Compound i patch composition, compound i patch, and preparation methods therefor

Abstract

The present invention belongs to the technical field of pharmaceutical formulations, and relates to a compound I patch composition, a compound I patch, and preparation methods therefor. The patch composition comprises the following components in parts by weight: 0.5-12 parts of an active pharmaceutical ingredient, 10-30 parts of a permeation enhancer, 15-56 parts of a crystallization inhibitor, and 35-57 parts of an acrylic pressure-sensitive adhesive. The materials for preparing the patch composition further comprise solvents dimethyl sulfoxide and absolute ethanol, and the residual amount of dimethyl sulfoxide should be no less than 2.0%. The active pharmaceutical ingredient is compound (I), and the structural formula of compound I is as shown below. The patch composition comprising compound I of the present invention has high drug stability, which effectively avoids or reduces drug crystallization and impurity generation, enabling the compound I patch comprising same to have higher stability and safety; the patch composition comprising compound I has more suitable drug permeability, enabling the compound I patch comprising same to have higher drug effectiveness.

Description

A compound I patch composition, a compound I patch, and a method for preparing the same. Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a compound I patch composition, a compound I patch, and a method for preparing the same. Background Technology

[0002] Compound I is N-amidinyl-2-(2,6-dichlorophenyl)acetamide, a selective α-2A adrenergic receptor agonist, and its chemical structure is shown below:

[0003] .

[0004] In 2009, a sustained-release tablet containing compound I hydrochloride as the active ingredient was approved by the FDA for the treatment of attention deficit hyperactivity disorder in children and adolescents aged 6-17. As of now, it has not been launched in China.

[0005] However, currently marketed oral extended-release tablets still have some drawbacks. They exhibit a food effect; when taken with a high-fat meal, the tmax and AUC increase by approximately 75% and 40%, respectively, increasing the likelihood of adverse reactions. Therefore, the safety and patient compliance of this medication need improvement. Furthermore, compound I hydrochloride is a moderately variable drug; patient weight affects drug exposure. Global mainstream clinical guidelines recommend that ADHD treatment follow the principle of individualized therapy, ideally adjusting the dosage of compound I based on body weight. Currently, extended-release tablets containing compound I hydrochloride as the active ingredient are only available in 1 mg, 2 mg, 3 mg, and 4 mg strengths, which is not flexible enough. There is an urgent need for a new formulation and administration method that offers better patient compliance, efficacy, and safety.

[0006] Topical formulations of Compound I hold promise for overcoming this limitation. However, preparing the hydrochloride salt of Compound I into a patch presents a series of technical challenges, as its physicochemical properties are not ideal for topical administration. First, the hydrochloride salt of Compound I has multiple primary amine or imine functional groups at its terminal end, resulting in excessive hydrophilicity (octanol / water partition coefficient < 1) and a high melting point (above approximately 220°C), making it difficult to penetrate the lipophilic stratum corneum of the skin to meet therapeutic needs. Second, the hydrochloride salt of Compound I exhibits poor solubility in traditional patch pressure-sensitive adhesive matrices, easily leading to crystallization and hindering the improvement of drug loading.

[0007] Therefore, providing a patch composition and patch containing Compound I that reduces or avoids drug crystallization while enhancing the permeability and stability of Compound I in the patch composition and patch is a technical problem that needs to be solved in this field. Technical issues

[0008] To address the shortcomings of existing technologies, the present invention aims to provide a compound I patch composition, a compound I patch, and a method for preparing the same. By controlling the residual amount of dimethyl sulfoxide (DMSO) in the patch composition, the drug in the patch composition containing compound I exhibits high stability, effectively avoiding or reducing drug crystallization and impurity formation, thus giving the compound I patch containing it higher stability and safety. By controlling the ratio of the penetration enhancer and DMSO in the patch composition, the drug permeation performance in the patch composition containing compound I is more suitable, thus giving the compound I patch containing it higher drug efficacy. Technical solutions

[0009] To achieve this objective, the present invention adopts the following technical solution:

[0010] In a first aspect, the present invention provides a patch composition of compound I, comprising, by weight, the following components: 0.5-12 parts of active pharmaceutical ingredient, 10-30 parts of penetration enhancer, 15-56 parts of crystal inhibitor, and 35-57 parts of acrylic pressure-sensitive adhesive. The patch composition further comprises the solvents dimethyl sulfoxide and anhydrous ethanol, wherein the residual amount of dimethyl sulfoxide should be not less than 2.0%; wherein the active pharmaceutical ingredient is compound I, and the structural formula of compound I is shown below: .

