CN108210484B - Tamoxifen gel patch and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to a tamoxifen gel patch and a preparation method thereof. The invention provides a tamoxifen gel patch, which is composed of tamoxifen, a solubilizer, a cross-linked polymer, a cross-linking agent, a cross-linking regulator, a carbomer, and the following parts by weight: Component preparation: Among them, the addition of carbomer effectively improves the forming problem of the gel patch base; the addition of solubilizer eucalyptus oil and diethylene glycol monoethyl ether significantly improves the tamoxifen in the gel The solubility in the plaster matrix solves the problem of drug precipitation; the tamoxifen gel plaster prepared by the invention has stable molding, complete appearance, good adhesion performance, high skin penetration rate, no sensitization and irritation, It is convenient to use, does not pollute clothes, can be peeled off repeatedly, and has the advantages of low production cost and the like.

Description

Tamoxifen gel patch and preparation method thereof

technical field

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a tamoxifen gel patch and a preparation method thereof.

Background technique

The prior art discloses that breast cancer is the most common malignant tumor in women, about 1.3 million people worldwide are diagnosed with breast cancer every year, about 400,000 people die from the disease, and the incidence rate is increasing year by year. The current clinical treatment options for breast cancer include surgery, chemotherapy, radiotherapy, endocrine therapy, molecular targeted therapy, and traditional Chinese medicine. Studies have shown that most breast cancer cells express estrogen receptors, and their growth and proliferation are obviously hormone-dependent. In recent years, endocrine therapy has gradually become a hot topic. Endocrine therapy can inhibit the growth of tumor cells by reducing the level of estrogen in the body or inhibiting the effect of estrogen. It is known in the industry that tamoxifen is the first-generation selective estrogen receptor modulator with dual effects of estrogen agonism and antagonism. It is the most effective and longest-lasting first-line endocrine therapy in hormone-dependent breast cancer. Therapeutic drug, suitable for postmenopausal women with estrogen receptor and progesterone receptor-positive breast cancer, is one of the first-choice drugs for endocrine adjuvant therapy after breast cancer surgery.

At present, the route of administration of tamoxifen is mainly oral, mainly tablets, granules, and capsules. Tamoxifen is almost insoluble in water. Therefore, clinical practice shows that the above oral dosage forms have poor gastrointestinal dissolution. , resulting in low bioavailability, and there is a liver first-pass effect, oral plasma concentration fluctuations, long-term use may easily lead to venous thrombosis and increase the risk of endometrial cancer and other defects. In order to reduce the side effects of tamoxifen and increase the clinical efficacy, researchers in the field consider changing the administration method from oral administration to transdermal administration. Fluctuation of drug concentration, reduction of drug toxicity and adverse reactions, reduction of the number of administrations, and convenient use; moreover, the application of transdermal preparations on the skin around the breast will allow the drug to directly enter the lesion through percutaneous diffusion and penetration, and last for a long time. The targeted administration of tamoxifen increases the concentration of tamoxifen in breast tissue, which is beneficial to improve the therapeutic effect of breast cancer.

Tamoxifen, also known as tamoxifen, has a molecular weight of 371 and a melting point of 96-98 °C. Studies have shown that it is almost insoluble in water, slightly soluble in ethanol, and easily soluble in glacial acetic acid. Glue, cream, cream, microemulsion, etc. CN101065120A discloses a 4-hydroxy tamoxifen gel preparation, which is a semi-solid preparation;

CN1857242A discloses an external preparation of tamoxifen citrate microemulsion, which is a liquid preparation and can also be made into a semi-solid preparation; CN101711754A further discloses a method for preparing tamoxifen citrate microemulsion into a patch, The plaster adopts a high-temperature heating process, and the rosin plasticizer, polyisobutylene pressure-sensitive adhesive and other components involved in its formula are likely to cause skin irritation and allergy.

There are no reports on tamoxifen gel patch.

