KR20140029467A - Tablet containing limaprost and ??-cyclodextrin - Google Patents

Abstract

The present invention provides a tablet containing lima frost and? -Cyclodextrin, wherein the tablet contains 100% by mass of the whole tablet and contains 30-99% by mass of? -Cyclodextrin.

Description

TABLET CONTAINING LIMAPROST AND β-CYCLODEXTRIN <br> <br> <br> Patents - stay tuned to the technology TABLET CONTAINING LIMAPROST AND β-CYCLODEXTRIN

The present invention relates to tablets containing lima frost and beta -cyclodextrin.

Limafost is known as a prophylactic and / or therapeutic agent for peripheral circulatory disorders, and is a very useful agent for improving symptoms such as obstructive thromboangiitis and lumbar spinal stenosis, which are chronic diseases.

Lima frost is hygroscopic and absorbs water and is liable to decompose. Therefore, commercially available Limafrost AlphaDex tablets are wrapped in PTP and then placed in aluminum pouches to avoid the influence of humidity.

Examples of stable tablets containing lima frost include (1) freeze-dried products containing lima frost alfadex (α-cyclodextrin inclusion body of Limafrost) and glucans, and (2) And the content of the glucan is from 1 to 15 mass%, the water activity value is not more than 0.2 at 25 占 폚, the drug composition is stable, and the adherence is reduced Have been reported (see Patent Document 1).

On the other hand, in general, cyclodextrin is used for solubilization of compounds, masking or stabilization of bitter taste, and the like. For example, it is known that cyclodextrin is dissolved in an aqueous solution together with a drug and the drug is stabilized by inclusion of the drug. However, stabilization effects can not necessarily be obtained by inclusion of cyclodextrin. For example, limafrost alpha-dex is a compound in which limafrost is embedded in alpha -cyclodextrin, but decomposition of lima frost is not greatly suppressed even when limaprost crystals are incorporated with alpha -cyclodextrin. In general, in order to encapsulate a lyophil with cyclodextrin, emulsification (for example, emulsifying with a homogenizer by adding a certain amount of lyophilized product to a 20 to 50% suspension of cyclodextrin), a saturated aqueous solution method (for example, cyclodextrin (For example, mixing water with a saturated aqueous solution of water for 30 minutes to several days and evaporating water or precipitating the precipitate by taking out the precipitate after drying the precipitate), kneading method (The obtained paste is dried on the basis of a regular method), and a mixed pulverization method (for example, a cyclodextrin and a liquor are put in a vibrating mill and pulverized) (Non-Patent Document 1), it is known that when cyclodextrin is simply dissolved in the absence of a solvent without dissolving the cyclodextrin in the absence of a solvent, Because they can not be expected, it can not be improved by the inclusion of stability juyak.

For example, it has been reported that stability is improved by combining? -Cyclodextrin with pravastatin (Patent Document 2). In this patent document, a step of applying a physical force to the mixture of? -Cyclodextrin and pravastatin by mixing and pulverizing? -Cyclodextrin to encapsulate pravastatin, and then kneading with a solution.

It is also known that cyclodextrin is used as an additive in the manufacture of a buccal cavity in the mouth for the purpose of improving collapsibility. Regarding the refinement using cyclodextrin as an additive, for example, in the oral cavity, a disintegration in the oral cavity characterized in that not less than 70% by mass in the tablet is cyclodextrin has been reported (see Patent Document 3). Cyclodextrins in this patent document also include? -Cyclodextrin. However, the use of cyclodextrin as an additive in order to improve the stability of a drug substance is not suggested nor described.

Patent Document 1: Japanese Patent No. 3646310 Patent Document 2: Japanese Patent Application Laid-Open No. 2003-517432 Patent Document 3: WO2005 / 004923 pamphlet

Non-Patent Document 1: Foods & Food Ingredients Journal of Japan (FFI Journal) Food and Food Additives Research Institute Terao, Konishi et al. Vol. 210, No. 3, 222-243, 2005

In the medical field, in order to improve the convenience of the patient such as prevention of erroneous and misuse, it is often the case that various preparations are uniformly saturated (single encapsulated) with polyethylene laminate glase paper for each dose, Even in a packaged state, a formulation stable for at least several days to 30 days or one month is required. Therefore, it is required to further improve the stability stability of Limafrost.

