CN110339398A - One kind Amvisc containing amino acid and preparation method thereof - Google Patents
One kind Amvisc containing amino acid and preparation method thereof Download PDFInfo
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- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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Abstract
The present invention relates to a kind of Amviscs containing amino acid and preparation method thereof, belong to medical cosmetology and bio-medical technology field.Amvisc containing amino acid provided by the invention, it is mainly comprised the following components in parts by weight: 1.7~17.2 parts of glycine, 0.5~5.2 part of L-PROLINE, 2.0~20.0 parts of L-Leu, 1.8~17.6 parts of L-lysine, 20.0~200.0 parts of Sodium Hyaluronate, 3.6~35.8 parts of excipient, 1.4~14.3 parts of stabilizer, 1000 parts of water for injection.The Amvisc containing amino acid prepared using method of the invention, can promote new dermal cell growth with the flaw on Fast Filling and greasy skin, such as wrinkle, striae of pregnancy, promote facial state rejuvenation, and have anti-senescence function.
Description
Technical field
The invention belongs to medical cosmetologies and bio-medical technology field, and in particular to a kind of note of Sodium Hyaluronate containing amino acid
Penetrate agent and preparation method thereof.
Background technique
Soft tissue defect is corrected by shaping and beauty technology and repairs the skin of aging shrinkage, keeps the perfection of facial shape
A kind of universal phenomenon is had become with the youth.In various shaping and beauty technologies, injection beautifying technique accounts for the largest percentage, and accounts for about whole
The 40% of a beauty market.Injection beautifying technique is to carry out local modification to human body by way of injection, reaches local form
The beautifying technique that exquisite, configuration is coordinated.The technology has the characteristics that zero restores, is quick and highly-safe, is that beauty needs
The first choice for the person of asking.
Injection beauty is one kind of non-operating shaping beauty, life that can be artificial synthesized by biomaterial using the method for injection
The good Material injection of object compatibility enters skin corium or subcutaneous, is reached by the different mechanism of action and reduces skinfold or moulding
A kind of shaping and beauty method.
Hyaluronic acid (also known as sodium hyaluronate, abbreviation HA) or its sodium salt are a kind of natural polymer mucopolysaccharide substances, extensively
It is distributed in the connective tissue, cockscomb and streptococcic folder film etc. of mammal, is humans and animals skin, vitreum, joint profit
The important component of synovia and cartilaginous tissue, it is by (1- β -4)-D- glucuronic acid and (1- β -3)-N- acetyl group-D- aminoglucose
Dissacharide units repeat to be formed by connecting, and are widely used in prosthesis, operated eye or fill wrinkle as beauty product.Hyalomitome
Sour sodium has good physicochemical property and biocompatibility, has the effects that crease-resistant, breast augmentation, fills pad, and makees to human body without pair
With.
However, hyaluronic acid is degraded rapidly by the enzymolysis of hyaluronidase in vivo, retention time is shorter, needs
Duplicate injection is wanted to can be only achieved curative effect.Cross-linked-hyaluronic acid is the Macromolecule that crosslinked dose of hyaluronic acid crosslinking modification obtains
Glue can make up the disadvantages of hyaluronic acid retention time is short, and presently used crosslinking agent mainly includes two major classes, i.e. divinylsulfone
(DVS) and bis- butanol diglycidyl ether (BDDE) of 1,4-.It is well known that above two crosslinking agent has very high bio-toxicity
Or potential carcinogenicity.Non-crosslinked Sodium Hyaluronate and the above-mentioned side effect for not having crosslinking hyaluronic acid sodium, but it is non-crosslinked transparent
Matter acid sodium is under free radical and hyaluronic acid enzyme effect, and half-life short in skin is easy to be degraded.
Amino acid is a kind of with compound bifunctional, is the basic unit of constitutive protein matter, can be inhaled by human body
It receives and utilizes.The degradation of Sodium Hyaluronate in vivo is mainly to be realized by the hyaluronidase of specificity, the spy of the process
Anisotropic recognition site is carboxyl；And the carboxyl and amino of amino acid and hyaluronic acid when being used in combination, in hyaluronic acid sodium molecule
Amino in acid, which forms amido bond, can delay the degradation speed of Sodium Hyaluronate in vivo to form competition.