Based on the current situation of the prior art, the inventor of the present application intends to provide a tamoxifen gel patch and a preparation method thereof. The present invention can overcome the defects of the existing dosage forms of tamoxifen, and is an endocrine therapy for breast cancer. A more convenient and effective dosage form is provided.

SUMMARY OF THE INVENTION

The object of the present invention is to overcome the defects of the existing dosage forms of tamoxifen in the prior art, and provide a tamoxifen gel patch and a preparation method thereof.

Gel-based plaster (original bab ointment or gel plaster) refers to the plaster (defined in Chinese Pharmacopoeia 2015 edition) made by mixing the raw material drug with a suitable hydrophilic matrix and then coating it on the backing material.

The invention provides a tamoxifen gel patch, which is composed of tamoxifen, a solubilizer, a cross-linked polymer, a cross-linking agent, a cross-linking regulator, a carbomer, and the following parts by weight: Component preparation: wherein the weight percentages of the components are: 0.1-2 of tamoxifen, 3-13 of solubilizers, 5-12 of cross-linking polymers, 0.2-0.4 of cross-linking agent, and cross-linking adjustment 0.2 to 0.6 for carbomer, 0.5 to 5 for carbomer. The tamoxifen gel patch prepared by the invention is stable in shape, complete in appearance, good in adhesion performance, high in skin penetration rate, free from sensitization and irritation, convenient to use, does not pollute clothes, and can be peeled off repeatedly.

In the present invention, the selected cross-linked polymer is a partial neutralization of polyacrylic acid, including the neutralization percentage of sodium polyacrylate, namely NP-600 (trade name: Vicomate ^TM ) with a neutralization degree of 70% and a neutralization degree of 50%. % NP-700 (trade name: Viscomate ^TM ), one or more of NP-800 (trade name: Viscomate ^TM ) with a neutralization degree of 35%; NP-800 is preferred in the embodiment of the present invention; The weight percentage of the cross-linked polymer is 5-12%.

In the present invention, the cross-linking agent includes one or more of aluminum glycerol, aluminum hydroxide, aluminum chloride, aluminum sulfate, and alum, preferably aluminum glycerol; the weight percent of the cross-linking agent is 0.2-0.4% .

In the present invention, the crosslinking regulator is one or more of tartaric acid, citric acid, lactic acid, EDTA or EDTA-2Na, wherein tartaric acid, citric acid, lactic acid, etc. The agent releases aluminum ions, and the aluminum ions are cross-linked with the cross-linked polymer, that is, the carboxyl group in the partially neutralized sodium polyacrylate structure, to form the matrix skeleton of the gel patch; in order to delay the speed of cross-linking in the present invention, the matrix formula also Adding EDTA or EDTA-2Na and the above-mentioned carboxyl groups competitively chelate with aluminum ions, thereby controlling the viscoelasticity and consistency of the cross-linked matrix, facilitating stirring and coating in the production process; the weight percent of the cross-linking regulator is 0.2 ~0.6%.

In the present invention, the carbomer selection model is one or more of Carbopol ^® 934, Carbopol ^® 934P, Carbopol ^® 940, Carbopol ^® 941, Carbopol ^® 971P, Carbopol ^® 974P, Carbopol ^® 980, the weight of the carbomer The percentage is 0.5-5%; the carbomer can effectively improve the forming of the gel patch base.

In the present invention, the solubilizer is selected from one or both of eucalyptus oil and diethylene glycol monoethyl ether (trade name can be TranscutolP); the weight percentage of the solubilizer is 3-13%; The solubilizer can improve the solubility of tamoxifen in the gel patch matrix, and solve the problem of drug precipitation on the glue surface.

In the present invention, the formulation of the tamoxifen gel patch can also add a transdermal enhancer, including one of azone, propylene glycol, oleic acid, lauryl alcohol, isopropyl myristate, and menthol or several, preferably azone; the weight percentage of the skin penetration enhancer is 0-3%.

