KR20040073492A - Coated tablets and process for producing the same - Google Patents

Abstract

The roughness of the tablet surface which occurs at the beginning of coating is further reduced by preheating a predetermined composition containing the hygroscopic polymer as a main component and applying or applying the coating solution after heating the tablet solution. Restoration provides coated tablets with good smoothness of the tablet surface.

In the case of coating a predetermined tablet made of a hygroscopic polymer to form a coated tablet, the coating solution widens while wetting a predetermined surface, thereby lowering the surface strength of the tablet, thereby causing roughness on the surface of the tablet at the beginning of the coating, resulting in coating The aesthetics of the tablets are impaired or the film thickness is nonuniform, which the present invention overcomes these drawbacks.

Description

Coated tablets and its manufacturing method {COATED TABLETS AND PROCESS FOR PRODUCING THE SAME}

DESCRIPTION OF RELATED ART Conventionally, as a coating method of the tablet which has a hygroscopic polymer as a main component, the film coating method, the sugar coating method, etc. are known. Among these, as the film coating method, for example, a method of coating predetermined uncoated tablets by containing a predetermined amount of water in an anion exchange resin with a coating liquid containing hydroxypropyl cellulose or the like is known. Japanese Patent Laid-Open No. 6-157325). Moreover, the method of coating the predetermined | prescribed addition of 14-20 weight% water and 2 weight% or less silicon dioxide with hydroxypropylmethylcellulose with respect to an anion exchange resin is known (JP-A-7-97330). ). However, these methods have a problem in that the strength of the tablet is lowered because a predetermined amount of water must be contained.

Moreover, the method of spray-coating the predetermined | prescribed tableting mixture which added silicon dioxide and crystalline cellulose without adding water to anion exchange resin with the coating liquid containing hydroxypropyl methylcellulose, etc. is also known (Japanese Unexamined Patent Publication). Japanese Patent Application Laid-open No. Hei 9-202732, Japanese Patent Laid-Open No. 10-114661). Moreover, about the tablet containing a hygroscopic polymer (polyallylamine type polymer), it is shown by Unexamined-Japanese-Patent No. 10-330269 (WO98 / 44933), and WO00 / 22008. In the above description, there is a description that a film tablet may be applied to form a film tablet, and in the latter example, an example in which a film tablet was manufactured using a commercially available coating machine is also described.

However, when the tablets of hygroscopic polymers such as polyallylamine-based polymers are coated by the above method, the film-former solution becomes wider while wetting the entire surface of the tablets, so that the surface strength of the tablets is lowered. There existed a problem that roughness generate | occur | produced and aesthetics was damaged, or a film thickness became nonuniform, and the target film function was not acquired.

It is an object of the present invention to provide a method for producing a coated tablet mainly containing a hygroscopic polymer, which is excellent in the smoothness of the tablet surface and uniformly coated, in particular a method for producing a film coated tablet. Moreover, it aims at providing the coated tablet which is excellent in the smoothness of a tablet surface.

TECHNICAL FIELD This invention relates to the manufacturing method of the coating tablet which has a hygroscopic polymer as a main component, and especially the manufacturing method of a film coating tablet. Moreover, it also relates to the coated tablet obtained by this manufacturing method.

1 is an example of a graph showing a time transition at various temperatures of a predetermined thickness increase amount obtained in Example 1. FIG.

FIG. 2 is an example of a graph showing the time course of the increase in thickness by heating the predetermined (water content 5.5 wt%) obtained in Example 1. FIG.

3 is an example of a graph showing the time course of the increase in thickness by heating the predetermined (water content 3.0% by weight) obtained in Example 2. FIG.

4 is an example of a graph showing the time course of the increase in thickness by heating the predetermined (moisture content 3.8 wt%) obtained in Example 2. FIG.

FIG. 5 is an example of a graph showing the time course of the increase in thickness by heating the predetermined (water content 8.0 wt%) obtained in Example 3. FIG.

FIG. 6 is an example of the upper surface photograph which shows the external appearance of the coated tablet manufactured in Example 4. FIG.

FIG. 7 is an example of the side photograph which shows the external appearance of the coated tablet manufactured in Example 4. FIG.

8 is an example of the top view photograph which shows the external appearance of the coated tablet manufactured in Example 5. FIG.

9 is an example of the upper surface photograph which shows the external appearance of the coated tablet manufactured by the comparative example 1. FIG.

FIG. 10 is an example of the side photograph which shows the external appearance of the coated tablet manufactured by the comparative example 1. FIG.

