CN111904951A

CN111904951A - Microneedle patch and preparation method thereof

Info

Publication number: CN111904951A
Application number: CN202010822082.3A
Authority: CN
Inventors: 李媚
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-08-15
Filing date: 2020-08-15
Publication date: 2020-11-10

Abstract

The invention relates to a microneedle patch and a preparation method thereof, in particular to a biodegradable microneedle patch capable of being inserted into skin painlessly. The micro-needle is characterized in that the micro-needle contains a certain proportion of cross-linked sodium hyaluronate or/and cross-linked collagen and a certain analgesic material, solves the technical problems of long-acting slow release, pain during insertion and hardness of the micro-needle, and can be used in the fields of biological medicine, medical cosmetology and the like.

Description

Microneedle patch and preparation method thereof

Technical Field

The invention relates to a microneedle patch and a preparation method thereof, in particular to a biodegradable microneedle patch which is inserted into human skin and can be used in the fields of biomedicine, medical cosmetology and the like.

Background

In the fields of biomedicine and medical cosmetology, traditional oral administration, subcutaneous injection administration, transdermal patch administration and the like are the most common administration modes. Oral administration is simple and convenient and is most common, but the absorption of the medicine is influenced by the functions of intestines and stomach, and certain medicines can generate adverse stimulation to the intestines and stomach; the subcutaneous injection is a transdermal (percutaneous) administration mode, although the barrier of stratum corneum is broken through, the subcutaneous injection can accurately and effectively administer the drug, but the biggest defect of the subcutaneous injection is that the subcutaneous injection can cause pain, bacterial infection, tissue injury and the like to a human body, and even the adverse effect that a needle head is broken and left on a patient frequently occurs; transdermal patch also belongs to transdermal (percutaneous) mode, mainly utilizes the medicine to carry out drug delivery to the infiltration of skin, its advantage is convenient, painless, but because it only applies on skin and doses, because the stratum corneum of skin is to the hindrance effect of drug absorption, lead to the drug absorption rate very low, and a lot of macromolecule medicine can't get into human inner loop through passive skin permeation mode at all, therefore drug delivery is restricted to the stratum corneum, and the drug absorption effect is than relatively poor.

In recent years, degradable microneedles containing a pharmaceutically effective ingredient have been studied as a solution to the above-mentioned drawbacks of administration methods. When the microneedles are inserted into the skin surface layer and/or the skin stratum corneum layer, the active ingredients in the microneedles are supplied under the skin, and thus the microneedles inserted into the skin can be dissolved or biodegraded to disappear under the skin. Further, since the microneedles are very thin, they do not generally cause pain or bleeding even when they penetrate the skin surface layer and/or the skin stratum corneum, and the puncture wound is closed rapidly, and therefore, they are suitable as a method for subcutaneously administering a pharmaceutically effective ingredient. There are some inventions of biological microneedles, for example, patent publication No. CN201180061175.8 discloses a scheme of microneedle arrays mainly made of silk fibroin as a microneedle raw material, patent publication No. CN201180061175.8 discloses a scheme of microneedles mainly made of silk fibroin as a raw material, patent publication No. CN201210057409.8 discloses a polymer microneedle array chip, patent application No. CN201380034546.2 introduces an applicator containing a microneedle array containing a cosmetic ingredient inserted into human skin, patent application nos. CN201180067944.5 and CN201380025634.6 respectively provide microneedle manufacturing methods, and patent application No. CN201410684523.2 provides a sericin microneedle for drug delivery and a preparation method thereof.

Although the technology of the nondegradable metal material and plastic micron-sized micro-needle is mature technology, the technology is limited to the development level of the degradable material micron-sized micro-needle patch technology, and the processing technology research or development of the stable and efficient degradable micron-sized micro-needle needs further research. At present, the research of the degradable microneedles mainly focuses on solving the problems of insufficient strength or hardness of the microneedles or improving the existing degradable microneedle manufacturing method. Patent No. CN200880015048.2, which relates to a microneedle system that easily penetrates the skin surface and can dissolve or swell in the skin, is a relatively early patent disclosing a microneedle manufacturing method, aiming at the disadvantages of insufficient drug administration means and the problem of breakage and residue in the body of undegradable (metal or plastic) microneedles when the conventional skin surface is smeared or applied. The patent with application number CN201480008397.7 relates to a method for three-dimensional manufacturing of microneedles, which applies the latest 3D technology to microneedle processing, which is a great improvement over the manufacturing method of degradable microneedles generally using molds, but we know that the principle of 3D printing technology is completed by layer-by-layer curing of "ink", which has the greatest disadvantages of too low manufacturing speed, residual photo-curing components, etc., and the patent does not have any reference about manufacturing speed and safety, so the patent is an attempt to 3D print microneedle patches. The patent No. CN201180067944.5 relates to a method for manufacturing microstructure with sufficient hardness, which mainly addresses the problem of insufficient hardness of microneedle patches at that time.

Due to the fact that degradable microneedle technology products gradually enter the market in recent years, until now, due to the fact that certain degradable microneedle technologies are not broken through, the degradable microneedle technologies cannot be pushed away on a large scale, and deeper technical problems appearing in the using process are gradually exposed. For example, the technical problems that the microneedle degrades too fast during use, causes pain when inserted into the skin, and the like, are rarely reported or studied.

Disclosure of Invention

How to realize the painless insertion and long-acting sustained-release degradable microneedle, and the enough hardness becomes the key problem to be solved by the invention.

Since the market promotion of the existing microneedles is slow, the applicant has found that the problem of pain upon insertion into the skin, which is overlooked by those in the art, is an important cause. The microneedles still cause pain when inserted into the skin, and bring an unexpected experience to the user, which directly makes popularization difficult. Applicants found, by experimentation and statistical analysis in conjunction with research feedback data, that 86.5% of users were most concerned about microneedle safety, pain, beyond what was previously recognized in the art as microneedle analgesia.

In addition, the applicant found that 30% of users had great concern about the persistence of the effect of the microneedle patch, and the duration of the feedback effect was too short. However, the prior published patents and research in the field are focused on the preparation method and strength of the microneedles, and the problem of sustained effect on the microneedles is hardly involved.

At present, microneedles are all level and can only meet a certain part of skin with a same thickness, but when the microneedles are used for the skin with different thicknesses, the microneedles with the same height are difficult to meet.

The above technical problems occurring in the using process are rarely noticed in the prior art or the field, and are rarely reported or researched.

The invention relates to a microneedle patch which can be inserted painlessly, slowly released for a long time, meets individual requirements and has enough hardness and a preparation method thereof.

Degradable material refers to material that is capable of being degraded by human body fluids, enzymes or microorganisms. Microneedle spacing refers to the distance between the tips of two microneedles. The crosslinked sodium hyaluronate or crosslinked collagen, also called crosslinked product, refers to linear or branched high molecular sodium hyaluronate or collagen, which is chemically or physically reacted to link molecular chains of sodium hyaluronate or collagen by covalent bonds to form a network structure of high molecules. The crosslinking degree refers to the percentage of hyaluronic acid disaccharide monomer combined with one crosslinking agent molecule, and is calculated by the molar ratio of the hyaluronic acid monomer to the crosslinking agent. The neutral physiological isotonic phosphate buffer solution is prepared from Na₂HPO4、NaH₂PO₄And NaCl or Na₂HPO₄、KH₂PO₄And NaCl at a pH of 6.5-7.5 and an osmotic pressure of 280-320 mOsmol/L. The hyaluronic acid with average molecular weight of 1.0MDa-4.0MDa is called high molecular weight hyaluronic acid, and the hyaluronic acid with average molecular weight of 0.2MDa-0.99MDa is called low molecular weight hyaluronic acid.

As mentioned above, the microneedles will penetrate the top layer and/or stratum corneum of the skin painlessly and then be dissolved or biodegraded to achieve the desired effect. In order to ensure that the microneedles are inserted painlessly, the microneedles are usually designed to be very thin, but the microneedles are too thin, so that the microneedles are insufficient in hardness and easy to break when inserted into the skin, and are easy to degrade, and the long-acting slow-release effect is poor. In order to solve the technical problem, the technical scheme provided by the invention is as follows: a micro-needle patch (shown in figure 1) mainly comprises a micro-needle (1) and a substrate (2), wherein the micro-needle (1) contains a certain proportion of cross-linked sodium hyaluronate or/and cross-linked collagen, so as to solve the technical problems of long-acting slow release effect and micro-needle hardness of the micro-needle.

