WO2010017056A1 - Orally administered solid formulations containing a hydrophobic drug and tpgs - Google Patents
Orally administered solid formulations containing a hydrophobic drug and tpgs Download PDFInfo
- Publication number
- WO2010017056A1 WO2010017056A1 PCT/US2009/051887 US2009051887W WO2010017056A1 WO 2010017056 A1 WO2010017056 A1 WO 2010017056A1 US 2009051887 W US2009051887 W US 2009051887W WO 2010017056 A1 WO2010017056 A1 WO 2010017056A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- range
- employed
- amount
- beads
- tpgs
- Prior art date
Links
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Definitions
- the present invention relates to solid formulations containing a hydrophobic drug, TPGS, and other ingredients, wherein the solid formulations are prepared in the form of beads using a spheronization process.
- the formulations can have a high drug load and a high level of TPGS.
- hydrophobic drugs When administered orally, hydrophobic drugs (i.e., drugs with low aqueous solubility) can exhibit poor absorption in the gastrointestinal tract and as a consequence low oral bioavailability.
- Suitable surfactants include tocopherol polyethylene glycol succinate (TPGS).
- TPGS tocopherol polyethylene glycol succinate
- a high level of TPGS may be required in the formulation in order to achieve a satisfactory oral bioavailability of a poorly soluble drug.
- High levels of TPGS can be employed in orally administered soft gelatin capsules (also referred to as "softgels").
- Agenerase® softgels contain the active pharmaceutical ingredient (API) amprenavir — an inhibitor of HIV-I protease — and includes a high level of vitamin E TPGS. Agenerase ⁇ softgels are indicated in combination with other antiretro viral agents for the treatment of HIV-I infection.
- API active pharmaceutical ingredient
- TPGS TPGS forms free flowing aqueous solutions at concentrations up to about 20 wt,% (i.e., weight percent is based on the weight of TPGS with respect to the weight of the solution), the viscosity of these solutions increases dramatically at concentrations above 20 wt.% with gel formation occurring at about 23 wt.%.
- aqueous solutions of TPGS typically at least a 5- fold higher amount of fluid must be added to incorporate solid TPGS, which would require the use of a relatively very large amount of fluid to obtain granules with high TPGS levels.
- the use of large amounts of granulation fluid will typically result in over-granulation (i.e., the formation of a non-uniform granulate that contains lumpy, oversized granules) that would require substantial milling to provide granules of appropriate size and uniformity.
- Post-granulation processes such as milling and compaction can be impractical irrespective of the amount of granulation fluid.
- Milling on high energy mills can result in significant heat generation which can result in blinding of the screens due to melting of the TPGS. Tabletting can be impractical because compaction on commercial tabletting equipment can exceed the melting temperature of TPGS. While it may be possible to monitor and control the temperature during post granulation processing, such controls can be complex and expensive. Furthermore, post-tabletting processes such as coating can be challenging as well, because aqueous dispersion coatings would require temperatures close to or higher than the melting temperatures of TPGS.
- the present invention circumvents the problems that can be encountered in preparing TPGS -containing solid formulations.
- the present invention involves the use of extrusion spheronization to provide immediate release solid formulations which can have high levels of vitamin E TPGS and optionally also high API levels.
- the present invention includes a solid pharmaceutical formulation for oral administration which comprises:
- the bead formulation of the present invention can contain a high load of API and a high level of vitamin E TPGS and thereby can provide relatively high oral bioavailabilities for hydrophobic drugs. It is believed that, at least for certain APIs, the bead formulation can provide a more intimate contact of the TPGS surfactant and the API which can result in an improved in vivo performance compared to the performance of solid formulations obtained by conventional granulation processes.
- the present invention also includes processes for preparing the bead formulation as described above.
- Figure 1 is an optical micrograph of a sample of dried beads prepared in the manner described in Example 1.
- Figure 2 is a plot of the roundness R of beads prepared in the manner described in Example 1.
- Figure 3 is a plot of the roundness R of beads prepared in Example 2.
- the bead formulation of the present invention contains an effective amount of a hydrophobic active pharmaceutical ingredient.
- active pharmaceutical ingredient refers herein to a substance which can be used in the treatment or prophylaxis of a disease or an unhealthy or undesirable condition (e.g., an infection, allergy, pain, inflammation, fever, and so forth).
- the API can be a free base, a free acid or a pharmaceutically acceptable salt thereof, it can be crystalline or amorphous or a mixture thereof, and it can be in any physical form (e.g., granules, coarse powder, or finely ground powder), provided that the API being employed is hydrophobic.
- An API is considered hydrophobic herein if it has a water solubility of less than about 1 mg/iiiL at 25°C.
- the solubility of the API is determined as follows: Excess solid API is added to each of two individual vials containing deionized water, after which the vials are agitated (e.g., in a rotating wheel apparatus) for a time sufficient to form a saturated, equilibrated solution at 25 0 C. The solution and residual solids are then separated (e.g., by centrifugation) and the amount of API dissolved in the solution is determined (e.g., by HPLC) for each vial. The solubility is reported as the arithmetic average of the values obtained for each of the vials.
- the term "bead formulation” is intended to encompass an orally administered, solid dosage product in the form of beads comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients to provide the beads.
- the formulation of the present invention is in the form of beads which can be obtained via spheronization; wherein spherical particles are formed from wet granulations.
- the wet granulation is typically passed first through an extruder to provide rod-shaped cylindrical segments which are then fed to a spinning friction plate and thrown against a Marumerizer bowl as a result of which the extruded segments are shaped into spheres, Spheronization is further described in Chapter 45 of Remington - The Science and Practice of Pharmacy, 21 st edition, Troy, editor, Lippincott Williams & Wilkins, 2006, pages 903-904.
- the term "effective amount” as used herein means that amount of the API that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
- the effective amount can be a "therapeutically effective amount” for the alleviation of the symptoms of the disease or condition being treated.
- the effective amount can also be a "prophylactically effective amount” for prophylaxis of the symptoms of the disease or condition being prevented.
- the API is an inhibitor of a particular target or targets (e.g., an enzyme), the term can also refer to the amount of API sufficient to inhibit the target and thereby elicit the response being sought (i.e., an "inhibition effective amount").
- the dosage required to provide an effective amount of API in a pharmaceutical composition can generally be adjusted by one skilled in the art, and will vary depending on the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy (if any) and the nature and scope of the desired effect(s) (see, e.g., Nies et at, Chapter 3 in: Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9 th edition, Hardman et al.., eds., McGraw-Hill, New York, N. Y., 1996).
- the bead formulation of the present invention contains vitamin E TPGS. It is available from Eastman Chemical Company under the trade name VITAMIN E TPGS. Alternatively, vitamin E TPGS can be prepared by esterifying the carboxyl group of crystalline d- ⁇ -tocopheryl acid succinate with polyethylene glycol 1000. The preparation of water-soluble tocopherol derivatives such as vitamin E TPGS and aqueous solutions thereof can be found in US 2680749 and US 3102078, the disclosures of which are incorporated by reference herein in their entireties. Vitamin E TPGS (which is alternatively and interchangeably referred to herein as
- TPGS is a non-ionic surfactant.
- surfactant refers to a compound having both a hydrophilic head group, which energetically prefers solvation by water, and a hydrophobic tail that is not well solvated by water.
- a non-ionic surfactant is a compound in which the hydrophilic head group is neither a cation nor an anion.
- the HLB value of Vitamin E TPGS is approximately 13.
- HLB value refers to a theoretical index value which describes the hydrophilicity-lipophilicity balance of a specific compound. Generally, it is recognized that the HLB index ranges from 0 (very hydrophobic) to 40 (very hydrophilic).
- HLB HLB
- Methods for calculating the HLB value of surfactants is provided in Surfactant Science Series, Vol. 1 : Nonionic Surfactants", pp 606-13, M. J. Schick (Marcel Dekker Inc., New York, 1966).
- vitamin E TPGS is believed to act as an emulsifier and/or solubilizer of hydrophobic active pharmaceutical ingredients leading to improved wettability, dissolution, permeability and bioavailability of the active ingredient in solid oral dosage formulations.
- the bead formulation of the present invention also includes a filler/spheronization agent, a binder, and a superdisintegrant.
- the filler/spheronization agent employed in the present invention can be any substance that can act as both a filler and a spheronization agent.
- suitable agents include any substance which (i) can impart bulk to the composition and (ii) can form, together with the other ingredients in the formulation, beads.
- the filler/spheronization agent can be a cellulosic derivative such as microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose.
- a filler/spheronization agent particularly suitable for use in the invention is a microcrystalline cellulose, such as AVICEL PH-112, AVICEL PH-IOl, AVICEL PH-102 (all of which are available from FMC Corporation), or a mixture of two or more thereof.
- the binder employed in the present invention can be any substance that can impart cohesive qualities to the bead formulation of the present invention. More particularly, the binder is employed to ensure that the individual beads will remain intact after formation of the beads via spheronization.
- Suitable binders include acacia, alginic acid, carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil (type I), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (i.e., polyvinyl pyrrolidone), sodium alginate, starch, and zein.
- a binder particularly suitable for use in the invention is hydroxypropyl cellulose, hydroxypropyl methylcellulose, or povidone.
- the superdisintegrant employed in the present invention can be any substance that in relatively small quantities can facilitate the breakup or disintegration of the beads after administration.
- Suitable superdisintegrants include croscarmellose sodium, crospovidone, and sodium starch glycolate.
- ingredients employed in the bead formulation of the invention are limited to pharmaceutically acceptable substances.
- pharmaceutically acceptable is meant that the ingredients of the bead formulation are compatible with each other and not deleterious to the recipient thereof.
- the formulation of the invention is in the form of solid beads.
- the beads are approximately spherical in shape and can alternatively be referred to as pellets.
- pellets can alternatively be referred to as pellets.
- the terms "bead” and "pellet” are used interchangeably.
- the beads can be described by their roundness.
- R for a perfect circle is:
- roundness number for an object is greater than or equal to 1 depending on the departure of the shape of the object from a perfect sphere.
- Roundness R can be determined via optical microscopy in conjunction with image analysis software.
- the beads in the formulation of the present invention typically have a roundness R in a range of from about 1.0 to about 1,8.
- the median R value for the beads is typically in a range of from about 1.0 to about 1.2.
- the beads can also be characterized by their diameters which can be measured via optical microscopy in conjunction with image analysis software.
- the beads in the formulation of the present invention typically have an average diameter in a range of from about 0.5 mm to about 1.8 mm, and at least 50% of the beads have a diameter in a range of from about 0.6 mm to about 1.3 mm.
- a first embodiment of the present invention is a solid pharmaceutical formulation for oral administration as originally defined above (i.e., as defined in the Summary of the Invention), wherein substantially all of the beads are approximately spherical in shape; the beads have an average diameter in a range of from about 0.6 mm to about 1.5 mm; at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1.2 mm; and the beads have a roundness value R in a range of from about 1.0 to about 1.5.
