LIQUID DOSAGE COMPOSITIONS OF STABLE NANOPARTICULATE ACTIVE AGENTS

• US 20110165251A1
• Filed: 03/09/2011
• Published: 07/07/2011
• Est. Priority Date: 07/16/2002
• Status: Abandoned Application

• Current Assignee: Alkermes Pharma Ireland Limited (Alkermes plc)
• Original Assignee: Elan Pharma International Limited (Perrigo Company PLC)
• Inventors: BOSCH, H. William, HILBORN, Matthew R., HOVEY, Douglas C., KLINE, Laura J., LEE, Robert W., RYDE, Tuula A., RYDE, Niels P., XU, Shuqian, PRUITT, John D.
• Application Number:
  US13/044,450
• Publication Number:
  US 20110165251A1
• Time in Patent Office: Days
• US Class Current: 424/489
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/143 with inorganic compounds
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/24 of the sex hormones

Abstract

The present invention relates to liquid dosage compositions of stable nanoparticulate active agents. The liquid dosage compositions of the invention include osmotically active crystal growth inhibitors that stabilize the nanoparticulate active agents against crystal and particle size growth of the active agent.

Claims

1-123. -123. (canceled)

124. A method of making a stable nanoparticulate liquid dosage composition comprising contacting particles of at least one active agent with at least one surface stabilizer for a time and under conditions sufficient to provide a nanoparticulate active agent composition wherein:

(a) the active agent particles have an effective average particle size of less than about 2 microns; and

(b) at least one osmotically active crystal growth inhibitor is added to the composition either before, during, or after the active agent particle size reduction.

125. The method of claim 124, wherein the contacting comprising grinding, wet grinding, homogenization, or any combination thereof.

126. The method of claim 124, wherein the contacting comprises:

(a) dissolving the particles of at least one active agent in a solvent;

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

(c) precipitating the solubilized active agent and at least one surface stabilizer by the addition thereto of a non-solvent.

127. The method of claim 124, wherein the active agent particles form crystals upon storage or heating in the absence of the crystal growth inhibitor.

128. The method of claim 124, wherein the osmotically active crystal growth inhibitor is at least partially water-soluble and does not solubilize the nanoparticulate active agent.

129. The method of claim 128, wherein the osmotically active crystal growth inhibitor is selected from the group consisting of glycerol, propylene glycol, mannitol, sucrose, glucose, fructose, mannose, lactose, xylitol, sorbitol, trehalose, a polysaccharide, a mono-polysaccharide, a di-polysaccharides, a sugars, a sugar alcohol, sodium chloride, potassium chloride, magnesium chloride, and an ionic salt.

130. The method of claim 124, wherein the amount of the crystal growth inhibitor present in the liquid dosage composition:

(a) ranges from about 0.1% to about 95% concentration, by weight;

or

(b) ranges from about 0.5% to about 90% concentration, by weight.

131. The method of claim 124, wherein the effective average particle size of the nanoparticulate active agent 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.

132. The method of claim 124, wherein at least about 70%, about 90%, or about 95% of the active agent particles have a particle size less than the effective average particle size.

133. The method of claim 124, wherein the liquid media of the liquid dosage composition is selected from the group consisting of water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, and glycol.

134. The method of claim 124, wherein:

(a) the at least one active agent 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 active agent 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% 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 active agent and at least one surface stabilizer, not including other excipients;

or

(c) any combination thereof.

135. The method of claim 124, wherein:

(a) the ratio of active agent to a polymeric surface modifier is selected from the group consisting of from about 20;

1 to about 1;

10, from about 10;

1 to about 1;

5, and from about 5;

1 to about 1;

1, by weight;

(b) the ratio of active agent to the second surface stabilizer is selected from the group consisting of from about 500;

1 to about 5;

1, from about 350;

1 to about 10;

1, and from about 100;

1 to about 20;

1, by weight;

or

(c) any combination thereof.

136. The method of claim 124, wherein the surface stabilizer is selected from the group consisting of an ionic surface stabilizer, a nonionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, a polymeric surface stabilizer, and a zwitterionic surface stabilizer.

137. The method of claim 124, 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, hydroxyethyl cellulose, 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, 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_12-15dimethyl 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 trimethyl ammonium 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.

138. The method of claim 124, wherein the active agent is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, and mixtures thereof.

139. The method of claim 124, wherein the one or more active agents have a solubility in water selected from the group consisting of less than about 30 mg/ml, less than about 20 mg/ml, less than about 10 mg/ml, and less than about 1 mg/ml, under ambient conditions.

