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Publication Number
US-8900636-B2
Publication Date
2014-12-02
Expiration Date
Abstract
The compositions disclosed herein are for use as controlled release therapeutics for the treatment of a wide variety of diseases. In particular, the compositions provide water soluble bioactive agents, organic ions and polymers where the bioactive agent is efficiently released over time with minimal degradation products. The resulting controlled release composition is capable of administration in a decreased dose volume due to the high drug content and predominance of non-degraded bioactive agent after release. Additionally, the compositions, of the present invention are capable of long term, sustained releases.
Core Innovation
The invention relates to controlled-release compositions that include a bioactive agent and a biodegradable polymer in an organic phase, together with an organic ion in an aqueous phase that forms a complex with the bioactive agent. The organic ion is selected from trifluoromethyl-p-toluate, 2-naphthalene sulfonate, 2,3-naphthalene dicarboxylate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, 2-naphthoate, or salicylsalicylate, or a mixture thereof.
The disclosure addresses conventional controlled-release formulations using pre-formed insoluble salts or no organic ion, which can lead to lower drug loading and degradation, including increased acylated/modified products for the disclosed peptide bioactive agents. The disclosed compositions use an organic ion in an aqueous phase that forms a complex with the bioactive agent, together with a biodegradable polymer, to enable sustained release while reducing degradation products.
The disclosure includes biodegradable PLGA microparticles and biodegradable nanoparticles, as well as specific organic ions and bioactive-agent examples such as octreotide acetate, leuprolide, oxytocin, and insulin. The document reports improved core load, more consistent drug/ion ratios compared with conventional formulations, and lower peptide acylation, alongside preliminary in vivo pharmacokinetics in rats showing serum octreotide levels over weeks after single subcutaneous dosing.
Claims Coverage
The independent claim set consists of a single independent claim. The claim contains 3 inventive features defining a two-phase controlled-release composition, a selected organic ion that forms a complex with the bioactive agent, and a stoichiometry range of about 1.0 to 1.5.
Two-phase composition with organic-phase biodegradable polymer and aqueous-phase complexing organic ion
A composition comprising a bioactive agent and a biodegradable polymer in an organic phase, and an organic ion in an aqueous phase that forms a complex with the bioactive agent.
Selected organic ion complexing agents in the aqueous phase
The organic ion comprises trifluoromethyl-p-toluate, 2-naphthalene sulfonate, 2,3-naphthalene dicarboxylate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, 2-naphthoate, or salicylsalicylate, or a mixture thereof.
Stoichiometry range of bioactive agent relative to organic ion
The stoichiometry of the bioactive agent relative to the organic ion ranges from about 1.0 to 1.5.
Coverage centers on a controlled-release composition defined by an organic-phase biodegradable polymer with a bioactive agent, an aqueous-phase organic ion that forms a complex with the bioactive agent, the named organic ions or mixtures, and bioactive-agent-to-organic-ion stoichiometry of about 1.0 to 1.5.
Stated Advantages
Higher drug loading compared with conventional formulations.
Sustained release enabled by the disclosed complex-forming composition.
Reduced degradation, including reduced acylated/modified products for disclosed peptide bioactive agents.
More consistent drug/ion ratios compared with conventional formulations.
Documented Applications
Preliminary in vivo pharmacokinetics in rats showing serum octreotide levels over weeks after single subcutaneous dosing.
Controlled-release compositions implemented in biodegradable microparticles and biodegradable nanoparticles.
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