JP5661630B2 - Weak ionic compound dosage forms - Google Patents

Description

The present disclosure relates to dosage forms comprising drug-containing emulsions, drug-containing microemulsions, self-emulsifying oil compositions, or self-microemulsifying oil compositions, each comprising a weak ionic drug and a pH adjusting agent. Also provided are pharmaceutical dosage forms, such as solid dosage forms, and methods of making the same.
[Background]
Certain drugs have the problem of balancing the need for a convenient oral dosage form with the required bioavailability. Depending on the drug, the absorption of an orally administered dose is as low as 30% or less. Such low absorption drugs often exhibit inter-patient and intra-patient variability with high bioavailability.
The absorption rate of most drugs is due to two factors: (1) dissolution of the drug in physiological fluid; (2) its own absorption process, ie the dissolved drug enters the cell at the site of absorption and finally enters the systemic circulation Depends on the process that enters. Many drugs are absorbed by passive diffusion, that is, by spontaneous migration of drug molecules from a high concentration region to a low concentration region. Other drugs are absorbed by active transport with energy consumption by the body. In general, for an orally administered solid drug that is absorbed either actively or passively, dissolution of the drug is the first step in the absorption process.
Prior art document information relating to the invention of this application includes the following (including documents cited in the international phase after the international filing date and documents cited when entering the country in other countries).
[Prior art documents]
[Patent Literature]

[Patent Document 01] Canadian Patent No. 1080500 [Patent Document 02] European Patent No. 0366277 [Patent Document 03] French Patent Invention No. 2356430 [Patent Document 04] French Patent Invention No. 2594693 [Patent Document 05] British Patent No. 1468815 [Patent Document 06] British Patent No. 1572718 [Patent Document 07] JP-A-60-224617 [Patent Document 08] JP-A 2000-044462 [Patent Document 09] JP-A-02-218609 [Patent Document 10] JP-A-49-007415 [Patent Document 11] JP-A-53-003512 [Patent Document 12] JP-A-58-58 Japanese Patent No. 213073 [Patent Document 13] Japanese Patent Laid-Open No. 08-099867 [Patent Document 14] [Patent Document 15] International Publication No. WO 97/09964 [Patent Document 16] International Publication No. 97/47290 [Patent Document 17] International Publication No. 00/09093 [Patent Document 18] International Publication No. 2010 No. 3,914,430 [Patent Document 19] US Pat. No. 3,914,430
Patent Document 20 US Pat. No. 3,961,041
[Patent Document 21] US Pat. No. 3,962,384
[Patent Document 22] US Pat. No. 4,353,806 [Patent Document 23] US Pat. No. 4,436,0061 [Patent Document 24] US Pat. No. 4,661,047 [Patent Document 25] US Pat. No. 4,751,241 [Patent Document] US Pat. No. 5,178,878 [Patent Document 27] US Pat. No. 5,206,219 [Patent Document 28] US Pat. No. 5,364,632 [Patent Document 29] US Pat. No. 5,393,527 [Patent Document 30] US Pat. No. 5,435,936 [Patent Document 31] US Pat. No. 5,444,401 [Patent Document 32] US Pat. No. 5,580,735 [Patent Document 33] US Pat. No. 5,593,843 [Patent Document 34] Patent No. 5620903 [Patent Document 35] US Patent US Pat. No. 5,633,226 [Patent Document 36] US Pat. No. 5,635,357 [Patent Document 37] US Pat. No. 5,646,109 [Patent Document 38] US Pat. No. 5,656,289 [Patent Document 39] US Pat. No. 5,688,697 [Patent Document 40] US Pat. No. 5,688,761 [Patent Document 41] US Pat. No. 5,698,219 [Patent Document 42] US Pat. No. 5,707,648 [Patent Document 43] US Pat. No. 5,800,844 [Patent Document 44] US Pat. No. 5,958,458 [Patent Document 45] US Pat. No. 5,997,905 [Patent Document 46] US Pat. No. 6,200,604 [Patent Document 47] US Pat. No. 6,228,400 [Patent Document] Document 48 US Pat. No. 6,280,770 Patent Document 49 US Pat. No. 6,350,470 [Patent Document 50] US Pat. No. 6,379,700 [Patent Document 51] US Pat. No. 6,613,332 [Patent Document 52] US Pat. No. 6,692,277 [Patent Document]. US Pat. No. 6,793,934 [Patent Document 54] US Pat. No. 7,070,802 [Patent Document 55] US Pat. No. 7,354,602 [Patent Document 56] US Pat. No. 7,354,603 [Patent Document 57] US Pat. No. 7,357,948 [Patent Document 58] US Pat. No. 7,390,503 [Patent Document 59] US Pat. No. 7,576,067 [Patent Document 60] US Pat. No. 7,585,521 [Patent Document 61] US Patent No. 7658945 [Non-Patent Document]

[Non-Patent Document 01] Aungst, "Novel Formation Strategies for Improving Oral Bioavailability of Drugs with Poor Membrane Permeation of Prestometics." 82 (10), pp. 1979-83, October 1993.
[Non-patent document 02] Canadian Intelligent Property Office Communication re CA2377762, Date November 9, 2007.
[Non-Patent Document 03] Ebert, "Soft Elastic Gelatin Capsules: A Unique Dosage Form", Pharm. Tech. , Vol. 1 (5), pp. 44-50, 1977.
[Non-Patent Literature 04] Eichman, John D. , "Mechanistic Studies on Effervescent-Induced Permeability Enhancement", A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the University of WI, Catalogued September 18, 1998, 32 pp.
EP Communication re 090111793.8, dated January 27, 2010.
[Non-patent Document 05] EP Office Communication re 09113012.9 (PCTUS0105978) Date September 18, 2007.
[Non-patent Document 06] Figueiras et al. , “The Role of L-arginine in Inclusion Complexes of Omplateles with Cycloetrins”, AAPS PharmSciTech, Vol. 11 (1), March 2010 DOI: 10.1208 / s12249-0099755-2, pp. 233-240.
[Non-Patent Document 07] Guilment et al. , "Interactions in Aqueous Mixtures of Hydrophobically Modified Polyelectrolyte and Oppositely Charged Surfactant", "Mixed Michile Formation FundA ss. Phys. Chem. , Vol. 99, pp. 9201-09, 1995.
[Non-Patent Document 08] International Search Report re: PCT / US2009 / 053622, dated May 11, 2010. "Microemulsion Technology in the Reformation of Cyclosporine: The Reason Behind the Pharmaceutical Properties of Neo", Universality of Innovation. Ctr. , Division of Pharmaceuticals and Drug Delivery Systems, Ohio 45267-0004, Abstract, 2 pp.
[Non-Patent Document 09] Nelson, "Part XVII Physicochemical and Pharmaceutical Properties of Drugs that Influence the Results of Clinical Trials", Universitary Trials. Ctr, School of Pharmacy, Vol. 3 (5), pp. 673-681.
[Non-Patent Document 10] Pather et al. , "A Comparison of Two Quality Assessment Methods for Emulsions", Journal of Pharmaceutical and Biomedical Analysis, Vol. 13, pp. 1283-89, 1995.
[Non-Patent Document 11] Ritschel, “Microemulsion Technology in the Reformation of Cyclosporine: The Reason Behind the Pharmaceutical Properties of Neo,” Transp. , Vol. 10, Abstract, 1996.
[Non-Patent Document 12] Sheth A. et al. et al. , "Use of Powdered Solution to Improv the Dissolution Rate of Polyoxide Tables", Drug Development and industrial Pharmacology, Vol. 16 (5), January 1, 1990, pp. 769-777, XP002923449 ISSN: 0363-9045.
[Non-Patent Document 13] S. et al. "Powdered Solution Technology: Principles and Mechanism", Pharmaceutical Research, Kluwer Academic Publishers, Vol. 9 (10), January 1, 1992, pp. 1351-58, XP002923448, ISSN: 0724-8741.

  The present disclosure relates to drug-containing emulsions, drug-containing microemulsions, self-emulsifying oil compositions, or self-emulsifying oil compositions each comprising a weak ionic drug and a pH adjusting agent (eg, solids Dosage form). Also provided are pharmaceutical dosage forms and methods of making the same.

  As used herein, (a) a drug-containing emulsion having globules with a diameter greater than 100 nm, the drug-containing emulsion comprising a weak ionic drug and a pH adjuster, wherein the pH adjuster is a non-pH adjuster A drug-containing emulsion that enhances the solubility of the weak ionic drug in the aqueous phase as compared to the solubility of the weak ionic drug in the presence of the weak ionic drug having a pKa of about 1 to about 14; (b) the drug There is provided a dosage form comprising: a solid particle adsorbent wherein a containing emulsion is adsorbed to form a free-flowing compressible powder.

  In some embodiments, the emulsion globules can have a diameter of about 120 nm to about 70 μm. In some embodiments, the drug-containing emulsion comprises from about 1 to about 50% by weight of the weak ionic drug based on the total weight of both phases of the emulsion. In some embodiments, the drug-containing emulsion is an oil-in-water emulsion or a water-in-oil emulsion.

  As used herein, (a) a drug-containing emulsion having small spheres with a diameter of less than 100 nm, the drug-containing emulsion comprising a weak ionic drug and a pH adjuster, wherein the pH adjuster is a non-pH adjuster A drug-containing microemulsion that enhances the solubility of the weakly ionic drug in the aqueous phase compared to the solubility of the weakly ionic drug in the presence of the weakly ionic drug having a pKa of about 1 to about 14; (b) A dosage form is provided comprising a solid particle adsorbent, onto which a drug-containing microemulsion is adsorbed to form a free-flowing compressible powder.

  In some embodiments, the drug-containing microemulsion comprises about 1 to about 50% by weight of the weak ionic drug based on the total weight of both phases of the microemulsion. In some embodiments, the drug-containing microemulsion is an oil-in-water emulsion or a water-in-oil emulsion.

  As used herein, (a) a self-emulsifying oil composition comprising one or more oils, a weakly ionic drug and a pH adjuster, the self-emulsifying oil when exposed to an aqueous phase The composition forms a drug-containing emulsion having globules with a diameter greater than 100 nm, and the pH adjuster is a weak ion in the aqueous phase compared to the solubility of the weakly ionic drug in the absence of the pH adjuster. A self-emulsifying oil composition which enhances the solubility of the ionic drug and the weak ionic drug has a pKa of about 1 to about 14; (b) a free-flowing compressible powder on which the self-emulsifying oil composition is adsorbed There is further provided a dosage form comprising: a solid particle adsorbent;

  In some embodiments, the self-emulsifying oil composition comprises about 1 to about 50% by weight of the weak ionic drug based on the total weight of the oil composition. In some embodiments, the emulsion globules can have a diameter of about 120 nm to about 70 μm.

  The present disclosure provides (a) a self-microemulsifying oil composition comprising one or more oils, a weak ionic drug and a pH adjuster, the self-microemulsification when exposed to an aqueous phase The neutral oil composition forms a drug-containing microemulsion having globules less than 100 nm in diameter, and the pH adjuster is in the aqueous phase compared to the solubility of the weak ionic drug in the absence of the pH adjuster. A self-microemulsifying oil composition that enhances the solubility of the weak ionic drug and the weak ionic drug has a pKa of about 1 to about 14; There is also provided a dosage form comprising a solid particle adsorbent;

  In some embodiments, the self-microemulsifying oil composition comprises about 1 to about 50% by weight of the weak ionic drug based on the total weight of the oil composition.

  In some embodiments, the dosage forms described herein are kaolin; bentonite; hectorite; colloidal aluminum magnesium silicate; silicon dioxide; magnesium trisilicate; aluminum hydroxide; magnesium hydroxide; And solid particles selected from the group consisting of talc.

  In some embodiments, the weakly ionic drug is meloxicam; atropine; chloramphenicol; chlorothiazide; chlorpromazine; cimetidine; diazepam; diltiazem; diphenhydramine; Selected from the group consisting of: phenytoin; procainamide; propafenone; propranolol; tetracaine; trimethoprim; and verapamil. In some embodiments, the weak ionic drug is meloxicam.

  In some embodiments, the weak ionic drug is poorly soluble. In some embodiments, the low solubility drug exhibits an absolute bioavailability greater than about 30%.

