CN110066500B - Degradable injection polylactic acid filler and preparation method thereof - Google Patents
Degradable injection polylactic acid filler and preparation method thereof Download PDFInfo
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- CN110066500B CN110066500B CN201910291250.8A CN201910291250A CN110066500B CN 110066500 B CN110066500 B CN 110066500B CN 201910291250 A CN201910291250 A CN 201910291250A CN 110066500 B CN110066500 B CN 110066500B
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
- C08L1/08—Cellulose derivatives
- C08L1/26—Cellulose ethers
- C08L1/28—Alkyl ethers
- C08L1/286—Alkyl ethers substituted with acid radicals, e.g. carboxymethyl cellulose [CMC]
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L67/00—Compositions of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Compositions of derivatives of such polymers
- C08L67/04—Polyesters derived from hydroxycarboxylic acids, e.g. lactones
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2201/00—Properties
- C08L2201/06—Biodegradable
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- C08L2205/00—Polymer mixtures characterised by other features
- C08L2205/02—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group
- C08L2205/025—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group containing two or more polymers of the same hierarchy C08L, and differing only in parameters such as density, comonomer content, molecular weight, structure
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- C—CHEMISTRY; METALLURGY
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- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2205/00—Polymer mixtures characterised by other features
- C08L2205/03—Polymer mixtures characterised by other features containing three or more polymers in a blend
- C08L2205/035—Polymer mixtures characterised by other features containing three or more polymers in a blend containing four or more polymers in a blend
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to a degradable injection polylactic acid filler and a preparation method thereof, wherein the degradable injection polylactic acid filler comprises 30-65% of levorotatory polylactic acid microspheres, 5-40% of sodium carboxymethylcellulose and 5-30% of mannitol. The invention creatively combines polylactic acid microspheres with different molecular weights together, and the polylactic acid microspheres are reasonably matched with mannitol and sodium carboxymethylcellulose, so that the prepared filler has the effect of remarkably promoting the growth of collagen fibers, the maintenance effect time can reach 30 months, the wrinkle eliminating effect is obvious, no adverse reaction event occurs, and the invention makes remarkable progress compared with the prior art.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a degradable injection polylactic acid filler and a preparation method thereof.
Background
With the rapid development of socioeconomic levels and medical techniques, orthopaedic treatment is increasingly being minimally invasive and occult. Under the large environment, injection of micro-plastic oil is natural and becomes a light focusing point for current plastic cosmetology. Injection micro-plastic, namely, natural or artificial synthetic filler is injected into the dermis or the hypodermis of a human body to achieve the purposes of five sense organs sculpturing and facial rejuvenation.
Polylactic acid is a new generation of completely degradable high molecular material which is rapidly developed in recent years, and is thermoplastic aliphatic resin which is polymerized by taking lactic acid which is a microbial fermentation product as a monomer through a chemical synthesis method. Polylactic acid has its uniqueness as a material for cosmetic injection, unlike conventional fillers, it can stimulate the production of subcutaneous collagen, during which the polylactic acid polymerization state and molecular structure are decomposed and destroyed, slowly degraded into lactic acid by non-enzymatic hydrolysis, and finally degraded into CO2And H2And O. During degradation, these lactic acids can stimulate collagen formation, leading to increased production of cellulose in the dermisThe desired cosmetic effect, which is a thickening of the dermal layer over time, completely replaces the filling site with new autologous tissue, resulting in a "permanent cosmetic" effect.
However, the current polylactic acid injection has the following problems: the degradation time is short, generally 10-13 months, and the polylactic acid degrades and stimulates collagen secretion to obtain an autologous filling effect, so that the integral beautifying time is not more than 20 months; ② the polylactic acid filling agent is difficult to ensure the injection uniformity. Therefore, there is still room for improvement in the current polylactic acid injection filler.
Disclosure of Invention
The invention aims to provide a degradable injection polylactic acid filler and a preparation method thereof, the whole beautifying time can reach 30 months after the filler is injected, and the degradable injection polylactic acid filler has an obvious effect of removing wrinkles.
In order to achieve the purpose, the invention adopts the following technical scheme: a degradable injection polylactic acid filler comprises 30-65% of levorotatory polylactic acid microspheres, 5-40% of sodium carboxymethylcellulose and 5-30% of mannitol.
Preferably, the levorotatory polylactic acid microspheres can be of a single molecular weight or a mixture of different molecular weights.
Preferably, when the levorotatory polylactic acid microspheres have a single molecular weight, the molecular weight of the levorotatory polylactic acid microspheres is 1-7 ten thousand.
