CN108721204A - A kind of solubility alkannin microneedle patch and preparation method thereof - Google Patents
A kind of solubility alkannin microneedle patch and preparation method thereof Download PDFInfo
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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Abstract
The invention discloses a kind of soluble alkannin microneedle patch and preparation method thereof, it is prepared into after embedded object together with hyaluronic acid, dipotassium glycyrrhizinate, vitamin E, allantoin, solubilizer, cosolvent, bio-soluble high molecular material to be dissolved in deionized water and be prepared into note film liquid using alkannin, gamma-cyclodextrin and cast in the microneedles template of specific structure, isolated solubility alkannin microneedle patch after solidification.It has the following advantages compared with prior art：The drug being wrapped in soluble micropin is gradually released as soluble high-molecular material dissolves in skin, the drugloading rate with better biocompatibility and bigger；Material used is high-molecular biologic soluble material, safe；And preparation method is simple, preparation condition is mild, can keep the stability of active constituent well, and active constituent content is high, mildly, plurality of active ingredients synergistic effect, the effect of reaching more preferably skin problem.
Description
Technical field
The present invention relates to medical microneedle patch field more particularly to a kind of soluble alkannin microneedle patch and its preparation sides
Method.
Background technology
The skin problems such as nowadays people increasingly pay attention to the maintenance of skin, and small pox, dark sore, acne, color spot, pore are coarse are very
It is common also to perplex very much.And the usual active ingredient for the treatment of for these skin problems is difficult completely by percutaneous absorption, into epidermis
Basal layer plays repair.
There are the utilization of many advantages, especially Chinese medicine compound prescription, clinical and experiments in terms for the treatment of skin disease for Chinese Drug Zicao
Research confirms that Asian puccoon has anti-inflammatory, antibacterial, antipruritic and reparation and other effects, and in the healing and reparation of wound, effect is fine.
Alkannin is cosmetically having prodigious utility value, is suitble to various skin quality, can promote the healing of wound, reaches removal dark sore, acne
Print, lighten the stain the effect of scar.
Hyaluronic acid moistens moisturizing skin as efficient moisture-retention ingredient, maintains skin repair environment.
The tocopherol molecule contained in vitamin E can penetrate into epidermis, even up to subcutaneous tissue.The side chain of vitamin E
The oxidation-reduction process for directly participating in sulfydryl reduces the formation of melanin to inhibit tyrosinase activity.Vitamin E also has
There is expansion peripheral vessel, improve the effect of blood vessel microcirculation, the conveying of nutritional ingredient can be promoted and is metabolized the row of rubbish in vivo
It lets out, to be also beneficial to dispelling for " spot ".External application vitamin E can accelerate skin metabolism, promote blood circulation, and accelerate cell
It repairs and regenerates, while Green Tea Extract ingredient can also be generated, anti-lipid peroxidation reaction keeps contacting between tissue, makes skin
It is smooth, flexible.Since vitamin E can protect cell membrane from the oxidative damage of free radical, so can help to repair and consolidate
The natural protective barrier of skin locks moisture in skin, and the deep layer provided from inside to outside is nourished.
Allantoin, which has, promotes cell growth, accelerates wound healing, the physiological functions such as cutin-softening albumen, are skin traumas
Good consolidant and antiulcer agents.It can in conjunction with many kinds of substance formed double salt, have be protected from light, sterilization and anticorrosion, analgesic, antioxygen
Change acts on, and skin can be made to keep moisture content, moistens and soft.
Dipotassium glycyrrhizinate has anti-inflammatory, antiallergy, moisturizing and other effects, can effectively prevent allergy, mitigates scytitis.
The above ingredient has certain effect effect in skin repair, can mutually promote changing aspect, there is collaboration to make
With.
Micropin is a diameter of tens microns, acicular texture of the length at 100 μm or more.Because the size of micropin is small, piercing
Skin corium will not be reached by entering in skin, be not easy to touch pain nerve and generate feeling of pain, active ingredient can be made to be formed along micropin
Microchannel reaches epidermis deep layer, diffuses into corium, active ingredient is made adequately to be absorbed, and plays curative effect.
The micropin used at present is mostly biological non-degradable solid microneedles, such as micropin idler wheel, silicon micropin, metal micro-needle etc.
This kind of micropin is very tiny, and it is possible that it is broken that fracture, which itself occurs, during being inserted into skin, although preparing the material of micropin
What is selected is all the metal and silicon of good biocompatibility.But it's hard to say these material over time stay in skin will not cause it is any
Adverse reaction.Empty micropin can inject various drug solutions under cuticula, greatly improve the application of active constituent, but be difficult to protect
Card empty micropin will not block, and apply inconvenience.