[0011] Preferably, the residual amount of dimethyl sulfoxide in the patch composition should be 2.0%-6.0%.

[0012] The residual amount of dimethyl sulfoxide is a percentage of the actual weight of the patch composition after drying.

[0013] The dimethyl sulfoxide is used to dissolve compound I, and the anhydrous ethanol is used to dissolve the crystal inhibitor. Compound I requires a large amount of dimethyl sulfoxide (DMSO) to dissolve completely, but during the drying process of the patch, both dimethyl sulfoxide and anhydrous ethanol will evaporate completely. Therefore, under normal circumstances, there will be no residue of dimethyl sulfoxide and anhydrous ethanol in the patch, or the residue amount will be less than 0.5%.

[0014] During the research, this invention discovered that drug crystallization is prone to occur during the preparation and storage of patches due to factors such as the drug's tendency to absorb water and crystallize, the raw materials existing in the form of droplets in the formulation, and the insufficient solubility of the active pharmaceutical ingredient in the formulation. Crystallization can often be inhibited by adding a crystallization inhibitor. However, this invention unexpectedly discovered that by controlling the residual amount of dimethyl sulfoxide in the patch composition, the solubility of the active pharmaceutical ingredient can be increased, the drug solution can be made more homogeneous, and the drug stability in the patch composition containing compound I can be improved, effectively avoiding or reducing drug crystallization and impurity formation. Simultaneously, by controlling the ratio of penetration enhancer and dimethyl sulfoxide in the patch composition, the drug permeability in the patch composition containing compound I can be improved, resulting in higher drug efficacy for the patch containing compound I.

[0015] The active pharmaceutical ingredient is present in a weight range of 0.5-12 parts, for example, 0.5 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts or 12 parts, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0016] The penetration enhancer is in the range of 10-30 parts by weight, for example, 10 parts, 15 parts, 16 parts, 17 parts, 18 parts or 30 parts, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0017] The crystal inhibitor is present in a weight range of 15-56 parts, for example, 15 parts, 20 parts, 25 parts, 30 parts, 45 parts or 56 parts, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0018] The acrylic pressure-sensitive adhesive is in the range of 35-57 parts by weight, for example, 35 parts, 37 parts, 39 parts, 45 parts, 48 ​​parts or 57 parts, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0019] Preferably, to achieve better drug release and penetration performance, the penetration enhancer includes one or more of isopropyl myristate, ethyl oleate, propylene glycol laurate, triethyl glycerol, oleic acid, propylene glycol, Span, and menthol.

[0020] Preferably, to achieve a better anti-crystallization effect, the anti-crystallization agent includes polyvinylpyrrolidone.

[0021] Preferably, to ensure that the anti-crystallizer dissolves more fully and rapidly, the solvent includes anhydrous ethanol.

[0022] Preferably, to improve the cohesiveness of the patch, the acrylic pressure-sensitive adhesive includes DURO-TAK-87-4098 and / or DURO-TAK-87-900A.

[0023] Preferably, the patch composition further includes 0-5 parts of an antioxidant, the antioxidant including one or more of butylated hydroxytoluene, butylated hydroxyanisole, α-tocopherol, ascorbyl palmitate, and sodium metabisulfite.

[0024] Preferably, the initial amount of dimethyl sulfoxide added is 10-70 parts.

[0025] Preferably, the weight ratio of the inhibitor to dimethyl sulfoxide in the initial addition is 0.25:1 to 3:1.

[0026] The weight ratio of the crystal inhibitor to the initial amount of dimethyl sulfoxide is 0.25:1 to 3:1, for example, it can be 0.25:1, 0.5:1, 1:1, 2:1 or 3:1, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0027] Preferably, the weight ratio of the penetration enhancer to the initial amount of dimethyl sulfoxide is 0.1:1 to 3:1.

