Amitriptyline gel as well as preparation method and application thereof

Abstract

The invention relates to amitriptyline gel as well as a preparation method and application thereof, and belongs to the technical field of medicines. The invention provides amitriptyline gel. The amitriptyline gel is prepared from the following components in parts by mass: 2 to 8 parts of amitriptyline hydrochloride, 16 to 24 parts of glycerol, 2 to 8 parts of hydroxypropyl methylcellulose, 16 to 24 parts of 70 to 80 percent ethanol solution, 0.05 to 0.15 part of ethylparaben, 0.2 to 0.8 part of laurocapram and 36 to 64 parts of water. The amitriptyline gel plaster prepared from the amitriptyline gel can effectively relieve postherpetic neuralgia, and compared with traditional oral tablets, the amitriptyline gel plaster can effectively reduce side effects.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to an amitriptyline gel and a preparation method and application thereof. Background Art

[0002] Amitriptyline, a representative tricyclic antidepressant, has a definite clinical efficacy in the treatment of postherpetic neuralgia (PHN). It exerts analgesic effects by inhibiting the reuptake of serotonin and norepinephrine in the central nervous system. However, the drug's current main dosage form is oral tablets, which have obvious limitations in clinical application: due to its strong anticholinergic effects, patients often experience adverse reactions such as dry mouth, constipation, and blurred vision; at the same time, its cardiovascular side effects (such as orthostatic hypotension and arrhythmias) and central sedative effects lead to a significant decrease in medication compliance in elderly patients and those with underlying diseases. Therefore, there is an urgent need to improve the dosage form of amitriptyline to reduce the side effects of oral tablets.

[0003] Based on this, the present invention is proposed. Summary of the Invention

[0004] The purpose of the present invention is to provide an amitriptyline gel and a preparation method and application thereof, so as to solve the problem that amitriptyline oral tablets in the prior art may produce side effects.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides an amitriptyline gel, which comprises the following components in parts by mass:

[0007] 2-8 parts of amitriptyline hydrochloride, 16-24 parts of glycerin, 2-8 parts of hypromellose, 16-24 parts of 70-80% ethanol solution, 0.05-0.15 parts of ethylparaben, 0.2-0.8 parts of laurocapram, and 36-64 parts of water.

[0008] Preferably, the amitriptyline gel comprises the following components in parts by mass:

[0009] 4-6 parts of amitriptyline hydrochloride, 18-22 parts of glycerin, 4-6 parts of hypromellose, 18-22 parts of 70-80% ethanol solution, 0.07-0.13 parts of ethylparaben, 0.4-0.6 parts of laurocapram, and 42-58 parts of water.

[0010] Preferably, the amitriptyline gel comprises the following components in parts by mass:

[0011] 5 parts of amitriptyline hydrochloride, 20 parts of glycerin, 5 parts of hypromellose, 20 parts of 70-80% ethanol solution, 0.1 part of ethylparaben, 0.5 part of laurocapram and 49.4 parts of water.

[0012] The present invention provides a method for preparing amitriptyline gel, comprising the following steps:

[0013] (1) mixing hypromellose with 1 / 2 to 3 / 4 of water to obtain a mixed solution, and mixing amitriptyline hydrochloride with an ethanol solution to obtain an amitriptyline hydrochloride solution;

[0014] (2) adding glycerin, ethylparaben, and laurocapram to the mixed solution to obtain a gel matrix;

[0015] (3) Mixing the amitriptyline hydrochloride solution, the gel base and the remaining water to obtain an amitriptyline gel.

[0016] The present invention provides the use of the amitriptyline gel or the amitriptyline gel prepared by the preparation method in preparing a medicine for treating postherpetic neuralgia.

[0017] The present invention provides an amitriptyline gel patch, which comprises an isolation layer, a gel drug layer and a backing layer;

[0018] The gel drug layer comprises the amitriptyline gel or the amitriptyline gel prepared by the preparation method.

[0019] Preferably, the amount of amitriptyline gel in the amitriptyline gel patch is 3 mg / cm 2 ~5mg / cm 2 .

[0020] Preferably, the isolation layer is siliconized paper, PVC transparent corrugated film or flat film.

[0021] Preferably, the backing layer is a composite film;

[0022] The composite film is formed by laminating non-woven fabric and polypropylene film.

