Method for preparing suspensions of low-solubility materials

• US 9,775,802 B2
• Filed: 10/21/2014
• Issued: 10/03/2017
• Est. Priority Date: 03/24/2009
• Status: Active Grant

• Current Assignee: Bausch & Lomb Incorporated (Bausch Health Cos., Inc.)
• Original Assignee: Bausch & Lomb Incorporated (Bausch Health Cos., Inc.)
• Inventors: MacLeod, Steven K., Stein, Daniel J., Hayes, James Donald, Herber, Donald L.
• Primary Examiner(s): Buckley, Audrea
• Application Number:
  US14/519,776
• Publication Number:
  US 20150038439A1
• Time in Patent Office: 1,078 Days
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00

Abstract

A process for producing a pharmaceutical suspension that comprises an active pharmaceutical ingredient (“API”) having low solubility, the process comprises: (a) preparing a first solution comprising a carboxy-containing vinyl polymer and a solvent; and (b) adding a compound of the API to said first solution under conditions of high-shear mixing for a time from about 5 minutes to about 5 hours, said compound being soluble in said solvent, thereby producing a suspension of particles of said API in a composition comprising said carboxy-containing vinyl polymer; wherein a concentration of said API in said suspension is higher than a solubility of said API in said solvent. The present invention also provides a suspension produced by such process.

Claims

1. A process for producing a pharmaceutical suspension that comprises an active pharmaceutical ingredient (“

API”

) having low solubility, the process comprising;

(a) preparing a first solution comprising a carboxy-containing vinyl polymer and water, said first solution having an acidic pH;

(b) adjusting said pH of said first solution to, and maintaining said pH at, 6.5-6.7;

(c) adjusting a temperature of said first solution to, and maintaining said temperature at, 20-30°

C.;

(d) adding a compound of the API to said first solution under conditions of high-shear mixing for a time from about 5 minutes to about 5 hours, said compound of the API being soluble in water, thereby producing a suspension of particles of said API in a composition comprising said carboxy-containing vinyl polymer;

(e) adjusting a pH of said suspension to, and maintaining said pH at, 6.5-6.7; and

(f) adjusting a temperature of said suspension to, and maintaining said temperature at, 20-30°

C. to produce said pharmaceutical suspension;

wherein said API is a quinolone, said compound is added in amount sufficient to yield a concentration of said API in said suspension that is higher than a solubility of said API in water;

said compound is a salt, a hydrate, or a solvate of said API; and

said compound is added in step (d) as a neat, solid material.

2. The process of claim 1, wherein the carboxy-containing vinyl polymer comprises a crosslinked polyacrylic add polymer.

3. The process of claim 1, wherein the crosslinked polyacrylic add polymer comprises polycarbophil.

4. The process of claim 1, wherein the carboxy-containing polymer is present at an amount of 0.01 to about 10 percent by weight of the final suspension.

5. The process of claim 1, wherein the particles of said API in said suspension have a mean particle diameter in the range from about 1 to about 4 μ

m, and a D₉₀ in the range from about 3 to about 7 μ

m.

6. The process of claim 5, wherein the suspension has a viscosity in the range from about 500 to about 3000 cp (or mPa·

s).

7. The process of claim 1, wherein the conditions of high-shear mixing are effected by a mixing implement at a rotational speed in the range from about 500 to about 2000 rpm.

8. The process of claim 7, wherein the rotational speed is in the range from about 1000 to about 1600 rpm.

9. The process of claim 1;

wherein the carboxy-containing polymer comprises a crosslinked polyacrylic acid polymer, the high-shear mixing conditions are effected by a mixing implement operating at about 500-2000 rpm, and the particles have a mean diameter in the range from about 1 to about 4 μ

m, and a D₉₀ in the range from about 3 to about 7 μ

m.