Brexpiprazole lactate, preparation and preparation method of brexpiprazole lactate

Abstract

The transdermal patch containing the polyisobutene pressure-sensitive adhesive has the advantages of being good in forming, free of devitrification, high in transdermal speed and / or capable of entering blood, and the patch can achieve the slow release effect in vivo for more than 168 hours.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to epiprazole lactate, a pharmaceutical composition and a preparation method thereof. Background Art

[0002] Brepiprazole, an oral treatment for schizophrenia and adjunctive treatment for major depression, was approved for marketing in the United States in 2015. Currently, the only available dosage form of brexpiprazole is oral preparation, which is difficult to meet the clinical needs of schizophrenia patients who have poor compliance with oral antipsychotics. From the perspective of clinical needs, schizophrenia patients have clinical manifestations such as refusing to take medicine.

[0003] The prior art attempts to solve the above problems by using injectable sustained-release preparations. Prior art CN201811171012.5 discloses an in-situ gel preparation, which is a drug-loaded in-situ reticular gel with phospholipids and mucopolysaccharide derivatives as the matrix, and has the characteristics of small burst release and sustained release. However, due to its poor compliance, multiple injections of injections can easily lead to phlebitis, which is a burden for patients who need multiple chemotherapy. Therefore, there is a continuous need to develop new preparations that can improve the drug compliance in the application of epiridol-related drugs, such as transdermal preparations. Summary of the invention

[0004] The present invention provides a transdermal patch comprising epiliprazole lactate and a polyisobutylene pressure-sensitive adhesive. The transdermal patch has the characteristics of good molding, no crystallization, fast skin penetration and / or the ability to enter the blood. The patch of the present invention can achieve a sustained release effect in the body for more than 168 hours. In certain embodiments, the patch of the present application can achieve high temperature (above 40 degrees) / light stability.

[0005] The inventors of the present application have found that the drug transdermal rate can be increased when a polyisobutylene pressure-sensitive adhesive is used. The polyisobutylene pressure-sensitive adhesive can be selected from commercially available polyisobutylene pressure-sensitive adhesive or self-made polyisobutylene pressure-sensitive adhesive.

[0006] Therefore, the present application provides a polyisobutylene pressure-sensitive adhesive on the one hand, the pressure-sensitive adhesive comprises 10.0-30.0% by weight of high molecular weight polyisobutylene, 30.0-50.0% of plasticizer, and 30.0-50.0% of one or more selected from low molecular weight polyisobutylene and / or tackifying resin. The high molecular weight polyisobutylene has a molecular weight of 400000-3000000, preferably 425000-2600000, preferably 1110000 or 425000 or 2600000.

[0007] Further, the pressure-sensitive adhesive comprises, by weight, 10.0-30.0% of high molecular weight polyisobutylene, 35.0-45.0% of plasticizer, and 35.0-45.0% of one or more selected from low molecular weight polyisobutylene and / or tackifying resin.

[0008] Furthermore, the plasticizer is liquid paraffin and / or naphthenic oil, preferably liquid paraffin.

[0009] Furthermore, the molecular weight of the low molecular weight polyisobutylene is less than 100,000, preferably 85,000.

[0010] Furthermore, the tackifying resin is selected from one or more of hydrogenated petroleum resin, petroleum resin and rosin resin.

[0011] Furthermore, the present invention provides a polyisobutylene pressure-sensitive adhesive, which comprises the following components by weight: 27.27% high molecular weight polyisobutylene, the high molecular weight polyisobutylene having a molecular weight of 425,000-2,600,000, 36.36% liquid paraffin, 36.36% hydrogenated petroleum resin or low molecular weight polyisobutylene, the low molecular weight polyisobutylene having a molecular weight of 85,000.

[0012] Furthermore, the pressure-sensitive adhesive preferably comprises the following components by weight: 27.27% high molecular weight polyisobutylene, wherein the molecular weight of the high molecular weight polyisobutylene is 1,110,000 or 425,000 or 2,600,000, 36.36% liquid paraffin, and 36.36% hydrogenated petroleum resin.

[0013] On the other hand, the present application provides a transdermal patch containing lactic acid epiliprazole, wherein the transdermal patch contains i) lactic acid epiliprazole, preferably the lactic acid epiliprazole content in the composition is 1.0-20.0% by weight, preferably 7.0-17.0%, preferably 7.0-11.0%, more preferably 11.0%, and ii) a polyisobutylene pressure-sensitive adhesive, wherein the polyisobutylene pressure-sensitive adhesive is selected from the above-mentioned pressure-sensitive adhesive or polyisobutylene pressure-sensitive adhesive 6908, and the content of the pressure-sensitive adhesive in the present application is 50.0-80.0% by weight, preferably 51.0-76.0%, preferably 53.0-70.0%, preferably 66.0%.

