Cimetidine external gel as well as preparation method and application thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses external cimetidine gel as well as a preparation method and application thereof. The cimetidine external gel is prepared from 2 to 4 parts of cimetidine, 2 to 4 parts of sodium carboxymethyl cellulose, 1 to 3 parts of gelatin, 3 to 5 parts of azone, 4 to 6 parts of glycerinum, 28 to 32 parts of absolute ethyl alcohol and 52 to 55 parts of distilled water. The cimetidine external gel provided by the invention has the advantages that the fineness, spreading property and uniformity of the gel are obviously improved, the gel is non-irritant to skin mucous membranes, continuous and stable release of cimetidine is realized through the synergistic effect of all the components, the bioavailability of cimetidine is improved, and meanwhile, the cimetidine external gel has a good application prospect. According to the cimetidine injection, the transdermal absorption performance of cimetidine is remarkably improved, the cimetidine injection has a very good relieving effect on skin itch, the acting time is long, the medication frequency can be remarkably reduced, the risk of adverse reaction is reduced, and an effective and rapid treatment scheme is provided for pruritus caused by various reasons.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a cimetidine external gel and a preparation method and application thereof. Background Art

[0002] Skin itching has become one of the 50 most common high-burden interdisciplinary symptoms in the world. Itching can bring great inconvenience and burden to patients' work and life, and the current treatment methods are not very ideal. There are currently three types of drugs commonly used for itching symptoms. The first category is antihistamines, the second category is commonly used Chinese patent medicines for oral administration, and the third category is topical antipruritic agents. The topical antipruritic agents used clinically include fusidic acid cream, dermatitis cream, etc., which are mostly carrier hormone drugs and cannot be used for a long time on a large area. Therefore, there is an urgent need to develop new antipruritic drugs.

[0003] Cimetidine is a histamine H2 receptor blocker, which is widely used in the treatment of heartburn and gastric acid reflux. In the treatment of skin diseases, it was found during the study that cimetidine has an excellent curative effect on the elimination time of rash, elimination of symptoms, etc., and it is effective relatively quickly, and the course of disease is short. At present, a lot of cimetidine research on skin diseases has been done at home and abroad, and it has been found that it has a significant effect. Topical application of cimetidine has been proved to be a valuable medicine for the treatment of skin diseases (such as inflammation and skin warts, etc.). However, the half-life of cimetidine is shorter, and frequent multiple medication is required every day, which affects the convenience and compliance of patients' medication. Moreover, traditional skin external preparations are difficult to realize the sustained and stable release of drugs, which affects the performance of cimetidine drug effect. Therefore, it is necessary to develop a cimetidine external sustained-release preparation to realize the sustained and stable release of cimetidine in the skin surface, improve the curative effect, reduce side effects, and provide new options for the quality of skin diseases. Summary of the invention

[0004] Aiming at the problems that cimetidine has a short half-life and needs to be taken frequently and multiple times a day, the present invention provides a cimetidine external gel and a preparation method thereof.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] A cimetidine external gel comprises the following components in parts by weight: 2-4 parts of cimetidine, 2-4 parts of sodium carboxymethyl cellulose, 1-3 parts of gelatin, 3-5 parts of laurocapram, 4-6 parts of glycerol, 28-32 parts of anhydrous ethanol and 52-55 parts of distilled water.

[0007] As a transdermal drug delivery preparation, the release of the drug from the matrix and the penetration of the drug through the skin barrier are key factors affecting drug absorption and effect. Furthermore, the compatibility between the drug and the carrier material will also affect the stability and efficacy of the preparation. Cimetidine has a small oil-water distribution, and its effective delivery in intact skin is difficult to achieve. The passive penetration of hydrophilic drug molecules can be inhibited by the lipid-rich membrane of the skin. Cimetidine is a low-permeability drug, and the rate of penetrating the biological membrane is the main factor limiting its absorption.

[0008] The cimetidine external gel provided by the invention selects sodium carboxymethyl cellulose and gelatin as the matrix of the gel, which has good compatibility with cimetidine, is conducive to maintaining the stability of the cimetidine drug, improves the chemical stability of cimetidine in the preparation, and can improve the sensory characteristics of the preparation, so that the prepared gel is uniform and delicate, has strong spreadability and no granularity, thereby being conducive to improving the patient's acceptance and medication compliance; at the same time, sodium carboxymethyl cellulose and gelatin are compounded in a specific ratio, so that the pH value of the gel can be stabilized at 5-6, so that in the drug release stage, cimetidine is an ionic drug, which is conducive to the dispersion and migration of cimetidine in the gel, thereby accelerating the drug release rate; through the action of skin penetration enhancers laurocapram and ethanol, the skin barrier is opened, which is conducive to drug absorption, and cimetidine contacts with ions in sweat and can be partially converted into a molecular drug, which is conducive to the drug passing through the lipid membrane and promoting drug absorption; in addition, the gelatin in the gel matrix is ​​affected by the ions in the sweat, which can reduce the local gel viscosity and is also conducive to the release of the drug.

