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Details for Patent: 7,998,507

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Details for Patent: 7,998,507

Title:Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors
Abstract: Nanoparticulate compositions comprising at least one poorly soluble MAP kinase inhibitor and at least one surface stabilizer are described. The nanoparticulate compositions have an average particle size of less than about 2000 nm. The invention also describes methods of making and using such compositions.
Inventor(s): Bosch; H. William (Bryn Mawr, PA), Cary; Greta G. (Landsdale, PA), Hovey; Douglas C. (Gilbertsville, PA), Jain; Rajeev A. (Framingham, MA), Kline; Laura J. (Harleysville, PA), Merisko-Liversidge; Elaine (West Chester, PA), Ostrander; Kevin D. (Ringoes, NJ), Ryde; Niels P. (Malvern, PA), Ruddy; Stephen B. (Schwenksville, PA)
Assignee: Elan Pharma International Ltd. (Athlone, County Westmeath, IE)
Filing Date:Dec 07, 2005
Application Number:11/275,069
Claims:1. A nanoparticulate mitogen-activated protein (MAP) kinase inhibitor composition comprising: (a) particles of a poorly soluble MAP kinase inhibitor or a salt thereof having an effective average particle size of less than about 2000 nm; and (b) associated with the surface thereof at least one surface stabilizer, wherein the at least one surface stabilizer is selected from the group consisting of a polymeric stabilizer, poloxamer, hydroxypropylcellulose, docusate sodium, sodium lauryl sulfate, and povidone.

2. The composition of claim 1, wherein the at least one MAP kinase inhibitor is selected from the group consisting of PD 184352, VX-745, SB 202190, Anisomycin, PD 98059, SB 203580, U0126, AG 126, Apigenin, HSP25 Kinase Inhibitor, 5-Iodotubercidin, MAP Kinase Antisense Oligonucleotide, Control MAP Kinase Oligonucleotide, MAP Kinase Cascasde Inhibitor, MAP Kinase Inhibitor Set 1, MAP Kinase Inhibitor Set 2, MEK Inhibitor Set, Olomoucine, Iso Olomoucine, N.sup.9 Isopropyl Olomoucine, p38 MAP Kinase Inhibitor, PD 169316, SB 202474, SB 202190 Hydrochloride, SB 202474 Dihydrochloride, SB 203580 Sulfone, Ioto-SB 203580, SB 220025, SC 68376, SKF-86002, Tyrphostin AG 126, U0124, U0125, and ZM 336372.

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

4. The composition of claim 1, wherein the effective average particle size of the nanoparticulate MAP kinase inhibitor 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.

5. The composition of claim 1, wherein the composition is formulated: (a) for administration selected from the group consisting of oral, pulmonary, rectal, opthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration; (b) into 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; or (c) a combination of (a) and (b).

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

7. The composition of claim 1, wherein: (a) the MAP kinase inhibitor 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 MAP kinase inhibitor and at least one surface stabilizer, not including other excipients; (b) 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 weight of the at least one MAP kinase inhibitor and at least one surface stabilizer, not including other excipients; or (c) a combination of (a) and (b).

8. The composition of claim 1, comprising at least two surface stabilizers.

9. The composition of claim 8, wherein the second surface stabilizer is selected from the group consisting of an anionic surface stabilizer, a cationic surface stabilizer, an ionic surface stabilizer, and a zwitterionic surface stabilizer.

10. The composition of claim 8, wherein the second 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 oils, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, dodecyl trimethyl ammonium bromide, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, hydroxypropyl celluloses, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose 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, C.sub.18H.sub.37CH.sub.2C(O)N(CH.sub.3)--CH.sub.2(CHOH).sub.4(CH.sub.2OH)- .sub.2, p-isononylphenoxypoly-(glycidol), decanoyl-N-methylglucamide; n-decyl .beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside; n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside; heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside; n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside; nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl .beta.-D-thioglucopyranoside; lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-vitamin A, PEG-vitamin E, random copolymers of vinyl acetate and vinyl pyrrolidone, 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.sub.12-15dimethyl hydroxyethyl ammonium chloride, C.sub.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).sub.4 ammonium chloride, lauryl dimethyl (ethenoxy).sub.4 ammonium bromide, N-alkyl (C.sub.12-18)dimethylbenzyl ammonium chloride, N-alkyl (C.sub.14-18)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl ammonium chloride, N-alkyl and (C.sub.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.sub.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, C.sub.12 trimethyl ammonium bromides, C.sub.15 trimethyl ammonium bromides, C.sub.17 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, polyquaternium 10, tetrabutylammonium bromide, benzyl trimethylammonium bromide, choline esters, benzalkonium chloride, stearalkonium chloride compounds, cetyl pyridinium bromide, cetyl pyridinium chloride, halide salts of quaternized polyoxyethylalkylamines, quaternized ammonium salt polymers, alkyl pyridinium salts; amines, amine salts, amine oxides, imide azolinium salts, protonated quaternary acrylamides, methylated quaternary polymers, and cationic guar.