- the beads have an average diameter in a range of from about 0.7 mm to about 1.3 mm; at least 50% of the beads have a diameter in a range of from about 0.8 mm to about 1.2 mm; and the beads have a roundness value R in a range of from about 1.0 to about 1.25.
- the term "substantially all" of the beads means suitably at least about 90 wt.% (e.g., from about 90 wt.% to about 99 wt.%), typically at least about 95 wt.%
- the solid pharmaceutical formulation of the present invention is in the form of beads.
- a second embodiment of the present invention is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in Embodiment El , wherein the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 40 wt.% (e.g., from about 1 wt.% to about 20 wt.%, or from about 5 wt.% to about 35 wt.%); the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.% to about 10 wt.%; and the superdisintegrant is employed in an amount in a range of from about 1 wt.% to about 10 wt.%.
- the concentration of the components in the formulation of the invention is given as a weight percent (wt.%) which is based on the total weight of the solid formulation.
- a third embodiment of the present invention is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in either Embodiment El or Embodiment E2, wherein the filler/spheronization agent is microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or povidone; and the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate.
- the filler/spheronization agent is microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose
- the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or povidone
- the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate.
- a fourth embodiment of the present invention is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in any of the preceding embodiments, wherein the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 40 wt.% (e.g., from about 5 wt.% to about 15 wt.%, or from about 10 wt.% to about 35 wt.%, or from about 10 wt.% to about 20 wt.%); the filler/spheronization agent is employed in an amount in a range of from about 5 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 2 wt.% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.
- a fifth embodiment of the present invention is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in any of the preceding embodiments, wherein the beads are encapsulated.
- encapsulating the beads means filling one or more capsules (e.g., hard gelatin capsules) with a suitable amount of the beads, and then sealing the capsule(s).
- a sixth embodiment of the present invention is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in any of the preceding embodiments, wherein the API is a compound of Formula I:
- X2 is:
- Rl is:
- the compounds of Formula I and their pharmaceutically acceptable salts are HIV integrase inhibitors. These compounds, their preparation, and uses are further described in US 2007/0179196, WO 2005/087767 and WO 2005/087768, the disclosures of which are incorporated by reference herein in their entireties.
- Embodiment E6 is the formulation as defined in Embodiment E6, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, Xl is fiuoro; ⁇ 2 is -H or chloro; R.4 is:
- the compound of Formula I is Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A is:
- a seventh embodiment of the present invention is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in any of the preceding embodiments, wherein the API is a compound of Formula II:
- R7 is hydrogen, Ci-6 alkyl, (CH2)l-3CF3, O-Ci-6 alkyl, halogen, OH, NO2, CN, 0 ⁇ CH2)2-3CF3 > CO2RA, CONRARB, O(CH2)2-3NR A R B , O(CH2)l-2CORA, S(O)2R A , or SO2NRARB;
- RA and RB are each independently H or Cl -6 alkyl; R3 and R ⁇ are each independently selected from the group consisting of hydrogen, halogen, Ci -6 alkyl and Ci_g fluoroalkyl; and
- R4, R5 and R ⁇ are each independently selected from the group consisting of hydrogen, halogen, CN, Ci .5 alkyl and C ⁇ g fluoroalkyl.
- the compounds of Formula II and their pharmaceutically acceptable salts are HIV non-nucleoside reverse transcriptase inhibitors. These compounds, their preparation and uses are further described in US 2007/0021442, WO 2007/015809 and WO 2007/015812, the disclosures of which are incorporated by reference herein in their entireties.
- the compound of Formula ⁇ is Compound B, or a pharmaceutically acceptable salt thereof, wherein Compound B is:
- alkyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range.
- C ⁇ g alkyl (or “Ci-Cg alkyl”) refers to any of the hexyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso- propyl, ethyl and methyl.
- Ci -4 alkyl refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
- halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
- fluoroalkyl 1 ' refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a fluorine.
- Ci _g fluoroalkyl (or “Ci-Cg fluoroalkyl”) refers to a Cl to Cg linear or branched alkyl group as defined above with one or more fluorine substituents.
- Suitable fluoroalkyls include the series (CH2) ⁇ -3CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.).
- a fluoroalkyl of particular interest is CF3.
- cycloalkyl refers to any monovalent monocyclic ring of an alkane having a number of carbon atoms in the specified range.
- C3-6 cycloalkyl (or “C3-C6 cycloalkyl”) refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- An asterisk (“*) as the end of an open bond in a chemical group denotes the point of attachment of the group to the rest of the compound.
- Process P for preparing a solid pharmaceutical formulation comprising a hydrophobic active pharmaceutical ingredient, vitamin E TPGS, a filler/spheronization agent, a binder and a superdisintegrant, said solid formulation being in the form of beads, wherein the process comprises: (A) granulating a dry mixture that has been wetted with a solution of the vitamin E TPGS in a granulation fluid to provide a granulated mass, wherein the dry mixture comprises the active pharmaceutical ingredient, the filler/spheronization agent, the binder and the superdisintegrant;
- Step C drying the beads from Step C at a temperature of less than about 35°C; wherein: the active pharmaceutical ingredient is employed in an effective amount; the vitamin E TPGS is employed in an amount of at least about 1 wt.%; the filler/spheronization agent is employed in an amount of at least about 5 wt.%; the binder is employed in an amount of at least about 0.5 wt.%; and the superdisintegrant is employed in an amount of at least about 0.5 wt.%; wherein all of the foregoing weight percents are based on the total weight of all individual components excluding the granulation fluid from the vitamin E TPGS granulation fluid solution.
- a first embodiment of Process P is Process P as originally described above, wherein: the concentration of vitamin E TPGS in the granulation fluid solution is in a range of from about 2 wt.% to about 20 wt.%, and the weight of the granulating solution added to the dry mixture is in a range of from about 20 to about 65 wt.% w/w based on the weight of the dry mixture; the granulation in Step A is conducted using a high shear granulator at an impeller speed in a range of from about 200 rpm to about 600 rpm and a chopper speed of from about 500 rprn to about 2000 rpm for a time in a range of from about 1 to about 10 minutes (e.g., from about 2 to about 8 minutes) to provide the granulated mass; the extrusion in Step B is conducted using a screw or basket extruder fitted with an axial radial or dome screw head at a screw speed in a range of from about
- the beads are approximately spherical in shape and have an average diameter in a range of from about 0.6 mm to about 1.5 mm;
- At least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1.2 mm;
- the beads have a roundness R in the range of from about 1.0 to about 1.5.
- a second embodiment of Process P is Process P as originally described or as described in Embodiment El-P, wherein: the granulation fluid employed in the vitamin E TPGS solution is water, a Cl -4 alkyl alcohol (e.g., methanol or ethano ⁇ ), or a mixture of water and a C 1-4 alkyl alcohol (e.g., water + methanol or water + ethanol); the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 20 wt.% (e.g., from about 1 wt.% to about 10 wt.%); the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.
- the granulation fluid is typically water in combination with an alcohol co-solvent.
- an alcohol co-solvent e.g., from about 13 wt.% to about 20 wt.%
- water alone or a water-alcohol mixture is suitable as the granulation fluid.
- a third embodiment of Process P is Process P as originally described or as described in either of Embodiments El-P or E2-P, wherein: the filler/spheronization agent is microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinyl pyrollidone; and the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate,
- a fifth embodiment of Process P is Process P as originally described or as described in any of the foregoing embodiments of Process P, wherein the active pharmaceutical ingredient is a compound of Formula I as defined above (see Embodiment E6), a compound of Formula II as defined above (see Embodiment E7), or a pharmaceutically acceptable salt thereof.
- a sixth embodiment of Process P is Process P as originally described or as described in any of the foregoing embodiments of Process P 5 wherein the active pharmaceutical ingredient is Compound A as defined above, Compound B as defined above, or a pharmaceutically acceptable salt thereof.
- a seventh embodiment of Process P is Process P as originally described or as described in any of the foregoing embodiments of Process P, wherein Process P further comprises:
- the present invention also includes the solid pharmaceutical formulations prepared in accordance with Process P as originally described and as described in the foregoing embodiments of Process P.
- the present invention includes another process (alternatively referred to herein as "Process Q") for preparing a solid pharmaceutical formulation comprising a hydrophobic active pharmaceutical ingredient, vitamin E TPGS, a filler/spheronization agent, a binder and a superdisintegrant, said solid formulation being in the form of beads, wherein the process comprises: (A) blending a dry mixture comprising the active pharmaceutical ingredient, the vitamin E TPGS in the form of spray-dried granules, the fi ⁇ ler/spheronization agent, the binder and the superdisintegrant;
- Step B wet granulating the blended mixture of Step A using a granulation fluid comprising water;
- Step C drying the beads from Step C at a temperature of less than about 35°C; wherein: the active pharmaceutical ingredient is employed in an effective amount; the vitamin E TPGS is employed in an amount of at least about 1 wt.%; the f ⁇ ller/spheronization agent is employed in an amount of at least about 5 wt.%; the binder is employed in an amount of at least about 0.5 wt.%; and the superdisintegrant is employed in an amount of at least about 0.5 wt.%; wherein all of the foregoing weight per cents are based on the total weight of all individual components excluding the granulation fluid.
- a first embodiment of Process Q is Process P as originally described above, wherein: the weight of the granulation fluid added to the blended mixture in Step B is in a range of from about 20 to about 65 wt.% w/w based on the weight of the dry mixture; the wet granulation in Step B is conducted using a high shear granulator at an impeller speed in a range of from about 200 rpm to about 600 rpm and a chopper speed of from about 500 rpm to about 2000 rpm for a time in a range of from about 1 to about 10 minutes to provide the granulated blend; the extrusion in Step C is conducted using a screw or basket extruder fitted with an axial radial or dome screw head at a screw speed in a range of from about 10 rpm to about 60 rpm; the spheronizing in Step D is conducted using a rotating disc spheronizer at a speed in a range of from about 800 rpm to about
- the beads are approximately spherical in shape and have an average diameter in a range of from about 0.6 mm to about 1.5 mm; (ii) at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1 ,2 mm; and
- a second embodiment of Process Q is Process Q as originally described or as described in Embodiment El-Q, wherein: the granulation fluid employed in Step B is water, a Ci_4 alkyl alcohol, or a mixture of water and a Ci_4 alkyl alcohol; the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.% (e.g., from about 5 wt.% to about 75 wt.%); the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 45 wt.% (e.g., from about 5 wt.% to about 45 wt.%); the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range
- a third embodiment of Process Q is Process Q as originally described or as described in either of Embodiments El-Q or E2-Q, wherein: the filler/spheronization agent is microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinyl pyrollidone; and the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate.
- the filler/spheronization agent is microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose
- the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinyl pyrollidone
- the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate.
- a fourth embodiment of Process Q is Process Q as originally described or as described in any of the foregoing embodiments of Process Q, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.% (e.g., from about 20 wt.% to about 50 wt.%); the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 40 wt.% (e.g., from about 10 wt.% to about 35 wt.%); the filler/spheronization agent is employed in an amount in a range of from about
- the binder is employed in an amount in a range of from about 2 wt.% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.% to about 6 wt.%.