[0009] The cimetidine provided by the present invention realizes the sustained and stable release of the drug, which is beneficial to reducing the number of drug administrations, improving the patient's acceptance and compliance, and at the same time reduces the fluctuation of blood drug concentration, reduces the risk of adverse reactions, and provides a safer and more effective treatment plan for the clinical treatment of skin diseases, and has high practical value.

[0010] Preferably, the cimetidine topical gel comprises the following components in parts by weight: 2.5 to 3.5 parts of cimetidine, 2.5 to 3.5 parts of sodium carboxymethyl cellulose, 1.5 to 2.5 parts of gelatin, 3.5 to 4.5 parts of laurocapram, 4.5 to 5.5 parts of glycerol, 29 to 31 parts of ethanol and 52 to 54 parts of distilled water.

[0011] Preferably, the cimetidine topical gel comprises the following components in parts by mass: 3 parts of cimetidine, 3 parts of sodium carboxymethyl cellulose, 2 parts of gelatin, 4 parts of laurocapram, 5 parts of glycerol, 30 parts of ethanol and 53 parts of distilled water.

[0012] The invention prepares gelatin and sodium carboxymethyl cellulose in a specific ratio, uses anhydrous ethanol as a solvent and a penetration enhancer, and cooperates with laurocapram to effectively improve the transdermal absorption rate of cimetidine, thereby facilitating the maintenance of the concentration of the drug in the skin surface layer and improving the therapeutic effect.

[0013] The present invention also provides a method for preparing a cimetidine external gel, comprising the following steps:

[0014] S1, weighing each component according to the designed ratio, and mixing the weighed cimetidine, anhydrous ethanol and distilled water evenly to obtain a mixed solution A;

[0015] S2, mixing the weighed glycerol and laurocapram uniformly to obtain a mixed solution B;

[0016] S3, mixing the weighed sodium carboxymethyl cellulose, gelatin and the mixed solution A evenly, and swelling them to obtain a mixed solution C;

[0017] S4, mixing the mixed liquid B and the mixed liquid C evenly, and swelling them to obtain a cimetidine external gel.

[0018] The preparation method of the cimetidine external gel provided by the invention has the advantages of simple operation, low cost, convenience for realizing industrial-scale production, and broad application prospects.

[0019] Preferably, in S3, the swelling temperature is 20° C. to 25° C., and the swelling time is 8 min to 12 min.

[0020] Preferably, in S4, the swelling temperature is 20° C. to 25° C., and the swelling time is 10 min to 15 min.

[0021] The invention also provides application of the cimetidine external gel as a medicine for treating skin diseases.

[0022] The cimetidine external gel provided by the present invention significantly improves the fineness, spreadability and uniformity of the gel, has excellent physical stability and chemical stability, is non-irritating to skin and mucous membranes, realizes the sustained and stable release of cimetidine through the synergistic effect of various components, is beneficial to improving the bioavailability of cimetidine, and at the same time, significantly improves the transdermal absorbability of cimetidine, has a good alleviating effect on skin itching, has a long action time, can significantly reduce the number of medications, reduces the risk of adverse reactions, provides an effective and rapid treatment plan for pruritus caused by various reasons, and has broad market prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is an in vitro release curve of the cimetidine gel prepared in Example 1 of the present invention;

[0024] Figure 2This is a comparison of the drug concentration-time curves in the blood samples of mice after oral and transdermal administration of cimetidine. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0026] In order to better illustrate the present invention, further examples are given below.

[0027] The enzyme-linked immunosorbent assay kit used in the following examples is ELISA Kit 96T, produced by Jiangsu ELISA Biotechnology Co., Ltd.

[0028] Example 1

[0029] This embodiment provides a cimetidine gel, comprising the following components:

[0030] 3 parts of cimetidine, 3 parts of sodium carboxymethyl cellulose, 2 parts of gelatin, 4 parts of laurocapram, 5 parts of glycerol, 30 parts of anhydrous ethanol and 53 parts of distilled water.

