5%
Dextrose (w~v~ in Dianeal, l.0~ Whey Protein Hydrolysate (in accordance with ~lein) (w/v) in l.5% Dextrose ~w/v) in Dianeal~, aIld 3 . 0% Whey Prstein Hydrolysate ( in accordance with l~a) (w/v) in 1. 5% Dextrose (wjv) in Dianeal~. Two sites were selected and shaved on two animals for each material . Each animal re ::eived two o. lOS-mL intradermal injections of the respective 3 0 undiluted material .
A positive control irritation screening was also conducted in the same manner with a 1% w~v concentration of sulfathiazole in sterile o . 9% saline. All sites were ~'094/14~8 PCT~S93/1207r 21 ~9 l scored for eirythema and edema at 24 and 48 hours after injection. Since all three test materials were ~hown to be nonirritating, they were administered undiluted on Day 8 and Day 22 (challenge phase) of the definitive study.
5The positive control animals received a 5% w/v suspension of sulfathiazole in sterile water for the Day 8 intradermal injections and as a 1% w/v suspension in sterile 0.9% ~aline for the Day 22 challenge procedure~
The study was conducted using 10 test animals and 10four naive control animals per test or positive control material. On Day 1, animals in each t~ist group received duplic~te 0.05-mL intradermal injections of a 1:1 ratio of Freund's Complete Adju~ant in sterile watar/ the respective test m~terial, and a 1:1 ratio of the 15respective test material in Freund's Complete Adjuvant.
~or the positive control group, ~h~ animals received duplicate 0. OS-mL intradermal injections of a 1:1 ratio of Freund's Compl~ite Adjuvant in sterile water, a 5% w/v suspension of sulfathiazole in ~terile wat~ir, and a 5%
20w/v suspension of ~;ulfathiazole in ~reund' s Complete Ad j u~ant ~ ~
On day 7 f animals in ~11 three test groups and the positive control group were pretr ated with 10% w/w sodium lauryl sulfate in petrolatum applied kopically at 2~the sha~ed area of the Day 1 intradermal injections. On Day ~, the respective test or positive control material was injected intradermally at a ~olume of 0.05 m~ into two separate areas located just posterior to ~he initial intradermal injections.
30All the test materials were administered undiluted and the positive con~rol was administered as a 5% w/v suspension of sulfathiazole in sterile water. All naive W094/14~8 ~1 2 9 9 9 ~ PCT~S93/12075 control animals were not treated during the induction phase.
Two weeks following the Day 8 intradermal injections, all animals in the respective test and naive control groups received a challenge intradermal injection. The respective undiluted test material was injected intradermally at a volume of 0.05-m~ into one site on the shaved right flank of each respe~tive animal.
The positive control anîmals were treated with a 1% w/v suspension of sulfathiazole in sterile 0.9% saline. The sites were examined for erythema and edema at 24, 48, and 72 hours following injection.
No dermal reactions at challenge were observed in the animals treated with 2.5% Dextrose ~w/v~ in Dianeal.
Dermal sensitization responses were observed in the test animals treated with 1.0~ and 2.0% Whey Protein Hydrolysate (wJv) in 1.5~ Dextrose ~w/v) in Dianeal and in the animals treated with the positive control material. ~here were no dermal reactions observed in the respective naive control animals.
Based upon the results obtairled, the materials are classified as present~d below:
Test Material Identification 2.5% Dextrose (w/v) in Dianeal~Not a sensitizer 1.0% Whey Protein HydrolysateSensitizer (w/v) in 1. 5~ Dextrose (w/v) in Dianeal 3.0% Whey Protein HydrolysateSensitizer (w~v~ in 1.5% Dextrose tw/v) in Dianeal~
Sulfathiazole (positive cont~ol)Sensitizer 9 ~t~ ~
MAT:E:RIALS (Example No . 2 ) Identif ication The materials were identified and described as fo~lows:
Material Test Ma~erial Lot Physlcal P~sianatiQn Identific~tion Numbe~ Abbr~v~tlon Des~i~tiQn Test 2.5% Dextrose C132365 2.5,6 D~x~ro~e C:lear, cdor- -(w/v~ in Dianeala less liquW
Test 1.0% Whey Protein P900510 1.0% WPH P a I e -yel I ow Hydrolysate ~w/v) In l~C1 in 1.59~ Dex~rose C127æ5 (w,/v) in Dbneal~
Test 3.0% Whey P,~otein P900~1û 3.0~ WPH Pale-yellow Hydrolysate (w/v, In liquid In 1.~% D~xtrose C127225 (wtv) in Dianeal~ .
P o s i t i v e Sulfathiazole 8~F440~ ~ Wh~e powder C:ontrd Storaae and Pcetention The test materials were stored refrigerated. The positive control material was stored at room temperature.
Test ~ni~al -Young adult albino ~uinea pigs/ Hra:(DH)SPF, wereprocured, maintained individually in screen-bottom stainless steel cages in temperature- and humidity~
controlled rooms, provided continuous access to Certified Guinea Pig Chow0 5Q26, Purina Mills, Inc., and water and held for an acclimation period of at least 7 days. If ~ariations from the prescribed environmental conditions existed, they were documented and considered to have no effect on the study outcome. No contaminants were expected to have been present in the feed or water which would have interfered with or affected the results of the study.
WO94/1~K8 ~1 2 9 9 9 1 PCT/US93/12075 GrouP Assianments Sixty-four healthy, acclimated male albino guinea pigs weighing from 354 to 562 g were chosen at random for this study. The animals were individually housed and S identified by animal number and corresponding ear tag.
The animals were divided into the following groups:
Number of GrouD Anirr~ls Test Mater~l Identi~tion 1. Irritation Screening 2 2.5% Dextrose (w/v~ in Dianeal~s 2. irrltationScreening 2 1.0%WheyProteinHydlrolysate(w/v) In 1.5% Dexlrose (w/v3 in Dbneal~
3. Irritation Scresnln~ 2 3.00~ Whey Protein Hydrdysate (w/v) in 1.596 Dextrose (w/v~ in Dianeal0 4. Irr~tatlon Screenin~ 2 Sulfathlazole (Positive Contrd) 5. Test 10 2.5% D~xtross ~w/v~ In D
TITL~
'~IHPROV~D P~RI~ON~AL DIALY8I8 80L~ION8 ~I~ POL~P~PTID~"
5BACKG~OUND OP THE INVENTION
The present invention relates generally to peritoneal dialysis. More specifically, the pr~sent invention relates ~o improved peritoneal dialysis ~olutions including polypeptide~. -It is known to use dialysis to suppor~ 21 patient whose renal function has decreased to the point where the kidneys no longer ~ufficiently function. Two principal dialysis methods are utilized: hemodialysi~; and p~ritoneal dialysis.
In hemodialysis, the patient'~ blood is passed through an artificial kidney dialysis machine. A
membrane in the machine acts as an artificial kidney for cleansing the blood. B~cause it is an extracorporeal traatment that requîres special machinery, there are certain inherent disadvantages with hem~dialysis.
To overcome the disadvantages as oci~ted with hemodialysis, peritoneal dialysis was developed.
Peritoneal dialysis utilizes the p~tient's own peritoneum as a ~emipermeable me~brane. The peritoneum is a membranous lining of the body cavity that due to the large number of blood ~essels and capillaries is c~pable of acting as a natural semipermeable mem~rane.
In peritoneal dialysis, a dialysis solution is introduced into the peritoneal cavity utilizing a catheter. After a sufficient period of time, an exchange of solutes between the dialysate and the ~lood is achieved. Fluid removal is achieved by providing a suitable osmotic gradient from the blood to the dialysate 21?~99l to permit water outflow from the blood~ This allows the proper acid-base, electrolyte and fluid balance to be returned to the blood and the dialysis 501ution is simply drained from the body cavity through the catheter.
Although there are many advantages to peritoneal dialysis, one of the difficulties that has been encountered is providing a dialysate that includes a suitable osmotic agent. What is re~uired is that a sufficient osmotic gradient is achieved. The osmotic agent is used in the dialysis solution to maintain the osmotic gradient reguired to cause transport of water and toxic substances across the peritoneum into the dialysis solution.
The appropriate osmotic agent needs to achieve at least a eouple criteria. First, it needs to be non-toxic and substantially biologically inert. However, the agent should be metabolizable~ Additionally, the agent should not rapidly cross the peritoneal membrane into the blood.
By achieving both these criteria, this would allow mainte~ance of the maximum ultrafiltration gradient, and also would pre~ent toxicity or accumulatiQn-~f unwanted substances in the blood.
No currently used substance completely sati fies the criteria for an osmotic agent in a dialysis solutionO
Presently, the osmotic agent that is most widely used is dextrose. Dextrose is fairly safe and is readily metaboli~ed if it enters the blood. However, one of the problems with dextrose is that it is readily taken up by the blood from the dialysate. Because dextrose crosses the peritoneum so rapidly, the osmotic gradient is dissipated within two to three hours of infusion. This can cause reversal of the direction of ultrafiltration, . W094/1~8 PCT~S93/12075 2:1~'Y9~1 causing water to be reabsorbed from the dialysate toward the end of the time allowed for the exchange.