[0028] The weight ratio of the penetration enhancer to the initial amount of dimethyl sulfoxide is 0.1:1 to 3:1, for example, it can be 0.1:1, 0.3:1, 0.5:1, 1:1, 2:1 or 3:1, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0029] Preferably, the weight ratio of the crystal inhibitor to the initial amount of anhydrous ethanol is 0.1:1 to 0.5:1.

[0030] The weight ratio of the crystal inhibitor to the initial amount of anhydrous ethanol is 0.1:1 to 0.5:1, for example, it can be 0.1:1, 0.3:1 or 0.5:1, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0031] Preferably, the patch composition comprises, by weight, the following components: 0.5-12 parts of active pharmaceutical ingredient, 10-30 parts of penetration enhancer, 15-56 parts of crystal inhibitor, 35-57 parts of acrylic pressure-sensitive adhesive, and 0-5 parts of antioxidant.

[0032] On the other hand, the present invention provides a method for preparing a patch composition, the method comprising: first mixing an inhibitor and anhydrous ethanol, second mixing compound I and dimethyl sulfoxide, third mixing the second mixture with the first mixture, a penetration enhancer and an optional antioxidant, and fourth mixing the third mixture with an acrylic pressure-sensitive adhesive.

[0033] Preferably, the first mixing method includes: mixing the crystal inhibitor and anhydrous ethanol to dissolve the crystal inhibitor in anhydrous ethanol.

[0034] Preferably, the second mixing method includes: mixing compound I and dimethyl sulfoxide to dissolve compound I in dimethyl sulfoxide.

[0035] Thirdly, the present invention provides a patch comprising a backing layer, a drug storage layer and a protective layer disposed sequentially, wherein the raw materials for preparing the drug storage layer include the patch composition.

[0036] Fourthly, the present invention provides a method for preparing a patch, the method comprising: coating the patch composition onto a backing layer to form a drug storage layer with a backing layer; and bonding a protective layer onto the drug storage layer to obtain the patch.

[0037] Preferably, the coating process further includes a drying step.

[0038] Preferably, the drying time is 5 min to 30 min, for example, it can be 5 min, 10 min, 17 min, 25 min or 30 min, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0039] Preferably, the drying temperature is 60-150℃, for example, it can be 60℃, 65℃, 70℃, 80℃, 85℃, 90℃, 95℃ or 100℃, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. Beneficial effects

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] The compound I patch composition provided by the present invention achieves high drug stability by controlling the residual amount of dimethyl sulfoxide, effectively avoiding or reducing drug crystallization and impurity generation. At the same time, by controlling the ratio of penetration enhancer and dimethyl sulfoxide in the patch composition, the drug permeability of the patch composition containing compound I is improved, resulting in higher drug efficacy of the compound I patch.

[0042] 1. By compounding an inhibitor with a certain proportion of DMSO and controlling the residual amount of DMSO in the patch composition and patch, a compound I patch composition and patch with better stability is provided to reduce or avoid drug crystallization, thereby improving the effectiveness of the drug.

[0043] 2. The permeability of compound I in the patch composition and patch was enhanced by compounding with a penetration enhancer and a certain proportion of DMSO, thereby improving the drug's penetration effect;

[0044] 3. By dissolving the crystal inhibitor in the formulation with a certain proportion of anhydrous ethanol, the difficulty of dissolving the crystal inhibitor and the difficulty of the preparation process are reduced, which improves the appearance of the drug formulation to a certain extent. Attached Figure Description

[0045] Figure 1 is a comparison of the crystallization of the patch prepared in Example 8 after being placed at 25°C and 90%RH for 5 days (left) and 10 days (right).

[0046] Figure 2 is a comparison of the crystallization of the patch prepared in Example 9 after being placed at 25°C and 90%RH for 5 days (left) and 10 days (right).

[0047] Figure 3 is a comparison of the crystallization of the patch prepared in Example 10 after being placed at 25°C and 90%RH for 5 days (left) and 10 days (right).

[0048] Figure 4 is a comparison of the crystallization of the patch prepared in Example 11 after being placed at 25°C and 90%RH for 5 days (left) and 10 days (right).

