Topiramate children preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to a topiramate children preparation and a preparation method thereof. The topiramate children preparation is a rectum enema liquid, and is prepared from the following components in percentage by mass: 1-5% of topiramate, 0.01-0.25% of a preservative and the balance of a solvent, wherein the solvent comprises glycerol, and the solvent is anhydrous. The topiramate anhydrous rectal enema provided by the invention adopts rectal administration, so that the problem of poor taste of an oral preparation is avoided; meanwhile, no water is contained, so that the problem of poor stability caused by hydrolysis can be avoided.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to a topiramate children's preparation and a preparation method thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Topiramate is a commonly used anti-epileptic drug, which is traditionally administered orally. However, topiramate tastes extremely bitter, and its oral solid preparation is not suitable for children and patients with dysphagia; at the same time, its oral liquid preparation, such as the oral liquid composition containing topiramate described in CN101257889A, also has the problem of poor taste. It is difficult to cover the taste of topiramate and solvent even if flavors and flavoring agents are added, and children have poor compliance.

[0004] In order to solve the problem of poor taste of topiramate, coating process can be used to cover it, such as CN1419444A, but topiramate is sensitive to water and prone to hydrolysis reaction. The coating process has hot and humid process conditions, which will reduce the stability of topiramate products. Others such as oral sprays and chewable gelatin soft capsules involved in US2003 / 0077227 and aqueous solutions or eye drops for injection described in WO02 / 102369 all have the effect of moisture on the quality of the finished product, increasing the storage cost. Therefore, it is necessary to provide a pharmaceutical preparation that can solve the bitterness and stability of topiramate. Summary of the invention

[0005] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a topiramate children's preparation and a preparation method thereof. The topiramate anhydrous rectal enema solution provided by the present invention is administered by rectum, thereby avoiding the problem of poor taste of oral preparations; and it does not contain water, thereby avoiding the problem of poor stability caused by hydrolysis.

[0006] In order to achieve the above object, the technical solution of the present invention is:

[0007] In a first aspect, a pediatric topiramate preparation is provided, which is a rectal enema solution and is composed of the following components in percentage by mass: 1-5% topiramate, 0.01-0.25% preservative, and the remainder being a solvent; wherein the solvent includes glycerol and the solvent is anhydrous.

[0008] The children's preparation provided by the present invention is a rectal enema solution for rectal administration. Compared with oral absorption, rectal administration mainly absorbs the drug through the rectal mucosa, which can avoid the first-pass effect of the liver; at the same time, glycerol is used as the solvent of the topiramate rectal enema solution, which is an oil-soluble solvent and can temporarily dissolve the lipids of the rectal mucosal cell membrane, increase the permeability of the drug, reduce the viscosity of the mucus, reduce the drug diffusion resistance, and accelerate the absorption rate of the rectal mucosa; and the solubility of topiramate in glycerol is relatively high, which is conducive to the dissolution of topiramate; in addition, experiments show that the rectal enema solution has a higher dissolution effect; therefore, the rectal enema solution of the present invention is conducive to improving the bioavailability of topiramate.

[0009] Secondly, in the rectal enema solution provided by the present invention, anhydrous means that no water is added separately, and the actual water content detected by a suitable detection method is 0.5 weight % or less. Therefore, the present invention can avoid hydrolysis, thereby improving stability.

[0010] In some embodiments, the solvent further comprises one or more of propylene glycol or polyethylene glycol. In the compatibility experiment of topiramate with glycerol, polyethylene glycol, and propylene glycol, the present invention found that glycerol has good compatibility with topiramate, and propylene glycol or polyethylene glycol is selected to increase the solubility of topiramate, ensuring that the solvent can meet the stability requirements of the drug, and at the same time, moderate viscosity and solubility ensure the release efficiency of the drug in the rectum.

