Patch containing diphenyl butyramide compound and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a patch containing a diphenyl butyramide compound and a preparation method of the patch. The invention provides a patch containing diphenyl butyramide compounds. The patch comprises a backing layer, drug-containing adhesive dispersion layers, a controlled release film and a release film layer, wherein the drug-containing adhesive dispersion layers are distributed on two sides of the controlled release film; the patch is a patch for 3-7 days, and the medicine penetration amount per day is not less than 110 micrograms; the patch is a long-acting transdermal drug delivery system which is constructed by adding a crystal inhibitor to inhibit drug crystallization, adding a penetration enhancer to promote drug penetration and adopting a controlled release membrane and contains the diphenylbutyramide compound, and the system is suitable for transdermal drug delivery of the diphenylbutyramide compound at a stable rate within 3-7 days.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and relates to a pharmaceutical preparation for treating overactive bladder, in particular to a patch containing a diphenylbutyramide compound and a preparation method thereof. Background Art

[0002] Overactive Bladder (OAB) refers to a chronic disease characterized by urinary urgency in the absence of urinary tract infection or other obvious pathologies, often accompanied by symptoms of frequent urination and nocturia, and may or may not be accompanied by urge urinary incontinence. These symptoms will seriously affect the quality of life of patients. Therefore, it is of great significance to carry out the treatment of OAB and improve the quality of life of patients.

[0003] The diphenylbutyramide compound, with the chemical name of 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutyramide, has the chemical structure of It is a new type of anticholinergic drug of diphenylbutyramide jointly developed by Ono Pharmaceutical Co., Ltd. and Kyorin Pharmaceutical Co., Ltd. in Japan. It has high bladder selectivity and is used to treat urinary urgency, frequent urination and urinary incontinence caused by overactive bladder. The diphenylbutyramide compound was approved for marketing in Japan in 2007 in the form of film-coated tablets, and was launched in Japan in June 2010 in the form of orally disintegrating tablets. However, the currently marketed diphenylbutyramide compound preparations have certain limitations. For example, there is no sustained-release preparation in the currently marketed dosage forms. The treatment period of OAB is as long as 3-6 months. The tablets need to be administered twice a day, which is more dependent on the patient's compliance with the drug. And the film-coated tablets need to be taken with water, which is likely to cause the urge to urinate in OAB patients after drinking water.

[0004] Therefore, there is a need to provide a drug delivery method with better therapeutic effects and good patient compliance. As one of the most widely used transdermal drug delivery systems (TDDSs), transdermal patches have the advantage of more stable blood drug concentrations compared with oral preparations. Considering the long treatment cycle of OAB, the long-acting transdermal patch formulation is expected to solve the above problems. However, there are certain challenges in preparing diphenylbutyramide compounds into long-acting transdermal patches. First, for the most common monolayer adhesive dispersion transdermal patches among the commercially available transdermal patch products, to meet the required penetration amount for clinical use, the drug loading amount is often increased to improve the drug penetration amount. However, due to the high concentration gradient difference between the patch and the skin surface layer after increasing the drug loading amount, the patch is prone to explosive penetration in the early stage, while the penetration rate decreases in the later stage, making it difficult to maintain a relatively stable penetration rate for a long time and unable to meet the requirement of stable penetration for 3 to 7 days. Second, diphenylbutyramide compounds have poor solubility in common pressure-sensitive adhesive matrices and are prone to crystallization, making it difficult to increase the drug loading amount to meet the drug loading requirements for long-term application. In addition, to meet the requirement of long-term application for 3 to 7 days, there are great challenges for the adhesion ability of the patch.

[0005] Patent CN 112791069 A requests protection for a monolayer patch that uses lauryl lactate, polyethylene glycol 200, and propylene glycol monolaurate as transdermal penetration enhancers. However, limited by the low drug loading amount caused by the poor solubility of the drug active ingredient in the patch matrix, the drug penetration amount of the patch is still low and difficult to meet the treatment requirements. Patent TW I514999B protects a patch that uses sorbitan monolaurate and triethyl glycerol as penetration enhancers and stearic acid as a crystallization inhibitor. Although the drug loading amount and penetration flux of the patch are improved to a certain extent, it is difficult to meet the requirement of long-term application.

[0006] Therefore, it is an urgent technical problem in the art to provide a patch containing diphenylbutyramide compounds that can maintain a stable blood drug concentration and has a sustained-release therapeutic effect. Summary of the Invention

[0007] To solve the above problems, the present invention provides a long-acting transdermal drug delivery system containing diphenylbutyramide compounds, which has a drug loading amount that meets the requirements of long-term application, a stable drug penetration rate within 3 to 7 days, and good adhesion performance.

[0008] To solve the above technical problems, on the one hand, the present invention provides a patch containing diphenylbutyramide compounds, the patch includes a backing layer, a drug-containing adhesive dispersion layer, a controlled-release membrane, and a release liner layer, wherein the drug-containing adhesive dispersion layers are distributed on both sides of the controlled-release membrane; the patch is a 3-7-day patch, and the daily drug permeation amount should not be less than 110 μg.

[0009] In some embodiments, the daily drug permeation amount of the patch should be not less than 120 μg.

[0010] In some embodiments, the daily drug permeation amount of the patch should be not less than 130 μg.

[0011] In some embodiments, the controlled-release membrane comprises ethylene-vinyl acetate copolymer (EVA), polyethylene membrane or polypropylene microporous membrane.

[0012] Preferably, the controlled-release membrane is an ethylene-vinyl acetate copolymer (EVA) controlled-release membrane.

[0013] More preferably, the controlled-release membrane is an EVA controlled-release membrane with a mass fraction of vinyl acetate monomer of 19%.

[0014] In some embodiments, the drug-containing adhesive dispersion layer comprises 1-10 parts by weight of a drug active ingredient, 30-90 parts by weight of a pressure-sensitive adhesive matrix, 1-30 parts by weight of a penetration enhancer, and 3-30 parts by weight of a crystal growth inhibitor; wherein the drug active ingredient (API) is a diphenylbutyramide compound or a pharmaceutically acceptable salt thereof.

[0015] The weight parts of the drug active ingredient are 1-10 parts, for example, it can be 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts or 9 parts, as well as the specific point values between the above point values. Due to space limitations and for the sake of brevity, the present invention does not exhaustively list the specific point values included in the above range.

[0016] The weight parts of the pressure-sensitive adhesive matrix are 30-90 parts, for example, it can be 40 parts, 50 parts, 60 parts, 70 parts, 80 parts or 90 parts, as well as the specific point values between the above point values. Due to space limitations and for the sake of brevity, the present invention does not exhaustively list the specific point values included in the above range.

[0017] The weight parts of the penetration enhancer are 1-30 parts, for example, it can be 2 parts, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 28 parts or 30 parts, as well as the specific point values between the above point values. Due to space limitations and for the sake of brevity, the present invention does not exhaustively list the specific point values included in the above range.

[0018] The weight parts of the crystal growth inhibitor are 3-30 parts, for example, it can be 3 parts, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 28 parts or 30 parts, as well as the specific point values between the above point values. Due to space limitations and for the sake of brevity, the present invention does not exhaustively list the specific point values included in the above range.

[0019] In some embodiments, the crystal growth inhibitor is selected from polyvinylpyrrolidone, poloxamer, Plasdone TMOne or more of S-630 copovidone and hypromellose, and the weight ratio of the crystallization inhibitor to the drug active ingredient is 2:1 - 5:1.

[0020] It can be understood that the addition of the crystallization inhibitor helps to meet the drug loading required for long-term application and inhibits the precipitation of drug crystals. When the proportion of the crystallization inhibitor relative to the drug active ingredient is too low, the effect of inhibiting drug crystallization cannot be achieved. When the proportion of the crystallization inhibitor to the drug active ingredient is too high, it will seriously affect the compatibility of the system, and the adhesion performance of the patch will decrease.

[0021] In some embodiments, the pressure-sensitive adhesive matrix is a hydroxyl pressure-sensitive adhesive and a non-functional group pressure-sensitive adhesive.

[0022] Preferably, the weight ratio of the hydroxyl pressure-sensitive adhesive to the non-functional group pressure-sensitive adhesive is 1:5 - 1:1.

[0023] It can be understood that a suitable pressure-sensitive adhesive helps to meet the release requirements of the drug active ingredient and the adhesion performance requirements for long-term application. When the hydroxyl pressure-sensitive adhesive and the non-functional group pressure-sensitive adhesive are compounded, they can provide the required adhesion performance.

[0024] In some embodiments, the penetration enhancer includes one or more of span 20, span 80, tween 80, isopropyl myristate, triethyl glycerol, diisopropyl adipate, and diethylene glycol monoethyl ether.

[0025] In some embodiments, the backing layer is a PET film with good air permeability, which is used to relieve skin irritation caused by long-term application.

[0026] On the other hand, the present invention provides a method for preparing a patch containing a diphenylbutyramide compound, which includes the following steps:

[0027] Step 1: Dissolve the drug active ingredient in a solvent to obtain a mixed solution of phase A;

[0028] Step 2: Dissolve the crystallization inhibitor in a solvent to obtain a crystallization inhibitor solution of phase B;

[0029] Step 3: Mix the mixed solution of phase A and the crystallization inhibitor solution of phase B;

[0030] Step 4: Mix the penetration enhancer and the pressure-sensitive adhesive matrix with the mixed solution obtained in step 3, and let it stand for defoaming;

[0031] Step 5: Parallelly coat the mixture obtained in step 4 onto two release films, dry it, attach a release film coated with the mixture to a backing film to obtain layer A, and attach the other release film coated with the mixture to a controlled-release film to obtain layer B;

[0032] Step 6: After uncovering the release film on layer A, combine it with layer B, roll and cut it into the required size to obtain the required patch.

[0033] In some embodiments, the solvent includes one or more of purified water, ethanol, methanol, dimethyl sulfoxide, glycerol, N-methylpyrrolidone, soybean oil, and ethyl acetate.

[0034] The patch containing the diphenylbutyramide compound of the present invention is a long-acting transdermal drug delivery system containing the diphenylbutyramide compound constructed by adding a crystallization inhibitor to inhibit drug crystallization, adding a penetration enhancer to promote drug penetration, and using a controlled-release membrane. This system is suitable for transdermal administration of the diphenylbutyramide compound at a stable rate for 3 to 7 days. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 It is a comparative diagram of drug crystallization of the patches containing the diphenylbutyramide compound prepared in Examples 1-10;

[0036] Figure 2 It is a comparative diagram of the cumulative permeation amount of the patches containing the diphenylbutyramide compound prepared in Examples 11-17;

[0037] Figure 3 It is a comparative diagram of the cumulative drug permeation amount of the patches containing the diphenylbutyramide compound prepared in Examples 18-21;

[0038] Figure 4 It is a comparative diagram of the cumulative drug permeation amount of the patches containing the diphenylbutyramide compound prepared in Examples 22-27;

[0039] Figure 5 It is a comparative diagram of the permeation rate of the patches containing the diphenylbutyramide compound prepared in Examples 28-30. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0040] The technical solution of the present invention will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments are only for helping to understand the present invention and should not be regarded as specific limitations on the present invention.

[0041] As used herein, the terms "comprising", "including", "having", "containing" or any other variation thereof are intended to cover non-exclusive inclusion. For example, a composition, step, method, article or device containing the listed elements is not necessarily limited to those elements, but may also include other elements not expressly listed or elements inherent to such composition, step, method, article or device.

[0042] "Optionally" or "any one" means that the matters or events described thereafter may or may not occur, and this description includes the cases where the events occur and the cases where the events do not occur.

[0043] The indefinite articles "a" and "an" before the elements or components of the present invention do not limit the quantity requirements (i.e., the number of occurrences) of the elements or components. Therefore, "a" or "an" should be construed to include one or at least one, and the singular form of the element or component also includes the plural form, unless the quantity clearly refers only to the singular form. In the present invention, the features defined with "first" and "second" may explicitly or implicitly include one or more of such features, which are used to distinguish and describe the features, without order or importance. In the description of the present invention, unless otherwise specified, "a plurality of" means two or more.

[0044] In the present invention, unless otherwise stated, the ratios, percentages and parts are weight ratios, weight percentages and weight parts.

[0045] Preparation of patches containing diphenylbutyramide compounds in Examples 1-10

[0046] Table 1 Prescription table of Examples 1-10

[0047]

[0048]

[0049] Preparation method: Dissolve the drug active ingredient in dimethyl sulfoxide, ultrasonicate for 5 min, and mix evenly to obtain a mixed solution. Slowly add the mixed solution to the ethanol solution of Plasdone TM S-630, polyvinylpyrrolidone or Plasdone TM S-630, the ethanol solution of the polyvinylpyrrolidone compound, and stir evenly. Subsequently, add the polyacrylate pressure-sensitive adhesive mixture, mix evenly to obtain a mixture, and let it stand to defoam. Coat the mixture parallelly onto two release films (PET 9707), dry at 70 °C for 30 min to remove the organic solvent. Attach a release film coated with the mixture to the backing film (layer A), and attach the other release film coated with the mixture to the controlled-release film (layer B). Finally, uncover the release film on layer A, combine it with layer B, roll and cut it into the required size to obtain the required patch.

[0050] Use a medicine spoon to scrape the colloidal drug-containing layer of the patches containing diphenylbutyramide compounds prepared in Examples 1-10, and carry out the characterization of the microscopic morphology of the colloid by using a polarized light microscope (transmission light mode) to observe the crystallization of the drug. As Figure 1 The results show that when Plasdone TM S-630 or polyvinylpyrrolidone and the drug ratio is lower than 3:1, obvious drug crystallization phenomenon occurs. As the proportion of Plasdone TM S-630 / or polyvinylpyrrolidone decreases, the crystallization situation becomes more serious. When Plasdone is selectedTM S-630 and polyvinylpyrrolidone are compounded together as a crystal growth inhibitor. As shown in the crystallization diagrams of Examples 7-10 Figure 1 when the ratio of Plasdone TM after compounding S-630 and polyvinylpyrrolidone with the drug is 2:1 or higher, the effect of inhibiting the precipitation of drug crystals can be achieved, and the system has good compatibility. At the same time, experiments found that when the proportion of this crystal growth inhibitor is relatively high, it may affect the compatibility of the mixture system. It is preferred that the ratio of the crystal growth inhibitor to the drug is not higher than 5:1.

[0051] Preparation of patches containing diphenylbutyramide compounds in Examples 11-17

[0052] Table 2 Prescription table of Examples 11-17

[0053]

[0054]

[0055] The preparation method refers to Examples 1-10.

[0056] Adhesion performance tests (initial adhesion and holding adhesion) and in vitro transdermal experiments were carried out on Examples 11-17

[0057] Ring initial adhesion detection: Cut 20 cm2 samples of the patches containing diphenylbutyramide compounds prepared in Examples 11-17 for ring initial adhesion detection. Place the samples at 18-25 °C and relative humidity of 40%-70% for more than 2 hours; keep the length of the sample in the coating direction unchanged, cut it into strips with a width of 2.40 cm, stick release films on both upper ends respectively, so that the remaining sticky surface length is greater than 2.40 cm, stick the release films on both ends of the sample and clamp them on the upper holder together, so that the lower test surface of the preparation is 4.00 cm away from the test plate, and conduct the detection.

[0058] Holding adhesion detection: Cut 10 cm 2 samples of the patches containing diphenylbutyramide compounds prepared in Examples 11-17 for holding adhesion detection. The placement conditions are the same as those for the ring initial adhesion test. Take 3 samples each, make the coating direction of the test article parallel to the longitudinal direction of the plate, and stick it flat in the middle of the adjacent test plate and loading plate (the width of the test plate is 12.50 cm). Roll a 2000 g pressure roller back and forth on the test article three times, place it for 20 minutes, hang a 1000 g weight below the sample, and hang it in a 32 °C constant temperature holding adhesion tester to start the test timing.

[0059] As shown in Table 3, the patch containing diphenylbutyramide compounds prepared with hydroxy pressure-sensitive adhesive can provide excellent initial adhesion, but has poor holding power and is prone to residual glue drawing during the removal process. The holding power can reflect to a certain extent the resistance ability of the patch to lateral friction during the application process. The patch containing diphenylbutyramide compounds prepared with non-functional pressure-sensitive adhesive has weak initial adhesion but strong holding power. Therefore, pressure-sensitive adhesive blending can be considered. For example, in Examples 13-15, a better adhesion ability is shown in the range of hydroxy pressure-sensitive adhesive: non-functional pressure-sensitive adhesive = 1:5 to 1:1.

[0060] Table 3 Evaluation of the adhesion performance of the patches containing diphenylbutyramide compounds prepared in Examples 11-17

[0061] Patch Initial loop tack (N) Holding tack (min) Example 11 26.3 23 Example 12 16.3 48 Example 13 18.5 40 Example 14 21.4 35 Example 15 23.2 30 Example 16 24.5 25 Example 17 18.2 45

[0062] In vitro transdermal experiment: A vertical Franz diffusion cell was used to evaluate the in vitro skin penetration behavior of diphenylbutyramide compounds in pressure-sensitive adhesive matrices with different blending ratios. The experimental permeation barrier was the excised skin on the back of 1-month-old Bama miniature pigs. After removing the release film, the patch was applied to the stratum corneum side of the pig skin, with the dermis layer facing the receiving solution side. At the start of the experiment, degassed (pH 7.0) PBS solution was added to the receiving pool, and gentamicin sulfate (0.25%, v / v) was added to prevent skin decay. The medium temperature was maintained at 32°C ± 0.5°C, and the stirring speed was ensured to be 600 rpm. At 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 60, and 72 h, all the receiving solution (12.0 mL) was taken out and replenished with fresh dissolution medium of the same temperature and volume.

[0063] Investigation of the adhesion force between the drug-containing adhesive dispersion layer and the control release membrane: The drug-containing adhesive dispersion layer was attached to the control release membrane, and after rolling, it was observed whether the laminated area was smooth and flat and whether there were bubbles. As Figure 2 shown, the cumulative permeation amount of diphenylbutyramide compounds in a single non-functional pressure-sensitive adhesive is better than that in a single hydroxy pressure-sensitive adhesive. When hydroxy pressure-sensitive adhesive and non-functional pressure-sensitive adhesive are blended, the cumulative permeation amount will increase to a certain extent compared with a single hydroxy-functional pressure-sensitive adhesive. This phenomenon can be analyzed from the adhesion degree between the drug-containing adhesive layer and the control release membrane. Obvious small bubbles appeared in the single pressure-sensitive adhesive group after visually attaching the control release membrane, while after attaching the control release membrane in the range of hydroxy pressure-sensitive adhesive: non-functional pressure-sensitive adhesive = 1:5 to 1:1, the drug-containing layer and the control release membrane fit closely, visually showing a smooth state and no obvious bubbles. Therefore, on the premise of ensuring a high permeation amount and appropriate adhesion ability, hydroxy pressure-sensitive adhesive and non-functional pressure-sensitive adhesive are selected for blending.

[0064] Preparation of the patches containing diphenylbutyramide compounds in Examples 18-21

[0065] Table 4 Prescription Table for Examples 18 - 21

[0066]

[0067] The preparation method refers to Examples 1 - 10; the in vitro transdermal experiment procedure refers to Examples 11 - 17.

[0068] In vitro skin permeability investigation was carried out on the patches containing diphenylbutyramide compounds prepared in Examples 18 - 21. The results are as Figure 3 shown. The best permeation - enhancing effect was achieved when Span 20 was used.

[0069] Preparation of Patches Containing Diphenylbutyramide Compounds in Examples 22 - 25

[0070] Table 5 Prescription Table for Examples 22 - 25

[0071]

[0072] Preparation method: refer to Examples 1 - 10; the in vitro transdermal experiment procedure refers to Examples 11 - 17.

[0073] In vitro transdermal investigation was carried out on the patches containing diphenylbutyramide compounds prepared with different types of controlled - release membranes. The results are as Figure 4 shown. Under the same prescription and process, the controlled - release membranes EVA - 9712, EVA - 9716, and EVA - 9728 all meet the permeation amount requirements. Among them, the 72 - hour cumulative permeation amount of the EVA - 9728 group of the controlled - release membrane is the highest. The difference between the controlled - release membrane 9728 and the controlled - release membrane 9712 lies only in whether corona treatment is carried out. The corona - treated 9728 controlled - release membrane has a higher surface free energy and adheres more tightly to the drug - containing adhesive dispersion layer, which further confirms that the adhesion effect between the controlled - release membrane and the drug - adhesive layer can directly affect the in vitro permeation phenomenon.

[0074] Preparation of Patches Containing Diphenylbutyramide Compounds in Examples 28 - 30

[0075] Table 6 Prescription Table for Examples 28 - 30

[0076]

[0077] Preparation method: refer to Examples 1 - 10. Among them, Example 30 is a single - layer transdermal patch without an attached controlled - release membrane, and the rest of the operation steps are the same; the in vitro transdermal experiment procedure refers to Examples 11 - 17.

[0078] In vitro transdermal investigation was carried out on the patches containing diphenylbutyramide compounds in Examples 28 - 30. The results are as Figure 5As shown, under the same prescription and preparation process, the 72-hour permeation rate curve of the group loaded with the controlled-release membrane is relatively stable, and the permeation rate still remains at about 1.05 μg / cm 2 / h at the detection points in the last 72 hours, having the property of slow release of drugs for a long-term patch application of 3 to 7 days. For the single-layer transdermal patch group without the loaded controlled-release membrane, the permeation rate is extremely fast in the early stage, showing a phenomenon of rapid permeation, but it is difficult to maintain a relatively stable permeation rate for a long time, and a permeation failure phenomenon occurs within 72 hours, making it difficult to achieve the effect of long-term patch application for 3 to 7 days.

[0079] Example 29

[0080] In the Japanese PMDA, the usage and dosage of the original research diphenylbutyramide compound film-coated tablets are specified as twice a day, one tablet of 0.1 mg each time. When the effect is not good and safety is ensured, it can be increased to two tablets each time, and the bioavailability is about 60%. To ensure that the self-developed patch can exert a good therapeutic effect, an efficacy evaluation was carried out on the premise of consistent pharmacokinetics. The evaluation method is mainly a voiding diary, recording the individual's voiding situation for at least 24 hours. The recorded content includes the number of voiding times, voiding time, single voiding volume, number of urinary incontinence times, urinary incontinence volume, etc. It was found that when the daily permeation amount of the self-developed transdermal patch is not less than 110 μg (the plasma exposure is equivalent to that of the tablet), it can effectively relieve the corresponding symptoms of overactive bladder.

Claims

1. A patch containing a diphenylbutyramide compound, characterized in that, The patch comprises a backing layer, a drug-containing adhesive dispersion layer, a controlled-release membrane and a release liner layer, wherein the drug-containing adhesive dispersion layers are distributed on both sides of the controlled-release membrane; the patch is a 3- to 7-day patch, and the daily drug permeation amount should be not less than 110 μg.

2. The patch containing the diphenylbutyramide compound according to claim 1, characterized in that, The daily drug permeation amount of the patch should be not less than 120 μg.

3. The patch containing the diphenylbutyramide compound according to claim 1, characterized in that, The controlled-release membrane is an ethylene-vinyl acetate copolymer controlled-release membrane.

4. The patch containing a diphenylbutyramide compound according to claim 3, characterized in that, The controlled-release membrane is an ethylene-vinyl acetate copolymer membrane with a vinyl acetate monomer mass fraction of 19%.

5. The patch containing the diphenylbutyramide compound according to any one of claims 1-4, characterized in that, The drug-containing adhesive dispersion layer comprises 1-10 parts by weight of a drug active ingredient, 30-90 parts by weight of a pressure-sensitive adhesive matrix, 1-30 parts by weight of a penetration enhancer, and 3-30 parts by weight of a crystal inhibitor; wherein the drug active ingredient is a diphenylbutyramide compound or a pharmaceutically acceptable salt thereof.

6. The patch containing the diphenylbutyramide compound according to claim 5, characterized in that, The crystal growth inhibitor is selected from one or more of polyvinylpyrrolidone, poloxamer, Plasdone TM S-630 copovidone, hypromellose, and the weight ratio of the crystal growth inhibitor to the active pharmaceutical ingredient is 2:1-5:

1.

7. The patch containing the diphenylbutyramide compound according to claim 5, characterized in that, The pressure-sensitive adhesive matrix is a hydroxyl pressure-sensitive adhesive and a non-functional group pressure-sensitive adhesive.

8. The patch containing the diphenylbutyramide compound according to claim 7, characterized in that, The weight ratio of the hydroxyl pressure-sensitive adhesive to the non-functional group pressure-sensitive adhesive is 1:5 - 1:

1.

9. The patch containing the diphenylbutyramide compound according to claim 5, characterized in that, The penetration enhancer includes one or more of Span 20, Span 80, Tween 80, isopropyl myristate, triethyl glycerol, diisopropyl adipate, and diethylene glycol monoethyl ether.

10. A method for preparing a patch containing a diphenylbutyramide compound according to any one of claims 5-9, characterized in that, It includes the following steps: Step 1: Dissolve the drug active ingredient in a solvent to obtain a phase A mixed solution; Step 2: Dissolve the crystal inhibitor in a solvent to obtain a phase B crystal inhibitor solution; Step 3: Mix the phase A mixed solution and the phase B crystal inhibitor solution; Step 4: Mix the penetration enhancer and the pressure-sensitive adhesive matrix with the mixed solution obtained in Step 3, and let it stand for defoaming; Step 5: Parallelly coat the mixture obtained in Step 4 onto two release liners, dry it. Attach the release liner coated with the mixture to the backing film to obtain layer A, and attach the release liner coated with the mixture to the controlled-release membrane to obtain layer B; Step 6: Uncover the release liner on layer A and combine it with layer B, roll and cut it into the required size to obtain the required patch.

11. The preparation method of the patch containing the diphenylbutyramide compound according to claim 10, characterized in that, The solvent includes one or more of purified water, ethanol, methanol, dimethyl sulfoxide, glycerol, N-methylpyrrolidone, soybean oil, and ethyl acetate.

Images