- a fifth embodiment of Process Q is Process Q as originally described or as described in any of the foregoing embodiments of Process Q, wherein the active pharmaceutical ingredient is a compound of Formula I as defined above (see Embodiment E6), a compound of Formula II as defined above (see Embodiment E7), or a pharmaceutically acceptable salt thereof.
- a sixth embodiment of Process Q is Process Q as originally described or as described in any of the foregoing embodiments of Process Q, wherein the active pharmaceutical ingredient is Compound A as defined above, Compound B as defined above, or a pharmaceutically acceptable salt thereof.
- a seventh embodiment of Process Q is Process Q as originally described or as described in any of the foregoing embodiments of Process Q, wherein Process Q further comprises:
- the present invention also includes the solid pharmaceutical formulations prepared in accordance with Process Q as originally described and as described in the foregoing embodiments of Process Q, All processing steps in Processes P and Q are conducted at temperatures less than the melting point of vitamin E TPGS, and typically all processing steps other than the drying step are conducted at ambient temperatures (i.e., 2O 0 C to 25°C). Bead drying is typically conducted at temperatures of about 35°C or less (e.g., from about 30 0 C to about 35°C). The extruding step in Processes P and Q is typically conducted under ambient pressure conditions.
- Process Q is typically more suitable for the preparation of bead formulations containing relatively large amounts (i.e., about 15 wt.% or more) of vitamin E TPGS.
- Process P utilizes a solution of TPGS and requires the use of a relatively large amount of granulation fluid in order to incorporate a large amount (i.e., more than about 15 wt.%) of TPGS in the bead formulation.
- Process Q employs TPGS in a solid form and thus increasingly larger quantities of granulation fluid are not required to prepare bead formulations with progressively higher TPGS concentrations.
- Process P and Process Q can avoid the problems associated with the preparation of formulations containing high TPGS levels using conventional process trains wherein the melting of the TPGS can occur under the thermal conditions typically encountered in the milling and compacting steps. Furthermore, the processes of the invention can accommodate relatively large amounts of granulation fluid and potential over-granulation in Step A, because, unlike in a conventional granulation process, downstream processing involves extruding to strands followed by spheronization to larger beads. The need for granule growth control is greater for a conventional process than the process of the invention and thus the described process is more forgiving with respect to granule size and uniformity. Because Process P can employ relatively large amounts of fluid, it permits the incorporation of higher levels of TPGS than is practical with conventional processing.
- API active pharmaceutical ingredient
- GFL Granulation fluid
- HPC hydroxypropyl cellulose
- TPGS tocopherol polyethylene glycol succinate.
- Compound A microcrystalline cellulose (Avicel PH 101), hydroxypropyl cellulose and croscarmellose sodium in the proportions set forth in Table 1 below (excluding the amount of the PH 101 that was sprinkled on extrudate as noted below) were transferred to the bowl of a high shear granulator (Bohle mini granulator Model No. A-Nr 60628) and dry mixed for 5 minutes at an impeller speed of 200 rpm and a chopper speed of 500 rpm. A 20 wt.% aqueous solution of vitamin E TPGS was then gradually added to the dry mixture. The impeller speed was increased to 250 rpm during the addition of the aqueous solution and the chopper speed was maintained at 500 rpm.
- vitamin E TPGS solution Approximately 12,5 g of the vitamin E TPGS solution was added to provide 2.5 g of vitamin E TPGS per se, thus providing for a theoretical total batch size of 25 g in which vitamin E TPGS represented 10 wt.% of the total weight of the dry components (i.e., excluding water).
- the resulting granulated wet mass was then extruded on a lab scale basket extruder (CaI eva Model No. 10) fitted with a screen having an aperture size of 1 mm and operated at 30 rpm, followed by spheronization of the extrudate in a spheronizer (Caleva Model No. 120 ) operated at a speed of 1000 rpm for 5 minutes to provide beads.
- Figure 1 is an optical micrograph of a sample of the dried beads prepared in the manner described above.
- the diameter of the beads obtained by this process is primarily dependent upon the aperture size of the screen used during the extrusion process. In the current case, an aperture size of 1 mm yielded beads in the size range of 0.8 to 1.2 mm.
- Figure 2 is a plot of R for beads prepared in the same manner as those described above.
- the R values were determined using an Olympus SZXl 6 microscope in conjunction with 'Image Pro Plus' version 4.5.0.29 for Windows 2000.
- a description of the software application can be found in the Image-Pro® Plus manual MAN 7841N42 20010530 (Media Cybernetics Inc, Silver Spring, MD), the disclosure of which is incorporated by reference herein in its entirety.
- the median R value is 1.11
- the range of R values is from about 1.09 to about 1 ,19,
- the optical microscope and Image Pro-Plus software described in the preceding paragraph were also used to measure the diameters of the beads.
- the bead diameters were determined to be in a range of from about 0.85 mm to 1.19 mm, and the median diameter of the beads was 0.96 mm.
- EXAMPLE 2 Preparation of a formulation of Compound A via extrusion spheronization
- a formulation containing Compound A was prepared as follows using a batch size of 200 g in which the components were employed in the relative amounts set forth in Table 1 of Example 1 above; Weighed amounts of Compound A, microcrystalline cellulose (Avicel PH 101) (excluding the amount sprinkled on the extrudate as describe below), HPC 3 and croscarmellose sodium were transferred to the bowl of a high shear granulator (Diosna Model No. P-l/6) and dry mixed for 90 seconds at an impeller speed of 300 rpm and a chopper speed of 2000 rpm.
- a high shear granulator Diosna Model No. P-l/6
- a 20 wt.% aqueous solution of vitamin E TPGS was then gradually added using a spray gun at a rate of 40 g/minute, wherein the impeller speed and the chopper speed were maintained at 300 rpm and 2000 rpm respectively during the addition.
- a total of approximately 100 g of the vitamin E TPGS solution was added resulting in the addition of 10 wt.% dry vitamin E TPGS.
- the wet mass obtained upon granulation was then extruded using a screw extruder (Fuji Paudal Model No. MG- 55) fitted with a dome extrusion head at a screw speed of 30 rpm, wherein the extrusion head had an opening size and a die thickness of 1 mm.
- the extrudate was spheronized using a rotating disc spheronizer (Fuji Paudal Model No. QJ230T) at around 1200 rpm.
- MicrocrystalHne cellulose (2-3 g of Avicel PH 101) was sprinkled on the extrudate during the spheronization to avoid aggregation of the beads.
- the beads were dried in an oven at 32°C for 24 hours to obtain 75 wt.% Compound A-loaded beads.
- FIG. 3 is a plot of R for the beads prepared as just described.
- the median R value is 1.11, and the range of R values is from about 1.07 to about 1.19.
- the beads had diameters in a range of from about 0.77 mm to about 1.19 mm, and a median diameter of 0.95 mm.
- a formulation containing Compound A was prepared as follows using a batch size of 200 g in which the components were employed in the relative amounts set forth in Table 2. Weighed amounts of Compound A, spray dried granular TPGS, microcrystalline cellulose (Avicel PH 101) (excluding the amount sprinkled on the extrudate as described below), HPC, and croscarmellose sodium were transferred to the bowl of a high shear granulator (Diosna Model No. P- 1/6) and dry mixed for 3 minutes at an impeller speed of 300 rpm and a chopper speed of 1000 rpm.
- a high shear granulator Diosna Model No. P- 1/6
- deionized water was gradually added using a spray gun at a rate of 26 g/minute, during which time the impeller speed and the chopper speed were maintained at 300 rpm and 1000 rpm respectively, A total of approximately 56 g of water as GFL was added.
- the wet mass obtained upon granulation was then extruded using a screw extruder (Fuji Paudal Model No. MG- 55) fitted with a dome extrusion head at a screw speed of 30 rpm, wherein the extrusion head had an opening size and a die thickness of 1 mm.
- the extrudate was spheronized using a rotating disc spheronizer (Fuji Paudal Model No.
- Microcrystalline cellulose (-20 g of Avicel PH 101) was sprinkled on the extrudate during the spheronization to avoid aggregation of the beads.
- the beads were dried in an oven at 32 0 C for 24 hours to obtain 37.4 % w/w Compound A-loaded beads.
- PK values for Compound A were determined in Beagle dogs orally dosed with encapsulated beads (pellets) prepared in the manner described in Example 1 and with encapsulated granules prepared in the manner described in Example 5. Fasted male beagle dogs (Marshall Farms) were used in the studies. The dogs were housed in an AAALAC- accredited facility in accordance with USDA guidelines. Studies were conducted under a protocol approved by the WP-IACUC. 3 dogs were employed in each study. The dose was approximately 10 mg per kg of body weight (i.e., 10 mpk).
- AUC ratio is the ratio of the AUCs in the table with respect to the AUC of Example 5.
- a bead formulation of Compound A (Formulation 7-1) was prepared via extrusion spheronization in a manner similar to that described in Example 1.
- a granule formulation of Compound A (Formulation 7-2) was prepared via conventional high shear granulation in a manner similar to that described in Example 4.
- the compositions of Formulations 7-1 and 7-2 are shown in Tables 6 and 7 respectively.
- Example 7-1 and the granule formulation of Example 7-2 have about the same surfactant to drug w/w ratios; i.e., 1 :7.2 and 1 :7.5 respectively.
- the results in Table 7 show that the bead formulation provided in vivo exposures the same or better than those achieved the granule formulation.
- the bead formulation of 7-1 had a C24 hr about 5x higher than that achieved by granulated formulation 7-2, indicating that the overall PK profile of the bead formulation is superior.
Abstract
A solid pharmaceutical formulation suitable for oral administration is described. The formulation is in the form of beads and contains a therapeutically effective amount of an hydrophobic active pharmaceutical ingredient (API), vitamin E TPGS, a filler/spheronization agent, a binder and a superdisintegrant. Processes for preparing the formulation are also described. One process involves wetting a dry mixture comprising the API, the filler/spheronization agent, the binder and the superdisintegrant with a solution of vitamin E TPGS in a granulation fluid (e.g., water optionally mixed with an alcohol), granulating the wetted mixture, extruding the resulting granulated mass, spheronizing the extrudate to provide beads, and drying the beads. Another process involves wet granulating a dry blend of API, spray-dried granules of vitamin E TPGS, filler/spheronization agent, binder and superdisintegrant, extruding the wet granulate, spheronizing the extrudate to beads, and drying the beads.
Description
TITLE OF THE INVENTION
ORALLY ADMINISTERED SOLID FORMULATIONS CONTAINING A HYDROPHOBIC
DRUG AND TPGS
FIELD OF THE INVENTION
The present invention relates to solid formulations containing a hydrophobic drug, TPGS, and other ingredients, wherein the solid formulations are prepared in the form of beads using a spheronization process. The formulations can have a high drug load and a high level of TPGS.