[0049] Figure 5 is a comparison of the crystallization of the patch prepared in Example 12 after being placed at 25°C and 90%RH for 5 days (left) and 10 days (right).

[0050] Figure 6 is a comparison of the crystallization of the patch prepared in Example 13 after being placed at 25°C and 90%RH for 5 days (left) and 10 days (right).

[0051] Figure 7 is a comparison of the crystallization of the patch prepared in Example 14 after being placed at 25°C and 90%RH for 5 days (left) and 10 days (right).

[0052] Figure 8 is a comparison of the crystallization of the patch prepared in Example 15 after being placed at 25°C and 90%RH for 5 days (left) and 10 days (right).

[0053] Figure 9 is a comparison of the crystallization of the patch prepared in Example 18 after being placed at 25°C and 90%RH for 5 days (left) and 10 days (right).

[0054] Figure 10 is a comparison of the crystallization of the patch prepared in Example 22 after being placed at 25°C and 90%RH for 5 days (left) and 10 days (right).

[0055] Figure 11 is a comparison of the crystallization of the patch prepared in Example 23 after being placed at 25°C and 90%RH for 5 days (left) and 10 days (right).

[0056] Figure 12 is a comparison of the crystallization of the patch prepared in Example 24 after being placed at 25°C and 90%RH for 5 days (left) and 10 days (right).

[0057] Figure 13 is a cumulative drug penetration curve of the patch prepared in Example 18;

[0058] Figure 14 is a cumulative drug penetration curve of the patch prepared in Example 19;

[0059] Figure 15 is a cumulative drug penetration curve of the patch prepared in Example 21;

[0060] Figure 16 is a cumulative drug penetration curve of the patch prepared in Example 23;

[0061] Figure 17 is a cumulative drug penetration curve of the patch prepared in Example 24;

[0062] Figure 18 is a cumulative drug penetration curve of the patch prepared in Example 25;

[0063] Figure 19 is a cumulative drug penetration curve of the patch prepared in Example 26;

[0064] Figure 20 is a cumulative drug penetration curve of the patch prepared in Example 27;

[0065] Figure 21 is a cumulative drug penetration curve of the patch prepared in Example 28;

[0066] Figure 22 shows a comparison of the crystallization of the patch prepared in Comparative Example 1 after 5 days (left) and 10 days (right) at 25°C and 90%RH.

[0067] Figure 23 shows a comparison of the crystallization of the patch prepared in Comparative Example 2 after 5 days (left) and 10 days (right) at 25°C and 90%RH.

[0068] Figure 24 shows a comparison of the crystallization of the patch prepared in Comparative Example 3 after 5 days (left) and 10 days (right) at 25°C and 90%RH.

[0069] Figure 25 shows a comparison of the crystallization of the patch prepared in Comparative Example 4 after 5 days (left) and 10 days (right) at 25°C and 90%RH.

[0070] Figure 26 shows a comparison of the crystallization of the patch prepared in Comparative Example 5 after 5 days (left) and 10 days (right) at 25°C and 90%RH.

[0071] Figure 27 shows a comparison of the crystallization of the patch prepared in Comparative Example 6 after 5 days (left) and 10 days (right) at 25°C and 90%RH.

[0072] Figure 28 shows the cumulative drug penetration curve of the patch prepared in Comparative Example 7;

[0073] Figure 29 shows the cumulative drug penetration curve of the patch prepared in Comparative Example 8;

[0074] Figure 30 is a cumulative drug penetration curve of the patch prepared in Example 36;

[0075] Figure 31 is a cumulative drug penetration curve of the patch prepared in Example 37;

[0076] Figure 32 is a cumulative drug penetration curve of the patch prepared in Example 40;

[0077] Figure 33 shows a comparison of the crystallization of the patch prepared in Comparative Example 7 after 5 days (left) and 10 days (right) at 25°C and 90%RH.