[0031] The preparation method of the above-mentioned cimetidine gel comprises the steps:

[0032] S1, weighing each component according to the designed ratio, and mixing the weighed cimetidine, anhydrous ethanol and distilled water evenly to obtain a mixed solution A;

[0033] S2, mixing the weighed glycerol and laurocapram uniformly to obtain a mixed solution B;

[0034] S3, mixing the weighed sodium carboxymethyl cellulose, gelatin and the mixed solution A uniformly, stirring in a 25° C. water bath for 10 min to make the solution swell, and obtaining a mixed solution C;

[0035] S4, mixing the mixed solution B and the mixed solution C evenly, and letting them stand at 25° C. for 12 hours to make them swell, thereby obtaining a cimetidine external gel.

[0036] Example 2

[0037] This embodiment provides a cimetidine gel, comprising the following components:

[0038] 2 parts of cimetidine, 4 parts of sodium carboxymethyl cellulose, 1 part of gelatin, 3 parts of laurocapram, 4 parts of glycerol, 28 parts of anhydrous ethanol and 52 parts of distilled water.

[0039] The preparation method of the above-mentioned cimetidine gel comprises the steps:

[0040] S1, weighing each component according to the designed ratio, and mixing the weighed cimetidine, anhydrous ethanol and distilled water evenly to obtain a mixed solution A;

[0041] S2, mixing the weighed glycerol and laurocapram uniformly to obtain a mixed solution B;

[0042] S3, mixing the weighed sodium carboxymethyl cellulose, gelatin and the mixed solution A uniformly, stirring in a 25° C. water bath for 8 minutes to make the solution swell, and obtaining a mixed solution C;

[0043] S4, mixing the mixed solution B and the mixed solution C evenly, and letting them stand at 25° C. for 10 hours to make them swell, thereby obtaining a cimetidine external gel.

[0044] Example 3

[0045] This embodiment provides a cimetidine gel, comprising the following components:

[0046] 4 parts of cimetidine, 2 parts of sodium carboxymethyl cellulose, 3 parts of gelatin, 5 parts of laurocapram, 6 parts of glycerol, 32 parts of anhydrous ethanol and 55 parts of distilled water.

[0047] The preparation method of the above-mentioned cimetidine gel comprises the steps:

[0048] S1, weighing each component according to the designed ratio, and mixing the weighed cimetidine, anhydrous ethanol and distilled water evenly to obtain a mixed solution A;

[0049] S2, mixing the weighed glycerol and laurocapram uniformly to obtain a mixed solution B;

[0050] S3, mixing the weighed sodium carboxymethyl cellulose, gelatin and the mixed solution A uniformly, stirring in a 20° C. water bath for 12 minutes to make the solution swell, and obtaining a mixed solution C;

[0051] S4, mixing the mixed solution B and the mixed solution C evenly, and letting them stand at 20° C. for 14 hours to make them swell, thereby obtaining a cimetidine external gel.

[0052] The cimetidine topical gel prepared in the above Examples 1 to 3 is a colorless, odorless, transparent colloid with good spreadability, no granularity, and uniform and fine texture. Moreover, according to the test, adding different concentrations of sodium chloride or potassium chloride (10 mmol / L to 70 mmol / L relative to the concentration of distilled water) to the mixed liquid A during the preparation process does not affect the gelling property, which proves that gelatin and sodium carboxymethyl cellulose are suitable as the gel matrix of cimetidine.

[0053] 9.0 g of cimetidine gel was weighed and placed in a beaker, ultrasonicated for 15 min, and its pH value was measured with a pH meter, and the measurement was repeated three times. The results showed that the pH of the three batches of gel prepared in the above embodiment was between 5.3 and 5.5, which would not irritate the skin and met the requirements of the pharmacopoeia.

[0054] The viscosity of the prepared cimetidine gel was accurately tested at room temperature using a NDJ-5s rotational viscometer according to the third method of viscosity determination method 0633 of Part IV of the Chinese Pharmacopoeia in 2020. Rotor No. 4 was selected with a rotation speed of 60 r / min. The measurements were performed three times in parallel. The results are shown in Table 1.

[0055] Table 1 Viscosity of cimetidine gel (mPa·s)

[0056] Viscosity Example 1 9450±5.4 Example 2 9376±7.2 Example 3 9547±4.6

[0057] The viscosity of cimetidine gel is relatively stable, which complies with the requirements of the pharmacopoeia, is beneficial for increasing the skin retention time, enabling the preparation to better exert its efficacy, and meets the standards for gel adhesion on the skin.

