Production method for easy-to-take solid preparation (nucleated tablet), and easy-to-take solid preparation

Abstract

The purpose of present invention to provide a method for the production of an easy-to-take solid preparation, which is mainly characterized in that an outer layer-forming processing to provide an easy-to-take property is simply performed in a dry process without going through a wet condition so as to make the formed outer layer thicker; the easy-to-take solid preparation and the like. The present invention relates to a dry-process method for the production of an easy-to-take solid preparation wherein an inner core tablet is coated with a compression-molded outer layer-forming agent comprising a gelling agent that will show slipperiness when it is brought into contact with water, comprising loading separately or simultaneously the inner core tablet and powder of the outer layer-forming agent to a mortar inner surface, the bottom end surface of an upper-pestle, and the top end surface of a lower-pestle, and subsequently compression-molding them; a powder composition for coating a solid preparation for use in the above method, which comprises the water-soluble polymer and water-soluble sugar or sugar alcohol.

Claims

1. A dry-process method for the production of an easy-to-take solid preparation, comprising: loading separately or simultaneously an inner core tablet and powder of an outer layer-forming agent comprising a gelling agent to a mortar inner surface, a bottom end surface of an upper-pestle, and a top end surface of a lower-pestle, and compression-molding the outer layer forming agent comprising the gelling agent onto the inner core tablet so that the gelling agent shows slipperiness when brought into contact with water, wherein the outer layer-forming agent further comprises a water-soluble sugar or sugar alcohol and wherein the gelling agent comprises at least one kind of a water-soluble polymer.

2. The method according to claim 1, wherein a core-molding material in the inner core tablet is subjected to compression-molding in a dry process.

3. The method according to claim 1, wherein the inner core tablet and the powder of the outer layer-forming agent are loaded after a lubricant has been applied to the mortar inner surface and the surfaces of the upper-pestle and the lower-pestle.

4. The method according to claim 1, wherein the water-soluble polymer is selected from the group consisting of sodium carboxylmethylcellulose, sodium alginate, carrageenan, xanthan gum and gelatin.

5. The method according to claim 4, wherein the water-soluble polymer is sodium carboxylmethylcellulose.

6. The method according to claim 1, wherein the outer layer-forming agent further comprises a lubricant.

7. The method according to claim 6, wherein the lubricant is selected from the group consisting of calcium stearate, magnesium stearate and sucrose fatty acid ester.

8. The method according to claim 1, wherein the sugar or sugar alcohol is erythritol, xylitol, mannitol or maltitol.

Description

EMBODIMENTS FOR CARRYING OUT THE INVENTION

(1) The present invention relates to a dry-process method for the production of an easy-to-take solid preparation wherein an inner core tablet is coated with a compression-molded outer layer-forming agent (an outer layer) comprising a gelling agent that will show slipperiness when it is brought into contact with water, comprising loading separately or simultaneously the inner core tablet and powder of the outer layer-forming agent to a mortar inner surface, the bottom end surface of an upper-pestle, and the top end surface of a lower-pestle, and subsequently compression-molding them.

(2) According to the present method, the inner core tablet may be prepared using the core-molding material by any means or method known for those skilled in the art, preferably being obtained by compression-molding the core-molding material in the dry process. The inner core tablet and the powder of the outer layer-forming agent may be loaded after a lubricant has been applied to the mortar inner surface, and the surfaces of the upper-pestle and the lower-pestle.

(3) In the method according to the present invention, the mortar, the upper-pestle, and the lower-pestle are a member for compressing the inner core tablet and the outer layer-forming agent along the four directions, so as to mold the easy-to-take solid preparation wherein the inner core tablet is coated with the compression-molded outer layer-forming agent. They comprise any other members that are named differently in any other powder compression-molding machines or devices as long as they have substantially the same functions and/or properties as the above ones.

(4) The method according to the present invention does not need any complicated machine, and it can be therefore carried out using such a simple tableting machine as disclosed in the present specification or the rotary-type nucleated-tableting machine conventionally used.

