Controlled release by extrusion of solid amorphous dispersions of drugs

• US 7,550,158 B2
• Filed: 03/11/2004
• Issued: 06/23/2009
• Est. Priority Date: 02/10/1999
• Status: Expired due to Fees

• Current Assignee: Bend Research Inc. (Lonza Group AG)
• Original Assignee: Bend Research Inc. (Lonza Group AG)
• Inventors: Appel, Leah E., Herbig, Scott M., Curatolo, William J., Nightingale, James A. S., Thombre, Avinash G.
• Primary Examiner(s): TRAN, SUSAN T
• Application Number:
  US10/799,536
• Publication Number:
  US 20040175428A1
• Time in Patent Office: 1,930 Days
• Field of Search: 424/464, 424/465, 424/468, 424/469, 424/470, 424/471, 424/472, 424/474, 424/489, 424/490, 424/491, 424/493, 424/494, 424/473
• US Class Current: 424/490
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer

Abstract

Controlled release dosage forms for low solubility drugs are disclosed wherein an amorphous solid dispersion of the drug is coated with a non-dissolving and non-eroding coating that controls the influx of water to the core so as to cause extrusion of a portion of the core, as well as a method of treating a disease or disorder comprising administering such dosage form to a person.

Claims

1. A controlled release dosage form, comprising:

(a) a core, having a drug layer composition and a sweller layer composition in a bi-layer geometry, comprising an osmotic agent contained in the sweller layer composition and, contained in the drug layer composition, a low solubility drug in the form of a solid dispersion of said drug in a dispersion polymer, wherein substantially all of said drug is amorphous, and wherein said drug in said solid dispersion exhibits amorphous character in at least one of x-ray diffraction analysis or differential scanning calorimetry; and

(b) a water-permeable coating around said core having at least one delivery port therein, said coating controlling the influx of water to said core from an aqueous environment of use to cause extrusion of at least a portion of said core through said at least one delivery port to said aqueous environment of use, said coating being non-dissolving and non-eroding during release of said drug;

wherein said dispersion polymer is selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, and carboxymethylethylcellulose

wherein said dosage form provides at least one of the following AUC in drug concentration selected from (i) and (ii);

(i) an AUC in drug concentration in a use environment that is at least 1.25-fold that of a control dosage form comprising an identical dosage form containing an equivalent quantity of undispersed drug, and

(ii) when said dosage form is dosed orally to a mammal, said dosage form provides an AUC in drug concentration in the blood that is at least 1.25-fold that of a control dosage form comprising an identical dosage form except containing an equivalent quantity of undispersed drug.

2. The dosage form of claim 1 wherein said solid dispersion is homogeneous.

3. The dosage form of claim 1 further comprising an osmotically effective solute.

4. The dosage form of claim 1 wherein said osmotic agent comprises a water-swellable hydrophilic polymer that is separate from said dispersion polymer.

5. The dosage form of claim 4 wherein said water-swellable hydrophilic polymer is selected from the group consisting of hydrophilic vinyl and acrylic polymers, polysaccharide alginates, poly(ethylene oxide), polyethylene glycol, polypropylene glycol, poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinyl pyrrolidone, crosslinked, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl pyrrolidone/polyvinyl alcohol copolymers, vinyl acetate, hydrophilic polyurethanes containing large polyethylene oxide blocks, carrageenan, hydroxethyl-cellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose, carboxymethylcellulose, carboxyethylcellulose, sodium alginate, polycarbophil, gelatin, xanthan gum, sodium croscarmellose, and sodium starch glycolate.

6. The dosage form of claim 1 wherein said solid dispersion is formed by spray-drying said low-solubility drug and said dispersion polymer together in a solvent.

7. The dosage form of claim 1 wherein said dispersion polymer is hydroxypropylmethyl cellulose acetate succinate.

8. The dosage form of claim 1 wherein said drug is selected from the group consisting of an anti-hypertensive, an antianxiety agent, an anticlotting agent, a blood glucose-lowering agent, a decongestant, an antihistamine, an antitussive, an anti-inflammatory, an anti-atherosclerotic agent, an antipsychotic agent, a cognitive enhancer, a cholesterol-reducing agent, an antiobesity agent, an autoimmune disorders agent, a hypnotic agent, an anti-Parkinsonism agent, an antibiotic, an antiviral agent, an anti-impotence agent, an anti-neoplastic, a sedative, a barbituate, a nutritional agent, a beta-blocker, an emetic, an anti-emetic, a diuretic, an anticoagulant, a cardiotonic, an androgen, a corticoid, an anabolic agent, an anti-depression agent, an anti-infective agent, a coronary vasodilator, a carbonic anhydrase inhibitor, an antifungal, an antiprotozoal, a gastrointestinal agent, a dopaminergic agent, an anti-Alzheimer'"'"'s Disease agent, an anti-ulcer agent, a platelet inhibitor, and a glycogen phosphorylase inhibitor.