CN110840823B - Transporter composite autolytic microneedle and preparation method thereof - Google Patents
Transporter composite autolytic microneedle and preparation method thereof Download PDFInfo
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract
The invention relates to a carrier composite autolytic microneedle and a preparation method thereof. The autolytic microneedle consists of a base and needle bodies distributed on the base, wherein each needle body consists of a needle point and a needle bottom; the needle tip is made of a soluble polysaccharide material and is tower-shaped, and a transmission body is embedded in the needle tip; the needle bottom and the base are made of soluble high polymer materials; the needle body can be penetrated into the skin to be dissolved by itself and releases the transmitter in the skin; the carrier may be loaded with a drug or active substance. The prepared carrier compound autolytic microneedle has the advantages that the carrier is condensed at the tower-shaped needle point of the microneedle, the administration efficiency and the administration accuracy can be greatly improved, the needle body can be quickly dissolved after penetrating into the skin, the released carrier keeps a multi-layer vesicle structure, the lymphatic absorption is promoted, and the carrier is gathered at the lymph node position through a lymphatic system. The microneedle of the invention has the advantages of simple preparation process conditions, stable preservation and cost saving, is suitable for mass production, and can be widely applied to the fields of drug delivery, vaccine immunization or cosmetics.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to a carrier composite autolytic microneedle and a preparation method thereof.
Background
The incidence of cancer in China is close to the average level in the world, but the mortality rate is higher than the average level in the world, because most of cancer discovery in China is in the middle and late stages. Tumor immunotherapy, which triggers an anti-tumor response of the immune system by acting on the immune system, has high specificity and low toxicity, and can show a sustained therapeutic effect in patients with advanced tumors that is significantly higher than that of conventional therapies. Tumor cell metastasis is the leading cause of death in tumor patients, and tumor draining lymph nodes are the portals for tumor cell metastasis and are the initial sites for the development of adaptive immune responses. The key of tumor immunotherapy is to deliver the vaccine to specific immune cells and tumor microenvironment in a targeted manner, effectively activate adaptive immune response, and the selection of the vaccine administration mode is crucial. Compared with systemic immunity, such as intravenous injection, and local targeted immunity, such as skin immunity, the preparation can reduce administration dosage and toxic and side effects, and simultaneously enhance immune effect by utilizing abundant inherent DCs and lymph distribution in skin tissues. The nano vaccine can realize targeted delivery and slow release of antigen or adjuvant, thus becoming a hot point of research. Vaccine vectors are first required to enhance lymphatic uptake for the unique localization of tumor draining lymph nodes.
The skin tissue is enriched with a large number of dendritic cells with strong immunogenicity, such as epidermal Langerhans cells and dermal dendritic cell subtypes, so that the skin becomes an ideal path for tumor immunity. In addition, the lymphatic system starts from lymphatic capillaries in the dermal tissue, and the 30-120 nm gap of lymphatic endothelial cells forms a porous structure on the surface of the lymphatic capillaries, allowing large granules and interstitial fluid to enter and exit. In view of this physiological property, protein or nucleic acid based vaccine drugs can be administered dermally to promote lymphatic absorption. Dermal injection can exert immune effect, but low patient compliance, needle trauma, needle handling, vaccine storage and transportation and the like restrict the application of the injection. The micro-needle can puncture the stratum corneum of the skin in a minimally invasive and painless way to complete the transdermal delivery of the load. Based on the novel polymer soluble microneedle which is biocompatible and degradable, the macromolecule drug can be blended in the polymer matrix, so that the carrying capacity is improved, the drug reservoir can be formed in dermis, the drug reservoir is slowly released along with the degradation of the matrix, and the long-term curative effect is maintained. These characteristics make microneedles extremely potent transdermal vaccine carriers.