The crosslinked sodium hyaluronate or crosslinked collagen and the (non-crosslinked) sodium hyaluronate or (non-crosslinked) collagen have very large difference in three-dimensional structure, the crosslinked sodium hyaluronate gel and the crosslinked collagen have high network structure, the physical properties before and after crosslinking are greatly different, the resistance to external force is stronger, and the crosslinked sodium hyaluronate or crosslinked collagen is a material with completely different properties. In the prior art, cross-linked sodium hyaluronate or cross-linked collagen is often used as a biocompatible or biodegradable material in a gel form to improve product stability, i.e., degradation performance, and few reports have been made on maintaining the stability of micro-sized, hard, solid degradable microneedles that are difficult to manufacture. Although the patent of application No. 201510556562.9 discloses that the crosslinked derivative can improve the degradation performance of microneedles, i.e., improve the sustained-release degradation effect, the applicant has further studied intensively and found that although the degradation performance of microneedles containing the crosslinked derivative is improved, there are other unpredictable problems that the higher the proportion of the crosslinked derivative in the microneedles is, the stronger the hardness is, and the pain is more and more intense when inserted into the skin, and there is no disclosure of any problem or solution thereof.

As described in the background art, in the prior art, due to the technical limitations of the processing technology of degradable microneedles, most of the related researches or patents on the degradable microneedles are focused on the manufacturing method of the degradable microneedles or the improvement of hardness, and little research is conducted on the technical problem that the degradable microneedles are degraded too fast during the market use. According to the general development logic of things, the problems of the use process can be solved after the things are manufactured. The technical problem of how to manufacture micron-sized solid degradable microneedles is solved in the art, and similar technical problems such as short degradation performance are rarely or hardly expected.

The applicant finds through experimental research that the degradation performance, namely the slow release effect, of the microneedle is improved by optimizing the constituent materials and the proportion of the microneedle, the lubricity of the microneedle is improved, the microneedle can be inserted into the skin painlessly, and the strength requirement is met. The technical scheme provided by the application is that a certain proportion of cross-linked sodium hyaluronate or/and cross-linked collagen is added into a microneedle (1).

One embodiment of the invention shows that the degradation performance of the microneedle can be improved by crosslinking sodium hyaluronate and/or crosslinking collagen in a certain proportion, namely the long-acting slow-release effect of the degradable microneedle is better improved. Through research, the microneedle of the present invention may contain the crosslinked sodium hyaluronate or/and the crosslinked collagen in a mass fraction of more than 0.01%, the mass fraction range may be 0.1% or more, 1% or 2% or more, or 3.0% or more, and the recommended mass fraction range of the crosslinked product in the microneedle is 5% or more.

In the application, the cross-linked sodium hyaluronate can be prepared by one or a mixture of high molecular weight sodium hyaluronate and low molecular weight hyaluronic acid, and the sodium hyaluronate can be water-soluble or oil-soluble. The sodium hyaluronate or collagen provided by the application is preferably extracted by gene recombination or microbial fermentation, and can also be extracted from animals.

The embodiment of the invention shows that the microneedle contains the cross-linked sodium hyaluronate and/or the cross-linked collagen in a certain proportion, so that the degradation performance, namely the long-acting slow-release effect, of the microneedle can be improved, the hardness of the microneedle can be improved, and the hardness is stronger along with the increase of the mass fraction.

The applicant is studying the degree of crosslinking to improve the degradation properties, but the applicant has surprisingly found that the degree of crosslinking may also improve the microneedle hardness, which increases with increasing degree of crosslinking. The cross-linking degree of the cross-linked sodium hyaluronate of the present invention ranges from 0.01% to 60%, and may also range from 0.1% to 50% or from 0.5% to 40%, and the recommended cross-linking degree ranges from 1% to 30% or from 2% to 20%, and preferably from 3% to 15% or from 5% to 10%. For safety, the present invention requires that the residue of the crosslinking agent is not more than 2ppm, preferably 1ppm or less.

The embodiment of the invention shows that the crosslinking degree not only can improve the degradation performance of the microneedle, namely the long-acting slow release effect, but also is beneficial to the hardness of the microneedle.

The microneedle (1) provided by the invention also comprises hyaluronic acid, collagen, gelatin, oligopeptide, carboxymethyl starch, starch sulfate, polycarboxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, pregelatinized starch, carboxymethyl cellulose, ethyl hydroxyethyl cellulose, cellulose acetate phthalate, methyl cellulose, carboxypropyl cellulose, hydroxyalkyl cellulose, alkyl cellulose, polyvinylpyrrolidone, polylactic acid, polyvinyl alcohol, polyacrylamide polymer, polydimethylsiloxane, chondroitin sulfate, polylactic acid-glycolic acid, dextrin, polyvinyl chloride, chitosan, xanthan gum, dextran and polyglutamic acid.

One embodiment of the present invention provides microneedles consisting entirely of cross-linked sodium hyaluronate or cross-linked collagen, which, although the rigidity of the microneedles is greatly improved by the entirely cross-linked product, also increases the feeling of pain of the microneedles inserted into the skin, and brings adverse effects to the test. However, when the microneedles further contain a non-crosslinked material component, the microneedles not only have excellent degradation properties, but also are more easily inserted into the skin without pain. Applicants have discovered that other non-crosslinked components are beneficial in improving the experience of microneedles when inserted into the skin because they increase the smoothness of the microneedle surface and more advantageously reduce the resistance to insertion into the skin. Therefore, the micro-needle provided by the invention contains a certain proportion of cross-linked sodium hyaluronate and/or cross-linked collagen, and some non-cross-linked materials in the micro-needle can increase the lubricating effect of the micro-needle and are beneficial to penetrating into the skin.

The diameter of the microneedle plays an important role in the hardness of the microneedle and the administration effect, but the diameter of the microneedle influences the pain feeling when the microneedle is inserted into the skin. The diameter of the microneedles is related to the number of insertions into the skin and the resistance to insertion into the skin. Generally, the larger the diameter of the microneedle is, the stronger the hardness of the microneedle is, the larger the number of the microneedles inserted into the skin is, the better the administration effect is, but the larger the diameter is, the larger resistance is generated, and the more pain is caused when the microneedles are inserted into the skin; the smaller the diameter of the microneedle, the less resistance and the easier painless insertion into the skin, but the smaller the number of microneedles, the easier the microneedles are broken when inserted into the skin, and the less the microneedles are inserted into the skin, the shorter the degradation period of the microneedles is, and the more the administration effect of the microneedles is affected.

In order to ensure the hardness of the microneedle and the administration effect, the diameter of the microneedle needs to be selected to be large enough. In order to solve the problem that the microneedle with a larger diameter can cause pain when inserted into the skin, the applicant finds that a certain amount of analgesic material can be added into or coated on the surface of the microneedle instead of reducing the diameter of the microneedle so as to selectively sacrifice the hardness and administration effect of the microneedle.

The analgesic material can be one or more of chemical composition, plant extract and biological gene engineering product, and is preferably local analgesic or anesthetic material. The concentration of the analgesic material in the microneedle of the present invention is 0.001% to 60% by mass, and it goes without departing from the spirit of the present invention that other concentration ranges or concentration forms are also included in the scope of the present invention. The analgesic material can be selected from proper concentrations within the safe use range, and any proportion adjustment without departing from the idea of the invention is within the protection scope of the invention.

The present invention provides, in one embodiment, examples of different concentrations of analgesic material that can greatly improve the pain sensation of microneedles when inserted into the skin. In the present invention, the analgesic material may be selected from stramonium, purslane, etc. containing chemical components such as alkaloids, flavones, saponins, terpenes, etc., or may be morphine, bupivacaine, lidocaine, ticarcine, cocaine, dibucaine, cinchocaine, etidocaine, prilocaine, tetracaine, benzocaine, butacaine, oxybuprocaine, procaine, phenoxycaine, tricaine, etc., or may be a genetic engineering product, and of course, other analgesic materials may also conform to the technical scheme of the present application.