  In some embodiments, the pH adjuster is sodium carbonate; potassium carbonate; magnesium carbonate; sodium bicarbonate; potassium bicarbonate; disodium hydrogen phosphate; sodium dihydrogen phosphate; dipotassium hydrogen phosphate; Selected from the group consisting of potassium hydrogen; tris (hydroxymethyl) aminomethane; citric acid; tartaric acid; amarinic acid; fumaric acid; adipic acid; and succinic acid. In some embodiments, the pH adjuster is tris (hydroxymethyl) aminomethane.

  As used herein, (a) a drug-containing emulsion having globules with a diameter greater than 100 nm, the drug-containing emulsion comprising meloxicam and a pH adjuster, and the pH adjuster in the absence of the pH adjuster A drug-containing emulsion that enhances the solubility of meloxicam in the aqueous phase as compared to the solubility of meloxicam in a solid phase; (b) the drug-containing emulsion is adsorbed thereto to form a free-flowing compressible powder A dosage form comprising an adsorbent is provided.

  As used herein, (a) a drug-containing microemulsion having globules less than 100 nm in diameter, wherein the drug-containing microemulsion comprises meloxicam and a pH adjuster, and the pH adjuster is absent of the pH adjuster A drug-containing microemulsion that enhances the solubility of meloxicam in the aqueous phase as compared to the solubility of meloxicam below; (b) the drug-containing microemulsion is adsorbed to form a free-flowing compressible powder A dosage form comprising a solid particle adsorbent is also provided.

  As used herein, (a) a self-emulsifying oil composition comprising one or more oils, meloxicam and a pH adjuster, the self-emulsifying oil composition having a thickness of 100 nm when exposed to an aqueous phase. Self-emulsification that forms a drug-containing emulsion with globules of greater diameter and the pH adjuster enhances the solubility of meloxicam in the aqueous phase compared to the solubility of meloxicam in the absence of pH adjuster There is further provided a dosage form comprising: a solid oil adsorbent; (b) a self-emulsifiable oil composition adsorbed thereon to form a free-flowing compressible powder.

  The present disclosure provides (a) a self-microemulsifying oil composition comprising one or more oils, meloxicam and a pH adjuster, wherein the self-microemulsifying oil composition has a diameter of less than 100 nm. A self-microemulsifying oil composition that forms a drug-containing microemulsion having a pH and the pH adjuster increases the solubility of meloxicam in the aqueous phase compared to the solubility of meloxicam in the absence of the pH adjuster Also provided is a dosage form comprising: (b) a solid particle adsorbent on which a self-microemulsifiable oil composition is adsorbed to form a free-flowing compressible powder.

In some embodiments, dosage forms described herein comprising meloxicam, when administered, do not include a pH adjusting agent and are administered by the same route, emulsions, microemulsions, self-emulsifying oil compositions, A short T _max is achieved compared to a composition comprising meloxicam, which is not a self-microemulsifying oil composition. In some embodiments, T _max can range from about 94 to about 142 minutes. In some embodiments, T _max can range from about 116 to about 120 minutes.

  In some embodiments, the dosage form comprising meloxicam is not an emulsion, microemulsion, self-emulsifying oil composition, self-microemulsifying oil composition that does not contain a pH adjusting agent and is administered by the same route. Compared to a composition containing meloxicam, it dissolves faster in water. In some embodiments, about 75 to about 100% of the 15 mg dosage form dissolves in 900 mL water within about 15 minutes. In some embodiments, about 90% of the 15 mg dosage form dissolves in 900 mL water within about 15 minutes.

  As used herein, a drug-containing emulsion having globules with a diameter greater than 100 nm, the drug-containing emulsion comprising a weak ionic drug and a pH adjuster, wherein the pH adjuster is in the absence of the pH adjuster. A drug-containing emulsion is provided that enhances the solubility of the weakly ionic drug in the aqueous phase as compared to the weakly ionic drug, and the weakly ionic drug has a pKa of about 1 to about 14.

  As used herein, a drug-containing microemulsion having globules less than 100 nm in diameter, the drug-containing microemulsion comprising a weak ionic drug and a pH adjuster, wherein the pH adjuster is in the absence of the pH adjuster. Also provided is a drug-containing microemulsion that enhances the solubility of the weakly ionic drug in the aqueous phase compared to the solubility of the weakly ionic drug in the aqueous phase and the weakly ionic drug has a pKa of about 1 to about 14. .

  As used herein, a self-emulsifying oil composition comprising one or more oils, a weak ionic drug, and a pH adjuster, the self-emulsifying property when exposed to an aqueous phase The oil composition forms a drug-containing emulsion with globules with a diameter greater than 100 nm, and the pH adjuster is in the aqueous phase compared to the solubility of the weak ionic drug in the absence of the pH adjuster. Further provided is a self-emulsifying oil composition that enhances the solubility of the weak ionic drug and the weak ionic drug has a pKa of about 1 to about 14.

  The present disclosure provides a self-microemulsifying oil composition comprising one or more oils, a weakly ionic drug, and a pH adjuster, the self-microemulsions when exposed to an aqueous phase. The emulsifiable oil composition forms a drug-containing microemulsion having globules less than 100 nm in diameter, and the pH adjuster is water soluble compared to the solubility of the weak ionic drug in the absence of the pH adjuster. Also provided is a self-microemulsifying oil composition that enhances the solubility of the weak ionic drug in the phase and the weak ionic drug has a pKa of about 1 to about 14.

  A solid dosage form for oral administration of a therapeutically effective amount of a drug is provided, the solid dosage form comprising one of the dosage forms described herein. In some embodiments, the solid dosage form is a tablet. In some embodiments, the solid dosage form also includes at least one blowing agent or foaming system. In some embodiments, the solid dosage form comprises at least one disintegrant that rapidly disperses the drug-containing emulsion in the target area after oral administration.

  Further provided herein are methods for making the dosage forms described herein. In some embodiments, the method comprises: (a) preparing a drug-containing emulsion or microemulsion comprising a weakly ionic drug having a pKa in the range of about 1 to about 14 and a pH adjusting agent; ) Converting the drug-containing emulsion or microemulsion into a free-flowing compressible powder by mixing the drug-containing emulsion with a solid particle adsorbent. In some embodiments, the method comprises: (a) a drug-containing self-emulsifying comprising one or more oils, a weakly ionic drug having a pKa in the range of about 1 to about 14, and a pH adjuster. Preparing a self-emulsifying or self-emulsifiable oil composition; (b) mixing the drug-containing self-emulsifying drug delivery system with a solid particle adsorbent to make the drug-containing self-emulsifiable oil composition free-flowing compressible Converting to powder.

  Also provided is a method of making a solid dosage form for oral administration of a therapeutically effective amount of a drug. The method includes producing a dosage form as described above and compressing a free-flowing compressible powder to form a solid dosage form.

  Also provided herein is a method of administering a drug to a mammal comprising the steps of making a dosage form described herein and orally administering a free-flowing compressible powder to the mammal.

  Further provided herein is a method of treating pain in a mammal comprising administering to the mammal a dosage form comprising meloxicam as described herein. In some embodiments, the pain includes lower back pain, acute pain, and pain associated with inflammation.

  The present disclosure also provides a method of treating arthritis in a mammal comprising administering to the mammal a dosage form comprising meloxicam as described herein. In some embodiments, arthritis includes osteoarthritis, rheumatoid arthritis, and juvenile rheumatoid arthritis.

  One or more of ankylosing spondylitis, fever, primary dysmenorrhea, pyrexia, asthma, bone resorption, cardiovascular disease, nephrotoxicity, atherosclerosis, or hypotension Also provided herein is a method of treatment comprising administering to a mammal a dosage form comprising meloxicam as described herein.

  About 20 to about 40% by weight of co-solvent; about 4 to about 9% by weight of pH adjusting agent; about 9 to about 18% by weight of purified water; about 28 to about 56% by weight of surfactant; Further provided herein is a composition having 10% by weight. In some embodiments, the composition comprises about 30% co-solvent; about 6.67% pH adjuster; about 13.33% purified water; about 42% surfactant; About 8% by weight.

  In some embodiments, the composition is a component of a drug-containing emulsion, a drug-containing microemulsion, a self-emulsifying oil composition, or a self-microemulsifying oil composition.

  In some embodiments, the composition further comprises a solid particle adsorbent. In some cases, the solid particle adsorbent is present in a ratio (by weight) of the composition of claim 101 to the solid particle adsorbent of from about 1: 5 to about 5: 1.

  About 10 to about 20% by weight of co-solvent; about 2 to about 5% by weight of pH adjuster; about 4 to about 9% by weight of purified water; about 14 to about 28% by weight of surfactant; Also provided herein are compositions having 6% by weight; about 35 to about 65% by weight solid particle adsorbent. In some embodiments, the composition comprises about 15 wt.% Co-solvent; about 3.33 wt.% PH adjuster; about 6.67 wt.% Purified water; about 21 wt. 4% by weight; about 50% by weight solid particle adsorbent.

  In some embodiments, the weakly ionic drug is meloxicam; atropine; chloramphenicol; chlorothiazide; chlorpromazine; cimetidine; diazepam; diltiazem; diphenhydramine; Selected from the group consisting of: phenytoin; procainamide; propafenone; propranolol; tetracaine; trimethoprim; verapamil; and mixtures thereof. In some embodiments, the weak ionic drug is meloxicam.

  About 20 to about 40% by weight co-solvent; about 4 to about 9% by weight pH adjuster; about 9 to about 18% by weight purified water; about 28 to about 56% by weight surfactant; about 5 to about 10% by weight meloxicam Further provided herein is a composition having: In some embodiments, the composition comprises about 30% co-solvent; about 6.67% pH adjuster; about 13.33% purified water; about 42% surfactant; about 8% meloxicam ;including. In some embodiments, the composition comprises about 3% by weight Captex 355®; about 5% by weight Capmul MCM®; about 2% by weight PVP K12; about 20% by weight propylene glycol; Methyl) aminomethane about 6.67%; purified water about 13.33%; Tween 80® about 42%; meloxicam about 8%.

  In some embodiments, the composition is a component of a drug-containing emulsion, a drug-containing microemulsion, a self-emulsifying oil composition, or a self-microemulsifying oil composition.

  In some embodiments, the composition further comprises a solid particle adsorbent. In some embodiments, the solid particle adsorbent is present in a ratio (by weight) of the composition of claim 118 to the solid particle adsorbent from about 1: 5 to about 5: 1. In some embodiments, the ratio is about 1: 1.

  About 10 to about 20% by weight of co-solvent; about 2 to about 5% by weight of pH adjusting agent; about 4 to about 9% by weight of purified water; about 14 to about 28% by weight of surfactant; about 2 to about 6% by weight of meloxicam Also provided herein is a composition having about 35 to about 65 weight percent solid particle adsorbent. In some embodiments, the composition comprises about 15% by weight co-solvent; about 3.33% by weight pH adjuster; about 6.67% purified water; about 21% by weight surfactant; about 4% by weight meloxicam. About 50% by weight of a solid particle adsorbent.

  In some embodiments, the composition comprises about 1.5% by weight Captex 355®; about 2.5% by weight Capmul MCM®; about 1% by weight PVP K12; about 10% by weight propylene glycol; About 3.33% by weight aqueous tris (hydroxymethyl) aminomethane; about 6.67% purified water; about 21.25% Tween 80®; about 4% meloxicam; about 50% silicon dioxide; Including.

  In the above composition, the co-solvent is Captex-355® (glyceryl tricaprylate / caprate); Labrasol® (caprylocaproyl macrogol glyceride); Labrafil M1944® (oleoyl) Macrogol glycerides); Lauroglycol 90® (propylene glycol monolaurate); Tween 80® (polyoxyethylene (20) sorbitan monooleate); PEG 400 (polyethylene glycol); Capmul MCM® (medium) Chain mono and diglycerides); Capmul PG8® (propylene glycol monocaprylate); Plrol Oleique® (polyglyceryl oleate); pan80® (sorbitan monooleate); Cremophor EL® (polyoxyl 35 castor oil); Phosal 53MCT® (phosphatidylcholine 53% in medium chain triglycerides); corn oil; oleic acid; citric acid Triethyl; ethanol; water; Acconon CC-6® (polyoxyethylene 6 caprylic / capric glycerides); PVP (polyvinylpyrrolidone) K12; PVP K17; PVP K30; PVP K90; propylene glycol; and mixtures thereof Selected from the group consisting of In some embodiments, the co-solvent is selected from the group consisting of Captex 355®; Capmul MCM®; PVP K12®; propylene glycol; and mixtures thereof. In some embodiments, the co-solvent can be Captex 355® about 3%; Capmul MCM® 5%; PVP K12® about 2%; propylene glycol about 20%; .