[0023] The present invention has the following technical effects and advantages:

[0024] The amitriptyline gel of the present invention is prepared from amitriptyline hydrochloride, glycerin, hypromellose, 70-80% ethanol solution, ethylparaben, laurocapram, and water. The preparation method of the amitriptyline gel is simple and can effectively reduce side effects. The amitriptyline gel patch prepared using the amitriptyline gel of the present invention can effectively relieve postherpetic neuralgia and can effectively reduce side effects compared to traditional oral tablets. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is a schematic diagram of the amitriptyline gel patch;

[0026] Figure 2 The figure is a flow chart for the preparation of amitriptyline gel patch;

[0027] Figure 3 is the UPLC chromatogram of the reference solution;

[0028] Figure 4 is the UPLC chromatogram of the test solution;

[0029] Figure 5 This is the standard curve of the reference solution;

[0030] Figure 6 Methods for constructing neuropathic pain models;

[0031] Figure 7 This is a diagram of the drug administration location for mice;

[0032] Figure 8 Results of mechanical pain threshold tests on mice treated with different methods;

[0033] Figure 9 Results of cold pain response measurements in mice treated with different methods;

[0034] Figure 10 These are the results of measuring thermal pain responses in mice treated with different methods. DETAILED DESCRIPTION

[0035] The present invention provides an amitriptyline gel, which comprises the following components in parts by mass:

[0036] 2-8 parts of amitriptyline hydrochloride, 16-24 parts of glycerin, 2-8 parts of hypromellose, 16-24 parts of 70-80% ethanol solution, 0.05-0.15 parts of ethylparaben, 0.2-0.8 parts of laurocapram, and 36-64 parts of water;

[0037] The amitriptyline hydrochloride is preferably 4 to 6 parts, more preferably 5 parts; the glycerin is preferably 18 to 22 parts, more preferably 20 parts; the hypromellose is preferably 4 to 6 parts, more preferably 5 parts; the 70 to 80% ethanol solution is preferably 18 to 22 parts, more preferably 20 parts, and the concentration of the ethanol solution is preferably 75%; the ethyl hydroxybenzoate is preferably 0.07 to 0.13 parts, more preferably 0.1 parts; the laurocapram is preferably 0.4 to 0.6 parts, more preferably 0.5 parts; and the water is preferably 42 to 58 parts, more preferably 49.4 parts.

[0038] The present invention provides a method for preparing amitriptyline gel, comprising the following steps:

[0039] (1) mixing hypromellose with 1 / 2 to 3 / 4 of water to obtain a mixed solution, and mixing amitriptyline hydrochloride with an ethanol solution to obtain an amitriptyline hydrochloride solution;

[0040] (2) adding glycerin, ethylparaben, and laurocapram to the mixed solution to obtain a gel matrix;

[0041] (3) Mixing the amitriptyline hydrochloride solution, the gel base and the remaining water to obtain an amitriptyline gel.

[0042] The present invention provides the use of the amitriptyline gel or the amitriptyline gel prepared by the preparation method in preparing a medicine for treating postherpetic neuralgia.

[0043] The present invention provides an amitriptyline gel patch, which comprises an isolation layer, a gel drug layer and a backing layer;

[0044] The gel drug layer comprises the amitriptyline gel or the amitriptyline gel prepared by the preparation method.

[0045] In the present invention, the dosage of amitriptyline gel in the amitriptyline gel patch is 3 mg / cm 2 ~5mg / cm 2 , preferably 4 mg / cm 2 .

[0046] In the present invention, the isolation layer is siliconized paper, PVC transparent corrugated film or flat film, preferably siliconized paper.

[0047] In the present invention, the backing layer is a composite film;

[0048] The composite film is formed by laminating non-woven fabric and polypropylene film.

[0049] The technical solutions provided by the present invention are described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0050] In the examples, amitriptyline hydrochloride was purchased from Hunan Dongting Pharmaceutical Co., Ltd., batch number: G2305003; amitriptyline hydrochloride standard was purchased from Shanghai Yeyuan Biotechnology Co., Ltd., batch number: B24332, purity ≥98%; methanol was purchased from Tianjin Tianli Chemical Reagent Co., Ltd.; triethylamine was purchased from Tianjin Beilian Fine Chemicals Development Co., Ltd.; phosphoric acid was homemade, content: 85%.

