CN116687784A - Beauty soluble microneedle, preparation method and application - Google Patents
Beauty soluble microneedle, preparation method and application Download PDFInfo
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- CN116687784A CN116687784A CN202310497196.9A CN202310497196A CN116687784A CN 116687784 A CN116687784 A CN 116687784A CN 202310497196 A CN202310497196 A CN 202310497196A CN 116687784 A CN116687784 A CN 116687784A
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- CN
- China
- Prior art keywords
- microneedle
- component
- hexapeptide
- palmitoyl
- acid
- Prior art date
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- 238000002360 preparation method Methods 0.000 title description 32
- 230000003796 beauty Effects 0.000 title description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000007524 organic acids Chemical group 0.000 claims abstract description 15
- 239000002537 cosmetic Substances 0.000 claims abstract description 12
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- 208000035473 Communicable disease Diseases 0.000 claims abstract 2
- 210000004400 mucous membrane Anatomy 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 30
- 238000010438 heat treatment Methods 0.000 claims description 12
- -1 tripeptide-4 Chemical compound 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 8
- 150000001413 amino acids Chemical group 0.000 claims description 7
- IHRKJQSLKLYWBQ-QKDODKLFSA-N (2s)-2-[[(2s)-1-[(2s)-5-amino-2-[[2-(hexadecanoylamino)acetyl]amino]-5-oxopentanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound CCCCCCCCCCCCCCCC(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN=C(N)N)C(O)=O IHRKJQSLKLYWBQ-QKDODKLFSA-N 0.000 claims description 6
- 208000005156 Dehydration Diseases 0.000 claims description 6
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 claims description 6
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 6
- 235000001014 amino acid Nutrition 0.000 claims description 6
- 238000007664 blowing Methods 0.000 claims description 6
- 238000005266 casting Methods 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 230000018044 dehydration Effects 0.000 claims description 6
- 238000006297 dehydration reaction Methods 0.000 claims description 6
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
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- AJLNZWYOJAWBCR-OOPVGHQCSA-N (4s)-4-acetamido-5-[[(2s)-1-[[(2s)-1-[[(2s)-5-amino-1-[[(2s)-1-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-4-car Chemical compound OC(=O)CC[C@H](NC(C)=O)C(=C)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(N)=O AJLNZWYOJAWBCR-OOPVGHQCSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- QRYRORQUOLYVBU-VBKZILBWSA-N Carnosic acid Natural products CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 claims description 4
- 108010087806 Carnosine Proteins 0.000 claims description 4
- MVORZMQFXBLMHM-QWRGUYRKSA-N Gly-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CN=CN1 MVORZMQFXBLMHM-QWRGUYRKSA-N 0.000 claims description 4
- 229940044199 carnosine Drugs 0.000 claims description 4
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 claims description 4
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000003910 polypeptide antibiotic agent Substances 0.000 claims description 4
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- XWZAWHJNTHSHGD-SIDOVBMKSA-N (2S)-6-amino-N-[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]-2-[[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]propanoyl]amino]hexanamide Polymers CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1ccccc1)C(N)=O XWZAWHJNTHSHGD-SIDOVBMKSA-N 0.000 claims description 2
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- ROTFCACGLKOUGI-JYJNAYRXSA-N (2s)-2-[[(2s)-2-[[(2s)-2-(3-acetamidopropanoylamino)-3-(1h-imidazol-5-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1h-imidazol-5-yl)propanoic acid Chemical compound C([C@H](NC(=O)CCNC(=O)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CN=CN1 ROTFCACGLKOUGI-JYJNAYRXSA-N 0.000 claims description 2
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- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000036559 skin health Effects 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000002759 woven fabric Substances 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a microneedle, which comprises a first component, a second component and water, wherein the first component is organic acid, the second component is amino acid and/or active peptide, and the mass ratio of the first component to the second component is 0.2-2:1, a step of; the mass percentage of the injectable water is 0.05-5%, and the elastic modulus of the microneedle is more than 1Gpa. The micro-needle provided by the invention has the advantages of good molding rate, high hardness of the needle tip and high skin penetration rate, and can effectively improve the percutaneous efficacy of active ingredients such as cosmetic peptides and the like, and the soluble micro-needle can be suitable for various infectious diseases of skin and mucous membrane and medical skin care.