[0011] In some embodiments, the preservative is selected from one or more of quaternary ammonium salts, organic acids or salts, or parabens. In the antibacterial efficacy test of the preservatives, the present invention found that benzalkonium chloride and benzalkonium bromide have the best antibacterial effect in glycerol or a combination of glycerol and other solvents, especially have better inhibitory effects on Staphylococcus aureus and Pseudomonas aeruginosa, so as to ensure the microbial stability of the rectal enema solution and facilitate rectal administration of the rectal enema solution.

[0012] Specifically, the preservative is one or more of benzalkonium chloride, benzalkonium bromide, sodium benzoate, potassium sorbate, and hydroxybenzoic acid esters; preferably benzalkonium chloride and / or benzalkonium bromide. When benzalkonium chloride and / or benzalkonium bromide are selected as preservatives, the content of the preservative can be greatly reduced, and the content of the preservative in the rectal enema solution is as low as 0.01-0.02%.

[0013] In some embodiments, the anhydrous topiramate rectal enema solution has a water content of no greater than 0.5% by weight.

[0014] In some embodiments, the active ingredient is topiramate or a pharmaceutically acceptable addition salt thereof. Acceptable addition salts include salts derived from inorganic and organic bases.

[0015] In a second aspect, a method for preparing the above-mentioned topiramate children's preparation is provided, comprising adding a preservative and topiramate into a solvent and mixing them evenly.

[0016] In some embodiments, the preservative is first added to the solvent and mixed evenly, and then topiramate is added and mixed evenly.

[0017] In some embodiments, the preservative and topiramate are added to the solvent and mixed well before filtering.

[0018] In a third aspect, a use of the above-mentioned topiramate children's preparation in the preparation of medicines for pediatric patients and / or patients who have difficulty swallowing tablets.

[0019] The beneficial effects of the present invention are:

[0020] 1. The topiramate children's preparation provided by the present invention is a rectal enema solution. By selecting a solvent and changing the route of administration, the bioavailability of topiramate is improved and the first-pass effect in the liver is avoided.

[0021] 2. The topiramate children's preparation provided by the present invention can be administered rectally, avoiding the problem of poor taste caused by oral administration, improving the patient's medication experience, especially for patients with dysphagia, thereby improving patient compliance and facilitating further improving the bioavailability of topiramate.

[0022] 3. The preparation method of the present invention is simple, low-cost and suitable for industrial production.

[0023] 4. The anhydrous formula of the topiramate children's preparation provided by the present invention has better stability, which is beneficial to reducing storage costs, and also has the advantages of accurate and flexible dosage. DETAILED DESCRIPTION

[0024] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in combination with specific embodiments and comparative examples.

[0025] Example 1

[0026] A pediatric preparation of topiramate is in the form of a rectal enema solution, and the prescription is shown in Table 1.

[0027] Table 1 Prescription of the topiramate rectal enema solution of Example 1

[0028] Element type Ratio (W / W) Topiramate Active ingredients 1％ glycerin Solvents 98.9％ Sodium Benzoate preservative 0.1％

[0029] The preparation method thereof comprises the following steps:

[0030] Mix sodium benzoate and glycerin as prescribed until the sodium benzoate is completely dissolved to obtain a preservative solution;

[0031] Adding the prescribed amount of topiramate to the preservative solution, stirring until uniformly dispersed, to obtain a mixed solution;

[0032] Filter the mixture and bottle.

[0033] Example 2

[0034] A pediatric preparation of topiramate is in the form of a rectal enema solution, and the prescription is shown in Table 2.

[0035] Table 2 Prescription of topiramate rectal enema solution of Example 2

[0036] Element type Ratio (W / W) Topiramate Active ingredients 5％ glycerin Solvents 32.75％ Polyethylene glycol 400 Solvents 62％ Methylparaben preservative 0.25％

[0037] The preparation method thereof comprises the following steps:

[0038] According to the prescription, glycerin and polyethylene glycol 400 are mixed evenly to prepare a mixed latent solvent;

[0039] Adding a prescribed amount of methyl parahydroxybenzoate to the mixed latent solvent and mixing until the methyl parahydroxybenzoate is completely dissolved to obtain a preservative solution;

[0040] Adding the prescribed amount of topiramate to the preservative solution, stirring until uniformly dispersed, to obtain a mixed solution;

[0041] Filter the mixture and bottle.

