Diazepam enema and preparation method thereof

Abstract

The invention discloses a diazepam enema liquid and a preparation method thereof, and relates to the field of pharmacy, and the key point of the technical scheme is that every 1000 ml of the diazepam enema liquid comprises 1-3 g of diazepam, 10-20 g of benzyl alcohol, 0.1-1.5 g of benzoic acid, 30-60 g of sodium benzoate, 90-100 g of ethanol, 350-500 g of propylene glycol, and the balance of purified water. The purposes of improving the solubility of diazepam, inhibiting volatilization and degradation of ethanol and reducing drug decomposition are achieved.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical preparation, and more particularly to a diazepam enema solution and a preparation method thereof. Background Art

[0002] Diazepam as a benzodiazepine It is a representative of a class of drugs and is widely used in the treatment of emergencies such as status epilepticus, acute anxiety and convulsions. Although traditional oral and injectable formulations are effective, they have significant limitations: oral formulations are not suitable for patients with dysphagia or vomiting, and injectable administration requires professional operation and may cause venous irritation. Rectal administration has become an ideal choice for pediatrics, emergency and other scenarios due to the rich blood circulation of the rectal mucosa and the advantage of avoiding the first-pass effect. However, the existing diazepam enema solution still faces the following technical bottlenecks: First, the water solubility of purified diazepam is extremely low (about 50μg / mL), and it needs to rely on organic solvents for solubilization. Existing technologies mostly use a single solvent (such as propylene glycol or ethanol), but high concentrations of propylene glycol (>70%) are prone to rectal irritation, and too high a proportion of ethanol may cause drug crystallization or degradation. Second, liquid preparations are susceptible to microbial contamination and preservatives need to be added. However, traditional solutions rely on a single ingredient (such as benzyl alcohol or sodium benzoate). Benzyl alcohol may cause hemolysis or neurotoxicity at high doses, and sodium benzoate alone has insufficient antibacterial efficiency, and the concentration needs to be increased, which increases the risk of compatibility. Although it meets the preservation requirements, it may exceed the safety threshold for children's medication. Third, in the traditional preparation process, whether it is a room temperature mixing or a heating dissolution step, there is a problem of large ethanol loss, resulting in the final solution failing to meet quality standards. Summary of the invention

[0003] In a first aspect, the present invention provides a diazepam enema solution having the characteristics of high solubility and strong stability.

[0004] The above technical purpose of the present invention is achieved through the following technical scheme: a diazepam enema solution, characterized in that: every 1000ml of the diazepam enema solution contains 1-3g of diazepam, 10-20g of benzyl alcohol, 0.1-1.5g of benzoic acid, 30-60g of sodium benzoate, 90-100g of ethanol, 350-500g of propylene glycol, and the balance is purified water.

[0005] Diazepam: The main active ingredient of the drug, it has anticonvulsant, sedative and muscle relaxant effects and is used to treat emergency conditions such as status epilepticus and acute anxiety. This class of drugs inhibits the central nervous system by enhancing the GABA neurotransmitter and is rapidly absorbed after rectal administration.

[0006] Benzyl alcohol: preservative, local anesthetic, inhibits microbial growth, and reduces the irritation of the enema solution to the rectal mucosa. It exerts its antibacterial effect by disrupting the microbial cell membrane, and at the same time slightly anesthetizes the mucosa to reduce discomfort.

[0007] Benzoic acid: synergistic preservative and pH buffer, forms a buffer system with sodium benzoate, maintains pH stability, and inhibits drug degradation. It enhances the antibacterial activity of the free state under acidic conditions, and it synergistically regulates the pH with sodium benzoate to reduce the alkaline purification hydrolysis of diazepam.

[0008] Sodium benzoate: main preservative, solubilizer, inhibits bacteria / fungi, and assists in the dispersion of diazepam through ionization. It dissociates into benzoate ions in the solution, forms a dynamic equilibrium with free benzoic acid, enhances the broad-spectrum anti-corrosion property, and at the same time reduces the dosage of benzyl alcohol.

