CN104027317A - Topiramate dispersible tablet and preparation method thereof - Google Patents

Abstract

The invention relates to a topiramate dispersible tablet used for treating epilepsy and a preparation method thereof. The invention aims at providing a new preparation, namely a topiramate dispersible tablet, which can be rapidly disintegrated and absorbed, is convenient to take, can improve biological availability and plasma drug concentration of a medicine and can improve anti-epileptic effect for the majority of patients and medical workers. Topiramate is taken as a raw material, auxiliary materials in specific kinds and proportions are added, and tablets are pressed by adopting a routine technique in pharmaceutics.

Description

A kind of topiramate dispersible tablet and preparation method thereof

field of invention

The invention relates to a pharmaceutical composition containing topiramate, more specifically, the invention relates to a topiramate dispersible tablet, which is mainly used for treating epilepsy and belongs to neurosurgical diseases. The present invention also relates to a preparation method of the topiramate dispersible tablet.

Background of the invention

Topiramate is a white crystalline powder with a bitter taste. It is easily soluble in alkaline solutions with a pH value of 9-10 such as sodium hydroxide or sodium phosphate, and easily soluble in acetone, chloroform, dimethyl sulfoxide and ethanol. The solubility in water is 9.8mg/mL, the pH value of its saturated solution is 6.3, and the melting point is 125-126°.

Its chemical name: 2,3:4,5-bis-O-(1-methylethylene)-β-D fructopyranose sulfamate, molecular formula = C ₁₂ H ₂₁ NO ₈ S, molecular weight: 339.36.

Its structural formula:

It is a new broad-spectrum antiepileptic drug, effective for all types of epileptic seizures, especially for primary and secondary generalized tonic-clonic seizures and simple or complex partial seizures. It is also effective for myoclonus and infantile spasms.

Fluctuations in the plasma concentration of antiepileptic drugs may lead to increased side effects in patients with epilepsy at peak concentrations, or seizures at peak and trough concentrations before the next dose is administered.

CN1988889 discloses a sustained-release topiramate preparation and a method for preparing a topiramate preparation. The sustained-release topiramate preparation is prepared by using secondary particles, wherein the secondary particles are prepared by a solid dispersion method using a solid dispersant to mix topiramate or its medicine Pharmaceutically acceptable salt granulation (primary granulation), and further dry or wet granulation, granulation of said granules with sustained release material (secondary granulation). The adopted solid dispersion method is a melting method, which needs to be heated at an excessively high temperature, which easily decomposes the medicine and the carrier.

CN1905857 discloses the controlled release of topiramate in liquid dosage form. The disclosed dosage form includes a semipermeable wall, a drug layer and an expandable layer, and the preparation process is relatively complicated.

Dispersible tablets are a new drug dosage form developed in recent years, and the British Pharmacopoeia recorded this dosage form as early as 1993. The Chinese Pharmacopoeia did not include it as a new dosage form until 2000. Compared with ordinary tablets, dispersible tablets require that the disintegration time of the tablet should be less than 3 minutes when the temperature of the disintegration medium is around 20°C, and all disintegrated particles should be able to pass through a 710 μm sieve. It has the advantages of fast speed, high bioavailability, and less adverse reactions. In clinical application, it can be taken as ordinary tablets, and can be quickly dispersed in water before delivery. In special cases, it can also be chewed or swallowed. It is convenient to carry and use, and has the advantages of both solid preparations and liquid preparations. Especially suitable for the elderly, children and patients with difficulty swallowing.

Using the technology of the present invention to prepare topiramate into dispersible tablets not only expands the application range of the dosage form of topiramate, especially through the selection of the formula of the present invention, it has good taste, rapid disintegration, fast absorption, convenient taking, and can improve the bioavailability of the drug. Degree and blood concentration, improve the new preparation of antiepileptic effect.

The invention provides a topiramate dispersible tablet, which has rapid disintegration, quick onset of action, high bioavailability, improved curative effect for treating epilepsy, convenient administration, simple preparation method and is suitable for large-scale production.

Contents of the invention

The object of the present invention is to provide a kind of topiramate oral dosage form-topiramate dispersible tablet and its preparation method that disintegrates fast, absorbs rapidly, can effectively improve the bioavailability of medicine and blood drug concentration, improve taste simultaneously, take conveniently, side effect is few. The concrete technical scheme that the present invention adopts is as follows:

In one aspect, the present invention relates to a topiramate dispersible tablet, wherein the weight percentage of topiramate is 5-50%, and the weight percentage of auxiliary materials is 50-95%.

In some of the embodiments, the dispersible tablet of the present invention, wherein the auxiliary material is selected from disintegrants, fillers, binders, lubricants, wherein the weight percentage of the filler is 20-90%, disintegration The weight percentage of the agent is 5-40%, the weight percentage of the binder is 1-20%, and the weight percentage of the lubricant is 0.1-5%.

