CN100404026C - A kind of oral pharmaceutical composition containing fudosteine - Google Patents

Abstract

The invention relates to an oral pharmaceutical composition containing fudosteine and a preparation process thereof. It is characterized in that the filler in the pharmaceutical composition is selected from inorganic salts and/or natural minerals, and the pharmaceutical composition exists in the form of powder or granules, which can make the preparation stable and will not change color after long-term storage.

Description

A kind of oral pharmaceutical composition containing fudosteine

technical field

The present invention relates to a pharmaceutical composition. Specifically, the present invention relates to a pharmaceutical composition containing fudosteine (chemical name (-)-(R)-2-amino-3-(3-hydroxypropylmercapto)propionic acid) The formulation and preparation process of oral tablets and capsules. The pharmaceutical composition can overcome the discoloration problem caused by the combination of fudosteine and other auxiliary materials.

Background technique

Chemicals with an expectorant effect that are widely used in clinical practice, such as bromhexine, acetylcysteine, and carboxymethylcysteine, all have varying degrees of phlegm-regulating effects. However, there are following defects in its pharmacology or clinical application: (1), the free sulfhydryl group in the molecular structure will adsorb the mucin in the gastrointestinal tract, and local damage to the gastrointestinal tract will occur after oral administration, with relatively large side effects; (2), it will weaken The antibacterial activity of penicillin, cephalosporin antibiotics, erythromycin, tetracycline, etc., should not be used in combination; (3), it will affect the internal process of theophylline and should not be used in combination with theophylline.

Fudosteine is a new type of expectorant, its basic pharmacological effects are inhibition of goblet cell hyperplasia, breaking of the disulfide bonds of mucin in bronchial secretions, and regulation of the normal state of mucus and mucosa in the respiratory tract , is a high-efficiency and low-toxic expectorant, and is expected to become a replacement product for similar drugs such as acetylcysteine and carboxymethylcysteine.

Fudosteine is an extremely stable compound. When it exists alone in the air, it is stable even at high humidity, and there is no discoloration. However, discoloration will occur when it is used together with fillers commonly used in solid preparations, such as various sugars, cellulose, and sugar alcohols. This discoloration phenomenon not only affects the appearance of the medicine, but also sometimes causes a decrease in the content, so the formulation of the pharmaceutical composition of the present invention is designed to resist this discoloration.

The fudosteine tablet involved in the present invention was first developed by Aisy Pharmaceutical Co., Ltd. and was launched in 2001. Aiming at the property that the drug will change color when it is used together with fillers often used in solid preparations, such as various sugars, celluloses, and sugar alcohols, Ai Shi Pharmaceutical Co., Ltd. elaborated a method in CN 1155373C Prescription composition and preparation process of fudosteine tablets. In the composition of the prescription, the filler is corn starch or potato starch, and the dosage is 0.01-8 times that of fudosteine.

During the research, we found that the filler used in the formulation, that is, corn starch or potato starch, has poor compressibility and fluidity, is easy to absorb moisture and affects the long-term stability of the preparation, and is likely to cause a large amount of dust during mass production. Not conducive to labor protection.

The Chinese published patent CN1463698A describes in detail the composition of another fudosteine tablet and its preparation process. In the composition of the prescription, the filler is sodium carboxymethyl starch, and the dosage is 0.01-5 times that of fudosteine.

During the research, we found that the high-viscosity carboxymethyl starch sodium is difficult to buy as the binder used in the composition of the prescription, and the proportion of carboxymethyl starch sodium in the prescription is also limited. not applicable.

technical content

According to the existing excipients and production conditions, under the premise of ensuring low production cost and simple and easy preparation process, so as to be suitable for large-scale industrial production, it is necessary to study a suitable prescription composition and preparation process. Fudosteine has good long-term storage and will not change color drug stability.

In the study of influencing factors, we found that the reason for the discoloration of fudosteine has nothing to do with humidity, so it is not feasible to achieve long-term storage without discoloration by reducing the water content of the preparation. At the same time, it is found through experiments that the addition of antioxidants cannot prevent its discoloration and improve its stability.

Coexisting components have a great influence on the discoloration of fudosteine. When its preparation is in the form of oral solid preparations, such as tablets and capsules, which excipients coexist with fudosteine can achieve long-term storage without discoloration It is one of the keys to prescription design. For this reason, we have carried out a lot of research work, and the results show that inorganic salts, such as calcium hydrogen phosphate, calcium sulfate and natural minerals, such as diatomaceous earth and kaolin, can significantly prevent the long-term storage of fudosteine. discoloration behavior.