That is, an object of the present invention is to provide a lima frost-containing tablet which is very stable against humidity. Specifically, the present invention is to provide a lima frost-containing preparation having a decomposition product production rate of 5% or less after storage for 30 days or 1 month under conditions of a temperature of 30 ° C and a relative humidity of 75%.

The present inventors have intensively studied to find a more stable Limafrost-containing tablet even with information on existing Limafrost. As a result, it has been found that the stability of Limafrost is improved when β-cyclodextrin is particularly added among many additives. It has also been found that lima frost is significantly improved in the stability against humidity only by adding? -Cyclodextrin as an additive without dissolving lima frost together with? -Cyclodextrin in a solvent. This is surprising and, from the conventional knowledge, it is not theoretically bound, but merely mixing limaprost and? -Cyclodextrin in the presence of solvent does not lead to the formation of lima frost by the? -Cyclodextrin I think it is not. Further, Limafrost is sometimes used as limaprost alpha-dex in which alpha -cyclodextrin is already incorporated, but the finding that stabilization is improved by adding cyclodextrin to a compound already encapsulated with cyclodextrin, Is not easily conceivable to those skilled in the art from the viewpoint of the conventional knowledge that the stabilization of the drug is due to the inclusion of cyclodextrin and the like. Further, it has been found that the tablets containing Limafrost and? -Cyclodextrin have significantly improved stability against humidity as compared with the existing Limafrost-containing tablets, and completed the present invention.

That is,

CLAIMS What is claimed is: 1. A tablet containing lima frost and? -Cyclodextrin, comprising: a tablet containing 30 to 99% by mass of? -Cyclodextrin, wherein the whole tablet is 100%

2. The tablet according to the above 1, which contains 50 to 95% by mass of? -Cyclodextrin by 100% by mass of the whole tablet,

3. Tablets according to any one of the above items 1 to 2, which may further contain 0.0165 to 2.5% by mass of glucans,

4. The method of claim 1, wherein lima frost is contained in said tablet as lima frost alfalfax, wherein said tablet contains at least (1) a lyophilisate containing lima frost alfadex and (2) A tablet according to any one of &lt; RTI ID = 0.0 &gt;

5. The tablet according to the above 4, which is prepared by mixing and adding the? -Cyclodextrin of (2) in the absence of a solvent,

6. The tablet according to the above 5, which further contains? -Cyclodextrin in the lyophilized product,

7. The tablet according to 6 above, wherein the total amount of the tablet is 100% by mass and the content of? -Cyclodextrin in the freeze-dried product is 0.1 to 1% by mass,

8. The tablet according to any one of the above 4 to 7, which further contains glucans in the lyophilized product,

9. The tablet according to the above 8, wherein lima frost alfadex and glucan are contained in a ratio of 1: 0.1 to 15,

10. The tablet according to the above 8, wherein lima frost alpha-dexse and glucans are contained in a ratio of 1: 0.1 to 6,

11. A pharmaceutical composition comprising a tablet containing 30 to 99% by mass of? -Cyclodextrin and 0.0165 to 2.5% by mass of glucans, which contains Limafrost alfadex,? -Cyclodextrin and glucans, wherein the whole tablet is 100%

12. A pharmaceutical composition comprising (1) a lyophilized alpha-dex, a lyophilized product containing? -Cyclodextrin and glucans, and (2) a mixture of? -Cyclodextrin, wherein the whole tablet is 100% By weight of a starch, 30 to 99% by weight of a starch, and 0.0165 to 1.0%

13. The method according to any _one of claims ₁ to 12, wherein after 17 months of storage at 30 占 폚 and 75% relative humidity, 17S, 20-dimethyl-trans-Δ ² -PGA ₁ is substantially not contained or 100% , 17S, 20-dimethyl-trans-Δ ² -PGA ₁ is 5% or less.

.

