Controlled Release Compositions Comprising Heterocyclic Amide Derivative Nanoparticles

• US 20080254114A1
• Filed: 03/02/2006
• Published: 10/16/2008
• Est. Priority Date: 03/03/2005
• Status: Abandoned Application

• Current Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Original Assignee: Elan Corporation PLC (Perrigo Company PLC)
• Inventors: Liversidge, Gary, Jenkins, Scott A.
• Application Number:
  US11/571,377
• Publication Number:
  US 20080254114A1
• Time in Patent Office: Days
• US Class Current: 424/456
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention is directed to compositions comprising nanoparticulate heterocyclic amide derivative and preferably zafirlukast nanoparticles, also collectively referred to as “active ingredient,” having improved solubility in water. The nanoparticles of the composition have an effective average particle size of less than about 2,000 nm, and are useful in the treatment of asthma. The invention also relates to a multiparticulate modified release composition comprising the active ingredient that in operation delivers the drug in a pulsed or bimodal manner for the treatment of asthma. The controlled release composition comprises an immediate release component and a modified release component. The immediate release component comprises a first population of heterocyclic amide derivative, and preferably zafirlukast particles, and the modified release component comprises a second population of heterocyclic amide derivative, and preferably zafirlukast nanoparticles, and a controlled release component, wherein the combination of the immediate release and modified release components in operation delivers the active ingredient in a pulsed or bimodal manner. The heterocyclic amide derivative can be released from the multiparticulate particles in an erosable, diffusion or osmotic controlled release system.

Claims

1. A stable nanoparticulate heterocyclic amide derivative composition comprising:

(a) zafirlukast particles having an effective average particle size of less than about 2,000 nm; and

(b) at least one surface stabilizer.

2. The composition of claim 1, wherein the zafirlukast is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.

3. The composition of claim 1, wherein the effective average particle size of the nanoparticulate zafirlukast 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 1,000 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.

4. The composition of claim 1, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, ocular, opthalmic, colonic, parenteral, intracistemal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration.

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

6. The composition of claim 1, wherein the zafirlukast is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined weight of the zafirlukast and at least one surface stabilizer, not including other excipients.

7. The composition of claim 1, wherein the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999% by weight, from about 5.0% to about 99.9% by weight, and from about 10% to about 99.5% by weight, based on the total combined dry weight of the zafirlukast and at least one surface stabilizer, not including other excipients.

8. The composition of claim 1, comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.

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

10. The composition of claim 9, wherein the at least one 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, and random copolymers of vinyl acetate and vinyl pyrrolidone.

11. The composition of claim 9, wherein the at least one cationic surface stabilizer is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a non-polymeric compound, and a phospholipid.

12. The composition of claim 9, wherein the surface stabilizer is selected from the group consisting of cationic lipids, polymethylmethacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, phosphonium compounds, quaternary 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, dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, alkyl pyridinium salts;

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

13. The composition of claim 9, wherein the zafirlukast is bioadhesive.

14. The composition of claim 1, comprising hypomellose, dioctyl sodium sulfosuccinate, and sodium lauryl sulfate as surface stabilizers.

15. An asthma treatment comprising the following components:

(a) about 50 to about 500 g/kg zafirlukast;

(b) about 10 to about 70 g/kg hypromellose;

(c) about 1 to about 10 g/kg docusate sodium;

(d) about 100 to about 500 g/kg sucrose;

(e) about 1 to about 40 g/kg sodium lauryl sulfate;

(f) about 50 to about 400 g/kg lactose monohydrate;

(g) about 50 to about 300 g/kg silicified microcrystalline cellulose;

(h) about 20 to about 300 g/kg crospovidone; and

(i) about 0.5 to about 5 g/kg magnesium stearate.

16. The composition of claim 15, further comprising a coating agent.

17. An asthma treatment composition comprising the following components:

(a) about 100 to about 300 g/kg zafirlukast;

(b) about 30 to about 50 g/kg hypromellose;

(c) about 0.5 to about 10 g/kg docusate sodium;

(d) about 100 to about 300 g/kg sucrose;

(e) about 1 to about 30 g/kg sodium lauryl sulfate;

(f) about 100 to about 300 g/kg lactose monohydrate;

(g) about 50 to about 200 g/kg silicified microcrystalline cellulose;

(h) about 50 to about 200 g/kg crospovidone; and

(i) about 0.5 to about 5 g/kg magnesium stearate.

18. The composition of claim 17, further comprising a coating agent.

19. An asthma treatment composition comprising the following components:

(a) about 200 to about 225 g/kg zafirlukast;

(b) about 42 to about 46 g/kg hypromellose;

(c) about 2 to about 6 g/kg docusate sodium;

(d) about 200 to about 225 g/kg sucrose;

(e) about 12 to about 18 g/kg sodium lauryl sulfate;

(f) about 200 to about 205 g/kg lactose monohydrate;

(g) about 130 to about 135 g/kg silicified microcrystalline cellulose;

(h) about 112 to about 118 g/kg crospovidone; and

(i) about 0.5 to about 3 g/kg magnesium stearate.