  In some embodiments, the pH adjuster is sodium carbonate; potassium carbonate; magnesium carbonate; sodium bicarbonate; potassium bicarbonate; disodium hydrogen phosphate; sodium dihydrogen phosphate; dipotassium hydrogen phosphate; Selected from the group consisting of potassium hydrogen; tris (hydroxymethyl) aminomethane; citric acid; tartaric acid; amarinic acid; fumaric acid; adipic acid; In some embodiments, the pH adjuster is tris (hydroxymethyl) aminomethane.

  In some embodiments, the surfactant is Tween 85® (polyoxyethylene (20) sorbitan trioleate); Tween 80® (polyoxyethylene (20) sorbitan monooleate); Tween 20 (poly Oxyethylene (20) sorbitan monolaurate); Labrasol® (caprylocaproyl macrogol glyceride); Cremophor EL® (polyoxyl 35 castor oil); Triton X-100® (octylphenol ethoxy) Rate); oleic acid; isopropyl myristate; ethyl oleate; and mixtures thereof. In some embodiments, the surfactant is Tween 80®.

  In some embodiments, the solid particle adsorbent consists of kaolin, bentonite, hectorite, colloidal magnesium aluminum silicate, silicon dioxide, magnesium trisilicate, aluminum hydroxide, magnesium hydroxide, magnesium oxide, and talc. Selected from the group. In some embodiments, the solid particle adsorbent is silicon dioxide.

  The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

2 shows dissolution profiles of meloxicam, meloxicam self-emulsifying oil composition, and meloxicam self-emulsifying oil composition adsorbed on two powders, silicon dioxide and magnesium aluminum silicate. Three formulations of meloxicam: 1) self-microemulsifying oil composition adsorbed on silicon dioxide particles (MicroSolv); 2) self-microemulsifying oil composition (liquid SMEDDS); and Mobic (tablets) Figure 2 shows pharmacokinetic data from in vivo studies in dogs. The dissolution profile of the self-microemulsifying oil composition adsorbed on the silicon dioxide particles will be described in detail. Three oral dosage formulations of meloxicam: A) human microemulsifying oil composition adsorbed on silicon dioxide particles; B) self microemulsifying oil composition; and C) Mobic (tablets). Shows pharmacokinetic data from in vivo studies. Demonstrating dissolution of a self-microemulsifying oil composition of meloxicam adsorbed on silicon dioxide particles in various aqueous media. Demonstrate dissolution of meloxicam tablets (Mobic) in various aqueous media.

  The present disclosure relates to drug-containing emulsions, drug-containing microemulsions, self-emulsifying oil compositions, or self-emulsifying oil compositions each comprising a weak ionic drug and a pH adjusting agent (eg, solids Dosage form). Also provided are pharmaceutical dosage forms and methods of making the same.

  The dosage form can be provided in the form of a drug-containing emulsion, a drug-containing microemulsion, a self-emulsifying oil composition, or a self-microemulsifying oil composition. The dosage form is a free-flowing compression comprising one or more of a drug-containing emulsion, a drug-containing microemulsion, a self-emulsifying oil composition, or a self-microemulsifying oil composition, and a solid particle adsorbent. Can be provided in the form of a conductive powder. The drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition or self-microemulsifying oil composition is adsorbed onto the solid particle adsorbent to form a free-flowing compressible powder.

  In some embodiments, the dosage form is provided as a liquid formulation comprising one of a drug-containing emulsion, a drug-containing microemulsion, a self-emulsifying oil composition, or a self-microemulsifying oil composition. Can do.

  The drug-containing emulsion and drug-containing microemulsion each comprise an emulsion or microemulsion comprising a weak ionic drug and a pH adjuster, respectively. Each of the self-emulsifying oil composition and the self-microemulsifying oil composition includes one or more oils, a weak ionic drug, and a pH adjusting agent. The drug-containing emulsion, microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition is one or more emulsifiers, antioxidants, or preservatives, as further described below, or The mixture can be included.

  An emulsion as used herein is a system of two immiscible liquid phases. One of the two phases (inner phase) is distributed as droplets or globules throughout the second phase (outer phase or continuous phase). Emulsions include oil-in-water (o / w) emulsions, generally referred to as oils, in which the low polarity liquid is in the internal phase; water-in-oil types (w / w) in which the aqueous solution or other liquid of relatively polarity is in the internal phase (w / O) An emulsion is mentioned. In general, the emulsion has a globular diameter of greater than about 100 nm. In some embodiments, the emulsion globule diameter ranges from about 120 nm to about 70 μm. See, for example, US Pat. No. 6,692,771. Emulsions can also be classified into fine particle emulsions having a small sphere diameter of less than about 5 μm and coarse particle emulsions having a small sphere diameter of greater than about 5 μm.

  Microemulsions are optically isotropic and thermodynamically or kinetically stable systems. Microemulsions are composed of an oil phase and an aqueous phase. In some embodiments, the microemulsion also contains an emulsifier. Generally, the microemulsion has a small sphere diameter of less than about 100 nm (eg, about 30 to about 60 nm). See for example US Pat. No. 6,280,770.

  The present disclosure relates to self-emulsifying and self-micro comprising all components of an o / w emulsion or microemulsion (eg, one or more of oils, emulsifiers, antioxidants, and preservatives), except for water. Also provided is the use of an emulsifiable oil composition. See, for example, US Pat. No. 5,444,041. In some cases, the self-emulsifying and self-microemulsifying oil compositions can each be a self-emulsifying drug delivery system (SEDDS) or a self-microemulsifying drug delivery system (SMEDDS). In some embodiments, a solid dosage form having a self-emulsifying or self-microemulsifying oil composition can be produced by adsorbing a self-emulsifying or self-microemulsifying oil composition onto an adsorbent powder. . After administration of a solid dosage form containing a self-emulsifying or self-microemulsifying oil composition, when mixed with a body fluid, an emulsion or microemulsion is formed.

The oil phase in an emulsion or microemulsion is a non-toxic oil and includes, but is not limited to, mono, di, and triglycerides, fatty acids and esters thereof, and ethers and esters of propylene glycol or other polyols. Fatty acids and esters (used by themselves or when it forms part of a glyceride) are short, medium or long chains. As used herein, the medium chain represents a C ₈ -C ₁₂ hydrocarbon chain, the short chain is a hydrocarbon chain less than C ₈ , and the long chain means a hydrocarbon chain greater than C ₁₂ .

  The oil phase is an oil phase derived from plants or animals. The oil phase is a synthetic or semi-synthetic oil phase and is non-toxic to the subject. Oils include, but are not limited to, cottonseed oil, soybean oil, sunflower oil; natural oils such as canola oil; CAPTEX® (various grades of propylene glycol esters such as propylene glycol didecanoate; glyceryl tricaprylate / caprate MIGLYOL® (caprylic acid / capric acid triglyceride; caprylic acid / capric acid / linoleic acid triglyceride; caprylic acid / capric acid / succinic acid triglyceride; or propylene glycol diester of caprylic acid / capric acid and Mixture with other drugs); CAPMUL® (available in different grades, eg Capmul MCM, mainly mono and diesters of glycerol, propylene glycol Bruno and diesters, such as glyceryl monooleate and propylene glycol monocaprylate. Other grades of polyethylene glycol glyceryl stearate).

  The aqueous phase in the emulsion or microemulsion can be, for example, water, an aqueous solution, an alcohol, and an alcohol solution.

Emulsifiers are required for emulsion and microemulsion formulations. Non-toxic emulsifiers used herein can be used. This emulsifier includes but is not limited to the following commercially available products: MYVACET® (distilled acetylated monoglyceride emulsifier); ARLACEL® (mainly sorbitan ester); TWEEN® (polyoxyethylene sorbitan) CENTROPHASE® (liquid lecithin); CREMOPHOR® (polyoxyl castor oil derivative; or macrogol ether; or macrogol ester); LABRAFAC® (caprylic acid / capric acid triglyceride); LABRAFIL® (polyoxyethylated glycolytic glycerides); LABRASOL (a mixture of mono-, di- and triglycerides and fatty acid mono- and diesters of polyethylene glycol; the main fatty acids are ₈ -C ₁₀ caprylic / capric acid); MYVEROL (R); and Tagat (R) (polyethylene glycol hydrogenated castor oil; or polyethylene glycol glyceryl esters); lecithin; such as cholesterol and casein proteins; the There are various grades. In some embodiments, multiple emulsifiers can be used to keep the inner phase distributed as globules throughout the outer phase and to delay the coalescing of the globules into large droplets. In this way, the relative stability of the two phases can be maintained for a longer time.

  In drug emulsions and microemulsions, one or both phases may contain one drug or a solution of one or more drugs. In some embodiments, either the water phase and the oil phase, or both, can contain drugs at the same time, and the drugs are the same or different. Two types of immiscible liquids can be used that are non-toxic and compatible with the parts of the mammalian body to which they are applied.

  Emulsions or microemulsions can be prepared using an oil phase, an aqueous phase, and optionally an emulsifier in a wide range of ratios. For example, oil-in-water emulsions and microemulsions can contain at least about 25% water (eg, about 60 to about 98% and about 70 to about 90% by weight) water. The oil phase in the o / w emulsion or microemulsion is at least about 1% (e.g., about 5 to about 69% and about 8 to about 40% by weight) of the emulsion or microemulsion, and the active drug ingredient is oil Included in the weight of the phase. The emulsifier in the emulsion or microemulsion is at least about 0.5% by weight (eg, about 2 to about 25% by weight and about 5 to about 10% by weight).

  Water-in-oil emulsions and microemulsions may contain at least about 25% by weight (eg, about 40 to about 98% and about 50 to about 95% by weight) of the oil phase relative to the w / o emulsion or microemulsion. . The aqueous phase in w / o emulsions and microemulsions is at least about 1% by weight relative to the w / o emulsion or microemulsion (eg, from about 2 to about 55% by weight and from about 5 to about 30% by weight) and active The drug component is included in the weight of the aqueous phase. The emulsifier in the w / o emulsion and microemulsion is at least about 0.5 wt% (eg, about 2 to about 20 wt% and about 4 to about 10 wt%) relative to the w / o emulsion or microemulsion.

  According to the HLB (Hydrophilic Lipophilic Balance) system, emulsifiers or drug combinations are used in o / w or w / o formulations. w / o emulsions or microemulsions require low HLB emulsification (HLB values about 1-7) and o / w systems require higher HLB emulsifiers (HLB values about 11-18). is there. In general, the type of emulsifier used and the relative ratio of oil to water determine whether the emulsion or microemulsion is a w / o or o / w emulsion or microemulsion. This means the emulsion or microemulsion as formed. Some emulsions or microemulsions may reverse when added to large amounts of the internal phase. For example, an emulsion or microemulsion prepared as a w / o emulsion or microemulsion may invert to an o / w emulsion or microemulsion in the patient's stomach when ingested by the patient.

  In general, emulsions can be prepared by mixing the components of the emulsion (eg, oil phase, aqueous phase, emulsifier, etc.) with a propeller mixer, turbine mixer or other high shear mixer and stirring the mixture vigorously.

  Sometimes a microemulsion is spontaneously prepared by combining the ingredients in the correct proportions. In some embodiments, light mixing with a propeller mixer can be used. There is no need to use heat to prepare the microemulsion unless solid ingredients are used at room temperature. Microemulsions have a long shelf life, low viscosity for easy transport and mixing, are translucent and can be monitored spectroscopically.

