Invented by Sung-Chul Kim, Eun-Ok Chang, In-Suk Song, Chaul-Min Pai, Samyang Biopharmaceuticals Corp
The Samyang Biopharmaceuticals Corp invention works as follows
The drug carrying micelle is capable of dissolving in water to form a solution thereof. It comprises an amphiphilic block copolymer having a hydrophilic poly(alkylene oxide) component, and a biodegradable hydrophobic polymer component selected from the group consisting of poly(lactic acid), poly(glycoloc acid), poly (lactic-co-glycolic acid), poly(?-caprolactone), a derivative thereof and a mixture thereof. The drug carrying micelle is capable of dissolving in water to form a solution thereof, and the drug carrier comprises an amphiphilic block copolymer having a hydrophilic poly(alkylene oxide) component, and a biodegradable hydrophobic polymer component selected from the group consisting of poly(lactic acid), poly(glycoloc acid), poly(lactic-co-glycolic acid), poly(?-caprolactone), a derivative thereof and a mixture thereof. The amphiphilic polymer block copolymer is preferably a block copolymer with a molecular mass between 1430 and 6000 Daltons, while the hydrophilic component ranges from 50 to 70 wt% of the total block copolymer weight.Background for The preparation of a biodegradable polymeric micelle drug composition
Many important drugs have limited solubilities when dissolved in water. It is often necessary to administer a solubilized version of the drug to the patient in order to achieve the therapeutic effect expected.
There are several methods that have been developed to achieve this goal. These include: auxiliary solvents, surfactants, soluble forms of drugs, such as salts and solutions, chemically modified drug forms, like prodrugs, soluble polymer/drug complexes, and special drug carriers, like liposomes. Each of the methods above is hindered by one or more specific problems. For example, the method that uses surfactant microparticles to solubilize hydrophobic drug has problems because most surfactants can be toxic, and hydrophobic drug precipitation occurs when diluted.
The use of amphiphilic micelles in block copolymers has attracted much attention as a potential drug carrier that is able to solubilize a hydrophobic substance in an aqueous medium. There have been many reports on studies involving amphiphilic micelles with surfactant-like characteristics. Of particular note are attempts to include hydrophobic drugs in block copolymer microelles stabilized due to the nature and properties the copolymer. EP No. 0 397307 A2 discloses a polymeric micelle of an AB-type amphiphilic biblock copolymer that contains poly(ethylene dioxide) as the waterphilic component, and poly(amino acid) as the waterphobic component. Therapeutically active agents can be chemically bonded with the hydrophobic polymer component. This polymeric micelle, although it can be used to administer a hydrophobic medication, is not ideal because it requires functional groups in the block copolymer. EP No. EP No. 0 397 307 A2. This method solves the disadvantage of polymeric micelles with chemical bonds. The poly(amino acids) segment can cause an immune reaction and using an organic solvent to prepare the formulation could be problematic. The peptide bond is cleaved in the body by enzymes, making it difficult to control drug release.
EP No. 0 552 802 A2 describes the formation of chemically-fixed micelles with poly(ethylene oxide), as the hydrophilic and poly(lactic acids), as the hydrophobic components, which can be crossedlinked in the aqueous phase. Chemically fixed micelles can be prepared by crosslinking hydrophobic components that form the core to create stabilized polymeric microparticles. To introduce crosslinking, it is necessary to use a crosslinking substance or another method such as heating or UV with or without peroxides. The biocompatibility and safety of these crosslinked polymer particle have yet to be determined.
U.S. Pat. No. No. 4,745,160 discloses an amphiphilic non-cross-linked linear, branched, or graft copolymer that is pharmaceutically or veterinarian-acceptable. The hydrophilic component of the block copolymer is polyethylene glycol, and the hydrophobic component are poly(D, L, and DL-lactic acid). The block copolymer can be used as a dispersing or suspending agent to help a hydrophobic medication, but it has a high molecular mass and is not soluble in water. The hydrophilic component must be at least 50% of the total weight of block copolymer, and the molecular mass of the hydrophobic ingredient should not exceed 5,000. A water-miscible, lyophilizable and organic solvent is employed in the preparation. The mixture of polymer, organic solvent and drug is first mixed with water to form precipitates, and then it is lyophilized directly into particles. When this particle is dispersed into water, it creates a colloidal solution containing fine particles containing hydrophilic and hydrophobic components mixed together.
U.S. Pat. No. No. 5,543,158 discloses a nanoparticle, or microparticle, formed from a block polymer consisting essentially poly(alkylene glycol) and a poly(lactic acid), a biodegradable material. The nanoparticles or microparticles contain biodegradable polymers in the core and poly(alkylene glycol) on the surface in a quantity that is effective in reducing uptake by the reticuloendothelial systems. The molecular weight is too high for the block-copolymer to dissolve in water. A nanoparticle can be prepared by dissolving a block-copolymer in an organic solvent and adding a drug, then forming an o/w solution by sonication, stirring or agitation, and collecting the precipitated particles containing the drug. The patent does not cover the idea of solubilizing hydrophobic drugs. “The nanoparticles prepared by this patent are fine, dispersed particles in water.
