阅读说明：本技术 一种水痘疫苗可溶性微针贴及其制备方法 (Varicella vaccine soluble microneedle patch and preparation method thereof ) 是由 张庶民 马凤森 周荔葆 廖辉 陈中秋 刘苗苗 吴铮 辛小韵 于 2018-07-04 设计创作，主要内容包括：本发明提供了一种水痘疫苗可溶性微针贴,包括针体和背衬,针体由水痘疫苗、基质材料、疫苗稳定剂组成,疫苗稳定剂为海藻糖、甘露醇、谷氨酸钠的混合。本发明通过选择一定比例的海藻糖、甘露醇、谷氨酸钠的混合作为疫苗稳定剂,既能保护疫苗制品的活性,又能有效保证疫苗制品的稳定性,还能有效刺入皮肤,大大提高了用药的安全性。(The invention provides a varicella vaccine soluble microneedle patch which comprises a needle body and a back lining, wherein the needle body consists of a varicella vaccine, a matrix material and a vaccine stabilizer, and the vaccine stabilizer is a mixture of trehalose, mannitol and sodium glutamate. According to the invention, the mixture of trehalose, mannitol and sodium glutamate in a certain proportion is selected as the vaccine stabilizer, so that the activity of the vaccine product can be protected, the stability of the vaccine product can be effectively ensured, the vaccine product can be effectively penetrated into the skin, and the safety of medication is greatly improved.)

1. The varicella vaccine soluble micro-needle patch comprises a needle body and a back lining, and is characterized in that the needle body consists of a varicella vaccine, a matrix material and a vaccine stabilizer, wherein the vaccine stabilizer is a mixture of trehalose, mannitol and sodium glutamate.

2. The varicella vaccine soluble microneedle patch according to claim 1, wherein said matrix material is a mixture of pullulan and carboxymethyl cellulose in a ratio of pullulan: carboxymethyl cellulose ═ 1: 3.

3. the varicella vaccine soluble microneedle patch according to claim 1, wherein the stabilizer comprises the following components in percentage by weight: trehalose: mannitol: sodium glutamate (5:2:1) - (5:2: 3).

4. The varicella vaccine soluble microneedle patch according to claim 3, wherein the stabilizer comprises the following components in percentage by weight: trehalose: mannitol: sodium glutamate is 5:2: 2.

5. The varicella vaccine soluble microneedle patch according to claim 1, wherein the content ratio of the stabilizer to the varicella vaccine is (4:1) to (1: 2).

6. The varicella vaccine soluble microneedle patch according to claim 5, wherein the content ratio of the stabilizer to the varicella vaccine is 1: 1.

7. The varicella vaccine soluble microneedle patch according to claim 1, wherein the content of the varicella vaccine is 25 to 35%.

8. The varicella vaccine soluble microneedle patch according to claim 1, wherein the content of the varicella vaccine is 35%.

9. A method for preparing a varicella vaccine soluble microneedle patch according to any one of claims 1 to 8, comprising the steps of:

① preparing a female die, namely preparing a male die of a microneedle body in advance, covering PDMS and a curing agent on the male die according to the ratio of 10:1, then vacuumizing and drying, and demoulding to obtain the female die;

② the microneedle patch is prepared by adding varicella vaccine, pullulan, and carboxymethyl cellulose, mixing, adding stabilizer, mixing, pouring into female mold, placing the female mold under roller mold, extruding with rotor, sequentially filling into needle body and backing, drying, and demolding.

Technical Field

The invention relates to the technical field of micro-needle administration of vaccines, and provides a soluble micro-needle patch of a varicella vaccine and a preparation method thereof.

Background

Chickenpox (chickenpox) is an acute infectious disease caused by the initial infection with varicella-zoster virus. It is mainly found in infants and preschool children, and the onset symptoms of adults are more severe than those of children. The disease condition of the individual who is not contacted with the varicella and the immunodeficiency when the individual is young is infected with the varicella is serious or serious complications are generated, and the death of the adult infected with the varicella due to the complications is 30-40 times that of children. Varicella is characterized in that the varicella is clinically manifested by mass eruption of the whole body skin mucosa, maculopapule, pimple, herpes and scab exist simultaneously, the clinical symptoms are obvious in 96% of cases, the recessive infection accounts for only 4%, and the secondary infection rate of the family close contact of the susceptible people is close to 90% in the temperate region of the northern hemisphere. The infection is strong in two seasons of winter and spring, the varicella patients are the only infection source, the infection is carried out from 1-2 days before the disease occurs until the dry and crusting period of the rash, the infection can be carried out by contact or inhalation of droplets, and the incidence rate of susceptible children can reach more than 95%. Chickenpox is also manifested by severe complications, most often secondary skin infections, followed by encephalitis, pneumonia and myocarditis.

Varicella-zoster virus (VZV) refers to varicella caused by primary infection in children, virus remains latent in the body after recovery, and virus recurs to cause shingles in a small number of patients after adults. VZV has only one serotype, and humans are the only natural host for the virus. Varicella is not negligible in harm to children and society, but has no specific drug therapy for VZV infection at present, and varicella-zoster immunoglobulin and anti-herpes virus drugs are very expensive, so that general immunization of children by using varicella attenuated live vaccines becomes an important means and trend for reducing or even cutting off the prevalence of varicella in various countries in the world.

The existing varicella vaccine is injected subcutaneously on the upper arm no matter children or adults, the method has accurate dosage, but needs professional medical personnel to operate, and the technical requirement is high. Meanwhile, the injection is painful, the compliance of children and infant groups is relatively poor, and the subcutaneous injection occasionally causes adverse reactions, such as injection scar suppurative infection and lymphangitis caused by improper nursing after the injection is clinically common. On the other hand, whether the safety of the sterile needle is guaranteed or not, whether the hidden danger of repeated cross infection exists or not, the cost of the needle and a plastic tube material is high, the environment pollution is serious during production and manufacturing, the factors of difficult subsequent treatment and the like become the defects of using intradermal injection for administration after use, and under the influence of various adverse factors, the finding of a safe and effective vaccine administration method with high compliance is the most critical problem at present.

