WO2003053419A1

WO2003053419A1 - Coated tablets and process for producing the same

Info

Publication number: WO2003053419A1
Application number: PCT/JP2002/013297
Authority: WO
Inventors: Takahiro Yamamura; Kenta Wada; Takeshi Nakamura
Original assignee: Chugai Seiyaku Kabushiki Kaisha
Priority date: 2001-12-20
Filing date: 2002-12-19
Publication date: 2003-07-03
Also published as: AU2002357611A1; TW200301140A; CN1604771A; KR20040073492A; HK1071524A1; CN1298315C; JPWO2003053419A1; TWI231760B; JP4398253B2

Abstract

It is intended to provide coated tablets having a high surface smoothness produced by pre-heating uncoated tablets comprising a hygroscopic polymer as the main component under such conditions as not completely damaging the thermal expansibility, and allowing further thermal expansion by heating the tablets while applying a coating solution or after applying the same to thereby smoothen the tablet surface having become rough in the early stage of the coating. In the case of forming coated tablets by coating uncoated tablets comprising a hygroscopic polymer, a coating solution is spread while moistening over the entire surface of the uncoated tablets and thus the surface strength of the tablets is lowered. As a result, the surface of the uncoated tablets becomes rough in the early stage of the coating and thus the appearance of the coated tablets is worsened, or the coating film thickness becomes uneven. These problems can be overcome by the above method.

Description

Description Coated tablets and production method thereof [Technical field]

The present invention relates to a method for producing a coated tablet containing a hygroscopic polymer as a main component, and more particularly to a method for producing a film-coated tablet. The present invention also relates to a coated tablet obtained by the production method.

[Background technology]

Conventionally, a film coating method, a sugar coating method and the like have been known as a coating method for tablets containing a hygroscopic polymer as a main component. Among these, as a film coating method, for example, a method of coating an uncoated tablet obtained by impregnating an anion exchange resin with a certain amount of water and compressing it with a coating liquid containing hydroxypropylcellulose or the like is known. (Japanese Unexamined Patent Publication No. Hei 6-157735). A method is also known in which uncoated tablets obtained by adding 14 to 20% by weight of water and 2% by weight or less of silicon dioxide to an anion exchange resin are coated with hydroxypropylmethylcellulose ( Japanese Patent Laid-Open No. 7-97330). However, these methods have a problem that the strength of the tablet is reduced because the uncoated tablet needs to contain a certain amount of water.

Also, a method is known in which an unexchanged tablet obtained by tableting a mixture obtained by adding silicon dioxide and crystalline cellulose to an anion exchange resin without adding water is spray-coated with a coating solution containing hydroxypropylmethylcellulose or the like. (Japanese Unexamined Patent Application Publication No. 9-220732, Japanese Unexamined Patent Application Publication No. 10-114661). Tablets containing a hygroscopic polymer (polyallylamine-based polymer) are disclosed in Japanese Patent Application Laid-Open No. 10-33069 (International Publication WO98 / 444933) and It is disclosed in International Publication No. WO 0220208, which states that film coating may be applied to form a film tablet.In the latter case, a commercially available coating machine is actually used. There is also described an example in which a film tablet was manufactured using the same. However, when a tablet of a hygroscopic polymer such as a polyallylamine-based polymer is coated by the above method, the surface strength of the tablet decreases because the film-forming agent solution spreads while wetting the entire surface of the tablet. However, the surface of the tablet was roughened in the early stage of coating, and the aesthetic appearance was impaired, and the thickness of the film was not uniform, so that the desired film function could not be obtained.

An object of the present invention is to provide a method for producing a coated tablet containing a hygroscopic polymer as a main component, and particularly a method for producing a film-coated tablet, which is excellent in tablet surface smoothness and is uniformly coated. Another object is to provide a coated tablet having excellent tablet surface smoothness.

[Disclosure of the Invention]

In view of the above problems, the present inventors have conducted intensive studies and as a result, obtained a plain tablet containing 50% or more of a hygroscopic polymer under the condition that the thermal expansion ability of the plain tablet is not completely lost (ie, Pre-heating under the condition that the thermal expansion capacity of the uncoated tablet remains at least partially), and then, during or after the application of the coating liquid, the heated tablet is thermally expanded to generate the initial stage of coating. The present inventors have found that the roughened surface of the prepared tablet is restored, and completed the present invention.

