阅读说明：本技术 延胡索总碱透皮制剂及其制备方法 (Corydalis total alkaloid transdermal preparation and preparation method thereof ) 是由 王英姿 张瑶 王志成 姜明瑞 于 2021-10-10 设计创作，主要内容包括：本发明涉及医药科技领域,具体涉及延胡索总碱透皮制剂及其制备方法。所述延胡索总碱透皮制剂为延胡索总碱透皮贴片、延胡索总碱凝胶贴膏或延胡索总碱微针贴片。本发明所述的延胡索总碱为延胡索饮片经乙醇提取、过滤、浓缩、离心、纯化、干燥得到。本发明克服了本领域的技术缺陷制备了延胡索总碱制剂,且该制剂具有延长药效时间,减少用药次数,用药方便,避免首过效应,减少胃肠道刺激的优点,而且同剂量延胡索总碱制剂的药效比延胡索乙素的药效更明显,作用时间更长,具有广泛的应用市场。(The invention relates to the field of medicine science and technology, in particular to a corydalis ambigua total alkaloid transdermal preparation and a preparation method thereof. The corydalis ambigua total alkaloid transdermal preparation is a corydalis ambigua total alkaloid transdermal patch, a corydalis ambigua total alkaloid gel plaster or a corydalis ambigua total alkaloid microneedle patch. The corydalis tuber total alkaloid is obtained by extracting corydalis tuber decoction pieces with ethanol, filtering, concentrating, centrifuging, purifying and drying. The invention overcomes the technical defects in the field, prepares the corydalis tuber total alkaloid preparation, has the advantages of prolonging the drug effect time, reducing the drug use times, being convenient for drug use, avoiding the first pass effect and reducing the gastrointestinal tract irritation, has more obvious drug effect and longer action time than tetrahydropalmatine in the same dose, and has wide application market.)

1. The corydalis ambigua total alkaloid transdermal preparation is characterized in that the transdermal preparation is a corydalis ambigua total alkaloid transdermal patch, a corydalis ambigua total alkaloid gel plaster or a corydalis ambigua total alkaloid microneedle patch.

2. The transdermal preparation of total alkaloids from corydalis tuber according to claim 1, wherein the transdermal patch comprises a drug-loaded layer, a back lining layer and an anti-sticking layer, the drug-loaded layer is composed of total alkaloids from corydalis tuber, penetration enhancer, silk fibroin and pressure-sensitive adhesive matrix, wherein the content of total alkaloids from corydalis tuber in the drug-loaded layer is 3-60 wt%; the content of the penetration enhancer in the drug-loaded layer is 1-15 wt%; the content of silk fibroin in the drug-loaded layer is 0.2-1 wt%.

3. The transdermal preparation of corydalis total alkaloids as claimed in claim 2, wherein the penetration enhancer is azone, oleum Menthae Dementholatum, propylene glycol, isopropyl myristate, oleic acid, dimethyl sulfoxide, ethanol, Borneolum Syntheticum, oleum Eucalypti or pyrrolidone; the back lining layer is an aluminum-polyester film, a polyester-polyethylene composite film, a polyethylene-aluminum-polyester/ethylene-vinyl acetate composite film, a multilayer polyester film or a polyester-ethylene vinyl acetate composite film; the anti-sticking layer is a siliconized polyester film, a fluoropolymer coated polyester film, an aluminum foil-silicone grease compound, a siliconized aluminum foil or a silicon paper.

4. The transdermal preparation of total alkaloids fumarate according to any one of claims 1-3, wherein the transdermal patch is prepared by the following steps:

(1) mixing rhizoma corydalis total alkali, penetration enhancer, silk fibroin, pressure sensitive adhesive, and appropriate amount of ethyl acetate, stirring thoroughly to obtain medicinal glue solution;

(2) coating the medicated glue solution on the anti-sticking layer to obtain medicated wet glue;

(3) drying the medicated wet glue, standing at room temperature, and cooling to obtain medicated dry glue;

(4) covering the backing layer on the medicated dry glue layer to obtain the rhizoma corydalis total alkaloids transdermal patch.

5. The transdermal preparation of corydalis total alkaloids as claimed in claim 1, wherein the gel plaster comprises a backing layer, a drug reservoir layer and a release film layer in sequence; the gel plaster comprises the following components in percentage by weight: 3-30% of corydalis tuber total alkali, 5-15% of cross-linked skeleton, 5-25% of humectant, 2-10% of thickening agent, 0.2-2% of cross-linking agent, 0.2-2% of PH regulator and the balance of solvent.

