JPH0129764B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a solid preparation of an oily liquid substance. More specifically, the present invention relates to a method of producing a solid preparation using a powdered oily liquid substance that is easy to form into a solid preparation and has excellent release and diffusion of ingredients. Conventionally, a well-known method for producing solid preparations of oily liquid substances is to adsorb the oily liquid substance to a porous or large adsorbent with a large specific surface area, and then use this as a secondary raw material to form powders, granules, or tablets. ing. However, this method has various problems in terms of release and diffusion of oily components from solid preparations. In other words, in order to adsorb substances that are inherently hydrophobic and poorly soluble to adsorbents with high adsorption capacity,
There is a strong tendency for the drug to have reduced diffusivity in water or digestive fluids, resulting in even worse absorption and reduced drug efficacy.
Even though an adsorbent that has adsorbed an oily liquid substance appears to be solid, in reality, the oily liquid substance is simply attached to the surface of the adsorbent, so the surface of the adsorbent itself becomes lipophilic, and therefore the individual The cohesion between particles of the adsorbent decreases, which tends to cause problems in forming into granules and tablets.Especially when adding and mixing appropriate excipients to form tablets, the oily liquid adhering to the surface of the adsorbent. As the substance gradually penetrates and diffuses into adjacent excipient particles, the compression moldability of the mixture deteriorates over time, making it more likely to cause tableting problems such as hardness reduction and capping. Since the oily liquid substance is adsorbed by an adsorbent with a large surface area, the contact area between the oily liquid substance and the air increases, making deterioration due to air oxidation more likely. Studies have been conducted to solve these problems, and several improvement methods have been proposed. For example, oily liquid substance and melting point 40℃
A method of melt-mixing the above-mentioned solid oil-based substances and a nonionic surfactant with an HLB of 8 or more, blending an adsorbent if necessary, and crushing the mixture after cooling to form granules or powder (Unexamined Japanese Patent Publication No. (Sho 52-66616).
However, although this method solves the problem to some extent, it is still not completely satisfactory. According to the above method, the contact area between the oily liquid substance and air is small, so there is little deterioration of the ingredients, and since it contains a solid oily substance, it easily becomes a solid lump when compressed, and has good moldability. Although it appears that nonionic surfactants have solved some problems, such as the diffusion of oily liquid substances by forming oil-in-water emulsions in water, there are still many problems. . In other words, the solid oil-based substance added is water-insoluble and water-repellent like the main component oil-based liquid substance, so even if some nonionic surfactant is present, the particle surface is lipophilic and water-repellent. The surface of formulated granules and tablets also has lipophilic and water-repellent properties, making them difficult to wet with water and causing problems in forming them into granules and tablets. As a result, the disintegration is significantly prolonged, the release and diffusion of oily components are reduced, and sufficient medicinal efficacy cannot be expected. A considerable amount of nonionic surfactant is required for a solid oil-based substance to completely form an oil-in-water emulsion, but when the necessary amount of surfactant is added, the surfactant itself takes effect. Although the contact between oil-based liquid substances and air has been reduced, it has not been completely quenched, so there is still the possibility of deterioration.
Furthermore, since the above-mentioned method is a method in which the mixture is melted and allowed to cool, the molten mixture becomes a lump after being allowed to cool, and when it is to be formulated into a formulation, it must be crushed into granules or powder. Therefore, an extra step is required to form a solid formulation. The present inventors have conducted extensive research in order to overcome the drawbacks of such conventional methods and to develop a method for producing solid preparations of oily liquid substances that are easy to form into solid preparations and have good release and diffusion of the main ingredient. As a result of stacking, the oily liquid substance is mixed with a nonionic surfactant, adsorbed on an adsorbent, and then melted and coated with polyethylene glycol having a molecular weight of 3000 or more.The resulting powdered oily liquid substance is used as a secondary raw material. The inventors have discovered that the object can be achieved by using the method as a method, and based on this finding, the present invention has been completed. That is, in the method of the present invention, a nonionic surfactant is uniformly dispersed in an oily liquid substance, mixed with a porous or large specific surface area adsorbent, and adsorbed.
