Polymer formulations for delivery of bioactive materials

• US 20090209558A1
• Filed: 10/10/2008
• Published: 08/20/2009
• Est. Priority Date: 12/04/2007
• Status: Active Grant

• Current Assignee: Landec Corporation
• Original Assignee: Landec Corporation
• Inventors: Bell, Adam, Ottensmann, Sandra, Bitler, Steven, Dai, Wei-Guo, Taft, David, Tzannis, Stelios, Zheng, Qiang
• Granted Patent: US 8,114,883 B2
• Time in Patent Office: Days
• US Class Current: 514/259.410
• CPC Class Codes: A61K 31/136 having the amino group directly attached to the aromatic ring, e.g. benzeneamine
• 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 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• 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 9/146 with organic macromolecular compounds
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

Delivery of drugs in association with PLGA polymers which have crystallinity resulting from the presence of long chain alkyl groups in terminal units.

Claims

1. A pharmaceutical formulation comprising a drug and a polymer which

(A) comprises a plurality of polymeric molecules each of which consists essentially of

(i) a polymer backbone which comprises a plurality of repeating units having the formula

—

CF¹F²—

CO—

O 

 

(1)

wherein

F¹ is hydrogen and F² is hydrogen or methyl, the repeating units being the same or different, and

(ii) at least one terminal unit which has the formula

-b-Cy 

 

(2)

wherein

Cy is an n-alkyl moiety containing 18-24 carbon atoms, and

b is a bond or a moiety which has a valence of at least 2 and which links the Cy moiety to the polymer backbone;

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

C., an onset of melting temperature, To, such that the value of (Tp−

To) is less than Tp^0.7, and a heat of fusion of at least 5 J/g, Tp, To and the heat of fusion being measured on a differential scanning calorimeter (DSC) as hereinafter described;

(C) has a number average molecular weight, Mn, measured as hereinafter described, of less than 10,000.

2. A formulation according to claim 1 wherein the drug is risperidone.

3. A formulation according to claim 1 wherein the drug is diclofenac sodium.

4. A formulation according to claim 1 wherein b is the residue of a polyol.

5. A formulation according to claim 1 wherein at least some of the polymeric molecules contain at least three Cy moieties, and the polymer has a heat of fusion of at least 10 J/g.

6. A formulation according to claim 1 wherein the Cy moiety includes a polyoxyalkylene unit.

7. A formulation according to claim 1 wherein the drug and the polymer are such that, when they are formulated into a release sample in the form of a thin flat disc by the procedure described in the Examples above and tested by each of the two release tests described in the Examples above, the drug is released, in at least one of the two tests, according to at least one of paragraphs (a)-(b) below

(a) at a substantially constant rate over a period of at least 10 days in the first 20 days, and in a total amount less than 30%,

(b) in a total amount less than 30% over the first 10 days, and

(c) at a substantially constant rate over the first 10 days and in a total amount less than 20% over the first 20 days.

8. A formulation according claim 1 wherein the formulation, when tested by a release test in which the formulation is exposed to a buffer solution which is maintained at a pH of 5.5, releases the drug according to at least one of paragraphs (a)-(c) below

(a) at a substantially constant rate over a period of at least 10 days in the first 20 days, and in a total amount less than 30%,

(b) in a total amount less than 30% over the first 10 days, and

(c) at a substantially constant rate over the first 10 days, and in a total amount less than 20% over the first 10 days.

9. A formulation according to claim 1 wherein the formulation, when tested by a release test in which the formulation is exposed to a buffer solution which is maintained at a pH of 7.4, releases the drug

(a) at a substantially constant rate over a period of at least 10 days in the first 20 days, and in a total amount less than 30% over the first 20 days, and

(b) in a total amount less than 30%, preferably less than 20%, over the first 10 days, preferably over the first 20 days, particularly over the first 30 days.