In the present invention, a target containing 50% by weight or more of the hygroscopic polymer is intended. Although such a predetermined has thermal expansion capability, if it heats too much, the thermal expansion capability which it originally has loses completely. That is, the present invention pre-heats such a predetermined tablet under conditions where its thermal expansion capacity is not completely lost (ie, at least part of its thermal expansion capacity is left), followed by applying or applying a coating solution, and then sufficiently expanding the tablet. The manufacturing method of the coated tablet which has a hygroscopic polymer as a main component is characterized by restoring the surface state of this tablet by maintaining on condition to make it.

Moreover, this invention relates also to the coated tablet obtained by the said manufacturing method.

In the present invention, the coating refers to a known coating method that can be applied to the coating of ordinary tablets, such as film coating and sugar coating. Among these, film coating is preferable. That is, as a coated tablet, a film coated tablet is preferable.

In the present invention, the absorbent polymer means a polymer having a water content of 10% by weight or more within one week at room temperature (22 to 28 ° C) of 50% relative humidity.

As such a hygroscopic polymer, for example

Acrylic Acid Polymer (Acrylic Acid-Vinyl Alcohol Polymer)

Methacrylic acid polymer

Acrylamide polymer

Allylamine polymer

Carboxymethyl Cellulose Polymer

Biopolymer that produces fructose and the like as a carbon source

Polymers, such as these, are illustrated and these salts, saponified products, and hydrolyzate are also included. In addition to the respective homopolymers, the polymers include copolymers of these copolymers, copolymers of these monomers with other monomers copolymerizable with these, and polymers capable of graft polymerization. Such copolymers may be random polymers, block polymers, graft polymers. Moreover, the crosslinked material of each polymer manufactured by the conventional method using various crosslinking agents is also included.

As the crosslinking agent, various kinds such as polyvalent allyls, polyvalent vinyls, polyvalent epoxy, haloepoxy, polyhydric alcohols, polyvalent amines and hydroxyvinyls can be used.

As another monomer copolymerizable, alkyl (meth), such as hydroxyethyl (meth) acrylate, (methoxy) polyethyleneglycol (meth) acrylate, glycerin (meth) acrylate, glycosylethyl (meth) acrylate, for example ) Acrylates; Acrylamide compounds such as N, N-dimethylacrylamide and acrylamide: carboxylic acid compounds such as maleic acid and metal salts thereof, itaconic acid and metal salts thereof; Sulfonic acid compounds such as 2-acrylamide-2-methylpropanesulfonic acid and its metal salts, vinylsulfonic acid and its metal salts, styrenesulfonic acid and its metal salts; In addition, N-vinylpyrrolidone etc. can be illustrated.

Moreover, as a polymer which can be graft-polymerized with (meth) acrylic acid, hydrophilic polysaccharides, such as starch, carrageenan, agarose, carboxymethylcellulose, etc. can be illustrated, for example.

As a typical crosslinking agent, the following can be illustrated.

Polyvalent allyls; N, N-diallylacrylamide and N, N-diallylmethacrylamide (these are referred to as "N, N-diallyl (meth) acrylamide" and are the same below), diallylamine, diallylmethacryl Polyvalent allyl type compounds, such as an amine, diallyl phthalate, and diallyl maleate.

Polyvinyl vinyls: divinylbenzene, N, N'-methylenebis (meth) acrylamide, ethylene glycol (meth) acrylate and polyethylene glycol di (meth) acrylate (these are called "(poly) ethylene glycol di (meth) acrylates) And the same below), polyvalent vinyl-based compounds such as (poly) propylene glycol di (meth) acrylate and trimetholpropane triacrylate.

Polyvalent epoxy: (poly) ethylene glycol diglycidyl ether, (poly) propylene glycol diglycidyl ether, glycerin-1,3- diglycidyl ether, trimethylolpropane triglycidyl ether, (poly) glycerin Polyepoxy compounds such as polyglycidyl ether.

Haloepoxys: epicrohydrin, α-methylcrohydrin and the like.

Polyhydric alcohols: (poly) glycerine, (poly) ethylene glycol, trimethylolpropane, pentaerythritol, and the like.

Polyvalent amines: ethylenediamine and the like.

The hygroscopic polymer used in the present invention is preferably a polyallylamine-based absorbent polymer, more preferably an absorbent polymer obtained by crosslinking and polymerizing polyallylamine with epichlorohydrin, and in particular, the following formula (1)

In the formula, the water absorbing polymer represented by (a + b): c is a molar ratio of 45: 1 to 2: 1 and m represents an integer. The absorbent polymer represented by Formula (1) can be obtained, for example, by the method described in Japanese Patent Application Laid-Open No. 9-504782 (International Publication No. WO95 / 05184), the method described in International Publication No. WO00 / 22008, or the like. have.