[0014] Further, the transdermal patch of the present invention comprises iii) a chemical penetration enhancer, which can be selected from one or more of azones, pyrrolidones, volatile oils, polysaccharides, ethers, alcohols, acids, and esters, including but not limited to: azone, povidone, 1-dodecyl-2-pyrrolidone, cross-linked povidone, copovidone, peppermint oil, turpentine, hydroxypropyl beta-cyclodextrin, levulinic acid, caprylic acid, myristic acid, oleic acid, lauric acid, linoleic acid, lactic acid, glycerol, propylene glycol, octyl lauryl alcohol, oleyl alcohol, benzyl alcohol, glyceryl monooleate, glyceryl triacetate, Brij 30, Brij 52, polyoxyethylene 40 hydrogenated castor oil, isopropyl acetate, isopropyl palmitate, isopropyl laurate, ethyl cellulose, hydroxypropyl methylcellulose, liquid paraffin, etc., preferably azone, pyrrolidones, volatile oils, acids, and fatty alcohols. Among them, the pyrrolidones can be preferably 1-dodecyl-2-pyrrolidone, and the acids are preferably one or more of lactic acid, oleic acid, linoleic acid, and lauric acid. The volatile oil is preferably peppermint oil. The fatty alcohols can be selected from common fatty alcohols such as oleyl alcohol, glycerol, propylene glycol, and octyl lauryl alcohol.

[0015] The content of the penetration enhancer of the present invention is 0.0-30.0%, 2.0-30.0%, preferably 3.9-30.0%, preferably 8.0-30.0%, preferably 15.0-30.0% by weight.

[0016] Furthermore, the transdermal patch of the present application may contain iv) a solvent, preferably an alcohol solvent, including but not limited to propylene glycol, glycerol, methanol, benzyl alcohol, etc. The content of the solvent is 6.0-30.0% by weight, preferably 6.0-20.0%, preferably 8.0-20.0%, preferably 15.0-20.0%, preferably 15.0%.

[0017] Furthermore, the present invention provides a transdermal patch comprising the following components and their weight percentages:

[0018] Epiprazole lactate: 1.0-20.0%

[0019] Chemical penetration enhancer: 0.0-30.0%

[0020] Solvent: 6.0-30.0%

[0021] Polyisobutylene pressure sensitive adhesive: 50.0-80.0%

[0022] The chemical penetration enhancer is selected from one or more of azones, pyrrolidones, volatile oils, ethers, alcohols, acids, and esters, preferably one or more of azones, pyrrolidones, volatile oils, acids, and fatty alcohols, preferably one or more of azone, 1-dodecyl-2-pyrrolidone, peppermint oil, lactic acid, oleic acid, linoleic acid, lauric acid, oleyl alcohol, and propylene glycol, preferably one or more of azone, peppermint oil, lactic acid, linoleic acid, lauric acid, oleyl alcohol, and propylene glycol, preferably linoleic acid, a combination of azone and oleyl alcohol, a combination of lactic acid and linoleic acid, a combination of lauric acid and peppermint oil, and a combination of lactic acid, linoleic acid, and lauric acid and peppermint oil. The solvent is preferably an alcohol solvent, preferably propylene glycol.

[0023] Furthermore, the present invention provides a transdermal patch comprising the following components and their weight percentages:

[0024] Epiprazole lactate: 7.0-17.0%

[0025] Chemical penetration enhancers: 2.0-30.0%

[0026] Solvent: 6.0-20.0%

[0027] Polyisobutylene pressure-sensitive adhesive: 51.0-72.0%

[0028] Furthermore, the present invention provides a transdermal patch comprising the following components and their weight percentages:

[0029] Epiprazole lactate: 7.0-17.0%

[0030] Chemical penetration enhancers: 2.0-30.0%

[0031] Propylene glycol: 6.0-20.0%

[0032] Polyisobutylene pressure sensitive adhesive 6908: 51.0-76.0%

[0033] The chemical penetration enhancer is selected from one or more of azones, pyrrolidones, volatile oils, ethers, alcohols, acids, and esters, preferably one or more of azones, pyrrolidones, volatile oils, acids, and fatty alcohols, preferably one or more of azone, 1-dodecyl-2-pyrrolidone, peppermint oil, lactic acid, oleic acid, linoleic acid, lauric acid, oleyl alcohol, and propylene glycol, preferably one or more of azone, peppermint oil, lactic acid, linoleic acid, lauric acid, oleyl alcohol, and propylene glycol, preferably linoleic acid, a combination of azone and oleyl alcohol, a combination of lactic acid and linoleic acid, a combination of lauric acid and peppermint oil, and a combination of lactic acid and linoleic acid and lauric acid and peppermint oil.

[0034] Furthermore, the present invention provides a transdermal patch comprising the following components and their weight percentages:

[0035] Epiprazole lactate: 7.0-17.0%

[0036] Chemical penetration enhancers: 15.0-30.0%

[0037] Propylene glycol: 8.0-20.0%

[0038] Polyisobutylene pressure sensitive adhesive 6908: 53.0-70.0%

[0039] The chemical penetration enhancer is selected from one or more of azone, volatile oils, acids, and fatty alcohols, preferably one or more of azone, peppermint oil, lactic acid, linoleic acid, lauric acid, oleyl alcohol, and propylene glycol, preferably a combination of linoleic acid, azone and oleyl alcohol, a combination of lauric acid and peppermint oil, a combination of lactic acid and linoleic acid, and a combination of lauric acid and peppermint oil.

