JP4741865B2 - Method for producing pergolide tablets - Google Patents

Description

  The present invention relates to a method for producing a pergolide tablet known as a therapeutic agent for Parkinson's disease.

  Pergolide is a natural ergot alkaloid derivative starting from dihydroerymoclavine, and is a dopamine receptor agonist that has affinity not only for the central nigrostriatal dopamine D2 receptor but also for the D1 receptor As used in the treatment of Parkinson's disease.

  However, this drug has the disadvantage that it is not only stable in temperature but also in light. Therefore, conventionally, studies have been made to improve the stability of pergolide formulations.

  As a technique for improving the stability of a pergolide formulation, a method of adding a stabilizer to the formulation is known. For example, Patent Document 1 includes methionine, cysteine, and cysteine hydrochloride as stabilizers for improving the oxidative stability of a pergolide formulation. Patent Document 2 discloses polyvinylpyrrolidone, α-tocopherol succinate and propyl gallate as stabilizers for improving light stability. Furthermore, in these prior arts, first, other preparation raw materials such as lactose are added to a solution of pergolide mesylate, this mixture is dried to form granules, and then the granules are compression-molded together with other additive ingredients to produce tablets. A method (granular compression method) is described.

  However, even with these conventional techniques, the stability of the pergolide formulation is not always satisfactory. This is also clear from the fact that commercially available pergolide mesylate tablets are packaged with aluminum foil (so-called cold foam packaging).

  Thus, the stability of commercial pergolide formulations is supplemented by the application of cold foam packaging. However, although cold foam packaging is superior in terms of light shielding and moisture resistance, it costs more than other packaging forms and has the disadvantages that the inside cannot be visually confirmed.

  By the way, in addition to those related to pergolide, various techniques for improving the stability of the preparation are known. For example, Patent Document 3 discloses a preparation containing yellow ferric oxide in order to improve the photostability of bromocriptine mesylate which is also used for the treatment of Parkinson's disease. Patent Document 4 describes that sugar alcohol and lactose contribute to the stability of compounds used in the treatment of Parkinson's disease. Patent Document 5 describes a method for producing a preparation containing midodrine hydrochloride and mannitol used for the treatment of hypotension by a wet granule compression method.

However, these Patent Documents 3 to 5 do not describe or suggest a technique for improving the stability of the pergolide preparation, particularly the light stability.
US Pat. No. 5,114,948 (column 4, lines 3 to 55, claim 1) Japanese Patent Laid-Open No. 1-146821 (Claim 1, Example 1) JP-A-4-346929 (Claim 1) Japanese Patent Laid-Open No. 11-322604 (Claim 1, Paragraph [0003]) JP-A-5-255080 (Claim 1, paragraph [0001])

  As described above, studies for improving the stability of the pergolide formulation have been made so far. Moreover, the technique which raises the formulation stability in another chemical | medical agent is known. However, the stability of conventional pergolide formulations has not been sufficient.

  Therefore, the problem to be solved by the present invention is to provide a method for producing a pergolide tablet exhibiting sufficient stability without using cold form packaging which is costly and the inside cannot be visually recognized.

  The present inventor has intensively studied to solve the above problems. As a result, it was found that the reason why the photostability is particularly low in the pergolide formulation is that the pergolide present near the surface of the formulation is decomposed. Therefore, in order to reduce the amount of pergolide on the surface of the preparation, a granule compression method was adopted in which granules containing the pergolide (main drug granules) were first granulated, and the granules were compression molded together with the shaped granules. In addition, the present invention was completed by successfully improving the stability of pergolide not only with respect to temperature and humidity but also with light by blending sugar alcohol.

  That is, the method for producing a pergolide tablet according to the present invention includes the step of preparing a main drug granule containing pergolide or a pharmaceutically acceptable salt thereof and a sugar alcohol; and does not contain pergolide and a pharmaceutically acceptable salt thereof. And a step of preparing a shaped granule containing a sugar alcohol; and a step of compression molding by the granule compression method using the main drug granule and the shaped granule.

  The blending ratio of the sugar alcohol in the tablet is preferably 500 to 7000 times by mass with respect to the pergolide or a pharmaceutically acceptable salt thereof. If it is the said range, while being able to obtain sufficient stability, it can suppress that a tablet becomes larger than necessary.

  In the said manufacturing method, it is preferable to mix | blend sugar alcohol also with the said shaped granule. This is because the stability to temperature, humidity and light can be further enhanced.