Moreover, as a hygroscopic polymer used by this invention, the polymer of following (2)-(9) can also be used preferably.

The polymer (2) has the following formula

It has a repeating unit represented by the polymer, or its copolymer. Wherein n is an integer, and each R independently contains H or a lower alkyl group (e.g., an alkyl group containing 1 to 5 carbon atoms), an alkylamino group (e.g., 1 to 5 carbon atoms such as an ethylamino group) An alkylamino group) or an aryl group (for example, an aryl group (for example, a phenyl group, a naphthyl group, etc.) containing 1 to 12 carbon atoms).

Polymer (3) has the following formula

It has a repeating unit represented by the polymer, or its copolymer. Wherein n is an integer, and each R independently contains H or a lower alkyl group (e.g., an alkyl group containing 1 to 5 carbon atoms), an alkylamino group (e.g., 1 to 5 carbon atoms such as an ethylamino group) Alkylamino group), or an aryl group (e.g., an aryl group containing 1 to 12 carbon atoms (e.g., a phenyl group, a naphthyl group, etc.)), and X ^- is a negatively charged pair ion each exchangeable.

Examples of the copolymer of the polymer (3) include the following formulas

[Wherein n is an integer, and each R independently represents H or a lower alkyl group (e.g., an alkyl group containing 1 to 5 carbon atoms), an alkylamino group (e.g., 1 to 5 carbon atoms such as an ethylamino group Containing alkylamino group), or an aryl group (e.g., an aryl group containing 1 to 12 carbon atoms (e.g., a phenyl group, a naphthyl group, and the like)), and X ^- are each exchangeable minus charged negative ions] And the first repeating unit represented by

[Wherein n is each independently an integer, R is each independently H or a lower alkyl group (e.g., an alkyl group containing 1 to 5 carbon atoms), an alkylamino group (e.g., 1 to 5, such as an ethylamino group) Alkylamino group containing a carbon atom), or an aryl group (for example, an aryl group containing 1 to 12 carbon atoms (for example, a phenyl group, a naphthyl group, etc.)). It is a polymer (polymer (4)).

The polymer (5) has the following formula

It has a repeating unit represented by the polymer, or its copolymer. Wherein n is an integer, R is H or a lower alkyl group (eg alkyl group containing 1 to 5 carbon atoms), alkylamino group (eg alkylamino group containing 1 to 5 carbon atoms such as ethylamino group) Or an aryl group (for example, an aryl group containing 1 to 12 carbon atoms (for example, a phenyl group, a naphthyl group, etc.)).

Another example of the copolymer of the polymer (3) is the following formula

[Wherein n is an integer, R is H or lower alkyl group (for example alkyl group containing 1 to 5 carbon atoms), alkylamino group (for example alkyl containing 1 to 5 carbon atoms such as ethylamino group Amino group) or an aryl group (for example, an aryl group containing 1 to 12 carbon atoms (for example, a phenyl group, a naphthyl group, etc.))], and the following formula

[Wherein n is each independently an integer, R is H or a lower alkyl group (e.g., an alkyl group containing 1 to 5 carbon atoms), an alkylamino group (e.g., 1 to 5 carbon atoms such as ethylamino group Containing an alkylamino group), or an aryl group (for example, an aryl group containing 1 to 12 carbon atoms (for example, a phenyl group, a naphthyl group, etc.)). (Polymer (6)).

The polymer (7) has the following formula

It has a repeating unit represented by the polymer, or its copolymer. Wherein n is an integer, and R ₁ and R ₂ are each independently H or a lower alkyl group (e.g., an alkyl group containing 1 to 5 carbon atoms), an alkylamino group (e.g., 1 to 5, such as an ethylamino group) Is an alkylamino group containing a carbon atom of C), or an aryl group (for example, an aryl group (for example, a phenyl group, a naphthyl group, etc.) containing 1 to 12 carbon atoms), and X ⁻ is a negatively charged pair each exchangeable. It is an ion.

In the said polymer (7), a preferable polymer is a polymer whose at least ₁ of R <_1> or R <_2> in a formula is hydrogen.

The polymer (8) has the following formula

It has a repeating unit represented by the polymer, or its copolymer. Wherein n is an integer, and R ₁ and R ₂ are each independently H or an alkyl group containing 1 to 20 carbon atoms, an alkylamino group (for example, an alkylamino group containing 1 to 5 carbon atoms such as ethylamino group) Or an aryl group containing 1 to 12 atoms (for example, an aryl group containing 1 to 12 carbon atoms (for example, a phenyl group, a naphthyl group, etc.)).

