WO2019221215A1 - Lubiprostone-containing particulate medicinal composition - Google Patents

Abstract

Provided is a lubiprostone-containing particulate medicinal composition which is easy to ingest and convenient to handle and which has outstanding stability and content uniformity. The particulate medicinal composition includes a solid dispersion containing: a lubiprostone or a pharmaceutically acceptable salt of a lubiprostone, or a lubiprostone or a hydrate of a pharmaceutically acceptable salt of a lubiprostone; and a high-molecular compound.

Description

Lubiprostone-containing particulate pharmaceutical composition

The present invention relates to a particulate pharmaceutical composition containing rubiprostone.

Rubiprostone (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 in chronic constipation drugs.

JP-T-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 a soft capsule.

Soft capsules containing rubiprostone and medium-chain fatty acid triglycerides are 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 rubiprostone is unstable to heat and humidity.

Special table 2003-511445 gazette

Amitya Capsule 24μg interview form (7th edition)

However, soft capsules are difficult to take for the elderly, children, and patients who have difficulty swallowing, and cannot be administered in divided doses, or they lack the convenience of being dispersed in water. It is also a dosage form with the disadvantage that special production equipment is required. Therefore, it is meaningful to prepare solid preparations such as tablets, granules, and fine granules that eliminate these disadvantages.

By the way, rubiprostone in soft capsules is contained in an ultra-low content of 24 μg in one capsule in a liquid state dissolved in a base, for example, medium-chain fatty acid triglyceride. This can be done because it is a soft capsule filled with a homogeneous liquid as it is, and it can be blended in the same liquid state to easily produce a solid preparation with a uniform content and firm strength. The inability to do so is a consensus that this is a challenge to be solved in making solid formulations.

In addition, rubiprostone 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 state in a solid preparation, it may be formulated in an amorphous form. There is a risk of recrystallization over time. When rubiprostone is recrystallized, the stability and dissolution of rubiprostone may be reduced.

Furthermore, Non-Patent Document 1 describes that rubiprostone is unstable to heat and humidity, and it is difficult to produce a formulation other than soft capsules, particularly a solid formulation with improved stability. Can easily be expected.

Accordingly, an object of the present invention is to provide a rubiprostone-containing particulate pharmaceutical composition having excellent stability and content uniformity, easy to take, and convenient to handle, and a solid pharmaceutical composition containing the same. Is to provide.

In view of the above situation, the present inventors have conducted extensive studies on a particulate pharmaceutical composition containing rubiprostone and a method for preparing a solid preparation such as a tablet, granule or fine granule containing the composition.

As a result, the present inventors have found that rubiprostone is unstable to heat and humidity, produces a related substance, and has a property of causing a decrease in content, as well as many preparations such as additives containing a large amount of hydroxyl groups. It has been found that its properties are accelerated by blending with a chemical additive. Therefore, rubiprostone is dissolved in a solvent together with an additive such as a binder, kneaded to be uniform with the additive powder, dried, and then dried into a solid agent using a granulated product made by a wet method. It was found that even if the content uniformity can be ensured by this method, it is not easy to ensure the stability.

The inventors have also found that rubiprostone crystals are unstable to heat and humidity, and are also destabilized by blending with many formulation additives, a stable solid formulation with a simple blending method. Knew that I could not get. Therefore, as a result of intensive research on a method for stabilizing rubiprostone, a particulate pharmaceutical composition was formed from a solution in which rubiprostone was dissolved or dispersed in a solvent together with a certain polymer compound, and rubiprostone was incorporated in the particulate pharmaceutical composition. The present inventors have found that rubiprostone can be stabilized by utilizing a method of maintaining an amorphous state.

Based on the above knowledge, the present invention is configured as follows. That is, the particulate pharmaceutical composition according to the present invention comprises rubiprostone or a pharmaceutically acceptable salt of rubiprostone, or a hydrate of rubiprostone or a pharmaceutically acceptable salt of rubiprostone (hereinafter simply referred to as “ And a solid dispersion containing a polymer compound.

In addition, the polymer compound includes a polymer compound having a glucose ring as a structural unit, a polymer compound obtained by addition polymerization of a monomer having a vinyl group, or a polymer compound having a glucose ring as a structural unit or a vinyl group. It is preferable that a polymer compound obtained by addition polymerization of a monomer is chemically modified.

