JP3012667B2 - Liquid buoyant hollow material - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a liquid floating hollow material useful as a carrier for products in the fields of pharmaceuticals, diagnostics, animal drugs, fish disease drugs, feed, foods, and the like.

2. Related Art and Problems to Be Solved Liquid buoyant materials are useful in various fields, and their development solves important problems, particularly in the fields of pharmaceuticals, diagnostics, and veterinary drugs. For example, in the field of pharmaceuticals, it is required that drugs acting in the stomach stay in the stomach for a long time and be fully utilized. If the drug quickly passes through the stomach and is sent to the intestine, the intended purpose cannot be achieved.

Various methods have been studied for keeping a drug or the like in the stomach for a long time. As gastric retentive preparations, gastric fluid floating preparations and digestive mucosa-adhesive preparations as disclosed in JP-A-63-101332 are known.

Gastric fluid floating preparations are classified into light-material preparations, intragastric hollow formation preparations, and hollow preparations.

The light-material preparation was prepared using a material having a specific gravity of 1 or less, and is disclosed in JP-B-63-8084, JP-A-61-246120, and JP-A-63-24.
3036, JP-A-1-70109 and JP-A-1-16715.

A gastric hollow-forming formulation is basically composed of a foaming agent and a membrane component for retaining foam inside the formulation, and forms a hollow only by foaming in contact with gastric juice to acquire buoyancy, JP-A-52-76418, JP-A-61-286322, JP-A-6
It is disclosed in a number of patent specifications, such as 2-195323 and 62-207208. However, these intragastric hollow-forming preparations have problems such as studying the amount of foaming agent used, studying gastric fluid permeability of membranes, controlling foaming, and blocking foaming agents from drugs. Structure. Also, patients with hyperacidity or anhydrosis have different foaming strengths and cannot obtain a constant buoyancy. In this case, a foaming aid such as citric acid must be used, and the structure is further complicated. Therefore, it is often not suitable for mass production. It should be noted that the intragastric hollow-forming preparation does not have a space provided inside the preparation from the beginning.

Hollow preparations use a hollow material from the beginning and have a drug or the like interposed in or on its surface.

Japanese Patent Publication No. 55-12411 discloses a gastro-suspended solid sustained-release preparation containing a drug in the outer skin of a hollow material.
As the hollow material here, hard capsules and soft capsules, styrene foamed in advance, rice (rice), and the like are used. However, these hollow materials are brittle and it is not easy to interpose a drug on the surface. In addition, all are simply diversions of well-known existing ones.

JP-A-63-22014 discloses a formulation in which a drug is filled in a hard capsule so as to leave a space for giving buoyancy. This preparation is an improvement over the above-mentioned hard capsule preparation disclosed in JP-B-55-12411, which makes it difficult to allow a drug to intervene on the capsule surface.

JP-A-62-145014 discloses a formulation in which a drug is compounded on the surface or inside of foamed ethyl cellulose small spheres containing a plurality of spaces. Although this formulation is evaluated in terms of miniaturization of the dosage form, the hollow agent used here is merely a diversion of a well-known material for a long time.

Japanese Patent Publication No. 1-57086 discloses a preparation containing a large number of fine spaces produced by melting a mixture of a gelling agent, oil and fat, and a drug and allowing the mixture to cool. Also,
Japanese Patent Application Laid-Open No. 1-224311 discloses a preparation in which a weakly acidic solution of chitosan and a drug is dispersed in an inert solvent, and sodium bicarbonate is added to the dispersion to foam and form granules. Further, Advance in Pharmaceuticals and Pharmaceutical Technology (page 1, 1989) discloses a hollow preparation called a microballoon.
This microballoon dissolves an acrylic acid copolymer such as Eudraggid RS and a drug in an organic solvent, disperses this in water to form an emulsion, and precipitates hollow particles.The drug is initially contained in the outer skin. It is contained. These and these preparations produce a hollow preparation of a drug and other components at once, and it is necessary to always consider the effect of the drug on other components. Thus, the choice of drugs and other ingredients that can be used is limited.