[0009] Ethanol: auxiliary solvent, antibacterial enhancer, solubilizes diazepam synergistically with propylene glycol, and enhances the antibacterial efficacy of benzyl alcohol. It reduces the polarity of the solvent and increases the solubility of diazepam.

[0010] Propylene glycol: main solvent, stabilizer, dissolves diazepam and inhibits its degradation, reduces the imbalance of the solvent ratio caused by the volatilization of ethanol. It reduces the loss of ethanol in the heating process, and its hygroscopicity maintains the purified water balance of the preparation to prevent crystal precipitation.

[0011] Furthermore, for every 1000 ml of the diazepam enema solution, it contains 1 g of diazepam, 20 g of benzyl alcohol, 0.1 g of benzoic acid, 30 g of sodium benzoate, 100 g of ethanol, 500 g of propylene glycol, and the balance is purified water.

[0012] Furthermore, for every 1000 ml of the diazepam enema solution, it contains 3 g of diazepam, 10 g of benzyl alcohol, 1.5 g of benzoic acid, 60 g of sodium benzoate, 90 g of ethanol, 350 g of propylene glycol, and the balance is purified water.

[0013] Furthermore, for every 1000 ml of the diazepam enema solution, it contains 2 g of diazepam, 15 g of benzyl alcohol, 1 g of benzoic acid, 49 g of sodium benzoate, 97 g of ethanol, 400 g of propylene glycol, and the balance is purified water.

[0014] Furthermore, the pH value of the enema solution is 6.2 - 7.2.

[0015] In a second aspect, the present invention provides a preparation method of a diazepam enema solution, and the prepared diazepam enema solution has a high solubility and ethanol is not easily lost.

[0016] The above technical objectives of the present invention are achieved through the following technical solutions, including the following steps:

[0017] A. Weigh the raw materials according to any one of the formulas in the first aspect;

[0018] B. After heating propylene glycol, add benzoic acid and diazepam and stir to obtain the first liquid preparation;

[0019] C. Prepare a sodium benzoate solution by adding sodium benzoate to purified water. After adding the sodium benzoate solution to the first liquid preparation and stirring, obtain the second liquid preparation;

[0020] D. Prepare an ethanol solution by adding ethanol to purified water. After adding the ethanol solution and benzyl alcohol to the second liquid preparation and stirring, obtain the third liquid preparation;

[0021] E. Measure the pH value of the third liquid preparation, make up the volume with purified water, and then filter to obtain the diazepam enema.

[0022] Further, in step B, the target temperature for heating the propylene glycol is 65 - 75°C; the stirring time for adding benzoic acid and diazepam is 15 - 30 minutes.

[0023] Further, in step C, it also includes the step of cooling the temperature of the second liquid preparation to below 30°C.

[0024] Further, in step D, the concentration of the ethanol solution is greater than 90%, and the stirring time after adding the ethanol solution and benzyl alcohol to the second liquid preparation is 5 - 10 min.

[0025] Further, in step E, the filtration is carried out using a filter, and the pore diameter of the filter element of the filter is 0.4 - 0.5 μm.

[0026] In summary, the present invention has at least one of the following beneficial effects:

[0027] 1. Through the synergistic solubilization of the composite solvent system, it not only avoids the problems of irritation or crystallization caused by too high concentration of a single solvent, but also significantly improves the solubility of diazepam. At the same time, the moisturizing property of propylene glycol can inhibit the drug degradation caused by the volatilization of ethanol. The buffer system formed by benzoic acid and sodium benzoate can stabilize the pH within the range of 6.2 - 7.2, reducing the decomposition of diazepam in an alkaline environment.

[0028] 2. Adopt a ternary anti-corrosion system of benzyl alcohol plus benzoic acid / sodium benzoate. By synergistic antibacterial action, the dosage of a single preservative is reduced, and the concentration of benzyl alcohol is controlled within the safe threshold for children, avoiding the risks of hemolysis or neurotoxicity. Sodium benzoate, as the main antibacterial agent, releases free benzoic acid at low pH to enhance the anti-corrosion effect, while reducing the irritation to the rectal mucosa.