In the particulate 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 the particulate pharmaceutical composition according to the present invention, the polymer compound obtained by addition polymerization of a monomer having a vinyl group preferably has 1 or less hydroxyl groups per structural unit.

In the particulate pharmaceutical composition according to the present invention, it is preferable that the polymer compound does not contain alkylacrylic acid.

In the particulate pharmaceutical composition according to the present invention, the polymer compound is selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, and crospovidone. It is preferably at least one polymer compound selected.

Moreover, it is preferable that the solid pharmaceutical composition according to the present invention includes any one of the particulate pharmaceutical compositions described above.

Also, the solid pharmaceutical composition according to the present invention is preferably a granule, fine granule, capsule capsule, powder, pill, dry syrup or tablet, and particularly preferably a tablet. The tablet is preferably a film-coated tablet or an orally disintegrating tablet. For example, a tablet (orally disintegrating tablet) formed by compressing a particulate pharmaceutical composition is preferable.

In general, when preparing a solid pharmaceutical composition such as a granular pharmaceutical composition or a powder, granule or tablet containing the same, it is used in an amount and form suitable for each dosage form from among various additives. By doing so, the target dosage form can be finished. Usually, even if a drug has a certain degree of destabilization factor, the intended preparation can be obtained by carefully selecting additives to be used to some extent.

However, rubiprostone itself has the property of being stored in a heat and humidity environment, producing a related substance, resulting in a decrease in content, and being accelerated in combination with most formulation additives. Therefore, solid preparations such as powders, granules, and tablets cannot be produced by a general formulation method that is widely used.

The inventors of the present invention have eagerly searched for a method for preparing rubiprostone that is stable even when stored in a heat and humidity environment, and stably using a non-crystallizing method by blending with a polymer compound. The pharmaceutical composition of the present invention that can be stored could be completed.

Also, it is impossible to mix the ultra-low content of rubiprostone with a dose of 24 μg homogeneously with the additive in powder form. Therefore, there is a need for a method in which rubiprostone is blended in a wet manner to ensure both content uniformity and stability at the same time.

Based on the above knowledge, the method for producing the particulate pharmaceutical composition of the present invention is constituted as follows. That is, a method for producing a particulate pharmaceutical composition according to one aspect of the present invention comprises: rubiprostone or a pharmaceutically acceptable salt of rubiprostone, or a hydrate of rubiprostone or a pharmaceutically acceptable salt of rubiprostone. And a polymer compound are dissolved or dispersed in a solvent to obtain a mixed solution, and a mixed solution is added to the additive, wet granulated and dried.

In addition, a method for producing a particulate pharmaceutical composition according to another aspect of the present invention includes rubiprostone or a pharmaceutically acceptable salt of rubiprostone, or a hydrate of rubiprostone or a pharmaceutically acceptable salt of rubiprostone. And a step of dissolving or dispersing the polymer compound in a solvent to obtain a mixed solution, and a step of removing the solvent from the mixed solution.

As described above, according to the present invention, a particulate pharmaceutical composition containing rubiprostone in a dosage form having excellent stability, easy administration, and improved convenience of administration, and a solid medicine containing the same A composition and a method for producing a particulate pharmaceutical composition can be provided.

The particulate pharmaceutical composition according to the present invention contains rubiprostone or a pharmaceutically acceptable salt of rubiprostone or a hydrate of rubiprostone or a pharmaceutically acceptable salt of rubiprostone and a polymer compound. Contains a solid dispersion.

By making rubiprostone and a polymer compound into a solid dispersion, at least a part of rubiprostone is present in an amorphous form in the solid dispersion with the polymer compound. The amorphous form of rubiprostone is inherently less stable than the crystalline form. However, as the present inventors have found, by making rubiprostone and a polymer compound into a solid dispersion, 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 particulate pharmaceutical composition containing rubiprostone can be provided.

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

The polymer compound includes a polymer compound having a glucose ring as a structural unit, a polymer compound obtained by addition polymerization of a monomer having a vinyl group, or a polymer compound having a glucose ring as a structural unit or a monomer having a vinyl group. A polymer compound obtained by addition polymerization is chemically modified.