[0058] Take 3.0g cimetidine gel sample prepared in three batches of Example 1, dilute 1000 times to prepare the test solution, start injection according to the following chromatographic conditions, record the liquid chromatogram area, calculate the concentration according to the standard curve, and measure the content of cimetidine. The results are shown in Table 2.

[0059] The chromatographic conditions are:

[0060] Chromatographic column: Xtimate C18 (4.6 mm × 150 mm, 5 μm);

[0061] Mobile phase: methanol: water: acetic acid = 20:75:5;

[0062] Detection wavelength: 217nm;

[0063] Flow rate: 1.0 mL / min;

[0064] Column temperature: 25°C;

[0065] Injection volume: 20 μL.

[0066] Table 2 Content of 3g cimetidine gel

[0067]

[0068] The RSD of each group of samples was less than 2%, indicating that the contents of the three batches of samples prepared in Example 1 remained relatively stable.

[0069] In vitro release determination

[0070] Weigh 2.0g of the cimetidine gel prepared in Example 1 and put it into the treated dialysis membrane, clamp the dialysis membrane with the equipped clip, and put the dialysis bag into 250mL of normal saline. The solubility of normal saline to cimetidine is 3.42±0.39mg / mL, which meets the sink condition. The water bath temperature is room temperature, the stirring speed is 500r / min, and 2mL of normal saline is taken at 0.5h, 1h, 1.5h, 2h, 4h, 6h, 12h, and 24h, respectively. At the same time, add 2mL of normal saline of equal volume and temperature. After the normal saline taken out is diluted in equal proportion, it is filtered with a 0.45μm microporous filter membrane, and HPLC detection is performed to calculate the cumulative release rate. Repeat three times, calculate the average value, and make a release curve with time t (h) as the X-axis and the cumulative release percentage as the Y-axis. The results are as follows: Figure 1 shown.

[0071] The results show that when the dialysis bag is used as a permeation barrier for the cimetidine gel sample, the 24h permeation percentage can be close to 90%, indicating that the dialysis bag does not limit the release of cimetidine, and when the dialysis bag is used as a barrier, the cimetidine gel has a sustained release effect.

[0072] Itch behavior test

[0073] Twenty-four mice were randomly selected and divided into a blank group, a model group, a dexamethasone group, and a cimetidine group. 12 hours before the experiment, 3% sodium sulfide was used to remove the hair on both sides of the spine of the mice (the area was about 8 cm 2 ), and fasted for 12h, the mice were fixed on the foam board, and the limbs and head of the mice were fixed with fine wires for easy administration. The blank group was not treated in any way; the model group was injected with diluted dextran injection (1.25mg / kg); the dexamethasone group was injected with diluted dextran injection (1.25mg / kg) and then smeared with dexamethasone gel (gel 0.3g, dexamethasone content 0.225mg); the cimetidine group was injected with diluted dextran injection (1.25mg / kg), and then smeared with cimetidine gel prepared in Example 1 (gel 0.3g, cimetidine content 9.0mg). Repeated measurements for three consecutive days, after medication, they were transferred to a quiet observation box, and the number of itching times within 30min after the mice were injected with diluted dextran injection (1.25mg / kg) was observed, recorded and averaged, and the results are shown in Table 3.

[0074] Table 3 Effect of cimetidine gel on the frequency of pruritus in mice

[0075] n Day 1 the next day Day 3 Blank group 6 1.23±0.27 0.93±0.20 0.85±0.26 Model Group 6 10.95±1.28 11.68±1.33 11.83±1.25 Dexamethasone group 6 4.86±0.39 5.02±0.74 6.52±0.59 Cimetidine group 6 3.78±0.75 3.94±0.55 3.59±0.43

[0076] The results showed that compared with the blank group, after the injection of dextran, the number of itching times of mice in the model group increased significantly (blank group and model group P < 0.05), with significant differences, indicating that dextran can cause an increase in the number of itching times of mice, proving that this method successfully established an itching model. Compared with the model group, the dexamethasone group, the dexamethasone gel can significantly reduce the number of itching times of mice (both groups P < 0.05). Compared with the model group, the number of scratching times of mice in the cimetidine group was significantly reduced, and compared with the dexamethasone group (P < 0.05), indicating that the anti-itching effect of cimetidine gel in the model established this time is stronger than that of dexamethasone gel.

