Granted Patent B2

US 6,908,626 · App. 10/268,928 · Granted Jun 21, 2005

Abstract

Claims (44)

1. A formulation comprising:

(a) at least one population of nanoparticulate of at least one poorly soluble active agent having an effective average particle size of less than about 1 micron;

(b) at least one surface stabilizer adsorbed onto the surface of the nanoparticulate active agent particles wherein the concentration of the surface stabilizer is from about 0.5% to about 99.999%(w/w), based upon the total weight of the nanoparticulate active agent and the surface stabilizer, and wherein the surface stabilizer is selected from the group consisting of a nonionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, and an ionic surface stabilize; and

(c) at least one population of microparticulate active agent, which is either the same as or different from the active agent of (a), and having an effective average particle size of greater than about 1 micron and less than about 10 microns wherein the concentration of the microparticulate agent is from about 5% to about 85%, based upon the total weight of the microparticulate active agent, nanoparticulate active agent, and surface stabilizer.

2. The composition of claim 1 , wherein the effective average particle size of the nanoparticulate active agent particles is selected from the group consisting of 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 404 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, and less than about 50 nm.

3. The composition of claim 1 , wherein the effective average particle size of the microparticulate active agent particles is greater than about 1 micron and less than the size selected from the group consisting of less than about 9 microns, less than about 8 microns, less than about 7 microns, less than about 6 microns, less than about 5 microns, less than about 4 microns, less than about 3 microns, and less than about 2 microns.

4. The composition of claim 1 comprising more than one population of nanoparticulate active agent particles, wherein each population of particles has an effective average particle size which is less than about 1 micron.

5. The composition of claim 1 comprising more than one population of microparticulate active agent particles, wherein each population of particles has an effective average particle size which is greater than about 1 micron and less than about 10 microns.

6. The composition of claim 1 , wherein the concentration of the nanoparticulate active agent is from about 99.5% to about 0.00 1%, based upon the total weight of the nanoparticulate active agent and the surface stabilizer.

7. The composition of claim 6 , wherein the concentration of the nanoparticulate active agent is from about 95% to about 0.1% (w/w), based upon the total weight of the nanoparticulate active agent and the surface stabilizer.

8. The composition of claim 7 , wherein the concentration of the nanoparticulate active agent is from about 90% to about 0.5% (w/w), based upon the total weight of the nanoparticulate active agent and the surface stabilizer.

9. The composition of claim 1 , wherein the concentration of the surface stabilizer is from about 5% to about 99.9% (w/w), based upon the total weight of the nanoparticulate active agent and the surface stabilizer.

10. The composition of claim 9 , wherein the concentration of the surface stabilizer is from about 10% to about 99.5% (w/w), based upon the total weight of the nanoparticulate active agent and the surface stabilizer.

11. The composition of claim 1 formulated into a solid, rapidly disintegrating, “waterless tablet” matrix.

12. The composition of claim 1 formulated into a pharmaceutically acceptable tablet.

13. The composition of claim 1 formulated into a pharmaceutically acceptable hard gelatin capsule.

14. The composition of claim 1 formulated into a pharmaceutically acceptable soft gelatin capsule.

15. The composition of claim 1 formulated into a pharmaceutically acceptable lozenge or troche.

16. The composition of claim 1 formulated into a pharmaceutically acceptable sachet, powder, or “sprinkle”.

17. The composition of claim 1 formulated into a dosage form for oral, rectal, intravaginal, injectable, pulmonary, nasal, buccal, topical, local, intracisternal, intraperitoneal, ocular, aural, buccal spray, or nasal spray administration.

18. The composition of claim 1 , wherein the formulation is made utilizing at least one method selected from the group consisting of spray drying, spray granulation, fluid bed granulation, high shear granulation, fluid bed drying, lyophilization, tableting, jet milling, pin milling, wet milling, rotogranulalion, and spray coating.

19. The composition of claim 1 , wherein the nanoparticulate and microparticulate active agents are selected from the group consisting of proteins, peptides, nucleotides, anti-obesity drugs, nutraceuticals, corticosteroids, elastase inhibitors, anti-fungals, oncology therapies, anti-emetics, analgesics, 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, beta-adrenoceptor blocking agents, blood products and 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 and anoretics, sympathomimetics, thyroid agents, vasodilators, and xanthines.