Although some patents have provided analgesic microneedles, their purpose of using analgesic materials is completely different from that of the present application, and they are carriers for inputting the microneedles into the human body as analgesic materials, and the pain solved by the analgesic materials is pain caused by other causes such as pathology or physiology, not pain caused by insertion of the microneedles themselves.

In order to satisfy the administration effect and the long-acting sustained-release effect, the diameter of the analgesic material of the microneedle is selected in a relatively large range, and the diameter of the microneedle recommended in the application is in the range of 10-1500 μm, can be in the range of 20-1200 μm or 50-1000 μm, preferably in the range of 80-800 μm or 100-600 μm, and the optimal range is in the range of 120-500 μm or 200-300 μm. Particularly, the microneedles are 250 μm in diameter, and the present application can be inserted into the skin painlessly without regard to the pain problems faced by other known microneedles. The microneedle of the present invention is a cone, a cylinder, an ellipsoid, a regular prism, a regular square prism, a regular hexagonal prism, a regular octagonal prism, a regular decaprism, a regular dodecaprism, a regular hexadecapentic prism, or a regular twenty-square prism, or any combination thereof, and may be any other shape as long as the gist of the present invention is not violated, and a cone and a cylinder are preferable. The microneedles with different shape combinations can be designed according to requirements.

The height of the microneedles (1) affects the depth of insertion into the skin, determining the effect of the drug delivery: the larger the height is, the deeper the skin is, the more the number of the microneedles which penetrate into the skin is, the more the microneedle can be inserted into the skin, the more the quantity of the microneedles which can be inserted into the skin is, and the degradation period is increased, namely, the more excellent the long-acting slow release of the microneedles is; the smaller the height, the shallower the depth of insertion into the skin, the smaller the number of microneedles penetrating the skin, the more easily the microneedles are degraded, the smaller the amount of drug inserted into the skin, and the worse the long-acting sustained release effect of the microneedles is. That is, the larger the height, the better the sustained release effect, but the stronger the tingling sensation, and the smaller the height, the worse the sustained release effect, but the weaker the tingling sensation.

An embodiment of the invention shows that the technical scheme of the invention not only improves the height of the microneedle, ensures the administration slow-release effect of the microneedle, but also does not increase the pain of the microneedle inserted into the skin. The height of the microneedle recommended by the invention is 0.15-2.0mm, also can be 0.20-1.5mm or 0.25-1.0mm, preferably 0.3-0.8mm or 0.4-0.6mm, and optimally is 0.5 mm. In order to meet some individual requirements, the microneedles of the invention can be selected to be equal in height or highly inconsistent; if necessary, the microneedle mixed type microneedle patch having different heights, containing the analgesic material and not containing the analgesic material may be selected, and other height forms without departing from the spirit of the present application are also within the scope of the present invention.

The applicant researches and discovers that the degradation performance and the slow release effect of the micro-needle (1) and the pain feeling when the micro-needle is inserted into the skin can be influenced by the distance between the micro-needles in the process of inserting the micro-needles into the skin, and the prior art does not report or research the relation between the pain feeling and the slow release effect and the distance between the micro-needles. The research of the applicant finds that the smaller the distance between the microneedles is, the higher the density of the microneedles in a unit area is, the more the microneedles are inserted into the skin, so that although the degradation period of the microneedles is increased, namely the longer the long-acting slow release of the microneedles is, the smaller the distance is, the stronger force is required to press the microneedles to be inserted into the skin, and the defect that the pain and discomfort are brought to a user is overcome; the larger the distance between the microneedles is, the lower the density of the microneedles per unit area is, the smaller the number of the microneedles penetrating into the skin is, and the easier the microneedles can be inserted into the skin without pain, but the density of the microneedles per unit area is reduced, the number of the microneedles inserted into the skin is reduced, the dosage is influenced, the degradation period of the microneedles is reduced, and the longer-acting slow-release effect of the microneedles is poor. In order to ensure good administration effect and insertion experience, the distance between the microneedles provided by the invention is 0.1-2.0mm, can be 0.15-1.5mm or 0.2-1.2mm, preferably 0.3-1.0mm or 0.4-0.8mm, and preferably 0.5-0.6 mm. Under the microneedle distance, the drug delivery slow-release effect of the microneedles is ensured, and the experience of inserting the microneedles into the skin is improved.

The diameter of the needle point of the microneedle (1) directly influences the pain feeling of the microneedle inserted into the skin, and in order to reduce the pain or painless insertion of the degradable microneedle into the skin, the smaller the diameter of the needle point of the microneedle is, the better the diameter is, but the smaller the diameter is, the breakage of the needle point of the microneedle is easy to occur. Under the scheme that the invention solves the problem of microneedle insertion pain, in order to ensure the hardness and the low possibility of breakage of the needle point, the diameter range of the needle point of the needle column recommended by the invention is wider, and the selectivity is higher, and the diameter of the needle point of the application is 5-60 μm, and can be 10-50 μm or 20-30 μm.

Of course, factors affecting the hardness and degradation properties of the microneedles (1) also include the proportion of the moisture content of the microneedles. In the present invention, the moisture content concentration of the microneedle is not higher than 95% (W/W), and may be 10% to 90% (W/W), or 20% to 80% (W/W), or may be 30% to 70% (W/W), and preferably 40% to 60% (W/W), although other concentration ranges are possible as long as they satisfy the requirements.

The substrate (2) of the microneedle patch can be selected from one or more of the following degradable material materials: gelatin, oligopeptides, carboxymethyl starch, starch sulfate, polycarboxymethyl cellulose, hydroxypropylmethyl cellulose, microcrystalline cellulose, pregelatinized starch, carboxymethyl cellulose, ethylhydroxyethyl cellulose, cellulose acetate phthalate, methyl cellulose, carboxypropyl cellulose, hydroxyalkyl cellulose, alkyl cellulose, polyvinylpyrrolidone, polylactic acid, PLGA, polyvinyl alcohol, polyglycolic acid, polyphosphazene, polyacrylamide polymers, polydimethylsiloxane, chondroitin sulfate, polylactic-co-glycolic acid, dextrin, polyvinyl chloride, chitosan, typhan, guar gum, xanthan gum, dextran, alginate, polyglutamic acid, and hyaluronic acid, collagen, and derivatives thereof.

In practical application, the micro-needle is added with or attached with a pharmaceutical or cosmetic component on the surface to achieve the purpose of drug administration.

In the fields of biomedicine and medical treatment, the substance as a medicinal component can be one or more of vaccines, hormones, genetically engineered drugs, polypeptides, polysaccharides, nucleosides, proteins, chemical drugs, natural drugs and nutritional ingredients, and the nucleosides comprise nucleosides and nucleotide drugs. The added medicament can be one or the combination of the following: anti-diabetic agents, acetylsalicylic acid, angiogenic agents, antidepressants, anti-inflammatory agents, butorphanol, calcitonin and analogs, antihistamines, COX-II inhibitors, follicle stimulating hormones, dermatological agents, dopamine agonists and antagonists, immunosuppressive agents, enkephalins and other opioid peptides, erythropoietin and analogs, epidermal growth factor, glucagon, growth hormone and analogs (including growth hormone releasing hormone), luteinizing hormone, growth hormone antagonists, heparin, hirudin and hirudin analogs such as hirudin, anti-cancer agents, IgE inhibitors and other protein inhibitors, insulin, insulinotropic agents and analogs, interferons, interleukins, luteinizing hormone releasing hormone and analogs, monoclonal or polyclonal antibodies, motion sickness agents, muscle relaxants, narcotic analgesics, cancer preventing agents, nicotine, and anti-inflammatory agents, Non-steroidal anti-inflammatory drugs, oligosaccharides, parathyroid hormone and analogs, parathyroid hormone antagonists, prostaglandin antagonists, prostaglandins, scopolamine, sedatives, serotonin agonists and antagonists, sexual hypofunction, tissue plasminogen activator, tranquilizers, vaccines with or without carrier/adjuvant, vasodilators, primary diagnostics such as tuberculin and other allergic agents. The vaccine includes antigens or antigen compositions capable of inducing an immune response against human antigens or antigens from other viral pathogens, and may be a novel coronavirus vaccine, a SARS virus vaccine, a MERS virus vaccine, an influenza vaccine, a cholera vaccine, a polio vaccine, a diphtheria-pertussis-tetanus vaccine, a measles vaccine, an epidemic encephalitis vaccine, a hepatitis A vaccine, a hepatitis B vaccine, a pneumonia vaccine, a hepatitis C vaccine, a varicella vaccine, a leprosy gill vaccine, a rabies vaccine, a bronchitis vaccine, a typhoid vaccine, a dysentery vaccine, a cervical cancer vaccine, a cholera vaccine, an AIDS vaccine, an H1N1 vaccine, and the like. The protein drug may be interferon (including natural interferon and genetically engineered interferon), insulin, immunoglobulin (such as IgG, IgM, IgA, IgE), TNF-alpha, antiviral drug, etc. The nucleotide drug can be a plasmid, siRNA, RNAi, active small molecule DNA, a nucleotide anti-cancer drug, a vaccine, and the like. The medicine can be prepared by genetic engineering, or natural extract or chemical synthesis.

