VMAT2 inhibitor 11-P4S-containing viscose dispersed transdermal patch and preparation method thereof

Abstract

The invention provides a viscose dispersing type transdermal patch of a VMAT2 (Vitamin Matrix Activator 2) inhibitor 11-P4S. The transdermal patch is composed of a backing layer, a drug-containing substrate layer and an anti-sticking layer, wherein the drug-containing layer comprises 11-P4S free alkali and pharmaceutically acceptable salts thereof, a polyacrylate pressure-sensitive adhesive, a crystallization inhibitor, a transdermal absorption enhancer and an antioxidant. The viscose dispersing type transdermal patch can continuously release drugs within 24 hours, is stable in drug release, high in bioavailability and good in safety, can greatly improve the medication compliance and medication convenience of a patient with delayed dyskinesia (TD) on the basis of ensuring the clinical curative effect, reduces the nursing burden of nursing personnel, and is suitable for treating TD diseases.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an adhesive dispersion type transdermal patch containing a VMAT2 inhibitor 11-P4S and a preparation method thereof. Background Art

[0002] Tardive dyskinesia (TD) is a special and persistent extrapyramidal adverse reaction characterized by abnormal involuntary movements such as akathisia, dystonia, buccal-tongue stereotypy, myoclonus, chorea, and convulsions, which occurs after long-term use of dopamine receptor blockers. In recent years, the prevalence of mental disorders has been on the rise. The latest epidemiological survey shows that the incidence of TD exceeds 20% for patients who use antipsychotic drugs for more than 3 months, and the annual incidence rate is 4-5%. Among them, the incidence of TD in patients taking typical antipsychotics is as high as 32.4%, and that of atypical antipsychotics is 13.1%.

[0003] Currently, there are only two drugs approved for the treatment of TD worldwide with clear clinical efficacy and safety evidence, both of which are vesicular monoamine transporter 2 (VMAT2) inhibitors, namely deuterated tetrabenazine and valbenazine. Tetrabenazine has a short half-life and requires multiple doses. Deuterated tetrabenazine, developed on the basis of tetrabenazine, reduces the drug metabolism rate through deuteration, increases the AUC in the body, reduces the clinical dosage, and reduces adverse reactions. However, there are many types of metabolites, which cause serious adverse reactions, and there are black-box adverse reaction warnings for depression and suicidal tendencies. Valbenazine is a prodrug of the main active metabolite of tetrabenazine, which improves the target selectivity and specificity of the drug, reduces the off-target effect, ensures the efficacy, reduces adverse reactions, and removes the black-box warnings for depression and suicide. However, valbenazine still has defects that can be improved: high metabolic and excretion pressure, active ingredients only account for 10%, and there are many inactive ingredients; it has potential cardiac safety, does not reach the maximum efficacy at 80mg, and is limited to valbenazine itself causing QTc prolongation.

[0004] TD has a large incidence rate, but there are few drugs on the market and they all have certain defects, which means there are major unmet clinical needs. The development of a new generation of VMAT2 inhibitors can meet the unmet clinical needs and serve TD and HD patients more efficiently. Patent CN115260186 discloses a VMAT2 inhibitor and its preparation method and application, involving compound 11-P4S.

[0005]

[0006] Transdermal patches can improve patients' medication compliance, facilitate interruption of medication at any time, avoid the first-pass effect of oral medication in the liver and the degradation of drugs in the gastrointestinal tract, and reduce individual differences in medication; they can keep blood drug concentrations stable within the effective therapeutic concentration, avoid the peak and valley phenomenon of blood drug concentrations caused by oral medication, and reduce toxic side effects. In combination with the characteristics of TD patients, if 11-P4S transdermal patches can be developed, it can greatly improve the medication compliance and convenience of TD patients on the basis of ensuring clinical efficacy, and reduce the care burden of caregivers. Summary of the invention

[0007] The 11-P4S adhesive dispersion transdermal patch disclosed in the present invention has stable drug release, high bioavailability, can continuously release drugs within 24 hours, and has good safety. The preparation method disclosed in the present invention is simple to operate, can continuously and stably prepare the patch, and is suitable for industrial production.

[0008] The 11-P4S adhesive dispersion transdermal patch of the present invention is characterized by being composed of a backing layer, a drug-containing base layer and an anti-adhesive layer; the drug-containing base layer contains 11-P4S free base and its pharmaceutically acceptable salt, polyacrylate pressure-sensitive adhesive, crystallization inhibitor, transdermal absorption accelerator and antioxidant.

[0009] The backing layer of the transdermal patch is selected from any one of polyethylene film, polyvinyl chloride film, polypropylene film, polyvinyl acetate film, polyurethane film, aluminum-plastic composite film, nylon, non-woven fabric or stretch fabric, preferably polyethylene film.

