JP2018184360A - Enteric-coated sustained release formulation for oral administration - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an enteric-coated sustained release pharmaceutical composition capable of both suppression of release in the stomach and long-term sigmoid-type zero-order release in the intestinal tract with a simple configuration. SOLUTION: The enteric sustained release preparation for oral administration contains an uncoated tablet containing a drug and a water-absorbing swelling gelling agent, and an uncoated tablet containing ethyl cellulose and / or acetyl cellulose and an enteric coating agent. A film to be coated is provided with a coating film. In the film, the relationship between the weight ratio of the content of ethyl cellulose and / or acetyl cellulose and the enteric film agent and the amount of the film per 1.5 cm2 of the surface area of the uncoated tablet is surrounded by points a to n shown in FIG. Within the area of [Selection diagram] Fig. 1

Description

  The present invention relates to an enteric sustained-release preparation for oral administration.

  In order to improve patient compliance and enhance the therapeutic effect, attempts to formulate the drug as a sustained-release preparation, reduce the number of doses and reduce the burden on the patient are important issues, and effective sustained release of the drug Development of pharmaceutical technology to make it effective, and development of pharmaceutical technology to maintain an effective blood concentration without side effects for a long time are required. The most ideal release to achieve such sustained release is a drug release mode (zero order type dissolution mode) that releases the drug at a uniform rate regardless of the drug concentration in the dosage form. Such an ideal zero-order type drug release method makes it possible to keep the drug concentration in the tissue constant, and as a result, it is possible to maintain the blood drug concentration in the safe region. In particular, the effect is exerted to the maximum extent in a drug in which a side effect appears at a concentration that can be achieved by medication. In addition, since the effect is sustained, it leads to a decrease in the number of doses.

  Many sustained-release preparations have been developed and commercialized, but there are few examples that show the 0th order in the drug release from the drug. As an example of achieving zero-order release in a normal sustained-release preparation, the Geomatrix system made into a multilayer tablet by combining an active layer made of a drug and a water-soluble gelling agent and a support platform layer for controlling the diffusion of the drug And tablets manufactured by coating at least one selected from ethyl cellulose and acetyl cellulose on tablets prepared by mixing a water-absorbing swellable gelling agent and a drug (Patent Documents 1 and 2) There exists patent document 3).

  In addition, as a special sustained release example, regarding drugs that cause the side effect of orthostatic hypotension caused by rapid rise in plasma concentration and drugs that are likely to develop nausea after oral administration, Enteric sustained-release preparations have been developed that sufficiently control drug release and gradually release the drug while avoiding rapid drug release over 5 to 6 hours or more after administration. The enteric sustained-release preparation developed for the purpose of preventing orthostatic hypotension is Harnal D Tablets (Tamsulosin Hydrochloride; Astellas Pharma Inc.), which was developed for the purpose of preventing nausea after oral administration. Is a Paxil CR tablet (paroxetine hydrochloride hydrate preparation; GlaxoSmithKline).

  Harnal D tablet is formulated by solidifying tamsulosin hydrochloride-containing enteric sustained-release fine particles produced by a fine particle coating method (see Patent Document 4) by a low pressure tablet humidification drying method (see Patent Document 5). It is an orally disintegrating tablet manufactured using a technique. In addition, as presented in Example 1 of Patent Document 4, this drug has an elution value of 2% or less in the Japanese Pharmacopoeia dissolution test first solution (pH 1.2 hydrochloric acid buffer) of 10% or less, It is an enteric preparation that is gradually released over 6 hours or more in the second solution of the Japanese Pharmacopoeia Dissolution Test (pH 6.8 phosphate buffer).

  Paxil CR tablets are tableted in a sophisticated and complex way by coating the enteric coating on tablets containing paroxetine hydrochloride hydrate produced by Geomatix system, and zero-order release in the intestinal tract Is an ideal sustained release tablet (see Patent Document 6).

U.S. Pat. No. 4,839,177 US Pat. No. 5,422,123 Japanese Patent No. 2861388 International Publication No. WO2004 / 066991 Japanese Patent No. 4019374 Japanese Patent No. 3922392

  However, the preparation methods described in Patent Documents 1 to 6 are all complicated in production methods.

  As for Harnal D tablet, as described in Patent Document 4, tamsulosin hydrochloride-containing enteric sustained-release fine particles produced by the fine particle coating method were used in the low pressure tableting humidification drying method described in Patent Document 5. The solidification method is adopted, and there are problems such as requiring advanced manufacturing techniques and taking a long time for manufacturing.

  In addition, the uncoated tablet produced by the Geomatrix system required for Paxil CR tablets is a combination of an active layer made of a drug and a water-soluble gelling agent and a support platform layer that controls the diffusion of the drug, It is necessary to make it into a very elaborate tablet, such as a tablet with a special tableting machine in the shape of a three-layer tablet. Furthermore, it is necessary to make the supporting platform layer not containing the drug as thick as the drug-containing layer, which inevitably increases the size of the tablet.

  In this way, enteric sustained-release preparations exhibit special drug release such as controlled release in the stomach and delayed sustained release in the intestinal tract, and have demonstrated excellent medical use. In order to achieve this, the adoption of complicated and laborious formulation methods has become absolute, and establishment of a method for formulating enteric sustained-release tablets that are zero-order released over a long period of time is required. It has been.

  Therefore, an object of the present invention is to provide an enteric sustained-release pharmaceutical composition capable of achieving both suppression of release in the stomach and sigmoid zero-order release over a long period of time in the intestinal tract with a simple configuration. Is to provide.

  The enteric sustained-release preparation hardly dissolves for at least 2 hours in the test solution corresponding to the pH in the stomach (pH 1.2) (the gastric residence time of enteric tablets in the Japanese Pharmacopoeia is assumed to be 2 hours). The drug is slowly released over several hours with a test solution (pH 6.8) corresponding to the pH in the intestinal tract. In the most ideal enteric-release sustained-release preparation, the drug is zero-order released over a long period of time, for example, 12 hours or longer, using a test solution in the intestinal tract.