(5) Each process of loading the inner core tablet and powder of the outer layer-forming agent to the mortar inner surface, the bottom end surface of the upper-pestle, and the top end surface of the lower-pestle, etc. may be performed by any means or method known for those skilled in the art depending on the production machine used and the like. For example, the loading of the inner core tablet and powder of the outer layer-forming agent to the mortar inner surface, the bottom end surface of the upper-pestle, and the top end surface of the lower-pestle may be simultaneously or separately carried out by using any appropriate means, or the powder of the outer layer-forming agent may be loaded repeatedly a few times. For example, the powder of the outer layer-forming agent is loaded, followed by the loading of the inner core tablet, and then followed by the loading of the powder of the outer layer-forming agent again. Furthermore, compression-molding of the inner core tablet and the powder of the outer layer-forming agent may be carried out all at once.

(6) The gelling agent that will show slipperiness when it is brought into contact with water according to the present invention means a material that will form a slippery surface of a solid tablet under the moisture condition in the oral cavity when it is taken without water so as to promote the slipperiness of the tablet itself. Such promotion of the slipperiness of the tablet will also make the tablet easy to swallow even when it is taken with water.

(7) The representative examples of the gelling agent include the water-soluble polymer that is selected from the group consisting of sodium carboxylmethylcellulose, sodium alginate, carrageenan, xanthan gum and gelatin. The water-soluble polymer may be naturally-occurring or synthetic one.

(8) The outer layer-forming agent may comprise the gelling agent only, or further comprise other ingredients as long as they will not inhibit the function of the gelling agent. For example, any material known as a lubricant in the art, for example, those selected from the group consisting of calcium stearate, magnesium stearate and sucrose fatty acid ester may be comprised in the outer layer-forming agent so as to obtain the advantage that tableting trouble will not likely occur. The outer layer-forming agent may comprise one or more water-soluble sugar or sugar alcohol known in the art, such as those selected from the group consisting of erythritol, xylitol, mannitol, sorbitol, lactitol, isomalt and maltitol so as to reduce the adhesiveness and to improve easiness to swallow of the tablet. These ingredients other than the gelling agent may be usually comprised less than 99% by weight, preferably less than 98% of the whole outer layer-forming agent.

(9) The powder in the present invention means the aggregate of solid particulates, which may include powder having finer size or shape than granules or grains. The whole or a part of the surface of the solid preparation may be in the coated condition according to the present invention.

(10) The ingredients comprised in the powder of the outer layer-forming agent and the core-molding material may be used as they are, or the powder of the outer layer-forming agent and the core-molding material may be prepared by any means or method known in the art such as a dry granulation process, a wet granulation process and the like.

(11) The dry granulation process includes crushing granulation and roll-compressing method, comprising the steps of compressing each powder components into small bulks with a pressure, and appropriately crushing and granulating them, for example.

(12) On the other hand, the wet granulation process is a method in which each component is dispersed in the presence of water, and the dispersion is dried to form complexes. As specific examples of the wet granulation process, spray methods such as spray drying, tumbling granulation, agitation granulation and fluidized-bed granulation; freeze-drying method; kneading granulation, and the like can be mentioned. They can be produced by any of these methods known to a person skilled in the art.

(13) The easy-to-take solid preparation produced by the method according to the present invention is an oral formulation that is called the nucleated tablet as well, and has uses, for example, as various foods such as supplemental foods, nutrition function foods and health foods; and as pharmaceuticals.

(14) The core-molding material in the present invention may therefore optionally comprise various components known for those skilled in the art depending on the above uses.

(15) For use as the foods, for example, it may comprise various nutritional components such as proteins, carbohydrates, lipids and minerals; components for health foods such as various extracts from microorganisms, plants and animals; various vitamins and their derivatives; and designated or existing additives according to Food Sanitation Law, Art. 10; and other components acceptable as a food component (a food additive) listed in a list of general additives for food and drink, such as acidulants, sweeteners, excipients, surfactants, lubricants, auxiliary agents, corrigents, flavoring agents, colorants, and stabilizing agents.

