WO2015145324A1 - Process for the preparation of cobicistat - Google Patents
Process for the preparation of cobicistat Download PDFInfo
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- WO2015145324A1 WO2015145324A1 PCT/IB2015/052101 IB2015052101W WO2015145324A1 WO 2015145324 A1 WO2015145324 A1 WO 2015145324A1 IB 2015052101 W IB2015052101 W IB 2015052101W WO 2015145324 A1 WO2015145324 A1 WO 2015145324A1
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- WIPO (PCT)
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- silicon dioxide
- dioxide particles
- cobicistat
- composition
- microns
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- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
-
- 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
- A61K9/1611—Inorganic compounds
-
- 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
- A61K9/1682—Processes
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Definitions
- the present invention relates generally to pharmaceutical compositions and more particularly to cobicistat adsorbed on silicon dioxide.
- Cobicistat is chemically known as l,3-thiazol-5-ylmethyl [(2R,5R)-5- ⁇ [(2S)2- [(methyl ⁇ [2-(propan-2-yl)-l,3-thiazol-4-yl]methyl ⁇ carbamoyl)amino]-4-(morpholin-4- yl)butanoyl]amino ⁇ -l,6-diphenylhexan-2-yl]carbamate (Formula I).
- Cobicistat is a potent inhibitor of cytochrome P450 3A enzymes, including the CYP3A4 subtype. It also inhibits intestinal transport proteins, increasing the overall absorption of several HIV medications, including atazanavir, darunavir, and tenofovir alafenamide fumarate. Cobicistat is often incorporated as a component of a four-drug, fixed-dose combination for HIV treatment known as STRIBILD® or the "Quad Pill", which contains elvitegravir, cobicistat, emtricitabine, and tenofovir. The "Quad Pill'VSTRIBILD® was approved by the FDA in August 2012 for use in the United States.
- U.S. Patent No. 8,148,374, which is hereby incorporated by reference discloses cobicistat and pharmaceutically acceptable salts thereof.
- U.S. publication No. 2009/0324729A1 which is hereby incorporated by reference, discloses cobicistat silica particles.
- cobicistat-silicon dioxide particles may be prepared from silicon dioxide particles having a mean particle diameter of about 1 to about 10 micron and a Brunauer-Emmett-Teller (BET) surface area of about 50 to about
- BET Brunauer-Emmett-Teller
- the cobicistat-silicon dioxide particles may be prepared from silicon dioxide particles having a mean particle diameter of about 120 microns to about 200 micron and a BET surface area of about 50 m 2 /g to about 400 m 2 /g .
- Another aspect of the present invention provides a process for the preparation of cobicistat-silicon dioxide particles.
- cobicistat-silicon dioxide particles will be used to mean particles of silicon dioxide having cobicistat adsorbed onto the surface of the silicon dioxide particles.
- cobicistat- silicon dioxide particles prepared from silicon dioxide particles having a mean particle diameter of about 1 micron to about 10 microns and a BET surface area of about 50 m 2 /g to about 400 m /g.
- silicon dioxide with a mean grain diameter of about 2 microns to about 6 microns has been found to be particularly useful as a starting material for making particles of the present invention.
- a mean grain of silicon dioxide having a diameter of 2.5 microns to about 3.7 microns has been found to be particularly useful.
- silicon dioxide with a BET surface area of at least 250 m 2 /g has been found to be particularly useful when preparing cobicistat-silicon dioxide particles.
- a BET surface area of at least 400 m 2 /g has been found to be particularly useful.
- Another embodiment of the present invention provides cobicistat-silicon dioxide particles prepared using silicon dioxide particles with a mean particle diameter of about 120 to about 200 microns and a BET surface area of about 50 m 2 /g to about 400 m 2 /g as a starting material.
- preparing cobicistat- silicon dioxide particles from silicon dioxide particles having a mean grain diameter of about 120 microns to about 180 microns has been found to be particularly useful.
- silicon dioxide particles with a mean grain diameter of about 120 microns to about 270 microns have been found to be particularly useful in this process.
- silicon dioxide with a BET surface area of at least 250 m 2 /g has been found to be particularly useful when preparing cobicistat-silicon dioxide particles. In other embodiments, a BET surface area of at least 400 m 2 /g has been found to be particularly useful.