  As described above, enteric sustained-release tablets currently on the market include Harnal D tablets, which are orally disintegrating tablets obtained by tableting enteric sustained-release fine particles produced by a fine particle coating method by low pressure molding humidification drying method, and Geomatrix. There is a Paxil CR tablet which is a tablet manufactured by a method of coating an enteric coating on a sustained release uncoated tablet produced by the system. Paxyl CR tablet is the only preparation that can achieve zero-order release over a long period of time in a test solution similar to the intestinal tract.

  The present inventors have prepared an enteric preparation listed in the Japanese Pharmacopoeia General Test Method Formulation Test Method for Paxil CR Tablets 25 mg (lot number: 12001) containing 28.51 mg as paroxetine hydrochloride hydrate (25 mg as paroxetine). In accordance with the dissolution test method, the dissolution test was performed at 50 rpm with the paddle method using the dissolution test first solution (pH 1.2) and dissolution test solution 2 (pH 6.8). As shown in Table 1, at pH 1.2 corresponding to the pH in the stomach, it does not elute for at least 12 hours, and at pH 6.8 corresponding to the pH in the intestinal tract, the dissolution up to 2 hours is suppressed and it takes 12 hours or more. It was an enteric preparation that realized zero-order release of sigmoid type (FIG. 12).

  However, as described above, Paxil CR tablets need to be made into very elaborate tablets, or the tablets inevitably become large.

  Therefore, as a result of intensive studies on a method for producing enteric sustained-release tablets that are more easily zero-order released by the present inventors, ethyl cellulose and an uncoated tablet prepared by mixing a water-absorbing swelling gelling agent and a drug are used. Slow release to prevent drug release in the first liquid and to release the drug in sigmoidal form in zero order over a long period of time by coating a film that is a mixture of acetylcellulose and enteric film. The present inventors have found that a tablet can be produced and completed the present invention.

  Specifically, the mixing ratio of ethyl cellulose and / or acetyl cellulose and the enteric film agent in the film, and the degree of release control with the test solution corresponding to the pH in the stomach, where the coating amount of the uncoated tablet is the coating amount. It was found that the drug release rate in the test solution corresponding to the pH in the intestinal tract was greatly affected, and in the course of the research, the drug release protection in the test solution corresponding to the pH in the stomach and the intestinal tract It was possible to find a method for producing a tablet having both zero-order release of the drug in the test solution corresponding to pH.

  By the way, Patent Document 3 describes a tablet in which at least one selected from ethyl cellulose and acetyl cellulose is coated on a tablet prepared by mixing a water-absorbing swelling gelling agent and a drug. However, as shown in Example 2, Example 6 and Example 7 of Patent Document 3, this tablet has 0 release at the same release rate in test solutions having different pH such as the first liquid, water, and second liquid. It is a formulation that realizes the next release. Patent Document 3 does not describe any drug release control taking into account the pH dependence from tablets, such as making it enteric.

  In addition, the tablet described in Patent Document 3 is special in the longitudinal direction as shown in FIG. 2 of Patent Document 3 while the coating film is fixed on the R surface of the tablet by water penetrating into the uncoated tablet. It is designed to swell the tablet into a proper shape and release the drug from the side, thereby realizing zero-order drug release. Therefore, it is an absolute condition that the film does not dissolve in the digestive fluid or the like but remains attached to the R surface of the tablet to swell the tablet into the shape shown in FIG. In addition, the tablet described in Patent Document 3 is a formulation in which the event occurs in the same way in solutions having different pH such as a test solution corresponding to the pH in the stomach and a test solution corresponding to the pH in the intestinal tract. It is. Therefore, in solutions with different pH such as a test solution corresponding to the pH in the stomach and a test solution corresponding to the pH in the intestinal tract, in some solutions, water intrusion and tablet swelling are completely prevented to suppress drug release, In addition, it is impossible to develop an event such as entericity that causes the tablet to swell into a special shape and achieve zero-order release with a certain solution.

  Originally, in the case of a water-absorbing swelling tablet in which a water-absorbing swelling uncoated tablet is coated with a semi-permeable membrane such as ethyl cellulose or acetyl cellulose which is insoluble in water and digestive fluid, the semi-permeable membrane has a different pH. Since various test liquids have the property of allowing tablets to swell by passing at the same speed, some liquids do not allow water to pass through, and tablets do not swell, and some liquids swell well through water to achieve zero-order release. It is not possible to realize the phenomenon of

  Accordingly, the present inventors did not dissolve in the dissolution test first solution (pH 1.2) for 2 hours by the tableting method in which the water-absorbing swelling uncoated tablet was coated with a film that maintained semipermeable membrane properties. An energetic study was conducted on a method for producing an enteric sustained-release tablet that releases sigmoid type zero order over a long period of time with two liquids.

  The specific development target preparation was a preparation having dissolution characteristics equivalent to those of Paxil CR tablets containing paroxetine hydrochloride hydrate, and the dissolution characteristics in the second solution of dissolution test were determined as follows. If the dissolution characteristics are measured in accordance with the bioequivalence test guidelines for generic drugs (oral sustained release preparations) and the average dissolution rate of the standard preparation reaches 80% or more at the specified test time, the average dissolution rate is 80%. When the average dissolution rate of the test formulation is within the range of ± 15% of the standard formulation at a nearby time point, the dissolution behavior of the standard formulation and the test formulation is judged to be similar. With regard to this preparation having an average dissolution rate of 12% in two liquids of 81%, a sustained release tablet in which 66% to 96% of the sigmoidal zero-order sustained release after 12 hours was used as a development target preparation. In the Japanese Pharmacopoeia, enteric tablets are allowed within an average dissolution rate of 2% in the first solution up to 10% in consideration of the residence time of the tablets in the stomach. Since it is a principle that it does not elute in the stomach, in this study, 5% was more strictly set as an acceptable range. In addition, it is a sigmoid-released enteric sustained-release tablet that was developed for the purpose of suppressing initial dissolution in the stomach, with the expectation of reducing gastrointestinal symptoms such as nausea at the beginning of administration. Even in the case of the second liquid, it is necessary to avoid that the average dissolution rate over 2 hours exceeds 10% in consideration of the gastric residence time of 2 hours in an acid-free person. From these facts, the development target formulation has 5% or less of elution after 2 hours in the first liquid, and in the second liquid, the value for 2 hours is 10% or less and is 12 hours or longer. A sustained-release tablet having sigmoid-type dissolution characteristics was obtained.