[0010] The anti-adhesive layer of the transdermal patch is selected from a polyester film coated with dimethyl silicone oil, a polyester film coated with siloxane, a fluoropolymer-coated polyester film, an aluminum foil-silicone grease composite, a siliconized aluminum foil or silicon paper; preferably, it is a polyester film coated with dimethyl silicone oil.

[0011] The active ingredient of the transdermal patch can be 11-P4S free base or its pharmaceutically acceptable salt, preferably free base and its p-toluenesulfonate. The amount of 11-P4S free base in the drug-containing base layer accounts for 1%-10% of the weight of the drug-containing base layer, preferably 5%.

[0012] The pressure-sensitive adhesive used in the drug-containing base layer of the transdermal patch is selected from any one or a combination of polyacrylate pressure-sensitive adhesive, polyisobutylene pressure-sensitive adhesive, silicone pressure-sensitive adhesive, hot-melt pressure-sensitive adhesive, and natural rubber. Preferably, it is one or more of polyacrylate pressure-sensitive adhesives Duro-TAK 2052, Duro-TAK2287, Duro-TAK3768, Duro-TAK 4098, and Duro-TAK 9301. The amount used accounts for 50-85% of the weight percentage of the drug-containing base layer, preferably 60-80%.

[0013] The transdermal patch, the transdermal absorption promoter used in the drug-containing basal layer is selected from one or more of laurocapram, oleic acid, isopropyl myristate, N-methyl pyrrolidone, glycerol, propylene glycol, menthol, sorbitan monooleate, lauric acid, triacetin, oleyl alcohol, and octyl lauryl alcohol. Triacetin, N-methyl pyrrolidone, and glycerol are preferred. Triacetin is most preferred. The dosage is 5%-15% of the weight percentage of the drug-containing basal layer, and 10% is most preferred.

[0014] The crystallization inhibitor used in the drug-containing base layer of the transdermal patch is selected from one or more of dimethyl sulfoxide and polyvinyl pyrrolidone, preferably a mixture of dimethyl sulfoxide and polyvinyl pyrrolidone, the total amount of which accounts for 10% of the weight percentage of the drug-containing base layer, and more preferably the ratio of the two is 1:1.

[0015] The antioxidant used in the drug-containing base layer of the transdermal patch is selected from one or more of sodium pyrosulfite, sodium sulfite, fumaric acid, tartaric acid, BHA, BHT, tocopherol, vitamin E, and ascorbyl palmitate, preferably vitamin E, tocopherol, sodium pyrosulfite, and sodium sulfite, and most preferably vitamin E. The amount used is 0.1%-1% by weight of the drug-containing base layer, and most preferably 0.1%.

[0016] The present invention also provides a method for preparing the transdermal patch. First, a drug-containing layer matrix is ​​prepared, and an antioxidant is added to the drug-containing layer matrix after the matrix is ​​evenly mixed; the active drug component is dissolved in a solvent and then added to the drug-containing layer matrix. The drug-loaded matrix is ​​coated on the protective layer, and after drying, a composite backing film is formed and cut into a suitable size.

[0017] The present invention also provides use of any of the above transdermal patches in treating diseases related to VMAT2.

[0018] The present invention also provides the use of any of the above transdermal patches in drugs for treating hyperkinetic disorders; preferably, the hyperkinetic disorders include Huntington's disease, tardive dyskinesia, Tourette syndrome or convulsions. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Pharmacokinetic curve of prescription patch 16 of Example 5 of the present invention DETAILED DESCRIPTION

[0020] The technical solution disclosed in the present invention is further described below in conjunction with embodiments, but the present invention is not limited thereto.

[0021] Example 1

[0022] Transdermal patches were prepared according to the prescription in Table 1 and the following preparation process, and the in vitro cumulative transdermal amounts of different pressure-sensitive adhesive patches were investigated.

[0023] Table 1

[0024]

[0025] Preparation process: Take the prescribed amount of active ingredients, pressure-sensitive adhesive, crystallization inhibitor, penetration enhancer, and antioxidant and add them to the solvent. Use a rotating shaking method to stir until they are completely dissolved. Use a coating machine to apply them on the protective layer. Control the thickness to be 300±50μm. Dry at 40-60℃. After compounding with the backing layer, cut into suitable areas.

[0026] In vitro transdermal test: After removing the protective layer of the transdermal patch, stick it on the intact skin of nude mice, and fix the skin with the transdermal patch in the vertical diffusion pool of the fully automatic transdermal diffusion system. The receiving pool of the fully automatic transdermal diffusion system has a built-in magnetic stirrer, and the receiving medium is a phosphate buffer with a pH of 7.40. The water bath temperature of the fully automatic transdermal diffusion system is set to 32°C, and the fully automatic transdermal diffusion system is started. Take 5 ml of samples at 3h, 6h, 9h, 12h, 18h, and 24h (add the same amount of receiving medium at the same temperature after sampling), analyze the content of free alkali in each sample by HPLC, and calculate the 24h permeation amount.

