JP2006045218A - Medicinal composition for oral administration - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a medicinal composition for oral administration that is free from quality deterioration in long-term preservation. <P>SOLUTION: This medicinal composition having a reduced amount of moisture, especially free of water therein can prevent its active ingredient from being decomposed by the internal moisture. Therefore, the medicinal composition having a moisture activity value of about 0.2 or less and being subjected to seal packaging such as PTP (press through package) can be preserved for a long time without decomposition of the active ingredient, even though the active ingredient are sensitive to humidity. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a pharmaceutical composition for oral administration which can be stored for a long period of time, which significantly prevents degradation of active ingredients.

  In general, pharmaceutical products are stored in a cool and dark place. However, if it is not a preparation that is stable even under other conditions (for example, under high temperature or high humidity), convenience is impaired when the pharmaceutical is stored or transported.

  Therefore, a pharmaceutical composition containing an active ingredient unstable to light is placed in a light-shielding container, or a pharmaceutical composition containing an active ingredient unstable to humidity is a PTP (press-through package; Press through package) or a desiccant is placed in a storage container.

  However, the stability of a pharmaceutical composition containing an active ingredient unstable to humidity may be impaired even if it is stored in a package with low moisture permeability. This is because packaging with low moisture permeability makes it difficult for external moisture to permeate into the package, while moisture contained in the raw material of the pharmaceutical composition and moisture mixed in the process of producing the pharmaceutical composition are released outside the package. However, it is considered that one reason is that the active ingredient is decomposed by moisture inherent in the pharmaceutical composition. Such a phenomenon is extremely difficult to predict and prevent, and becomes a serious problem in quality control.

  For example, carbon dioxide foamed preparations used as fragrances are decomposed while giving out carbon dioxide gas and water due to slight moisture in the preparation, and the generated carbon dioxide gas causes the phenomenon that the packaging material swells or even ruptures. There is a risk of happening. In order to avoid such inconveniences, it is disclosed that the amount of free water in the water content of the carbon dioxide foamed formulation should be specified (see Patent Document 1).

  Japanese Patent No. 3646310 discloses a pharmaceutical composition for oral administration containing limaprost alphadex (see Patent Document 2).

JP 2001-170153 A.

Japanese Patent No. 3646310.

  A pharmaceutical composition for oral administration that can be stored for a long time without an active ingredient being decomposed by moisture in the pharmaceutical composition has been desired.

  The water in the pharmaceutical composition is classified into bound water and free water. Free water easily moves and evaporates under the influence of temperature and humidity, compared to bound water that is firmly bonded to the constituents of the pharmaceutical composition. As a result of intensive studies to solve the above-mentioned problems, the present inventors have determined that the active ingredient is decomposed by endogenous moisture in a pharmaceutical product in which the amount of free water in the pharmaceutical composition is reduced to a water activity value of 0.2 or less. I found for the first time that it was difficult to be done. That is, by limiting the water activity value in a pharmaceutical composition to 0.2 or less, it is difficult to pass moisture such as PTP packaging through a pharmaceutical composition containing an active ingredient unstable to humidity (eg, limaprost). The present invention has been completed by finding that the active ingredient is not decomposed by moisture even when sealed for a long period of time.