  As a result of various studies, drug release after 2 hours in the first solution (pH 1.2) corresponding to the gastric residence time is 5% or less, and over 12 hours in the second solution (pH 6.8). Sigmoid type zero-release sustained-release tablets are produced by coating a plain tablet made by mixing a water-absorbing swelling gelling agent and a drug with a mixed film agent of ethyl cellulose and / or acetyl cellulose and an enteric film agent. I found out that I can do it.

As described above, it is not easy to impart pH dependency of entericity to drug release from a sustained-release tablet produced by a method of coating a water-swellable plain tablet with a semipermeable membrane, but ethyl cellulose and / or Coating ratio of acetylcellulose and enteric coating agent in the range of 1: 0.5 to 1: 6 (ethylcellulose content is 66.6 to 14.2%) and tablet surface area is 1.5 cm ² It was found that the desired sustained-release tablet can be produced by applying a film coating with an appropriate coating amount in the range of 3 mg to 50 mg.

  By doing so, even if the film in which ethylcellulose is in a slightly porous state after the enteric coating agent has dissolved, it remains firmly adhered to the tablet R surface to achieve zero-order release. I understood.

  Based on the above knowledge, the enteric sustained-release preparation for oral administration of the present invention is constituted as follows.

An enteric sustained-release preparation for oral administration according to the present invention comprises an uncoated tablet containing a drug and a water-swellable gelling agent, ethylcellulose and / or acetylcellulose and an enteric coating agent. And a film coating film to be coated. In the film, the weight ratio of the contents of ethyl cellulose and / or acetyl cellulose and the enteric film agent and the amount of the film per 1.5 cm ² of the surface area of the uncoated tablet are in the range surrounded by points an in FIG. Is within.

In other words, the weight ratio of the content of ethylcellulose and / or acetylcellulose and the enteric coating agent is taken as the value on the X-axis, and the amount of the coating per 1.5 cm ² of the surface area of the uncoated tablet (or “coating amount”). .) Is a value on the Y axis, the enteric sustained-release preparation for oral administration according to the present invention comprises an uncoated tablet containing a drug and a water-swelling gelling agent, ethylcellulose and / or acetyl. A film coating film containing cellulose and an enteric coating agent to coat the uncoated tablet, wherein the weight ratio of the content of ethylcellulose and / or acetylcellulose and the enteric coating agent in the coating; The amount (mg) of the film per 5 cm ² means that (X, Y) is a (1: 7, 30), b (1: 6, 20), c (1: 4, 10) shown in FIG. d (1: 2, 7), (1: 1,3), f (1: 0.5,3), g (1: 0.4,3), h (1: 0.4,10), i (1: 0.5,15) ), J (1: 1, 25), k (1: 2, 27), l (1: 4, 45), m (1: 6, 50), n (1: 7, 50) Within the specified range (excluding values on the boundary).

In the enteric sustained-release preparation according to the present invention, the weight ratio (X) of the content of ethylcellulose and / or acetylcellulose and the enteric coating agent in the film and the surface area of 1.5 cm ² of the surface area of the uncoated tablet. The amount of film (Y) (mg) means that (X, Y) is A (1: 6, 30), B (1: 4, 20), C (1: 2, 7.5) shown in FIG. , D (1: 1, 4), E (1: 0.5, 4), F (1: 0.5, 10), G (1: 1, 20), H (1: 2, 25), It is preferably within the range surrounded by the points I (1: 4, 40) and J (1: 6, 40) (however, the values on the boundary line are included).

  In the enteric sustained-release preparation according to the present invention, the water-swellable gelling agent is sodium carboxymethylcellulose, polyethylene oxide, sodium alginate, carrageenan, guar gum, gum arabic, tara gum, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose. , Hydroxyethyl cellulose, carboxyvinyl polymer, locust bean gum, collagen, casein, and agar.

  In the enteric sustained-release preparation according to the present invention, the water-absorbing and swelling gelling agent is preferably contained in the uncoated tablet in an amount of 10% by weight or more.

  In the enteric sustained-release preparation according to the present invention, the enteric coating agent preferably contains at least one of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and methacrylic acid copolymer L. .

  In the enteric sustained-release preparation according to the present invention, the film preferably contains a plasticizer.

  In the enteric sustained-release preparation according to the present invention, the plasticizer preferably contains at least one of polyethylene glycol, triethyl citrate, diethyl phthalate, dibutyl phthalate, castor oil, glycerin, and propylene glycol.

  According to the present invention, enteric sustained release for oral administration capable of achieving both suppression of release in the stomach and sigmoid type zero-order sustained release over a long period of time in the intestinal tract with a simple configuration. A pharmaceutical composition can be provided.

It is a figure which shows the relationship between the weight ratio of content of ethyl cellulose and / or acetylcellulose, and an enteric coating agent in a film | membrane, and the quantity of the said film | membrane per surface area of 1.5 cm < ² > of the said uncoated tablet. It is a figure which shows the result of the elution test in Example 1A-C and pH 6.8 (Comparative Example 1A is pH 6.9) of Comparative Example 1A. It is a figure which shows the result of the elution test in pH1.2 and pH6.8 of comparative example 1B. It is a figure which shows the result of the elution test in pH1.2 and pH6.8 of comparative example 1C. It is a figure which shows the result of the elution test in Example 2A, B and the comparative example 2 in pH6.8. It is a figure which shows the result of the elution test in pH 6.8 of Example 3A-C. It is a figure which shows the result of the elution test in pH 6.8 of Example 4A-C. It is a figure which shows the result of the elution test in pH 6.8 of the comparative example 3 and Example 5A-C. It is a figure which shows the result of the elution test in pH 6.8 of the comparative example 4 and Example 6A, B. It is a figure which shows the result of the elution test in pH6.8 of Example 7. It is a figure which shows the result of the elution test in pH 6.8 of Example 8. It is a figure which shows the result of the dissolution test in pH6.8 of Paxil CR tablet 25mg.

  Embodiments of the present invention will be described below.

