Nanoparticulate and Controlled Release Compositions Comprising Cefditoren

• US 20080279929A1
• Filed: 02/05/2007
• Published: 11/13/2008
• Est. Priority Date: 11/02/1998
• Status: Active Grant

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Elan Corporation PLC (Perrigo Company PLC)
• Inventors: Rekhi, Gurvinder Singh, Stark, Paul, Devane, John G., Liversidge, Gary, Jenkins, Scott A., Fanning, Nial M. N.
• Granted Patent: US 8,119,163 B2
• Time in Patent Office: Days
• US Class Current: 424/456
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides a composition comprising a cefditoren, or a salt, derivative, prodrug, or other form thereof, for example, cefditoren pivoxil, useful in the treatment and prevention of infections and related conditions. The invention provides a composition which comprises nanoparticulate particles comprising the cefditoren, or a salt, derivative, prodrug, or other form thereof and at least one surface stabilizer. The nanoparticulate particles have an effective average particle size of less than about 2000 nm. The invention provides also a composition that delivers a cefditoren, or a salt, derivative, prodrug, or other form thereof, or nanoparticles comprising the same, in a pulsatile or continuous manner.

Claims

1. A stable nanoparticulate composition comprising:

(A) particles comprising a cefditoren, or a salt, derivative, prodrug, or other form thereof, said particles having an effective average particle size of less than about 2000 nm in diameter; and

(B) at least one surface stabilizer.

2. The composition of claim 1, wherein said particles are in a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi amorphous phase, or a mixture thereof.

3. The composition of claim 1, wherein the effective average particle size of said particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 1000 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm in diameter.

4. The composition of claim 1, wherein the composition is formulated:

(A) for administration selected from the group consisting of via injection, oral, vaginal, nasal, rectal, otically, ocular, local, buccal, intracisternal, intraperitoneal, or topically;

(B) into a dosage form selected from the group consisting of tablets, capsules, sachets, solutions, dispersions, gels, aerosols, ointments, creams, and mixtures thereof;

(C) into a dosage form selected from the group consisting of controlled release formulations, fast melt formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations;

or

(D) any combination of (A), (B), or (C).

5. The composition of claim 1 further comprising one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.

6. The composition of claim 1, wherein:

(A) said cefditoren, or a salt, derivative, prodrug, or other form thereof is present in said composition in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, or from about 90% to about 0.5%, by weight of the total combined dry weight of cefditoren, or a salt, derivative, prodrug, or other form thereof and surface stabilizer in the composition, not including other excipients;

(B) said surface stabilizer or surface stabilizers are present in a total amount of from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5% by weight, based on the total combined dry weight of cefditoren, or a salt, derivative, prodrug, or other form thereof and surface stabilizer in the composition not including other excipients;

or

(C) a combination of (A) and (B).

7. The composition of claim 1, wherein the surface stabilizer is selected from the group consisting of a non-ionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer.

8. The composition of claim 1, wherein the surface stabilizer is selected from the group consisting of cetyl pyridinium chloride, gelatin, casein, phosphatides, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hypromellose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde, poloxamers;

poloxamines, a charged phospholipid, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide;

n-decyl β

-D-glucopyranoside;

n-decyl β

-D-maltopyranoside;

n-dodecyl β

-D-glucopyranoside;

n-dodecyl β

-D-maltoside;

heptanoyl-N-methylglucamide;

n-heptyl-β

-D-glucopyranoside;

n-heptyl β

-D-thioglucoside;

n-hexyl β

-D-glucopyranoside;

nonanoyl-N-methylglucamide;

n-noyl β

-D-glucopyranoside;

octanoyl-N-methylglucamide;

n-octyl-β

-D-glucopyranoside;

octyl β

-D-thioglucopyranoside;

lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random copolymers of vinyl acetate and vinyl pyrrolidone, a cationic polymer, a cationic biopolymer, a cationic polysaccharide, a cationic cellulosic, a cationic alginate, a cationic nonpolymeric compound, a cationic phospholipid, cationic lipids, polymethylmethacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, phosphonium compounds, quarternary ammonium compounds, benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride, coconut trimethyl ammonium bromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyl dihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride bromide, C_12-15-dimethyl hydroxyethyl ammonium chloride, C_12-15-dimethyl hydroxyethyl ammonium chloride bromide, coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethyl hydroxyethyl ammonium bromide, myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethyl benzyl ammonium bromide, lauryl dimethyl (ethenoxy)₄ ammonium chloride, lauryl dimethyl (ethenoxy)₄ ammonium bromide, N-alkyl (C_12-18)dimethylbenzyl ammonium chloride, N-alkyl (C_14-18)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C_12-14) dimethyl 1-napthylmethyl ammonium chloride, trimethylammonium halide, alkyl-trimethylammonium salts, dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride, ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkyl ammonium salt, dialkylbenzene dialkylammonium chloride, N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl ammonium, chloride monohydrate, N-alkyl(C_12-14) dimethyl 1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyl dimethyl ammonium bromide, C₁₂ trimethyl ammonium bromides, C₁₅ trimethyl ammonium bromides, C₁₇ trimethyl ammonium bromides, dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, POLYQUAT 10™

, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, MIRAPOL™

, ALKAQUAT™

, alkyl pyridinium salts;

amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.