[0029] 3. The staged temperature control process significantly reduces the ethanol volatilization loss rate, ensures that the ethanol concentration meets the standard, and maintains the solvent polarity and antibacterial efficacy. In addition, the gradual mixing of the sodium benzoate solution and the ethanol solution avoids the drug precipitation caused by local pH mutation or sudden change in solvent polarity, improving the uniformity of the preparation. Description of the Drawings

[0030] Figure 1 It is the process flow chart of Example 1 Specific implementation manners

[0031] In order to make the technical problems, technical solutions and beneficial effects to be solved by the present invention more clear and understandable, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments.

[0032] The terms "first" and "second" are only used for descriptive purposes, and cannot be understood as indicating or implying relative importance or implicitly specifying the quantity of the indicated technical features. Thus, the features defined with "first" and "second" may explicitly or implicitly include one or more of such features. In the description of the present invention, "a plurality of" means two or more, unless otherwise specifically defined.

[0033] Example 1:

[0034] A method for preparing diazepam enema solution, comprising the following steps:

[0035] Step 1: Weigh the raw materials according to the formula of diazepam enema solution; during the weighing process, one person weighs and one person checks and mixes the ingredients in sequence according to the weighing SOP and the batching SOP; verify the data through an independent checker to significantly reduce the feeding error rate.

[0036] Step 2: Heat propylene glycol to 65-75°C in a batching tank, add benzoic acid and diazepam, start the internal circulation and stirring after the feeding is completed, and stir for 30 minutes to obtain the first liquid preparation; propylene glycol is heated to 65-75°C to reduce the viscosity, accelerate the dissolution of diazepam and benzoic acid, and double the solubility of diazepam in propylene glycol compared with normal temperature. The internal circulation stirring ensures the uniformity of the solution, avoiding local overheating or undissolved particles. Precise temperature control effectively avoids the high-temperature degradation of diazepam.

[0037] Step 3: Stir sodium benzoate with purified water until sodium benzoate is completely dissolved to obtain a sodium benzoate solution, add the sodium benzoate solution to the first liquid preparation and stir, then cool to below 30°C to obtain the second liquid preparation; the purified aqueous solution of sodium benzoate provides an alkaline environment, forms a buffer system with benzoic acid, and inhibits the purified hydrolysis of diazepam. Cooling to below 30°C prevents the loss of ethanol volatilization at high temperature.

[0038] Step 4: Prepare an ethanol solution of 96% ± 0.5% by adding ethanol to purified water, add the ethanol solution and benzyl alcohol to the second liquid preparation, then start the internal circulation and stirring, stir for 5 minutes, and keep the solution temperature below 30°C to obtain the third liquid preparation; mix below 30°C to reduce ethanol volatilization, and at the same time avoid the oxidation of benzyl alcohol at high temperature. Ethanol is retained to the maximum extent, maintaining the stability of the solvent polarity.

[0039] Step 5: Measure the pH value of the third liquid preparation and make up the volume with purified water. After the volume making-up is completed, turn on the internal circulation and stirring. After stirring for 15 minutes, filter to obtain the diazepam enema solution. The pH value is maintained between 6.2 and 7.2; the filtration is carried out using a filter, the filter element material is 361L stainless steel, and the pore size of the filter element is 0.45 μm. The 0.45 μm stainless steel filter element filters out particles and microorganisms to ensure sterility. The 361L material is corrosion-resistant and non-adsorbent, avoiding the adsorption loss of benzyl alcohol by the traditional nylon filter membrane.

[0040] Step 6: Fill and package the diazepam enema solution through a special enema hose to obtain the finished product of diazepam enema solution, and the finished product specification is 2.5 ml / each. Before filling, measure data such as microorganisms, relative density, pH value, etc. The time from the start to the end of filling does not exceed 24 hours, and the hose is required to be clean and free of liquid leakage. After filling, inspect the finished product.