Next, polyethylene glycol with a molecular weight of 3,000 or more is added to this, mixed well, and then heated to above the melting point while stirring and kneaded to melt and coat the powder with polyethylene glycol with a molecular weight of 3,000 or more to create a powdered oily liquid substance. The present invention provides a method for producing a solid preparation of an oil-based liquid substance, which is characterized in that the solid preparation is prepared by adding an excipient to the preparation. In the powdered oily liquid substance obtained by the method of the present invention, the oily liquid substance and the nonionic surfactant are uniformly dispersed and adsorbed on the adsorbent, and the surface of the adsorbent is made of water-soluble polyethylene glycol. It is melt coated. Therefore, this powdered oily liquid substance has a hydrophilic and water-soluble surface, and solid preparations such as powders, granules, and tablets made from it as a secondary raw material naturally also have a hydrophilic surface and a water-soluble surface. Since it has an internal structure, water can be introduced into the interior quickly. From this, all of the various solid preparations obtained by the method of the present invention show extremely good disintegration and dispersibility in water or digestive fluids, and the coating material on the surface of the dispersed adsorbent particles is water-soluble. The oily liquid substance that is quickly dissolved and disappears, and is adsorbed or encapsulated on the particle surface and inside forms an oil-in-water emulsion due to the emulsification effect of the coexisting surfactant, and is released and diffused. As a result, the component oily liquid substance is well absorbed and its medicinal effects are fully exerted. In addition, since the powdered oily liquid substance obtained by the method of the present invention is granulated and the particle surface is coated with solid polyethylene glycol, it has good fluidity and good bonding between individual particles, making it suitable for formulation. In addition, when an appropriate excipient is added and molded, the oily liquid substance is prevented from penetrating into adjacent excipient particles, so the compression moldability of the mixed powder does not deteriorate. , certain good solid preparations can be obtained. Furthermore, since the solid preparation according to the present invention completely prevents contact between the oily liquid substance and air, deterioration due to oxidation, moisture absorption, etc. is extremely low, and stability can be significantly improved. According to the method of the present invention, since the solidified product of the oily liquid substance is obtained in the form of powder or granules, manufacturing processes such as crushing and granulation, which are performed before the formulation thereof, are not necessary, and therefore, the solidified product of the oil-based liquid substance is not required. When manufacturing, it is possible to simplify the process and equipment. The method of the present invention has such characteristics. The adsorbent used in the method of the present invention is preferably a porous material or a finely powdered material with a large specific surface area, which contains an oily liquid substance in as high a concentration as possible and can be easily solidified. Examples of such adsorbents include magnesium alumina hydroxide, magnesium aluminate metasilicate, magnesium oxide, aluminum hydroxide, calcium phosphate, aluminum silicate, and colloidal silicic anhydride. It is preferable to use such an adsorbent in an amount of 30 to 300 parts by weight per 100 parts by weight of the oily liquid substance. Further, the nonionic surfactant used in the method of the present invention preferably has an HLB of 7 or more,
Particularly preferred are those that are liquid at room temperature. Such surfactants include polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan monooleate (polysorbate 80),
Polyoxyethylene fatty acid esters such as polyoxyethylene sorbitan monolaurate, sucrose fatty acid esters such as sucrose tristearate, sucrose distearate, sucrose distearate, sucrose tristearate, sucrose distearate, etc. Sugar monopalmitate, sucrose monolaurate, sucrose monooleate, etc.
Examples include glycerin fatty acid esters, such as glycerin monostearate, and propylene glycol fatty acid esters. The amount of such surfactant to be used is preferably selected in the range of 5 to 100 parts by weight per 100 parts by weight of the oily liquid substance. Further, examples of the polyethylene glycol having a molecular weight of 3,000 or more used in the method of the present invention include polyethylene glycol 4,000 and polyethylene glycol 6,000, with polyethylene glycol 6,000 being preferred. These polyethylene glycols with a molecular weight of 3000 or more are adsorbents that adsorb oily liquid substances and surfactants.
It is desirable that the amount is in the range of 5 to 100 parts by weight. To suitably carry out the method of the present invention, 5 to 50 parts by weight of a nonionic surfactant, such as polysorbate 80, is uniformly dispersed in the oily liquid material per 100 parts by weight of the oily liquid material. substance 100
It is adsorbed to 50 to 200 parts by weight of an adsorbent, for example, magnesium aluminate metasilicate. Next, 10 to 10 parts by weight of the adsorbent adsorbing the mixture of oily liquid substance and surfactant is added to this.