The present inventors are able to maintain an amorphous form of rubiprostone particularly well and to improve stability compared to crystalline rubiprostone depending on the polymer compound that forms a solid dispersion with rubiprostone. I found. By using the above-mentioned polymer compound as a polymer compound that forms a solid dispersion with rubiprostone, the particulate pharmaceutical composition can be made more stable.

Specifically, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol / methacrylic acid methyl methacrylate copolymer, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate Copolymer RS, low substituted hydroxypropyl cellulose, crospovidone and the like.

In the particulate 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 the particulate pharmaceutical composition according to the present invention, the polymer compound obtained by addition polymerization of a monomer having a vinyl group preferably has 1 or less hydroxyl groups per structural unit.

In the particulate pharmaceutical composition according to the present invention, it is preferable that the polymer compound does not contain alkylacrylic acid.

In the particulate pharmaceutical composition according to the present invention, the polymer compound is selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, and crospovidone. It is preferably at least one polymer compound selected.

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

Moreover, it is preferable that the solid pharmaceutical composition according to the present invention includes any one of the particulate pharmaceutical compositions described above.

The solid pharmaceutical composition according to the present invention is preferably a granule, fine granule, capsule, powder, pill, dry syrup or tablet.

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, but is 12 to 12 per formulation of the solid pharmaceutical composition. 48 μg is preferred.

The polymer compound blended in the present invention is an essential blending agent for stabilizing rubiprostone, but is a potent additive that can be blended as a binder or a disintegrant in producing the pharmaceutical composition of the present invention. This is also extremely useful and convenient. The blending amount is 0.5 parts by weight or more with respect to 1 part by weight of rubiprostone, and there is no upper limit of blending as long as the purpose of use and the characteristics of the pharmaceutical composition to be manufactured are matched. If it is 0.5 parts by weight or less, the stability of rubiprostone may not be ensured.

Next, a method for producing a particulate pharmaceutical composition according to the present invention will be described.

A method for producing a particulate pharmaceutical composition according to one aspect of the present invention comprises a combination of a high hydrate of lubiprostone or a pharmaceutically acceptable salt of rubiprostone or a pharmaceutically acceptable salt of rubiprostone or rubiprostone. The method includes a step of dissolving or dispersing the molecular compound in a solvent to obtain a mixed solution, and a step of adding the mixed solution to the additive to perform wet granulation and drying.

The step of adding the liquid mixture to the additive to obtain particles by obtaining particles is, for example, a wet granulation step or a step of spraying the liquid mixture from a spray nozzle to perform fluidized bed granulation, but is limited to these steps. It is not something. In the wet granulation step, for example, devices such as a stirring granulator, a kneader, and a cylindrical extrusion granulator can be used. In the step of fluidized bed granulation, for example, a fluidized bed granulation dryer or a rolling fluidized coating granulator can be used.

As the additive, one that does not affect the stability of rubiprostone can be used to further improve the stability of the particulate pharmaceutical composition.

By doing so, rubiprostone is stabilized, and it is possible to uniformly disperse rubiprostone in formulation additives such as excipients and disintegrants, and it is advantageous because it can ensure uniformity in content.

Further, in the wet granulation method, it is necessary to add a solution in which rubiprostone and a polymer compound are dissolved or dispersed to an additive such as an excipient to perform a granulation operation to produce particles or granules. Depending on the additive used, the stability of rubiprostone may be adversely affected.

Therefore, we investigated the compatibility with rubiprostone for additives that are likely to be used as excipients. Those that are used as excipients and do not affect the stability of rubiprostone are crospovidone, low substitution It is found to be hydroxypropylcellulose, crystalline cellulose, corn starch and the like, and these components are preferably used.

In addition, a method for producing a particulate pharmaceutical composition according to another aspect of the present invention includes rubiprostone or a pharmaceutically acceptable salt of rubiprostone, or a hydrate of rubiprostone or a pharmaceutically acceptable salt of rubiprostone. And a step of dissolving or dispersing the polymer compound in a solvent to obtain a mixed solution, and a step of removing the solvent from the mixed solution.

The step of removing the solvent from the mixed solution is, for example, a spray drying step or a spray chilling step, but is not limited to these steps.