That is, the present invention
1. A pharmaceutical composition for oral administration having a water activity value of 0.2 or less at 25 ° C.,
2. 2. The pharmaceutical composition according to 1 above, which is a sealed package
3. 2. The pharmaceutical composition according to 2 above, wherein the sealed package is a PTP package or a bottle;
4). The pharmaceutical composition according to 2 above, which is a tablet,
5. 4. The pharmaceutical composition according to 4 above, which is produced using a raw material having an overall water activity value of 0.4 or less at 25 ° C. after mixing the drug substance and the preparation base,
6). 4. The pharmaceutical composition according to 4 above, which is produced by drying an uncoated tablet,
7). 5. The pharmaceutical composition according to 4 above, which comprises limaprost alphadex.
8). (1) Limaprost alphadex, and (2) one or more selected from glucans and excipients,
9. (1) A lyophilized product containing limaprost alphadex and glucans, and (2) one or more selected from glucans and excipients,
10. 10. The pharmaceutical composition according to 9 above, wherein the glucan is one or more selected from dextrin, dextran and pullulan,
11. 10. The pharmaceutical composition according to 9 above, wherein the excipient is one or more selected from lactose, trehalose and corn starch,
12 6. The pharmaceutical composition according to 5 above, wherein the drug substance is a lyophilized product containing limaprost alphadex and glucans, and the formulation base is one or more selected from glucans, excipients and additives,
13. The above-mentioned 6 produced by adding glucans and excipients to lyophilized products containing Limaprost alphadex and glucans, and further adding additives as necessary, and drying the uncoated tablets. The pharmaceutical composition described,
14 A sealed packaging tablet containing limaprost alphadex and having a water activity value of 0.2 or less at 25 ° C.,
15. (1) Limaprost, a freeze-dried product containing alphadex and glucans, and (2) one or more selected from glucans and excipients, and the sealed packaging tablet according to 14 above,
16. 16. A method for producing a pharmaceutical composition as described in 4 above, wherein a raw material having an overall water activity value mixed with the drug substance and the preparation base is 0.4 or less at 25 ° C. is used. 5. The method for producing a pharmaceutical composition according to 4 above, wherein the uncoated tablet is dried.

  In this specification, the water activity value means the ratio of free water in the total water contained in the pharmaceutical composition, and the water vapor pressure in the sealed container containing the pharmaceutical composition and the vapor pressure of pure water at that temperature. It is defined by the ratio of The water activity value at 25 ° C. can be easily measured by using a known method, and for example, it can be measured using AQUA LAB (manufactured by Decagon; Cat. No. CX-3TE).

  In the pharmaceutical composition of the present invention, the water activity value at 25 ° C. is adjusted to about 0.2 or less, preferably about 0.15 or less, more preferably about 0.12 or less. In order to adjust the water activity value of the pharmaceutical composition to about 0.2 or less, either (1) using a raw material with a low water content or producing a pharmaceutical composition using a dried raw material, or (2) The tablet may be dried at 25 ° C. until the water activity value is about 0.2 or less.

  Here, the raw material refers to a component of the pharmaceutical composition, and includes a drug substance or a formulation base. The drug substance means an active ingredient in a pharmaceutical composition, and of course, lyophilized products containing the active ingredient are also included. The formulation base means components other than the drug substance in the pharmaceutical composition necessary for molding the formulation. In order to produce a pharmaceutical composition having a water activity value of about 0.2 or less at 25 ° C., the water activity value after mixing the drug substance and the formulation base should be 0.4 or less at 25 ° C.

  An uncoated tablet refers to a tableted raw material.

  Examples of the method for drying the raw material and the uncoated tablet include gas blow drying, vacuum drying, and heating vacuum drying. Examples of the gas used in the gas blow drying include hot air, warm air, inert gas (for example, oxygen, nitrogen, argon, etc.) and the like.

  The method for drying the raw material is preferably hot air drying.

  The method for drying the uncoated tablet is preferably drying under reduced pressure.

  A pharmaceutical composition containing a drug substance that is unstable with respect to humidity can block external moisture by applying sealed packaging with low moisture permeability. Furthermore, by setting the water activity value of the pharmaceutical composition to about 0.2 or less, it is possible to avoid the decomposition of the active ingredient by the endogenous water in the pharmaceutical composition, and it can be stably stored for a long time. .

  The sealed package with low moisture permeability may be anything as long as it is difficult to permeate moisture, and includes a hermetic package that prevents intrusion of moisture or a sealed package that prevents intrusion of gas and microorganisms. Sealed packaging refers to packaging made of materials that prevent intrusion of moisture, such as glass, plastic, aluminum, moisture-proof paper, and the like, and examples include bottles (glass bottles, plastic bottles, etc.), PTP packaging, and strip packaging. PTP packaging is preferable. Further, in order to further improve moisture resistance, a sealed package and a desiccant may be combined, or the above-mentioned pharmaceutical composition packed in PTP may be further filled in an aluminum pillow.

  PTP packaging is one of the packaging forms of tablets or capsules. After forming a sheet according to the type of pharmaceutical product, the hollow is filled with the pharmaceutical product and sealed with aluminum foil. In general, polyvinyl chloride is used for the sheet, but polyvinyl chloride and polyvinylidene chloride may be used in combination as a type having improved moisture resistance. Any material may be used as long as the material has excellent moisture resistance, and the thickness of the material may be increased in order to improve moisture resistance.