106215244 A of Chinese patent CN provides the compound solution and its correction wrinkle of skin of a kind of Sodium Hyaluronate
Application.In the compound solution concentration of Sodium Hyaluronate be 1.000~5.000mg/mL, amino acid concentration be 0.100~
0.500mg/mL, concentration is diluter, and filling effect is unobvious.And under solution state, amino absolute acid stability is poor, degradable.
Summary of the invention
It, can the purpose of the present invention is on the basis of existing technology, providing a kind of Amvisc containing amino acid
With the flaw on Fast Filling and greasy skin, such as wrinkle, striae of pregnancy, promotes new dermal cell growth, promote face
State rejuvenation, and there is anti-senescence function.
It is a further object of the present invention to provide a kind of preparation methods of above-mentioned Amvisc containing amino acid.
Technical scheme is as follows:
A kind of Amvisc containing amino acid, it is mainly comprised the following components in parts by weight: glycine 1.7~
17.2 parts, 0.5~5.2 part of L-PROLINE, 2.0~20.0 parts of L-Leu, 1.8~17.6 parts of L-lysine, Sodium Hyaluronate
20.0~200.0 parts, 3.6~35.8 parts of excipient, 1.4~14.3 parts of stabilizer, 1000 parts of water for injection.
In a preferred embodiment, Amvisc containing amino acid provided by the invention, it mainly includes following
The component of parts by weight: 4.3~13.8 parts of glycine, 1.3~4.2 parts of L-PROLINE, 5.0~16.0 parts of L-Leu, L- relies ammonia
4.4~14.1 parts of acid, 50.0~160.0 parts of Sodium Hyaluronate, 9.0~28.7 parts of excipient, 3.6~11.5 parts of stabilizer, note
It penetrates with 1000 parts of water.
In a kind of more preferable scheme, Amvisc containing amino acid provided by the invention, it mainly include with
The component of lower parts by weight: it is mainly comprised the following components in parts by weight: 7.0~10.0 parts of glycine, L-PROLINE 2.0~3.0
Part, 8.0~12.0 parts of L-Leu, 7.0~10.5 parts of L-lysine, 80.0~120.0 parts of Sodium Hyaluronate, excipient 14.3
~21.5 parts, 5.7~8.6 parts of stabilizer, 1000 parts of water for injection.
The excipient that the present invention refers to can with but be not limited to sorbierite or mannitol, do not influencing prepared by the present invention contain
In the case where the effect of amino acid Amvisc, excipient can be preferably mannitol.
The stabilizer that the present invention refers to can with but be not limited to glucan or dextran, do not influence it is prepared by the present invention
In the case where the effect of the Amvisc containing amino acid, excipient can be preferably dextran.
Glycine (Glycine, abridge Gly) also known as amion acetic acid, a kind of nonessential amino acid of human body, but belong to non-pole
Acidic amino acid is a kind of nutritional supplement, has antioxidation, is pharmaceutically used as antiacid (hyperchlorhydria), muscle is sought
Support imbalance therapeutic agent, antidote etc..
L-PROLINE (L-Proline), alpha-imino acid, neutral, a kind of naturally occurring amino acid, chemical name is pyrrole
Pyrrolidone carboxylic acid is a kind of cricoid imino acid, is the nonessential amino acid of human body, is lacked for malnutritive, protein
Disease, Severe gastrointestinal tract disease, the Protein intake of scald and surgical site infections.Without obvious toxic-side effects.In vivo, dried meat ammonia
Acid is not only ideal osmotic adjustment, and is alternatively arranged as the Protective substances and free radical scavenger of film and enzyme, thus
It plays a protective role to growth of the plant under osmotic stress, for another important osmotic adjustment in potassium ion organism
Accumulation of the substance in vacuole, proline can play the adjustment effect to cytoplasm osmotic equilibrium again.