[0078] Figure 34 shows a comparison of the crystallization of the patch prepared in Comparative Example 8 after 5 days (left) and 10 days (right) at 25°C and 90%RH. Embodiments of the present invention

[0079] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0080] The terms “comprising,” “including,” “having,” “containing,” or any other variations thereof, as used herein, are intended to cover non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not limited to those elements and may also include other elements not expressly listed or elements inherent to such composition, step, method, article, or apparatus.

[0081] "Optional" or "any one" means that the matter or event described thereafter may or may not occur, and the description includes both the possibility that the event may occur and the possibility that the event may not occur.

[0082] The indefinite articles “a” and “an” preceding an element or component of this invention do not impose any limitation on the quantity (i.e., number of occurrences) of the element or component. Therefore, “an” or “a” should be interpreted as including one or at least one, and the singular form of an element or component also includes the plural form, unless the quantity clearly refers only to the singular form.

[0083] In this invention, features specified as "first" and "second" may explicitly or implicitly include one or more of these features, used to distinguish and describe features, without any order or emphasis. In the description of this invention, unless otherwise stated, "multiple" means two or more.

[0084] (1) Drugs

[0085] The purity is 101.52%, and it was prepared by the applicant.

[0086] (2) Acrylic pressure-sensitive adhesive

[0087] The acrylic pressure-sensitive adhesive was purchased from Henkel.

[0088] (3) Antioxidants

[0089] Butylated hydroxytoluene was purchased from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd.

[0090] (4) Crystallization inhibitor

[0091] Povidone was purchased from BASF (China) Co., Ltd.; PEG400 and PEG3350 were purchased from China National Pharmaceutical Foreign Trade Co., Ltd.; hydroxypropyl β-cyclodextrin was purchased from Xi'an Deli Chemical Co., Ltd.; copovidone was purchased from Asland Company; and EVONIK E100 was purchased from EVONIK Company.

[0092] (5) Penetration enhancer

[0093] Isopropyl myristate was purchased from Hubei Gedian Renfu Pharmaceutical Excipients Co., Ltd.; triethyl glycerol was purchased from Jiangxi Alpha High-Tech Pharmaceutical Co., Ltd.; soybean lecithin was purchased from Jiangsu Manshi Biotechnology Co., Ltd.

[0094] solvent

[0095] Dimethyl sulfoxide was purchased from Hunan Jiudian Hongyang Pharmaceutical Co., Ltd.

[0096] Anhydrous ethanol was purchased from Nanjing Chemical Reagent Co., Ltd.

[0097] Backing layer

[0098] Aluminized polyester film, purchased from Shanghai Yingfa Medical Composite Materials Co., Ltd.

[0099] protective layer

[0100] Polyester release film, purchased from Shanghai Yingfa Medical Composite Materials Co., Ltd.

[0101] In this invention, the in vitro release experiment was conducted using the following implementation scheme: a paddle-disc method was used, employing a Huarong dissolution apparatus. The patch was fixed in the center of a large paddle dish with the paste-containing side facing upwards; the experimental temperature was set to 32℃±0.5℃; the rotation speed to 50 rpm; and the dissolution medium was 900 mL of pH 4.0 acetate buffer. Partial samples of the receiving solution were collected at 0.25, 2, and 12 hours, and an equal volume of constant-temperature receiving solution was added. The receiving solution was filtered through a 0.45 μm microporous membrane, and the filtrate was used as the test sample solution. The content of compound I was determined by HPLC, and the average release rate was calculated to obtain a graph showing the change in release rate over time.

[0102] In this invention, residual solvents were detected during the screening process. The detection method was as follows: a gas chromatograph was used with methanol as the blank solvent; the reference standard was prepared with ethanol, ethyl acetate, dimethyl sulfoxide, and methanol; a capillary column with 6% cyanopropylphenyl-94% dimethyl polysiloxane as the stationary phase was used as the chromatographic column; the temperature program was set as follows: initial temperature 65℃, maintained for 8 min, increased to 240℃ at a rate of 45℃ per minute, and maintained for 20 min; an FID detector was used, with an injection port temperature of 200℃, a detector temperature of 250℃, a split ratio of 15:1, a column flow rate of 3 mL / min, nitrogen as the carrier gas, hydrogen as the fuel gas, and air as the combustion-supporting gas; the test solution was prepared by ultrasonicating the patch with methanol solution, shaking and filtering, and then injecting 1 μL of the prepared test solution directly for detection.