In the present invention, fillers can also be added to the formulation of the tamoxifen gel patch, including kaolin, micropowder silica gel, cross-linked polyvinylpyrrolidone (PVPP), titanium dioxide, silica gel, bentonite, calcium carbonate, zinc oxide , one or more of kaolin, and the weight percentage of filler is 0-3%; the filler can change the structure of the gel paste matrix to be honeycomb, which is beneficial to increase the glue strength of the matrix and peel off performance.

In the present invention, the formulation of the tamoxifen gel patch can also be added with a thickening agent, including sodium carboxymethyl cellulose (CMC-Na), methyl cellulose, polyvinyl alcohol (PVA), polymer One or more of vinylpyrrolidone (PVP), gelatin, and gum arabic, preferably polyvinyl alcohol, and the weight percentage of the tackifier is 0 to 3%; The viscosity and consistency of the cream base can improve the adhesion of the skin.

In the present invention, one or more of preservatives, moisturizing agents and surfactants can also be added to the tamoxifen gel patch formulation; wherein, the preservatives are benzoic acid, methylparaben, One or more of ethylparaben, propylparaben and butylparaben; the surfactant is a kind of polysorbate, polyoxyethylene castor oil, OP emulsifier, peregalin or several; the moisturizing agent is one or more of propylene glycol, glycerin, 1,3 butanediol and polyethylene glycol.

The tamoxifen gel patch of the present invention adopts a non-woven fabric as a backing material, and the backing material supports the gel patch matrix, has strong flexibility and good extensibility, and can adapt to body sensitivities such as breasts. At the same time, it has good air permeability, which can minimize the irritation of the patch to the skin.

The tamoxifen gel patch of the present invention adopts polyethylene, polypropylene and other materials as a protective film, which has a protective effect on the surface of the paste, and can be torn off during use.

The invention provides a preparation method of tamoxifen gel patch, which comprises the steps:

(1) Mix the solubilizer, skin penetration enhancer and other appropriate additives evenly, and then add tamoxifen to dissolve to obtain the main drug solution or suspension;

(2) Add the main drug solution or suspension, filler, cross-linking agent, cross-linking auxiliary material, and other appropriate types of additives into glycerol, and stir evenly to obtain phase A;

(3) Dissolving the tackifier, carbomer, crosslinking regulator and appropriate types of additives in purified water to prepare a mixed solution as phase B;

(4) Add phase B to phase A, stir quickly to an appropriate viscosity, apply, cut, and package to obtain tamoxifen gel patch.

The gel patch prepared by the invention has the advantages of stable molding, complete appearance, good adhesion performance, no sensitization and irritation, direct application without repeated application, convenient use, no pollution to clothes, repeated peeling and the like. It can significantly improve the compliance of the patient's medication; the gel patch has high water content and large drug loading, and can especially carry high content of solubilizers and transdermal enhancers, thereby increasing the solubility of the main drug and promoting the effective penetration of the drug into the skin. The breast lesions can significantly reduce the concentration and fluctuation of the drug in the blood circulation, and reduce or even avoid side effects such as venous thrombosis and susceptibility to endometrial cancer caused by oral tamoxifen. In addition, the gel paste also has the advantages of not using a large amount of organic solvents in the production process, taking explosion-proof measures, not requiring high temperature, not polluting the environment, and low cost.

The specific embodiments of the present invention will be described in further detail below, but the protection scope of the present invention should not be limited by this. All technologies implemented based on the content of the present invention belong to the scope of the present invention. Obviously, according to the content of the present invention, in accordance with the common technical knowledge and customary means in the field, without departing from the basic technical idea of the present invention, other modifications, substitutions and changes can also be made.