140. The method of claim 124, wherein:

(a) the active agent comprises anti-inflammatory and analgesic properties;

(b) the active agent is selected from the group consisting of COX-2 inhibitors, anticancer agents, NSAIDS, proteins, peptides, nutraceuticals, anti-obesity agents, corticosteroids, elastase inhibitors, analgesics, 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, 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, xanthines, acne medication, alpha-hydroxy formulations, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, and respiratory illness therapies associated with acquired immune deficiency syndrome;

(c) the active agent is a nutraceutical and the nutraceutical is selected from the group consisting of dietary supplements, vitamins, minerals, herbs, healing foods that have medical or pharmaceutical effects on the body, folic acid, fatty acids, fruit and 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 and marine animal oils, and probiotics;

(d) the active agent is selected from the group consisting of acyclovir, alprazolam, altretamine, amiloride, amiodarone, benztropine mesylate, bupropion, cabergoline, candesartan, cerivastatin, chlorpromazine, ciprofloxacin, cisapride, clarithromycin, clonidine, clopidogrel, cyclobenzaprine, cyproheptadine, delavirdine, desmopressin, diltiazem, dipyridamole, dolasetron, enalapril maleate, enalaprilat, famotidine, felodipine, furazolidone, glipizide, irbesartan, ketoconazole, lansoprazole, loratadine, loxapine, mebendazole, mercaptopurine, milrinone lactate, minocycline, mitoxantrone, nelfinavir mesylate, nimodipine, norfloxacin, olanzapine, omeprazole, penciclovir, pimozide, tacolimus, quazepam, raloxifene, rifabutin, rifampin, risperidone, rizatriptan, saquinavir, sertraline, sildenafil, acetyl-sulfisoxazole, temazepam, thiabendazole, thioguanine, trandolapril, triamterene, trimetrexate, troglitazone, trovafloxacin, verapamil, vinblastine sulfate, mycophenolate, atovaquone, atovaquone, proguanil, ceftazidime, cefuroxime, etoposide, terbinafine, thalidomide, fluconazole, amsacrine, dacarbazine, teniposide, and acetylsalicylate;

or

(e) any combination thereof.

141. A method of treating a subject with a stable nanoparticulate liquid dosage composition comprising administering to the subject an effective amount of a composition comprising:

(a) particles of at least one active agent having an effective average particle size of less than about 2000 nm;

(b) at least one surface stabilizer; and

(c) at least one osmotically active crystal growth inhibitor.

142. The method of claim 141, wherein said subject is a human.

143. The method of claim 141, wherein:

(a) the condition to be treated is selected from the group consisting of neoplastic diseases, breast cancer, endometrial cancer, uterine cancer, cervical cancer, prostate cancer, renal cancer, hormone replacement therapy in post-menopausal women, endometriosis, hirsutism, dysmenorrhea, uterine bleeding, HIV wasting, cancer wasting, migraine headache, cachexia, anorexia, castration, oral contraception, motion sickness, emesis related to cytotoxic drugs, gastritis, ulcers, dyspepsia, gastroenteritis, including collitis and food poisoning, inflammatory bowel disease, Crohn'"'"'s disease, migraine headaches, and any other condition which is accompanied by the symptoms of nausea and vomiting;

(b) the condition to be treated is selected from the group consisting of pain, inflammation, arthritis, cancer, kidney disease, osteoporosis, Alzheimer'"'"'s disease, and familial adenomatous polyposis;

(c) the condition to be treated is selected from the group consisting of osteoarthritis, rheumatoid arthritis, juvenile arthritis, gout, ankylosing spondylitis, systemic lupus erythematosus, bursitis, tendinitis, myofascial pain, carpal tunnel syndrome, fibromyalgia syndrome, infectious arthritis, psoriatic arthritis, reiter'"'"'s syndrome, and scleroderma;

or

(d) any combination thereof.

144. The method of claim 141, wherein the active agent particles form crystals upon storage or heating in the absence of the crystal growth inhibitor.

145. The method of claim 141, wherein the osmotically active crystal growth inhibitor is at least partially water-soluble and does not solubilize the nanoparticulate active agent.

146. The method of claim 145, wherein the osmotically active crystal growth inhibitor is selected from the group consisting of glycerol, propylene glycol, mannitol, sucrose, glucose, fructose, mannose, lactose, xylitol, sorbitol, trehalose, a polysaccharide, a mono-polysaccharide, a di-polysaccharides, a sugars, a sugar alcohol, sodium chloride, potassium chloride, magnesium chloride, and an ionic salt.

147. The method of claim 141, wherein:

(a) the amount of the crystal growth inhibitor present in the liquid dosage composition ranges from about 0.1% to about 95% concentration, by weight;

or

(b) the amount of the crystal growth inhibitor present in the liquid dosage composition ranges from about 0.5% to about 90% concentration, by weight.