Soluble microneedle patch is prepared using bio-soluble high molecular material, if can by alkannin active constituent,
The active ingredients such as hyaluronic acid, dipotassium glycyrrhizinate, allantoin combine with soluble microneedle patch to be studied, when piercing skin
Soluble micropin dissolves under liquid effects after skin stays in skin, and not only active constituent is also greatly utilized, in conjunction with upper
State the synergistic effect of compound, it will solve the above problems.
There are also the researchs of relevant microneedle patch, such as a kind of multiple-effect reparations of Chinese patent CN104921961A at present
Degradable biological microneedle patch, disclose a kind of degradable biological microneedle patch of the multiple-effect reparation of different release gradient, it is described
Biological microneedle patch, including substrate, and solid first microneedle array positioned at upper surface of substrate, the second microneedle array and the back of the body apply
Layer.Preparation method is complicated, and the direct coating of active constituent, on micropin, drugloading rate is few, and work is not ensured that in skin
Property ingredient can be absorbed by skin well.
Invention content
Goal of the invention：In order to overcome problems of the prior art, the present invention proposes that a kind of usage comfort is high, peace
Full performance is high, bio-compatible performance is good, does not cause any wound of skin, pain and stimulation, and that improves active constituent utilization rate can
Dissolubility alkannin microneedle patch and preparation method thereof.
Technical solution：In order to solve the above-mentioned technical problem, the technical solution adopted in the present invention is：
A kind of solubility alkannin microneedle patch, prepares raw material including following by weight：Alkannin 0.05%~
0.15%, gamma-cyclodextrin 0.5%~1.5%, hyaluronic acid 0.05%~0.5%, dipotassium glycyrrhizinate 0.05%~0.5%, dimension
Raw element E 0.05%~1%, allantoin 0.1%~1%, solubilizer 0.5%~5%, cosolvent 0.5%~10%, biology can
The deionized water of soluble macromolecular material 25%~40% and surplus.
In order to obtain superior anti-inflammatory fungistatic effect, the alkannin purity is not less than 80%.
The alkannin purity is not less than 80%；The extraction process of the alkannin is:
(1) it digests：Asian puccoon is crushed to 20~40 mesh, is scattered in the water of 10~16 times of quality, Asian puccoon quality is added
0.2%~0.8% complex enzyme formulation carries out enzymolysis 6-15h；35~55 DEG C of the temperature of enzymolysis；The complex enzyme formulation is with quality
Percentages group becomes the enzyme pectase of 50%~80% cellulose 15%~30% and the zytase of surplus；It is described multiple
The average enzyme activity of synthase preparation is 10000~50000 units；
(2) buck extracts：Sodium hydroxide is added into system after enzymolysis and extracts 1~2h, obtains Asian puccoon extract；Hydrogen-oxygen
Change final concentration of 0.2~0.5M of the sodium in system；
(3) it isolates and purifies：It parses, concentration, done through alumina column chromatography, methanol after the alkannin extract is filtered
Dry to obtain alkannin crude product, alkannin crude product obtains the alkannin through alcohol crystal after filtering and drying.
More preferably, the solubilizer be Families of poloxamers, in Crodaret series at least
It is a kind of.
More preferably, the cosolvent be glycerine, propylene glycol, 1,3-BDO, polyethylene glycol, in sorbierite at least
It is a kind of.
More preferably, the bio-soluble high molecular material is polyvinyl alcohol, povidone, carboxymethyl cellulose, gathers
At least one of glutamic acid, polyethylene glycol；Above-mentioned material has security performance height, the good characteristic of compatibility.
More preferably, the molecular weight of the bio-soluble high molecular material is 10KDa~25KDa.
The invention also discloses the preparation methods of above-mentioned soluble alkannin microneedle patch, include the following steps：
A) each raw material is weighed first, in accordance with ratio requirement；
B) alkannin is subjected to embedding treatment with gamma-cyclodextrin, specifically dissolves alkannin 1~5mL ethyl acetate,
It is mixed with gamma-cyclodextrin, is concentrated under reduced pressure at 35~55 DEG C and is dried to powder and obtains alkannin embedded object；
C) by hyaluronic acid, dipotassium glycyrrhizinate, vitamin E, allantoin, solubilizer, cosolvent, bio-soluble macromolecule
Alkannin embedded object is dissolved in deionized water obtained by material, step b), is stirred evenly, de-bubbled must note film liquid；
D) note film liquid is cast in the microneedles template mold of specific structure, is dried in vacuo 5~12 hours at 35~55 DEG C,
It is to be solidified completely after, stripping mold has the soluble alkannin microneedle patch of microneedle array to get being stood in substrate.