Detailed ways

Example 1 Solubility test of tamoxifen in different media

The excess tamoxifen was added to the 10 media shown in Table 1, stirred and sonicated for 30 minutes, shaken in a constant temperature shaker for 24 hours, and 1 ml of the supernatant was placed in a test tube, and centrifuged at 10,000 r/min for 10 minutes. , accurately draw the supernatant and dilute it with the mobile phase to perform HPLC determination; the solubility of tamoxifen in each medium is shown in Table 1, among which, tamoxifen in ethanol, N-methyl-2-pyrrolidone The medium solubility is the highest, followed by eucalyptus oil, propylene glycol, and diethylene glycol monoethyl ether.

Table 1 Solubility of tamoxifen in different media

medium Solubility (μg/g) water 0.32±0.25 Ethanol 37.94±1.88 PEG400 16.67±0.81 Oleic acid 13.93±0.59 Azone 17.07±0.57 Propylene Glycol 19.37±0.85 glycerin 6.18±0.21 Eucalyptus Oil 20.35±0.33 Diethylene glycol monoethyl ether 17.90±1.09 N-Methyl-2-pyrrolidone 28.00±0.86

Example 2 Influence test of solubilizer on the solubility of tamoxifen in water-glycerol (ratio 50/50)

In a mixed solution consisting of 28 parts of glycerol, 28 parts of water and 15 parts of different solubilizers (as shown in Table 2), an excess of tamoxifen was added respectively, stirred and sonicated for 30 minutes, and placed in a constant temperature oscillator to shake for 24 hours. Take 1ml of the supernatant into a test tube, centrifuge at 10000r/min for 10min, accurately aspirate the supernatant, dilute it with mobile phase to an appropriate multiple, and perform HPLC measurement. The results show (as shown in Table 2), in water-glycerol (50 /50) in the mixed system using diethylene glycol monoethyl ether as the solubilizer has the best effect.

Table 2 Effects of different solubilizers on the solubility of tamoxifen in water-glycerol (50/50 ratio)

Example 3 Comparative experiment

Table 3 Recipe of Example 1 and Comparative Examples 1-4

prescription Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Example 1 water 30.00 32.12 30.16 26.04 26.04 tartaric acid 0.15 0.13 0.13 0.14 0.14 Tamoxifen 0.50 0.51 0.08 0.10 0.10 glycerin 15.70 12.86 12.74 13.02 13.02 Aluminum Glycolate 0.15 0.13 0.13 0.14 0.14 NP-800 3.50 3.22 3.19 3.62 3.62 carbomer 1.03 1.02 1.16 1.16 Eucalyptus Oil 1.53 1.73 1.73 Diethylene glycol monoethyl ether 2.89 N-Methyl-2-pyrrolidone 2.89 Azone 0.51 0.58 0.58 Twain 0.51 0.58 0.58 total 50.00 50.00 50.00 50.00 50.00 Carbomer/TAM 2 12 12 12

The gel patches of Comparative Examples 1-4 and Example 1 were prepared according to the above-mentioned preparation method, and the forming situation of the patch and the drug precipitation were observed, and the results were shown in Table 4; wherein,

The gel patch prepared by Comparative Example 1 could not be formed, was semi-solid gel-like, and a large amount of medicine could be seen to separate out;

Adding carbomer in the prescription of Comparative Example 2, it can be seen that the gel patch matrix is cross-linked and formed, and has a certain skin adhesion, and a large amount of drugs are precipitated on the adhesive surface of the patch by naked eye observation;

Comparative example 3 adds solubilizer eucalyptus oil on the basis of comparative example 2, and the gel patch matrix is cross-linked and formed, but a small amount of medicine is precipitated;

In Comparative Example 4, N-methyl-2-pyrrolidone was added on the basis of Comparative Example 3, and the gel patch matrix was cross-linked and formed, but there was still a small amount of drug precipitation;

The results show. In Example 1, on the basis of Comparative Example 3, diethylene glycol monoethyl ether was added, and the gel patch matrix was cross-linked and formed, and the adhesive surface was complete and uniform, and no drug precipitation was found.

