CN111514109B - Preparation method of poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microspheres and product - Google Patents

Abstract

The invention discloses a preparation method of poly L-lactic acid/poly D-lactic acid-glucose copolymer drug-carrying microspheres and a product thereof, the invention adopts an emulsion-solvent volatilization method to prepare poly L-lactic acid/poly D-lactic acid-glucose copolymer drug-carrying microspheres for encapsulating ibuprofen, poly L-lactic acid, poly D-lactic acid-glucose copolymer and ibuprofen are all dissolved in chloroform to obtain a blended solution, the blended solution is dripped into a polyvinyl alcohol aqueous solution under high-speed stirring to obtain an oil-in-water emulsion, the emulsion is frozen and dried in vacuum to obtain poly L-lactic acid/poly D-lactic acid-glucose copolymer drug-carrying microspheres powder, and the biocompatibility of the drug-carrying microspheres is improved by utilizing the stereo composite effect of the poly D-lactic acid-glucose copolymer and the poly L-lactic acid and the hydrophilicity of glucose groups thereof, The drug loading rate and the encapsulation rate are improved.

Description

A kind of preparation method and product of poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microspheres

Technical field:

The invention relates to a degradable drug carrier material, in particular to a preparation method of a poly-L-lactic acid/poly-D-lactic acid-glucose copolymer composite drug-carrying microsphere.

The present invention also relates to the composite drug-carrying microspheres obtained by the above method.

Background technique:

Ibuprofen (IBF) is favored because its anti-inflammatory, analgesic and antipyretic effects are superior to drugs such as aspirin, phenylbutazone and paracetamol. It is recognized as the first-choice anti-inflammatory drug for children. The side effects of ibuprofen are small, limited to mild indigestion, rash, elevated transaminase, etc., but this drug has strong gastric toxicity, and the incidence of various gastrointestinal irritation symptoms is extremely high, generally between 30 and 40. % or so, renal failure may occur with excessive or long-term overdose of ibuprofen. Because of its poor water solubility and low bioavailability, ibuprofen needs to be administered repeatedly, in large doses or for a long time, resulting in toxic and side effects, which seriously affects the clinical effect of the drug. In order to increase the convenience of administration and improve the clinical effect, drug-loaded microspheres have become an effective way to avoid drug resistance and improve the effectiveness of drug combinations, and biodegradable polymer drug-loaded microspheres have received extensive attention.

Polylactic acid (PLA), as a pharmaceutical excipient approved by the US Food and Drug Administration (FDA), is widely used in the field of biomedicine because it can be safely degraded in the human body, and has huge applications in the field of gene delivery or new drug carriers prospect. However, PLA also has shortcomings as a drug carrier material: (1) When the molecular weight of PLA is low, its heat resistance and mechanical strength are poor, and the drug-loaded microspheres are easily damaged. However, when the molecular weight of PLA is high, its dispersibility is poor, and the particle size and controlled release rate are difficult to control. All these may make the drug-loaded microspheres unable to be released for a long time, resulting in drug waste and increased drug side effects; (2) PLA microspheres have low hydrophilicity, lack of specific binding with body cells, poor cellular uptake ability, and drug absorption. not effectively.

Blending or copolymerizing polylactic acid with hydrophilic monomers or polymers can improve the performance. By adjusting the molecular weight of the polymer, system composition and molecular chain structure and other factors, the crystallization properties, degradation speed, hydrophilicity and other factors of polylactic acid materials can be controlled. and cytocompatibility. Chinese patent CN104739783B discloses a method for preparing polylactic-co-glycolic acid copolymer (PLGA)/chitosan (CS) drug-loaded microspheres containing hydrophilic protein drugs by an improved physical method. Surface hydrolysis modification increases its carboxyl content and increases its charge. In order to further improve the drug loading rate and prolong the sustained release time, the multi-layer composite PLGA-CS drug-loaded composite microspheres were prepared by layer-by-layer self-assembly technology. The preparation process is complicated, and the drug loading rate is not significantly improved. Carbohydrates play an important role in the process of life activities and are the main source of energy for all living organisms to maintain life activities. Liu Yaowen et al. used oil-in-water (O/W) emulsion and ion gel method to successfully encapsulate cinnamon essential oil (CEO) in chitosan (CS) nanoparticles with different loadings, and prepared by electrospinning method. Polylactic acid and CS-CEO composite fiber. The fiber has good antibacterial properties and has broad application prospects in food packaging (Nanomaterials, 2017, 7(7): 194-207.). Hafezur Rahaman et al. used the solution mixing method and the film method to prepare the composite material of polylactic acid and oligomeric lactic acid grafted α-cellulose, and the thermal stability of the composite material was improved (Journal of Applied Polymer Science, 2019: 47424-47430.). PLA includes two optical isomers, poly-L-lactic acid (PLLA) and poly-D-lactic acid (PDLA), and their optical activity has a significant effect on the properties of PLA. The degradation rate of polylactic acid and its copolymers varies with molecular weight and composition. In order to improve the crystalline and thermal properties of PLA materials, enantiostereocomplex blending to form stereocomplex crystals has become one of the most effective and simple modification methods. Hydrophilic glucose has a simple structure, a wide range of sources, low price, and is green and pollution-free. In order to improve the hydrophobicity and cytocompatibility of PLA materials, glucose can be directly melt polycondensed with L-lactic acid or D-lactic acid to prepare amphiphilic polylactic acid-glucose copolymers. Although the molecular weight of PLA and its copolymers prepared by direct melt polycondensation is lower, it is more conducive to the formation of a stereocomplex crystal structure in sc-PLA, thereby comprehensively improving the properties of PLA. Cao Dan, Gao Qinwei and others used lactic acid and glucose as raw materials to prepare poly-L-lactic acid-glucose copolymer and poly-D-lactic acid-glucose copolymer by melt polymerization, and prepared polylactic acid containing glucose group by solution blending method. Stereocomplexes improve the crystallinity, hydrophilicity and thermal properties of PLA materials (Forest Products Chemistry and Industry, 2018, 38(5): 17-22).