[0041] Every 1000 ml of the said diazepam enema solution contains 1 - 3 g of diazepam, 10 - 20 g of benzyl alcohol, 0.1 - 1.5 g of benzoic acid, 30 - 60 g of sodium benzoate, 90 - 100 g of ethanol, 350 - 500 g of propylene glycol, and the balance is purified water.

[0042] Diazepam, as a class of central nervous system inhibitors, enhances the postsynaptic inhibitory effect of γ-aminobutyric acid (GABA) neurotransmitter by specifically binding to the α subunit in the GABA_A receptor-Cl- channel complex.

[0043] Benzyl alcohol destroys the phospholipid bilayer of the microbial cell membrane through hydrophobic interaction, causing the intracellular enzyme system to leak out to exert broad-spectrum antibacterial effect. At the same time, it reversibly blocks the sodium channel to produce surface anesthesia and reduce the burning sensation during rectal administration.

[0044] Benzoic acid / sodium benzoate constitutes a dynamic buffer system to maintain a weakly acidic environment.

[0045] Propylene glycol increases the apparent solubility of diazepam by forming intermolecular hydrogen bonds, which is 80 times higher than that of pure water. At the same time, it plays a role in inhibiting the volatilization of ethanol and preventing crystallization.

[0046] Ethanol reduces the dielectric constant of the system, enhances the dissolution of the lipophilic components of diazepam, quickly volatilizes to form a local high-concentration drug layer, and promotes rectal mucosa absorption.

[0047] Example 2:

[0048] This example provides a method for preparing diazepam enema solution at room temperature:

[0049] Step 1: Weigh the raw materials according to the formula of diazepam enema solution. During the weighing process, one person weighs and another person checks and doses the ingredients in sequence according to the weighing SOP and dosing SOP. Verify the data through an independent checker to significantly reduce the dosing error rate.

[0050] Step 2: Add benzoic acid and diazepam to 96% ethanol and stir at room temperature for 15 min until completely dissolved. 96% ethanol, as a highly polar solvent, significantly improves the dissolution rate of diazepam. Benzoic acid is fully dissolved in ethanol to form a buffer system with sodium benzoate subsequently.

[0051] Step 3: Add propylene glycol and benzyl alcohol to the above drug-containing ethanol solution and stir for 5 min to mix them evenly. Propylene glycol and ethanol form a composite solvent, reducing the concentration of a single solvent and decreasing rectal irritation. The moisture retention of propylene glycol inhibits the volatilization of ethanol to ensure the stability of the solvent ratio.

[0052] Step 4: Add sodium benzoate to purified water and stir for 3 min to prepare an aqueous solution of sodium benzoate in purified water. After sodium benzoate is dissolved in purified water, it forms a dynamic buffer pair with benzoic acid in Step 2 to inhibit the alkaline degradation of diazepam. Sodium benzoate dissociates into benzoate ions in the solution, synergistically enhancing the broad-spectrum antibacterial effect with free benzoic acid.

[0053] Step 5: Add the aqueous solution of sodium benzoate in purified water to the dosing tank of the alcoholic solution and stir for 5 min to mix them evenly. The solution is clear and no solid precipitates to obtain diazepam enema solution. Through gradient mixing and stirring speed control, drug precipitation caused by sudden change of solvent polarity is avoided to ensure the clarity of the solution.

[0054] Step 6: Fill and package the diazepam enema solution through a special enema hose to obtain the finished product of diazepam enema solution, with the finished product specification of 2.5 ml / each. Measure data such as microorganisms, relative density, and pH value before filling. The time from the start to the end of filling does not exceed 24 hours. The hose is required to be clean and free of liquid leakage. Inspect the finished product after filling.

[0055] Example 3:

[0056] This example provides another method for heating and preparing diazepam enema solution:

[0057] Step 1: Weigh the raw materials according to the formula of diazepam enema solution. During the weighing process, one person weighs and another person checks and doses the ingredients in sequence according to the weighing SOP and dosing SOP. Verify the data through an independent checker to significantly reduce the dosing error rate.

