JP2020075874A - Film-form pharmaceutical composition containing lubiprostone - Google Patents

Abstract

To provide film-form pharmaceutical compositions containing Lubiprostone, having excellent stability and content uniformity, easy ingestibility, and excellent handling convenience.SOLUTION: Provided is a film-like pharmaceutical composition that is a solid dispersion containing Lubiprostone or a pharmaceutically acceptable salt of Lubiprostone, or hydrate of Lubiprostone or a pharmaceutically acceptable salt of Lubiprostone, and a polymer compound. The polymer compound is a polymer compound in which a polymer compound having a glucose ring as a constitutional unit, a polymer compound obtained by addition-polymerizing a monomer having a vinyl group, or a polymer compound having a glucose ring as a constitutional unit or a polymer compound obtained by addition-polymerizing a monomer having a vinyl group has been chemically modified.SELECTED DRAWING: None

Description

  The present invention relates to a film-form pharmaceutical composition containing lubiprostone, a preparation containing the film-form pharmaceutical composition, and a method for producing the same.

  Lubiprostone (7-[(2R, 4aR, 5R, 7aR) -2- (1,1-difluoropentan-1-yl) -2-hydroxy-6-oxooctahydrosilopenta [b] pyran-5-yl] Heptanoic acid) is used as an active ingredient of a drug for chronic constipation.

  Japanese Patent Publication No. 2003-511445 (Patent Document 1) shows that rubiprostone is unstable to heat, and describes a pharmaceutical composition in which rubiprostone and glyceride are mixed and stabilized. As the glyceride, for example, medium-chain fatty acid triglyceride is used, and it is described that it is formulated into a preparation for oral administration, particularly a preparation for oral administration such as soft capsules.

  A soft capsule containing lubiprostone and a medium-chain fatty acid triglyceride is manufactured and sold by Mylan EPD LLC (Amitiza Capsule 24 μg Interview Form (7th Edition) (Non-Patent Document 1)). Non-Patent Document 1 describes that lubiprostone is unstable to heat and humidity.

Special table 2003-511445 gazette

Amitiza Capsule 24μg Interview Form (7th Edition)

  However, soft capsules are dosage forms that are difficult to take for elderly people, children, and patients who have difficulty swallowing, and do not have the convenience that they cannot be administered in divided doses or cannot be used by dispersing them in water. It is also a dosage form having the drawback of requiring special manufacturing equipment. Therefore, it is significant to make a solid preparation without these drawbacks.

  By the way, lubiprostone in a soft capsule is contained in a base material, for example, a medium-chain fatty acid triglyceride in a liquid state at an extremely low content of 24 μg in one capsule. This is possible because it is a soft capsule that can be filled with a homogeneous liquid as it is, and it can be easily compounded in the same liquid state to form a solid formulation with a uniform content and strong strength. The inability to do so, in line with the general public, is a problem to be solved in making solid dosage forms.

  Lubiprostone is in a liquid state dissolved in a base such as a medium-chain fatty acid triglyceride in a soft capsule, but when it is contained in a solid formulation in a solid state, it may be formulated as an amorphous substance. , May be recrystallized over time. The recrystallization of lubiprostone may reduce the stability and elution of lubiprostone.

  Furthermore, Non-Patent Document 1 describes that lubiprostone is unstable to heat and humidity, and it is difficult to produce a preparation other than soft capsules, particularly a solid preparation having improved stability. Can be easily predicted.

  Therefore, an object of the present invention is to provide a film-form pharmaceutical composition containing lubiprostone, which has excellent stability and content uniformity, is easy to take, and is convenient to handle.

  In view of the above situation, the present inventors have conducted earnest studies on a film-form pharmaceutical composition containing lubiprostone, a film agent and a film coating agent containing the same, and a method for producing them.

  As a result, the present inventors have found that lubiprostone is unstable to heat and humidity, and has the property that related substances are generated and the content is reduced, but by forming a solid dispersion with a polymer compound, It has been found that it is possible to ensure homogeneity of the content of lubiprostone in the formulation, while at the same time stabilizing it. In addition, it was found that lubiprostone can be particularly stabilized by forming a solid dispersion using a specific polymer compound into a film-like pharmaceutical composition.

  Based on the above findings, the present invention is configured as follows. That is, the film-form pharmaceutical composition according to the present invention comprises lubiprostone or a pharmaceutically acceptable salt of rubiprostone, or a hydrate of rubiprostone or a pharmaceutically acceptable salt of rubiprostone (hereinafter, simply referred to as Also referred to as "Lubiprostone") and a polymer compound.

  Further, the polymer compound has a polymer compound having a glucose ring as a constituent unit, a polymer compound obtained by addition-polymerizing a monomer having a vinyl group, or a polymer compound having a glucose ring as a constituent unit or a vinyl group. It is preferable that a polymer compound obtained by addition-polymerizing a monomer is chemically modified.

  In addition, in the film-form pharmaceutical composition according to the present invention, the polymer compound having a glucose ring as a constituent unit preferably has an average number of hydroxyl groups per glucose ring unit of 2 or less.

  In addition, in the film-form pharmaceutical composition according to the present invention, the polymer compound obtained by addition-polymerizing a monomer having a vinyl group preferably has 1 or less hydroxyl groups per structural unit.

  Further, in the film-shaped pharmaceutical composition according to the present invention, it is preferable that the polymer compound does not contain alkyl acrylic acid.