  To produce a dosage form, place the adsorbent in a suitable mixer bowl such as a planetary mixer and mix the drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition or self-microemulsifying oil composition. Can be added slowly. The rate of addition should not be so fast that wet masses of material form or areas that are much wetter than other areas of the powder. If a powder mass or wet part of the powder occurs, the rate of addition should be reduced or temporarily stopped until the wet part of the powder is well distributed throughout the bulk of the powder.

  A mixer that can uniformly mix the liquid and powder is used to produce the dosage forms described herein. For example, planetary mixers are well suited for this task because they include a scraper bar that scrapes material from the side walls of the container. Excessively damp material often accumulates on the sidewalls and will not mix well with the bulk powder without operation of the scraper bar. Mixers with dead space should be avoided. For the purposes of the present discussion, a dead space is a space where powder collects but cannot be subjected to the mixing operation of the apparatus. A mixer having a secondary mixing operation in addition to the primary operation is preferred. The secondary mixer operation can be a scraper (in a planetary mixer) or an intensifier bar or a high shear component. In general, the mixing operation of a mixer is a vigorous mixing zone where high shear of the powder takes place, as well as a further mixing operation in which all of the powder moves through the vigorous mixing zone, i.e. the bulk powder is mixed in three dimensions. provide.

  Add drug-containing emulsion, powder-containing microemulsion, self-emulsifying oil composition or self-microemulsifying oil composition to powder, add drug-containing emulsion, drug-containing microemulsion, self-emulsifying from beaker or graduated cylinder to mixer bowl This is accomplished by the operator by simply pouring the oil composition or self-microemulsifying oil composition, or by other means such as a means of spraying the liquid onto the powder at a controlled rate. In some embodiments, a peristaltic pump can be used to add liquid at a controlled rate. In some embodiments, a spray nozzle used in conjunction with a peristaltic pump can be used to provide a fine spray.

  The present disclosure provides a weak ionic drug formulated with a pH adjuster. The drug is combined with either the oil phase or the aqueous phase, depending on its solubility and other properties. A drug dissolved in one phase splits into some other phase to some extent, which affects the bioavailability of the drug.

  Weak ionic substances (drugs) are used in drug-containing emulsions, drug-containing microemulsions, self-emulsifying oil compositions or self-microemulsifying oil compositions. Liquid drugs, drug solutions, small molecule drugs and nutritional supplements such as vitamins and minerals are all suitable for use.

  As used herein, the expression “small molecule” includes inorganic and organic chemical molecules having a molecular weight of less than 3,000 daltons.

  Weak ionic drugs include meloxicam; atropine; chloramphenicol; chlorothiazide; chlorpromazine; cimetidine; diazepam; diazepam; diphenhydramine; disopyramide; Propafenone; propranolol; tetracaine; trimethoprim; and verapamil.

  The weakly ionic drugs described herein can range from about 1 to about 14 (eg, from about 1 to about 13; from about 1 to about 12; from about 1 to about 11; from about 1 to about 10; from about 1 to about 9 From about 1 to about 7; from about 1 to about 6; from about 1 to about 5; from about 1 to about 4; from about 1 to about 3; from about 1 to about 2; from about 2 to about 14; From about 4 to about 14; from about 6 to about 14; from about 7 to about 14; from about 8 to about 14; from about 9 to about 14; from about 10 to about 14; About 14; about 12 to about 14; about 13 to about 14; about 2 to about 13; about 3 to about 12; about 4 to about 10; about 5 to about 12; about 6 to about 9; It may have a pKa of 8).

  In some embodiments, the drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition or self-microemulsifying oil composition provides a weak ionic drug for the entire emulsion (both phases) or oil composition. About 0.5 to about 60% by weight (eg, about 1 to about 55% by weight; about 3 to about 45% by weight; about 5 to about 40% by weight; about 10 to about 35% by weight; about 15 to about 25% by weight %; About 6 to about 48% by weight; about 8 to about 52% by weight; about 4 to about 36% by weight). The weakly ionic drug is about 2 to about 50% by weight (eg about 5 to about 40%) based on the total weight of the drug-containing emulsion or drug-containing microemulsion (both phases) or self-emulsifying or microemulsifying oil composition. % By weight and from about 10 to about 30% by weight).

  The drug-containing emulsion or microemulsion can be from 1 to 400,000 cps (eg, from about 400 to about 200,000 cps; from about 5,000 to about 150,000 cps; from about 10,000 to about 100,000 cps; from about 20,000 to about 80,000 cps; about 30,000 to about 50,000 cps; about 500 to about 10,000 cps).

  Suitable and pharmaceutically acceptable pH adjusting agents are used in drug-containing emulsions, drug-containing microemulsions, self-emulsifying oil compositions or self-microemulsifying oil compositions. In some embodiments, the choice of pH adjusting agent is based on the properties of the drug, such as its pKa, solubility, and reactivity. A pH adjuster is used with a weak ionic drug to increase the solubility of the weak ionic drug in the aqueous phase compared to the solubility of the weak ionic drug in the absence of the pH adjuster. Non-limiting examples of pH adjusters include sodium carbonate; potassium carbonate; magnesium carbonate; sodium bicarbonate; potassium bicarbonate; disodium hydrogen phosphate; sodium dihydrogen phosphate; dipotassium hydrogen phosphate; Examples include potassium hydrogen; tris (hydroxymethyl) aminomethane; citric acid; tartaric acid; amarinic acid; fumaric acid; adipic acid; and succinic acid. In some embodiments, the pH adjuster is tris (hydroxymethyl) aminomethane. Other pH adjusting agents described in US patent application Ser. No. 09 / 302,105 and US patent application Ser. No. 09 / 327,814, incorporated herein by reference, can also be used.

  In some embodiments, the drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition or self-microemulsifying oil composition has a pH adjusting agent about the total emulsion (both phases) or oil composition. 0.5 to about 60% by weight. The pH adjuster is about 2 to about 50% by weight (e.g., about 5 to about 40% by weight and based on the total weight of the drug-containing emulsion or microemulsion (both phases) or self-emulsifying or microemulsifying oil composition). About 10 to about 30% by weight).

  In some embodiments, the dosage form may also contain additional excipients such as preservatives, antioxidants, colorants, flavors, and aromas. Non-limiting examples of preservatives include methylparaben, propylparaben, benzoic acid, and cetylpyridinium chloride.

Emulsions such as drug-containing emulsions have different properties compared to, for example, microemulsions and drug-containing microemulsions. In general, both emulsions and microemulsions consist of another phase, for example one phase in oil, such as water globules, the emulsion globules having a larger diameter than the microemulsion globules. In general, emulsions have small spheres with an average diameter (average diameter of all globules in the emulsion) of greater than 0.1 μm or 100 nm (eg, about 0.16 μm to about 40 μm), and microemulsions have a diameter of 0 Contains globules having a size of less than 1 μm. However, emulsions and microemulsions are not necessarily distinguished only by the globule size of the inner phase. Instead, they may differ for one or more of the following defining characteristics:
(A) Microemulsions are easily formed with little mixing energy required, often without heating. They form naturally. That is, the exact proportion of ingredients spontaneously forms a microemulsion when placed in a container. On the other hand, emulsions are thermodynamically unstable and need to be vigorously stirred with a high shear mixer and usually heated to a high temperature, for example 75 ° C.
(B) The physical appearance of the microemulsion is different from that of the emulsion. The microemulsion is transparent (like water) because the globules in the microemulsion are very small and do not refract light. Emulsions are usually white or cream colored.
(C) The microemulsion is thermodynamically stable at room temperature. Once formed, the microemulsion is stable for many years in closed containers and under normal storage conditions. Emulsions tend to coalesce (join together) into smaller droplets over time as individual globules of the internal phase. Thus, compared to an otherwise identical microemulsion, the emulsion breaks or breaks down to form a completely independent phase, so that if the emulsion is left undisturbed, Is generally stable in bulk solutions for a relatively short time. However, when an emulsion is adsorbed on the adsorbent, it is believed to remain stable for a longer time than the same emulsion in the bulk solution. Without being bound by theory, it is believed that when adsorbed, the dispersion of the emulsion on the adsorbent delays the coalescence of the small spheres of the internal phase.
(D) The addition of each specific proportion of ingredients and their order of mixing play a role in the formation of the emulsion, which also distinguishes between emulsions and microemulsions. Such knowledge and information regarding the formation of emulsions will be understood by those skilled in the art (see, for example, Physical Pharmacy by Alfred Martin, Lea and Febiger, 4th Ed. (1993)).

  In some embodiments, the drug-containing emulsion comprises emulsion globules having an average or modal diameter of greater than 100 nm (eg, from about 120 nm to about 70 μm and from about 160 nm to about 10 μm). Generally, the microemulsion has a small sphere diameter of less than about 100 nm (eg, about 30 to about 60 nm). In some embodiments, the drug-containing emulsion of the solid dosage form composition is stable for at least 1 year when left at 25 ° C. in a closed container and is an oil-in-water emulsion or a water-in-oil emulsion. Can do.

  Drug-containing emulsions, drug-containing microemulsions, self-emulsifying oil compositions, or self-microemulsifying oil compositions are adsorbents / absorbents (these two terms are collectively referred to as “adsorbents (one or more) Adsorbed / absorbed on). The adsorbent is non-toxic and can include fine particles having a diameter in the range of about 25 nm to 300 μm (eg, about 50 nm to about 30 μm and about 100 nm to about 20 μm). Suitable adsorbents include, but are not limited to, clays such as kaolin, bentonite, hectorite and colloidal magnesium aluminum silicate; silicon dioxide (CAB-O-SIL or AEROSIL®); magnesium trisilicate; water Aluminum oxide; magnesium hydroxide, magnesium oxide or talc. In some embodiments, the adsorbent is silicon dioxide.

  The dosage forms described herein include one of a drug-containing emulsion, a drug-containing microemulsion, a self-emulsifying oil composition, and a self-microemulsifying oil composition; a pH adjusting agent; and a solid particle adsorbent; Or it can be in the form of a free-flowing compressible powder including a plurality. In some embodiments, the drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition is adsorbed onto a solid particle adsorbent to form a free-flowing compressible powder. To do. Direct compression tableting excipients can be added to the free-flowing compressible powder to improve its compressibility. Solid dosage forms are obtained from tableting a free-flowing powder using techniques understood by those skilled in the art.

  The ratio of drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition to solid particles is about 1:20 to about 10: 1 (eg, about 1: 5 to about 2: 1; about 1:15 to about 3: 1; about 1:10 to about 1: 1; about 1: 5 to about 5: 1; about 1: 1 to about 8: 1; about 1: 2 to about 4: 1; and about 1: 8 to about 6: 1).

  The dosage form can be prepared by adsorbing a drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition on the adsorbent. In some embodiments, adsorbent is placed in a mixer and then a drug-containing emulsion, a drug-containing microemulsion, a self-emulsifying oil composition, and a self-microemulsifying oil composition having a predetermined ratio to the adsorbent. Pour into a mixer with constant stirring to achieve uniform adsorption of the emulsion on the adsorbent.

  The resulting dosage form is a free-flowing compressible powder. In some embodiments, when a drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition is adsorbed onto solid particles, the powder resembles a dry powder. (As long as it is identified by visual observation). In some embodiments, the powder is free flowing as defined by the angle of repose test described below. Due in part to the fact that water in the external phase can partially evaporate during the incorporation process, such properties can be more easily achieved with o / w emulsions or microemulsions. There is an equilibrium amount of water that is retained on the solid particles. When adsorbing w / o emulsions or microemulsions, the powder tends to appear slightly “moist”. The ratio of emulsion or microemulsion to solid carrier is an important factor in determining the extent to which the powder remains free-flowing and dry. However, it is possible to obtain a non-agglomerated mixture using the ratio of the solid carrier and emulsion or microemulsion described above. This mixture can then be combined with other tableting ingredients to produce a compressible blend to produce a solid dosage form (eg, a compressed tablet). In some embodiments, the compressible blend is free flowing.

  The degree to which a powder blend is free-flowing is described in detail in “The Theory and Practice of Industrial Pharmacy” by Lechman, Lieberman and Kanig (Lea and Febiger, public texts such as Pharma Standards), incorporated herein by reference. Estimated by performing the angle of repose test described. A static angle of repose test is preferred. When performing such a test, the final powder blend has an angle of repose of less than about 42 degrees (eg, less than about 40 degrees).

