CN105713211A - Preparation method of novel skin filler - Google Patents
Preparation method of novel skin filler Download PDFInfo
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- CN105713211A CN105713211A CN201410715492.2A CN201410715492A CN105713211A CN 105713211 A CN105713211 A CN 105713211A CN 201410715492 A CN201410715492 A CN 201410715492A CN 105713211 A CN105713211 A CN 105713211A
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Abstract
The invention relates to a preparation method of a novel skin filler. According to the preparation method, low toxicity amino acids and derivatives of the low toxicity amino acids are taken as crosslinking agents to prepare cross-linked sodium hyaluronate gel; advantages of DMTMM method, such as high reaction activity, mild conditions, and simple treatment, are achieved; human essential alkaline amino acids lysine and arginine, or derivatives of lysine and arginine are taken as the crosslinking agents so as to realize crosslinking reaction with carboxyl terminals of sodium hyaluronate molecules, in vivo hyaluronidase recognition sites are blocked, enzyme recognition and degradation are delayed, and in vivo residue time is prolonged at last. The novel preparation method is provided for development of safe long-acting sodium hyaluronate injection beautifying fillers, and the market development prospect is promising.
Description
Technical field
The present invention relates to medical biomaterial technical field, the preparation method relating to a kind of saturating hyaluronic acid sodium gel of novel crosslinking, this cross-linking sodium hyaluronate gel fills beauty treatment for medical science.
Background technology
Hyaluronate sodium is the important component of humans and animals skin, vitreous body, joint lubrication liquid and cartilaginous tissue, and it is by (1-β-4)D-glucuronic acid and (1-β-3)N-acetyl group-D-aminoglucose dissacharide units repeats to be formed by connecting, and is widely used in prosthesis, operated eye or fills wrinkle as cosmetics.Hyaluronic acid has good physicochemical property and biocompatibility.But, it is subject to the zymolysis of hyaluronidase in vivo and degrades rapidly, and retention time is shorter, it is necessary to duplicate injection can be only achieved curative effect.Cross-linked-hyaluronic acid is that the high-molecular gel that obtains is modified in the crosslinking of crosslinked dose of hyaluronic acid, it is possible to makes up the shortcomings such as hyaluronic acid retention time is short, still has good biocompatibility and effect simultaneously.
Through fast development in recent years and market integra thereof, nowadays the state of the art of cross-linking sodium hyaluronate gel tends to be steady and duplicates, product competition in market is also into fieriness, only just there is 4-5 family's product in Chinese market and deposit, but from crosslinking technological aspect, type mainly includes two big classes and divinylsulfone (DVS) and BDDE (BDDE) as cross-linking agent；Existing product is be all that the site of consistent i.e. crosslinking/modify is all on-OH in the chemical constitution of gel simultaneously；It is known that above two cross-linking agent has significantly high bio-toxicity or potential carcinogenecity, although each manufacturer takes strict control measure guarantees the safety of product, but cross-linking sodium hyaluronate gel is be chronically implanted three internal class medical apparatus and instruments, therefore also lack the long-term follow data of large sample clinically to prove the biological safety of this series products；Simultaneously because the trend of the market demand, nowadays including external manufacturer and all pursuing the longer internal residence time, this certainly will improve the crosslinking/degree of modification of product, strengthens the introduction volume of cross-linking agent, more exacerbates people's worry to this series products.