Another concern with respect to dextrose i5 that because it i8 taken up so rapidly by the blood, it can represent a large proportion of the patient's energy ~ntake. While this may not significantly eff~ct a non-diabetic patient, it can represent a severe metabolic burden to a patient whos~ glucose tolerance is already impaired. Dextrose can also caus~ problems with respect to hyperglycemia and obesity.
Still further, a problem with dextrose is with respect to the prepar~tion of a dialysis solution.
Typically, dialysis solutions, similar to oth2r medical products, are sterilized by heating. Unfortunately, heat sterilization of dextro~e at physiological pH's will cause dextrose to caramelize. To compensate for this problem, it is known to adjuæt the pH of the dialysate to within the range of S to 5.5; at this low pH dextrose will not carameliæe when heated. However, it is believed that this low pH may be responsible for the pain experienced by some patients on in flow of dialysis solution and may cause other problems, e.g., may effect peritoneal host defense.
To address some of the above concerns, a number of substances have been proposed as alternatives to dextrose. However, none of the proposed materials has proven to be an adequate substitute for dextrose.
For example, dextrans, polyanions, and ~lucose polymers have been suggested as replacements for dextrose. Because of their high molecular weight, it is belie~ed that their diffusion across the peritoneum and into the blood should bP minimized. But, the low osmotic activity per unit mass of these materials dictates the WO94/14~8 PCT/US93/12075 need for larger concentrations (w/v) of these materials in the dialysis fluids in order for them to be effective.
Additionally, systemic absorption of these concentrations, mainly through the lymphatics, along with slow metabolism, raise~ serious concern about the long term safety of these agents.
Small molecular weight substances have also been explored. These substances include glycerol, sorbitol, xylitol, and fructose. However, these substances are believed to raise a number of safety concerns while offering no substantial advantages over dextrose.
Amino acids appear to be an attractive ~ubstitute for dex~rose in peritoneal dialysis solution. Short term studies have indicated that they are well tolerat~d.
Howe~er, because of their low molecular weights, they are transported quite rapidly through the peritoneum, resulting in rapid lo~s of the osmotic gradient. In addition, rapid uptake of amino acids leads to a considerable nitrogen burden and limits the use of amino acids to one to two exchanges per day.
Recently, polypeptides have been explored as a potential class of o motic agents. It is b21 ieved that polypeptides will have a low transport across the peritoneum, and therefore, maintain a prolonged osmo~ic gradient between dialysate and blood, U.S. Patent No. 4,906,616 to Gilchrist et al and European Patent No. 0218900 to Klein set forth polypeptides as the osmotic agent in a peritoneal dialysis solution. Each of these patents discusses the substitution of polypeptides for dextrose; polypeptides are the only osmotic agent utilized in the formulations disclosed.
. WO94il4~8 PCT~S93/12075 212~3g~31 In Gilchrist et al, the bulk of the polypeptides have a molecular weight of 1100 or greater. Indeed, approximately 50% of the peptides have in exce~s of 18 amino acid residue~. The polypeptides are the only 5osmotic agent used (s~e, e.g., col. 4, lines 33-35).
In Klein, the polypeptides are a mixture of relatively low molecular weight, including an alleged substantial portion between 300 to 2,000 daltons, peptides derived from the enzymatic hydrolysis of a high 10quality protein. The polypeptides are t~e only osmotic agents used. Further, as long as the mixture of polypeptide falls within an equivalent weight of 150 to 1,500 an~ the molecular weight of the polypeptides is between 300 to 2,000 daltons, the polypeptide mixture is 15sufficient for the needs of Kle~.
As ~et forth in detail in the examples hereinafter in this application, the polypeptide ~olutions proposed by Klein and Gilchrist et_al have very limited clinical utility. Although larger in size, like amino acids, 20these polypep~ide compositions are absorb2d from the peritoneum quite rapidly. This leads to uremic ~ymptoms.
In addition, these materials contain polypeptides that have the potential of producing allergic reactions. This is due to the size of the polypeptides that are used.
25There is therefore a need for an improved peritoneal dialysis solution~
SUMMARY OF THE INVENTIO~
The present inventio~ provides an improv~d dialysis solution. The improved dialysis solution provides for 30the use of specific polypeptides as an osmotic ~gent with an additional osmotic agent such as dextrose.
To this end, the present invention provides, in an embodiment, a peritoneal dialysis solution comprising as wos4/1~8 PCT~S93/12075~
2 ~
osmotic agents approximately 0.25 to about 4.0% (w/v) polypeptides and approximately 0.5% to about 4.0% (w/v) dextrose.
In an ~mbodiment, the peritoneal dialysis solution includes: approximately 120.00 to about 150.00 (mEq/L~
of sodium; approximately 80.0 to about llO.00 (mEqJL) of chloride; 0 to about 45.00 (mEqJL) of lactate; 0 to about 45.00 (m~q/L) of bicarbonate, 0 to about 4.00 (~Eq/L) of calcium; and 0 to about 4O00 (mEqJL) of magnesium.
Preferably, the pH of the solution is approximately 6.0 to about 7.4. ::
In an embodiment, the polypeptides are synthetic -~
peptides.
In an embodiment, the present invention provides a peritoneal dialysis solution comprising a polypeptide ~ixture as an osmotically active agent in an csmotically effective amount. The polypeptide mixture consists of not more than approximately 0.~0% of polypeptides having a molecular weight of greater than 1200, not more than approximately 25% of polypeptides having a molecular weight of les~ than 400, and the weight ave~age of the polypeptide mixture being within the range of approximately 400 to about 900 daltons.
In an embodiment, the periton2al dialysis solution provides: less than approximately 5 ppm of total heavy metals; and less than approximately 500 ppb aluminum.
Additionally, the peptides should have: less than approximately 50 mg/gm sodium; less than approximately 10 mg/gm chloride; less than approximately 0.2 mg/gm potassium; less than approximately l mg/gm magnesium;
less than approximately l mg/gm calcium; less than approximately l mg/gm phosphorus; and less than approximately 5 mg/gm lactose.
. W094/14~8 212 9 9 .9 I PCT~S93/12075 In an embodiment, a two part peritoneal dialysis solution designed to be mixed prior to infusion into a patient is provided. The two part solution comprises:
a first part housed in a first ~tructure including approximately l.0% to about 8% (w/v~ dextrose and a pH
of approximately 4.0 to ~bout 5.5; a second part housed in a second structure including approximately 0.5 to about 8.~ (w/v) polypeptides and a pH of approximately 6.0 to about 7.5; and including in either the first or 10the second structure: 0 to about 300 (mEq/L) ~odium; 0.0 to about 250.00 (mEq~L) chloride; 0.0 to about lO0.0 (mEq/L) lactate; 0.0 to about lO0.0 (mEq/L) bic~rbonate;
O.O to about lO.0 (mEq/L) calcium; and 0.0 to about lO.0 (mEq/L) magnesium.
15The present in~ention also provides for the use of polypeptides that have an amino acid composition that provides a nutritionally effe~tive solution.
In an embodimentl the present invention also provides a solution for delivering drugs to the 2~ peritoneum~
An advantage of the present invention -is that it provides an improved periton~al dialysis solutiun.
Stil~ further, an advantage of the present invention is that it provides an improved osmotic agent for use in a peritoneal dialysis solution.
A further advantage of the present invention is that it provides for the use of synthetic polypeptides for making an improved peritoneal dialy~is solution.
Furthermore, an advantage of the present inventi~n is that it provides for the ability to create peritoneal dialysis solutions ~hat are at a physiological pH to help reduce the pain of infusion.
WOs4/14K8 PCT~S93/12075 !
2~ 9 ~
Moreover, an advantage of the present invention is that it has reducad osmolalities along with physiologic pH to restore pha~ocytic function of macrophages.
Additionally, an advantage of the present invention is that it allows the use of dextrose in the solution and sterilization of same at a pH 4.0 to 5.5 to reduce the degradation products of dextrose.
Still further, an advantage of the present invention is that it provides higher weight average ~ol~cular weight of osmotic agents to improve ultrafiltration profile.
Another advantage of the present invention is that it provides balanced sup~lementation of polypeptides (protei~ source~ and dextrose (energy source) through a dialysis solution to improve the nutritional status of the renal patient.
Noreover, an advantage of the present invention is that it provides for the a~ility to increase infusion volumes and herlce small ~olute clearances as a result of decrease in molar concentrations of 05motic: agents.
Further, an advantage of th2 present ~nvention is that it provides a solution for intraperitoneal drug delivery .
Additional features and advantages of the present invention are described in, and will be apparent from, the detailed description of the presently preferred embodiments and from the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1-3 illustrate, graphically, molerular weight distributions for the peptide mixtures tested in Example No. l.
Figure 4 illustrates, graphically, volume profiles for Example No. 1.
WO94/1~8 212 9 9 9 I PCT~S93/1207~
Figure 5 illustrates, graphically, absorption of dextrose and peptides for Example No. l.