[0040] Furthermore, the present invention provides a transdermal patch comprising the following components and their weight percentages:

[0041] Epiprazole lactate: 7.0-17.0%

[0042] Oleyl alcohol: 5.0-10.0%

[0043] Azone: 5.0-20.0%

[0044] Propylene glycol: 15.0-20.0%

[0045] Polyisobutylene pressure sensitive adhesive 6908: 53.0-55.0%

[0046] Furthermore, the present invention provides a transdermal patch comprising the following components and their weight percentages:

[0047] Epiprazole lactate: 7.0%

[0048] Oleyl alcohol: 10.0%

[0049] Azone: 10.0%

[0050] Propylene glycol: 20.0%

[0051] Polyisobutylene pressure sensitive adhesive 6908: 53.0%

[0052] Furthermore, the present invention provides a transdermal patch comprising the following components and their weight percentages:

[0053] Epiprazole lactate: 8.0%

[0054] Oleyl alcohol: 9.2%

[0055] Azone: 9.2%

[0056] Propylene glycol: 18.4%

[0057] Polyisobutylene pressure sensitive adhesive 6908: 55.2%

[0058] Furthermore, the present invention provides a transdermal patch comprising the following components and their weight percentages:

[0059] Epiprazole lactate: 7.0-11.0%

[0060] Chemical penetration enhancers: 0.0-8.0%

[0061] Propylene glycol: 15.0%-20.0%

[0062] Polyisobutylene pressure-sensitive adhesive: 66.0%-74.0%

[0063] The chemical penetration enhancer is selected from acids, preferably one or more of lactic acid and linoleic acid, preferably a combination of lactic acid and linoleic acid. The polyisobutylene pressure-sensitive adhesive contains 10.0-30.0% high molecular weight polyisobutylene, 35.0-45.0% plasticizer, and 35.0-45.0% hydrogenated petroleum resin or low molecular weight polyisobutylene. The low molecular weight polyisobutylene has a molecular weight of 85,000, and the high molecular weight polyisobutylene has a molecular weight of 425,000-2,600,000.

[0064] Furthermore, the present invention provides a transdermal patch comprising the following components and their weight percentages:

[0065] Epiprazole lactate: 11.0%

[0066] Lactic acid: 2.0%

[0067] Linoleic acid: 6.0%

[0068] Propylene glycol: 15.0%

[0069] Polyisobutylene pressure sensitive adhesive: 66.0%

[0070] The polyisobutylene pressure-sensitive adhesive comprises 10.0-30.0% of high molecular weight polyisobutylene, 35.0-45.0% of plasticizer, and 35.0-45.0% of hydrogenated petroleum resin or low molecular weight polyisobutylene, wherein the molecular weight of the low molecular weight polyisobutylene is 85,000, and the molecular weight of the high molecular weight polyisobutylene is 425,000-2,600,000.

[0071] Furthermore, the present invention provides a transdermal patch comprising the following components and their weight percentages:

[0072] Epiprazole lactate: 11.0%

[0073] Lactic acid: 2.0%

[0074] Linoleic acid: 6.0%

[0075] Propylene glycol: 15.0%

[0076] Polyisobutylene pressure sensitive adhesive: 66.0%

[0077] The polyisobutylene pressure-sensitive adhesive comprises 27.27% high molecular weight polyisobutylene, the molecular weight of the high molecular weight polyisobutylene is 425000-2600000, 36.36% liquid paraffin, 36.36% hydrogenated petroleum resin or low molecular weight polyisobutylene, the molecular weight of the low molecular weight polyisobutylene is 85000.

[0078] Furthermore, the present invention provides a transdermal patch comprising the following components and their weight percentages:

[0079] Epiprazole lactate: 11.0%

[0080] Lactic acid: 2.0%

[0081] Linoleic acid: 6.0%

[0082] Propylene glycol: 15.0%

[0083] Polyisobutylene pressure sensitive adhesive: 66.0%

[0084] The polyisobutylene pressure-sensitive adhesive comprises 27.27% of high molecular weight polyisobutylene, wherein the molecular weight of the high molecular weight polyisobutylene is 1,110,000 or 425,000 or 2,600,000, 36.36% of liquid paraffin, and 36.36% of hydrogenated petroleum resin.

[0085] The present invention further provides a method for preparing the above-mentioned patch, which comprises: adding a prescribed amount of API and excipients other than the pressure-sensitive adhesive to a solvent, mixing, then adding the pressure-sensitive adhesive, mixing to obtain a glue solution, coating the glue solution on a release film to form a wet glue, drying, and pressing with a backing film to obtain a finished product.

[0086] The present application further provides a compound, which is epiprazole lactate.

[0087] Furthermore, the present application provides a method for preparing the above-mentioned lactic acid epiliperazine, the preparation method comprising: weighing lactic acid and anhydrous ethanol, adding epiliperazine and stirring until dissolved, continuing stirring until solid precipitates, filtering and drying the precipitated solid to obtain lactic acid epiliperazine.

[0088] The NMR of the lactic acid epiprazole described in the present application is: 1HNMR (400MHz, DMSO-d6) δ11.60 (br, 1H) 7.80 (d, J = 9.5Hz, 1H), 7.69 (d, J = 5.5Hz, 1H), 7.65-7.52 (m, 2H), 7.41 (d, J = 5.5Hz, 1H), 7.27 (t, J = 7.8Hz, 1H), 6.88 (d, J = 6.9Hz, 1H), 6.80 (d, J = 7.3Hz, 2H), 6.30 (d, J = 9. 4Hz,1H),4.10–3.98(m,3H),3.08(t,J=4.7Hz,3H),2.68(d,J=4.9Hz,3H),2.49(d,J=7.2Hz,4H),1.80(dq,J=12.0 ,6.6Hz,2H),1.67(dt,J=9.7,6.1Hz,2H),1.40(dd,7.1Hz,0.9Hz,0.48H),1.29(dd,0.55H),1.24(d,J=6.9Hz,3H).

