A transdermal sustained-release patch for treating depression and its preparation method

Abstract

This invention belongs to the field of pharmaceutical formulation technology, specifically a transdermal sustained-release patch for antidepressants and its preparation method. The transdermal sustained-release patch for antidepressants provided by this invention comprises compounds as shown in Formula I. This invention provides a transdermal sustained-release patch for antidepressants that can maintain stable blood drug concentrations for a long period, reduce the frequency of administration, and improve treatment adherence and efficacy stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically a transdermal sustained-release patch for treating depression and its preparation method. Background Technology

[0002] Depression, also known as depressive disorder, is a mental disorder with a high incidence, high clinical cure rate but low treatment acceptance rate and high relapse rate. Its main characteristic is significant and persistent low mood. Some patients may engage in self-harm or suicidal behavior, and may even experience psychotic symptoms such as delusions and hallucinations.

[0003] Treatment for depression mainly includes medication, psychotherapy, and physical therapy. Among these, the antidepressants used clinically primarily include serotonin reuptake inhibitors, such as fluoxetine S-isomer. Tricyclic antidepressant protriptyline (TCA) The above-mentioned drugs are usually taken orally.

[0004] However, oral administration has drawbacks such as a significant first-pass effect, large fluctuations in blood drug concentration, and poor patient compliance. This is particularly true for patients with depression requiring long-term treatment, where maintaining stable and effective blood drug concentrations is difficult, easily leading to insufficient therapeutic effect or withdrawal symptoms. To improve the administration method, transdermal drug delivery systems have gradually gained attention, offering potential advantages such as avoiding the first-pass effect, reducing blood drug concentration fluctuations, and improving patient compliance.

[0005] Therefore, it is necessary to provide a transdermal sustained-release patch that can achieve continuous and stable release of antidepressants, so as to provide a stable blood drug concentration over a long period of time, reduce the frequency of administration, improve treatment compliance and efficacy stability, which has important social significance and commercial value for the treatment of depression. Summary of the Invention

[0006] The technical problem to be solved by this invention is to overcome the deficiencies of existing technologies. To address this problem, this invention provides a transdermal sustained-release patch for treating depression and its preparation method. This transdermal sustained-release patch can maintain stable blood drug concentrations for a long period, reduce the frequency of administration, and improve treatment adherence and efficacy stability.

[0007] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0008] This invention provides a method for preparing a transdermal sustained-release patch for treating depression, which is prepared through the following steps: S1: Mix the stabilizer (e.g., PVP K90) with solvent A (e.g., water or ethanol) to form a viscous solution; S2: Mix the compound as shown in Formula I, the penetration enhancer, and solvent B (e.g., water or ethanol) to form a drug solution; S3: Stir the pressure-sensitive adhesive, viscous solution and drug solution evenly to obtain a drug-containing matrix; S4: Coat the drug-containing matrix onto the anti-sticking release film with a coating thickness of 30-50 μm. S5: The drug-containing matrix of the liner film is covered on the release liner film and then punched to obtain the transdermal patch; Among them, compounds of Formula I or their pharmaceutically acceptable salts are included.

[0009] Wherein, R1 is H, F, Cl, Br, C1-6 alkyl, C1-6 alkoxy, or C3-6 cycloalkyl; R2 is H, a C1-6 alkyl group, or a C3-6 cycloalkyl group. Ring A is a C6-10 aromatic or C5-10 heteroaryl, wherein the heteroatom in the heteroaryl is selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; R3 is H, F, Cl, Br, or a C1-6 alkyl group optionally substituted with one or more R3-1 groups; R3-1 is F, Cl, or a C1-6 alkyl group; n and m are each independently 1, 2, 3, 4, 5 or 6.

[0010] In this invention, the compound shown in Formula I is , , , or .

[0011] In this invention, the compound as shown in Formula I .

[0012] In this invention, the stabilizer is one or more of carbomer, carboxymethyl cellulose, and xanthan gum.

[0013] In this invention, the penetration enhancer is one or more of azone, oleic acid, propylene glycol, menthol, and eucalyptus oil.

[0014] In this invention, the pressure-sensitive adhesive is an acrylic pressure-sensitive adhesive.