In this production method, particles can be produced only with a polymer compound and rubiprostone, which is particularly advantageous as a production method for improving the stability of rubiprostone. However, it goes without saying that additives such as excipients in the solution can be simultaneously dispersed in the solution to produce particles, but in this case also, the additive to be blended is preferably crospovidone, low Substitution degree hydroxypropyl cellulose, crystalline cellulose, corn starch and the like.

In addition, about the high molecular compound which stabilizes a rubiprostone, it is free to mix | blend and use 2 or more types, and the solvent used for melt | dissolving or disperse | distributing a rubiprostone and a high molecular compound is methanol, ethanol, isopropanol, etc. An organic solvent and water can be used, but ethanol or a mixed solution of ethanol and water is preferable.

Next, a method for tableting the particulate pharmaceutical composition of the present invention will be described.

Using the particulate pharmaceutical composition produced by the production method of the present invention, it is possible to produce a solid pharmaceutical composition such as fine granules, granules and tablets containing stabilized rubiprostone. The solid pharmaceutical composition of the present invention means a composition that is included in particles, granules, and tablets containing rubiprostone that can be used in various oral dosage forms.

In the case of tableting, it is convenient if the particulate pharmaceutical composition produced by the above method is used, and it can be tableted by adding an excipient, a disintegrant, and a lubricant that do not adversely affect the stability of rubiprostone. is there. In addition, to a mixture of excipients and disintegrants that do not adversely affect the stability of rubiprostone, a solution in which a polymer compound having a function as a binder and rubiprostone are dissolved or dispersed is added and stirred. It would be advantageous if a method of blending a small amount of a lubricant or the like into particles produced by the granulation method or spray granulation method and press-molding them into tablets can be adopted. Excipients and disintegrants that do not adversely affect the stability of rubiprostone are crospovidone, low-substituted hydroxypropylcellulose, crystalline cellulose, corn starch, etc., and try to make tablets by making effective use of these additives Is significant, and there is a high possibility that rubiprostone can be stabilized and tableted.

However, in addition to the stability of rubiprostone, tablets have various conditions to be secured such as tablet strength, disintegration, solubility, and appearance change after opening and storage. For the purpose of contributing to these characteristics, Even additives that adversely affect stability may have to be formulated and used. Examples of additives that contribute to the moldability, disintegration, dissolution, appearance change, etc. of such tablets include lactose, lactose hydrate, D-mannitol, erythritol, anhydrous calcium hydrogen phosphate, carmellose, carmellose Examples thereof include calcium, croscarmellose sodium, magnesium aluminate metasilicate, and light anhydrous silicic acid. When blending such additives, separate from the particles and granules that have stabilized rubiprostone, use a binder solution that blends these additives and dissolves the polymer compound, and does not contain any drug. Made into particles and granules, mixed with particles and granules consisting of rubiprostone and a polymer compound, mixed with a small amount of lubricant, etc., and pressed into tablets to reduce contact with rubiprostone Thus, a method of simultaneously achieving stabilization can be employed.

When preparing a mixture of particles and granules for tableting by such a method, in addition to excipients and disintegrants, lubricants, fluidizing agents, sour agents, sweeteners, refreshing agents, fragrances, coloring agents, etc. These additives can be contained, and the tablets to be produced can be freely made into orally disintegrating tablets.

The lubricant is not particularly limited, and examples thereof include magnesium stearate, calcium stearate, talc, stearic acid, and sodium stearyl fumarate.

Examples of the fluidizing agent include silicates such as calcium silicate, anhydrous silicic acid such as light anhydrous silicic acid, and hydrated silicon dioxide.

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

The sweetener is not particularly limited, and examples thereof include aspartame, sucralose, acesulfame potassium, saccharin sodium, dipotassium glycyrrhizin, stevia, and thaumatin.

As the refreshing agent, one or more kinds selected from fennel oil, camphor, mint oil, mint, peppermint, menthol and the like can be used.

Examples of flavors include menthol, vanilla, mint, lemon, orange, grapefruit, and yogurt flavor.

Examples of the colorant include edible blue No. 2, edible red No. 3, edible yellow No. 4, edible yellow No. 5, ferric oxide, yellow ferric oxide, aluminum chelate, titanium oxide, talc, etc. It is not limited to.