20. The composition of claim 19, further comprising a coating agent.

21. An asthma treatment composition comprising the following components:

(a) about 119 to about 224 g/kg zafirlukast;

(b) about 42 to about 46 g/kg hypromellose;

(c) about 2 to about 6 g/kg docusate sodium;

(d) about 119 to about 224 g/kg sucrose;

(e) about 12 to about 18 g/kg sodium lauryl sulfate;

(f) about 119 to about 224 g/kg lactose monohydrate;

(g) about 129 to about 134 g/kg silicified microcrystalline cellulose;

(h) about 112 to about 118 g/kg crospovidone; and

(i) about 0.5 to about 3 g/kg magnesium stearate.

22. The composition of claim 21, further comprising a coating agent.

23. A stable nanoparticulate zafirlukast composition comprising:

(a) particles of a zafirlukast active or a salt thereof; and

(b) associated with the surface thereof dioctyl sodium sulfosuccinate and hypromellose;

wherein the zafirlukast particles have an effective average particle size of less than about 2,000 nm.

24. The composition of claim 23, further comprising sodium lauryl sulfate.

25. A method of making a nanoparticulate zafirlukast composition comprising contacting zafirlukast particles with at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate zafirlukast composition having an effective average particle size of less than about 2,000 nm.

26. The method of claim 25, wherein said contacting comprises grinding.

27. The method of claim 26, wherein said grinding comprises wet grinding.

28. The method of claim 25, wherein said contacting comprises homogenizing.

29. The method of claim 25, wherein said contacting comprises supercritical fluids processing.

30. The method of claim 25, wherein said contacting comprises:

(a) dissolving the zafirlukast particles in a solvent;

(b) adding the resulting zafirlukast solution to a solution comprising at least one surface stabilizer; and

(c) precipitating the solubilized zafirlukast having at least one surface stabilizer adsorbed on the surface thereof by the addition thereto of a non-solvent.

31. The method of claim 25, wherein the zafirlukast is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.

32. The method of claim 25, wherein the effective average particle size of the nanoparticulate zafirlukast 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 1,000 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.

33. The method of claim 25, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, ocular, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration.

34. The method of claim 25, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.

35. The method of claim 25, wherein the zafirlukast is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined weight of the zafirlukast and at least one surface stabilizer, not including other excipients.

36. The method of claim 25, wherein the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999%, from about 5.0% to about 99.9%, and from about 10% to about 99.5% by weight, based on the total combined dry weight of the zafirlukast and at least one surface stabilizer, not including other excipients.

37. The method of claim 25, comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.

38. The method of claim 25, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer.

39. The method of claim 25, wherein the at least one 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, and random copolymers of vinyl acetate and vinyl pyrrolidone.

40. The method of claim 38, wherein the at least one cationic surface stabilizer is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, and a phospholipid.

41. The method of claim 25, wherein the surface stabilizer is selected from the group consisting of cationic lipids, polymethylmethacrylate trimethylammonium bromide, sulfonium compounds, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, phosphonium compounds, quaternary 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_12-15dimethyl hydroxyethyl ammonium chloride, C_12-15dimethyl 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, dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, alkyl pyridinium salts;

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

42. The method of claim 38, wherein the zafirlukast composition is a bioadhesive.

43. The method of claim 25, wherein the composition comprises hypromellose, dioctyl sodium sulfosuccinate, and sodium lauryl sulfate as surface stabilizers.

44. A method for the treatment of asthma with a nanoparticulate zafirlukast comprising administering to the subject an effective amount of a nanoparticulate composition comprising particles of a zafirlukast having at least one surface stabilizer associated with the surface thereof, wherein the zafirlukast particles have an effective average particle size of less than about 2,000 nm.

45. The method of claim 44, wherein the zafirlukast is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, a semi-amorphous phase, and mixtures thereof.

46. The method of claim 44, wherein the effective average particle size of the nanoparticulate zafirlukast 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 1,000 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.

47. The method of claim 44, wherein the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, ocular, opthalmic, colonic, parenteral, intracistemal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration.

48. The method of claim 44, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.

49. The method of claim 44, wherein the zafirlukast is present in an amount selected from the group consisting of from about 99.5% to about 0.001%, from about 95% to about 0.1%, and from about 90% to about 0.5%, by weight, based on the total combined weight of the zafirlukast and at least one surface stabilizer, not including other excipients.

50. The method of claim 44, wherein the at least one surface stabilizer is present in an amount selected from the group consisting of from about 0.5% to about 99.999% by weight, from about 5.0% to about 99.9% by weight, and from about 10% to about 99.5% by weight, based on the total combined dry weight of the zafirlukast and at least one surface stabilizer, not including other excipients.