  For a mixture of adsorbent and drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition to form a free-flowing powder that can be easily compressed, the drug The ratio of containing emulsion, drug-containing microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition is kept relatively low in the dosage form. As a result, drug loading in drug-containing emulsions, drug-containing microemulsions, self-emulsifying oil compositions, or self-microemulsifying oil compositions is stable, bioavailable and high drug loading compositions It is an important factor in the formulation.

  It has been discovered that a wide range of drug loadings can be incorporated into a free-flowing compressible powder while increasing the stability of a drug emulsion or microemulsion. The emulsions and microemulsions provided herein can be formed from a wide range of weight ratios of water, oil, and emulsifier and adsorb on solid particulate adsorbent to form a free-flowing compressible powder. be able to.

  Applying a coating to individual particles of a dosage form powder, to agglomerates, granules or other larger particles incorporating multiple particles of the composition, or to a part of a dosage form or dosage form Can do. As used herein, “multiparticulate” means a composition that takes the form of multiple types of particles. Each particle is an individual particle of the dosage form composition, or incorporates a plurality of particles of the powder composition or formed from a plurality of particles of the powder composition, agglomerates, granules or other Can be large particles.

  The final solid dosage form contains from about 0.1 mg to about 1,000 mg / tablet (eg, 2.4 grams) of weak ionic drug. In some embodiments, the solid dosage form contains about 5 mg to about 500 mg (eg, about 10 mg to about 200 mg and about 15 mg to about 100 mg) / tablet of a weak ionic drug.

  The solid dosage form can further comprise an excipient, such as at least one of a foaming agent and / or a disintegrant; the disintegrant rapidly disperses and disintegrates the solid dosage form after oral administration.

  The present disclosure includes a step of preparing a drug-containing emulsion, a drug-containing microemulsion, a self-emulsifying oil composition, or a self-emulsifying oil composition, and a drug-containing emulsion, a drug-containing microemulsion, and a self-emulsifying oil composition Or by mixing a self-microemulsifying oil composition with a solid particle adsorbent to make a drug-containing emulsion, drug-containing microemulsion, self-emulsifiable oil composition, or self-microemulsifiable oil composition free-flowing compressible There is also provided a method of producing a solid dosage form comprising converting to a powder. Then, optionally including excipients (fillers, disintegrants, etc.) and subsequently producing solid dosage forms from free-flowing compressible powders by methods known to those skilled in the art (eg tableting methods) Can do.

  The drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition is, for example, about 20 to about 40% by weight of co-solvent (eg, about 20 to about 35% by weight; about 20 About 25 wt.% To about 40 wt.%; About 28 wt. To about 40 wt.%; About 25 wt. To about 35 wt.%; And about 28 to about 32 wt.%); (About 4 to about 8%; about 4 to about 7%; about 4.5 to about 9%; about 5 to about 9%; about 5 to about 8%; and about 5 to about 7% About 9 to about 18% by weight of purified water (about 9 to about 16% by weight; about 9 to about 14.5% by weight; about 9 to about 14% by weight; about 10 to about 18% by weight; About 18% by weight; about 13 to about 18% by weight; about 10 to about 16% by weight; and about 12 to about 14% by weight); 8 to about 56% by weight (eg, about 28 to about 50% by weight; about 28 to about 46% by weight; about 32 to about 56% by weight; about 38 to about 56% by weight; about 30 to about 50% by weight; about 34 to about 47% by weight; and about 38 to about 44% by weight); about 5 to about 10% by weight of a weak ionic drug (eg, about 5 to about 9% by weight; about 5 to about 8% by weight; about 6 to about About 10% by weight; about 7 to about 10% by weight; about 6 to about 9% by weight; and about 7 to about 9% by weight). In some embodiments, the drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition is about 30 wt% co-solvent; about 6.67 wt% pH adjusting agent; About 13.33% by weight purified water; about 42% by weight surfactant; about 8% by weight weakly ionic drug.

  In some embodiments, the formulation includes a drug-containing emulsion, a drug-containing microemulsion, a self-emulsifying oil composition, or a weight ratio of self-microemulsifying oil composition to solid particle adsorbent of about 1: 5. About 5: 1 (eg, about 1: 5 to about 3: 1; about 1: 5 to about 2: 1; about 1: 3 to about 5: 1; about 1: 2 to about 5: 1; about 1: 3 to about 3: 1; and about 1: 2 to about 2: 1).

  In some embodiments, the dosage forms described herein comprise about 10 to about 20% by weight of co-solvent (eg, about 10 to about 18% by weight; about 10 to about 16% by weight; about 12 to about 20%. About 14 to about 20% by weight; about 12 to about 18% by weight; and about 14 to about 16% by weight); pH adjusting agent about 2 to about 5% by weight (about 2 to about 4.5% by weight; About 2 to about 4% by weight; about 2.5 to about 5% by weight; about 3 to about 5% by weight; about 2.5 to about 4.5% by weight; and about 3 to about 4% by weight); purified water About 4 to about 9% by weight (about 4 to about 8% by weight; about 4 to about 7% by weight; about 4.5 to about 9% by weight; about 5 to about 9% by weight; about 5 to about 8% by weight; And about 5 to about 7 weight percent); about 14 to about 28 weight percent surfactant (about 14 to about 24 weight percent; about 14 to about 22 weight percent; about 16 to about 28 weight percent; about 18 to about 28 weight percent). % By weight; about 16 to about 24 weight And about 18 to about 22% by weight); about 2 to about 6% by weight of a weak ionic drug (eg, about 2 to about 5% by weight; about 2 to about 4.5% by weight; about 3 to about 6% by weight); About 3.5 to about 6% by weight; about 2.75 to about 4.75% by weight; about 3 to about 4.5% by weight; and about 3.5 to about 4.5% by weight); solid particle adsorption About 35 to about 65% by weight of the agent (eg, about 35 to about 60% by weight; about 35 to about 55% by weight; about 40 to about 65% by weight; about 45 to about 65% by weight; about 40 to about 60% by weight) And from about 45 to about 55% by weight). In some embodiments, the formulation comprises about 15% by weight co-solvent; about 3.33% by weight pH adjuster; about 6.67% purified water; about 21% surfactant; 4% by weight; about 50% by weight solid particle adsorbent.

  Co-solvents are Captex-355® (glyceryl tricaprylate / caprate); Labrasol® (caprylocaproyl macrogol glyceride); Labrafil M1944® (oleoyl macrogol glyceride); Lauroglycol 90 (Registered trademark) (propylene glycol monolaurate); Tween 80 (registered trademark) (polyoxyethylene (20) sorbitan monooleate); PEG 400 (polyethylene glycol); Capmul MCM (registered trademark) (medium chain mono and diglycerides); Capmul PG8 (registered trademark) (propylene glycol monocaprylate); Plrol Oleique (registered trademark) (polyglyceryl oleate); Span 80 (registered trademark) (Sorbitan monooleate); Cremophor EL® (polyoxyl 35 castor oil); Phosal 53MCT® (phosphatidylcholine 53% in medium chain triglycerides); corn oil; oleic acid; triethyl citrate; ethanol; water Accon CC-6® (polyoxyethylene 6 caprylic / capric glyceride); PVP (polyvinylpyrrolidone) K12; PVP K17; PVP K30; PVP K90; propylene glycol; and mixtures thereof The In some embodiments, the co-solvent is selected from Captex 355®; Capmul MCM®; PVP K12®; propylene glycol; and mixtures thereof. In some embodiments, the co-solvent is Captex 355® about 3%; Capmul MCM® 5%; PVP K12® about 2%; propylene glycol about 20%.

  The pH adjusting agent can be any of the pH adjusting agents described above, or a mixture thereof.

  Surfactants are: Tween 85® (polyoxyethylene (20) sorbitan trioleate); Tween 80® (polyoxyethylene (20) sorbitan monooleate); Tween 20 (polyoxyethylene (20) sorbitan mono) Labrasol® (caprylocaproyl macrogol glyceride); Cremophor EL® (polyoxyl 35 castor oil); Triton X-100® (octylphenol ethoxylate); oleic acid; myristin Selected from the group consisting of isopropyl acid; ethyl oleate; and mixtures thereof.

  The weak ionic drug can be any of the above drugs or a mixture thereof.

  The solid particle adsorbent can be any of the adsorbents described above or a mixture thereof.

  In conjunction with the dosage forms described herein, for example, drug-containing emulsions, drug-containing microemulsions, self-emulsifying oil compositions, or agents that aid in site-specific delivery of self-microemulsifying oil compositions, and dissolution Various components and / or techniques can be used to increase bioavailability, such as the inclusion of drugs that increase speed. The enhancement technique chosen is related to the drug absorption pathway, ie paracellular or transcellular. Such techniques include, but are not limited to, additional chemical penetration enhancers; mucoadhesive materials; foaming agents such as, but not limited to, effervescent couples; ion pairing or complexing agents; And / or the use of surfactant drug carriers. Enhanced bioavailability is achieved through structural changes and fluidity changes to biological membranes induced by the use of specific surfactants.

  Further provided herein are dosage forms containing substances that help release the drug to specific sites in the gastrointestinal tract to facilitate site-specific delivery. The site selected for drug release is the most efficiently absorbing part of the gastrointestinal tract with respect to the drug in question or the part having other therapeutic benefits. The added substance facilitates site-specific delivery by various mechanisms, and the present disclosure is not limited to any one such mechanism. For example, the substance is metabolized by enzymes present in specific parts of the gastrointestinal tract, thus releasing the drug at that site. Substances used to promote site-specific absorption can be used as coatings and / or matrix materials, including, for example, sugars, polysaccharides, starches, polymers, and the like.

  In some embodiments, a bioadhesive polymer can be included in the dosage form to increase contact time between the dosage form and the mucosa of the most efficiently adsorbing site of the gastrointestinal tract. Non-limiting examples of bioadhesive materials include Carbopol (various grades), sodium carboxymethylcellulose, methylcellulose, polycarbophil (Noveon AA-1), hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium alginate, and sodium hyaluronate Is mentioned.

  For example, disintegrants can be used to help disperse the drug in the gastrointestinal tract.

  In some embodiments, the disintegrant may include a pharmaceutically acceptable blowing agent or foaming system. See, for example, US Pat. No. 5,178,878. In some embodiments, the foaming agent or foaming system generates gas through a chemical reaction that occurs when the foaming disintegrant is exposed to oral water and / or saliva. The bubble or gas evolution reaction is the result of the reaction of a soluble acid source and an alkali metal carbonate or carbonate source in some embodiments. By the reaction of these two general types of compounds, carbon dioxide gas is generated when contacted with water contained in saliva.

  Acid sources or acids are either safe for human consumption and generally include food acids, acid anhydrides and acid salts. Examples of the food acid include citric acid, tartaric acid, amarinic acid, fumaric acid, adipic acid, and succinic acid. Because these acids are ingested directly, their overall solubility in water is less important than if the effervescent tablet formulation of the present invention is intended to be dissolved in a glass of water. . The acid anhydrides and acid salts of the aforementioned acids can also be used. Acid salts include sodium dihydrogen phosphate, disodium dihydrogen pyrophosphate, citrate and sodium bisulfite.

  Carbonate reduction includes dry solid carbonates and bicarbonates such as sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and sodium sesquicarbonate, sodium glycine carbonate, L-lysine carbonate, arginine carbonate and amorphous An example is calcium carbonate.

  The effervescent disintegrant (s) or system (s) of the present invention are not always based on a reaction that forms carbon dioxide. Reactants that generate oxygen or other gases that are safe for children can also be used. When the blowing agent includes two mutually reactive components such as an acid source and a carbonate source, it is preferred that both components react completely. Accordingly, an equivalent ratio of components that provide equal equivalents is preferred. For example, if the acid used is a dibasic acid, either twice the amount of monoreactive carbonate base or an equal amount of direactive base is used to achieve complete neutralization. However, in some embodiments, the amount of acid or carbonate source may exceed the amount of the other component. This is useful to enhance the taste and / or performance of tablets containing excessive amounts of any ingredients. In this case, it is permissible for the excess amount of either component to remain unreacted.