148. The method of claim 141, wherein the effective average particle size of the nanoparticulate active agent 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.

149. The method of claim 141, wherein at least about 70%, about 90%, or about 95% of the active agent particles have a particle size less than the effective average particle size.

150. The method of claim 141, wherein the amount of the active agent per ml is equal to or greater than the amount of the active agent per ml of a standard conventional non-nanoparticulate liquid dosage composition of the same active agent.

151. The method of claim 141, wherein the liquid media of the liquid dosage composition is selected from the group consisting of water, safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol (PEG), hexane, and glycol.

152. The method of claim 141, wherein:

(a) the composition is formulated for administration selected from the group consisting of oral, pulmonary, rectal, ophthalmic, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, local, buccal, nasal, and topical administration;

(b) the composition is formulated into a dosage form selected from the group consisting of liquid dispersions, oral suspensions, 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) any combination thereof.

153. The method of claim 141, wherein:

(a) the at least one active agent 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 active agent and at least one surface stabilizer, not including other excipients;

(b) the 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 active agent and at least one surface stabilizer, not including other excipients;

or

(c) any combination thereof.

154. The method of claim 141, wherein:

(a) the ratio of active agent to a polymeric surface modifier is selected from the group consisting of from about 20;

1 to about 1;

10, from about 10;

1 to about 1;

5, and from about 5;

1 to about 1;

1, by weight;

(b) the ratio of active agent to the second surface stabilizer is selected from the group consisting of from about 500;

1 to about 5;

1, from about 350;

1 to about 10;

1, and from about 100;

1 to about 20;

1, by weight;

or

(c) any combination thereof.

155. The method of claim 141, comprising at least two surface stabilizers.

156. The method of claim 141, wherein the composition further comprises one or more pharmaceutically acceptable excipients, carriers, or a combination thereof.

157. The method of claim 141, wherein the surface stabilizer is selected from the group consisting of an ionic surface stabilizer, a nonionic surface stabilizer, an anionic surface stabilizer, a cationic surface stabilizer, a polymeric surface stabilizer, and a zwitterionic surface stabilizer.

158. The method of claim 141, 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 13-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 thioglucopyranoside;

lysozyme, PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, 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.

159. The method of claim 141, wherein the active agent is selected from the group consisting of a crystalline phase, an amorphous phase, a semi-crystalline phase, and mixtures thereof.

160. The method of claim 141, wherein the one or more active agents have a solubility in water selected from the group consisting of less than about 30 mg/ml, less than about 20 mg/ml, less than about 10 mg/ml, and less than about 1 mg/ml, under ambient conditions.

161. The method of claim 141, wherein:

(a) the active agent comprises anti-inflammatory and analgesic properties;

(b) the active agent is selected from the group consisting of COX-2 inhibitors, anticancer agents, NSAIDS, proteins, peptides, nutraceuticals, anti-obesity agents, corticosteroids, elastase inhibitors, analgesics, 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, 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, xanthines, acne medication, alpha-hydroxy formulations, cystic-fibrosis therapies, asthma therapies, emphysema therapies, respiratory distress syndrome therapies, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, organ-transplant rejection therapies, therapies for tuberculosis and other infections of the lung, and respiratory illness therapies associated with acquired immune deficiency syndrome;

(c) the active agent is a nutraceutical and the nutraceutical is selected from the group consisting of dietary supplements, vitamins, minerals, herbs, healing foods that have medical or pharmaceutical effects on the body, folic acid, fatty acids, fruit and 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 and marine animal oils, and probiotics;

(d) the active agent is selected from the group consisting of acyclovir, alprazolam, altretamine, amiloride, amiodarone, benztropine mesylate, bupropion, cabergoline, candesartan, cerivastatin, chlorpromazine, ciprofloxacin, cisapride, clarithromycin, clonidine, clopidogrel, cyclobenzaprine, cyproheptadine, delavirdine, desmopressin, diltiazem, dipyridamole, dolasetron, enalapril maleate, enalaprilat, famotidine, felodipine, furazolidone, glipizide, irbesartan, ketoconazole, lansoprazole, loratadine, loxapine, mebendazole, mercaptopurine, milrinone lactate, minocycline, mitoxantrone, nelfinavir mesylate, nimodipine, norfloxacin, olanzapine, omeprazole, penciclovir, pimozide, tacolimus, quazepam, raloxifene, rifabutin, rifampin, risperidone, rizatriptan, saquinavir, sertraline, sildenafil, acetyl-sulfisoxazole, temazepam, thiabendazole, thioguanine, trandolapril, triamterene, trimetrexate, troglitazone, trovafloxacin, verapamil, vinblastine sulfate, mycophenolate, atovaquone, atovaquone, proguanil, ceftazidime, cefuroxime, etoposide, terbinafine, thalidomide, fluconazole, amsacrine, dacarbazine, teniposide, and acetylsalicylate;

or

(e) any combination thereof.