Lima frost

In the present specification, Limafrost means a compound represented by the following formula (I)

And the chemical name is (E) -7 - [(1R, 2R, 3R) -3-hydroxy-2 - [(3S, 5S) - 1-nonenyl] -5-oxocyclopentyl] -2-heptenoic acid (Registry No. 74397-12-9).

In the present specification, Limafrost may be contained in a form encapsulated with? -Cyclodextrin. The? -Cyclodextrin inclusion compound of Limafrost is represented by the following formula (II)

(Wherein n represents an integer). The general name is (E) -7 - [(1R, 2R, 3R) -3-hydroxy-2 - [(3S, 5S) - (E) -3- hydroxy- (Limafost: α-cyclodextrin = 1: 1), 88852-12-4 (Limafrost: α-cyclodextrin) -Cyclodextrin = 1: n)] and is generally known as lima frost alpha dex. This is in agreement with Lima Frost Alphadex, which is described in the 16th Revised Japanese Pharmacopoeia.

In the present invention, unless explicitly stated otherwise, as apparent to those skilled in the art,

(I.e.,? -Position) on the opposite side of the paper surface,

(I.e., the? -Position) of the paper.

In the present invention, it is preferable that lima frost be contained as the alpha-cyclodextrin inclusion compound of lima frost represented by the formula (II), that is lima frost alpha dex.

In a preferred embodiment, the tablets of the present invention contain about 5 to 10 μg of Limafrost per tablet. It is also preferable that lima frost is contained as lima frost alfadex in an amount of about 5 to 10 μg per tablet in terms of lima frost.

Lima frost and lima frost alfadex are known and can be produced by a known method such as the method described in Japanese Patent Application Laid-open No. 55-100360.

When lima frost is decomposed, as a decomposition product,

17S, 20-dimethyl-trans- ^2- PGA ₁ (hereinafter abbreviated as 11-deoxy)

17S, 20-dimethyl-trans-Δ ² -8-iso-PGE ₁ (hereinafter abbreviated as 8-iso) is produced. It is known that 11-deoxychain is mainly produced as a decomposition product. If the production amount of these decomposition products is increased, there is a fear that the efficacy is reduced. Since the lima frost-containing tablets of the present invention are very stable, even if they are stored for a long period of time at a medical site, the amount of 11-deoxides is limited to a detection limit of not less than about 10%, preferably not more than a detection limit of not more than about 8% Limit to less than about 5%. In addition, in the preservation test under the humidification and heating conditions performed for predicting the storage stability at the medical site, the amount of the 11-deoxcone can be suppressed to a low level. Concretely, for example, the amount of 11-deoxyne produced after 30 days or 1 month of storage at a temperature of 30 ° C and a relative humidity of 75% is preferably not less than the detection limit but not more than about 5% It can be suppressed to 3.5% or less. Further, at a temperature of 60 ° C, the amount of 11-deoxyne produced after 30 days or 1 month of storage can be controlled preferably to a detection limit of not less than about 5%, more preferably to a detection limit of not more than about 3.5% .

The production rate of the 11-deoxcans can be represented, for example, by the ratio (mass ratio) of the amount of 11-decoxime in the composition to the total amount of limafrost and 11-decoxidate or 8-isocyte.

The production rate of the 11-deoxcylate can be calculated by quantifying the decomposition products (8-isomer, 11-decoxy) of lima frost and lima frost, and taking the sum of lima frost and decomposition product as 100.

The amount of lima frost, 11-dioxaic acid and 8-isomer can be measured by a known analytical method (for example, high performance liquid chromatography, gas chromatography, thin layer chromatography, etc.) It is preferable to measure it by the liquid chromatography method. By using the high-performance liquid chromatography method, the amounts of lima frost, 11-deoxc and 8-iso can be measured with high sensitivity using the same conditions and using the same sample. The high-performance liquid chromatography method is carried out by a known method.

Concretely, it is carried out according to the test conditions of the following high performance liquid chromatography (HPLC). By using this method, it is possible to measure the amount of lima frost and decomposition products to calculate the ratio of lima frost and decomposition products.