Preferably, when the levorotatory polylactic acid microspheres are a mixture with different molecular weights, the levorotatory polylactic acid microspheres with the molecular weights of 7 ten thousand, 5 ten thousand, 3 ten thousand and 0.8 ten thousand are prepared according to the weight ratio of 1: (0.5-1): (0.5-1): (0.1-0.5) in mass ratio.
Preferably, the levorotatory polylactic acid microspheres with the molecular weights of 7 ten thousand, 5 ten thousand, 3 ten thousand and 0.8 ten thousand in the mixture are prepared according to the weight ratio of 1: 0.5: 0.5: 0.3 in mass ratio.
Preferably, the average particle size of the levorotatory polylactic acid microspheres is 1-100 μm.
The invention also provides a preparation method of the degradable injection polylactic acid filler, which comprises the following steps:
A) preparing the levorotatory polylactic acid microspheres: comprises the steps of S1 to S4:
s1, weighing the levorotatory polylactic acid and dichloromethane, and stirring to obtain a 5-8% PLLA/DCM solution;
s2, weighing polyvinyl alcohol, adding pure water, stirring to fully dissolve the polyvinyl alcohol, standing and cooling to obtain 0.1-1% PVA/pure water solution;
s3, introducing helium into the prepared PVA/pure water solution, maintaining the helium atmosphere, sealing, stirring, and setting the rotation speed at 300-600 r/min; dripping PLLA/DCM solution into the PVA/pure water solution, setting the dripping speed to be 90ml/h, fully reacting for 1-3 h, and keeping the water bath temperature not to exceed 20 ℃ in the dripping process and the reaction process; wherein the volume ratio of the PVA/pure water solution to the PLLA/DCM solution is 1: (1-2);
s4, stirring overnight after the reaction is finished; standing, removing an upper water phase, repeatedly washing with pure water for 1-3 times, taking a lower product, naturally drying, grinding, sequentially sieving with 200-400-mesh sieves, and collecting a sample to obtain the product;
B) mixing sodium carboxymethylcellulose, mannitol and the polylactic acid microspheres prepared above in proportion, and stirring well to obtain the final product.
The invention also aims to provide a wrinkle removing preparation which comprises the degradable injection polylactic acid filling.
The invention has the following advantages:
the inventor finds that the filling material prepared by adopting the polylactic acid microsphere combination with specific molecular weight and reasonably matching with mannitol and sodium carboxymethylcellulose has the function of remarkably promoting the growth of collagen fibers, and surprisingly finds that the collagen fibers can grow more uniformly by adding the polylactic acid microspheres with small molecular weight of 0.8 ten thousand, and the filling material is clinically used for removing wrinkles, found in a wrinkle removing test, has the maintenance effect of 30 months and obvious wrinkle removing effect, and makes remarkable progress compared with the prior art.
Drawings
FIG. 1 shows the results of tissue sections of example 7 and comparative example 1.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples.
Example 1 preparation of polylactic acid microspheres PLLA1 with a molecular weight of 7 tens of thousands
S1, stirring levorotatory polylactic acid with the molecular weight of 7 ten thousand and dichloromethane to obtain a PLLA/DCM solution with the concentration of 8%;
s2, weighing polyvinyl alcohol, adding pure water, stirring to fully dissolve the polyvinyl alcohol, standing and cooling to obtain a 1% PVA/pure water solution;
s3, introducing helium into the PVA/pure water solution obtained by the preparation, maintaining the helium atmosphere, sealing, stirring, and setting the rotating speed at 600 r/min; adding PLLA/DCM solution into the PVA/pure water solution dropwise at a speed of 90ml/h, reacting for 3h, and keeping the temperature of the water bath in the dropwise adding process and the reaction process not to exceed 20 ℃; wherein the volume ratio of the PVA/pure water solution to the PLLA/DCM solution is 1: 2;
s4, stirring overnight after the reaction is finished; standing, removing the upper water phase, washing with pure water for 3 times, taking the lower product, air drying, grinding, sieving with 200 mesh and 400 mesh sieves in sequence, and collecting the product.
Preparation of L-polylactic acid microspheres having molecular weights of 5 ten thousand, 3 ten thousand, 1 thousand and 0.8 thousand referring to example 1, the microspheres were named PLLA2, PLLA3, PLLA4 and PLLA5, respectively, and the average particle diameters of the prepared L-polylactic acid microspheres were all 45 μm.