162. The method of claim 141, wherein:

(a) the viscosity of the composition, at a shear rate of 0.1 (1/s), is selected from the group consisting of from about 2000 mPa·

s to about 1 mPa·

s, from about 1900 mPa·

s to about 1 mPa·

s, from about 1800 mPa·

s to about 1 mPa·

s, from about 1700 mPa·

s to about 1 mPa·

s, from about 1600 mPa·

s to about 1 mPa·

s, from about 1500 mPa·

s to about 1 mPa·

s, from about 1400 mPa·

s to about 1 mPa·

s, from about 1300 mPa·

s to about 1 mPa·

s, from about 1200 mPa·

s to about 1 mPa·

s, from about 1100 mPa·

s to about 1 mPa·

s, from about 1000 mPa·

s to about 1 mPa·

s, from about 900 mPa·

s to about 1 mPa·

s, from about 800 mPa·

s to about 1 mPa·

s, from about 700 mPa·

s to about 1 mPa·

s, from about 600 mPa·

s to about 1 mPa·

s, from about 500 mPa·

s to about 1 mPa·

s, from about 400 mPa·

s to about 1 mPa·

s, from about 300 mPa·

s to about 1 mPa·

s, from about 200 mPa·

s to about 1 mPa·

s, from about 175 mPa·

s to about 1 mPa·

s, from about 150 mPa·

s to about 1 mPa·

s, from about 125 mPa·

s to about 1 mPa·

s, from about 100 mPa·

s to about 1 mPa·

s, from about 75 mPa·

s to about 1 mPa·

s, from about 50 mPa·

s to about 1 mPa·

s, from about 25 mPa·

s to about 1 mPa·

s, from about 15 mPa·

s to about 1 mPa·

s, from about 10 mPa·

s to about 1 mPa·

s, and from about 5 mPa·

s to about 1 mPa·

s;

(b) the viscosity of the composition is selected from the group consisting of less than about 1/200, less than about 1/100, less than about 1/50, less than about 1/25, and less than about 1/10 of the viscosity of a standard conventional non-nanoparticulate liquid dosage composition of the same active agent at about the same concentration per ml of active agent;

(c) the viscosity of the composition is selected from the group consisting of less than about 5%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, less than about 50%, less than about 55%, less than about 60%, less than about 65%, less than about 70%, less than about 75%, less than about 80%, less than about 85%, and less than about 90% of the viscosity of a standard conventional non-nanoparticulate liquid dosage composition of the same active agent at about the same concentration per ml of active agent;

or

(d) any combination thereof.

163. The method of claim 141, wherein:

(a) the T_max of the active agent, when assayed in the plasma of a mammalian subject following administration, is less than the T_max for a conventional, non-nanoparticulate form of the same active agent, administered at the same dosage;

(b) the T_max is selected from the group consisting of not greater than about 90%, not greater than about 80%, not greater than about 70%, not greater than about 60%, not greater than about 50%, not greater than about 30%, not greater than about 25%, not greater than about 20%, not greater than about 15%, and not greater than about 10% of the T_max, exhibited by a non-nanoparticulate formulation of the same active agent, administered at the same dosage;

(c) the C_max of the active agent, when assayed in the plasma of a mammalian subject following administration, is greater than the C_max for a conventional, non-nanoparticulate form of the same active agent, administered at the same dosage;

(d) the C_max is selected from the group consisting of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, and at least about 100% greater than the C_max exhibited by a non-nanoparticulate formulation of the same active agent, administered at the same dosage;

(e) the AUC of the active agent, when assayed in the plasma of a mammalian subject following administration, is greater than the AUC for a conventional, non-nanoparticulate form of the same active agent, administered at the same dosage;

(f) the AUC is selected from the group consisting of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, and at least about 100% greater than the AUC exhibited by a non-nanoparticulate formulation of the same active agent, administered at the same dosage;

or

(g) any combination thereof.

164. The method of claim 141, wherein:

(a) the method does not produce significantly different absorption levels when administered under fed as compared to fasting conditions;

(b) the difference in absorption of the active agent 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 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

(c) any combination thereof.

165. The method of claim 141, 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, when administered to a human.

166. The method of claim 165, wherein:

(a) “

bioequivalency”

is established by a 90% Confidence Interval of between 0.80 and 1.25 for both C_max and AUC, when administered to a human;

or

(b) “

bioequivalency”

is established by a 90% Confidence Interval of between 0.80 and 1.25 for AUC and a 90% Confidence Interval of between 0.70 to 1.43 for C_max, when administered to a human.