HPLC Test conditions of:

Detector: ultraviolet absorbance photometer (measuring wavelength: 215 nm);

Column: A stainless steel tube having an inner diameter of about 5 mm and a length of 10 to 20 cm is filled with an octadecylsilylated silica gel for a liquid chromatograph of 3 to 5 占 퐉;

Mobile phase: 0.02 M potassium dihydrogen phosphate (pH 4.3) / acetonitrile / isopropanol mixture (9: 5: 2);

Flow rate: Adjust the lima frost to a holding time of about 12 minutes;

Internal standard solution: acetonitrile solution of testosterone (13 → 20000).

As described above, the amount of the decomposition products can be measured by a known method other than the high-performance liquid chromatography method. Even in the high-performance liquid chromatography method, other measurement conditions and other calculation methods (for example, external standard method) . Even if the amount of the produced 11-deoxcylate after storage for 30 days or 1 month exceeds 5% in the stability test at a temperature of 30 ° C and a relative humidity of 75% using a method other than the high-performance liquid chromatography method, Method, if the amount of produced 11-deoxcans is not less than the detection limit of not more than about 5%, it is included in the present invention. It is also included in the present invention that the 11-decanoate can not be measured substantially.

In the present invention, among cyclodextrins such as? -Cyclodextrin,? -Cyclodextrin,? -Cyclodextrin and hydroxypropyl? -Cyclodextrin,? -Cyclodextrin is particularly used as the cyclodextrin to be combined with Limafrost.

The compounding method of? -cyclodextrin may be carried out by mixing limaprost clathrate (limafrost alpha-dex) and? -cyclodextrin by limaprost or? -cyclodextrin by a known method. In the present invention, when? -Cyclodextrin is mixed,? -Cyclodextrin may be mixedly added in the absence of a solvent without adding a solvent or the like.

In addition, the method of blending? -Cyclodextrin may be a method of grinding after being made into a lyophilized product containing lima frost or lima frost alpha-dex and? -Cyclodextrin. The lyophilized product containing lima frost or lima frost alfadex and [beta] -cyclodextrin can be obtained, for example, by dissolving lima frost or lima frost alfadex and beta -cyclodextrin in a solvent (e.g., water, an organic solvent (e.g., ethanol, , And can be produced by a conventional method. In addition, as a method for blending? -Cyclodextrin,? -Cyclodextrin may be further added to a lyophilized product containing lima frost or lima frost alfadex and? -Cyclodextrin, and for example, a lyophilized product prepared by the above- May be pulverized, and then? -Cyclodextrin may be further mixed.

The β-cyclodextrin in the present invention may be blended by any method, but when β-cyclodextrin is mixed, β-cyclodextrin is mixed in the absence of solvent, without adding water or an organic solvent In particular, it is preferable to grind the lyophilized product containing lima frost or lima frost alfadex and? -Cyclodextrin, and further mix? -Cyclodextrin.

When the mass of the whole tablet is taken as 100%, the compounding ratio of? -Cyclodextrin is preferably about 30% by mass to 99% by mass, more preferably about 50% by mass to 95% by mass, And about 50% by mass to 85% by mass. Here, the blending amount of? -Cyclodextrin refers to the total amount of? -Cyclodextrin to be added and? -Cyclodextrin to be added at the time of preparing the lyophilized product, that is, the total amount of? -Cyclodextrin contained in the whole tablet.

When a lyophilized product containing lima frost and? -Cyclodextrin is pulverized and further mixed with? -Cyclodextrin, the? -Cyclodextrin used for preparing a lyophilized product containing lima frost and? -Cyclodextrin is mixed with a trace amount , And it is preferably about 0.1 to 1 mass%, and more preferably about 0.1 to 0.5 mass%, based on 100 mass% of the total mass of the tablets. On the other hand, the? -Cyclodextrin to be mixed is used in an amount of about 30 to 99% by mass, preferably about 50 to 95% by mass, and more preferably about 50 to 85% by mass, based on 100% desirable.