[Brief description of drawings]

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

FIG. 2 is an example of a graph showing the time change of the amount of increase in thickness of the uncoated tablet (water content: 5.5% by weight) obtained in Example 1 due to heating.

FIG. 3 is an example of a graph showing the time change of the amount of increase in thickness of the uncoated tablet (water content: 3.0% by weight) obtained in Example 2 due to heating.

FIG. 4 is an example of a graph showing the time change of the amount of increase in thickness of the uncoated tablet (water content: 3.8% by weight) obtained in Example 2 due to heating.

FIG. 5 is an example of a graph showing the time transition of the increase in thickness of the uncoated tablet (water content: 8.0% by weight) obtained in Example 3 due to heating.

FIG. 6 is an example of a top photograph showing the appearance of the coated tablet produced in Example 4. FIG. 7 is an example of a side photograph showing the appearance of the coated tablet manufactured in Example 4.

FIG. 8 is an example of a top photograph showing the appearance of the coating tablet produced in Example 5.

FIG. 9 is an example of a top photograph showing the appearance of the coated tablet produced in Comparative Example 1.

FIG. 10 is an example of a side photograph showing the appearance of the coated tablet produced in Comparative Example 1.

The present invention is directed to uncoated tablets containing 50% by weight or more of a hygroscopic polymer. Such uncoated tablets have a thermal expansion capability, but if heated sufficiently, the original thermal expansion capability is completely lost. That is, the present invention pre-heats such uncoated tablets under the condition that the thermal expansion ability is not completely lost (that is, the condition that at least a part of the thermal expansion ability is left), and then the coating liquid is heated. A coated tablet containing a hygroscopic polymer as a main component, wherein the surface condition of the tablet is restored by maintaining the tablet under sufficient conditions during or after the application. And a method for producing the same.

The present invention also relates to a coated tablet obtained by the above production method. In the present invention, the coating means a known coating method applicable to coating of ordinary tablets, such as film coating and sugar coating, and among them, film coating is preferable. That is, the coated tablet is preferably a film-coated tablet.

In the present invention, the term "absorbent polymer" refers to a high-absorbent polymer having a water content of 10% by weight or more within one week under a room temperature (22 to 28 ^) at a relative humidity of 50%. Means molecule.

As such a hygroscopic polymer, for example,

Acrylic acid polymer (acrylic acid-vinyl alcohol polymer) Methacrylic acid polymer

Acrylamide polymer

Arylamine-based polymer Carboxymethyl cellulose polymer

Biopolymer that produces fructose etc. as a carbon source

And their salts, saponified products and hydrolysates. In addition to the homopolymers, the above-mentioned polymers also include these copolymers, and copolymers of these monomers with other monomers copolymerizable with them and graft-polymerizable polymers. Such a copolymer may be a random polymer, a block polymer, or a graft polymer. In addition, a crosslinked product of each polymer prepared according to a conventional method using various crosslinking agents is also included.

As the cross-linking agent, various kinds of polyaryls, polyhydric pinyls, polyhydric epoxies, halo epoxies, polyhydric alcohols, polyhydric amines, hydroxyvinyls and the like can be used. .

Other copolymerizable monomers include, for example, alkyl (e.g., hydroxyethyl (meth) acrylate, (methoxy) polyethylene glycol (meth) acrylate, dariserine (meth) acrylate, and glycosylethyl (meth) acrylate. (Meth) acrylates; acrylamide compounds such as N, N-dimethylacrylamide and acrylamide; carboxylic acid compounds such as maleic acid and its metal salts, itaconic acid and its metal salts; 2-acrylamide Examples thereof include sulfonic acid compounds such as 2-methylpropanesulfonic acid and its metal salt, vinylsulfonic acid and its metal salt, styrenesulfonic acid and its metal salt; and N-vinylpyrrolidone.

Examples of the polymer that can be graft-polymerized with (meth) acrylic acid include starch, carrageenan, agarose, and hydrophilic polysaccharides such as carboxymethyl cellulose.

The following can be exemplified as typical crosslinking agents.