[0089] The beneficial effects of the present invention are as follows: compared with the common epiriprazole transdermal patch, the transdermal patch of the present application can enter the blood, does not crystallize, has a good transdermal rate, can achieve 7-day release, and has good properties after being placed at room temperature for 1 month, and there is no obvious change in impurities when placed at high temperature of 40 degrees / 60 degrees and under light conditions for 1 month. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] Figure 1 Animal Experimental Results of Epiprazole Transdermal Patch and Epiprazole Lactate Transdermal Patch DETAILED DESCRIPTION

[0091] The present invention is further described in detail by the following examples, which are not intended to limit the scope of protection of the present invention. The instruments, reagents or auxiliary materials used in this application can be purchased from the market, etc. In the following specific implementations, the drugs, reagents and instruments used are as follows:

[0092] Instruments and equipment:

[0093] Instrument Name Model / Specification company Electronic balance BS224S Sartorius Adjustable film applicator BEVS1806B Guangzhou Shenghua Industrial Co., Ltd. Heating automatic coating machine BEVS1811 / 3 Guangzhou Shenghua Industrial Co., Ltd. Transdermal Diffusion Tester TK-12H Shanghai Kaikai Technology Trading Co., Ltd. Mixer WB2000-D WIGGENS Blast drying oven DHG-9246A Shanghai Jinghong Experimental Equipment Co., Ltd.

[0094] Drugs, excipients and reagents:

[0095]

[0096]

[0097] The preparation process, in vitro skin permeation and stability test methods in the following examples are as follows:

[0098] Preparation process of transdermal preparation: Add the prescribed amount of API and excipients except pressure-sensitive adhesive into the solvent, mix, then add the pressure-sensitive adhesive, mix to obtain glue solution, apply the glue solution on the release film to form wet glue, dry at 40-90℃, and press with a backing film to obtain the finished product.

[0099] Preparation process of homemade pressure-sensitive adhesive: Add the prescribed amount of high molecular weight polyisobutylene and / or low molecular weight polyisobutylene into n-heptane, seal and slowly stir to dissolve completely. Add other auxiliary materials and stir and mix, seal and mix evenly to obtain the product.

[0100] In vitro transdermal experiment: Take the back skin of commercially available 1.5-month-old Bama Xiang pigs, carefully remove the subcutaneous fat (skin thickness is generally less than 1mm), thaw and place in 60-degree purified water for 1 minute, filter paper to absorb the moisture. Use a vertical and horizontal diffusion cell with an effective diffusion area of ​​1.44cm2 and a volume of 74ml for skin flux research. Place the skin between the donor and receptor compartments of the diffusion cell. Add pH7.220*PBS solution diluted with 5030% ethanol aqueous solution to the receiving compartment, stir at 200rpm, keep the temperature at 32±0.5 degrees, and take out 74ml samples from the receiving solution regularly (2h, 4h, 6h, 24h, 48h, 72h4h, 8h, 24h, 48h, 72h, 96h, 120h, 144h, 168h), and replace the receiving solution with fresh phosphate buffer. HPLC was used to measure the amount of drug in the receiving solution at each time point and calculate the permeation rate. Each result was obtained by averaging three times, and all values ​​were statistically significant.

[0101] Stability test: Place under high temperature (40℃ / 60℃) and light (4500lx±500lx) conditions for 5 days / 10 days / 30 days respectively, and try to avoid cross-influence caused by other conditions.

[0102] Example 1 Preparation of Epiprazole Transdermal Patch

[0103] The epiriprazole transdermal patch was prepared according to the prescription shown in Table 1 to obtain prescription 1. The preparation results showed that epiriprazole could not be dissolved and could not be prepared into a transdermal patch.

[0104] Table 1

[0105] Components Prescription 1 Epiprazole 11.00％ Propylene glycol 15.00％ Linoleic acid 6.00％ Polyisobutylene pressure sensitive adhesive 68.00％

[0106] Example 2 Preparation of Epiprazole Lactate

[0107] Lactic acid and anhydrous ethanol were weighed according to the ratio in Table 2, and the prescribed amount of epiriprazole was added and stirred. At this time, the epiriprazole was completely dissolved. The stirring was continued, and solid was precipitated. The precipitated solid was filtered and dried to obtain epiriprazole lactate.

[0108] Table 2

[0109] Components Weight % Epiprazole 24.6 lactic acid 15.1 Anhydrous ethanol* 60.3

[0110] The structure was confirmed by NMR and DSC, and the melting point was determined by DSC to be 109±2 degrees. The 1HNMR (400MHz, DMSO-d6) of epiridol lactate was 11.60 (br, 1H) 7.80 (d, J = 9.5Hz, 1H), 7.69 (d, J = 5.5Hz, 1H), 7.65–7.52 (m, 2H), 7.41 (d, J = 5.5Hz, 1H), 7.27 (t, J = 7.8Hz, 1H), 6.88 (d, J = 6.9Hz, 1H), 6.80 (d, J = 7.3Hz, 2H), 6.30 (d, J = 9.4Hz, 1H),4.10–3.98(m,3H),3.08(t,J=4.7Hz,3H),2.68(d,J=4.9Hz,3H),2.49(d,J=7.2Hz,4H),1.80(dq,J=12.0,6 .6Hz, 2H), 1.67 (dt, J = 9.7, 6.1Hz, 2H), 1.40 (dd, 7.1Hz, 0.9Hz, 0.48H), 1.29 (dd, 0.55H), 1.24 (d, J = 6.9Hz, 3H).