  As the sugar alcohol, it is preferable to use one or more selected from the group consisting of mannitol, sorbitol, xylitol, maltitol, and erythritol. This is because these excellent effects have been demonstrated by examples described later.

  In the said manufacturing method, it is preferable to mix | blend a coloring agent further. This is because the light stability of pergolide can be further enhanced.

  Moreover, it is preferable that the tablet manufactured by the said manufacturing method packages the said tablet with the material which does not permeate | transmit substantially the light whose wavelength is 600 nm or less. According to the knowledge found by the present inventor, light having a wavelength of 600 nm or less causes the photolysis of pergolide. Therefore, it is considered that the light stability of the tablet according to the present invention can be further improved by packaging the tablet with a material capable of cutting light having a wavelength of 600 nm or less.

  According to the method for producing a pergolide preparation according to the present invention, the stability of pergolide, which is prone to decomposition not only by temperature and humidity but also by light, is remarkable even without using cold foam packaging that is expensive and invisible inside. Enhanced tablets can be obtained. Therefore, the method of the present invention is very useful as a method for obtaining a stable tablet of pergolide mainly used for treating Parkinson's disease.

  The method for producing a pergolide tablet according to the present invention comprises a step of preparing a main drug granule containing pergolide or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “pergolide etc.”) and a sugar alcohol; And a step of preparing a shaped granule containing a sugar alcohol; and a step of compression molding by granule compression using the main drug granule and the shaped granule. Below, the preparation process of a main drug grain is demonstrated first.

  Pergolide, which is a medicinal component of the preparation according to the present invention and is to be added to the main drug granule, has a chemical name of (−)-8β-[(methylthio) methyl] -6-propylergoline and has already been used as a treatment for Parkinson's disease. It is used. In the method of the present invention, it may be used in a free form, as a salt, or a mixture thereof. The type of the salt is not particularly limited as long as it is pharmaceutically acceptable. For example, mesylate, sulfate, nitrate, phosphate, acetate, propionate, caprylate, oxalate , Malonate, phenylacetate, citrate, lactate, malate, tartrate, maleate, and toluenesulfonate. Of these, mesylate is the most common.

  What is necessary is just to match | combine the compounding quantity of pergolide etc. per tablet with dosage amount. For example, when starting with administration of 50 μg pergolide twice a day and finally administering 750 to 1250 μg per day, the dosage can be 50 to 250 μg per tablet.

  As the sugar alcohol blended in the present invention, those generally used as an excipient can be used. Examples of such sugar alcohols include mannitol, sorbitol, xylitol, maltitol, and erythritol, from which one or more can be selected and used. The main drug granules may contain pharmaceutically acceptable excipients such as sugar alcohol and the like, sugars such as lactose and sucrose, cellulose derivatives, and starch.

In the method of the present invention, a colorant may be added in addition to the above essential components. The colorant can improve the light stability of the pergolide tablet because it exhibits a light-shielding effect on light of a specific wavelength. Such colorants include, for example, yellow ferric oxide (Fe ₂ O ₃ .H ₂ O), iron oxide (Fe ₂ O ₃ ), blue No. 1 (brilliant blue FCF), blue No. 2 (indigo carmine), These aluminum lakes can be mentioned, and yellow iron sesquioxide is preferably used. Further, the amount of the colorant added is not particularly limited as long as the effect of improving the light stability can be exhibited and the disadvantage does not become a problem. For example, it is 1% or less of the tablet mass, preferably 0. It can be 5% or less, more preferably 0.1% or less.

  The method for producing the granule is not particularly limited. For example, it is a wet type using a liquid binder, and a stirring and mixing granulation method, a rolling fluidized bed granulation method, an extrusion granulation method, a fluidized bed granulation method, or the like is used. be able to. As the liquid binder, a common one such as a hydroxypropylcellulose solution may be used. As the solvent, purified water, distilled water, pure water, etc., absolute ethanol, a mixed solvent of water and ethanol, or the like can be used.

  As a specific granule production method, for example, a liquid binder obtained by adding pergolide and other components and the liquid binder is sprayed on the other components being flowed, and the resulting particles are obtained. The method of drying can be mentioned. Since the granule obtained in this way has a wide particle size distribution, the particle size may be made uniform to some extent by sieving or the like.