The micro-needle is a micron-sized fine needle-shaped object, is very tiny and very sharp, can pierce the stratum corneum into the specific depth of the active epidermis by acting on a specific area of the skin with a micro-needle array with proper length, can provide a drug transmission channel without touching the nerves of deep tissues, does not cause any pain and stimulation, and is known as painless infusion. Hundreds of micron-sized micro cavities generated by the microneedles on the horny layer are used as transmission channels, so that drugs with different molecular weights from low to high can pass through the micro cavities, the transdermal penetration of the drugs, particularly macromolecular vaccine drugs, is effectively promoted, the concentration of the active epidermal layer is effectively improved, and the transdermal administration efficiency of the drugs is improved. Since microneedles are too small and have limited effects, scientists have combined tens or hundreds of microneedles to form a microneedle array and then act in the form of a microneedle array, which can greatly improve efficiency. The hyaluronic acid exists in human body, has low irritation to organism, and the prepared micro-needle has good biological performance.
The main constituent of the carrier is a phospholipid molecule, which has a vesicular structure of single or multiple bilayer lipid membranes. The carrier has the advantages of large drug carrying amount, protection of the encapsulated drug from degradation, easy fusion with a biological membrane, slow release, reduction of the dosage of the drug and the like. The carrier is used as the carrier of the antitumor drug by utilizing the characteristics that the carrier has affinity with tumor cells and can reduce the toxic and side effects of the wrapped drug, and the like, so that the purposes of reducing the dosage, improving the curative effect and the like that the tumor cells usually contain high-concentration enzymes can be achieved, and the release of the drug can be promoted. In addition, the carrier can promote lymph absorption, and can deliver tumor chemotherapy drugs or vaccines to lymph sites to exert the effect of treating or immunotherapy of metastatic tumors at lymph sites. However, the transfersome has a drawback of low transdermal efficiency, and most of the transfersome remains in the epidermal layer and fails to exert the drug effect.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to prepare the transfersome composite autolysis microneedle, which combines the characteristics that the microneedle can efficiently deliver macromolecular drugs and particles through skin and the transfersome can promote lymphatic absorption, the transfersome is condensed at the tower-shaped needle point of the microneedle through the combination of the microneedle and the transfersome, so that the transfersome is delivered to a real cortex layer accurately without loss, and the transfersome and carried drugs are released in dermis through microneedle autolysis, so that the lymphatic absorption efficiency is enhanced, and the drug treatment effect is improved.
To solve the above problems, the embodiment of the present invention includes the following steps:
the invention relates to a transfersome composite autolytic microneedle, which is characterized in that the autolytic microneedle consists of a base and needle bodies distributed on the base, wherein the needle bodies consist of needle points and needle bottoms; the needle tip is made of a soluble polysaccharide material and is tower-shaped, and a transmission body is embedded in the needle tip; the needle bottom and the base are made of soluble high polymer materials; the needle body can be penetrated into the skin to be dissolved by itself and releases the transmitter in the skin; the carrier may carry a drug or active;
wherein the soluble polysaccharide material is one or more of dextran, hyaluronic acid, chondroitin sulfate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium alginate, starch, etc., preferably hyaluronic acid; the soluble high polymer material is prepared from one or more of gelatin, polyglutamic acid, polyvinyl alcohol, polyvinylpyrrolidone and the like, and the polyvinyl alcohol is preferred;
the carrier is composed of phospholipid, sodium cholate or sodium deoxycholate, is in a monolayer or multilayer vesicle structure, and the surface of the carrier is modified with amphiphilic hyaluronic acid ester, so that the absorption of the carrier by lymph can be promoted;
the preparation method comprises the following steps:
(1) preparing a carrier suspension modified by amphiphilic hyaluronic acid;
(2) dissolving a soluble polysaccharide material in the carrier suspension prepared in the step (1), stirring at room temperature until the soluble polysaccharide material is completely dissolved, and removing bubbles to obtain uniform microneedle injection molding liquid containing a carrier, wherein the mass percentage concentration of the carrier in the microneedle injection molding liquid containing the carrier is 0.1-50%, and the mass percentage concentration of the soluble polysaccharide is 20-50%;
(3) uniformly dispersing a soluble high polymer material in deionized water, stirring at room temperature until the soluble high polymer material is completely dissolved, and removing bubbles to obtain a microneedle bottom and a base injection molding liquid, wherein the treatment percentage concentration of the soluble high polymer material is 1% -10%;
(4) injecting the needle point injection molding liquid prepared in the step (2) into the surface of a microneedle array female die prepared from Polydimethylsiloxane (PDMS), uniformly coating, removing redundant solution, centrifuging at room temperature for 10min, taking out and standing for 30 min; and (4) injecting the needle bottom and the base injection molding liquid prepared in the step (3) into a microneedle PDMS mold containing a needle point, centrifuging for 10min at room temperature, naturally drying at room temperature under the condition that the relative humidity is over 75%, and demolding to obtain the carrier composite autolytic microneedle.