In some embodiments, the dispersible tablet of the present invention, wherein, the disintegrant is selected from sodium carboxymethyl starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, carboxymethyl starch Sodium Methylcellulose, Croscarmellose Sodium, Calcium Carmellose, Calcium Carboxymethylcellulose, Microcrystalline Cellulose, Sodium Lauryl Sulfate, Sodium Cetylsulfosuccinate , one or more of dioctyl sodium sulfosuccinate, Tween-80; the filler is selected from lactose, sucrose, sorbitol, mannitol, xylitol, erythritol, pregelatin One or more of starch, starch; wherein the binder is selected from ethanol, water, ethanol-water solution, syrup, starch slurry, sodium carboxymethylcellulose solution, povidone solution, magnesium aluminum silicate, seaweed one or a mixture of several of them; wherein the lubricant is selected from micropowder silica gel, magnesium stearate, calcium stearate, stearic acid, talcum powder, silicon dioxide, magnesium lauryl sulfate, One or more mixtures of PEG4000 and PEG6000.

In some embodiments, the dispersible tablet of the present invention, wherein the dispersible tablet also contains a flavoring agent selected from orange flavor, mint flavor, grape flavor, cherry flavor, banana flavor, pineapple flavor, vanilla flavor One or a mixture of essence, lemon essence, aspartame, sodium saccharin, stevioside, the dosage is 0.5-5%.

In some embodiments, the dispersible tablet of the present invention, wherein the dispersible tablet further includes: 0.1-0.5% by weight of a colorant, the colorant is selected from the colorant fruit green or fruit orange.

In some of the embodiments, the dispersible tablet of the present invention, wherein, the formulation of the dispersible tablet consists of:

In some of the embodiments, the dispersible tablet of the present invention, wherein, the formulation of the dispersible tablet consists of:

In some of the embodiments, the dispersible tablet of the present invention, wherein, the formulation of the dispersible tablet consists of:

In some of the embodiments, the dispersible tablet of the present invention, wherein, the formulation of the dispersible tablet consists of:

On the other hand, the present invention relates to a preparation method of the dispersible tablet of the present invention, which adopts wet granulation and tabletting, comprising the following steps: pulverizing the drug and various auxiliary materials, passing through a 80-100 mesh sieve, and mixing uniformly; Use an appropriate amount of binder to make soft materials, granulate with a 12-24 mesh sieve, dry at 40-80°C for 4-5 hours, granulate with a 18-20 mesh sieve, add other auxiliary materials and mix evenly, and then press into tablets; disintegrate The drug can be added externally, internally or by mixing internally and externally. It can also be directly compressed into tablets by crushing the drug and various auxiliary materials. After passing through a 80-100 mesh sieve, mix evenly, adjust the pressure, and compress the preparation into tablets.

Detailed ways

The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given for the purpose of illustration only, and are not intended to be construed as limitations of the invention, which may have many variations without departing from the spirit and scope of the invention.

Example 1

prescription:

Preparation method: first crush the above-mentioned materials through a 100-mesh sieve, mix topiramate, mannitol, and microcrystalline cellulose evenly, add an appropriate amount of starch slurry to make a soft material, granulate with a 16-mesh sieve, and dry at 60°C After 3-4 hours, granulate with a 16-mesh sieve, add disintegrating agent cross-linked sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, flavoring agent grape essence, coloring agent fruit green and lubricant magnesium stearate, mix After uniformity, it is compressed into topiramate dispersible tablets.

Example 2:

prescription:

Preparation method: first crush the above-mentioned materials through a 100-mesh sieve, mix topiramate, mannitol, and microcrystalline cellulose evenly, add an appropriate amount of starch slurry to make a soft material, granulate with a 16-mesh sieve, and dry at 80°C After 3 hours, the granules were sieved with a 16-mesh sieve, and the disintegrating agent croscarmellose starch sodium and the flavoring agent aspartame were added externally.

Colorant fruit green, lubricant talcum powder, after mixing, press into topiramate dispersible tablets.

Example 3:

prescription:

Preparation method: first crush the above materials through a 100-mesh sieve, thoroughly mix topiramate, lactose, pregelatinized starch, and microcrystalline cellulose, and then add an appropriate amount of low-substituted hydroxypropyl cellulose to make a soft material. Mesh sieve granulation, dry at 60°C for 2-3 hours, granulate with 20 mesh sieve, add disintegrating agent low-substituted hydroxypropyl cellulose, flavoring agent lemon essence, coloring agent fruit orange, lubricant micropowder silica gel, mix After uniformity, it is compressed into topiramate dispersible tablets.

Example 4:

prescription:

Preparation method: firstly crush the above materials respectively through a 100-mesh sieve, fully mix topiramate, xylitol, and microcrystalline cellulose, add polyvinylpyrrolidone 50% alcohol solution to make a soft material, and granulate with a 24-mesh sieve. After drying at 60°C for 1-2 hours, granulate with a 20-mesh sieve, add disintegrating agent cross-linked polyvinylpyrrolidone, L-HPC, flavoring agent stevioside, cherry essence, coloring agent fruit orange, lubricant PEG6000, mixed After uniformity, it is compressed into topiramate dispersible tablets.

