Sustained-release drug-loaded microspheres and preparation process thereof

Abstract

The invention relates to the technical field of medical cosmetology, and discloses a sustained-release drug-loaded microsphere and a preparation process thereof.Epoxy groups of epoxy polyester react with terminal carboxyl groups of polylactic acid to obtain comb-type polylactic acid with polyester as a main chain and polylactic acid molecular chains as side chains, the comb-type polylactic acid has a three-dimensional comb-type network structure, and the sustained-release drug-loaded microsphere is prepared through a single emulsion solvent evaporation method. The prepared microspheres have a large space network, coating and loading required by a target are effectively achieved, a main chain contains a large number of hydroxyl groups, the hydroxyl groups and substances such as sapogenin, polysaccharide and polyphenol in saponin and essential oil can form acting force such as hydrogen bonds, and the adsorption performance and the drug loading capacity of the microspheres on a target drug are further improved. The side chain of the microsphere is degradable polylactic acid, and the main chain contains a large number of degradable ester groups and a large number of hydroxyl groups, so that the water absorption of the microsphere can be improved, the hydrolysis of the microsphere is accelerated, and the microsphere has higher biological decomposition rate and degradation performance and is green and environment-friendly.

Description

Technical Field

[0001] This invention relates to the field of medical aesthetics technology, specifically to a sustained-release drug-loaded microsphere and its preparation process. Background Technology

[0002] Drug-loaded microspheres are a novel type of drug carrier that can encapsulate or adsorb drugs inside or on the surface of the microsphere, exhibiting excellent sustained-release properties. They hold broad application prospects in medical pharmaceuticals, cosmetic repair, and other fields. Microsphere carriers mainly include starch, chitosan, polylactic acid, and polycaprolactone. These microsphere carriers possess excellent biocompatibility and biodegradability, and are non-toxic and environmentally friendly. However, they suffer from relatively low drug loading rates, which affects the efficacy of the drugs.

[0003] Currently, the main methods for preparing drug-loaded microspheres such as polylactic acid (PLA) include emulsification-curing, coagulation, and polymerization. Patent CN111514118B discloses a method and product for preparing glucose-modified PLA stereocomplex drug-loaded microspheres. The glucose-modified PLA stereocomplex drug-loaded microspheres prepared by the emulsion-solvent evaporation method exhibit good drug loading and encapsulation efficiency. Compared to this patented technology, this invention not only improves the drug loading rate of PLA microspheres but also possesses excellent biodegradability. Summary of the Invention

[0004] This invention solves the problem of disclosing the drug loading rate of polylactic acid microspheres.

[0005] The technical solution of this invention: a preparation process for sustained-release drug-loaded microspheres.

[0006] (1) In an ice-water bath, dichloromethane, 1,4-butenediol, triethylamine and diacyl chloride were added to a flask. After the reaction, the solution was filtered and then evaporated by rotary evaporation. The product was washed with an aqueous ethanol solution and dried to obtain polyester.

[0007] (2) Add dichloromethane and polyester to the flask, stir, and then add m-chloroperoxybenzoic acid to oxidize the alkenyl group into an epoxy group. After the reaction, extract and wash with saturated sodium carbonate solution, rotate and evaporate the organic layer, and dry to obtain epoxy polyester.

[0008] (3) Add the reaction solvent, polylactic acid, and epoxy polyester to the flask, stir, add the catalyst, and proceed with the reaction. After cooling, filter, wash the product with water and ethanol, and dry to obtain comb-shaped polylactic acid. The reaction formula is:

[0009] .

[0010] (4) Add dichloromethane and comb-type polylactic acid to the flask, stir, add the target drug, disperse by sonication, add polyvinyl alcohol aqueous solution dropwise while stirring, heat and stir to remove dichloromethane, recover dichloromethane through condenser, filter the reaction solution, wash with water and dry to obtain sustained-release drug-loaded microspheres.

[0011] Furthermore, in (1), the ratio of 1,4-butenediol, triethylamine, and diacyl chloride is (1-1.04 mol): (2-2.2) mol: 1 mol.

