Oral transmucosal drug delivery system

1. An oral transmucosal dosage form comprising

(a) a primary vehicle comprising

(i) a crystallization inhibition agent (CIA), selected from the group consisting of

I. a hydrophilic CIA selected from the group consisting of one or more polyethylene glycols (PEG) having a molecular weight ≧2000 which is solid at room temperature, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate co-polymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymers, synthetic copolymers of ethylene oxide and propylene oxide, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, polyethylene oxide, disaccharides, trioses, tetroses, sugar, trisaccharides, tetrasaccharides, oligosaccarides, polysaccharides, maltodextrin, polyols, or mixtures thereof;

II. a lipophilic CIA selected from the group consisting of oleic acid, a hydrogenated vegetable oil, cocoa butter, carnauba wax, beeswax. or mixtures thereof;

III. an amphiphilic CIA selected from the group consisting of polyethylene glycol glycerides, vitamin E-TPGS (d-alpha tocopherol polyethylene glycol 1000 succinate), mono-, di- and tri-esters of sucrose with fatty acids, lecithin or mixtures thereof;

IV. or any combination of I-III; and

(ii) testosterone;

wherein the testosterone is combined with the CIA to form the primary vehicle, and wherein the CIA reduces the crystallinity of the testosterone by at least 50% as measured by DSC relative to essentially pure testosterone not combined with the CIA; and

(b) a secondary vehicle comprising

(i) a hydrophilic water soluble component, and

(ii) a texturizing agent,

wherein said oral transmucosal dosage form weighs about 250 mg to about 5000 mg, said oral transmucosal dosage form erodes in about 5 to about 60 minutes, but does not disintegrate, and said oral transmucosal dosage form is solid at 37 ° C.

2. The oral transmucosal dosage form of claim 1 , wherein said oral transmucosal dosage form comprises testosterone having at least a 95% reduction in crystalinity.

3. The dosage form of claim 1 , wherein the primary vehicle comprises at least two CIAs.

4. The dosage form of claim 1 , wherein the primary vehicle comprises at least two CIAs, wherein the CIAs are selected from the group consisting of at least two of:

a hydrophilic crystallization inhibition agent;

a lipophilic crystallization inhibition agent; and

an amphiphilic crystallization inhibition agent.

5. The transmucosal oral dosage form of claim 1 , wherein the primary vehicle comprises a binary crystallization inhibition agent system, wherein the binary crystallization inhibition agent system is monophasic.

6. The oral transmucosal dosage form of claim 1 , wherein the primary vehicle comprises a ternary crystallization inhibition agent system, wherein the ternary crystallization inhibition agent system is monophasic.

7. The oral transmucosal dosage form claim 1 , wherein said primary vehicle is monophasic.

8. The oral transmucosal dosage form of claim 1 , wherein at least 40% of the testosterone is released from said dosage form within 5 minutes, as measured using the glass bead rotating bottle method with 150 ml SSF.

9. The oral transmucosal dosage form of claim 1 , wherein said crystallization inhibition agent is vitamin E-TPGS.

10. The oral transmucosal dosage form of claim 1 , wherein said crystallization inhibition agent is a PEG having a molecular weight greater than or equal to about 1450.

11. The transmucosal dosage form of claim 1 , wherein the dosage form is packaged in a moisture and/or oxygen barrier polymer film blister package.

12. The oral transmucosal dosage form of claim 1 , wherein the dosage form is made by a process in which the CIA is molten when combined with the testosterone.

13. The oral transmucosal dosage form of claim 1 , wherein the dosage form is made by a process in which the CIA and the testosterone are solubilized in a solvent or mixture of solvents.