BACKGROUND OF THE INVENTION
When administered orally, hydrophobic drugs (i.e., drugs with low aqueous solubility) can exhibit poor absorption in the gastrointestinal tract and as a consequence low oral bioavailability. Among the possible approaches for improving the oral bioavailability of such drugs is increasing the hydrophilicity and solubility of the drug with a surfactant. Suitable surfactants include tocopherol polyethylene glycol succinate (TPGS). A high level of TPGS may be required in the formulation in order to achieve a satisfactory oral bioavailability of a poorly soluble drug. High levels of TPGS can be employed in orally administered soft gelatin capsules (also referred to as "softgels"). For example, Agenerase® softgels contain the active pharmaceutical ingredient (API) amprenavir — an inhibitor of HIV-I protease — and includes a high level of vitamin E TPGS. Agenerase© softgels are indicated in combination with other antiretro viral agents for the treatment of HIV-I infection.
The use of high levels of TPGS in solid formulations for oral administration is challenging, because the surfactant is a waxy semi-solid with a relatively low melting point of 370C. Furthermore, although TPGS forms free flowing aqueous solutions at concentrations up to about 20 wt,% (i.e., weight percent is based on the weight of TPGS with respect to the weight of the solution), the viscosity of these solutions increases dramatically at concentrations above 20 wt.% with gel formation occurring at about 23 wt.%. These properties make the use of conventional techniques for preparing solid formulations with high TPGS levels problematic. For example, when using aqueous solutions of TPGS as a granulation fluid, typically at least a 5- fold higher amount of fluid must be added to incorporate solid TPGS, which would require the use of a relatively very large amount of fluid to obtain granules with high TPGS levels. The use of large amounts of granulation fluid will typically result in over-granulation (i.e., the formation of a non-uniform granulate that contains lumpy, oversized granules) that would require substantial milling to provide granules of appropriate size and uniformity. Post-granulation processes such as milling and compaction can be impractical irrespective of the amount of granulation fluid. Milling on high energy mills, for example, can result in significant heat
generation which can result in blinding of the screens due to melting of the TPGS. Tabletting can be impractical because compaction on commercial tabletting equipment can exceed the melting temperature of TPGS. While it may be possible to monitor and control the temperature during post granulation processing, such controls can be complex and expensive. Furthermore, post-tabletting processes such as coating can be challenging as well, because aqueous dispersion coatings would require temperatures close to or higher than the melting temperatures of TPGS.
In view of the challenges presented by conventional processes, an alternative approach is needed for the preparation of solid, orally administrate formulations with high TPGS levels.
SUMMARY OF THE INVENTION
The present invention circumvents the problems that can be encountered in preparing TPGS -containing solid formulations. The present invention involves the use of extrusion spheronization to provide immediate release solid formulations which can have high levels of vitamin E TPGS and optionally also high API levels. More particularly, the present invention includes a solid pharmaceutical formulation for oral administration which comprises:
(a) an effective amount of a hydrophobic active pharmaceutical ingredient,
(b) at least about 1 wt.% of vitamin E TPGS,
(c) at least about 5 wt.% of a filler/spheronization agent, (d) at least about 0.5 wt.% of a binder, and
(e) at least about 0.5 wt.% of a superdisintegrant; wherein the formulation is in the form of beads.
The bead formulation of the present invention can contain a high load of API and a high level of vitamin E TPGS and thereby can provide relatively high oral bioavailabilities for hydrophobic drugs. It is believed that, at least for certain APIs, the bead formulation can provide a more intimate contact of the TPGS surfactant and the API which can result in an improved in vivo performance compared to the performance of solid formulations obtained by conventional granulation processes.
The present invention also includes processes for preparing the bead formulation as described above.
Various embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples, and appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an optical micrograph of a sample of dried beads prepared in the manner described in Example 1.
Figure 2 is a plot of the roundness R of beads prepared in the manner described in Example 1.
Figure 3 is a plot of the roundness R of beads prepared in Example 2.
DETAILED DESCRIPTION OF THE INVENTION
The bead formulation of the present invention contains an effective amount of a hydrophobic active pharmaceutical ingredient. The term "active pharmaceutical ingredient" refers herein to a substance which can be used in the treatment or prophylaxis of a disease or an unhealthy or undesirable condition (e.g., an infection, allergy, pain, inflammation, fever, and so forth). The API can be a free base, a free acid or a pharmaceutically acceptable salt thereof, it can be crystalline or amorphous or a mixture thereof, and it can be in any physical form (e.g., granules, coarse powder, or finely ground powder), provided that the API being employed is hydrophobic. An API is considered hydrophobic herein if it has a water solubility of less than about 1 mg/iiiL at 25°C. The solubility of the API is determined as follows: Excess solid API is added to each of two individual vials containing deionized water, after which the vials are agitated (e.g., in a rotating wheel apparatus) for a time sufficient to form a saturated, equilibrated solution at 250C. The solution and residual solids are then separated (e.g., by centrifugation) and the amount of API dissolved in the solution is determined (e.g., by HPLC) for each vial. The solubility is reported as the arithmetic average of the values obtained for each of the vials. As used herein, the term "bead formulation" is intended to encompass an orally administered, solid dosage product in the form of beads comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients to provide the beads.
The formulation of the present invention is in the form of beads which can be obtained via spheronization; wherein spherical particles are formed from wet granulations. The wet granulation is typically passed first through an extruder to provide rod-shaped cylindrical segments which are then fed to a spinning friction plate and thrown against a Marumerizer bowl as a result of which the extruded segments are shaped into spheres, Spheronization is further described in Chapter 45 of Remington - The Science and Practice of Pharmacy, 21st edition, Troy, editor, Lippincott Williams & Wilkins, 2006, pages 903-904.
The term "effective amount" as used herein means that amount of the API that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The effective amount can be a "therapeutically effective amount" for the alleviation of the symptoms of the disease or condition being treated. The effective amount can also be a "prophylactically effective amount" for prophylaxis of the symptoms of the disease or condition being prevented. If the API is an inhibitor of a particular target or targets (e.g., an enzyme), the term can also refer to the amount
of API sufficient to inhibit the target and thereby elicit the response being sought (i.e., an "inhibition effective amount"). Although individual needs may vary, suitable ranges of effective amounts of API can be determined by the person of ordinary skill in the art without undue experimentation. Human doses can be extrapolated from animal studies (see, e.g., Katocs et al., Chapter 27 in: Remington's Pharmaceutical Sciences., 18th edition, Gennaro, ed., Mack
Publishing Co., Easton, Pa., 1990). The dosage required to provide an effective amount of API in a pharmaceutical composition can generally be adjusted by one skilled in the art, and will vary depending on the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy (if any) and the nature and scope of the desired effect(s) (see, e.g., Nies et at, Chapter 3 in: Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th edition, Hardman et al.., eds., McGraw-Hill, New York, N. Y., 1996).
The bead formulation of the present invention contains vitamin E TPGS. It is available from Eastman Chemical Company under the trade name VITAMIN E TPGS. Alternatively, vitamin E TPGS can be prepared by esterifying the carboxyl group of crystalline d- α-tocopheryl acid succinate with polyethylene glycol 1000. The preparation of water-soluble tocopherol derivatives such as vitamin E TPGS and aqueous solutions thereof can be found in US 2680749 and US 3102078, the disclosures of which are incorporated by reference herein in their entireties. Vitamin E TPGS (which is alternatively and interchangeably referred to herein as
"TPGS") is a non-ionic surfactant. The term "surfactant" refers to a compound having both a hydrophilic head group, which energetically prefers solvation by water, and a hydrophobic tail that is not well solvated by water. A non-ionic surfactant is a compound in which the hydrophilic head group is neither a cation nor an anion. The HLB value of Vitamin E TPGS is approximately 13. The term "HLB value" refers to a theoretical index value which describes the hydrophilicity-lipophilicity balance of a specific compound. Generally, it is recognized that the HLB index ranges from 0 (very hydrophobic) to 40 (very hydrophilic). Further description of HLB and methods for calculating the HLB value of surfactants is provided in Surfactant Science Series, Vol. 1 : Nonionic Surfactants", pp 606-13, M. J. Schick (Marcel Dekker Inc., New York, 1966).
Without wishing to be bound by any particular theory, vitamin E TPGS is believed to act as an emulsifier and/or solubilizer of hydrophobic active pharmaceutical ingredients leading to improved wettability, dissolution, permeability and bioavailability of the active ingredient in solid oral dosage formulations. The bead formulation of the present invention also includes a filler/spheronization agent, a binder, and a superdisintegrant. The filler/spheronization agent employed in the present invention can be any substance that can act as both a filler and a spheronization agent. Thus,
suitable agents include any substance which (i) can impart bulk to the composition and (ii) can form, together with the other ingredients in the formulation, beads. The filler/spheronization agent can be a cellulosic derivative such as microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose. A filler/spheronization agent particularly suitable for use in the invention is a microcrystalline cellulose, such as AVICEL PH-112, AVICEL PH-IOl, AVICEL PH-102 (all of which are available from FMC Corporation), or a mixture of two or more thereof.
The binder employed in the present invention can be any substance that can impart cohesive qualities to the bead formulation of the present invention. More particularly, the binder is employed to ensure that the individual beads will remain intact after formation of the beads via spheronization. Suitable binders include acacia, alginic acid, carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydrogenated vegetable oil (type I), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (i.e., polyvinyl pyrrolidone), sodium alginate, starch, and zein. A binder particularly suitable for use in the invention is hydroxypropyl cellulose, hydroxypropyl methylcellulose, or povidone.
The superdisintegrant employed in the present invention can be any substance that in relatively small quantities can facilitate the breakup or disintegration of the beads after administration. Suitable superdisintegrants include croscarmellose sodium, crospovidone, and sodium starch glycolate.
Unless expressly stated to the contrary, ingredients employed in the bead formulation of the invention are limited to pharmaceutically acceptable substances. By "pharmaceutically acceptable" is meant that the ingredients of the bead formulation are compatible with each other and not deleterious to the recipient thereof. As made clear in the above description, the formulation of the invention is in the form of solid beads. The beads are approximately spherical in shape and can alternatively be referred to as pellets. For the purposes of this invention, the terms "bead" and "pellet" are used interchangeably. The beads can be described by their roundness. The roundness R of a bead is defined as: R = (P2)/4πA, wherein P is the perimeter of the cross section of the bead and A is the area defined by the cross section. R for a perfect circle is:
(2πr)2 = L 4π (πr2) Hence the roundness number for an object is greater than or equal to 1 depending on the departure of the shape of the object from a perfect sphere. Roundness R can be determined via
optical microscopy in conjunction with image analysis software. The beads in the formulation of the present invention typically have a roundness R in a range of from about 1.0 to about 1,8. The median R value for the beads is typically in a range of from about 1.0 to about 1.2.
The beads can also be characterized by their diameters which can be measured via optical microscopy in conjunction with image analysis software. The beads in the formulation of the present invention typically have an average diameter in a range of from about 0.5 mm to about 1.8 mm, and at least 50% of the beads have a diameter in a range of from about 0.6 mm to about 1.3 mm.