[0012] Furthermore, in (1), the diacyl chloride substance is malonyl chloride, succinic chloride, glutaryl chloride or adipyl chloride.

[0013] Furthermore, the reaction in (1) is stirred at 20-30℃ for 12-18h.

[0014] Furthermore, in (2), the ratio of polyester to metachloroperoxybenzoic acid is 100g: (114-130)g.

[0015] Furthermore, the reaction in (2) is carried out at 25-30℃ for 3-4 hours.

[0016] Furthermore, in (3), the reaction solvent is toluene or xylene.

[0017] Furthermore, in (3), the reaction temperature is 70-90℃ and the reaction time is 3-5h.

[0018] Furthermore, in (3), the ratio of epoxy polyester, polylactic acid and catalyst is 100g: (20-35)g: (0.3-0.5)g.

[0019] Furthermore, (3) the catalyst is triethylamine, tetrabutylammonium bromide, or benzyltriethylammonium chloride.

[0020] Furthermore, the mass fraction of the polyvinyl alcohol aqueous solution in (4) is 0.5-0.8%.

[0021] Furthermore, (4) the target drugs include saponins and essential oils.

[0022] (III) Beneficial Technical Effects: This invention uses triethylamine and other catalysts to react the epoxy groups of epoxy polyester with the terminal carboxyl groups of polylactic acid to obtain comb-shaped polylactic acid with polyester as the main chain and polylactic acid molecular chains as the side chains. It has a three-dimensional comb-shaped network structure. The microspheres prepared by the single emulsion solvent evaporation method have a large spatial network, which can effectively achieve the coating and loading of the target, which is beneficial to improving the drug loading capacity of the microspheres. In addition, the main chain contains a large number of hydroxyl groups, which can form hydrogen bonds and other forces with saponins, saponins in essential oils, polysaccharides, polyphenols and other substances, further improving the adsorption performance and drug loading capacity of the microspheres for the target drug.

[0023] The side chains of the microspheres of the present invention are biodegradable polylactic acid, and the main chain contains a large number of biodegradable ester groups and a large number of hydroxyl groups, which can improve the water absorption of the microspheres, accelerate the hydrolysis of the microspheres, and make the microspheres have higher biodegradability and degradation performance, making them green and environmentally friendly. Detailed Implementation

[0024] The present invention will be further illustrated below with reference to specific embodiments. It should be noted that the embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention. Various modifications or alterations made to the present invention by those skilled in the art after reading this description are also within the scope of the appended claims.

[0025] The following polylactic acid has an effective component content of 99% and an average molecular weight of 2300. It is produced by Hubei Shuaiyan Ligao Biomedical.

[0026] Example 1

[0027] (1) In an ice-water bath, add 150 mL of dichloromethane, 31.2 mmol of 1,4-butenediol, 60 mmol of triethylamine and 30 mmol of succinyl chloride to a flask, stir and react at 20 °C for 18 h, filter, evaporate the solution by rotary evaporation, wash the product with ethanol aqueous solution, dry, and obtain polyester.

[0028] (2) Add 100 mL of dichloromethane and 5 g of polyester to the flask, stir, add 6.2 g of m-chloroperoxybenzoic acid, stir and react at 25 °C for 4 h, extract and wash with saturated sodium carbonate solution, evaporate the organic layer by rotary evaporation, and dry to obtain epoxy polyester.

[0029] (3) Add 500 mL of toluene, 20 g of polylactic acid, and 6 g of epoxy polyester to a flask, stir, add 8 mg of triethylamine, heat to 75 °C, stir for 5 h, cool and filter, wash the product with water and ethanol, and dry to obtain comb-type polylactic acid.

[0030] (4) Add 300 mL of dichloromethane and 20 g (mass m) of comb-type polylactic acid to the flask, stir, add 0.4 g of total saponins from Panax notoginseng root, sonicate for 20 min, add 160 mL of 0.5% polyvinyl alcohol aqueous solution while stirring, stir for 4 h, heat to 40 °C, stir to remove dichloromethane, recover dichloromethane through a condenser, filter the reaction solution, wash with water and dry to obtain sustained-release drug-loaded microspheres, weigh (mass M), calculate the drug loading rate W, W = (Mm) / m = 100%.