[0015] This invention provides a transdermal sustained-release patch prepared by the above-described method for preparing an antidepressant transdermal sustained-release patch.

[0016] The present invention also provides a compound, said compound being .

[0017] This invention also provides the use of the above-mentioned compounds in the preparation of drugs for treating depression.

[0018] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0019] The reagents and raw materials used in this invention are all commercially available.

[0020] Compared with the prior art, the beneficial effects of the present invention are: the present invention provides a transdermal sustained-release patch for antidepressants and its preparation method. This transdermal sustained-release patch can maintain a stable blood drug concentration for a long time, reduce the frequency of administration, and improve treatment compliance and efficacy stability. Attached Figure Description

[0021] Figure 1 The image shows the 1H NMR spectrum of compound 1.

[0022] Figure 2 The NMR spectrum of compound 2 is shown in Figure 1 (1H NMR).

[0023] Figure 3 The 1H NMR spectrum of compound 3 is shown.

[0024] Figure 4 The 1H NMR spectrum of compound 4.

[0025] Figure 5 The 1H NMR spectrum of compound 5 is shown. Detailed Implementation

[0026] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0027] Preparation of intermediate compounds

[0028] first step

[0029] Benzyl ketone (10.0 g, 83.23 mmol), N,N-dimethylformamide methyl acetal (9.9 g, 83.23 mmol) were mixed with 100 mL of toluene, heated under reflux overnight, then cooled to room temperature, and toluene was removed under reduced pressure. Compound A (13.4 g, yield 91.88%) was purified by rapid column chromatography (PE:EA = 5:1).

[0030] 1 H NMR (400 MHz, CDCl3) δ7.90 - 7.89 (m, 2H), 7.78 (d, J = 12.4 Hz,1H), 7.45 - 7.38 (m, 3H), 5.70 (d, J = 12.4 Hz, 1H), 3.10 (s, 3H), 2.89 (s,3H).

[0031] MS (ESI) m / z [M+H]+ : 176.1. Step 2

[0032] Compound A (10.0 g, 57.1 mmol) and methylamine hydrochloride (3.0 g, 57.1 mmol) were thoroughly mixed in 100 mL of ethanol and heated under reflux until the reaction of compound A was complete as monitored by TLC. The solvent ethanol was removed under reduced pressure, and compound B (6.7 g, yield 72.8%) was purified by rapid column chromatography (PE:EA = 1:1).

[0033] 1 H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 7.89 – 7.80 (m, 2H), 7.45 –7.36 (m, 3H), 6.91 (dd, J = 12.8, 7.4 Hz, 1H), 5.70 (d, J = 7.4 Hz, 1H), 3.06(d, J = 5.1 Hz, 3H).

[0034] MS (ESI, m / z) [M+H) + :162.1.

[0035] Step 3

[0036] Compound B (6.70 g, 57.07 mmol) was mixed with palladium on carbon (5% Pd, 0.3 g) in 100 mL of tetrahydrofuran under a hydrogen atmosphere and stirred at 40-60 °C for 8 hours. The black solid was removed by filtration, and compound C (3.3 g, yield 48.05%) was purified by rapid column chromatography (EA:TEA=97:3).

[0037] 1H NMR (400 MHz, CDCl3) δ7.36-7.31 (m, 4H), 7.25-7.20 (m, 1H), 4.91-4.88 (q, J = 3.2, 8.4 Hz, 1H), 3.75 (s, br, 1H), 2.84-2.79 (m, 2H), 2.40 (s,3H), 1.87-1.72 (m, 2H).

[0038] MS (ESI, m / z): 166.1.

[0039] Example 1

[0040] Compound C (0.2 g, 1.21 mmol), 2-chloro-3-fluorobenzoic acid (0.211 g, 1.21 mmol), 0.2 g DIEA, and 0.5 g BOP were thoroughly mixed in DMF and stirred at 60 °C for 2 h. 50 mL of water was added, and the mixture was extracted with 3 × 50 mL ethyl acetate. The solvent was removed under reduced pressure, and compound 1 (176 mg, yield 45.19%) was obtained by high performance liquid chromatography.