11. The composition of claim 10, wherein the composition is bioadhesive.

12. The composition of claim 1, wherein the composition comprises more than one MAP kinase inhibitor.

13. The composition of claim 12, wherein at least one MAP kinase inhibitor has an effective average particle size which is greater than about 2 microns.

14. The composition of claim 1, additionally comprising at least one nanoparticulate MAP kinase inhibitor composition having an effective average particle size of less than about 2 microns, wherein said additional nanoparticulate MAP kinase inhibitor composition has an effective average particle size which is different than the particle size of the nanoparticulate MAP kinase inhibitor composition of claim 1.

15. The composition of claim 1, additionally comprising at least one non-MAP kinase inhibitor active agent.

16. The composition of claim 15, wherein said active agent is selected from the group consisting of amino acids, proteins, peptides, nucleotides, anti-obesity drugs, nutraceuticals, dietary supplements, central nervous symptom stimulants, carotenoids, corticosteroids, elastase inhibitors, anti-fungals, alkylxanthine, oncology therapies, anti-emetics, analgesics, opioids, antipyretics, cardiovascular agents, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytics, sedatives, astringents, alpha-adrenergic receptor blocking agents, beta-adrenoceptor blocking agents, blood products, blood substitutes, cardiac inotropic agents, contrast media, corticosteroids, cough suppressants, diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics, haemostatics, immunological agents, lipid regulating agents, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergic agents, stimulants, anoretics, sympathomimetics, thyroid agents, vasodilators, vasomodulator, xanthines, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic analgesics, monoamine uptake inhibitors, adenosine regulating agents, cannabinoid derivatives, Substance P antagonists, neurokinin-1 receptor antagonists, and sodium channel blockers.

17. The composition of claim 16, wherein said nutraceutical is selected from the group consisting of lutein, folic acid, fatty acids, fruit extracts, vegetable extracts, vitamin supplements, mineral supplements, phosphatidylserine, lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul, glutamine, amino acids, green tea, lycopene, whole foods, food additives, herbs, phytonutrients, antioxidants, flavonoid constituents of fruits, evening primrose oil, flax seeds, fish oils, marine animal oils, and probiotics.

18. The composition of claim 15, wherein: (a) at least one non-MAP kinase inhibitor active agent has an effective average particle size of less than about 2 microns; or (b) at least one non-MAP kinase inhibitor active agent has an effective average particle size of greater than about 2 microns.

19. The composition of claim 1, wherein upon administration the composition redisperses such that the MAP kinase inhibitor particles have a particle size selected from the group consisting of less than about 2 microns, 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 150 nm, less than about 100 nm, less than about 75 nm, and less than about 50 nm.

20. The composition of claim 19, wherein the composition is a solid dosage form.

21. The composition of claim 1, wherein the composition has been sterile filtered.

22. The composition of claim 1, wherein: (a) the composition does not produce significantly different absorption levels when administered under fed as compared to fasting conditions; (b) the composition does not produce significantly different rates of absorption (T.sub.max) when administered under fed as compared to fasting conditions; or (c) a combination of (a) and (b).

23. The composition of claim 1, wherein: (a) the difference in absorption of the nanoparticulate MAP kinase inhibitor composition of the invention, when administered in the fed versus the fasted state, is selected from the group consisting of less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 35%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, and less than about 3%; or (b) the difference in the T.sub.max for the nanoparticulate MAP kinase inhibitor composition of the invention, when administered in the fed versus the fasted state, is less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, and less than about 3%; or (c) a combination of (a) and (b).