DETAILED DESCRIPTION
OF THE PRESENTLY PREFERR~D ~MBOPIMENT~
5The present inv~ntion provides improved peritoneal dialysis solutions containing polypeptides having well defined characteristics (e.g., molecular weight, distribution, amino acid composition, purity, etc.) ~or use in peritoneal dialysis solutions and intraperitoneal lOdrug delivery. The polypeptides are pre~erably used with another osmotic agent such as dextrose, polyglucose, amino acids, and ~lycerol.
As set forth in detail below, by selecting well defined polypeptides and utilizing same with an 15additional osmotic agent, the disadvantages of polypeptides alone and dextrose alone can be overcome.
To this end, prefer~bly, approximately 0.25% to a~out 4%
(w/v) polypeptides and approximately 0.5% to about 4%
(w/v) dextrose are used as the osmotic agent pursuant to 20the present invention.
In an embodiment, the polypeptides are obtained from enzymatic or acid hydroly~is of high biological value proteins. These proteins can be derived from milk, egg, potato, or soy. The polypeptides are prepared using 25enzymatic or chemical hydrolysis, dialysis, ultrafiltration, ion exchange, solvent fractionation, chromatography, or other related separation techniques.
For example5 whey can be ~ydroly2ed with a pro~eolytic enzyme, such as trypsin. The desired 30molecular weight fraction of the pre~ent invention, set forth below, is then separated using ultrafiltration and dialysis. By using ion exchange absorption, ions and heavy metals can be removed. A variety of methods can Wo94/14K8 PCT~S93/12075 2~,99~ 10-be used, as known in the art, for preparing such polypeptides.
The polypeptides can, in an embodiment, be synthetic polypeptides. The use of synthetic polypeptides allows one to provide peptides that have better defined characteristics and contain less impurities as compared with polypeptides that are obtained by hydrolysis proteins.
In order to determine the solutions of the present invention, the Klein solutions were tested.
Specifically, immunogenicity and ultrafiltration and absorption were evaluated. Accordingly, the following experiments were perfor~ed.
EXAMP~ N0. 1 ~he purpose of this study wa~ to evaluate peptides/
as disclosed in Klein, diff ering in weight average and number average molecular weights, as alternative osmotic agents t~ dextrose in dialysate solutions. These experiments were conducted in a nephric unanesthetized rat model.
The following peptide powders were received from E.
Klein (University of LouisYille)O
Run #123 & 132 Mw=695, Mn=640 Run ~138 Mw--2985, Mn=885 Run #140 Mw=6647, Mn=1020 Due to the presence of high levels of endo~oxin (>500 EU/ml) in each of the above preparations, a "clean up" procedure was performed as follows: 7% solutions of each peptide preparation was centrifuged to remove black particulate. Each solution was then passed through a 0.2 filter directly into a pre-washed Fresenius F-~0 dialyzer to remove endotoxin. The dialyzer was rinsed with sterile water following a single pass of peptide . W094/14~8 21~ 9 9 9 ~ PCT~S93/12075 solution. The peptide solutions were transferred into depyrogenated pans and lyophilized. All three peptide preparations were reanalyzed for endotoxin. Results indicated levPls below the pyrogenic response level of 0.5 EU/ml.
After removal of endotoxin from the peptides, molecular weight and mean profile changed due to a loss of high molecular weight peptides after passing through the F-60 dialyzer. The final results are shown below:
Run #123 & 132 ~w=1128, Mn=734 Run #138 ~w=2004, MnzlO08 Run #140 Mw=2388, Mn-1016 Molecular distributions for each pe~tide mixture are shown in ~igures 1-3.
Peptide powders were formulated to match the electrolyte composition of Dianeal PD-2 as summarized in Table 1.
Table 1 Compo~itio~ of Perito~e~l Dialy~i~ 801utio~s 2.5% DQxtros~ Ru~
Co~po~t Di~al~ ~32 138 ~40 ~ . -- - --e --_ _ _ Peptide (g~dl) ___ 3.5 5.5 4.3 _ . _ . _ _ Dextrose (g/L) 25 ___ ___ __ _ _ , _ Sodium bound (mEq/L) ___ 25 31 31 . _ . .. _ _, Sodium (mEqJL) 132 148 153 15S
~ _ I
Chloride (mEq/L) 96 86 85 84 _ _ I
Lactate (mEq/L) 40 40 40 40 Calcium (mg/dl) 3.5 3.S 3.5 3.5 Magnesium (mEq/L) O.5 0.5 O~5 0.5 W094/1~8 PCT~S93/12075 c~
¦~loctrolyt~ total 272 278 2B2 283 I _ _ _ I
Osmolality (mOsm/kg) ~ 383 338 355 335 _ __ _._ _ _ ~ _ pH 5.1 7.7 7.3 7.3 _ - . ._ ~ = _ _ Rats were anesthetized by Metafane inhalation. The abdominal area of the rats was shaved. Dialysate solution (90 ml/kg) was injected intraperitoneally using a 23G needle. The dialysis solution contain~id approximately l ~ Ci 94C Dextran as a dilution marker.
Rats were allowed to rPcover and penmitted free access to water.
Dialysate samples (0.2 ml) were collected at 0.5, l, 2, and 4 hours during the dwell period.
~t the end of a 4 hour dwell period, a 1 ml blood sample was collected via the tail art~iry, plasma separated and frozen. Rats were euthanized by tail vein injection of solution.
The abdominal cavity was opened by midline incision, dialysate collected~ and vol~me recorded.
The experimental procedure was performed as described below.
Rats, n=6 peir group were randomly dosed with one of the following dialysate solutions: 1.5% Dextrose DIANEAL, 2.5% Dextrose DIANEAL~, Peptide run 132, Pep~ide run 138, or Peptide run 140~
Analyses: ~4C Dextran, all dialysate samples.
Osmolality in all dialysate samples and in all t=4 hr plasma samples.
Amino acids in all dialysate samples containing peptide runs Pre and 4 hr.
O.5, 1, and 2 hr samples run for some rats in Peptide groups.
Glucose, all Pre and 4 hr dialysate samples in DIANEAL group~.
Volume profiles for the experim~nt are s~own in Figure 4. Volumes between t=0 and the end of the dwell are based on 14C Dextran concentra~ions assuming a constant rate for disappearance of l~C Dextran.
Dialysate ~ampl~s were analyzed for ami.no acids following acid hydrolysis to generate free amino acids.
These analyses were used to calculate the percent of pep~ides absorbed during an exchange as co~1pared to dextrose. The results are sho~n in Figur~ 5.
The experiments demonstrate that a dialy5is solution containin~ peptides can produce ultrafiltration pro~iles similar to that seen with dextrose but with a lower initial osmolality.
Additionally, the experiments demonstra~e that peritoneal absorption of peptides at 4 hours is approximately 50-60%.
EXAMPLE NO. 2 An irritation screening was conducted using 2.5%
Dextrose (w~v~ in Dianeal, l.0~ Whey Protein Hydrolysate (in accordance with ~lein) (w/v) in l.5% Dextrose ~w/v) in Dianeal~, aIld 3 . 0% Whey Prstein Hydrolysate ( in accordance with l~a) (w/v) in 1. 5% Dextrose (wjv) in Dianeal~. Two sites were selected and shaved on two animals for each material . Each animal re ::eived two o. lOS-mL intradermal injections of the respective 3 0 undiluted material .
A positive control irritation screening was also conducted in the same manner with a 1% w~v concentration of sulfathiazole in sterile o . 9% saline. All sites were ~'094/14~8 PCT~S93/1207r 21 ~9 l scored for eirythema and edema at 24 and 48 hours after injection. Since all three test materials were ~hown to be nonirritating, they were administered undiluted on Day 8 and Day 22 (challenge phase) of the definitive study.
5The positive control animals received a 5% w/v suspension of sulfathiazole in sterile water for the Day 8 intradermal injections and as a 1% w/v suspension in sterile 0.9% ~aline for the Day 22 challenge procedure~
The study was conducted using 10 test animals and 10four naive control animals per test or positive control material. On Day 1, animals in each t~ist group received duplic~te 0.05-mL intradermal injections of a 1:1 ratio of Freund's Complete Adju~ant in sterile watar/ the respective test m~terial, and a 1:1 ratio of the 15respective test material in Freund's Complete Adjuvant.
~or the positive control group, ~h~ animals received duplicate 0. OS-mL intradermal injections of a 1:1 ratio of Freund's Compl~ite Adjuvant in sterile water, a 5% w/v suspension of sulfathiazole in ~terile wat~ir, and a 5%
20w/v suspension of ~;ulfathiazole in ~reund' s Complete Ad j u~ant ~ ~
On day 7 f animals in ~11 three test groups and the positive control group were pretr ated with 10% w/w sodium lauryl sulfate in petrolatum applied kopically at 2~the sha~ed area of the Day 1 intradermal injections. On Day ~, the respective test or positive control material was injected intradermally at a ~olume of 0.05 m~ into two separate areas located just posterior to ~he initial intradermal injections.
30All the test materials were administered undiluted and the positive con~rol was administered as a 5% w/v suspension of sulfathiazole in sterile water. All naive W094/14~8 ~1 2 9 9 9 ~ PCT~S93/12075 control animals were not treated during the induction phase.