Polyvalent aryls: N, N-diarylacrylamide and N, N-diarylmethylacrylamide (these are referred to as “N, N-diaryl (meth) acrylamide”, the same applies hereinafter), diarylamine, Polyvalent aryl compounds such as diaryl methacrylamine, diaryl phthalate, and diaryl malate;

Polyvinyls: divinylbenzene, N, N "-methylenebis (meth) acryl Amide, ethylene glycol di (meth) acrylate and polyethylene glycol di (meth) acrylate (these are referred to as “(poly) ethylene glycol di (meth) acrylate”, the same applies hereinafter), and (poly) propylene glycol (Meta) Polyvalent vinyl compounds such as acrylate and trimetalol propane triacrylate.

Polyepoxys: (poly) ethylene glycol diglycidyl ether, (poly) propylene glycol diglycidyl ether, glycerin-1,3-diglycidyl ether, trimethylolpropane triglycidyl ether, (poly) glycerin polyglycidyl ether, etc. Polyepoxy compound.

Haloepoxys: epichlorohydrin, α-methylchlorohydrin and the like.

Polyhydric alcohols: (poly) glycerin, (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 water-absorbing polymer, and more preferably a water-absorbing polymer obtained by crosslinking and polymerizing polyallylamine with epichlorohydrin.

[Wherein the molar ratio of (a + b): c is 45: 1 to 2: 1, and m represents an integer]. The water-absorbing polymer represented by the formula (1) can be prepared, for example, by the method described in Japanese Patent Publication No. 9-504782 (International Publication WO 95Z05184) or the international publication WO 00/22008. Can be obtained according to the method described in, for example.

Further, as the hygroscopic polymer used in the present invention, the following polymers (2) to (9) can also be suitably used.

The polymer (2) has the following formula

Or a copolymer thereof having a repeating unit represented by the formula: In the formula, n is an integer, and R is each independently H or a lower alkyl group (for example, an alkyl group containing 1 to 5 carbon atoms), an alkylamino group (for example, 1 to 4 such as an ethylamino group). An alkylamino group containing 5 carbon atoms) or an aryl group (eg, an aryl group containing 1 to 12 carbon atoms (eg, phenyl, naphthyl, etc.)).

The polymer (3) has the following formula

Or a copolymer thereof having a repeating unit represented by the formula: In the formula, n is an integer, and R is each independently H or a lower alkyl group (for example, an alkyl group containing 1 to 5 carbon atoms), an alkylamino group (for example, 1 to 4 such as an ethylamino group). Alkylamino group containing 5 carbon atoms), or aryl (Eg, an aryl group containing 1 to 12 carbon atoms (eg, phenyl, naphthyl, etc.)), and X is an exchangeable negatively charged counterion.

Examples of the copolymer of the above polymer (3) include the following formula:

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

[Wherein, n is each independently an integer, and R is each independently H or a lower alkyl group (for example, an alkyl group containing 1 to 5 carbon atoms), an alkylamino group (for example, an ethylamino group). An alkylamino group containing 1 to 5 carbon atoms) or an aryl group (for example, an aryl group containing 1 to 12 carbon atoms (for example, phenyl, naphthyl, etc.)). (Polymer (4)) characterized by having a second repeating unit.

The polymer (5) has the following formula

Or a copolymer thereof having a repeating unit represented by the following formula: Wherein n is an integer, R is H or a lower alkyl group (eg, an alkyl group containing 1 to 5 carbon atoms), an alkylamino group (eg, containing 1 to 5 carbon atoms such as an ethylamino group) An alkylamino group) or an aryl group (eg, an aryl group containing 1 to 12 carbon atoms (eg, a phenyl group, a naphthyl group, etc.)).

As another example of the copolymer of the polymer (3), the following formula:

Wherein n is an integer, R is H or a lower alkyl group (eg, an alkyl group containing 1-5 carbon atoms), an alkylamino group (eg, 1-5 carbon atoms such as an ethylamino group) An alkyl group containing 1 to 12 carbon atoms (for example, an aryl group containing 1 to 12 carbon atoms (for example, a phenyl group, a naphthyl group, etc.)) and a first repeating unit represented by the following formula:

X "

(6)

Wherein n is independently an integer; R is H or a lower alkyl group (eg, an alkyl group containing 1 to 5 carbon atoms); an alkylamino group (eg, 1 to 5 such as an ethylamino group); An alkylamino group containing a carbon atom) or an aryl group (For example, an aryl group containing 1 to 12 carbon atoms (for example, phenyl group, naphthyl group, etc.)). 6))).