51. The method of claim 44, comprising at least one primary surface stabilizer and at least one secondary surface stabilizer.

52. The method of claim 44, wherein the surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, a zwitterionic surface stabilizer, and an ionic surface stabilizer.

53. The method of claim 50, wherein the at least one 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, and random copolymers of vinyl acetate and vinyl pyrrolidone.

54. The method of claim 52, wherein the cationic surface stabilizer is selected from the group consisting of a polymer, a biopolymer, a polysaccharide, a cellulosic, an alginate, a nonpolymeric compound, and a phospholipid.

55. The method of claim 44, wherein the surface stabilizer is selected from the group consisting of benzalkonium chloride, polymethylmethacrylate trimethylammonium bromide, polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, cationic lipids, sulfonium compounds, phosphonium compounds, quaternary 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_12-15dimethyl hydroxyethyl ammonium chloride, C_12-15dimethyl 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, dimethyl ammonium chlorides, alkyldimethylammonium halogenides, tricetyl methyl ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium bromide, tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, alkyl pyridinium salts;

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

56. The method of claim 52, wherein the zafirlukast composition is bioadhesive.

57. The method of claim 44, wherein the composition comprises hypromellose, dioctyl sodium sulfosuccinate, and sodium lauryl sulfate as surface stabilizers.

58. The method of claim 44, wherein the method is used for the treatment of asthma in a subject which is a mammal.

59. The method of claim 58, wherein said subject is a human.

60. The method of claim 44, wherein said composition is an oral suspension.

61. The method of claim 44, wherein said composition is a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, controlled release formulations, fast melt formulations, lyophilized formulations, tablets, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations.

62. The method of claim 44, wherein the effective amount is 10 to 20 mg per day.

63. A controlled release composition consisting essentially of:

(A) a first component comprising a first population of heterocyclic amide derivative nanoparticles; and

(B) at least one subsequent component or formulation comprising a subsequent population of heterocyclic amide derivative nanoparticles and a modified release constituent comprising a modified release coating, a modified release matrix material or mixtures thereof;

wherein the composition, following oral delivery to a subject, delivers the heterocyclic amide derivative nanoparticles in the first and subsequent populations in a pulsatile manner.

64. The composition of claim 63, wherein the heterocyclic amide derivative in the first and subsequent populations is zafirlukast and said modified release constituent delivers to a subject the subsequent population of zafirlukast over a period of up to twenty-four hours after administration.

65. The composition according to claim 64, comprising a modified release coating.

66. The composition according to claim 63, wherein the first population comprises immediate-release particles and the formulation comprising the subsequent population is an erodable formulation.

67. The composition according to claim 63, wherein the formulation comprising the subsequent population is a diffusion controlled formulation.

68. The composition according to claim 63, wherein the formulation comprising the subsequent population is an osmotic controlled formulation.

69. The composition of claim 63, wherein the formulation comprises a modified release matrix material.

70. The composition according to claim 69, wherein the composition further comprises an enhancer.

71. The composition according to claim 70, wherein the amount of zafirlukast contained in each of the first and subsequent populations is from about 10 mg to about 20 mg.

72. The composition according to claim 64, wherein the first and subsequent populations have different in vitro dissolution profiles.

73. The composition according to claim 72, which in operation releases substantially all of the zafirlukast from the first population prior to release of the zafirlukast nanoparticles from the subsequent population.

74. The composition according to claim 64, comprising a blend of the particles of each of the first and subsequent populations contained in a hard gelatin or soft gelatin capsule.

75. The composition according to claim 64, wherein the particles of each of the populations are in the form of mini-tablets and the capsule contains a mixture of the mini-tablets.

76. The composition according to claim 64, in the form of a multilayer tablet comprising a first layer of compressed zafirlukast nanoparticles of the first population and another layer of zafirlukast-containing particles of the subsequent population

77. The composition according to claim 76, wherein the first and subsequent populations of zafirlukast-containing nanoparticles are provided in a rapidly dissolving dosage form.

78. The composition according to claim 77, wherein the particles of each of the populations are compressed into a fast-melt tablet.

79. A method for the treatment of asthma comprising administering a therapeutically effective amount of a composition according to claim 64.

80. The composition according to claim 64, wherein the subsequent formulation comprises a pH-dependent polymer coating which is effective in releasing a pulse of the active ingredient following a time delay.

81. The composition according to claim 80, wherein the polymer coating comprises methacrylate copolymers.

82. The composition according to claim 81, wherein the polymer coating comprises a mixture of methacrylate and ammonio methacrylate copolymers in a ratio sufficient to achieve a pulse of the active ingredient following a time delay.

83. The composition according to claim 82, wherein the ratio of methacrylate to ammonio methacrylate copolymers is 1:

1.