Table 4 Formulation and solubilization evaluation of formulations of Example 1 and Comparative Examples 1-4

prescription Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Example 1 Whether to shape × √ √ √ √ A large amount of drug precipitation √ √ A small amount of drug precipitation √ √ No drug precipitation √

Example 4 Comparative experiment

Table 5 Examples 2-6 recipes

prescription Example 2 Example 3 Example 4 Example 5 Example 6 water 26.85 26.85 23.43 24.75 24.24 tartaric acid 0.12 0.12 0.29 0.13 0.11 Tamoxifen 0.08 0.08 0.08 0.08 0.08 glycerin 11.74 11.74 12.3 12.58 11.28 Aluminum Glycolate 0.12 0.12 0.18 0.13 0.11 NP-800 2.93 2.93 5.36 3.14 NP-700 2.68 carbomer 0.94 0.94 0.34 1.01 2.8 Eucalyptus Oil 1.41 1.41 1.35 1.51 1.45 Diethylene glycol monoethyl ether 2.35 2.35 4.02 2.58 3.86 Azone 0.94 1.01 0.65 Oleic acid 0.94 Twain 0.47 0.47 0.51 0.50 0.52 PVA 0.98 0.98 1.07 1.07 CMC-Na 1.07 PVPP 1.07 1.07 1.51 1.07 Micro powder silica 1.07 EDTA 0.08 total 50.00 50.00 50 50.00 50 Carbomer/TAM 12 12 12 12 35

Preparation Example 2

Diethylene glycol monoethyl ether, eucalyptus oil, Tween 80 and azone were weighed and mixed uniformly, the tamoxifen of the recipe was added, stirred and sonicated for 30 min to prepare a tamoxifen suspension for subsequent use; Add tamoxifen suspension, aluminum carboxylate, and PVPP into glycerin, stir evenly, then add Vicomate NP-800, stir evenly to obtain phase A, and add tartaric acid, PVA, and carbomer to distilled water to dissolve, Stir for 12h, as phase B, add phase B into phase A, quickly stir to appropriate viscosity, coat with a coating machine with a thickness of 1.5mm, cut it, and pack it in an aluminum foil bag to obtain tamoxifen Fen gel patch;

The preparation of example 3 is the same as that of example 2, wherein the skin penetration enhancer azone is mainly replaced with oleic acid;

The preparation of example 4 is the same as that of example 2, wherein the filler PVPP is mainly replaced with micropowder silica gel;

Example 5 is prepared with Example 2, wherein the tackifier PVA is mainly replaced by CMC-Na;

Example 6 The preparation was the same as that of Example 2, except that NP800 was mainly changed to NP700, and the dosage was adjusted.

Evaluative test:

Test Example . In vitro percutaneous penetration test

The in vitro percutaneous penetration test was carried out by using a modified Franz diffusion cell. The effective diffusion area of the skin was 3.14 cm ² , and the volume of the receiving cell was about 8 ml. The isolated pig ear skin was fixed between the supply cell and the receiving cell. On, the receiving tank was filled with 50% ethanolic saline, and ensured that the isolated pig ear skin was in contact with the receiving fluid without air bubbles. Apply the tamoxifen gel patch of Examples 2, 3, 4, and 7 to the stratum corneum, turn on the magnetic stirrer (200 r·min-1) and the constant temperature (37±0.5) °C water bath cycle, and start timing. , at 6, 12, 24, and 48 h respectively, take 0.6 ml of the receiving solution, and immediately add 0.6 ml of the receiving solution at the same temperature. After the taken-out receiving solution is filtered through a 0.45 μm microporous membrane, the concentration of tamoxifen is determined by HPLC. Calculate the cumulative permeation amount per unit area Q _n (µg/cm ² ), record the cumulative permeation amount for 48 hours as Q ₄₈ (µg · cm ^-2 ); perform linear regression analysis on the cumulative permeation amount (Q _n ) versus time (t), A linear regression equation was obtained, and the slope of the equation was the skin penetration rate J [μg/(cm ² ·h) ]. The penetration enhancement ratio (ER) is the ratio of the penetration rate of each skin penetration enhancer test group to the penetration rate of Example 4 without penetration enhancer;