The invention relates to a transfersome composite autolytic microneedle which is characterized in that a microneedle body is conical or pyramid, preferably pyramid.
The transfersome composite autolytic microneedle is characterized in that the axial breaking stress of a single microneedle of the microneedle is not less than 0.1N, and the single microneedle can effectively puncture the stratum corneum of skin.
The carrier compound autolytic microneedle is characterized in that the amphiphilic hyaluronic acid is a hyaluronic acid ester compound.
The invention discloses a carrier compound autolytic microneedle which is characterized in that the drug is vaccine, adjuvant, protein, chemical drug and the like.
The invention relates to a carrier composite autolytic microneedle which is characterized in that the embedded carrier can keep a multi-layer vesicle structure of the carrier after being dissolved out of the microneedle.
The carrier compound autolytic microneedle is characterized in that the needle point of the autolytic microneedle can be dissolved in the skin within 30 min.
The carrier composite autolytic microneedle is characterized in that the carrier composite autolytic microneedle can improve the lymphatic absorption efficiency of a medicament.
The invention discloses a carrier composite autolytic microneedle which is characterized by being used in the fields of drug delivery, vaccine immunization or cosmetics.
Compared with the prior art, the carrier compound autolytic microneedle has the advantages that the carrier is condensed at the tower-shaped needle point of the microneedle, and the needle bottom almost has no residual carrier, so that the administration efficiency and the administration accuracy are greatly improved. The part of the needle body entering the subcutaneous tissue can be quickly dissolved and then completely degraded, and is digested and absorbed by the tissue without toxic and side effects. The released carrier can maintain the structure of the multi-layer vesicle, promote lymph absorption, gather at the lymph node position through the lymphatic system, and exert the treatment effect of the drug on the metastatic tumor at the lymph position or the immunotherapy effect of the vaccine. In addition, the microneedle of the invention has the advantages of simple preparation process conditions, stable preservation and cost saving, is suitable for mass production, and can be widely applied to the fields of drug delivery, vaccine immunization or cosmetics
The attached drawings of the specification.
FIG. 1: and preparing a scanning electron microscope photo of the primary transfersome and the transfersome regenerated after the transfersome is dissolved in the self-dissolving micro needle.
FIG. 2: a flow chart for preparing the carrier composite autolytic microneedle.
FIG. 3: and (3) a scanning electron microscope, a microscope bright field and a fluorescence microscope picture of the carrier compound autolytic microneedle.
FIG. 4: and (3) a transfersome composite autolytic microneedle displacement-stress change curve.
FIG. 5: and (3) carrying out intracutaneous dissolution photograph on the carrier compounded with the autolysis microneedle.
FIG. 6: the result of the whole skin puncture of the rat is shown.
FIG. 7: tissue distribution of transfersome after rat puncture with transfersome compounded autolytic microneedle
Detailed Description
The present invention will be further specifically described below with reference to examples, but the present invention is not limited to these examples.