The polymer (9) has the following formula

It has a repeating unit represented by the polymer, or its copolymer. Wherein n is an integer, and R ₁ and R ₂ are each independently H or an alkyl group containing 1 to 20 carbon atoms, an alkylamino group (for example, an alkylamino group containing 1 to 5 carbon atoms such as ethylamino group) ), Or an aryl group containing 1 to 12 atoms (e.g., an aryl group containing 1 to 12 carbon atoms (e.g., a phenyl group, a naphthyl group, etc.)), and each X ^- is negatively exchanged It is a pair ion.

The negatively charged pair ions in each of the polymers may be organic ions, inorganic ions, or a combination thereof. Inorganic ions suitable for use in the present invention are the respective ions of halides (particularly chlorides), phosphates, phosphites, carbonates, bicarbonates, sulfates, hydrogen sulphates, hydroxides, nitrates, persulfates, sulfites and sulfides. Preferred organic ions include acetate, ascorbate, benzoate, citrate, dihydrogen citrate, monohydrogen citrate, oxalate, succinate, tartarate, taurocholate, glycocholate, and cholate. It is an ion.

In addition, a super-absorbent polymer is a water-absorbent polymer that absorbs 10 mL or more of water at 1 g to change into a gel without fluidity, and exhibits a strong water holding capacity that does not drain the absorbed water even when a little pressure is applied. It means a polymer. As the absorbent polymer, a polymer exemplified as the hygroscopic polymer can be exemplified.

Certain containing 50% by weight or more of the hygroscopic polymer of the present invention can be produced by a conventional method such as direct powder compression method or indirect powder compression method. In tabletting, additives such as excipients, disintegrants, fluidizing agents, binders, lubricants, colorants, and fragrances, which are preferably used, may be contained within a range not impairing the object of the present invention.

The amount of glidant to contain is preferably 1% by weight or less based on the total weight. The amount of binder to be contained is preferably 20% by weight or less based on the predetermined total weight. The amount of the lubricant contained is preferably 0.05 to 1% by weight based on the total weight.

Examples of the excipient include cellulose or cellulose derivatives such as crystalline cellulose and low-substituted hydroxypropyl cellulose; Starch or starch derivatives such as corn starch and dextrin; Sugars or sugar alcohols such as lactose, white sugar and D-mannitol; Inorganic excipients such as dry aluminum hydroxide gel, precipitated calcium carbonate, synthetic aluminum silicate, magnesium metasilicate aluminate, hard silicic anhydride and calcium hydrogen phosphate.

Examples of the binder include cellulose or cellulose derivatives such as hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose and carboxymethyl ethyl cellulose; Starch, such as corn starch, or alpha-alpha; Starch derivatives such as hydroxypropyl starch; Flulan, polyvinyl alcohol, polyvinylpyrrolidone, gum arabic, gelatin, tragant and the like.

Examples of disintegrating agents include cellulose derivatives such as carmellose or disodium salt, calcium salt and croscarmellose sodium; Starch or starch derivatives such as wheat starch and carboxymethyl starch sodium; Sodium alginate, and the like.

Examples of the fluidizing aid include fatty acid esters of anhydrous sorbitol, such as hardened oil, polyoxyethylene hardened castor oil, polyoxyl stearate, polyoxyethylene polyoxypropylene glycol, polysorbate, and sorbitan sesquioleate, and glycerin monostearate. , Lauro macro, etc. are mentioned.

As the lubricant, for example, higher fatty acids such as stearic acid, magnesium stearate and calcium stearate and metal salts thereof; Talc, sodium lauryl sulfate, sucrose fatty acid ester, colloidal silica and the like.

The predetermined | prescribed thing containing 50 weight% or more of the hygroscopic polymer of this invention can be manufactured by mixing and tableting each component. There is no restriction | limiting in particular as a tablet manufacturing method used by this invention, Well-known methods, such as the direct powder compression method, the semi-direct powder compression method, the dry granulation compression method, and the wet granulation compression method, can be used preferably.

A predetermined content of 50% by weight or more of the hygroscopic polymer of the present invention is preferably 10% by weight or less in preheating under conditions in which the thermal expansion ability is not completely lost.

Specific examples containing 50% or more of the hygroscopic polymer of the present invention are specifically described in, for example, the method described in JP-A-10-330269 (WO98 / 44933) and WO00 / 22008. It can manufacture according to the method as described.

