CA2423335A1 - Spray drying process and compositions of fenofibrate - Google Patents

Spray drying process and compositions of fenofibrate Download PDF

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Publication number
CA2423335A1
CA2423335A1 CA002423335A CA2423335A CA2423335A1 CA 2423335 A1 CA2423335 A1 CA 2423335A1 CA 002423335 A CA002423335 A CA 002423335A CA 2423335 A CA2423335 A CA 2423335A CA 2423335 A1 CA2423335 A1 CA 2423335A1
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CA
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Prior art keywords
fenofibrate
dosage form
active species
phospholipid
patient
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CA002423335A
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French (fr)
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CA2423335C (en
Inventor
Gary Pace
Robert A. Snow
Indu Parikh
Pol-Henri Guivarc'h
Awadhesh K. Mishra
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Skyepharma Canada Inc
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Individual
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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
    • A61K31/66—Phosphorus compounds
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/145—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 organic 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Abstract

The present invention relates to a novel spray drying process for the preparation of pharmaceutical compositions containing small particles of phospholipid-stabilized fenofibrate. This invention also relates to spray dried powdered compositions prepared according to this process and to dosage forms of fenofibrate (capsules, tablets, powders, granules, and dispersions) prepared from these powdered compositions. The powdered compositions and dosage forms are useful in the treatment of dyslipidemia and dyslipoproteinemia and have the advantage that they provide reduced in vivo variability in the bioavailability of fenofibrate active species among fed and fasted patients when administered orally.

Claims (60)

1. A process for the preparation of small particles or microparticles containing fenofibrate and a phospholipid surface stabilizing substance comprising the steps of:

a) mixing at high shear an admixture of fenofibrate and a phospholipid substance in an aqueous carrier in the absence of an organic solvent and optionally in the presence of one or more than one surface active substances within a first temperature range at or above the melting point of the drug to form a heated suspension containing the drug, then b) homogenizing said heated suspension in a first pressure range and within said first temperature range to form a heated homogenate containing the drug, then c) spray drying the heated homogenate to form dried small particles containing the drug wherein one or more bulking agents is added at any stage of either of steps (a) or (b) and wherein at least one surface active agent is a phospholipid.
2. The process of claim 1 wherein the bulking agent is selected from the group consisting of a monosaccharide, a disaccharide, a trisaccharide, sucrose, lactose, mannitol, sorbitol, trehalose, glycerol, dextrose, fructose, a sugar, a pentose, a hexose, xylitol, and mixtures thereof.
3. The process of claim 1 wherein the bulking agent is selected from the group consisting of sucrose, lactose, mannitol, sorbitol, trehalose, and mixtures thereof.
4. The process of claim 1 wherein the phospholipid is selected from the group consisting of Lipoid E80, Lipoid EPC, Lipoid SPC, DMPG, Phospholipon 100H, Lipoid SPC-3, and mixtures thereof.
5. The process of claim 1 wherein the phospholipid is Lipoid E80.
6. The process of claim 1 wherein the first temperature range is from the melting point of fenofibrate to 20°C higher than the melting point of fenofibrate.
7. The process of claim 1 wherein the aqueous carrier is selected from the group consisting of water, sterile water, water for injection, and phosphate buffered water having a pH from 4 to 10.
8. The process of claim 1 wherein the aqueous Garner is phosphate buffered water having a pH from 7 to 9.
9. The process of claim 1 wherein the aqueous carrier is phosphate buffered water having a pH from 7.5 to 8.5.
10. The process of claim 1 wherein the first pressure range is from 2,000 to 30.000 psi.
11. The process of claim 1 wherein the small particles containing fenofibrate have an average size in the range from 0.1 to 10 micrometers.
12. The process of claim 1 wherein the small particles containing fenofibrate have an average size in the range from 0.1 to 5 micrometers.
13. The process of claim 1 wherein the small particles containing fenofibrate have an average size in the range from 0.1 to 2 micrometers.
14. A composition comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance that is prepared,according to the process of claim 1 further containing from 0.1 to about 5% water.
15. An orally administered pharmaceutical composition comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1, wherein a therapeutically effective amount of said pharmaceutical composition provides a quantity of fenofibrate active species to a fasted human patient in need of treatment by said fenofibrate that is Greater than 90% of the quantity of said fenofibrate active species provided by said amount to said patient when fed a high fat meal.
16. A capsule or tablet or powder or granular dosage form for oral administration comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein said amount of said dosage form provides a level of fibrate active species into the blood of a patient in a fasted state that differs by less than 25% of the level of said fibrate active species that said patient receives in a fed state.
17. A capsule or tablet or powder or granular dosage form for oral administration comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein said amount of said dosage form provides a level of fibrate active species into the blood of a patient in a fasted state that differs by less than 20% of the level of said fibrate active species that said patient receives in a fed state.
18. A capsule or tablet or powder or granular dosage form for oral administration comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein said amount of said dosage form provides a level of fibrate active species into the blood of a patient in a fasted state that differs by less than 15% of the level of said fibrate active species that said patient receives in a fed state.
19. A capsule or tablet or powder or granular dosage form for oral administration comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein said amount of said dosage form provides a level of fibrate active species into the blood of a patient in a fasted state that differs by less than 10% of the level of said fibrate active species that said patient receives in a fed state.
20. A capsule or tablet or powder or granular dosage form for oral administration comprising microparticles containing fenofibrate, and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein said amount of said dosage form provides a level of fibrate active species, into the blood of a patient in a fasted state that differs by less than 5% of the level of said fibrate active species that said patient receives in a fed state.
21. A tablet dosage form in any of claims 16 to 20 that further comprises a dried film-coating.
22. A tablet dosage form in any of claims 16 to 20 that further comprises a pharmaceutically acceptable polymer in a coating.
23. A tablet dosage form in any of claims 16 to 20 that further comprises a pharmaceutically acceptable carbohydrate in a coating.
24. The tablet dosage form of claim 23 where the carbohydrate in the coating is a sugar.
25. The dosage form in any of claims 16 to 20 further comprising one or more excipients selected from the group consisting of monosaccharides, disaccharides, trisaccharides, sucrose, raffinose, lactose, mannitol, sorbitol, trehalose, glycerol, dextrose, maltodextrose, fructose, sugars, pentoses, hexoses, xylitol, and mixtures thereof.
26. The dosage form in any of claims 16 to 20 wherein the phospholipid surface stabilizing substance comprises a mixture of phospholipids.
27. The dosage form in any of claims 16 to 20 wherein the phospholipid surface stabilizing substance is selected from the group consisting of egg phospholipid, Lipoid E80, Lipoid EPC, Lipoid SPC, DMPG, Phospholipon 100H, a hydrogenated soybean phosphatidylcholine, Phospholipon 90H, Lipoid SPC-3, and mixtures thereof.
28. The dosage form in any of claims 16 to 20 wherein the fenofibrate is crystalline.
29. The dosage form in any of claims 16 to 20 wherein the microparticles are smaller than 5 micrometers.
30. The dosage form in any of claims 16 to 20 wherein the microparticles are smaller than 4 micrometers.
31. The dosage form in any of claims 16 to 20 wherein the microparticles are smaller than 3 micrometers.
32. The dosage form in any of claims 16 to 20 wherein the microparticles are smaller than 2 micrometers.
33. The dosage form in any of claims 16 to 20 wherein the microparticles are smaller than 1 micrometers.
34. The dosage form in any of claims 16 to further containing from 0.1 to about 5%.water.
35. The dosage form of any claims 16 to 34 wherein the therapeutically effective amount is selected from the group consisting of 50 mg of fenofibrate, 51 mg of fenofibrate, 52 mg of fenofibrate, 53 mg of fenofibrate, 54 mg of fenofibrate, 67 mg of fenofibrate, 100 mg of fenofibrate, 102 mg of fenofibrate, 103 mg of fenofibrate, 104 mg of fenofibrate, 134 mg of fenofibrate, 150 mg of fenofibrate, 153 mg of fenofibrate, 156 mg of fenofibrate, 159 mg of fenofibrate, 160 mg of fenofibrate, 200 mg of fenofibrate. 213 mg of fenofibrate, 250 mg of fenofibrate, and 300 mg of fenofibrate.
36. An orally administered pharmaceutical composition comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein a therapeutically effective amount of said orally administered pharmaceutical composition provides a quantity of fenofibrate active species to a fasted human patient in need of treatment by fenofibrate that is greater than 85% of the quantity of fenofibrate active species provided by said amount to said patient when fed at least 1000 calories 50 % of which are from fat.
37. An orally administered pharmaceutical composition comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein a therapeutically effective amount of said orally administered pharmaceutical composition provides a quantity of fenofibrate active species to a fasted human patient in need of treatment by fenofibrate that is greater than 90% of the quantity of fenofibrate active species provided by said amount to said patient when fed at least 1000 calories 50 % of which are from fat.
38. An orally administered pharmaceutical composition comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein a therapeutically effective amount of said orally administered micrometers.