14. An oral transmucosal dosage form comprising

(a) a primary vehicle comprising

(i) a crystallization inhibition agent (CIA), selected from the group consisting of

I. a hydrophilic CIA selected from the group consisting of one or more polyethylene glycols (PEG) having a molecular weight ≧2000 which is solid at room temperature, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate co-polymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymers, synthetic copolymers of ethylene oxide and propylene oxide, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, polyethylene oxide, disaccharides, trioses, tetroses, sugar, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides, maltodextrin, polyols, or mixtures thereof;

II. a lipophilic CIA selected from the group consisting of oleic acid, a hydrogenated vegetable oil, cocoa butter, carnauba wax, beeswax, or mixtures thereof;

III. an amphiphilic CIA selected from the group consisting of polyethylene glycol glycerides, vitamin E-TPGS (d-alpha tocopherol polyethylene glycol 1000 succinate), mono-, di- and tri-esters of sucrose with fatty acids, lecithin or mixtures thereof;

IV. or any combination of I-III; and

(ii) testosterone; and

(b) a secondary vehicle comprising

(i) a hydrophilic water soluble component, and

(ii) a texturizing agent,

wherein the CIA reduces the crystallinity of the testosterone by at least a 50% reduction as measured by DSC relative to a dosage form not comprising a CIA but otherwise substantially identical in composition.

15. The oral transmucosal dosage form of claim 14 , wherein said dosage form erodes at a rate of about 5 mg/min to about 500 mg/min.

16. An oral transmucosal dosage form comprising

(a) a primary vehicle comprising

(i) a crystallization inhibition agent (CIA), selected from the group consisting of

I. a hydrophilic CIA selected from the group consisting of one or more polyethylene glycols (PEG) having a molecular weight ≧2000 which is solid at room temperature, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate co-polymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymers, synthetic copolymers of ethylene oxide and propylene oxide, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, polyethylene oxide, disaccharides, trioses, tetroses, sugar, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides, maltodextrin, polyols, or mixtures thereof;

II. a lipophilic CIA, selected from the group consisting of oleic acid, a hydrogenated vegetable oil, cocoa butter, carnauba wax, beeswax, or mixtures thereof;

III. an amphiphilic CIA, selected from the group consisting of polyethylene glycol glycerides, vitamin E-TPCS (d-alpha tocopherol polyethylene glycol 1000 succinate), mono-, di- and tri-esters of sucrose with fatty acids, lecithin or mixtures thereof;

IV. or any combination of I-III; and

(ii) testosterone; and

(b) a secondary vehicle comprising

(i) a hydrophilic water soluble component, and

(ii) a texturizing agent,

wherein the testosterone in said oral transmucosal dosage form has increased permeability across a polysulfone membrane relative to testosterone in a dosage form not combined with the CIA.

17. An oral transmucosal dosage form comprising

(a) a primary vehicle comprising

I. a hydrophilic crystallization inhibition agent selected from the group consisting of one or more polyethylene glycols (PEG) having a molecular weight ≧2000 which is solid at room temperature, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate co-polymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymers, synthetic copolymers of ethylene oxide and propylene oxide, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, polyethylene oxide, disaccharides, trioses, tetroses, sugar, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides, maltodextrin, polyols, or mixtures thereof;

(ii) a lipophilic crystallization inhibition agent selected from the group consisting of oleic acid, a hydrogenated vegetable oil, cocoa butter, carnauba wax, beeswax, or mixtures thereof;

(iii) an amphiphilic crystallization inhibition agent selected from the group consisting of polyethylene glycol glycerides, vitamin E-TPGS (d-alpha tocopherol polyethylene glycol 1000 succinate), mono-, di- and tri-esters of sucrose with fatty acids, lecithin or mixtures thereof; and

(iv) testosterone; and

(b) a secondary vehicle comprising

I. a hydrophilic water soluble component, and

(ii) a texturizing agent,

wherein said oral transmucosal dosage form weighs about 250 mg to about 5000 mg, said oral transmucosal dosage form erodes in about 5 to about 60 minutes, but does not disintegrate, and said oral transmucosal dosage form is solid at 37° C.

18. An oral transmucosal dosage form comprising testosterone, polyethylene glycol having a molecular weight of about 1450 or above, and a secondary vehicle wherein the testosterone and the polyethylene glycol are combined to form the primary vehicle, and wherein the polyethylene glycol reduces the crystallinity of the testosterone by at least 50% as measured by DSC relative to testosterone not combined with the CIA, wherein said oral transmucosal dosage form weighs about 250 mg to about 5000 mg, said oral transmucosal dosage form erodes in about 10 to about 30 minutes, but does not disintegrate, and said oral transmucosal dosage form is solid at 37° C.