  As the drug substance unstable to humidity, for example, limaprost, its α-cyclodextrin inclusion compound, or a lyophilized product containing them (for example, lyophilized product containing limaprost alphadex and glucans) Can be mentioned.

  In this specification, limaprost means the following formula:

(Where

Represents a β-configuration,

Represents an α-configuration. The chemical name is (E) -7-[(1R, 2R, 3R) -3-hydroxy-2-[(3S, 5S)-(E) -3-hydroxy-5-methyl] -1-nonenyl] -5-oxocyclopentyl] -2-heptanoic acid.

  In this specification, Limaprost Alphadex is the following formula:

(Wherein all symbols have the same meaning as described above), and the chemical name is (E) -7-[(1R, 2R, 3R) -3-hydroxy-2-[(3S , 5S)-(E) -3-Hydroxy-5-methyl-1-nonenyl] -5-oxocyclopentyl] -2-heptanoic acid α-cyclodextrin inclusion compound (Registry No. 74397-12-9) . This compound is known and can be produced by a known method, for example, the method described in JP-A No. 55-100300.

  Limaprost is a compound that is unstable with respect to humidity.

(Wherein all symbols have the same meaning as described above) 17S, 20-dimethyl-trans-Δ ² -PGA ₁ (hereinafter abbreviated as 11-deoxy form), or the following formula

(Wherein all symbols have the same meaning as described above) 17S, 20-dimethyl-trans-Δ ² -8-iso-PGE ₁ (hereinafter abbreviated as 8-iso form) and the like. Generated. It is known that the 11-deoxy form is mainly produced as a decomposition product.

  The production rate of 11-deoxy form can be shown, for example, by the amount (mass ratio) of 11-deoxy form relative to the total amount of limaprost, 11-deoxy form and 8-iso form in the composition. Specifically, the determination of limaprost and degradation products of limaprost (8-iso form, 11-deoxy form) can be performed, and the sum of limaprost and degradation products can be calculated as 100.

  The amount of limaprost, 11-deoxy isomer, and 8-iso isomer can be measured using a known analysis method (for example, high performance liquid chromatography, gas chromatography, thin layer chromatography, etc.). The measurement is preferably performed using a high performance liquid chromatographic method. By using the high performance liquid chromatographic method, the amount of limaprost, 11-deoxy form, and 8-iso form can be measured with high sensitivity under the same conditions and using the same sample. The high performance liquid chromatographic method is performed by a known method.

Specifically, the test is performed under the following high performance liquid chromatography (HPLC) test conditions. By using this method, it is possible to measure the amount of limaprost and degradation products and calculate the ratio of limaprost and degradation products. Whether or not the amount of 11-deoxy form is not less than the detection limit and not more than about 10%, preferably not less than the detection limit and not more than about 8%, more preferably not less than the detection limit and not more than about 5% by using this method. Can be judged.
HPLC test conditions :
Detector: ultraviolet absorptiometer (measurement wavelength: 215 nm);
Column: a stainless tube having an inner diameter of about 5 mm and a length of 10 to 20 cm is packed with 3 to 5 μm of octadecylsilylated silica gel for liquid chromatography;
Mobile phase: 0.02 M potassium dihydrogen phosphate (pH 4.3) / acetonitrile / isopropanol mixture (9: 5: 2);
Flow rate: Adjust so that the retention time of limaprost is about 12 minutes;
Internal standard solution: A solution of testosterone in acetonitrile (13 → 20000).

  In the present specification, any formulation base may be used as long as it is generally used, and examples thereof include glucans, excipients or additives.

  In the present specification, glucan means a glucan or a product obtained by treating glucan with a chemical or enzymatic method. Glucan is a general term for polysaccharides composed of D-glucose, and is divided into α-glucan and β-glucan. α-glucan has α1 → 4 glucoside bond (eg, starch, glycogen, etc.), α1 → 6 glucoside bond (dextran, etc.), or α1 → 4 and α1 → 6 glucoside bond (eg, , Pullulan, etc.). Typical examples of β-glucan include cellulose having a β1 → 4 glucoside bond. Examples of those obtained by treating glucan with a chemical or enzymatic method include those obtained by treating starch with a chemical or enzymatic method, such as dextrin or pregelatinized starch. The glucans used to produce a lyophilized product containing Limaprost alphadex and glucans may be the same as or different from the glucans added, for example, to produce tablets. In the present invention, preferable glucans include α-glucan. More preferably, dextran (for example, dextran, dextran 40, dextran 70 etc.), dextrin, pullulan, etc. are mentioned. Dextran is preferably used as a glucan used for producing a lyophilized product containing limaprost alphadex and glucans, and dextrin is preferably used as a glucan added to produce tablets.