Leucine ((2R) -2-amino-3,3-dimethylbutanoic acid), chemical name are L-2- ammonia -4- first
The effects of base valeric acid has reparation muscle, controls blood glucose, and energy is provided to bodily tissue.Leucine, isoleucine and valine
It is all branched-chain amino acid, they peomote the muscle recovery after training.Wherein leucine is a kind of most effective branch ammonia
Base acid, can be effectively prevented muscle loss, because it can decomposition and inversion be faster glucose.Leucine can be used as nutrition increasing
Tonic, seasoning fumet.Amino acid transfusion and comprehensive amino acid preparation, Hypoylycemic agents, plant growth promoter can be prepared.This hair
The Amvisc containing amino acid of bright offer can promote protein to synthesize and reduce breaks down proteins, may advantageously facilitate
The regeneration and reparation of liver cell, and Hypoproteinemia can be improved.
Lysine is one of essential amino acid, can promote human development, enhancing immune function, and be improved maincenter mind
Effect through function of organization.The symptom for lacking lysine includes fatigue, and weak, nausea, vomiting is dizzy, and without appetite, development is slow
It is slow, anaemia etc..It is some studies have shown that the effect of lysine, which is also possible that, prevents bone-loss (can cause osteoporosis),
It can help bodily tissue to absorb calcium, can promote bone vigor in conjunction with other amino acid, and by increasing women collagen egg
White pre- anti-osteoporosis.Increasing collagen can promote bone and connective tissue more powerful and more flexible.Human body cannot be certainly
Body synthesizes L-lysine, it is necessary to draw lysine from food and be to aid in other nutriments by human body fully absorbs and utilizes
Key substance, human body, which only supplements enough L-lysines, could improve the absorption and utilization of food protein, reach balanced
Nutrition, enhancing development.In the various amino acid of synthetic proteins matter, L-lysine is most important one kind, has lacked it,
Its amino acid is just restricted or is not used, scientist it be referred to as the first essential amino acid of human body.
The present invention also provides the preparation methods of the above-mentioned Amvisc containing amino acid, it mainly includes following step
It is rapid:
(1) prepared by amino acid freeze-dried powder: by glycine, L-PROLINE, L-Leu, L-lysine, excipient and stabilization
Agent is dissolved in water for injection, is added pH adjusting agent and is adjusted pH value of solution to 5.5~7.0, active carbon is added and is filtered, is lyophilized
Afterwards, amino acid freeze-dried powder is obtained；
(2) prepared by sodium hyaluronate solution: Sodium Hyaluronate being dissolved in phosphate buffer solution, pH adjusting agent is added
PH value of solution is adjusted to 5.5~7.0, filtering obtains sodium hyaluronate solution.
The present invention is in step (1) and step (2), and the pH adjusting agent used is sodium hydroxide solution, hydrochloric acid solution or phosphorus
Acid solution.
In a preferred embodiment, in step (2), the phosphate buffer solution is sodium dihydrogen phosphate, phosphoric acid
The mixed solution of disodium hydrogen solution or both；For example, the biphosphate that phosphate buffer solution can be 5.0~7.5 selected from pH
The sodium dihydrogen phosphate and disodium hydrogen phosphate that the disodium phosphate soln or pH that sodium solution, pH are 5.0~7.5 are 5.0~7.5
The mixed solution of solution.
In a preferred embodiment, in step (2), the mass volume ratio of Sodium Hyaluronate and phosphate buffer solution is
0.02~0.2:1000g/ml；Preferably 0.05~0.15:1g/ml.
The excipient that the present invention refers to can with but be not limited to sorbierite or mannitol, do not influencing prepared by the present invention contain
In the case where the effect of amino acid Amvisc, excipient can be preferably mannitol.
The stabilizer that the present invention refers to can with but be not limited to glucan or dextran, do not influence it is prepared by the present invention
In the case where the effect of the Amvisc containing amino acid, excipient can be preferably dextran.
The present invention is filtered in step (1) using active carbon, and the mass ratio of active carbon and L-Leu is 0.1~
1:1；Preferably 0.15~0.6:1；More preferably 0.6:1.
The preparation method of the above-mentioned Amvisc containing amino acid referred to, it may include in further detail below
Step:
(1) prepared by amino acid freeze-dried powder: by glycine, L-PROLINE, L-Leu, L-lysine, excipient and stabilization
Agent is dissolved in water for injection, is added pH adjusting agent and is adjusted pH value of solution to 5.5~7.0, active carbon is added and is filtered, will filter
Liquid carries out refined filtration with miillpore filter, and refined filtration liquid is packed into cillin bottle, is put into refrigerator and is lyophilized, obtain amino acid freeze-dried powder；
(2) prepared by sodium hyaluronate solution: Sodium Hyaluronate being dissolved in phosphate buffer solution, pH adjusting agent is added
PH value of solution is adjusted to 5.5~7.0, filtering obtains sodium hyaluronate solution.
