Method for the preparation of controlled release formulations
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Publication Number
US-8871269-B2
Publication Date
2014-10-28
Expiration Date
Abstract
The methods disclosed herein are of use for the production of controlled release compositions. In particular, the methods provide the contacting of an organic phase containing a bioactive agent and a polymer with an aqueous phase containing an organic ion to create controlled release compositions containing bioactive agents. The present invention also includes controlled release compositions including a polymer, an organic ion and a bioactive agent. The present invention also includes methods of using such controlled release compositions. The usefulness of the present invention is that the methods result in the production of controlled release compositions containing bioactive agent capable of administration in a concentrated low-dose form, having low burst and reduced production of degraded bioactive agent.
Core Innovation
The invention relates to a controlled release composition and to methods of making it by combining an organic phase and an aqueous phase in an emulsion process. The organic phase includes a water-soluble bioactive peptide and a polymer, and the aqueous phase includes an organic ion. The organic ion is present in the aqueous phase to reduce degradation of the water-soluble bioactive peptide, and the organic ion is selected from trifluoromethyl-p-toluate, 2-naphthalene sulfonate, 2,3-naphthalene dicarboxylate, 2-naphthoate, and salicylsalicylate.
The methods recover controlled release compositions produced by contacting the organic and aqueous phases through an emulsion process. The controlled release compositions include microparticles or nanoparticles containing the bioactive agent in the polymer, and the organic-ion incorporation is used to reduce burst release and bioactive degradation, including acylation of water-soluble peptides such as octreotide.
The described formulations include polymer and peptide categories and can be evaluated in vitro for release profiles and for formation of acylated species. The disclosed examples include preparation of controlled release microparticles using PLGA and water-soluble peptide octreotide, followed by pharmacokinetic evaluation, with sustained release reported over a time period in rats.
Claims Coverage
The partial claims include three independent claims. Across the independent claims, the main inventive concept centers on introducing a selected organic ion into an aqueous phase to reduce degradation of a water-soluble bioactive peptide during an organic/aqueous phase emulsion process, producing controlled release compositions including microparticles.
Organic ion in aqueous phase to reduce peptide degradation
Combining an organic phase comprising a water-soluble bioactive peptide and a polymer with an aqueous phase comprising an organic ion, wherein the organic ion is present in the aqueous phase to reduce degradation of the water-soluble bioactive peptide, and wherein the organic ion is selected from the group consisting of trifluoromethyl-p-toluate, 2-naphthalene sulfonate, 2,3-naphthalene dicarboxylate, 2-naphthoate, and salicylsalicylate.
Controlled release composition by emulsifying organic and aqueous phases
Contacting the resulting organic and aqueous phases through an emulsion process to produce a controlled release composition including an organic ion-bioactive peptide complex.
Microparticle production using biodegradable polymer and emulsion
A process for the production of a microparticle comprising a bioactive agent in a polymer, comprising combining a biodegradable polymer and an organic phase; combining a water-soluble bioactive peptide and said organic phase; combining an organic ion and an aqueous phase to reduce degradation of said water-soluble bioactive peptide, wherein said organic ion is selected from the group consisting of trifluoromethyl-p-toluate, 2-naphthalene sulfonate, 2,3-naphthalene dicarboxylate, 2-naphthoate, and salicylsalicylate; contacting the organic and aqueous phases through an emulsion process; and recovering said microparticles.
All independent claims use the same core approach: a water-soluble bioactive peptide is combined with a polymer in an organic phase, and a selected organic ion is combined with an aqueous phase to reduce peptide degradation, followed by contacting the phases through an emulsion process to form controlled release compositions and/or recovered microparticles that include an organic ion-bioactive peptide complex.
Stated Advantages
Reduces degradation of the water-soluble bioactive peptide.
Reduces burst release.
Reduces bioactive degradation, including acylation of water-soluble peptides such as octreotide.
Alters in vitro release profiles and reduces formation of acylated species, as described for illustrative examples.
Provides sustained release over a time period in pharmacokinetic evaluation described in rats.
Documented Applications
Controlled release of water-soluble bioactive peptides, including octreotide (described with PLGA microparticles and pharmacokinetic evaluation in rats).
In vitro evaluation of release profiles and acylated species formation for peptide-loaded controlled release formulations (described for illustrative examples).
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