(16) For use as the pharmaceuticals, for example, it may comprise in addition to a medicinal or active ingredient, other any pharmaceutically acceptable components, such as excipients, surfactants, lubricants, auxiliary agents, acidulants, sweeteners, corrigents, flavoring agents, colorants, and stabilizing agents, when needed. As these optional components, for example, appropriate ingredients described in Japanese Pharmaceutical Excipients Directory (YAKUJI NIPPO LIMITED) or the Japanese Pharmacopoeia; designated or existing additives according to Food Sanitation Law, Art. 10; natural flavor; and additives listed in a list of general additives for food and drink can be used. There is no limitation in the kind of the medicinal ingredient and the above auxiliaries. Also, the blending ratios of each optional ingredient (component) are not particularly limited as long as the desired effects of the present invention are brought about, and the blending ratios can properly be determined by those skilled in the art.

(17) There is no limitation on an application or kind of the medicinal ingredients, which may include, for example, agents affecting each organ such as the central nervous system, peripheral nervous system, a sensory organ, a circulatory organ, a respiratory organ and a digestive organ and an urogenital organ; hormone drug; agents affecting metabolism such as a vitamin drug, an analeptic, an agent affecting blood and body fluid; agents affecting the function of tissue and cell such as an agent activating cellular function, an agent affecting tumors, an radioactive medicine, an anti-allergic agent; medicines based on a medical prescription relating to herbal medicines and Chinese medicines; antibiotics; agents for chemotherapy, biological drug; agents for pathogenic organisms such as parasites; agents for formulation use, diagnosis, public health and in-vitro diagnosis.

(18) Those skilled in the art may optionally select the various conditions in the processes of the production method according to the present invention, such as pressure and time of the compression-molding, and amounts of the outer layer-forming agent and the core-molding material, depending on the scale and kind of the machine to be used in the method, the size and application of a desired easy-to-take solid preparation and the like. For example, tablet compression force in the compression-molding usually ranges from 2 to 100 kN.

(19) There is no limitation on the size, shape and the like of the easy-to-take solid preparation according to the present invention. It is usually within a range of from 3 to 20 mm in diameter and of from 15 to 2000 mg in weight. And, the inner core tablet usually has a diameter with a range of from 1.8 to 18 mm and a weight with a range of from 10 to 1800 mg. They may have any shape known for those skilled in the art such as those of a flat with bevel-edge tablet and a truly-flat tablet. The thickness of the outer layer (coating) consisting of the outer layer-forming agent ranges from about 0.1 to about 5 mm. These values can be determined by any method known for those skilled in the art.

(20) The present invention further relates to the easy-to-take solid preparation that is produced by any one of the above methods; and the powder composition for coating a solid preparation for use as the outer layer-forming agent in the above methods, especially that comprising the water-soluble polymer and water-soluble sugar or sugar alcohol. A preferable example of the composition comprises sodium carboxylmethylcellulose as the water-soluble polymer, and erythritol, xylitol, mannitol or maltitol as the sugar alcohol.

(21) In addition, contents of all related art documents cited in the present specification are incorporated herein by reference.

(22) Hereinafter, the present invention will more specifically be described with reference to Examples. However, the present invention is not considered to be limited to the Examples.

(23) [Evaluation on Hardness, Thickness of the Outer Layer, Slipperiness and Adhesiveness]

(24) Values of the hardness, thickness of the outer layer, slipperiness and adhesiveness of the tablets obtained in the Examples and Comparative Example were measured based on the following conditions/methods.

(25) Hardness: Hardness (N) was measured with a digital Kiya hardness tester (Fujiwara Scientific Company Co., Ltd.). The measurement for the hardness was repeated six times for each tablet, and an average value thereof was regarded as a measurement result.