Although tablets containing lima frost and? -Cyclodextrin exhibit very high stability against humidity, glucans (such as dextran) may be further blended. By adding glucans, stability against heat is improved. In the present specification, the term &quot; glucans &quot; refers to glucans or glucans treated chemically or enzymatically. Glucan is a general term for polysaccharides composed of D-glucose, and is classified into? -Glucan and? -Glucan. Examples of the? -glucan include those having an? 1? 4 glucoside bond (such as starch, glycogen, etc.), those having an? 1? 6 glucoside bond (such as dextran) (E.g., pullulan), and the like. Representative examples of? -glucan include cellulose having? 1? 4 glucosidic bond and the like. Examples of the treatment of glucans by chemical or enzymatic methods include those obtained by treating starch chemically or enzymatically, and examples thereof include dextrin and alpha starch. In the present invention, preferable examples of the glucans include dextran (e.g., dextran, dextran 40, dextran 70, etc.), dextrin, pullulan, corn starch, potato starch, wheat starch, rice starch, And dextran is particularly preferable. Examples of the mixing method of the glucans include simply mixing them and dissolving lima frost, beta -cyclodextrin and glucans in a solvent (e.g., water, an organic solvent (e.g., ethanol, acetone, etc.) Or the like, to prepare a lyophilized product. When the glucan is added, the stability against heat is improved while the stability against humidity tends to deteriorate. Therefore, the amount of the glucan to be incorporated may be a very small amount, and the total amount of the tablets may be about 0.0165 to 2.5 By mass, preferably about 0.0165 to 1.0% by mass, and more preferably about 0.08 to 1.0% by mass. In the case of mixing glucans in the tablet, the blending ratio of Limafrost alpha-dex and dextran is preferably Limafrost Alphadex: Dextran = 1: 0.1 to 15, more preferably Limafost Alphadex: Dex Tran = 1: 0.1 to 6, even more preferably Limafrost Alphadex: Dextran = 1: 0.5 to 6. By further blending the glucans, the hardness of the lyophilized product is increased and the formability of the tablet is also improved.

The tablets (for example, predetermined tablets, coated tablets, three-layer tablets, etc.) of the present invention may further contain additives in addition to the above-mentioned additives. The additive is not particularly limited as long as it is generally used in the production of tablets and examples thereof include additives such as excipients, lubricants, disintegrators, fluidizers, binders, mating agents, fodders, surfactants, perfumes, colorants, antioxidants, An antiseptic agent, a wetting agent and the like may be suitably used in combination.

Examples of excipients include excipients such as glucose, fructose, maltose, lactose (lactose hydrate, spray dried lactose, fluidized lactose, isomerized lactose, reduced lactose, etc.), sucrose, D- mannitol, erythritol, maltitol, xylitol, Trehalose, sorbitol, crystalline cellulose, talc, silicic anhydride, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate and the like. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, stearyl sodium fumarate, stearic acid, talc, polyethylene glycol and the like. Examples of the disintegrator include low-substituted hydroxypropylcellulose, carmelose, carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidone, hydroxypropyl starch and corn starch. Examples of the fluidizing agent include light anhydrous silicic acid, talc, hydrous silicon dioxide and the like. Examples of the binding agent include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, carboxymethylcellulose, sodium alginate, arabic rubber powder and gelatin. May be used alone or in combination of two or more. Examples of the wetting agent include sodium salt, potassium salt, sodium glutamate, sodium salt, potassium salt, sodium salt, potassium salt, potassium salt, potassium salt, - sodium inosinate, sodium 5'-guanylate, and the like. Examples of the replenisher include trehalose, malic acid, maltose, potassium gluconate, anise essential oil, vanilla essential oil, cardamid 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. Examples of the perfume include lemon oil, orange oil, menthol, peppermint oil and the like. Examples of the coloring agent include titanium oxide, edible yellow No. 5, edible blue No. 2, ferric oxide, yellow ferric oxide and the like. Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, vitamin E and the like. Examples of the concealing agent include titanium oxide and the like. Examples of the antistatic agent include talc, titanium oxide, and the like. Examples of the wetting agent include polysorbate 80, sodium lauryl sulfate, sucrose fatty acid ester, macrogol, and hydroxypropylcellulose (HPC).