[0077] Pharmacokinetic studies

[0078] Eight mice were randomly selected and divided into two groups. 12 h before the experiment, 3% sodium sulfide was used to remove the hair on the back of the mice's neck (an area of ​​about 4 cm 2 ), the test mice were fasted for 12 hours, and water was not restricted. One group of mice was gavaged with 20 mg / kg of cimetidine solution. Another group of mice was fixed in a fixed position, and the limbs and head of the mice were fixed with fine wires for transdermal administration. The cimetidine gel was evenly applied to the depilated part of the back spine, and the cimetidine gel was accurately drawn with a syringe and administered at 20 mg / kg. To prevent licking, medical gauze and tape were used to fix the mice during administration. At 15min, 30min, 1h, 2h, 3h, 4h, and 5h after administration, 0.1mL of blood was collected by tail cutting. The plasma samples were placed in centrifuge tubes, mixed evenly, and centrifuged at 5000r / min for 20min. The plasma was centrifuged out, and 10μL of supernatant plasma was accurately weighed and placed in a centrifuge tube. 20μL of internal standard solution (100μg / mL of metronidazole in methanol solution) was added, vortexed for 30s to mix evenly, 500μL of ethyl acetate was added, mixed evenly, vortexed for 3min, centrifuged for 10min (13000r / min), and the upper organic phase was taken; 500μL of ethyl acetate was added to the lower layer, mixed evenly, vortexed for 3min, centrifuged for 10min (13000r / min), and the upper organic phase was taken; the two organic phases were combined, evaporated to dryness under N2 at room temperature, 50μL of mobile phase was added for re-dissolution, centrifuged at 13000r / min for 5min, and 20μL of supernatant was taken for direct HPLC analysis.

[0079] The blood drug concentration-time curve of each mouse was fitted and analyzed using the pharmacokinetic program in DAS2.0 software to calculate the pharmacokinetic parameters and the peak time of blood drug (T max ) and peak plasma concentration (C max ) are all actual measured values, and parameters such as the area under the blood drug-time curve (AUC) were calculated using DAS2.0 software. Figure 2 As shown in Tables 4 and 5.

[0080] Table 4 Pharmacokinetic parameters of transdermal cimetidine gel in mouse plasma (n=4)

[0081]

[0082]

[0083] Table 5 Pharmacokinetic parameters of cimetidine gel in mouse plasma after oral administration (n=4)

[0084]

[0085] The results show that under the same dosage, the cimetidine gel administered by transdermal administration can reach the highest blood concentration in 120 minutes, which is about 90 minutes faster than the peak time of blood concentration in the oral administration group. And compared with oral administration, it has a sustained release effect. The highest blood concentration of transdermal administration can reach 758.46 mg / L, which is nearly three times that of oral administration. Compared with transdermal administration, oral administration conforms to the one-compartment model, while transdermal administration conforms to the two-compartment model. The blood concentration of the transdermal administration group decreases more slowly and is maintained for a longer time. At the same time, transdermal administration avoids the gastrointestinal inactivation effect and effectively improves bioavailability.

[0086] Mouse serum histamine content test

[0087] 1. Detection method: The concentration of histamine in mouse serum was determined by enzyme-linked immunosorbent assay. The kit was purchased from Jiangsu ELISA Biotechnology Co., Ltd. and the operation was performed according to the instructions.

[0088] 2. Experimental modeling: 12 mice were randomly selected and divided into a model group, a dexamethasone group, and a cimetidine group. 12 hours before the experiment, 3% sodium sulfide was used to remove the hair on both sides of the spine of the mice (the area was about 8cm 2 ), and fasted for 12h, the mice were fixed on the foam board, and the limbs and head of the mice were fixed with fine wires for easy administration. The model group was injected with diluted dextran injection (1.25mg / kg); the dexamethasone group was injected with diluted dextran injection (1.25mg / kg) and then applied with dexamethasone gel (gel 0.3g, dexamethasone content 0.225mg); the cimetidine group was injected with diluted dextran injection (1.25mg / kg) and then applied with cimetidine gel prepared in Example 1 (gel 0.3g, cimetidine content 9.0mg).

[0089] In the model group, the tail was cut off and blood was collected 15 minutes before the injection of dextran injection, and 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 60 minutes after the injection of dextran. In the dexamethasone group, dexamethasone gel was applied after the injection of dextran, and blood was collected by tail cutting 15 minutes before the injection of dextran injection, and 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 60 minutes after the injection of dextran. In the cimetidine group, cimetidine gel was applied after the injection of dextran injection, and blood was collected by tail cutting 15 minutes before the injection of dextran injection, and 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 60 minutes after the injection of dextran. Each time the tail was cut, 0.1 mL of blood was collected, and the plasma was collected in a centrifuge tube, mixed evenly, and centrifuged at 5000 r / min for 20 min to centrifuge the plasma. 20 μL of supernatant plasma was accurately weighed and placed in a centrifuge tube. The serum histamine content of mice was measured using an enzyme-linked immunosorbent assay kit to analyze the effect of cimetidine gel on the time and concentration of histamine secretion in mice in the mouse model. The results are shown in Table 6.