Microneedle arrays (microneedle arrays) are used as a novel percutaneous immunization method, and have the characteristics of practicability and convenience after being put forward and continuously developed for decades, and can be operated by common people without professional medical staff. The microneedle does not touch the skin nerve, has no pain and good compliance of special people, and the needle point of the drug-loaded needle just reaches the cortical part with the most immune cells under the condition of fully penetrating the skin cuticle, so the clinical effect is better.

According to the research progress and characteristics of loading small molecular compounds on soluble microneedles (Mafengsen, Hao Hui, Huang Ying, Zhao, Fine chemical engineering, 2018,35 (4): 541) and 548), the microneedles can be divided into solid microneedles, hollow microneedles, coated microneedles and soluble microneedles according to different morphological and functional characteristics. The micro-needle can form self-repairing micro-channels after penetrating into the skin, has good safety, and can be dissolved in the skin automatically, so that the transdermal transfer efficiency of macromolecules and water-soluble medicines is greatly improved, and the effect exceeds that of the traditional skin preparation. Compared with soluble microneedles, other microneedles are relatively simple to prepare and have respective defects: for example, the coated microneedle has small drug loading capacity and is only suitable for drugs with small treatment dose, and the coating dose is difficult to accurately control; the micro-channel is easy to close quickly after the solid micro-needle is pretreated, so that the administration effect is poor, and the micro-channel has the risk of residual harmful substances after the breakage of the needle head like the hollow micro-needle.

At present, no relevant literature report about the varicella vaccine soluble microneedle is found, and no relevant patent is found, so that the patent provides a preparation method of the varicella vaccine soluble microneedle patch.

The varicella vaccine on the market in China initially contains gelatin and human serum albumin, and the human serum albumin in the protective agent can generate allogeneic rejection in a small part of people because the human serum albumin is macromolecular protein, and the varicella vaccine serving as a blood product has a plurality of hidden dangers in the aspects of biological safety and the like; in addition, most of the vaccination allergy reaction to the varicella vaccine is caused by gelatin as a protective agent in the vaccine, and the gelatin component in the protective agent is also a main source of endotoxin in the vaccine, which can cause a fever reaction of a vaccinee, so that the removal of gelatin from the protective agent has become common knowledge in the industry.

Based on the above problems, how to develop a varicella vaccine micro-needle patch which has a proper prescription, can effectively puncture the skin and can be dissolved quickly in the skin, and meanwhile, how to change a stabilizer of the varicella vaccine to make the varicella vaccine more stable and safer becomes a technical problem to be solved by technical personnel in the field.

Disclosure of Invention

The invention aims to provide a varicella vaccine soluble microneedle patch and a preparation method thereof, which solve the bottleneck existing in the prior art.

The present invention aims to enhance the stability of a varicella vaccine. Because most of the protective agents of the varicella vaccine on the market at present contain gelatin and human serum albumin, the optimal prescription of the water-soluble microneedle of the varicella vaccine is found mainly by screening the formula of the stabilizer.

The technical scheme adopted by the invention is as follows:

the invention provides a varicella vaccine soluble microneedle patch which comprises a needle body and a back lining, wherein the needle body consists of a varicella vaccine, a matrix material and a vaccine stabilizer, and the vaccine stabilizer is a mixture of trehalose, mannitol and sodium glutamate.

Preferably, the matrix material is a mixture of amylopectin and carboxymethylcellulose in the ratio of amylopectin: carboxymethyl cellulose ═ 1: 3.

preferably, the content ratio of each component in the stabilizer is as follows: trehalose: mannitol: sodium glutamate (5:2:1) - (5:2: 3).

More preferably, the content ratio of each component in the stabilizer is as follows: trehalose: mannitol: sodium glutamate is 5:2: 2.

Preferably, the content ratio of the stabilizer to the varicella vaccine is (4:1) to (1: 2).

More preferably, the content ratio of the stabilizer to the varicella vaccine is 1: 1.

Preferably, the content of the varicella vaccine accounts for 25 to 35 percent.

More preferably, the content of the varicella vaccine is 35%.

The invention also provides a preparation method of the varicella vaccine soluble microneedle patch, which comprises the following steps:

① preparing a female die, namely preparing a male die of a microneedle body in advance, covering PDMS and a curing agent (10:1) on the male die, then vacuumizing and drying, and demoulding to obtain the female die;

② the microneedle patch is prepared by adding varicella vaccine, pullulan, and carboxymethyl cellulose (CMC) at a given ratio, mixing, adding stabilizer at a given ratio, mixing, pouring into female mold, placing the female mold under a roller mold, rotating with a rotor, drying, adding backing, and demolding.

Compared with the prior art, the soluble micro-needle patch for the varicella vaccine provided by the invention has the following beneficial effects:

according to the invention, the mixture of trehalose, mannitol and sodium glutamate in a certain proportion is selected as the vaccine stabilizer, so that the activity of the vaccine product can be protected, the stability of the vaccine product can be effectively ensured, the vaccine product can be effectively penetrated into the skin, and the safety of medication is greatly improved.

Detailed Description

In order to make the technical solution of the present invention better understood by those skilled in the art, the technical solution in the present embodiment will be specifically described below. It should be noted that the following examples are only for illustrating the present invention and are not to be construed as limiting the present invention, and any modifications and changes made to the present invention within the spirit and scope of the claims are included in the scope of the present invention.