[0051] Example 1: Preparation of Amitriptyline Gel

[0052] (1) 5 g of hypromellose was mixed with 30 g of water, and the mixture was swollen to obtain a mixed solution, and 5 g of amitriptyline hydrochloride was mixed with 20 g of a 75% ethanol solution to obtain an amitriptyline hydrochloride solution;

[0053] (2) adding 20 g of glycerol, 0.1 g of ethylparaben, and 0.5 g of laurocapram to the mixed solution, and stirring to dissolve them completely to obtain a colorless and odorless gel matrix with uniformly distributed bubbles;

[0054] (3) The amitriptyline hydrochloride solution was slowly added to the gel matrix while stirring continuously, and then 19.4 g of water was added and stirred thoroughly to obtain the amitriptyline gel.

[0055] Example 2: Preparation of Amitriptyline Gel

[0056] (1) 8 g of hypromellose was mixed with 35 g of water, and the mixture was swollen to obtain a mixed solution, and 6 g of amitriptyline hydrochloride was mixed with 17 g of a 75% ethanol solution to obtain an amitriptyline hydrochloride solution;

[0057] (2) adding 22 g of glycerol, 0.1 g of ethylparaben, and 0.5 g of laurocapram to the mixed solution, and stirring to dissolve them completely to obtain a colorless and odorless gel matrix with evenly distributed bubbles;

[0058] (3) Slowly add the amitriptyline hydrochloride solution into the gel matrix while stirring continuously, then add 11.4 g of water and stir thoroughly to obtain the amitriptyline gel.

[0059] Example 3: Preparation of Amitriptyline Gel

[0060] (1) 4 g of hypromellose was mixed with 28 g of water, and the mixture was swollen to obtain a mixed solution, and 4 g of amitriptyline hydrochloride was mixed with 23 g of a 75% ethanol solution to obtain an amitriptyline hydrochloride solution;

[0061] (2) adding 23 g of glycerol, 0.1 g of ethylparaben, and 0.5 g of laurocapram to the mixed solution, and stirring to dissolve them completely to obtain a colorless and odorless gel matrix with uniformly distributed bubbles;

[0062] (3) Slowly add the amitriptyline hydrochloride solution into the gel matrix while stirring continuously, then add 17.4 g of water and stir thoroughly to obtain the amitriptyline gel.

[0063] Example 4: Preparation of Amitriptyline Gel

[0064] (1) 7 g of hypromellose was mixed with 33 g of water, and the mixture was swollen to obtain a mixed solution, and 3 g of amitriptyline hydrochloride was mixed with 22 g of a 75% ethanol solution to obtain an amitriptyline hydrochloride solution;

[0065] (2) adding 19 g of glycerol, 0.1 g of ethylparaben, and 0.5 g of laurocapram to the mixed solution, and stirring to dissolve them completely to obtain a colorless and odorless gel matrix with evenly distributed bubbles;

[0066] (3) Slowly add the amitriptyline hydrochloride solution into the gel matrix while stirring continuously, then add 15.4 g of water and stir thoroughly to obtain the amitriptyline gel.

[0067] Example 5: Preparation of Amitriptyline Gel

[0068] (1) 3 g of hypromellose was mixed with 28 g of water, and the mixture was swollen to obtain a mixed solution, and 7 g of amitriptyline hydrochloride was mixed with 18 g of a 75% ethanol solution to obtain an amitriptyline hydrochloride solution;

[0069] (2) adding 18 g of glycerol, 0.1 g of ethylparaben, and 0.5 g of laurocapram to the mixed solution, and stirring to dissolve them completely to obtain a colorless and odorless gel matrix with evenly distributed bubbles;

[0070] (3) Slowly add the amitriptyline hydrochloride solution into the gel matrix while stirring continuously, then add 25.4 g of water and stir thoroughly to obtain the amitriptyline gel.

[0071] Example 6: Preparation method of amitriptyline gel patch

[0072] The amitriptyline gel patch preparation machine uses the GSPH-TB400 all-in-one coating and slicing machine, which consists of two major components: the mechanical section and the electrical control system. The mechanical section primarily comprises the main frame, melt mechanism, coating mechanism, unwinding mechanism, laminating mechanism, cooling mechanism, feeding mechanism, slicing mechanism, discharging mechanism, waste handling mechanism, and exterior protection plate. The electrical control system comprises the main power switch, measurement and control components, and controls the heating and motor components to achieve each step of the operation.