[0090] Table 6 Comparison of serum histamine levels in mice of different groups before and after administration at different times

[0091]

[0092]

[0093] As shown in Table 6, the histamine content in the model group increased significantly after dextran injection, indicating that dextran increases the histamine content in the mice and causes itching. The dexamethasone group was compared with the model group (P < 0.01), with a statistically significant difference, indicating that dexamethasone gel can reduce the increased histamine content in the mice caused by dextran injection. The cimetidine group was compared with the model group (P < 0.01), indicating that cimetidine gel can also reduce the histamine content, thereby reducing the degree of itching.

[0094] Comparative Example 1

[0095] This comparative example provides a cimetidine external gel, which is different from Example 1 only in that gelatin is replaced with an equal amount of xanthan gum. The specific formula is as follows:

[0096] 3 parts of cimetidine, 3 parts of sodium carboxymethyl cellulose, 2 parts of xanthan gum, 4 parts of laurocapram, 5 parts of glycerol, 30 parts of anhydrous ethanol and 53 parts of distilled water.

[0097] The above-mentioned cimetidine external gel was prepared in exactly the same manner as in Example 1, which will not be repeated herein.

[0098] The prepared cimetidine external gel is a yellow colloid with poor spreadability and strong granularity. Therefore, xanthan gum is not suitable as a gel matrix for cimetidine.

[0099] Comparative Example 2

[0100] This comparative example provides a cimetidine external gel, which is different from Example 1 only in that sodium carboxymethyl cellulose is replaced with an equal amount of gelatin. The specific formula is as follows:

[0101] 3 parts of cimetidine, 5 parts of gelatin, 4 parts of laurocapram, 5 parts of glycerol, 30 parts of anhydrous ethanol and 53 parts of distilled water.

[0102] The above cimetidine external gel was prepared in the same manner as in Example 1. In order to verify the effect of metal ions on the gelling property of the gel, different concentrations of NaCl were added during the preparation of the mixed solution A. The concentration of sodium chloride relative to distilled water was 10mmol / L, 20mmol / L, 30mmol / L, 40mmol / L, 50mmol / L, 60mmol / L, and 70mmol / L. It was found that gelatin alone as a matrix did not form a gel under the influence of alkali metal ions.

[0103] Comparative Example 3

[0104] This comparative example provides a cimetidine external gel, which is different from Example 1 only in that glycerol is replaced by an equal amount of polyethylene glycol or an equal amount of sorbitol. The specific formula is as follows:

[0105] 3 parts of cimetidine, 3 parts of sodium carboxymethyl cellulose, 2 parts of gelatin, 4 parts of laurocapram, 5 parts of polyethylene glycol (sorbitol), 30 parts of anhydrous ethanol and 53 parts of distilled water.

[0106] The above-mentioned cimetidine external gel was prepared in exactly the same manner as in Example 1, which will not be repeated herein.

[0107] The cimetidine gel prepared in Example 1 and this comparative example was placed in a 60° C. thermostat, and the water loss rate at different times was tested. The results are shown in Table 7.

[0108] Table 7 Water loss rate in 60℃ constant temperature box (%)

[0109] 15min 30min 45min 60min 90min 120min Example 1 9.85±0.76 14.56±0.54 18.54±0.78 24.35±0.85 27.66±0.54 31.32±0.74 Polyethylene glycol 12.54±0.62 16.45±0.54 21.75±0.85 26.82±0.45 30.22±0.78 35.45±0.64 Sorbitol 19.05±0.42 26.42±0.35 31.45±0.75 37.24±0.47 42.31±0.81 48.66±0.82

[0110] The cimetidine gel prepared in Example 1 and this comparative example was naturally placed in a room temperature environment, and the water loss rate at different times was tested. The results are shown in Table 8.

