CN108210484B

CN108210484B - Tamoxifen gel plaster and preparation method thereof

Info

Publication number: CN108210484B
Application number: CN201611134835.1A
Authority: CN
Inventors: 沈腾; 岳素荣; 李悦; 芦晓彤; 接强; 马田
Original assignee: Fudan University
Current assignee: Fudan University
Priority date: 2016-12-11
Filing date: 2016-12-11
Publication date: 2021-06-25
Anticipated expiration: 2036-12-11
Also published as: CN108210484A

Abstract

The invention belongs to the technical field of medicinal preparations, and relates to tamoxifen gel plaster and a preparation method thereof. The invention provides tamoxifen gel emplastrum which is prepared from tamoxifen, a solubilizer, a cross-linking polymer, a cross-linking agent, a cross-linking regulator and carbomer in parts by weight as follows: wherein, the addition of carbomer effectively improves the forming problem of the gel plaster matrix; the addition of the solubilizing agents eucalyptus oil and diethylene glycol monoethyl ether obviously improves the solubility of tamoxifen in a gel plaster matrix, and solves the problem of drug precipitation; the tamoxifen gel plaster prepared by the invention has the advantages of stable forming, complete appearance, good adhesion performance, high transdermal rate, no sensitization and irritation, convenient use, no pollution to clothes, repeated uncovering and sticking, low production cost and the like.

Description

Tamoxifen gel plaster and preparation method thereof

Technical Field

The invention belongs to the technical field of medicinal preparations, and particularly relates to tamoxifen gel plaster and a preparation method thereof.

Background

The prior art discloses that breast cancer is the most common malignancy in women, about 130 million people are diagnosed with breast cancer every year worldwide, about 40 million people die from the disease, and the incidence rate is on the rising trend year by year. The current clinical treatment scheme for breast cancer comprises surgical treatment, chemotherapy, radiotherapy, endocrine treatment, molecular targeted treatment, traditional Chinese medicine treatment and the like. Research shows that most breast cancer cells express estrogen receptors, and the growth and proliferation of the breast cancer cells are obviously hormone-dependent. In recent years, the secretion treatment scheme gradually becomes a hot point, and the endocrine treatment is to reduce the estrogen level in vivo or inhibit the action of estrogen so as to inhibit the growth of tumor cells. It is known in the art that tamoxifen is a first-generation selective estrogen receptor modulator, has dual effects of estrogen stimulation and antagonism, is a first-line endocrine treatment drug which is most effective and has the longest application time in hormone-dependent breast cancer endocrine treatment, is suitable for postmenopausal breast cancer women with positive estrogen receptors and positive progestogen receptors, and is one of the first-choice drugs for postoperative endocrine adjuvant therapy of breast cancer.

At present, the administration route of tamoxifen is mainly oral administration, mainly tablets, granules and capsules, and tamoxifen is almost insoluble in water, so clinical practice shows that the oral dosage form has the defects of poor gastrointestinal tract dissolution, low bioavailability, liver first-pass effect, large fluctuation of oral blood concentration, easy venous thrombosis and increased probability of endometrial cancer after long-term administration and the like. In order to reduce the side effect of tamoxifen and increase the clinical efficacy, researchers in the field consider that the administration mode is changed from oral administration to transdermal administration, and expect that the transdermal preparation can avoid the liver first-pass effect possibly generated by the oral administration, avoid the fluctuation of blood concentration, reduce the drug toxicity and adverse reaction, reduce the administration frequency and is convenient to use; moreover, the transdermal preparation applied to the skin around the mammary gland can ensure that the medicine directly enters the focus part by a transdermal diffusion and permeation way, and the long-time targeted administration is continued, so that the concentration of the tamoxifen in the mammary tissue is increased, and the treatment effect of the breast cancer is favorably improved.