  The enteric sustained-release preparation of the present invention can be produced as an uncoated tablet by an ordinary production method, and can be produced by an operation in which the uncoated tablet is usually sprayed and coated with a film coating solution. However, it is a film-coated tablet with a low manufacturing cost. The specific manufacturing method and the like will be described below.

An enteric sustained-release preparation for oral administration according to the present invention comprises an uncoated tablet containing a drug and a water-swellable gelling agent, ethylcellulose and / or acetylcellulose and an enteric coating agent. And a film coating film to be coated. In the film, the weight ratio of the content of ethyl cellulose and / or acetyl cellulose and the enteric film agent is 1: 0.5 to 1: 6, and the amount of the film per 1.5 cm ² surface area of the uncoated tablet is 3 mg to 50 mg.

An enteric sustained-release preparation for oral administration according to the present invention comprises an uncoated tablet containing a drug and a water-swellable gelling agent, ethylcellulose and / or acetylcellulose and an enteric coating agent. And a film coating film to be coated. In the film, the weight ratio of the contents of ethyl cellulose and / or acetyl cellulose and the enteric film agent and the amount of the film per 1.5 cm ² of the surface area of the uncoated tablet are in the range surrounded by points an in FIG. Is within.

In other words, the weight ratio of the content of ethylcellulose and / or acetylcellulose and the enteric coating agent is taken as the value on the X-axis, and the amount of the coating per 1.5 cm ² of the surface area of the uncoated tablet (or “coating amount”). .) Is a value on the Y axis, the enteric sustained-release preparation for oral administration according to the present invention comprises an uncoated tablet containing a drug and a water-swelling gelling agent, ethylcellulose and / or acetyl. A film coating film containing cellulose and an enteric coating agent to coat the uncoated tablet, wherein the weight ratio of the content of ethylcellulose and / or acetylcellulose and the enteric coating agent in the coating; The amount (mg) of the film per 5 cm ² means that (X, Y) is a (1: 7, 30), b (1: 6, 20), c (1: 4, 10) shown in FIG. d (1: 2, 7), (1: 1,3), f (1: 0.5,3), g (1: 0.4,3), h (1: 0.4,10), i (1: 0.5,15) ), J (1: 1, 25), k (1: 2, 27), l (1: 4, 45), m (1: 6, 50), n (1: 7, 50) Within the specified range (excluding values on the boundary).

In the enteric sustained-release preparation according to the present invention, the weight ratio (X) of the content of ethylcellulose and / or acetylcellulose and the enteric coating agent in the film and the surface area of 1.5 cm ² of the surface area of the uncoated tablet. The amount of film (Y) (mg) means that (X, Y) is A (1: 6, 30), B (1: 4, 20), C (1: 2, 7.5) shown in FIG. , D (1: 1, 4), E (1: 0.5, 4), F (1: 0.5, 10), G (1: 1, 20), H (1: 2, 25), It is preferably within the range surrounded by the points I (1: 4, 40) and J (1: 6, 40) (however, the values on the boundary line are included).

  As the water-absorbing swelling gelling agent used for uncoated tablets, sodium carboxymethylcellulose, polyethylene oxide, sodium alginate, carrageenan, guar gum, gum arabic, tara gum, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, carboxyvinyl polymer, There are locust bean gum, collagen, casein, agar, etc., and these can be used alone or in combination. The blending amount of the gelling agent depends on the nature of the drug to be applied, the type of gelling agent to be used and other additives to be blended, but is generally 10% by weight or more, preferably 20% per uncoated tablet. It is preferable to mix and use at least wt%.

  In addition, by devising the type and blending amount of the water-absorbing swelling gelling agent and properly blending and using excipients such as lactose and corn starch, which will be described later, in the second dissolution test solution (pH 6.8) It is possible to freely control the drug release rate from the uncoated tablet.

  As the film agent to be coated on the uncoated tablet, a film agent insoluble in water and digestive fluid and an enteric film agent are mixed and used. As a film agent insoluble in water and digestive fluid, ethyl cellulose and acetyl cellulose can be used alone or in combination. As the enteric coating agent, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, methacrylic acid copolymer L and the like can be used alone or in combination. About a coating agent, it is made into a solution by either the method of melt | dissolving in the organic solvent or the liquid mixture of an organic solvent, and water, or the method of emulsifying-dispersing in water, and it uses for uncoated tablet coating.

  Ethyl cellulose is preferred as a film coating base insoluble in water and digestive fluids, and as an enteric coating agent, hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, methacrylic acid copolymer L and the like are used. It is preferable to select and blend so as to match the elution characteristics. Examples of the organic solvent include methylene chloride, isopropyl alcohol, ethanol, methanol and the like. Most preferred is ethanol, and water may be added up to about 30%. In the case of the film-coated tablet of this form, the method of dissolving the film coating base in an organic solvent is insoluble in water and digestive fluid, and compared with coating with an aqueous dispersion. A tough film that does not cause deformation such as swelling with a liquid can be formed.

  In addition, in the case of the enteric sustained-release preparation according to the present invention, it is of course important to ensure that the efficacy effect of the drug at the time of internal use is expressed without variation, and it is necessary to reduce the variation in dissolution of each tablet. For this purpose, it is important to uniformly coat the coating agent on the uncoated tablet and reduce the variation of the infiltration rate of water through the coating for each tablet. This coating agent and intestine which are insoluble in water and digestive fluid are important. It has been found that the object can be achieved by blending a plasticizer in a coating formulation containing a soluble coating agent. Examples of the plasticizer used include polyethylene glycol, triethyl citrate, diethyl phthalate, dibutyl phthalate, castor oil, glycerin, and propylene glycol, and any plasticizer may be used as long as it contributes to film forming properties.

  For the production of the enteric sustained-release preparation of the present invention, first, a water-swelling gelling agent and a drug, and if necessary, a preparation additive are mixed, and an uncoated tablet is produced by a wet method or a dry method. Next, film coating is performed with a film coating base obtained by dissolving a base mainly composed of a mixture of ethyl cellulose and / or acetyl cellulose and an enteric coating agent in an organic solvent.

  Film coating of the enteric sustained-release preparation of the present invention is usually performed by a conventional coating pan method, and the coating method is preferably a spray method, and may be either an automatic method or a manual method.