More preferably, microneedle array length described in step d) is 100~1000 μm.
Advantageous effect：A kind of soluble alkannin microneedle patch provided by the invention and preparation method thereof, using alkannin,
Gamma-cyclodextrin is prepared into after embedded object and hyaluronic acid, dipotassium glycyrrhizinate, vitamin E, allantoin, solubilizer, cosolvent, life
Object soluble high-molecular material be dissolved in together deionized water be prepared into note film liquid cast in the microneedles template of specific structure, cure
Isolated soluble alkannin microneedle patch afterwards.It has the following advantages compared with prior art：It is wrapped in soluble micropin
Drug gradually released as soluble high-molecular material dissolves in skin, have better biocompatibility and bigger
Drugloading rate；Material used is high-molecular biologic soluble material, safe；And preparation method is simple, preparation condition temperature
With can keep the stability of active constituent well, active constituent content is high, and mildly, plurality of active ingredients synergistic effect reaches
More preferably skin problem the effect of.
Specific implementation mode
With reference to embodiment, the present invention is described in further detail：
Embodiment 1：
A kind of solubility alkannin microneedle patch, prepares raw material including following by weight：Alkannin 0.05%, γ-
Cyclodextrin 0.5%, hyaluronic acid 0.1%, dipotassium glycyrrhizinate 0.05%, vitamin E 0.05%, allantoin 0.2%, Bo Luosha
Nurse 188 1%, propylene glycol 2%, polyvinyl alcohol 25%, surplus are deionized water.
The preparation method of above-mentioned solubility alkannin microneedle patch, specifically comprises the following steps：
A) each raw material is weighed first, in accordance with ratio requirement；
B) alkannin is subjected to embedding treatment with gamma-cyclodextrin, specifically dissolves alkannin 3mL ethyl acetate, with
Gamma-cyclodextrin mixes, and is concentrated under reduced pressure at 45 DEG C and is dried to powder and obtains alkannin embedded object；
C) by hyaluronic acid, dipotassium glycyrrhizinate, vitamin E, allantoin, PLURONICS F87, propylene glycol, polyvinyl alcohol, step
Rapid b) gained alkannin embedded object is dissolved in deionized water, is stirred evenly, de-bubbled must note film liquid；
D) note film liquid is cast in the microneedles template mold of specific structure, 8h is dried in vacuo at 45 DEG C, it is to be solidified complete
Afterwards, stripping mold is to get the vertical soluble alkannin microneedle patch for having microneedle array in substrate；The microneedle array length is
100~1000 μm.
Embodiment 2：
A kind of solubility alkannin microneedle patch, prepares raw material including following by weight：Alkannin 0.08%, γ-
Cyclodextrin 0.8%, hyaluronic acid 0.5%, dipotassium glycyrrhizinate 0.2%, vitamin E 0.8%, allantoin 0.2%, poloxamer
188 5%, propylene glycol 10%, povidone 30%, surplus are deionized water.
The preparation method of above-mentioned solubility alkannin microneedle patch, specifically comprises the following steps：
A) each raw material is weighed first, in accordance with ratio requirement；
B) alkannin is subjected to embedding treatment with gamma-cyclodextrin, specifically dissolves alkannin 1mL ethyl acetate, with
Gamma-cyclodextrin mixes, and is concentrated under reduced pressure at 35 DEG C and is dried to powder and obtains alkannin embedded object；
C) by hyaluronic acid, dipotassium glycyrrhizinate, vitamin E, allantoin, PLURONICS F87, propylene glycol, povidone, step
B) gained alkannin embedded object is dissolved in deionized water, is stirred evenly, de-bubbled must note film liquid；
D) note film liquid is cast in the microneedles template mold of specific structure, 5h is dried in vacuo at 55 DEG C, it is to be solidified complete
Afterwards, stripping mold is to get the vertical soluble alkannin microneedle patch for having microneedle array in substrate；The microneedle array length is
100~1000 μm.
Embodiment 3：
A kind of solubility alkannin microneedle patch, prepares raw material including following by weight：Alkannin 0.1%, γ-ring
Dextrin 1%, hyaluronic acid 0.15%, dipotassium glycyrrhizinate 0.5%, vitamin E 0.3%, allantoin 0.8%, PEG-60 hydrogenate castor
Sesame oil 3%, propylene glycol 5%, carboxymethyl cellulose 33%, surplus are deionized water.