In the field of skin care and beauty, one or more of the following combinations can be included as cosmetic efficacy ingredients: whitening component, moisturizing component, anti-aging component, acne removing component, acne scar removing component, red blood streak removing component, scar removing component, freckle removing component, skin tendering component, chloasma treating component, sunscreen component, moisturizing component, water locking component, wrinkle removing component, anti-inflammatory component, anti-allergy component, toxin expelling component, and blood circulation promoting component. The whitening ingredient may be Sym white377, vitamin C and its derivatives or other whitening ingredients such as ascorbyl glucoside, ascorbyl palmitate, BV-OSC-tetrahexyldecanol ascorbyl ester, disodium ascorbyl phosphate, ascorbyl glucoside, other whitening ingredients are trametes, glycyrrhiza extract, aspergillus, resveratrol and its derivatives resveratrol phosphate, aleyromeles, resveratrol acetyl ferulate, yeast extract, grape seed extract, oxyresveratrol, kojic acid, ellagic acid, hinokitiol, soybean extract, scutellaria extract, glycyrrhetinic acid, mulberry extract, mellowtree molasses, ferulic acid and its derivatives, tetrahydrocurcumin, alpha (beta) -arbutin, pomegranate, resorcinol and tranexamic acid, and the like. The anti-wrinkle component may be retinol, TGF-beta, tretinoin, retinol acetate, lipoic acid, vitamin A palmitate, etc. The high molecular weight cosmetic ingredient may be bioactive peptides and derivatives thereof, nucleic acids, oligonucleotides, various antigens, bacteria, viral fragments, the bioactive peptides and derivatives thereof may be calcitonin, beta-endorphin, EGF, oxytocin, hPTH (1 → 34), glucagon, parathyroid hormone (PTH), insulin, somatostatin, adrenocorticotropic hormone, glutathione peroxidase, G-CSF, secretin, angiotensin, gastrin, enkephalin, neurotensin, somatomedin, growth hormone, luteinizing hormone releasing hormone, substance P, endothelin, interferon, atrial natriuretic peptide, vasopressin, growth hormone releasing hormone, superoxide dismutase, desmopressin, bradykinin, dynorphin, thyroid stimulating hormone, prolactin, interleukins, placental extract and salts thereof, and the like. The antigen component cosmetics include HBe antigen, HBs surface antigen, diphtheria toxoid, tetanus toxoid, beta-amyloid and the like. The blood circulation promoting component comprises unsaturated fatty acid such as catechol and DHA, alginic acid, nattokinase, citric acid, lentinacin, beta-glucan, allicin, carotene, prostaglandin A, diallyl disulfide, and sulfur amino acid.

The microneedle patch provided by the invention has the advantages of enough hardness, painless insertion, long-acting slow release and the like, can be inserted into the skin painless, so that the functional components of the medicine or the cosmetics are slowly degraded and controllably released in the skin tissue, and the optimal administration effect is achieved.

The microneedle patch of the present application can also be applied to an administration carrier for animal drugs.

The method for preparing the microneedle patch comprises the following steps:

preparing a base gel: the degradable material is prepared into gel by water or buffer solution, and the degradable material can be selected from one or more of the following combinations: gelatin, oligopeptides, carboxymethyl starch, starch sulfate, polycarboxymethyl cellulose, hydroxypropylmethyl cellulose, microcrystalline cellulose, pregelatinized starch, carboxymethyl cellulose, ethylhydroxyethyl cellulose, cellulose acetate phthalate, methyl cellulose, carboxypropyl cellulose, hydroxyalkyl cellulose, alkyl cellulose, polyvinylpyrrolidone, polylactic acid, PLGA, polyvinyl alcohol, polyglycolic acid, polyphosphazene, polyacrylamide polymers, polydimethylsiloxane, chondroitin sulfate, polylactic-co-glycolic acid, dextrin, polyvinyl chloride, chitosan, typhan, guar gum, xanthan gum, dextran, alginate, polyglutamic acid, and hyaluronic acid, collagen, and derivatives thereof. The buffer solution may be one of a common neutral buffer solution, a neutral physiological isotonic phosphate buffer solution, and a physiological saline.

Preparing a microneedle gel: the cross-linked sodium hyaluronate gel or cross-linked collagen gel is provided, and analgesic materials are mixed into the gel to be used as a base gel of the microneedle, so that the gel can be used for preparing microneedle gel.

One or more of the following degradable materials can be uniformly mixed into the basic gel to be used for preparing the microneedle gel: hyaluronic acid, collagen, gelatin, oligopeptide, carboxymethyl starch, starch sulfate, polycarboxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, pregelatinized starch, carboxymethyl cellulose, ethyl hydroxyethyl cellulose, cellulose acetate phthalate, methyl cellulose, carboxypropyl cellulose, hydroxyalkyl cellulose, alkyl cellulose, polyvinyl pyrrolidone, polylactic acid, polyvinyl alcohol, polyacrylamide polymers, polydimethylsiloxane, chondroitin sulfate, polylactic acid-glycolic acid, dextrin, polyvinyl chloride, chitosan, xanthan gum, dextran, polyglutamic acid; the mass fraction of the crosslinked sodium hyaluronate gel or/and the crosslinked collagen gel in the microneedle exceeds 0.1%, the mass fraction range can be more than 0.5%, also can be more than 1%, or more than 2.0% or more than 3%, and the mass fraction range of the recommended crosslinked product of the microneedle is more than 5%.

The microneedle gel can also be prepared by adding medicinal or cosmetic functional components into the base gel or the gel mixed with various degradable materials.

Microneedles are achieved by:

the first mode is as follows: providing a mould (1), wherein a hole (2) is formed in the mould, and the hole (2) does not penetrate through the mould (1); the diameter range of the holes (2) is 10-1500 μm, especially the finest diameter range of the holes is 10-60 μm, the depth range of the holes is 0.15-2.0mm, and the distance 3 between the holes is 0.1-2.0 mm;

injecting microneedle gel into the hole 2 of the mould, and then filling the mould 1 with the prepared substrate gel;

drying and curing, and then demoulding and sterilizing;

the mould (1) can be made of a single metal material, an alloy material or a high molecular polymer material, such as titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, aluminum alloy, copper alloy, polystyrene, polytetrafluoroethylene and the like, and has the characteristics of high hardness, high rigidity, smooth surface and the like; the shape of the hole (2) can be one or more combinations of a cone, a cylinder, an ellipsoid, a regular prism, a regular square prism, a regular hexagonal prism, a regular octagonal prism, a regular decagon prism, a regular dodecagon prism, a regular hexadeca prism and a regular twenty-four prism, and can be other shapes, and different shapes of combinations can be designed according to different requirements;

the second mode is as follows: spreading the prepared substrate gel into a flat plate, and drying to form a flat flexible substrate;

dropping microneedle gel on the substrate at a distance of 0.1-2.0mm, contacting the dropped gel with a mold capable of generating adhesive force, moving in the opposite direction of 10-5000 μm/s relative to the substrate, and drawing the dropped gel into microneedles by adhesive force; the diameter and height of the microneedle can be controlled according to the moving speed;

drying, curing, cutting into equal-height microneedles, and finally sterilizing;

wherein the drying and solidifying can adopt one or more of heating drying, air drying, freeze drying, room temperature drying and reduced pressure drying; in order to protect the functional components of the medicine or the cosmetics from being adversely affected by drying and curing, the invention requires a better combination of drying and curing temperature and curing time, wherein the curing temperature ranges from 25 ℃ to 60 ℃, and the curing time ranges from 5s to 36 h; the sterilization mode adopts ethylene oxide or irradiation sterilization.