6. The transdermal preparation of total alkaloids fumarate of claim 5, wherein the cross-linked matrix is sodium polyacrylate or carbomer; the humectant is one or more of glycerol, propylene glycol and urea; the thickening agent is one or more of polyvinylpyrrolidone K30, polyvinylpyrrolidone K60, polyvinylpyrrolidone K90 and silk fibroin; the cross-linking agent is one or more of aluminum hydroxide, aluminum trichloride and aluminum glycollate; the pH regulator is tartaric acid or citric acid; the solvent is water.

7. The transdermal preparation of total alkaloids from corydalis as claimed in claim 5 or 6, wherein the preparation method of the gel plaster of total alkaloids from corydalis comprises the following steps:

(1) uniformly mixing the crosslinking skeleton and the crosslinking agent, adding the humectant, and fully and uniformly stirring to obtain an A-phase solution;

(2) adding tackifier into water, stirring, adding crosslinking regulator, rhizoma corydalis total alkali or tetrahydropalmatine and solvent, and stirring to dissolve completely to obtain B phase solution;

(3) adding the phase A solution in the step (1) into the phase B solution in the step (2), and stirring to obtain a drug-containing ointment;

(4) and (4) coating the hydrogel paste obtained in the step (3) to obtain the corydalis tuber total alkaloid gel plaster.

8. The transdermal preparation of corydalis total alkaloids, wherein the weight percentage of each component in the transdermal patch of corydalis total alkaloids is as follows: 1-30% of corydalis tuber total alkali, 5-50% of soluble matrix and the balance of solvent.

9. The transdermal preparation of corydalis total alkaloids, as claimed in claim 8, wherein the soluble matrix is one or more of polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, carboxymethyl chitosan, polyvinyl alcohol-polyethylene glycol, PVP-VA64, sodium hyaluronate, sodium alginate, chitosan and silk fibroin; the solvent is water or absolute ethyl alcohol.

10. The transdermal preparation of corydalis total alkaloids according to claim 9, wherein the corydalis total alkaloids-soluble microneedle patch comprises the following steps:

(1) adding corydalis tuber total alkali into a high molecular material to obtain a medicine-containing matrix material solution;

(2) dripping the drug-containing matrix material solution into a microneedle mould, placing the microneedle mould under a reduced pressure condition, enabling the solution to completely enter a microneedle mould hole, and drying at room temperature;

(3) and (3) adding the corydalis tuber total alkali solution into the high polymer material, dripping the solution into the microneedle mould dried in the step (2), drying at room temperature, and demoulding to obtain the corydalis tuber total alkali microneedle patch.

Technical Field

The invention relates to the field of medicine science and technology, in particular to a corydalis ambigua total alkaloid transdermal preparation and a preparation method thereof.

Background

The chronic pain seriously harms the physical and psychological health of human beings, and brings huge economic burden to families and society. The pathogenesis of chronic pain is complex, the most effective analgesic drug therapy such as opioid is carried out in western medicine at present, but the problems of side effect, tolerance, addiction, drug abuse and the like generally exist.

The traditional Chinese medicine has unique advantages in the aspect of treating chronic pain, and can be expected to play a role in treating both symptoms and root causes by exerting the double effects of acupoint stimulation and medicine curative effect. Corydalis tuber is used as an analgesic drug, the analgesic effective part is total alkaloids of the corydalis tuber, and the corydalis tuber can regulate downstream biological signal transduction pathways by acting on central analgesic related protein, smooth muscle related receptor protein, thromboxane, angiotensin and the like, so that the effects of relieving pain, regulating qi, promoting blood circulation and the like are exerted, and the analgesic effect of the corydalis tuber total alkaloids is superior to that of corydalis tuber which is a single traditional Chinese medicine and tetrahydropalmatine which is a monomer component. In addition, the corydalis alkaloid also has obvious clinical effect of resisting opioid addiction, can reduce the problems of opioid analgesic addiction and drug abuse, and can fully exert the advantages of safety, effectiveness and small toxic and side effects of the traditional Chinese medicine for treating chronic pain.

The transdermal patch is a thin skin preparation which can be attached to the skin, can generate a systemic effect or a local treatment effect by percutaneous absorption of the medicine, has the advantages of no liver first pass effect, no influence of the gastric emptying rate, high bioavailability, convenient use, no pain, capability of cancelling or interrupting the treatment at any time, accurate administration dosage, fixed absorption area, stable blood concentration, prolonged action time, reduction of the administration frequency and the like, and has obvious clinical application advantages for chronic diseases needing to be maintained and treated for a long time, such as diabetes, hypertension, Alzheimer's disease and the like.

The gel plaster is prepared by uniformly mixing the raw material medicines with a proper hydrophilic matrix and coating the mixture on a backing material, has the advantages of large medicine-loading rate, strong moisture retention, good compatibility with skin, small irritation, no use of organic solvent in production, easy uncovering and pasting and the like, and is mainly applied to the aspects of promoting blood circulation to remove blood stasis, resisting inflammation and easing pain, dispelling wind and removing dampness and the like at present.