  In some embodiments, the disintegrant can be a suitable non-foaming disintegrant. Non-limiting examples of disintegrants include microcrystalline cellulose, croscarmellose sodium, crospovidone, starch and modified starch.

  The various components described above can be present in layers within the dosage form, or special forms and geometries can be used. In some embodiments, the dosage forms described herein include drug-containing emulsions, drug-containing microemulsions, self-emulsifying oil compositions, or drugs retained in addition to those retained in self-microemulsifying oil compositions. Can be included.

  The particles are produced by granulation (wet or dry process), layering techniques, extrusion and spheronization or other pellet making methods. Dry granulation is accomplished by slugging or chilsonation of a powder mixture (including adsorbed emulsion) having the appearance of a dry powder. Layering takes place in a fluid bed apparatus or a coating pan. A fine powder with an adsorbed emulsion (having the appearance of a dry powder) is layered on the starting material or core. Aqueous or non-aqueous binders can be used to help adhere the material added on the core. The choice of binder is dictated in part by the nature of the emulsion or microemulsion, weak ionic drug, and pH adjuster used in the particular manufacture. The binding agent should be tested for its effect on drug stability. Only binders that do not negatively affect the stability of the drug in the emulsion are used. In some embodiments, stratification can be performed in a fluid bed coater. In this device, the bed of material remains moist for a very short time, so it is possible to use a binder that appears to be incompatible at first glance. In addition to the fine particle adsorption emulsion, other materials can be layered on the starting material. These include, but are not limited to, drugs or additional amounts of drugs, pH adjusters, penetration enhancers and other excipients. Non-limiting examples of starting materials or cores are nonpareil (sucrose) or microcrystalline cellulose seeds. The size of the multiparticulates is preferably up to about 3 mm. Dosage form or coating of the dosage form can be accomplished in a fluid bed coater or by other coating techniques. Multiparticulates are filled into capsules.

  When wet processes such as wet granulation or extrusion and spheronization are used, the emulsion or microemulsion is used in a liquid phase or granulating liquid. In some embodiments, this type of emulsion or microemulsion was formed in a product that was diluted with water to obtain the correct consistency for processing with the solid components and further had a dry appearance. O / w emulsions or microemulsions are used in the liquid phase in wet processes because of incomplete drying of the particles. For example, inclusion of a water miscible, non-toxic, volatile organic solvent such as isopropyl alcohol or ethyl alcohol in the outer aqueous phase facilitates evaporation of the emulsion or a portion of the outer phase of the microemulsion from the formed particles. Is advantageous.

  Also provided herein are substances that do not contain an enteric coating but are retained in the oral cavity where the drug is released for absorption by the oral mucosa. If this material is used, the tablet may contain additional penetration enhancers, mucoadhesive materials or other agents that facilitate absorption in the oral cavity.

  Tablets can be manufactured by wet granulation, dry granulation, direct compression, or other tablet manufacturing techniques. Orally disintegrating tablets are relatively soft and can be produced by direct compression in accordance with the disclosure in US Pat. No. 5,178,878, incorporated herein by reference. For peptides and other biomolecules, low compressive forces are preferred because these materials are weak to compressive forces. With such compounds, the conformation and biological activity of the compounds can be changed with the high compression forces conventionally used in tablet manufacture.

  In some embodiments, the tablet can be a layered tablet consisting of layers of the active ingredients described above in layers of different compositions. In some embodiments, the tablet can be a single tablet of uniform composition. In some embodiments, the tablets can be up to about 3/4 inch in size. The hardness of the tablet is about 1 Newton (“N”) to about 50 N (eg, about 15 to about 35 N) for uncoated tablets. For example, a tablet intended to be coated with an enteric coating is slightly hard and has a hardness value in the range of about 20 to about 70 N (eg, about 25 to about 50 N). These values relate to the uncoated core, and as expected, the tablet hardness value increases with the addition of the coating layer.

  In some embodiments, tablets intended for intravaginal administration may include particulate powder as a filler and other excipients that reduce the possibility of physical irritation or friction. Furthermore, the tablet has a shape that facilitates insertion into the vagina. Non-limiting examples of such shapes include oval and diamond shapes. Tablet insertion can be facilitated by using special applicator devices well known in the art for this purpose.

  Tablets containing solid dosage forms can be coated with enteric materials. This is done in a coating pan. Many of the current perforated breads have features that make the coating more efficient. As an example, Hicoater (Vector Corporation, Iowa) is used. In some embodiments, the tablets in the pan are preheated and the pan is rotated at a speed that can gently tumbl the tablets. Many of the processes described above (such as the rate of material wetting) performed on a fluid bed coater also apply to a pan coater. When the effervescent material is incorporated into the formulation, the coating solution is non-aqueous and the blowing agent is separated from the emulsion by the coating.

  In some embodiments, a pre-coating material can also be used. Non-limiting examples of pre-coating materials include cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, materials commercially available under the trademark EUDRAGIT® (combined with various grades), and mixtures thereof It is done.

  In some embodiments, excipients such as fillers can be added to aid tableting. Non-limiting examples of fillers include mannitol, glucose, lactose, sucrose, and calcium carbonate. For tablets intended to disintegrate in the oral cavity, the tablet mass does not exceed about 2.5 g. When a foaming agent is included, the foaming agent level in the tablet is from about 5 to about 65% by weight based on the weight of the finished tablet.

  The drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition adsorbed onto the particulate adsorbent can be incorporated into a suppository formed, for example, by molding. In some embodiments, a free-flowing powder can be mixed with a molten suppository base (s), poured into molds and allowed to set by cooling to ambient temperature. Suitable suppository bases include, but are not limited to, cocoa butter, polyethylene glycol, polyvinyl pyrrolidone, gelatin, gelatin / glycerin combinations, esterified fatty acids, polyoxyethylene sorbitan and polyoxyethylene sorbitan fatty acid esters. Various proprietary bases are also available that can contain a mixture of different ingredients. Examples of proprietary bases are those marketed under the trade names Imhausen, Witepsol and Gelucire. Each of these various grades are available for specific applications. Various base mixtures can also be used to obtain suppositories with the necessary properties.

Surfactant and a medium chain (C 8 _{-C 12)} fatty acids and fatty acid esters such as glycerol mono-, various additives such as absorption enhancers, such as di- and tri-esters can be incorporated into the suppository of the present invention. Other molding methods for forming suppositories such as cold molding and compression can also be used.

  In some embodiments, the hydrophilic / hydrophobic nature of the suppository base can be different from the external phase of the emulsion. For example, if an o / w emulsion or microemulsion is used, the suppository base is a fatty (hydrophobic) base such as cocoa butter; if a w / o emulsion or microemulsion is used, Suppository bases are hydrophilic, for example gelatin / glycerin. These formulations help maintain the stability of the emulsion or microemulsion by preventing the formation of a miscible mixture between the external phase of the emulsion or microemulsion and the suppository base.

The dosage forms described herein do not contain a pH adjusting agent when administered and are administered by the same route (eg, oral or intravenous administration), emulsions, microemulsions, self-emulsifying oil compositions, _{Alternatively} , it achieves a short T _max for a weak ionic drug compared to a weak ionic drug composition, not as a self-microemulsifying oil composition. In some embodiments, weakly ionic drugs exhibit sufficient bioavailability when not formulated as a composition described herein, but by using the dosage forms described herein, a short T _max is obtained.

In some cases, dosage forms described herein do not contain a pH adjusting agent and are administered by the same route upon administration, emulsions, microemulsions, self-emulsifying oil compositions, or self-microemulsifying About 105 to about 195% (eg, about 105 to about 190%; about 105 to about 180%; about 105 to about 175%) of the C _max exhibited by a composition containing a weak ionic drug that is not an oil composition About 105 to about 160%; about 105 to about 155%; about 105 to about 150%; about 110 to about 195%; about 120 to about 195%; about 125 to about 195%; About 130 to about 195%; about 140 to about 195%; about 145 to about 195%; about 150 to about 195%; about 115 to about 185%; about 125 to about 175%; about 130 to about 170%; 140 to about 160%; indicating the _{C max} value and from about 145 to about 155%).

In some cases, the dosage form is not an emulsion, microemulsion, self-emulsifying oil composition, or self-emulsifying oil composition that, when administered, does not contain a pH adjusting agent and is administered by the same route. , about 25 to about 50% of the _{T max} of the composition of the weakly ionizable drug (e.g., from about 25 to about 45%; from about 25 to about 42%; about 25 to about 40%; about 25 to about 38%; about 30 to about 50%; about 33 to about 50%; about 35 to about 50%; about 38 to about 50%; about 28 to about 47%; about 32 to about 44%; and about 35 to about 41%) A certain T _max can be achieved. In some embodiments, the dosage form is not an emulsion, microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition that does not contain a pH adjusting agent and is administered by the same route. A T _{max that} is about 36 to about 40% of the T _max of a composition comprising a weak ionic drug can be achieved.

Compared to values of emulsions, microemulsions, self-emulsifying oil compositions, or weakly ionic drug compositions that are not pH adjusting agents and are administered by the same route, but not self-emulsifying oil compositions In some cases, for compositions of weakly ionic drugs that are emulsions, microemulsions, self-emulsifying oil compositions, or self-microemulsifying oil compositions that contain a pH adjuster but no solid particle adsorbent. Similar percentage values of C _max and T _max are obtained.

As illustrated in Example 7, the dosage forms described herein contain an emulsion, microemulsion, containing a pH adjuster, but no solid particle adsorbent and administered by the same route. It exhibits a C _max value approximately equivalent to that achieved with a weakly ionic drug composition that is a self-emulsifying oil composition or a self-microemulsifying oil composition. In some embodiments, the C _max value is ± 8% (eg, ± 6%; ± 4%; and ± 2%) of the C _max value of a dosage form that does not contain a solid particle adsorbent. Similarly, this dosage form contains an emulsion, microemulsion, self-emulsifying oil composition, or self-microemulsifying agent that contains a pH adjuster but no solid particle adsorbent and is administered by the same route. It shows a T _max value that is approximately equivalent to that achieved with a weak ionic drug composition that is an oil composition. In some embodiments, the T _max value is ± 20% (eg, ± 17%; ± 15%; and ± 12%) of the T _max value of a dosage form that does not contain a solid particle adsorbent.

In some embodiments, the weak ionic drugs used in the dosage forms described herein are poorly soluble but exhibit acceptable absolute bioavailability. In general, less soluble drugs have measured solubilities in the slightly soluble to insoluble range as shown in the table below. The dosage forms described herein reduce the T _{max of} such drugs.

  Absolute bioavailability can be determined by measuring the AUC achieved with a particular dosage form and route of administration compared to the IV dosage form of the drug solubilized formulation. A bioavailable drug is less than about 30% (eg, less than about 25%; less than about 20%; less than about 15%; less than about 10%; and less than about 5%) of the IV dosage form of the drug Have an absolute bioavailability. Drugs that exhibit low bioavailability include drugs that are poorly adsorbed and drugs that degrade during passage through the gastrointestinal system, such as proteins, peptides, and other substances of biological origin. On the other hand, compared to the IV dosage form of the drug, greater than about 30% (eg, greater than about 35%; greater than about 40%; greater than about 45%; greater than about 50%; greater than about 55%; More than about 60%; more than about 65%; more than about 70%; more than about 75%; more than about 80%; more than about 85%; more than about 90%; and more than about 95%) The drug has acceptable bioavailability when the potential bioavailability is measured.

In some embodiments, the dosage forms described herein contain a weakly ionic drug that is poorly soluble but exhibits acceptable bioavailability (eg, greater than about 30% absolute bioavailability). obtain. In some embodiments, a drug dosage form has an absolute bioavailability of greater than about 85% as compared to the drug IV dosage form. In some embodiments, a drug dosage form measures about 89% absolute bioavailability as compared to the drug IV dosage form. Such formulations also exhibit a shorter T _max than drugs that are not formulated as described herein.