[0103] The active ingredient (API) content in the following examples is based on dried or anhydrous quantities. (DMSO and anhydrous ethanol are added during patch preparation and removed during the drying process, but their dosage is still reflected in the formulation table as an evaluation item.)

[0104] Examples 1-14 Investigation of Crystal Inhibitors

[0105] Table 1 Prescription Table for Examples 1-8

[0106] ;

[0107] Table 2 Prescription Table for Examples 9-14

[0108] ;

[0109] The crystal inhibitor was added to anhydrous ethanol (second solvent) at a volume of 1-2 times that of dimethyl sulfoxide for the first mixture. Compound I was added to DMSO (first solvent) for the second mixture. The second mixture was added to the first mixture, and a penetration enhancer was added for the third mixture. Acrylic pressure-sensitive adhesive was added to the third mixture for the fourth mixture. The mixture was stirred using a mixer for 60 minutes, and then allowed to stand to allow the solution to completely defoam.

[0110] The solution is applied to a 0.075mm thick release film, and then the coating is dried in an 80℃ oven. After drying and cooling, a backing film is laminated on. Finally, the adhesive is cut to the required size using a cutting machine.

[0111] Immediately place the cut patches into aluminum-plastic packaging bags for storage.

[0112] Table 3. Experimental data on crystallization of patches prepared in Examples 1-14

[0113] ;

[0114] The patches prepared in Examples 1-14 were subjected to microscopic observation of their crystallization. The crystallization results of Examples 8-14 are shown in Figures 1-7. It was found that the residual amount of DMSO in the patches prepared in Examples 8-14 was effective in inhibiting crystallization. The residual amount of DMSO in the patches prepared in Examples 8-14 is shown in Table 4 below.

[0115] Table 4. DMSO residue in the patches prepared in Examples 8-14

[0116] ;

[0117] Therefore, the residual amount of DMSO and the amount of povidone and DMSO used in the patch were further investigated.

[0118] Examples 15-24: Investigation of the dosage of povidone and DMSO and the residual amount of DMSO

[0119] Table 5 Prescription Table for Examples 15-24

[0120] ;

[0121] The preparation method is the same as in Examples 1-14. The residual amount of DMSO is controlled by controlling the drying temperature and drying time of the patch. The drying temperature and drying time of the patches prepared in each example are shown in Table 6 below.

[0122] Table 6. Drying temperatures and schedules for Examples 15-24

[0123] ;

[0124] Table 7. Experimental data on crystallization of the patches prepared in Examples 15-24

[0125] ;

[0126] The crystallization results of the patches prepared in Examples 15, 18, 22, 23, and 24 are shown in Figures 8-12.

[0127] Table 8. Detection results of related substances in the patches prepared in Examples 15-24

[0128] ;

[0129] The patch prepared in Example 24 showed increased impurities after complete DMSO drying. This is because the impurities were generated under high-temperature conditions (above 50°C). (If drying is done at temperatures below 50°C, the drying time will be too long, affecting the stability of other excipients, the appearance of the formulation, and the overall product quality.) The high-temperature conditions during complete drying pose a risk of increased impurities. Patches with a DMSO residue level in the range of 2.0%-6.0% exhibit the best impurity levels and crystal-inhibiting effect. Furthermore, while ensuring the DMSO residue level in the patch, a povidone-to-DMSO weight ratio between 0.25:1 and 3:1 meets the requirements.

[0130] The transdermal effects of the preparations obtained in Examples 18, 19, 20, 21, 23, and 24 were monitored, and the results are shown in Table 10. Figures 13-17 are the drug cumulative permeation curves of the corresponding Examples 18, 19, 21, 23, and 24. The transdermal effect was better when the residual DMSO content was in the range of 2.0%-6.0%. In order to achieve better transdermal effects, the dosage of the permeation enhancer was further investigated.

[0131] Examples 25-28: Investigation of the Dosage of Penetration Enhancer

[0132] Table 9 Prescription Table for Examples 25-28

[0133] ;

[0134] The preparation method is the same as in Examples 1-14, and the residual amount of DMSO is controlled by controlling the drying temperature and drying time of the patch.

