COMPOSITIONS FOR SITE-SPECIFIC DELIVERY OF IMATINIB AND METHODS OF USE

• US 20090238884A1
• Filed: 03/19/2009
• Published: 09/24/2009
• Est. Priority Date: 03/21/2008
• Status: Abandoned Application

• Current Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Original Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Inventors: Liversidge, Gary, Jenkins, Scott
• Application Number:
  US12/407,684
• Publication Number:
  US 20090238884A1
• Time in Patent Office: Days
• US Class Current: 424/490
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/28 Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention provides an oral formulation for administering to a subject comprising an imatinib compound and an enteric matrix or enteric coating or a combination thereof, whereby at least 80% of the imatinib compound is released in the small intestine of the subject. Methods of using such formulation is also provided.

Claims

1. An oral formulation for administering to a subject comprising

a) an imatinib compound;

and

b) an enteric matrix or enteric coating or a combination thereof;

whereby at least 80% of the imatinib compound is released in the small intestine of the subject.

2. The formulation of claim 1, wherein the imatinib compound is imatinib mesylate.

3. The formulation of claim 1, wherein the enteric coating is selected from cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, ammonio methacrylate copolymers, poly acrylic acid and poly acrylate and methacrylate copolymers, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate, shellac, hydrogels and gel-forming materials, carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, aminoacryl-methacrylate copolymer, pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers) poly(hydroxyalkyl methacrylate) (m. wt. about 5 k-5,000 k), polyvinylpyrrolidone (m. wt. ˜

10 k-360 k), anionic and cationic hydrogels, polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (m. wt. ˜

30 k-300 k), agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, POLYOX®

, polyethylene oxides (m. wt. ˜

100 k-5,000 k), AQUAKEEP®

acrylate polymers, diesters of polyglucan, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glucolate, polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, polyethylene oxides, methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of methacrylic acid or methacrylic acid, sorbitan esters, natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, arabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan, scleroglucan and mixtures and blends thereof and any combination thereof.

4. The formulation of claim 1, whereby at least 85 % of the imatinib compound is released in the small intestine of the subject.

5. The formulation of claim 4, whereby at least 90% of the imatinib compound is released in the small intestine of the subject.

6. The formulation of claim 5, whereby at least 95% of the imatinib compound is released in the small intestine of the subject.

7. The formulation of claim 6, whereby at least 99% of the imatinib compound is released in the small intestine of the subject.

8. The formulation of claim 1, wherein at least a portion of the imatinib compound is in a nanoparticulate form, and wherein the nanoparticles of the imatinib compound further comprise at least one surface stabilizer.

9. The formulation of claim 8, 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 ≠

-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, 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 phospholipids, 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_12-14)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 quatemized polyoxyethylalkylamines, alkyl pyridinium salts;

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

10. The formulation of claim 8, wherein the nanoparticles have an average diameter of less than about 2000 nm.

11. The formulation of claim 1, comprising a first population of imatinib compound-containing particles and at least one subsequent population of active ingredient-containing particles, wherein the subsequent population of at least a second active ingredient-containing particles further comprises a modified release coating or, alternatively or additionally, a modified release matrix material, such that the imatinib compound and at least the second active ingredient reach their respective peak plasma concentrations in a pre-determined time interval.

12. The formulation of claim 11, wherein at least the second active ingredient is not the imatinib compound.

13. The formulation of claim 12, wherein at least the second active ingredient is selected from anti-emetic compounds, anti-diarrhea compounds, and H₂ antagonists.

14. The formulation of claim 11, wherein members of the first and the subsequent populations of particles each have a diameter of less than approximately 2000 nm.

15. The formulation of claim 1, wherein the imatinib compound is present in the amount equivalent to at least about 400 mg of imatinib.

16. The formulation of claim 15, wherein the imatinib compound is present in the amount equivalent to at least about 600 mg of imatinib.

17. The formulation of claim 16, wherein the imatinib compound is present in the amount equivalent to at least about 800 mg of imatinib.

18. The formulation of claim 1, further comprising a non-toxic amount of iron.

19. A method of treating a subject having a disease amenable to imatinib therapy, comprising administering to a subject the formulation of claim 1.

20. The method of claim 19, wherein a single daily dose of the formulation comprises the imatinib compound in the amount equivalent to about 800 mg of imatinib.