[0027] The results of the transdermal penetration of each group of patches in Example 1 are shown in Table 2.

[0028] Table 2

[0029] index Prescription 1 Prescription 2 Prescription 3 Prescription 4 <![CDATA[24-hour permeation amount (μg / cm 2 )]]> 350.22 348.38 250.68 280.87

[0030] Example 2

[0031] A transdermal patch was prepared according to the prescription in Table 3 and the preparation process in Example 1, and the effect of the transdermal absorption enhancer on the transdermal amount was investigated according to the in vitro transdermal test in Example 1.

[0032] Table 2

[0033]

[0034] The results of the transdermal penetration of each group of patches in Example 2 are shown in Table 3.

[0035] Table 3

[0036] index Prescription 1 Prescription 5 Prescription 6 Prescription 7 Prescription 8 <![CDATA[24-hour permeation amount (μg / cm 2 )]]> 350.22 328.34 300.45 278.65 204.78

[0037] Example 3

[0038] A transdermal patch was prepared according to the prescription in Table 4 and the preparation process in Example 1 to investigate the effect of the crystallization inhibitor on crystallization.

[0039] Table 4

[0040]

[0041] The investigation results of Example 3 are shown in Table 5:

[0042] Table 5

[0043]

[0044]

[0045] Example 4

[0046] A transdermal patch was prepared according to the prescription in Table 6 and the preparation process in Example 1, and the effect of antioxidants on the accelerated stability of the patch was investigated.

[0047] Table 6

[0048]

[0049] The investigation results of Example 4 are shown in Table 6:

[0050] Table 6

[0051] Prescription Number 3 months 6 months Prescription 15 Good stability Good stability Prescription 16 Good stability Good stability Prescription 17 Good stability Good stability Prescription 18 Good stability Good stability Prescription 19 Good stability Increased content of related substances

[0052] Example 5

[0053] Transdermal patches were prepared according to the prescription in Table 7 and the preparation process in Example 1. The in vitro transdermal test in Example 1 was used to investigate the transdermal penetration of the transdermal patches of various prescriptions.

[0054] Table 7

[0055] Prescription Number 11-P4S free base Duro-TAK 2052 Triacetin DMSO+PVP Vitamin E Prescription 20 3％ 76.9％ 10％ 5％+5％ 0.1％ Prescription 21 5％ 79.9％ 5％ 5％+5％ 0.1％ Prescription 16 5％ 74.9％ 10％ 5％+5％ 0.1％ Prescription 22 5％ 69.9％ 15％ 5％+5％ 0.1％ Prescription 23 10％ 64.9％ 15％ 5％+5％ 0.1％ Prescription 24 15％ 64.9％％ 10％ 5％+5％ 0.1％

[0056] The transdermal amounts of the patches of each prescription in Example 5 are shown in Table 8.

[0057] Table 8

[0058] index Prescription 20 Prescription 21 Prescription 16 Prescription 22 Prescription 23 Prescription 24* <![CDATA[24-hour permeation amount (μg / cm 2 )]]> 227.87 347.65 400.08 357.82 456.91 -

[0059] (*Prescription 24 had a large amount of crystals precipitated, and the amount of transdermal penetration was not investigated)

[0060] Skin irritation test:

[0061] Embodiment 5 Prescription 16 is tested for skin irritation: 6 rabbits are taken and randomly divided into two groups (3 in each), an intact skin group and a damaged skin group. The local hair removal treatment of the back is carried out 24 hours before the test. The self-contrast method of the same body is adopted, and the near head end is the intact skin area, and the near tail end is the damaged skin area. The test substance and the control blank patch are respectively applied to the test area and the control area on the back of the rabbit, and each patch is applied for 1 day for 7 consecutive days. After removing the patch, the administration site is cleaned with warm water and applied again after 1 hour. Before the first administration, and 1 hour after each cleaning, 12 hours after the last administration and 24 hours after the drug is removed, the application site is observed for erythema and edema, as well as the recovery of the above changes and the time are scored, and the stimulation evaluation intensity of the test substance is evaluated according to the scoring results. The test shows that the general condition and weight gain of the rabbits of this product during the administration process and the observation period are good. In the intact skin area, no edema was found in the test area and the control area. On the 7th day, one animal developed mild erythema, which subsided 24 hours after drug withdrawal. The average scores of the test area and the control area were 0 and 0.05, respectively. According to the skin irritation intensity evaluation standard, it was evaluated as non-irritating. For the damaged skin area, most animals in the test area and the control area developed mild erythema after the first application, which may be a natural manifestation of wound healing. The damaged area was completely healed after 7 days of the test. During the drug administration process and observation period, the average scores of the damaged skin test area and the control area were less than 0.35, and the irritation intensity was non-irritating. Therefore, the 11-P4S transdermal patch and the blank patch were non-irritating to the intact skin and damaged skin of rabbits after continuous transdermal administration for 7 days.

