Amorphous efavirenz and the production thereof
Efavirenz compositions of enhanced bioavailability are described that contain efavirenz with at least one solubility-enhancing polymer. Described methods to produce the bioenhanced products comprise solvent spray drying. One aspect of the method includes the steps of providing a mixture comprising efavirenz, a solubility-enhancing polymer and a single solvent, a solvent blend or solvent/non-solvent blend removing and then evaporating the mixture to form amorphous efavirenz.
1 . A composition comprising efavirenz and a solubility-enhancing polymer wherein said efavirenz exhibits enhanced bioavailability compared to a control composition without the solubility-enhancing polymer.
2 . The composition of claim 1 wherein said efavirenz is substantially amorphous.
3 . The composition of claim 2 wherein said efavirenz is almost completely amorphous.
4 . The composition of claim 3 wherein said efavirenz is completely amorphous.
5 . The composition of claim 4 wherein the efavirenz is stable over a period of at least 180 days in the amorphous form.
6 . The composition of claim 1 wherein the polymer is selected from the group consisting of: aliphatic polyesters, carbohydrates, carboxyalkylcelluloses, alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, hydroxyalkylalkylcellulose derivatives, polyamines, polyethylene glycols, methacrylic acid polymers and copolymers, homo- and copolymers of N-vinyl pyrrolidone, homo- and copolymers of vinyllactam, polysaccharides, poly glycols, polyvinyl esters, refined/modified shellac, and mixtures thereof.
7 . The composition of claim 6 wherein the polymer comprises polyvinylpyrrolidone.
8 . The composition of claim 1 wherein the ratio of efavirenz to total polymer is between about 5% efavirenz:95% total polymer to about 95% efavirenz:5% total polymer.
9 . The composition of claim 8 wherein the ratio of efavirenz to solubility-enhancing polymer is between about 25% efavirenz:75% polymer to about 75% efavirenz:25% polymer.
10 . The composition of claim 1 wherein the composition comprises spray dried particles of efavirenz and polymer.
11 . The composition of claim 10 wherein the spray dried particles of efavirenz and polymer have an average particle size of from about 0.5 μm-500 μm
12 . A pharmaceutical dosage form comprising the composition of claim 1 .
13 . The pharmaceutical dosage form of claim 12 wherein the dosage form comprises an oral, solid-dosage form.
14 . The pharmaceutical dosage form of claim 13 wherein the dosage form comprises an oral, solid-dosage form selected from the group consisting of tablets, coated tablets, chewable tablets, capsules and gelatin capsules.
15 . The pharmaceutical dosage form of claim 14 wherein the efavirenz is substantially amorphous.
16 . A composition in accordance with claim 15 wherein the amorphous efavirenz provides a maximum efavirenz plasma concentration that is at least 1.25 times greater than that of a control composition containing crystalline efavirenz.
17 . A composition in accordance with claim 16 wherein the amorphous efavirenz provides a maximum efavirenz plasma concentration that is at least 2 times greater than that of a control composition containing crystalline efavirenz.
18 . A composition in accordance with claim 17 wherein the amorphous efavirenz provides a maximum efavirenz plasma concentration that is at least 3 times greater than that of a control composition containing crystalline efavirenz.
19 . A composition in accordance with claim 15 wherein the amorphous efavirenz provides an increase in the exposure (AUC 0-8 ) of at least 1.25 times that of a control composition containing crystalline efavirenz.
20 . A composition in accordance with claim 19 wherein the amorphous efavirenz provides an increase in the exposure (AUC 0-8 ) of at least 2 times that of a control composition containing crystalline efavirenz.
21 . A composition in accordance with claim 20 wherein the amorphous efavirenz provides an increase in the exposure (AUC 0-8 ) of at least 3 times that of a control composition containing crystalline efavirenz.
22 . The composition of claim 1 further comprising one or more ingredients selected from the group consisting of surfactant(s), pH modifier(s), filler(s), complexing agent(s), solubilizer(s), pigment(s), lubricant(s), glidant(s), flavor agent(s), plasticizer(s), taste masking agent(s), release-modifying polymer(s), and mixtures thereof.
23 . A composition in accordance with claim 1 wherein the composition is in the form of a paste, solution, slurry, ointment, or dispersion.
24 . The composition of claim 1 wherein at least one of the efavirenz and the polymer is melt-processable.
25 . A composition in accordance with claim 24 wherein the composition is in the form of an oral, solid-dosage form.
26 . A composition in accordance with claim 25 wherein the oral, solid-dosage form comprises a tablet, a coated tablet, a chewable tablet, a capsule or a gelatin capsule.
27 . A composition in accordance with claim 23 wherein the composition comprises pastes, solutions, slurries, ointments, or dispersions made from the efavirenz-polymer melt product.
28 . A method of preparing a composition comprising efavirenz comprising:
contacting a quantity of efavirenz with a solubility-enhancing polymer in a solvent for the polymer, thereby forming a mixture containing efavirenz of enhanced bioavailability.
29 . The method of claim 28 further compromising removing the solvent to form an efavirenz-polymer composition.
