CONTROLLED-RELEASE CLOZAPINE COMPOSITIONS
A composition for delivery of a drug is disclosed. The composition has a semipermeable coating, particles of clozapine having an effective average particle size of less than or about 2 μm and at least one surface stabilizer adsorbed on the surface of the clozapine particles, and a solubilizing agent.
1 . A composition comprising:
a semipermeable coating;
particles of clozapine having an effective average particle size of less than or about 2 μm and a surface stabilizer adsorbed on the surface of the clozapine particles; and
a solubilizing agent.
2 . The composition of claim 1 , wherein the semipermeable coating is a controlled-porosity microporous coating.
3 . The composition of claim 2 , wherein the controlled-porosity microporous coating comprises a polymer that is insoluble in an environment of use and a pore forming additive that is soluble in the environment of use.
4 . The composition of claim 3 , wherein the polymer is selected from the group consisting of cellulosic polymers, methacrylates and phthalates, and
wherein the pore forming additive is selected from the group consisting of HPMC, PVP, polyhydric alcohols, and sugars.
5 . The composition of claim 3 , wherein the percent by weight of pore forming additive in the controlled-porosity microporous coating is selected from the group consisting of 0.5%. 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 13%, 15%, 17%, 19%, 21%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 41%, 43%, 45%, 47%, 49%, and 50%.
6 . The composition of claim 1 , wherein the effective average particle size is selected from the group consisting of less than or about 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm (1 μm), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm, 150 nm, 100 nm, 75 nm, and 50 nm.
7 . The composition of claim 1 , wherein the particles of clozapine have a D 90 selected from the group consisting of less than or about 5000 nm, 4900 nm, 4800 nm, 4700 nm, 4600 nm, 4500 nm, 4400 nm, 4300 nm, 4200 nm, 4100 nm, 3000 nm, 3900 nm, 3800 nm, 3700 nm, 3600 nm, 3500 nm, 3400 nm, 3300 nm, 3200 nm, 3100 nm, 3000 nm 2900 nm, 2800 nm, 2700 nm, 2600 nm, 2500 nm, 2400 nm, 2300 nm, 2200 nm, 2150 nm, 2100 nm, 2075 nm, and 2000 nm.
8 . The composition of claim 1 , wherein the surface stabilizer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hypromellose, dioctyl sodium sulfosuccinate (DOSS), sodium lauryl sulfate (SLS), hydroxypropyl cellulose, polyvinylpyrrolidone, sodium deoxycholate, block copolymers based on ethylene oxide and propylene, copolymers of vinylpyrrolidone and vinyl acetate, lecithin, polyoxyethylene sorbitan fatty acid esters, albumin, lysozyme, gelatin, macrogol 15 hydroxystearate, tyloxapol, and polyethoxylated castor oil.
9 . The composition of claim 1 , wherein the solubilizing agent is of a type and present in an amount sufficient to dissolve the clozapine particles within the composition prior to delivery of clozapine to an environment of use.
10 . The composition of claim 9 , wherein the solubilizing agent is a surface-active agent or a pH-modulating agent.
11 . The composition of claim 10 , wherein the surface-active agent is selected from the group consisting of anionic, cationic, zwitterionic and nonionic surface-active agents.
12 . The composition of claim 10 , wherein the solubilizing agent is a pH-modulating agent and, when exposed to fluid of the environment of use, modifies the pH environment within the composition to favor an ionized form of the clozapine.
13 . The composition of claim 12 , wherein the pH-modulating agent is a weak acid selected from the group consisting of adipic acid, ascorbic acid, citric acid, fumaric acid, gallic acid, glutaric acid, lactic acid, malic acid, maleic acid, succinic acid, tartaric acid, and mixtures and combinations thereof.
14 . The composition of claim 1 , wherein the composition delivers to an environment of use a solution of clozapine having a concentration that is higher than that defined by the native solubility of clozapine in the environment of use.
15 . The composition of claim 14 , wherein the concentration of clozapine dissolved in the fluid of the environment of use is 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 300, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 390%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, 500%, 510%, 520%, 530%, 540%, 550%, 560%, 570%, 580%, 590%, 600%, 700%, 800% or 1000% higher than that defined by the native solubility of clozapine in the environment of use.
16 . A method of treating a patient afflicted with schizophrenia comprising administering to the patient a pharmaceutical dosage form of clozapine having a therapeutic effect for up to 24 hours, the dosage form comprising a semipermeable coating, particles of clozapine having an effective average particle size of less than or about 2 μm and a surface stabilizer adsorbed on the surface of the clozapine particles, and a pH-modulating agent.
17 . A method of reducing the risk of recurrent suicidal behavior in a patient with schizophrenia or schizoaffective disorder comprising administering a single dose over a 24 hour period of a composition comprising a semipermeable coating, particles of clozapine having an effective average particle size of less than or about 2 μm and a surface stabilizer adsorbed on the surface of the clozapine particles, and a pH-modulating agent.