[0062] Animal in vivo PK test:

[0063] The in vivo PK test of Bama miniature pigs was carried out with prescription 16 in Example 5, with 6 animals in each group.

[0064] Transdermal patch group (TDS): 1 mL of venous blood was collected into heparinized tubes before administration (0 hours) and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after administration, and the supernatant was centrifuged and stored at -80°C for testing. The concentration of free alkali in plasma of each administration group was determined by LC-MS / MS method.

[0065] Animal PK curves are shown in Figure 1 The results showed that transdermal patches release drugs more smoothly, have high bioavailability, and can improve drug delivery efficiency and stability.

Claims

1. A viscose-dispersed transdermal patch containing the VMAT2 inhibitor 11-P4S, characterized in that It is composed of a backing layer, a drug-containing base layer and an anti-adhesive layer; the drug-containing base layer contains 11-P4S free base and its pharmaceutically acceptable salt, polyacrylate pressure-sensitive adhesive, crystallization inhibitor, transdermal absorption accelerator and antioxidant; 2. The transdermal patch according to claim 1, characterized in that The backing layer is selected from any one of polyethylene film, polyvinyl chloride film, polypropylene film, polyvinyl acetate film, polyurethane film, aluminum-plastic composite film, nylon, non-woven fabric or stretch fabric, preferably polyethylene film.

3. The transdermal patch according to any one of claims 1 or 2, characterized in that The anti-sticking layer is selected from a polyester film coated with dimethyl silicone oil, a polyester film coated with silicone, a fluoropolymer-coated polyester film, an aluminum foil-silicone grease composite, a siliconized aluminum foil or a silicon paper; preferably, a polyester film coated with dimethyl silicone oil.

4. The transdermal patch according to any one of claims 1 to 3, characterized in that The active ingredient can be 11-P4S free base or a pharmaceutically acceptable salt thereof, preferably the free base and its p-toluenesulfonate; the amount used is 1-10% by weight of the drug-containing base layer, preferably 5%.

5. The transdermal patch according to any one of claims 1 to 4, characterized in that The pressure-sensitive adhesive used for the drug-containing base layer is selected from any one or a combination of polyacrylate pressure-sensitive adhesive, polyisobutylene pressure-sensitive adhesive, silicone pressure-sensitive adhesive, hot-melt pressure-sensitive adhesive, and natural rubber; preferably one or more of the polyacrylate pressure-sensitive adhesives Duro-TAK 2052, Duro-TAK2287, Duro-TAK3768, Duro-TAK 4098, and Duro-TAK 9301; the amount used accounts for 50-85% of the weight percentage of the drug-containing base layer, preferably 60-80%.

6. The transdermal patch according to any one of claims 1 to 5, characterized in that The transdermal absorption enhancer used in the drug-containing base layer is selected from one or more of laurocapram, oleic acid, isopropyl myristate, N-methylpyrrolidone, glycerol, propylene glycol, menthol, sorbitan monooleate, lauric acid, triacetin, oleyl alcohol, and octyl lauryl alcohol; preferably triacetin, N-methylpyrrolidone, and glycerol, and most preferably triacetin; the amount used accounts for 5%-15% of the weight percentage of the drug-containing base layer, and most preferably is 10%.

7. The transdermal patch according to any one of claims 1 to 6, characterized in that The crystallization inhibitor used in the drug-containing base layer is selected from one or more of dimethyl sulfoxide and polyvinyl pyrrolidone; preferably, it is a mixture of dimethyl sulfoxide and polyvinyl pyrrolidone, the total amount of which accounts for 10% of the weight percentage of the drug-containing base layer, and the ratio of the two is most preferably 1:

1.

8. The transdermal patch according to any one of claims 1 to 7, characterized in that The antioxidant used in the drug-containing base layer is selected from one or more of sodium pyrosulfite, sodium sulfite, fumaric acid, tartaric acid, BHA, BHT, tocopherol, vitamin E, and ascorbyl palmitate, preferably vitamin E, tocopherol, sodium pyrosulfite, and sodium sulfite, and most preferably vitamin E. The amount used is 0.1%-1% by weight of the drug-containing base layer, and most preferably 0.1%.

9. A method for preparing a transdermal patch according to any one of claims 1 to 8, characterized in that The method comprises the following steps: firstly preparing a drug-containing layer matrix, adding an antioxidant to the drug-containing layer matrix after the matrix is ​​evenly mixed; dissolving the active drug component with a solvent and adding the solvent to the drug-containing layer matrix; coating the drug-loaded matrix on a protective layer, drying it, and then compounding it with a backing film, and cutting it into a suitable size.

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