The soluble microneedle is prepared by mixing the drug and the degradable biopolymer material, injecting the mixture in a solvent dissolving or melting state, drying and demoulding. The preparation method has the characteristics of simple preparation process and rich preparation materials, and solves the problem that the needle tip of the solid micro-needle (silicon, glass and the like) is broken in vivo and cannot be degraded. Is currently used for disease diagnosis, transdermal drug delivery, beauty and body care, and the like.

At present, there are no reports of corydalis ambigua total alkaloid transdermal patches, gel plasters and soluble microneedles, so that the development of corydalis ambigua total alkaloid transdermal patches, gel plasters and soluble microneedles which have relatively definite ingredients, easily-controlled quality, obvious analgesic effect, convenient use, good patient compliance and high safety have important significance for treating chronic pain.

Disclosure of Invention

The invention aims to provide a corydalis ambigua total alkaloid transdermal patch, a corydalis ambigua total alkaloid gel plaster and a corydalis ambigua total alkaloid soluble micro-needle for treating chronic pain.

The invention also aims to provide a preparation method of the corydalis total alkaloid transdermal patch, the corydalis total alkaloid gel plaster and the corydalis total alkaloid soluble microneedle patch.

In order to realize the purpose of the invention, the invention adopts the technical scheme that:

the transdermal preparation of the corydalis ambigua total alkaloid is a corydalis ambigua total alkaloid transdermal patch, a corydalis ambigua total alkaloid gel plaster or a corydalis ambigua total alkaloid microneedle patch.

Further, the transdermal patch comprises a drug-loaded layer, a back lining layer and an anti-sticking layer, wherein the drug-loaded layer consists of corydalis tuber total alkaloid, a penetration enhancer, silk fibroin and a pressure-sensitive adhesive matrix, and the content of the corydalis tuber total alkaloid in the drug-loaded layer is 3-60 wt%; the content of the penetration enhancer in the drug-loaded layer is 1-15 wt%; the content of the fibroin in the drug-loaded layer is 0.2-1 wt%.

Further, the penetration enhancer is azone, peppermint oil, propylene glycol, isopropyl myristate, oleic acid, dimethyl sulfoxide, ethanol, borneol, eucalyptus oil or pyrrolidone; the back lining layer is an aluminum-polyester film, a polyester-polyethylene composite film, a polyethylene-aluminum-polyester/ethylene-vinyl acetate composite film, a multilayer polyester film or a polyester-ethylene vinyl acetate composite film; the anti-sticking layer is a siliconized polyester film, a fluoropolymer coated polyester film, an aluminum foil-silicone grease compound, a siliconized aluminum foil or a silicon paper.

Preferably, the preparation method of the transdermal patch adopts the following steps:

(1) mixing rhizoma corydalis total alkali, penetration enhancer, silk fibroin, pressure sensitive adhesive, and appropriate amount of ethyl acetate, stirring thoroughly to obtain medicinal glue solution;

(2) coating the medicated glue solution on the anti-sticking layer to obtain medicated wet glue;

(3) drying the medicated wet glue, standing at room temperature, and cooling to obtain medicated dry glue;

(4) covering the backing layer on the medicated dry glue layer to obtain the rhizoma corydalis total alkaloids transdermal patch.

Further, the corydalis ambigua total alkaloid gel plaster sequentially comprises a back lining layer, a drug storage layer and a release film layer; the gel plaster comprises the following components in percentage by weight: 3-30% of corydalis tuber total alkali, 5-15% of cross-linked skeleton, 5-25% of humectant, 2-10% of thickening agent, 0.2-2% of cross-linking agent, 0.2-2% of PH regulator and the balance of solvent.

Preferably, the cross-linked backbone is sodium polyacrylate or carbomer; the humectant is one or more of glycerol, propylene glycol and urea; the thickening agent is one or more of polyvinylpyrrolidone K30, polyvinylpyrrolidone K60, polyvinylpyrrolidone K90 and silk fibroin; the cross-linking agent is one or more of aluminum hydroxide, aluminum trichloride and aluminum glycollate; the pH regulator is tartaric acid or citric acid; the solvent is water.

Preferably, the preparation method of the corydalis tuber total alkaloid gel plaster comprises the following steps:

(1) uniformly mixing the crosslinking skeleton and the crosslinking agent, adding the humectant, and fully and uniformly stirring to obtain an A-phase solution;

(2) adding tackifier into water, stirring, adding crosslinking regulator, rhizoma corydalis total alkali or tetrahydropalmatine and solvent, and stirring to dissolve completely to obtain B phase solution;

(3) adding the phase A solution in the step (1) into the phase B solution in the step (2), and stirring to obtain a drug-containing ointment;

(4) and (4) coating the hydrogel paste obtained in the step (3) to obtain the corydalis tuber total alkaloid gel plaster.