EP 0,520.888 A1 discloses nanoparticles made from a block copolymer of poly(lactic acids) and poly(alkylene dioxide). In order to prepare a colloidal nanoparticle suspension, a high molecular-weight poly(lactic acid), along with a surfactant, is used. This patent describes the preparation of nanoparticles by dissolving a block copolymer with a drug in emulsifying water and then evaporating organic solvents to precipitate nanoparticles that contain the drug. The nanoparticles that result are fine particles with both hydrophilic components and hydrophobic ones. They are not soluble when they are dissolved in water. The patent above does not reveal the concept of hydrophobic drug solubilization when nanoparticles dispersed in a water. “There has not been a serious attempt to solubilize drugs that are hydrophobic in water using a micelle which is water-soluble and whose inner core can physically trap drugs.
Accordingly, the present inventors have endeavored to develop an improved water soluble solubilizer which is free of the problems mentioned above, and it has been unexpectedly found that an amphiphilic block copolymer micelle composed of a poly(ethylene oxide) hydrophilic component covering the surface of a hydrophobic core component made of poly(lactic acid), poly(lactic-co-glycolic acid), poly(glycolic acid), poly(?-caprolactone) or a mixture thereof, is very effective in solubilizing hydrophobic drugs by physically incorporating them therewithin.
The resulting polymeric micelle, which is biodegradable and water-soluble, is an effective solubilizer for a drug that is hydrophobic.” The composition is a solution containing micelles that carry the hydrophobic drug and is suitable for sustained drug release in vivo. This enhances the therapeutic effect. This effect can be enhanced by controlling the molecular mass and relative ratios between the hydrophilic blocks and hydrophobic ones.
The present invention aims to provide a biodegradable micelle-type polymeric composition capable of resolving a drug hydrophobic in a waterphilic environment, which can be used in the preparation of a pharmaceutically efficient solution of a drug hydrophobic.
Another objective of the present invention is the provision of a method of effectively solubilizing hydrophobic drugs in a water-loving environment, and a technique for administering hydrophobic drugs to warm-blooded animals using a selection from the group consisting oral, parenteral topical transdermal or mucosal administration.
The present invention provides a biodegradable, polymeric micelle drug composition that includes a micelle drug carrier having a hydrophobic substance physically trapped inside and not covalently bound to the micelle drug carrier. This micelle can dissolve in water and form a solution. The drug carrier micelle comprises an amphiphilic block copolymer having a hydrophilic poly(alkylene oxide) component, and a biodegradable hydrophobic polymer component selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(?-caprolactone). The molecular weight of the amphiphilic polymer is between 1430 and 6000 Daltons, while the hydrophilic component ranges from 50 to 70 wt% of the total block copolymer weight.
The amphiphilic polymer micelle compositions of the present invention are very effective at solubilizing hydrophobic drug by physically incorporating them into the micelle. The biodegradable micelle composition that contains the hydrophobic drug solubilized is soluble in the water and can be used for sustained release of the drug. This therapeutic effect can be enhanced by controlling the molecular mass and relative ratios between the hydrophilic blocks and hydrophobic ones.
BRIEF DESCRIPTION DES DRAWINGS
FIG. 1 is the GPC(gel permeation chromatography) trace of the monomethoxy poly(ethylene oxide)-poly(lactic acid) diblock copolymer(EL-2L-3)(column: MT3-MT4(Waters, U.S.A.), flow rate: 10 ml/min, eluent: tetrahydrofuran).
FIG. 2 is the GPC(gel permeation chromatography) trace of the monomethoxy poly(ethylene oxide)-polycaprolactone diblock copolymer(EC-2C-1 )(column: Asahipak GS 520H, eluent: distilled water).
FIG. “FIG.
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The biodegradable micelle-type drug formulation of the present invention consists of a polymeric micelle composed of a biodegradable block copolymer, with one or more hydrophobic substances physically entrapped within. When administered, the hydrophobic polymer biodegradable decomposes in vivo by simple hydrolysis into non-toxic, small molecules.
The use of biodegradable polymeric microparticles with an average diameter between 10 and 100 nm is particularly useful for the formulation of a soluble injectable composition of hydrophobic drug which are insoluble or barely soluble in water.
The biodegradable polymeric micelle of the amphiphilic block copolymer of the present invention may be prepared by combining a biodegradable hydrophobic polymer, e.g., poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(?-caprolactone), and derivatives thereof with a hydrophilic polymer such as poly(alkylene oxide). The polymeric micelle can be used to deliver a hydrophobic drug more efficiently to warm-blooded animals.
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