PREPARATION OF INJECTABLE SUSPENSIONS HAVING IMPROVED INJECTABILITY
Injectable compositions having improved injectability. The injectable compositions include microparticles suspended in an aqueous injection vehicle having a viscosity of at least 20 cp at 20° C. The increased viscosity of the injection vehicle that constitutes the fluid phase of the suspension significantly reduces in vivo injectability failures. The injectable compositions can be made by mixing dry microparticles with an aqueous injection vehicle to form a suspension, and then mixing the suspension with a viscosity enhancing agent to increase the viscosity of the fluid phase of the suspension to the desired level for improved injectability.
1 . A composition suitable for injection through a needle into a host, comprising:
microparticles comprising a polymeric binder and an active agent encapsulated within the polymeric binder, the microparticles having a mass median diameter of at least about 10 μm; and
an injection vehicle, wherein the microparticles are suspended in the injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein a fluid phase of the suspension has a viscosity greater than about 20 cp and less than about 600 cp at 20° C., wherein the viscosity of the fluid phase of the suspension provides injectability of the composition through a needle into a host,
wherein the polymeric binder is selected from the group consisting of poly(glycolic acid), poly-d,l-lactic acid; poly-l-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, polyphosphazines, albumin, and casein,
wherein the injection vehicle comprises a viscosity enhancing agent comprising sodium carboxymethyl cellulose; a wetting agent selected from the group consisting of polysorbate 20, polysorbate 40, and polysorbate 80; and a tonicity adjusting agent comprising sodium chloride, and
wherein the viscosity of the fluid phase of the suspension provides injectability of the composition into a host through a needle of medically acceptable size.
2 . The composition of claim 1 , wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.
3 . The composition of claim 1 , wherein the polymeric binder is poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 85:15 to about 50:50.
4 . The composition of claim 1 , wherein the microparticles are suspended in the injection vehicle at a concentration of from about 100 mg/ml to about 400 mg/ml.
5 . The composition of claim 1 , wherein the viscosity of the fluid phase of the suspension provides injectability of the composition into the host through a needle ranging in diameter from 18-22 gauge.
6 . The composition of claim 1 , wherein the injection vehicle is aqueous.
7 . A method of making a composition suitable for injection through a needle into a host, comprising:
(a) providing microparticles comprising a polymeric binder and an active agent encapsulated within the polymeric binder, the microparticles having a mass median diameter of at least about 10 μm;
(b) providing an injection vehicle having a viscosity of at least 20 cp at 20° C.; and
(c) suspending the microparticles in the injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein the viscosity of a fluid phase of the suspension is in the range of from about 20 cp to about 600 cp at 20° C., wherein the viscosity of the fluid phase of the suspension provides injectability of the composition into a host through a needle of medically acceptable size, wherein the polymeric binder is selected from the group consisting of poly(glycolic acid), poly-d,l-lactic acid; poly-l-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, polyphosphazines, albumin, and casein, and
wherein the viscosity enhancing agent comprises sodium carboxymethyl cellulose.
8 . The method of claim 7 , wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.
9 . The method of claim 7 , wherein the polymeric binder is poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 85:15 to about 50:50.
10 . The method of claim 7 , wherein the viscosity of the fluid phase of the suspension provides injectability of the composition into the host through a needle ranging in diameter from 18-22 gauge.
11 . The method of claim 7 , wherein the microparticles are suspended in the injection vehicle at a concentration of from about 100 mg/ml to about 400 mg/ml.
12 . The method of claim 7 , wherein the injection vehicle is aqueous.