[0042] Example 3

[0043] A pediatric preparation of topiramate is in the form of a rectal enema solution, and the prescription is shown in Table 3.

[0044] Table 3 Prescription of topiramate rectal enema solution of Example 3

[0045] Element type Ratio (W / W) Topiramate Active ingredients 3％ glycerin Solvents 64.5％ Polyethylene glycol 600 Solvents 32.3％ Potassium Sorbate preservative 0.2％

[0046] The preparation method thereof comprises the following steps:

[0047] According to the prescription, glycerin and polyethylene glycol 600 are mixed evenly to prepare a mixed latent solvent;

[0048] Adding a prescribed amount of potassium p-sorbate to the mixed latent solvent and mixing until the potassium sorbate is completely dissolved to obtain a preservative solution;

[0049] Adding the prescribed amount of topiramate to the preservative solution, stirring until uniformly dispersed, to obtain a mixed solution;

[0050] Filter the mixture and bottle.

[0051] Example 4

[0052] A pediatric preparation of topiramate is in the form of a rectal enema solution, and the prescription is shown in Table 4.

[0053] Table 4 Prescription of the topiramate rectal enema solution of Example 4

[0054] Element type Ratio (W / W) Topiramate Active ingredients 4％ glycerin Solvents 48％ Propylene glycol Solvents 47.99％ Benzalkonium bromide preservative 0.01％

[0055] The preparation method thereof comprises the following steps:

[0056] Glycerin and propylene glycol are mixed evenly according to the prescription to prepare a mixed co-solvent;

[0057] Adding a prescribed amount of benzalkonium bromide to the mixed latent solvent and mixing until the benzalkonium bromide is completely dissolved to obtain a preservative solution;

[0058] Adding the prescribed amount of topiramate to the preservative solution, stirring until uniformly dispersed, to obtain a mixed solution;

[0059] Filter the mixture and bottle.

[0060] Example 5

[0061] A pediatric preparation of topiramate is in the form of a rectal enema solution, and the prescription is shown in Table 5.

[0062] Table 5 Prescription of the topiramate rectal enema solution of Example 5

[0063] Element type Ratio (W / W) Topiramate Active ingredients 2.5％ glycerin Solvents 49％ Polyethylene glycol 400 Solvents 48.48％ Benzalkonium chloride preservative 0.02％

[0064] The preparation method thereof comprises the following steps:

[0065] According to the prescription, glycerin and polyethylene glycol 400 are mixed evenly to prepare a mixed latent solvent;

[0066] Adding a prescribed amount of benzalkonium chloride to the mixed latent solvent and mixing until the benzalkonium chloride is completely dissolved to obtain a preservative solution;

[0067] Adding the prescribed amount of topiramate to the preservative solution, stirring until uniformly dispersed, to obtain a mixed solution;

[0068] Filter the mixture and bottle.

[0069] Comparative Example 1

[0070] A pediatric preparation of topiramate is in the form of a rectal enema solution, and the prescription is shown in Table 6.

[0071] Table 6 Prescription of Topiramate Rectal Enema Solution of Comparative Example 1

[0072] Element type Ratio (W / W) Topiramate Active ingredients 2.5％ water Solvents 1％ glycerin Solvents 48％ Polyethylene glycol 400 Solvents 48.48％ Benzalkonium chloride preservative 0.02％

[0073] The preparation method thereof comprises the following steps:

[0074] According to the prescription, water, glycerin and polyethylene glycol 400 are mixed evenly to prepare a mixed latent solvent;

[0075] Adding a prescribed amount of benzalkonium chloride to the mixed latent solvent and mixing until the benzalkonium chloride is completely dissolved to obtain a preservative solution;

[0076] Adding the prescribed amount of topiramate to the preservative solution, stirring until uniformly dispersed, to obtain a mixed solution;

[0077] Filter the mixture and bottle.

[0078] The stability of the topiramate anhydrous rectal enema solution prepared in Example 5 and the topiramate anhydrous rectal enema solution prepared in Comparative Example 1 was investigated. The results are shown in Table 7.