Add 40 parts by weight of polyethylene glycol having a molecular weight of 3,000 or more, such as polyethylene glycol 6,000, and mix well. Heat kneading at 60 to 80° C. for 3 to 10 minutes while stirring, and allow to cool to obtain fine granular powder. Appropriate excipients and the like are added to this powdered oily liquid substance and molded to obtain a solid preparation. For example, powders can be obtained by adding and mixing excipients, such as lactose, depending on the required dispersion. Granules contain, as an excipient,
For example, it is obtained by adding and mixing microcrystalline cellulose, lactose, etc., adding water with an aqueous solution containing a binder, passing through a sieve to form granules, and drying. For tablets, excipients such as microcrystalline cellulose and calcium stearate are added, mixed well, and then compressed to obtain uncoated tablets. Such uncoated tablets can be coated with a suitable coating, if necessary. Furthermore, other compounding agents such as flavoring agents, sweeteners, etc. may be added as appropriate during such formulation. The method of the present invention can be applied to a wide range of oily liquid substances, regardless of the type, as long as the oily liquid substance used is liquid at room temperature and pressure. Such oily liquid substances include various natural and synthetic oily liquid substances, such as dimethylpolysiloxane, creosote, benzaldehyde, vitamin A oil,
α-tocopherol, phytonadione, vitamin A esters, α-tocopherol esters,
Examples include oil-based medicines such as cod liver oil, safflower oil, eucalyptus oil, henopodium oil, cinnamon oil, cinnamon oil, etc., fat-soluble vitamins, vegetable oils, and fragrances. The solid preparation of an oily liquid substance obtained by the method of the present invention is extremely easy to disintegrate and disperse in water, and is easily absorbed because the oily liquid substance as the main component becomes an oil-in-water emulsion and diffuses. , medicinal effects are effectively exerted. In addition, when manufacturing tablets as solid preparations, the compression moldability of the mixture before tableting does not deteriorate over time, so consistently good tablets can be obtained and tableting problems such as hardness reduction and capping can be avoided. It never happens. Furthermore, the oil-based liquid substance is extremely unlikely to undergo deterioration such as oxidation or moisture absorption due to contact with air, and is stable, so its shelf life can be significantly extended. According to the method of the present invention, a solidified oil-based liquid substance can be obtained in the form of powder or granules, so there is no need to add manufacturing processes such as crushing and granulation that are normally performed before formulating solid preparations. Solid formulations can be manufactured. As described above, compared to conventional production methods, the method of the present invention improves the stability, disintegration, dispersibility, absorption, and effectiveness of the oil-based liquid substances and solid preparations, as well as ease of operation during production. This is an excellent method in many respects, including the simplification of equipment. The method of the present invention will be explained in more detail with reference to the following examples. Example 1 Prescription Dimethylpolysiloxane 100g Polysorbate 80 50g Magnesium aluminate metasilicate 100g Polyethylene glycol 6000 50g Lactose 1700g 50g of polyoxyethylene sorbitan monooleate (polysorbate 80) was uniformly dispersed in 100g of dimethylpolysiloxane, and metasilicic acid Adsorb it onto 100g of magnesium aluminate to form a powder.
50 g of polyethylene glycol 6000 is mixed with this, stirred at 80° C. for 5 minutes, and allowed to cool to obtain a fine granular powder. Mix 1700 g of lactose as an excipient to obtain 2000 g of a homogeneous 20% dimethylpolysiloxane dispersion. Example 2 Recipe Dimethylpolysiloxane 100g Polysorbate 80 20g Magnesium alumina hydroxide 200g Polyethylene glycol 6000 60g Lactose 1620g According to the above recipe, using magnesium alumina hydroxide as an adsorbent, dimethylpolysiloxane was prepared in the same manner as in Example 1. Obtain 2000 g of homogeneous 20x powder. Example 3 Recipe Dimethylpolysiloxane 200g Polysorbate 80 60g Magnesium aluminate metasilicate 200g Polyethylene glycol 6000 150g Lactose 1390g According to the above recipe, operate in the same manner as in Example 1 to obtain 2000g of a homogeneous 10-fold dispersion of dimethylpolysiloxane. . Example 4 Prescription Phytonadione 200g Polyoxyethylene stearate 30g Magnesium aluminate metasilicate 200g Polyethylene glycol 6000 100g Lactose 1470g 30g of polyoxyethylene stearate was uniformly dispersed in 200g of phytonadione and adsorbed on 200g of magnesium aluminate metasilicate. Make into powder. Add to this 100g of polyethylene glycol 6000
Mix, stir at 60°C for 5 minutes, and leave to cool to obtain a fine powder. Add to this 1470g of lactose as an excipient.
2000g of homogeneous 10x powder of phytonadione mixed with
get. Example 5 Recipe Safflower oil 200g Polysorbate 80 20g Magnesium aluminate metasilicate 150g Polyethylene glycol 6000 70g Lactose 1560g 20g of polyoxyethylene sorbitan monooleate (polysorbate 80) was uniformly dispersed in 200g of safflower oil, and aluminate metasilicate Adsorb it on 150g of magnesium and make it into powder. Mix 70g of polyethylene glycol 6000 with this and heat it at 80℃ for 50 minutes.