Description
Technical Field
The invention belongs to the field of biological materials, and relates to a beauty soluble microneedle, a preparation method and application thereof.
Background
The micro needle is composed of an array of fine needle structures with a micron-sized diameter and a base support layer. The microneedle drug delivery is realized by penetrating the stratum corneum on the skin to generate a micron-sized channel which allows the functional molecules to enter the skin, is a novel transdermal drug delivery mode, and has the advantages of painless, good patient compliance, convenience for autonomous drug delivery and high-efficiency delivery.
Microneedles have proven to be an effective drug delivery means, and japanese Cosmed pharmaceutical companies have developed microneedle products using sodium hyaluronate and collagenHas been successfully marketed for whitening and freckle removing applications. There are also parts of microneedle products already in clinical use, coated microneedles developed by zosan Pharma>For parathyroid hormone delivery, phase I/II studies; nanoPass Technologies develop->Hollow microneedles are used in clinical studies to deliver insulin, influenza vaccine and lidocaine (for local anesthesia). The literature and patents also report microneedles for use in a variety of small molecule drugs, such as lidocaine, insulin, artemether, fentanyl, alendronate, levonorgestrel, huperzine AAnd the delivery of caffeine, etc. Chinese patent CN111991344B discloses a microneedle patch suitable for local anesthesia, which has painless administration and high patient compliance; fast anesthetic effect, high drug administration efficiency and the like.
Microneedles can be classified into solid microneedles, hollow microneedles, coated microneedles, soluble microneedles, hydrogel microneedles, and the like, according to the mechanism of drug release. Different microneedles have different release characteristics: 1) "poking and pasting" is a two-step administration process of solid microneedles. The microneedles are applied to the skin, followed by complete removal of the microneedles and application of the patch containing the drug formulation to the microneedle application site so that the drug diffuses into the skin through the micropores created by the solid microneedles, the amount of drug administered being dependent primarily on the pore size and number. The advantageous technique of this approach is simple, does not require encapsulation or coating processes of the drug, but delivers the drug with less efficacy. 2) The release mode of the hollow microneedle is poking and flowing, and the hollow microneedle has the advantages that the drug can be accurately controlled by adjusting the drug delivery rate, but the hollow pore canal of the microneedle is blocked, and the strength of the microneedle is damaged; and the preparation of the microneedles requires more complicated equipment and the like. 3) The "coating and poking" method, i.e., the release of coated microneedles, which have been coated with a variety of drugs to form a dry coating, is commonly used for vaccine delivery. Release occurs by separation or dissolution of the coating from the microneedle surface. This method requires the development of an efficient coating procedure, and the partial drug coating reduces the sharpness and/or penetration capability of the microneedles. 4) "poking and release" is generally the manner in which soluble microneedles and hydrogel microneedles are released. In the preparation process, the medicine is encapsulated in a needle tip matrix, and after the microneedle is inserted into the skin, the medicine is dissolved and locally released after the needle body is contacted with interstitial fluid of the skin. Coated microneedles or soluble microneedles have been a trend in development due to their simple manufacturing process, efficient delivery efficiency, and safety.
However, in practical applications, the loading of the active ingredient has a negative correlation with the strength of the microneedles, and the increase of the dosage of the microneedles is limited. In the microneedle preparation process, a mould casting method is a common production process for preparing microneedles, however, defective products are formed due to precipitation of part of active ingredients in a microneedle mould, bubble aggregation and the like. In addition, in the case of skin application, especially facial skin application, conventional application time is mainly 10 minutes to 8 hours (overnight), and thus, controlling the dissolution rate of the soluble microneedles is also a problem to be solved. How to optimize the microneedle formulation and solve the problems in the application are of great importance.
Disclosure of Invention
Aiming at the background technical problems, the invention provides a carrier-free and high-dosage formulation which has high dry hardness and can be dissolved quickly in water. Can be used alone or conveniently added into other product formulations, and is especially suitable for being used as a functional coating of the micro-needle and a soluble micro-needle for medical repair of skin.
Active peptides have been used in various cosmetics as active ingredients of cosmetic products, and thus this part is applied to active peptides in the field of skin health, also called cosmetic peptides. Cosmetic peptides have numerous advantages, for example, their composition is well-defined, mostly consisting of 2-10 amino acids, with specific amino acid sequences; the mechanism of action is clear, and specific receptor genes acting on the skin are generally clarified.