Amvisc containing amino acid provided by the invention consists of two parts: (1) amino acid freeze-dried powder and (2)
Sodium hyaluronate solution.Amino acid freeze-dried powder mainly by four kinds of Amino acid profiles, is stablized, and is not easy oxygen in storage, transportational process
Change, solubility is good when aqueous solution is made in the dissolution of amino acid freeze-dried powder using sodium hyaluronate solution when clinical use, clarity
Good, nodeless mesh is precipitated；Sodium hyaluronate solution is thick liquid, can be individually filling in prefilled syringe, uses preceding note
Enter in the cillin bottle equipped with amino acid freeze-dried powder, mixes well rear direct injection.Amino acid freeze-dried powder and sodium hyaluronate solution
It can individually pack, be conducive to the stabilization of product.It is mixed before use, the synergistic effect of both performances that can be bigger.
Using technical solution of the present invention, advantage is as follows:
The present invention provides a kind of Amvisc containing amino acid, and the addition of amino acid can effectively antagonize free radical
Degradation, hence it is evident that delayed the degradation speed of Sodium Hyaluronate in vivo, filling effect is obvious, surrounding tissue variation without exception.
The Amvisc containing amino acid prepared using method of the invention, with Fast Filling and can lubricate skin
Flaw on skin, such as wrinkle, striae of pregnancy, promote new dermal cell growth, promote facial state rejuvenation, and have anti-ageing
Old function.
Specific embodiment
The following description is intended to explain the principle of the present invention and main feature, not to the raw material group in the present invention
There is specific restriction effect at, ratio.
Embodiment 1
1) amino acid freeze-dried powder prepare: respectively precision weigh glycine 4.0g, L-PROLINE 1.2g, L-Leu 5.0g,
L-lysine 4.5g adds water for injection 3000ml to be completely dissolved, and adds mannitol 9.0g and dextran 3.5g, and stirring is equal
It is even, pH value of solution is adjusted to 6.5 with sodium hydroxide solution or hydrochloric acid solution, adds 3g active carbon to filter, by 0.22 μm of micropore of filtrate
Filter membrane carries out refined filtration, and refined filtration liquid is packed into cillin bottle, and every bottle of 3ml is put into refrigerator and is lyophilized, and obtains amino acid freeze-dried powder.
2) prepared by sodium hyaluronate solution: precision weighs Sodium Hyaluronate 50.0g, and adding pH is 6.5 phosphate buffer solutions
1000ml dissolution adjusts pH value of solution to 6.5 with 1mol/L sodium hydroxide solution, stirs evenly, with 0.22 μm of filtering with microporous membrane,
Obtain sodium hyaluronate solution.
Embodiment 2
1) amino acid freeze-dried powder prepare: respectively precision weigh glycine 8.6g, L-PROLINE 2.6g, L-Leu 10.0g,
L-lysine 8.8g adds water for injection 3000ml to be completely dissolved, and adds mannitol 17.9g and dextran 7.2g, and stirring is equal
It is even, pH value of solution is adjusted to 7.0 with sodium hydroxide solution or hydrochloric acid solution, adds 6g active carbon to filter, by 0.22 μm of micropore of filtrate
Filter membrane carries out refined filtration, and refined filtration liquid is packed into cillin bottle, and every bottle of 3ml is put into refrigerator and is lyophilized, and obtains amino acid freeze-dried powder.
2) prepared by sodium hyaluronate solution: precision weighs Sodium Hyaluronate 100.0g, adds pH7.0 phosphate buffer solution
1000ml dissolution adjusts pH value of solution to 7.0 with 1mol/L sodium hydroxide solution, stirs evenly, with 0.22 μm of filtering with microporous membrane,
Obtain sodium hyaluronate solution.