The polymer (7) has the following formula

X

Or a copolymer thereof having a repeating unit represented by the formula: In the formula, n is an integer, and R and R ₂ are each independently H or a lower alkyl group (for example, an alkyl group containing 1 to 5 carbon atoms), an alkylamino group (for example, 1 to 4 such as ethylamino group). An alkylamino group containing 5 carbon atoms, or an aryl group (eg, an aryl group containing 1 to 12 carbon atoms (eg, phenyl, naphthyl, etc.)), and X is each interchangeable This is a negatively charged pair.

Of the polymer (7), preferred polymers are also one and less of R ## or R ₂ in the formula is a hydrogen, a polymer.

The polymer (8) has the following formula

Or a copolymer thereof having a repeating unit represented by the formula: In the formula, n is an integer, and 1 ^ and R ₂ are each independently H or an alkyl group containing 1 to 20 carbon atoms, an alkylamino group (for example, 1 to 5 carbon atoms such as ethylamino group). Alkyl groups containing 1 to 12 atoms (eg, aryl groups containing 1 to 12 carbon atoms) (eg, phenyl Group, naphthyl group, etc.))

The polymer (9) has the following formula

X "

Or a copolymer thereof having a repeating unit represented by the formula: Where n is an integer and! R and R ₂ and R ₃ 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 an ethylamino group), Or an aryl group containing from 1 to 12 atoms (eg, an aryl group containing from 1 to 12 carbon atoms (eg, phenyl, naphthyl, etc.)), where X is each exchangeable negatively charged It is a counter ion.

In each of the above polymers, the negatively charged counterion may be an organic ion, an inorganic ion, or a combination thereof. Inorganic ions suitable for use in the present invention include halides (especially chlorides), phosphates, phosphites, carbonates, carbonates, sulfates, hydrogensulfates, hydroxides, nitrates, These are persulfate, sulfite and sulfide ions. Preferred organic ions include acetate, ascorbate, benzoate, citrate, dihydrogenate, monohydrogenate, oxalate, succinate, tartrate, taurocholate Salt, glycocholate, and cholate ions.

Also, a super-absorbent polymer is a substance that absorbs more than 10 mL of water by lg, changes into a gel without fluidity, and absorbs water even if a slight pressure is applied. Means a polymer that exhibits a strong water retention capacity that does not escape. Examples of the water-absorbing polymer include the polymers exemplified as the hygroscopic polymer. An uncoated tablet containing 50% by weight or more of the hygroscopic polymer of the present invention can be produced by a conventional method such as a direct powder compression method or an indirect powder compression method. In tableting, a suitable excipient, disintegrant, fluidizing agent, Additives such as a mixture, a lubricant, a coloring agent, and a fragrance may be contained within a range not to impair the object of the present invention.

The amount of the fluidizing agent contained is preferably 1% by weight or less based on the total weight of the uncoated tablet. The amount of the binder contained is preferably not more than 20% by weight based on the total weight of the uncoated tablet. The amount of the lubricant contained is preferably 0.05 to 1% by weight based on the total weight of the uncoated tablet.

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 such as lactose, sucrose, and D-mannitol; Sugar alcohols; inorganic excipients such as dried aluminum hydroxide gel, precipitated calcium carbonate, synthetic aluminum silicate, magnesium aluminate metasilicate, light anhydrous silicic acid, hydrogen phosphate and the like.

Examples of the binder include cellulose or cellulose derivatives such as hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, and carboxymethylethylcellulose; starch such as corn starch; Starch derivatives such as hydroxypropyl starch; pullulan, polyvinyl alcohol, polyvinylpyrrolidone, acacia, gelatin, tragacanth, and the like.

Examples of the disintegrating agent include carmellose or a cellulose derivative such as sodium salt or calcium salt thereof and croscarmellose sodium; starch or a starch derivative such as wheat starch and carboxymethyl starch sodium; sodium alginate; Can be.

Examples of the fluidization aid include hydrogenated oil, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, polyoxyethylene polyoxypropylene glycol, polysorbate, and fatty acid esters of anhydrous sorbitol such as sorbitan sesquioleate; Glycerin monostearate, lauromacrogol and the like can be mentioned.

Lubricants include, for example, stearic acid, magnesium stearate, stearic Higher fatty acids such as calcium phosphate and metal salts thereof; talc, sodium lauryl sulfate, sucrose fatty acid ester, colloid silica and the like. The uncoated tablet containing 50% by weight or more of the hygroscopic polymer of the present invention can be produced by mixing each component and tableting. The tablet manufacturing method used in the present invention is not particularly limited, and known methods such as a direct powder compression method, a semi-direct powder compression method, a dry granulation compression method, and a wet granulation compression method can be suitably used.