Therefore, nontoxic or low toxicity cross-linking agent is worldwide selected to become the inexorable trend in cross-linking sodium hyaluronate gel field.Aminoacid is the compound that a class has difunctional, it it is the ultimate unit of constitutive protein matter, can be absorbed by the body utilization, compare other traditional chemical cross-linking agents, its toxicity substantially reduces (table 1), therefore selects aminoacid and derivant thereof to prepare cross-linking sodium hyaluronate gel regrowth safety aspect as cross-linking agent and have greater advantage；On the molecular structure of the gel of crosslinking, also there is the unique advantage being substantially distinguished from existing product simultaneously, namely the carboxyl in hyaluronic acid sodium molecule is utilized to form amido link with the amino in amino acid crosslinks agent thus reaching the effect of crosslinking, substantial amounts of literature research result shows the excellent heat stability that amido link has, and this displays that and utilizes aminoacid to have the characteristic of potential high temperature resistance sterilizing as hyaluronic acid sodium gel prepared by cross-linking agent；It is known that what hyaluronate sodium degraded in vivo realized mainly by specific hyaluronidase, the specific recognition site of this process is carboxyl, and utilizing aminoacid is just carboxyl as the reaction site of cross-linking agent, there is as gel prepared by cross-linking agent hence with aminoacid the resistance to enzymolysis being substantially distinguished from traditional product.
Table 1 lysine and conventional cross-linking agent toxicity relative analysis table
The method introducing amido link conventional in hyaluronic acid sodium molecule has 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide (EDC) activation, 2-chloro-1-methyl pyridinium iodide (CMPI) activation etc., but these methods mostly also exist many drawbacks, if EDC activation method is to the dependency of pH value is relatively strong and grafting efficiency is low, it is unsuitable for large-scale industrialization and amplifies；And CMPI activation rule also exists and there is the drawbacks such as reactivity is low, post processing is complicated.
In view of the deficiency of said method, the present invention adopts morpholine derivative to be prepared cross-linking sodium hyaluronate gel (hereinafter referred to as DMTMM method) as coupling reagent.DMTMM is one of method generating amido link ideal at present, and it has following several advantage: 1. reactivity is high, and the percent grafting of single amino acid can reach more than 70%；2. reaction temperature and, can react under low temperature and room temperature；3. the dependency of couple PH is weak, it is easy to industrialization produces；4. side reaction is few, and the morpholine derivative not participating in reaction does not react with hyaluronate sodium, and is easily removed, and is conducive to the quality control of product.
The present invention utilizes DMTMM method, basic amino acid-the lysine in the essential amino acids in human body and arginine and derivant thereof is adopted to prepare cross-linking sodium hyaluronate gel as cross-linking agent and fundamentally avoid the use of the bigger cross-linking reagent of the toxicity such as DVS, BDDE, the safety of the hyaluronic acid sodio-derivative ensured, imparts gel with unique physical characteristic and heat stability and antihyaluronidase solution simultaneously.
Summary of the invention
Advantages of the present invention:
1. adopting the basic amino acid-lysine in the essential amino acids in human body and derivant thereof as cross-linking agent, above-mentioned cross-linking agent has non-toxic nature and has the biologic activity of uniqueness simultaneously.
2. the cross-linking sodium hyaluronate gel of preparation is by molecule crosslinked for hyaluronate sodium one-tenth 3 D stereo network structure by amido link, is different from tradition DVS and BDDE cross-linking sodium hyaluronate gel.
3. utilizing DMTMM method to prepare cross-linking sodium hyaluronate gel, this reaction condition is gentle, by-product is few and is prone to large-scale production.
4. utilize the recognition site of hyaluronidase in cross-linking sodium hyaluronate gel obturator prepared by the present invention, extend the residence time.
Accompanying drawing illustrates:
Fig. 1 sample clear matter acid sodium enzymatic degradation rate comparison diagram.
Detailed description of the invention
In conjunction with embodiment, for lysine, the present invention is described in detail, but the enforcement of the present invention is not limited only to this.