There is no restriction | limiting in particular in the coating agent used for coating in this invention, Usually, the coating agent used for coating of a tablet can be used. For example, a film coating agent can be obtained by dissolving a film base using purified water as a solvent, dispersing a lubricant, a light-shielding agent, a pigment | dye, etc. in this, and mixing solid content and water.

Moreover, the coating agent used by this invention may contain various additives, such as a plasticizer, a lubricating agent, a light-shielding agent, and a pigment, as solid content. The density | concentration of the said solid content is 1-20 weight% normally.

As a film base used for the said coating agent, what is generally added can be used, The gas-soluble film coating base, an enteric or slow-release film coating base etc. can be suitably selected according to the objective of a tablet.

As a gas-soluble film coating base, For example, Cellulose derivatives, such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose; Synthetic polymers such as polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name), rom palma company], polyvinylpyrrolidone; Dextrin, pullulan, zein, sodium alginate, gelatin, sucrose and the like.

As an enteric or sustained-release film coating base, For example, Cellulose derivatives, such as ethyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; Acrylics, such as methacrylic acid copolymer L or LD [oidragit L, L-30D55, (brand name), rom palma company], aminoalkylacrylate copolymer RS [oidragit RS (brand name), rom palma company] Acid-based polymers; Natural products, such as a cerac, etc. are mentioned.

These can be used individually or in mixture of 2 or more types. Among these, a cellulose derivative is preferable, hydroxypropyl cellulose is more preferable, and hydroxypropyl methyl cellulose is still more preferable. The usage-amount of a film base material does not need to be a special value, but may be 50 weight% or more with respect to a film layer.

Examples of the plasticizer used in the coating agent include macrogol (polyethylene glycol), triethyl citrate, triacetin, medium chain fatty acid triglycerides, glycerin, and the like. The amount of plasticizer added is usually less than 50% by weight based on the total solids in the coating liquid.

Examples of the lubricant used in the coating agent include talc, stearic acid, magnesium stearate, and sucrose fatty acid esters. The amount of the lubricant added is usually less than 50% by weight based on the total solids in the coating liquid.

As a light-shielding agent or pigment | dye used for the said coating agent, metal oxides, such as titanium oxide, yellow iron trioxide, red iron trioxide, black iron trioxide, tar type pigment | dye, etc. are mentioned, for example. The amount of the light-shielding agent or pigment added is usually less than 50% by weight based on the total solids in the coating liquid.

There is no restriction | limiting in particular in the coating method of the coating liquid used by this invention, A well-known method can be used suitably, It is preferable to coat a predetermined | prescribed by spraying using a commercially available coating apparatus. Although the coating amount of a coating liquid does not have a restriction | limiting in particular, It is preferable that the amount of coating amount will be 1-10 weight% with respect to a predetermined | prescribed amount.

Moreover, after the said coating amount coat | covers predetermined | prescribed and the roughness of the tablet surface which generate | occur | produced in the initial stage of coating is restored, if sufficient strength (film strength if it is a film coating agent) is obtained, the same or another coating liquid can be continuously apply | coated by a conventional method.

The coating in the production method of the present invention is preheated to a predetermined content containing at least 50% of the hygroscopic polymer under conditions in which the thermal expansion capability is not completely lost (that is, at least part of the thermal expansion capability is left), and then the coating liquid. The coating can be carried out by applying or holding the tablet under conditions that sufficiently expand the tablet. Thermal expansion means here the deformation | transformation with the thickness increase of the tablet generate | occur | produced by heating.

In addition, the conditions which the said predetermined | prescribed thermal expansion capability does not lose completely, and the conditions which fully expand | stretch subsequent tablets can be calculated | required by measuring the thickness increase amount of the tablet (predetermined) by heating. The increase in the thickness of the tablet by heating keeps the tablet at a constant temperature (eg, 30 ° C., 40 ° C., 50 ° C., 60 ° C., 70 ° C., 80 ° C., etc.), and maintains the tablet at a constant time (eg, every 5 minutes, Every 10 minutes, etc.) can be obtained by measuring the thickness of the tablet and comparing it with the thickness of the tablet before heating.

The conditions in which the tablets are sufficiently inflated are conditions under which the increase in thickness of the tablets measured as described above is close to the maximum. When the coating liquid is applied or after the coating is applied, appropriate temperatures must be set for both. Specifically, the condition of increasing the thickness when the tablet is kept under the above conditions for a predetermined time is 0.5% or more of the predetermined thickness, preferably 2.5% or more, and more preferably 5.0% or more. to be.

