MICROSPHERES FOR RELEASING AN OCTREOTIDE COMPOUND WITHOUT AN INITIAL TIME LAG
Microspheres for releasing an octreotide compound without an initial time lag include a poly(D,L-lactide-co-glycolide) polymer (PLGA polymer) matrix having a ratio of lactide to glycolide ranging from 80:20 to 90:10 mol %. The polymer has a molecular weight ranging from about 6000 to 16000. The octreotide compound is dispersed in the polymer matrix. The microspheres can be made by forming a dispersed phase by combining the above polymer, dichloromethane, the octreotide compound, methanol and acetic acid. A target loading of the octreotide compound in the dispersed phase ranges from 7 to 12% by weight. Polyvinyl alcohol is dissolved in water to form a continuous phase. The dispersed phase is mixed in the continuous phase to form a microsphere suspension. The dichloromethane, acetic acid, methanol and polyvinyl alcohol are removed from the microsphere suspension. Residual dichloromethane and methanol are removed from the microspheres by washing.
1 . Microspheres for releasing an octreotide compound without an initial time lag, comprising a poly(D,L-lactide-co-glycolide) polymer matrix in which a ratio of lactide to glycolide ranges from 80:20 to 90:10 mol %, said polymer having a molecular weight ranging from about 6000 to 16000, and wherein said octreotide compound is dispersed in said polymer matrix.
2 . The microspheres of claim 1 wherein said polymer has an acid end group.
3 . The microspheres of claim 1 wherein said ratio of lactide to glycolide in said polymer is 85:15.
4 . The microspheres of claim 1 adapted for a 15 day formulation of said microspheres in which said polymer has a molecular weight of about 6000-8000.
5 . The microspheres of claim 1 adapted for a one month formulation of said microspheres in which said polymer has a molecular weight of about 8000 to 14000.
6 . The microspheres of claim 1 adapted for a two month formulation of said microspheres in which said polymer has a molecular weight of about 13000 to 16000.
7 . The microspheres of claim 1 wherein said octreotide compound is octreotide acetate.
8 . An injectable formulation comprising said microspheres of claim 1 and a diluent, said formulation being suitable for injection into a mammal in need thereof through a needle having an inner diameter of 394 microns or less.
9 . The microspheres of claim 1 wherein said microspheres have an average size ranging from about 25 to 35 microns.
10 . The microspheres of claim 3 wherein said microspheres are adapted to release octreotide acetate as said octreotide compound in serum of a rat to a concentration of >1 ng/mL in a first day of said release at a dose of 5 mg per rat.
11 . The microspheres of claim 3 adapted for a one month formulation of said microspheres in which said polymer has a molecular weight of about 8000 to 14000, wherein said microspheres are adapted to release octreotide acetate as said octreotide compound in serum of a rat to a concentration of >3 ng/mL in a first day of said release at a dosage of 5 mg per rat.
12 . The microspheres of claim 11 wherein said microspheres are adapted to release said octreotide acetate in serum of a rat to a concentration of >2 ng/mL at said dosage throughout a 30 day release period.
13 . Microspheres for releasing octreotide acetate without an initial time lag, comprising a poly(D,L-lactide-co-glycolide) polymer matrix in which a ratio of lactide to glycolide is 85:15 mol %, said polymer having a molecular weight ranging from about 6000 to 16000 and an acid end group, and wherein said octreotide acetate is dispersed in said polymer matrix.
14 . A method of administering an injectable octreotide compound to a mammal in need thereof without an initial time lag, comprising:
providing said microspheres of claim 1 ;
adding diluent to lyophilized said microspheres to form a first reconstituted formulation or providing said microspheres along with diluent in a lyophilized formulation;
reconstituting said lyophilized formulation with water to form a second reconstituted formulation; and
injecting said first or second reconstituted formulation to said mammal through a needle having an inner diameter of 394 microns or less.
15 . The method of claim 14 wherein said diluent comprises mannitol, carboxymethyl cellulose and polysorbate.
16 . A process for preparing microspheres for extended release of an octreotide compound without an initial time lag comprising:
providing poly(D,L-lactide-co-glycolide) in which a ratio of lactide to glycolide ranges from 80:20 to 90:10 mol %, said polymer having a molecular weight ranging from about 6000 to 16000;
a. preparing a dispersed phase by combining said polymer, dichloromethane, an octreotide compound, methanol, and acetic acid;
b. wherein a target loading of said octreotide compound in said dispersed phase ranges from 7 to 12% by weight;
c. dissolving polyvinyl alcohol in water to form a continuous phase;
d. mixing said dispersed phase in said continuous phase to form a microsphere suspension;
e. removing said dichloromethane, said acetic acid, said methanol and said polyvinyl alcohol from said microsphere suspension; and
f. removing residual dichloromethane and methanol from said microspheres by washing.
17 . The method of claim 16 comprising exchanging diluent for said water, said diluent comprising sodium carboxymethylcellulose, mannitol and polysorbate to form an octreotide microsphere suspension.
18 . The method of claim 17 comprising adjusting a concentration of said octreotide compound in said octreotide microsphere suspension.
19 . The method of claim 18 comprising filling a formulation of said octreotide microsphere suspension into multiple containers and lyophilizing a single dosage of an entire said formulation in each of said containers.
20 . The process according to claim 19 wherein said lyophilized octreotide formulation is a pharmaceutical formulation for injection.
21 . The process of claim 16 wherein said target loading ranges from 9 to 11%.