Example 2 degradable injectable polylactic acid Filler
The preparation method comprises the following steps:
mixing sodium carboxymethylcellulose, mannitol and L-polylactic acid microspheres in proportion, and stirring uniformly to obtain the product.
Test I, animal test
The absorbable injection microspheres in the embodiment 7 and the comparative example 1 are used as filling materials, the immune safety of the materials is preliminarily verified, then a soft tissue increment model is built on the face of a rabbit, and objective image analysis and test data are used as the basis for observing the tissue increment effect and returning mechanism through a parallel control experiment.
1.1 protocol
Taking 9 big-ear rabbits, selecting 2 injection areas on the left face and the right face of each rabbit, injecting a corresponding test sample on the selected injection areas, then obtaining samples at 1 week and 3 weeks after transplantation respectively, carrying out tissue section, and analyzing results.
1.2 test results
It can be seen that collagen fibrils were generated from the tissue sections in both the example 7 group and the comparative example 1, but the collagen fibril growth pattern was more uniform in the example 7 group (fig. B).
From the above, the addition of absorbable injection microspheres with a molecular weight of 0.8 ten thousand enables more uniform growth of collagen fibers.
Second, clinical test
1 data and method
1.1 clinical data
70 people with facial soft tissue appearance defects and facial wrinkles are randomly divided into 7 groups of 10 people in the age range of 27-48 years.
1.2 methods of injection
367.5mg of the filler described in examples 2-7 and comparative example 1 are respectively taken, 5ml of sterile physiological saline is added, the mixture is shaken to form a uniform suspension, the suspension is injected into deep dermis or subcutaneous tissue by using a syringe, the dosage of an injection point is determined by the range and the depth of wrinkles and the loss degree of facial subcutaneous fat and skin collagen, and the injection site of a subject is wiped and disinfected by 75% ethanol before injection. After injection, the injection area was massaged 3 minutes each time 3 times with fingers every day, the medicine solution was evenly distributed by massaging for 1 week, and the injection was performed 4 times with 3 weeks interval for each injection as described above.
1.3 evaluation of clinical Effect
Establishing a picture file before operation, revisiting at 16 weeks, 24 weeks, 48 weeks, 96 weeks and 120 weeks after operation, comparing the treatment effect and the existence of complications of each group, scoring the treatment effect according to the following scoring standard according to the comparison of wrinkle symptoms of patients before operation and after operation, and calculating the reduction rate of symptom score, wherein the result is shown in the following table 1, and the average score before operation of all tested patients is 3.
0 minute: when the facial muscles move, no wrinkles appear;
1 minute: when the facial muscles of the part move, fine and shallow wrinkles can be seen, the movement stops, and the wrinkles disappear along with the movement;
and 2, dividing: when the part is static, wrinkles can be seen, and when the skin on two sides of the wrinkles is stretched, the wrinkles disappear;
and 3, dividing: the part is static, has thick and deep wrinkles, and does not disappear when the skin is pulled on two sides.
Symptom score reduction rate ═ (pre-treatment score-post-treatment score)/pre-treatment score 100%
1.4 evaluation of clinical Properties
And (3) healing: the symptom sign disappears, the symptom integral is 0, the skin of the injection part is bright, smooth and elastic, and the tissue is full;
the effect is shown: the symptom sign is obviously improved and not completely disappeared, the integral reduction rate of the symptom is more than or equal to 66.7 percent and less than 100 percent, the skin glossiness of the injection part is increased, and the tissue is full;
the improvement is as follows: the symptom sign is reduced, the symptom integral is reduced by more than or equal to 33 percent and less than 66.7 percent, the skin at the injection part has certain glossiness, but the tissue is not full and still has slight dent;
and (4) invalidation: the symptom constitution is not improved, the symptom integral is reduced by less than 33.3 percent, the skin of an injection part is not glossy, and the skin tissue is not improved.
1.5 adverse event observations
All subjects were carefully observed for any adverse events that occurred during the clinical trial, and their clinical manifestations, severity, time of occurrence, duration, treatment and prognosis, etc. were recorded in time.
2. Results
2.1 therapeutic Effect
TABLE 1 symptom scores at different periods
Note: in the same way, compared with example 7,*P＜0.05，**P＜0.01。
as can be seen from Table 1 above, the longest lasting effect of the fillers of example 7 on wrinkle treatment can be up to 30 months in each group; when the polylactic acid filler with a single molecular weight is adopted, the maintenance time is obviously reduced compared with that of example 7, wherein when the molecular weight of the lactic acid microspheres is 0.8 ten thousand, the maintenance time is the shortest and can only be maintained for 12 months.