Further, the corydalis tuber total alkaloid microneedle patch comprises the following components in percentage by weight: 1-30% of corydalis tuber total alkali, 5-50% of soluble matrix and the balance of solvent.

Preferably, the soluble matrix is one or more of polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, carboxymethyl chitosan, polyvinyl alcohol-polyethylene glycol, PVP-VA64, sodium hyaluronate, sodium alginate, chitosan and silk fibroin; the solvent is water or absolute ethyl alcohol.

Preferably, the corydalis ambigua total alkali transdermal preparation adopts the following steps:

(1) adding corydalis tuber total alkali into a high molecular material to obtain a medicine-containing matrix material solution;

(2) dripping the drug-containing matrix material solution into a microneedle mould, placing the microneedle mould under a reduced pressure condition, enabling the solution to completely enter a microneedle mould hole, and drying at room temperature;

(3) and (3) adding the corydalis tuber total alkali solution into the high polymer material, dripping the solution into the microneedle mould dried in the step (2), drying at room temperature, and demoulding to obtain the corydalis tuber total alkali microneedle patch.

The corydalis tuber total alkaloid is obtained by extracting corydalis tuber decoction pieces with ethanol, filtering, concentrating, centrifuging, purifying and drying.

Advantageous effects

Tetrahydropalmatine is always considered as a main analgesic and sedative active ingredient in corydalis tuber, so most of research is carried out on tetrahydropalmatine, but the tetrahydropalmatine has low content in the corydalis tuber, is not beneficial to preparation and has high cost.

Drawings

FIG. 1 is a high performance liquid chromatography determination chart of 3 index components in total alkaloids of corydalis tuber;

FIG. 2 is a diagram of total alkaloids from rhizoma corydalis obtained by ethanol extraction, filtration, concentration, centrifugation, purification and drying of rhizoma corydalis decoction pieces;

figure 3 is a diagram of the transdermal patch of total alkaloids from corydalis tuber of example 1;

figure 4 is a diagram of a transdermal patch of tetrahydropalmatine of comparative example 1;

FIG. 5 is a diagram of corydalis ambigua total alkaloid gel patch of example 8;

FIG. 6 is a drawing of a comparative example 5 tetrahydropalmatine gel patch;

fig. 7 is a picture of total alkali-soluble microneedles from corydalis tuber of example 10;

fig. 8 is a diagram of a comparative example 7 tetrahydropalmatine soluble microneedle.

Detailed Description

The transdermal patch, gel patch and soluble microneedle of total alkaloids of corydalis as described in the present invention are further illustrated by the following examples, which are only used for illustrating the technical solutions of the present invention, but not for limiting the same, and it should be understood by those skilled in the art that the modifications of the technical solutions as described in the foregoing examples, or the equivalent replacement of some technical features may still be made, and these modifications or replacements do not depart from the scope of the technical solutions of the present invention.

The backing layer in the following examples is made of low density polyethylene film, and the release layer is made of polyethylene terephthalate (PET).

The percentages referred to in the following examples 1-6 are all weight percentages, for example, corydalis ambigua total alkaloid or tetrahydropalmatine 1% -refers to the weight percentage of corydalis ambigua total alkaloid or tetrahydropalmatine in the drug-loaded layer of 1% based on the dry weight of the pressure-sensitive adhesive. The percentages referred to in examples 7-12 are weight percentages, e.g. 1% total alkaloids from corydalis tuber-referring to the weight of all materials in the drug-loaded layer or microneedle solution, and 1% total alkaloids from corydalis tuber or tetrahydropalmatine.

Example 1

Mixing rhizoma corydalis total alkali 30%, azone 3%, silk fibroin 0.2%, appropriate amount of ethyl acetate and acrylate pressure sensitive adhesive, coating on the anti-sticking layer, drying at 50 deg.C, compounding with backing layer, and cutting into desired size to obtain rhizoma corydalis total alkali transdermal patch.

Example 2

Mixing rhizoma corydalis total alkali 30%, azone 1%, silk fibroin 0.2%, appropriate amount of ethyl acetate and acrylate pressure sensitive adhesive, coating on the anti-sticking layer, drying at 80 deg.C, compounding with backing layer, and cutting into desired size to obtain rhizoma corydalis total alkali transdermal patch.

Example 3

Mixing rhizoma corydalis total alkaloids 30%, isopropyl myristate 1%, silk fibroin 0.2%, appropriate amount of ethyl acetate and acrylate pressure sensitive adhesive, coating on the anti-sticking layer, drying at 60 deg.C, compounding with backing layer, and cutting into desired size to obtain rhizoma corydalis total alkaloids transdermal patch.