(26) Thickness of the outer layer: The tablet was fractured and thickness of the resulting cross section was measured with a loupe equipped with 10 scale (0.1 mm per scale). An average value was regarded as a measurement result. In case where it was hard to distinguish the outer layer from the inner core tablet, an edible dye was added in advance into the inner core tablet, and the thickness of the outer layer was measured.

(27) Slipperiness: Three men and women, respectively (six in total) took the tablet without water, and slipperiness was evaluated in accordance with four-stage criteria below:

(28) 4: slipperiness is maintained and very easy to swallow

(29) 3: slippery and easy to swallow

(30) 2: slightly slippery but hard to swallow

(31) 1: hardly slippery and hard to swallow

(32) Adhesiveness: Three men and women, respectively (six in total) took the tablet without water, and adhesiveness was evaluated in accordance with three-stage criteria below:

(33) 3: not adhered to the inner of an oral cavity

(34) 2: slightly adhered to the inner of an oral cavity

(35) 1: strongly adhesive to the inner of an oral cavity

Example 1

(36) 18.0 g of lactose (FlowLac90, MEGGLE JAPAN Co., LTD) and 2.0 g of hydroxypropylcellulose (HPC-SSL-SFP, NIPPON SODA CO., LTD.) were mixed to give a mixture. The resulting mixture was then subjected to tableting at a tablet compression force of 4 kN with a simple tableting machine (HANDTAB-100, ICHIHASHI-SEIKI Co., Ltd.) to thereby obtain an inner core tablet (a truly-flat tablet) having a diameter of 7.6 mm and a weight of 210 mg, wherein a small amount of calcium stearate (Taihei Chemical Industrial Co. Ltd.) had been applied in advance to a mortar inner surface, and the surfaces of an upper-pestle and a lower-pestle in the above tableting machine.

(37) 210 mg of the resulting inner core tablet and 40 mg of the outer layer-forming agent (the outer layer) of sodium carboxylmethylcellulose (CMC Daicel, Daicel FineChem Ltd.) were loaded to the simple tableting machine (HANDTAB-100, ICHIHASHI-SEIKI Co., Ltd.) and subjected to tableting at a tablet compression force of 12 kN to thereby obtain a nucleated tablet (a truly-flat tablet) having a diameter of 8.0 mm and a weight of 250 mg, wherein a small amount of calcium stearate (Taihei Chemical Industrial Co. Ltd.) had been applied in advance to the mortar inner surface, and the surfaces of the upper-pestle and the lower-pestle in the above tableting machine.

Example 2

(38) A nucleated tablet (a truly-flat tablet) having a diameter of 8.0 mm and a weight of 250 mg was obtained by the same way as in Example 1 except that 40 mg of xanthan gum (KELTROL CG, SANSHO CO., LTD.) was used as the outer layer.

Example 3

(39) A nucleated tablet (a truly-flat tablet) having a diameter of 8.0 mm and a weight of 250 mg was obtained by the same way as in Example 1 except that 40 mg of sodium alginate (JUNSEI CHEMICAL CO., LTD.) was used as the outer layer.

Example 4

(40) A nucleated tablet (a truly-flat tablet) having a diameter of 8.0 mm and a weight of 250 mg was obtained by the same way as in Example 1 except that 40 mg of carrageenan (CSL-1, San-Ei Gen F.F.I., Inc.) was used as the outer layer.

Example 5

(41) 18.0 g of lactose (FlowLac90, MEGGLE JAPAN Co., LTD) and 2.0 g of hydroxypropylcellulose (HPC-SSL-SFP, NIPPON SODA CO., LTD.) were mixed to give a mixture. The resulting mixture was then subjected to tableting at a tablet compression force of 4 kN with the simple tableting machine (HANDTAB-100, ICHIHASHI-SEIKI Co., Ltd.) to thereby obtain an inner core tablet (a truly-flat tablet) having a diameter of 7.6 mm and a weight of 210 mg, wherein a small amount of calcium stearate (Taihei Chemical Industrial Co. Ltd.) had been applied in advance to a mortar inner surface, and the surfaces of an upper-pestle and a lower-pestle in the above tableting machine.