pharmaceutical composition provides a quantity of fenofibrate active species to a fasted human patient in need of treatment by fenofibrate that is greater than 95% of the quantity of fenofibrate active species provided by said amount to said patient when fed at least 1000 calories 50 % of which are from fat.
39. The orally administered pharmaceutical composition of any of claims 36 to 38 further comprising one or more excipients selected from the group consisting of monosaccharides, disaccharides, trisaccharides, sucrose, raffinose, lactose, mannitol, sorbitol, trehalose, glycerol, dextrose, maltodextrose, fructose, sugars, pentoses, hexoses, xylitol, and mixtures thereof.
40. The orally administered pharmaceutical composition of any of claims 36 to 38 wherein the phospholipid surface active substance is selected from the group consisting of egg phospholipid, Lipoid E80, Lipoid EPC, Lipoid SPC, DMPG, Phospholipon 100H a hydrogenated soybean phosphatidylcholine, Phospholipon 90H, Lipoid SPC-3, and mixtures thereof.
41. The process of claim 1 wherein the phospholipid is present in an amount from about 0.1 %
to about 15%.
42. The process of claim 1 wherein the phospholipid is present in an amount from about 0.5%
to about 5%.
43. The process of claim 1 wherein the dried small particles further contain from 0.1 to 5%
water.
44. The process of claim 1 wherein the dried small particles further contain from 0.1% to 3%
water.
45. The process of claim 1 wherein the dried small particles further contain from 0.1 % to 2%
water.
46. The process of claim 1 wherein the dried small particles further contain from 0.1% to 1%
water.
47. A method of treating dyslipidemia and dyslipoproteinemia in a mammal which comprises administering to said mammal once a day a therapeutically effective oral dosage form comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance prepared according to the process of claim 1 wherein said dosage form provides into the blood of said patient in a fasted state a therapeutically effective amount of fenofibrate active species that is at least 90% of the AUC amount of fenofibrate active species provided by said dosage form into the blood of said patient in a fed state.
48. The method of claim 47 wherein dyslipidemia comprises hypercholesterolemia, hyperlipidemia, hypertrigylceridaemia or combinations thereof.
49. The process of claim 1 where the heated homogenate further comprises a statin.
50. The process of claim 49 wherein the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin.
51. A composition comprising microparticles containing fenofibrate and a phospholipid surface stabilizing substance that is prepared according to the process of claim 1 further containing a statin.
52. The composition of claim 51 wherein the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin.
53. The orally administered pharmaceutical composition of claim 15 further comprising a statin present in a therapeutically effect dose range.
54. The orally administered pharmaceutical composition of claim 53 wherein the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin.
55. The capsule or tablet or powder or granular dosage form of claims 16 to 20 further comprising a statin present in a therapeutically effect dose range.
56. The capsule or tablet or powder or granular dosage form of claim 56 wherein the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin.
57. The orally administered pharmaceutical composition of claims 36 to 40 further comprising a statin present in a therapeutically effect dose range.
58. The orally administered pharmaceutical composition of claim 57 wherein the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin present in a therapeutically effect dose range.
59. The therapeutically effective oral dosage form of claim 47 further comprising a statin present in a therapeutically effect dose range.
60. The therapeutically effective oral dosage form of claim 59 wherein the statin is selected from the group consisting of lovastatin, pravastatin, simvastatin, atorvastatin, rosuvastatin, fluvastatin, itavastatin, and cerivastatin.
CA2423335A 2000-09-20 2001-04-20 Spray drying process and compositions of fenofibrate Expired - Fee Related CA2423335C (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US23418600P 2000-09-20 2000-09-20
US60/234,186 2000-09-20
US24176100P 2000-10-20 2000-10-20
US60/241,761 2000-10-20
US27015701P 2001-02-22 2001-02-22
US60/270,157 2001-02-22
PCT/US2001/012746 WO2002024169A1 (en) 2000-09-20 2001-04-20 Spray drying process and compositions of fenofibrate

Publications (2)

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CA2423335A1 true CA2423335A1 (en) 2002-03-28
CA2423335C CA2423335C (en) 2011-03-01

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US (1) US6696084B2 (en)
EP (1) EP1322289B1 (en)
AT (1) ATE367802T1 (en)
AU (2) AU2001262945B2 (en)
CA (1) CA2423335C (en)
DE (1) DE60129573T2 (en)
NZ (1) NZ525306A (en)
TW (1) TWI293877B (en)
WO (1) WO2002024169A1 (en)

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