Embodiment 3
1) prepared by amino acid freeze-dried powder: precision weighs glycine 14.0g, L-PROLINE 4.5g, L-Leu respectively
16.0g, L-lysine 14.0g, add water for injection 3000ml to be completely dissolved, and add mannitol 28.5g and dextran
11.5g is stirred evenly, and is adjusted pH value of solution to 5.5 with sodium hydroxide solution or hydrochloric acid solution, is added 3g active carbon to filter, by filtrate
Refined filtration is carried out with 0.22 μm of miillpore filter, refined filtration liquid is packed into cillin bottle, every bottle of 3ml is put into refrigerator and is lyophilized, obtains amino
Sour freeze-dried powder.
2) prepared by hyaluronic acid sodium injection: precision weighs Sodium Hyaluronate 115.0g, adds pH5.5 phosphate buffer solution
1000ml dissolution adjusts pH value of solution to 5.5 with 1mol/L hydrochloric acid solution, stirs evenly, with 0.22 μm of filtering with microporous membrane, obtain
Bright matter acid sodium injection.
Comparative example 1
Referring to a kind of patent " application of the compound solution and its correction wrinkle of skin of Sodium Hyaluronate " (CN 106215244
A), in the compound solution Sodium Hyaluronate concentration be 1.000~5.000mg/mL, amino acid concentration be 0.100~
0.500mg/mL, the compound solution that preparation is adapted with the patent concentration, as a comparison case 1.
Compare compound solution preparation: respectively precision weigh Sodium Hyaluronate 5g, glycine 0.1g, L-PROLINE 0.2g,
L-Leu 0.1g, L-lysine 0.1g, add water for injection 1000ml, and stirring is completely dissolved each component, adds 1mol/L hydrogen-oxygen
Change sodium solution and 1mol/L hydrochloric acid solution adjust solution ph to 7.2 to get.
Amvisc containing amino acid prepared by the present invention, when in use as the case may be, using appropriate
The injection of hyaluronic acid sodium injection equipped in the cillin bottle of amino acid freeze-dried powder, is sufficiently mixed, can inject need to fill by syringe
Fill out position.
The quality condition of the Amvisc prepared by the present invention containing amino acid:
Character, pH have been carried out to the quality of the Amvisc containing amino acid prepared by the embodiment of the present invention 1~3
Value, clarity, sterile, bacterial endotoxin, heavy metal and assay, the results showed that hyalomitome containing amino acid prepared by the present invention
The quality of sour sodium injection is preferable.
The stability of the Amvisc containing amino acid prepared by the embodiment of the present invention 1~3 is studied, is wrapped
Include influence factor test, accelerated test and long term test.The results show that the injection of Sodium Hyaluronate containing amino acid prepared by the present invention
Agent carries out influence factor test after removing outer packing, places 10 days under the conditions of high temperature (60 DEG C), illumination (4500 ± 500lx),
Character, pH value, clarity, content etc. are showed no apparent variation, there is hygroscopic effect under conditions of high humidity.It is wet at 40 DEG C of temperature
It is placed 6 months under the conditions of degree RH75%, product quality is basicly stable, and indices have no significant change.At 25 DEG C of temperature, humidity
It is placed 12 months under the conditions of RH60%, moisture is increased slightly, and character, content, pH value, clarity etc. have no significant change, and 6 months
Sterile and baterial endotoxin test was not carried out with 12 months, it is qualified, illustrate Sodium Hyaluronate containing amino acid prepared by the present invention
Injection quality is stablized.
Vascular stimulation tests: after hyaluronic acid sodium injection and amino acid freeze-dried powder are sufficiently mixed, with 100mg/
The dosage of 10ml/kg is slowly injected to rabbit auricular vein, once a day, for three days on end.It visually observes within 24 hours after the last administration
Injection site situation, materials carry out histopathologic examination after last observation.Visual results show, administration group and control
Each example of group is showed no obvious abnormalities in different time points.Histopathologic examination is the results show that control group and each example rabbit of administration group
Auricular vein structural integrity, lumen have no vascular endothelial cell swelling, denaturation, necrosis, wall of vein and its surrounding without obvious expansion
For tissue without obvious cell infiltration, lumen is interior without obvious thrombosis.