[0031] Comparative Example 1

[0032] (1) Add 300 mL of dichloromethane and 20 g (m) of polylactic acid to a flask, stir, add 0.4 g of total saponins from Panax notoginseng root, sonicate for 20 min, add 160 mL of 0.5% polyvinyl alcohol aqueous solution while stirring, stir for 4 h, heat to 40 °C, stir to remove dichloromethane, recover dichloromethane through a condenser, filter the reaction solution, wash with water and dry to obtain sustained-release drug-loaded microspheres, weigh (m).

[0033] Comparative Example 2

[0034] (1) Add 500 mL of toluene, 20 g of polylactic acid, and 6 g of polyester (the same preparation process as in Example 1) to a flask, stir, add 8 mg of triethylamine, heat to 75 °C, stir for 5 h, cool and filter, wash the product with water and ethanol, and dry to obtain a polyester-polylactic acid blend.

[0035] (2) Add 300 mL of dichloromethane and 20 g (m) of polyester-polylactic acid blend to the flask, stir, add 0.4 g of total saponins from Panax notoginseng root, sonicate for 20 min, add 160 mL of 0.5% polyvinyl alcohol aqueous solution while stirring, stir for 4 h, heat to 40 °C, stir to remove dichloromethane, recover dichloromethane through a condenser, filter the reaction solution, wash with water and dry to obtain sustained-release drug-loaded microspheres, weigh (m).

[0036] Comparative Example 3

[0037] (1) Add 500 mL of toluene, 20 g of polylactic acid, and 6 g of epoxidized soybean oil to a flask, stir, add 8 mg of triethylamine, heat to 75 °C, stir and react for 5 h, cool and filter, wash the product with water and ethanol, and dry to obtain soybean oil grafted polylactic acid.

[0038] (2) Add 300 mL of dichloromethane and 20 g (m) of soybean oil grafted with polylactic acid to the flask, stir, add 0.4 g of total saponins from Panax notoginseng root, sonicate for 20 min, add 160 mL of 0.5% polyvinyl alcohol aqueous solution dropwise while stirring, stir for 4 h, heat to 40 °C, stir to remove dichloromethane, recover dichloromethane through a condenser, filter the reaction solution, wash with water and dry to obtain sustained-release drug-loaded microspheres, weigh (m).

[0039] Example 2

[0040] (1) In an ice-water bath, add 200 mL of dichloromethane, 30.4 mmol of 1,4-butenediol, 60 mmol of triethylamine and 30 mmol of malonyl chloride to a flask, stir and react at 30 °C for 12 h, filter, evaporate the solution by rotary evaporation, wash the product with ethanol aqueous solution, dry, and obtain polyester.

[0041] (2) Add 120 mL of dichloromethane and 5 g of polyester to the flask, stir, add 5.7 g of m-chloroperoxybenzoic acid, stir and react at 25 °C for 4 h, extract and wash with saturated sodium carbonate solution, evaporate the organic layer by rotary evaporation, and dry to obtain epoxy polyester.

[0042] (3) Add 500 mL xylene, 20 g polylactic acid, and 4 g epoxy polyester to the flask, stir, add 8 mg benzyltriethylammonium chloride, heat to 70 °C, stir for 5 h, cool and filter, wash the product with water and ethanol, dry, and obtain comb-type polylactic acid.

[0043] (4) Add 250 mL of dichloromethane and 20 g (m) of comb-type polylactic acid to the flask, stir, add 1.5 g of clove oil, sonicate for 20 min, add 180 mL of 0.6% polyvinyl alcohol aqueous solution while stirring, stir for 4 h, heat to 40 °C, stir to remove dichloromethane, recover dichloromethane through a condenser, filter the reaction solution, wash with water and dry to obtain sustained-release drug-loaded microspheres, weigh (m).

[0044] Example 3

[0045] (1) In an ice-water bath, add 200 mL of dichloromethane, 30.6 mmol of 1,4-butenediol, 66 mmol of triethylamine and 30 mmol of glutaryl chloride to a flask, stir and react at 25 °C for 18 h, filter, evaporate the solution by rotary evaporation, wash the product with ethanol aqueous solution, dry, and obtain polyester.