An uncoated tablet containing 50% by weight or more of the hygroscopic polymer of the present invention should have a water content of 10% by weight or less for preheating under the condition that the thermal expansion ability is not completely lost. It is good.

The uncoated tablet containing 50% or more of the hygroscopic polymer of the present invention is specifically described in, for example, Japanese Patent Application Laid-Open No. H10-33069 (International Publication WO98444993). Publication), the method described in International Publication WO 00Z2208, and the like.

The coating agent used for coating in the present invention is not particularly limited, and a coating agent usually used for coating tablets 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-blocking agent, a dye, and the like, and mixing the solid content with water. .

Further, the coating agent used in the present invention may contain various additives such as a plasticizer, a lubricant, a light shielding agent, and a pigment as a solid content. The concentration of the solid content is usually 1 to 20% by weight.

As the film base used in the above-mentioned coating agent, those generally added can be used. Depending on the purpose of the tablet, a gastric film coating base or an enteric or sustained release film coating can be used. The base and the like can be appropriately selected.

Examples of the gastrosoluble film coating base include cellulose derivatives such as hydroxypropylcellulose and hydroxypropylmethylcellulose; polyvinylacetate ylethylethyl acetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) , ROHM FALMA, Inc. Synthetic polymers such as pyrrolidone; dextrin, pullulan, zein, sodium alginate, gelatin, sucrose and the like.

Examples of the enteric or sustained release film coating base include cellulose derivatives such as ethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate fluorate. Acrylic such as methacrylic acid copolymer L or LD (Eudragit L-30D55, (trade name), Rohm Pharma Co.), aminoalkyl acrylate copolymer RS (Eudragit RS (trade name), Rohm Pharma Co.) Acid-based polymers; natural products such as shellac;

These can be used alone or in combination of two or more. Of these, cellulose derivatives are preferred, and hydroxypropyl cellulose and hydroxypropylmethyl cellulose are more preferred. The use amount of the film base does not need to be a special value, and may be 50% by weight or more based on the film layer.

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

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

Examples of the light-shielding agent or pigment used in the coating agent include metal oxides such as titanium oxide, yellow sesquioxide, red sesquioxide, and black sesquioxide, and evening dyes. The addition amount of the light-shielding agent or the dye is usually less than 50% by weight based on the total solid content in the coating solution.

The method of applying the coating liquid used in the present invention is not particularly limited, and a known method can be suitably used. However, it is preferable to coat the uncoated tablet by spraying using a commercially available coating apparatus. There is no particular limitation on the amount of coating liquid applied. However, it is preferable that the amount of the coating be 1 to 10% by weight based on the uncoated tablet. In addition, after the uncoated tablet is coated with the above film amount and the surface of the tablet is repaired at the initial stage of coating, if sufficient strength (film strength for film coating agent) is obtained, The same or different coating liquids can be applied by conventional methods.

The coating in the production method of the present invention is performed under the condition that the thermal expansion capacity of the uncoated tablet containing 50% or more of the hygroscopic polymer is not completely lost (that is, at least a part of the thermal expansion capacity is left). Under such conditions), and then, while or after applying the coating solution, maintaining the tablet under conditions such that the tablet is sufficiently expanded. Here, the thermal expansion means deformation accompanied by an increase in the thickness of the tablet caused by heating.

The conditions under which the thermal expansion capacity of the uncoated tablet is not completely lost, and the conditions under which the tablet is sufficiently expanded thereafter, are determined by measuring the increase in the thickness of the uncoated tablet (heating tablet) due to heating. be able to. The amount of increase in the thickness of the tablet due to heating can be determined by maintaining the tablet at a specified temperature (for example, at 30, 40, 50, 60 ° C, 70, 80, etc.) for a predetermined period of time. It can be obtained by measuring the thickness of the tablet every time (for example, every 5 minutes, every 10 minutes, etc.) and comparing it with the thickness of the tablet before heating.

