Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2001-07-13
2003-09-09
Venkat, Jyothsan (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S427000, C424S435000, C424S449000, C424S486000, C424S078180, C424S078220, C424S078230
Reexamination Certificate
active
06616941
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a biodegradable polymeric composition containing a block copolymer having a hydrophilic poly(alkylene glycol) component and a hydrophobic biodegradable polymer component suspended in a poly(ethylene glycol) medium, and to a method for the preparation thereof. The composition can effectively solubilize a hydrophobic drug and forms a solution which can be stored as a stable liquid formulation. Furthermore, the composition can be injected into the body undiluted or as a diluted solution in an aqueous medium, and therefore is useful for the intravenous administration of poorly water soluble drugs.
BACKGROUND ART
Many important drugs are hydrophobic and have limited solubility in water. In order to attain the expected therapeutic effect from such drugs, it is usually required that a solubilized form of the drug be administered to a patient. Therefore, solubilization of a poorly water soluble drug is key technology in the preparation of a formulation for oral or parenteral, especially intravenous, administration of the drug. Common methods used for solubilization of poorly water soluble drugs are: i) dissolving the drug in a co-solvent of a water-miscible organic solvent and water; ii) modifying the drug as a salt that can be soluble in water; iii) forming a soluble drug-complex using a complexing agent; and iv) micellizing the drug in an aqueous medium with a surfactant. (Leon Lachman, “The Theory and Practice of Industrial Pharmacy”, Lea & Febiger, Philadelphia, 1986).
Solubilization methods using surfactants without requiring any changes in the chemical structure of a drug has been widely used to solubilize various drugs. Non-ionic surfactants, eg. polyoxyethylene sorbitan fatty acid esters(Tween®) and polyoxyethylene alkyl ethers(Brij™ or Myrj™), are commonly used as the surface active agents. European Patent EP 0645145 discloses a method of solubilizing a typical poorly water soluble drug, paclitaxel, by use of Cremophor EL™, a polyoxyethylene castor oil derivative. The use of these surfactants, however, is restricted due to their toxic side effects such as hypersensitivity, and they have limitations in that their poor ability to stabilize micelles can cause precipitation of the drug when the micellar solution is either stored or is to remain in place for an extended period of time.
Other solubilization methods using a polymeric micelle, wherein the polymer is a diblock or triblock copolymer consisting of a hydrophilic poly(alkylene glycol) derivative and a hydrophobic biodegradable aliphatic polyester or poly(amino acid), has been developed (see U.S. Pat. Nos. 5,449,513 and 5,429,826). However, poly(amino acid) derivatives or other crosslinked polymers used in the formation of polymeric micelles, cannot be hydrolyzed or degraded in the body, which can cause undesired immune reactions.
X. Zhang et al. reported that a polymeric micelle prepared with a diblock copolymer of poly(lactic acid) and monomethoxy poly(ethylene glycol) was useful as a carrier of paclitaxel. (X. Zhang et al., Int. J. Pharm. 132(1996) 195-206), and Shin et al. disclose a solubilization method for indomethacin using a diblock copolymer of poly(ethylene glycol) and polycaprolactone(I. Gyun Shin et al., J. Contr. Rel., 51(1998) 13-22). In these methods, a poorly water soluble drug is incorporated in a polymeric micelle, wherein the polymers are biocompatible and biodegradable. According to their methods, a drug and a block copolymer are dissolved together in an organic solvent, especially in a water-miscible organic solvent such as tetrahydrofuran or dimethyl formamide. The polymeric micelles are prepared by dialyzing the solution in water first and then freeze-drying the aqueous micellar solution. Alternatively, a solution of a polymer and drug in a water-miscible organic solvent, acetonitrile, is prepared. The organic solvent is slowly evaporated to give a homogeneous drug-polymer matrix and the matrix is then dispersed in an aqueous medium at ca. 60° C. to form the polymeric micelles.
As described above, a conventional solubilizing method for a poorly water soluble drug using polymeric micelles employs complicated steps including formation of an aqueous polymeric micellar solution containing a poorly water soluble drug, followed by preparation of a freeze-dried powder. Moreover, the powdered product must then be reconstituted when used in a hospital or other setting and it is not possible to store the product in an aqueous solution because of the hydrolyzable and biodegradable component in the polymer. Another disadvantage is that this method cannot be applied to a polymer having a melting temperature below about 50° C.
DISCLOSURE OF THE INVENTION
The present invention provides a composition capable of forming a micelle in body fluids or in an aqueous medium and that can be injected into the body in neat or undiluted form or in diluted form as an aqueous solution. The present invention also provides a composition capable of solubilizing a poorly water soluble drug and a method for the preparation thereof.
The composition of the present invention comprises a block copolymer of a hydrophilic poly(alkylene glycol) block and a hydrophobic biodegradable polymer block dispersed or suspended in a poly(ethylene glycol) matrix or its derivatives. The term poly(ethylene glycol) or PEG, as used herein, shall also be deemed to include derivatives of PEG unless otherwise specifically stated. Such derivatives will be more specifically described in the disclosure that follows. Since only the hydrophilic component block, not the hydrophobic component block, of the copolymer has an affinity or attraction for the poly(ethylene glycol) matrix, the block copolymer forms a core-shell structure wherein the hydrophobic biodegradable polymer block occupies the inner core and the hydrophilic poly(alkylene glycol) block forms the outer shell in the poly(ethylene glycol) medium.
Preferably, the block copolymer content in the composition of the invention is within the range of 5~95 wt %, and more preferably within the range of 10~50 wt %, and the content of the water soluble poly(ethylene glycol) is within the range of 5~95 wt %, and more preferably 50~90 wt %. In a composition containing a poorly water soluble drug, the drug content is preferably within the range of 0.1~50 wt %, and more preferably 5~30 wt % based on the weight of the block copolymer.
A biocompatible water-miscible organic solvent may be added into the composition of the present invention to facilitate better solubility of a drug. The added amount of the organic solvent depends on the solubility of a drug, and preferred content of the solvent is less than 50 wt % based on the amount of poly(ethylene glycol) or its derivatives. The present invention is described in detail hereinafter.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is directed to a composition containing an amphiphilic block copolymer having a hydrophilic poly(alkylene glycol) component and a hydrophobic biodegradable polymer component dispersed or suspended in a poly(ethylene glycol) medium, and to a method for the preparation thereof.
The combined block copolymer and poly(ethylene glycol) composition is a liquid that is shelf stable over extended periods of time. The block copolymer portion of such compositions have a core-shell structure in the poly(ethylene glycol) medium wherein the hydrophobic biodegradable polymer block occupies the inner core and the hydrophilic poly(alkylene glycol) block forms the outer shell in the water soluble poly(ethylene glycol) matrix or medium. When administered, the poly(ethylene glycol) functions as a dispersant to facilitate water solubility and the block copolymer portion of the composition forms a micelle structure in body fluids or in an aqueous medium. When a drug is added to the block copolymer and poly(ethylene glycol) composition the poorly water soluble drug is contained within the inner hydrophobic core. Accordingly, a pharmaceutical formulation containing the polymer composition of the pre
Choi In-Ja
Seo Min-Hyo
Samyang Corporation
Thorpe North & Western LLP
Venkat Jyothsan
LandOfFree
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