[0111] Example 3 Preparation of Epiprazole Lactate Transdermal Patch

[0112] On the basis of Example 1, the active ingredient was replaced with epiliprazole lactate to prepare a transdermal patch, as shown in Table 3.

[0113] Table 3

[0114]

[0115]

[0116] In vitro transdermal results: Prescription 2 was subjected to an in vitro transdermal test, and the results are shown in Table 4:

[0117] Table 4

[0118] Prescription 2 <![CDATA[24-hour transmittance μg / cm 2 / h]]> 1.95

[0119] Example 4 Investigation of different types of pressure-sensitive adhesives

[0120] Transdermal patches of different types of pressure-sensitive adhesives were prepared according to the prescriptions shown in Table 5 to obtain prescriptions 3-7.

[0121] Table 5

[0122]

[0123] In vitro transdermal results: Prescriptions 3-7 were subjected to in vitro transdermal experiments. The results are shown in Table 6:

[0124] Table 6

[0125] Prescription 3 Prescription 4 Prescription 5 Prescription 6 Prescription 7 <![CDATA[24-hour transmittance μg / cm 2 / h]]> 1.1198 0.2933 0.4947 0.4488 Unable to form

[0126] Example 5 Preparation of polyisobutylene pressure-sensitive adhesive

[0127] Different types of polyisobutylene pressure-sensitive adhesives were prepared according to the formulation shown in Table 7 to obtain pressure-sensitive adhesives 1-6.

[0128] Table 7

[0129]

[0130]

[0131] Example 6 Preparation of transdermal patches containing different polyisobutylene pressure-sensitive adhesives

[0132] The pressure-sensitive adhesive shown in Example 5 was used to prepare a transdermal patch according to the prescription shown in Table 8 to obtain Prescription 8-13.

[0133] Table 8

[0134] Excipients Prescription 8 Prescription 9 Prescription 10 Prescription 11 Prescription 12 Prescription 13 Epiprazole lactate 11％ 11％ 11％ 11％ 11％ 11％ Propylene glycol 15％ 20％ 15％ 15％ 15％ 15％ lactic acid \ \ \ 2％ 2％ 2％ Linoleic acid \ \ \ 6％ 6％ 6％ Pressure sensitive adhesive 1 74％ \ \ \ \ \ Pressure sensitive adhesive 2 \ 69％ \ \ \ \ Pressure sensitive adhesive 3 \ \ 74％ \ \ \ Pressure sensitive adhesive 4 \ \ \ 66％ \ \ Pressure sensitive adhesive 5 \ \ \ \ 66％ \ Pressure sensitive adhesive 6 \ \ \ \ \ 66％

[0135] In vitro transdermal results: Prescriptions 8-14 were subjected to in vitro transdermal tests. The results are shown in Table 9:

[0136] Table 9

[0137]

[0138]

[0139] Example 7 Preparation of transdermal patches with different excipients

[0140] The epiriprazole lactate transdermal patch was prepared according to the prescription shown in Table 10 to obtain Prescriptions 14 to 19.

[0141] Table 10

[0142] Components Prescription 14 Prescription 15 Prescription 16 Prescription 17 Prescription 18 Prescription 19 Epiprazole lactate 7.00％ 7.00％ 7.00％ 7.00％ 7.00％ 7.00％ Propylene glycol 15.00％ 15.00％ 15.00％ 15.00％ 15.00％ 20.00％ Oleyl alcohol / / 10.00％ / 10.00％ 10.00％ peppermint / / / 12.00％ / / Azone / 10.00％ / / 10.00％ 10.00％ Oleic acid 2.00％ / / / / / Polyisobutylene pressure sensitive adhesive 6908 76.00％ 68.00％ 68.00％ 66.00％ 58.00％ 53.00％

[0143] In vitro transdermal results: Prescriptions 14-19 were subjected to in vitro transdermal tests. The results are shown in Table 11:

[0144] Table 11

[0145] Prescription 14 Prescription 15 Prescription 16 Prescription 17 Prescription 18 Prescription 19 <![CDATA[24-hour transmittance μg / cm 2 / h]]> 1.13 1.63 1.68 1.71 1.33 2.36

[0146] Example 8 Preparation of transdermal patches with different excipients

[0147] The epiliprazole lactate transdermal patch was prepared according to the prescription shown in Table 12 to obtain Prescription 20 to Prescription 24.

[0148] Table 12

[0149] In vitro transdermal results: Prescriptions 20-24 were subjected to in vitro transdermal tests. The results are shown in Table 13:

[0150] Table 13

[0151] Prescription 20 Prescription 21 Prescription 22 Prescription 23 Prescription 24 <![CDATA[24-hour transmittance μg / cm 2 / h]]> 2.32 1.45 1.44 1.03 1.16

[0152] Example 9 Preparation of transdermal patches with different excipients

[0153] The epiriprazole lactate transdermal patches were prepared according to the prescriptions shown in Table 14 and Table 15 to obtain prescriptions 25 to 43.