Embodiment one
Lysine 0.0914g is dissolved in 15mL water, is 4 with salt acid for adjusting pH, weigh 1g hyaluronate sodium dry powder, after stirring, put 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.6918g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 50g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment two
Lysine 0.0914g is dissolved in 15mL water, is 6 with salt acid for adjusting pH, weigh 1g hyaluronate sodium dry powder, after stirring, put 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.6918g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 50g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment three
Lysine 0.0914g is dissolved in 15mL water, is 6.5 with salt acid for adjusting pH, weigh 1g hyaluronate sodium dry powder, after stirring, put 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.6918g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 50g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment four
Lysine 0.0914g is dissolved in 15mL water, is 7 with salt acid for adjusting pH, weigh 1g hyaluronate sodium dry powder, after stirring, put 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.6918g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 50g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment five
Lysine 0.0914g is dissolved in 15mL water, is 7.4 with salt acid for adjusting pH, weigh 1g hyaluronate sodium dry powder, after stirring, put 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.6918g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 50g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment six
Lysine 0.1828g is dissolved in 15mL water, is 7.4 with salt acid for adjusting pH, weigh 1g hyaluronate sodium dry powder, after stirring, put 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.6918g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 50g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment seven
Lysine 0.0731g is dissolved in 15mL water, is 7.4 with salt acid for adjusting pH, weigh 0.8g hyaluronate sodium dry powder, after stirring, put 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.5534g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 40g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment eight
Lysine 0.0731g is dissolved in 15mL water, is 7.4 with salt acid for adjusting pH, weigh 0.8g hyaluronate sodium dry powder, after stirring, put 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.2767g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 40g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment nine
Lysine 0.1462g is dissolved in 15mL water, is 7.4 with salt acid for adjusting pH, weigh 0.8g hyaluronate sodium dry powder, after stirring, put 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.5534g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 40g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment ten
Lysine 0.1462g is dissolved in 15mL water, is 7.4 with salt acid for adjusting pH, weigh 0.8g hyaluronate sodium dry powder, after stirring, put 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.2767g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 40g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment 11
Being dissolved in 15mL water by ethyl ester of lysine dihydrochloride 0.309g, regulating pH with sodium hydroxide is 7.4, weighs 1g hyaluronate sodium dry powder, after stirring, puts 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.6918g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 50g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment 12
Lysine one hydrochlorate 0.1142g is dissolved in 15mL water, with equimolar sodium hydroxide by hydrochloric acid and after, then be 7.4 with salt acid for adjusting pH, weigh 1g hyaluronate sodium dry powder, after stirring, put 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.6918g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 50g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment 13
Weigh 1g hyaluronate sodium dry powder, with 15mL water dissolution uniformly after, put 4 DEG C overnight.Within second day, weigh and add in gel after DMTMM0.6918g 5mL water is completely dissolved, after stirring completely, react 3 days at 4 DEG C.
After completely reacted gel is cut into block, dialysing with PBS, every 1h changes dialysis solution 1 time and weighs, until gel quality terminates dialysis after 50g, is pulverized by this gel after granulating, obtains cross-linking sodium hyaluronate gel.
Embodiment 14
The sample obtained by embodiment five, seven, 11,12,13 is through steam sterilization, after (121 DEG C, 20min).Take gel 0.32g, add hyaluronidase liquid 8ml (240UI)；Taking control sample 0.32g equally, add hyaluronidase liquid 8ml (240UI), 37 DEG C of water-bath 48h, centrifuging and taking supernatant measures glucuronic acid content, draws degradation curve, and with commercially available auspicious indigo plant, moisten hundred face products compared with.The enzyme of products obtained therefrom 48h drops rate below 60%, is substantially less than main flow in the market crosslinked.
Claims (7)
1. the preparation method of a novel skin filler, it is mainly characterized by with hyaluronate sodium for raw material, adopt 4-(4,6-dimethoxy-triazine-2-base)-4-methyl morpholine hydrochloride (DMTMM) is as condensing agent, select appropriate natural amino acid and derivant thereof as cross-linking agent, control the initial concentration of hyaluronate sodium, the addition of condensing agent, reaction temperature, pH value and response time, after reaction terminates, it is cut into small pieces to put in phosphate buffer by gel and dialyses, be then passed through granulation and sterilization process obtains cross-linking sodium hyaluronate gel.
2. the cross-linking agent described in claim 1 refers to natural amino acid and derivant thereof, including 1B, 1B one hydrochlorate, 1B dihydrochloride, 1B ethyl ester dihydrochloride, L-arginine, L-arginine one hydrochlorate, L-arginine dihydrochloride, prioritizing selection 1B and L-arginine.