  In the present invention, shaped particles are separately prepared. This shaped particle can be produced by the same method as the main drug particle described above except that it does not contain pergolide or the like. However, it does not mean that the same manufacturing method as the main drug particles is employed, and specific manufacturing conditions may be appropriately selected within the above-described range.

  In the present invention, sugar alcohol is added to both the main drug particle and the shaped particle. The total sugar alcohol content in the tablet is preferably 500 to 7000 times by mass with respect to the pergolide or a pharmaceutically acceptable salt thereof. If the amount is less than 500 times the mass, the stabilizing effect may not be sufficiently exhibited. On the other hand, if the amount exceeds 7000 times the mass, the tablet may become unnecessarily large and may be difficult to drink. Since sugar alcohol etc. can exhibit the stabilization effect of pergolide, so that there are many compounding quantities, 1000 mass times or more are more preferable in the said range, 2000 mass times or more are further more preferable, 3000 mass times or more are further more preferable. However, considering the size of the tablet, 6000 mass times or less is more preferable.

  The blending ratio of the sugar alcohol in each of the main drug particles and the shaped particles is not particularly limited, but preferably the amount in the shaped particles is increased. This is because by reducing the volume ratio of the main drug grains to the whole tablet, the amount of pergolide present in the vicinity of the tablet surface can be reduced, and as a result, the stability can be further enhanced. The blending ratio in such a case is not particularly limited. For example, sugar alcohol is 5 to 40% in the main drug particle (95 to 60% in the shaped particle), more preferably 5 to 30% in the main drug particle (shaped). By adding 95 to 70%) to the grains, and further 5 to 20% (95 to 80% to the shaped grains), the stability can be improved.

  In the method for producing a pergolide tablet according to the present invention, previously prepared granules (main drug granules and shaped granules) and other ingredients are mixed and compression molded. This is because the effects of temperature and humidity and light are suppressed by reducing pergolide and the like present on the tablet surface as much as possible. As a specific compression molding method (tablet compression method), a general method can be adopted.

  Ingredients to be added in addition to granules are not particularly limited as long as they are generally added to tablets by the granule compression method. For example, starch such as corn starch, carmellose sodium, croscarmellose sodium, carmellose calcium, hydroxypropyl Examples include disintegrants such as cellulose; lubricants such as stearic acid, calcium stearate, and magnesium stearate.

  The pergolide tablet manufactured by the method of the present invention described above has significantly improved stability against temperature and humidity and light. However, in order to further enhance the stability during storage, the tablet of the present invention is preferably packaged with a material that does not substantially transmit light having a wavelength of 600 nm or less.

  For example, it is conceivable to form a prestar pack (PTP) by forming a pocket for putting a tablet in a red polyvinyl chloride film (PVC film), packaging the tablet with aluminum foil after putting the tablet. If the tablet of the present invention is stored in such a manner, light having a wavelength of 600 nm or less that particularly adversely affects pergolide can be shielded, so that the light stability of the tablet can be further improved. Further, unlike cold foam packaging, it can be packaged in a form that is inexpensive and allows the inside to be visually confirmed.

  Here, “substantially does not transmit light having a wavelength of 600 nm or less” means that the light having the wavelength can be completely blocked, or to the extent that the stability of the tablet of the present invention is hardly affected. It means that light can be cut. For example, it means that the stability of the tablet of the present invention can be improved under the conditions of Test Example 1 or 2 described later or under severer conditions.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. It is also possible to implement, and they are all included in the technical scope of the present invention.

Production Example 1 Production of Pergolide Tablets by Compressing Main Drug Granules and Shaped Grains After the pergolide mesylate was dissolved in absolute ethanol in the amounts shown in Table 1, yellow ferric oxide was dispersed. Hydroxypropylcellulose was dissolved here to obtain a binding solution. The binding solution and sugar alcohol or lactose were put into a granulator (Freund Sangyo Co., Ltd., FRC-1) and granulated. This was dried at 60 ° C. and sieved with a 32M sieve to obtain main drug granules. Separately, yellow iron sesquioxide, hydroxypropylcellulose, and absolute ethanol were mixed to form a binding solution, and sugar alcohol or lactose was further added, and granulated in the same manner to obtain shaped particles. Croscarmellose sodium and magnesium stearate were further mixed into the mixture of the main drug particles and the shaped particles, and compression-molded with a rotary tableting machine (Kirsui Corporation, VIRG19) to produce tablets.