Example 5

prescription:

Preparation method: first crush the above materials through a 100-mesh sieve, topiramate, lactose, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, aspartame, lemon essence, fruit orange, micronized powder After the silica gel is fully mixed and uniform, the pressure is adjusted and pressed into topiramate dispersible tablets.

biological test

Precision and Reproducibility

A sample solution was taken for 6 consecutive injections, and the intraday RSD was 0.55% (η=6). The same sample was sampled once a day for 3 consecutive days, and the interday RSD was 0.67% (η=3). The assay results of topiramate in the three batches of samples are shown in Table 1, which meets the requirements.

, the assay result of 3 batches of samples of table 1 embodiment 1 (marked amount %)

batch number batch 1 batch 2 batch 3

Relative labeled amount (%) 100.05 99.98 100.25

The research results show that the samples prepared according to the above prescription and process flow have good dispersion uniformity and dissolution uniformity, and the content uniformity of topiramate meets the regulations, indicating that the process is stable, reliable and highly repeatable.

Effect of factors and conditions on sample stability

Get test product (embodiment 1) batch 3 dispersible tablets, place under conditions such as strong light (4500 ± 500LX), high temperature (60 ℃), high humidity (RH75%) respectively, and respectively at 0, 5, 10 Take a sample every day, check its appearance, measure quality indicators such as its weight, content, related substances, dissolution rate (method is the same as above), and determine the impact of different factors and conditions on this product. The results are shown in Table 2 below.

Table 2 Preliminary Stability Investigation Factors Affecting Test Results (Batch 3)

The above data show that the topiramate dispersible tablet of the present invention disperses rapidly, has high dissolution rate, stable and controllable quality, and impurities and content all meet the pharmacopoeia standards.

Claims (10)

1. a topiramate dispersible tablet, wherein, the percentage by weight of topiramate is 5-50%, the percentage by weight of adjuvant is 50-95%.

2. dispersible tablet according to claim 1, wherein, wherein said adjuvant is selected from disintegrating agent, filler, binding agent, lubricant, wherein the percentage by weight of filler is 20-90%, the percentage by weight of disintegrating agent is 5-40%, and the percentage by weight of binding agent is that the percentage by weight of 1-20%, lubricant is 0.1-5%.

3. dispersible tablet according to claim 2, wherein, described disintegrating agent is selected from one or more in carboxymethyl starch sodium, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, sodium carboxymethyl cellulose, cross-linking sodium carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethylcellulose calcium, microcrystalline Cellulose, sodium lauryl sulphate, cetyl sulfo-sodium succinate, sodium dioctyl sulfosuccinate, tween 80; Described filler is selected from one or more of lactose, sucrose, sorbitol, mannitol, xylitol, erythritol, pregelatinized Starch, starch; Binding agent is wherein selected from a kind of in ethanol, water, ethanol-water solution, syrup, starch slurry, carboxymethylcellulose sodium solution, povidone solution, Magnesiumaluminumsilicate, sodium alginate or several mixture wherein; Lubricant is wherein selected from one or more the mixture in micropowder silica gel, magnesium stearate, calcium stearate, stearic acid, Pulvis Talci, silicon dioxide, Stepanol MG, PEG4000, PEG6000.

4. dispersible tablet according to claim 3, wherein, described dispersible tablet also contains correctives, correctives is selected from one or more the mixture in flavoring orange essence, Mint Essence, grape essence, cherry essence, flavoring banana essence, flavoring pineapple essence, vanilla, Fructus Citri Limoniae essence, Aspartame, saccharin sodium, steviol glycosides, and consumption is 0.5-5%.

5. dispersible tablet according to claim 3, wherein said dispersible tablet also comprises: the coloring agent of 0.1-0.5% percentage by weight, described coloring agent is selected from the green or fruit orange of coloring agent fruit.

6. according to the dispersible tablet described in claim 1-5 any one, wherein, the formula of described dispersible tablet consists of:

7. according to the dispersible tablet described in claim 1-5 any one, wherein, described dispersible tablet formula consists of:

8. according to the dispersible tablet described in claim 1-5 any one, wherein, described dispersible tablet formula consists of:

9. according to the dispersible tablet described in claim 1-5 any one, wherein, described dispersible tablet formula consists of:

10. a preparation method for dispersible tablet described in claim 1-9 any one, it adopts wet granule compression tablet, comprises following steps: medicine and various adjuvant are pulverized, crossed after 80-100 mesh sieve mix homogeneously; With suitable amount of adhesive soft material processed, granulate with 12-24 mesh sieve, 40-80 DEG C of dry 4-5 hour, 18-20 mesh sieve granulate, adds tabletting after other adjuvant mix homogeneously; Wherein disintegrating agent can adopt the method that additional, Nei Jia or inside and outside mixing add, and also can adopt direct powder compression, and medicine and various adjuvant are pulverized, and crosses after 80-100 mesh sieve, and mix homogeneously, regulates pressure, preparation tabletting.