[0073] Amitriptyline gel patch was prepared using siliconized paper as the isolation layer and a composite film formed by laminating non-woven fabric and polypropylene film as the backing layer using a GSPH-TB400 coating and slicing machine. The specific method is as follows:

[0074] Connect the main power supply, turn on the power switch, power the system, install the patch base material (silicone oil paper) on the front discharge mechanism, raise the glue by hand, and adjust the height of the baffles on the front and rear sides of the tank. Flatten the base material and feed it from the top of the glue tank bottom plate to the feeding rubber roller. Reduce the gap between the front and rear baffles and the bottom plate to allow the base material to pass smoothly; adjust the baffles on the left and right sides of the glue tank bottom plate to the coating width. Install the composite coil (a composite film composed of non-woven fabric and polypropylene film layers). The composite material and base material are completely overlapped and fed to the feeding rubber roller. Turn on the heating switch and adjust the glue tank temperature control instrument to the appropriate temperature (around 100°C). When the glue tank temperature reaches the set temperature value, it will automatically enter the insulation state. Pour the pre-cooked glue into the glue tank. Turn on the fan switch to cool the backing layer during the coating process. 500 g of amitriptyline gel was prepared by the preparation method of Example 1. 500 g of amitriptyline gel was introduced into the medicine tank, the motor switch was turned on, the rubber roller motor and the knife roller motor were started, and the prepared plaster was rolled and cut to obtain a drug loading of 4 mg / cm 2 Amitriptyline gel patch, the structure of Amitriptyline gel patch is as follows Figure 1 The preparation process is as shown in Figure 2 shown.

[0075] Test Example 1: Determination of Amitriptyline Gel Content

[0076] 1. Experimental instruments and reagents

[0077] Thermo Fisher Vanquish UPLC instrument (quaternary gradient pump, autosampler, constant temperature column chamber, VWD-3400 four-wavelength detector, Chromeleon 3.2 software processing system); AUW-120D electronic analytical balance (produced by Shimadzu Corporation, Japan, sensitivity: 0.01 mg); KM-410D ultrasonic cleaner (produced by Guangzhou Kejiemeng Experimental Instrument Co., Ltd., 240 W, 40 kHz); YP1002N electronic balance (produced by Shanghai Jinghai Instrument Co., Ltd., sensitivity: 0.01 g).

[0078] 2. Chromatographic conditions

[0079] Chromatographic column: Hypersil QOLD (100×2.1mm, 9μm); mobile phase: methanol: water: triethylamine 60:40:0.3 (pH adjusted to 3.1 with phosphoric acid); flow rate: 0.2mL / min; detection wavelength: 240nm; injection volume: 2μL; column temperature: 30℃.

[0080] 3. Prepare the solution

[0081] 3.1 Preparation of reference solution

[0082] Take 13.32 mg of amitriptyline hydrochloride standard, accurately weigh it into a 25 mL volumetric flask, dissolve it in methanol and dilute it to the mark, shake it well, and obtain the amitriptyline hydrochloride reference stock solution (0.533 mg mL -1 ), accurately transfer 1 mL to a 10 mL volumetric flask, add mobile phase to dilute to the mark, shake well, and obtain 0.0533 mg mL -1 Reference solution, set aside.

[0083] 3.2 Preparation of test solution

[0084] Accurately weigh 1 g of amitriptyline gel and place it in a 100 mL conical flask with a stopper. Add 50 mL of pure water and sonicate until completely dissolved. Cool to room temperature, add pure water to the scale line of the conical flask with a stopper, shake well, and use it as the stock solution of amitriptyline hydrochloride (1 mg mL -1 ).

[0085] 3.3UPLC chromatography detection

[0086] Accurately measure 1 mL of amitriptyline hydrochloride reference stock solution into a 10 mL volumetric flask, add mobile phase to dilute to 10 mL, shake well, 0.0533 mg mL -1 Reference solution.

[0087] A test stock solution was prepared using the amitriptyline gel prepared in Example 1. Then, 0.5 mL to 10 mL of the test stock solution was accurately measured into a volumetric flask, and the mobile phase was added to dilute to the scale and shaken to obtain a test solution.