Whole body active sensitivity test: 4 groups of cavy point injects 10mg/ml high concentration and 2mg/ml low concentration gives two respectively
Group 0.5ml/ sensitization of guinea pig intraperitoneal injection, the next day it is primary, continuous 5 times.The 10th day each group is respectively with 2 times of agent after last sensitization
Amount is attacked, and using 4% egg protein as positive control, 5% glucose injection is as negative control.The results show that for examination
After group and positive controls are attacked to immunized guinea pigs, do not occur allergic reaction；And then there is typical case in positive controls animal
Systemic anaphylaxis reaction, show as having difficulty in breathing, spasm of twitching, fall down to the ground death, level of reaction is ++++grade.
Hemolytic test: routinely the injection of the method observation 10mg/ml concentration of hemolysis in vitro test is red to rabbit thin
The influence of born of the same parents.The results show that Amvisc containing amino acid prepared by the present invention in 3 hours to family's rabbit erythrocyte without
Obvious haemocylolysis, also has no hemagglutination.
Above-mentioned pharmacological tests show that Amvisc containing amino acid prepared by the present invention carries out vascular stimulation
Property, the test of anaphylaxis, hemolytic, as a result have no the reaction of significant vascular stimulation, to animal subject without sensitization, also have no haemolysis
Phenomenon.
Stability test:
Influence factor hot test: sample made from sample made from Examples 1 to 3 and comparative example 1 is set 60 DEG C respectively
It is placed 10 days in baking oven.
The test of influence factor strong illumination: sample made from sample made from Examples 1 to 3 and comparative example 1 is set respectively
In lighting box equipped with fluorescent lamp, placed 10 days under conditions of illumination is 4500lx scholar 500lx.
Accelerated test: by sample made from sample made from Examples 1 to 3 and comparative example 1, respectively in 40 DEG C of scholars 2 of temperature
DEG C, place 6 months under conditions of relative humidity 75% ± 5%.
Long term test: by sample made from sample made from Examples 1 to 3 and comparative example 1, at 25 DEG C ± 2 DEG C of temperature, phase
It is placed 12 months under conditions of humidity 60% ± 10%.Stability test the results are shown in Table 1.
1 stability test result of table
Stability test the results show that the product for preparing of the embodiment of the present invention 1~3 and comparative example 1 test in influence factor,
It is placed under the conditions of accelerated test, long term test etc., the results show that Examples 1 to 3 is in each condition, each component content has no bright
Aobvious variation, and each component has apparent reduction in comparative example 1, and it is steady under lyophilised state to illustrate that each composition does not have under solution state
It is fixed.
Degradation cycle:
Test specimen: amino acid and the mixed sample of Sodium Hyaluronate are implemented as test specimen in Examples 1 to 3
The hyaluronic acid sodium gel prepared in example 1~3 is the contrast sample of each embodiment.
Experimental method: being randomly divided into 4 groups for the BALB/c mouse in 48 7~August ages, and every group 12,7 after respectively injecting
30 days detection groups after its detection group, injection, 90 days detection groups after injection.It sheds at left and right sides of back of mice backbone, 75% alcohol
After disinfection, it is pure transparent that amino acid and the mixed sample of Sodium Hyaluronate, right side injected sample in Examples 1 to 3 are injected in left side
Matter acid sodium gel.In test point, experimental animal is put to death, splits injection site, sample carryover situation is observed, the results are shown in Table 2.
2 degradation cycle test result of table
The results show that the addition of amino acid has obviously delayed the degradation speed of Sodium Hyaluronate in vivo.
Free radical resisting Degrading experiment:
Experimental material: cupric sulfate pentahydrate, 30% hydrogen peroxide, amino in hyaluronic acid sodium gel, the embodiment of the present invention 1~3
Acid and the mixed sample of Sodium Hyaluronate, 1mol/L hydrochloric acid solution, cow's serum, potassium acetate, glacial acetic acid, sodium chloride, purified water.
Experimental method: take 1.0ml sodium hyaluronate solution, 1.0ml sodium hyaluronate solution and 1.0ml amino acid with it is transparent
The mixed sample solution of matter acid sodium, tri- groups of number A, B and C.0.2ml purified water is added to A group, is added to B group and C group
The copper sulphate of the 100mM of 0.1ml and the hydrogen peroxide of 0.1mM.It is placed in 37 DEG C of water-baths for tri- groups of A, B and C to react 1 hour, respectively
20 times of sampling dilution is to be measured.