To achieve the above object, the first aspect of the present invention provides a microneedle, which comprises a first component, a second component and water, wherein the first component is an organic acid, and the second component is an amino acid and/or an active peptide, and wherein the mass ratio of the first component to the second component is 0.2-2:1, a step of; the mass percentage of the injectable water is 0.05-5%, and the elastic modulus of the microneedle is more than 1GPa; preferably, the microneedles are transparent or translucent microneedles.
The active peptide is antibacterial peptide and cosmetic peptide with net positive charges.
Preferably, the cosmetic peptide refers to peptide raw materials listed in the catalogue of raw materials for cosmetics used (2021 edition) issued by the national drug administration, and/or peptide raw materials recorded in the international dictionary and handbook of raw materials for cosmetics, and/or peptide raw materials recorded in the database of official cosmetic ingredients of the european union.
More preferably, the cosmetic peptide is selected from carnosine (H-beta-Ala-His-OH), decarboxylated carnosine, dipeptide-2, acetylDipeptide-1, dipeptide-like snake venom peptide (H-beta-Ala-Pro-Dab-NHBzl), palmitoyl dipeptide-7, copper peptide (Gly-D-His-Lys-Cu) 2+ ) Tripeptide-1, tripeptide-4, citrulline tripeptide-10 (H-Lys-Asp-Ile-Cit-OH), palmitoyl tripeptide-1, palmitoyl tripeptide-5, tetrapeptide-7, tetrapeptide-30, acetyl tetrapeptide-5, acetyl tetrapeptide-9, palmitoyl tetrapeptide-3, palmitoyl tetrapeptide-7 (Pal-Gly-Gln-Pro-Arg-OH), pentapeptide-3, acetyl pentapeptide-1, palmitoyl pentapeptide-3, palmitoyl pentapeptide-4, palmitoyl pentapeptide-33, myristoyl pentapeptide-11, myristoyl pentapeptide-17 (Myr-Lys-Leu-Ala-Lys-Lys-NH) 2 ) HB1518 (Ser-Leu-Tyr-Gln-Ser), hexapeptide-2, hexapeptide-5, hexapeptide-8, hexapeptide-9, hexapeptide-10, hexapeptide-11, acetyl hexapeptide-3 (8) (Ac-Glu-Glu-Met-Gln-Arg-Arg-NH) 2 ) Acetyl hexapeptide-38, acetyl hexapeptide-39, myristoyl hexapeptide-16, palmitoyl hexapeptide-21 (Pal-FALLKL-NH) 2 )、HB1061(MGRNIRN-NH 2 ) Acetyl octapeptide-1, nonapeptide-1 (Met-Pro-D-Phe-Arg-D-Trp-Phe-Lys-Lys-Pro-Val), oligopeptide-10 (FAKALKALLKALKAL-NH) 2 ) And palmitoyl dipeptide-5 double salts, etc.
The antibacterial peptide with net positive charge and separated hydrophobic and hydrophilic region amphiphilic structure is selected from human LL-37, magainin2, human beta defensin 2 (HBD 2), human alpha defensin 5 (HD 5), CATH-2, SGX942 (H-Arg-Ile-Val-Pro-Ala-NH) 2 ) One or more of silk peptide, brilaceidin and Niu Baka mycin.
Aiming at the problems that the loading amount of the active ingredient is negatively related to the strength of the micro-needle and the dosage of the micro-needle is limited, the invention obtains the formulation which is completely composed of the active ingredient and can be used for preparing the micro-needle through phase regulation. By regulating the intermolecular project action, a ternary supermolecular network system of organic acid, active peptide and water is proposed, and the lattice energy of the active peptide component is reduced, so that the ternary system forms a new liquid phase under the condition of heating. The new liquid phase has high viscosity, is solidified after cooling, and the solidified system has both hardness and toughness, thus being suitable for the preparation of microneedles.
In a second aspect, a method for preparing the microneedle is provided, which mainly comprises the following steps:
1) Preparing a first component solution, adding a second component with a formula amount into the first component solution, and uniformly mixing;
2) Carrying out system dehydration and solidification treatment on the mixed solution in the step 1;
3) When the water content in the system in the step 2 is reduced to a certain value, the preparation is obtained after the preparation is placed at room temperature.