10. A pharmaceutical formulation comprising a drug and a polymer which

(A) consists essentially of a plurality of polymeric molecules each of which consists essentially of

(i) a polymer backbone which consists essentially of a plurality of repeating units having the formula

—

CH₂—

CO—

O—

 

 

(1A)

and a plurality of repeating units having the formula

—

CH(CH₃)—

CO—

O—

 

 

(1B)

and

(ii) a plurality of terminal units each of which has the formula

-b-Cy 

 

(2)

wherein

Cy is an n-alkyl moiety containing 18-24 carbon atoms, and

b is a bond or a moiety which has a valence of at least 2 and which links the Cy moiety to the polymer backbone;

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

C., an onset of melting temperature, To, such that the value of (Tp−

To) is less than 10°

C., and a heat of fusion of at least 5 J/g, Tp, To and the heat of fusion being measured on a differential scanning calorimeter (DSC) as hereinbefore described;

(C) has a number average molecular weight, Mn, measured as hereinbefore described, of less than 8,000.

11. A pharmaceutical formulation according to claim 10 wherein the polymer has molecular weight less than 5000.

12. A formulation according to claim 10 wherein the polymer contains 2-30 molar percent of the terminal units.

13. A formulation according to claim 10 wherein the polymer contains 10-40% by weight of Cy moieties.

14. A formulation according to claim 10 wherein at least one of the terminal units has a formula selected from the group consisting of

-Cy 

 

(2A)

—

CO—

O-Cy 

 

(2B)

—

R_pbalc—

CO-Cy 

 

(2C)

where R_pbalc is the residue of a polyol.

15. A formulation according to claim 10 wherein at least one of the terminal units has a formula selected from the group consisting of

—

CH₂—

CH(OH)—

CH₂—

O—

CO-Cy

and

—

CH₂—

CH(O—

CO-Cy)-CH₂—

O—

CO-Cy.

16. A formulation according to claim 10 wherein at least some of the polymeric molecules contain at least three Cy moieties.

17. A formulation according to claim 10 wherein the polymer contains less than 170 repeating units of the formulas (1A) and (1B).

18. A method of making a pharmaceutical formulation which comprises mixing a drug with a polymer which

(A) comprises a plurality of polymeric molecules each of which consists essentially of

(i) a polymer backbone which comprises a plurality of repeating units having the formula

—

CF¹F²—

CO—

O—

 

 

(1)

wherein

F¹ is hydrogen and F² is hydrogen or methyl, the repeating units being the same or different, and

(ii) at least one terminal unit which has the formula

-b-Cy 

 

(2)

wherein

Cy is an n-alkyl moiety containing 18-24 carbon atoms, and

b is a bond or a moiety which has a valence of at least 2 and which links the Cy moiety to the polymer backbone;

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

C., an onset of melting temperature, To, such that the value of (Tp−

To) is less than Tp^0.7, and a heat of fusion of at least 5 J/g, Tp, To and the heat of fusion being measured on a differential scanning calorimeter (DSC) as hereinafter described;

(C) has a number average molecular weight, Mn, measured as hereinafter described, of less than 10,000.

19. A method according to claim 18 wherein the drug has a maximum temperature to which it can be exposed without damage, and the drug is mixed with the polymer at a temperature at which the polymer is liquid and which is below the maximum temperature.

20. A method according to claim 18 wherein the mixing is carried out in the absence of any liquid other than the polymer.

21. A method according to claim 18 wherein the mixing is carried out in the presence of a liquid which is a solvent for one or both of the drug and the polymer.

22. A method of treating a human being which comprise administering a therapeutically effective amount of a drug to the human being, the polymer and the drug being associated with each other in a pharmaceutical formulation comprising the drug and a polymer which

(A) comprises a plurality of polymeric molecules each of which consists essentially of

(i) a polymer backbone which comprises a plurality of repeating units having the formula

—

CF¹F²—

CO—

O—

 

 

(1)

wherein

F¹ is hydrogen and F² is hydrogen or methyl, the repeating units being the same or different, and

(ii) at least one terminal unit which has the formula

-b-Cy 

 

(2)

wherein

Cy is an n-alkyl moiety containing 18-24 carbon atoms, and

b is a bond or a moiety which has a valence of at least 2 and which links the Cy moiety to the polymer backbone;

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

C., an onset of melting temperature, To, such that the value of (Tp−

To) is less than Tp^0.7, and a heat of fusion of at least 5 J/g, Tp, To and the heat of fusion being measured on a differential scanning calorimeter (DSC) as hereinafter described;

(C) has a number average molecular weight, Mn, measured as hereinafter described, of less than 10,000.