The preparation method of above-mentioned solubility alkannin microneedle patch, specifically comprises the following steps：
A) each raw material is weighed first, in accordance with ratio requirement；
B) alkannin is subjected to embedding treatment with gamma-cyclodextrin, specifically dissolves alkannin 5mL ethyl acetate, with
Gamma-cyclodextrin mixes, and is concentrated under reduced pressure at 55 DEG C and is dried to powder and obtains alkannin embedded object；
C) by hyaluronic acid, dipotassium glycyrrhizinate, vitamin E, allantoin, PEG-60 rilanit specials, propylene glycol, carboxymethyl
Alkannin embedded object is dissolved in deionized water obtained by cellulose, step b), is stirred evenly, de-bubbled must note film liquid；
D) note film liquid is cast in the microneedles template mold of specific structure, 12h is dried in vacuo at 35 DEG C, it is to be solidified complete
Afterwards, stripping mold is to get the vertical soluble alkannin microneedle patch for having microneedle array in substrate；The microneedle array length is
100~1000 μm.
Embodiment 4：
A kind of solubility alkannin microneedle patch, prepares raw material including following by weight：Alkannin 0.12%, γ-
Cyclodextrin 1.2%, hyaluronic acid 0.15%, dipotassium glycyrrhizinate 0.3%, vitamin E 0.2%, allantoin 0.2%, poloxamer
188 2%, polyethylene glycol-400 5%, povidone 35%, surplus are deionized water.
According to the above proportioning, the preparation of soluble alkannin microneedle patch is carried out by the preparation method of embodiment 1.
Embodiment 5：
A kind of solubility alkannin microneedle patch, prepares raw material including following by weight：Alkannin 0.15%, γ-
Cyclodextrin 1.5%, hyaluronic acid 0.15%, dipotassium glycyrrhizinate 0.3%, vitamin E 0.2%, allantoin 0.5%, poloxamer
407 3%, 1,3-BDO 5%, polyvinyl alcohol 40%, surplus are deionized water.
According to the above proportioning, the preparation of soluble alkannin microneedle patch is carried out by the preparation method of embodiment 1.
The extracting method of alkannin is specific as follows in embodiment 1- embodiments 5：
(1) it digests：Asian puccoon is crushed to 20 mesh, is scattered in the water of 12 times of quality, addition is equivalent to Asian puccoon quality 0.4%
Complex enzyme formulation digested；Enzymolysis time 10 hours, 45 DEG C of hydrolysis temperature, is stirred continuously in enzymolysis process；It is described compound
Calculation group becomes enzyme preparation by percentage to the quality：60% cellulase, 25% pectase, remaining is zytase, compound
The average enzyme activity of enzyme preparation is 45000 units.
(2) buck extracts：The sodium hydroxide that mass fraction is 20% is added into system after enzymolysis to extract, until hydrogen-oxygen
Change the final concentration of 0.3M of sodium, 2h extraction alkannins are stirred at room temperature, obtain alkannin extract；
(3) it isolates and purifies：Methanol through 6 times of amount alumina column chromatographies, 3 times of column volumes after extract is filtered parses, is dense
It contracts, be dried to obtain alkannin crude product；Alkannin crude product crystallizes three times through ethyl alcohol, and the Asian puccoon of purity 98.5% is obtained after filtering and drying
Plain sterling, yield 84.6%.
Specifically, being added to after extract is filtered in the chromatographic column that filler is aluminium oxide, then with the first of 3 times of column volumes
Alcohol is eluted, and the solution eluted is concentrated, is dried to obtain alkannin crude product, wherein 6 times of amounts refer to that column volume is upper
Six times of sample amount.
Applying clinical is tested：
1) implementation：The patient on the face with small pox phenomenon is chosen, using effect is observed.Randomly select 70 patients；
10 patients are one group, are divided into embodiment 1, embodiment 2, embodiment 3, embodiment 4, embodiment 5, control group, blank group seven
Group；The microneedle patch that wherein embodiment 1-5 is prepared using embodiment 1-5 using twice, waits for that micropin is completely dissolved, removes for one week
?；Control group is pasted using commercially available micropin small pox, using twice, waits fully absorbing within one week；Blank group is without using any interior with outer
Use treatment articles.