[0154] Table 14

[0155]

[0156] Table 15

[0157]

[0158]

[0159] In vitro transdermal results: Prescriptions 25-43 were subjected to in vitro transdermal tests. The results are shown in Table 16:

[0160] Table 16

[0161] prescription <![CDATA[24 h per μg / cm 2 / h]]> Prescription 25 1.78 Prescription 26 1.74 Prescription 27 2.19 Prescription 28 1.27 Prescription 29 1.24 Prescription 30 2.14 Prescription 31 1.83 Prescription 32 1.27 Prescription 33 1.47 Prescription 34 1.34 Prescription 35 1.21 Prescription 36 1.40 Prescription 37 1.31 Prescription 38 2.22 Prescription 39 1.04 Prescription 40 1.22 Prescription 41 1.27 Prescription 42 1.17 Prescription 43 1.50

[0162] Example 10 Preparation of transdermal patches with different excipients

[0163] The epiriprazole lactate transdermal patch was prepared according to the prescription shown in Table 17 to obtain Prescription 44 to Prescription 46.

[0164] Table 17

[0165] Components Prescription 44 Prescription 45 Prescription 46 Epiprazole lactate 13.00％ 13.00％ 13.00％ Propylene glycol 10.00％ 10.00％ 15.00％ lactic acid 4.00％ / / Linoleic acid 6.00％ 6.00％ / Lauric acid / 6.00％ / Azone / / 5.00％ Oleyl alcohol / / 5.00％ Polyisobutylene pressure sensitive adhesive 6908 67.00％ 65.00％ 62.00％

[0166] In vitro transdermal results: Prescriptions 44-46 were subjected to in vitro transdermal tests. The results are shown in Table 18:

[0167] Table 18

[0168] Prescription 44 Prescription 45 Prescription 46 <![CDATA[24-hour transmittance μg / cm 2 / h]]> 1.35 1.59 1.96

[0169] Example 11 Preparation of transdermal patches with different excipients

[0170] The epiriprazole lactate transdermal patch was prepared according to the prescription shown in Table 19 to obtain Prescription 47-Prescription 48.

[0171] Table 19

[0172] Components Prescription 47 Prescription 48 Epiprazole lactate 9.00％ 17.00％ Propylene glycol 15.00％ 15.00％ Azone 5.00％ 5.00％ Oleyl alcohol 5.00％ 10.00％ Polyisobutylene pressure sensitive adhesive 6908 66％ 53％

[0173] In vitro transdermal results: Prescriptions 47-48 were subjected to in vitro transdermal tests. The results are shown in Table 20:

[0174] Table 20

[0175] Prescription 47 Prescription 48 <![CDATA[24-hour transmittance μg / cm 2 / h]]> 1.37 2.01 Experimental Example 1 Animal Experiment of Transdermal Patches with Different APIs

[0176] The epiriprazole transdermal patch was prepared according to the prescription shown in Table 21.

[0177] Table 21

[0178] Components Prescription 49 Epiprazole 6.44％ lactic acid 6.00％ Oleic acid 2.00％ BHA 0.02％ BHT 0.10％ Acrylic pressure sensitive adhesive 4301 85.44％

[0179] 1) Preparation: Transdermal patches were prepared from Prescription 2 and Prescription 49, and cut into small pieces according to the dosage for Bama miniature pigs. The release films were removed and the pieces were named Group 1 and Group 2, respectively.

[0180] 2) Animals: 6 male Bama miniature pigs aged 1.5 to 2 months were purchased from Wujiang Tianyu Biotechnology Co., Ltd. The average body weight at the time of purchase and modeling was 4-8 kg, and the individual body weight values ​​were within the range of the mean ± 20%.

[0181] 3) Experimental plan: See Table 22.

[0182] Table 22

[0183]

[0184] 4) Collection time:

[0185] Group 1 and Group 2: Before administration on Day 1, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h (Day 2), 48h (Day 3, blood was collected before the first post), 72h (Day 4), 96h (Day 5, blood was collected before the second post), 120h (Day 6), 144h (Day 7, blood was collected before the third post) and 168h (Day 8) after administration. A total of 15 collection time points were collected in each group.

[0186] 5) Sample collection and processing:

[0187] Blood was collected from animals in groups 1 and 2 through the jugular vein. About 1 mL of blood was collected from each sample, anticoagulated with K2EDTA, and placed on ice after collection. Blood samples were centrifuged within 2 hours after collection to separate plasma. LC-MS was used to determine the drug concentration in blood samples.

[0188] Experimental results: The results showed that the irinotecan transdermal patch could not enter the blood, while the irinotecan lactate transdermal patch could enter the blood and achieve sustained release for 168 hours. Figure 1 .

Claims

1. A polyisobutylene pressure-sensitive adhesive, characterized in that The pressure-sensitive adhesive comprises, by weight, 10.0-30.0% of high molecular weight polyisobutylene, 35.0-45.0% of a plasticizer, and 35.0-45.0% of one or more selected from low molecular weight polyisobutylene and / or tackifying resin.