The method of pressure molding is not particularly limited, and examples thereof include a method using a single-punch tableting machine, a rotary tableting machine, etc., using a tabletting mortar, a tableting upper punch and a lower punch. . The tableting pressure is not particularly limited, and is, for example, in the range of 2 to 15 kN / cm ² , preferably 5 to 110 kN / cm ² , and the strength and disintegration property of the manufactured preparation can withstand the market handling. Anything is acceptable.

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.
Hydroxypropylmethylcellulose (TC-5R, Shin-Etsu Chemical Co., Ltd.), Hydroxypropylcellulose (HPC-L, Nippon Soda Co., Ltd.), Povidone (Collidon 90F, BASF Japan Ltd.), Copolyvidone (Collidon VA64, BASF Japan Ltd.) , Polyvinyl alcohol (Gohsenol EG-05, Nippon Synthetic Chemical Industry Co., Ltd.), aminoalkyl methacrylate copolymer E (Eudragit E100, Evonik Japan Co., Ltd.), polyvinyl acetal diethylaminoacetate (AEA, Mitsubishi Chemical Foods Co., Ltd.), low substituted hydroxy Propylcellulose (LH-31, Shin-Etsu Chemical Co., Ltd.), Crospovidone (Polyplastone XL-10, ASHLAND), Lactose hydrate (Pharmacos) 200, DFE pharma), lactose hydrate (Dilactose S, Freund Sangyo Co., Ltd.), corn starch (corn starch, Nippon Food Processing Co., Ltd.), crystalline cellulose (Theolas, Asahi Kasei Co., Ltd.), magnesium stearate (Taihei Chemical Industrial Co., Ltd.) Company), D-mannitol (Pearlitol, Rocket Japan).

Example 1
24 mg of rubiprostone dissolved in ethanol (Examples 1-1 to 1-3, 1-6 to 1-11, comparative example) or a 1: 1 mixture of ethanol and water (Examples 1-4 and 1-5) And adjusted to 100 mL (240 μg / mL). 100 mg of the sample (polymer compound) shown in Table 1 was weighed into a cylindrical glass container having an internal volume of about 30 mL. Next, 0.1 mL of the solution was added to the sample in the glass container, and the amount added was accurately measured, and then lightly mixed. After leaving for a while, the solvent was evacuated in a draft chamber and dried to prepare samples of the particulate pharmaceutical compositions of Examples 1-1 to 1-11.

Comparative Examples 1 to 3
In the same manner as in Example 1, 24 mg of rubiprostone was dissolved in ethanol and prepared to be 100 mL (240 μg / mL). A sample of Comparative Example 1 was prepared by adding 0.1 mL of the solution to a cylindrical glass container having an internal volume of about 30 mL, evacuating the solvent in a draft chamber, and drying. A sample of Comparative Example 2 was prepared by weighing 24 μg of rubiprostone crystals into a cylindrical glass container having an internal volume of about 30 mL. Further, samples of Comparative Examples 3-1 and 3-2 were prepared in the same manner as in Example 1 except that the excipient shown in Table 1 was used instead of the polymer compound of Example 1 as a sample.

Test example 1
The glass container containing the sample manufactured in Example 1 and Comparative Examples 1 to 3 was sealed in an aluminum bag together with PharmaKeep (KD-20, Mitsubishi Gas Chemical Industries, Ltd.), and placed in a thermostat at 60 ° C. for one week or After storage for 2 weeks, the residual amount of rubiprostone was measured. The results are shown in Table 1.

Measuring method of residual amount of rubiprostone 10 mL of 50% acetonitrile was added to a glass container containing a sample. The sample was irradiated with ultrasonic waves for 30 minutes and filtered through PTFE (0.45 μm) to obtain a sample solution (2.4 μg / mL). Separately, about 6 mg of rubiprostone was accurately weighed and adjusted to 50 mL with acetonitrile. 1 mL of this solution was accurately taken and made exactly 50 mL with 50% acetonitrile to obtain a standard solution (2.4 μg / mL). The analysis conditions were as follows.
Column: Waters ACQUITY UPLC, 1.8 μm, 2.1I. D. × 50mm
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 rubiprostone amorphous (Comparative Example 1) and crystals (Comparative Example 2) decomposed to a residual amount of 30% or less after storage for 1 week. On the other hand, the particulate pharmaceutical compositions using the polymer compounds of Examples 1-1 to 1-11 contained lubiprostone after 1 week and after 2 weeks as compared with Comparative Examples 1 to 3. The amount was high. Particularly in Examples 1-1 to 1-8, 70% or more remained after 1 week and about 60% or more after 2 weeks, indicating that rubiprostone was stabilized.