メロキシカムは、４−ヒドロキシ−２−メチル−Ｎ−（５−メチル−２−チアゾリル）−２Ｈ−１，２−ベンゾチアジン−３−カルボキサミド−１，１−ジオキシドとしても知られている。メロキシカムは、ｐＫａ値１．１および４．２を有する弱イオン性薬物である。 Dosage Forms Comprising Meloxicam In some embodiments, dosage forms can be made in which the weakly ionic drug is meloxicam. Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) having the following structure:

Meloxicam is also known as 4-hydroxy-2-methyl-N- (5-methyl-2-thiazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. Meloxicam is a weakly ionic drug with pKa values 1.1 and 4.2.

  In any of the dosage forms described above (ie, as an emulsion, microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition) using a pH adjusting agent and optional excipients as described above. Meloxicam can be used.

  The drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition is, for example, about 20 to about 40% by weight of co-solvent (eg, about 20 to about 35% by weight; about 20 About 25 wt.% To about 40 wt.%; About 28 wt. To about 40 wt.%; About 25 wt. To about 35 wt.%; And about 28 to about 32 wt.%); (About 4 to about 8%; about 4 to about 7%; about 4.5 to about 9%; about 5 to about 9%; about 5 to about 8%; and about 5 to about 7% About 9 to about 18% by weight of purified water (about 9 to about 16% by weight; about 9 to about 14.5% by weight; about 9 to about 14% by weight; about 10 to about 18% by weight; About 18% by weight; about 13 to about 18% by weight; about 10 to about 16% by weight; and about 12 to about 14% by weight); 8 to about 56% by weight (eg, about 28 to about 50% by weight; about 28 to about 46% by weight; about 32 to about 56% by weight; about 38 to about 56% by weight; about 30 to about 50% by weight; about 34 to about 47% by weight; and about 38 to about 44% by weight); and meloxicam from about 5 to about 10% by weight (eg, from about 5 to about 9% by weight; from about 5 to about 8% by weight; from about 6 to about 10%). About 7 to about 10%; about 6 to about 9%; and about 7 to about 9% by weight). In some embodiments, the drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition is about 30 wt% co-solvent; about 6.67 wt% pH adjusting agent; About 13.33% by weight purified water; about 42% by weight surfactant; and about 8% by weight meloxicam.

  Drug-containing emulsion, drug-containing microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition is about 3% by weight Captex 355®; about 5% by weight Capmul MCM®; about PVP K12 2% by weight; about 20% by weight propylene glycol; about 20% by weight aqueous tris (hydroxymethyl) aminomethane; about 42% by weight Tween 80®; and about 8% by weight meloxicam.

  In some embodiments, the formulation includes a drug-containing emulsion, a drug-containing microemulsion, a self-emulsifying oil composition, or a weight ratio of self-microemulsifying oil composition to solid particle adsorbent of about 1: 5. To about 5: 1 (eg, about 1: 5 to about 3: 1; about 1: 5 to about 2: 1; about 1: 3 to about 5: 1; about 1: 2 to about 5: 1; about 1 : 3 to about 3: 1; and about 1: 2 to about 2: 1). In some embodiments, the formulation is a solid particle adsorbent in a drug-containing microemulsion, a self-emulsifying oil composition, or a weight ratio of 1: 1 self-microemulsifying oil composition to solid particle adsorbent. Combined with.

  In some embodiments, the dosage forms described herein comprise about 10 to about 20% by weight of co-solvent (eg, about 10 to about 18% by weight; about 10 to about 16% by weight; about 12 to about 20%. About 14 to about 20% by weight; about 12 to about 18% by weight; and about 14 to about 16% by weight); pH adjusting agent about 2 to about 5% by weight (about 2 to about 4.5% by weight; About 2 to about 4% by weight; about 2.5 to about 5% by weight; about 3 to about 5% by weight; about 2.5 to about 4.5% by weight; and about 3 to about 4% by weight); purified water About 4 to about 9% by weight (about 4 to about 8% by weight; about 4 to about 7% by weight; about 4.5 to about 9% by weight; about 5 to about 9% by weight; about 5 to about 8% by weight; And about 5 to about 7 weight percent); about 14 to about 28 weight percent surfactant (about 14 to about 24 weight percent; about 14 to about 22 weight percent; about 16 to about 28 weight percent; about 18 to about 28 weight percent). % By weight; about 16 to about 24 weight And about 18 to about 22% by weight); about 2.5 to about 5% by weight of meloxicam (eg, about 2.5 to about 4.5% by weight; about 2.5 to about 4% by weight; about 3 to about About 3.5 to about 5% by weight; about 2.75 to about 4.75% by weight; about 3 to about 4.5% by weight; and about 3.5 to about 4.25% by weight); And from about 35 to about 65% by weight; for example, from about 35 to about 60% by weight; from about 35 to about 55% by weight; from about 40 to about 65% by weight; from about 45 to about 65% by weight; About 60% by weight; and about 45 to about 55% by weight). In some embodiments, the formulation comprises about 15% by weight co-solvent; about 3.33% by weight pH adjuster; about 6.67% purified water; about 21.25% by weight surfactant; about 3% meloxicam 75% by weight; and about 50% by weight solid particle adsorbent. In some embodiments, the formulation is about 1.5% by weight Captex 355®; about 2.5% by weight Capmul MCM®; about 1% by weight PVP K12; about 10% by weight propylene glycol; About 10% by weight aqueous tris (hydroxymethyl) aminomethane; about 21% by weight Tween 80®; about 4% by weight meloxicam; and about 50% by weight silicon dioxide.

A dosage form comprising meloxicam, when administered, contains no meloxicam that is not an emulsion, microemulsion, self-emulsifying oil composition, or self-emulsifying oil composition, which does not contain a pH adjusting agent and is administered by the same route. A short T _max is achieved compared to the formulation (see Example 5 and Busch, U. et al. Drug Metabolism and Disposition 26 (6): 576-584 1998). In some embodiments, the T _max is about 94 to about 142 minutes (eg, about 94 to about 135 minutes; about 94 to about 130 minutes; about 94 to about 125 minutes; about 94 to about 122 minutes; 94 to about 118 minutes; about 98 to about 142 minutes; about 105 to about 142 minutes; about 110 to about 142 minutes; about 114 to about 142 minutes; about 118 to about 142 minutes; about 100 to about 130 minutes; To about 126 minutes; and about 115 to about 121 minutes). In some embodiments, T _max ranges from about 116 to about 120 minutes. In some embodiments, dosage forms comprising meloxicam also comprise tris (hydroxymethyl) aminomethane and silicon dioxide (eg, Zeopharm 5170).

When administered, dosage forms comprising meloxicam are about 1.43 to about 2.14 μg / mL (eg, about 1.43 to about 2.10 μg / mL; about 1.43 to about 2.06 μg / mL; about 1 .43 to about 1.98 μg / mL; about 1.43 to about 1.92 μg / mL; about 1.43 to about 1.86 μg / mL; about 1.43 to about 1.80 μg / mL; To about 2.14 μg / mL; from about 1.55 to about 2.14 μg / mL; from about 1.62 to about 2.14 μg / mL; from about 1.67 to about 2.14 μg / mL; from about 1.76 to about 2.14 μg / mL; about 1.50 to about 2.10 μg / mL; about 1.58 to about 1.98 μg / mL; about 1.66 to about 1.89 μg / mL; and about 1.72 to about 1 Achieve a C _max in the range of .84 μg / mL). In some embodiments, C _max ranges from about 1.75 to about 1.81 μg / mL.

In some cases, a dosage form comprising meloxicam, when administered, does not contain a pH adjuster and is administered by the same route, emulsion, microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition About 120 to about 180% (eg, about 120 to about 175%; about 120 to about 166%; about 120 to about 160%; about 120 to about 156%) of the C _max exhibited by a composition containing non-meloxicam About 125 to about 180%; about 140 to about 180%; about 147 to about 180%; about 125 to about 175%; about 132 to about 168%; about 138 to about 162%; And C _max values of about 145 to about 155%). In such cases, the dosage form does not contain a pH adjusting agent upon administration and is administered by the same route in an emulsion, microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition. about 30 to about 46% of the _{T max} of the composition containing no meloxicam (e.g., from about 30 to about 44%; from about 30 to about 42%; about 30 to about 40%; about 32 to about 46%; about 34 to about 46%; from about 36 to about 46%; to achieve _{T max} is and about 34 to about 42%); from about 32 to about 44%. In some embodiments, the dosage form is not an emulsion, microemulsion, self-emulsifying oil composition, or self-microemulsifying oil composition that does not contain a pH adjusting agent and is administered by the same route. A T _{max that} is about 36 to about 40% of the T _max of the composition containing meloxicam is achieved.

For example, in Example 4, Mobic's C _max (ie, an emulsion, microemulsion, self-emulsifying oil composition, or a formulation of meloxicam that is not a self-microemulsifying oil composition and does not contain a pH modifier) is Studies conducted in dogs showed a C _{max of} about 3.175 μg / mL, whereas dosage forms containing meloxicam, pH adjuster, and solid particle adsorbent (ie, self adsorbed on a carrier) The microemulsifiable oil composition) showed a C _{max of} 4.549 μg / mL. Furthermore, in that same study, the T _max of the Mobic formulation was 480 minutes, whereas the self-microemulsifying oil composition dosage form containing meloxicam and pH adjuster showed a T _{max of} 82.5 minutes. It was.

In another example (see Example 7), Mobic's C _max (ie, not an emulsion, microemulsion, self-emulsifying oil composition, or self-emulsifying oil composition and containing no pH modifier) Formulation) showed a C _{max of} about 1.192 μg / mL in studies conducted in humans, whereas a dosage form containing meloxicam, a pH adjusting agent, and a solid particle adsorbent (ie, on a carrier) The self-microemulsifying oil composition adsorbed on the product showed a C _{max of} 1.783 μg / mL. Similar to the latter formulation, a dosage form containing meloxicam and a pH adjuster but no solid particle adsorbent (ie, a self-microemulsifying oil composition) exhibited a C _{max of} 1.803 μg / mL. Furthermore, in that same study, the T _max of the Mobic formulation was 308.4 minutes, whereas the self-microemulsifying oil composition adsorbed on a solid particle carrier containing meloxicam and a pH adjuster was T _{max was} 118.2 minutes. Similar to C _max , the non-adsorbed self-microemulsifying oil composition exhibited approximately equivalent T _max with a value of 105 minutes.

  In some embodiments, the dosage forms containing meloxicam described herein are not emulsions, microemulsions, self-emulsifying oil compositions, or self-emulsifying oil compositions, but contain pH adjusting agents. And dissolves faster compared to compositions containing meloxicam administered by the same route. In some embodiments, about 75 to about 100% of a dosage form of 15 mg (eg, about 75%; about 80%; about 85%; about 90%; about 92%; about 94%; about 96%; and about 99%) dissolves in 900 mL of deionized water within about 15 minutes. In some embodiments, about 90% of the 15 mg dosage form dissolves in 900 mL deionized water within about 15 minutes. The dissolution rate of the dosage forms containing meloxicam described herein is not an emulsion, microemulsion, self-emulsifying oil composition, or self-emulsifying oil composition, does not contain a pH adjuster, and is the same Compared to the dissolution rate of the composition containing meloxicam administered by route. In some embodiments, about 40 to about 60% of 15 mg of meloxicam dissolves in 900 mL of deionized water within about 15 minutes. In some embodiments, about 50% of 15 mg of meloxicam dissolves in 900 mL of deionized water within about 15 minutes. The dissolution rate described above is measured using an in vitro dissolution assay, USP Dissolution, Apparatus 2.

  Meloxicam exhibits anti-inflammatory, analgesic, and antipyretic activity. For example, meloxicam can be used to treat inflammation and pain. In some embodiments, meloxicam is arthritis (eg, osteoarthritis, rheumatoid arthritis, and juvenile rheumatoid arthritis), ankylosing spondylitis, fever, primary dysmenorrhea, pyrexia, Methods to treat asthma, bone resorption, cardiovascular disease, nephrotoxicity, atherosclerosis, hypotension, lower back pain, and acute pain (eg, pain after surgery, pain due to battlefield wounds , And migraine treatment). Meloxicam is particularly effective in the treatment of all pain associated with inflammation.

  Various publications are described throughout this application. These publications are incorporated herein by reference.