24. The composition of claim 1, wherein: (a) upon administration the T.sub.max is less than that of a conventional non-nanoparticulate composition of the same MAP kinase inhibitor, administered at the same dosage; (b) upon administration the C.sub.max of the composition is greater than the C.sub.max of a conventional non-nanoparticulate composition of the same MAP kinase inhibitor, administered at the same dosage; or (c) a combination of (a) and (b).

25. The composition of claim 1, wherein in comparative pharmacokinetic testing with a non-nanoparticulate composition of the same MAP kinase inhibitor, administered at the same dosage, the nanoparticulate composition exhibits a T.sub.max selected from the group consisting of less than about 100%, less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 25%, less than about 20%, less than about 15%, and less than about 10% of the T.sub.max exhibited by the non-nanoparticulate composition of the MAP kinase inhibitor.

26. The composition of claim 1, wherein following administration the composition has a T.sub.max selected from the group consisting of less than about 2.5 hours, less than about 2.25 hours, less than about 2 hours, less than about 1.75 hours, less than about 1.5 hours, less than about 1.25 hours, less than about 1.0 hours, less than about 50 minutes, less than about 40 minutes, less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, and less than about 10 minutes.

27. The composition of claim 1, wherein in comparative pharmacokinetic testing with a non-nanoparticulate composition of the same MAP kinase inhibitor, administered at the same dosage, the nanoparticulate composition exhibits a C.sub.max selected from the group consisting of greater than about 5%, greater than about 10%, greater than about 15%, greater than about 20%, greater than about 30%, greater than about 40%, greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, greater than about 100%, greater than about 110%, greater than about 120%, greater than about 130%, greater than about 140%, and greater than about 150% than the C.sub.max exhibited by the non-nanoparticulate composition of the MAP kinase inhibitor.

28. A method of making a mitogen-activated protein (MAP) kinase inhibitor composition comprising contacting particles of at least one poorly soluble MAP kinase inhibitor with at least one surface stabilizer for a time and under conditions sufficient to provide a MAP kinase inhibitor composition having an effective average particle size of less than about 2 microns, wherein the at least one surface stabilizer is selected from the group consisting of a polymeric stabilizer, poloxamer, hydroxypropylcellulose, docusate sodium, sodium lauryl sulfate, and povidone.

29. A method of treating a subject in need with a mitogen-activated protein (MAP) kinase inhibitor composition comprising administering to the subject an effective amount of a MAP kinase inhibitor composition comprising: (a) particles of a poorly soluble MAP kinase inhibitor or a salt thereof having an effective average particle size of less than about 2000 nm; and (b) associated with the surface thereof at least one surface stabilizer, wherein the at least one surface stabilizer is selected from the group consisting of a polymeric stabilizer, poloxamer, hydroxypropylcellulose, docusate sodium, sodium lauryl sulfate, and povidone.

30. The method of claim 29, wherein the at least one MAP kinase inhibitor is selected from the group consisting of PD 184352, VX-745, SB 202190, Anisomycin, PD 98059, SB 203580, U0126, AG 126, Apigenin, HSP25 Kinase Inhibitor, 5-Iodotubercidin, MAP Kinase Antisense Oligonucleotide, Control MAP Kinase Oligonucleotide, MAP Kinase Cascasde Inhibitor, MAP Kinase Inhibitor Set 1, MAP Kinase Inhibitor Set 2, MEK Inhibitor Set, Olomoucine, Iso Olomoucine, N.sup.9 Isopropyl Olomoucine, p38 MAP Kinase Inhibitor, PD 169316, SB 202474, SB 202190 Hydrochloride, SB 202474 Dihydrochloride, SB 203580 Sulfone, Ioto-SB 203580, SB 220025, SC 68376, SKF-86002, Tyrphostin AG 126, U0124, U0125, and ZM 336372.

31. The method of claim 29, wherein the effective average particle size of the nanoparticulate MAP kinase inhibitor 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.

32. The method of claim 29, wherein the method is used to treat an condition where a selective MAP kinase inhibitor is indicated.

33. The method of claim 29, wherein the method is used to treat an inflammatory disease.

34. The method of claim 29, wherein the method is used to treat a condition selected from the group consisting of rheumatoid arthritis and Crohn's disease.

35. The method of claim 29, wherein the subject is a human.
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