(42) 4 g of erythritol (Erythritol T, Mitsubishi-Chemical Foods Corporation) and 1 g of sodium carboxylmethylcellulose (CMC Daicel, Daicel FineChem Ltd.) were mixed to give a mixture for an outer layer.

(43) 210 mg of the resulting inner core tablet and 40 mg of the mixture for the outer layer were loaded to the simple tableting machine (HANDTAB-100, ICHIHASHI-SEIKI Co., Ltd.) and subjected to tableting at a tablet compression force of 12 kN to thereby obtain a nucleated tablet (a truly-flat tablet) having a diameter of 8.0 mm and a weight of 250 mg, wherein a small amount of calcium stearate (Taihei Chemical Industrial Co. Ltd.) had been applied in advance to the mortar inner surface, and the surfaces of the upper-pestle and the lower-pestle in the above tableting machine. The thickness of the resulting tablet was about 3.6 mm, and a coating layer (the outer layer) consisting of the outer layer-forming agent had thickness of about 0.2 mm on an average in upper and lower sections of the tablet.

Example 6

(44) A nucleated tablet (a truly-flat tablet) having a diameter of 8.0 mm and a weight of 250 mg was obtained by the same way as in Example 5 except that 210 mg of the inner core tablet and 90 mg of the mixture for the outer layer were used. The thickness of the resulting tablet was about 4.4 mm, and a coating layer (the outer layer) consisting of the outer layer-forming agent had thickness of about 0.6 mm on an average in upper and lower sections of the tablet.

Example 7

(45) A nucleated tablet (a truly-flat tablet) having a diameter of 8.0 mm and a weight of 250 mg was obtained by the same way as in Example 5 except that 4 g of xylitol (Xylite fine powder, Mitsubishi-Chemical Foods Corporation) and 1 g of sodium carboxylmethylcellulose (CMC Daicel, Daicel FineChem Ltd.) were mixed to give a mixture for the outer layer.

Comparative Example 1

(46) 18 g of lactose (FlowLac90, MEGGLE JAPAN Co., LTD) and 2 g of hydroxypropylcellulose (HPC-SSL-SFP, NIPPON SODA CO., LTD.) were mixed to give a mixture. The resulting mixture was then subjected to tableting at a tablet compression force of 8 kN with the simple tableting machine (HANDTAB-100, ICHIHASHI-SEIKI Co., Ltd.) to thereby obtain a flat with bevel-edge tablet having a diameter of 8.0 mm and a weight of 250 mg, wherein a small amount of calcium stearate (Taihei Chemical Industrial Co. Ltd.) had been applied in advance to the mortar inner surface, and the surfaces of the upper-pestle and the lower-pestle in the above tableting machine.

(47) Tablet Compression Force, Tablet Hardness, Slipperiness and Adhesiveness of each tablet produced in the above Examples are shown in Table 1.

(48) TABLE-US-00001 TABLE 1 Comp. Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 1 Tablet 12 12 12 12 12 12 12 8 Compression Force (kN) Tablet 120 117 103 114 127 128 132 82 Hardness (N) Slipperiness 3 3 3 3 3 4 3 1 Adhesive- 2 2 1 2 3 3 3 3 ness

(49) The results shown in Table 1 demonstrate that the nucleated tablets produced in Examples 1 to 4 were more slippery and easier to swallow, which were produced using the water soluble polymer in the outer layer, than the inner core tablet (Comparative Example 1). Examples 5 to 7 showed that trituration of the water soluble polymer in the outer layer with the sugar alcohol reduced Adhesiveness and improved easiness to swallow of the tablets. Examples 5 and 6 further showed that the tablet is maintained to be slippery and become very easy to swallow by increasing the thickness of the outer layer.

INDUSTRIAL APPLICABILITY

(50) The present invention significantly contributes to research and development of the method for the production of the easy-to-take solid preparation, the easy-to-take solid preparation and the like.