[0111] Table 8 Water loss rate at room temperature (%)

[0112] 15min 30min 45min 60min 90min 120min Example 1 5.92±0.75 8.25±0.66 10.71±0.45 12.13±0.63 14.26±0.98 15.67±0.75 Polyethylene glycol 7.23±0.58 11.61±0.78 13.75±0.42 14.56±0.52 16.73±0.51 18.63±0.77 Sorbitol 14.51±1.64 16.75±1.56 18.27±1.55 22.47±1.30 25.92±1.27 27.64±1.39

[0113] The results show that when glycerin is used as a humectant, the water loss rate is the lowest and the moisturizing effect is the best when placed at room temperature or in a constant temperature box at 60℃.

[0114] Comparative Example 4

[0115] This comparative example provides a cimetidine gel for external use, which is different from Example 1 only in that the amount of gelatin and sodium carboxymethyl cellulose added is changed so that the pH of the cimetidine gel is 7.5. The specific formula is as follows:

[0116] 3 parts of cimetidine, 4 parts of sodium carboxymethyl cellulose, 1 part of gelatin, 4 parts of laurocapram, 5 parts of glycerol, 30 parts of anhydrous ethanol and 53 parts of distilled water.

[0117] The above-mentioned cimetidine external gel was prepared in exactly the same manner as in Example 1, which will not be repeated herein.

[0118] Comparative Example 5

[0119] This comparative example provides a cimetidine gel for external use, which is different from Example 1 only in that the amount of gelatin and sodium carboxymethyl cellulose added is changed so that the pH of the cimetidine gel is 4.5. The specific formula is as follows:

[0120] 3 parts of cimetidine, 1 part of sodium carboxymethyl cellulose, 4 parts of gelatin, 4 parts of laurocapram, 5 parts of glycerol, 30 parts of anhydrous ethanol and 53 parts of distilled water.

[0121] The above-mentioned cimetidine external gel was prepared in exactly the same manner as in Example 1, which will not be repeated herein.

[0122] The cimetidine topical gel prepared in Example 1 and Comparative Examples 4 to 5 was tested for release rate, and the specific steps were as follows:

[0123] Accurately measure 1mL of the prepared cimetidine gel, place it in an activated dialysis bag, place the dialysis bag in 200mL of buffered release medium, select a phosphate buffer with a pH of 6.0 as the buffered release medium, set the water bath temperature to 32±0.5°C, and the stirring speed to 250r / min. Take 1mL of buffered release medium at a certain interval, and add 1mL of fresh buffered release medium at the same time. Take 20μL of sample and enter HPLC to detect the content of released cimetidine. Filter the test solution taken out at each time point through a 0.45μm microporous filter membrane, take 20μL of the filtrate and enter HPLC for detection and analysis, calculate the cumulative release rate, repeat 3 times, and average the data. The results are shown in Table 9.

[0124] Table 9 Release rate (%)

[0125]

[0126]

[0127] The results show that if the pH of cimetidine gel is not within the range of 5 to 6, the release rate of cimetidine will be significantly reduced. In addition, pH 5 to 6 has good skin tolerance and will not cause skin irritation.

[0128] Comparative Example 6

[0129] This comparative example provides a cimetidine topical gel, which is different from Example 1 in that laurocapram is replaced with menthol, propylene glycol or limonene at an optimal dosage. The specific formula is as follows:

[0130] 3 parts of cimetidine, 3 parts of sodium carboxymethyl cellulose, 2 parts of gelatin, 3 parts of menthol, 5 parts of glycerol, 30 parts of anhydrous ethanol and 54 parts of distilled water;

[0131] 3 parts of cimetidine, 3 parts of sodium carboxymethyl cellulose, 2 parts of gelatin, 3 parts of propylene glycol, 5 parts of glycerol, 30 parts of anhydrous ethanol and 54 parts of distilled water;

[0132] 3 parts of cimetidine, 3 parts of sodium carboxymethyl cellulose, 2 parts of gelatin, 4 parts of citric acid, 5 parts of glycerol, 30 parts of anhydrous ethanol and 53 parts of distilled water.

[0133] The above-mentioned cimetidine external gel was prepared in exactly the same manner as in Example 1, which will not be repeated herein.

[0134] The cimetidine external gel prepared in Example 1 and this comparative example was subjected to a release rate test, and the specific steps were as follows:

[0135] The TPY-2 medicinal transdermal diffusion tester was used to conduct the transdermal permeation experiment of cimetidine gel. Half an hour before the experiment, an appropriate amount of distilled water was injected into the medicinal transdermal diffusion tester, and the transdermal experiment was conducted using the "vertical wet method". The vertical beaker was placed in the container, the temperature was set to 37°C, the speed was set to 800r / min, the cover was closed, and the cover was sealed with the original sealing cap. The experiment can be carried out when the temperature in the diffusion instrument container reaches the preset temperature.