In particular, Example 1-1 (hydroxypropylmethylcellulose), Example 1-3 (copolyvidone), Example 1-4 (povidone), Example 1-5 (polyvinyl alcohol), Example 1-6 (polyvinyl acetal diethylamino) Acetate) and Example 1-8 (crospovidone) were found to be extremely stabilized with a residual amount of 90% or more after 2 weeks. These polymer compounds are polymer compounds having a glucose ring as a constituent unit, and are composed of a polymer compound having an average number of hydroxyl groups per glucose ring unit of 2 or less and a monomer having a vinyl group. This is a polymer compound produced by polymerization, and the proportion of the hydroxyl group in the structural unit of the compound is 1 or less and corresponds to any polymer compound not containing alkylacrylic acid.

It was also found that lactose hydrate and D-mannitol, which are commonly used excipients, have no effect of particularly stabilizing rubiprostone (Comparative Examples 3-1 and 3-2).

Example 2
Tablets were made according to the formulation shown in Table 2. 1.5 parts by weight of hydroxypropylmethylcellulose (TC-5R) and 0.024 parts by weight of rubiprostone were taken and dissolved in 82 parts by weight of a 4: 1 mixed solvent of ethanol and water to prepare a drug solution. 14 g of lactose hydrate (Pharmacatose 200), 4.88 g of corn starch (corn starch), 2 g of crystalline cellulose (Theolas PH101), 1 g of crospovidone (polyplastidone XL-10), hydroxypropylmethylcellulose (TC-5R) ) Was mixed in a mortar, and 8.3524 g of the drug solution was added and kneaded, sieved, and dried. Magnesium stearate was added to and mixed with the particles obtained by drying, and a tablet having a weight of 230 mg was prepared using an 8 mm 2 stage R punch.

Example 3
Tablets were produced in the same manner as in Example 2 except that hydroxypropylcellulose (HPC-L) was used instead of hydroxypropylmethylcellulose (TC-5R) used in Example 2.

Test example 2
The tablets produced in Examples 2 to 3 were sealed in an aluminum bag together with PharmaKeep KD-20, stored in a thermostat at 60 ° C. for 1 week, and then the residual amount of rubiprostone was measured. It was shown in 3.

A solution in which rubiprostone is dissolved in a solvent together with hydroxypropylcellulose (HPC-L) or hydroxypropylmethylcellulose (TC-5R) as a binder and stabilizer is used as a binder solution. Tablets using particles made by granulating as a unitary lubiprostone, binder and stabilizer, and excipients added to a mixture of lactose hydrate, corn starch, crystalline cellulose and crospovidone In the modified Examples 2 and 3, it was found that rubiprostone was clearly stabilized as compared with Comparative Example 2. At the same time, in Example 3 using hydroxypropyl cellulose (HPC-L), which is a polymer compound having a glucose ring as a structural unit and the average number of hydroxyl groups per glucose ring unit is 3, The residual amount at 1 ° C. for one week was 80% or less, and it was found that the contribution to stabilization was small.

Example 4
In accordance with the formulation shown in Table 4, 1.5 parts by weight of hydroxypropylmethylcellulose (TC-5R) and 0.024 parts by weight of rubiprostone are dissolved in 22.5 parts by weight of a mixed solvent of 4: 1 parts by weight of ethanol and water. A drug solution was prepared. 4.5 g of crospovidone (polyplastidone XL-10) was added, 7.2072 g of drug solution was added, kneaded in a mortar, sieved, and dried to produce particles containing rubiprostone. Lubiprostone-containing particles (3.3048 g) were mixed with 30.16 g of lactose hydrate (Dilactose S), 8 g of crystalline cellulose (Theolas PH301), 4.4 g of corn starch, and 0.24 g of magnesium stearate. A tablet having a weight of 230.5 mg was prepared using an R-shaped scissors.

