Organic Compounds

Abstract

A pharmaceutical composition comprises octreotide acetate microparticles of linear poly (lactide-co-glycolide) polymer wherein the polymer contains less than 1% silicone oil or heptane.

Claims

1. A process for the production of octreotide acetate microparticles, comprising the steps of: a) forming a solution or dispersion by combining a first mixture which comprises octreotide acetate dissolved in a polar organic solvent that is miscible with methylene dichloride, with a second mixture which comprises a linear poly (lactide-co-glycolide) free from silicone oil or heptane dissolved in methylene chloride; b) combining said solution or dispersion with an effective amount of an aqueous process medium to form an emulsion that contains said process medium and microdroplets which are free from silicone oil or heptane comprising said octreotide acetate, said methylene dichloride and said linear poly (lactide-co-glycolide); and c) forming said microparticles by combining said emulsion with an effective amount of an extraction medium.

2. A process of claim 1 wherein said polar organic solvent that is miscible with methylene dichloride is methanol.

3. A process of claim 1 wherein said second mixture contains from about 1% to about 40% of linear poly (lactide-co-glycolide).

4. A process of claim 3 wherein said second mixture contains from 2% to 2.5% of linear poly (lactide-co-glycolide).

5. A process of claim 1 wherein said first mixture contains from about 1% to about 20% of octreotide acetate.

6. A process of claim 5 wherein said first mixture contains from 4% to 10% of octreotide acetate.

7. A process of claim 6 wherein said polar organic solvent that is miscible with methylene dichloride is methanol.

8. A process of claim 1 wherein said aqueous process medium is water saturated with methylene dichloride.

9. A process of claim 8 wherein said aqueous process medium comprises a stabilizing agent.

10. A process of claim 9 wherein said stabilizing agent is selected from the group consisting of polyvinyl pyrolidone, carboxymethyl cellulose sodium, polyvinyl alcohol and gelatin.

11. A process of claim 9 wherein said stabilizing agent is polyvinyl alcohol.

12. A process of claim 1 wherein said extraction medium is aqueous.

13. A process of claim 12 wherein said extraction medium is an aqueous sodium dihydrogen phosphate/disodium hydrogen phosphate buffer solution.

14. A process of claim 12 wherein said extraction medium has a pH of 7 or higher.

15. A process of claim 12 wherein said extraction medium is distilled water.

16. A process of claim 1 wherein said linear poly (lactide-co-glycolide) has a molecular weight in the range from about 30,000 to 70,000 daltons.

17. A pharmaceutical composition which comprises microparticles obtained according to the process of claim 1.

18. Microparticles obtainable according to the process of claim 1.

19. Microparticles of claim 18 which are free from silicone oil or heptane.

Description

EXAMPLE 1: MICROPARTICLES

[0125] Step a): Approximately 2.5 g of poly(DL-lactide-co-glycolide) [polymer] are dissolved in 25 g methylene chloride to prepare a 9 wt. % polymer solution. After the polymer is completely dissolved, 188 mg octreotide acetate [drug] in 3.7 g methanol are added and allowed to dissolve.

[0126] Step b): This polymer/drug solution is then poured into a 1-L vessel containing 400 g of 5.0 wt. % polyvinyl alcohol (PVA). The PVA is stirred at about 750 rpm by a 2.5 inch impeller (e.g. TEFLON driven by a Fisher Stedi-speed motor). The PVA is also saturated with 7 ml of methylene chloride prior to the addition of the polymer/drug solution. The resulting emulsion is allowed to stir for 7 min.

[0127] Step c): The vessel contents are transferred all at once to 12.0 litres of stirred deionized water. The microparticles are stirred in the deionized water for approximately 30 min and then were collected over 45-μm mesh size meter and 212-μm mesh size stainless steel mesh steel sieves arranged in series. The microparticles are rinsed with additional deionized water and allowed to air dry.

[0128] The microparticles of the invention obtained have the characteristics described above.

EXAMPLE 2

Vehicle Composition

[0129] The microparticles of example 1 are mixed with mannitol and aseptically filled into two chamber syringe (TCS) consisting of one compartment containing the microparticles and one compartment containing a vehicle for suspension of the microparticles.

TABLE-US-00001 Vehicle composition: mg/ml Pluronic F68 2.0 Sodium-carboxymethylcellulose 10.0 (Blanose 7LFD) Mannitol 6.0 Water for injections ad 2.0 ml Nitrogen q.s.

[0130] The components are for a 10 mg dose of octreotide in the microparticles of the invention for a dry pharmaceutical composition. 2 ml of water are provided.