Tamoxifen, also known as tamoxifen, has a molecular weight of 371 and a melting point of 96-98 ℃, and researches show that the tamoxifen is almost insoluble in water, slightly soluble in ethanol and easily soluble in glacial acetic acid, so that tamoxifen gels, creams, microemulsions and the like are reported at present, and CN101065120A discloses a 4-hydroxy tamoxifen gel preparation, which belongs to a semisolid preparation;

CN1857242A discloses a tamoxifen citrate microemulsion external preparation, which belongs to a liquid preparation and can also be prepared into a semisolid preparation; CN101711754A further discloses a method for preparing the tamoxifen citrate microemulsion into a plaster, wherein the plaster adopts a high-temperature heating process, and the components such as rosin plasticizer, polyisobutylene pressure-sensitive adhesive and the like in the formula are easy to cause skin irritation and allergy.

At present, no reports related to tamoxifen gel plaster exist.

Based on the current situation of the prior art, the inventor of the application intends to provide a tamoxifen gel emplastrum and a preparation method thereof, the invention can overcome the defects of the existing tamoxifen dosage form at present, and provides a more convenient and effective dosage form for the endocrine treatment of breast cancer.

Disclosure of Invention

The invention aims to overcome the defects of the existing tamoxifen dosage form in the prior art and provides tamoxifen gel plaster and a preparation method thereof.

The gel-based plaster (original cataplasm or gel plaster) refers to a plaster prepared by uniformly mixing the raw material medicine with a suitable hydrophilic matrix and coating the mixture on a backing material (defined by the Chinese pharmacopoeia 2015 edition).

The invention provides tamoxifen gel emplastrum which is prepared from tamoxifen, a solubilizer, a cross-linking polymer, a cross-linking agent, a cross-linking regulator and carbomer in parts by weight as follows: wherein the weight percentage of the components is as follows: 0.1-2% of tamoxifen, 3-13% of solubilizer, 5-12% of cross-linked polymer, 0.2-0.4% of cross-linking agent, 0.2-0.6% of cross-linking regulator and 0.5-5% of carbomer. The tamoxifen gel plaster prepared by the invention has the advantages of stable molding, complete appearance, good adhesion performance, high transdermal rate, no sensitization and irritation, convenient use, no pollution to clothes and repeated uncovering and pasting.

In the invention, the selected crosslinking polymer is partially neutralized polyacrylic acid, and comprises NP-600 (trade name: Viscomate) with sodium polyacrylate neutralization degree of 70%^TM) NP-700 having a neutralization degree of 50% (trade name: viscomate^TM) And NP-800 having a neutralization degree of 35% (trade name: viscomate^TM) One or more of the above; NP-800 is preferred in embodiments of the invention; the weight percentage of the crosslinking polymer is 5-12%.

In the invention, the cross-linking agent comprises one or more of dihydroxyaluminum glycinate, aluminum hydroxide, aluminum chloride, aluminum sulfate and alum, preferably dihydroxyaluminum glycinate; the weight percentage of the cross-linking agent is 0.2-0.4%.

In the invention, the crosslinking regulator is one or more of tartaric acid, citric acid, lactic acid, EDTA or EDTA-2Na, wherein the tartaric acid, citric acid, lactic acid and the like provide an acid proton environment, the crosslinking agent releases aluminum ions, and the aluminum ions and crosslinking type polymers, namely carboxyl in a partially neutralized sodium polyacrylate structure, are crosslinked to form a matrix skeleton of the gel plaster; in order to delay the crosslinking speed, EDTA or EDTA-2Na is added into the formula of the substrate to competitively chelate with aluminum ions with the carboxyl, thereby controlling the viscoelasticity and consistency of the crosslinked substrate and facilitating the stirring and coating in the production process; the weight percentage of the crosslinking regulator is 0.2-0.6%.

In the invention, the carbomer is selected from Carbopol^®934、Carbopol^®934P、Carbopol^®940、Carbopol^®941、Carbopol^®971P、Carbopol^®974P、Carbopol^®980, the weight percentage of carbomer is 0.5-5%; the carbomer can effectively improve the forming of the gel plaster matrix.

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

In the invention, a transdermal enhancer comprising one or more of azone, propylene glycol, oleic acid, lauryl alcohol, isopropyl myristate and menthol can be added into the formula of the tamoxifen gel plaster, preferably azone; the transdermal enhancer is 0-3% by weight.

In the invention, a filler can be added into the formula of the tamoxifen gel plaster, wherein the filler comprises one or more of kaolin, superfine silica powder, crosslinked polyvinylpyrrolidone (PVPP), titanium dioxide, silica gel, bentonite, calcium carbonate, zinc oxide and kaolin, and the weight percentage of the filler is 0-3%; the filler can change the structure of the matrix of the gel plaster to be honeycomb-shaped, and is beneficial to increasing the adhesive strength and the peeling performance of the matrix.

In the invention, a tackifier can be added into the formula of the tamoxifen gel plaster, wherein the tackifier comprises one or more of sodium carboxymethylcellulose (CMC-Na), methylcellulose, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), gelatin and Arabic gum, the polyvinyl alcohol is preferably selected, and the weight percentage of the tackifier is 0-3%; the tackifier can inhibit crystallization of the medicine, increase viscosity and consistency of the matrix of the gel plaster, and improve adhesion of skin.

In the invention, one or more of a preservative, a humectant and a surfactant can be added into the formula of the tamoxifen gel plaster; wherein the antiseptic is one or more of benzoic acid, methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, and butyl hydroxybenzoate; the surfactant is one or more of polysorbate, polyoxyethylene castor oil, OP emulsifier and peregal O; the humectant is one or more of propylene glycol, glycerol, 1, 3-butanediol, and polyethylene glycol.

The tamoxifen gel plaster provided by the invention adopts non-woven fabrics as backing materials, the backing materials have a supporting effect on gel plaster substrates, are strong in flexibility and good in extensibility, can adapt to sensitive parts of bodies such as breasts, and meanwhile, are good in air permeability, and can reduce irritation of the plaster to the skin to the greatest extent.

The tamoxifen gel plaster adopts materials such as polyethylene, polypropylene and the like as protective films, has a protective effect on the surface of the plaster, and can be torn off when in use.

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

(1) uniformly mixing solubilizer, transdermal enhancer and other additives of proper types, and adding tamoxifen to dissolve to prepare main drug solution or suspension;

(2) adding the main drug solution or suspension, filler, cross-linking agent, cross-linking type auxiliary material and other additives of proper types into glycerol, and uniformly stirring to obtain phase A;

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

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

The gel plaster prepared by the invention has the advantages of stable forming, complete appearance, good adhesion performance, no sensitization and irritation, direct application without repeated smearing, convenient use, no pollution to clothes, repeated uncovering and sticking and the like, and can obviously improve the medication compliance of patients; the gel plaster has high water content and large drug loading rate, and can particularly bear high-content solubilizer and transdermal enhancer, thereby increasing the solubility of main drugs, promoting the drugs to effectively permeate the skin to directly reach the focus of breasts, obviously reducing the concentration and fluctuation degree of the drugs in blood circulation, and reducing or even avoiding the side effects of venous thrombosis, endometrial carcinoma proneness and the like caused by oral administration of tamoxifen. In addition, the gel plaster also has the advantages of no use of a large amount of organic solvents and explosion-proof measures in the production process, no need of high temperature, no environmental pollution, low cost and the like.

The following detailed description of the present invention is provided for further illustration of the specific embodiments of the present invention, but should not be construed to limit the scope of the present invention. All the technologies realized based on the contents of the present invention belong to the scope of the present invention. It will be apparent that various other modifications, substitutions and alterations can be made in the present invention without departing from the basic technical concept of the invention, according to the common technical knowledge and common practice in the field.

Detailed Description

Example 1 solubility testing of tamoxifen in different media

Respectively adding excessive tamoxifen into 10 media shown in table 1, stirring and performing ultrasonic treatment for 30min, oscillating in a constant-temperature oscillator for 24h, taking 1ml of supernatant, placing the supernatant in a test tube, performing high-speed centrifugation for 10min at 10000r/min, accurately sucking the supernatant, diluting the supernatant by a proper multiple with a mobile phase, and performing HPLC (high performance liquid chromatography) determination; the solubility of tamoxifen in each medium is shown in table 1, where tamoxifen has the highest solubility in ethanol, N-methyl-2-pyrrolidone, followed by eucalyptus oil, propylene glycol, and diethylene glycol monoethyl ether.

Table 1 solubility of tamoxifen in different media

Medium	Solubility (. mu.g/g)
		Water (W)	0.32±0.25
Ethanol	37.94±1.88
		PEG400	16.67±0.81
Oleic acid	13.93±0.59
		Azone compounds	17.07±0.57
Propylene glycol	19.37±0.85
		Glycerol	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 effect of solubilizer on solubility of tamoxifen in water-glycerol (ratio 50/50)

Adding excessive tamoxifen into a mixed solution consisting of 28 parts of glycerol, 28 parts of water and 15 parts of different solubilizers (shown in table 2), stirring and carrying out ultrasonic treatment for 30min, placing the mixed solution in a constant-temperature oscillator for oscillation for 24h, taking 1ml of supernatant into a test tube, carrying out high-speed centrifugation for 10min at 10000r/min, precisely sucking the supernatant, diluting the supernatant by a proper multiple with a mobile phase, and carrying out HPLC (high performance liquid chromatography) determination, wherein the result shows that (shown in table 2) the effect of adopting diethylene glycol monoethyl ether as the solubilizer in a water-glycerol (50/50) mixed system is best.

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

Example 3 comparative experiment

TABLE 3 formulation of example 1 and comparative examples 1-4

Prescription	Comparative example 1	Comparative example 2	Comparative example 3	Comparative example 4	Example 1
						Water (W)	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
Glycerol	15.70	12.86	12.74	13.02	13.02
						Aluminium glycollate	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 compounds			0.51	0.58	0.58
Twain (T)			0.51	0.58	0.58
						In total	50.00	50.00	50.00	50.00	50.00
carbomer/TAM		2	12	12	12

Gel patches of comparative examples 1 to 4 and example 1 were prepared according to the above preparation method, and the patch formation and drug deposition were observed, with the results shown in Table 4; wherein,

the gel plaster prepared in comparative example 1 could not be molded, was in the form of a semisolid gel, and was seen to have a large amount of drug precipitated;

in the comparative example 2, carbomer is added into the formula, so that the gel plaster matrix is formed in a cross-linking manner, certain skin adhesion is achieved, and a large amount of medicine can be separated out on the plaster surface through visual observation;

comparative example 3 the solubilizing agent eucalyptus oil is added on the basis of comparative example 2, the matrix of the gel plaster is formed by crosslinking, but a small amount of medicine is separated out;

comparative example 4N-methyl-2-pyrrolidone was added to comparative example 3, and the matrix of the gel patch was cross-linked and molded, but a small amount of drug was still precipitated;

and (6) displaying the result. Example 1 diethylene glycol monoethyl ether was added to comparative example 3, and the gel patch was formed by cross-linking the base material, with the surface intact and uniform, and no drug precipitation was observed.

TABLE 4 formulation formation and solubilization evaluation of example 1 and comparative examples 1 to 4

Prescription	Comparative example 1	Comparative example 2	Comparative example 3	Comparative example 4	Example 1
						Whether or not to shape	×	√	√	√	√
Large amount of medicine is separated out	√	√
						Small amount of medicine separated out			√	√
No drug precipitation					√

Example 4 comparative experiment

Table 5 examples 2-6 formulations

Prescription	Example 2	Example 3	Example 4	Example 5	Example 6
						Water (W)	26.85	26.85	23.43	24.75	24.24
Tartaric acid	0.12	0.12	0.29	0.13	0.11
						Tamo (r) TamoXifen	0.08	0.08	0.08	0.08	0.08
Glycerol	11.74	11.74	12.3	12.58	11.28
						Aluminium glycollate	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 compounds	0.94			1.01	0.65
Oleic acid		0.94
						Twain (T)	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
						Silica gel micropowder		1.07
EDTA					0.08
						In total	50.00	50.00	50	50.00	50
carbomer/TAM	12	12	12	12	35

Preparation of example 2

Weighing diethylene glycol monoethyl ether, eucalyptus oil, tween 80 and azone, uniformly mixing, adding tamoxifen in a prescription amount, stirring and carrying out ultrasonic treatment for 30min to prepare tamoxifen suspension for later use; adding tamoxifen suspension, dihydroxyaluminium glycolate and PVPP into glycerol, stirring uniformly, adding Viscomate NP-800, stirring uniformly to obtain phase A, adding tartaric acid, PVA and carbomer into distilled water for dissolving, stirring for 12h to obtain phase B, adding phase B into phase A, stirring rapidly to proper viscosity, coating with a coating machine according to the thickness of 1.5mm, cutting, and packaging with aluminum foil bags to obtain tamoxifen gel plaster;

example 3 the same example 2 was prepared wherein the transdermal enhancer azone was mainly replaced by oleic acid;

example 4 the same example 2 was prepared, wherein the filler PVPP was mainly exchanged for aerosil;

example 5 the same example 2 was prepared, wherein the tackifier PVA was mainly replaced by CMC-Na;

example 6 the same as example 2 was prepared, wherein predominantly NP800 was changed to NP700 and the dose was adjusted.

Evaluation test:

test example in vitro transdermal penetration test

An in-vitro transdermal permeation test is carried out by adopting an improved Franz diffusion cell, and the transdermal effective diffusion area is 3.14 cm²The receiving pool is about 8 ml in volume, the skin of the in vitro pig ear is fixed between the supply pool and the receiving pool, the cuticle surface of the skin faces upwards, the receiving pool is filled with 50% ethanol physiological saline, and the skin of the in vitro pig ear is ensured to be in full contact with the receiving liquid without bubbles. Applying the tamoxifen gel plaster prepared in examples 2, 3, 4 and 7 on the stratum corneum, starting a magnetic stirrer (200 r.min < -1 >) and a constant-temperature (37 +/-0.5) ° C water bath circulation, starting timing, taking 0.6 ml of receiving solution respectively at 6, 12, 24 and 48 hours, immediately supplementing 0.6 ml of receiving solution with equal temperature, filtering the taken receiving solution through a 0.45-micrometer microporous filter membrane, measuring the concentration of tamoxifen by HPLC, and calculating the accumulated permeation quantity Q in unit area_n（µg/cm²) The cumulative permeation over 48h is recorded as Q₄₈（μg · cm^-2) (ii) a In order to accumulate the permeation quantity (Q)_n) Linear regression analysis is carried out on the time (t) to obtain a linear regression equation, and the slope of the equation is the transdermal rate J [ mu.g/(cm)²H) ]. The penetration enhancement factor (ER) is the ratio of the transdermal rate of each transdermal enhancer test group to that of example 4 without the permeation enhancer;

detecting the concentration of tamoxifen in the penetrating fluid by an HPLC method, wherein the chromatographic conditions are as follows: platisil^TMODS column (150X 4.6 mm, 5 μm); the mobile phase is methanol: triethylamine 1% (adjusting pH to 8.5 with glacial acetic acid) 89:11 (V/V); the volume flow is 1.0 mL/min; the detection wavelength is 238 nm; the column temperature is 25 ℃; the sample amount is 10 mul, an external standard method is adopted for quantification, and the mass concentration of the tamoxifen standard solution is subjected to linear regression by peak area to obtain a regression equation: c = 0.053A-0.0048 (r =0.9998), and tamoxifen has good linear relation with peak area in the range of 0.081-2.42 mu g-ml < -1 >. The recovery rate and precision of the method meet the requirements;

the transdermal parameters are shown in table 6, and the results show that the permeation rates of examples 2, 3 and 7 with the addition of the accelerator are significantly better than those of example 4 compared to example 4 without the addition of the accelerator; compared with example 3, in which oleic acid is used as an accelerator, the transdermal rates of examples 2 and 7 of the azone are superior;

TABLE 6 Effect of transdermal enhancers on the transdermal Rate of tamoxifen gel Patches

Test examples initial adhesion test for tamoxifen gel patch

The first method (measurement of initial adhesion) was measured by 0952 adhesion method according to the four general rules of the pharmacopoeia of China (2015 edition). The initial adhesion was measured by rolling ball ramp stop method, 3 samples of examples 1 to 6 were taken, the protective layer was removed, and the samples were placed in the center of an inclined plate having an inclination angle of 15 °, with the plaster surface facing upward, 10cm above and 15cm below the inclined surface being covered with a 0.025mm thick polyester film, leaving a plaster surface of 5cm in the middle. Taking steel balls with different diameters, freely rolling down from the top end of the inclined plane, and evaluating the initial viscosity according to the ball number of the largest steel ball which can be adhered to the rubber surface, wherein the result is shown in table 7, and shows that the initial viscosity performance of the embodiment is good, and the result shows that the number of the steel balls which can be adhered to the embodiment 1 is relatively small because no tackifier or filler is added; examples 2-6 all showed good initial adhesion, with PVA added to the gel patch slightly better than CMC-Na;

TABLE 7 Steel ball number adhered in initial adhesion test of examples 1-6 gel plasters

Sample (I)	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 examples tamoxifen gel patch adhesion test

The fourth method (measurement of adhesion) was performed according to 0952, a fourth guideline of the pharmacopoeia of China (2015 edition). The adhesion force is performed by adopting a BLD-200N testing machine, 3 gel plasters (70 cm multiplied by 50 cm) of examples 1-6 are taken, the stickness faces upwards, the gel plasters are arranged on a sample loading module, the sample loading module is aligned with scale marks, a little of cover linings on two sides are respectively torn, the stickness faces exposed on two sides are respectively pressed by pressing strips, the cover linings are carefully removed, the gel plasters are naturally arranged on a bottom plate of a clamp in the middle, a sample is smoothly attached to the bottom plate, the pressing plate is horizontally pressed down, the bottom plate and the pressing plate are fixed by bolts on two sides, the stickness faces of the sample on a rectangular strip are uniformly tightened, the gel plasters are placed on an instrument, and the forward speed^-1The backward speed was 21 mm/min^-1The measurement is carried out, the measurement results of the adhesive force are shown in table 8, the adhesive force of the gel plaster meets the standard that the adhesive force of 2015 version of Chinese pharmacopoeia is 1000-2000 mN, and in example 1, no tackifier or filler is added, and the adhesive force is relatively low; examples 2-6 all showed good adhesion, with PVA applied to the gel patch being more adhesive than CMC-Na.

TABLE 8 adhesive force of gel plasters prepared in examples

Sample (I)

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Adhesive force (mN)

1106±61

1543±65

1586±30

1606±65

1356±32

1610±26

Test examples tamoxifen gel patch skin irritation test

Taking 6 rabbits for test, shearing off hairs on two sides of a spinal column of the rabbits 24 hours before the test, and carrying out unhairing treatment by using unhairing cream, wherein the unhairing range is 3cm multiplied by 3cm on the left and right sides respectively, and examining whether the skin is damaged or not, dividing animals into two groups after unhairing, namely a complete skin group and a damaged skin group, wherein the damaged skin group uses a sterilized 16-gauge needle head to scratch the skin of an unhairing area before administration, so that a # -shaped opening is formed, the depth is based on blood seepage, and the damage degrees of the skin on the left side and the right side are kept consistent;

by adopting a homomorphic left-right self-contrast method, the gel plaster in example 2 is applied to the left depilatory areas of two groups of rabbits, the blank matrix gel plaster is applied to the right depilatory areas, after the plaster is applied, the ointment is covered by two layers of gauze, then the ointment is fixed by a medical adhesive tape, each animal is raised in cages, after the application is carried out for 24 hours, the gauze and the ointment are removed, the application areas are cleaned by warm water, and after 1 hour, 24 hours, 48 hours and 72 hours respectively, the application parts are observed to have erythema or edema phenomena, as shown in table 9, the result shows that no erythema or edema phenomena exist on the skin of the depilatory area after the gel plaster is applied to the rabbits in the complete skin group and the damaged skin group, the skins of the left depilatory area and the right depilatory area of the same rabbit are compared, no abnormity occurs, and the tamoxifen gel plaster has no stimulation to the skins;

TABLE 9 rabbit skin irritation test

Group of	1h	24h	48h	72h
					Complete skin group	No erythema or edema was observed	No erythema or edema was observed	No erythema or edema was observed	No erythema or edema was observed
Damaged skin group	No erythema or edema was observed	No erythema or edema was observed	No erythema or edema was observed	No erythema or edema was observed

Test examples tamoxifen gel patch skin allergy test

According to the national food and drug administration guidance principle of research on irritation, allergy and hemolysis of chemical drugs,

taking 30 test guinea pigs, half male and female, and 24h before experiment, shearing off hair on both sides of spinal column at back, and depilating with depilatory cream with depilatory area of 3 × 3cm on each side²Randomly divided into 3 groups, each group comprises 10 male and female halves;

the guinea pig skin area was swabbed with warm water and the left skin of 3 groups of animals was loaded with tamoxifen gel patch 3cm each as example 2²Blank matrix gel plaster 3cm²0.2ml of 1 percent 2, 4-dinitrochlorobenzene, covering with two layers of gauze after administration, fixing with medical adhesive tape, removing the gauze and the ointment after lasting for 24 hours, scrubbing with warm water, and repeating the steps for 7 th and 14 th days by the same method to observe whether the skin of the depilated area of the guinea pig has erythema and edema;

and (3) exciting contact: 14 days after the last sensitization contact, each group of corresponding medicines are respectively given to the right depilatory area of the guinea pig, after the medicines are given, two layers of gauze are used for covering, then the medicines are fixed by a medical adhesive tape, after the medicines are continuously applied for 6 hours, the gauze and the ointment are removed, the medicines are scrubbed by warm water, the skin allergy condition of the depilatory area of the guinea pig is immediately observed, the skin allergy condition of the depilatory area of the guinea pig is observed again at 24 hours, 48 hours and 72 hours, and the sensitization rate and the average reaction value are calculated:

sensitization rate = erythema or edema animals/total animals) × 100%, the statistical results of sensitization rate are shown in table 11, and the criteria for sensitization response intensity are shown in table 10;

mean reaction = (total score of erythema formation + total score of edema formation) ÷ total animal number

Wherein the skin allergy score evaluation criteria are: the scores of the mild erythema, the moderate erythema, the severe erythema and the edematous erythema are 1 score, 2 scores, 3 scores and 4 scores in turn; the scores of mild edema, moderate edema and severe edema are 1 score, 2 scores and 3 scores in turn;

analysis of guinea pig allergy statistics showed: the skin of the hair removal area of the guinea pigs in the blank matrix gel plaster group and the tamoxifen gel plaster group has no erythema or edema in each observation period, which indicates that the tamoxifen gel plaster has no anaphylaxis to the skin.

TABLE 10 criteria for the evaluation of the intensity of the sensitization reaction

Sensitization Rate (%)	Reaction intensity
		0～10	Weak sensitization
20～30	Mild sensitization
		40～60	Moderate sensitization
70～80	High sensitization
		90～100	Extreme sensitization

TABLE 11 statistical Table of allergy conditions in guinea pigs

Index (I)	Medicine	At once	24h	48h	72h
						Average value of reaction	Blank gel plaster	0	0	0	0
	EXAMPLE 2 gel plaster	0	0	0	0
							2, 4-dinitrochlorobenzene	3.1	2.3	1.8	0.5
Sensitization Rate (%)	Blank gel plaster	0	0	0	0
							EXAMPLE 2 gel plaster	0	0	0	0
	2, 4-dinitrochlorobenzene	100	100	100	50

Claims

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.