- Yet another aspect of the present invention provides a process for the preparation of cobicistat-silicon dioxide particles which may be carried out according to the following steps: a) dissolving cobicistat in an organic solvent to form a solution, b) adding silicon dioxide to the above solution, c) optionally adding aliphatic hydrocarbon solvents, and d) isolating cobicistat-silicon dioxide particles.
- cobicistat is dissolved at about 25 - 30 °C in an organic solvent.
- the organic solvent may be ethanol, methanol, n-heptane, n-hexane, or a chlorinated hydrocarbon.
- suitable chlorinated hydrocarbons include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, and mixtures thereof.
- an aliphatic hydrocarbon solvent may then be optionally added to this solution and the mixture is stirred to get a uniform solution. While not wishing to be bound by theory, it is believed that the inclusion of the aliphatic hydrocarbon solvent aids in formation, enrichment, isolation of the cobicistat-silicon dioxide particles by creating an environment where the cobicistat-silicon dioxide particles are not soluble.
- the aliphatic hydrocarbon solvent may be, for example, n-heptane, hexane, pentane, cyclohexane, toluene, xylene, or mixtures thereof.
- the silicon dioxide starting material may take a variety of forms, however, in particularly effective embodiments the silicon dioxide particles possess a surface and pores.
- Syloid® 244 FP, Syloid® XDP 3150 may also be used.
- the weight percentage of cobicistat (formula I) in the final form, the cobicistat-silicon dioxide particles may be about 50% ⁇ 10% of the silicon dioxide particles.
- the chlorinated solvent may be removed.
- the chlorinated solvent is removed by placing the reaction mass under reduced pressure, maintaining the reaction mass at a temperature less than about 40 °C, resulting in a slurry mixture.
- the slurry mixture may then be cooled to between about 25 °C to about 30 °C.
- a solid may then be isolated, for example, by filtering, to obtain the desired product.
- the cobicistat-silicon dioxide particles of the present invention may be included in tablets for oral administration to patients suffering from HIV.
- a tablet formulation including lactose monohydrate, microcrystalline cellulose, silicon dioxide, croscarmelose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and magnesium stearate.
- the tablets may be coated with a film that may include the following ingredients: indigo carmine aluminum lake (and other natural and artificial colors), polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
- cobicistat-silicon dioxide particles disclosed herein may be combined with additional active pharmaceutical components for the treatment of viral infections, including HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, G6PD inhibitors, NADH-oxidase inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, other drugs for treating HIV, interferons, ribavirin, NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, NS5a inhibitors, NS5b polymerase inhibitors, other drugs for treating HCV, and combinations thereof.
- additional active pharmaceutical components for the treatment of viral infections including HIV protease inhibitors, HIV
- the cobicistat-silicon dioxide particles disclosed herein may be formulated in a solid dosage form that may include elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil fumarate, atazanavir, or combinations thereof.
- Cobicistat 100 g was dissolved in dichloromethane (600 rriL) and the reaction mixture was stirred for 20 - 30 minutes at 24 ⁇ 3 °C.
- n-heptane 500 rriL was added at 22 ⁇ 3 °C to get a uniform solution.
- Silicon dioxide 92 g was added to the above solution and the reaction mass continued to stir for 2-3 hours at same temperature until a uniform slurry was formed.
- Pre-filtered n-heptane 1000 rriL was slowly added to the slurry at uniform rate for 3-4 hours at same temperature.
- Dichloromethane solvent is distilled out under reduced pressure below 40 °C until the volume reaches 1000 mL.
- the resulting product slurry was cooled to 25-30 °C; stirring continued for 20-40 minutes.
- the product was filtered, suck dried thoroughly, and then washed with pre-filtered n-heptane.
- the product was dried under reduced pressure (20 - 400 mm Hg) below 40 °C until the product contained less than 2.0% w/w of water and residual solvents.
- the material was cooled to below 23 ⁇ 3 °C and unloaded.
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Abstract
Cobicistat-silicon dioxide particles and pharmaceutical compositions containing the same. The compositions and processes disclosed herein provide cobicistat-silicon dioxide particles that possess satisfactory processability for incorporation into a pharmaceutical composition.