The concentration of tamoxifen in the permeate was detected by HPLC. Chromatographic conditions: PLATISIL ^TM ODS column (150×4.6 mm, 5 μm); mobile phase: methanol: triethylamine 1% (pH adjusted to 8.5 with glacial acetic acid) The volume flow was 1.0 mL/min; the detection wavelength was 238 nm; the column temperature was 25 °C; the injection volume was 10 μl, and the external standard method was used for quantification. The linear regression was performed on the mass concentration, and the regression equation was obtained as: C=0.053 A-0.0048 (r=0.9998). Tamoxifen has a good linear relationship with the peak area in the range of 0.081～2.42μg·ml-1. Method recovery and precision meet the requirements;

The skin penetration parameters are shown in Table 6. The results show that compared with Example 4 without the accelerator, the permeation rates of Examples 2, 3, and 7 with the accelerator are significantly better than those of Example 4; 3 In contrast, the skin penetration rates of Examples 2 and 7 containing nitrogen ketones are better;

Table 6 The effect of penetration enhancers on the penetration rate of tamoxifen gel patch

Test Example Tamoxifen Gel Patch Initial Adhesion Test

According to "Chinese Pharmacopoeia" (2015 edition) Four General Principles 0952 Adhesion Determination Method 1 (Determination of Initial Adhesion). The initial viscosity is measured by the rolling ball slope stop method. Take 3 samples of each of the examples 1-6, remove the protective layer, and place them in the center of the inclined plate with an inclination angle of 15°. Covered with thick polyester film, leaving 5cm of cream in the middle. Take steel balls of different diameters and roll them down freely from the top of the inclined surface. According to the ball number of the largest steel ball that the rubber surface can stick to, evaluate the size of its initial viscosity. The results are shown in Table 7, showing the initial viscosity performance of the example. Good, the results show that the number of steel balls that can stick is relatively small in Example 1 because no tackifier and filler are added; Examples 2-6 all show good initial adhesion, wherein the gel paste is added with PVA. The viscosity is slightly better than CMC-Na;

Table 7 The number of steel balls adhered in the initial adhesion test of the gel patch of Example 1-6

sample Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 1 18 29 25 30 26 27 2 18 27 26 29 26 25 3 19 28 26 28 25 27

Test Example Tamoxifen Gel Patch Adhesion Test

According to "Chinese Pharmacopoeia" (2015 edition) Four General Principles 0952 Adhesion Determination Method 4 (Determination of Adhesion). Adhesion was tested by BLD-200N testing machine. Take 3 pieces of gel patch (70cm×50cm) of Example 1-6, with the adhesive side facing up, put it on the sample loading module, align with the scale line, and separate the cover linings on both sides. Tear off a little, press the sticky surfaces exposed on both sides with pressure strips, carefully remove the cover lining, and place it naturally on the bottom plate of the fixture in the center, so that the test sample is flat on the bottom plate, press the pressure plate horizontally, and use both sides. Fix the bottom plate and the pressure plate with bolts, so that the sticky surface of the test product on the rectangular strip is evenly stretched, and place it on the instrument. After fixing, set the forward speed of the pressure roller to 600mm·min ^-1 and the backward speed to 21mm·min ^-1 The measurement results are shown in Table 8, which are all in line with the 2015 edition of the Chinese Pharmacopoeia, which stipulates that the adhesive force of the gel patch should be 1000-2000 mN. Example 1 does not add tackifiers and fillers, and the adhesive force is relatively biased. Low; Examples 2-6 all show good adhesion, and the adhesion of the gel patch with PVA is better than that of CMC-Na.