  The coating amount of the film is an important component in the enteric sustained-release preparation of the present invention. If the coating amount is too small and the film is too thin, the film is weak and easily peeled off, and it is difficult to control elution with the test solution corresponding to the pH in the stomach. It is difficult to control elution with the test solution corresponding to the intestinal tract. There are problems such as difficulty in obtaining swelling. Also, depending on the film formulation, if the coating amount increases and the film becomes too thick, the semi-permeable property of the film decreases, the initial elution lag time becomes longer, and the intended sustained release is inferior. There is a problem that the desired swelling is difficult to be obtained, and it is the present invention that has solved these problems. The thickness of the film can be easily measured by comparing the thickness of the tablet before film coating and the thickness of the side of the tablet after film coating, and either a manual thickness measuring machine or an automatic thickness measuring machine can be used as the thickness measuring device. It can be used.

  The uncoated tablet of the present invention includes conventionally used excipients such as lactose, corn starch and crystalline cellulose, lubricants such as magnesium stearate and talc, starches, sucrose, gelatin and gum arabic powder. Binders such as methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, copolyvidone, polyvinyl alcohol / polyethylene glycol graft copolymer, carmellose calcium, carmellose, low substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, etc. Disintegrants, other colorants, flavoring agents, adsorbents, preservatives, wetting agents, antistatic agents and the like can be freely blended.

  The technology according to the present invention is not limited to the water-solubility and poor water-solubility of the main drug by selectively blending the gelling agent and selectively blending the appropriate formulation additive that contributes to solubility. Since a tablet having an arbitrary dissolution rate can be produced, application to various drugs is possible if it is a zero-order release enteric sustained-release tablet.

  In addition, the enteric sustained-release preparation of the present invention can be produced if there is an ordinary wet stirring granulator, fluidized bed granulator / dryer, box dryer, sieving device, tableting machine, pan coating device, etc. It is also a great merit that the manufacturing process is simple and no special device is required, and it is ideal as an enteric sustained-release preparation.

  The tablet according to the present invention is prepared by mixing a water-swelling gelling agent and a drug to produce tableting particles by an ordinary wet method or a dry method, and using these particles, It can be produced by coating a tablet with a film obtained by mixing ethyl cellulose and / or acetyl cellulose and an enteric coating agent by a usual film coating method. Thus, it is an enteric zero-order release formulation that can be produced by a very simple formulation method, and its utility value is high.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these.

  The drug substance used in the experiment is as follows. Polyvinylpyrrolidone (PVP-K30, BASF Japan Ltd.), hypromellose (trade name: Metroles 60SH50, Shin-Etsu Chemical), hypromellose (trade name: TC-5R, Shin-Etsu Chemical), magnesium stearate (Taihei Chemical Industry), ethyl cellulose (Etocel) STD7, Dow Chemical), hypromellose phthalate (HP-55, Shin-Etsu Chemical), hypromellose acetate succinate (AQOAT AS-LF, Shin-Etsu Chemical), Macrogol 6000 (Nippon Yushi), castor oil (Kosuge) Pharmaceutical), triethyl citrate (Morimura Corporation)

(Experimental example 1)
27 g of PVP-K30 was taken and dissolved in a mixed solution of 121.5 g of purified water and 121.5 g of absolute ethanol to prepare a povidone solution. 171.06 g of paroxetine hydrochloride hydrate, 348.72 g of Metroze 60SH50 and 348.72 g of TC-5R were mixed and lightly mixed. The solution is sprayed, granulated, dried and sized with 18 mesh. 4.5 g of magnesium stearate is added to the sized powder and mixed, and a plain tablet with a diameter of 4 mm and a tablet surface area of 1.5 cm ² is manufactured with a weight of 7.5 mg and a weight of 8.5 R, each tablet 150 mg. (Contains 25 mg paroxetine in one tablet: 28.51 mg as paroxetine hydrochloride hydrate).

  Next, a coating solution of 900 g for a, 360 g for b, and 1080 g for c was prepared according to the formulation shown in Table 2. 210 g of uncoated tablets were charged into a breathable coating apparatus (Dria Coater DRC-200, Powrec), and three types of film-coated tablets were produced using the required amounts of each coating solution. About coating by prescription a, it sampled when it became the film amount of 10 mg, 15 mg, and 20 mg in the middle of coating operation, and made the final coating amount of 25 mg (10 mg coated product is Example 1A, 15 mg coated product is an example. The 1B and 20 mg coated products were Example 1C, and the 25 mg coated product was Comparative Example 1A). Regarding the coating by the prescription b, only one level of the coating amount of 10 mg was set as Comparative Example 1B. Moreover, regarding the coating by the prescription c, the coating amount was only one level of 30 mg, and this was designated as Comparative Example 1C.

  About these various samples, the elution test was implemented by the paddle method 50rpm using the elution test 1st liquid and the elution test 2nd liquid, and the result was shown in Table 3 and FIGS.

The tablet with a coating amount of 10 mg shown in Example 1C has controlled drug release in the first liquid, and the drug can efficiently achieve a sigmoidal zero-order release over 12 hours in the second liquid. As a result, it was suggested that there is a possibility that the coating amount is less than this amount. In addition, it was found that the tablet of Comparative Example 1A having a coating amount of 25 mg has a decreased release rate with the second liquid and the 12-hour value is unsuitable. From data such as Example 1C and Comparative Example 1A, it is suggested that for this example where Etocel 7: HP-55 is 1: 1, the appropriate coverage for tablets with a tablet surface area of 1.5 cm ² is less than 25 mg. It was done.

  Moreover, in the case of the tablet of the coating film formulation of only etosel of Comparative Example 1B, both the first liquid and the second liquid showed the same elution. Therefore, the principle is not to dissolve in the stomach, that is, a true enteric sustained-release tablet that does not dissolve in the first dissolution test and exhibits significant sustained release only in the second dissolution test cannot be made. I understood. In the case of a tablet having a coating film formulation containing only the enteric coating agent (HP-55) of Comparative Example 1C, the release amount of the second liquid over 2 hours exceeds 10%, and the sigmoidal type sustained release tablet with a clean dissolution pattern is I found out I couldn't get it.