9. The composition of claim 1, wherein the composition does not produce significantly different absorption levels when administered under fed as compared to fasting conditions.

10. The composition of claim 1, wherein administration of the composition to a subject in a fasted state is bioequivalent to administration of the composition to a subject in a fed state.

11. The composition of claim 1, wherein the pharmacokinetic profile of the composition is not significantly affected by the fed or fasted state of a subject ingesting said composition.

12. A composition according to claim 1 wherein, upon administration of said composition to a mammal, the composition produces therapeutic results at a dosage which is less than that of a non-nanoparticulate dosage form of the same cefditoren, or a salt, derivative, prodrug, or other form thereof.

13. A composition according to claim 1 which has:

(a) a C_max for the cefditoren, or a salt, derivative, prodrug, or other form thereof, when assayed in the plasma of a mammalian subject following administration, that is greater than the C_max for the same cefditoren, or a salt, derivative, prodrug, or other form thereof administered at the same dose using a non-nanoparticulate formulation;

(b) an AUC for the cefditoren, or a salt, derivative, prodrug, or other form thereof, when assayed in the plasma of a mammalian subject following administration, that is greater than the AUC for the same cefditoren, or a salt, derivative, prodrug, or other form thereof administered at the same dose using a non-nanoparticulate formulation;

(c) a T_max for the cefditoren, or a salt, derivative, prodrug, or other form thereof, when assayed in the plasma of a mammalian subject following administration, that is less than the T_max for the same cefditoren, or a salt, derivative, prodrug, or other form thereof administered at the same dose using a non-nanoparticulate formulation;

or

(d) any combination of (a), (b), and (c).

14. The composition of claim 1, additionally comprising one or more active compounds useful for the prevention and treatment of infections and other related conditions.

15. The composition of claim 14, wherein the one or more active compounds is selected from the group consisting of compounds useful in the treatment of a condition selected from the group consisting of headaches, soreness, fever, and combinations thereof.

16. The composition of claim 1 wherein said cefditoren, or a salt, derivative, prodrug, or other form thereof is cefditoren pivoxil.

17. A composition according to claim 1 wherein said particles contain a reservoir which contains cefditoren, or a salt, derivative, prodrug, or other form thereof, said reservoir being enclosed by a semi-permeable membrane which allows for water to be imbibed into said particles, thus generating pressure which forces said cefditoren, or a salt, derivative, prodrug, or other form thereof, out of said particles.

18. A composition according to claim 1 wherein said reservoir comprises also an osmotic agent.

19. A method of preparing the composition of claim 1 comprising contacting particles comprising said cefditoren, or a salt, derivative, prodrug, or other form thereof, with at least one surface stabilizer for a period of time and under conditions sufficient to provide a nanoparticulate composition comprising a cefditoren, or a salt, derivative, prodrug, or other form thereof, having an effective average particle size of less than about 2000 nm in diameter.

20. The method of claim 19, wherein the contacting comprises grinding, wet grinding, homogenization, precipitation, template emulsion, or supercritical fluid particle generation techniques.

21. The method of claim 19, wherein the effective average particle size of the nanoparticulate particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1000 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm in diameter.

22. The method of claim 19 wherein said cefditoren, or a salt, derivative, prodrug, or other form thereof is cefditoren pivoxil.

23. A method of preventing and/or treating infections and conditions related thereto comprising administering a composition according to claim 1.

24. The method of claim 23, wherein the effective average particle size of the particles is selected from the group consisting of less than about 1900 nm, less than about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than about 1500 nm, less than about 1000 nm, less than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less than about 1100 nm, less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 200 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm in diameter.

25. The method of claim 23 wherein said cefditoren, or a salt, derivative, prodrug, or other form thereof, is cefditoren pivoxil.

26. A controlled release composition comprising a population of particles containing cefditoren, or a salt, derivative, prodrug, or other form thereof, wherein said particles further comprise a modified release coating or, alternatively or additionally, a modified release matrix material, such that the composition following oral delivery to a subject delivers the cefditoren, or a salt, derivative, prodrug, or other form thereof, in a pulsatile or continuous manner

27. The controlled release composition of claim 26 wherein said cefditoren, or a salt, derivative, prodrug, or other form thereof, is cefditoren pivoxil.

28. The composition according to claim 26, wherein the population comprises modified-release particles.

29. The composition according to claim 26, wherein the population is an erodible formulation.

30. The composition according to claim 26, wherein said particles are each in the form of an osmotic device.

31. The composition according to claim 28, wherein the modified release particles have a modified-release coating.

32. The composition according to claim 28, wherein the modified release particles comprise a modified-release matrix material.