The tablet of the present invention can be produced by the following method. For example, a granulated product obtained by pulverizing a lyophilized product containing lima frost, lima frost alfadex or Limafrost is granulated by using a rotary granulator, a stirring granulator, a flow granulator, a centrifugal transfer granulator, a dry granulator or the like, The additives may be evenly mixed and then subjected to compression molding with a rotary tableting machine or the like to give a predetermined amount. The predetermined amount may be used as a tablet as it is, and further coated with a coating agent if necessary. Alternatively, a freeze-dried product containing lima frost, lima frost alfadex, or lima frost may be pulverized without being assembled, and a mixed powder containing an additive may be prepared and then tableted by a rotary tablet machine or the like. The tablets of the present invention surprisingly have an advantage that they have no problems in moldability, although they contain a relatively large amount of? -Cyclodextrin, which may cause degradability to tablets and the like.

Also, the lubricant may be mixed by an internal lubricating method or an external lubricating method.

The tablets of the present invention may be dried after tableting or tableting. As a method of drying the tablets, it is preferably hot air drying, vacuum drying or vacuum drying under reduced pressure.

As a method of drying the tablet, it is preferably reduced-pressure drying or hot-reduced-pressure drying.

The tablets of the present invention are useful for the treatment of peripheral circulatory disorders such as obstructive thrombotic or lumbar spinal stenosis.

The tablets of the present invention are very stable in humidity and can inhibit the production of decomposed products of lima frost, and thus can be stored for a long period of time, and there is no problem of formability into tablets. Therefore, the tablet of the present invention can be clinically provided in a state of being saturated with other medicaments.

EXAMPLES Hereinafter, formative examples and experimental examples are shown as examples, but they are for the purpose of deepening the understanding of the present invention and do not limit the scope of the present invention.

Experimental Example  1: Comparison of stability in various additives

(1) Preparation of lyophilized product

In 37.5 g of purified water, 1 g of Limafrost Alphadex was dissolved, and 7 g of dextran 40 was further dissolved. This liquid was transferred to a metal tray and lyophilized according to a conventional method. After lyophilization, the mixture was pulverized with induction and passed through a sieve (No. 42 sieve) to obtain a lyophilized powder.

(2) Preparation of mixed powder

The lyophilized alpha-dex / dextran 40 freeze-dried product (200 mg) and various additives (15 g) were mixed in a mortar, and then 1 g was subdivided into glass bottles. The sample was dried in a decompression dryer (50 ° C, 12 hours or longer), and the sample was placed in a stability tester having a temperature of 30 ° C and a relative humidity of 75% with a stopper opened. The sample was periodically sampled and evaluated.

(3) Purity test

The yield of the degradation product (11-deoxy) of lima frost was analyzed by high performance liquid chromatography (HPLC).

The results are shown below.

When? -cyclodextrin was mixed, the decomposition products were less than 3% after 2 weeks and less than 5% after 1 month of storage. On the other hand, the powder obtained by mixing other additives such as? -Cyclodextrin with Limafrost increased decomposition products with the lapse of time, and exceeded 5% after 1 month of storage.

Therefore, it has been shown that the stability of Limafrost is improved in the mixed powder of? -Cyclodextrin and Limafrost.

Experimental Example  2: Cyclodextrin  Effect of content

Formulation Example 1:? -Cyclodextrin content 30%

In 62.25 g of purified water, 1.67 g of Limafrost Alphadex was dissolved, 1.67 g of? -Cyclodextrin was added and dissolved, and 3.32 g of Dextran 40 was further dissolved. This liquid was transferred to a metal tray and lyophilized according to a conventional method. After lyophilization, it was pulverized with induction and passed through a sieve (No. 30 sieve) to obtain a lyophilized powder.

20 g of carmelose, 30 g of? -Cyclodextrin, 50 g of lactose, 0.2 g of light silicic anhydride and 2 g of stearic acid were mixed with 0.664 g of the lyophilized powder, and the mixture was transferred to a rotary tablet press ) To obtain 1000 tablets containing 5 μg of lima frost per one tablet by tableting (one tablet 102.9 mg, 6.5 mmφ) at a tabletting pressure of 800 to 1000 kg / cm 2.