3. the ratio referring to cross-linking agent and hyaluronate sodium during appropriate cross-linking agent described in claim 1 is 1/10～2/1(mol/mol).
4. the hyaluronate sodium initial action concentration described in claim 1 is 2～10%(m/m%).
5. the condensing agent addition described in claim 1 is 1/10～2/1(mol/mol with the ratio of hyaluronate sodium).
6. the temperature range of the reaction described in claim 1 is 4～50 DEG C.
7. the time range of the reaction described in claim 1 is 4～120h.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653818A (en) * | 2018-05-24 | 2018-10-16 | 上海其胜生物制剂有限公司 | A kind of reversible collagen stimulation filler and preparation method thereof |
| CN109224127A (en) * | 2018-12-04 | 2019-01-18 | 上海其胜生物制剂有限公司 | A kind of self assembly collagen stimulation microballoon of the shell-core structure naturally formed and preparation method thereof |
| CN110339398A (en) * | 2019-07-18 | 2019-10-18 | 王月玲 | One kind Amvisc containing amino acid and preparation method thereof |
| CN112675125A (en) * | 2020-12-31 | 2021-04-20 | 上海昊海生物科技股份有限公司 | Non-toxic cross-linked sodium hyaluronate gel articular cavity injection and preparation method thereof |
| IT201900024117A1 (en) * | 2019-12-16 | 2021-06-16 | St Ganassini Spa Di Ricerche Biochimiche | PROCEDURE FOR THE SYNTHESIS OF CROSS-LINKED HYALURONIC ACID |
| CN114539636A (en) * | 2022-02-16 | 2022-05-27 | 成都微沃科技有限公司 | Alginic acid-chitosan bioinert hydrogel with viscoelasticity |
| WO2023082084A1 (en) | 2021-11-10 | 2023-05-19 | 爱美客技术发展股份有限公司 | Gel material, preparation method therefor, and use thereof |
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| CN101611063A (en) * | 2006-11-10 | 2009-12-23 | 施泰福实验室股份有限公司 | Cross-linked-hyaluronic acid and preparation method thereof |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653818A (en) * | 2018-05-24 | 2018-10-16 | 上海其胜生物制剂有限公司 | A kind of reversible collagen stimulation filler and preparation method thereof |
| CN109224127A (en) * | 2018-12-04 | 2019-01-18 | 上海其胜生物制剂有限公司 | A kind of self assembly collagen stimulation microballoon of the shell-core structure naturally formed and preparation method thereof |
| CN109224127B (en) * | 2018-12-04 | 2021-02-02 | 上海其胜生物制剂有限公司 | Self-assembled collagen stimulation microsphere with naturally-composed shell-core structure and preparation method thereof |
| CN110339398A (en) * | 2019-07-18 | 2019-10-18 | 王月玲 | One kind Amvisc containing amino acid and preparation method thereof |
| IT201900024117A1 (en) * | 2019-12-16 | 2021-06-16 | St Ganassini Spa Di Ricerche Biochimiche | PROCEDURE FOR THE SYNTHESIS OF CROSS-LINKED HYALURONIC ACID |
| WO2021124147A1 (en) * | 2019-12-16 | 2021-06-24 | Istituto Ganassini S.P.A. Di Ricerche Biochimiche | Cross-lynked hyaluronic acid synthesis process |
| CN112675125A (en) * | 2020-12-31 | 2021-04-20 | 上海昊海生物科技股份有限公司 | Non-toxic cross-linked sodium hyaluronate gel articular cavity injection and preparation method thereof |
| WO2023082084A1 (en) | 2021-11-10 | 2023-05-19 | 爱美客技术发展股份有限公司 | Gel material, preparation method therefor, and use thereof |
| CN114539636A (en) * | 2022-02-16 | 2022-05-27 | 成都微沃科技有限公司 | Alginic acid-chitosan bioinert hydrogel with viscoelasticity |
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Application publication date: 20160629 |