The conditions under which the tablet is sufficiently expanded are conditions under which the increase in the thickness of the tablet measured as described above is close to the maximum, and when the coating liquid is applied or after the coating liquid is applied, or when the coating liquid is applied. Appropriate temperatures must be set for both. Specifically, the condition is such that the amount of increase in thickness when the tablet is held for a certain time under the condition is 0.5% or more of the thickness of the uncoated tablet, preferably 2.5% or more. More preferably, the condition is 5.0% or more.

The tablet temperature under such conditions that the tablet is sufficiently expanded is usually a temperature at which the amount of increase in thickness when the tablet is held at that temperature for 20 minutes is 0.5% or more of the thickness of the uncoated tablet, and is preferable. Is a temperature at which the above-mentioned increase in thickness becomes 2.5% or more of the thickness of the uncoated tablet, and more preferably a temperature at which the above-mentioned thickness increase becomes 5.0% or more of the thickness of the uncoated tablet.

The tablet temperature under conditions that cause the tablet to swell sufficiently is coating It is preferable that the tablet temperature is maintained at 40 ° C. or higher when the liquid is applied, and the tablet temperature is maintained at 50 or higher after the coating liquid is applied.

When the hygroscopic polymer is a polyallylamine-based polymer, the tablet temperature under conditions that sufficiently swell the tablet is as follows: when the coating liquid is applied, the tablet temperature is 40: to 70: After the coating liquid is applied, the tablet temperature is preferably maintained at 55 to 85.

The time required to maintain the tablet under sufficient conditions to swell the tablet is the time required for the smoothness of the tablet surface to reach the desired state, and is usually 30 minutes or more, and preferably 60 minutes or more. More preferably, it is 90 minutes or more. As mentioned 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 in a conventional manner. For purposes other than surface smoothness improvement, improvement of stability of the active substance, improvement of usability, control of release time of the active substance, etc.) can be performed for a time longer than sufficient.

When the hygroscopic polymer is a polyallylamine-based polymer, conditions for sufficiently swelling the tablet while applying the coating liquid are usually at a tablet temperature of 40 to 60 ° C for 60 minutes to 40 ° C. 0 minutes, and preferably 120 to 400 minutes at a tablet temperature of 40 to 60 ^.

In addition, when the hygroscopic polymer is a polyallylamine-based polymer, the conditions under which the tablet is coated with a coating liquid and then sufficiently swelled are usually at a tablet temperature of 55 to 85 at a temperature of 10 to 10 minutes. The tablet temperature is preferably at least 30 minutes at a tablet temperature of 55 to 85 t :, and more preferably at least 30 minutes at a tablet temperature of 60 to 80.

Preheating the uncoated tablet under the condition that its thermal expansion capacity is not completely lost means that the tablet (uncoated tablet) after preheating is kept under such conditions that the thickness increase of the uncoated tablet causes the tablet to expand sufficiently. Means preheating under the condition that the thickness increase of the tablet at the time is 3 Z 5 or less, and when the thickness increase of the tablet after preheating is maintained under conditions that allow the tablet to expand sufficiently Preheating is preferably performed under conditions that are 2/5 or less of the thickness increase of the tablet, and when the thickness increase of the tablet after preheating is maintained under conditions that allow the tablet to expand sufficiently. 1 to 5 or less of the thickness increase of tablets It is preferable to preheat under the conditions.

When the hygroscopic polymer is a polyallylamine-based water-absorbing polymer, when pre-heating the uncoated tablet under the condition that its thermal expansion capacity is not completely lost, the tablet temperature should be reduced to ~ 60 ^ at a tablet temperature of 40. It is preferred to preheat until reaching.

When the hygroscopic polymer is a polyallylamine-based polymer, the time required for preheating the uncoated tablet under the condition that its thermal expansion capacity is not completely lost is usually about 5 to 60 minutes, and is preferable. Is 5 to 20 minutes. The preheating in this case is preferably performed at a supply air temperature of 50 to 70.

In order to preheat the uncoated tablet within a range in which the thermal expansion capacity is not completely lost, the water content of the uncoated tablet must be within the range where the shape and hardness of the tablet do not significantly change, and the thickness increase of the tablet is limited. It is preferable that the amount varies depending on the holding temperature.For example, the thickness increase when the tablet is held at 50 for 10 minutes is 1 Z 2 of the thickness increase when the tablet is held at 80 and 10 minutes. The following is preferred.