[0058] Step 2: Mix propylene glycol and purified water evenly and heat to 70°C. When the solution temperature reaches 70°C, add sodium benzoate, keep warm and stir for 3 min until completely dissolved. Use the mixed solvent of propylene glycol and purified water to heat and promote the rapid dissolution of sodium benzoate. Propylene glycol is used as the main solvent to reduce the subsequent ethanol dosage and reduce rectal irritation.

[0059] Step 3: Add diazepam raw material to the solution, keep warm and stir until completely dissolved. Keep warm and stir to avoid drug precipitation caused by sudden temperature drop.

[0060] Step 4: After cooling the above solution to room temperature, weigh and add benzyl alcohol to it and stir evenly. By adding after cooling, the problems of high-temperature volatilization and oxidation are avoided, and the anti-corrosion efficiency is improved.

[0061] Step 5: Add benzoic acid to 96% ethanol and stir to dissolve it. Weigh the total weight and make up for the lost ethanol. By adding ethanol in real time by weighing, the concentration deviation problem caused by volatilization in the traditional process is solved.

[0062] Step 6: Add the benzoic acid alcohol solution obtained in Step 5 to the solution in Step 4, stir and mix evenly; after mixing evenly, make up the volume with purified water to obtain diazepam enema solution.

[0063] Step 7: Fill and package the diazepam enema solution through a special enema hose to obtain the finished diazepam enema solution, and the finished product specification is 2.5 ml / each. Before filling, measure data such as microorganisms, relative density, and pH value. The time from the start to the end of filling does not exceed 24 hours, and the hose is required to be clean and free of liquid leakage. After filling, inspect the finished product.

[0064] Example 4:

[0065] This example provides a diazepam enema solution formula. For every 1000 ml of the diazepam enema solution, it contains 2 g of diazepam, 15 g of benzyl alcohol, 1 g of benzoic acid, 49 g of sodium benzoate, 97 g of ethanol, 400 g of propylene glycol, and the balance is purified water.

[0066] The raw material sources of this example are as follows:

[0067]

[0068]

[0069] Using this diazepam enema solution formula, adopt the preparation methods provided in Example 1, Example 2 and Example 3 respectively to prepare diazepam enema solution. Detect the properties of the finished product.

[0070]

[0071] The diazepam enema solution was prepared according to the process of Example 1. Diazepam and benzoic acid can be rapidly dissolved in hot propylene glycol (70 °C). The prescription of the original research reference preparation is clear, and the proportion of propylene glycol in the prescription is about 40%, which is relatively large. According to this preparation process, the diazepam raw material can be directly put into the liquid preparation tank and stirred for dissolution, meeting the requirements of industrial production and GMP management. Instead of using 96% ethanol to dissolve any raw and auxiliary materials, it is directly added for preparation, avoiding the loss of ethanol volatilization. From the test results of the finished product, the diazepam enema solution prepared by the process of the example is a colorless and transparent liquid, and its pH value and relative density are the same as those of the original research reference preparation; at 40 °C ± 2 °C, 75% ± 5% RH for 6 months, no crystals precipitate. No other impurities other than the raw material impurities were detected in the three batches of samples, indicating that the preparation process of Example 1 will not produce other process impurities. The content of the excipients in the sample was determined by reverse engineering analysis, and the contents of the excipients propylene glycol, benzyl alcohol, benzoic acid, sodium benzoate, and 96% ethanol are basically consistent with the theoretical values.

[0072] The diazepam enema solution prepared by the normal temperature preparation process of Example 2 is a colorless and transparent liquid. At 40 °C ± 2 °C, 75% ± 5% RH for 6 months, no crystals precipitate. Its pH value and relative density are the same as those of the original research reference preparation. Only the process impurities of the raw drug are detected, which are the same as the impurity content in the raw drug, indicating that no other process impurities will be produced under the normal temperature preparation process. The content of the excipients in the sample was determined by reverse engineering analysis. The results show that the contents of propylene glycol, benzyl alcohol, benzoic acid, and sodium benzoate are basically consistent with the theoretical amounts, but the content of 96% ethanol is significantly lower. The reason may be that during the liquid preparation process, ethanol volatilizes when dissolving the diazepam raw material and benzoic acid with 96% ethanol for a long time by stirring, resulting in a lower ethanol content.