Two weeks following the Day 8 intradermal injections, all animals in the respective test and naive control groups received a challenge intradermal injection. The respective undiluted test material was injected intradermally at a volume of 0.05-m~ into one site on the shaved right flank of each respe~tive animal.
The positive control anîmals were treated with a 1% w/v suspension of sulfathiazole in sterile 0.9% saline. The sites were examined for erythema and edema at 24, 48, and 72 hours following injection.
No dermal reactions at challenge were observed in the animals treated with 2.5% Dextrose ~w/v~ in Dianeal.
Dermal sensitization responses were observed in the test animals treated with 1.0~ and 2.0% Whey Protein Hydrolysate (wJv) in 1.5~ Dextrose ~w/v) in Dianeal and in the animals treated with the positive control material. ~here were no dermal reactions observed in the respective naive control animals.
Based upon the results obtairled, the materials are classified as present~d below:
Test Material Identification 2.5% Dextrose (w/v) in Dianeal~Not a sensitizer 1.0% Whey Protein HydrolysateSensitizer (w/v) in 1. 5~ Dextrose (w/v) in Dianeal 3.0% Whey Protein HydrolysateSensitizer (w~v~ in 1.5% Dextrose tw/v) in Dianeal~
Sulfathiazole (positive cont~ol)Sensitizer 9 ~t~ ~
MAT:E:RIALS (Example No . 2 ) Identif ication The materials were identified and described as fo~lows:
Material Test Ma~erial Lot Physlcal P~sianatiQn Identific~tion Numbe~ Abbr~v~tlon Des~i~tiQn Test 2.5% Dextrose C132365 2.5,6 D~x~ro~e C:lear, cdor- -(w/v~ in Dianeala less liquW
Test 1.0% Whey Protein P900510 1.0% WPH P a I e -yel I ow Hydrolysate ~w/v) In l~C1 in 1.59~ Dex~rose C127æ5 (w,/v) in Dbneal~
Test 3.0% Whey P,~otein P900~1û 3.0~ WPH Pale-yellow Hydrolysate (w/v, In liquid In 1.~% D~xtrose C127225 (wtv) in Dianeal~ .
P o s i t i v e Sulfathiazole 8~F440~ ~ Wh~e powder C:ontrd Storaae and Pcetention The test materials were stored refrigerated. The positive control material was stored at room temperature.
Test ~ni~al -Young adult albino ~uinea pigs/ Hra:(DH)SPF, wereprocured, maintained individually in screen-bottom stainless steel cages in temperature- and humidity~
controlled rooms, provided continuous access to Certified Guinea Pig Chow0 5Q26, Purina Mills, Inc., and water and held for an acclimation period of at least 7 days. If ~ariations from the prescribed environmental conditions existed, they were documented and considered to have no effect on the study outcome. No contaminants were expected to have been present in the feed or water which would have interfered with or affected the results of the study.
WO94/1~K8 ~1 2 9 9 9 1 PCT/US93/12075 GrouP Assianments Sixty-four healthy, acclimated male albino guinea pigs weighing from 354 to 562 g were chosen at random for this study. The animals were individually housed and S identified by animal number and corresponding ear tag.
The animals were divided into the following groups:
Number of GrouD Anirr~ls Test Mater~l Identi~tion 1. Irritation Screening 2 2.5% Dextrose (w/v~ in Dianeal~s 2. irrltationScreening 2 1.0%WheyProteinHydlrolysate(w/v) In 1.5% Dexlrose (w/v3 in Dbneal~
3. Irritation Scresnln~ 2 3.00~ Whey Protein Hydrdysate (w/v) in 1.596 Dextrose (w/v~ in Dianeal0 4. Irr~tatlon Screenin~ 2 Sulfathlazole (Positive Contrd) 5. Test 10 2.5% D~xtross ~w/v~ In D
6. NaiveControl 4 2.5% Dextrose (w/v) inDiar~al~
7. Test 10 1.0~ Whey P~oteln Hydrolysate (w/v) in 1.5% Dextrose (w/v) in D~nea10 8. NaNe Control 4 1.0,6 Whey Protein Hydrolysate (w/v) 2 0 in 1.~% Dextrose (w/v~ in Dianeal0 . Test 10 3.0%WheyProtein~ydrolysate(w/v) in 1.5% Dextrose (w/v~ in Dianeal~
10. NaiveC;ontrol 4 3.0%WheyProteinHydrdysate(w/v) in 1.59~ Dex~rose ~w/v~ Dian 2S 11. Positive Control 10 Sulfathsazole 12. Nah/e Control 4 Suifath~ole PROCEDURES (Example No. 2) Test Material Pre~aration The test materials, 1.0% WPH and 3.0% WPH, were supplied in sterile glass bottles and were reconstituted with lOO-mL of Dianeal PD-l with 1.5% Dextrose. Mixing and ali~uoting was performed under a hood with static air conditions using aseptic techniques. Using a transfer W094/14~8 PCT~S93/1207' 2~9l~91 set, the Dianeal bag port was spiked, the septum was swabbed with alcohol, and a needle was inæerted into th~i test material vial. The transfer set clamp was opened to allow solution to flow into the vial. The needle was then withdrawn from the vial and the vial was swirled to dissolve the powder into the solution. This procedure constitutes an "undiluted" test material. ~he 2.5%
Dextrose solution was administered as received.
Irritation Screeninq The purpose of the irritation screening wais to show that each undiluted test material wais nonirritating and could be used for the induction and challenge treatments.
Two sites were selected and shaved on each of two ani~als per material. Each animal received two 0.05-mL
intradermal injections of the respective undiluted material. A positive control irritation ~creening was also conducted in the same manner with a 1% w/v concentration of sulfathiazole in sterile 0.9% saline.
All sites were scored for erythema and edema at 24 and 48 hours after injection.
Based upon the results obtained ~rom th~ irxitation screening, materials 2.5% Dextrose, l.0~ WPH, and 3.0%
WPH were administered undiluked for the Day 8 intradermal injections and thei Day 22 challenge procedure. The positive control animals received a 5% w/v suspension of sulfathiazole in sterile water for t~e Day 8 intradermal injections and a 1% w/v suspension in sterile 0.9% saline for the Day 22 challenge proceidure.
Definitive Study - Induction Phase Intradermal In~ections (~ay l) A 4-cm x 6-cm area was clipped along the midline over the shoulder region of each animal in the test and positive control groups. Six intradermal injections were ~0 94ll4468 PC~IUS93/12075 2~ ~.999I
made within the boundaries of a 2-cm x 4-cm area, one row of three injections on each side of the midline as follows:
S ites A and B :~
Groups 5, 7, 9, and 11 - 0. 05 mL of the 1:1 ratio of Freund's Complete Adjuvant in sterile water S ites C and D
Groups 5, 7, and 9 - O . 05 mL of the respective undiluted test material Group 11 - 0~,05 mL OI the 5% w/v suspension of sulfathiaæole in ~terile w~ter Sites E and F
Groups 5, 7, and 9 - 0.05 mL of the re~pective test material as a 1: 1 dilution in Freund ' C~mplete Adjuv~nt Group 11 - 0. 05 mL of the 5% w~v suspension of sulfathiazole in a 1:1 Freund's Complete Adjuvant/water solution d :' Sodium Laurvl Sulfate (~
One week after the initial intradermal lnj ections ~
all injection ~reas c3f the test ~roup animals and po~itive e~ontrol animals were ::losely shaved and a 10% w~v mixture of SLS in petrolatum was massaged into the skin with a glass rod.
Intradermal Ini ections LDa~8 ) The respective t~st or positive control ( ~% w/v suspension of ulfathiazole in sterile water) material was injected intradermally at a volume of 0.05 mL into two separate ~reas located just posterior to the initial intradermal injections.
The naive control animals were not treated during the induction phase of the study.
W094/14K8 PCT~S9311207~ ~
2~2~91 Challenqe Phase Two weeks after the Day 8 intradermal injections all test and nai~e control (prevlously untreated) groups received a challenge injection. All test and naive control groups were treated with the respective undiluted material. The positive cont,ol and naive positive control animals received treatment with a 1% w/v suspension and sulfathiazole in sterile 0.9% saline. The hair was removed from a 5.0-cm x 5.0 cm area on the right flank by shaving as before. The respective te~t or positive contxol material was injected intradermally at a volume of 0 .05 mL into one site of the right flank of each respecti~re animal. Approximately 21 hours later, the test ~ites were closely shaved.
ObservatiQns Twenty-four hours following challenge injection the test sites were examined for erythema and edema. The sites were examined again at 48 and 72 hours after injection to detect any weak, slowly deveIoping reactions~ Redness constituted a minimum criterion of all~rgic reaction. Strongly sensitized animals displayed a vivid redness, a~sociated with indurated swelling. The reactions were scored according to the following ~cale:
0 = No reaction l = Scattered mild redness 2 = Moderate and diffuse redness 3 = Intense redness and swelling The animals were observed for clinical signs daily throughout the study. Individual bGdy weights were recorded just prior to initiation of treatment, at weekly intervals throughout the study, and at termination of the experimental phase.
--WO94/1~8 PCT/US93112075 212~9~ ' Blood Collection At experimental termination, all animals from Groups S, 7, and 9 were anesthetized with carbon dioxide.