A first embodiment of the present invention (alternatively referred herein to as Embodiment El) is a solid pharmaceutical formulation for oral administration as originally defined above (i.e., as defined in the Summary of the Invention), wherein substantially all of the beads are approximately spherical in shape; the beads have an average diameter in a range of from about 0.6 mm to about 1.5 mm; at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1.2 mm; and the beads have a roundness value R in a range of from about 1.0 to about 1.5. In an aspect of Embodiment El, the beads have an average diameter in a range of from about 0.7 mm to about 1.3 mm; at least 50% of the beads have a diameter in a range of from about 0.8 mm to about 1.2 mm; and the beads have a roundness value R in a range of from about 1.0 to about 1.25.
As used herein, the term "substantially all" of the beads means suitably at least about 90 wt.% (e.g., from about 90 wt.% to about 99 wt.%), typically at least about 95 wt.%
(e.g., from about 95 wt.% to about 99 wt.%, or from about 98 wt.% to 100 wt.%), and preferably at least about 99 wt.% (e.g., 100 wt.%) of the solid pharmaceutical formulation of the present invention is in the form of beads.
A second embodiment of the present invention (Embodiment E2) is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in Embodiment El , wherein the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 40 wt.% (e.g., from about 1 wt.% to about 20 wt.%, or from about 5 wt.% to about 35 wt.%); the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.% to about 10 wt.%; and the superdisintegrant is employed in an amount in a range of from about 1 wt.% to about 10 wt.%.
Unless expressly stated to the contrary or otherwise clear from the context, the concentration of the components in the formulation of the invention is given as a weight percent (wt.%) which is based on the total weight of the solid formulation.
A third embodiment of the present invention (Embodiment E3) is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in
either Embodiment El or Embodiment E2, wherein the filler/spheronization agent is microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or povidone; and the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate.
A fourth embodiment of the present invention (Embodiment E4) is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in any of the preceding embodiments, wherein the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 40 wt.% (e.g., from about 5 wt.% to about 15 wt.%, or from about 10 wt.% to about 35 wt.%, or from about 10 wt.% to about 20 wt.%); the filler/spheronization agent is employed in an amount in a range of from about 5 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 2 wt.% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.% to about 6 wt.%. A fifth embodiment of the present invention (Embodiment E5) is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in any of the preceding embodiments, wherein the beads are encapsulated. As used herein, encapsulating the beads means filling one or more capsules (e.g., hard gelatin capsules) with a suitable amount of the beads, and then sealing the capsule(s). A sixth embodiment of the present invention (Embodiment E6) is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in any of the preceding embodiments, wherein the API is a compound of Formula I:
(D -H,
(2) bromo,
(3) chloro,
(4) fiuoro, or
(5) methoxy;
X2 is:
(1) -H,
(2) bromo,
(3) chloro,
(4) fluoro,
(5) methoxy,
(6) -Ci-4 alkyl,
(7) -CF3,
(8) -OCF3,
(9) -CN, or
(10) -SO2(Ci-4 alkyl);
Rl is:
(D -CO2H,
(2) -C(O)-O-C 1-4 alkyl,
(3) -C(=O)NH2,
(4) -C(=O)NH-Ci-4 alkyl,
(5) -C(=O)N(Ci-4 alkyl)2,
(6) -C(=O)-NH-(CH2)2-3-O-Ci-4 alkyl,
(7) -C(=O)-N(Ci-4 alkyl)-(CH2)2-3-O-Ci-4 alkyl,
(8) -NHC(=O)-Ci-4 alkyl,
(9) -N(CM alkyl)C(=O)-Ci_4 alkyl,
(10) -NHSO2-C1-4 alkyl,
(11) -N(Ci_4 alkyl)SO2-Ci-4 alkyl,
, wherein the asterisk * denotes the point of attachment to the rest of the compound,
(13) -C(=O)NH-(CH2)0-l -(C3.6 cycloalkyl),
(14) -C(=0)N(Ci-4 alkyl)-(CH2)0-l-(C3-6 cycloalkyl),
( 15) -C(=O)NH-CH2-phenyl> or
(16) -C(=O)N(Ci -4 alkyl)-CH2-phenyl; and R2 is:
(1) -H,
(2) -Ci -4 alkyl,
(3) cyclopropyl,
(4) cyclobutyl, (5) -CH2-oyclopropyl,
(6) -CH2-cyclobutyl, or
(7) -CH2-phenyl.
The compounds of Formula I and their pharmaceutically acceptable salts are HIV integrase inhibitors. These compounds, their preparation, and uses are further described in US 2007/0179196, WO 2005/087767 and WO 2005/087768, the disclosures of which are incorporated by reference herein in their entireties.
An aspect of Embodiment E6 is the formulation as defined in Embodiment E6, wherein in the compound of Formula I, or a pharmaceutically acceptable salt thereof, Xl is fiuoro; χ2 is -H or chloro; R.4 is:
(1) -C(=O)N(Ci-3 alkyl)2,
(3) -C(O)N(Ci -3 alkyl)-(CH2)0-l-cyclopropyl, or
(4) -C(O)N(Ci_3 alkyl)-(CH2)0-l-cyclobutyl; and R5 is -Ci-4 alkyl
In a feature of this aspect, the compound of Formula I is Compound A, or a pharmaceutically acceptable salt thereof, wherein Compound A is:
A seventh embodiment of the present invention (Embodiment E7) is a solid pharmaceutical formulation for oral administration as originally defined above or as defined in any of the preceding embodiments, wherein the API is a compound of Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R7 is hydrogen, Ci-6 alkyl, (CH2)l-3CF3, O-Ci-6 alkyl, halogen, OH, NO2, CN, 0<CH2)2-3CF3> CO2RA, CONRARB, O(CH2)2-3NRARB, O(CH2)l-2CORA, S(O)2RA, or SO2NRARB;
RA and RB are each independently H or Cl -6 alkyl; R3 and R^ are each independently selected from the group consisting of hydrogen, halogen, Ci -6 alkyl and Ci_g fluoroalkyl; and
R4, R5 and Rό are each independently selected from the group consisting of hydrogen, halogen, CN, Ci .5 alkyl and Cμg fluoroalkyl.
The compounds of Formula II and their pharmaceutically acceptable salts are HIV non-nucleoside reverse transcriptase inhibitors. These compounds, their preparation and uses are further described in US 2007/0021442, WO 2007/015809 and WO 2007/015812, the disclosures of which are incorporated by reference herein in their entireties.
In an aspect of Embodiment E7, the compound of Formula π is Compound B, or a pharmaceutically acceptable salt thereof, wherein Compound B is:
As used herein, the term "alkyl" refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. Thus, for example, "Cμg alkyl" (or "Ci-Cg alkyl") refers to any of the hexyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso- propyl, ethyl and methyl. As another example, "Ci -4 alkyl" refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
The term "fluoroalkyl1' refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a fluorine. Thus, for example, "Ci _g fluoroalkyl" (or "Ci-Cg fluoroalkyl") refers to a Cl to Cg linear or branched alkyl group as defined above with one or more fluorine substituents. Suitable fluoroalkyls include the series (CH2)θ-3CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.). A fluoroalkyl of particular interest is CF3.
The term "cycloalkyl" refers to any monovalent monocyclic ring of an alkane having a number of carbon atoms in the specified range. Thus, for example, "C3-6 cycloalkyl" (or "C3-C6 cycloalkyl") refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
An asterisk ("*") as the end of an open bond in a chemical group denotes the point of attachment of the group to the rest of the compound.
Combinations of substituents and/or variables are permissible for compounds of Formula I and Formula II only if such combinations result in a stable compound. The present invention includes a process {alternatively referred to herein as
"Process P") for preparing a solid pharmaceutical formulation comprising a hydrophobic active pharmaceutical ingredient, vitamin E TPGS, a filler/spheronization agent, a binder and a superdisintegrant, said solid formulation being in the form of beads, wherein the process comprises: (A) granulating a dry mixture that has been wetted with a solution of the vitamin E TPGS in a granulation fluid to provide a granulated mass, wherein the dry mixture comprises the active pharmaceutical ingredient, the filler/spheronization agent, the binder and the superdisintegrant;
(B) extruding the granulated mass to form an extrudate; (C) spheronizing the extrudate from Step B to provide the beads; and
(D) drying the beads from Step C at a temperature of less than about 35°C; wherein: the active pharmaceutical ingredient is employed in an effective amount; the vitamin E TPGS is employed in an amount of at least about 1 wt.%; the filler/spheronization agent is employed in an amount of at least about 5 wt.%; the binder is employed in an amount of at least about 0.5 wt.%; and the superdisintegrant is employed in an amount of at least about 0.5 wt.%; wherein all of the foregoing weight percents are based on the total weight of all individual components excluding the granulation fluid from the vitamin E TPGS granulation fluid solution.
A first embodiment of Process P (Embodiment El-P) is Process P as originally described above, wherein: the concentration of vitamin E TPGS in the granulation fluid solution is in a range of from about 2 wt.% to about 20 wt.%, and the weight of the granulating solution added to the dry mixture is in a range of from about 20 to about 65 wt.% w/w based on the weight of the dry mixture; the granulation in Step A is conducted using a high shear granulator at an impeller speed in a range of from about 200 rpm to about 600 rpm and a chopper speed of from about 500 rprn to about 2000 rpm for a time in a range of from about 1 to about 10 minutes (e.g., from about 2 to about 8 minutes) to provide the granulated mass;
the extrusion in Step B is conducted using a screw or basket extruder fitted with an axial radial or dome screw head at a screw speed in a range of from about 10 rpm to about 60 rpm; the spheronizing in Step C is conducted using a rotating disc spheronizer at a speed in a range of from about 800 rpm to about 2000 rpm, for a time in a range of from about 1 minute to about 15 minutes to provide beads; and the drying in Step D is conducted in an oven at a temperature in a range of from about 300C to about 35°C (e.g., from about 300C to about 320C) to obtain dried beads; wherein:
(i) the beads are approximately spherical in shape and have an average diameter in a range of from about 0.6 mm to about 1.5 mm;
(ii) at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1.2 mm; and
(iii) the beads have a roundness R in the range of from about 1.0 to about 1.5.
A second embodiment of Process P (Embodiment E2-P) is Process P as originally described or as described in Embodiment El-P, wherein: the granulation fluid employed in the vitamin E TPGS solution is water, a Cl -4 alkyl alcohol (e.g., methanol or ethanoϊ), or a mixture of water and a C 1-4 alkyl alcohol (e.g., water + methanol or water + ethanol); the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 20 wt.% (e.g., from about 1 wt.% to about 10 wt.%); the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.% to about 10 wt.%; and the super disintegrant is employed in an amount in a range of from about 1 wt.% to about 10 wt.%.