When the hygroscopic polymer is a polyallylamine-based polymer, the water content of the uncoated tablet is preferably from 3% by weight to 10% by weight based on a drying loss method for 105 hours. It is more preferable that the content be 3% by weight or more and 8% by weight or less. There is no particular limitation on the method of adjusting the water content of the uncoated tablet, but the simplest method is to mix the raw material hygroscopic polymer and various additives in a state where the water content is adjusted in advance to the desired water content, and then press the tablet. It is. Other methods include manufacturing uncoated tablets and storing them in a conditioned environment, or drying them using a commonly used drying method such as a vacuum drying method. Care must be taken to avoid this. The water content of the tablet can be measured by, for example, a loss on drying method, and the measurement condition is preferably 105 to 3 hours.

When storing uncoated tablets, it is necessary to consider moisture-proof packaging to prevent moisture absorption.

The above-mentioned tablet temperature can be measured using various commercially available devices, for example, using a non-contact thermometer or the like. The measurement error with a non-contact thermometer is generally about ± 1% (or ± 2) of the reading.

The present invention will be described in more detail by the following examples and test examples. The tablet temperature is The measurement was performed using a portable non-contact thermometer PT-3 LF (made by Optex Corporation).

[Example 1]

Polyallylamine epichlorohydrin cross-linked polymer (generic name: sevelamer hydrochloride (r-INN), water content 5.5% by weight) 86.2 1% by weight, crystalline cellulose 1 3.62% by weight, Lubriwax 101 0.12% by weight was put into a mold mixer, mixed at 15 rpm for 15 minutes, then 0.05% by weight of magnesium stearate was added thereto, and further mixed at 15 rpm for 1 minute. . This mixed powder was tableted with a single-tally tableting machine (X-45 manufactured by Hattetsu Corporation) to produce uncoated tablets (water content: 5.5% by weight, hardness: 10 kgf). The water content was measured by the loss on drying method (105, 3 hours).

[Example 2]

The uncoated tablet obtained in Example 1 was dried overnight in a desiccator containing silica gel to prepare an uncoated tablet having a water content of 3.0% by weight and an uncoated tablet having a water content of 3.8% by weight. The water content was measured by the drying loss method (105 ° C, 3 hours).

[Example 3]

The uncoated tablet obtained in Example 1 was absorbed in a room to prepare an uncoated tablet having a water content of 8.0% by weight. The water content was measured by the loss on drying method (105 hours, 3 hours).

[Test Example 1]

The uncoated tablets obtained in Example 1 were placed in a constant temperature bath at 40, 501 :, 60 ° C. and 70, sampling was performed every 5 minutes up to 60 minutes, and the thickness of the tablets was measured with a thickness gauge. Fig. 1 shows an example of the results showing the time course of the tablet thickness increase (difference from before heating) at each temperature.

[Test Example 2]

The uncoated tablet obtained in Example 1 (water content 5.5% by weight), the uncoated tablet obtained in Example 2 (water content 3.0% by weight and water content 3.8% by weight) and The uncoated tablets (water content 8.0% by weight) obtained in Example 3 were placed in an 80 "constant temperature bath at 60 and 70, respectively, and sampled every 10 minutes until 30 minutes. Example of the results showing the time change of the tablet thickness increase at each temperature Are shown in FIGS. 2 to 5, respectively.

[Example 4]

6.5% by weight of hydroxypropyl methylcellulose, 600% by weight of macrogol, 2% by weight of titanium oxide and 0.5% by weight of talc were dissolved or dispersed in 90% by weight of purified water to prepare a coating solution.

Next, 5.0 kg of the uncoated tablets prepared in Example 1 were put into a coating machine (PAREX, 0 (: -500 type)) and preliminarily dried for 10 minutes at a set air supply temperature of 55. The tablet temperature was 51. Then, at the set air supply temperature of 53 ° C, the spray amount of the spray liquid was sprayed at 6 mgZ minutes until 60 minutes later, and then sprayed at 12 mgZ minutes, and 2 1 Spraying was performed for 0 minutes, and the tablet temperature during this period was 45 to 49. After spraying, the air supply set temperature was set to 70, and post-drying was performed for 180 minutes. Was 73 ° C.