Table 8 Adhesion of the gel patches prepared in each example

sample Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Adhesion (mN) 1106±61 1543±65 1586±30 1606±65 1356±32 1610±26

Test Example Tamoxifen Gel Patch Skin Irritation Test

6 experimental rabbits were taken. 24 hours before the experiment, the hair on both sides of the spine of the rabbits was trimmed and depilated with depilatory cream. The depilation range was 3 cm × 3 cm on the left and right. The animals were divided into two groups, namely the intact skin group and the damaged skin group. In the damaged skin group, the skin of the depilation area was scratched with a sterilized 16-gauge needle before administration to make a well-shaped break. The degree of skin damage on both sides remains the same;

Using the self-contrast method on the left and right sides of the same body, the gel patch of Example 2 was given to the left depilation area of the two groups of rabbits, and the blank matrix gel patch was applied to the right depilation area. After the patch was completed, the ointment was covered with two layers of gauze. , and then fixed with medical tape, and each animal was kept in separate cages. After 24 hours of administration, the gauze and ointment were removed, and the administration area was cleaned with warm water. The edema phenomenon, as shown in Table 9, the results show that after the rabbits in the intact skin group and the damaged skin group were given the gel patch, there was no erythema or edema on the skin in the depilation area. Compared with the skin, no abnormality was found, indicating that the tamoxifen gel patch is not irritating to the skin;

Table 9 Rabbit skin irritation test

group 1h 24h 48h 72h full skin set No erythema or edema found No erythema or edema found No erythema or edema found No erythema or edema found Broken skin group No erythema or edema found No erythema or edema found No erythema or edema found No erythema or edema found

Test Example Tamoxifen Gel Patch Skin Allergy Test

In accordance with the State Food and Drug Administration's "Technical Guiding Principles for Research on Irritability, Allergy and Hemolysis of Chemical Drugs",

Thirty guinea pigs, half male and half male, were taken for the test. 24 hours before the experiment, the hair on both sides of the back spine was trimmed and treated with depilatory cream. The depilation area was 3 × 3 cm ² on each side. half male and female

The medicated skin area of the guinea pig was wiped with warm water, and the left skin of the 3 groups of animals was medicated, respectively Example 2 tamoxifen gel patch 3cm ² , blank matrix gel patch 3cm ² , 1% 2,4-di Nitrochlorobenzene 0.2ml, covered with two layers of gauze after administration, and then fixed with medical tape. After 24 hours, the gauze and ointment were removed, and washed with warm water. Repeat the same method on the 7th and 14th day. Observe Whether there is erythema and edema on the skin of the guinea pig depilation area;

Provocative exposure: 14 days after the last sensitizing exposure, the corresponding drugs of each group were administered to the right depilation area of the guinea pigs. After administration, they were covered with two layers of gauze, and then fixed with medical tape. After 6 hours, the gauze and ointment were removed. Scrub with warm water, immediately observe the skin allergy in the depilation area of the guinea pig, and observe the skin allergy in the depilation area of the guinea pig again at 24h, 48h and 72h, and calculate the sensitization rate and the average value of the reaction:

Sensitization rate = number of animals with erythema or edema ÷ total number of animals) × 100%, the statistical results of sensitization rate are shown in Table 11, and the evaluation criteria of sensitization reaction intensity are shown in Table 10;

Mean response = (total score for erythema formation + total score for edema formation) ÷ total number of animals

Among them, the evaluation criteria for skin allergy scores are: mild erythema, moderate erythema, severe erythema and edematous erythema are scored as 1 point, 2 points, 3 points, 4 points; mild edema, moderate edema and severe erythema The scores for edema are 1, 2, and 3 in turn;

The statistical analysis of allergy in guinea pigs showed that no erythema or edema appeared in the hair removal area of the guinea pigs in the blank matrix gel patch group and the tamoxifen gel patch group during each observation period, indicating that the tamoxifen gel patch group did not have erythema or edema. The cream is non-allergenic to the skin.