Therefore, the present inventors have studied variously to create a new hollow material for floating in a liquid, and have developed a hollow material of the present invention which can be easily mass-produced and can be used in various fields.

JP-A-59-193901 discloses that an aqueous phase / monomer phase / aqueous phase emulsion is polymerized and washed to have an average particle size of 0.5 to 50 μm and an apparent specific gravity of 1 to 50 μm.
The following discloses a spherical polymer useful as a cosmetic base having a spherical space therein. This spherical polymer is characterized by being small particles, having a particle diameter of 50
It is pointed out that if it exceeds μ, the feeling of foreign matter (grainy feeling) when applied as a cosmetic becomes stronger, and is not intended for use as a liquid floating material.

The present invention relates to a liquid buoyant hollow material having the following various properties (hereinafter sometimes referred to as a hollow material), a method for producing the same, and a liquid buoyant product using the same.

The properties of the hollow material of the present invention have an average diameter of about 0.1 mm or more, and are composed of an outer shell made of a water-insoluble substance and a hollow portion,
The whole is almost air balloon, the hollow part is a single almost spherical space, the outer skin is porous, when put in water and not stirred, it keeps floating for at least 24 hours and has an average diameter of 4 mm or less Sometimes, even if the hollow material is tableted together with other excipients, the floating property of the hollow material remains.

The hollow material of the present invention is usually in a spherical shape, and has an average diameter of about 0.1 mm or more, and the average diameter can take a very large width. The upper limit of the average diameter is not particularly limited, but may be about 30 mm. However, from a practical point of view, the average diameter is about 10 mm or less, preferably 0.1 to 4 mm, particularly preferably
It is in the range of 0.5-1.5 mm. The hollow material of the present invention is composed of a shell made of a water-insoluble substance and a hollow portion, and is generally almost balloon-shaped as a whole. When the hollow material is large, it may take the form of a tablet as a whole. The hollow portion is usually a single substantially spherical space, and is clearly distinguished from materials such as styrene foam and foam rice which contain a large number of amorphous spaces. The hull is composed of a porous, water-insoluble substance, which does not contain useful substances such as drugs. As the water-insoluble substance that is a constituent of the hull, any water-insoluble substance or a film-forming substance having low solubility that is not soluble in acidic water may be used, such as pharmaceutically acceptable ethyl cellulose and methyl cellulose. Cellulosics such as: Ethyl methacrylate-trimethylammonium methacrylate, methacrylic acid-methyl methacrylate, methacrylic acid-ethyl acrylate, methacrylic acid commercially available under the trade name Eudragit (Rohm Farm) Acrylic acid-based copolymers such as dimethylaminoethyl-methyl methacrylate; magnesium stearate; polishing wax (Freund Sangyo Co., Ltd.) under the trade name Carnauba wax, Lubriwax-101 (Freund Sangyo Co., Ltd.) ) Hardness marketed under the trade name Castor oil, Lubri wax -102H and the same 103
Waxes such as hardened rapeseed oil marketed under the trade name (Freund Sangyo Co., Ltd.); fat-soluble substances such as sucrose fatty acid esters marketed under the trade name Ryoto Sugar Ester (Mitsubishi Chemical Foods); Alternatively, a mixture thereof is mentioned as an example, and ethyl cellulose is particularly preferable. When the hollow material of the present invention is put into water and not stirred, it continues to float for at least 24 hours, and when its average diameter is about 4 mm or less, it is tableted together with other excipients under normal pressure. Then, even if the hollow part is deformed, its floating property remains. If a coating layer such as wax is provided on the surface of the hollow material of the present invention, the mechanical strength is further increased.