The research of the application finds that the sterilization mode can influence the degradation performance of the product, and the sterilization mode accelerates the degradation of the microneedles. In order to reduce the adverse effect of sterilization on the microneedles, the sterilization mode of the present application is selected to be performed under freezing conditions of 0 ℃ or lower, and may be-5 ℃ or lower than-10 ℃, and is preferably performed at-20 ℃ or lower. One embodiment of the present invention shows a comparison of the performance of degradation under freezing conditions.

The microneedle prepared by the method has the advantages of no pain, enough hardness, excellent administration slow release effect, simple and efficient preparation method, and can be used in the fields of biological medicine and medical cosmetology and also can be used as a carrier of medicines in the field of animals.

Drawings

FIG. 1 is a schematic view of a microneedle patch having equal height microneedles containing an analgesic material; in the figure, 1 is a schematic representation of a microneedle, 2 is a schematic representation of a substrate, and 3 is a schematic representation of an analgesic material.

Fig. 2 is a schematic diagram of a microneedle patch with equal height mixed microneedles containing no analgesic material; in the figure, a and C represent microneedles containing an analgesic material, and B represents microneedles not containing an analgesic material; 1 is a schematic representation of a microneedle containing an analgesic material, 2 is a schematic representation of a substrate, and 3 is a schematic representation of an analgesic material.

Fig. 3 is a schematic diagram of a microneedle patch containing highly non-uniform microneedles of an analgesic material; in the figure, a and D represent high microneedles, and B and C represent low microneedles; in the figure, 1 is a schematic representation of a microneedle, 2 is a schematic representation of a substrate, and 3 is a schematic representation of an analgesic material.

Fig. 4 is a schematic representation of a microneedle patch containing highly non-uniform microneedles mixed with and without an analgesic material; in the figure, A and B represent microneedles without an analgesic material, C and D represent microneedles with an analgesic material, B and C represent microneedles with small height, and A and D represent microneedles with large height; in the figure, 1 is a schematic representation of a microneedle, 2 is a schematic representation of a substrate, and 3 is a schematic representation of an analgesic material.

Fig. 5 is a schematic representation of a microneedle patch containing highly non-uniform microneedles mixed with and without an analgesic material; in the figure, a and D represent high-sized microneedles containing an analgesic material, and B and C represent low-sized microneedles containing no analgesic material; in the figure, 1 is a schematic representation of a microneedle, 2 is a schematic representation of a substrate, and 3 is a schematic representation of an analgesic material.

FIG. 6 is a schematic view of the entire mold of the present invention, in which FIG. 1 is a schematic view of the mold, FIG. 2 is a schematic view of holes, FIG. 3 is a schematic view of the depth of the holes, FIG. 4 is a schematic view of the pitch of the holes, and FIG. 5 is a schematic view of the diameter of the holes.

Examples

The first embodiment is as follows: microneedle degradation Performance comparison

In the experiment, the degradation performance and hardness of the microneedles are compared, the pH of the microneedles is 7.2, the diameter of the microneedles containing the cross-linked sodium hyaluronate is 300 micrometers, the height of the microneedles is 0.25mm, the distance between the microneedles is 0.3mm, the diameter of the needle point is 10 micrometers, the cross-linking degree of the cross-linked sodium hyaluronate is 2%, the residual cross-linking agent is 1ppm, and relevant performance parameters of the microneedles are shown in table 1.

The degradation properties are expressed as the percentage (%) remaining: 300mg of the microneedle is put into a 1ml centrifuge tube, 1ml of injection water is added, and after the microneedle is fully and uniformly mixed, hyaluronidase is added into each tube, wherein the concentration is 30 IU/ml. Samples which were not added with enzyme and kept consistent in other operations were used as controls. Keeping the temperature at 37 ℃ for half an hour. After the reaction, each tube was centrifuged, the supernatant was decanted, and the weight of the sample remaining at the bottom of the tube was measured. The results of the sample weight measurements of the test sample and the control sample were calculated as the theoretical residual sample percentage (%).

Table 1.

The larger the residual percentage, the more the residue and the less the enzymolysis, which indicates the better the degradation performance, i.e. the better the sustained release effect. From the above table 1, it can be seen that the theoretical residual percentage is in direct proportion to the mass fraction of the cross-linked sodium hyaluronate in the microneedles, and the theoretical residual percentage gradually increases with the increase of the mass fraction of the cross-linked sodium hyaluronate, which indicates that the degradation performance of the product can be greatly improved by the content of the cross-linked sodium hyaluronate, and also proves that the cross-linked sodium hyaluronate has a better promotion effect on the long-acting slow-release effect of the microneedles even in a solid state.

Example two: microneedle degradation Performance comparison

In the experiment, the degradation performance and hardness of the microneedles are compared, the pH of the microneedles is 7.5, the diameter of the microneedles containing the cross-linked collagen is 500 micrometers, the height of the microneedles is 0.2mm, the distance between the microneedles is 0.5mm, the diameter of the needle point is 10 micrometers, the residue of the cross-linking agent is 2ppm, and the related performance parameters of the microneedles are shown in table 2.

The degradation properties are expressed as the percentage (%) remaining: 300mg of the microneedle is put into a 1ml centrifuge tube, 1ml of injection water is added, and after the mixture is fully mixed, collagenase is added into each tube, wherein the concentration is 20 IU/ml. Samples which were not added with enzyme and kept consistent in other operations were used as controls. Keeping the temperature at 37 ℃ for half an hour. After the reaction, each tube was centrifuged, the supernatant was decanted, and the weight of the sample remaining at the bottom of the tube was measured. The results of the sample weight measurements of the test sample and the control sample were calculated as the theoretical residual sample percentage (%).

Table 2.

Numbering	Microneedle material	Mass fraction of crosslinked product (W/W)	Percentage (%)
				2-1	Collagen protein	——	1.2％
2-2	Crosslinked collagen and collagen	0.1％	2.0％
				2-3	Crosslinked collagen and collagen	1.0％	3.5％
2-4	Crosslinked collagen and collagen	5％	6.2％
				2-5	Crosslinked collagen and collagen	10％	15.2％
2-6	Crosslinked collagen and collagen	20％	25.7％
				2-7	Crosslinked collagen and collagen	30％	33.6％
2-8	Crosslinked collagen and collagen	50％	42.1％
				2-9	Crosslinked collagen and collagen	60％	48.2％
2-10	Crosslinked collagen	100％	65.4％

From the above table 2, it can be seen that the residual percentage is in direct proportion to the mass fraction of the crosslinked collagen product in the microneedle, and the percentage is gradually increased along with the increase of the mass fraction of the crosslinked product, which indicates that the crosslinked collagen can greatly improve the degradation performance of the product, that is, even in a solid state, the crosslinked collagen has a better effect of improving the long-acting slow-release effect of the microneedle.

Example three: microneedle Performance comparison

In this experiment, applicants further investigated the hardness and feel of the microneedles of examples one and two in comparison, and the resulting parameters are shown in table 3.

The hardness test method comprises the following steps: the needle point of the microneedle is inserted into an eraser with the thickness of 2.5mm, the insertion speed is 6mm/s, and the maximum force when the eraser is inserted is measured, namely the hardness of the microneedle. The greater the insertion force, the higher the stiffness.

The experience sensing test method comprises the following steps: subjective assessment of skin insertion showed no pain at score 0, general pain at score 1, pain at score 2, very pain at score 3, and unacceptable score 4.

Table 3.

Numbering	Hardness (N)	Experience score
			1-1	0.312	1
1-2	0.328	1
			1-3	0.354	1
1-4	0.373	1
			1-5	0.394	1
1-6	0.395	1
			1-7	0.493	2
2-1	0.332	2
			2-2	0.338	2
2-3	0.354	2
			2-4	0.386	2
2-5	0.434	2
			2-6	0.521	3

As shown in table 3, the microneedles contain cross-linked sodium hyaluronate or cross-linked collagen, and the hardness of the microneedles tends to increase along with the increase of the content of the cross-linked products, that is, the cross-linked products improve the degradation performance of the microneedles, that is, the long-acting slow-release effect; furthermore, it is seen that the cross-linked product can increase microneedle hardness, with greater hardness as the percent concentration of the cross-linked product is higher.