Example 4

Mixing rhizoma corydalis total alkaloids 30%, isopropyl myristate 3%, silk fibroin 0.8%, appropriate amount of ethyl acetate and acrylate pressure sensitive adhesive, coating on the anti-sticking layer, drying at 50 deg.C, compounding with backing layer, and cutting into desired size to obtain rhizoma corydalis total alkaloids transdermal patch.

Example 5

Mixing rhizoma corydalis total alkaloids 30%, propylene glycol 3%, silk fibroin 1%, appropriate amount of ethyl acetate and acrylate pressure-sensitive adhesive, coating on the anti-sticking layer, drying at 50 deg.C, compounding with backing layer, and cutting into desired size to obtain rhizoma corydalis total alkaloids transdermal patch.

Example 6

Mixing rhizoma corydalis total alkaloids 30%, propylene glycol 5%, silk fibroin 0.2%, appropriate amount of ethyl acetate and acrylate pressure sensitive adhesive, coating on the anti-sticking layer, drying at 50 deg.C, compounding with backing layer, and cutting into desired size to obtain rhizoma corydalis total alkaloids transdermal patch.

Example 7

Mixing 5% sodium polyacrylate, 0.3% aluminum glycollate and 25% glycerin as phase A; mixing 0.3% tartaric acid, 3% polyvinylpyrrolidone K90, 20% rhizoma corydalis total alkali and water to obtain phase B; adding phase A into phase B, stirring, coating on anti-sticking layer, drying at 60 deg.C, mixing with backing layer, and cutting into desired size to obtain rhizoma corydalis total alkaloids gel plaster.

Example 8

Mixing 10% sodium polyacrylate, 0.5% aluminum glycollate and 20% glycerin as phase A; mixing 0.5% tartaric acid, 5% polyvinylpyrrolidone K90, 20% rhizoma corydalis total alkali and water to obtain phase B; adding phase A into phase B, stirring, coating on anti-sticking layer, drying at 50 deg.C, mixing with backing layer, and cutting into desired size to obtain rhizoma corydalis total alkaloids gel plaster.

Example 9

Mixing 15% sodium polyacrylate, 0.75% aluminum glycollate and 20% glycerin as phase A; mixing 0.75% tartaric acid, 5% polyvinylpyrrolidone K90, 20% rhizoma corydalis total alkali and water to obtain phase B; adding phase A into phase B, stirring, coating on anti-sticking layer, drying at 80 deg.C, mixing with backing layer, and cutting into desired size to obtain rhizoma corydalis total alkaloids gel plaster.

Example 10

Mixing 2% corydalis tuber total alkali and 58% ethanol water with the alcohol content of 20%, adding 30% polyvinylpyrrolidone and 10% polyvinyl alcohol, mixing at 50 deg.C to obtain a drug-containing matrix material solution, injecting the drug-containing matrix material solution into a microneedle mould, removing bubbles under reduced pressure to fill the needle tip with the drug-containing solution, drying at normal temperature, dripping the drug-containing matrix material solution into the dried microneedle mould, drying at room temperature, and demoulding to obtain corydalis tuber total alkali soluble microneedle.

Example 11

Mixing 2% corydalis tuber total alkali and 68% ethanol water with the alcohol content of 20%, adding 20% polyvinylpyrrolidone and 10% polyvinyl alcohol, mixing at 80 deg.C to obtain a drug-containing matrix material solution, injecting the drug-containing matrix material solution into a microneedle mould, removing bubbles under reduced pressure to fill the needle tip with the drug-containing solution, drying at normal temperature, dripping the drug-containing matrix material solution into the dried microneedle mould, drying at room temperature, and demoulding to obtain corydalis tuber total alkali soluble microneedle.

Example 12

Mixing 2% rhizoma corydalis total alkali with 78% ethanol water with 20% alcohol content, adding 10% polyvinylpyrrolidone and 10% polyvinyl alcohol, mixing at 50 deg.C to obtain a drug-containing matrix material solution, injecting the drug-containing matrix material solution into a microneedle mould, removing bubbles under reduced pressure to fill the needle tip with the drug-containing solution, drying at room temperature, dripping the drug-containing matrix material solution into the dried microneedle mould, drying at room temperature, and demoulding to obtain rhizoma corydalis total alkali soluble microneedle.

Comparative example 1

Mixing tetrahydropalmatine 30%, isopropyl myristate 1%, silk fibroin 0.2%, ethyl acetate and acrylate pressure-sensitive adhesive, coating on the anti-sticking layer, drying at 50 deg.C, compounding with backing layer, and cutting into desired size to obtain tetrahydropalmatine transdermal patch.