[0135] Table 10 Transdermal data of the patches prepared in Examples 18-24

[0136] ;

[0137] Table 11 Transdermal data of the patches prepared in Examples 25-28

[0138] ;

[0139] Figures 18-21 are the drug cumulative penetration curves corresponding to Examples 25-28. The patches prepared in Examples 25-28 have good transdermal effects.

[0140] Comparative Examples 1-8: Investigation of different residual solvents, different crystal inhibitors, and different active ingredients

[0141] Table 12 Prescription Table for Comparative Examples 1-8

[0142] ;

[0143] The preparation method is the same as in Examples 1-14.

[0144] Table 13 Crystallization of patches prepared in Comparative Examples 1-8

[0145] ;

[0146] The crystallization situation of Comparative Examples 1-6 is shown in Figures 22-27, and the crystal suppression effect is not good in any of them.

[0147] Table 14 Transdermal results of patches prepared in Comparative Examples 7-8

[0148] ;

[0149] Figures 28-29 show the cumulative drug penetration curves corresponding to Comparative Examples 7-8. The results indicate that the transdermal penetration rate of the patches prepared in Comparative Examples 7-8 is relatively slow, so compound I hydrochloride was not selected as the API.

[0150] Other commercially available patches typically contain around 5% povidone, while the formulation of this invention contains 24% povidone. This results in poor solubility and risks to coating properties, necessitating further investigation into the solvent and dosage.

[0151] Comparative Examples 9-10: Investigation of Crystallizer Content (Comparative Examples)

[0152] Table 15 Prescription Table for Comparative Examples 9-10

[0153] ;

[0154] The preparation method is the same as in Examples 1-14, and the residual amount of DMSO is controlled by controlling the drying temperature and drying time of the patch.

[0155] Table 16. Experimental data on crystallization of patches prepared in Comparative Examples 9-10

[0156] ;

[0157] The results show that the patch prepared in Comparative Example 9 had poor anti-crystallization effect, and the patch prepared in Comparative Example 10 did not meet the appearance requirements.

[0158] Comparative Examples 11-12: Investigation of Penetration Enhancer Dosage (Comparative Examples)

[0159] Table 17 Prescription Table for Comparative Examples 11-12

[0160] ;

[0161] The preparation method is the same as in Examples 1-14, and the residual amount of DMSO is controlled by controlling the drying temperature and drying time of the patch.

[0162] Table 18 Transdermal data of the patches prepared in Comparative Examples 11-12

[0163] ;

[0164] The results show that when the amount of penetration enhancer and dimethyl sulfoxide is too high or too low, the transdermal effect will be worse.

[0165] Examples 29-35: Investigation of different second solvents and proportions

[0166] Table 19 Prescription Table for Examples 29-35

[0167] ;

[0168] The preparation method is the same as in Examples 1-14.

[0169] Table 20. Dissolution time and appearance of povidone in the patches prepared in Examples 29-35

[0170] ;

[0171] When anhydrous ethanol is used as the second solvent in a specific ratio, povidone dissolves completely in a shorter time, and the resulting formulation has a smooth appearance.

[0172] Examples 36-41 Preparation of Compound I patch

[0173] Table 21 Prescription Table for Examples 36-41

[0174] ;

[0175] The crystal inhibitor was added to anhydrous ethanol (second solvent) for a first mixture, and compound I was added to DMSO (first solvent) for a second mixture. The second mixture was then added to the first mixture, along with a penetration enhancer and an antioxidant, for a third mixture. Acrylic pressure-sensitive adhesive was then added to the third mixture for a fourth mixture. The mixture was stirred using a mixer for 60 minutes, and then allowed to stand to allow the solution to completely defoam.

[0176] The solution is applied to a 0.075mm thick release film, and then the coating is dried in an 80℃ oven for 5-30 minutes, controlling the residual DMSO content between 2% and 6%. After drying and cooling, a backing film is laminated on. The adhesive is then cut to the required size using a cutting machine.