Specifically, the dehydration curing treatment comprises one or a combination of more of heating drying, decompression drying, air blowing, hot air blowing, nitrogen blowing and supercritical drying.
The heating and drying temperature is 40-100 ℃, preferably 40-80 ℃.
The water content is in the range of 0.05% -5%.
The formula preparation regulates and controls multiple non-covalent bond actions, particularly hydrogen bond interactions, between the organic acid and the active peptide through bound water in the system to form a supermolecule hydrogen bond network and strengthen the mechanical strength of the material, so that the mechanical strength of the microneedle can be enhanced in micro-processing described below, and the microneedle can successfully puncture skin. And because of the relatively stable bound water network in the preparation, the stability of the reservoir of the active peptide is obviously improved, so that the preparation is more suitable for application of peptide active molecules.
Other skin valuable substances can be loaded in the formula preparation provided by the invention, including but not limited to effective components such as antioxidants, moisturizers, whitening agents, anti-inflammatory agents, spot-removing agents, wrinkle-removing agents, hair growth promotion agents, sun-screening agents and the like. The content of the valuable substances in the skin is not more than 5% of the total mass of the formulation.
In a third aspect, the formulations of the present invention may be used as tip coatings for the preparation of coated microneedles.
Specifically, the preparation of the invention can be coated on solid microneedles by means of heating, flowing-cooling and solidifying (fusion method) to obtain coated microneedles. The solid microneedles may be selected from solid or porous microneedles made from silicon-based, glass, ceramic, metal, polymer, sugar, and the like.
Preparation of microneedle arrays
In a fourth aspect, the formulations of the present invention may be used as a pre-formed liquid to prepare microneedle arrays by casting, stretching, atomizing spraying, microfluidics or 3D printing.
In a fifth aspect, the present invention also provides a method for preparing a microneedle array by casting from the formulation as a pre-cast solution, comprising the steps of:
1) Heating the formulation of the first aspect to obtain a flowable pre-formulation, and preheating a microneedle negative mold;
2) Pouring a proper amount of the prefabricated liquid in the step 1 into a preheated microneedle female die, filling the needle point matrix liquid into a cavity of the microneedle die through defoaming treatment, and removing bubbles;
3) Cooling the mould, and stripping and demoulding the micro-needle after the micro-needle body is solidified to obtain the micro-needle array.
Or the preparation method of the microneedle array can be combined with a preparation process and a prefabricated liquid pouring process, and the preparation method comprises the following steps of:
1) Respectively preparing an organic acid solution and an active peptide solution;
2) Uniformly mixing the organic acid solution and the active peptide solution in the step 1 according to a certain proportion, pouring the mixture into a microneedle mould, and performing system dehydration and solidification treatment;
3) When the water proportion in the system in the step 2 is reduced below a certain value, defoaming treatment is carried out;
4) And after the micro-needles are solidified, stripping and demolding the micro-needles to obtain the micro-needle array.
The water content is in the range of 0.05% -5%. The method comprises the steps of carrying out a first treatment on the surface of the
Preferably, the casting comprises high pressure spraying, centrifugation, vacuum adsorption or self-leveling;
in some of these embodiments, air is removed from the needle tip matrix liquid and/or from the microneedle mould cavity by centrifugation.
In some of these embodiments, air is removed from the needle tip matrix liquid and/or from the microneedle mould cavity by pressurization.
In some of these embodiments, reduced pressure (e.g., a vacuum) is used to remove air from the needle tip matrix solution and/or from the microneedle mould cavity.
In a sixth aspect, the method according to the fourth and fifth aspects may also be used in combination with other conventionally known manufacturing processes for manufacturing bubble microneedles, porous microneedles, layered microneedles, segmented microneedles, slow release microneedles, etc.
Specifically, in some of these embodiments, a multi-layer microneedle array is prepared comprising a microneedle substrate layer and a microneedle body comprising a microneedle root portion and a microneedle tip, the microneedle root portion being a portion connecting the microneedle substrate and the microneedle tip.
Wherein the microneedle root and/or the microneedle substrate is made of a hydrophilic polymer.
