Method for formulating a controlled-release pharmaceutical formulation

• US 20090252777A1
• Filed: 09/25/2008
• Published: 10/08/2009
• Est. Priority Date: 12/05/2006
• Status: Active Grant

• Current Assignee: Landec Corporation
• Original Assignee: Landec Corporation
• Inventors: Bitler, Steven, Dai, Wei-Guo, Bell, Adam, Taft, David, Tzannis, Stelios, Zheng, Qiang, Ottensmann, Sandra
• Granted Patent: US 8,399,007 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/146 with organic macromolecular compounds
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Abstract

Methods for making formulations of drugs and crystalline side chain polymers which formulations provide controlled and/or sustained release drug formulations.

Claims

1. A method for making a drug formulation comprising a polymer and a drug distributed in the polymer, the polymer being a crystalline side chain (CYSC) polymer which:

(A) comprises a plurality of repeating units having the formula;

 

where R¹ is hydrogen or methyl, and

 

Cy is a moiety comprising an n-alkyl moiety containing 18-24 carbon atoms;

(B) has a crystalline melting temperature (Tp) of at least 40°

C., an onset-of-melting temperature (To) such that Tp-To is less than Tp^0.7, and a heat of fusion of at least 5 J/g;

(C) has a number average molecular weight (Mn) less than 10,000;

(D) is not a thermoplastic elastomer, is not a block copolymer and is not a graft copolymer; and

(E) is not cross-linked;

the method comprising the steps of (1) distributing the drug in the polymer by mixing the drug with the polymer while the polymer is at a temperature above its crystalline melting temperature, and (2) cooling the mixture.

2. The method of claim 1 wherein the CYSC polymer does not possess main chain crystallinity.

3. The method of claim 1 wherein the step (1) is carried out at a temperature of less than about 60°

C., and the drug is a drug which is damaged by exposure to a temperature above about 60°

C.

4. The method of claim 1 wherein the CYSC polymer has a Tp of between 40°

C. and 60°

C.

5. The method of claim 1 wherein Cy is an n-alkyl moiety containing either 18 carbon atoms or 22 carbon atoms.

6. The method of claim 1 wherein the CYSC polymer is a homopolymer.

7. The method of claim 1 wherein the CYSC polymer is a random copolymer comprising two or more randomly polymerized monomers.

8. The method of claim 1 wherein the weight of the drug is at least 5% of the total weight of the formulation.

9. The method of claim 1 wherein the drug is selected from the group consisting of one, some or all of the following:

anti-pain medications, anti-psychotics, neurotransmitter agonists, neurotransmitter antagonists, anti-inflammatories, hormones, anti-osteoporosis drugs, anti-angeogenics, cytotoxic agents, chemotherapeutics and contraceptives.

10. The method of claim 1 wherein the drug is an antipsychotic drug.

11. The method of claim 10 wherein the drug is selected from the group consisting of one, some or all of the group consisting of:

a compound containing functional groups of benzisoxazole and/or piperidine, olanzapine, fluphenazine maleate, chlorpromazine, chlorpromazine hibenzoate, sulpiride, carpipramine hydrochloride, carpipramine maleate, clocapramine hydrochloride, risperidone, fluoenthixole, perphenazine, quetiapine, mosapramine hydrochloride, clozapine, sertindole, an SSRI and a pharmacologically active derivative, congener or metabolite of any of the foregoing.

12. The method of claim 10 wherein the drug is Risperidone or a pharmacologically active derivative, congener, pro-drug or metabolite thereof.

13. The method of claim 1 wherein the drug is Diclofenac or a pharmacologically active derivative, congener, pro-drug or metabolite thereof.