30 . The method of claim 28 wherein the ratio of efavirenz to total polymer is between about 5% efavirenz:95% total polymer to about 95% efavirenz:5% total polymer.
31 . The method of claim 28 wherein the composition further comprises one or more pharmaceutically acceptable ingredients.
32 . The method of claim 28 wherein the polymer is selected from the group consisting of: aliphatic polyesters, carboxyalkylcelluloses, carbohydrates, alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, hydroxyalkylalkylcellulose derivatives, polyamines, polyethylene glycols, methacrylic acid polymers and copolymers, homo- and copolymers of N-vinyl pyrrolidone, homo- and copolymers of vinyllactam, polysaccharides, poly glycols, polyvinyl esters, refined/modified shellac, and mixtures thereof.
33 . The method of claim 32 wherein the polymer comprises polyvinylpyrrolidone.
34 . The method of claim 28 wherein the mixture further comprises a non-solvent for the polymer.
35 . The method of claim 34 wherein the solvent and non-solvent are present at a ratio of from about 5% solvent:95% non-solvent to about 95% solvent:5% non-solvent.
36 . The method of claim 35 wherein the ratio of solvent to non-solvent is selected such that the polymer is dissolved in the solvent blend.
37 . The method of claim 36 wherein the efavirenz of enhanced bioavailability exhibits faster dissolution, greater extent of dissolution, or both compared to a efavirenz composition made without a non-solvent for the polymer.
38 . The method of claim 28 wherein the concentration of the polymer in the mixture is from about 1% to about 90%.
39 . The method of claim 29 wherein the solvent is removed by spray drying the mixture to form particles comprising efavirenz.
40 . The method of claim 39 wherein said particles contain less than about 2% residual solvent.
41 . The method of claim 28 wherein a major portion of said efavirenz in said mixture is amorphous.
42 . The method of claim 41 wherein the efavirenz in said mixture is almost completely amorphous.
43 . A composition comprising particles produced in accordance with claim 39 .
44 . An oral, solid-dosage form comprising particles produced in accordance with claim 39 .
45 . The oral, solid dosage form of claim 44 in the form of a capsule, a tablet, a chewable tablet, a granule, a bead, a gelatin capsule, or a pellet.
46 . An efavirenz product produced in accordance with claim 28 .
47 . A method for providing efavirenz to a subject comprising administering to said subject the oral, solid dosage form of claim 45 .
48 . The method of claim 47 wherein said dosage form is administered to treat HIV-1.
49 . A composition comprising a solid dispersion of an efavirenz and at least one solubility-enhancing polymer wherein said efavirenz in said dispersion is substantially amorphous.
50 . The composition of claim 49 wherein said efavirenz in said dispersion is almost completely amorphous.
51 . The method of claim 50 wherein the efavirenz in said mixture is completely amorphous.
52 . A method for preparing a composition comprising amorphous efavirenz comprising:
a. providing a mixture comprising efavirenz and an organic material in a solvent or a blend of a solvent and non-solvent for the organic material;
b. distributing the mixture into either droplets or granules, and
c. evaporating the solvent or solvent and non-solvent from the mixture to form a composition comprising particles wherein the particles comprise amorphous efavirenz.
53 . The method of claim 52 wherein the particles have an average size of from about 0.5 μm to about 5000 μm.
54 . The method of claim 52 wherein the mixture comprises a blend of a solvent and non-solvent for the organic material.
55 . The method of claim 54 wherein said particles possess less crystalline drug than particles produced from a mixture containing solvent alone.
56 . The method of claim 53 wherein the mixture comprises a primary polymer/solvent/non-solvent combination selected from the group consisting of polyvinylpyrrolidone/dichloromethane/acetone, polyvinylpyrrolidone-co-vinyl acetate/acetone/hexane, and ethylcellulose/acetone/water.
57 . A composition comprising efavirenz and a solubility-enhancing polymer wherein said composition exhibits at least one of the following compared to a control composition without the solubility-enhancing polymer:
a) an increase in initial release of at least about 25%
b) an increase in extent of release of at least about 25%
c) an increase in maximum plasma concentration of at least about 25%
d) an increase in AUC 0-8 of at least about 25%.
58 . The composition of claim 57 wherein the solubility-enhancing polymer is selected from the group consisting of aliphatic polyesters, carboxyalkyl celluloses, alkylcelluloses, hydroxyalkyl celluloses, hydroxyalkylalkyl celluloses, hydroxyalkylalkyl cellulose derivatives, polyamines, polyethylene glycols, methacrylic acid polymers and copolymers, homo- and copolymers of N-vinyl pyrrolidone, homo- and copolymers of vinyllactam, polysaccharides, poly glycols, polyvinyl esters, refined/modified shellac and mixtures thereof.
59 . The composition of claim 57 wherein said composition comprises spray dried particles of efavirenz and solubility-enhancing polymer.
60 . The composition of claim 57 wherein the efavirenz is substantially amorphous.
61 . The composition of claim 60 wherein said efavirenz in said composition is almost completely amorphous.
62 . The method of claim 61 wherein the efavirenz in said composition is completely amorphous.