The hydrophilic polymer includes, but is not limited to, at least one of hyaluronic acid, chitosan, polyvinyl alcohol, chondroitin sulfate, polyvinylpyrrolidone, trehalose, dextran, maltose, sucrose, and carboxymethyl cellulose.
Wherein the needle tip is prepared from the formulation of the first aspect.
Specifically, in some of these embodiments, when a porogen is added to the pre-solution, a multi-hollow microneedle may be prepared.
The pore-forming agent comprises one or more of sodium chloride, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, trehalose, maltose, polyethylene glycol, cyclodextrin and derivatives thereof, polymethyl pyrrolidone (PVP), low molecular weight hyaluronic acid and sodium salt thereof (molecular weight is 5-100 kDa), and low molecular weight cellulose derivatives (molecular weight is 5-100 kDa).
Microneedle patch
In a seventh aspect, the microneedle array of the present invention may be used alone as a soluble microneedle for application to the cheek, or may be made in the form of a microneedle patch for the purpose of maintaining the integrity of needle tip penetration. The microneedle patch refers to a substrate layer comprising the microneedle array and the back side of the microneedle array matrix. The back surface refers to the surface of the substrate opposite to the protruding surface of the microneedle. The backing layer is not an essential component and is primarily intended to help more evenly conduct the force of the pressing when the microneedles are applied so that the microneedles pierce the skin to a uniform depth.
In order to stably apply and hold the microneedle patch to the skin, it is not necessary, but more preferable, to provide an adhesive support on the back of the patch. Here, "back surface" refers to the surface of the microneedle opposite to the surface on which the needle stands. The adhesive support is a support film having an adhesive layer on one side.
As the adhesive layer in the present invention, an adhesive sheet formed of a commercially available adhesive can be used. Rubber-based adhesives, silicone-based adhesives, acrylic-based adhesives, and the like can be used.
The support film is preferably a film formed of a synthetic polymer, and is required to have excellent adhesion to an adhesive, to be capable of retaining strength, and to be easily formed into a thin film. Specifically, the resin is selected from polyethylene, PET (polyethylene terephthalate), polyvinylpyrrolidone, polyvinyl alcohol and acrylic resins. In the acrylic resin, the hardness is preferably 3N or more. The hardness is more preferably 4 to 50. If the hardness is less than 3, the support film may have tackiness, which may make use inconvenient. Nonwoven fabrics, woven fabrics, and the like may also be preferable supports.
In an eighth aspect, the use of the soluble microneedle product of the present invention in transdermal formulations for dermatological disorders and/or in medical repair procedures. The skin diseases include, but are not limited to, treatment of acne, skin infection, anti-inflammatory repair, wound healing, etc. The medical and beauty repair items include, but are not limited to, anti-aging items for promoting collagen regeneration, wrinkle removal items, free radical oxidation and carbonylation resistance, whitening and freckle removal, slimming, eyelash (hair) growth promotion, breast enlargement and other items for improving the appearance or health state of the skin.
As used herein, the terms "peptide", "active peptide" refer to a molecule having at least two amino acids linked by peptide bonds, the number of amino acids being 50 or less. The term also includes peptides and derivatives thereof (e.g., glycosylated derivatives and pegylated derivatives).
Compared with the prior art, the invention has the following beneficial effects:
1) According to the invention, through a supermolecular hydrogen bond dynamic network formed among the organic acid, the active peptide and the water, the problems of hardness and toughness of the microneedle body are effectively solved, and the formability and skin penetration capability of the microneedle are improved.
2) The invention effectively solves the problem of poor storage stability of the active peptide through a supermolecular hydrogen bond dynamic network formed among the organic acid, the active peptide and the water, so that the active peptide can be stored for a long time at normal temperature.
3) According to the invention, through a supermolecule hydrogen bond dynamic network formed among the organic acid, the active peptide and the water, the release rate of the microneedle is improved, so that the microneedle can be completely released within one hour.
Description of the drawings:
FIG. 1 is a photograph of a formulation obtained in example 1;
FIG. 2 is a photograph of a PDMS negative mold 1 and a mold 2 for use in the preparation of microneedles using a casting method;
FIG. 3 shows photographs before (left) and after (right) degassing in example 13;
FIG. 4 shows photographs before (left) and after (right) degassing in example 15;
FIG. 5 is a photograph of a microneedle array prepared in examples 9-12;
FIG. 6 is a photograph of a microneedle array prepared in example 16;
FIG. 7 is a photograph of a microneedle array prepared in example 14;
FIG. 8 is a photograph of a microneedle fabricated in example 14 simulating piercing of a sealing membrane.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the invention are not limited thereto. The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications.