[0088] The test solution and reference solution were analyzed using Thermo Fisher Vanquish UPLC according to "2. Chromatographic conditions". The UPLC chromatogram of the reference solution is shown in the figure below. Figure 3 As shown, the UPLC chromatogram of the test solution is as follows Figure 4 shown.

[0089] according to Figure 3 and Figure 4 It can be seen that this method can detect amitriptyline hydrochloride in amitriptyline gel.

[0090] 4. Methodological Investigation

[0091] 4.1 Investigation of linear relationships

[0092] Accurately pipette an appropriate amount of the amitriptyline hydrochloride reference solution obtained in "3.1 Preparation of Reference Solution" and add the mobile phase to dilute it into 5 series of concentrations (0.0106, 0.0266, 0.0533, 0.1066, 0.2665 mg mL -1) of the reference solution, and inject the reference solution from low concentration to high concentration in accordance with "2. Chromatographic Conditions". Draw a standard curve with the concentration X of the reference solution as the horizontal axis and the peak area Y as the vertical axis for linear relationship analysis. The results are as follows Figure 5 shown.

[0093] according to Figure 5 It can be seen that the linear regression equation is Y = 264.88X-0.027, R 2 =0.9996, and the linear range is 0.0106~0.2665mg / mL.

[0094] 4.2 Precision test

[0095] The reference solution under "3.1 Preparation of Reference Solution" was selected and injected six times according to "2. Chromatographic Conditions". The peak area of ​​amitriptyline hydrochloride was measured and the RSD value was calculated. The results are shown in Table 1.

[0096] Table 1 Precision test results

[0097] Serial number 1 2 3 4 5 6 mean RSD Peak area 14.89 15.08 14.78 15.11 14.87 14.89 14.94 0.86％

[0098] According to Table 1, the peak areas of amitriptyline hydrochloride for 6 times were not much different, and the RSD value was 0.86%, indicating that the instrument had good precision.

[0099] 4.3 Repeatability test

[0100] Six batches of amitriptyline gel were prepared according to the preparation method of Example 1, and the amitriptyline hydrochloride stock solutions (1 mg mL -1 Accurately measure 0.5 mL of the amitriptyline hydrochloride stock solution numbered 1 to 6 into a 10 mL volumetric flask, add the mobile phase to dilute to the scale, shake well, and obtain the test solution numbered 1 to 6. Samples were injected and measured according to "2. Chromatographic Conditions". The average content of amitriptyline hydrochloride and RSD were calculated. The results are shown in Table 2.

[0101] Table 2 Repeatability test results

[0102] Serial number 1 2 3 4 5 6 mean RSD content 5.1％ 4.9％ 5.1％ 4.9％ 5.0％ 5.1％ 5.06％ 1.81％

[0103] According to Table 2, the amitriptyline hydrochloride content in the test solutions numbered 1 to 6 was not much different, with an average value of 5.06% and an RSD of 1.81% (n=6), indicating that the method had good repeatability.

[0104] 4.4 Sample recovery test

[0105] Weigh 0.5209g, 0.5163g, 0.4916g, 0.4991g, 0.5311g and 0.5079g of the amitriptyline gel prepared in Example 1 respectively, put into a 100mL stoppered conical flask, add 50mL of pure water, ultrasonically dissolve completely, cool to room temperature, add pure water to the scale line of the stoppered conical flask, shake up, and obtain amitriptyline hydrochloride test sample storing solutions of different gel masses. Accurately weigh 0.25mL of amitriptyline hydrochloride test sample storing solutions of different gel masses to 10mL volumetric flasks, respectively add 0.2665mg of amitriptyline hydrochloride standard, add mobile phase and dilute to the scale, shake up, and measure the amitriptyline hydrochloride content by sample introduction according to "2. chromatographic conditions", and calculate the recovery of sample addition. The results are as shown in Table 3.

[0106] Table 3 Sample recovery results

[0107]

[0108] According to Table 3, the mean recovery rate was 99.20% and the RSD value was 1.79%, indicating that the test method had good accuracy.