When the amount of vitamin E TPGS employed is relatively high (e.g., from about 13 wt.% to about 20 wt.%), the granulation fluid is typically water in combination with an alcohol co-solvent. For lower amounts of TPGS, either water alone or a water-alcohol mixture is suitable as the granulation fluid.
A third embodiment of Process P (Embodiment E3-P) is Process P as originally described or as described in either of Embodiments El-P or E2-P, wherein: the filler/spheronization agent is microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose;
the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinyl pyrollidone; and the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate, A fourth embodiment of Process P (Embodiment E4-P) is Process P as originally described or as described in any of the foregoing embodiments of Process P, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 15 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 5 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 2 wt.% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.% to about 6 wt.%.
A fifth embodiment of Process P (Embodiment E5-P) is Process P as originally described or as described in any of the foregoing embodiments of Process P, wherein the active pharmaceutical ingredient is a compound of Formula I as defined above (see Embodiment E6), a compound of Formula II as defined above (see Embodiment E7), or a pharmaceutically acceptable salt thereof.
A sixth embodiment of Process P (Embodiment E6-P) is Process P as originally described or as described in any of the foregoing embodiments of Process P5 wherein the active pharmaceutical ingredient is Compound A as defined above, Compound B as defined above, or a pharmaceutically acceptable salt thereof.
A seventh embodiment of Process P (Embodiment E7-P) is Process P as originally described or as described in any of the foregoing embodiments of Process P, wherein Process P further comprises:
(E) encapsulating the dried beads. The present invention also includes the solid pharmaceutical formulations prepared in accordance with Process P as originally described and as described in the foregoing embodiments of Process P.
The present invention includes another process (alternatively referred to herein as "Process Q") for preparing a solid pharmaceutical formulation comprising a hydrophobic active pharmaceutical ingredient, vitamin E TPGS, a filler/spheronization agent, a binder and a superdisintegrant, said solid formulation being in the form of beads, wherein the process comprises:
(A) blending a dry mixture comprising the active pharmaceutical ingredient, the vitamin E TPGS in the form of spray-dried granules, the fiϊler/spheronization agent, the binder and the superdisintegrant;
(B) wet granulating the blended mixture of Step A using a granulation fluid comprising water;
(C) extruding the granulated blend to form an extrudate;
(D) spheronizing the extrudate from Step C to provide the beads; and
(E) drying the beads from Step C at a temperature of less than about 35°C; wherein: the active pharmaceutical ingredient is employed in an effective amount; the vitamin E TPGS is employed in an amount of at least about 1 wt.%; the fϊller/spheronization agent is employed in an amount of at least about 5 wt.%; the binder is employed in an amount of at least about 0.5 wt.%; and the superdisintegrant is employed in an amount of at least about 0.5 wt.%; wherein all of the foregoing weight per cents are based on the total weight of all individual components excluding the granulation fluid.
A first embodiment of Process Q (Embodiment El-Q) is Process P as originally described above, wherein: the weight of the granulation fluid added to the blended mixture in Step B is in a range of from about 20 to about 65 wt.% w/w based on the weight of the dry mixture; the wet granulation in Step B is conducted using a high shear granulator at an impeller speed in a range of from about 200 rpm to about 600 rpm and a chopper speed of from about 500 rpm to about 2000 rpm for a time in a range of from about 1 to about 10 minutes to provide the granulated blend; the extrusion in Step C is conducted using a screw or basket extruder fitted with an axial radial or dome screw head at a screw speed in a range of from about 10 rpm to about 60 rpm; the spheronizing in Step D is conducted using a rotating disc spheronizer at a speed in a range of from about 800 rpm to about 2000 rpm, for a time in a range of from about 1 minute to about 15 minutes to provide beads; and the drying in Step E is conducted in an oven at a temperature in a range of from about 300C to about 35°C to obtain dried beads; wherein:
(i) the beads are approximately spherical in shape and have an average diameter in a range of from about 0.6 mm to about 1.5 mm; (ii) at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1 ,2 mm; and
(iii) the beads have a roundness R in the range of 1.0 to 1.5.
A second embodiment of Process Q (Embodiment E2-Q) is Process Q as originally described or as described in Embodiment El-Q, wherein: the granulation fluid employed in Step B is water, a Ci_4 alkyl alcohol, or a mixture of water and a Ci_4 alkyl alcohol; the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.% (e.g., from about 5 wt.% to about 75 wt.%); the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 45 wt.% (e.g., from about 5 wt.% to about 45 wt.%); the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.% to about 10 wt.%; and the superdisintegrant is employed in an amount in a range of from about 1 wt.% to about 10 wt.%. A third embodiment of Process Q (Embodiment E3-Q) is Process Q as originally described or as described in either of Embodiments El-Q or E2-Q, wherein: the filler/spheronization agent is microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinyl pyrollidone; and the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate.
A fourth embodiment of Process Q (Embodiment E4-Q) is Process Q as originally described or as described in any of the foregoing embodiments of Process Q, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.% (e.g., from about 20 wt.% to about 50 wt.%); the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 40 wt.% (e.g., from about 10 wt.% to about 35 wt.%); the filler/spheronization agent is employed in an amount in a range of from about
5 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 2 wt.% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.% to about 6 wt.%.
A fifth embodiment of Process Q (Embodiment E5-Q) is Process Q as originally described or as described in any of the foregoing embodiments of Process Q, wherein the active
pharmaceutical ingredient is a compound of Formula I as defined above (see Embodiment E6), a compound of Formula II as defined above (see Embodiment E7), or a pharmaceutically acceptable salt thereof.
A sixth embodiment of Process Q (Embodiment E6-Q) is Process Q as originally described or as described in any of the foregoing embodiments of Process Q, wherein the active pharmaceutical ingredient is Compound A as defined above, Compound B as defined above, or a pharmaceutically acceptable salt thereof.
A seventh embodiment of Process Q (Embodiment E7-Q) is Process Q as originally described or as described in any of the foregoing embodiments of Process Q, wherein Process Q further comprises:
(F) encapsulating the dried beads.
The present invention also includes the solid pharmaceutical formulations prepared in accordance with Process Q as originally described and as described in the foregoing embodiments of Process Q, All processing steps in Processes P and Q are conducted at temperatures less than the melting point of vitamin E TPGS, and typically all processing steps other than the drying step are conducted at ambient temperatures (i.e., 2O0C to 25°C). Bead drying is typically conducted at temperatures of about 35°C or less (e.g., from about 300C to about 35°C). The extruding step in Processes P and Q is typically conducted under ambient pressure conditions. While either Process P or Process Q can be employed to prepare bead formulations of the present invention, Process Q is typically more suitable for the preparation of bead formulations containing relatively large amounts (i.e., about 15 wt.% or more) of vitamin E TPGS. Process P utilizes a solution of TPGS and requires the use of a relatively large amount of granulation fluid in order to incorporate a large amount (i.e., more than about 15 wt.%) of TPGS in the bead formulation. On the other hand, Process Q employs TPGS in a solid form and thus increasingly larger quantities of granulation fluid are not required to prepare bead formulations with progressively higher TPGS concentrations.
Process P and Process Q can avoid the problems associated with the preparation of formulations containing high TPGS levels using conventional process trains wherein the melting of the TPGS can occur under the thermal conditions typically encountered in the milling and compacting steps. Furthermore, the processes of the invention can accommodate relatively large amounts of granulation fluid and potential over-granulation in Step A, because, unlike in a conventional granulation process, downstream processing involves extruding to strands followed by spheronization to larger beads. The need for granule growth control is greater for a conventional process than the process of the invention and thus the described process is more forgiving with respect to granule size and uniformity. Because Process P can employ relatively
large amounts of fluid, it permits the incorporation of higher levels of TPGS than is practical with conventional processing.
Abbreviations employed herein include the following: API = active pharmaceutical ingredient; g = gram(s); GFL = Granulation fluid; HPC = hydroxypropyl cellulose; TPGS = tocopherol polyethylene glycol succinate.
The following examples serve only to illustrate the invention and its practice. The examples are not to be construed as limitations on the scope or spirit of the invention.
In Examples 1 to 5, all processing steps prior to the oven drying step the temperature was at or close to ambient (i.e., 20 to 25°C).
EXAMPLE 1 Preparation of a formulation of Compound A via extrusion spheronization
Compound A, microcrystalline cellulose (Avicel PH 101), hydroxypropyl cellulose and croscarmellose sodium in the proportions set forth in Table 1 below (excluding the amount of the PH 101 that was sprinkled on extrudate as noted below) were transferred to the bowl of a high shear granulator (Bohle mini granulator Model No. A-Nr 60628) and dry mixed for 5 minutes at an impeller speed of 200 rpm and a chopper speed of 500 rpm. A 20 wt.% aqueous solution of vitamin E TPGS was then gradually added to the dry mixture. The impeller speed was increased to 250 rpm during the addition of the aqueous solution and the chopper speed was maintained at 500 rpm. Approximately 12,5 g of the vitamin E TPGS solution was added to provide 2.5 g of vitamin E TPGS per se, thus providing for a theoretical total batch size of 25 g in which vitamin E TPGS represented 10 wt.% of the total weight of the dry components (i.e., excluding water). The resulting granulated wet mass was then extruded on a lab scale basket extruder (CaI eva Model No. 10) fitted with a screen having an aperture size of 1 mm and operated at 30 rpm, followed by spheronization of the extrudate in a spheronizer (Caleva Model No. 120 ) operated at a speed of 1000 rpm for 5 minutes to provide beads. Approximately 1 g of the Avicel PH 101 was sprinkled on the extrudate during the spheronization to avoid aggregation of the beads. The beads were dried in an oven at 320C for 24 hours to obtain 75 wt.% Compound A-loaded beads.
Table 1
Figure 1 is an optical micrograph of a sample of the dried beads prepared in the manner described above. The diameter of the beads obtained by this process is primarily dependent upon the aperture size of the screen used during the extrusion process. In the current case, an aperture size of 1 mm yielded beads in the size range of 0.8 to 1.2 mm.
Figure 2 is a plot of R for beads prepared in the same manner as those described above. The R values were determined using an Olympus SZXl 6 microscope in conjunction with 'Image Pro Plus' version 4.5.0.29 for Windows 2000. A description of the software application can be found in the Image-Pro® Plus manual MAN 7841N42 20010530 (Media Cybernetics Inc, Silver Spring, MD), the disclosure of which is incorporated by reference herein in its entirety. The median R value is 1.11 , and the range of R values is from about 1.09 to about 1 ,19,
The optical microscope and Image Pro-Plus software described in the preceding paragraph were also used to measure the diameters of the beads. The bead diameters were determined to be in a range of from about 0.85 mm to 1.19 mm, and the median diameter of the beads was 0.96 mm.