The hollow material of the present invention can be easily produced by coating the surface of a core substance composed of a water-soluble substance with a film of a water-insoluble substance, and then eluting the internal core substance with water. Therefore, a hollow material having a shape and a size corresponding to the shape and the size of the core material is formed. As the water-soluble substance, any substance that dissolves in water can be used, and saccharides such as sucrose, lactose, mannitol, sorbitol, xylit, dextrose, and confectionery sugar are particularly preferably used. Organic acids and salts thereof such as ascorbic acid, citric acid, malic acid, benzoic acid and EDTA; inorganic salts such as sodium chloride, sodium bicarbonate and sodium metabisulfite; carbomer; chlorobutanol; saccharin and its salts; diethanolamine; cetrimide Gelatin; thimerosal; dextrin; cellulose derivatives such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium carboxymethylcellulose; propylparaben; propylene glycol alginate; Pitone; polyethylene glycol; polyoxyethylene stearate; polyoxyethylene sorbitan fatty acid ester; polyvinyl alcohol; poloxamer; sodium lauryl sulfate; The core substance can be produced by granulating a water-soluble substance together with an auxiliary component such as a binder, or by a method similar to the method for producing pills or tablets. It is convenient to use spherical granules made of only sucrose called Non-Parel 103 or spherical granules made of a mixture of sucrose and corn starch called Non-Parel 101, which are commercially available from Freund Corporation. As the water-insoluble substance, those described above are used, and the surface of the core substance is coated so as to be porous and continuous. The coating is performed by a method such as a powder coating method or a solution coating method, and the former is particularly preferable. The powder coating method is a method of spraying a powder of a water-insoluble substance while spraying a binder solution on a core substance, and the solution coating method is a method of spraying a coating liquid containing a water-insoluble substance or a binder on the core substance. is there. Examples of the binder include sugars such as sucrose, cellulose derivatives such as hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and methylcellulose, as well as pullulan, starch, polyvinylpyrrolidone, gelatin, and gum arabic.
The core material inside is eluted with water, usually with a sufficient amount of boiling water. Elution does not need to be performed completely and can be adjusted according to the purpose. Next, by drying the material, the hollow material of the present invention having the properties described above can be produced.

As described above, the method for producing a hollow material of the present invention has a wide range of choices of materials, and can be carried out on an industrial scale under rigorous operating conditions irrespective of the properties of useful substances.

The buoyancy of the hollow material of the present invention can be adjusted by adjusting the size of the core material, adjusting the degree of elution of the core material (that is, adjusting the size of the hollow portion), selecting the outer shell material and adjusting its thickness, It can be easily controlled by adjusting the size and number of holes in. The size and number of the pores can be controlled, for example, by further coating the surface of the hollow material with a water-insoluble substance or by changing the powder coating conditions.

The hollow material of the present invention thus obtained is useful as a carrier for products in various fields. These several products can be manufactured by providing a useful substance layer on the surface of the hollow material of the present invention. For example, such a product can be manufactured by coating the surface of the hollow material of the present invention with various useful substances. Coating is performed by the powder coating method or solution coating method described above. If necessary, the surface of the coated useful substance layer may be further coated with a film-forming component. For example, to delay the release of a useful substance to a liquid or to mask the bitterness of a useful substance, use hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, hydrogenated castor oil, hydrogenated rapeseed oil, carnauba wax, acrylic acid copolymer, etc. Coated with sustained release film forming ingredients such as coalesce, magnesium stearate, sucrose fatty acid ester, talc, and the like. In addition, sugar coating can be applied with syrup.

As the useful substance, any substance may be used. For example, analgesics such as intomethacin, ibuprofen, and acetoneaminophen; anti-inflammatory enzymes such as α-chymotrypsin; antihistamines such as chlorpheniramine maleate and diphenhydramine hydrochloride; nifedipine and isosorbide dinitrate Cardiovascular drugs such as propranolol, cardiotonic drugs such as digitalis and digoxin, vasodilators such as nitroglycerin and papaverine, antiepileptic drugs such as sodium valproate, antiasthmatic drugs such as theophylline, and antibiotics such as erythromycin Fish drugs such as Pimarin, sucrose, starch,
Yogurt coaton, food base of chocolate sugar, and the like.

Specific Example Next, the present invention will be described in more detail with reference to examples.