Stir for a minute and allow to cool to obtain a fine powder. Add 1,560 g of lactose as an excipient and mix well to obtain 2,000 g of a homogeneous 10-fold powder of safflower oil. Example 6 Prescription Henoposi oil 200g Polyethylene laurate 30g Alumina magnesium hydroxide 200g Polyethylene glycol 6000 80g Lactose 1490g Polyoxyethylene laurate 30g was uniformly dispersed in Henoposi oil 200g and adsorbed on 200g of alumina magnesium hydroxide to form a powder. shall be. 80 for this
Mix 6000g of polyethylene glycol and heat at 80℃
Stir for 5 minutes and allow to cool to obtain a fine powder. Add 1,490 g of lactose as an excipient and mix well to obtain 2,000 g of homogeneous 10x henopodium powder. Example 7 Recipe Dimethylpolysiloxane 100g Polysorbate 80 30g Magnesium aluminate metasilicate 90g Polyethylene glycol 6000 80g Microcrystalline cellulose 400g Lactose 300g 30g of polyoxyethylene sorbitan monooleate (Polysorbate 80) was uniformly dispersed in 100g of dimethylpolysiloxane. Then, adsorb it on 90 g of magnesium aluminate metasilicate to form a powder. Add and mix 80g of polyethylene glycol 6000 to this, stir at 80°C for 5 minutes, and allow to cool to obtain fine granular powder. Add and mix 400 g of microcrystalline cellulose and 300 g of lactose to this, HPC-L (manufactured by Nippon Soda Co., Ltd.)
After adding water with a 2% aqueous solution of a binder, the mixture is granulated using a 16-mesh sieve and dried at 50° C. under blowing air to obtain 1000 g of dimethylpolysiloxane 10 times powdered granules. Example 8 Recipe Dimethylpolysiloxane 100g Polysorbate 80 40g Magnesium alumina hydroxide 200g Polyethylene glycol 6000 60g Lactose 1580g Sodium carboxymethylcellulose 20g According to the above recipe, using magnesium alumina hydroxide as an adsorbent and sodium carboxymethylcellulose as a binder, A 20x powdered granule of dimethylpolysiloxane was prepared in the same manner as in Example 7.
Obtain 2000g. Example 9 Recipe Dimethylpolysiloxane 200g Polysorbate 80 80g Magnesium aluminate metasilicate 180g Polyethylene glycol 6000 100g Lactose 1420g Hydroxypropyl cellulose 20g According to the above recipe, 10-fold dispersed granules of dimethylpolysiloxane were prepared in the same manner as in Example 7. Obtain 2000g of agent. Example 10 Prescription Dimethylpolysiloxane 400g Polysorbate 80 50g Magnesium aluminate metasilicate 200g Polyethylene glycol 6000 150g Microcrystalline cellulose 1190g Magnesium stearate 10g 50g of polyoxyethylene sorbitan monooleate (Polysorbate 80) was uniformly added to 400g of dimethylpolysiloxane. Disperse and adsorb onto 200 g of magnesium aluminate metasilicate to form a powder.
150 g of polyethylene glycol 6000 was mixed with this, stirred at 80°C for 5 minutes, and allowed to cool to obtain a fine granular powder. Add 1190 g of microcrystalline cellulose and 10 g of magnesium stearate to this and mix well.
Compress into 200 mg tablets to obtain 2000 g of white tablets each containing 40 mg of dimethylpolysiloxane. Example 11 Recipe Dimethylpolysiloxane 400g Polysorbate 80 40g Magnesium alumina hydroxide 450g Polyethylene glycol 6000 100g Microcrystalline cellulose 950g Calcium carboxymethyl cellulose 50g Calcium stearate 10g According to the above recipe, magnesium alumina hydroxide was used as an adsorbent and microcrystalline magnesium hydroxide was used as an excipient. Using crystalline cellulose, carboxymethyl cellulose calcium, and calcium stearate, the same procedure as in Example 10 is carried out to obtain 2000 g of white tablets each weighing 200 mg. (1
Example 12 Prescription Dimethylpolysiloxane 400g Polysorbate 80 20g Magnesium aluminate metasilicate 200g Polyethylene glycol 6000 80g Microcrystalline cellulose 1290g Calcium stearate 10g According to the above recipe, calcium stearate was added as a lubricant. 1 tablet using the same procedure as in Example 10.