Description
PROCESS FOR THE PREPARATION OF COBICISTAT
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application No. 1562/CHE/2014, filed on March 24, 2014.
BACKGROUND OF THE INVENTION FIELD OF THE INVENTION
The present invention relates generally to pharmaceutical compositions and more particularly to cobicistat adsorbed on silicon dioxide. BACKGROUND OF THE INVENTION
Cobicistat is chemically known as l,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)2- [(methyl{[2-(propan-2-yl)-l,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4- yl)butanoyl]amino}-l,6-diphenylhexan-2-yl]carbamate (Formula I).
Formula I
Cobicistat is a potent inhibitor of cytochrome P450 3A enzymes, including the CYP3A4 subtype. It also inhibits intestinal transport proteins, increasing the overall absorption of several HIV medications, including atazanavir, darunavir, and tenofovir alafenamide fumarate.
Cobicistat is often incorporated as a component of a four-drug, fixed-dose combination for HIV treatment known as STRIBILD® or the "Quad Pill", which contains elvitegravir, cobicistat, emtricitabine, and tenofovir. The "Quad Pill'VSTRIBILD® was approved by the FDA in August 2012 for use in the United States. U.S. Patent No. 8,148,374, which is hereby incorporated by reference, discloses cobicistat and pharmaceutically acceptable salts thereof. U.S. publication No. 2009/0324729A1, which is hereby incorporated by reference, discloses cobicistat silica particles.
There is a need in the art to reduce the cobicistat silica particle diameter to improve the processability of the pharmaceutical agent.
SUMMARY OF THE INVENTION
One aspect of the present invention provides cobicistat-silicon dioxide particles. In one embodiment of the present invention, the cobicistat-silicon dioxide particles may be prepared from silicon dioxide particles having a mean particle diameter of about 1 to about 10 micron and a Brunauer-Emmett-Teller (BET) surface area of about 50 to about
400 m2/g.
In another embodiment of the present invention, the cobicistat-silicon dioxide particles may be prepared from silicon dioxide particles having a mean particle diameter of about 120 microns to about 200 micron and a BET surface area of about 50 m2/g to about 400 m2/g.
Another aspect of the present invention provides a process for the preparation of cobicistat-silicon dioxide particles.
DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known. The present invention relates to cobicistat-silicon dioxide particles and processes for the preparation of the same. As used herein, the phrase "cobicistat-silicon dioxide particles" will be used to mean particles of silicon dioxide having cobicistat adsorbed onto the surface of the silicon dioxide particles.
Through application of the methods of the present invention, there is provided cobicistat- silicon dioxide particles prepared from silicon dioxide particles having a mean particle diameter of about 1 micron to about 10 microns and a BET surface area of about 50 m2/g to about 400 m /g. In some embodiments, silicon dioxide with a mean grain diameter of about 2 microns to about 6 microns has been found to be particularly useful as a starting material for making particles of the present invention. In other embodiments a mean grain of silicon dioxide having a diameter of 2.5 microns to about 3.7 microns has been found to be particularly useful. In some embodiments, silicon dioxide with a BET surface area of at least 250 m2/g has been found to be particularly useful when preparing cobicistat-silicon dioxide particles. In other embodiments, a BET surface area of at least 400 m2/g has been found to be particularly useful. Another embodiment of the present invention provides cobicistat-silicon dioxide particles prepared using silicon dioxide particles with a mean particle diameter of about 120 to about 200 microns and a BET surface area of about 50 m2/g to about 400 m2/g as a starting material. In some embodiments of the present invention, preparing cobicistat- silicon dioxide particles from silicon dioxide particles having a mean grain diameter of about 120 microns to about 180 microns has been found to be particularly useful. In other embodiments, silicon dioxide particles with a mean grain diameter of about 120 microns to about 270 microns have been found to be particularly useful in this process.
In some embodiments, silicon dioxide with a BET surface area of at least 250 m2/g has been found to be particularly useful when preparing cobicistat-silicon dioxide particles. In other embodiments, a BET surface area of at least 400 m2/g has been found to be particularly useful.