[0073] The diazepam enema solution prepared by the heating preparation process of Example 3 is a colorless and transparent liquid. Its pH value and relative density are the same as those of the original research reference preparation. At 40 °C ± 2 °C, 75% ± 5% RH for 6 months, no crystals precipitate. Only the process impurities of the raw drug are detected, which are the same as the content in the raw drug, indicating that the heating preparation process will not produce other process impurities. The content of the excipients in the sample was determined by reverse engineering analysis. The results show that the contents of propylene glycol, benzyl alcohol, benzoic acid, and sodium benzoate are basically consistent with the theoretical amounts. When using 96% ethanol to dissolve benzoic acid, there is a certain loss of ethanol, and the content is slightly lower than the theoretical value. The diazepam raw material is directly added to hot propylene glycol (70 °C) and rapidly dissolved, and the dissolution rate is significantly faster than that of the mixed solution of hot propylene glycol and purified water. After the diazepam raw material is completely dissolved, purified water is added, and no white turbidity or precipitation appears, indicating that no diazepam raw material precipitates.

[0074] Example 5:

[0075] This embodiment provides a diazepam enema solution containing a single solvent and a preservative, and a preparation method thereof.

[0076] For every 1000 ml of the diazepam enema solution, it contains 2 g of diazepam, 20 g of benzyl alcohol, 500 g of propylene glycol, and the balance is purified water.

[0077] The preparation method is as follows:

[0078] Raw material weighing: Weigh diazepam, propylene glycol, and benzyl alcohol according to the formula.

[0079] Dissolve the main drug: Heat propylene glycol to 70 °C, add diazepam, and stir for 30 minutes until completely dissolved.

[0080] Add the preservative: Wait for the solution to cool below 40 °C, add benzyl alcohol, and stir for 10 minutes.

[0081] Volume fixing and filtration: Add purified water to 1000 mL, stir and mix evenly, and filter with a 0.45 μm nylon filter membrane.

[0082] Filling: Fill into a light-proof hose of 2.5 mL per piece and seal and package. After filling, inspect the finished product.

[0083] Detect aerobic bacteria, molds and yeasts according to the membrane filtration method in the Chinese Pharmacopoeia. The detected aerobic bacteria > 10 3 CFU / mL, which indicates that the antibacterial effect of a single preservative is not ideal.

[0084] At 40 °C ± 2 °C, 75% ± 5% RH, for 6 months, flocculants appear.

[0085] Example 5:

[0086] This embodiment provides another diazepam enema solution containing a single solvent and a preservative, and a preparation method thereof.

[0087] For every 1000 ml of the diazepam enema solution, it contains 2 g of diazepam, 20 g of sodium benzoate, 500 g of anhydrous ethanol, and the balance is purified water.

[0088] Preparation method

[0089] Raw material weighing: Weigh diazepam, ethanol, and sodium benzoate according to the formula.

[0090] Dissolve the main drug: Mix ethanol and purified water until the ethanol concentration is 40%, add diazepam, and stir at room temperature for 60 minutes until completely dissolved.

[0091] Add the preservative: Add sodium benzoate and stir for 15 minutes to dissolve.

[0092] Volume fixing and filtration: Make up purified water to 1000 mL and filter with a 0.45 μm nylon filter membrane.

[0093] Filling: Fill into light-proof hoses of 2.5 mL per piece and seal the packages.

[0094] Detect aerobic bacteria, molds and yeasts according to the membrane filtration method in the Chinese Pharmacopoeia. The detected aerobic bacteria are > 10 3 CFU / mL, indicating that the antibacterial effect of a single preservative is not ideal.

[0095] During the production process, ethanol volatilizes and is lost, and its concentration decreases, resulting in the crystallization of diazepam.