20. The composition of claim 1 , 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, stearic acid esters and salts, 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, 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, dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate, dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkyl aryl polyether sulfonates, mixtures of sucrose stearate and sucrose distearate, triblock copolymers of the structure: -(-PEO)—(-PBO-)—(-PEO-)-, 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, a PEG derivatized phospholipid, PEG derivatized cholesterol, a PEG derivatized cholesterol derivative, PEG derivatized vitamin A, PEG derivatized vitamin E, and random copolymers of vinyl acetate and vinyl pyrrolidone.

21. The composition of claim 1 , 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.

22. The composition of claim 1 , wherein the at least one surface stabilizer is selected from the group consisting of cationic lipids, benzalkonium chloride, sulfonium compounds, 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-diclecyldimethyl 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, C 12 trimethyl ammonium bromides, C 15 trimethyl ammonium bromides, C 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, 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, cationic guar, polymethylmethacrylate trimethylammonium bromide, polyvinylpyrrolidone-2-dimetbylaminoethyl methacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide, poly (2-methacryloxyethyltrimethylammonium bromide) (S1001), poly(N-vinylpyrrolidone/2-dimethylaminoethyl methacrylate) di methylsulphate quarternary (S1002), and poly(2-methylacryloxyamidopropyltrimethylammonium chloride) (S1004).

23. The composition of claim 1 , comprising two or more surface stabilizers.

24. The composition of claim 1 , comprising sodium lauryl sulfate, dioctyl sodium sulfosuccinate, or a combination thereof, as surface stabilizers.

25. A method of preparing a formulation comprising:

(a) combining

(i) population of at least one nanoparticulate poorly soluble active agent and at least one surface stabilizer adsorbed to the surface thereof, (a) wherein the nanoparticulate active agent has an effective average particle size of less than about 1000 nm, (b) wherein the concentration of the surface stabilizer is from about 0.5% to about 99.999%(w/w), based upon the total weight of the nanoparticulate active agent and the surface stabilizer, and (c)wherein the surface stabilizer is selected from the group consisting of a nonionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, and an ionic surface stabilizer and

(ii) at least one population of microparticulate active agent having an effective average particle size of greater than about 1 micron and less than about 10 microns wherein the concentration of the microparticulate agent is from about 5% to about 85%, based upon the total weight of the microparticulate active agent, nanoparticulate active agent, and surface stabilize; and

b) forming a suitable dosage formulation.

26. The method of claim 25 , wherein the nanoparticulate active agent particles having at least one surface stabilizer adsorbed onto the surface of the particles are incorporated into a dry powder matrix by spray drying, spray granulation, lyophilization, or a related pharmaceutically acceptable drying process, and then combined with bulk microparticulate active agent particles by dry blending or a similar mixing process.

27. The method of claim 25 , wherein:

(a) the nanoparticulate active agent particles having at least one surface stabilizer adsorbed on to the surface of the particles are incorporated into a dry powder matrix by spray drying, spray granulation, lyophilization, or a related pharmaceutically acceptable drying process;

(b) the microparticulate active agent particles are incorporated into a dry powder matrix by spray drying, spray granulation, lyophilization, or a related pharmaceutically acceptable drying process; and

(c) the resulting matrices from (a) and (b) are combined by dry blending or a similar mixing process.

28. The method of claim 25 , wherein the microparticulate active agent particles are prepared by dry milling.

29. The method of claim 25 , wherein the microparticulate, nanoparticulate, or both active agent particles are prepared by wet milling.

30. The method of claim 25 , wherein the microparticulate active agent particles are coated with the nanoparticulate active agent/surface stabilizer particles.

31. The method of claim 30 , wherein the coating is accomplished by a method selected from the group consisting of spray granulation, rotogranulation, spray coating, or a related pharmaceutical process.

32. The method of claim 25 , wherein the microparticulate active agent particles are employed as a substrate in a high-shear granulation or related pharmaceutical wet-mixing process, upon which nanoparticulate active agent/surface stabilizer particles are applied in the form of a granulating fluid, wherein upon drying the nanoparticulate active agent particles and microparticulate active agent particles are homogeneously distributed in the resulting solid matrix.

33. The method of claim 25 , wherein the nanoparticulate active agent/surface stabilizer particles and microparticulate active agent particles are formulated into a dry powder or powder blend for incorporation into a solid, rapidly disintegrating matrix, followed by compressing the dry powder or powder blend using a tablet press or similar pharmaceutically acceptable compression machine to form tablets.

34. A method of treating a mammal comprising administering to the mammal an effective amount of a composition according to claim 1 .

Assignments (19)