Example 1.
(1) Preparation of amphiphilic hyaluronic acid-modified transfersome suspension
Referring to Chinese patent ZL201310033655.4, amphiphilic hyaluronic acid-mono-di-fatty acid glyceride (HA-GMS) is prepared, and white solid is obtained by freeze-drying. Dissolving egg yolk lecithin in chloroform/ethanol (1: 1, v/v) mixed solvent, stirring for dissolving completely, placing in pear-shaped flask, and rotary steaming at 40 deg.C to obtain membrane; HA-GMS was dissolved in PBS (pH 7.4) with a final concentration of 1mg/mL HA-GMS and a final concentration of 5mg/mL sodium cholate. Adding the solution into a pear-shaped flask containing phospholipid membrane, and hydrating at 55 deg.C for 30min to obtain amphipathic hyaluronic acid modified transfersome suspension. The obtained carrier has a particle diameter of 110.9nm, uniform size, and multi-layer bubble shape, and the transmission electron micrograph is shown in FIG. 1.
(2) Preparing the microneedle tip by using soluble polysaccharide hyaluronic acid, dissolving hyaluronic acid and rhodamine B in the carrier suspension prepared in the step (1), stirring at room temperature until the hyaluronic acid and rhodamine B are completely dissolved, wherein the final concentration of rhodamine B is 0.5% (m/v), and removing bubbles to obtain the uniform microneedle tip injection molding liquid containing the carrier.
(3) Preparing the microneedle base and the base by using soluble high-molecular polyvinyl alcohol, uniformly dispersing the polyvinyl alcohol in deionized water, stirring at room temperature, and removing bubbles to obtain the microneedle base and the base injection molding liquid.
(4) And (3) injecting the needle point injection molding liquid prepared in the step (2) into the surface of a microneedle array female die prepared from clean Polydimethylsiloxane (PDMS) by using a liquid-moving gun, adjusting the volume of the dropwise added solution according to the dosage, uniformly coating, removing the redundant solution, centrifuging for 10min at room temperature, taking out and standing for 30 min. And (3) injecting the needle bottom and the base injection molding liquid prepared in the step (3) into a microneedle PDMS mold containing a needle point, centrifuging for 10min at room temperature, naturally drying at room temperature under the condition that the relative humidity is over 75%, demolding to obtain the carrier composite autolyzed microneedle, and hermetically storing at low temperature, wherein the preparation process is as shown in figure 2, and the whole appearance and the local microscopic image of the microneedle are as shown in figure 3.
The prepared transfersome composite autolytic microneedle consists of a base and needle bodies distributed on the base, wherein each needle body consists of a needle point and a needle bottom; the needle tip is made of a soluble polysaccharide material and is tower-shaped, and a transmission body is embedded in the needle tip; the needle bottom and the base are made of soluble high polymer materials; the needle body can be penetrated into the skin to be dissolved by itself and releases the transmitter in the skin; the carrier may be loaded with a drug or active substance. The transfersome composite autolysis micro-needle is in a quadrangular pyramid shape, the height of a needle body is 500 micrometers, the diameter of the bottom end of a needle point is 15 micrometers, the length of the bottom end of the needle is 300 micrometers, and the distance between the needle points is 500 micrometers. The specification of the carrier composite autolytic microneedle array is 15 multiplied by 15.
And (5) testing the performance.
(1) Fracture stress test of carrier composite autolytic microneedle
The carrier composite autolyzed microneedle prepared in example 1 is adopted, the specification is 15 multiplied by 15, the needle point is upward at room temperature and is placed on a physical property analyzer test workbench, an axial compression mode is adopted to measure a displacement-stress change curve, the compressive stress rapidly rises along with the increase of the compressive displacement, when the stress suddenly drops, the axial critical bearing maximum stress of the microneedle is obtained, and the recorded compressive stress value is the fracture stress of the microneedle. The breaking stress of the microneedles prepared at different concentrations is shown in figure 4, the breaking stress of the microneedle body is increased along with the increase of the concentration of hyaluronic acid, the breaking stress of a single needle is 0.11-0.19N, which is greater than the minimum stress of 0.1N required for puncturing the stratum corneum of the skin of a person, and the requirement of the stress for puncturing the skin of the person is met.