  In the present specification, examples of the excipient include glucose, fructose, maltose, lactose, isomerized lactose, reduced lactose, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, corn starch, Potato starch, wheat starch, rice starch, crystalline cellulose, talc, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate and the like. Preferably, lactose, trehalose, corn starch or the like is used.

  A pharmaceutical composition containing limaprost, for example, dissolves limaprost alphadex and glucans in a solvent (for example, water, organic solvent (eg, ethanol, acetone, etc.)), freeze-dried according to a conventional method, and pulverizes the freeze-dried product After that, a stable preparation can be produced by further adding glucans and adding additives such as a lubricant as necessary. However, although a preparation containing a large amount of glucan is excellent in stability, there is a problem that it has adhesiveness. Therefore, an arbitrary excipient (for example, lactose, trehalose or corn starch) is added to the lyophilized product containing Limaprost alphadex and glucans in a proportion that does not impair the glucans and / or stability. By adding an additive such as a lubricant as necessary, a stable preparation with reduced adhesion can be produced. In order to produce a tablet economically and efficiently, the content of the lyophilized product in one tablet is preferably as low as possible, specifically about 5% or less.

  One tablet of the pharmaceutical composition of the present invention contains, for example, about 5 to 10 μg of limaprost. As for the amount of glucan compounded, when the weight of the final preparation is 100%, the compounded content of glucan is mass%, preferably about 0.1% to 99%, more preferably about 0.5% to 30%. %, More preferably about 1% to 15%. Further, the blending content of the excipient is preferably about 1 to 99.5%, more preferably about 70 to 99%, and still more preferably about 85 to 98.5%. Here, the blending amount of glucans refers to the total amount of glucans used to produce lyophilized products containing limaprost alphadex and glucans and glucans added to produce tablets.

  For example, in the case of a tablet containing about 5 to 10 μg of limaprost in a 90 mg tablet, about 0.9 to 13.5 mg of glucan and about 76.5 to 88.7 mg of excipient are blended.

  For example, in the case of a tablet containing about 5 to 10 μg of limaprost in a 100 mg tablet, about 1 to 15 mg of glucan and about 84 to 98.5 mg of excipient are blended.

  For example, in the case of a tablet containing about 5 to 10 μg of limaprost in a 200 mg tablet, about 2 to 30 mg of glucan and about 168 to 197 mg of excipient are blended.

  Examples of the pharmaceutical composition of the present invention include, for example, 1 tablet of a pharmaceutical composition containing about 5 to 10 μg of limaprost, about 0.5 to 15% of dextran, about 1 to 15% of dextrin, and about 60 of lactose. Those containing 95% and about 0.5% to 10% corn starch are preferred.

  The pharmaceutical composition of the present invention is preferably a solid preparation (eg, tablet, granule, capsule, etc.). More preferred are tablets (for example, uncoated tablets, dry-coated tablets, coated tablets, trilayer tablets, etc.).

  The pharmaceutical composition containing limaprost may further contain an additive in addition to limaprost alphadex and glucans and / or excipients. The additive may be any one that is generally used in the production of solid preparations. For example, binders, lubricants, disintegrating agents, flavoring agents, flavoring agents, surfactants, fragrances, and coloring agents. Antioxidants, masking agents, antistatic agents, fluidizing agents, wetting agents, and the like can be used by appropriately blending one or more.

  Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin, dextrin and the like. These may be used alone or in combination of two or more. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol and the like. Examples of the disintegrant include low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, hydroxypropyl starch, corn starch and the like. Examples of the corrigent include sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, sodium saccharine, dipotassium glycyrrhizin, sodium glutamate, 5′-sodium inosinate, 5 ′ -Sodium guanylate etc. are mentioned. Examples of the flavoring agent include trehalose, malic acid, maltose, potassium gluconate, anise essential oil, vanilla essential oil, cardamom essential oil and the like. Examples of the surfactant include polysorbate (polysorbate 80 and the like), polyoxyethylene / polyoxypropylene copolymer, sodium lauryl sulfate, and the like. As a fragrance | flavor, lemon oil, orange oil, menthol, brackish oil etc. are mentioned, for example. Examples of the colorant include titanium oxide, food yellow No. 5, food blue No. 2, iron sesquioxide, yellow iron sesquioxide, and the like. Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like. Examples of the masking agent include titanium oxide. Examples of the antistatic agent include talc and titanium oxide. Examples of the fluidizing agent include light anhydrous silicic acid, talc, hydrous silicon dioxide and the like. Examples of the wetting agent include polysorbate 80, sodium laurate sulfate, sucrose fatty acid ester, macrogol, and hydroxypropyl cellulose (HPC).

  The preparation of the present invention can be produced by a known method, for example, using a tumbling granulator, a stirring granulator, a fluid granulator, a centrifugal tumbling granulator, a dry granulator, etc. By doing so, granules can be produced.

  For the solid preparation of the preparation of the present invention, for example, the granules obtained by the above method can be used as they are as granules. The solid preparation of the present invention also includes capsules containing the above granules. Capsules can be produced by a known method. For example, the above-mentioned granules, and those to which additives are added as necessary are hard capsules (for example, gelatin capsules, hydroxypropylmethylcellulose (HPMC) capsules, pullulan capsules, polyvinyl alcohol) (PVA) capsule or the like) can be filled by using a capsule filling machine. The preparation of the present invention also includes a tablet containing the granule. The tablet can be produced by a known method. For example, the above granules and additives as necessary may be mixed evenly, and compression-molded by a rotary tableting machine to obtain an uncoated tablet, which may be used as a tablet as it is, Further, it may be coated with a coating base. It is also possible to prepare a mixed powder containing a drug or the like without granulation and tablet it with a rotary tableting machine or the like.

  The pharmaceutical composition containing limaprost of the present invention is useful for the treatment of peripheral circulatory disorders such as obstructive thromboangiitis or lumbar spinal stenosis.

  The pharmaceutical composition having a water activity value of about 0.2 or less according to the present invention can avoid degradation of the active ingredient due to the influence of moisture in the pharmaceutical composition. It can be stored stably for a long time.

