External patch with analgesic effect and preparation method thereof

Abstract

The invention provides an external patch with analgesic and analgesic effects and a preparation method thereof, and belongs to the technical field of external preparations of medicines. The external patch comprises a backing layer, an adhesion layer and a protective layer, wherein the adhesion layer comprises active pharmaceutical ingredients, a pressure-sensitive adhesive matrix, a plasticizer, a tackifier, an antioxidant, a penetration enhancer, a sun-screening agent and a stabilizer; according to the invention, the stabilizer is added into the components, so that the obtained external patch has better stability and does not have a crystallization phenomenon after being placed for a long time; in the implementation process, it is found that the mass ratio of the pressure-sensitive adhesive matrix to the plasticizer to the tackifier is controlled to be 1: (1-1.5): (0.3-1.0), so that the external patch can have better initial adhesion, stability and adhesivity, effective components of the medicine can better play roles, and the analgesic and analgesic effects are achieved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical external preparations, and in particular relates to an external patch with analgesic and analgesic effects and a preparation method thereof. Background Art

[0002] Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or experiences similar to this. Pain can be categorized by its cause as nociceptive pain, inflammatory pain, neuropathic pain, cancer pain, psychogenic pain, and pain from other causes. Pain has complex clinical manifestations and diverse characteristics, severely impacting patients' quality of life and placing a heavy financial and psychological burden on them.

[0003] Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently the most commonly used analgesics and anti-inflammatory drugs. While they offer excellent anti-inflammatory and analgesic effects, oral administration can cause significant gastrointestinal disturbances. To mitigate these side effects, transdermal absorption systems have been developed, including ointments, plasters (adhesives), patches, patches, suspensions, emulsions, lotions, and other liquid preparations, as well as aerosols, as topical formulations containing NSAIDs.

[0004] A transdermal drug delivery system (TDDS) refers to a new formulation for transdermal drug delivery. Through transdermal administration, drugs are absorbed through the skin through capillaries, enter the bloodstream, reach effective blood concentrations, and are transported to the affected area, thereby treating or preventing local or systemic diseases. Patches are typically used as a dosage form. Patches not only offer excellent targeting, avoiding the first-pass effect in the liver and improving bioavailability, but also produce sustained, constant, and controllable blood drug concentrations, reducing the frequency and dosage of dosing and allowing for discontinuation of medication at any time, thereby mitigating adverse reactions.

[0005] Chinese patent CN1181931A discloses a composition for a transdermal drug delivery system containing a nonsteroidal anti-inflammatory drug, such as a propionic acid derivative (ketoprofen, etc.), and particularly relates to an improved composition for a transdermal drug delivery system, wherein the nonsteroidal anti-inflammatory drug is dispersed in a non-polar polymer that continuously maximizes thermodynamic activity. If necessary, a fatty acid, a fatty acid ester, a fatty acid alcohol, propylene glycol, a propylene glycol fatty acid ester, oleic acid, oleyl alcohol, ethylene glycol monoethyl ether, or a mixture thereof can be used as a solubilizer or penetration enhancer to increase the skin permeability of the active ingredient. However, this patent does not effectively solve the problem of the adhesiveness of the patch.

[0006] Chinese patent CN1304321A discloses a composition for transdermal administration of nonsteroidal anti-inflammatory drugs, comprising: a therapeutically effective amount of the drug, an absorption enhancer consisting essentially of diethylene glycol ether and sorbitan ester, and a pharmaceutically acceptable adhesive matrix. This patent also fails to effectively address the issues of permeability and adhesion of the patch.

[0007] Moreover, when the drug loading of the patch increases, crystallization occurs in the patch, which seriously affects the stability and therapeutic effect of the patch.

[0008] Chinese patent CN107148269A discloses a topical composition containing S-flurbiprofen, which discloses that, for a topical composition containing S-flurbiprofen and peppermint oil as a transdermal absorption enhancer, the decrease in S-flurbiprofen content over time is suppressed only when the composition is combined with certain medium-chain fatty acid esters of a specific polyol, namely, one or more selected from esters having two medium-chain fatty acids bonded to propylene glycol and esters having three medium-chain fatty acids bonded to glycerol. Furthermore, the S-flurbiprofen remains stable even during long-term storage. However, its stability still fails to meet the demand for better results.

[0009] Therefore, it is necessary to develop an external-use patch with good permeability, strong adhesion and excellent stability and analgesic and analgesic effects and a preparation method thereof. Summary of the Invention

[0010] In response to the deficiencies in the prior art, the present invention aims to provide an external-use patch with analgesic and analgesic effects and a preparation method thereof. The external-use preparation avoids the first-pass effect by delivering the drug through the skin, reduces the adverse reactions caused by oral medications, and has good permeability, strong adhesion, excellent stability, and significant therapeutic effects.

[0011] In order to achieve the above object, one aspect of the present invention provides an external patch with analgesic and analgesic effects, wherein the external patch comprises a backing layer, an adhesive layer and a protective layer.

[0012] The adhesive layer comprises active pharmaceutical ingredients, a pressure-sensitive adhesive matrix, a plasticizer, a tackifier, an antioxidant, a penetration enhancer, a sunscreen and a stabilizer.

[0013] The adhesive layer comprises, by weight percentage:

[0014]

[0015] Preferably, the adhesive layer comprises, by weight percentage:

[0016]

[0017]

[0018] More preferably, the adhesive layer comprises, by weight percentage:

[0019]

[0020] Wherein, the pharmaceutical active ingredient is selected from one or more of ketoprofen or its pharmaceutical salt, dexketoprofen or its pharmaceutical salt, loxoprofen sodium, flurbiprofen or its pharmaceutical salt, ifluprofen or its pharmaceutical salt, ibuprofen or its pharmaceutical salt, diclofenac or its pharmaceutical salt, anisodamine or its pharmaceutical salt and indomethacin or its pharmaceutical salt.

[0021] The pressure-sensitive adhesive matrix is selected from one or more of styrene-isoprene-styrene triblock copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), polyacrylate, polyisobutylene, polybutylene, silicone rubber, polyvinyl ether and polyurethane.

[0022] Preferably, the pressure-sensitive adhesive matrix is a mixture of styrene-isoprene-styrene triblock copolymer (SIS) and polyisobutylene.

[0023] The present invention has found that when the amount of the mixture of styrene-isoprene-styrene triblock copolymer and polyisobutylene is too small, the cohesion of the adhesive layer is poor, and the problem of colloid residue on the skin after attachment is likely to occur; when the amount of the mixture of styrene-isoprene-styrene triblock copolymer and polyisobutylene is too large, the cohesion of the adhesive layer is too strong, the colloid is too thick, and the ductility and coating process are affected.

[0024] Preferably, the mass ratio of the styrene-isoprene-styrene triblock copolymer to polyisobutylene is 1.5-3:1.

[0025] More preferably, the mass ratio of the styrene-isoprene-styrene triblock copolymer to polyisobutylene is 2:1.

[0026] The tackifier is selected from one or more of rosin resins, petroleum resins and terpene resins based on rosin or rosin derivatives;

[0027] Preferably, the tackifier is a rosin-based resin with rosin or a rosin derivative as a matrix;

[0028] More preferably, the tackifier is hydrogenated rosin.

[0029] The plasticizer is selected from one or more of white oil, naphthenic oil, liquid paraffin, lanolin and vaseline;

[0030] Preferably, the plasticizer is liquid paraffin.

[0031] During the implementation process, it was found that the viscosity of liquid paraffin ranged from 30-100 mm 2 / s, the colloid properties are better; when the amount of plasticizer is too little, the colloid properties are thicker and the texture is harder, affecting subsequent coating; when the amount of plasticizer is too much, it is easy to affect the cohesion and adhesion properties of the colloid.

[0032] The antioxidant is selected from one or more of butylated hydroxytoluene, ascorbic acid, tocopherol acetate and propyl gallate;

[0033] Preferably, the antioxidant is butylated hydroxytoluene.

[0034] The penetration enhancer is selected from one or more of azone compounds, crotamiton, N-methylpyrrolidone, oleic acid, isopropyl myristate, dimethyl sulfoxide and menthol;

[0035] Preferably, the penetration enhancer is oleic acid and / or isopropyl myristate.

[0036] The sunscreen is selected from one or more of avobenzone, etocrylene, octocrylene, titanium dioxide and zinc oxide;

[0037] Preferably, the sunscreen is avobenzone.

[0038] The stabilizer is one or more of poloxamer, zinc stearate, isostearic acid, povidone, copovidone, polysorbate 80, lauryl lactate, propylene glycol dicaprylate, propylene glycol caprylate / caprate, propylene glycol monocaprylate, polyoxyethylene hydrogenated castor oil, hydrogenated castor oil hydroxystearate, polyoxyethylene sorbitan monolaurate, glyceryl mono- and distearate, and polyethylene glycol cetearyl ether;

[0039] Preferably, the stabilizer is one or more of polyoxyethylene hydrogenated castor oil, hydrogenated castor oil hydroxystearate, polyoxyethylene sorbitan monolaurate and polyethylene glycol cetearyl ether;

[0040] More preferably, the stabilizer is a mixture of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate and polyethylene glycol ceteareth-20.

[0041] Further preferably, the mass ratio of the polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate and polyethylene glycol cetearyl ether is 1:3-5:2.

[0042] More preferably, the mass ratio of the polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate and polyethylene glycol cetearyl ether is 1:4:2.

[0043] As some preferred embodiments, the mass ratio of the pressure-sensitive adhesive matrix, plasticizer and tackifier is 1:1-1.5:0.3-1.0.

[0044] Furthermore, the topical patch may also include some functional excipients commonly used in topical patches, such as anti-irritants, cosolvents, pH regulators, fillers, etc. The amount of the functional excipients added is determined according to actual needs. Generally, in the adhesive layer, by weight, the anti-irritant is used in an amount of 0-3%, the cosolvent is used in an amount of 0-12%, the pH regulator is used in an amount of 0-3%, and the filler is used in an amount of 0-10%.

[0045] In another aspect, the present invention also provides a method for preparing the above-mentioned external patch, the preparation method comprising the following steps:

[0046] 1) adding the active pharmaceutical ingredient, penetration enhancer and cosolvent to a portion of the plasticizer, stirring and dispersing the mixture uniformly to obtain a liquid mixture;

[0047] 2) heating and mixing the pressure-sensitive adhesive matrix, tackifier, antioxidant, and remaining plasticizers at 120-170° C. to obtain a paste;

[0048] 3) After the paste of step 2) is cooled to 120-160° C., a stabilizer and a sunscreen are added, and the mixture is stirred and mixed evenly. After the paste is cooled to 100-130° C., the liquid mixture of step 1) is added, and the mixture is stirred evenly to obtain a medicated paste;

[0049] 4) The drug-containing ointment of step 3) is evenly coated on the protective layer, and then compounded with the backing layer, and cut to obtain the external patch.

[0050] Compared with the prior art, the present invention has the following beneficial effects:

[0051] (1) Good adhesion: The present invention uses a mixture of styrene-isoprene-styrene triblock copolymer and polyisobutylene as a pressure-sensitive adhesive matrix; when the amount of the pressure-sensitive adhesive matrix is too small, the cohesion of the adhesive layer is poor, and the problem of colloid residue on the skin is likely to occur after attachment; when the amount is too large, the cohesion of the adhesive layer is too large, the colloid is too thick, and the ductility and coating processing are affected; during the implementation of the present invention, by controlling the content of the pressure-sensitive adhesive matrix to 25-45% and the mass ratio of styrene-isoprene-styrene triblock copolymer and polyisobutylene to 1.5-3:1, the obtained external patch has better adhesion performance and will not cause the problem of colloid residue on the skin after attachment.

[0052] (2) Good stability: The present invention uses a mixture of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate and polyethylene glycol ceteareth-20 ether as a stabilizer. By controlling the mass ratio of the three to be 1:3-5:2, the obtained external-use patch has better stability. Even if it is placed for a long time, crystallization will not occur, and it still has good stability for long-term storage.

[0053] (3) Excellent initial adhesion: During the implementation of the present invention, it was found that the mass ratio of the pressure-sensitive adhesive matrix, plasticizer and tackifier was controlled to be 1:1-1.5:0.3-1.0. The colloid prepared by this ratio has good cohesive strength and good compatibility with the drug, while meeting the adhesion requirements and being able to better release the active ingredients of the drug. The plasticizer weakens the intermolecular force of the pressure-sensitive adhesive matrix, thereby increasing the mobility of the chain segments, providing a larger free volume and activity space for the drug molecules, making it easier to disperse and dissolve in the matrix. The plasticizer used in the present invention is 1-1.5 times the amount of the matrix, which can effectively improve the compatibility and promote drug release. On the other hand, the pressure-sensitive adhesive matrix itself does not have initial adhesion. The tackifier is added to enhance the wetting ability of the matrix on the surface of the material, thereby giving it the necessary pressure sensitivity and initial adhesion. Excessive tackifier will significantly reduce the cohesion of the system, causing the patch to leave residual adhesive or slide and shift on the skin (cold flow) when removed. The present invention controls the proportion of the tackifier to 0.3-1.0 times the mass of the base (much lower than the proportion of the plasticizer), which can provide sufficient initial adhesion while avoiding excessive sacrifice of cohesive strength. DETAILED DESCRIPTION

[0054] The present invention will be further described in detail below through specific examples. The following examples are only provided to further illustrate the present application and should not be construed as limiting the present application.

[0055] Unless otherwise specified, the reagents, materials, and instruments used in the present invention are all conventional products that can be purchased through regular commercial channels.

[0056] Example 1-5: An external-use patch with analgesic and analgesic effects and its preparation method

[0057] The specific prescription is shown in Table 1 below.

[0058] Table 1

[0059]

[0060]

[0061] Preparation method: the following steps:

[0062] 1) adding the active pharmaceutical ingredient, penetration enhancer and cosolvent to a portion of the plasticizer, stirring and dispersing the mixture uniformly to obtain a liquid mixture;

[0063] 2) heating and mixing the pressure-sensitive adhesive matrix, tackifier, antioxidant, and remaining plasticizers at 150° C. to obtain a paste;

[0064] 3) After the paste of step 2) is cooled to 120-160° C., a stabilizer and a sunscreen are added, and the mixture is stirred and mixed evenly. After the paste is cooled to 100-130° C., the liquid mixture of step 1) is added, and the mixture is stirred evenly to obtain a medicated paste;

[0065] 4) The drug-containing ointment of step 3) is evenly coated on the protective layer, and then compounded with the backing layer, and cut to obtain the external patch.

[0066] Example 7-9: An external-use patch with analgesic and analgesic effects and its preparation method

[0067] The specific prescription is shown in Table 2 below.

[0068] Table 2

[0069]

[0070] Preparation method: the following steps:

[0071] 1) adding the active pharmaceutical ingredient, penetration enhancer and cosolvent to a portion of the plasticizer, stirring and dispersing the mixture uniformly to obtain a liquid mixture;

[0072] 2) heating and mixing the pressure-sensitive adhesive matrix, tackifier, antioxidant, and remaining plasticizers at 150° C. to obtain a paste;

[0073] 3) After the paste of step 2) is cooled to 120-160° C., a stabilizer and a sunscreen are added, and the mixture is stirred and mixed evenly. After the paste is cooled to 100-130° C., the liquid mixture of step 1) is added, and the mixture is stirred evenly to obtain a medicated paste;

[0074] 4) The drug-containing ointment of step 3) is evenly coated on the protective layer, and then compounded with the backing layer, and cut to obtain the external patch.

[0075] Comparative Example 1

[0076] The difference from Example 7 is that no stabilizer is added, the content of the plasticizer is increased to 42%, and the rest is the same as Example 7.

[0077] Comparative Example 2

[0078] The difference from Example 7 is that only polyoxyethylene hydrogenated castor oil is used as a stabilizer, that is, the content of polyoxyethylene hydrogenated castor oil is 3.5%. Other aspects are the same as Example 7.

[0079] Comparative Example 3

[0080] The difference from Example 7 is that only polyoxyethylene sorbitan monolaurate is used as a stabilizer, that is, the content of polyoxyethylene sorbitan monolaurate is 3.5%. Other aspects are the same as Example 7.

[0081] Comparative Example 4

[0082] The difference from Example 7 is that the content of the plasticizer is increased to 60.5%, the content of the tackifier is reduced to 8%, and the content of the pressure-sensitive adhesive matrix is reduced to 18%. The specific formula is shown in Table 3 below.

[0083] Table 3

[0084]

[0085] The rest is the same as Example 7.

[0086] Comparative Example 5

[0087] The difference from Example 7 is that the content of the plasticizer is reduced to 20%, the content of the tackifier is increased to 27.5%, and the content of the pressure-sensitive adhesive matrix is reduced to 39%. The specific formula is shown in Table 4 below.

[0088] Table 4

[0089]

[0090]

[0091] The rest is the same as Example 7.

[0092] Effect data:

[0093] 1. Adhesion test

[0094] Testing method: The external-use patches prepared in Examples 1-9 of the present invention and Comparative Examples 1-5 were tested according to the following method.

[0095] Cut the sample into 5cm x 10cm pieces and place it on the inclined surface of the adhesion tester, adhesive side up, ensuring there is no gap between the adhesive and the thick paper. Set the center of the ball at a point above the inclined surface, at least 10cm from the test sample. Follow the procedure (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, Method 1, 0952). When quickly removing the protective layer, record the number of the largest ball that the adhesive surface prevents from falling. Repeat the test three times.

[0096] The test results are shown in Table 5 below.

[0097] Table 5 Initial adhesion test results of each embodiment and comparative example

[0098] sample Test results Example 1 22# Example 2 21# Example 3 24# Example 4 23# Example 5 22# Example 6 21# Example 7 26# Example 8 25# Example 9 24# Comparative Example 1 20# Comparative Example 2 23# Comparative Example 3 20# Comparative Example 4 15# Comparative Example 5 28#

[0099] According to the test results in the table above, Examples 1-9 all have good initial tack, with Example 7 showing the best effect, and Examples 8-9 being better than Examples 1-6. In Comparative Examples 1-3, not adding a stabilizer or changing the type of stabilizer has little effect on the initial tack of the topical patches. However, in Comparative Examples 4 and 5, changing the mass ratio of the pressure-sensitive adhesive matrix, plasticizer, and tackifier significantly affects the initial tack of the topical patches, thereby affecting the therapeutic efficacy of the topical patches.

[0100] 2. Evaluation of adhesion and peeling sensation

[0101] The external-use patches prepared in Examples 1-9 of the present invention and Comparative Examples 1-5 were tested according to the following method.

[0102] Samples were cut into 5 cm × 10 cm pieces and applied to the abdomens of several healthy female subjects for 8 hours. The patches were removed after application and the presence of curled edges, residual adhesive on the skin, and pain during removal were recorded.

[0103] The test results are shown in Table 6 below.

[0104] Table 6

[0105] sample Attachment Application experience Peeling feeling Example 1 No warping, no residual glue No skin irritation No pain Example 2 No warping, no residual glue No skin irritation No pain Example 3 No warping, no residual glue No skin irritation No pain Example 4 No warping, no residual glue No skin irritation No pain Example 5 No warping, no residual glue No skin irritation No pain Example 6 No warping, no residual glue No skin irritation No pain Example 7 No warping, no residual glue No skin irritation No pain Example 8 No warping, no residual glue No skin irritation No pain Example 9 No warping, no residual glue No skin irritation No pain Comparative Example 1 No warping, slight adhesive residue No skin irritation No pain Comparative Example 2 Slightly warped edge, no residual glue No skin irritation No pain Comparative Example 3 No warping, no residual glue No skin irritation No pain Comparative Example 4 Warping edge, slight adhesive residue No skin irritation, easy to slip off No pain Comparative Example 5 No warping, little residual glue No skin irritation Significant pain

[0106] According to the test results in Table 6 above, the skin of Examples 1-9 did not feel any discomfort such as irritation during application, and the patches were firmly attached without warping. There was no obvious pain during the peeling process, and no residual colloid was left on the skin, indicating that the patient compliance was good. In Comparative Examples 1-3, not adding a stabilizer or changing the type of stabilizer had little effect on the peeling effect and peeling feeling of the external patch, and did not affect the use. However, in Comparative Examples 4 and 5, changing the mass ratio of the pressure-sensitive adhesive matrix, plasticizer, and tackifier significantly affected the user experience of the external patch, and different degrees of warping, residual adhesive, and peeling pain would occur.

[0107] 3. Stability test

[0108] The external patches prepared in Examples 1-9 and Comparative Examples 1-5 were placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 3 months to investigate the thermal stability of the patches and test the changes in properties and content of the samples. The test results are shown in Table 7 below.

[0109] Table 7

[0110]

[0111] According to the test results in Table 7 above, after being placed for 3 months under the conditions of temperature 40°C ± 2°C and relative humidity 75% ± 5%, the properties of the samples in Comparative Examples 1-5 changed to varying degrees, the content decreased significantly, and the stability was poor. The properties of the samples in Examples 1-9 did not change significantly, and the content changed little. Among them, the content of Examples 1-6 was all higher than 96%, and the content of Examples 7-9 was all above 98%, which was better than Examples 1-6 and had good stability.

[0112] 4. Pharmacodynamic experiment

[0113] Select the external patches prepared in Examples 7-9 of the present invention and Comparative Examples 4-5 for testing according to the following method.

[0114] (1) Test animals

[0115] ICR female mice, 6-7 weeks old, purchased from Guangdong Vital River Laboratory Animal Technology Co., Ltd., experimental animal production license number: SCXK(Yue)2022-0063. Quarantine and observation for 4 days, and no obvious abnormalities were found in all animals during the quarantine and adaptability observation period. The animals had been approved by the project leader and veterinarian before use.

[0116] (2) Test substances

[0117] Samples of Examples 7-9 and Comparative Examples 4-5; ketoprofen patch (commercially available); positive drug: dexketoprofen trometamol tablets; model control group: blank patch;

[0118] (3) Construction of dysmenorrhea mouse model

[0119] Subcutaneously inject estradiol benzoate (dose 10 mg / kg, enhancing the sensitivity of the uterus to oxytocin), once a day for 10 consecutive days, and the first and last injection doses are 4 mg / kg. 1 hour after the last injection of estradiol benzoate, inject oxytocin intraperitoneally at 30 U / kg to prepare a mouse dysmenorrhea model. The normal control group was given an equal amount of normal saline.

[0120] (4) Dose design and administration method

[0121] The dexketoprofen trometamol tablets are usually 1-2 tablets / capsules (12.5 mg - 25 mg) each time, and the maximum daily dose does not exceed 100 mg. According to the human and animal body surface area-body weight calculation formula, the clinical equivalent dose for mice is 18.74 mg / kg, and the designed mouse administration dose is 18.74 mg / kg. Each test substance is directly converted according to the human and animal body surface area, and the equivalent dose for mice is 0.57 mg / cm 2 and the designed mouse administration dose is 0.57 mg / cm 2All were cut into appropriate sizes and used directly. On days 8-10 of modeling, except for the positive control group, the topical group received the drug via oral gavage. The drug was removed 6 hours after administration for three consecutive days, once daily. The first day of administration was designated D1, the previous day D0, and so on. Groups and dosages are shown in Table 8.

[0122] Table 8 Grouping and dosage design

[0123]

[0124] (5) Index detection

[0125] On D10, after the injection of oxytocin, the time when the mice first showed writhing reaction was immediately observed and recorded, the writhing latency was calculated, and the number of writhing times within 30 min was recorded.

[0126] Animals were anesthetized with an intramuscular injection of a 10:1 solution of Shutai-Sumenxin (0.05 ml / mouse) and sacrificed by exsanguination via the abdominal aorta. The ovaries and uterus of the female mice were completely removed after dissection. The fascia and adipose tissue surrounding the ovaries and uterus were removed and washed with saline. Excess liquid was removed by filter paper and weighed. Changes in the ovarian and uterine coefficients were calculated according to the following formula.

[0127] Ovarian coefficient = ovarian wet weight (g) / body weight (g) × 100;

[0128] Uterine coefficient = uterine wet weight (g) / body weight (g) × 100.

[0129] Drug concentration in terminal uterus: The removed uterus was quickly frozen in liquid nitrogen and stored at -80°C, and the drug concentration in the uterus was tested.

[0130] (6) Data processing

[0131] The experimental measurement data were summarized in Excel and expressed as mean ± standard deviation. SPSS28.0 was used for analysis and statistics were performed using one-way analysis of variance. When the variances were equal, the LSD test was used for inter-group comparison, and when the variances were unequal, the Dunnett's T3 test was used for inter-group comparison. When the mean difference between the normal control group and the model control group was large, the independent sample t test was used for inter-group comparison; P < 0.05 was considered statistically significant.

[0132] (7) Test results

[0133] Table 9 Effects on the number of writhing times and writhing latency in dysmenorrhea model mice

[0134]

[0135] Note: vs normal control group, ##P<0.01; vs model control group, *P<0.05, **P<0.01.

[0136] The test results showed that mice in the normal control group showed no writhing reactions, with a writhing frequency of 0 and a writhing latency of 30 minutes. Compared with the normal control group, mice in the model control group showed a significant increase in writhing frequency (P < 0.01) and a significant decrease in writhing latency (P < 0.01). Compared with the model control group, the number of writhing reactions in the positive control group and test substance groups 1-6 was significantly reduced (P < 0.01 or 0.05), while the writhing latency was significantly increased (P < 0.05). Compared with test substance group 6, test substance groups 1-3 showed fewer writhing reactions and longer writhing latency, demonstrating a superior analgesic effect.

[0137] Table 10 Effects on organ coefficients of dysmenorrhea model mice

[0138]

[0139] Note: vs normal control group, ##P<0.01; vs model control group, *P<0.05.

[0140] The test results showed that compared with the normal control group, the uterine coefficient and ovarian coefficient of the animals in the model control group were significantly increased (P<0.01). Compared with the model control group, the uterine coefficient and ovarian coefficient of the animals in the positive control group and test substance groups 1-6 were all reduced, with statistically significant differences between the positive control group and test substance groups 1-3 (P<0.05). This indicates that the positive control group and test substances 1-3 can effectively alleviate the increase in uterine weight.

[0141] Table 11 Effects on tissue and plasma drug concentrations

[0142]

[0143] The test results in Table 11 above indicate that the drug is distributed in all tissues and plasma. The distribution of blood drug concentrations follows the order of plasma > uterus > ovary. The drug concentrations in all tissues and plasma of animals in Test Groups 1-3 were higher than those in Test Groups 4-6.

[0144] The above content is a further detailed description of the present application in conjunction with specific implementation methods, and it cannot be considered that the specific implementation of the present application is limited to these descriptions. For ordinary technicians in the technical field to which the present application belongs, they can make several simple deductions or substitutions without departing from the concept of the present application, which should be considered to fall within the scope of protection of the present application.

Claims

1. A topical patch with analgesic and analgesic effects, comprising a backing layer, an adhesive layer, and a protective layer, characterized in that: The adhesive layer comprises a pharmaceutical active ingredient, a pressure-sensitive adhesive matrix, a plasticizer, a tackifier, an antioxidant, a penetration enhancer, a sunscreen and a stabilizer; The stabilizer is one or more of poloxamer, zinc stearate, isostearic acid, povidone, copovidone, propylene glycol monolaurate, polysorbate 80, caprylic and capric mono- and diglycerides, lauryl lactate, propylene glycol dicaprylate, caprylic and capric propylene glycol, monocaprylate, polyoxyethylene hydrogenated castor oil, hydrogenated castor oil hydroxystearate, polyoxyethylene sorbitan monolaurate, glyceryl mono- and distearate, and polyethylene glycol ceteareth-20; The mass ratio of the pressure-sensitive adhesive matrix, the plasticizer and the tackifier is 1:1-1.5:0.3-1.

0.

2. The external-use patch according to claim 1, wherein: The adhesive layer comprises, by weight percentage:

3. The external-use patch according to claim 2, wherein: The adhesive layer comprises, by weight percentage:

4. The external-use patch according to claim 3, characterized in that: The pressure-sensitive adhesive matrix is selected from one or more of styrene-isoprene-styrene triblock copolymer, styrene-butadiene-styrene block copolymer, polyacrylate, polyisobutylene, polybutylene, silicone rubber, polyvinyl ether and polyurethane.

5. The external-use patch according to claim 4, characterized in that: The pressure-sensitive adhesive matrix is a mixture of styrene-isoprene-styrene triblock copolymer and polyisobutylene; the mass ratio of the styrene-isoprene-styrene triblock copolymer to the polyisobutylene is 1.5-3:

1.

6. The external-use patch according to claim 3, characterized in that: The plasticizer is selected from one or more of white oil, naphthenic oil, liquid paraffin, lanolin and vaseline, and the viscosity of the liquid paraffin is in the range of 30-100 mm. 2 / s.

7. The external-use patch according to claim 1, characterized in that: The stabilizer is a mixture of polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate and polyethylene glycol cetearyl ether; the mass ratio of the polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate and polyethylene glycol cetearyl ether is 1:3-5:

2.

8. The external-use patch according to claim 7, characterized in that: The mass ratio of the polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monolaurate and polyethylene glycol ceteareth-20 is 1:4:

2.

9. The external-use patch according to claim 3, characterized in that: The sunscreen is one or more of avobenzone, etocrylene, octocrylene, titanium dioxide and zinc oxide.

10. The method for preparing the external-use patch according to any one of claims 1 to 9, characterized in that: The preparation method comprises the following steps: 1) adding the active pharmaceutical ingredient, penetration enhancer and cosolvent to a portion of the plasticizer, stirring and dispersing the mixture uniformly to obtain a liquid mixture; 2) heating and mixing the pressure-sensitive adhesive matrix, tackifier, antioxidant, and remaining plasticizer at 120-170° C. to obtain a paste; 3) After the paste of step 2) is cooled to 120-160° C., a stabilizer and a sunscreen are added, and the mixture is stirred and mixed evenly. After the paste is cooled to 100-130° C., the liquid mixture of step 1) is added, and the mixture is stirred evenly to obtain a medicated paste; 4) The drug-containing ointment of step 3) is evenly coated on the protective layer, and then compounded with the backing layer, and cut to obtain the external patch.

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