[0041] 1 H NMR (400 MHz, CDCl3) δ 7.50 (m, 1H), 7.43 (dd, 1H), 7.38 – 7.22 (m,6H), 4.83 (q, 1H), 3.94 (s, 1H), 3.32 (m, 2H), 3.01 (s, 3H), 2.11 – 1.92 (m,2H).

[0042] MS (ESI, m / z): 322.1.

[0043] Example 2

[0044] Compound C (0.2 g, 1.21 mmol), 2,6-dichloro-3-fluorobenzoic acid (0.25 g, 1.21 mmol), 0.2 g DIEA, and 0.5 g BOP were thoroughly mixed in DMF and stirred at 60 °C for 2 h. 50 mL of water was added, and the mixture was extracted with 3 × 50 mL ethyl acetate. The solvent was removed under reduced pressure, and compound 2 (202 mg, yield 46.8%) was obtained by high performance liquid chromatography.

[0045] 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.43 (m, 2H), 7.37 – 7.25 (m, 5H), 4.83 (q, 1H), 3.94 (s, 1H), 3.43 – 3.27 (m, 2H), 3.02 (s, 3H), 2.10 – 1.96(m, 2H).

[0046] MS (ESI, m / z): 356.1.

[0047] Example 3

[0048] Compound C (0.2 g, 1.21 mmol), 2-chloroisonicotinic acid (0.19 g, 1.21 mmol), 0.2 g DIEA, and 0.5 g BOP were thoroughly mixed in DMF and stirred at 60 °C for 2 h. 50 mL of water was added, and the mixture was extracted with 3 × 50 mL ethyl acetate. The solvent was removed under reduced pressure, and compound 3 (246 mg, yield 66.69%) was obtained by high performance liquid chromatography.

[0049] 1 H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H), 7.67 (d, 1H), 7.52 (d, 1H), 7.37 – 7.26 (m, 5H), 4.83 (q, 1H), 3.93 (s, 1H), 3.41 – 3.30 (m, 2H), 3.00(s, 3H), 2.09 – 1.95 (m, 2H).

[0050] MS (ESI, m / z): 305.1.

[0051] Example 4

[0052] Compound C (0.2 g, 1.21 mmol), 2-(trifluoromethyl)isonicotinic acid (0.23 g, 1.21 mmol), 0.2 g DIEA, and 0.5 g BOP were thoroughly mixed in DMF and stirred at 60 °C for 2 h. 50 mL of water was added, and the mixture was extracted with 3 × 50 mL of ethyl acetate. The solvent was removed under reduced pressure, and compound 4 (304 mg, yield 74.23%) was obtained by high performance liquid chromatography.

[0053] 1H NMR (400 MHz, CDCl3) δ 8.70 (d, 1H), 7.83 (d, 1H), 7.55 (d, 1H), 7.37 – 7.26 (m, 5H), 4.83 (q, 1H), 3.93 (s, 1H), 3.39 – 3.27 (m, 2H), 3.00(s, 3H), 2.12 – 1.92 (m, 2H).

[0054] MS (ESI, m / z): 339.1.

[0055] Example 5

[0056] Compound C (0.2 g, 1.21 mmol), 4-isopropoxy-3-(trifluoromethyl)benzoic acid (0.3 g, 1.21 mmol), 0.2 g DIEA, and 0.5 g BOP were thoroughly mixed in DMF and stirred at 60 °C for 2 h. 50 mL of water was added, and the mixture was extracted with 3 × 50 mL of ethyl acetate. The solvent was removed under reduced pressure, and compound 5 (230 mg, yield 47.7%) was obtained by high performance liquid chromatography.

[0057] 1 H NMR (400 MHz, CDCl3) δ 8.03 (d, 1H), 7.64-7.56 (m, 1H), 7.35 – 7.26(m, 5H), 7.11 (d, 1H), 4.83 (q, 1H), 4.73 – 4.55 (m, 1H), 3.93 (s, 1H), 3.42– 3.23 (m, 2H), 3.01 (s, 3H), 2.15 – 1.89 (m, 2H), 1.44 – 1.22 (m, 6H).

[0058] MS (ESI, m / z): 396.2.