However, it can be seen from Table 3 that while microneedles composed of fully crosslinked products are sufficiently rigid, they are more painful, while microneedles containing other components that are not crosslinked experience a significantly reduced sensation. The micro-needle contains some non-crosslinked materials, so that a certain lubricating effect of the micro-needle can be increased, the resistance of the micro-needle inserted into the skin is reduced, and the skin penetrating experience is improved.

Example four: microneedle Properties

In the embodiment, the microneedle is composed of crosslinked sodium hyaluronate, high-molecular sodium hyaluronate and hydroxyethyl cellulose, the mass concentration of the crosslinked sodium hyaluronate is 20%, the residue of the crosslinking agent is less than 1ppm, the height of the microneedle is 0.4mm, the diameter of the microneedle is 400 μm, and the diameter of a needle point is 10 μm, and the embodiment compares the influence of the crosslinking degree on the degradation performance and hardness of the microneedle, and the parameters are shown in table 4.

The degradation performance test method is the same as the first embodiment, and the hardness test method is the same as the third embodiment.

Table 4.

As shown in table 4, the larger the residual percentage of the microneedle is with the increase of the crosslinking degree of the crosslinked sodium hyaluronate, the better the degradation performance of the microneedle, i.e. the better the sustained release effect, i.e. the crosslinking degree can improve the degradation performance of the crosslinked sodium hyaluronate microneedle.

In addition, it can be seen that the hardness of the microneedles gradually increases with the increase of the crosslinking degree of the crosslinked sodium hyaluronate, indicating that the crosslinking degree of the crosslinked hyaluronic acid in the microneedles can improve the hardness of the microneedles.

Example five: microneedle Properties

In the embodiment, the micro-needle is composed of cross-linked collagen, high-molecular sodium hyaluronate and sodium alginate, the mass concentration of the cross-linked collagen is 40%, the height of the micro-needle is 0.2mm, the diameter of the micro-needle is 400 μm, and the diameter of the needle point is 10 μm. Collagen crosslinking conditions: the crosslinker was 0.01% genipin, reaction time 25 ℃. The effect of the length of crosslinking on microneedle hardness is shown in table 5.

The degradation performance test method is the same as the second embodiment, and the hardness test method and the experience sensing test method are the same as the third embodiment.

Table 5.

Since the longer the crosslinking time, the greater the degree of crosslinking of the crosslinked collagen, the degree of crosslinking is characterized by the length of crosslinking. As shown in table 5, the larger the residual percentage of the microneedle is with the increase of the crosslinking duration of the crosslinked collagen, the better the degradation performance of the microneedle, i.e. the better the sustained release effect, i.e. the crosslinking degree can improve the degradation performance of the crosslinked collagen microneedle.

In addition, it can be seen that the hardness of the microneedles tends to increase with the length of crosslinking, i.e., the degree of crosslinking, indicating that the length of crosslinking of crosslinked collagen in the microneedles, i.e., the degree of crosslinking, can improve the hardness of the microneedles.

Example six: microneedle Properties

In this example, the height of the microneedle was 0.3mm, the mass concentration of the crosslinked product was 20%, the degree of crosslinking of the crosslinked sodium hyaluronate was 5%, and the crosslinking time of the crosslinked collagen was 120 hours. The applicant studied the effect of different microneedle diameters on the stiffness and the experience of the microneedles, the parameters are shown in table 6.

The hardness test method and the experience sensing test method are the same as the third embodiment.

Table 6.

Numbering	MicroneedleMaterial	Diameter of microneedle (μm)	Hardness (N)	Experience score
					6-1	Crosslinked sodium hyaluronate, gelatin, polylactic acid-glycolic acid	50	0.228	0
6-2	Crosslinked sodium hyaluronate, gelatin, polylactic acid-glycolic acid	80	0.254	1
					6-3	Crosslinked sodium hyaluronate, gelatin, polylactic acid-glycolic acid	200	0.273	1
6-4	Crosslinked sodium hyaluronate, gelatin, polylactic acid-glycolic acid	300	0.294	1
					6-5	Crosslinked sodium hyaluronate, gelatin, polylactic acid-glycolic acid	500	0.341	2
6-6	Crosslinked sodium hyaluronate, gelatin, polylactic acid-glycolic acid	800	0.493	3
					6-7	Crosslinked sodium hyaluronate, gelatin, polylactic acid-glycolic acid	1200	0.432	4
6-8	Crosslinked sodium hyaluronate, gelatin, polylactic acid-glycolic acid	1500	0.512	4
					6-9	Crosslinked collagen and sodium alginate	30	0.238	0
6-10	Crosslinked collagen and sodium alginate	100	0.254	1
					6-11	Crosslinked collagen and sodium alginate	200	0.286	2
6-12	Crosslinked collagen and sodium alginate	500	0.334	3
					6-13	Crosslinked collagen and sodium alginate	1000	0.471	3
6-14	Crosslinked collagen and sodium alginate	1500	0.573	4

As seen from table 6, the diameter of the microneedle containing crosslinked sodium hyaluronate or crosslinked collagen has a great influence on the hardness of the microneedle and pain upon insertion into the skin.

Example seven: properties of analgesic Material-containing microneedles

In this example, the applicant sprayed lidocaine with a concentration of 10% by mass on the surface of the microneedle of example four, and dried it. Applicants further compared the effect of different microneedle diameters on microneedle stiffness and feel, with the parameters shown in table 7.

Table 7.

Numbering	Hardness (N)	Experience score
			7-1	0.227	0
7-2	0.253	0
			7-3	0.273	0
7-4	0.293	0
			7-5	0.344	1
7-6	0.492	1
			7-7	0.432	3
7-8	0.510	3
			7-9	0.239	0
7-10	0.254	0
			7-11	0.285	0
7-12	0.332	1
			7-13	0.474	2
7-14	0.575	3

It can be seen from the seventh example that the addition of the lidocaine analgesic material in an amount of 10% to the microneedles has little effect on the hardness of the microneedles, but the feeling experienced when the microneedles are inserted into the skin can be significantly improved, i.e., the analgesic material can reduce the pain of the microneedles when the microneedles are inserted into the skin.

Example eight: properties of analgesic Material-containing microneedles

In the present embodiment, the height of the microneedle is 0.4mm, the diameter of the microneedle is 500 μm, the distance between the microneedles is 0.5mm, the microneedle materials are mainly cross-linked sodium hyaluronate (the cross-linking degree is 3%, and the mass concentration is 5%) and oily low molecular weight sodium hyaluronate, and the applicant researches the influence of lidocaine with different concentrations on the hardness and the experience of the microneedle, and the parameters are shown in table 8.

Table 8.

Numbering	Analgesic material	Concentration (%)	Hardness (N)	Experience score
					8-1	Lidocaine	0	0.351	2
8-2	Lidocaine	0.01	0.352	2
					8-3	Lidocaine	0.1	0.347	2
8-4	Lidocaine	1	0.348	2
					8-5	Lidocaine	2	0.349	1
8-6	Lidocaine	5	0.347	1
					8-7	Lidocaine	10	0.348	0
8-8	Lidocaine	20	0.349	0
					8-9	Lidocaine	30	0.348	0
8-10	Lidocaine	40	0.348	0
					8-11	Lidocaine	50	0.346	0
8-12	Lidocaine	60	0.348	0

As can be seen from the eighth example, the addition of the analgesic material to the microneedles has no effect on the hardness of the microneedles, but the mass fraction concentration of 5% lidocaine can significantly improve the feeling experienced when the microneedles are inserted into the skin. That is, it is proved that the analgesic material can reduce the pain when the microneedle is inserted into the skin, and particularly, the higher the concentration is, the better the experience feeling of the microneedle is.

Example nine: properties of analgesic Material-containing microneedles

In the embodiment, the height of the microneedle is 0.35mm, the diameter of the microneedle is 300 μm, the microneedle material mainly comprises crosslinked collagen (content is 15%), hydroxyethyl cellulose and sodium alginate, and the applicant researches the influence of analgesic materials with different concentrations on the hardness and experience of the microneedle, and the parameters are shown in table 9. The hardness test method and the experience sensing test method are the same as the third embodiment.