[Example 5]

The test was carried out using the uncoated tablet produced in Example 1 and the coating solution prepared in Example 4. 195.8 kg of the uncoated tablet prepared in Example 1 was put into a coating machine (HCF-150, manufactured by Freund Corporation). Preliminary drying was performed at a set air supply temperature of 70 for 9 minutes. The tablet temperature at the end of predrying was 52. Next, at the set air supply temperature of 58 to 80, the spraying amount of the spray liquid was 24 OmLZ minutes until 60 minutes later, 30 OmL / minute until 120 minutes later, and 36 OmLZ minutes thereafter. Sprayed and sprayed for 222 minutes. The tablet temperature during this period was 48-54. After the end of spraying, the air supply set temperature was set to 70, and post-drying was performed for 360 minutes. The tablet temperature at the end of post-drying was 75.

[Example 6]

The test was performed using the same uncoated tablet as in Example 1 and the coating liquid prepared in Example 4. 200,4 kg of uncoated tablets prepared according to Example 1 were charged into a coating machine (AQC-150F, manufactured by Freund Corporation). It was pre-dried for 18 minutes at a set air supply temperature of 50-75. The tablet temperature at the end of the preliminary drying was 42 t :. Next, at the set air supply temperature of 57 to 75, the spray amount of the spray liquid was 32 OmLZ minutes until 60 minutes later, and 40 OmL / minute until 120 minutes thereafter. Spray at 48 OmL / min. Sprayed for 80 minutes. The tablet temperature during this time was 42-48. After the spraying, the set air supply temperature was set at 70, and post-drying was performed for 120 minutes. The tablet temperature at the end of post-drying was 68.

[Comparative Example 1]

The test was carried out using the uncoated tablet produced in Example 1 and the coating solution prepared in Example 4. 5.0 kg of the uncoated tablet prepared in Example 1 was charged into a coating machine (PARC, DRC-500 type). Preliminary drying was performed at an air supply set temperature of 70 for 105 minutes. The tablet temperature at the end of predrying was 72. Next, at the set air supply temperature of 55 to 60, spray the spray liquid at 6 mg Z minutes until 30 minutes later, spray at 12 mg Z minutes thereafter, and spray for 170 minutes. went. The tablet temperature during this period was 44-65. After the spraying, the air supply set temperature was set at 70 and post-drying was performed for 60 minutes. The tablet temperature after the post-drying was 68.

[Test Example 3]

The surface smoothness of the coated tablets manufactured in Examples 4 and 5 and Comparative Example 1 was compared by visual observation. Table 1 shows the results. Examples of photographs of each tablet are shown in FIGS.

In addition, a significant difference in Ra (arithmetic mean roughness) was confirmed between the tablets determined to be good and those determined to be poor by visual observation. In addition, Ra (arithmetic mean roughness) can be measured by image analysis using a scanning laser microscope or a commercially available device such as a surface roughness measuring device.

[table 1 ]

[Industrial applicability]

As is clear from the above test examples, the production method of the present invention solves the problems of the prior art, has excellent tablet surface smoothness that could not be provided conventionally, has a uniform coating, and has a hygroscopic property. Providing coated tablets based on polymers It is possible.

Further, as in the present invention, the uncoated tablet containing 50% or more of the hygroscopic polymer is preliminarily subjected to the condition that the thermal expansion ability is not completely lost (that is, the condition that at least a part of the uncoated tablet has the thermal expansion ability). A new and unique manufacturing method that repairs the rough surface of the tablet that occurred at the beginning of coating by heating and then thermally expanding the heated tablet with or after applying the coating liquid. It is a very useful and useful tool that opens a new perspective in tablet manufacturing.

Claims

The scope of the claims

1. Pre-heat a plain tablet containing 50% by weight or more of a hygroscopic polymer under the condition that its thermal expansion capacity is not completely lost, and then apply the coating solution or after applying the coating solution. A method for producing a coated tablet containing a hygroscopic polymer as a main component, wherein the surface shape of the tablet is restored by maintaining the tablet under conditions that allow it to expand sufficiently.

2. The method according to claim 1, wherein the coated tablet is a film-coated tablet.

3. The method according to claim 1, wherein the uncoated tablet has a water content of 10% by weight or less.

4. The production method according to any one of claims 1 to 3, wherein the unabsorbed tablet contains 70% by weight or more of the hygroscopic polymer.

5. The method according to claim 1, wherein the hygroscopic polymer is a polyallylamine-based polymer.

6. The production method according to any one of claims 1 to 5, wherein the hygroscopic polymer is a polymer obtained by crosslinking and polymerizing polyallylamine with epichlorohydrin.

7. Coating tablets obtained by the production method according to any one of claims 1 to 6.