Yet another aspect of the present invention provides a process for the preparation of cobicistat-silicon dioxide particles which may be carried out according to the following steps: a) dissolving cobicistat in an organic solvent to form a solution, b) adding silicon dioxide to the above solution, c) optionally adding aliphatic hydrocarbon solvents, and d) isolating cobicistat-silicon dioxide particles.
According to the present disclosure, cobicistat is dissolved at about 25 - 30 °C in an organic solvent. Within the context of the present invention, the organic solvent may be ethanol, methanol, n-heptane, n-hexane, or a chlorinated hydrocarbon. Examples of suitable chlorinated hydrocarbons include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, and mixtures thereof.
An aliphatic hydrocarbon solvent may then be optionally added to this solution and the mixture is stirred to get a uniform solution. While not wishing to be bound by theory, it is believed that the inclusion of the aliphatic hydrocarbon solvent aids in formation, enrichment, isolation of the cobicistat-silicon dioxide particles by creating an environment where the cobicistat-silicon dioxide particles are not soluble. Within the context of the present invention, the aliphatic hydrocarbon solvent may be, for example, n-heptane, hexane, pentane, cyclohexane, toluene, xylene, or mixtures thereof.
Silicon dioxide is then added to the solution and stirring is continued, maintaining the solution temperature below about 30 °C until the reaction mass becomes a substantially uniform slurry. According to the present invention, the silicon dioxide starting material
may take a variety of forms, however, in particularly effective embodiments the silicon dioxide particles possess a surface and pores. In some embodiments of the present invention, Syloid® 244 FP, Syloid® XDP 3150. However, other materials having similar physical and chemical properties to the silicon dioxide materials described herein, for example, similar porosity and surface area, may also be used. According to the present disclosure, the weight percentage of cobicistat (formula I) in the final form, the cobicistat-silicon dioxide particles may be about 50% ± 10% of the silicon dioxide particles.
Next, the chlorinated solvent may be removed. In some embodiments of the present invention, the chlorinated solvent is removed by placing the reaction mass under reduced pressure, maintaining the reaction mass at a temperature less than about 40 °C, resulting in a slurry mixture. The slurry mixture may then be cooled to between about 25 °C to about 30 °C. A solid may then be isolated, for example, by filtering, to obtain the desired product. In some embodiments, the cobicistat-silicon dioxide particles of the present invention may be included in tablets for oral administration to patients suffering from HIV. One of skill in the art will recognize a wide variety of pharmaceutically acceptable excipients that may be included in such a tablet formulation, including lactose monohydrate, microcrystalline cellulose, silicon dioxide, croscarmelose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and magnesium stearate. The tablets may be coated with a film that may include the following ingredients: indigo carmine aluminum lake (and other natural and artificial colors), polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
The cobicistat-silicon dioxide particles disclosed herein may be combined with additional active pharmaceutical components for the treatment of viral infections, including HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, G6PD inhibitors, NADH-oxidase inhibitors, CCR5 inhibitors, capsid
polymerization inhibitors, other drugs for treating HIV, interferons, ribavirin, NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, NS5a inhibitors, NS5b polymerase inhibitors, other drugs for treating HCV, and combinations thereof. In some particularly useful embodiments, the cobicistat-silicon dioxide particles disclosed herein may be formulated in a solid dosage form that may include elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil fumarate, atazanavir, or combinations thereof.
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following example that details certain procedures for the preparation of molecules, compositions, and formulations according to the present invention. All references made to the example are for the purposes of illustration. The following example should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
Example:
Cobicistat (100 g) was dissolved in dichloromethane (600 rriL) and the reaction mixture was stirred for 20 - 30 minutes at 24 ± 3 °C. To this solution, n-heptane (500 rriL) was added at 22 ± 3 °C to get a uniform solution. Silicon dioxide (92 g) was added to the above solution and the reaction mass continued to stir for 2-3 hours at same temperature until a uniform slurry was formed. Pre-filtered n-heptane (1000 rriL) was slowly added to the slurry at uniform rate for 3-4 hours at same temperature. Dichloromethane solvent is distilled out under reduced pressure below 40 °C until the volume reaches 1000 mL. The resulting product slurry was cooled to 25-30 °C; stirring continued for 20-40 minutes. The product was filtered, suck dried thoroughly, and then washed with pre-filtered n-heptane. The product was dried under reduced pressure (20 - 400 mm Hg) below 40 °C until the product contained less than 2.0% w/w of water and residual solvents. The material was cooled to below 23 ± 3 °C and unloaded.