Taking the preparation form as tablet or capsule as an example, in a preferred embodiment of the present invention, calcium hydrogen phosphate is selected as filler, accelerated test for 6 months, long-term test for 18 months without discoloration, and other test results This formulation also proved to be very stable. Moreover, the oral solid preparation is prepared with the inorganic salts of the present invention, diatomaceous earth, and kaolin as fillers in the prescription composition, and the remaining auxiliary materials in the prescription composition, such as disintegration auxiliary materials, adhesive auxiliary materials, and lubricating auxiliary materials The range of selection and dosage of commonly used excipients such as auxiliary materials for flow aid and flavoring are wide, and they are not limited by the process, which avoids the limitation of the production process caused by the nature of the excipients.

The invention provides a pharmaceutical composition containing fudosteine, a filler and other auxiliary materials, wherein the filler is selected from inorganic salts and natural minerals, and calcium hydrogen phosphate is preferred in the present invention, and the consumption is 10% of the weight of the composition. -95%, the optimal amount is 20-60% by weight of the composition. The composition is prepared into tablets and hard capsules. The preparation method can be tableting or capsule filling after preparing granules, or direct tableting or capsule filling without granulation. The preparation method of the granules may be dry granulation or wet granulation. Other auxiliary materials also include disintegrants, binders, lubricants, glidants, flavoring agents, etc.

The disintegrating agent is selected from common auxiliary materials such as sodium carboxymethyl starch, starch, cross-linked polyvinylpyrrolidone, etc., and sodium carboxymethyl starch and cross-linked polyvinylpyrrolidone are preferred in the present invention; the dosage of the disintegrating agent is 1%-20%.

Lubricants can be selected such as stearic acid, magnesium stearate, hydrogenated vegetable oil, talcum powder, polyethylene glycol, etc., the present invention preferably magnesium stearate, talcum powder.

The preparation method of the mixture or particles provided by the present invention can be any preparation method known in the art.

The method for preparing the pharmaceutical composition by direct mixing of powders and dry granulation has the advantage that the method is simple and easy to implement. The selected auxiliary materials should ensure that the prepared powder or granules have good fluidity, so that the powder can be smoothly filled in the die, and must also have good compressibility.

Since the wet granulation method can significantly improve the fluidity of the mixture, the selection of other necessary auxiliary materials other than fillers is wider, but attention should be paid to the influence of the properties of other auxiliary materials on stability.

Further illustrate this patent with embodiment below, should be understood that, embodiment of the present invention is for illustrating the present invention rather than limitation of the present invention.

Example:

Example 1:

Fordosteine 200g

Calcium hydrogen phosphate 107g

Cross-linked polyvinylpyrrolidone 36g

Talc powder 3.5g

Magnesium stearate 3.5g

             

Made into 1000 pieces

Preparation Process

Fudosteine is crushed through an 80-mesh sieve, mixed with calcium hydrogen phosphate and cross-linked polyvinylpyrrolidone in a rapid stirring granulator according to the prescription amount, added with water to granulate, and after drying, add talcum powder and magnesium stearate to compress into tablets. Tablet weight is about 350mg. Coating with OPADRY Y-1-7000, the weight gain is about 2% to 3%.

Example 2:

Fordosteine 200g

Calcium hydrogen phosphate 92g

Sodium carboxymethyl starch 16g

Talc powder 3.5g

Magnesium stearate 3.5g

           

Made into 1000 capsules

Preparation Process

Fudosteine was crushed through an 80-mesh sieve, mixed with calcium hydrogen phosphate and sodium carboxymethyl starch in a rapid stirring granulator according to the prescription amount, added water to granulate, dried and added talcum powder and magnesium stearate in V-type Mix in a mixer, fill capsules, and the filling capacity is about 315mg.

Example 3:

Fordosteine 200g

Calcium sulfate 150g

Cross-linked polyvinylpyrrolidone 40g

Talc powder 5g

Magnesium Stearate 5g

             

Made into 1000 pieces

Preparation Process

The prescribed amount of fudosteine and auxiliary materials are passed through an 80-mesh sieve and mixed in equal amounts, and mixed in a V-type mixer or a three-dimensional motion mixer. The tablet weight is about 400mg, and the powder well-known to those skilled in the art can be directly compressed into tablets. .

Example 4:

Fordosteine 100g

Diatomaceous earth 150g

Cross-linked polyvinylpyrrolidone 40g

Talc powder 5g

Magnesium Stearate 5g

             

Made into 1000 pieces

Preparation Process

The prescribed amount of fudosteine and auxiliary materials are mixed through an 80-mesh sieve in equal amounts, and mixed in a V-shaped mixer or a three-dimensional motion mixer. The tablet weight is about 300 mg, and the powder well-known to those skilled in the art can be directly compressed into tablets. .

