Pharmaceutical compositions containing buffered ortho ester polymers

• US 6,440,460 B1
• Filed: 07/27/1998
• Issued: 08/27/2002
• Est. Priority Date: 03/05/1996
• Status: Expired due to Fees

• Current Assignee: Allergan Incorporated (Abbvie Incorporated)
• Original Assignee: Allergan Sales LLC (Abbvie Incorporated)
• Inventors: Gurny, Robert, Zignani, Monia, Tabatabay, Cyrus
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US09/117,359
• Time in Patent Office: 1,492 Days
• Field of Search: 424/486, 424/426, 424/428, 514/772.3
• US Class Current: 424/486
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/204 Polyesters, e.g. poly(lactide-co-glycolide)

Abstract

A pharmaceutical composition for the controlled release of therapeutic agents from carboxylic acid ortho ester polymers contains a pharmaceutically acceptable salt of an acid, which together with the acid R1-COOH liberated from the decomposition of the ortho ester polymer forms a buffer system in a physiologically acceptable pH range.

Claims

1. A pharmaceutical composition for the controlled release of therapeutic agents from a polymer matrix comprising:

a) the therapeutic agent or a combination of therapeutic agents to be administered;

b) a bioerodible carboxylic acid ortho ester polymer consisting essentially of monomer repeating units of the partial formula;

 

wherein R1 represents hydrogen or C1-4-alkyl and A represents a hydrocarbon chain of the formula

wherein Ra, Rb, and Rc independently represent hydrogen or C1-4-alkyl, and m and n independently represent zero or integers from one to three;

c) a pharmaceutically acceptable salt of an acid, which together with the acid R1-COOH being liberated from the decomposition of the ortho ester polymer (I) forms a buffer system in a physiologically acceptable pH range; and

the following optional components;

d) further pharmaceutically acceptable additives; and

or

e) a pharmaceutically acceptable carrier liquid.

2. A pharmaceutical composition according to claim 1 comprising:

a) the therapeutic agent or a combination of therapeutic agents to be administered;

b) a bioerodible carboxylic acid ortho ester polymer consisting essentially of monomer repeating units of the partial formula

c) a pharmaceutically acceptable salt of an acid, which together with the acid CH₃COOH being liberated from the decomposition of the ortho ester polymer (I′

) forms a buffer system in a physiologically acceptable pH-range; and

, optionally,

d) further pharmaceutically acceptable additives.

3. A pharmaceutical composition according to claim 2 comprising:

a) the therapeutic agent or a combination of therapeutic agents to be administered;

b) a bioerodible carboxylic ortho ester polymer consisting essentially of monomer repeating units of the partial formula (I′

);

c) the alkali metal salt X⁺CH₃COO⁻

, which together with the acid CH₃COOH being liberated from the decomposition of the ortho ester polymer (I′

) forms a buffer system in the physiologically acceptable pH-range of 5.5-7.5; and

, optionally,

d) further pharmaceutically acceptable additives.

4. A pharmaceutical composition according to claim 3 comprising:

a) the therapeutic agent or a combination of therapeutic agents to be administered;

b) a non-rigid, bioerodible ortho ester polymer consisting essentially of monomer repeating units of the partial formula (I′

);

c) the sodium salt Na⁺CH₃COO⁻

, which together with the acid CH₃COOH being liberated from the decomposition of the ortho ester polymer (I′

), forms a buffer system;

d) further pharmaceutically acceptable additives suitable for intraocular administration.

5. A process for the preparation of the pharmaceutical composition according to claim 1, which comprises reacting under the conditions of a condensation reaction a triol of the formula

wherein A represents the alkylene chain of the formula IA defined in claim 1, with a carboxylic acid ortho ester of the formula

wherein Oalk represents the C_1-4-alkoxy group, to give a carboxylic acid ortho ester polymer consisting essentially of monomer repeating units of the partial formula

wherein A represents the alkylene chain of the formula IA defined in claim 1;

and adding, in any order of the subsequent process steps, component a), the therapeutic agent or a combination of therapeutic agents to be administered;

component c), a pharmaceutically acceptable salt of an acid, which together with the acid R₁—

COOH being liberated from the decomposition of the ortho ester polymer (I), forms a buffer system in a physiologically acceptable pH-range; and

, optionally, component d), further pharmaceutically acceptable additives; and

/or component e), a pharmaceutically acceptable carrier liquid.

6. A process for the preparation of the pharmaceutical composition according to claim 5, which comprises reacting under the conditions of a condensation reaction the triol of the formula

with the acetic acid ester of the formula

wherein Oalk represents the C_1-4-alkoxy group, to give an ortho ester polymer consisting essentially of monomer repeating units of the partial formula

and adding, in any order of the subsequent process steps, component a), the therapeutic agent or a combination of therapeutic agents to be administered;

component c), a pharmaceutically acceptable salt of an acid, which together with the acid CH₃COOH being liberated from the decomposition of the ortho ester polymer (I′

), forms a buffer system in a physiologically acceptable pH-range; and

, optionally, component d), further pharmaceutically acceptable additives; and

/or component e), a pharmaceutically acceptable carrier liquid.

7. A process according to claim 6, which comprises adding component c), the alkali metal salt X⁺CH₃COO⁻

, which together with the acid CH₃COOH being liberated from the decomposition of the ortho ester polymer (I′

) forms a buffer system in the physiologically acceptable pH-range of 5.5-7.5.

8. A process according to claim 7, which comprises adding component c), the sodium salt Na⁺CH₃COO⁻

, which together with the acid CH₃COOH being liberated from the decomposition of the ortho ester polymer (I′

) forms a buffer system.