The present invention adopts an emulsion-solvent evaporation method to prepare drug-loaded microspheres of poly-L-lactic acid/poly-D-lactic acid-glucose copolymer, and dissolves poly-L-lactic acid, poly-D-lactic acid-glucose copolymer and ibuprofen in trichloride The organic mixed solution is prepared from methane, the polyvinyl alcohol and the emulsifier are dissolved in the water phase, the organic phase and the water phase are mixed to form an emulsion, and the organic solvent is removed by freeze-drying to obtain high polymer microspheres. The present invention utilizes the stereocomplex effect of poly-L-lactic acid and poly-D-lactic acid-glucose copolymer and the hydrophilicity of glucose group to improve the biocompatibility of drug-carrying microspheres, increase drug-carrying rate and prolong sustained release time.

Invention content:

The present invention is accomplished in order to solve the above-mentioned deficiencies in the prior art, and the purpose of the present invention is to provide a preparation method of poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microspheres.

The technical scheme adopted to realize the purpose of the present invention is as follows:

The invention uses poly-L-lactic acid (PLLA) and poly-D-lactic acid-glucose copolymer (PDLAG) as raw materials, and prepares poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microspheres by an emulsion-solvent evaporation method.

The preparation steps of the poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microspheres include: (1) preparation of a blended solution of poly-L-lactic acid, PDLAG, and ibuprofen (IBF): weighing, etc. The amount of PLLA and PDLAG was dissolved in chloroform at room temperature, stirred evenly, and prepared into a PLLA-PDLAG blend solution with a total polymer mass fraction of 10%. Add a certain amount of ibuprofen to the blended solution to obtain a PLLA-PDLAG-IBF blended solution; (2) Preparation of PLLA-PDLAG drug-loaded microspheres: weigh a certain amount of polyvinyl alcohol (PVA) and emulsify The agent was dissolved in deionized water to prepare a PVA aqueous solution with a concentration of 1%. The reactor was placed in an ice-salt bath for cooling, and a homogenizer was used to stir at high speed for a period of time to stabilize the water phase. Add the PLLA-PDLAG-IBF blend solution dropwise to the polyvinyl alcohol aqueous solution (control the water-oil volume ratio ≤ 100:1), stir at a high speed for a period of time, and obtain a white emulsion. Freeze-drying under vacuum for 24 h to prepare dry powder, which is PLLA-PDLAG drug-loaded microspheres.

Further, in the poly-D-lactic acid-glucose copolymer, the mass content of glucose groups in the molecular chain is 0-5%.

Further, in the poly-L-lactic acid, poly-D-lactic acid-glucose copolymer and ibuprofen blend solution, the mass of ibuprofen is 10-100% of the total mass of PLLA and PDLAG.

Further, in the polyvinyl alcohol aqueous solution, the content of the emulsifier is 0-1%.

The present invention further claims the poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microspheres prepared by the above method.

Description of drawings:

Fig. 1 is a particle size distribution diagram of the poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microspheres of the present invention.

2 is a transmission electron microscope image of the poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microspheres of the present invention.

Detailed ways:

The present invention will be described in detail below with reference to the accompanying drawings, specific embodiments and comparative examples. The specific material ratios, process conditions and results described in the examples are only used to illustrate the present invention, and are not intended to limit the present invention.