[0109] 5. Determination of Sample Content

[0110] Three batches of amitriptyline gel were prepared according to the preparation method of amitriptyline gel in Example 1. Test solutions were prepared from these batches and the amitriptyline content in the test solutions was determined using a Thermo Fisher Scientific Vanquish UPLC instrument. The chromatographic conditions were: column: Hypersil QOLD (100×2.1 mm, 9 μm); mobile phase: methanol:water:triethylamine (60:40:0.3) (pH adjusted to 3.1 with phosphoric acid); flow rate: 0.2 mL / min; detection wavelength: 240 nm; injection volume: 2 μL; column temperature: 30°C. Each batch of samples was measured in parallel three times, and the chromatograms were recorded. The amitriptyline content was calculated using the external standard method.

[0111] The results showed that the contents of amitriptyline in the three batches of amitriptyline gel prepared according to the method of Example 1 were 5.16%, 4.32% and 4.33%, respectively.

[0112] Test Example 2: Animal Test of Amitriptyline Gel Patch

[0113] 1. Animal Modeling

[0114] Twenty-eight adult male C57BL / 6J mice were divided into four groups, namely experimental group A, experimental group B, control group, and blank group, with 7 mice in each group. The mice in experimental group A, experimental group B, and control group were anesthetized by intraperitoneal injection of 50 mg / kg of sodium pentobarbital. The mice were then placed in a prone position, the surface hair near the right femur of the mice was cleaned, and after disinfection with iodine, an 8 mm longitudinal incision was made in the midline of the right femur to expose the subcutaneous muscle. The muscle was bluntly separated with hemostatic forceps to expose the sciatic nerve. Four 0 surgical sutures were loosely ligated around the sciatic nerve at intervals of 1 mm, and the ligation was repeated three times to obtain a neuropathic pain model (CCI model). Figure 6 As shown; mice in the control group did not undergo sciatic nerve ligation. The key features of the CCI model are: moderate sciatic nerve ligation causes a degree of damage, which in turn affects distal nerve fibers. Mechanical compression of the nerve by surgical sutures induces a chronic inflammatory response, mimicking the characteristics of neuropathic and inflammatory pain, accompanied by intraneural edema, focal ischemia, and axonal degeneration. Following surgery, the sciatic nerve is repositioned, the muscles are trimmed, and the wound is sutured.

[0115] 2. Experimental Methods

[0116] The amitriptyline gel patch used in the experimental method is the amitriptyline gel patch prepared by the method of Example 6.

[0117] The experiment was started on the 7th day after the successful establishment of the mouse model. The mice in experimental group A and experimental group B were given amitriptyline gel patches near the right femur starting from the 7th day, each application lasting 20 minutes, 3 times a day. The modeling mice in the control group were given placebo patches (containing only dressing ingredients but not amitriptyline) without amitriptyline. The mice in the blank group were not treated in any way. It should be noted that all experimental mice were placed in a special container to prevent them from biting the patches. The dosing position of the mice was as follows: Figure 7 As shown, one week after the experiment, behavioral indicators of mice in each group were measured. The mice in experimental group A were given amitriptyline gel patch 0.5 h before the behavioral indicator measurement, while the mice in experimental group B were not given any drug 0.5 h before the behavioral indicator measurement.

[0118] 3. Determination of Mouse Behavioral Indices

[0119] a. Determination of mechanical pain threshold of mice: Each group of mice was placed in a plexiglass cage with a metal mesh bottom (10×10×10 cm). After acclimating to the environment for 15 minutes and being in a quiet state, the mechanical pain threshold of each group of mice was measured using a 37450 Ugo basile paw tactile tester. Specifically, the mechanical needle was controlled to vertically stimulate the skin of the middle plantar of each group of mice from bottom to top. The stimulation intensity was set to gradually increase from 0g to 10g within 20s. When each group of mice showed a rapid paw withdrawal reaction, the stimulation was stopped and the stimulation pressure value was recorded. The measurement was performed three times, with an interval of 5 minutes between each time. The average of the three stimulation pressure values ​​was taken as the mechanical pain threshold. The test results are shown in the figure. Figure 8 As shown in the figure, the horizontal axis represents the mouse number, and the vertical axis represents the mechanical pain threshold of the mouse (g).