[0059] Example 6 Evaluation of the 5-HT reuptake inhibitory activity of the compound The test compounds (e.g., the compounds prepared in Examples 1-4 and the positive control drug (vilazorone)) were prepared into 0.01 mol / L solutions using DMSO, and further diluted to 1000 μmol / L with distilled water. 50 μl of the test compound was transfected into HEK 293 cells using the pcDNA3.0-hSERT vector plasmid (430 μl) and added to the reaction tube. After incubation for 15 minutes, 20 μl of radioactive [3H]-5-HT was added to bring the final concentration of the test compounds to 1 μmol / L. After further incubation for 15 minutes, the mixture was transferred to -5°C to terminate the reaction. Cell samples were rapidly filtered through GF / B glass fiber filter paper using a BRANDEL 24-well cell sample collector and washed three times with ice-cold elution buffer (50 mM Tris, 5 mM EDTA, pH 7.4). After drying, the filter paper was placed in a 0.5 ml centrifuge tube, and 500 μl of lipid-soluble scintillation solution was added. The radiation intensity was measured using a MicroBeta liquid scintillation counter. The experiment consisted of three separate tests: total reuptake tubes (blank control), nonspecific reuptake tubes (1 μmol / L vilazorone), and sample reuptake tubes (1 μmol / L compounds prepared in Examples 1-4). Two replicates were used for each concentration, and three independent experiments were performed. The test results are shown in Table 1.

[0060] Table 1

[0061] The results in Table 1 indicate that the compounds provided by this invention exhibit good inhibitory activity against 5-HT reuptake. In particular, compounds 1, 2, and 5 show significantly better inhibitory activity against 5-HT reuptake than the positive control vilazone.

[0062] Example 7 Evaluation of the inhibitory activity of compounds on AMPA receptors This assay was used to test the ability of the compound to inhibit TARPγ8-dependent AMPA receptor activity. The AMPA receptor is a non-selective cation channel activated by glutamate. Proionotropic glutamate receptors typically desensitize too quickly, thus calcium flux is undetectable in the FLIPR assay. However, this desensitization is incomplete, and a significant amount of steady-state current remains in the persistent presence of glutamate. An in vitro assay was used to determine the potency of the test compound as a glutamate-responsive inhibitor of the channel formed by GluA1o-γ8. To ensure a 1:1 stoichio-to-γ8 subunit ratio in the expressed channel, cDNA fusions of GRIA1o and CACNG8 were used. The channel expressed with this construct appears to have similar properties to that formed by co-expression of GRIA1o with overexpression of CACNG8. Clonal cell lines stably expressing this construct in HEK293 cells with a genimycin selection marker were generated for this assay.

[0063] HEK293 cells expressing the GRIA1o-CACNG8 fusion construct were grown as monolayers in 96-well or 384-well microtiter plates. These cells were washed with assay buffer (135 mM NaCl, 4 mM KCl, 3 mM CaCl2, 1 mM MgCl2, 5 mM glucose, 10 mM HEPES, pH 7.4, 300 mOs) using a Biotek 135 washer. The cells were then loaded with calcium-sensitive dyes (Calcium-5 or Calcium-6) and test compounds at specific concentrations.

[0064] Calcium flux after the addition of 15 μM glutamate was monitored using a Molecular Devices FLIPR Tetra. Fluorescence in each well was normalized to the fluorescence of the negative and positive control wells. No compound was added to the negative control wells, and the positive control wells were incubated with 10 μM CP-465022 (a non-subtype-selective AMPA receptor antagonist). The response to glutamate was fitted as a function of the test compound concentration to a four-parameter logistic function. The fitted parameter corresponding to the midpoint was considered the inhibitory potency of the compound. The experimental results are shown in Table 2.

[0065] Table 2

[0066] The results in Table 2 show that the compounds provided by this invention have excellent inhibitory activity against AMPA receptors.