  Further, in the film-like pharmaceutical composition according to the present invention, the polymer compound is a group consisting of hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, ethylcellulose, and crospovidone. It is preferably at least one polymer compound selected from

  The film preparation according to the present invention includes any one of the above-mentioned film-shaped pharmaceutical compositions.

  Further, the film-coated tablet according to the present invention comprises a core, and the core is coated with the film-shaped pharmaceutical composition according to any one of the above.

  In addition, in general, when producing solid preparations such as films, granules, capsules, tablets, etc., by using an amount or form suitable for each dosage form among various additives, It can be finished into a dosage form. Usually, even for a drug having a destabilizing factor to some extent, the intended formulation can be obtained by carefully selecting the additive to be used to some extent.

  However, lubiprostone itself has the property that when stored in a heat and humidity environment, it produces a related substance, which causes a decrease in content, and that the property is accelerated when blended with most formulation additives. Therefore, it is not possible to produce a film-shaped pharmaceutical composition by a commonly used ordinary formulation method.

  The present inventors have keenly sought a method for formulating lubiprostone which is stable even when stored in a heat and humidity environment, and by utilizing an amorphization method by blending with a polymer compound, rubiprostone can be stabilized. A storable pharmaceutical composition of the invention could be completed.

  Further, it is not possible to uniformly mix the additive with the additive as a powder, which is an extremely low content of 24 μg of lubiprostone at one time. Therefore, it is necessary to develop a method in which lubiprostone is mixed in a system dissolved in a solvent to produce a solid preparation in which both content uniformity and stability are ensured at the same time.

  Based on the above findings, the method for producing the film-shaped pharmaceutical composition of the present invention is configured as follows. That is, a step of dissolving or dispersing rubiprostone or a pharmaceutically acceptable salt of rubiprostone, or a hydrate of rubiprostone or a pharmaceutically acceptable salt of rubiprostone and a polymer compound in a solvent to obtain a mixed solution, , A step of removing the solvent from the mixed solution to form a film.

  The step of removing the solvent from the mixed solution to form a film preferably includes a step of uniformly applying the mixed solution on a liner and drying. In this way, a film preparation containing the film-form pharmaceutical composition according to the present invention can be produced.

  Further, the step of removing the solvent from the mixed solution to form a film preferably includes a step of coating the core with the mixed solution and drying to form a film on the core. In this way film-coated pharmaceutical tablets according to the invention can be produced, for example, coated film-coated tablets.

  As described above, according to the present invention, it is possible to provide a film-form pharmaceutical composition containing lubiprostone, which has excellent stability, is easy to take, and has improved convenience of administration.

  The film-like pharmaceutical composition according to the present invention contains rubiprostone or a pharmaceutically acceptable salt of rubiprostone, or hydrate of rubiprostone or a pharmaceutically acceptable salt of rubiprostone, and a polymer compound. Includes solid dispersion.

  By making lubiprostone and the polymer compound into a solid dispersion, at least a part of lubiprostone exists as an amorphous substance in the solid dispersion with the polymer compound. The amorphous form of lubiprostone is inherently less stable than the crystalline form. However, as found by the present inventors, by making a solid dispersion of rubiprostone and a polymer compound, at least a part of rubiprostone is kept in an amorphous state, and more stable than crystalline rubiprostone. Can be increased. In this way, a stable film-like pharmaceutical composition containing lubiprostone can be provided.

  Amorphous (also referred to as amorphous) lubiprostone is an amorphous state having no crystal structure. Whether or not it is amorphous can be determined by X-ray diffraction. Lubiprostone (crystalline Lubiprostone) can be made amorphous by following the method for producing a film-shaped pharmaceutical composition described below. The film-form pharmaceutical composition thus formed is composed of a solid dispersion in which amorphous lubiprostone is dispersed in a matrix.

  The polymer compound is a polymer compound having a glucose ring as a constituent unit, a polymer compound obtained by addition-polymerizing a monomer having a vinyl group, or a polymer compound having a glucose ring as a constituent unit or a monomer having a vinyl group. A polymer compound obtained by addition polymerization is chemically modified.

  The present inventors have found that, depending on the polymer compound that forms a solid dispersion with rubiprostone, it is possible to maintain an amorphous form of rubiprostone particularly well and to improve stability more than that of crystalline form of rubiprostone. Found. By using the above-mentioned polymer compound as the polymer compound forming a solid dispersion with lubiprostone, the film-form pharmaceutical composition can be made more stable.

  Specifically, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, methyl cellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol / methyl methacrylate acrylate copolymer, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate. Copolymer RS, low-substituted hydroxypropyl cellulose, ethyl cellulose, crospovidone and the like.

  In addition, in the film-form pharmaceutical composition according to the present invention, the polymer compound having a glucose ring as a constituent unit preferably has an average number of hydroxyl groups per glucose ring unit of 2 or less.

  In addition, in the film-form pharmaceutical composition according to the present invention, the polymer compound obtained by addition-polymerizing a monomer having a vinyl group preferably has 1 or less hydroxyl groups per structural unit.

  Further, in the film-shaped pharmaceutical composition according to the present invention, it is preferable that the polymer compound does not contain alkyl acrylic acid.

  Further, in the film-like pharmaceutical composition according to the present invention, the polymer compound is a group consisting of hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, ethylcellulose, and crospovidone. It is preferably at least one polymer compound selected from

  The present inventors have found that these polymer compounds dramatically improve the stability of lubiprostone.