[0136] Place the specific rotor No. 1 in the receiving pool, place the treated and completely thawed pig skin between the supply pool and the receiving pool, with the stratum corneum of the pig skin facing the supply pool and the dermis facing the receiving pool, and use a phosphate buffer with a pH of 7.4 as the receiving solution. Ensure that the receiving pool is filled with the receiving solution and there is no gap with the upper layer, and suck out the bubbles with a syringe to avoid the generation of bubbles in the receiving pool. Use a syringe to draw an appropriate amount of cimetidine gel, place it on the pig skin, apply it evenly, and fill the supply pool with gel, put the set device into the transdermal diffusion tester, take 0.2mL of sample solution at 0.5h, 1.0h, 1.5h, 2.0h, 4.0h, 6.0h, 12.0h, and 24.0h, respectively, and add 0.2mL of pH7.4 phosphate buffer with a syringe each time to remove bubbles. The sample was placed in a 10 mL volumetric flask and fixed to volume with methanol, then placed in an ultrasonic cleaner for 2 minutes, and the solution to be tested after ultrasonication was filtered three times with a 0.45 μm microporous filter membrane, and then tested by HPLC to calculate the drug permeation amount. The results are shown in Table 10.

[0137]

[0138] J S =dQ / dt

[0139] ER=J / J0

[0140] Where V n - represents the volume of the receiving cell (8 mL);

[0141] C m - represents the cimetidine concentration measured at the mth sampling;

[0142] C i - represents the cimetidine concentration measured at the i-th sampling;

[0143] V i - indicates the volume of liquid removed from the receiving pool;

[0144] A- represents the effective skin penetration area (d=17 mm).

[0145] Calculate (Q, mg·cm -2 ), permeation rate (Js) and permeation enhancement ratio (ER). The transdermal release curve is drawn with Q as the ordinate and time (t) as the abscissa. The straight line part of the curve is regressed, and the slope of the straight line part is the steady-state permeation rate of the drug (Js, μg / cm 2 h).

[0146] Table 10 Cimetidine gel penetration enhancement Qt equation, Jss and ER parameters

[0147]

[0148]

[0149] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A cimetidine gel for external use, characterized in that: The invention comprises the following components in parts by weight: 2 to 4 parts of cimetidine, 2 to 4 parts of sodium carboxymethyl cellulose, 1 to 3 parts of gelatin, 3 to 5 parts of laurocapram, 4 to 6 parts of glycerol, 28 to 32 parts of anhydrous ethanol and 52 to 55 parts of distilled water.

2. The cimetidine external gel according to claim 1, wherein The invention comprises the following components in parts by weight: 2.5 to 3.5 parts of cimetidine, 2.5 to 3.5 parts of sodium carboxymethyl cellulose, 1.5 to 2.5 parts of gelatin, 3.5 to 4.5 parts of laurocapram, 4.5 to 5.5 parts of glycerol, 29 to 31 parts of ethanol and 52 to 54 parts of distilled water.

3. The cimetidine external gel as claimed in claim 2, characterized in that The invention comprises the following components in parts by weight: 3 parts of cimetidine, 3 parts of sodium carboxymethyl cellulose, 2 parts of gelatin, 4 parts of laurocapram, 5 parts of glycerol, 30 parts of ethanol and 53 parts of distilled water.

4. The cimetidine external gel according to claim 1, wherein The pH of the cimetidine external gel is 5-6.

5. The method for preparing the cimetidine external gel according to any one of claims 1 to 4, characterized in that: The steps include: S1, weighing each component according to the designed ratio, and mixing the weighed cimetidine, anhydrous ethanol and distilled water evenly to obtain a mixed solution A; S2, mixing the weighed glycerol and laurocapram uniformly to obtain a mixed solution B; S3, mixing the weighed sodium carboxymethyl cellulose, gelatin and the mixed solution A evenly, and swelling them to obtain a mixed solution C; S4, mixing the mixed liquid B and the mixed liquid C evenly, and swelling them to obtain a cimetidine external gel.

6. The method for preparing the cimetidine external gel according to claim 5, wherein In S3, the swelling temperature is 20°C to 25°C, and the swelling time is 8min to 12min.

7. The method for preparing the cimetidine external gel according to claim 5, wherein: In S4, the swelling temperature is 20°C to 25°C, and the swelling time is 10 min to 15 min.

8. Use of the cimetidine external gel according to any one of claims 1 to 4 as a drug for treating skin diseases.

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