Microsphere formulations comprising nalmefene and methods for making and using the same
Microsphere formulations comprising nalmefene are provided. In one aspect, the microsphere formulations are characterized in that the nalmefene is released over a period of about 60 days or more. Methods for making and using the microsphere formulations are also provided.
1 . A microsphere formulation, comprising:
polymer microspheres, each polymer microsphere comprising:
(i) nalmefene; and
(ii) a biodegradable polymer,
wherein each polymer microsphere comprises a drug load of nalmefene of at least about 25% by weight of the polymer microsphere, and
wherein the polymer microspheres have an average particle size of from about 10 μm to about 40 μm (D 50 ), and
wherein the formulation releases the nalmefene at an amount of at least 0.5 ng/ml over a sustained period of at least 60 days.
2 . The microsphere formulation of claim 1 , wherein the nalmefene comprises a free base.
3 . The microsphere formulation of claim 1 , wherein the biodegradable polymer comprises an acid end-capped poly (D,L-lactide-co-glycolide) polymer.
4 . The microsphere formulation of claim 1 , wherein the biodegradable polymer comprises an acid end-capped, 85:15 poly (D,L-lactide-co-glycolide) polymer.
5 . The microsphere formulation of claim 1 , wherein the biodegradable polymer comprises an acid end-capped poly (D,L-lactide-co-glycolide) polymer having an inherent viscosity (IV) of between about 0.6 dL/g and 0.8 dL/g.
6 . The microsphere formulation of claim 1 , wherein the biodegradable polymer comprises an acid end-capped poly (D,L-lactide-co-glycolide) polymer having an IV of about 0.62 dL/g.
7 . The microsphere formulation of claim 1 , wherein each polymer microsphere has a nalmefene drug load of about 35 wt/wt % to about 45 wt/wt %.
8 . The microsphere formulation of claim 1 , wherein the polymer microspheres have an average particle size of between about 15 μm and about 30 μm (D 50 ).
9 . The microsphere formulation of claim 1 , characterized in that about 75% to 100% of the nalmefene is released over a period of within about 60 days of injection into a subject, but not more than about 20% of the nalmefene is released within about 24 hours of injection into the subject.
10 . A microsphere formulation comprising polymer microspheres, each polymer microsphere comprising:
(i) nalmefene; and
(ii) a biodegradable polymer comprising an acid end-capped poly (D,L-lactide-co-glycolide) polymer having an inherent viscosity (IV) of between about 0.6 dL/g and 0.8 dL/g,
wherein each polymer microsphere comprises a drug load of greater than 25 wt/wt %, and wherein the polymer microspheres have an average particle size of between about 10 μm to about 40 μm (D 50 ), for use as a medicament for the treatment of alcohol and/or opioid dependence,
wherein the formulation releases nalmefene at an amount of at least 0.5 ng/mL over a sustained period of at least 60 days.
11 . The microsphere formulation of claim 10 , wherein each polymer microsphere has a nalmefene drug load of about 40 wt/wt % to about 45 wt/wt %.
12 . The microsphere formulation of claim 10 , wherein the polymer microspheres have an average particle size of between about 15 μm and about 25 μm (D 50 ).
13 . The microsphere formulation of claim 10 , wherein the treatment comprises intramuscular or subcutaneous injection of the microsphere formulation to a patient in need thereof no more frequently than about every 60 days.
14 . A nalmefene formulation, comprising:
a. a microsphere comprising poly(lactic-co-glycolic acid) (PLGA) with a ratio of lactide to glycolide of between 80:20 to 90:10; and
b. a nalmefene base loaded into the microsphere at an amount of at least 20% w/w, relative to the microparticle,
wherein the formulation releases nalmefene at an amount of at least 0.5 ng/ml over a sustained period of at least 80 days.
15 . The nalmefene formulation of claim 14 , wherein the ratio of lactide to glycolide is between 82:18 to 88:12.
16 . The nalmefene formulation of claim 15 , wherein the ratio of lactide to glycolide is about 85:15.
17 . The nalmefene formulation of claim 14 , wherein the nalmefene base is loaded in to the microsphere in an amount of at least 25% w/w, relative to the microsphere.
18 . The nalmefene formulation of claim 14 , wherein the formulation releases nalmefene at an amount of at least 1.3 ng/ml over a sustained period of at least 90 days.
19 . The nalmefene formulation of claim 14 , wherein the formulation releases nalmefene over a sustained period of 80 days to 100 days.
20 . The nalmefene formulation of claim 14 , wherein the PLGA has a molecular weight of between 50-80 kDa.
21 . The nalmefene formulation of claim 14 , wherein the PLGA comprises acid endcaps.
22 . The nalmefene formulation of claim 14 , wherein the microsphere has an average particle size of between about 60 μm to about 100 μm.
23 . The nalmefene formulation of claim 14 , wherein the nalmefene base has an average particle size of between about 2 μm to about 5 μm.
24 . The nalmefene formulation of claim 14 , wherein the formulation is lyophilized.
25 . The nalmefene formulation of claim 14 , further comprising a diluent including water, carboxymethylcellulose sodium, polysorbate 20, and sodium chloride.
26 . A nalmefene formulation, comprising:
a. a microsphere comprising poly(lactic-co-glycolic acid) (PLGA) with a ratio of lactide to glycolide of between 82:18 to 88:12, a molecular weight of between 50-80 kDa, and an average particle size of between about 60 μm to about 100 μm; and
b. a nalmefene base having an average particle size of about 2 μm to about 5 μm, loaded into the microsphere at an amount of at least 30% w/w, relative to the microsphere,
wherein the formulation releases nalmefene at an amount of at least 1.0 ng/ml over a sustained period of at least 90 days.
27 . The nalmefene formulation of claim 26 , wherein the ratio of lactide to glycolide is about 85:15.
28 . The nalmefene formulation of claim 26 , wherein the formulation releases nalmefene at an amount of at least 1.3 ng/ml over a sustained period of 80 days to 100 days.
29 . The nalmefene formulation of claim 26 , wherein the PLGA comprises of acid end-caps.
30 . The nalmefene formulation of claim 26 , wherein the microsphere has an average particle size of between about 75 μm to about 85 μm.
31 . The nalmefene formulation of claim 26 , wherein the formulation is lyophilized.
32 . The nalmefene formulation of claim 26 , further comprising a diluent including water, carboxymethylcellulose sodium, polysorbate 20, and sodium chloride.