  The film-shaped pharmaceutical composition of the present invention described above can be used for pharmaceutical preparations such as film agents and film-coated tablets. The pharmaceutical preparation containing the film-form pharmaceutical composition according to the present invention may be a granule, a fine granule, or a capsule in addition to the film agent and the film-coated tablet.

  Next, a method for producing a film-shaped pharmaceutical composition, a film agent and a film-coated tablet according to the present invention will be described.

  A step of dissolving or dispersing rubiprostone or a pharmaceutically acceptable salt of rubiprostone, or a hydrate of rubiprostone or a pharmaceutically acceptable salt of rubiprostone and a polymer compound in a solvent to obtain a mixed solution; The step of removing the solvent from the liquid to form a film is included.

[Film agent]
The step of removing the solvent from the mixed solution to form a film preferably includes a step of uniformly applying the mixed solution on a liner and drying. In this way, a film preparation containing the film-form pharmaceutical composition according to the present invention can be produced.

  To manufacture the film agent, specifically, first, a solvent such as ethanol is added to and dissolved in rubiprostone, and then water, a plasticizer, and a polymer compound as a base material of the film agent, for example, hydroxypropyl cellulose and hydroxy. Propyl methyl cellulose is added, and the mixture is stirred until it dissolves to form a drug solution (mixture). The obtained drug solution is uniformly applied onto a liner (liner plate, support surface) so that the thickness after drying becomes a desired thickness, and then dried. The obtained film is punched into a desired size to produce a film agent. The film agent is, for example, packaged with a laminate film (PAN / AL / PET) having three or more layers having heat sealability.

  The solvent used when producing the film-shaped pharmaceutical composition may be an organic solvent such as methanol, ethanol, isopropanol and water, but is preferably ethanol or a mixed solvent of ethanol and water.

  In the film agent, as a polymer compound forming a solid dispersion with lubiprostone, a polymer compound having a glucose ring as a constitutional unit, a polymer compound obtained by addition-polymerizing a monomer having a vinyl group, or a glucose ring is constituted. It is preferable to use a polymer compound having a unit or a polymer compound obtained by addition-polymerizing a monomer having a vinyl group, which is chemically modified, and particularly preferably hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, and methylcellulose. , Povidone, copolyvidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, ethyl cellulose, and crospovidone. When ensuring the disintegration property in the oral cavity, it is preferable to mainly use a water-soluble polymer compound, and it is free to mix two or more polymer compounds.

  The film agent of the present invention may contain various additives described below, if necessary, within a range that does not impair the effects of the present invention. The type and amount of additives that the film agent may include are not particularly limited. Examples of various additives include plasticizers, excipients, disintegrants, corrigents, coloring agents and the like.

  As the plasticizer, triacetin, triethyl citrate, castor oil, and the like can be used, and it is also free and meaningful to add a polymer compound such as povidone or copolyvidone as a plasticizer.

  Examples of the excipient include sugars (glucose, fructose, lactose (including lactose hydrate), sucrose, trehalose, maltose, oligosaccharides, etc.), crystalline celluloses (crystalline celluloses), starches (corn starch, Potato starch, rice starch, wheat starch, etc.), sugar alcohols (mannitol, erythritol, xylitol, sorbitol, maltitol, etc.), sodium phosphates, calcium phosphates (calcium hydrogen phosphate, etc.), gelatin and the like. It is not limited to these. Excipients can be used alone or in combination of two or more.

Examples of the binder include, but are not limited to, hydroxypropyl starch, carrageenan, dextrin, pregelatinized starch, partially pregelatinized starch, pullulan, pectin, gum arabic and the like. The binder may be used alone or in combination of two or more.

  Examples of the disintegrant include carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, cellulose and its derivatives (for example, low-substituted hydroxypropylcellulose), pregelatinized starch, partially pregelatinized starch, starch. Examples include, but are not limited to, sodium glycolate and the like. Of these, crospovidone is preferred. The disintegrant can be used alone or in combination of two or more.

  The corrigent is one or more selected from the group consisting of an acidulant, a sweetener, and a cooling agent.

  As the sour agent, one or more selected from the group consisting of ascorbic acid, tartaric acid, citric acid, malic acid and salts thereof can be used.

  As the sweetener, one or more kinds selected from the group consisting of aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin and salts thereof can be used.

  As the cooling agent, one or more kinds selected from the group consisting of fennel oil, camphor, peppermint oil, peppermint water, mint, peppermint and menthol can be used. The amount of the flavoring agent added per formulation is preferably 1 to 20% by mass, more preferably 2 to 10% by mass.

  Examples of the fragrance include menthol, vanilla, orange, strawberry, raspberry, chocolate, grapefruit, cranberry, ume, cactus, herb, coffee, tea, cinnamon, honey lemon, and the like. Among them, menthol, orange, grapefruit are preferable. Is.

  Examples of the colorant include food blue No. 2, food red No. 3, food yellow No. 4, food yellow No. 5, iron sesquioxide, yellow iron sesquioxide, aluminum chelate, titanium oxide, talc, etc. Not limited to. The colorants may be used alone or in combination of two or more.

  The content of rubiprostone or a pharmaceutically acceptable salt of rubiprostone or a hydrate of rubiprostone or a pharmaceutically acceptable salt of rubiprostone is not particularly limited per formulation of the above-mentioned film preparation or the like. Is preferably 12 to 48 μg.

