Sustained release dosage form

• US 5,126,147 A
• Filed: 02/08/1990
• Issued: 06/30/1992
• Est. Priority Date: 02/08/1990
• Status: Expired due to Fees

• Current Assignee: Biotechnology Management Associates, Incorporated
• Original Assignee: Biosearch, Inc.
• Inventors: Silvestri, Loui J., Pyle, H. Ruth
• Primary Examiner(s): Pace, Thurman K.
• Assistant Examiner(s): Azpuru, Carlos
• Application Number:
  US07/476,049
• Time in Patent Office: 873 Days
• Field of Search: 424/422, 424/424, 424/489, 424/490, 424/497, 514/922, 514/885
• US Class Current: 424/497
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077

Abstract

A multiphasic sustained release injectable delivery system is provided, as well as a method for treating humans and other mammals with that multiphasic sustained release system. The multiphasic sustained release system comprises prolonged, controlled delivery of microencapsulated macromolecular bioactive agent of biological origin comprising the bioactive agent encapsulated in microcapsules of bioerodible encapsulating polymer, which permits a sustained, multiphasic release of said bioactive agent, including (i) a first portion of said bioactive agent that upon injection is capable of being released from said microcapsules of bioerodible encapsulating polymer in a manner whereby only a relatively small amount of said bioactive agent is released during said first phase, whereby initial biological reaction is minimized due to said first portion producing a mild reaction similar to that normally observed with low doses of conventional administration; and (ii) secondary portions of said bioactive agent that provide a substantially higher level of bioactive agent in doses which could provoke a serious reaction in the patient, but for the prior release of said first portion.

Claims

1. A multiphasic sustained release delivery system for prolonged, controlled delivery of microencapsulated macromolecular bioactive agent, comprising a macromolecular bioactive agent of a biological origin encapsulated in microcapsules of bioerodible encapsulating polymer, which permits a sustained, multiphasic release of said macromolecular bioactive agent, including:

(i) a first portion of said macromolecular bioactive agent that upon injection is capable of being released from said microcapsules of bioerodible encapsulating polymer in a manner whereby only a relatively small amount of said macromolecular bioactive agent is released during a first phase, whereby initial biological reaction is minimized due to said first portion producing a mild local reaction similar to that normally observed with low doses of conventional administration; and

(ii) a second portion of said macromolecular bioactive agent for release from said microcapsules after said initial biological reaction is minimized by said first portion to provide a substantially higher level of the macromolecular bioactive agent in doses which could provoke a serious reaction in the patient, but for the prior release of said first portion.

2. A multiphasic sustained release delivery system according to claim 1 wherein the macromolecular bioactive agent is selected from the group consisting of allergen-related substances, cytokines, anti-hemophilic factors and Receptor CD4.

3. A multiphasic sustained release delivery system according to claim 1 wherein the first and second portions of said macromolecular bioactive agent provide a controlled release providing a dosage profile having an accelerating or crescendoing release.

4. A multiphasic sustained release injectable delivery system for prolonged, controlled delivery of microencapsulated macromolecular bioactive agent in accordance with claim 1, wherein the harmful effects of the released macromolecular bioactive agents are controlled by the synchronous release of an agent for symptomatic treatment of initial adverse reactions to the initial dose.

5. A multiphasic sustained release injectable delivery system of claim 4 wherein said agent for symptomatic treatment comprises a non-steroidal anti-inflammatory agent, an anti-histamine, a corticosteroid, or a bronchodilator.

6. A multiphasic sustained release injectable delivery system for prolonged, controlled delivery of microencapsulated macromolecular bioactive agent of claim 1, wherein said bioerodible encapsulating polymer is a member selected from the group of poly(lactides), poly(glycolides), and copolymers and derivatives thereof;

non-peptide polyamino acids;

poly (ortho esters);

low and high molecular weight polyanhydrides;

polyiminocarbonates;

poly alpha-aminoacids;

polyalkyl-cyano-acrylate;

polyphosphazenes; and

acyloxymethyl polyaspartate and polyglutamate copolymers.

7. A multiphasic sustained release injectable delivery system for prolonged, controlled delivery of microencapsulated bioactive agent of claim 1, wherein the multiphasic release rate is achieved by providing a mixture of microspheres, those corresponding to said first portion (i) including hydrolysis retarding agents impregnated in the microsphere polymer layers, while the microspheres corresponding to said second portion (ii) either contain hydrolysis accelerating agents, or no accelerating agent at all.

8. A multiphasic sustained release injectable delivery system of claim 7 wherein said hydrolysis retarding and accelerating agents are non-toxic organic acids or bases, or an acidic, neutral or basic inorganic salt, or a solution thereof.

9. A multiphasic sustained release injectable delivery system for prolonged, controlled delivery of microencapsulated bioactive agent of claim 1, wherein the multiphasic release rate is achieved by providing a mixture of microspheres, those corresponding to said first portion (i) may include no hydrolysis retarding agents impregnated in the microsphere polymer layers, while the microspheres corresponding to said second portion (ii) contain hydrolysis accelerating agents.

10. A multiphasic sustained release injectable delivery system of claim 9 wherein said hydrolysis retarding and accelerating agents are non-toxic organic acids or bases, or an acidic, neutral or basic inorganic salt, or a solution thereof.

11. A multiphasic sustained release injectable delivery system of claim 1 wherein a stabilizing agent is encapsulated along with the bioactive agent.

12. A multiphasic sustained release injectable delivery system of claim 11 wherein said stabilizing agent is the thermopreservative glycerine or mannitol.

13. A multiphasic sustained release injectable delivery system of claim 1 wherein an adjuvant is encapsulated along with the bioactive agent.

14. A multiphasic sustained release injectable delivery system of claim 13 wherein said adjuvant is tyrosine, polytyrosine, dimethylglycine (DMG), or muramyl dipeptide.

15. A multiphasic sustained release injectable delivery system of claim 1 wherein the encapsulated bioactive agent is in aqueous form.

16. A multiphasic sustained release injectable delivery system of claim 1 wherein the encapsulated bioactive agent is in lyophilized form.

17. A multiphasic sustained release injectable delivery system of claim 1 wherein the macromolecular bioactive agent is unextracted allergen source material.