Examples and Experimental Examples are shown below, but these are for deepening the understanding of the present invention and do not limit the scope of the present invention.
Example 1
1) Production of dextran body powder Dextran 40 (350 g) was dissolved in 1875 g of purified water. 50 g of limaprost alphadex was dissolved in this, and then this solution was transferred to a freeze-drying tray and freeze-dried according to a conventional method. After freeze-drying, the material crushed with a sieve was pulverized with a pulverizer to obtain dextran powder.
2) Manufacture of tablets 39.9 g of the above dextran powder is mixed with 260 g of dextrin, 2679 g of lactose, 6 g of light anhydrous silicic acid, and 15 g of stearic acid, and using a rotary tableting machine (manufactured by Kikusui Seisakusho). Tableting was performed at a tableting pressure of 800 kg / cm ² (1 tablet 100 mg, 6.5 mmφ) to obtain 20000 tablets containing 5 μg of limaprost per tablet.
<Composition in one tablet (100 mg)>
Limaprost Alphadex 0.167 mg
Dextran 40 (for lyophilization) 1.167 mg
Dextrin (for addition) 8.67 mg
Lactose 89.3 mg
Light anhydrous silicic acid 0.20 mg
Stearic acid 0.50 mg
100 mg total
Example 2 (Production of corn starch 2.5% formulation)
1) Production of dextran body powder Dextran 40 (350 g) was dissolved in 1875 g of purified water. 50 g of limaprost alphadex was dissolved in this, and then this solution was transferred to a freeze-drying tray and freeze-dried according to a conventional method. After freeze-drying, the material crushed with a sieve was pulverized with a pulverizer to obtain dextran powder.
2) Manufacture of tablets Dextrin 26g, lactose 260.4g, corn starch 7.5g, light anhydrous silicic acid 0.6g, and stearic acid 1.5g were mixed with 4g of the above dextran powder, and a rotary tableting machine (Kikusui) 2,000 tablets with 5 μg of limaprost per tablet were obtained by tableting with a tableting pressure of 800 kg / cm ² (100 mg, 6.5 mmφ).
<Composition in one tablet (100 mg)>
Limaprost Alphadex 0.167 mg
Dextran 40 (for lyophilization) 1.167 mg
Dextrin (for addition) 8.67 mg
Lactose 89.3 mg
Corn starch 2.5 mg
Light anhydrous silicic acid 0.20 mg
Stearic acid 0.50 mg
100 mg total
Example 3 (Production of 5% corn starch preparation)
1) Production of dextran body powder Dextran 40 (350 g) was dissolved in 1875 g of purified water. 50 g of limaprost alphadex was dissolved in this, and then this solution was transferred to a freeze-drying tray and freeze-dried according to a conventional method. After freeze-drying, the material crushed with a sieve was pulverized with a pulverizer to obtain dextran powder.
2) Preparation of tablets 4 g of the above dextran powder was mixed with 26 g of dextrin, 252.9 g of lactose, 15 g of corn starch, 0.6 g of light anhydrous silicic acid, and 1.5 g of stearic acid, and a rotary tableting machine (Kikusui Seisakusho ( ), And tableting was performed at a tableting pressure of 800 kg / cm ² (1 tablet 100 mg, 6.5 mmφ) to obtain 2000 tablets containing 5 μg of limaprost per tablet.
<Composition in tablet (100 mg)>
Limaprost Alphadex 0.167 mg
Dextran 40 (for lyophilization) 1.167 mg
Dextrin (for addition) 8.67 mg
Lactose 84.3 mg
Corn starch 5.0 mg
Light anhydrous silicic acid 0.20 mg
Stearic acid 0.50 mg
100 mg total
Example 4 (Production of a corn starch 7.5% formulation)
1) Production of dextran body powder Dextran 40 (350 g) was dissolved in 1875 g of purified water. 50 g of limaprost alphadex was dissolved in this, and then this solution was transferred to a freeze-drying tray and freeze-dried according to a conventional method. After freeze-drying, the material crushed with a sieve was pulverized with a pulverizer to obtain dextran powder.
2) Manufacture of tablets Dextrin 26g, lactose 245.4g, corn starch 22.5g, light anhydrous silicic acid 0.6g, and stearic acid 1.5g were mixed with 4g of the above dextran powder and a rotary tableting machine (Kikusui). 2,000 tablets with 5 μg of limaprost per tablet were obtained by tableting with a tableting pressure of 800 kg / cm ² (100 mg, 6.5 mmφ).
<Composition in one tablet (100 mg)>
Limaprost Alphadex 0.167 mg
Dextran 40 (for lyophilization) 1.167 mg
Dextrin (for addition) 8.67 mg
Lactose 81.8 mg
Corn starch 7.5 mg
Light anhydrous silicic acid 0.20 mg
Stearic acid 0.50 mg
100 mg total
Example 5 (Production of corn starch 10% formulation)
1) Production of dextran body powder Dextran 40 (350 g) was dissolved in 1875 g of purified water. 50 g of limaprost alphadex was dissolved in this, and then this solution was transferred to a freeze-drying tray and freeze-dried according to a conventional method. After freeze-drying, the material crushed with a sieve was pulverized with a pulverizer to obtain dextran powder.
2) Manufacture of tablets 13.3 g of the above dextran powder is mixed with 86.7 g of dextrin, 795 g of lactose, 100 g of corn starch, and 5 g of stearic acid, and using a rotary tableting machine (manufactured by Kikusui Seisakusho) By tableting at a tableting pressure of 800 kg / cm ² (1 tablet 100 mg, 6.5 mmφ), 7000 tablets containing 5 μg of limaprost per tablet were obtained.
<Composition in one tablet (100 mg)>
Limaprost Alphadex 0.167 mg
Dextran 40 (for lyophilization) 1.167 mg
Dextrin (for addition) 8.67 mg
Lactose 79.5 mg
Corn starch 10.0 mg
Stearic acid 0.50 mg
100 mg total
Experimental Example 1: Effect of water activity value on 11-deoxy body production amount The water activity value was reduced to 0.032 by drying the tablet (uncoated tablet) of Example 1 under reduced pressure. The tablet in the low water activity state was arbitrarily humidified to change the water activity value, and the tablet was PTP packaged by a conventional method, filled in an aluminum pillow, and hermetically packaged. This packaged preparation was stored in a stability test apparatus at a temperature of 60 ° C. The preparation was sampled over time, and the production rate of the degradation product (11-deoxy form) of limaprost was analyzed by high performance liquid chromatography (HPLC). The production rate of the decomposition product was calculated with the sum of limaprost and decomposition product being 100. The water activity value (25 ° C.) was measured with Aqua Rab (Dekagon; Cat. No. CX-3TE). The analysis results are shown in Table 1.