(Experimental example 2)
22.5 g of PVP-K30 is taken and dissolved in a mixed solution of 101.25 g of purified water and 101.25 g of absolute ethanol to prepare a povidone solution. 142.55 g of paroxetine hydrochloride hydrate, 290.6 g of Metrose 60SH50 and 290.6 g of TC-5R were mixed and lightly mixed. The solution is sprayed, granulated, dried and sized with 18 mesh. Two batches of sized powder were produced and mixed, and then 7.5 g of magnesium stearate was added and mixed. The weight of each tablet was 150 mg using a 7.5 mm diameter, 8.5R punch, thickness 4 mm, tablet surface area A 1.5 cm ² uncoated tablet was prepared (containing 25 mg of paroxetine in one tablet: 28.51 mg as paroxetine hydrochloride hydrate).

  Next, 540 g of a coating solution is prepared according to the formulation shown in Table 4. 210 g of uncoated tablets were charged into a breathable coating apparatus (Dria Coater DRC-200, Powrec), and a film coating of 15 mg per tablet was applied using the required amount of coating solution. During the coating operation, sampling was performed when the film amounts reached 4 mg and 10 mg. The 4 mg and 10 mg coated products were Examples 2A and 2B, respectively, and the 15 mg coated product was Comparative Example 2.

  About these 3 types of samples, the elution test was implemented by the paddle method 50rpm using the elution test 1st liquid and the elution test 2nd liquid, and the result was shown in Table 5 and FIG.

From the results of Example 2A, in the case of this film formulation, the coating amount is 4 mg, the amount of elution for 2 hours in the first liquid can be suppressed to 5% or less, and the desired sigmoid type zero-order release can be achieved. confirmed. From this result, it was suggested that if the coating amount is more than 3 mg, the elution at pH 1.2 can achieve 5% or less and the elution at pH 6.8 can be adapted. Moreover, from the results of Example 2B and Comparative Example 2, it was suggested that if the coating amount exceeds 12 mg, the release rate in the second liquid is decreased and the 12-hour value becomes unsuitable. Therefore, in the case of this example in which Etocel 7: HP-55 is 1: 0.5, an appropriate coating amount for a tablet having a tablet surface area of 1.5 cm ² is more than 3 mg and less than 15 mg, preferably 4 mg or more and 12 mg or less, More preferably, it was found to be 4 mg or more and 10 mg or less. In addition, from the results of Example 2, if Etocel 7: HP-55 is 1: 0.4, it is considered that the appropriate coating amount for tablets with a tablet surface area of 1.5 cm ² is more than 3 mg and less than 10 mg. It is done.

(Experimental example 3)
720 g of coating solution is prepared according to the formulation shown in Table 6. 210 g of the uncoated tablet produced in Experimental Example 2 was charged into a breathable coating apparatus (Dria Coater DRC-200, POWREC), and a film coating of 20 mg per tablet was applied using the required amount of coating solution. During the coating operation, sampling was performed when the film amounts reached 4 mg and 10 mg. The 4 mg, 10 mg, and 20 mg coated articles were designated as Example 3A, Example 3B, and Example 3C, respectively.

  For these three types of samples, the dissolution test was performed at 50 rpm using the first dissolution test and the second dissolution test, and the results are shown in Table 7 and FIG.

As shown in Example 3A, in the case of this film, it was found that the release of the first liquid can be controlled even when the film amount is 4 mg, and the sigmoid zero-order release in the second liquid can be achieved. From this result, it was suggested that if the coating amount is more than 3 mg, the elution at pH 1.2 can achieve 5% or less and the elution at pH 6.8 can be adapted. Further, from the results of the 12-hour elution amounts of Example 3B and Example 3C, the release of the first liquid can be controlled if the coating amount is less than 25 mg, preferably 22 mg or less, and the sigmoid type zero-order release in the second liquid It was suggested that can be achieved. Therefore, in the case of this example in which Etocel 7: HP-55 is 1: 1, an appropriate coating amount for a tablet having a tablet surface area of 1.5 cm ² is more than 3 mg and less than 25 mg, more preferably 4 mg or more and 22 mg or less, and further preferably Was found to be 4 mg or more and 20 mg or less.

(Experimental example 4)
900 g of coating solution is prepared according to the formulation shown in Table 8. 210 g of the uncoated tablets produced in Experimental Example 2 were charged into an air-permeable coating apparatus (Dria Coater DRC-200, POWREC), and a film coating of 25 mg per tablet was performed using the required amount of coating solution. In the course of the coating operation, sampling was performed when the coating amounts reached 7.5 mg and 20 mg. The 7.5 mg and 20 mg coated articles were designated as Example 4A and Example 4B, respectively, and the 25 mg coated article was designated as Example 4C.

  About these 3 types of samples, the elution test was carried out by the paddle method 50 rpm using the elution test 1st liquid and the elution test 2nd liquid, and the result was shown in Table 9 and FIG.

From Example 4A, it was found that when the film amount was 7.5 mg, the release control for 2 hours in the first liquid could be sufficiently controlled, and the sigmoid type zero-order release in the second liquid could be achieved. From this result, it was suggested that if the coating amount is more than 7 mg, the elution at pH 1.2 can achieve 5% or less and the elution at pH 6.8 can be adapted. Moreover, it was suggested from the result of the 12-hour elution amount of Example 4B and Example 4C that the coating amount is preferably about 27 mg or less. Therefore, in the case of this example where Etocel 7: HP-55 is 1: 2, the appropriate coverage for tablets with a tablet surface area of 1.5 cm ² is more than 7 mg and less than 27 mg, preferably 7.5 mg or more and 25 mg or less. I understood it.

(Experimental example 5)
1440 g of coating solution is prepared according to the formulation shown in Table 10. 210 g of the uncoated tablets produced in Experimental Example 2 were charged into an air-permeable coating apparatus (Dria Coater DRC-200, POWREC), and a film coating of 40 mg per tablet was applied using the required amount of coating solution. In the course of the coating operation, sampling was performed when the film amounts reached 10 mg, 20 mg, and 30 mg. The 10 mg coated product was designated as Comparative Example 3, 20 mg, 30 mg and 40 mg coated product as Example 5A, Example 5B and Example 5C, respectively.