[0067] Example 8 This study aims to investigate the effects of antidepressant compounds in the preparation of transdermal sustained-release patches, specifically: 0.5g of PVP K90 was mixed with 4mL of ethanol to prepare a viscous solution; 0.5g of compound 1 or compound 5, 0.5g of propylene glycol and 1g of ethanol were mixed to prepare a drug solution; 5g of acrylate pressure-sensitive adhesive, the above viscous solution and the above drug solution were stirred and mixed evenly and then coated on a PET 4400B release film with a coating thickness of 30-50μm. Then the backing film was covered on the drug-containing matrix of the release film, and after punching, a transdermal patch was obtained.

[0068] Hair was removed from the abdomen of the experimental pigs. After euthanasia, the abdominal skin was peeled off, and skin without wounds was selected. Subcutaneous fat was removed, and the skin was repeatedly washed with physiological saline until it was clear. The pigs were then stored in a -20°C refrigerator. One day before the experiment, the pigs were transferred to a 4°C refrigerator for later use.

[0069] Remove the anti-adhesive layer from the prepared transdermal patch and apply it to the surface of the pigskin, gently pressing with your fingers to ensure good adhesion between the pigskin and the patch. Then, place the pigskin between the Franz diffusion cell equipped with a rotor and the supply chamber, leaving the backing layer in contact with air, and secure it with clamps. Pipette 9 mL of receiving medium into the receiving chamber, add a magnetic stir bar, and stir under constant temperature (32 ± 0.5 °C) and constant speed (180 r / min). At predetermined time points, take 0.8 mL of sample using a 1 mL syringe, simultaneously replenishing with an equal volume of blank receiving medium at the same temperature.

[0070] The extracted samples were immediately sent to a high-performance liquid chromatography (HPLC) instrument for content determination. The results of in vitro transdermal diffusion are shown in Table 3 below.

[0071] Table 3

[0072] As shown in Table 3, the transdermal sustained-release patch for antidepressants provided by the present invention can maintain a stable blood drug concentration for a long time, reduce the frequency of administration, and improve treatment compliance and efficacy stability.

Claims

1. A method for preparing a transdermal patch for the sustained release of an antidepressant, characterized in that, It is prepared through the following steps: S1: Mix the stabilizer with ethanol to form a viscous solution; S2: Mix the compound as shown in Formula I, the penetration enhancer, and ethanol to form a drug solution; S3: Stir the pressure-sensitive adhesive, viscous solution and drug solution evenly to obtain a drug-containing matrix; S4: Coat the drug-containing matrix onto the anti-sticking release film with a coating thickness of 30-50 μm. S5: The drug-containing matrix of the liner film is covered on the release liner film and then punched to obtain the transdermal patch; Among them, compounds of Formula I or their pharmaceutically acceptable salts are included. ； Wherein, R1 is H, F, Cl, Br, C1-6 alkyl, C1-6 alkoxy, or C3-6 cycloalkyl; R2 is H, a C1-6 alkyl group, or a C3-6 cycloalkyl group. Ring A is a C6-10 aromatic or C5-10 heteroaryl, wherein the heteroatom in the heteroaryl is selected from N, O and S, and the number of heteroatoms is 1, 2 or 3; R3 is H, F, Cl, Br, or a C1-6 alkyl group optionally substituted with one or more R3-1 groups; R3-1 is F, Cl, or a C1-6 alkyl group; n and m are each independently 1, 2, 3, 4, 5 or 6.

2. The method for preparing the transdermal sustained-release patch for antidepressants as described in claim 1, characterized in that, The compound shown in Formula I is , , , or .

3. The method for preparing the transdermal sustained-release patch for antidepressants as described in claim 1, characterized in that, The stabilizer is one or more of PVP K90, carbomer, carboxymethyl cellulose, and xanthan gum.

4. The method for preparing the transdermal sustained-release patch for antidepressants as described in claim 1, characterized in that, The penetration enhancer is one or more of azone, oleic acid, propylene glycol, menthol, and eucalyptus oil.

5. The method for preparing the transdermal sustained-release patch for antidepressants as described in claim 1, characterized in that, The pressure-sensitive adhesive is an acrylic pressure-sensitive adhesive.

6. A transdermal sustained-release patch for antidepressants prepared by the method of preparing the transdermal sustained-release patch for antidepressants according to any one of claims 1-5.

7. A compound, which is .

8. The use of the compound of claim 7 in the preparation of a medicament for treating depression.

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