2.2 adverse reaction observations
The routine of blood and urine and the function of liver and kidney of all patients after operation and the comparison between electrocardiogram and before operation have no abnormal changes and no adverse events.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.
Claims (3)
1. A degradable injection polylactic acid filler is characterized by comprising 55 percent of levorotatory polylactic acid microspheres, 25 percent of sodium carboxymethylcellulose and 20 percent of mannitol;
the levorotatory polylactic acid microspheres are prepared from levorotatory polylactic acid microspheres with the molecular weights of 7 ten thousand, 5 ten thousand, 3 ten thousand and 0.8 ten thousand according to the weight ratio of 1: 0.5: 0.5: 0.3 in mass ratio.
2. The degradable injection polylactic acid filler according to claim 1, wherein the preparation method of the polylactic acid microspheres with the molecular weight of 7 ten thousand comprises the following steps:
s1, stirring levorotatory polylactic acid with the molecular weight of 7 ten thousand and dichloromethane to obtain a PLLA/DCM solution with the concentration of 8%;
s2, weighing polyvinyl alcohol, adding pure water, stirring to fully dissolve the polyvinyl alcohol, standing and cooling to obtain a 1% PVA/pure water solution;
s3, introducing helium into the PVA/pure water solution obtained by the preparation, maintaining the helium atmosphere, sealing, stirring, and setting the rotating speed at 600 r/min; adding PLLA/DCM solution into the PVA/pure water solution dropwise at a speed of 90ml/h, reacting for 3h, and keeping the temperature of the water bath in the dropwise adding process and the reaction process not to exceed 20 ℃; wherein the volume ratio of the PVA/pure water solution to the PLLA/DCM solution is 1: 2;
s4, stirring overnight after the reaction is finished; standing, removing the upper water phase, repeatedly washing with pure water for 3 times, taking the lower product, naturally air drying, grinding, sequentially sieving with 200 mesh and 400 mesh sieves, and collecting;
preparation of L-polylactic acid microspheres with molecular weights of 5 ten thousand, 3 ten thousand and 0.8 ten thousand referring to a preparation method of polylactic acid microspheres with molecular weights of 7 ten thousand, and average particle sizes of the prepared L-polylactic acid microspheres are 45 micrometers.
3. A wrinkle-removing preparation comprising the degradable injectable polylactic acid filling according to claim 1.
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| CN113117142B (en) * | 2020-01-14 | 2023-09-19 | 渼颜空间(河北)生物科技有限公司 | Biodegradable injection filler, preparation method and application thereof |
| CN116077358A (en) * | 2021-11-05 | 2023-05-09 | 长春圣博玛生物材料有限公司 | Nutrient solution and preparation method and application thereof |
| CN114712559B (en) * | 2022-05-05 | 2023-03-17 | 湖北翎美生物科技有限公司 | Injectable poly-L-lactic acid microsphere capable of promoting stable regeneration of collagen in vivo and preparation and application thereof |
| CN115920125A (en) * | 2022-11-30 | 2023-04-07 | 爱美客技术发展股份有限公司 | Composite gel and preparation method thereof |
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| WO2018098343A1 (en) * | 2016-11-23 | 2018-05-31 | University Medical Pharmaceuticals Corp. | Microneedle delivery system and method |
| CN108619524A (en) * | 2017-03-18 | 2018-10-09 | 浙江臻我生物技术有限公司 | A kind of poly (lactic acid) composition and preparation method thereof |
| CN108619564A (en) * | 2017-03-18 | 2018-10-09 | 浙江臻我生物技术有限公司 | A kind of composition and preparation method thereof for skin filling |
| CN109010910A (en) * | 2018-08-24 | 2018-12-18 | 普丽妍（南京）医疗科技有限公司 | A kind of preparation method of injectable l-lactic acid microballoon |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018098343A1 (en) * | 2016-11-23 | 2018-05-31 | University Medical Pharmaceuticals Corp. | Microneedle delivery system and method |
| CN108619524A (en) * | 2017-03-18 | 2018-10-09 | 浙江臻我生物技术有限公司 | A kind of poly (lactic acid) composition and preparation method thereof |
| CN108619564A (en) * | 2017-03-18 | 2018-10-09 | 浙江臻我生物技术有限公司 | A kind of composition and preparation method thereof for skin filling |
| CN109010910A (en) * | 2018-08-24 | 2018-12-18 | 普丽妍（南京）医疗科技有限公司 | A kind of preparation method of injectable l-lactic acid microballoon |
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