Approximately 4-5 mL of whole blood was collected via cardiac puncture.
DISCUSSION (Example No. 2) General Behavior and A~pearance All animals in all groups appeared norm~l through out the study. There was no significant effect: on body weight gain tsignificant = greater than lO% loss from previously body weight) in any animal throughout the ~tudy with the exception of one Group 9 test animal (~17259) treated with 3.0% WPH that exhibited a 52-g loss during the first week on test, another Group 9 animal (El7229) that had a 62-~ loss during the second week of the study and one Group ll positive control animal (E17221) with a 76-g loss during the third week of the study.
CONCLUSION (Example No. ~) Based on the results obtained, the materials tested are considered to be classified as follows:`
# of Posit~
Reactions/~
.~ Materlal in rou~ Cla,ssiflcatlon 2.5% Dextrose (w/v) in Dianeal~ OtlO Not a sensitizer 7 1.0% Whey Protein Hydrolysate (w/v) 10/10 Sensisker in t.5% Dextrose (w/v) in Dianeal~
10. NaiveC;ontrol 4 3.0%WheyProteinHydrdysate(w/v) in 1.59~ Dex~rose ~w/v~ Dian 2S 11. Positive Control 10 Sulfathsazole 12. Nah/e Control 4 Suifath~ole PROCEDURES (Example No. 2) Test Material Pre~aration The test materials, 1.0% WPH and 3.0% WPH, were supplied in sterile glass bottles and were reconstituted with lOO-mL of Dianeal PD-l with 1.5% Dextrose. Mixing and ali~uoting was performed under a hood with static air conditions using aseptic techniques. Using a transfer W094/14~8 PCT~S93/1207' 2~9l~91 set, the Dianeal bag port was spiked, the septum was swabbed with alcohol, and a needle was inæerted into th~i test material vial. The transfer set clamp was opened to allow solution to flow into the vial. The needle was then withdrawn from the vial and the vial was swirled to dissolve the powder into the solution. This procedure constitutes an "undiluted" test material. ~he 2.5%
Dextrose solution was administered as received.
Irritation Screeninq The purpose of the irritation screening wais to show that each undiluted test material wais nonirritating and could be used for the induction and challenge treatments.
Two sites were selected and shaved on each of two ani~als per material. Each animal received two 0.05-mL
intradermal injections of the respective undiluted material. A positive control irritation ~creening was also conducted in the same manner with a 1% w/v concentration of sulfathiazole in sterile 0.9% saline.
All sites were scored for erythema and edema at 24 and 48 hours after injection.
Based upon the results obtained ~rom th~ irxitation screening, materials 2.5% Dextrose, l.0~ WPH, and 3.0%
WPH were administered undiluked for the Day 8 intradermal injections and thei Day 22 challenge procedure. The positive control animals received a 5% w/v suspension of sulfathiazole in sterile water for t~e Day 8 intradermal injections and a 1% w/v suspension in sterile 0.9% saline for the Day 22 challenge proceidure.
Definitive Study - Induction Phase Intradermal In~ections (~ay l) A 4-cm x 6-cm area was clipped along the midline over the shoulder region of each animal in the test and positive control groups. Six intradermal injections were ~0 94ll4468 PC~IUS93/12075 2~ ~.999I
made within the boundaries of a 2-cm x 4-cm area, one row of three injections on each side of the midline as follows:
S ites A and B :~
Groups 5, 7, 9, and 11 - 0. 05 mL of the 1:1 ratio of Freund's Complete Adjuvant in sterile water S ites C and D
Groups 5, 7, and 9 - O . 05 mL of the respective undiluted test material Group 11 - 0~,05 mL OI the 5% w/v suspension of sulfathiaæole in ~terile w~ter Sites E and F
Groups 5, 7, and 9 - 0.05 mL of the re~pective test material as a 1: 1 dilution in Freund ' C~mplete Adjuv~nt Group 11 - 0. 05 mL of the 5% w~v suspension of sulfathiazole in a 1:1 Freund's Complete Adjuvant/water solution d :' Sodium Laurvl Sulfate (~
One week after the initial intradermal lnj ections ~
all injection ~reas c3f the test ~roup animals and po~itive e~ontrol animals were ::losely shaved and a 10% w~v mixture of SLS in petrolatum was massaged into the skin with a glass rod.
Intradermal Ini ections LDa~8 ) The respective t~st or positive control ( ~% w/v suspension of ulfathiazole in sterile water) material was injected intradermally at a volume of 0.05 mL into two separate ~reas located just posterior to the initial intradermal injections.
The naive control animals were not treated during the induction phase of the study.
W094/14K8 PCT~S9311207~ ~
2~2~91 Challenqe Phase Two weeks after the Day 8 intradermal injections all test and nai~e control (prevlously untreated) groups received a challenge injection. All test and naive control groups were treated with the respective undiluted material. The positive cont,ol and naive positive control animals received treatment with a 1% w/v suspension and sulfathiazole in sterile 0.9% saline. The hair was removed from a 5.0-cm x 5.0 cm area on the right flank by shaving as before. The respective te~t or positive contxol material was injected intradermally at a volume of 0 .05 mL into one site of the right flank of each respecti~re animal. Approximately 21 hours later, the test ~ites were closely shaved.
ObservatiQns Twenty-four hours following challenge injection the test sites were examined for erythema and edema. The sites were examined again at 48 and 72 hours after injection to detect any weak, slowly deveIoping reactions~ Redness constituted a minimum criterion of all~rgic reaction. Strongly sensitized animals displayed a vivid redness, a~sociated with indurated swelling. The reactions were scored according to the following ~cale:
0 = No reaction l = Scattered mild redness 2 = Moderate and diffuse redness 3 = Intense redness and swelling The animals were observed for clinical signs daily throughout the study. Individual bGdy weights were recorded just prior to initiation of treatment, at weekly intervals throughout the study, and at termination of the experimental phase.
--WO94/1~8 PCT/US93112075 212~9~ ' Blood Collection At experimental termination, all animals from Groups S, 7, and 9 were anesthetized with carbon dioxide.
Approximately 4-5 mL of whole blood was collected via cardiac puncture.
DISCUSSION (Example No. 2) General Behavior and A~pearance All animals in all groups appeared norm~l through out the study. There was no significant effect: on body weight gain tsignificant = greater than lO% loss from previously body weight) in any animal throughout the ~tudy with the exception of one Group 9 test animal (~17259) treated with 3.0% WPH that exhibited a 52-g loss during the first week on test, another Group 9 animal (El7229) that had a 62-~ loss during the second week of the study and one Group ll positive control animal (E17221) with a 76-g loss during the third week of the study.
CONCLUSION (Example No. ~) Based on the results obtained, the materials tested are considered to be classified as follows:`
# of Posit~
Reactions/~
.~ Materlal in rou~ Cla,ssiflcatlon 2.5% Dextrose (w/v) in Dianeal~ OtlO Not a sensitizer 7 1.0% Whey Protein Hydrolysate (w/v) 10/10 Sensisker in t.5% Dextrose (w/v) in Dianeal~
9 3.0%WheyProtainHydrolysate(w/v) 10/10 Sensitizer in 1.5% DexSrose (w/v) in Dianeal~
11 Posit~ve Control (Sulfathiazde) 9/10 Sensitker The abo~e examples ~Example Nos. l and 2) demonstrated that the use of only a polypeptide mixture such as that set forth in Klein and/or Gilchrist et al wos~ 8 ~ 9 ~ PCT~S93/12n7~
is not clinically acceptable in a peritoneal dialysis solution.
In order for the polypeptide composition of Klein to obtain the absorption equivalent to a 2.5% dextrose solution, one needs at least a 5.5% polypeptide solution.
However, Example No. 1 demonstrates that the a~sorption of the polypeptide is at least 50% to 60%. If polypeptides, at an at least S% concentration in a dialysis solution are used at every exchange, the patient would receive at least 200 grams of amino acids per day~
It has been found that peritoneal absorptio~ of more than 40 grams of amino acids per 24 hours causes uremia in dialysis patients.
Accordingly, due to the absorption characteristics of the polypepti~es, it has been determined that preferably only a 1 to 2% concentration of a polypeptide solution, such as lein, should be used. Ho~ever, at such a concentration, the polypeptides do not provide a sufficient osmotic agent. It has also been found that in order to control uremia problems, it is necessary to control the proportion of lower molecular weight peptides.
Example No. 2 demonstrates that the polypeptides of Rlein have the potential for immunogenicity. The problem stems from the fact th~t too great a proportion of peptides in Kleîn have a molecular weight above 1200.
Accordingly, pursuant to the present invention, the polypeptides are used in a concentration of 0.25 to 4 with an osmotic agent, suc~ as dextrose which is used in a concentration of 0.5 to 4. The polypeptides have an avérage molecular weight of 400 to 900 daltons. It has been found that not more than 0.10% of the polypeptides should have a molecular weight of greater than l,200.
--Wo94/1~K8 21~ Y Y 91 PCT~S93t1207~
This minimizes the risk of immunogenic response~
Additionally, not more than 25~ of the polypeptides should have a molecular w~ight of less than 400. This prevents the uremic problems that will occur with the solution proposed in Xlein.