Example 1 1000 g of nonpareil 103 (20 to 24 mesh; core material)
Centrifugal flow type coating granulator (CF 0.7-0.8mm)
-Granulator; Freund industry)
While spraying a 5% ethyl cellulose (EC10) / ethanol solution (binder) at a rate of about 15 ml / min, 200 g of powdered ethyl cellulose (EC10, 80 mesh pass) is sprayed from a hopper at a rate of 7 g / min to perform coating. . Coating material
Put in 10Kg of boiling water and stir for 30 minutes. After repeating this operation three times, the hollow material 23 of the present invention was dried at 70 ° C. for 24 hours.
Get 6g. The properties of this product are as follows.

Appearance White spherical granules Average particle size 0.8-0.9mm Buoyancy 1g of this product was left in 100ml of water and left floating for more than 24 hours. In addition, 10 g of this product colored red with an oil-based color spray is mixed with 40 g of microcrystalline cellulose (Avicel), and the mixture is pressurized at 1500 kg / c.
When the tablet was pressed with m ² and one of the tablets was put into 100 ml of water, the tablet immediately collapsed while floating, and most of the red material (this product) floated.

Example 2 A hollow material having an average particle diameter of about 0.9 to 1.3 mm is obtained by treating in the same manner as in Example 1 except that the nonpareil 103 (14 to 20 mesh) having a particle diameter of 0.8 to 1.2 mm is used.

Example 3 A hollow material having an average particle diameter of about 0.5 to 0.6 mm is obtained by performing the same treatment as in Example 1 except that the non-pareil 103 (32 to 42 mesh) having a particle diameter of 0.4 to 0.5 mm is used.

Example 4 Lactose 60 g, 18 g of microcrystalline cellulose (Avicel PH10
1), 20 g of low-substituted hydroxypropylcellulose (L
-HPC) and 1 g of hydroxypropylcellulose (L-HPC) serving as a binder to prepare granules for tableting by a conventional method, and tableting (1.5 ton / cm ² ) with 1 g of magnesium stearate (lubricant). ) And make tablets 4mm in diameter. 1000 g of the tablet was tumbled on a CF-Granulator, and sprayed with a 4.55% ethyl cellulose / ethanol solution.
Spray 200 g of ethyl cellulose powder on a mesh pass. This coated tablet is treated with hot water in the same manner as in Example 1 to obtain a hollow material having a diameter of about 5 to 6 mm.

Example 5 A pill having a diameter of about 4 mm was prepared according to the Japanese Pharmacopoeia (11th edition) using a mixture consisting of 80 g of lactose, 18 g of Avicel PH101 and 2 g of hydroxypropylcellulose (HPC-L), and used as a core substance. The same procedure as in Example 4 is carried out to obtain a hollow material having a diameter of 5 to 6 mm.

Example 6 A hollow material having an average particle diameter of 0.2 to 0.3 mm is obtained by treating in the same manner as in Example 1 except that 1000 g of granulated sugar having a particle size of 0.1 to 0.2 mm (80 to 100 mesh) is used instead of the non-pareil.

Example 7 A hollow material having an average particle diameter of 0.5 to 0.6 mm was treated in the same manner as in Example 1 except that tablets (lactose for tableting made of lactose: Taiyo Kagaku, 32-48 mesh) were used instead of the non-pareil. obtain.

Example 8 Produced by wet spherical granulation instead of non-pareil
A hollow material having an average particle size of 0.8 to 0.9 mm is obtained by performing the same treatment as in Example 1 except that spherical particles of 20 to 24 mesh mannite are used.

Example 9 A hollow material having an average particle diameter of 0.8 to 0.9 mm was treated in the same manner as in Example 1 except that methylcellulose powder was used instead of ethylcellulose powder, and methylcellulose / ethanol solution was used instead of ethylcellulose / ethanol solution. obtain.

Example 10 1000 g of nonpareil 103 (32 to 42 mesh) was added to CF-Gran
Rolling on a ulator, spraying a 4.55% ethylcellulose (EC10) / ethanol solution (binder) at a rate of about 15 ml / min, and spraying 200 g of Lubriwax 101 (hardened castor oil) for coating. . The coating is placed in boiling water and slowly stirred. After repeating this operation three times, the resultant is dried at 70 ° C. for 24 hours to obtain a hollow material having an average particle diameter of 0.5 to 0.6 mm.