  Further, the polymer compound compounded in the present invention is an essential compounding agent for stabilizing lubiprostone, but it can be compounded as a film agent or a disintegrant in the production of the pharmaceutical composition and the pharmaceutical preparation of the present invention. It is a useful additive and is very useful and convenient in this respect as well. The compounding amount is 0.5 part by weight or more relative to 1 part by weight of lubiprostone, and there is no upper limit of the compounding as long as the purpose of use and the characteristics of the pharmaceutical composition to be produced can be matched. If it is 0.5 parts by weight or less, the stability of lubiprostone may not be ensured.

[Film coated tablets]
The step of removing the solvent from the mixed solution to form a film preferably includes the step of coating the core with the mixed solution and drying the film to form a film on the core. In this way, a film-coated tablet coated with the film-form pharmaceutical composition according to the present invention can be produced.

  In the production of film coating agents, the core is produced mainly from an excipient that is usually used as a pharmaceutical additive, and the core is a drug-free particle, granule or plain tablet (tablet core). , Also referred to as placebo tablets), capsules and the like.

  The core used in the present invention is preferably a) at least one excipient, b) optionally at least one binder, c) optionally at least one disintegrant, and d ) If necessary, at least one lubricant is used for the production, but the method for producing the additive and the core used in the present invention will be described below.

  Excipients are the main additives incorporated into the core used in the present invention in an amount in the range of 1 to about 100% by weight of the core composition, preferably 10 to 85% by weight. Examples of excipients suitable for use in the invention include crystalline cellulose, D-mannitol, lactose, sucrose, fructose, xylitol, inorganic salts such as calcium carbonate, calcium hydrogen phosphate, etc., but are preferable. Is crystalline cellulose, D-mannitol, and lactose.

  The binder is an additive for binding the additive powder and solidifying it into particles or granules. Examples of the binder suitable for use in the present invention include hydroxypropyl cellulose, methyl cellulose, and hydroxypropyl methyl cellulose. , Povidone, copolyvidone, corn starch, ethyl cellulose and the like, and an appropriate binder is used depending on the occasion.

  The disintegrant is an additive for disintegrating or dissolving the core as necessary, but examples of the disintegrant suitable for use in the present invention include carmellose, croscarmellose sodium, carmellose calcium, crospovidone, and corn starch. , Sodium starch glycolate, low-substituted hydroxypropyl cellulose, etc., and a suitable disintegrant is used depending on the occasion.

  Lubricants are additives that are added to improve the fluidity and adhesiveness of particles and granules. Lubricants suitable for use in the present invention include magnesium stearate, calcium stearate, talc, and carnauba wax. , Stearic acid, palmitic acid, sodium stearyl fumarate, hydrogenated vegetable oil and the like, but magnesium stearate, calcium stearate and sodium stearyl fumarate are preferable.

  In the present invention, in addition to the above-mentioned excipients, binders, disintegrants, and lubricants, various additives that are pharmaceutically acceptable and can be used as additives can be blended. Examples thereof include acidulants, foaming agents, artificial sweeteners, flavors, colorants, stabilizers, and the like, and the additives may be used alone or in combination of two or more. The compounding amount thereof is not particularly limited as long as it is within the range that is usually used pharmaceutically by those skilled in the art and does not impair the effects of the present invention.

  When the core used in the present invention is produced, the above-mentioned excipients, binders, disintegrants, lubricants and the like are used, and wet granulation such as stirring granulation, tumbling fluidized bed granulation and rolling granulation Particles or granules can be produced by a granulation method, a dry granulation method or the like and used as a core. In addition, particles or granules produced by a wet granulation method such as a fluidized bed granulation method, a stirring granulation method, or a dry granulation method may be added with a disintegrating agent, a lubricant, etc., and then subjected to ordinary rotary milling. A tablet or capsule manufactured by a tablet machine or a capsule filling machine can be used as the core. It should be noted that commercially available particles and granules can be used as the core, and commercially available particles and granules include spherical particles and granules made of crystalline cellulose, D-mannitol, lactose, sucrose and the like. ..

In the present invention, using the core described above, the outer layer is coated with a film made of a film-like pharmaceutical composition.
a) a method of directly coating a drug coat layer containing rubiprostone on the outer layer of the nucleus, b) forming an inner seal coat layer with at least one film coating agent on the outer layer of the nucleus, and then containing rubiprostone in the outer layer A method of coating a drug coat layer,
However, the outer layer of the layer containing lubiprostone produced by the above method may be further coated with an outer protective coat layer for improving the stability of lubiprostone.

  The film coating agent that can be used for the drug coat layer of the present invention is essential to contribute to the stability of lubiprostone, and a polymer compound having a glucose ring as a constitutional unit and a monomer having a vinyl group are subjected to addition polymerization. It is preferable to use a polymer compound obtained by chemically modifying a polymer compound having a glucose ring as a constituent unit or a polymer compound obtained by addition-polymerizing a monomer having a vinyl group, Preferred are hydroxypropylmethyl cellulose, methyl cellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, ethyl cellulose and crospovidone, and it is free to use two or more polymer compounds in combination.

The film coating agent that can be used for the inner seal coating layer and the outer protective coating layer may be any as long as it does not affect the stability of lubiprostone in the drug coating layer that coats the outer layer and the inner layer, and hydroxypropyl methylcellulose. , Methyl cellulose, hydroxypropyl cellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol / methyl methacrylate acrylic acid copolymer, ethyl cellulose, acetyl cellulose, cellulose acetate phthalate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, dimethyl Aminoethylmethacrylate / methylmethacrylate Copo Polymers, methyl acrylate / methacrylic acid copolymer, aminoalkyl methacrylate copolymer RS, dry methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer S, polyvinyl acetal diethylaminoacetate, and the like, and preferably hydroxypropylmethylcellulose and hydroxyethylmethylcellulose. , Methyl cellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, ethyl cellulose and the like, and preferably the same film coating agent used in the drug coat layer is preferably used.
Hereinafter, a method for producing a pharmaceutical preparation in the form of a core coated with a film, which comprises the film-shaped pharmaceutical composition of the present invention, will be described.