2. The pressure-sensitive adhesive according to claim 1, characterized in that The plasticizer is liquid paraffin and / or cyclohexane oil, preferably liquid paraffin, the high molecular weight polyisobutylene has a molecular weight of 400,000-3,000,000, preferably 425,000-2,600,000, preferably 2,600,000, 425,000, the low molecular weight polyisobutylene has a molecular weight less than 100,000, preferably 85,000, and the tackifying resin is selected from one or more of hydrogenated petroleum resin, petroleum resin, and rosin resin.

3. The pressure-sensitive adhesive according to claim 2, characterized in that The pressure-sensitive adhesive comprises the following components by weight: 27.27% high molecular weight polyisobutylene, the molecular weight of the high molecular weight polyisobutylene is 425000-2600000, 36.36% liquid paraffin, 36.36% hydrogenated petroleum resin or low molecular weight polyisobutylene, the molecular weight of the low molecular weight polyisobutylene is 85000.

4. The pressure-sensitive adhesive according to claim 3, characterized in that The pressure-sensitive adhesive preferably comprises the following components by weight: 27.27% high molecular weight polyisobutylene, wherein the molecular weight of the high molecular weight polyisobutylene is 1,110,000, 425,000 or 2,600,000, 36.36% liquid paraffin, and 36.36% hydrogenated petroleum resin.

5. A transdermal patch, characterized in that The transdermal patch comprises i) epiliprazole lactate, preferably the epiliprazole lactate content in the transdermal patch is 1.0-20.0% by weight, preferably 7.0-17.0%, preferably 7.0-11.0%, more preferably 11.0%, and ii) a polyisobutylene pressure-sensitive adhesive, the polyisobutylene pressure-sensitive adhesive is selected from the pressure-sensitive adhesive according to any one of claims 1 to 4 or polyisobutylene pressure-sensitive adhesive 6908, and the content of the pressure-sensitive adhesive is 50.0-80.0% by weight, preferably 51.0-76.0%, preferably 53.0-70.0%, preferably 66.0%.

6. The transdermal patch according to claim 5, characterized in that The transdermal patch comprises iii) a chemical penetration enhancer, wherein the penetration enhancer is selected from one or more of azones, pyrrolidones, volatile oils, polysaccharides, ethers, alcohols, acids, and esters, preferably one or more of azones, pyrrolidones, volatile oils, acids, and fatty alcohols, preferably one or more of azones, 1-dodecyl-2-pyrrolidone, peppermint oil, oleic acid, lauric acid, linoleic acid, lactic acid, glycerol, propylene glycol, and oleyl alcohol, preferably one or more of 1-dodecyl-2-pyrrolidone, peppermint oil, lactic acid, linoleic acid, lauric acid, oleyl alcohol, and glycerol, preferably a combination of linoleic acid, azone and oleyl alcohol, or a combination of lauric acid and peppermint oil. A combination of lactic acid and linoleic acid and lauric acid and peppermint oil, a combination of lactic acid and oleic acid, preferably the content of the penetration enhancer is 0.0-30.0% by weight, 2.0-30.0%, preferably 3.9-30.0%, preferably 8.0-30.0%, preferably 15.0-30.0%, and / or iv) a solvent, the solvent is preferably an alcohol solvent, preferably propylene glycol, glycerol, methanol, benzyl alcohol, preferably the content of the solvent is 6.0-30.0% by weight, preferably 6.0-20.0%, preferably 8.0-20.0%, preferably 15.0-20.0%, preferably 15.0%.