It should be noted that the lower weight peptides ::
are readily absorbed. For a 1% polypeptide solution, if the solution contains mors than 25% polypeptides having a molecular weight less than 400, greater than 40 gms amino acid will be absorbed by the patient causing uremia. Accordingly, the polypeptides, pursuant to the present invention, are limited to less than or equal to 25% having a molecular weight less than 400.
Polypeptides can be used alone or in c~mblnation with amino acids as nutritional supplements in a dialy~i~
solutio~ to correct protein malnutrition. ~-Preferably, in an embodiment, the polypeptides used in the present invention include the following amino acid profile.
~mino Acid Composition ASX ~0.3 GLX 20.3 SER 4 . 5 GLY 2.3 HIS 2.4 A~G 2 . 3 THR 5 . 7 AI~ 6 . 4 PR0 5 . 8 3 0 TYR 3 . 7 VAL 4 . 6 MET 2.3 ILE 4.7 W094/14~8 PCT~S93/1207' .
21~g~9~
LEU ~1.7 PHE 3.4 To this mixture 50 to 150 mg valine and 15 to 30 mg tryptophan are added per gm of peptides. This composition provides improved nutritional benefits to the patient.
To provide a balanced nutritional solution, preferably, the ratio of polypeptides to dextrose, in the solution is 0.3 to 2 by weight.
By way of example, and not limitation, the dialysis 801ution should co~lprise, in addition to the polypaptides and dextros~:
Total heavy metals ~ 5 pp~
Aluminum < 500 ppb With respect to peptides used, they should comprise:
Sodium < S0 mg/~m Chloride ~ lO mg/gm Potassium c 0.2 mg/~m . M~gnesium ~ 1 mg~gm Calcium < 1 mg/gm Phosphorus ~ 1 mg/gm Lactose ~ 5 mg/gm The polypeptides dialysis solution can be formulated in a single bag or in two separate containers. In an embodiment, the polypeptides can be formulated in a single bag with glycerol as an additional osmotic agent.
In an embodiment, the present invention provides a peritoneal dialysis solution that is housed in two separate units and then mixed prior to use. These units can be two~separate containers or they can ~e two chambers of a single bag.
W094114K8 212 9 9 91 PCT~S93/1207~
By way of example, and not limitation, the composition contained in separate chambers can be as -~
follo~s:
Chamber 1 5h~b~_2 :~
D~xtrose (% w/v) l.0-8.0 Polypeptides (% w/v) 0.0 0.5-8.0 Sodium ~mEq/L) 0-300 0-300 Chloride (mEq/L) 0-250 0~250 Lactate (mEq/L) 0-lO0 0-lO0 Bicarbonate (mEq/L) 0-lO0 0-lO0 Calcium (mEq/L) 0-lO 0-lO
Magnesium (mEq/L) 0-5.0 0-5.0 pH 4.0-5.~ 6.0-7.5 Preferably, only dextrose is contained in chamber 1. In an embodiment, lactate is contained in chamber 1 :~
along with dextrose. ~`
The contents of the two chambers are mixed prior to ~.
infusion into the peritoneal cavity of the patient~ The combined solution has the following composition: ~ :
Dextrose ~%w~v~ 0.5-4.Q ~:~
Polypeptides (~ w/v) 0.~5-4~0 :~
Sodium (mEq/L) 120.0-150.0 Chloride ~mE~/L~ 80.0-llO.0 Lactate (mEq/L) 0.0-45.0 -`
Bicarbonate (mEq/L) 0.0-45.0 Calcium (mEgJL) 0.0~4.0 Magnesium (mEqjL) 0.0 4.0 pH 6.0-7.4 ~s previously noted, pursuant to ~he present invention, synthetic peptides can also be utilized.
Synthetic peptides provide better defined characteristics ~
and contain less impurities compared to peptides obtained ~-by hydrolysis of proteins. The synthetic peptides should WO94/1 ~ 2999 ~ PCT/US93/12075 be approximately 2 to about 15 amino acids long.
Preferably, the synthetic peptides comprise ~ to about lO amino acids in length.
Pursuant to the present invention, the solution can be used for intraperitoneal drug delivery. Due to the size of peptides, one is able to keep the fluid in the peritoneum and thus a~oid the problems of too rapid absorption expe~ienced with saline and d~extrose solutions.
It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to thos~ ~killed in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and w~thout diminishing its attendant advantages. It is therefore intended that such changes and modi~ications be covered by the appended claim~.
11 Posit~ve Control (Sulfathiazde) 9/10 Sensitker The abo~e examples ~Example Nos. l and 2) demonstrated that the use of only a polypeptide mixture such as that set forth in Klein and/or Gilchrist et al wos~ 8 ~ 9 ~ PCT~S93/12n7~
is not clinically acceptable in a peritoneal dialysis solution.
In order for the polypeptide composition of Klein to obtain the absorption equivalent to a 2.5% dextrose solution, one needs at least a 5.5% polypeptide solution.
However, Example No. 1 demonstrates that the a~sorption of the polypeptide is at least 50% to 60%. If polypeptides, at an at least S% concentration in a dialysis solution are used at every exchange, the patient would receive at least 200 grams of amino acids per day~
It has been found that peritoneal absorptio~ of more than 40 grams of amino acids per 24 hours causes uremia in dialysis patients.
Accordingly, due to the absorption characteristics of the polypepti~es, it has been determined that preferably only a 1 to 2% concentration of a polypeptide solution, such as lein, should be used. Ho~ever, at such a concentration, the polypeptides do not provide a sufficient osmotic agent. It has also been found that in order to control uremia problems, it is necessary to control the proportion of lower molecular weight peptides.
Example No. 2 demonstrates that the polypeptides of Rlein have the potential for immunogenicity. The problem stems from the fact th~t too great a proportion of peptides in Kleîn have a molecular weight above 1200.
Accordingly, pursuant to the present invention, the polypeptides are used in a concentration of 0.25 to 4 with an osmotic agent, suc~ as dextrose which is used in a concentration of 0.5 to 4. The polypeptides have an avérage molecular weight of 400 to 900 daltons. It has been found that not more than 0.10% of the polypeptides should have a molecular weight of greater than l,200.
--Wo94/1~K8 21~ Y Y 91 PCT~S93t1207~
This minimizes the risk of immunogenic response~
Additionally, not more than 25~ of the polypeptides should have a molecular w~ight of less than 400. This prevents the uremic problems that will occur with the solution proposed in Xlein.
It should be noted that the lower weight peptides ::
are readily absorbed. For a 1% polypeptide solution, if the solution contains mors than 25% polypeptides having a molecular weight less than 400, greater than 40 gms amino acid will be absorbed by the patient causing uremia. Accordingly, the polypeptides, pursuant to the present invention, are limited to less than or equal to 25% having a molecular weight less than 400.
Polypeptides can be used alone or in c~mblnation with amino acids as nutritional supplements in a dialy~i~
solutio~ to correct protein malnutrition. ~-Preferably, in an embodiment, the polypeptides used in the present invention include the following amino acid profile.
~mino Acid Composition ASX ~0.3 GLX 20.3 SER 4 . 5 GLY 2.3 HIS 2.4 A~G 2 . 3 THR 5 . 7 AI~ 6 . 4 PR0 5 . 8 3 0 TYR 3 . 7 VAL 4 . 6 MET 2.3 ILE 4.7 W094/14~8 PCT~S93/1207' .
21~g~9~
LEU ~1.7 PHE 3.4 To this mixture 50 to 150 mg valine and 15 to 30 mg tryptophan are added per gm of peptides. This composition provides improved nutritional benefits to the patient.
To provide a balanced nutritional solution, preferably, the ratio of polypeptides to dextrose, in the solution is 0.3 to 2 by weight.
By way of example, and not limitation, the dialysis 801ution should co~lprise, in addition to the polypaptides and dextros~:
Total heavy metals ~ 5 pp~
Aluminum < 500 ppb With respect to peptides used, they should comprise:
Sodium < S0 mg/~m Chloride ~ lO mg/gm Potassium c 0.2 mg/~m . M~gnesium ~ 1 mg~gm Calcium < 1 mg/gm Phosphorus ~ 1 mg/gm Lactose ~ 5 mg/gm The polypeptides dialysis solution can be formulated in a single bag or in two separate containers. In an embodiment, the polypeptides can be formulated in a single bag with glycerol as an additional osmotic agent.
In an embodiment, the present invention provides a peritoneal dialysis solution that is housed in two separate units and then mixed prior to use. These units can be two~separate containers or they can ~e two chambers of a single bag.