19. A method of making an oral transmucosal dosage form comprising the steps of

i) providing a crystallization inhibition agent selected from the group consisting of

I. a hydrophilic CIA selected from the group consisting of one or more polyethylene glycols (PEG) having a molecular weight ≧2000 which is solid at room temperature, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate co-polymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymers, synthetic copolymers of ethylene oxide and propylene oxide, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, polyethylene oxide, disaccharides, trioses, tetroses, sugar, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides, maltodextrin, polyols, or mixtures thereof;

II. a lipophilic CIA selected from the group consisting of oleic acid, a hydrogenated vegetable oil, cocoa butter, carnauba wax, beeswax, or mixtures thereof;

III. an amphiphilic CIA selected from the group consisting of polyethylene glycol glycerides, vitamin E-TPGS (d-alpha tocopherol polyethylene glycol 1000 succinate), mono-, di- and tri-esters of sucrose with fatty acids, lecithin or mixtures thereof;

IV. or any combination of I-III;

ii) applying heat to melt said crystallization inhibition agent, and mixing to create a molten mixture;

iii) adding testosterone to said molten mixture, and mixing the testosterone and the molten mixture;

iv) cooling the molten mixture alone or in combination with secondary vehicle and milling the mixture to form a powder blend;

v) adding a secondary vehicle to the powder blend and mixing; and

vi) compressing the mixture of (v) into an oral transmucosal dosage form, wherein said transmucosal dosage form is about 250 mg to about 5000 mg, erodes in about

5 to about 60 minutes, but does not disintegrate, and is solid at 37° C.,

wherein the secondary vehicle comprises

(i) a hydrophilic water soluble component, and

(ii) a texturizing agent, and

wherein the CIA reduces the crystallinity of the testosterone by at least 50% as measured by DSC relative to essentially pure testosterone not combined with the CIA.

20. A method of making an oral transmucosal dosage form comprising:

i) mixing testosterone with one or more crystallization inhibition agent(s); selected from the group consisting of

I. a hydrophilic CIA selected from the group consisting of one or more polyethylene glycols (PEG) having a molecular weight ≧2000 which is solid at room temperature, polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate co-polymers, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymers, synthetic copolymers of ethylene oxide and propylene oxide, hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, polyethylene oxide, disaccharides, trioses, tetroses, sugar, trisaccharides, tetrasaccharides, oligosaccharides, polysaccharides, maltodextrin, polyols, or mixtures thereof;

II. a lipophilic CIA selected from the group consisting of oleic acid, a hydrogenated vegetable oil, cocoa butter, carnauba wax, beeswax, or mixtures thereof;

III. an amphiphilic CIA selected from the group consisting of polyethylene glycol glycerides, vitamin E-TPGS (d-alpha tocopherol polyethylene glycol 1000 succinate), mono-, di- and tri-esters of sucrose with fatty acids, lecithin or mixtures thereof;

IV. or any combination of I-III;

ii) solubilizing the mixture of (i) in a solvent or a mixture of solvents;

iii) mixing the solution of (ii) with secondary vehicle;

iv) evaporating the solvent(s), forming a combination of testosterone and crystallization inhibition agent(s) mixed uniformly with secondary vehicle, which will act as the primary blend;

v) milling the primary blend to form a powder;

vi) mixing the powder from the previous step with additional secondary vehicle; and

vii) compressing said blend from step (vi) into an oral transmucosal dosage form;

wherein said transmucosal dosage form is about 250 mg to about 5000 mg, erodes in about 5 to 60 minutes, but does not disintegrate and is solid at 37° C.,

wherein the secondary vehicle comprises

(i) a hydrophilic water soluble component, and

(ii) a texturizing agent, and

wherein the CIA reduces the crystallinity of the testosterone by at least 50% as measured

by DSC relative to essentially pure testosterone not combined with the CIA.