Comparative example 2

Mixing tetrahydropalmatine 30%, isopropyl myristate 3%, silk fibroin 0.8%, ethyl acetate and acrylate pressure-sensitive adhesive, coating on the anti-sticking layer, drying at 50 deg.C, compounding with backing layer, and cutting into desired size to obtain tetrahydropalmatine transdermal patch.

Comparative example 3

Mixing tetrahydropalmatine 30%, propylene glycol 3%, silk fibroin 1%, ethyl acetate and acrylate pressure-sensitive adhesive, coating on the anti-sticking layer, drying at 50 deg.C, compounding with backing layer, and cutting into desired size to obtain tetrahydropalmatine transdermal patch.

Comparative example 4

Mixing 5% sodium polyacrylate, 0.3% aluminum glycollate and 25% glycerin as phase A; mixing 0.3% tartaric acid, 3% polyvinylpyrrolidone K90, 20% tetrahydropalmatine and water as phase B; adding phase A into phase B, stirring, coating on anti-sticking layer, drying at 50 deg.C, mixing with backing layer, and cutting into desired size to obtain tetrahydropalmatine gel plaster.

Comparative example 5

Mixing 10% sodium polyacrylate, 0.5% aluminum glycollate and 20% glycerin as phase A; mixing 0.5% tartaric acid, 5% polyvinylpyrrolidone K90, 20% tetrahydropalmatine and water as phase B; adding phase A into phase B, stirring, coating on anti-sticking layer, drying at 50 deg.C, mixing with backing layer, and cutting into desired size to obtain tetrahydropalmatine gel plaster.

Comparative example 6

Mixing 15% sodium polyacrylate, 0.75% aluminum glycollate and 20% glycerin as phase A; mixing 0.75% tartaric acid, 5% polyvinylpyrrolidone K90, 20% tetrahydropalmatine and water as phase B; adding phase A into phase B, stirring, coating on anti-sticking layer, drying at 50 deg.C, mixing with backing layer, and cutting into desired size to obtain tetrahydropalmatine gel plaster.

Comparative example 7

Mixing 2% tetrahydropalmatine and 58% ethanol water with alcohol content of 20%, adding 30% polyvinylpyrrolidone and 10% polyvinyl alcohol, mixing at 50 deg.C to obtain a solution containing matrix material, injecting the solution into microneedle mould, removing bubbles under reduced pressure to fill the needle tip with the solution, drying at room temperature, dripping the solution into the dried microneedle mould, drying at room temperature, and demoulding to obtain tetrahydropalmatine soluble microneedle.

Comparative example 8

Mixing 2% tetrahydropalmatine and 68% ethanol water with the alcohol content of 20%, adding 20% polyvinylpyrrolidone and 10% polyvinyl alcohol, mixing at 50 deg.C to obtain a solution containing matrix material, injecting the solution into a microneedle mould, removing bubbles under reduced pressure to fill the needle tip with the solution containing drug, drying at room temperature, dripping the solution into the dried microneedle mould, drying at room temperature, and demoulding to obtain tetrahydropalmatine soluble microneedle.

Comparative example 9

Mixing 2% tetrahydropalmatine and 78% ethanol water with 20% alcohol content, adding 10% polyvinylpyrrolidone and 10% polyvinyl alcohol, mixing at 50 deg.C to obtain a solution containing matrix material, injecting the solution into microneedle mould, removing bubbles under reduced pressure to fill the needle tip with the solution, drying at room temperature, dripping the solution into the dried microneedle mould, drying at room temperature, and demoulding to obtain tetrahydropalmatine soluble microneedle.

By examining the patches of examples 1-6, it was found that the properties, content uniformity, release rate, initial adhesion, holding power and peel strength all meet the specifications of the patch according to the four-part general rules of the 2020 th edition of the Chinese pharmacopoeia.

Pharmacological example 1 in vitro transdermal penetration test of transdermal patch containing total alkaloids of corydalis tuber

Adopts a three-dimensional diffusion cell, and the effective diffusion area is 3.14cm²The skin used was the abdominal skin of unhaired rats. The patch is attached to one side of the horny layer of the abdominal skin of the unhaired rat and is placed between the diffusion pool and the receiving pool, wherein the horny layer faces to the diffusion pool, and the dermis layer faces to the receiving pool. The volume of the receiving pool is 8ml, the receiving pool is filled with 10% ethanol physiological saline solution and bubbles are removed, the receiving pool is placed in a circulating water bath magnetic stirring pool, the rotating speed of magnetons is 300r/min, and the temperature of the water bath is 37 ℃. After the start of transdermal delivery, 0.2ml was sampled at 1h, 2h, 4h, 6h, 8h, 12h and 24h, fresh receiving solution was replenished immediately after sampling, the sampling solution was filtered through a 0.22 μm microporous filter membrane, the concentrations of 3 index components were measured by high performance liquid chromatography, and the transdermal permeation rate and cumulative permeation amount were calculated, and the results are shown in table 1 (means ± SD, where n is 3).