  About these 4 types of samples, the elution test was carried out by the paddle method 50 rpm using the elution test 1st liquid and the elution test 2nd liquid, and the result was shown in Table 11 and FIG.

  From the results of Comparative Example 3 and Example 5A, it was found that the release amount of the second liquid over 2 hours exceeded 10% and the sigmoid type zero-order release was not achieved when the amount of the film was less than 20 mg.

In addition, it was found that if the amount of the coating was increased as shown in Example 5A, Example 5B, and Example 5C, the target sigmoid type zero-order release was achieved, but this adhered to the tablet R surface. It is thought that the amount of remaining etcelle increases as the coating amount increases.
From the results of 12 hours of dissolution in pH 6.8 of Examples 5B and 5C, if the amount of coating is less than 45 mg, elution at pH 1.2 will be 5% or less, and pH 6.8 will be compatible. It has been suggested that Therefore, in the case of this example in which Etocel 7: HP-55 is 1: 4, an appropriate coating amount for a tablet having a tablet surface area of 1.5 cm ² is more than 10 mg and less than 45 mg, preferably 20 mg or more and 40 mg or less. all right.

(Experimental example 6)
1440 g of coating solution is prepared according to the formulation shown in Table 12. 210 g of the uncoated tablets produced in Experimental Example 2 were charged into an air-permeable coating apparatus (Dria Coater DRC-200, POWREC), and a film coating of 40 mg per tablet was applied using the required amount of coating solution. In the course of the coating operation, sampling was performed when the coating amount reached 20 mg and 30 mg. The 20 mg coated product was used as Comparative Example 4, 30 mg and 40 mg coated product as Example 6A and Example 6B.

  For these three types of samples, the dissolution test was performed at 50 rpm using the first dissolution test and the second dissolution test, and the results are shown in Table 13 and FIG.

  In the case of a tablet with a coating amount of 20 mg in Comparative Example 4, it was found that the amount of the second liquid released in 2 hours was large, and a clean sigmoid type zero-order release was not achieved. In addition, as shown in Example 6A and Example 6B, it can be seen that the target sigmoid type zero-order release is achieved if the coating amount is 30 mg or more, and if the coating amount is less than 50 mg, the pH is 1.2. It was suggested that the elution of 5% or less can be achieved and the pH 6.8 elution can be adapted.

From the results of Example 5 and Example 6, it can be seen that if the amount of the enteric coating agent increases, it becomes difficult to release a sigmoid type, while the coating amount increases even if the amount of the enteric coating agent increases. It has been found that if the film is increased and the film thickness is increased, sigmoid type zero-order release tends to occur. However, in order to swell the tablet into a specific shape, it is important that etosel remains attached to the R-side of the tablet, and it is necessary to add 15% or more of etose in the blending ratio with the enteric coating agent. is there. In addition, regarding the amount of film to be coated, if the film becomes too thick, there is a possibility that the time to start elution in a living body after administration may be delayed more than necessary, which is inferior in practicality and has a high production cost. Therefore, the coating amount of the film is preferably less than 50 mg as a coating amount for a tablet having a tablet surface area of 1.5 cm ² . Therefore, in the case of this example in which Etocel 7: HP-55 is 1: 6, an appropriate coating amount for a tablet having a tablet surface area of 1.5 cm ² is more than 20 mg and less than 50 mg, preferably 30 mg or more and 40 mg or less. I understood. Moreover, from the result of Example 6, if Etocel 7: HP-55 is 1: 7, it is considered that an appropriate coating amount for a tablet having a tablet surface area of 1.5 cm ² is more than 30 mg and less than 50 mg.

(Example 7)
An uncoated tablet was prepared in the weight of 150 mg per tablet by the same method as in Experimental Example 2. Etocel STD7 (18 g), AQOAT (AS-LF) (18 g), and Macrogol 6000 (4 g) were dissolved in a mixed solution of ethanol (544 g) and purified water (136 g) to prepare a coating solution. The uncoated tablet 210g was prepared to Doria coater DRC-200, and the coating liquid was spray-sprayed and 20 mg of film coating per tablet was performed. About this sample, the elution test was implemented by the paddle method 50rpm using the elution test 1st liquid and the elution test 2nd liquid, and the result was shown in Table 14 and FIG.

  It was found that the tablet of Example 7 can control the release of the first liquid and can achieve the sigmoid type zero-order release in the second liquid.

(Example 8)
71.275 g of paroxetine hydrochloride hydrate and 301.85 g of TC-5R were mixed and lightly mixed, and then charged into a spray-drying fluidized bed granulator (MP-01, Paulek). Spray, granulate, dry and size with 18 mesh. To the sized powder, 1.875 g of magnesium stearate was added and mixed to prepare tablets with a weight of 1 tablet 150 mg. Next, 14.4 g of etosel STD7, 21.6 g of HP-55 and 4 g of triethyl citrate were taken and dissolved in a mixed solution of 544 g of ethanol and 136 g of purified water to prepare a coating solution. The uncoated tablet 210g was prepared to Doria coater DRC-200, and the coating liquid was spray-sprayed and 20 mg of film coating per tablet was performed. The thickness of the coated film was about 100 μm.

  About this sample, the elution test was implemented by the paddle method 50rpm using the elution test 1st liquid and the elution test 2nd liquid, and the result was shown in Table 15 and FIG.

  The tablet of Example 8 was able to control the release of the first liquid over 12 hours, and it was found that the desired sigmoid type zero-order release could be achieved in the second liquid.

(Experimental example 9)
An uncoated tablet was prepared in the weight of 150 mg per tablet by the same method as in Experimental Example 2. In the formulation shown in Table 16, a coating solution of 900 g for formulation i and 895 g for formulation j was prepared. A doria coater DRC-200 was charged with 210 g of uncoated tablets, sprayed with a coating solution of formulation h and formulation i to give 20 mg film coating per tablet, and coated with formulation i in Example 9A and formulation j The coated product was designated as Example 9B.

  This sample was subjected to a dissolution test using the second solution of dissolution test at a paddle method of 50 rpm, and the dissolution rate and standard deviation (SD) are shown in Table 17.