33. The compositions of claim 28 wherein said modified release particles are combined in a formulation that releases said cefditoren, or a salt, derivative, prodrug, or other form thereof by erosion to the surrounding environment.

34. The composition according to claim 26, wherein at least one portion of the dose further comprises an enhancer.

35. The composition according to claim 26, wherein the amount of active ingredient contained therein is from about 0.1 mg to about 1 g.

36. The composition according to claim 26 comprising a blend of the particles contained in a hard gelatin or soft gelatin capsule.

37. The composition according to claim 26, wherein the particles are in the form of mini-tablets and the capsule contains a mixture of the mini-tablets.

38. The composition according to claim 26, in the form of tablet comprising layer of compressed particles comprising cefditoren, or a salt, derivative, prodrug, or other form thereof.

39. The composition according to claim 26, wherein said particles are provided in a rapidly dissolving dosage form.

40. The composition according to claim 26, comprising a fast-melt tablet.

41. A method for the prevention and/or treatment of infections and conditions related thereto comprising administering a therapeutically effective amount of a composition according to claim 26.

42. The composition according to claim 28, wherein the modified-release particles comprise a pH-dependent polymer coating which is effective in releasing a pulse of the active ingredient following a time delay of six to twelve hours.

43. The composition according to claim 42, wherein the polymer coating comprises methacrylate copolymers.

44. The composition according to claim 42, wherein the polymer coating comprises a mixture of methacrylate and ammonio methacrylate copolymers in a ratio sufficient to achieve a pulse of release of the active ingredient following a time delay.

45. The composition according to claim 44, wherein the ratio of methacrylate to ammonio methacrylate copolymers is approximately 1:

1.

69. The composition according to claim 26, wherein said particles are each in the form of an osmotic device.

46. A controlled release composition comprising a population of nanoparticulate particles which comprise:

(A) cefditoren, or a salt, derivative, prodrug, or other form thereof; and

(B) a modified release coating or, alternatively or additionally, a modified release matrix material;

such that the composition, following oral delivery to a subject, delivers the cefditoren, or a salt, derivative, prodrug, or other form thereof, in a pulsatile or continuous manner.

47. The composition of claim 46, wherein said composition does not produce significantly different absorption levels when administered under fed as compared to fasting conditions.

48. The composition of claim 46, wherein the pharmacokinetic profile of said composition is not significantly affected by the fed or fasted state of a subject ingesting said composition.

49. The composition of claim 46, wherein administration of said composition to a subject in a fasted state is bioequivalent to administration of said composition to a subject in a fed state.

50. The composition according to claim 46, wherein the population comprises modified-release particles.

51. The composition according to claim 46, wherein the population is an erodable formulation.

52. The composition according to claim 46, wherein said particles are each in the form of an osmotic device.

53. The composition according to claim 50, wherein the modified release particles have a modified-release coating.

54. The composition according to claim 50, wherein the modified release particles comprise a modified-release matrix material.

55. The compositions of claim 50 wherein said modified release particles are combined in a formulation that releases said cefditoren, or a salt, derivative, prodrug, or other form thereof, by erosion to the surrounding environment.

56. The composition according to claim 46, wherein at least one portion of the dose further comprises an enhancer.

57. The composition according to claim 46, wherein the amount of active ingredient contained therein is from about 0.1 mg to about 1 g.

58. The composition according to claim 46 comprising a blend of the particles contained in a hard gelatin or soft gelatin capsule.

59. The composition according to claim 46, wherein the particles are in the form of mini-tablets and the capsule contains a mixture of the mini-tablets.

60. The composition according to claim 46 in the form of tablet comprising layer of compressed particles which comprise a cefditoren, or a salt, derivative, prodrug, or other form thereof.

61. The composition according to claim 46, wherein the particles are provided in a rapidly dissolving dosage form.

62. The composition according to claim 46, comprising a fast-melt tablet.

63. The composition according to claim 46 wherein said cefditoren, or a salt, derivative, prodrug, or other form thereof is cefditoren pivoxil.

64. A method for the prevention and/or treatment of infections and conditions related thereto comprising administering a therapeutically effective amount of a composition according to claim 46.

65. The composition according to claim 50, wherein the modified-release particles comprise a pH-dependent polymer coating which is effective in releasing a pulse release of the active ingredient following a time delay of six to twelve hours.

66. The composition according to claim 65, wherein the polymer coating comprises methacrylate copolymers.

67. The composition according to claim 65, wherein the polymer coating comprises a mixture of methacrylate and ammonio methacrylate copolymers in a ratio sufficient to achieve a pulse release of the active ingredient following a time delay.

68. The composition according to claim 67, wherein the ratio of methacrylate to ammonio methacrylate copolymers is approximately 1:

1.