TABLE 1

Pharmacological example 2 skin allergy test of transdermal patch of total alkaloids from corydalis Tuber

The hairs of 6 New Zealand rabbits were removed from both sides of the back 24h before administration, and the hair-removed area ranged from about 4cm by 4cm on each side. Randomly dividing into 2 groups, sticking rhizoma corydalis total alkaloid patch prepared in example 6 to group 1, sticking blank patch (containing rhizoma corydalis total alkaloid and penetration enhancer) to group 2, sticking on the depilated area of the left back of animal, and fixing with gauze and adhesive plaster. Each animal was kept in cages for 6 h. The same procedure was repeated on day 7 and day 14. And feeding the animals for 14d, sticking the patch on the right depilated area on the back of the rabbit, removing the tested medicine after 6h, immediately observing the skin anaphylactic reaction condition, and then observing again at 24h, 48h and 72h to evaluate the anaphylaxis of the corydalis tuber total alkaloid patch. The results were scored according to the skin response criteria, and the mean response values were all zero for 6 animals (total of erythema and edema formation was zero), as well as the sensitization rate. And (4) conclusion: the corydalis ambigua total alkaloid transdermal patch belongs to a non-sensitizing medicament.

Pharmacological example 3 Hot plate analgesia experiment in mice

70 female mice were anesthetized with 4% chloral hydrate (10 ml/kg) and then subjected to abdominal depilation after anesthesia, and the mice were randomly divided into 7 groups, i.e., a blank group, a corydalis total alkaloid patch group prepared in example 4, a tetrahydropalmatine patch group prepared in comparative example 2, a corydalis total alkaloid gel patch group prepared in example 7, a tetrahydropalmatine gel patch group prepared in comparative example 4, a corydalis total alkaloid microneedle group prepared in example 10, and tetrahydropalmatine microneedle groups prepared in comparative example 7, each of which was 10. Blank group: blank patch administration; rhizoma corydalis total alkaloid patch group, rhizoma corydalis B patch group, rhizoma corydalis total alkaloid gel patch group, and rhizoma corydalis B gel patch group are all 2.56cm²Only applying on the skin of the depilatory; the rhizoma corydalis total alkaloids micro needle set and tetrahydropalmatine micro needle set are applied to skin at depilation position by 1 tablet/piece. Applied daily for 5 days. Before administration, mice were placed on a hot plate, the temperature was controlled at (55.0 + -0.5) C, the time(s) required from placement on the hot plate to the time the mice lick the hindpaw was recorded, the test was performed 2-3 times (5 min intervals), and the mean value was taken as their basal pain threshold. After the 5 th dose, the test drug is removed, the patient is wiped clean with warm water, and the pain threshold is measured according to the basic pain threshold measurement method, wherein the pain threshold is measured in 60s for patients with pain exceeding 60 s. The results are shown in Table 2.

TABLE 2

As a result, for the pain of mice caused by the hot plate method, compared with the blank group, the pain threshold value of the mice in each administration group is obviously increased (P < 0.05), the effect of the rhizoma corydalis total alkaloid microneedle group for increasing the pain threshold level is more obvious (P < 0.01) than that of the rhizoma corydalis total alkaloid patch group, and the pain threshold increasing percentages are in sequence from high to low: the corydalis ambigua total alkaloid micro needle group > corydalis ambigua total alkaloid patch group > corydalis ambigua total alkaloid gel plaster group > corydalis B gel patch group > corydalis B gel plaster group > corydalis B micro needle group, and the pain threshold improvement percentage is respectively 38.67%, 36.18%, 21.96%, 21.18%, 18.54% and 17.40%. The rhizoma corydalis total alkaloid patch group has similar numerical values and no obvious difference (P is more than 0.05) compared with the rhizoma corydalis total alkaloid microneedle group, which indicates that the effect of improving the hot plate pain threshold of the mice is equivalent.

Compared with the rhizoma corydalis total alkaloid patch group, the rhizoma corydalis total alkaloid microneedle group is superior to the rhizoma corydalis total alkaloid gel paste group, the rhizoma corydalis total alkaloid microneedle group is obviously superior to the rhizoma corydalis total alkaloid gel paste group (P < 0.05), but has no significant difference (P > 0.05) with the rhizoma corydalis total alkaloid patch group, and the rhizoma corydalis total alkaloid patch is superior to the rhizoma corydalis total alkaloid gel paste group but has no significant difference (P > 0.05). The comparison of the tetrahydropalmatine administration groups shows that the tetrahydropalmatine gel plaster group is superior to the tetrahydropalmatine micro-needle group, but the difference between the three groups is not significant (P > 0.05).