Measurement method:
Acetic acid-potassium acetate buffer preparation: potassium acetate 14g, glacial acetic acid 20.5ml is taken to add water and be diluted to 1000ml.
Serum solution: taking 1 part of fresh bovine serum, adds acetic acid -9 parts of potassium acetate buffer solution dilution, then with 4mol/L hydrochloric acid
Solution adjusts pH value to 3.1, after placing 18~24 hours, dilutes 3 times with acetic acid-liquor kalii acetici.
It takes aforementioned prepare liquid that 4ml serum solution is added, while taking 1ml purified water that 4ml is added as blank control, shake up,
30 minutes are being placed at room temperature for, is being shaken up, absorbance is measured at 640nm wavelength, the degradation rate of each group is calculated according to absorbance.Measurement
It the results are shown in Table 3.
3 free radical resisting Degrading experiment result of table
From the experimental results, amino acid is added, the degradation of free radical can be effectively antagonized.
In conclusion one kind quality of hyaluronic acid injections containing amino acid disclosed in this invention is stablized, preparation process is closed
Reason, easy to use, the duration is long, degradable in vivo, and using safe, and it is low that adverse reaction happens rate, without it is serious simultaneously
Hair disease happens；Non-carcinogenesis, hereditary-less toxicity, cytotoxicity meet national sector standard and cure to biology no more than I grades
With the regulation of material.The addition of amino acid can effectively antagonize the degradation of free radical, hence it is evident that delay Sodium Hyaluronate in vivo
Degradation speed.
It is subcutaneously implanted effect:
Sample prepared by the sample and comparative example 1 for taking the 0.5ml embodiment of the present invention 1~3 to prepare, is implanted into rat skin respectively
Under, observation.
After sample injection prepared by Examples 1 to 3 sample and comparative example 1, the reaction such as red, swollen, livid purple is not found.
It is subcutaneously implanted 1 month, sample implant site filling effect prepared by comparative example 1 is unobvious, illustrates active principle
Concentration is relatively low, do not have answer it is effective.The sample filling effect of Examples 1 to 3 preparation is obvious, surrounding tissue variation without exception.
In order to verify the effect of product of the present invention, following trial test is carried out:
Subject:
40,30~60 one full year of life of age, health, face has obvious decree line, crow's feet, glabella line, eye rill, volume
Head line, lower eyelid recess and other Facial Depression persons etc., male or female.
Test method:
It takes the embodiment of the present invention 2 to prepare resulting product, is injected with 25G needle or 27G syringe needle, injection depth and dosage
Depending on position and degree.By needle in about 30 ° of angle insertion corium deep layer, inclined-plane downward, by being applied on plunger rod
Heating and continuous pressure carry out injected gel, while slowly extracting syringe needle out, thus solidifying organizing the formation of single uniform injection
Tree lace.
Conclusion:
Injection is observed after 48 hours, and in 40 people, injection site does not occur phenomena such as red and swollen, ecchymosis, no allergic reaction.
Injection is observed after 3 months, is had 30 people's wrinkles or recess to completely disappear in 40 people, is reached and fill and lead up effect, accounting 75%；
There are 6 people's wrinkles or recess to improve obvious, reaches satisfied and fill and lead up effect, but wrinkle or recess naked eyes are still seen, accounting 15%；Have
3 people's wrinkles or recess have a degree of improvement, but improve result and be unsatisfied with, wrinkle or more obvious, the accounting 7.5% that is recessed；
There are 1 people's wrinkle or recess preceding without significant change, wrinkle or high-visible, the accounting 2.5% that is recessed with injection.
Verified, product of the present invention is safe to the human body effectively, and total effective rate is up to 97.5%.
In conclusion one kind quality of hyaluronic acid injections containing amino acid disclosed in this invention is stablized, preparation process is closed
Reason, easy to use, the duration is long, degradable in vivo, and using safe, and it is low that adverse reaction happens rate, without it is serious simultaneously
Hair disease happens；Non-carcinogenesis, hereditary-less toxicity, cytotoxicity meet national sector standard and cure to biology no more than I grades
With the regulation of material.