[0096] Compared with Example 5 and Example 6, the formulation of Example 4 synergistically solubilizes through a composite solvent system, which not only avoids the problems of irritation or crystallization caused by too high concentration of a single solvent, but also significantly improves the solubility of diazepam. At the same time, the moisturizing property of propylene glycol can inhibit the drug degradation caused by ethanol volatilization. The buffer system formed by benzoic acid and sodium benzoate can stabilize the pH within the range of 6.2 - 7.2, reducing the decomposition of diazepam in an alkaline environment. A ternary anti-corrosion system of benzyl alcohol plus benzoic acid / sodium benzoate is adopted to reduce the dosage of a single preservative through synergistic antibacterial action. The concentration of benzyl alcohol is controlled within the safe threshold for children to avoid the risks of hemolysis or neurotoxicity. Sodium benzoate is used as the main antibacterial agent, releasing free benzoic acid at low pH to enhance the anti-corrosion effect while reducing the irritation to rectal mucosa.

[0097] This specific embodiment is only an explanation of the present invention, and it is not a limitation of the present invention. After reading this specification, those skilled in the art can make modifications to this embodiment without creative contributions as needed, but as long as it is within the scope of the claims of the present invention, it is protected by the patent law.

Claims

1. A diazepam enema solution, characterized in that: For every 1000 ml of the diazepam enema solution, it contains 1 - 3 g of diazepam, 10 - 20 g of benzyl alcohol, 0.1 - 1.5 g of benzoic acid, 30 - 60 g of sodium benzoate, 90 - 100 g of ethanol, 350 - 500 g of propylene glycol, and the balance is purified water.

2. The diazepam enema solution according to claim 1, wherein: For every 1000 ml of the diazepam enema solution, it contains 1 g of diazepam, 20 g of benzyl alcohol, 0.1 g of benzoic acid, 30 g of sodium benzoate, 100 g of ethanol, 500 g of propylene glycol, and the balance is purified water.

3. The diazepam enema solution according to claim 1, characterized in that: For every 1000 ml of the diazepam enema solution, it contains 3 g of diazepam, 10 g of benzyl alcohol, 1.5 g of benzoic acid, 60 g of sodium benzoate, 90 g of ethanol, 350 g of propylene glycol, and the balance is purified water.

4. The diazepam enema according to claim 1, characterized in that: For every 1000 ml of the diazepam enema solution, it contains 2 g of diazepam, 15 g of benzyl alcohol, 1 g of benzoic acid, 49 g of sodium benzoate, 97 g of ethanol, 400 g of propylene glycol, and the balance is purified water.

5. The diazepam enema solution according to claim 1, characterized in that: The pH value of the enema solution is 6.2 - 7.

2.

6. A preparation method of diazepam enema, characterized in that It includes the following steps: A. Weigh the raw materials according to the formula of any one of claims 1 - 4; B. After heating propylene glycol, add benzoic acid and diazepam and stir to obtain the first prepared solution; C. Prepare a sodium benzoate solution by adding sodium benzoate to purified water, and add the sodium benzoate solution to the first prepared solution and stir to obtain the second prepared solution; D. Prepare an ethanol solution by adding ethanol to purified water, and add the ethanol solution and benzyl alcohol to the second prepared solution and stir to obtain the third prepared solution; E. Measure the pH value of the third prepared solution, make up the volume with purified water and then filter to obtain the diazepam enema solution.

7. The preparation method of a diazepam enema solution according to claim 6, characterized in that: in In step B, the target temperature for heating propylene glycol is 65 - 75 °C; the stirring time for adding benzoic acid and diazepam is 15 - 30 minutes.

8. The preparation method of a diazepam enema according to claim 6, characterized in that: In step C, it also includes the step of cooling the temperature of the second prepared solution to below 30 °C.

9. The preparation method of a diazepam enema according to claim 6, characterized in that: in In step D, the concentration of the ethanol solution is greater than 90%, and the stirring time after adding the ethanol solution and benzyl alcohol to the second prepared solution is 5 - 10 min.

10. The preparation method of a diazepam enema according to claim 6, characterized in that: In step E, the filtration is carried out using a filter, and the pore diameter of the filter element of the filter is 0.4 - 0.5 μm.

Images