EXAMPLE 2 Preparation of a formulation of Compound A via extrusion spheronization A formulation containing Compound A was prepared as follows using a batch size of 200 g in which the components were employed in the relative amounts set forth in Table 1 of Example 1 above; Weighed amounts of Compound A, microcrystalline cellulose (Avicel PH 101) (excluding the amount sprinkled on the extrudate as describe below), HPC3 and croscarmellose sodium were transferred to the bowl of a high shear granulator (Diosna Model No. P-l/6) and dry mixed for 90 seconds at an impeller speed of 300 rpm and a chopper speed of 2000 rpm. A 20 wt.% aqueous solution of vitamin E TPGS was then gradually added using a spray gun at a rate of 40 g/minute, wherein the impeller speed and the chopper speed were maintained at 300 rpm and 2000 rpm respectively during the addition. A total of approximately
100 g of the vitamin E TPGS solution was added resulting in the addition of 10 wt.% dry vitamin E TPGS. The wet mass obtained upon granulation was then extruded using a screw extruder (Fuji Paudal Model No. MG- 55) fitted with a dome extrusion head at a screw speed of 30 rpm, wherein the extrusion head had an opening size and a die thickness of 1 mm. The extrudate was spheronized using a rotating disc spheronizer (Fuji Paudal Model No. QJ230T) at around 1200 rpm. MicrocrystalHne cellulose (2-3 g of Avicel PH 101) was sprinkled on the extrudate during the spheronization to avoid aggregation of the beads. The beads were dried in an oven at 32°C for 24 hours to obtain 75 wt.% Compound A-loaded beads.
The resulting beads were characterized in the manner described in Example 1. Figure 3 is a plot of R for the beads prepared as just described. The median R value is 1.11, and the range of R values is from about 1.07 to about 1.19. The beads had diameters in a range of from about 0.77 mm to about 1.19 mm, and a median diameter of 0.95 mm.
EXAMPLE 3 Preparation of a formulation of Compound A via extrusion spheronization
Table 2
A formulation containing Compound A was prepared as follows using a batch size of 200 g in which the components were employed in the relative amounts set forth in Table 2. Weighed amounts of Compound A, spray dried granular TPGS, microcrystalline cellulose (Avicel PH 101) (excluding the amount sprinkled on the extrudate as described below), HPC, and croscarmellose sodium were transferred to the bowl of a high shear granulator (Diosna Model No. P- 1/6) and dry mixed for 3 minutes at an impeller speed of 300 rpm and a chopper speed of 1000 rpm. After the dry mixing deionized water was gradually added using a spray gun
at a rate of 26 g/minute, during which time the impeller speed and the chopper speed were maintained at 300 rpm and 1000 rpm respectively, A total of approximately 56 g of water as GFL was added. The wet mass obtained upon granulation was then extruded using a screw extruder (Fuji Paudal Model No. MG- 55) fitted with a dome extrusion head at a screw speed of 30 rpm, wherein the extrusion head had an opening size and a die thickness of 1 mm. The extrudate was spheronized using a rotating disc spheronizer (Fuji Paudal Model No. QJ230T) at around 1200 rpm. Microcrystalline cellulose (-20 g of Avicel PH 101) was sprinkled on the extrudate during the spheronization to avoid aggregation of the beads. The beads were dried in an oven at 320C for 24 hours to obtain 37.4 % w/w Compound A-loaded beads.
EXAMPLE 4
Preparation of a formulation of Compound A via conventional high shear wet granulation Compound A, microcrystalline cellulose (Avicel PH 101), hydroxypropyl cellulose and croscarmellose sodium in the proportions shown in Table 3 were transferred to a high shear granulator (Bohle mini granulator) bowl and dry mixed for 5 minutes at an impeller speed of 200 rprn and a chopper speed of 500 rpm, after which a 20% w/w solution of vitamin E TPGS in water was gradually added while the impeller speed was increase to 250 rpm and the chopper speed was maintained 500 rpm. A total of approximately 12.5 g of the TPGS solution was added to a theoretical total batch size of 25 g resulting in the addition of 10% w/w dry vitamin E TPGS. The granulation was dried in an oven at 32°C for 24 hours to obtain 61.54% w/w/ of drug-loaded granules. An attempt to encapsulate the granules was unsuccessful - the encapsulator became stuck and would not run.
Table 3
A formulation containing the components and amounts shown in Table 4 was prepared using the procedure set forth in Example 4.
Table 4
EXAMPLE 6 Bioperformance Study
Pharmacokinetic (PK) values for Compound A were determined in Beagle dogs orally dosed with encapsulated beads (pellets) prepared in the manner described in Example 1 and with encapsulated granules prepared in the manner described in Example 5. Fasted male beagle dogs (Marshall Farms) were used in the studies. The dogs were housed in an AAALAC- accredited facility in accordance with USDA guidelines. Studies were conducted under a protocol approved by the WP-IACUC. 3 dogs were employed in each study. The dose was approximately 10 mg per kg of body weight (i.e., 10 mpk).
Dosing: Following an overnight fast, the dogs were orally administered encapsulated formulations followed by 3.5 mL/kg of water. Food was returned 4 hours after dosing. Blood was drawn from 21 gauge catheters placed in the cephalic vein at pre-dose, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 24 hours after dosing. The plasma was separated by centrifugation (15 minutes at 2500 g) and stored overnight at -7O0C for LC/MS/MS the following day.
Sample preparation and analysis: The plasma samples were extracted using protein precipitation. Plasma extracts were injected onto a Waters Atlantis dC18, 2.1 x 50 mm, 5 μm HPLC column and analyzed using a 4.11 minute gradient consisting of mobile phase A = 0.1% formic acid in water and mobile phase B = 0.1% formic acid in acetonitrile. The following
gradient was used: 20%B to 95% B in 1.0 minute, hold at 95%B for 2.0 minutes, then re- equilibrate to 20%B for 1.1 minutes. Column oven temperature was 400C. The flow rate was 0.3 mL/min. The sample extracts were ionized using a Turbolonspray interface and were monitored by selected reaction monitoring (SRM) in the negative ionization mode. The dynamic range of the LC/MS/MS assay was 5-3000 ng/mL based on a 50 μL aliquot of dog plasma
PK Calculations: Area under the curve (AUCθ-24hr)> observed maximum plasma concentration (Cmaχ), and time of Cmax (Tmax) were calculated using a linear trapezoidal, non- compartmental model of WinNonLin v5.01. Means and SE were calculated using WinNonlin v5.01 or Microsoft® Excel 2002 SP3. Plasma profiles were generated using Sigmaplot 9.0 or WinNonlin v5.01 The results are shown in Table 5.
Table 5
1. The value in parentheses in each table entry is the standard deviation.
2. AUC ratio is the ratio of the AUCs in the table with respect to the AUC of Example 5.
The results in Table 5 show that the bead formulation of Example 1 with a surfactant to drug w/w ratio of 1 : 7.5 provided in vivo exposures comparable to those achieved with the granulated formulation of Example 5 having a surfactant to drag w/w ratio of 1 : 2.5. In other words, the bead formulation obtained via extrusion spheronization provided a PK profile comparable to that of an analogous granulated formulation containing 3 -fold more surfactant obtained by high-shear extrusion but without spheronization.
EXAMPLE 7 Bioperformance Study
A bead formulation of Compound A (Formulation 7-1) was prepared via extrusion spheronization in a manner similar to that described in Example 1. A granule formulation of Compound A (Formulation 7-2) was prepared via conventional high shear granulation in a manner similar to that described in Example 4. The compositions of Formulations 7-1 and 7-2 are shown in Tables 6 and 7 respectively.
Table 6- Formulation 7-1
Formulations 7-1 and 7-2 were tested in dogs using a protocol similar to that described above in Example 6. The results are shown in Table 7
Table 7
The bead formulation of Example 7-1 and the granule formulation of Example 7-2 have about the same surfactant to drug w/w ratios; i.e., 1 :7.2 and 1 :7.5 respectively. The results in Table 7 show that the bead formulation provided in vivo exposures the same or better than those achieved the granule formulation. However, the bead formulation of 7-1 had a C24 hr
about 5x higher than that achieved by granulated formulation 7-2, indicating that the overall PK profile of the bead formulation is superior.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, the practice of the invention encompasses all of the usual variations, adaptations and/or modifications that come within the scope of the following claims. All publications, patents, and patent applications cited herein are incorporated by reference herein in their entireties into the disclosure.
Claims
1. A solid pharmaceutical formulation for oral administration which comprises: (a) an effective amount of a hydrophobic active pharmaceutical ingredient,
(b) at least about 1 wt.% of vitamin E TPGS,
(c) at least about 5 wt.% of a filler/spheronization agent,
(d) at least about 0.5 wt.% of a binder, and
(e) at least about 0.5 wt.% of a superdisintegrant; wherein the formulation is in the form of beads.
2. The formulation according to claim 1, wherein substantially all of the beads are approximately spherical in shape; the beads have an average diameter in a range of from about 0.6 mm to about 1.5 mm; at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1.2 mm; and the beads have a roundness value in a range of from about 1.0 to about 1.5.
3. The formulation according to claim 1 or claim 2, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 40 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.% to about 10 wt.%; and the superdisintegrant is employed in an amount in a range of from about 1 wt.% to about 10 wt.%.
4. The formulation according to claim 3, wherein: the filler/spheronization agent is microcrystallme cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose ; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or povidone; and the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate.
5. The formulation according to claim 4, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 40 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 5 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 2 wt.% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.% to about 6 wt.%.
6. The formulation according to any one of claims 1 to 5, wherein the active pharmaceutical ingredient is a compound of Formula I:
XMs:
0) -H3 (2) bromo,
(3) chloro,
(4) fluoro, or
(5) methoxy;
X2 is: (1) -H,
(2) bromo,
(3) chloro,
(4) fluoro,
(5) methoxy, (6) -Ci_4 alkyl,
(V) -CF3,
(8) -OCF3,
(9) -CN, or
(10) -SO2(Ci-4 alkyl);
Rl is:
(1) -CO2H,
(2) -C(O)-O-CM alkyl,
(3) -C(O)NH2,
(4) -C(=O)NH-C i_4 alkyl,
(5) -CCO)N(Ci-4 alkyl)2,
(6) -C(O)-NH-(CH2)2-3-0-Ci-4 alkyl,
(7) -C(O)-NCCM alkyrKCH2)2-3-O-Ci-4 alkyl,
(8) -NHC(O)-C 1-4 alkyl,
(9) -N(C 1.4 alkyl)C(O)-Ci-4 alkyl,
(10) -NHSO2-C 1-4 alkyl,
(11) -N(CM alkyl)Sθ2-Cμ4 alkyl,
(12)
(13) -C(O)NH-(CH2)O-I ~(C3-ό cycloalkyl), (14) -C(O)N(CM alkyl)-(CH2)0-l-(C3-6 cycloalkyl),
(15) -C(O)NH-CH2-ρhenyl, or
(16) -C(O)N(Ci-4 alkyl)-CH2-ρhenyl; and R2 is:
(1) -H, (2) -Ci -4 alkyl,
(3) cyclopropyl,
(4) cyclobutyl,
(5) -CH2- cyclopropyl,
(6) -CH2-cycIobutyl, or (7) -CH2-phenyl.