Example 1:

Weigh 1 g of PLLA and 1 g of PDLAG (with a glucose content of 5%), dissolve them in 20 mL of chloroform at room temperature, stir evenly, and prepare a PLLA-PDLAG blended solution with a total polymer mass fraction of 10%. 2g of ibuprofen was added to the blended solution to obtain a PLLA-PDLAG-IBF blended solution; 1g of polyvinyl alcohol (PVA) and 1g of emulsifier were weighed and dissolved in deionized water to prepare a concentration of 1% PVA Aqueous solution, put the reactor under ice-salt bath cooling, use a homogenizer to stir at a stirring speed of 25000rpm for 30s to stabilize the water phase; add PLLA-PDLAG-IBF blend solution dropwise to the PVA aqueous solution to control the volume of water and oil The ratio was 100:1, and the mixture was stirred at 25,000 rpm for 300 s to obtain a white emulsion. The particle size distribution of the obtained emulsion was determined after standing under vacuum for 10 hours at room temperature, and then vacuum freeze-dried at -70°C for 24 hours to obtain dry powder. The water contact angle, drug loading rate, encapsulation rate and average particle size of the obtained product are shown in Table 1.

Example 2:

Weigh 1 g of PLLA and 1 g of PDLAG (with a glucose content of 0.5%), dissolve them in 20 mL of chloroform at room temperature, stir evenly, and prepare a PLLA-PDLAG blended solution with a total polymer mass fraction of 10%. Then add 2g of ibuprofen to obtain a PLLA-PDLAG-IBF blend solution; weigh 1g of polyvinyl alcohol and 1g of emulsifier and dissolve in deionized water to prepare a 1% PVA aqueous solution, and place the reactor in an ice-salt bath for cooling Then, use a homogenizer to stir at a stirring speed of 25000rpm for 30s to stabilize the water phase; add PLLA-PDLAG-IBF solution dropwise to the PVA aqueous solution, control the water-oil ratio to be 30:1, and continue stirring at 25000rpm for 300s to prepare A white emulsion is obtained. The particle size distribution of the obtained emulsion was measured after standing in vacuum for 10 hours at room temperature, and finally vacuum freeze-dried at -70°C for 24 hours to obtain dry powder. The water contact angle, drug loading rate, encapsulation rate and average particle size of the obtained product are shown in Table 1.

Example 3:

Weigh 1g PLLA and 1g PDLAG (with a glucose content of 2%), dissolve them in 20mL chloroform at room temperature, stir evenly, and prepare a PLLA-PDLAG blend solution with a total polymer mass fraction of 10%, and then add 2g ibuprofen to obtain a PLLA-PDLAG-IBF blend solution; weigh 1 g polyvinyl alcohol (PVA) and 0.5 g emulsifier, dissolve in deionized water to prepare a 1% PVA aqueous solution, and place the reactor in ice salt Under bath cooling, use a homogenizer to stir at a stirring speed of 25000 rpm for 30 s to stabilize it; add the PLLA-PDLAG-IBF blend solution dropwise to the PVA aqueous solution, control the water-oil ratio to be 60:1, and continue stirring for 300 s at 25,000 rpm. , a white emulsion was obtained, the particle size distribution was measured after standing in vacuum at room temperature for 10 hours, and finally, the dried powder was prepared by vacuum freeze-drying at -70 °C for 24 hours. The water contact angle, drug loading rate, encapsulation rate and average particle size of the obtained product are shown in Table 1.

Example 4:

Weigh 1g PLLA and 1g PDLAG (with a glucose content of 4%), dissolve them in 20mL chloroform at room temperature, stir evenly, and prepare a PLLA-PDLAG blend solution with a total polymer mass fraction of 10%, and then add 1g ibuprofen to obtain a PLLA-PDLAG-IBF blend solution; without using an emulsifier, weigh 1 g of polyvinyl alcohol and dissolve it in deionized water to prepare a 1% PVA aqueous solution, and place the reactor in an ice-salt bath for cooling. Use a homogenizer to stir at a stirring speed of 25,000 rpm for 30 s to stabilize the water phase; add the PLLA-PDLAG-IBF blend solution dropwise to the PVA aqueous solution, control the water-oil ratio to be 100:1, and continue stirring at 25,000 rpm for 300 s to obtain The white emulsion was vacuumed at room temperature for 10 hours, and the particle size distribution was measured. Finally, it was vacuum freeze-dried at -70 °C for 24 hours to prepare a dry powder. The water contact angle, drug loading rate, encapsulation rate and average particle size of the obtained product are shown in Table 1.