The tablet temperature under the condition that the tablet is sufficiently inflated is usually a temperature at which the thickness increase when the tablet is held at that temperature for 20 minutes is 0.5% or more of the predetermined thickness, and preferably the thickness increase amount is a predetermined thickness. The temperature is 2.5% or more, and more preferably the temperature increase amount is 5.0% or more of the predetermined thickness.

As a tablet temperature in the conditions which make a tablet fully expand | flate, it is preferable to maintain a tablet temperature of 40 degreeC or more, and to apply | coat a coating liquid, and to maintain a tablet temperature of 50 degreeC or more when apply | coating a coating liquid.

In the case where the hygroscopic polymer is a polyallylamine-based polymer, the tablet temperature under the conditions of sufficiently expanding the tablet is a tablet temperature of 40 ° C. to 70 ° C. when the coating liquid is applied and a tablet temperature of 55 ° C. to 85 ° C. after the coating liquid is applied. It is preferred to remain at.

The time for keeping the tablet under sufficient swelling conditions is the time until the smoothness of the tablet surface reaches the desired state, which is usually 30 minutes or more, preferably 60 minutes or more, and more preferably 90 minutes or more. . As described above, if sufficient strength (film strength in the case of a film coating agent) is obtained, the same or different coating liquid can be applied by the conventional method, so that the purpose of coating the tablet (for purposes other than improving the smoothness of the surface of the tablet, Stability improvement, usability improvement, control of the release time of the drug, etc.) can be performed for longer than enough time.

In the case where the hygroscopic polymer is a polyallylamine polymer, the conditions for sufficiently expanding the tablet while applying the coating liquid are usually 60 minutes to 400 minutes at a tablet temperature of 40 ° C. to 60 ° C., and 120 minutes to 400 minutes at a tablet temperature of 40 ° C. to 60 ° C. Minutes are preferred.

In the case where the hygroscopic polymer is a polyallylamine-based polymer, after coating the coating liquid on the tablet, the conditions to be sufficiently expanded are usually at least 10 minutes at a tablet temperature of 55 ° C. to 85 ° C., and 30 at a tablet temperature of 55 ° C. to 85 ° C. Minutes or more are preferable, More preferably, they are 30 minutes or more at 60 degreeC-80 degreeC.

Preheating a predetermined temperature under conditions in which the thermal expansion capability thereof is not completely lost means that the thickness increase of the tablet (predetermined) after preheating is maintained at 3/5 or less of the increase in the thickness of the tablet when the tablet is kept under the condition of sufficiently expanding the tablet. It means that preheating is carried out under the conditions of the preliminary heating, and preheating is preferably carried out under the condition that the thickness increase of the tablet after preheating is kept at the condition of 2/5 or less of the increase in thickness of the tablet when the tablet is kept under the condition of sufficiently expanding the tablet. It is more preferable to preheat on the conditions which are 1/5 or less of the thickness increase of the tablet when the thickness increase of the tablet after heating is maintained on the conditions which make a tablet fully expand.

In the case where the hygroscopic polymer is a polyallylamine-based absorbent polymer, in preheating a predetermined condition under which the thermal expansion ability is not completely lost, it is preferable to preheat the tablet temperature to reach 40 ° C to 60 ° C.

In the case where the hygroscopic polymer is a polyallylamine polymer, the required time for preheating a predetermined time under the condition that its thermal expansion ability is not completely lost is usually about 5 to 60 minutes, and preferably 5 to 20 minutes. In this case, it is preferable to perform preheating at the air supply temperature of 50-70 degreeC.

In order to preheat a predetermined amount in a range in which thermal expansion capacity is not completely lost, it is preferable that the predetermined moisture content is an amount which is different depending on the holding temperature within a range in which the shape and hardness of the tablet do not change significantly. . For example, it is preferable that the thickness increase amount at the time of holding a tablet at 50 degreeC for 10 minutes is 1/2 or less of the amount increase thickness at the time of holding it for 10 minutes at 80 degreeC.

When the hygroscopic polymer is a polyallylamine-based polymer, the predetermined moisture content is preferably at least 3% by weight and at most 10% by weight, and more preferably at least 3% by weight and at most 8% by weight, based on a drying loss method of 105 ° C-3 hours. desirable.

Although there is no restriction | limiting in particular as a method of adjusting predetermined water content, The method of mixing and tableting in the state which adjusted the hygroscopic polymer and various additives of a raw material to desired water content beforehand is the simplest. In addition, there is a method of manufacturing a predetermined, and then stored in a humidity-controlled environment, or a method of drying by a commonly used drying method such as vacuum drying method, in which case, care should be taken not to apply heat to the thermal expansion. .