Additional advantages and features of the present invention will become readily apparent to those skilled in the art from the following detailed description, which, taken in conjunction with the specific embodiments, illustrate the practice of the invention. The invention may be practiced or carried out in other embodiments that depart from the specific details, and the details of the present description may be modified or varied from the spirit and scope of the present invention. Before the embodiments of the invention are explained in further detail, it is to be understood that the invention is not limited in its scope to the particular embodiments described below; it should also be understood that the terminology used in the examples of the present invention is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. The invention is not limited to the source of the raw materials, and the reagents or instruments used in the invention are conventional products commercially available through regular channels without specifying the manufacturer.
Formulation preparation
The formulations described in examples 1-8 were prepared using the formulations in Table 1 according to the following procedure:
1) Preparing a first component solution, adding a second component with a formula amount into the first component solution, and uniformly mixing;
2) Carrying out system heating and drying treatment on the mixed solution in the step 1;
3) When the water content in the system in the step 2 is reduced to a certain value, the preparation is obtained after the preparation is placed at room temperature.
The modulus of elasticity of the resulting formulation material was measured and the results are shown in Table 1.
The physical picture of the formulation obtained in example 1 of fig. 1 shows that the obtained formulation material has good plasticity and hardness, which lays a foundation for the subsequent preparation of the microneedle.
PDMS microneedle female die
The PDMS microneedle negative mold in the present invention was purchased from the state microchip pharmaceutical technologies ltd.
The specific parameters are shown in table 2 below:
fig. 2 shows photographs of the mold 1 (left) and the mold 2 (right).
Examples 9-12 preparation of microneedle arrays
The preparation of the formulation in the above example was used as a pre-solution, and the microneedle was prepared by the following procedure.
1) Heating the formulations described in examples 1-4 to obtain a flowable pre-form, and preheating the microneedle negative mould 1;
2) Pouring a proper amount of the prefabricated liquid in the step 1 into a preheated microneedle female die, filling the needle point matrix liquid into a cavity of the microneedle die through centrifugal defoaming treatment, and removing bubbles;
3) Cooling the mould, and stripping and demoulding the micro-needle after the micro-needle body is solidified to obtain the micro-needle array.
Example 13 preparation of microneedle array
The preparation of the formulation in the above example was used as a pre-solution, and the microneedle was prepared by the following procedure.
1) Heating the formulation described in example 5 to obtain a flowable pre-form, and preheating microneedle negative mould 2;
2) Pouring a proper amount of the prefabricated liquid in the step 1 into a preheated microneedle female die, filling the needle point matrix liquid into a cavity of the microneedle die through centrifugal defoaming treatment, and removing bubbles;
3) Cooling the mould, and stripping and demoulding the micro-needle after the micro-needle body is solidified to obtain the micro-needle array.
FIG. 3 shows photographs of example 13, after the preform solution was introduced into the mold in step 2, before (left) and after (right) degassing.
Example 14 preparation of microneedle array
The preparation of the formulation in the above example was used as a pre-solution, and the microneedle was prepared by the following procedure.
1) Heating the formulation described in example 6 to obtain a flowable pre-form, and preheating microneedle negative mould 1;
2) Pouring a proper amount of the prefabricated liquid in the step 1 into a preheated microneedle female die, filling the needle point matrix liquid into a cavity of the microneedle die through vacuum defoaming treatment, and removing bubbles;
3) Cooling the mould, and stripping and demoulding the micro-needle after the micro-needle body is solidified to obtain the micro-needle array.
Example 15 preparation of microneedle array
1) According to the formulation of example 7, an organic acid solution and an active peptide solution were prepared, respectively;
2) Uniformly mixing the organic acid solution and the active peptide solution in the step 1 according to a certain proportion, pouring the mixture into the microneedle mould 1, and performing system heating, drying and dehydration treatment;
3) When the water content in the system in the step 2 is reduced to 5%, carrying out centrifugal defoaming treatment;
4) And cooling the mould, solidifying the micro-needles, and stripping and demoulding the micro-needles to obtain the micro-needle array.