Formulation Example 2:? -Cyclodextrin content 50%

20 g of carmellose, 50 g of? -Cyclodextrin, 30 g of lactose, and 0.2 g of light silicic anhydride were mixed with 0.664 g of the same lyophilized powder as in Preparation Example 1, and the mixture was dispersed in a rotary tablet machine (manufactured by Kikusui Seiyaku Co., ) To obtain 1000 tablets containing 5 μg of lima frost per tablet by tableting (one tablet 100.9 mg, 6.5 mmφ) at a tablet pressure of 800 to 1000 kg / cm 2. Magnesium stearate was sprayed on the tablet machine using an external rocking device (manufactured by Kikusui Seisakusho Co., Ltd.).

Formulation Example 3:? -Cyclodextrin content 60%

20 g of carmellose, 60 g of? -Cyclodextrin, 20 g of lactose, and 0.2 g of light silicic anhydride were mixed with 0.664 g of the same lyophilized dried powder as in Preparation Example 1, and the mixture was transferred to a rotary tablet press (manufactured by Kikusui Seisakusho Co., ) To obtain 1000 tablets containing 5 μg of lima frost per tablet by tableting (one tablet 100.9 mg, 6.5 mmφ) at a tablet pressure of 800 to 1000 kg / cm 2. Magnesium stearate was sprayed on the tablet machine using an external rocking device (manufactured by Kikusui Seisakusho Co., Ltd.).

Formulation Example 4:? -Cyclodextrin content of 70%

20 g of carmellose, 70 g of? -Cyclodextrin, 10 g of lactose and 0.2 g of light silicic anhydride were mixed with 0.664 g of the same freeze-dried powder as in Preparation Example 1, and the mixture was dispersed in a rotary tablet machine (manufactured by Kikusui Seiyaku Co., ) To obtain 1000 tablets containing 5 μg of lima frost per tablet by tableting (one tablet 100.9 mg, 6.5 mmφ) at a tablet pressure of 800 to 1000 kg / cm 2. Magnesium stearate was sprayed on the tablet machine using an external rocking device (manufactured by Kikusui Seisakusho Co., Ltd.).

Formulation Example 5:? -Cyclodextrin content 80%

20 g of carmellose, 80 g of? -Cyclodextrin and 0.2 g of light silicic anhydride were mixed with 0.664 g of the same freeze-dried powder as in Preparation Example 1, and using a rotary tablet press (manufactured by Kikusui Seisakusho Co., Ltd.) 1000 tablets containing 5 μg of lima frost per 1 tablet were obtained by tableting (one tablet 100.9 mg, 6.5 mmφ) at a static pressure of 800 to 1000 kg / cm 2. Magnesium stearate was sprayed on the tablet machine using an external rocking device (manufactured by Kikusui Seisakusho Co., Ltd.).

Formulation Example 6:? -Cyclodextrin content 90%

10 g of carmellose, 90 g of? -Cyclodextrin and 0.2 g of light silicic anhydride were mixed with 0.664 g of the same lyophilized powder as in Preparation Example 1, and using a rotary tablet press (manufactured by Kikusui Seiyaku Co., Ltd.) 1000 tablets containing 5 μg of lima frost per 1 tablet were obtained by tableting (one tablet 100.9 mg, 6.5 mmφ) at a static pressure of 800 to 1000 kg / cm 2. Magnesium stearate was sprayed on the tablet machine using an external rocking device (manufactured by Kikusui Seisakusho Co., Ltd.).

<Comparative Formulation Example 1>

Comparative Preparation Example 1 was prepared in the same manner as in Example 13 of Japanese Patent No. 3646310.

<Comparative preparation example 2: β-cyclodextrin content 0.2% (mixed addition amount 0%)>

A mixture of 20 g of carmelose, 80 g of lactose and 0.2 g of hard silicic anhydride was mixed with 0.664 g of the same lyophilized powder as in Preparation Example 1, and the mixture was extruded using a rotary tablet press (manufactured by Kikusui Seisakusho Co., Ltd.) (1 tablet 102.9 mg, 6.5 mm phi) at 1000 kg / cm 2 to obtain 1000 tablets containing 5 μg of lima frost per tablet.