  In producing a pharmaceutical preparation in the form of a core coated with a film comprising the film-form pharmaceutical composition of the present invention, when the core is particles or granules having a diameter of 2 mm or less, the fluidized bed coating method is preferably adopted. Also, when the core is a tablet or capsule, it is preferably manufactured using a perforated pan coater. The coating of the core with the coating solution preferably employs a spray coating method.

  The coating solution for coating the inner seal coating layer comprises at least one film coating agent as described above and a coating solvent. The coating layer polymer used is as described above, and any polymer may be used as long as it does not affect the stability of lubiprostone of the drug coating layer. As the solvent used in the inner seal coating, water or an organic solvent such as methanol or ethanol is used alone or in a mixture. It is free to add a plasticizer, a lubricant, a colorant and the like to the coating solution, if necessary. As the plasticizer, for example, triacetin, triethyl citrate, diethyl phthalate, or polyethylene glycol, preferably triacetin or triethyl citrate is used, and as the lubricant, for example, talc, fumed silica, or magnesium stearate is used. As the colorant, for example, titanium dioxide, iron oxide-based colorant or the like is used.

The purpose of coating the inner seal coating layer is mainly to prevent direct contact between the surface of the core and the drug coating layer coating the outer layer, and in principle, when the surface of the core does not adversely affect the drug, No inner seal coating layer is required.
The drug coat layer is an important coating layer for stabilizing the presence of lubiprostone, and the coating solution for coating comprises at least one film coating agent and a coating solvent. The film coating agent used is particularly preferably hydroxypropylmethylcellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol / methyl methacrylate acrylate copolymer, and polyvinyl acetal diethylaminoacetate. Since the usual single dose of lubiprostone as a drug is as small as 24 μg, the amount of lubiprostone contained in the drug coat layer is 1% at most, which is convenient because it can be easily dissolved in the film coating solution. Is.

  The solvent used for drug coating is preferably an organic solvent such as methanol or ethanol, and it is free to mix and use water as necessary. If necessary, a plasticizer, a lubricant, a colorant, etc. may be added to the coating solution, but lubiprostone is blended with most additives other than the above film coating agent over time. Since it is known that the content will decrease, it is necessary to pay particular attention to the components to be mixed. In the case of a plasticizer that is likely to be incorporated in the film, it is preferable to use copolyvidone, triacetin, triethyl citrate, or the like. It should be noted that crospovidone, which is a polymer compound that contributes to the stabilization of lubiprostone, can be blended simultaneously in the film layer.

  The outer protective coating layer is coated on the outer layer of the drug coat layer for the purpose of protecting the drug coat layer. For the outer protective coating layer, it is preferable to use the film coating agent and coating solvent used in the inner seal coating layer or the drug coat layer. Further, since the purpose is protection, it is free to include a stabilizer such as an antioxidant and a colorant.

  When the particles or granules are cores, the inner seal coating layer is about 3 to about 20% by weight, preferably about 5 to about 15% by weight with respect to the core, and the weight of the drug coat layer is the core or the inner seal coating. It is about 3 to about 25% by weight, preferably about 5 to about 20% by weight, based on the layer coating, and the weight of the outer protective coating layer is about 5 to about 25% by weight, preferably on the drug coating layer coating. Is about 7 to about 20% by weight. When the core is a tablet (plain tablet), the weight of the inner seal coating layer is about 1 to about 10% by weight, preferably about 1 to about 7% by weight, based on the plain tablet. Is about 1 to about 15% by weight, preferably about 2 to about 10% by weight, based on the plain tablet or the inner seal coating layer-coated tablet, and the weight of the outer protective coating layer is about 2 to the drug coating layer-coated tablet. To about 10% by weight, preferably about 2 to about 7% by weight.

  As mentioned above, the film agent comprising the film-shaped pharmaceutical composition, or the method for producing a pharmaceutical preparation in a form in which the film-shaped pharmaceutical composition is coated on the core has been described. Since it is produced from a dissolved solution, it is possible to contain lubiprostone uniformly, which is convenient in terms of content uniformity, and it is possible to provide a pharmaceutical preparation with improved stability of lubiprostone.

  Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto.

  The drug substance used in the experiment is as follows. Hydroxypropyl methyl cellulose (TC-5R, Shin-Etsu Chemical Co., Ltd.), hydroxypropyl methyl cellulose (60SH-50, Shin-Etsu Chemical Co., Ltd.), hydroxypropyl cellulose (HPC-L, Nippon Soda Co., Ltd.), povidone (Kolidon 90F, BASF). Japan Co., Ltd.), copolyvidone (Kolidon VA64, BASF Japan Co., Ltd.), polyvinyl alcohol (Gosenol EG-05, Nippon Synthetic Chemical Industry Co., Ltd.), aminoalkyl methacrylate copolymer E (Eudragit E100, Evonik Japan Co., Ltd.), methacrylic acid copolymer. L (Eudragit L100, Evonik Japan Co., Ltd.), aminoalkyl methacrylate copolymer RS (Eudragit RL, Evonik Japan Co., Ltd.), polyvinyl acetal diethylaminoacetate (AEA, Mitsubishi Chemical Foods Co., Ltd.), low-substituted hydroxypropylcellulose (LH-31) , Shin-Etsu Chemical Co., Ltd.), crospovidone (polyplasdone XL-10, ASHLAND), lactose hydrate (Dilactose S, Freund Sangyo Co., Ltd.), corn starch (corn starch, Nippon Food Processing Co., Ltd.), crystalline cellulose ( CEOLUS PH301, Asahi Kasei Co., Ltd., Magnesium stearate (Taihei Chemical Industry Co., Ltd.).