The water content of a tablet can be measured by a drying loss method, for example, and 105 degreeC-3 hours are preferable as the measurement conditions.

In addition, when preserving certain, moisture-proof packaging or the like should be considered to prevent moisture absorption.

In addition, the purification temperature mentioned above can be measured using a various apparatus commercially available, for example, it can measure using a non-contact thermometer etc. Measurement errors with non-contact thermometers are typically about ± 1% (or ± 2 ° C) of readings.

The present invention is explained in more detail by the following examples and test examples. In addition, the purification temperature was measured using the portable type non-contact thermometer PT-3LF (made by Optex Corporation).

Example 1

Polyallylamine / Epicrohydrin crosslinked polymer (common name: Severamer hydrochloride (r-INN), water content 5.5% by weight) 86.21% by weight, crystalline cellulose 13.62% by weight, Lubri Wax 101 0.12% by weight Was added to a V-type mixer, mixed at 15 rpm for 15 minutes, and then 0.05 wt% of magnesium stearate was added thereto and mixed at 15 rpm for 1 minute. This mixed powder was compressed into tablets using a rotary tablet press (X-45, manufactured by Hata Tekshosho) to prepare a predetermined amount (water content of 5.5% by weight and hardness of 10 kgf). Moisture content was measured by the drying loss method (105 degreeC, 3 hours).

Example 2

The predetermined product obtained in Example 1 was dried in a desiccator containing silica gel to prepare a predetermined content of 3.0% by weight and a predetermined content of 3.8% by weight. Moisture content was measured by the drying loss method (105 degreeC, 3 hours).

Example 3

The predetermined | prescribed in Example 1 was moisture-absorbed indoors, and the predetermined | prescribed content of 8.0 weight% was prepared. Moisture content was measured by the drying loss method (105 degreeC, 3 hours).

[Test Example 1]

The tablets obtained in Example 1 were placed in a constant temperature bath at 40 ° C., 50 ° C., 60 ° C., and 70 ° C., and sampled at intervals of 5 minutes for up to 60 minutes, and the thickness of the tablets was measured by a thickness meter. An example of the result which shows the time transition of (the difference with before heating) is shown in FIG.

[Test Example 2]

60 each of the predetermined (water content 5.5 wt%) obtained in Example 1, the predetermined (water content 3.0 wt% and water content 3.8 wt%) obtained in Example 2 and the predetermined (water content 8.0 wt%) obtained in Example 3, respectively. It put into the thermostat of 70 degreeC, 70 degreeC, and 80 degreeC, it sampled for 10 minutes at 10 minute intervals, and measured the thickness of the tablet with the thickness meter. Examples of the results showing the time course of the increase in thickness of the tablet at each temperature are shown in FIGS. 2 to 5, respectively.

Example 4

6.5 wt% of hydroxypropylmethylcellulose, 1 wt% of macrogol 6000, 2 wt% of titanium oxide, and 0.5 wt% of talc were dissolved or dispersed in 90 wt% of purified water to prepare a coating solution.

Subsequently, the predetermined 5.0 kg prepared in Example 1 was put into the coating machine (the powder made by the powder, DRC-500 type). It preliminarily dried for 10 minutes at the air supply set temperature of 55 ° C. The purification temperature at the end of preliminary drying was 51 ° C. Subsequently, the spray amount of the spray liquid was sprayed at 6 mg / min until 60 minutes after that at an air supply setting temperature of 53 ° C., and then sprayed at 12 mg / min for 210 minutes. The purification temperature during this time was 45-49 degreeC. After the completion of spraying, the air supply setting temperature was set at 70 ° C., and the subsequent drying was performed for 180 minutes. The purification temperature after completion of the post-drying was 73 ° C.

Example 5

It carried out using predetermined | prescribed manufactured in Example 1 and the coating liquid prepared in Example 4. The predetermined 195.8 kg prepared in Example 1 was put into the coating machine (Frund Sankyo, HCF-150 type). Preliminary drying was performed for 9 minutes at an air supply setting temperature of 70 deg. The purification temperature at the end of preliminary drying was 52 ° C. Subsequently, the spray amount of the spray liquid was sprayed at 240 mL / min until 60 minutes, 300 mL / min until after 120 minutes, and 360 mL / min after that at the air supply setting temperature of 58-80 degreeC, and sprayed for 222 minutes. The purification temperature during this time was 48-54 degreeC. After the completion of spraying, the air supply setting temperature was set at 70 ° C, and post-drying was performed for 360 minutes. The purification temperature at the end of postdrying was 75 ° C.