Example 1-Meloxicam Self-Emulsifying Oil Composition Formulation A meloxicam self-emulsifying oil composition was prepared using the following ingredients expressed in weight percent:

  A Trizma® buffer was prepared by mixing 7.5 g of tris (hydroxymethyl) aminomethane base with 15 g of water. The remaining ingredients except meloxicam were blended using an electromagnetic stirrer in a glass beaker in the order shown in the above blending ingredients. The beaker was placed in a 60 ° C. water bath and the ingredients were blended for about 30 minutes until a clear solution was obtained. Meloxicam (7.5%) was then added to the blend. The beaker was covered with paraffin film and maintained in a 60 ° C. water bath, and the solution was further mixed until a clear yellow solution was obtained. If the formulation turned cloudy, orange or dark yellow, the mixing method failed to solubilize meloxicam and the blend was discarded.

Example 2 Adsorption of Meloxicam Self-Emulsifying Oil Composition on Silica and Silicate Add the meloxicam self-emulsifying oil composition of Example 1 in small aliquots and add three powders: silicon dioxide 3.6 μm (GL100) , Silicon dioxide 300 μm (ZeoPharm 5170), and magnesium aluminum silicate 80 μm (Neusilin US2), each adsorbed at a weight ratio of 1: 1 with gentle mixing. All three powder blends were stored in a tightly closed glass container until use.

Example 3-In Vitro Dissolution Study The meloxicam self-emulsifying oil composition adsorbed on both types of silicon dioxide and aluminum magnesium silicate from Example 3 was studied in vitro dissolution. . Dissolution was performed in 900 mL of deionized water. Dissolution studies were performed at USP type 2 apparatus (Varian Inc., Cary, NC). The paddle speed and bath temperature were set to 50 rpm and 37 ° C., respectively. Samples (5 mL) were removed at 5, 10, 15, 30, 45, and 60 minutes and analyzed at 360 nm by UV spectroscopy (Varian Cary, Australia). Unless otherwise specified, dissolution experiments were performed in duplicate.

  FIG. 1 shows meloxicam (powdered drug), non-adsorbed self-emulsifying oil composition, and self-emulsifying adsorbed on both types of silicon dioxide and magnesium aluminum silicate described in Example 2. The dissolution profile in deionized water of an oil composition is shown. Each formulation contains 15 mg of meloxicam. When introduced into the dissolution medium, only 12% of the meloxicam powder was dissolved in water. In contrast, over 96% meloxicam dissolved after 60 minutes when introduced as a self-emulsifying oil formulation (see FIG. 3). Similarly, over 90% of meloxicam dissolved after 60 minutes when introduced as a meloxicam self-emulsifying oil composition adsorbed on silicon dioxide and magnesium aluminum silicate. Both silicon dioxide adsorbents showed a release profile similar to that of the oil formulation alone, whereas the release of meloxicam from the aluminum magnesium silicate formulation was slow at the initial time point.

Example 4-In vitro studies in dogs Formulations of meloxicam self-microemulsifying oil compositions adsorbed on solid particles were evaluated in a dog model awakened with a non-random protocol design in the same dog group. Two forms of meloxicam self-microemulsifying oil composition formulation were used in the study as test articles. One formulation consists of a hard gelatin capsule filled with a self-microemulsifying oil composition containing tris (hydroxy) aminomethane and meloxicam adsorbed on a carrier, Zeopharm 5170, and the other formulation is meloxicam And a hard gel capsule containing only the self-microemulsifying oil composition of tris (hydroxy) aminomethane. Both formulations were administered orally. Two commercial formulations containing meloxicam were also evaluated, with Mobic® tablets administered orally and Metacam® administered intravenously. The meloxicam dose was 7.5 mg or 8.1 mg for orally administered subjects and 2 mg for intravenously administered subjects.

  For each formulation, 4 or 5 dogs were studied. Prior to dosing, the animals were fasted overnight and approximately 2 hours after dosing, the animals had access to diet for the remainder of the study. During the study, animals were dosed multiple times with a recovery period of at least 2 weeks between dosing phases. Each formulation was administered once and intravenous administration was performed via the cephalic vein.

  Depending on the route of administration, whole blood and serum samples were collected at various time points from 480 to 1440 minutes after administration. Blood samples were taken from the cephalic vein or saphenous vein. Samples were stored at room temperature for approximately 1 hour or until processed into serum. The sample was centrifuged at 3200 RPM for about 10 minutes at 22-26 ° C. Serum samples were stored at 4 ± 5 ° C. until analyzed.

  Samples were evaluated using LC / MS / MS. Table 1 and FIG. 2 show the results of the calculated pharmacokinetic parameters obtained in this study.

  The pharmacokinetic profile shows a slow elimination phase for meloxicam, as known from the literature. However, formulations of meloxicam orally administered self-microemulsifying oil compositions exhibit faster absorption in both pharmacokinetic profiles and pharmacokinetic parameter calculations than achieved with orally administered Mobic.

Example 5-Meloxicam Self-Emulsifying Oil Composition Formulation A meloxicam self-emulsifying oil composition was prepared using the following ingredients, expressed in weight percent:

  The ingredients except meloxicam were blended using an electromagnetic stirrer in a glass beaker in the order indicated by the above ingredients. The beaker was placed in a 60 ° C. water bath and the ingredients were blended for about 30 minutes until a clear solution was obtained. Meloxicam (8%) was then added to the blend. The beaker was covered with paraffin film and maintained in a 60 ° C. water bath and the solution was mixed for an additional hour until a clear yellow solution was obtained. If the formulation turned cloudy, orange or dark yellow, the mixing method failed to solubilize meloxicam and the blend was discarded.

Example 6 Adsorption of Meloxicam Self-Emulsifying Oil Composition onto Silica and Silicate Add the meloxicam self-emulsifying oil composition of Example 5 in small aliquots and onto Zeopharm 5170 (silicon dioxide (precipitated amorphous silica)). And adsorbed with gentle mixing at a weight ratio of 1: 1. The powder blend was stored in a tightly closed glass container until use.

Example 7-In vivo studies in humans In normal healthy volunteers, meloxicam self-microemulsifying oil composition adsorbed on solid particles in a partially randomized, open-label study of specific pharmacokinetic parameters The formulations were evaluated. Two forms of meloxicam self-microemulsifying oil composition formulation were used as subjects in the study. One formulation (Formulation A) consists of a hard gelatin capsule filled with a self-microemulsifying oil composition containing carrier, tris (hydroxy) aminomethane adsorbed on Zeopharm 5170 and meloxicam (see Example 6). ), Another formulation (Formulation B) consists of a liquid formulation containing only the self-microemulsifying oil composition of meloxicam and tris (hydroxy) aminomethane (see Example 5). Two commercial tablet formulations containing meloxicam (Formulation C), Mobic®, were also evaluated. Regardless of the formulation, the meloxicam dose was 15 mg and all formulations were administered orally.

  The study consisted of a total of 18 healthy adult volunteers (male and female). The study was conducted over three phases with a minimum 14-day withdrawal period between each phase of the study. Test formulations A and C were randomly administered during phase 1 and phase 2, and test formulation B was administered completely during phase 3. Prior to dosing, subjects were fasted for at least 10.5 hours and at least 24 hours after each dosing phase. Each formulation was administered once with approximately 240 mL of room temperature water.

  At various time points over 96 hours after dosing, 27 blood samples were collected per subject per phase. Within 90 minutes before administration (0 hour) and after administration of the dose 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 Pharmacokinetic sampling at time points 6, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12, 16, 24, 48, 72, and 96 hours It was. Samples were stored at room temperature for approximately 1 hour or until processed into serum. Samples were centrifuged at 3000 RPM for 10 minutes at 4 ± 10 ° C. Serum samples were stored at −20 ± 10 ° C. until analyzed. The time between sampling and freezer storage did not exceed 1.5 hours.

  Samples were evaluated using valid bioanalytical methods and according to Bioanalytical Laboratory's Standard Operating Procedures and FDA guidelines. Table 2 and FIG. 4 show the results of the calculated pharmacokinetic parameters obtained in this study.

  Similar to Example 4, the pharmacokinetic profile shows a slow elimination phase for meloxicam. However, Formulations A and B show faster absorption in both pharmacokinetic profile and pharmacokinetic parameter calculations than achieved with the commercial Formulation C.

Example 8-In vitro dissolution studies In vitro dissolution studies were performed with a meloxicam self-emulsifying oil composition adsorbed on silicon dioxide and a meloxicam tablet formulation (Mobic). Dissolution was performed in 900 mL deionized water, an aqueous solution having pH values of pH 6.8 and pH 4.5 and a solution of 0.1 N HCl. Dissolution studies were performed at USP type 2 apparatus (Varian Inc., Cary, NC). The paddle speed and bath temperature were set to 50 rpm and 37 ° C., respectively. Samples (5 mL) were removed at 5, 10, 15, 30, 45, and 60 minutes and analyzed at 360 nm by UV spectroscopy (Varian Cary, Australia). Unless otherwise specified, dissolution experiments were performed in duplicate.

  As shown in FIGS. 5 and 6, the meloxicam self-emulsifying oil composition adsorbed on the silicon dioxide formulation showed an excellent dissolution profile compared to the tablet formulation.

  A number of embodiments of the invention have been described. However, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims (8)

a) a drug-containing emulsion having small spheres with a diameter greater than 100 nm, the drug-containing emulsion comprising a weak ionic drug and a pH adjuster, wherein the pH adjuster is weak in the absence of a pH adjuster Enhances the solubility of the weak ionic drug in the aqueous phase as compared to the solubility of the ionic drug, wherein the weak ionic drug has a pKa of about 1 to about 14, and the weak ionic drug is meloxicam; Atropine; chloramphenicol; chlorothiazide; chlorpromazine; cimetidine; diazepam; diltiazem; diphenhydramine; disopyramide; flufenamic acid; furosemide; haloperidol; ; Fine verapamil; is selected from the group consisting of, the pH adjusting agent is Ru tris (hydroxymethyl) aminomethane der, drug-containing emulsion;
b) solid particle adsorbent;
A dosage form comprising:
A dosage form in which the drug-containing emulsion is adsorbed to the solid particle adsorbent to form a free-flowing compressible powder.   The dosage form of claim 1, wherein the emulsion globules have a diameter of about 120 nm to about 70 μm.   The dosage form of claim 1, wherein the drug-containing emulsion comprises from about 1 to about 50% by weight of the weakly ionic drug, based on the total weight of both phases of the emulsion.   The dosage form of claim 1, wherein the drug-containing emulsion is an oil-in-water emulsion.   The dosage form of claim 1, wherein the drug-containing emulsion is a water-in-oil emulsion.   The solid particles are selected from the group consisting of kaolin; bentonite; hectorite; colloidal magnesium aluminum silicate; silicon dioxide; magnesium trisilicate; aluminum hydroxide; magnesium hydroxide; magnesium oxide; Item 2. The dosage form according to Item 1. A self-emulsifying oil composition comprising one or more oils, a weak ionic drug, and a pH adjuster that is tris (hydroxymethyl) aminomethane , wherein the self-emulsifying oil composition comprises water Form a drug-containing emulsion with globules with a diameter greater than 100 nm when exposed to the phase, the pH adjuster being water soluble compared to the solubility of the weak ionic drug in the absence of the pH adjuster. Enhances the solubility of the weak ionic drug in the phase, the weak ionic drug has a pKa of about 1 to about 14, and the weak ionic drug is meloxicam; atropine; chloramphenicol; chlorothiazide; chlorpromazine; Cimetidine; diazepam; diltiazem; diphenhydramine; disopyramide; flufenamic acid; furosemide; haloperidol; imipramine; ; Phenobarbital; phenytoin; procainamide; propafenone; propranolol; tetracaine; trimethoprim; and verapamil; is selected from the group consisting of, self-emulsifying oil composition. Captex 355® about 3% by weight;
Capmul MCM® about 5% by weight;
About 2% by weight of PVP K12;
About 20% by weight of propylene glycol;
About 6.67 wt% aqueous tris (hydroxymethyl) aminomethane;
About 13.33% by weight of purified water;
Tween 80® about 42% by weight; and meloxicam about 8% by weight;
The dosage form of claim 1 comprising:

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