Compared with the tetrahydropalmatine administration groups, the tetrahydropalmatine patch group is superior to the tetrahydropalmatine patch group, the tetrahydropalmatine gel patch group and the tetrahydropalmatine micro-needle group in significance difference (P < 0.05), the tetrahydropalmatine gel patch group is superior to the tetrahydropalmatine patch group, the tetrahydropalmatine gel patch group and the tetrahydropalmatine micro-needle group but has no significance difference (P > 0.05), and the tetrahydropalmatine micro-needle group is superior to the tetrahydropalmatine patch group, the tetrahydropalmatine gel patch group and the tetrahydropalmatine micro-needle group in significance difference (P < 0.05).

Pharmacological example 4 mouse writhing pain test

70 female mice were anesthetized with 0.4% chloral hydrate (0.1 ml/kg), and after anesthesia, abdominal hair was removed, and the groups were randomly divided and administered according to the above method, and the dosage was the same as above. After 5 days of continuous administration, 0.2ml of glacial acetic acid with concentration of 0.7% was injected into the abdominal cavity of each mouse after 5 days of administration, and the times of writhing (abdomen concave, hind limb stretching, hip rising) of the mouse were measured within 10min and 20min, respectively. Calculating the inhibition rate of the drug on writhing response to judge the analgesic effect of the drug: inhibition% = (blank group writhing mean-administration group writhing mean)/blank group writhing mean × 100%. The results are shown in the following table.

As a result, the pain threshold value of the mice in each administration group is obviously increased (P is less than 0.05) compared with that in a blank group, and the inhibition rate of the corydalis total alkaloid patch group, the corydalis total alkaloid microneedle group, the corydalis total alkaloid gel patch group and the tetrahydropalmatine gel patch group on writhes is more obvious (P is less than 0.01). The inhibition rates of the writhing reaction are sequentially from high to low: the corydalis total alkaloid patch group, the corydalis total alkaloid micro needle group, the corydalis total alkaloid gel plaster group, the corydalis B gel patch group, the corydalis B gel plaster group and the corydalis B micro needle group respectively have inhibition rates of 58.97%, 56.65%, 39.56%, 35.21%, 27.19% and 26.74%. Compared with the corydalis tuber total alkaloid microneedle group, the corydalis tuber total alkaloid patch group has no obvious difference (P is more than 0.05), and the effect of inhibiting writhing of mice is equivalent.

The comparison of the rhizoma corydalis total alkaloid administration groups shows that the rhizoma corydalis total alkaloid patch group is superior to the rhizoma corydalis total alkaloid microneedle group in comparison with the rhizoma corydalis total alkaloid gel patch group, but the three groups have no significant difference (P > 0.05). The comparison of the tetrahydropalmatine administration groups shows that the tetrahydropalmatine patch group is superior to the tetrahydropalmatine gel patch group, but the differences among the three groups are not significant (P is more than 0.05).

Comparing the rhizoma corydalis total alkaloid administration groups with the tetrahydropalmatine administration groups, the rhizoma corydalis total alkaloid patch group is superior to the tetrahydropalmatine patch group, the tetrahydropalmatine gel patch group and the tetrahydropalmatine micro-needle group, and has significant difference (P < 0.05); the corydalis total alkaloid gel plaster group is superior to the corydalis B plaster group, the corydalis B gel plaster group and the corydalis B micro-needle group, but has no significant difference (P is more than 0.05); the corydalis total alkaloid microneedle set is superior to the tetrahydropalmatine patch set and the tetrahydropalmatine gel patch set, but has no significant difference (P is greater than 0.05), is superior to the tetrahydropalmatine microneedle set, and has significant difference (P is less than 0.05).

In conclusion, the corydalis ambigua total alkaloid patch, the tetrahydropalmatine patch, the corydalis ambigua total alkaloid gel patch, the tetrahydropalmatine gel patch, the corydalis ambigua total alkaloid microneedle and the tetrahydropalmatine microneedle (which are supplemented in front) have analgesic effects on a hot plate analgesic model and a mouse acetic acid writhing model, wherein the analgesic effect of the corydalis ambigua total alkaloid preparation with the same dosage form is stronger than that of the tetrahydropalmatine preparation, which indicates that the corydalis ambigua total alkaloid has stronger analgesic effect, and the corydalis ambigua total alkaloid patch group and the corydalis ambigua total alkaloid microneedle have the strongest analgesic effect.

This patent was supported by the national focus development program (project number 2018YFE 0197900).