Comparative Production Example 1 Production of Pergolide Tablets by Compressing Main Drug Particles Using the ingredients shown in Table 2 excluding croscarmellose sodium and magnesium stearate, the main drug granules were prepared in the same manner as in Production Example 1. Croscarmellose sodium and magnesium stearate were mixed into the main drug granules, and directly compressed and molded by a rotary tableting machine (Kirsui Corporation, VIRG19) without using shaped granules, to produce tablets.

Test Example 1 Stability test against temperature and humidity The tablet produced above was left in a thermo-hygrostat under the conditions of temperature: 55 ° C. and relative humidity: 75%, and the residual rate of pergolide mesylate after 2 weeks. Was measured. The measurement was performed by analyzing the tablet in a diluent solvent (dissolving 5.0 mg of DL-methionine in 500 mL of 0.01 mol / L hydrochloric acid and adding 500 mL of methanol) by HPLC. It was. The conditions of the HPLC method are as shown below.
Column: Octadecylsilylated silica gel column (Wakosil II 5C18 HG, inner diameter: about 4.6 mm, length: about 15 cm)
Moving bed: 2.0 g of sodium 1-octanesulfonate dissolved in 1 to 1000 times aqueous acetic acid solution / Methanol: acetonitrile (1: 1) 45/55 mixed liquid flow rate: retention time of pergolide is about 6 minutes Adjust column temperature to be about 40 ℃
Detection: Ultraviolet absorptiometer (measurement wavelength: 280 nm).

  The results are shown in Table 3.

  As described above, the preparations containing only the main drug granules as granules and not using the shaped granules use erythritol as the excipient (formulation E), when using lactose as the excipient (formulation F) In both cases, the stability to temperature and humidity was not sufficient. On the other hand, when the main drug granules and the shaped granules are blended as granules, both the one using sugar alcohol as the excipient (preparation A and B), the one using lactose as the excipient (preparation C), Good stability against humidity. Moreover, even when only the main drug particles were blended as granules, the stability of those using mannitol as an excipient (Formulation D) was good.

Test Example 2 Light Stability Test The tablets were exposed to visible light of 1700 lux for 2 weeks, and the residual ratio of pergolide mesylate thereafter was measured in the same manner as in Test Example 1 above. Moreover, after covering each tablet with the red PVC film which can interrupt | block the short wavelength light of wavelength 600nm or less, what was exposed on the same conditions also measured the pergolide mesilate residual rate. The results are shown in Table 4.

  As described above, the photostability of the preparations (formulations D to F) in which only the main drug granules are blended as granules and no shaped granules are used is satisfactory regardless of the presence or absence of sugar alcohol as an excipient. It was not a thing. This is considered due to the relatively large amount of pergolide mesylate on the tablet surface. Moreover, even when the main drug granules and the shaped granules were blended as granules, the photostability was still insufficient if no sugar alcohol was blended (Formulation C). On the other hand, in the preparations (formulations A and B) in which the main drug granules and the shaped granules were blended as granules and the sugar alcohol was used as an excipient, the photostability was remarkably improved.

Considering these results together with the results of Test Example 1 above, in the Belgolide tablet, in order to remarkably improve the stability to temperature, humidity and light, both the main drug granules and shaped granules containing pergolide as granules are used. It was revealed that sugar alcohol should be used and added as an excipient.

Claims (5)

A method for producing a pergolide tablet comprising:
Preparing a main drug granule comprising pergolide or a pharmaceutically acceptable salt thereof and a sugar alcohol;
A step of preparing a shaped granule which does not contain pergolide and its pharmaceutically acceptable salt and contains a sugar alcohol, and a step of compression molding by the granule compression method using the main drug granule and the shaped granule,
The manufacturing method of the pergolide tablet characterized by including these.   The manufacturing method of the pergolide tablet of Claim 1 WHEREIN: The mixing | blending ratio of the said sugar alcohol to the said tablet is 500-7000 mass times with respect to the said pergolide or its pharmaceutically acceptable salt. The manufacturing method as described.   The production method according to any one of claims 1 to 3, wherein one or more selected from the group consisting of mannitol, sorbitol, xylitol, maltitol, and erythritol is used as the sugar alcohol.   Furthermore, the manufacturing method in any one of Claims 1-5 which mix | blends a coloring agent.   The manufacturing method according to any one of claims 1 to 5, wherein the tablet is packaged with a material that does not substantially transmit light having a wavelength of 600 nm or less.