Example 11 The average particle system was 0.9 in the same manner as in Example 10 except that the nonpareil 103 (14 to 20 mesh) was used instead of the nonpareil 103 (32 to 42 mesh), and magnesium stearate was used instead of the Raburi wax 101. A hollow material of ~ 1.5 mm is obtained.

Example 12 In addition to using nonpareil 103 (14 to 20 mesh) in place of nonpareil 103 (32 to 42 mesh) and lyoto-sugar ester S-370 (sucrose fatty acid ester: Mitsubishi Kasei Foods) in place of laburi wax In the same manner as in Example 10, a hollow material having an average particle diameter of 0.9 to 1.5 mm is obtained.

Example 13 The same treatment as in Example 1 was carried out except that Eudragit RC powder was used instead of the ethylcellulose powder, and 5.0% Eudragit / dichloromethane solution was used instead of the ethylcellulose / ethanol solution, and the average particle diameter was 0.8 to 0.8%.
Obtain 0.9mm hollow material.

Example 14 22 g of the hollow material obtained in Example 1 was tumbled with a CF-Granulator, and 107 g of a 4.55% ethyl cellulose EC-10 / ethanol solution (binder) was sprayed at a rate of about 15 ml / min.
The powdered sodium valproate was dropped from the hopper at a rate of 8 g / min for coating, and dried at 60 ° C. for 24 hours to obtain granules. The granules are powder-coated with 26 g of Lapriwax 101 and 102 g of magnesium stearate in the same manner as described above, and then dried in the same manner to obtain hollow sustained-release sodium valproate granules. In a dissolution test by the paddle method (50 rpm, 90 ml of water) according to the Japanese Pharmacopoeia (11th edition), it took about 10 hours for sodium valproate to elute, during which time it showed an almost zero-order elution pattern.

Example 15 Sustained-release sodium valproate granules produced in Example 14
200 g and 790 g of Avicel PH101 are mixed well, and tableted (about 1.5 ton / cm ² ) with 10 g of magnesium stearate (lubricant) to obtain a gastric fluid floating sodium valproate sustained release tablet.

Example 16 50 g of the hollow material obtained in Example 1 was rolled on a CF-Granulator, and granulated sugar (powdered sugar) was used using a single syrup as a binder.
200g, Yogol Courton 0.5g, Food Blue No. 1 dye 0.
Spray a mixture of 2 g and do coaching. This product floats in addition to coffee, tea, soup, etc. and enjoys the sight, taste, and aroma.

Example 17 50 g of the hollow material obtained in Example 1 was rolled on a CF-Granulator, and 5% hydroxypropyl cellulose (HPC-
L, equivalent to 20 g) with corn starch 1
A powder mixture consisting of 80 g and 20 g of marine pimarin is sprayed and coated. This product is a fish disease drug and floats on the water surface.

 ──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-50-121418 (JP, A)

Claims (6)

(57) [Claims] 1. A liquid buoyant hollow material having the following properties: an average diameter of about 0.1 mm or more, comprising a shell made of a water-insoluble substance and a hollow portion;
The whole is almost air balloon, the hollow part is a single almost spherical space, the outer skin is porous, when put in water and not stirred, it keeps floating for at least 24 hours and has an average diameter of 4 mm or less Sometimes, even if the hollow material is tableted together with other excipients, the floating property of the hollow material remains. 2. The liquid floating hollow material according to claim 1, wherein the hollow material has an average diameter of 4 mm or less. 3. The liquid floating hollow material according to claim 1, wherein the water-insoluble substance is ethyl cellulose, methyl cellulose, acrylic copolymer, magnesium stearate, wax, sucrose fatty acid ester, or a mixture thereof. . 4. The liquid floating hollow material according to claim 1, wherein the surface of the core material comprising a water-soluble substance is coated with a film of a water-insoluble substance, and then the internal core material is eluted with water. Manufacturing method. 5. The method according to claim 4, wherein the water-soluble substance is mainly a saccharide. 6. A liquid-floating product comprising a useful substance layer provided on the surface of the liquid-floating hollow material according to claim 1.