[0120] b. Determination of cold pain response in mice: After the administration of each group of mice, the cold pain response was measured using an Ugo Basile cold / hot combination plate. Specifically, the temperature of the cold plate was lowered to 5±0.5°C and isolated from the external environment with a fiberglass plate to maintain a constant temperature. Each group of mice was placed on the cold plate. The mice licked or lifted their feet due to pain. The time when the mice licked or withdrew their paws was observed and recorded. The test results were as follows: Figure 9 As shown in the figure, the vertical axis represents the time (s) of licking or paw withdrawal, and the horizontal axis represents the mouse number;

[0121] c. Determination of thermal pain response in mice: After the administration of each group of mice, the thermal pain response was measured using an Ugo Basile hot / cold combination plate. Specifically, the hot plate was heated to 55±0.5°C and isolated from the external environment with a fiberglass board to maintain a constant temperature. Each group of mice was placed on the hot plate. The mice licked or lifted their paws due to pain. The time when the mice licked or withdrew their paws was observed and recorded. The test results were as follows: Figure 10 As shown in the figure, the vertical axis represents the time (s) of licking or paw withdrawal action, and the horizontal axis represents the mouse number.

[0122] The results of behavioral tests showed that amitriptyline gel patch had a rapid analgesic effect on CCI model mice, and no central nervous system or skin side effects were found during use.

[0123] As can be seen from the above embodiments, the present invention provides an amitriptyline gel, a preparation method thereof, and an application thereof. The amitriptyline gel of the present invention is prepared from amitriptyline hydrochloride, glycerin, hypromellose, 70-80% ethanol solution, ethylparaben, laurocapram, and water. The preparation method of the amitriptyline gel is simple and can effectively reduce side effects. The amitriptyline gel patch prepared using the amitriptyline gel of the present invention can effectively relieve postherpetic neuralgia and can effectively reduce side effects compared to traditional oral tablets.

[0124] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. An amitriptyline gel, characterized in that The amitriptyline gel comprises the following components in parts by mass: 2-8 parts of amitriptyline hydrochloride, 16-24 parts of glycerin, 2-8 parts of hypromellose, 16-24 parts of 70-80% ethanol solution, 0.05-0.15 parts of ethylparaben, 0.2-0.8 parts of laurocapram, and 36-64 parts of water.

2. The amitriptyline gel according to claim 1, wherein The amitriptyline gel comprises the following components in parts by mass: 4-6 parts of amitriptyline hydrochloride, 18-22 parts of glycerin, 4-6 parts of hypromellose, 18-22 parts of 70-80% ethanol solution, 0.07-0.13 parts of ethylparaben, 0.4-0.6 parts of laurocapram, and 42-58 parts of water.

3. The amitriptyline gel according to claim 1, wherein The amitriptyline gel comprises the following components in parts by mass: 5 parts of amitriptyline hydrochloride, 20 parts of glycerin, 5 parts of hypromellose, 20 parts of 70-80% ethanol solution, 0.1 part of ethylparaben, 0.5 part of laurocapram and 49.4 parts of water.

4. The method for preparing the amitriptyline gel according to any one of claims 1 to 3, characterized in that: The steps include: (1) mixing hypromellose with 1 / 2 to 3 / 4 of water to obtain a mixed solution, and mixing amitriptyline hydrochloride with 70 to 80% ethanol solution to obtain an amitriptyline hydrochloride solution; (2) adding glycerin, ethylparaben, and laurocapram to the mixed solution to obtain a gel matrix; (3) Mixing the amitriptyline hydrochloride solution, the gel base and the remaining water to obtain an amitriptyline gel.

5. Use of the amitriptyline gel according to any one of claims 1 to 3 or the amitriptyline gel prepared by the preparation method according to claim 4 in the preparation of a medicament for treating postherpetic neuralgia.

6. An amitriptyline gel patch, characterized in that: The amitriptyline gel patch comprises an isolation layer, a gel drug layer and a backing layer; The gel drug layer comprises the amitriptyline gel according to any one of claims 1 to 3 or the amitriptyline gel prepared by the preparation method according to claim 4.

7. The amitriptyline gel patch according to claim 6, wherein The dosage of amitriptyline gel in the amitriptyline gel patch is 3 mg / cm 2 ~5mg / cm 2 .

8. The amitriptyline gel patch according to claim 6, wherein The isolation layer is siliconized paper, PVC transparent corrugated film or flat film.

9. The amitriptyline gel patch according to claim 6, wherein The backing layer is a composite film; The composite film is formed by laminating non-woven fabric and polypropylene film.

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