Table 10 Criteria for judging the intensity of sensitization

Sensitization rate (%) Reaction intensity 0～10 weak sensitization 20～30 mild sensitization 40～60 Moderate sensitization 70～80 highly sensitizing 90～100 extreme sensitization

Table 11 Statistics of guinea pig allergy

index drug immediately 24h 48h 72h response mean Blank Gel Patch 0 0 0 0 Example 2 Gel patch 0 0 0 0 2,4-Dinitrochlorobenzene 3.1 2.3 1.8 0.5 Sensitization rate (%) Blank Gel Patch 0 0 0 0 Example 2 Gel patch 0 0 0 0 2,4-Dinitrochlorobenzene 100 100 100 50

Claims (7)

1. The tamoxifen gel plaster is characterized by comprising the following components in percentage by weight: tamoxifen, a solubilizer, a cross-linking polymer, a cross-linking agent, a cross-linking regulator and carbomer,

0.1-2% of tamoxifen

5-12% of cross-linking polymer

0.2 to 0.4 percent of cross-linking agent

0.2 to 0.6 percent of crosslinking regulator

3-13% of solubilizing agent and 0.5-5% of carbomer

The preparation method comprises the following steps:

(1) uniformly mixing a solubilizer, a transdermal enhancer and a surfactant, and adding tamoxifen to dissolve to prepare a main drug solution or suspension;

(2) adding the main drug solution or suspension, filler, cross-linking agent and cross-linked polymer into glycerol, and uniformly stirring to obtain phase A;

(3) dissolving tackifier, carbomer and crosslinking regulator in purified water to obtain mixed solution as phase B;

(4) adding the phase B into the phase A, quickly stirring to proper viscosity, coating, cutting and packaging to obtain tamoxifen gel plaster;

the solubilizer is eucalyptus oil and diethylene glycol monoethyl ether.

2. The tamoxifen gel patch of claim 1 wherein said cross-linked polymer is a polyacrylic acid partial neutralization selected from the group consisting of sodium polyacrylate NP-600 with a neutralization degree of 70%, NP-700 with a neutralization degree of 50%, and NP-800 with a neutralization degree of 35%.

3. The tamoxifen gel patch as claimed in claim 1, wherein said cross-linking agent is selected from one or more of dihydroxyaluminium glycinate, aluminium hydroxide, aluminium chloride, aluminium sulphate and alum;

the crosslinking regulator is one or more selected from tartaric acid, citric acid, lactic acid, EDTA or EDTA-2 Na.

4. The tamoxifen gel patch according to claim 1, wherein the composition further comprises a skin penetration enhancer selected from one or more of azone, propylene glycol, oleic acid, isopropyl myristate, menthol; the weight percentage of the transdermal enhancer is 0-3%.

5. A tamoxifen gel patch according to claim 1, wherein the composition further comprises a filler selected from one or more of kaolin, aerosil, cross-linked polyvinylpyrrolidone, titanium dioxide, bentonite, calcium carbonate, zinc oxide, kaolin; the weight percentage of the filler is 0-3%.

6. The tamoxifen gel patch according to claim 1, wherein the composition further comprises a viscosity increasing agent selected from one or more of sodium carboxymethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, gelatin and acacia; the weight percentage of the tackifier is 0-3%.

7. A tamoxifen gel patch according to claim 1, wherein the components further comprise preservatives, humectants and surfactants; wherein the antiseptic is selected from one or more of benzoic acid, methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, and butyl hydroxybenzoate; the surfactant is one or more selected from polysorbate, polyoxyethylene castor oil, OP emulsifier and peregal O; the humectant is one or more selected from propylene glycol, glycerol, 1, 3-butanediol, and polyethylene glycol.