Example 6

It carried out using the predetermined | prescribed equivalent to Example 1 and the coating liquid prepared in Example 4. The predetermined 207.4 kg prepared according to Example 1 was put into the coating machine (Frund Sankyo, AQC-150F type). It preliminarily dried for 18 minutes at the air supply set temperature of 50-75 degreeC. The purification temperature at the end of preliminary drying was 42 ° C. Subsequently, the spray amount of the spray liquid was sprayed at 320 mL / min until 60 minutes, 400 mL / min until after 120 minutes, and 480 mL / min after that at the air supply setting temperature 57-75 degreeC, and sprayed for 180 minutes. The purification temperature during this time was 42-48 degreeC. After the completion of spraying, the air supply setting temperature was set to 70 ° C and post-drying was performed for 120 minutes. The purification temperature at the end of post-drying was 68 ° C.

Comparative Example 1

It carried out using predetermined | prescribed manufactured in Example 1 and the coating liquid prepared in Example 4. The predetermined 5.0 kg prepared in Example 1 was put into the coating machine (Powrec, DRC-500 type). It preliminarily dried for 105 minutes at the air supply set temperature of 70 ° C. The purification temperature at the end of preliminary drying was 72 ° C. Subsequently, the spray amount of the spray liquid was sprayed at 6 mg / min until 30 minutes after that at an air supply setting temperature of 55 to 60 ° C, and then sprayed at 12 mg / min for 170 minutes. The purification temperature during this time was 44-65 degreeC. After the completion of spraying, the air supply setting temperature was set to 70 ° C and post-drying was performed for 60 minutes. The purification temperature after the end of post-drying was 68 ° C.

[Test Example 3]

The smoothness of the coated tablet surface prepared in Examples 4, 5 and Comparative Example 1 was compared by visual observation. The results are shown in Table 1. Moreover, an example of each refined photograph is shown to FIGS. 6-10.

In addition, significant differences were found in Ra (arithmetic mean roughness) between the tablets judged to be good and the tablets judged to be poor by visual observation. In addition, Ra (arithmetic mean roughness) can be measured by commercially available instruments, such as an image analysis using a scanning laser microscope, and a surface roughness measuring instrument.

Smoothness of tablet surface Example 4 Good Example 5 Good Comparative Example 1 Bad

The present inventors have made intensive studies in view of the above problems, and as a result, a condition containing 50% or more of hygroscopic polymer is used under conditions in which the predetermined thermal expansion capacity is not completely lost (that is, at least part of the predetermined thermal expansion capacity is left. The present invention was completed by finding that the roughness of the surface of the tablet which occurred at the beginning of coating was restored by pre-heating under the conditions), followed by applying or applying the coating solution, and then thermally expanding the heated tablet.

As can be seen from the above test example, the manufacturing method of the present invention solves the problems of the prior art, and provides a coated tablet mainly composed of hygroscopic polymers having excellent smoothness and uniformly coated surface of the tablet which could not be provided in the prior art. can do.

In addition, as described in the present invention, the predetermined content containing the hygroscopic polymer 50% or more is preheated under the condition that the thermal expansion capacity is not completely lost (that is, the predetermined thermal expansion capacity is at least partially left), and then the coating liquid is applied or after the application. The manufacturing method of restoring the roughness of the tablet surface generated at the beginning of the coating by thermal expansion of the heated tablet is novel and unique and is very beneficial and useful to open a new perspective in the manufacture of tablets.

Claims (7)

The surface of this tablet is maintained by preheating a predetermined content containing at least 50% by weight of the hygroscopic polymer under conditions in which its thermal expansion ability is not completely lost, followed by applying or applying a coating solution, and then maintaining the tablet under sufficient expansion conditions. The manufacturing method of the coating tablet which has a hygroscopic polymer as a main component characterized by restoring a shape. The method of claim 1 wherein the coated tablet is a film coated tablet. The manufacturing method of Claim 1 or 2 whose predetermined moisture content is 10 weight% or less. The manufacturing method in any one of Claims 1-3 whose hygroscopic polymer | macromolecule contained is 70 weight% or more. The production method according to any one of claims 1 to 4, wherein the hygroscopic polymer is a polyallylamine polymer. The production method according to any one of claims 1 to 5, wherein the hygroscopic polymer is a polymer obtained by cross-polymerizing polyallylamine with epichlorohydrin. The coated tablet obtained by the manufacturing method in any one of Claims 1-6.