7. The transdermal patch according to claim 5-6, characterized in that Contains the following components and weight percentage: Epiprazole lactate: 1.0-20.0% Chemical penetration enhancer: 0.0-30.0% Solvent: 6.0-20.0% Polyisobutylene pressure-sensitive adhesive: 51.0-72.0% The chemical penetration enhancer is selected from one or more of azones, pyrrolidones, volatile oils, ethers, alcohols, acids, and esters, preferably one or more of azones, pyrrolidones, volatile oils, acids, and fatty alcohols, preferably one or more of azone, 1-dodecyl-2-pyrrolidone, peppermint oil, lactic acid, oleic acid, linoleic acid, lauric acid, oleyl alcohol, and propylene glycol, preferably one or more of azone, peppermint oil, lactic acid, linoleic acid, lauric acid, oleyl alcohol, and propylene glycol, preferably linoleic acid, a combination of azone and oleyl alcohol, a combination of lactic acid and linoleic acid, a combination of lauric acid and peppermint oil, a combination of lactic acid and linoleic acid and lauric acid and peppermint oil, the solvent is preferably an alcohol solvent, preferably propylene glycol, glycerol, methanol, and benzyl alcohol, Preferably contain the following components and weight percentage: Epiprazole lactate: 7.0-17.0% Chemical penetration enhancers: 2.0-30.0% Propylene glycol: 6.0-20.0% Polyisobutylene pressure sensitive adhesive 6908: 51.0-76.0% The chemical penetration enhancer is selected from one or more of azones, pyrrolidones, volatile oils, ethers, alcohols, acids, and esters, preferably one or more of azones, pyrrolidones, volatile oils, acids, and fatty alcohols, preferably one or more of azone, 1-dodecyl-2-pyrrolidone, peppermint oil, lactic acid, oleic acid, linoleic acid, lauric acid, oleyl alcohol, and propylene glycol, preferably one or more of azone, peppermint oil, lactic acid, linoleic acid, lauric acid, oleyl alcohol, and propylene glycol, preferably linoleic acid, a combination of azone and oleyl alcohol, a combination of lactic acid and linoleic acid, a combination of lauric acid and peppermint oil, a combination of lactic acid and linoleic acid and lauric acid and peppermint oil, Preferably contain the following components and weight percentage: Epiprazole lactate: 7.0-17.0% Chemical penetration enhancers: 15.0-30.0% Propylene glycol: 8.0-20.0% Polyisobutylene pressure sensitive adhesive 6908: 53.0-70.0% The chemical penetration enhancer is selected from one or more of azone, volatile oils, acids, and fatty alcohols, preferably one or more of azone, peppermint oil, lactic acid, linoleic acid, lauric acid, oleyl alcohol, and propylene glycol, preferably a combination of linoleic acid, azone and oleyl alcohol, a combination of lauric acid and peppermint oil, a combination of lactic acid and linoleic acid, and a combination of lauric acid and peppermint oil. Preferably contain the following components and weight percentage: Epiprazole lactate: 7.0-17.0% Oleyl alcohol: 5.0-10.0% Azone: 5.0-20.0% Propylene glycol: 15.0-20.0% Polyisobutylene pressure-sensitive adhesive 6908: 53.0-55.0%, Preferably contain the following components and weight percentage: Epiprazole lactate: 7.0% Oleyl alcohol: 10.0% Azone: 10.0% Propylene glycol: 20.0% Polyisobutylene pressure-sensitive adhesive 6908: 53.0%, or Epiprazole lactate: 8.0% Oleyl alcohol: 9.2% Azone: 9.2% Propylene glycol: 18.4% Polyisobutylene pressure-sensitive adhesive 6908: 55.2%.

8. The transdermal patch according to claim 7, characterized in that Contains the following components and weight percentage: Epiprazole lactate: 7.0-11.0% Chemical penetration enhancers: 0.0-8.0% Propylene glycol: 15.0%-20.0% Polyisobutylene pressure-sensitive adhesive: 66.0%-74.0% The chemical penetration enhancer is selected from acids, preferably one or more of lactic acid and linoleic acid, preferably a combination of lactic acid and linoleic acid. The polyisobutylene pressure-sensitive adhesive comprises 10.0-30.0% high molecular weight polyisobutylene, 35.0-45.0% plasticizer, and 35.0-45.0% hydrogenated petroleum resin or low molecular weight polyisobutylene, wherein the low molecular weight polyisobutylene has a molecular weight of 85,000, and the high molecular weight polyisobutylene has a molecular weight of 425,000-2,600,000. Preferably contain the following components and weight percentage: Epiprazole lactate: 11.0% Lactic acid: 2.0% Linoleic acid: 6.0% Propylene glycol: 15.0% Polyisobutylene pressure sensitive adhesive: 66.0% The polyisobutylene pressure-sensitive adhesive comprises 10.0-30.0% of high molecular weight polyisobutylene, 35.0-45.0% of plasticizer, and 35.0-45.0% of hydrogenated petroleum resin or low molecular weight polyisobutylene, wherein the molecular weight of the low molecular weight polyisobutylene is 85,000, and the molecular weight of the high molecular weight polyisobutylene is 425,000-2,600,000.

9. The transdermal patch according to claim 8, characterized in that Contains the following components and weight percentage: Epiprazole lactate: 11.0% Lactic acid: 2.0% Linoleic acid: 6.0% Propylene glycol: 15.0% Polyisobutylene pressure sensitive adhesive: 66.0% The polyisobutylene pressure-sensitive adhesive comprises 27.27% high molecular weight polyisobutylene, wherein the molecular weight of the high molecular weight polyisobutylene is 425,000-2,600,000, 36.36% liquid paraffin, 36.36% hydrogenated petroleum resin or low molecular weight polyisobutylene, wherein the molecular weight of the low molecular weight polyisobutylene is 85,000, Preferably contain the following components and weight percentage: Epiprazole lactate: 11.0% Lactic acid: 2.0% Linoleic acid: 6.0% Propylene glycol: 15.0% Polyisobutylene pressure sensitive adhesive: 66.0% The polyisobutylene pressure-sensitive adhesive comprises 27.27% of high molecular weight polyisobutylene, wherein the molecular weight of the high molecular weight polyisobutylene is 1,110,000 or 425,000 or 2,600,000, 36.36% of liquid paraffin, and 36.36% of hydrogenated petroleum resin.

10. A method for preparing the patch according to any one of claims 5 to 9, the method comprising: adding a prescribed amount of API and excipients other than a pressure-sensitive adhesive to a solvent, mixing, then adding the pressure-sensitive adhesive, mixing to obtain a glue solution, coating the glue solution on a release film to form a wet glue, drying, and pressing with a backing film to obtain a finished product.

11. A compound characterized in that The compound is epiprazole lactate.

12. A method for preparing the epiprazole lactate according to claim 11, characterized in that The preparation method comprises: weighing lactic acid and anhydrous ethanol, adding epiriprazole and stirring until dissolved, continuing stirring until solid is precipitated, filtering and drying the precipitated solid to obtain epiriprazole lactate.

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