2) test result：After a week, the results are shown in Table 1：
1 embodiment 1-5 of table and control group and blank group Comparison of therapeutic clinical observation result
Healing+the ratio of being relieved that data shown by the table 1 can be seen that 1- of embodiment of the present invention embodiments 5 is
100%；Healing ratio is 40%-80%；And control group only cures 20%, 20% to no effect, and blank group cures only 10%,
70% to no effect, and soluble alkannin microneedle patch prepared by 1-5 of the embodiment of the present invention for control group, blank group compared to having
There is apparent advantage curative effect.
It should be pointed out that the above specific implementation mode is only illustrative of the invention and is not intended to limit the scope of the invention,
After having read the present invention, those skilled in the art fall within appended by the application the modification of the various equivalent forms of the present invention and weigh
Profit requires limited range.
Claims (8)
1. a kind of solubility alkannin microneedle patch, it is characterised in that prepare raw material including following by weight：Alkannin
0.05%~0.15%, gamma-cyclodextrin 0.5%~1.5%, hyaluronic acid 0.05%~0.5%, dipotassium glycyrrhizinate 0.05%~
0.5%, vitamin E 0.05%~1%, allantoin 0.1%~1%, solubilizer 0.5%~5%, cosolvent 0.5%~
10%, the deionized water of bio-soluble high molecular material 25%~40% and surplus.
2. solubility alkannin microneedle patch according to claim 1, it is characterised in that the alkannin purity is not less than
80%；The extraction process of the alkannin is:
(1) it digests：Asian puccoon is crushed to 20~40 mesh, is scattered in the water of 10~16 times of quality, addition Asian puccoon quality 0.2%~
0.8% complex enzyme formulation carries out enzymolysis 6-15h；35~55 DEG C of the temperature of enzymolysis；The complex enzyme formulation is with mass percent
Meter group becomes the zytase of 50%~80% cellulase, 15%~30% pectase and surplus；The complex enzyme
The average enzyme activity of preparation is 10000~50000 units；
(2) buck extracts：Sodium hydroxide is added into system after enzymolysis and extracts 1~2h, obtains Asian puccoon extract；Sodium hydroxide
Final concentration of 0.2~0.5M in system；
(3) it isolates and purifies：Will the alkannin extract filter after through alumina column chromatography, methanol parsing, concentration, dry
To alkannin crude product, alkannin crude product obtains the alkannin through alcohol crystal after filtering and drying.
3. solubility alkannin microneedle patch according to claim 1, it is characterised in that：The solubilizer is that pool Lip river is husky
At least one of nurse series, Crodaret series.
4. solubility alkannin microneedle patch according to claim 1, it is characterised in that：The cosolvent be glycerine,
At least one of propylene glycol, 1,3-BDO, polyethylene glycol, sorbierite.
5. solubility alkannin microneedle patch according to claim 1, it is characterised in that：The bio-soluble macromolecule
Material is at least one of polyvinyl alcohol, povidone, carboxymethyl cellulose, polyglutamic acid, polyethylene glycol.
6. solubility alkannin microneedle patch according to claim 1, it is characterised in that：The bio-soluble macromolecule
The molecular weight of material is 10KDa~25KDa.
7. a kind of preparation method of soluble alkannin microneedle patch described in claim 1, it is characterised in that including walking as follows
Suddenly：
A) each raw material is weighed first, in accordance with ratio requirement；
B) alkannin is subjected to embedding treatment with gamma-cyclodextrin, specifically dissolves alkannin 1~5mL ethyl acetate, with
Gamma-cyclodextrin mixes, and is concentrated under reduced pressure at 35~55 DEG C and is dried to powder and obtains alkannin embedded object；
C) by hyaluronic acid, dipotassium glycyrrhizinate, vitamin E, allantoin, solubilizer, cosolvent, bio-soluble macromolecule material
Alkannin embedded object is dissolved in deionized water obtained by material, step b), is stirred evenly, de-bubbled must note film liquid；
D) note film liquid is cast in the microneedles template mold of specific structure, is dried in vacuo 5~12 hours at 35~55 DEG C, waited for solid
After changing completely, stripping mold is to get the vertical soluble alkannin microneedle patch for having microneedle array in substrate.
8. the preparation method of solubility alkannin microneedle patch according to claim 7, it is characterised in that micro- described in d)
Needle array length is 100~1000 μm.
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| RU2804809C1 (en) * | 2023-04-19 | 2023-10-06 | Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр онкологии имени Н.Н. Блохина" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ онкологии им. Н.Н. Блохина" Минздрава России) | Method for manufacturing biodegradable microneedle skin patch for delayed hemostimulation of cancer patients |
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