[0046] (2) Add 100 mL of dichloromethane and 5 g of polyester to the flask, stir, add 5.9 g of m-chloroperoxybenzoic acid, stir and react at 30 °C for 3 h, extract and wash with saturated sodium carbonate solution, evaporate the organic layer by rotary evaporation, and dry to obtain epoxy polyester.

[0047] (3) Add 500 mL of toluene, 20 g of polylactic acid, and 5 g of epoxy polyester to a flask, stir, add 8 mg of triethylamine, heat to 70 °C, stir for 5 h, cool and filter, wash the product with water and ethanol, and dry to obtain comb-type polylactic acid.

[0048] (4) Add 300 mL of dichloromethane and 20 g (m) of comb-type polylactic acid to the flask, stir, add 0.4 g of clove oil, sonicate for 20 min, add 160 mL of 0.5% polyvinyl alcohol aqueous solution while stirring, stir for 3 h, heat to 40 °C, stir to remove dichloromethane, recover dichloromethane through a condenser, filter the reaction solution, wash with water and dry to obtain sustained-release drug-loaded microspheres, weigh (m).

[0049] Example 4

[0050] (1) In an ice-water bath, add 200 mL of dichloromethane, 31.2 mmol of 1,4-butenediol, 60 mmol of triethylamine and 30 mmol of succinyl chloride to a flask, stir and react at 25 °C for 18 h, filter, evaporate the solution by rotary evaporation, wash the product with ethanol aqueous solution, dry, and obtain polyester.

[0051] (2) Add 120 mL of dichloromethane and 5 g of polyester to the flask, stir, add 6.5 g of m-chloroperoxybenzoic acid, stir and react at 30 °C for 3 h, extract and wash with saturated sodium carbonate solution, rotate evaporate the organic layer and dry to obtain epoxy polyester.

[0052] (3) Add 500 mL xylene, 20 g polylactic acid, and 7 g epoxy polyester to the flask, stir, add 6 mg tetrabutylammonium bromide, heat to 90 °C, stir for 3 h, cool and filter, wash the product with water and ethanol, dry, and obtain comb-type polylactic acid.

[0053] (4) Add 300 mL of dichloromethane and 20 g (m) of comb-type polylactic acid to the flask, stir, add 1.5 g of clove oil, sonicate for 30 min, add 220 mL of 0.8% polyvinyl alcohol aqueous solution while stirring, stir for 3 h, heat to 40 °C, stir to remove dichloromethane, recover dichloromethane through a condenser, filter the reaction solution, wash with water and dry to obtain sustained-release drug-loaded microspheres, weigh (m).

[0054] The degradation performance of the microspheres was tested using Example 1 as an example: 300 mL of dichloromethane and 20 g of comb-type polylactic acid were added to a flask and ultrasonically dispersed for 20 min. While stirring, 160 mL of a 0.5% (w / w) aqueous solution of polyvinyl alcohol was added dropwise. The mixture was stirred for 4 h, heated to 40 °C, and stirred to remove the dichloromethane. The dichloromethane was recovered through a condenser. The reaction solution was filtered, washed with water, and dried to obtain the microspheres. The degradation performance of the microspheres was tested according to GB / T 19277.1-2025 for 30 days.

[0055] Table 1 Performance Tests

[0056] Drug loading rate (%) Biodegradation rate (%) Example 1 1.92 45.9 Comparative Example 1 1.35 43.2 Comparative Example 2 1.27 40.9 Comparative Example 3 1.77 43.8 Example 2 7.24 47.6 Example 3 1.86 47.0 Example 4 7.08 44.3

[0057] Compared to Comparative Example 1, the comb-shaped polylactic acid in each embodiment uses polyester as the main chain and polylactic acid molecular chains as side chains to form a three-dimensional comb-shaped network structure. The microspheres prepared via a single-emulsion solvent evaporation method possess a large spatial network, effectively achieving the required coating and loading of the target, which is beneficial for increasing drug loading. Simultaneously, the main chain contains a large number of hydroxyl groups, which can form hydrogen bonds and other forces with saponins, aglycones in essential oils, polysaccharides, polyphenols, etc., improving the adsorption performance of the microspheres for the target drug and further increasing the drug loading. Furthermore, the main chain of the microspheres contains a large number of degradable ester groups, and the large number of hydroxyl groups can improve the water absorption of the microspheres, accelerate the hydrolysis of the microspheres, and give the microspheres a higher biodegradability and degradation performance.