[Sample A and Sample B]
Lubiprostone 24 mg was dissolved in ethanol to prepare 100 mL (240 μg / mL), 0.1 mL of the solution was added to a cylindrical glass container having an internal volume of about 30 mL, the amount of the solution was accurately measured, and then the draft was prepared. A sample of Sample A was prepared by exhausting the solvent in the chamber and drying it. In sample A, lubiprostone was amorphized into an oily substance. Further, 24 μg of lubiprostone crystals was weighed into a cylindrical glass container having an internal volume of about 30 mL to obtain a sample B.

[Experimental Example 1]
A contact stability test was conducted between lubiprostone and a polymer compound or an excipient. Lubiprostone 24 mg was dissolved in ethanol (Experimental Examples 1-1 to 1-3, 1-6 to 1-15) or a 1: 1 mixture of ethanol and water (Experimental Examples 1-4 and 1-5) to obtain 100 mL. (240 μg / mL). 100 mg of the sample (polymer compound or excipient) shown in Table 1 was weighed into a cylindrical glass container having an inner volume of about 30 mL. Next, 0.1 mL of the solution was added to a sample in a glass container, the addition amount was accurately measured, and then the mixture was lightly mixed. After standing for a while, the solvent was evacuated and dried in a draft chamber to obtain a sample of the particulate pharmaceutical composition of Experimental Example 1-1 to Experimental Example 1-15.

[Test Example 1]
The glass container containing the sample manufactured in Experimental Example 1 was sealed in an aluminum bag together with PharmaKeep (KD-20, Mitsubishi Gas Chemical Industry Co., Ltd.) and stored in a thermostat at 60 ° C. for 1 week or 2 weeks, The remaining amount of lubiprostone was measured. Similarly, the glass containers containing the samples made of Sample A and Sample B were similarly sealed in an aluminum bag and stored in a thermostat at 60 ° C. for 1 week or 2 weeks, and then the residual amount of lubiprostone was measured. Samples A and B are shown as samples of Experimental Examples 1-16 and 1-17, respectively. The results are shown in Table 1.

[Measurement method of residual amount of lubiprostone]
10 mL of 50% acetonitrile was added to the glass container containing the sample. It was irradiated with ultrasonic waves for 30 minutes and filtered through PTFE (0.45 μm) to give a sample solution (2.4 μg / mL). Separately, about 6 mg of lubiprostone was precisely weighed and made exactly 50 mL with acetonitrile. Exactly 1 mL of this solution was adjusted to 50 mL with 50% acetonitrile to prepare a standard solution (2.4 μg / mL). The analysis conditions were as follows.
Column: Waters ACQUITY UPLC, 1.8 μm, 2.1I. D. × 50 mm
Column temperature: Constant temperature around 40 ° C Mobile phase A: Mobile phase B (50:50)
Mobile phase A: 0.1% formic acid solution Mobile phase B: Acetonitrile Flow rate: 0.2 mL / min Injection volume: 1 μL
Ionization method: ESI
Ion mode: Negative ion

  Both the amorphous substance (experimental example 1-16) and crystal (experimental example 1-17) of lubiprostone decomposed to a residual amount of 30% or less after storage for 1 week. In contrast, the particulate pharmaceutical composition using the polymer compound had a high content of lubiprostone after 1 week and after 2 weeks. Particularly in Experimental Examples 1-1 to 1-8, 70% or more after 1 week and about 60% or more after 2 weeks were observed, and it was found that the contribution to the stabilization of lubiprostone was high. ..

  Among them, Experimental Example 1-1 (hydroxypropylmethylcellulose), Experimental Example 1-3 (copolyvidone), Experimental Example 1-4 (povidone), Experimental Example 1-5 (polyvinyl alcohol), Experimental Example 1-6 (polyvinyl acetal diethylamino). Acetate) and Experimental Example 1-8 (crospovidone) had a residual amount of 90% or more after 2 weeks and were found to be extremely stabilized. These polymer compounds are polymer compounds having a glucose ring as a constitutional unit and have an average number of hydroxyl groups per glucose ring unit of 2 or less, or are composed of monomers having a vinyl group. The polymer compound produced by polymerization corresponds to any polymer compound in which the proportion of hydroxyl groups in the constitutional unit of the compound is 1 or less and which does not contain alkyl acrylic acid.

  Further, it is composed of Experimental Example 1-2 (hydroxypropyl cellulose) and Experimental Example 1-7 (low-substituted hydroxypropyl cellulose) having an average number of hydroxyl groups per glucose ring unit of 3, and a monomer having a vinyl group. A polymer compound produced by addition polymerization, which contains alkyl acrylic acid in the constitutional unit of the compound even if the proportion of the hydroxyl groups in the constitutional unit of the compound is 1 or less. Although Experimental Examples 1-9 (aminoalkylmethacrylate copolymer E), Experimental Examples 1-10 (methacrylic acid copolymer L) and Experimental Examples 1-11 (aminoalkylmethacrylate copolymer RS) are involved in the stabilization of lubiprostone, It can be seen that the contribution is relatively small.