W094114K8 212 9 9 91 PCT~S93/1207~
By way of example, and not limitation, the composition contained in separate chambers can be as -~
follo~s:
Chamber 1 5h~b~_2 :~
D~xtrose (% w/v) l.0-8.0 Polypeptides (% w/v) 0.0 0.5-8.0 Sodium ~mEq/L) 0-300 0-300 Chloride (mEq/L) 0-250 0~250 Lactate (mEq/L) 0-lO0 0-lO0 Bicarbonate (mEq/L) 0-lO0 0-lO0 Calcium (mEq/L) 0-lO 0-lO
Magnesium (mEq/L) 0-5.0 0-5.0 pH 4.0-5.~ 6.0-7.5 Preferably, only dextrose is contained in chamber 1. In an embodiment, lactate is contained in chamber 1 :~
along with dextrose. ~`
The contents of the two chambers are mixed prior to ~.
infusion into the peritoneal cavity of the patient~ The combined solution has the following composition: ~ :
Dextrose ~%w~v~ 0.5-4.Q ~:~
Polypeptides (~ w/v) 0.~5-4~0 :~
Sodium (mEq/L) 120.0-150.0 Chloride ~mE~/L~ 80.0-llO.0 Lactate (mEq/L) 0.0-45.0 -`
Bicarbonate (mEq/L) 0.0-45.0 Calcium (mEgJL) 0.0~4.0 Magnesium (mEqjL) 0.0 4.0 pH 6.0-7.4 ~s previously noted, pursuant to ~he present invention, synthetic peptides can also be utilized.
Synthetic peptides provide better defined characteristics ~
and contain less impurities compared to peptides obtained ~-by hydrolysis of proteins. The synthetic peptides should WO94/1 ~ 2999 ~ PCT/US93/12075 be approximately 2 to about 15 amino acids long.
Preferably, the synthetic peptides comprise ~ to about lO amino acids in length.
Pursuant to the present invention, the solution can be used for intraperitoneal drug delivery. Due to the size of peptides, one is able to keep the fluid in the peritoneum and thus a~oid the problems of too rapid absorption expe~ienced with saline and d~extrose solutions.
It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to thos~ ~killed in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and w~thout diminishing its attendant advantages. It is therefore intended that such changes and modi~ications be covered by the appended claim~.
Claims (46)
1. A peritoneal dialysis solution comprising as osmotic agents:
approximately 0.25 to about 4.0% (w/v) polypeptides;
and approximately 0.5% to about 4.0% (w/v) dextrose.
approximately 0.25 to about 4.0% (w/v) polypeptides;
and approximately 0.5% to about 4.0% (w/v) dextrose.
2. The peritoneal dialysis solution of Claim 1 wherein the solution includes:
approximately 120.00 to about 150.00 (mEq/L) of sodium; and approximately 80.0 to about 110.00 (mEq/L) of chloride.
approximately 120.00 to about 150.00 (mEq/L) of sodium; and approximately 80.0 to about 110.00 (mEq/L) of chloride.
3. The peritoneal dialysis solution of Claim 1 wherein the solution includes sodium, chloride, lactate, bicarbonate, calcium, and magnesium.
4. The peritoneal dialysis solution of Claim 2 wherein the solution includes:
0 to about 45.00 (mEq/L) of lactate;
0 to about 45.00 (mEq/L) of bicarbonate;
0 to about 4.00 (mEq/L) of calcium; and 0 to about 4.00 (mEq/L) of magnesium.
0 to about 45.00 (mEq/L) of lactate;
0 to about 45.00 (mEq/L) of bicarbonate;
0 to about 4.00 (mEq/L) of calcium; and 0 to about 4.00 (mEq/L) of magnesium.
5. The peritoneal dialysis solution of Claim 1 wherein the pH of the solution is approximately 6.0 to about 7.4.
6. The peritoneal dialysis solution of Claim 1 wherein the molecular weight average of the polypeptides is approximately 400 to about 900 daltons.
7. The peritoneal dialysis solution of Claim 1 wherein the polypeptides are synthetic peptides.
8. The peritoneal dialysis solution of Claim 7 wherein the synthetic peptides are approximately 2 to about 15 amino acids long.
9. The peritoneal dialysis solution of Claim 7 wherein the synthetic peptides are approximately 4 to about 10 amino acids long.
10. A peritoneal dialysis solution comprising a polypeptide mixture as an osmotically active agent in an osmotically effective amount, the polypeptide mixture consisting of:
not more than approximately 0.10% of polypeptides having a molecular weight of greater than 1200;
not more than approximately 25% of polypeptides having a molecular weight of less than 400; and the weight average of the polypeptide mixture being within the range of approximately 400 to about 900 daltons.
not more than approximately 0.10% of polypeptides having a molecular weight of greater than 1200;
not more than approximately 25% of polypeptides having a molecular weight of less than 400; and the weight average of the polypeptide mixture being within the range of approximately 400 to about 900 daltons.
11. The peritoneal dialysis solution of Claim 10 wherein the polypeptides include not less than 40% as essential amino acids.
12. The peritoneal dialysis solution of Claim 10 wherein the solution provides less than approximately 5 ppm of total heavy metals.
13. The peritoneal dialysis solution of Claim 10 wherein the solution provides less than approximately 500 ppb aluminum.
14. The peritoneal dialysis solution of Claim 10 wherein the polypeptides in the solution provide less than approximately 50 mg/gm sodium.
15. The peritoneal dialysis solution of Claim 10 wherein the polypeptides in the solution provide less than approximately 10 mg/gm chloride.
16. The peritoneal dialysis solution of Claim 10 wherein the polypeptides in the solution provide less than approximately 0.2 mg/gm potassium.
17. The peritoneal dialysis solution of Claim 10 wherein the polypeptides in the solution provide less than approximately 1 mg/gm magnesium.
18. The peritoneal dialysis solution of Claim 10 wherein the polypeptides in the solution provide less than approximately 1 mg/gm calcium.
19. The peritoneal dialysis solution of Claim 10 wherein the polypeptides in the solution provide less than approximately 1 mg/gm phosphorus.
20. The peritoneal dialysis solution of Claim 10 wherein the polypeptides in the solution provide less than approximately 5 mg/gm of lactose.
21. The peritoneal dialysis solution of Claim 10 including an additional osmotic agent.
22. The peritoneal dialysis solution of Claim 10 wherein the solution includes as an osmotic agent dextrose.
23. The peritoneal dialysis solution of Claim 10 wherein the polypeptides comprise approximately 0.25 to about 4.0% (w/v) of the solution.
24. The peritoneal dialysis solution of Claim 10 wherein the pH of the solution is approximately 6.0 to about 7.4.
25. The peritoneal dialysis solution of Claim 10 wherein the polypeptides are synthetic polypeptides.
26. The peritoneal dialysis solution of Claim 25 wherein the synthetic peptides are approximately 2 to about 15 amino acids long.
27. The peritoneal dialysis solution of Claim 25 wherein the synthetic peptides are approximately 4 to about 10 amino acids long.
28. A two part peritoneal dialysis solution designed to be mixed prior to infusion into a patient comprising:
a first part housed in a first structure including approximately 1.0 to about 8% (w/v) dextrose and a pH of approximately 4.0 to about 5.5;
a second part housed in a second structure including approximately 0.5 to about 8.0% (w/v) polypeptides and a pH of approximately 6.0 to about 7.5; and including in either the first or the second structure a sufficient amount of the following ingredients so when the first part and second part are mixed the following is provided: 120 to about 150 (mEq/L) sodium; 80.0 to about 110.00 (mEq/L) chloride;
0.0 to about 5.0 (mEq/L) lactate; 0.0 to about 45.0 (mEq/L) bicarbonate; 0.0 to about 4.0 (mEq/L) calcium;
and 0.0 to about 4.0 mEq/L) magnesium).
a first part housed in a first structure including approximately 1.0 to about 8% (w/v) dextrose and a pH of approximately 4.0 to about 5.5;
a second part housed in a second structure including approximately 0.5 to about 8.0% (w/v) polypeptides and a pH of approximately 6.0 to about 7.5; and including in either the first or the second structure a sufficient amount of the following ingredients so when the first part and second part are mixed the following is provided: 120 to about 150 (mEq/L) sodium; 80.0 to about 110.00 (mEq/L) chloride;
0.0 to about 5.0 (mEq/L) lactate; 0.0 to about 45.0 (mEq/L) bicarbonate; 0.0 to about 4.0 (mEq/L) calcium;
and 0.0 to about 4.0 mEq/L) magnesium).
29. The two part peritoneal dialysis solution of Claim 28 wherein the first and second structures are two separate chambers of a single container.
30. The two part peritoneal dialysis solution of Claim 28 wherein the pH of a resultant solution, comprising a mixture of the first part and the second part, is approximately 6.0 to about 7.4.
31. The two part peritoneal dialysis solution of Claim 28 wherein the molecular weight average of the polypeptides is approximately 400 to about 900 daltons.
32. The two part peritoneal dialysis solution of Claim 28 wherein the polypeptides comprise:
not more than approximately 0.10% of the polypeptides having a molecular weight of greater than 1200;
not more than approximately 25% of the polypeptides having a molecular weight of less than 400; and the weight average of polypeptides being within the range of approximately 400 to about 900 daltons.
not more than approximately 0.10% of the polypeptides having a molecular weight of greater than 1200;
not more than approximately 25% of the polypeptides having a molecular weight of less than 400; and the weight average of polypeptides being within the range of approximately 400 to about 900 daltons.
33. The two part peritoneal dialysis solution of Claim 28 wherein the polypeptides include synthetic polypeptides.
34. The two part peritoneal dialysis solution of Claim 28 wherein the synthetic polypeptides are approximately 2 to about 15 amino acids long.