Comparative Example 1:

Weigh 1 g of PLLA, dissolve it in 10 mL of chloroform at room temperature, stir evenly, and prepare a PLLA solution with a total polymer mass fraction of 10%, and then add 1 g of ibuprofen to obtain a PLLA-IBF blend solution; 1 g of polyvinyl alcohol and 1 g of emulsifier were dissolved in deionized water to prepare a 1% PVA aqueous solution, the reactor was placed in an ice-salt bath for cooling, and a homogenizer was used to stir at a stirring speed of 25,000 rpm for 30 s to stabilize the water phase; Add the PLLA-IBF blend solution dropwise to the PVA aqueous solution, control the water-oil volume ratio to be 100:1, and continue stirring at 25,000 rpm for 300 s to obtain a white emulsion. Vacuum freeze-drying at 70 °C for 24 h to prepare dry powder. The water contact angle, drug loading rate, encapsulation rate and average particle size of the obtained product are shown in Table 1.

Comparative Example 2:

Weigh 1 g of poly-D-lactic acid-glucose copolymer (its glucose content is 5%), dissolve it in 10 mL of chloroform at room temperature, stir evenly, and prepare a PDLAG solution with a total polymer mass fraction of 10%, then add 1 g of ibuprofen to obtain a PDLAG-IBF blended solution; 1 g of polyvinyl alcohol (PVA) and 1 g of emulsifier were weighed and dissolved in deionized water to prepare a 1% PVA aqueous solution, and the reactor was placed in an ice-salt bath for cooling Then, use a homogenizer to stir at a stirring speed of 25000rpm for 30s to stabilize the water phase; add PDLAG-IBF blend solution dropwise to the PVA aqueous solution, control the water-oil volume ratio to be 100:1, and continue stirring at 25000rpm for 300s, A white emulsion was obtained, and after standing in vacuum at room temperature for 10 hours, the particle size distribution was measured, and finally, the dried powder was prepared by vacuum freeze drying at -70° C. for 24 hours. The water contact angle, drug loading rate, encapsulation rate and average particle size of the obtained product are shown in Table 1.

beneficial effect

It can be seen from Comparative Examples 1 and 2 that when equal amounts of poly-L-lactic acid and poly-D-lactic acid-glucose copolymer are mixed, the obtained stereocomplex nano-microspheres have high hydrophilicity, drug loading rate and encapsulation rate. According to the corresponding optical activity of poly-L-lactic acid and poly-D-lactic acid-glucose copolymer, it is shown that the polylactic acid stereocomplex formed by poly-L-lactic acid and amphiphilic poly-D-lactic acid-glucose copolymer has a nano-micron size. Balls are more suitable as drug carriers for ibuprofen.

The above only describes several specific embodiments of the present invention, but cannot be regarded as the protection scope of the present invention. Any equivalent changes or modifications made according to the design spirit of the present invention, or proportional enlargement or reduction, etc. It should be considered to fall within the protection scope of the present invention.

Table 1. Performance parameters of PLLA, PDLAG and PLLA/PDLAG drug-loaded microspheres

Claims (4)

1. a preparation method of poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microspheres, is characterized in that described method comprises the following steps: (1) Preparation of the blended solution of poly-L-lactic acid, poly-D-lactic acid-glucose copolymer and ibuprofen: weigh equal amounts of poly-L-lactic acid (PLLA) and poly-D-lactic acid-glucose copolymer (PDLAG) , dissolved in chloroform at room temperature to obtain a PLLA-PDLAG blended solution with a total polymer mass fraction of 10%, and a certain amount of ibuprofen (IBF) was dissolved in the blended solution to obtain a PLLA-PDLAG-IBF blend solution. mixed solution; (2) Preparation of poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microspheres: Weigh a certain amount of polyvinyl alcohol (PVA) and emulsifier and dissolve them in deionized water to prepare a 1% concentration of PVA aqueous solution, place the reactor under ice-salt bath cooling, use a homogenizer to stir the PVA aqueous solution at a high speed for a period of time to stabilize the water phase, add the PLLA-PDLAG-IBF blend solution dropwise to the PVA aqueous solution, and the PVA aqueous solution and The volume ratio of PDLA-PLLAG-IBF trichloromethane solution is ≤100:1, and a white oil-in-water emulsion is obtained by stirring at high speed for a period of time. Pharmaceutical microsphere powder products. 2. poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microspheres according to claim 1, is characterized in that: described poly-D-lactic acid-glucose copolymer, in its molecular chain, the glucose group The mass content is 0.05% to 5%. 3. the preparation method of poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microspheres according to claim 1, is characterized in that: the quality of ibuprofen in the described PLLA-PDLAG-IBF blended solution 10-100% of the total mass of PLLA and PDLAG. 4. A poly-L-lactic acid/poly-D-lactic acid-glucose copolymer drug-loaded microsphere is characterized in that the ibuprofen drug-loaded microsphere prepared according to the method of claim 1.

Images