7. The formulation according to claim 6, wherein the active pharmaceutical ingredient is Compound A:
Compound A,
or a pharmaceutically acceptable salt thereof.
8. The formulation according to any one of claims 1 to 5, wherein the active pharmaceutical ingredient is a compound of Formula II:
R7 is hydrogen, C\.(, alkyl, (CH2)l-3CF3, OCi -6 alkyl, halogen, OH, NO2, CN, O(CH2)2-3CF3, CC>2RA > CONRARB, O(CH2)2 -3NRARB5 0(CH2)1-2CORAJ S(O)2RA, or SO2NRARB;
RA and RB are each independently H or Ci_6 alkyl;
R3 and R8 are each independently selected from the group consisting of hydrogen, halogen, C\~β alkyl and Ci_6 fluoroalkyl; and
R4? R5 and R6 are each independently selected from the group consisting of hydrogen, halogen, CN, Cl -6 alkyl and Cl -6 fluoroalkyl.
9. The formulation according to claim 8, wherein the active pharmaceutical ingredient is Compound B:
10. The formulation according to any one of claims 1 to 9, wherein the beads are encapsulated.
I L A process for preparing a solid pharmaceutical formulation comprising a hydrophobic active pharmaceutical ingredient, vitamin E TPGS, a filler/spheronization agent, a binder and a superdisintegrant, said solid formulation being in the form of beads, wherein the process comprises:
(A) granulating a dry mixture that has been wetted with a solution of vitamin E TPGS in a granulation fluid to provide a granulated mass, wherein the dry mixture comprises the active pharmaceutical ingredient, the filler/spheronization agent, the binder and the superdisintegrant;
(B) extruding the granulated mass to form an extradate;
(C) spheronizing the extrudate from Step B to provide the beads; and (D) drying the beads from Step C at a temperature of less than about 35°C; wherein: the active pharmaceutical ingredient is employed in an effective amount; the vitamin E TPGS is employed in an amount of at least about 1 wt.%; the filler/spheronization agent is employed in an amount of at least about 5 wt.%; the binder is employed in an amount of at least about 0.5 wt.%; and the superdisintegrant is employed in an amount of at least about 0.5 wt.%; wherein all of the foregoing weight percents are based on the total weight of all individual components excluding the granulation fluid from the vitamin E TPGS granulation fluid solution.
12. The process according to claim 11 , wherein: the concentration of vitamin E TPGS in the granulation fluid solution is in a range of from about 2 wt.% to about 20 wt.%, and the weight of the granulating solution added to the dry mixture is in a range of from about 20 to about 65 wt.% w/w based on the weight of the dry mixture; the granulation in Step A is conducted using a high shear granulator at an impeller speed in a range of from about 200 rpm to about 600 rpm and a chopper speed of from about 500 rpm to about 2000 rpm for a time in a range of from about 1 to about 10 minutes to provide the granulated mass; the extrusion in Step B is conducted using a screw or basket extruder fitted with an axial radial or dome screw head at a screw speed in a range of from about 10 rpm to about 60 rpm;
the spheronizing in Step C is conducted using a rotating disc spheronizer at a speed in a range of from about 800 rpra to about 2000 rpm, for a time in a range of from about 1 minute to about 15 minutes to provide beads; and the drying in Step D is conducted in an oven at a temperature in a range of from about 300C to about 350C to obtain dried beads; wherein:
(i) the beads are approximately spherical in shape and have an average diameter in a range of from about 0.6 mm to about 1.5 mm',
(ii) at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1.2 mm; and (iii) the beads have a roundness R in the range of 1 ,0 to 1.5.
13. The process according to claim 11 or claim 12, which further comprises: (E) encapsulating the dried beads from Step D.
14. The process according to any one of claims 11 to 13, wherein: the granulation fluid employed in the vitamin E TPGS solution is water, a C\ -.4 alkyl alcohol, or a mixture of water and a C] .4 alkyl alcohol; the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 20 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.% to about 10 wt.%; and the superdisintegrant is employed in an amount in a range of from about 1 wt.% to about 10 wt.%.
15. The process according to claim 14, wherein: the filler/spheronization agent is microcrystalline cellulose, carboxymethylcellulose, starch or a mixture of microcrystalline cellulose and carboxymethylcellulose; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinyl pyrollidone; and the superdisintegrant is croscarmellose Na, crospovidone or sodium starch glycolate.
16. The process according to claim 14 or claim 15, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 15 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 5 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 2 wt.% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.% to about 6 wt.%.
17. The process according to any one of claims 11 to 16, wherein the active pharmaceutical ingredient is a compound of Formula I as defined in claim 6, a compound of Formula II as defined in claim 8, or a pharmaceutically acceptable salt thereof.
18. The process according to any one of claims 11 to 16, wherein the active pharmaceutical ingredient is Compound A as defined in claim 7, Compound B as defined in claim 9, or a pharmaceutically acceptable salt thereof.
19. A solid pharmaceutical formulation prepared according to the process recited in any one of claims 11 to 18.
20. A process for preparing a solid pharmaceutical formulation comprising a hydrophobic active pharmaceutical ingredient, vitamin E TPGS, a filler/spheronization agent, a binder and a superdisintegrant, said solid formulation being in the form of beads, wherein the process comprises:
(A) blending a dry mixture comprising the active pharmaceutical ingredient, the vitamin E TPGS in the form of spray-dried granules, the filler/spheronization agent, the binder and the superdisintegrant;
(B) wet granulating the blended mixture of Step A using a granulation fluid comprising water;
(C) extruding the granulated blend to form an extrudate;
(D) spheronizing the extrudate from Step C to provide the beads; and (E) drying the beads from Step C at a temperature of less than about 350C; wherein: the active pharmaceutical ingredient is employed in an effective amount;
the vitamin E TPGS is employed in an amount of al least about 1 wt.%; the filler/spheronization agent is employed in an amount of at least about 5 wt.%; the binder is employed in an amount of at least about 0.5 wt.%; and the superdisintegrant is employed in an amount of at least about 0.5 wt.%; wherein all of the foregoing weight percents are based on the total weight of all individual components excluding the granulation fluid.
21. The process according to claim 20, wherein: the weight of the granulation fluid added to the blended mixture in Step B is in a range of from about 20 to about 65 wt.% w/w based on the weight of the dry mixture; the wet granulation in Step B is conducted using a high shear granulator at an impeller speed in a range of from about 200 rpm to about 600 rpm and a chopper speed of from about 500 rpm to about 2000 rpm for a time in a range of from about 1 to about 10 minutes to provide the granulated blend; the extrusion in Step C is conducted using a screw or basket extruder fitted with an axial radial or dome screw head at a screw speed in a range of from about 10 rpm to about 60 rpm; the spheronizing in Step D is conducted using a rotating disc spheronizer at a speed in a range of from about 800 rpm to about 2000 rpm, for a time in a range of from about 1 minute to about 15 minutes to provide beads; and the drying in Step E is conducted in an oven at a temperature in a range of from about 3O0C to about 35°C to obtain dried beads; wherein:
(i) the beads are approximately spherical in shape and have an average diameter in a range of from about 0.6 mm to about 1.5 mm; (ii) at least 50% of the beads have a diameter in a range of from about 0.7 mm to about 1.2 mm; and
(iii) the beads have a roundness R in the range of 1.0 to 1.5.
22. The process according to claim 20 or claim 21 , which further comprises: (F) encapsulating the dried beads from Step E.
23. The process according to any one of claims 20 to 22, wherein: the granulation fluid employed in Step B is water, a C 1-4 alkyl alcohol, or a mixture of water and a Cl -4 alkyl alcohol; the active pharmaceutical ingredient is employed in an amount in a range of from about 1 wt.% to about 75 wt.%;
the vitamin E TPGS is employed in an amount in a range of from about 1 wt.% to about 45 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 1 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 1 wt.% to about 10 wt.%; and the superdisintegrant is employed in an amount in a range of from about 1 wt.% to about 10 wt.%.
24. The process according to claim 23, wherein: the filler/spheronization agent is microcrystalline cellulose, carboxymethyl cellulose, starch or a mixture of microcrystalline cellulose and carboxymethyl cellul ose; the binder is hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or polyvinyl pyrollidone; and the superdisintegrant is croscarrnellose Na, crospovidone or sodium starch glycolate.
25. The process according to claim 23 or claim 24, wherein: the active pharmaceutical ingredient is employed in an amount in a range of from about 10 wt.% to about 75 wt.%; the vitamin E TPGS is employed in an amount in a range of from about 5 wt.% to about 40 wt.%; the filler/spheronization agent is employed in an amount in a range of from about 5 wt.% to about 75 wt.%; the binder is employed in an amount in a range of from about 2 wt,% to about 6 wt.%; and the superdisintegrant is employed in an amount in a range of from about 2 wt.% to about 6 wt.%.
26. The process according to any one of claims 20 to 25, wherein the active pharmaceutical ingredient is a compound of Formula I as defined in claim 6, a compound of Formula H as defined in claim 8, or a pharmaceutically acceptable salt thereof.
27. The process according to any one of claims 20 to 25 , wherein the active pharmaceutical ingredient is Compound A as defined in claim 7, Compound B as defined in claim 9, or a pharmaceutically acceptable salt thereof.
28. A solid pharmaceutical formulation prepared according to the process recited in any one of claims 20 to 27.
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US18825208P | 2008-08-07 | 2008-08-07 | |
US61/188,252 | 2008-08-07 |
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WO2010017056A1 true WO2010017056A1 (en) | 2010-02-11 |
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PCT/US2009/051887 WO2010017056A1 (en) | 2008-08-07 | 2009-07-28 | Orally administered solid formulations containing a hydrophobic drug and tpgs |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2022072099A1 (en) * | 2020-09-30 | 2022-04-07 | Eirgen Pharma, Ltd | Immediate release dosage forms, methods of making and using |
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US5780055A (en) * | 1996-09-06 | 1998-07-14 | University Of Maryland, Baltimore | Cushioning beads and tablet comprising the same capable of forming a suspension |
US20030064097A1 (en) * | 1999-11-23 | 2003-04-03 | Patel Mahesh V. | Solid carriers for improved delivery of hydrophobic active ingredients in pharmaceutical compositions |
US20070298103A1 (en) * | 2004-02-12 | 2007-12-27 | Euro-Celtique S.A. | Particulates |
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2009
- 2009-07-28 WO PCT/US2009/051887 patent/WO2010017056A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US5780055A (en) * | 1996-09-06 | 1998-07-14 | University Of Maryland, Baltimore | Cushioning beads and tablet comprising the same capable of forming a suspension |
US20030064097A1 (en) * | 1999-11-23 | 2003-04-03 | Patel Mahesh V. | Solid carriers for improved delivery of hydrophobic active ingredients in pharmaceutical compositions |
US20070298103A1 (en) * | 2004-02-12 | 2007-12-27 | Euro-Celtique S.A. | Particulates |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2022072099A1 (en) * | 2020-09-30 | 2022-04-07 | Eirgen Pharma, Ltd | Immediate release dosage forms, methods of making and using |
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