35. A peritoneal dialysis solution comprising as an osmotic agent synthetic polypeptides that are approximately 4 to about 10 amino acids long and dextrose.
36. The peritoneal dialysis solution of Claim 35 wherein the synthetic polypeptides comprise 0.25% to about 4.0% (w/v) of the solution.
37. The peritoneal dialysis solution of Claim 35 wherein the synthetic polypeptides includes essential and non-essential amino acids.
38. The peritoneal dialysis solution of Claim 35 wherein the dextrose comprise approximately 0.5 to about 400% (w/v) of the solution.
39. The peritoneal dialysis solution of Claim 35 wherein the molecular weight average of the synthetic polypeptides is approximately 400 to about 900 daltons.
40. The peritoneal dialysis solution of Claim 35 wherein the synthetic polypeptides comprise:
not more than approximately 0.10% of the polypeptides having a molecular weight of greater than 1200, not more than approximately 25% of the polypeptides having a molecular weight of less than 400; and the weight average of polypeptides being within the range of approximately 400 to about 900 daltons.
not more than approximately 0.10% of the polypeptides having a molecular weight of greater than 1200, not more than approximately 25% of the polypeptides having a molecular weight of less than 400; and the weight average of polypeptides being within the range of approximately 400 to about 900 daltons.
41. A peritoneal dialysis solution comprising as one of at least two osmotic agents a polypeptide having the following amino acid composition:
and including 50 to 150 mg of valine and 15 to 30 mg tryptophan per gm of polypeptide.
and including 50 to 150 mg of valine and 15 to 30 mg tryptophan per gm of polypeptide.
42. The peritoneal dialysis solution of Claim 41 wherein the solution includes dextrose as an osmotic agent.
43. The peritoneal dialysis solution of Claim 42 wherein the ratio of polypeptides to dextrose is 0.3 to 2 by weight.
44. An intraperitoneal drug delivery solution comprising approximately 0.25 to about 4.0% (w/v) polypeptides.
45. The intraperitoneal drug delivery solution of Claim 44 wherein the molecular weight average of the polypeptides is approximately 400 to about 900 daltons.
46. The intraperitoneal drug delivery solution of Claim 44 wherein the polypeptides comprise:
not more than approximately 0.10% of the polypeptides having a molecular weight of greater than 1200;
not more than approximately 25% of the polypeptides having a molecular weight of less than 400: and the weight average of polypeptides being within the range of approximately 400 to about 900 daltons.
not more than approximately 0.10% of the polypeptides having a molecular weight of greater than 1200;
not more than approximately 25% of the polypeptides having a molecular weight of less than 400: and the weight average of polypeptides being within the range of approximately 400 to about 900 daltons.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/995,106 US6380163B1 (en) | 1992-12-22 | 1992-12-22 | Peritoneal dialysis solutions with polypeptides |
| US7/995,106 | 1992-12-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2129991A1 true CA2129991A1 (en) | 1994-07-07 |
Family
ID=25541397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002129991A Abandoned CA2129991A1 (en) | 1992-12-22 | 1993-12-10 | Improved peritoneal dialysis solutions with polypeptides |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US6380163B1 (en) |
| EP (3) | EP0827749B2 (en) |
| JP (2) | JP3676362B2 (en) |
| AT (3) | ATE200866T1 (en) |
| AU (1) | AU683863B2 (en) |
| CA (1) | CA2129991A1 (en) |
| DE (3) | DE69330189T3 (en) |
| DK (3) | DK0827748T3 (en) |
| ES (3) | ES2180002T3 (en) |
| SG (3) | SG93822A1 (en) |
| WO (1) | WO1994014468A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US8927505B2 (en) | 2008-07-07 | 2015-01-06 | Pentec Health, Inc. | Nutritive compositions and methods of using same |
| US9326963B2 (en) | 2008-07-07 | 2016-05-03 | Pentec Health, Inc. | Nutritive compositions and methods of using same |
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| AU2003238691A1 (en) * | 2002-07-01 | 2004-01-19 | Jms Co., Ltd. | Peritoneal dialysate containing taurine |
| US20050148647A1 (en) * | 2003-10-31 | 2005-07-07 | Landry Donald W. | Hemodialysis solutions and uses thereof |
| US7236975B2 (en) * | 2004-04-13 | 2007-06-26 | Bea Systems, Inc. | System and method for controlling access to anode in a virtual content repository that integrates a plurality of content repositories |
| US7935070B2 (en) | 2005-01-28 | 2011-05-03 | Fresenius Medical Care North America | Systems and methods for dextrose containing peritoneal dialysis (PD) solutions with neutral pH and reduced glucose degradation product |
| JPWO2006115067A1 (en) * | 2005-04-20 | 2008-12-18 | 株式会社林原生物化学研究所 | Peritoneal dialysate |
| US20100099628A1 (en) | 2007-03-02 | 2010-04-22 | Zyto-Protec Gmbh | Carbohydrate-based peritoneal dialysis fluid comprising glutamine residue |
| EP2273995B2 (en) * | 2008-03-20 | 2023-11-15 | Baxter International Inc. | Destruction of microbial products by enzymatic digestion |
| US9585810B2 (en) | 2010-10-14 | 2017-03-07 | Fresenius Medical Care Holdings, Inc. | Systems and methods for delivery of peritoneal dialysis (PD) solutions with integrated inter-chamber diffuser |
| TW201338803A (en) * | 2012-03-23 | 2013-10-01 | zheng-yi Lin | Pharmaceutical composition for pet renal failure treatment |
| AU2018231016B2 (en) | 2017-03-08 | 2024-03-07 | Hope Medical Enterprises, Inc. Dba Hope Pharmaceuticals | Intradialytic use of sodium nitrite |
| KR102647836B1 (en) | 2017-03-08 | 2024-03-15 | 호프 메디칼 엔터프라이즈스, 인크, 디비에이, 호프파마수으티칼즈 | Uses of Sodium Thiosulfate During Dialysis |
| EP3766529A4 (en) | 2018-03-14 | 2022-03-23 | Beacon Medcare (HK) Limited | Composition for purification of biofluids |
| ES2750642A1 (en) * | 2018-09-26 | 2020-03-26 | Univ Vigo | Pharmaceutical composition comprising serum amyloid P protein to treat acute or chronic kidney failure (Machine-translation by Google Translate, not legally binding) |
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-
1992
- 1992-12-22 US US07/995,106 patent/US6380163B1/en not_active Expired - Fee Related
-
1993
- 1993-12-10 DK DK97203410T patent/DK0827748T3/en active
- 1993-12-10 DK DK97203411T patent/DK0827749T3/en active
- 1993-12-10 ES ES97203410T patent/ES2180002T3/en not_active Expired - Lifetime
- 1993-12-10 AT AT97203411T patent/ATE200866T1/en not_active IP Right Cessation
- 1993-12-10 CA CA002129991A patent/CA2129991A1/en not_active Abandoned
- 1993-12-10 ES ES97203411T patent/ES2157523T3/en not_active Expired - Lifetime
- 1993-12-10 AU AU58485/94A patent/AU683863B2/en not_active Ceased
- 1993-12-10 AT AT94904432T patent/ATE168010T1/en not_active IP Right Cessation
- 1993-12-10 SG SG9803417A patent/SG93822A1/en unknown
- 1993-12-10 WO PCT/US1993/012075 patent/WO1994014468A1/en active IP Right Grant
- 1993-12-10 DE DE69330189T patent/DE69330189T3/en not_active Expired - Lifetime
- 1993-12-10 DK DK94904432T patent/DK0626857T3/en active
- 1993-12-10 SG SG9803430A patent/SG89264A1/en unknown
- 1993-12-10 DE DE69319583T patent/DE69319583T2/en not_active Expired - Lifetime
- 1993-12-10 DE DE69332106T patent/DE69332106T3/en not_active Expired - Lifetime
- 1993-12-10 EP EP97203411A patent/EP0827749B2/en not_active Expired - Lifetime
- 1993-12-10 AT AT97203410T patent/ATE220328T1/en not_active IP Right Cessation
- 1993-12-10 ES ES94904432T patent/ES2119161T3/en not_active Expired - Lifetime
- 1993-12-10 SG SG1995002035A patent/SG50379A1/en unknown
- 1993-12-10 EP EP94904432A patent/EP0626857B1/en not_active Expired - Lifetime
- 1993-12-10 EP EP97203410A patent/EP0827748B2/en not_active Expired - Lifetime
- 1993-12-10 JP JP51523394A patent/JP3676362B2/en not_active Expired - Fee Related
-
2001
- 2001-07-20 US US09/909,733 patent/US6730660B2/en not_active Expired - Fee Related
-
2005
- 2005-02-23 JP JP2005047926A patent/JP2005162767A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8927505B2 (en) | 2008-07-07 | 2015-01-06 | Pentec Health, Inc. | Nutritive compositions and methods of using same |
| US9326963B2 (en) | 2008-07-07 | 2016-05-03 | Pentec Health, Inc. | Nutritive compositions and methods of using same |
| US9937125B2 (en) | 2008-07-07 | 2018-04-10 | Pentec Health, Inc. | Intradialytic parenteral nutrition compositions |
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |