Cyclic ether side group-containing amphiphilic polymer lyophilized powder and composition thereof, and applications of composition

A technology based on amphiphilic polymers and cyclic ether side groups, which can be used in drug combinations, freeze-dried delivery, and medical preparations containing active ingredients, etc., and can solve problems such as non-degradability, difficult large-scale preparation, and difficult injections

Inactive Publication Date: 2015-05-20
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The current temperature-sensitive in-situ gel system has the following disadvantages: 1. The hydrophobic drug and polymer aqueous solution need to be dispersed at 4°C for more than 24 hours during use, and drug crystallization will affect the release of the drug; 2. Natural polymer and synthetic peptide aqueous solution Viscosity is high, injection is difficult, it is not suitable for the delivery of hydrophobic therapeutic agents, and the uncontrollable structure brings difficulties to the control of gel properties; Fast and non-degradable; 3. PLGA-PEG-PLGA is viscous at room temperature, difficult to transfer and weigh, the prepared sol needs to be stored frozen and must be melted before use; 4. The preparation of polyphosphoric acid is cumbersome and difficult to scale Preparation
The above problems greatly limit the development and application of injectable thermosensitive gel formulations

Method used

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  • Cyclic ether side group-containing amphiphilic polymer lyophilized powder and composition thereof, and applications of composition
  • Cyclic ether side group-containing amphiphilic polymer lyophilized powder and composition thereof, and applications of composition
  • Cyclic ether side group-containing amphiphilic polymer lyophilized powder and composition thereof, and applications of composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add polyethylene glycol (1.50g) with a relative molecular mass of 1000 into the reactor, heat it to melt the polyethylene glycol, vacuum to remove water and cool it naturally; add caprolactone (2.79g), TOSUO (0.21g) and Stannous octoate (14mg), after adding each reactant, vacuum, fill with nitrogen, finally vacuum seal, react at 120°C for 24 hours under stirring; add dichloromethane to the reactor to dissolve the synthesized polymer, then Pour into cold n-hexane for precipitation, filter and collect the precipitate. This operation is repeated three times. The precipitate is separated by suction filtration and dried in vacuum to obtain ABA type amphiphilic polymer P-1. The heavy metal content is less than 0.001% (mass), and the residual monomer and solvent content is less than 0.05% (mass).

Embodiment 2

[0024] Polyethylene glycol monomethyl ether (7.2g) with a molecular weight of 700 was added to the reactor, heated to melt, vacuumed to remove water and then cooled naturally; add caprolactone (18.36g), TOSUO (3.24g) and caprylic acid in sequence Stannous (108mg), after adding each reactant, vacuumize, fill with nitrogen, finally vacuum seal, react at 160℃ for 10 hours; add dichloromethane to the reactor to dissolve the synthesized polymer, then pour into cold n-hexane The precipitate was collected by filtration. This operation was repeated three times. The precipitate was separated by suction filtration and dried under vacuum to obtain a diblock copolymer containing pendant cyclic ether groups; the above product (22.4g) was dissolved in anhydrous toluene (100ml ), heat and vacuum, remove the water absorbed by the polymer to the remaining 50ml of toluene, then add hexamethylene diisocyanate (432mg), stir and react at 60℃ for 8-24 hours, pour the reaction liquid into cold n-hexan...

Embodiment 3

[0026] The device and operation are the same as those in Example 1 and Example 2, except that the relative molecular weight of polyethylene glycol and the ratio between monomers are changed to the data in Table 1. According to the raw material composition shown in Table 1, Table 1 is prepared. In other block copolymers. Two or more precipitation purifications are required until the content of heavy metals and their compounds in the polymer (mainly stannous octoate) is less than 0.001%, and the residual monomer and solvent content is less than 0.05%.

[0027] The content of heavy metals is detected in accordance with the national FDA Pharmacopoeia standard method, and the monomer and organic solvent residues are determined by gas chromatography. The composition of the amphiphilic polymer is shown in Table 1

[0028] Table 1 Composition of biodegradable amphiphilic block copolymer containing cyclic ether side groups

[0029]

[0030] M B Represents the relative molecular mass of the ...

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Abstract

The present invention relates to cyclic ether side group-containing amphiphilic polymer lyophilized powder and a composition thereof, and applications of the composition, wherein the lyophilized powder is the lyophilized powder of a cyclic ether side group-containing amphiphilic polymer or the drug-loaded lyophilized powder adopting a cyclic ether side group-containing amphiphilic polymer as an auxiliary material, the amphiphilic polymer is selected from one or a plurality of ABA type and BAB type amphiphilic block copolymers comprising a degradable polyester A containing a 1,4,8-trioxaspiro[4.6]-9-undecanone (TOSUO) unit and a polyethylene glycol block B, and the polyester A is a copolymer of caprolactone, lactide, glycolide and TOSUO. According to the present invention, the lyophilized powder can be rapidly dispersed into an aqueous medium at a temperature of 4-25 DEG C to form a flowable liquid and can be rapidly gelated under the body temperature environment; and the pyrogen-free powder injection after the sterilization treatment can be used for the clinical topical drug administration application, is sued for the topical drug administration on the intratumoral position, the peritumoral position, the thoracic cavity, the peritoneal cavity, the Intravesical position, the position in the liver, the intranasal position, the intraocular position, the intravaginal position and other positions, and the drug can be subjected to long-acting slow-release.

Description

Technical field [0001] The drug sustained-release dosage form with degradable polymer as auxiliary material and its preparation technology and application are used for long-acting sustained-release of topical administration. Background technique [0002] The injectable amphiphilic polymer thermosensitive in situ gel provides a new means for long-term sustained release of topical administration. The polymer temperature-sensitive hydrogel with sol-gel transition properties is a flowable liquid at room temperature. When injected into the body, it will form a gel in situ at the injection site (without chemical reactions and organic solvents), which can be controlled for a long time The local release of the drug in the gel and the morphological adaptability to the injection site are very suitable for tumor positioning. Polymer thermosensitive in situ gels for topical administration mainly include natural polymers such as chitosan, synthetic polypeptides (ELPs) and aqueous dispersions...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/19A61K9/06A61K47/34A61K45/00A61P35/00
Inventor 董岸杰邓联东许舒欣张建华
Owner TIANJIN UNIV
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