[0079] Table 7 Comparison of stability between Example 5 and Comparative Example 1

[0080]

[0081]

[0082] The results in Table 7 show that when water is added to the topiramate anhydrous rectal enema solution, its stability is significantly reduced.

[0083] The solubility of topiramate in different solvents was tested, and the results are shown in Table 8.

[0084] Table 8 Solubility of Topiramate

[0085] Solvents Solubility Solubility water 9.8mg / ml Slightly soluble glycerin >10mg / ml Slightly soluble Polyethylene glycol 400 >50mg / ml Dissolve

[0086] The results showed that the solubility of topiramate in glycerol and polyethylene glycol was significantly higher than that in water. The increase in the solubility of topiramate in the selected solvent was beneficial to the release of the drug in the body, thereby improving the bioavailability.

[0087] The antibacterial efficacy test was carried out on Examples 1 to 5, and the results are shown in Table 9.

[0088] Table 9 Antibacterial efficacy test results

[0089]

[0090]

[0091] In Examples 1 to 5, the examples containing benzalkonium chloride and benzalkonium bromide have the best antibacterial effect, and their dosage is also the least in the examples, indicating that benzalkonium chloride and benzalkonium bromide have the best antibacterial effect in glycerol or a combination of glycerol and other solvents, especially having a better inhibitory effect on Staphylococcus aureus and Pseudomonas aeruginosa.

[0092] The topiramate anhydrous rectal enema solution of Example 5 and commercially available topiramate tablets were subjected to dissolution tests. The results are shown in Table 10.

[0093] Table 10 Dissolution curve comparison

[0094]

[0095] The results show that the improved solubility of topiramate in glycerol and polyethylene glycol is beneficial to drug release. At the same time, since the present invention provides an enema solution for rectal administration, the improved drug release is beneficial to the rectal mucosa contacting topiramate, thereby improving the absorption of topiramate by the rectum, and further improving the bioavailability.

[0096] A BE experiment was conducted between rectal administration of the topiramate anhydrous rectal enema solution of Example 5 and oral administration of commercially available topiramate tablets. The results are shown in Table 11. The Cmax and AUC of the rectal administration were both about 20% to 30% higher than those of the oral administration.

[0097] Table 11BE experimental results

[0098]

[0099] This proves that the topiramate anhydrous rectal enema solution prepared by the present invention has higher bioavailability.

[0100] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A children's preparation of topiramate, characterized in that: The topiramate children's preparation is a rectal enema solution, which is composed of the following components in terms of mass percentage: 1-5% topiramate, 0.01-0.25% preservative, and the balance is solvent; wherein the solvent includes glycerol, and the solvent is anhydrous.

2. The topiramate children's preparation according to claim 1, characterized in that: The solvent also includes one or more of propylene glycol or polyethylene glycol.

3. The topiramate children's preparation according to claim 1, characterized in that: The preservative is selected from one or more of quaternary ammonium salts, organic acids or salts, or parabens.

4. The topiramate children's preparation according to claim 3, characterized in that: The preservative is benzalkonium chloride and / or benzalkonium bromide.

5. The topiramate children's preparation according to claim 1, characterized in that: The water content of the topiramate anhydrous rectal enema solution is not higher than 0.5% by weight.

6. The topiramate children's preparation according to claim 1, characterized in that: The active ingredient is topiramate or a pharmaceutically acceptable addition salt thereof.

7. A method for preparing the topiramate children's preparation according to claim 1, characterized in that: Add the preservative and topiramate into the solvent and mix well to obtain the product.

8. The preparation method according to claim 7, characterized in that: First, add the preservative to the solvent and mix well, and then add topiramate and mix well.

9. The preparation method according to claim 7, characterized in that: The preservative and topiramate are added to the solvent, mixed evenly, and then filtered.

10. Use of the topiramate children's preparation according to any one of claims 1 to 6 in the preparation of medicines for pediatric patients and / or patients who have difficulty swallowing tablets.

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