Long-acting semi-solid lipid formulations

• US 10,220,093 B2
• Filed: 12/06/2017
• Issued: 03/05/2019
• Est. Priority Date: 02/28/2013
• Status: Active Grant

• Current Assignee: Huzhou Hui Zhong JI SHI Biotechnology Company Limited
• Original Assignee: Mira Pharma Corporation
• Inventors: Shen, Hui Rong, Gan, Na
• Primary Examiner(s): Shiao, Rei Tsang
• Application Number:
  US15/833,899
• Publication Number:
  US 20180104340A1
• Time in Patent Office: 454 Days
• Field of Search: 514277
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• 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 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00

Abstract

What is described is a semi-solid controlled release composition comprising a semi-solid lipid and bupivacaine in a solution or a homogenous suspension, methods of using the composition for treating a disease, and methods of manufacturing the composition.

Claims

1. A pharmaceutical composition, comprising

(i) a glyceride mixture comprising one or more glycerides selected from the group consisting of (a) a mixture of caprylic, capric, myristic, and stearic triglycerides (S378);

(b) a mixture of caprylic, capric, isostearic, hydroxyl-stearic, and adipic glycerides (S645);

(c) a mixture of ricinoleic acid partial glycerides (S701);

(d) a mixture of glycerides of C12-C18 fatty acids (G39/01);

(e) a mixture of glycerides of C10-C18 fatty acids (Sup A); and

(f) polyglyceryl-2-diisostearate (PGDS); and

(ii) active agents consisting of (a) bupivacaine; and

(b) a corticosteroid, an analgesic or an anti-inflammatory agent;

wherein the active agents are solubilized in the glyceride mixture at a concentration of 0.01-60 wt %;

wherein the pharmaceutical composition is a semi-solid gel which is a biocompatible, bioerodible, homogeneous, and single phase; and

wherein the semi-solid gel consists of a soft paste with a viscosity of 50-2000 cPs at 30°

C.; and

wherein the semi-solid gel forms a depot releasing bupivacaine for at least five days when measured in vitro at 37°

C.

2. The pharmaceutical formulation of claim 1, wherein the corticoid is a glucocorticosteroid.

3. The pharmaceutical formulation of claim 1, wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory agent (NSAID) selected from the group consisting of naproxen, meloxicam, ketoprofen, COX-1 inhibitors, and COX-2 inhibitors.

4. The pharmaceutical formulation of claim 1, wherein the glyceride mixture comprises S378.

5. The pharmaceutical composition of claim 4, further comprising S701, wherein less than 80% of the bupivacaine is released from the depot in five days when measured in vitro at 37°

C.

6. The pharmaceutical composition of claim 5, wherein the weight ratio S378:

S701 is 80;

20.

7. The pharmaceutical formulation of claim 1, wherein the glyceride mixture comprises S645.

8. The pharmaceutical composition of claim 7, further comprising G39/10, wherein less than 80% of the bupivacaine is released from the depot in five days when measured in vitro at 37°

C.

9. The pharmaceutical composition of claim 8, wherein the weight ratio S645:

G39/10 is 90;

10 to 80;

20.

10. The pharmaceutical formulation of claim 1, wherein the glyceride mixture comprises S701.

11. The pharmaceutical composition of claim 10, further comprising G39/10, wherein less than 80% of the bupivacaine is released from the depot in five days when measured in vitro at 37°

C.

12. The pharmaceutical composition of claim 11, wherein the weight ratio S701:

G39/10 is 90;

10 to 70;

30.

13. The pharmaceutical formulation of claim 1, wherein the active agents are solubilized in the glyceride mixture at a concentration of 5 to 40 wt %.

14. The pharmaceutical composition of claim 1, wherein the viscosity is less than 1528 cPs at 30°

C.

15. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition releases bupivacaine for at least one week when measured in vitro at 37°

C.

16. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition releases bupivacaine for at least two weeks when measured in vitro at 37°

C.

17. The pharmaceutical composition of claim 1, wherein glyceride mixture has an aqueous solubility of less than 1 mg/ml or less than 0.1 mg/ml in a buffer of physiological pH at 37°

C.