14. The method of claim 1 wherein the drug comprises a protein or a polypeptide.

22. The method of claim 1 wherein the weight of the drug is at least 15% of the total weight of the formulation.

15. A method of making a formulation comprising a polymer and a drug dissolved in the polymer, the polymer being a crystalline side chain (CYSC) polymer which:

(A) comprises a plurality of repeating units having the formula;

 

where R¹ is hydrogen or methyl, and

 

Cy is a moiety comprising an n-alkyl moiety containing 18-24 carbon atoms;

(B) has a crystalline melting temperature (Tp) of at least 40°

C., an onset-of-melting temperature (To) such that Tp-To is less than Tp^0.7, and a heat of fusion of at least 5 J/g;

(C) has a number average molecular weight (Mn) less than 10,000;

(D) is not a thermoplastic elastomer, is not a block copolymer and is not a graft copolymer; and

(E) is not cross-linked;

the method comprising the steps of (1) dissolving the drug in the polymer while the polymer is at a temperature above its crystalline melting temperature, and (2) cooling the mixture, thereby obtaining a formulation wherein the drug is dissolved in the polymer.

16. A method for delivering a drug to a subject over a period of at least 30 days, the method comprising:

(1) making an implantable sustained-release formulation which comprises a crystalline side chain (CYSC) polymer and a drug distributed in the polymer, the weight of the drug being at least 5% of the total weight of the formulation, (2) implanting the formulation within the subject, and (3) releasing a therapeutic dose of the drug from the formulation over a period of at least 30 days,

wherein step (1), above, comprises the steps of (i) distributing the drug in the polymer by mixing the drug with the polymer while the polymer is at a temperature above its crystalline melting temperature, and (ii) cooling the mixture,

wherein the polymer is a CYSC polymer which;

(A) comprises a plurality of repeating units having the formula;

 

where R¹ is hydrogen or methyl, and

 

Cy is a moiety comprising an n-alkyl moiety containing 18-24 carbon atoms;

(B) has a crystalline melting temperature (Tp) of at least 40°

C., an onset-of-melting temperature (To) such that Tp-To is less than Tp^0.7, and a heat of fusion of at least 5 J/g;

(C) has a number average molecular weight (Mn) less than 10,000;

(D) is not a thermoplastic elastomer, is not a block copolymer and is not a graft copolymer; and

(E) is not cross-linked.

17. The method of claim 16 further comprising shaping the formulation into a dosage form suitable for subcutaneous or intramuscular delivery to the subject and implanting the dosage form by subcutaneous or intramuscular delivery.

18. The method of claim 17 wherein the drug is an antipsychotic drug.

19. The method of claim 17 wherein, having been implanted either subcutaneously or intramuscularly into a subject, the dosage form releases the drug with a profile selected from the group consisting of:

(i) release of drug no greater than 20 milligrams per day averaged over any 24 hour period during the first 168 hours of elution;

(ii) release of drug continuously between 0.1 milligram and 20 milligrams per day over a period of at least 30 days;

(iii) release of drug between 0.1 milligram and 20 milligrams per day, averaged over any 24 hour period during a period from 12 hours to 168 hours following inception of elution; and

(iv) release of no more than 20% by weight of total drug loaded into the formulation over any period of 24 hours.

20. A method for orally delivering a polypeptide or protein drug to a subject, the method comprising:

(1) making a formulation comprising a side-chain crystalline (CYSC) polymer and a drug distributed in the polymer (2) orally administering to the subject the controlled-release pharmaceutical formulation, and (3) releasing a therapeutic dose of the drug from the formulation within the gastrointestinal tract only after the formulation had passed through the acid environment of the stomach into the small intestine, large intestine or colon,

wherein step (1), above, comprises the steps of (i) distributing the drug in the polymer by mixing the drug with the polymer while the polymer is at a temperature above its crystalline melting temperature, and (ii) cooling the mixture,

wherein the polymer is a CYSC polymer which;

(A) comprises a plurality of repeating units having the formula;

 

where R¹ is hydrogen or methyl, and

 

Cy is a moiety comprising an n-alkyl moiety containing 18-24 carbon atoms;

(B) has a crystalline melting temperature (Tp) of at least 40°

C., an onset-of-melting temperature (To) such that Tp-To is less than Tp^0.7, and a heat of fusion of at least 5 J/g;

(C) has a number average molecular weight (Mn) less than 10,000;

(D) is not a thermoplastic elastomer, is not a block copolymer and is not a graft copolymer; and

(E) is not cross-linked.

21. The method of claim 20 wherein a therapeutic dose of the polypeptide or protein drug is released from the formulation within the alkaline environment of the small intestine and not within the acidic environment of the stomach.