As the water activity value increased, the production rate of 11-deoxy form at 60 ° C./1 week also increased. In particular, in the case of a water activity value of 0.384, the production rate of the 11-deoxy form was as large as 5.7%, which exceeded the standard limit value of 5% for pharmaceuticals containing limaprost. Thus, it became clear that the stability in the sealed package form can be improved by lowering the water activity value.
Experimental Example 2: Production rate of 11-deoxy compound at 60 ° C. By drying the tablets of Examples 2, 3, 4 and 5 under reduced pressure, the water activity value was reduced to a range of 0.029 to 0.042, respectively. It was. The tablets in a low water activity state were PTP-packed by a conventional method, filled in an aluminum pillow, and hermetically sealed. This packaged preparation was stored in a stability test apparatus at a temperature of 60 ° C. The preparation was sampled over time, and the production rate of the degradation product (11-deoxy form) of limaprost was analyzed by high performance liquid chromatography (HPLC). The production rate of the decomposition product was calculated with the sum of limaprost and decomposition product being 100. The water activity value (25 ° C.) was measured with Aqua Rab (Decagon Corp .; Cat. No. CX-3TE). The analysis results are shown in Table 2.

Even in the tablets produced in Examples 2, 3, 4 and 5 in which the components were changed, the water activity value of the tablets was lowered, thereby suppressing the production rate of the degradation product (11-deoxy form) of limaprost low. It was clarified that the stability in the sealed package form can be improved.

By adjusting the water activity value to about 0.2 or less, the pharmaceutical composition of the present invention can avoid the active ingredient from being decomposed by the water in the pharmaceutical composition. Therefore, it is very useful as a medicine for clinical provision in which quality does not deteriorate even when stored for a long time.

Claims (17)

A pharmaceutical composition for oral administration having a water activity value of 0.2 or less at 25 ° C. The pharmaceutical composition according to claim 1, which is a sealed package. The pharmaceutical composition according to claim 2, wherein the sealed package is a PTP package or a bottle. The pharmaceutical composition according to claim 2, which is a tablet. The pharmaceutical composition according to claim 4, which is produced using a raw material having an overall water activity value of 0.4 or less at 25 ° C after mixing the drug substance and the preparation base. The pharmaceutical composition according to claim 4, which is produced by drying an uncoated tablet. The pharmaceutical composition according to claim 4, comprising limaprost alphadex. The pharmaceutical composition according to claim 7, comprising (1) limaprost alphadex, and (2) one or more selected from glucans and excipients. The pharmaceutical composition according to claim 7, comprising (1) a lyophilized product containing alphadex and glucans, and (2) one or more selected from glucans and excipients. The pharmaceutical composition according to claim 9, wherein the glucan is one or more selected from dextrin, dextran and pullulan. The pharmaceutical composition according to claim 9, wherein the excipient is one or more selected from lactose, trehalose and corn starch. The pharmaceutical composition according to claim 5, wherein the drug substance is a lyophilized product containing limaprost alphadex and glucan, and the formulation base is one or more selected from glucans, excipients and additives. Claims manufactured by adding glucans and excipients to lyophilized products containing Limaprost alphadex and glucans, and further adding additives as necessary, and drying the uncoated tablets. 6. The pharmaceutical composition according to 6. A sealed packaging tablet containing Limaprost Alphadex and having a water activity value of 0.2 or less at 25 ° C. The sealed packaging tablet according to claim 14, comprising (1) a lyophilized product containing alphadex and glucan, and (2) one or more selected from glucans and excipients. The method for producing a pharmaceutical composition according to claim 4, wherein a raw material having a total water activity value of not more than 0.4 at 25 ° C mixed with the drug substance and the preparation base is used. The method for producing a pharmaceutical composition according to claim 4, wherein the uncoated tablet is dried.