  From this result, it was found that the film to which triethyl citrate was added as a plasticizer had less variation in elution, and it was preferable to add a plasticizer in the case of this single unit tablet.

  The present invention is summarized as follows.

(1) An enteric sustained-release preparation for oral administration according to the present invention comprises an uncoated tablet containing a drug and a water-swellable gelling agent, ethylcellulose and / or acetylcellulose and an enteric coating agent. A film coating film covering the uncoated tablet. In the film, the weight ratio of the contents of ethyl cellulose and / or acetyl cellulose and the enteric film agent and the amount of the film per 1.5 cm ² of the surface area of the uncoated tablet are in the range surrounded by points an in FIG. Is within.

In other words, the weight ratio of the content of ethyl cellulose and / or acetyl cellulose and the enteric coating agent is the value on the X-axis, and the amount of coating per 1.5 cm ² of the surface area of the uncoated tablet is the value on the Y-axis. For example, an enteric sustained-release preparation for oral administration according to the present invention comprises an uncoated tablet containing a drug and a water-swellable gelling agent, ethylcellulose and / or acetylcellulose and an enteric coating agent. A film coating film for coating the tablet, wherein in the film, the weight ratio of the content of ethyl cellulose and / or acetyl cellulose and the enteric film agent, and the amount of the film (mg) per 1.5 cm ² surface area of the uncoated tablet (X, Y) is a (1: 7,30), b (1: 6,20), c (1: 4,10), d (1: 2,7), e shown in FIG. (1: 1, 3), f (1: 0. , 3), g (1: 0.4, 3), h (1: 0.4, 10), i (1: 0.5, 15), j (1: 1, 25), k (1: 2, 27), l (1: 4, 45), m (1: 6, 50), and n (1: 7, 50). It is.

(2) In the enteric sustained-release preparation according to the present invention, the weight ratio (X) of the content of ethylcellulose and / or acetylcellulose and the enteric coating agent in the film, and the surface area of the plain tablet 1.5 cm The amount of film per ² (Y) (mg) means that (X, Y) is A (1: 6, 30), B (1: 4, 20), C (1: 2, 7) shown in FIG. .5), D (1: 1, 4), E (1: 0.5, 4), F (1: 0.5, 10), G (1: 1, 20), H (1: 2, 25), I (1: 4, 40), and J (1: 6, 40), preferably within a range (including values on the boundary line).

  (3) In the enteric sustained release preparation according to the present invention, the water-swellable gelling agent is sodium carboxymethylcellulose, polyethylene oxide, sodium alginate, carrageenan, guar gum, gum arabic, tara gum, hydroxypropyl methylcellulose, hydroxypropyl It preferably contains at least one of cellulose, methylcellulose, hydroxyethylcellulose carboxyvinyl polymer, locust bean gum, collagen, casein, and agar.

  (4) In the enteric sustained-release preparation according to the present invention, it is preferable that the water-absorbing swelling gelling agent is contained in the uncoated tablet in an amount of 10% by weight or more.

  (5) In the enteric sustained-release preparation according to the present invention, the enteric coating agent contains at least one of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and methacrylic acid copolymer L. It is preferable.

  (6) In the enteric sustained-release preparation according to the present invention, the film preferably contains a plasticizer.

  (7) In the enteric sustained-release preparation according to the present invention, the plasticizer may contain at least one of polyethylene glycol, triethyl citrate, diethyl phthalate, dibutyl phthalate, castor oil, glycerin, and propylene glycol. preferable.

  It should be considered that the embodiments and examples disclosed above are illustrative and non-restrictive in every respect. The scope of the present invention is defined by the terms of the claims, rather than the description above, and includes all modifications within the scope and meaning equivalent to the terms of the claims.

Claims (7)

An uncoated tablet containing a drug and a water-swellable gelling agent;
A film coating film comprising ethyl cellulose and / or acetyl cellulose and an enteric film agent for coating the uncoated tablet,
In the film, the weight ratio (X) of the content of ethyl cellulose and / or acetylcellulose and the enteric film agent and the amount of the film (Y) (mg) per 1.5 cm ² surface area of the uncoated tablet , (X, Y) are a (1: 7, 30), b (1: 6, 20), c (1: 4, 10), d (1: 2, 7), e (1) shown in FIG. : 1,3), f (1: 0.5,3), g (1: 0.4,3), h (1: 0.4,10), i (1: 0.5,15), Range surrounded by points j (1: 1, 25), k (1: 2, 27), l (1: 4, 45), m (1: 6, 50), n (1: 7, 50) An enteric sustained-release preparation that is within (but does not include values on the borderline). In the film, the weight ratio (X) of the content of ethyl cellulose and / or acetylcellulose and the enteric film agent and the amount of the film (Y) (mg) per 1.5 cm ² surface area of the uncoated tablet , (X, Y) are A (1: 6,30), B (1: 4,20), C (1: 2,7.5), D (1: 1,4), E shown in FIG. (1: 0.5,4), F (1: 0.5,10), G (1: 1,20), H (1: 2,25), I (1: 4,40), J ( The enteric sustained-release preparation according to claim 1, which is within a range surrounded by a point of 1: 6, 40) (however, a value on a boundary line is included).   The water-swellable gelling agent is sodium carboxymethylcellulose, polyethylene oxide, sodium alginate, carrageenan, guar gum, gum arabic, tara gum, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, carboxyvinyl polymer, locust bean gum, collagen The enteric sustained-release preparation according to claim 1 or 2, which contains at least one of, casein and agar.   The enteric sustained-release preparation according to any one of claims 1 to 3, wherein the water-swelling gelling agent is contained in the uncoated tablet in an amount of 10% by weight or more.   5. The enteric coating agent according to claim 1, comprising at least one of hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and methacrylic acid copolymer L. 6. Enteric sustained-release preparation.   The enteric sustained-release preparation according to any one of claims 1 to 5, wherein the film contains a plasticizer.   The enteric sustained-release preparation according to claim 6, wherein the plasticizer contains at least one of polyethylene glycol, triethyl citrate, diethyl phthalate, dibutyl phthalate, castor oil, glycerin, and propylene glycol.

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