[0058] The polyester in Comparative Example 2 does not contain epoxy groups and cannot react with the terminal carboxyl groups of polylactic acid. No polylactic acid molecular chains are introduced into the side chains of the polyester. The blend does not form a three-dimensional comb-like network structure and does not contain hydroxyl groups. The drug loading of the microspheres is very low.

[0059] Comparative Example 3 involved reacting the terminal carboxyl groups of polylactic acid with the epoxy groups of epoxidized soybean oil. The superior epoxidized soybean oil had a low content of epoxy groups, and the prepared soybean oil grafted with polylactic acid did not form a good three-dimensional comb network structure. The drug loading of the microspheres was lower than that of Example 1. Furthermore, the soybean oil contained multiple hydrophobic alkyl chains, which affected the hydrophilicity and hydrolysis performance of the microspheres, resulting in a lower biodegradation rate than that of Example 1.

[0060] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make several improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention.

Claims

1. A process for preparing sustained-release drug-loaded microspheres, characterized in that, The preparation process includes: S1. Add reaction solvent, polylactic acid, and epoxy polyester to a flask, stir, add catalyst, react, cool, filter, wash product, and dry to obtain comb-type polylactic acid. S2. Add dichloromethane and comb-type polylactic acid to the flask, stir, add the target drug, disperse by ultrasound, add polyvinyl alcohol aqueous solution dropwise while stirring, heat and stir to remove dichloromethane, recover dichloromethane through a condenser, filter, wash and dry to obtain sustained-release drug-loaded microspheres.

2. The preparation process of sustained-release drug-loaded microspheres according to claim 1, characterized in that, The reaction solvent in S1 is toluene or xylene.

3. The preparation process of sustained-release drug-loaded microspheres according to claim S1, characterized in that, The reaction temperature in S1 is 70-90℃, and the reaction time is 3-5h.

4. The preparation process of sustained-release drug-loaded microspheres according to claim 1, characterized in that, The ratio of epoxy polyester, polylactic acid, and catalyst in S1 is 100g:(20-35)g:(0.3-0.5)g.

5. The preparation process of sustained-release drug-loaded microspheres according to claim 4, characterized in that, The catalyst is triethylamine, tetrabutylammonium bromide, or benzyltriethylammonium chloride.

6. The preparation process of sustained-release drug-loaded microspheres according to claim 1, characterized in that, The mass fraction of the polyvinyl alcohol aqueous solution in S2 is 0.5-0.8%.

7. The preparation process of sustained-release drug-loaded microspheres according to claim 1, characterized in that, The target drugs in S2 include saponins and essential oils.

8. The preparation process of sustained-release drug-loaded microspheres according to claim 4, characterized in that, The preparation process of the epoxy polyester is as follows: (1) In an ice-water bath, add dichloromethane, 1,4-butenediol, triethylamine, and diacyl chloride in a ratio of (1-1.04 mol): (2-2.2) mol: 1 mol to a flask, then stir the reaction at 20-30℃ for 12-18 h, filter, evaporate the solution by rotary evaporation, wash the product, and dry to obtain polyester; (2) Add dichloromethane, polyester in a ratio of 100g:(114-130)g and m-chloroperoxybenzoic acid to a flask, stir and react at 25-30℃ for 3-4h, extract and wash, evaporate the organic layer by rotary evaporation and dry to obtain epoxy polyester.

9. The preparation process of sustained-release drug-loaded microspheres according to claim 8, characterized in that, The diacyl chloride substance is malonyl chloride, succinic chloride, glutaryl chloride, or adipyl chloride.

10. A sustained-release drug-loaded microsphere obtained by the preparation process according to any one of claims 1-9.