(2) Intradermal solubility of transfersome compounded autolytic microneedle
Adopting the rhodamine B marked carrier compound autolysis microneedle prepared in the example 1, taking 5 groups of dry microneedles with the specification of 15 multiplied by 15 at room temperature, observing the shape of the microneedles by a fluorescence microscope, and marking the shape of the microneedles as 0 min; then, the microneedle vertically penetrates into the whole skin of the unhairing SD male rat in vitro, the unhairing SD male rat is pressed for 1min, 3 min, 5 min, 10min and 20 min respectively, and the shape change of the microneedle is observed and photographed by a fluorescence microscope. The form change of the carrier compounded from the dissolved microneedle in the rat skin is shown in fig. 5.
(3) Transfersome composite autolysis micro needle external pricking skin performance test
The transfersome composite autolytic microneedle prepared in example 1 is adopted, the specification is 15 multiplied by 15, a dry microneedle 5 group is taken at room temperature, the microneedle is vertically penetrated into the whole skin of a unhairing SD male rat in vitro, the pressing is carried out for 1min, then 0.2% trypan blue is used for dyeing for 2 h, the surface of the pigskin is cleaned by 0.9% physiological saline, the number of dyed pinholes is observed and counted, and the dyed pinholes are formed by dyeing exposed lipid after the cuticle is punctured by the microneedle. The skin pricking rate of the micro-needles is = (number of dyeing needle holes/total number of micro-needles) × 100%. The results showed that the rate of skin penetration of the carrier-autolyzed composite microneedle was 90%, as shown in FIG. 6.
(4) Tissue distribution of transfersome after rat puncture with transfersome compounded autolytic microneedle
The transfersome composite autolytic microneedle prepared in example 1 is adopted, SD male rats are experimental animals, the backs of the rats are unhaired 24h before skin pricking, after fasting for 24h, dry microneedles with the specification of 15 × 15 are taken at room temperature, the microneedles are vertically inserted into the back skins of the unhaired SD male rats, 4 microneedles are inserted into the skins of each rat, the microneedles are pressed for 1min respectively, and the microneedles are fixed by bandages. The carrier suspension containing the same rhodamine B concentration was injected into rats through tail vein as a control group. After 24h of administration, the rat is sacrificed, the lymph, the heart, the liver, the spleen and the kidney of the rat are taken out, the fluorescence intensity of rhodamine B in the organ of the rat is recorded by using a small animal living body imager, and photographing and recording are carried out, as shown in figure 7, a very strong fluorescence signal of the carrier rhodamine B is found in the lymph of the rat, and the situation that the absorption efficiency of the lymph to the medicine can be obviously enhanced by the transdermal administration of the carrier composite autolytic microneedle is shown.