FIG. 4 shows photographs of example 15, after the preform solution was introduced into the mold in step 2, before (left) and after (right) degassing.
EXAMPLE 16 preparation of microneedle array
1) According to the formulation of example 8, an organic acid solution and an active peptide solution were prepared, respectively;
2) Uniformly mixing the organic acid solution and the active peptide solution in the step 1 according to a certain proportion, pouring the mixture into a microneedle mould 3, and performing system heating, drying and dehydration treatment;
3) When the water content in the system in the step 2 is reduced to 0.05%, carrying out centrifugal defoaming treatment;
4) And cooling the mould, solidifying the micro-needles, and stripping and demoulding the micro-needles to obtain the micro-needle array.
FIG. 5 is a photograph of the microneedle arrays prepared in examples 9 to 12.
FIG. 6 is a photograph of a microneedle array prepared in example 16.
FIG. 7 is a photograph of a microneedle array prepared in example 14.
Micro-needle mechanical property measurement and puncture experiment method
The penetration ability of the microneedle array was determined using a ta.newplus texture analyzer (ISENSO, usa). The literature reports that the penetration force required by the micro needle to pierce the skin is larger than 0.05N, so that the trigger force is set to be 0.05N, the pre-measurement speed is 0.5mm/s, the post-measurement speed is 15mm/s, and the relation between the stress born by the micro needle point in the probe pressing process and the probe displacement is measured through a texture analyzer, so that the breaking force is judged. The stress of the microneedle tips increased slowly with increasing needle tip variation, and the results showed that no significant breaking point was observed in the tested range (deformation 0.5 mm). In each example, the pressure applied to the tip of the microneedle was greater than 1N (table 3) when the amount of deformation of the tip of the microneedle was 0.2mm, indicating that the tip of the microneedle could easily puncture the skin. The elastic modulus and hardness of the microneedles were measured by a G200 nanoindenter (Agilent corporation). The measuring method comprises the following steps: using a triangular pyramid diamond indenter at a constant strain rate (0.05 s -1 ) The microneedle material was pressed into and the load force plotted against displacement to give its average modulus of elasticity and hardness data.
To intuitively determine the depth of penetration of the microneedle into the skin, the penetration performance of the microneedle was further evaluated by a Parafilm insertion test. The specific method comprises the following steps: after the prepared microneedle array is fixed on a microneedle insertion device, 8 layers of sealing films (Parafilm M Laboratory Film sealing films) are overlapped together (the thickness is about 1 mm) to simulate skin cuticle, and as for a foam plate, the microneedle array vertically applies pressing force to the 8 layers of sealing films for 2min, then the sealing films are peeled layer by layer, and the penetration condition of the sealing films and the integrity of a needle body are observed. The results are shown in fig. 8, which shows that the sealing film is completely punctured and the needle tip is not broken.
Table 3: evaluation of mechanical Property parameters of microneedles
The results show that the micropins prepared from the formulation provided by the invention have high hardness and toughness. The prepared soluble microneedle has good molding rate, high hardness of the needle tip and good puncture performance under the condition of keeping high active matter loading.
Rapid dissolution evaluation after skin penetration by microneedles
Wistar ST rats were shaved on the backs to form a 2cm hairless area. After 24 hours, the solution of the microneedle was observed after 15 minutes and 60 minutes after the application of a force of about 15N to the site with the microneedle array for 3 minutes.
And feeding back the dissolution condition of the micro needle by using the counted percentage of the height of the needle point of the residual micro needle to the height of the needle point of the original micro needle.
Table 4: rapid dissolution evaluation after skin penetration by microneedles
As can be seen from the data in the table, the microneedle improved by the invention can complete more than 80% of the dissolution of the needle body within one hour, and can rapidly release active molecules.
The applicant states that the detailed method of the present invention is illustrated by the above examples, but the present invention is not limited to the detailed method described above, i.e. it does not mean that the present invention must be practiced in dependence upon the detailed method described above. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (10)
1. A microneedle comprising a first component, a second component and water, wherein the first component is an organic acid and the second component is an amino acid and/or an active peptide, wherein the mass ratio of the first component to the second component is 0.2-2:1, a step of; the mass percentage of the injectable water is 0.05-5%, and the elastic modulus of the microneedle is more than 1GPa; preferably, the microneedles are transparent or translucent microneedles.