Example 5
To 3.3048 g of rubiprostone-containing particles produced in the same manner as in Example 4, 41.96 g of crystalline cellulose (Theolas PH301), 0.6 g of crospovidone (polyplastidone XL10), and 0.24 g of magnesium stearate are added. The mixture was mixed to produce a tablet having a weight of 230.5 mg using an 8 mm 2-stage R punch.

Example 6
Rubiprostone-containing particles were produced in the same manner as in Example 4. 1 part by weight of hydroxypropylmethylcellulose (TC-5R) was taken and dissolved in 7.5 parts by weight of a mixed solvent of 4: 1 part by weight of ethanol and water to prepare a binder solution. Add 18.5 parts by weight of lactose hydrate, 4.58 parts by weight of crystalline cellulose (Theolas PH101) and 1.9 parts by weight of corn starch, and add 8.5 parts by weight of the binder solution. After kneading in a mortar, sieving and drying, hydroxypropylmethylcellulose (TC-5R) granulated particles were produced. Take 3.3048 g of rubiprostone-containing particles, 42.56 g of hydroxypropylmethylcellulose (TC-5R) granulated particles and 0.24 g of magnesium stearate, mix and mix using an 8 mm 2 stage R sputum and weighing 230.5 mg Tablets were made.

Test example 3
The tablets produced in Examples 4 to 6 and sealed in an aluminum bag together with Pharmakeep KD-20 were stored in a thermostat at 60 ° C. for 1 week, and the residual amount of rubiprostone was measured. This is shown in FIG.

A solution in which rubiprostone is dissolved in a solvent together with hydroxypropylmethylcellulose (TC-5R) as a binder and stabilizer is used as a binder solution, and this solution is added to crospovidone (polyplastidone XL-10). Using particles made of propylmethylcellulose and crospovidone so as to be united, other additives were mixed with this to make a tablet.

Hydroxypropylmethylcellulose and crospovidone are polymer compounds having a glucose ring as a constituent unit, and are composed of a polymer compound having an average number of hydroxyl groups per glucose ring unit of 2 or less, and a monomer having a vinyl group. It is a polymer compound produced by addition polymerization, and the proportion of the hydroxyl group in the structural unit of the compound is 1 or less, and it does not contain any alkyl acrylic acid. It was expected that rubiprostone in the particles was very preferably stabilized.

The result was as expected and the remaining amount at 60 ° C. for 1 week was the worst, 97.3%, and a highly stable tablet was obtained. Among them, in Example 5 in which particles used for granulating a commonly used excipient with hydroxypropylmethylcellulose to reduce the surface exposure of the excipient were mixed, and a component that does not accelerate the decrease in the content of rubiprostone by contact with rubiprostone. It was found that Example 6 using a certain crystalline cellulose (Ceolus) showed almost no decrease in content at 60 ° C. for 1 week.

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 (10)

A particulate pharmaceutical composition comprising 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 polymerization of 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 particulate pharmaceutical composition according to claim 1, wherein the polymer compound obtained by addition polymerization of is chemically modified. The particulate pharmaceutical composition according to claim 2, wherein the polymer compound having a glucose ring as a structural unit has an average number of hydroxyl groups per glucose ring unit of 2 or less. The particulate pharmaceutical composition according to claim 2, wherein the polymer compound obtained by addition polymerization of a monomer having a vinyl group has 1 or less hydroxyl groups per structural unit. The particulate pharmaceutical composition according to any one of claims 1 to 4, wherein the polymer compound does not contain alkylacrylic acid. The polymer compound is at least one polymer compound selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl acetal diethylaminoacetate, and crospovidone. The particulate pharmaceutical composition according to any one of claims 1 to 5. A solid pharmaceutical composition comprising the particulate pharmaceutical composition according to any one of claims 1 to 6. The solid pharmaceutical composition according to claim 7, which is a granule, fine granule, capsule, powder, pill, dry syrup, or tablet. 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 mixture;
The method for producing a particulate pharmaceutical composition according to any one of claims 1 to 6, comprising a step of adding the mixed solution to an additive, wet granulating and drying. 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 mixture;
The method for producing a particulate pharmaceutical composition according to any one of claims 1 to 6, comprising a step of removing the solvent from the mixed solution.