Claims (8)
1. A transfersome compound autolysis micro-needle is characterized in that the autolysis micro-needle is composed of a base and needle bodies distributed on the base, wherein the needle bodies are composed of needle points and needle bottoms; the needle tip is made of a soluble polysaccharide material and is tower-shaped, and a transmission body is embedded in the needle tip; the needle bottom and the base are made of soluble high polymer materials; the needle body can be penetrated into the skin to be dissolved by itself and releases the transmitter in the skin; the carrier may carry a drug;
wherein the soluble polysaccharide material is one or more of dextran, hyaluronic acid, chondroitin sulfate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium alginate and starch; the soluble high polymer material is made of one or more of gelatin, polyglutamic acid, polyvinyl alcohol and polyvinylpyrrolidone;
the carrier is composed of phospholipid, sodium cholate or sodium deoxycholate and has a multi-layer vesicle structure, and the surface of the carrier is modified with amphiphilic hyaluronic acid which can promote the absorption of the carrier by lymph;
the embedded carrier can keep the multi-layer vesicle structure of the carrier after being dissolved out of the microneedle;
the preparation method comprises the following steps:
(1) preparing a carrier suspension modified by amphiphilic hyaluronic acid;
(2) dissolving a soluble polysaccharide material in the carrier suspension prepared in the step (1), stirring at room temperature until the soluble polysaccharide material is completely dissolved, and removing bubbles to obtain uniform carrier-containing microneedle tip injection molding liquid, wherein the carrier mass percentage concentration in the carrier-containing microneedle tip injection molding liquid is 0.1-50%, and the soluble polysaccharide mass percentage concentration is 20-50%;
(3) uniformly dispersing a soluble high polymer material in deionized water, stirring at room temperature, and removing bubbles to obtain a microneedle base and a base injection molding liquid, wherein the mass percentage concentration of the soluble high polymer material is 1-10%;
(4) injecting the needle point injection molding liquid prepared in the step (2) into the surface of a microneedle array female die prepared from Polydimethylsiloxane (PDMS), adjusting the volume of the dropwise added solution according to the dosage, uniformly coating, removing the redundant solution, centrifuging for 10min at room temperature, taking out and standing for 30 min; and (4) injecting the needle bottom and the base injection molding liquid prepared in the step (3) into a microneedle PDMS mold containing a needle point, centrifuging for 10min at room temperature, naturally drying at room temperature under the condition that the relative humidity is over 75%, and demolding to obtain the carrier composite autolytic microneedle.
2. A carrier composite autolyzed microneedle according to claim 1 wherein the microneedle body is in the form of a cone or pyramid.
3. A carrier composite autolyzed microneedle according to claim 2 wherein the microneedle body is in the form of a pyramid.
4. The carrier composite autolytic microneedle according to claim 1, wherein the axial breaking stress of the microneedle is not less than 0.1N, and is effective in piercing the stratum corneum.
5. The carrier conjugate autolytic microneedle of claim 1, wherein the amphiphilic hyaluronic acid is a hyaluronate conjugate.
6. A carrier complex autolytic microneedle according to claim 1, wherein the drug is a protein, a chemical drug.
7. The conjugate autolytic microneedle of claim 1, wherein the tip of the autolytic microneedle is capable of dissolving intradermally within 30 min.
8. The carrier composite autolytic microneedle according to claim 1, wherein the carrier composite autolytic microneedle can be used in the fields of drug delivery or cosmetics.
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| CN103113494A (en) * | 2013-01-19 | 2013-05-22 | 中国海洋大学 | Preparation method of hyaluronate compound |
| CN107405313A (en) * | 2015-04-06 | 2017-11-28 | 株式会社Lg生活健康 | The soluble micropin of insoluble drug transmission |
| CN108403617A (en) * | 2018-02-24 | 2018-08-17 | 中山大学 | Triamcinolone acetonide solubility micropin and preparation method thereof |
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| CN103113494A (en) * | 2013-01-19 | 2013-05-22 | 中国海洋大学 | Preparation method of hyaluronate compound |
| CN107405313A (en) * | 2015-04-06 | 2017-11-28 | 株式会社Lg生活健康 | The soluble micropin of insoluble drug transmission |
| CN108403617A (en) * | 2018-02-24 | 2018-08-17 | 中山大学 | Triamcinolone acetonide solubility micropin and preparation method thereof |
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| Enhanced transdermal lymphatic drug delivery of hyaluronic acid modified transfersomes for tumor metastasis therapy;Kong, Ming，et al.;《CHEMICAL COMMUNICATIONS 》;20150128;第51卷(第8期);第1页右栏第3段，第2页Scheme 1 * |
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