Example 5:

Fordosteine 100g

Kaolin 150g

Cross-linked polyvinylpyrrolidone 40g

Talc powder 5g

Magnesium Stearate 5g

             

Made into 1000 pieces

Preparation Process

The prescribed amount of fudosteine and auxiliary materials are mixed through an 80-mesh sieve in equal amounts, and mixed in a V-shaped mixer or a three-dimensional motion mixer. The tablet weight is about 300 mg, and the powder well-known to those skilled in the art can be directly compressed into tablets. .

Comparative Example 1:

Fordosteine 200g

Microcrystalline Cellulose 107g

Cross-linked polyvinylpyrrolidone 36g

Talc powder 3.5g

Magnesium stearate 3.5g

             

Made into 1000 pieces

Preparation Process

Fudosteine is crushed through 80 mesh sieve, mixed with microcrystalline cellulose and cross-linked polyvinylpyrrolidone in a fast stirring granulator according to the prescription amount, added with water to granulate, dried and added with talcum powder and magnesium stearate to press into tablets , tablet weight is about 350mg. Coating with OPADRYY-1-7000, the weight gain is about 2% to 3%.

Comparative example 2:

Fordosteine 100g

Lactose 150g

Cross-linked polyvinylpyrrolidone 40g

Talc powder 5g

Magnesium Stearate 5g

             

Made into 1000 pieces

Preparation Process

The prescribed amount of fudosteine and the auxiliary materials are mixed through an 80-mesh sieve in equal increments, and mixed in a V-shaped mixer or a three-dimensional motion mixer. The tablet weight is about 300 mg. Can.

The preparations produced in Examples 1 to 5 and Comparative Examples 1 and 2 were tested in the influence factor test, accelerated test (40 ± 2 °C of temperature, 75% ± 5% of humidity) and long-term stability test (25 ± 2 °C of temperature). , Humidity 60%±5%), the discoloration conditions are shown in Table 1, Table 2 and Table 3 respectively.

Table 1. Experimental results of influencing factors

Table 2. Acceleration experiment results

1 month 2 months 3 months 6 months Example 1 - - - - Example 2 - - - - Example 3 - - - - Example 4 - - - - Example 5 - - - - Comparative Example 1 - + + ++ Comparative Example 2 + + ++ ++

Table 3. Long-term stability test results

0 months 3 months 6 months 9 months 12 months 18 months Example 1 - - - - - - Example 2 - - - - - - Example 3 - - - - - - Example 4 - - - - - - Example 5 - - - - - - Comparative Example 1 - - + + + ++ Comparative Example 2 - + + + + +

-: no color change

+: discoloration

++: severe discoloration

Therefore, from the results shown in Tables 1 to 3, it can be seen that the oral pharmaceutical composition containing fudosteine of the present invention will not change color when stored for a long time, and other various test results have also proved that this preparation is very stable. Stable and therefore an excellent formulation.

Comparative example 3 (Japanese patent prescription embodiment 1):

Fudosteine 200g

Lactose 78g

Talc powder 1g

Magnesium stearate 1g

           

Made into 1000 pieces

Preparation Process

The prescribed amount of fudosteine and auxiliary materials are mixed through an 80-mesh sieve in an equal amount and mixed in a V-shaped mixer or a three-dimensional motion mixer. The tablet weight is about 280 mg, and the powder well-known to those skilled in the art can be directly compressed into tablets. .

Embodiment 1 and comparative example 3 are carried out the comparison of granule fluidity and compressibility, and the results are listed in table 4 and table 5 respectively:

Table 4. Comparative results of particle fluidity of embodiment 1 and comparative example 3

Example 1 Comparative Example 3 angle of repose 40.35° 47.17° Compression 14.32% 31.80%

The comparative result of table 5 embodiment 1 and comparative example 3 compressibility

Example 1 Comparative Example 3 Exterior One-sided smooth, no astringent phenomenon One-sided smooth, side astringent Hardness (Newton) 60.33 50.67 Friability (%) <0.01 1.43

Description: The weight of each tablet is 200mg, and the thickness of the tablet is 3.56-3.85mm

Therefore, as can be seen from the results shown in Table 4 to Table 5, the prescription and technology used in the present invention are superior to the composition and technology of the fudosteine tablets set forth in CN 1155373C in terms of fluidity and compressibility of granules .

Claims (4)

1. pharmaceutical composition, it is characterized by and contain Fudosteine, filler, disintegrating agent and lubricant, described filler is selected from calcium hydrogen phosphate, calcium sulfate, kieselguhr or kaolin, described disintegrating agent is selected from carboxymethyl starch sodium, crospolyvinylpyrrolidone, and described lubricant is selected from magnesium stearate and talcous mixture.

2. the described pharmaceutical composition of claim 1 is characterized in that this compositions is tablet or hard capsule.

3. the described pharmaceutical composition of claim 1, wherein filler loading is the 10-95% of composition total weight.

4. the described pharmaceutical composition of claim 1, wherein filler loading is the 20-60% of composition total weight.