  It was also found that lactose hydrate and D-mannitol, which are commonly used excipients, do not have an effect of particularly stabilizing lubiprostone (Experimental Examples 1-14, 1-15).

[Example 1]
In Example 1, the polymer compounds shown in Table 2 were used to prepare a film agent containing lubiprostone. 0.21 parts by mass of lubiprostone and 99.79 parts by mass of the polymer compound shown in Table 2 were weighed in a glass container, dissolved in a 1: 1 part by mass mixture of ethanol and water, and the obtained drug solution was dried on a liner. It was evenly applied so that the subsequent thickness would be about 40 μm, and dried at 80 ° C. for 15 minutes. The obtained film was punched into a size of 1.4 × 2.0 cm (2.8 cm ² ) to produce a film agent, and the sample of Example 1 was obtained. The mass per sheet of the obtained film preparation was about 11 mg, and the drug content was about 24 μg.

[Comparative Examples 1 and 2]
Hereinafter, the glass containers containing the samples made of Sample A and Sample B are treated as samples of Comparative Example 1 and Comparative Example 2, respectively.

[Test Example 2]
Each sample of Example 1 was sealed in an aluminum bag together with PharmaKeep (KD-20, Mitsubishi Gas Chemical Industry Co., Ltd.) and stored at 60 ° C. and 75% RH. The content of lubiprostone in the film preparation was measured at the start of storage and after storage for 2 weeks and 4 weeks. Further, the samples of Comparative Example 1 and Comparative Example 2 were sealed in an aluminum bag together with Pharmakeep (KD-20, Mitsubishi Gas Chemical Industry Co., Ltd.) and stored at 60 ° C. and 75% RH, and the content of rubiprostone was also measured. did. The results are shown in Table 2.

  Also for the film agent, it is a polymer compound having a glucose ring as a constitutional unit and has Example 1-1 (hydroxypropylmethylcellulose) having an average number of hydroxyl groups per glucose ring unit of 2 or less, and a vinyl group. Example 1-3 (povidone), which is a polymer compound composed of a monomer and produced by addition polymerization, in which the proportion of hydroxyl groups in the structural unit of the compound is 1 or less and does not contain alkyl acrylic acid In Examples 1 to 4 (polyvinyl alcohol) and Examples 1 to 5 (polyvinyl acetal diethylaminoacetate) as a base, there is a residual amount of 90% or more after 2 weeks, which is extremely stabilized. I found out. Further, Example 1-2 (hydroxypropyl cellulose) having an average number of hydroxyl groups per glucose ring unit of 3, and a polymer compound composed of a monomer having a vinyl group and produced by addition polymerization, Even if the proportion of hydroxyl groups in the constitutional unit of 1 is 1 or less, Example 1-6 (aminoalkylmethacrylate copolymer E), which is a polymer compound including alkylacrylic acid in the constitutional unit of the compound, is prepared. It was found that the film made as the base had a small contribution even though it was stabilized.

[Example 2 Film agent]
0.21 parts by mass of rubiprostone, 69.853 parts by mass of hydroxypropylmethylcellulose (60SH-50), and 29.937 parts by mass of hydroxypropylcellulose were weighed and dissolved in a mixture of 1: 1 parts by mass of ethanol and water. .. The obtained chemical solution (mixed solution) was uniformly applied on a liner so that the thickness after drying was 40 μm, and dried at 80 ° C. for 15 minutes. The obtained film was punched into a size of 1.4 × 2.0 cm (2.8 cm ² ) to obtain a film agent. This film preparation was orally disintegrating, the mass per sheet was 11.2 mg, and the drug content was 24 μg.

[Test Example 3]
The X-ray diffraction profile of the film preparation of Example 2 (orally disintegrating film preparation) was measured. The measurement conditions of the X-ray diffraction profile were as follows.
X-ray output: 40 kV, goniometer: SmartLab, attachment: ASC6-reflection, filter: Cu_K-beta, CBO selection slit: BB, detector: D / teX Ultra, scan mode: CONTINUUS, scan speed 10 deg / min, step width. : 0.02 deg, scan axis: 2θ / θ, scan range: 5-40 deg, incident slit 1/2 deg, length limiting slit: 10 mm, light receiving slit 1: 8 mm, light receiving slit 2:13 mm

  In the film agent of Example 2, no peak peculiar to crystalline lubiprostone having a crystal structure was observed and a halo pattern was observed. This means that lubiprostone in the orally disintegrating film agent obtained in Example 2 is amorphous.

  The film agent of Example 2 was sealed in an aluminum bag together with PharmaKeep (KD-20, Mitsubishi Gas Chemical Industry Co., Ltd.) and stored at 60 ° C. and 75% RH, at the start of storage and after 1 week and 2 weeks of storage. The content of lubiprostone in the film preparation was measured. Further, the film preparation of Example 2 and the samples of Comparative Examples 1 and 2 were sealed in an aluminum bag together with PharmaKeep (KD-20, Mitsubishi Gas Chemical Industry Co., Ltd.) and stored at 40 ° C. and 75% RH. The content of lubiprostone after storage for 2 weeks and 4 weeks was measured. The remaining amount (%) of lubiprostone under each storage condition is shown in Table 3.