The above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations；Although with reference to the foregoing embodiments
Invention is explained in detail, those skilled in the art should understand that: it still may be to aforementioned each implementation
Technical solution documented by example is modified or equivalent replacement of some of the technical features；And these modification or
Replacement, the range for technical solution of various embodiments of the present invention that it does not separate the essence of the corresponding technical solution.
Claims (10)
1. a kind of Amvisc containing amino acid, which is characterized in that it is mainly comprised the following components in parts by weight: sweet ammonia
1.7~17.2 parts of acid is 0.5~5.2 part of L-PROLINE, 2.0~20.0 parts of L-Leu, 1.8~17.6 parts of L-lysine, transparent
20.0~200.0 parts of matter acid sodium, 3.6~35.8 parts of excipient, 1.4~14.3 parts of stabilizer, 1000 parts of water for injection.
2. Amvisc containing amino acid according to claim 1, which is characterized in that it mainly includes following heavy
The component of amount part: 4.3~13.8 parts of glycine, 1.3~4.2 parts of L-PROLINE, 5.0~16.0 parts of L-Leu, L-lysine
4.4~14.1 parts, 50.0~160.0 parts of Sodium Hyaluronate, 9.0~28.7 parts of excipient, 3.6~11.5 parts of stabilizer, injection
With 1000 parts of water.
3. Amvisc containing amino acid according to claim 2, which is characterized in that it mainly includes following heavy
The component of amount part: 7.0~10.0 parts of glycine, 2.0~3.0 parts of L-PROLINE, 8.0~12.0 parts of L-Leu, L-lysine
7.0~10.5 parts, 80.0~120.0 parts of Sodium Hyaluronate, 14.3~21.5 parts of excipient, 5.7~8.6 parts of stabilizer, injection
With 1000 parts of water.
4. Amvisc containing amino acid according to claim 2, which is characterized in that the excipient is sorb
Alcohol or mannitol；Preferably mannitol.
5. Amvisc containing amino acid according to claim 2, which is characterized in that the stabilizer is poly- for Portugal
Sugar or dextran；Preferably dextran.
6. the preparation method of the Amvisc described in claim 1 containing amino acid, which is characterized in that it mainly includes
Following steps:
(1) prepared by amino acid freeze-dried powder: glycine, L-PROLINE, L-Leu, L-lysine, excipient and stabilizer is molten
Solution adds pH adjusting agent and adjusts pH value of solution to 5.5~7.0, active carbon is added and is filtered in water for injection, after freeze-drying,
Obtain amino acid freeze-dried powder；
(2) prepared by sodium hyaluronate solution: Sodium Hyaluronate being dissolved in phosphate buffer solution, pH adjusting agent adjusting is added
For pH value of solution to 5.5~7.0, filtering obtains sodium hyaluronate solution.
7. the preparation method of the Amvisc according to claim 6 containing amino acid, which is characterized in that in step
(1) and in step (2), the pH adjusting agent is sodium hydroxide solution, hydrochloric acid solution or phosphoric acid solution.
8. the preparation method of the Amvisc according to claim 6 containing amino acid, which is characterized in that in step
(2) in, the phosphate buffer solution is the mixed solution of sodium dihydrogen phosphate, disodium phosphate soln or both；It is preferred that
, the disodium hydrogen phosphate that phosphate buffer solution is selected from the sodium dihydrogen phosphate that pH is 5.0~7.5, pH is 5.0~7.5 is molten
The mixed solution of sodium dihydrogen phosphate and disodium phosphate soln that liquid or pH are 5.0~7.5.
9. the preparation method of the Amvisc according to claim 6 containing amino acid, which is characterized in that in step
(1) in, the excipient is sorbierite or mannitol；Preferably mannitol；The stabilizer is glucan or dextran；It is excellent
It is selected as dextran；The mass ratio of active carbon and L-Leu is 0.1~1:1；Preferably 0.15~0.6:1；More preferably
0.6:1。
10. the preparation method of the Amvisc according to claim 6 containing amino acid, which is characterized in that in step
Suddenly in (2), the mass volume ratio of Sodium Hyaluronate and phosphate buffer solution is 0.02~0.2:1g/ml；Preferably 0.05~
0.15:1g/ml。
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| CN113230452A (en) * | 2021-05-28 | 2021-08-10 | 易生彬 | Face filler and preparation method thereof |
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