[0177] The cut adhesive strips were immediately placed in aluminum-plastic packaging bags for storage. Crystallization was observed after 5 and 10 days at 25°C and 90%RH. No crystals were precipitated.

[0178] Table 22 Crystallization experimental data of the patches prepared in Examples 36-41

[0179] ;

[0180] The transdermal effects of the patches prepared in Examples 36, 37, and 40 were monitored, and the results are shown in Table 23. Figures 30-32 show the corresponding drug cumulative penetration curves, indicating good transdermal effects.

[0181] Table 23 Transdermal data of the patches prepared in Examples 36, 37, and 40

[0182] .

[0183] The applicant declares that the present invention is illustrated by the above embodiments to describe the patch composition, patch, and preparation method thereof, but the present invention is not limited to the above process steps, that is, it does not mean that the present invention must rely on the above process steps to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials used in the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A compound I patch composition, characterized in that, The patch composition comprises, by weight, the following components: 0.5-12 parts of active pharmaceutical ingredient, 10-30 parts of penetration enhancer, 15-56 parts of crystallization inhibitor, and 35-57 parts of acrylic pressure-sensitive adhesive. The materials used in the preparation of the patch composition also include the solvents dimethyl sulfoxide and anhydrous ethanol, wherein the residual amount of dimethyl sulfoxide should be not less than 2.0%. The active pharmaceutical ingredient is compound I, and the structural formula of compound I is shown below: .

2. The patch composition according to claim 1, characterized in that, The residual amount of dimethyl sulfoxide in the patch composition is 2.0%-6.0%.

3. The patch composition according to claim 1, wherein The penetration enhancer includes one or more of the following: isopropyl myristate, ethyl oleate, propylene glycol laurate, triethyl glycerol, oleic acid, propylene glycol, Span, and menthol.

4. The patch composition according to any one of claims 1-3, characterized in that, The crystallization inhibitor includes povidone.

5. The patch composition according to any one of claims 1-4, characterized in that, The acrylic pressure-sensitive adhesive includes DURO-TAK-87-4098 and / or DURO-TAK-87-900A.

6. The patch composition according to any one of claims 1-5, characterized in that, The initial amount of dimethyl sulfoxide added is 10-70 parts.

7. The patch composition according to any one of claims 1 to 6, wherein The patch composition further includes 0-5 parts of an antioxidant, which includes one or more of butylated hydroxytoluene, butylated hydroxyanisole, α-tocopherol, ascorbyl palmitate, and sodium metabisulfite.

8. The patch composition according to any one of claims 1-7, characterized in that, The weight ratio of the crystal inhibitor to the initial amount of dimethyl sulfoxide is 0.25:1 to 3:

1.

9. The patch composition according to any one of claims 1-8, characterized in that, The weight ratio of the penetration enhancer to dimethyl sulfoxide in the initial addition is from 0.1:1 to 3:

1.

10. The patch composition according to any one of claims 1-9, characterized in that, The weight ratio of the crystal inhibitor to anhydrous ethanol in the initial addition is 0.1:1 to 0.5:

1.

11. The patch composition according to any one of claims 1-10, characterized in that, The patch composition comprises, by weight, the following components: 0.5-12 parts of active pharmaceutical ingredient, 10-30 parts of penetration enhancer, 15-56 parts of crystal inhibitor, 35-57 parts of acrylic pressure-sensitive adhesive, and 0-5 parts of antioxidant.

12. A method for preparing the patch composition according to any one of claims 1-11, characterized in that, The preparation method includes: first mixing an inhibitor and anhydrous ethanol; second mixing compound I and dimethyl sulfoxide; third mixing the second mixture with the first mixture, a penetration enhancer, and an optional antioxidant; and fourth mixing the third mixture with acrylic pressure-sensitive adhesive.

13. A compound I patch, characterized in that, The patch comprises a backing layer, a drug storage layer, and a protective layer arranged sequentially, wherein the raw materials for preparing the drug storage layer include the patch composition as described in any one of claims 1-11.

14. A method for preparing the patch as described in claim 13, characterized in that, The preparation method includes: coating the patch composition onto a backing layer to form a drug storage layer with a backing layer; and laminating a protective layer onto the drug storage layer to obtain the patch.

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