2. The microneedle of claim 1, wherein said active peptide is an antibacterial peptide having a net positive charge, a cosmetic peptide selected from the group consisting of carnosine (H-beta-Ala-His-OH), decarboxylated carnosine, dipeptide-2, acetyl dipeptide-1, dipeptidyl snake venom peptide (H-beta-Ala-Pro-Dab-NHBzl), palmitoyl dipeptide-7, copper peptide (Gly-D-His-Lys-Cu) 2+ ) Tripeptide-1, tripeptide-4, citrulline tripeptide-10 (H-Lys-Asp-Ile-Cit-OH), palmitoyl tripeptide-1, palmitoyl tripeptide-5, tetrapeptide-7, tetrapeptide-30, acetyl tetrapeptide-5, acetyl tetrapeptide-9, palmitoyl tetrapeptide-3, palmitoyl tetrapeptide-7 (Pal-Gly-Gln-Pro-Arg-OH), pentapeptide-3, acetyl pentapeptide-1, palmitoyl pentapeptide-3, palmitoyl pentapeptide-4, palmitoyl pentapeptide-33, myristoyl pentapeptide-11, myristoyl pentapeptide-17 (Myr-Lys-Leu-Ala-Lys-Lys-NH) 2 ) HB1518 (Ser-Leu-Tyr-Gln-Ser), hexapeptide-2, hexapeptide-5, hexapeptide-8, hexapeptide-9, hexapeptide-10, hexapeptide-11, acetyl hexapeptide-3 (8) (Ac-Glu-Glu-Met-Gln-Arg-Arg-NH) 2 ) Acetyl hexapeptide-38, acetyl hexapeptide-39, myristoyl hexapeptide-16, palmitoyl hexapeptide-21 (Pal-FALLKL-NH) 2 )、HB1061(MGRNIRN-NH 2 ) Acetyl octapeptide-1, nonapeptide-1 (Met-Pro-D-Phe-Arg-D-Trp-Phe-Lys-Lys-Pro-Val), oligopeptide-10 (FAKALKALLKALKAL-NH) 2 ) And one or more of palmitoyl dipeptide-5 double salts; the antimicrobial peptide is selected from human LL-37, magainin2, human beta defensin 2 (HBD 2), human alpha defensin 5 (HD 5), CATH-2, SGX942 (H-Arg-Ile-Val-Pro-Ala-NH) 2 ) One or more of silk peptide, brilaceidin and Niu Baka mycin.
3. The microneedle of claim 1, wherein the amino acid is selected from one or more of arginine, histidine, lysine, tryptophan, tyrosine, valine, alanine, and proline.
4. The microneedle of claim 1, wherein the organic acid is one or more selected from the group consisting of salicylic acid, citric acid, tartaric acid, oxalic acid, malic acid, ascorbic acid, benzoic acid, caffeic acid, chlorogenic acid, and acetic acid.
5. The microneedle according to claim 1, wherein the microneedle is obtained by dehydrating and solidifying a system containing a first component, a second component and water; preferably, the dehydration curing treatment comprises one or a combination of more of heating drying, decompression drying, air blowing, hot air blowing, nitrogen blowing and supercritical drying.
6. The microneedle of claim 1, which is a coated microneedle, a bubble microneedle, a porous microneedle, a layered microneedle, a segmented microneedle, or a slow release microneedle.
7. A microneedle array, wherein at least a portion of the microneedles of the microneedle array are the microneedles of any one of claims 1-6.
8. The microneedle array of claim 7, wherein the microneedle array is obtained by one or more of a fusion method, a casting method, a stretching method, an atomizing spray method, a microfluidic method, or a 3D printing method.
9. The microneedle array of claim 7 or 8, wherein the microneedle array is not loaded with other active ingredients or is further loaded with delivery antioxidants, moisturizers, whitening agents, anti-inflammatory agents, spot-removing agents, wrinkle-removing agents, hair growth-promoting, sun-protecting agents, and/or other cosmetic active ingredients.
10. Use of a microneedle array according to any one of claims 7-9, comprising: for the treatment of various infectious diseases of the skin, mucous membranes or for skin care.
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