Table 9.

In the ninth embodiment, it can be seen that the hardness of the microneedles is hardly affected by adding different analgesic materials into the microneedles. Although different analgesic materials have different effects of improving the experience of inserting the microneedles into the skin, the experience tends to be better as the concentration of the analgesic material is higher.

Example ten: properties of analgesic Material-containing microneedles

In this embodiment, the height of the microneedle is 0.4mm, the microneedle material mainly comprises cross-linked sodium hyaluronate (the cross-linking degree is 3%, the content is 5%) and sodium alginate, and the applicant researches the hardness and experience of microneedles containing analgesic materials with different diameters, and the parameters are shown in table 10. The hardness test method and the experience sensing test method are the same as the third embodiment.

Table 10.

Numbering	Diameter of microneedle (μm)	Analgesic material	Concentration (%)	Hardness (N)	Experience score
						10-1	500	——	0	0.452	3
10-2	500	Lidocaine and purslane	5	0.547	1
						10-3	500	Lidocaine and purslane	10	0.548	0
10-4	800	Lidocaine and purslane	15	0.549	1
						10-5	800	Lidocaine and purslane	20	0.547	0
10-6	800	Lidocaine and purslane	30	0.547	0
						10-7	1200	Lidocaine and purslane	10	0.622	2
10-8	1500	——	0	0.686	4
						10-9	1500	Lidocaine and purslane	15	0.682	3
10-10	1500	Lidocaine and purslane	25	0.684	2

It can be seen from the example ten that the content of the analgesic material has no obvious influence on the hardness of the microneedle, while the microneedle without the analgesic material is poor in experience when inserted into the skin, and the addition of the analgesic material has an obvious improvement effect on the experience of the diameter microneedle. Therefore, under the condition of containing the analgesic material, the diameter of the microneedle can be properly larger so as to improve the drug carrying capacity, the pain feeling during skin insertion can not be increased, and the microneedle can be used as a good drug carrying tool.

Example eleven: properties of analgesic Material-containing microneedles

In this embodiment, the diameter of the microneedle is 0.3mm, the microneedle material mainly comprises cross-linked sodium hyaluronate (cross-linking degree is 15%, content is 5%), sodium alginate and gelatin, and the analgesic material is lidocaine, so that the applicant compares the hardness and experience of microneedles with different concentrations and heights, and the parameters are shown in table 11. The hardness test method and the experience sensing test method are the same as the third embodiment.

Table 11.

Numbering	Micro-needle height (mum)	Concentration of analgesic Material (%)	Hardness (N)	Experience score
					11-1	100	0	0.312	1
11-2	120	10	0.317	0
					11-3	150	10	0.311	0
11-4	180	10	0.317	0
					11-5	200	10	0.317	0
11-6	250	10	0.315	0
					11-7	400	10	0.320	1
11-8	800	10	0.352	1
					11-9	1000	0	0.357	2
11-10	1000	20	0.358	0
					11-11	1200	0	0.369	3
11-12	1200	20	0.373	0
					11-13	1500	0	0.392	4
11-14	1500	20	0.388	1
					11-15	2000	0	0.422	4
11-16	2000	20	0.421	1

As can be seen from table 11, in the case where no analgesic material was added, the pain feeling when the microneedles were penetrated into the skin tended to be increased as the height of the microneedles increased. The analgesic material in the microneedle can obviously improve the pricking feeling caused by the height of the microneedle when the microneedle is penetrated into the skin, but when the height of the microneedle exceeds 1.5mm, even if the analgesic material with higher concentration is added, the microneedle can slightly prick into the skin.

Example twelve: properties of analgesic Material-containing microneedles

In the embodiment, the diameter of the micro-needle is 0.3mm, the height is 0.25mm, the distance between the micro-needles is 0.3mm, the micro-needle material mainly comprises cross-linked sodium hyaluronate (the cross-linking degree is 5 percent and the content is 10 percent), gelatin and analgesic material is 5 percent procaine, wherein the content is 12-2 percent^#、12-8^#No analgesic material was added. The applicant studied the experience of different tip diameters, the parameters of which are shown in table 10. The test method is the same as that described above.

Table 12.

Numbering	Needle tip diameter (mum)	Experience score
			12-1	5	0
12-2^#	10	1
			12-3	10	0
12-4	20	0
			12-5	30	1
12-6	40	1
			12-7	50	1
12-8^#	60	2
			12-9	60	1

As can be seen from table 12, in the case where the analgesic material was not added, the pain feeling when the microneedles were inserted into the skin was stronger as the diameter of the needle tip was larger, and the analgesic material could significantly improve the pain feeling when the microneedles were inserted into the skin caused by the diameter of the needle tip.

Example thirteen: properties of analgesic Material-containing microneedles

In the present embodiment, the diameter of the microneedle is 0.3mm, the height is 0.2mm, the distance between the microneedles is 0.3mm, and the diameter of the needle point is 5 μm, the microneedle material is mainly cross-linked sodium hyaluronate (the cross-linking degree is 2.5%, the content is 20%), the analgesic material is 2% morphine, the applicant researches the influence of different moisture contents on the hardness of the microneedle, the hardness testing method is the same as the above, and the parameters are shown in table 13.

Table 13.

As can be seen from table 13, there is a tendency for the hardness of the microneedles to decrease as the moisture content of the microneedles increases. However, when the moisture content is too low, the toughness is insufficient and the fracture problem is liable to occur although the hardness is sufficient, and when the moisture content is too high, the drawing is liable to occur at the time of production, so that the moisture content is recommended to be in the range of 40 to 60%.

Example fourteen: microneedle performance with additives

In the embodiment, the diameter of the microneedle is 0.3mm, the height is 0.2mm, the distance between the microneedles is 0.3mm, the diameter of the needle point is 5 μm, the moisture content of the microneedle is 55%, the microneedle material mainly comprises cross-linked sodium hyaluronate (the cross-linking degree is 5%, the content is 15%), high molecular weight sodium hyaluronate, the analgesic material is 2% lidocaine, wherein 14-11^#、14-12^#The applicant compared the degradation rate, hardness and experience of the microneedles with different additives, the percentage (%), hardness (N) and experience score test methods are the same as those described above, and the performance parameters are shown in Table 14.

Table 14.

As can be seen from table 14, the additive concentration has little influence on the degradation performance and hardness of the microneedles. In addition, it can be seen that the degradation performance of the microneedle containing the cross-linked sodium hyaluronate is obviously better than that of the microneedle not containing the cross-linked sodium hyaluronate. In addition, the microneedle is used as an administration carrier, and the microneedle contains an analgesic material, so that the experience feeling can be improved.

Example fifteen: preparation of microneedles

Preparing a base gel: collagen gel was formed by dissolving 5.2g of collagen in 100ml of water.

Preparing a microneedle gel: 9.5g of sodium hyaluronate was added to 120ml of water and mixed to form a gel, which was divided into six portions, and one portion of the sodium hyaluronate gel was used to prepare a microneedle gel. BDDE was then added to the remaining five gels at 0.001% (W/W) and crosslinked at pH9.0 for 6 hours under basic conditions, and the gels were swollen with neutral physiological isotonic phosphate buffer at a viscosity of 34300cSt, and two of them were used as crosslinked sodium hyaluronate gels for microneedle preparation. The remaining two portions were mixed with lidocaine at a ratio of 10% by mass, and the mixture was stirred uniformly to prepare a crosslinked sodium hyaluronate gel containing lidocaine for microneedle preparation.

Preparing a microneedle patch in a first mode: providing three molds made of high molecular polymer material with holes, wherein the diameter of the holes is 5-300 μm, the depth of the holes is 0.35mm, and the distance between the holes is 0.3 mm. Respectively dripping the sodium hyaluronate gel, the cross-linked sodium hyaluronate gel and the cross-linked sodium hyaluronate gel containing lidocaine for preparing the micro-needles into holes of different molds, dripping the molds with the collagen gel, leveling, drying and curing in a vacuum drying oven at 45 ℃ for 2 hours, and then demolding. The microneedles prepared from the three gels are evenly divided into two groups, wherein one group is sterilized by electron beams of 25K Gy, and the other group is sterilized by electron beams of 25K Gy under the condition of-20 ℃.