Claims
1. A composition comprising a plurality of silicon dioxide particles and cobicistat or a pharmaceutically acceptable salt thereof, where each of said plurality of silicon dioxide particles has a surface and pores, where cobicistat or a pharmaceutically acceptable salt thereof is adsorbed onto the surface and into the pores of the plurality of silicon dioxide particles.
2. The composition according to claim 1, wherein the plurality of silicon dioxide particles has a mean grain diameter of about 1 micron to about 10 microns and wherein each of the silicon dioxide particles has a BET surface area of about 50 m2/g to about 400 m2/g.
3. The composition according to claim 1, wherein the plurality of silicon dioxide particles has a mean grain diameter of about 120 microns to about 200 microns and wherein each of the silicon dioxide particles has a BET surface area of about 50 m2/g to about 400 m2/g.
4. The composition of claim 1 , wherein the plurality of silicon dioxide particles has a mean grain diameter of about 1 micron to about 10 microns.
5. The composition of claim 1, wherein the plurality of silicon dioxide particles has a mean grain diameter of about 120 to about 200 microns.
6. The composition of claim 1, wherein the plurality of silicon dioxide particles have a BET surface area of at least 100 m2/g.
7. The composition of claim 1, wherein a weight percentage of cobicistat or a pharmaceutically acceptable salt thereof to the plurality of silicon dioxide particles is between about 40% and about 60%.
8. The composition of claim 7, wherein the weight percentage is about 50%.
9. The composition of claim 1, further comprising one or more pharmaceutically acceptable excipients.
10. A process for preparation of cobicistat-silicon dioxide particles, comprising the steps of:
a) dissolving cobicistat in an organic solvent to form a solution;
b) adding silicon dioxide particles to the solution; and
c) isolating the cobicistat-silicon dioxide particles.
11. The process according to claim 10, further comprising the step of adding a aliphatic hydrocarbon solvent after adding silicon dioxide particles and before isolating the cobicistat-silicon dioxide particles.
12. The process according to claim 10, wherein the organic solvent is selected from the group consisting of ethanol, methanol, n-heptane, hexane, a chlorinated solvent, and mixtures thereof.
13. The process according to claim 12, wherein the chlorinated solvent is selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, and mixtures thereof.
14. The process according to claim 11, wherein the aliphatic hydrocarbon solvent is selected from the group consisting of n-heptane, hexane, pentane, cyclohexane, toluene, xylene, and mixture thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IN1562CH2014 | 2014-03-25 | ||
IN1562/CHE/2014 | 2014-03-25 |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003037379A1 (en) * | 2001-10-30 | 2003-05-08 | Degussa Ag | Use of granular materials based on pyrogenically produced silicon dioxide in pharmaceutical compositions |
WO2009135179A2 (en) * | 2008-05-02 | 2009-11-05 | Gilead Sciences, Inc. | The use of solid carrier particles to improve the processability of a pharmaceutical agent |
US8148374B2 (en) | 2007-02-23 | 2012-04-03 | Gilead Sciences, Inc. | Modulators of pharmacokinetic properties of therapeutics |
-
2015
- 2015-03-23 WO PCT/IB2015/052101 patent/WO2015145324A1/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003037379A1 (en) * | 2001-10-30 | 2003-05-08 | Degussa Ag | Use of granular materials based on pyrogenically produced silicon dioxide in pharmaceutical compositions |
US8148374B2 (en) | 2007-02-23 | 2012-04-03 | Gilead Sciences, Inc. | Modulators of pharmacokinetic properties of therapeutics |
WO2009135179A2 (en) * | 2008-05-02 | 2009-11-05 | Gilead Sciences, Inc. | The use of solid carrier particles to improve the processability of a pharmaceutical agent |
US20090324729A1 (en) | 2008-05-02 | 2009-12-31 | Gilead Sciences, Inc. | Use of solid carrier particles to improve the processability of a pharmaceutical agent |
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