Next, the film preparation of Example 2 was stored at 60 ° C. 75% RH for 2 weeks and 40 ° C. 75% RH for 4 weeks. The dissolution test of the film agent was performed at the start of storage and after storage, and the results are shown in Table 4.
The dissolution test conditions were as follows.
Rotating basket method: 100 rpm
Test liquid: distilled water Test liquid amount: 900 mL (27 ng / mL)
Test solution temperature: 37 ± 0.5 ℃
Sampling time: 2, 5, 10 and 20 minutes

  As shown in Tables 3 and 4, the orally disintegrating film agent (Example 2) produced by using hydroxypropylmethylcellulose as the main film base did not show a decrease in dissolution when stored at 40 ° C, It was found that the content did not decrease. In addition, even after storage at 60 ° C for 2 weeks, there was no significant change in the content and the dissolution property. On the other hand, in Comparative Examples 1 and 2, when stored at 40 ° C. and 75% RH for 4 weeks, there was a decrease in the content of lubiprostone crystals themselves by about 10% and an amorphous substance content by about 90%. It can also be seen that the internally disintegrating film agent is extremely stabilized.

[Example 3 Film-coated tablet]
0.05 g of lubiprostone and 21 g of hydroxypropylmethylcellulose (TC-5R) were taken and dissolved in a mixture of 245 g of ethanol and 105 g of water to prepare a drug coating solution (mixed solution).

  Lactose hydrate (1518 g), crystalline cellulose (44 g) and corn starch (22 g) were mixed well and 2.2 g of magnesium stearate was added and mixed to prepare a mixed powder for tableting, which was a rotary tablet. Using a manufacturing machine, tablets (core) having a diameter of 8 mm, 9.5 R and a weight of 220 mg were produced.

  High Coater Mini (Freund Industrial) was charged with 420 g of tablets (core) and coating operation was performed using the entire amount of the drug coating solution to obtain a film-coated tablet in which the core was coated with a film-like pharmaceutical composition. The weight gain per film-coated tablet was about 7.8 mg.

[Test Example 4]
The film-coated tablet of Example 3 was sealed in an aluminum bag together with PharmaKeep (KD-20, Mitsubishi Gas Chemical Industry Co., Ltd.) and stored at 40 ° C. 75% RH and 60 ° C. 75% RH. Also, the content of lubiprostone after storage for 4 weeks was measured, and the residual amount (%) of lubiprostone was shown in Table 5 with Comparative Examples 1 and 2 as controls.

  It can be seen that the pharmaceutical preparation of Example 3 in which the core is coated with the film-shaped pharmaceutical composition (film-coated tablet) has extremely improved stability when compared with the non-crystallized product of rubiprostone or the crystal of rubiprostone.

  As described above, according to the present invention, it is possible to provide a preparation for oral administration containing lubiprostone in a dosage form which has excellent stability and drug dissolution and is easy to take.

  It should be considered that the embodiments and examples disclosed above are illustrative in all points and not restrictive. The scope of the present invention is shown not by the above-described embodiments and examples but by the scope of the claims, and includes meanings equivalent to the scope of the claims and all modifications and variations within the scope.

Claims (11)

  A film-like pharmaceutical composition, which is a solid dispersion containing rubiprostone or a pharmaceutically acceptable salt of rubiprostone or a hydrate of rubiprostone or a pharmaceutically acceptable salt of rubiprostone, and a polymer compound.   The polymer compound is a polymer compound having a glucose ring as a constituent unit, a polymer compound obtained by addition-polymerizing a monomer having a vinyl group, or a polymer compound having a glucose ring as a constituent unit or a monomer having a vinyl group. The film-form pharmaceutical composition according to claim 1, wherein the polymer compound obtained by addition-polymerizing is a compound chemically modified.   The film-form pharmaceutical composition according to claim 2, wherein the polymer compound having a glucose ring as a constituent unit has an average number of hydroxyl groups per glucose ring unit of 2 or less.   The film-form pharmaceutical composition according to claim 2, wherein the polymer compound obtained by addition-polymerizing the monomer having a vinyl group has 1 or less hydroxyl groups per constitutional unit.   The film-form pharmaceutical composition according to any one of claims 1 to 4, wherein the polymer compound does not contain alkyl acrylic acid.   The polymer compound is at least one polymer compound selected from the group consisting of hydroxypropylmethyl cellulose, hydroxyethyl methyl cellulose, methyl cellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, ethyl cellulose, and crospovidone. The film-form pharmaceutical composition according to any one of claims 1 to 5.   A film preparation comprising the film-form pharmaceutical composition according to any one of claims 1 to 6. Equipped with a core,
A film-coated tablet, wherein the core is coated with the film-form pharmaceutical composition according to any one of claims 1 to 6. A step of dissolving or dispersing rubiprostone or a pharmaceutically acceptable salt of rubiprostone, or a hydrate of rubiprostone or a pharmaceutically acceptable salt of rubiprostone and a polymer compound in a solvent to obtain a mixed solution;
The manufacturing method of the film-shaped pharmaceutical composition of any one of Claim 1 to 6 including the process of removing a solvent from the said mixed liquid, and forming it into a film.   The manufacturing method according to claim 9, wherein the step of removing the solvent from the mixed solution to form a film includes the step of uniformly applying the mixed solution on a liner and drying. The manufacturing method according to claim 9, wherein the step of removing the solvent from the mixed solution to form a film includes the step of coating the core with the mixed solution and drying the core to form a film on the core.