Preparing the microneedle patch in the second mode: spreading the rest collagen gel into three gel plates with the thickness of 0.5mm, dripping sodium hyaluronate gel, cross-linked sodium hyaluronate gel and cross-linked sodium hyaluronate gel containing lidocaine of the microneedle on the gel plates at intervals of 0.3mm to prepare the sodium hyaluronate gel, the cross-linked sodium hyaluronate gel and the cross-linked sodium hyaluronate gel containing the lidocaine, then dripping the gel into a polytetrafluoroethylene mould to contact, moving at the speed of 150 mu m/s in the opposite direction, then drying and curing in a vacuum drying box at the temperature of 45 ℃ for 2 hours, and cutting to form the microneedle. The microneedles prepared from the three gels are evenly divided into two groups, wherein one group is sterilized by electron beams of 25K Gy under the normal temperature condition, and the other group is sterilized by electron beams of 25K Gy under the temperature of-20 ℃.

The prepared microneedles and the similar microneedles are compared in performances such as degradation rate, hardness and experience feeling, the testing and calculating methods are the same as those described above, and the results are shown in the following table 15.

Table 15.

As can be seen from table 15, the crosslinked sodium hyaluronate microneedles are significantly better in degradation performance than non-crosslinked; under the same condition, the hardness of the microneedle prepared by crosslinking sodium hyaluronate is superior to that of the microneedle which is not crosslinked; the microneedle containing the analgesic material can reduce pain when the microneedle is inserted into the skin, namely, improve experience feeling of the microneedle.

In addition, in the same preparation mode, by comparing the residual percentage results of the microneedles sterilized under different conditions, the degradation effect of the microneedles in the freezing sterilization mode is obviously superior to that in the normal-temperature sterilization mode.

Claims

1. A microneedle patch mainly comprises microneedles and a substrate, wherein the diameter range of the microneedles is 10-1500 mu m, the height of the microneedles is 0.15-2.0mm, the distance between the microneedles is 0.1-2.0mm, and the diameter of the tip of the microneedle is 10-60 mu m, and the microneedle patch is characterized by containing more than 0.1% of one or two of cross-linked sodium hyaluronate and cross-linked collagen by mass fraction.

2. A microneedle patch according to claim 1, wherein said microneedles are uniform in height or non-uniform.

3. The microneedle patch according to claim 2, wherein the degree of crosslinking of the crosslinked product in the microneedles is 0.1% to 50%.

4. A microneedle patch according to claim 3, wherein said microneedles contain 0.001-60.0% by mass of analgesic material.

5. A microneedle patch according to claim 4, wherein the analgesic material of the microneedles is one or more of a chemical composition, a plant extract, a bio-genetic engineering product.

6. A microneedle patch according to claim 5, wherein said microneedles further comprise one or more of the following degradable materials: hyaluronic acid, collagen, gelatin, oligopeptide, carboxymethyl starch, starch sulfate, polycarboxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, pregelatinized starch, carboxymethyl cellulose, ethyl hydroxyethyl cellulose, cellulose acetate phthalate, methyl cellulose, carboxypropyl cellulose, hydroxyalkyl cellulose, alkyl cellulose, polyvinylpyrrolidone, polylactic acid, polyvinyl alcohol, polyacrylamide polymers, polydimethylsiloxane, chondroitin sulfate, polylactic acid-glycolic acid, dextrin, polyvinyl chloride, chitosan, xanthan gum, dextran, polyglutamic acid.

7. A microneedle patch according to claim 6, wherein said microneedles contain one or more of the following drugs in combination: vaccine, hormone, genetic engineering medicine, polypeptide, polysaccharide, nucleoside, protein, chemical medicine, and natural medicine.

8. A microneedle patch according to claim 6, wherein said microneedles contain one or more combinations of the following cosmetic effect ingredients: whitening component, moisturizing component, anti-aging component, acne removing component, acne scar removing component, red blood streak removing component, scar removing component, freckle removing component, skin tendering component, chloasma treating component, sunscreen component, moisturizing component, water locking component, wrinkle removing component, anti-inflammatory component, anti-allergy component, toxin expelling component, anti-light component, hair regeneration component, and hair loss preventing component.

9. The preparation method of the microneedle patch comprises the following steps:

preparing a base gel: the degradable material is prepared into gel by water or buffer solution, and the degradable material can be selected from one or more of the following combinations: gelatin, oligopeptides, carboxymethyl starch, starch sulfate, polycarboxymethyl cellulose, hydroxypropylmethyl cellulose, microcrystalline cellulose, pregelatinized starch, carboxymethyl cellulose, ethylhydroxyethyl cellulose, cellulose acetate phthalate, methyl cellulose, carboxypropyl cellulose, hydroxyalkyl cellulose, alkyl cellulose, polyvinylpyrrolidone, polylactic acid, PLGA, polyvinyl alcohol, polyglycolic acid, polyphosphazene, polyacrylamide polymers, polydimethylsiloxane, chondroitin sulfate, polylactic-glycolic acid, dextrin, polyvinyl chloride, chitosan, typhan, guar gum, xanthan gum, dextran, alginate, polyglutamic acid, hyaluronic acid, collagen, and derivatives thereof; the buffer solution can be one of common neutral buffer solution, neutral physiological isotonic phosphate buffer solution and physiological saline;

preparing a microneedle gel: one of the following three is selected, namely, cross-linked sodium hyaluronate gel or cross-linked collagen gel is provided to be used as the base gel of the microneedle; secondly, one or more combinations of hyaluronic acid, collagen, gelatin, oligopeptide, carboxymethyl starch, starch sulfate, polycarboxymethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, pregelatinized starch, carboxymethyl cellulose, ethyl hydroxyethyl cellulose, cellulose acetate phthalate, methyl cellulose, carboxypropyl cellulose, hydroxyalkyl cellulose, alkyl cellulose, polyvinylpyrrolidone, polylactic acid, polyvinyl alcohol, polyacrylamide polymer, polydimethylsiloxane, chondroitin sulfate, polylactic acid-glycolic acid, dextrin, polyvinyl chloride, chitosan, xanthan gum, dextran and polyglutamic acid are uniformly mixed in the first basic gel; thirdly, adding medicinal or cosmetic functional components into the first or second gel;

microneedles are achieved by:

the first mode is as follows: providing a mould 1, wherein a hole 2 is formed in the mould, and the hole 2 does not penetrate through the mould 1; the diameter range of the holes is 10-1500 μm, and the diameter range of the finest parts of the holes is 10-60 μm; the depth of the hole ranges from 0.15 mm to 2.0mm, and the distance between holes 3 ranges from 0.1 mm to 2.0 mm;

drying and curing, and then demoulding and sterilizing;

the mold 1 may be made of a single metal material, an alloy material, or a high molecular polymer material, such as titanium, copper, aluminum, nickel, tungsten, stainless steel, titanium alloy, nickel alloy, aluminum alloy, copper alloy, or polystyrene, polytetrafluoroethylene, etc., and has the characteristics of high hardness and rigidity, smooth surface, etc.; the shape of the hole 2 can be one or a plurality of combinations of a cone, a cylinder, an ellipsoid, a regular prism, a regular square prism, a regular hexagonal prism, a regular octagonal prism, a regular decagon, a regular dodecagon, a regular hexadecapex prism and a regular twenty-square prism, and can be other shapes, and different shapes of combinations can be designed according to different requirements;

then drying, curing and cutting to form the microneedle patch, and finally sterilizing;

the drying and curing in the two modes can adopt one or more of heating drying, air drying, freeze drying, room temperature drying and reduced pressure drying; in order to protect the functional components of the medicine or the cosmetics from being adversely affected by drying and curing, the invention requires a better combination of drying and curing temperature and curing time, wherein the curing temperature ranges from 25 ℃ to 60 ℃, and the curing time ranges from 5s to 36 h;

in the two modes, ethylene oxide or irradiation sterilization is adopted as a sterilization mode;

wherein, analgesic material is mixed in the base gel for preparing the microneedle gel, or the analgesic material is added on the surface of the microneedle before sterilization.

10. The method for preparing a microneedle patch according to claim 9, characterized in that: the sterilization is performed under freezing conditions of zero degrees centigrade or less.