Obtain 2000 g of 400 mg white tablets. (One tablet contains 80 mg of dimethylpolysiloxane) Example 13 Prescription α-tocopherol acetate 500g Polysorbate 80 50g Magnesium aluminate metasilicate 250g Polyethylene glycol 6000 150g Microcrystalline cellulose 600g Corn starch 430g Calcium stearate 20g α-tocopherol acetate 500g 50 g of polyoxyethylene sorbitan monooleate (polysorbate 80) was uniformly dispersed in the mixture, and the mixture was adsorbed onto 250 g of magnesium aluminate metasilicate to form a powder.
150 g of polyethylene glycol 6000 is mixed with this, stirred at 60°C for 5 minutes, and allowed to cool to obtain a fine granular powder. To this, 600 g of microcrystalline cellulose, 430 g of corn starch, and 20 g of calcium stearate are added as excipients, and the mixture is thoroughly mixed and compressed into 200 mg tablets to obtain 2000 g of uncoated tablets each containing 50 mg of α-tocopherol acetate. Comparative Example Tablet A Prescription Dimethylpolysiloxane 400g Polysorbate 80 50g Magnesium aluminate metasilicate 1910g Polyethylene glycol 6000 300g Microcrystalline cellulose 1000g Carboxymethylcellulose calcium 300g Magnesium stearate 40g 50g of polysorbate 80 was uniformly dispersed in 400g of dimethylpolysiloxane. , and adsorbed on 1910 g of magnesium aluminate metasilicate to form a powder. Add to this 300g of polyethylene glycol 6000
Mix, stir at 70°C for 5 minutes, and leave to cool to obtain a fine powder. This was supplemented with 1000 g of microcrystalline cellulose, 300 g of carboxymethyl cellulose calcium and magnesium stearate as excipients.
40 g was added and mixed well, and after being left for 5 and 10 days, it was compressed into 400 mg tablets. Tablet B Prescription Dimethylpolysiloxane 400g Magnesium aluminate metasilicate 2260g Microcrystalline cellulose 1000g Calcium carboxymethylcellulose 300g Magnesium stearate 40g 400g of dimethylpolysiloxane is uniformly adsorbed on 2260g of magnesium aluminate metasilicate with stirring and powdered. To this were added 1000 g of microcrystalline cellulose, 300 g of carboxymethyl cellulose calcium and 40 g of magnesium stearate as excipients, mixed well, and after standing for 5 and 10 days in the same manner as Tablet A, each tablet was 400 mg. After being left for 10 days, the sample could not be compressed into tablets due to catpigment. Note that tablets A and B were both compressed using a rotary tablet press RTM-S15 manufactured by Kikusui Seisakusho at a tableting pressure of 900 kg. Hardness measurement tests for tablets A and B, which were obtained as above after being left for 5 days and 10 days, and tablets A and B, respectively, which were left to be left for 5 days and then compressed. A disintegration test was conducted for B and the two were compared. The results were as shown in the table below. Note that the tablet hardness was measured using an Oelwayker hardness meter, and the disintegration time was measured based on the disintegration test method of the Japanese Pharmacopoeia.

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Claims (1)

[Claims] 1. An oily liquid substance and a nonionic surfactant are adsorbed onto an adsorbent, and then polyethylene glycol having a molecular weight of 3,000 or more is added thereto, and the adsorbent surface is heated and kneaded to a temperature above the melting point. 1. A method for producing a solid preparation of an oily liquid substance, which comprises melt-coating the substance to obtain a powdered oily liquid substance, and adding excipients to form a formulation. 2. The manufacturing method according to claim 1, wherein the oily liquid substance is dimethylpolysiloxane. 3 The nonionic surfactant is polysorbate 80
The manufacturing method according to claim 1. 4. The manufacturing method according to claim 1, wherein the adsorbent is magnesium aluminate metasilicate or magnesium alumina hydroxide. 5. The manufacturing method according to claim 1, wherein the polyethylene glycol having a molecular weight of 3000 or more is polyethylene glycol 6000. 6. The manufacturing method according to claim 1, in which 5 to 100 parts by weight of a nonionic surfactant is used with respect to 100 parts by weight of the oily liquid substance. 7 Molecular weight for 100 parts by weight of adsorbent adsorbing a mixture of oily liquid substance and nonionic surfactant.
The manufacturing method according to claim 1, using 5 to 100 parts by weight of polyethylene glycol of 3,000 or more. 8. The manufacturing method according to claim 1, wherein the solid preparation is a powder. 9 Claim 1 in which the solid preparation is a granule
Manufacturing method described in section. 10 Claim 1 in which the solid preparation is a tablet
Manufacturing method described in section.