The formulations of Formulation Examples 1 to 6 and Comparative Formulation Examples 1 and 2 are shown in the following table.

Each prescription, about 100 tablets, was filled in a glass bottle and placed in a stable tester at a temperature of 30 ° C and a relative humidity of 75% with a cap open, and the tablets were evaluated by regularly sampling. The yield of the degradation product (11-deoxy) of lima frost was analyzed by high performance liquid chromatography (HPLC).

The generation rate of the degradation product was calculated by taking the sum of lima frost and degradation product as 100. The analysis results are shown below.

(Comparative Preparation Example 1) described in Example 13 of Patent Document 1 that does not contain? -Cyclodextrin in the tablet, and? -Cyclodextrin equivalent to? -Cyclodextrin encapsulating lima frost in the freeze-dried product Compared with Comparative Formulation Example 2, tablets (Formulation Example 1-6) in which 30% or more of? -Cyclodextrin was added as an additive had remarkably improved stability.

Therefore, it has been shown that the tablets obtained by adding 30% or more of? -Cyclodextrin to the tablets have improved storage stability.

Experimental Example  3: Glucan  By addition To thermal stability  Impact

Preparations of various dextran contents of the following composition, Formulation Examples 7 to 13, were prepared in the same manner as in Formulation Example 1.

The obtained tablets were filled in a glass bottle, and the filled glass bottle was (1) kept at a temperature of 30 ° C and a relative humidity of 75% in a state that the cap was opened and (2) the cap was sealed and kept at a temperature of 60 ° C. The product was sampled as time elapsed, and the rate of production of the degradation product of lima frost (11-deoxo production rate (%)) was analyzed by high performance liquid chromatography (HPLC). The generation rate of the degradation product was calculated by taking the sum of lima frost and degradation product as 100. The analysis results are shown below.

As described above, depending on the dextran content in the lyophilized product, the stability of the tablets against heat was improved.

The lima frost-containing tablets of the present invention are very stable against humidity. Therefore, it is very useful as a medicament since it can be singulated (packaged) with other preparations and can be clinically provided without degradation of quality.

Claims (13)

A tablet containing limaprost and β-cyclodextrin, wherein the entire tablet is 100% by mass and contains 30 to 99% by mass of β-cyclodextrin. The tablet according to claim 1, which contains 50 to 95% by mass of? -Cyclodextrin, wherein the whole tablet is 100% by mass. The tablet according to claim 1 or 2, which may further contain 0.0165 to 2.5% by mass of glucans. The lyophilizate according to any one of claims 1 to 3, wherein limaprost is contained in the tablet as limaprost alphadex, wherein the tablet comprises at least (1) a lyophilized body containing limaprost alphadex and (2). ) Tablets containing a mixture of β-cyclodextrins. The tablet according to claim 4, comprising a step of mixing and adding (3) the? -Cyclodextrin in the presence of a solvent. The tablet according to claim 5, further comprising? -Cyclodextrin in the lyophilized product. The tablet according to claim 6, wherein the total amount of the tablet is 100% by mass and the content of? -Cyclodextrin in the freeze-dried product is 0.1 to 1% by mass. The tablet according to any one of claims 4 to 7, further comprising glucans in a freeze-dried body. The tablet according to claim 8, wherein the lima frost alfadex and the glucans are contained in a ratio of 1: 0.1 to 15. The tablet according to claim 8, wherein the lima frost alfadex and the glucan are contained in a ratio of 1: 0.1 to 6. A tablet containing 30-99 mass% of? -Cyclodextrin and 0.0165-2.5 mass% of glucans, wherein the whole of the tablet is 100% by mass, and contains Limafrost aldex,? -Cyclodextrin and glucans. (1) a lyophilized alpha-dex, a lyophilized product containing beta -cyclodextrin and glucans, and (2) a mixture of beta -cyclodextrin, wherein the whole of the tablet is 100 mass%, beta -cyclodextrin is 30 To 99% by mass, and 0.0165 to 1.0% by mass of glucans. The method according to any one of claims 1 to 12, wherein after purification for one month under conditions of a temperature of 30 ° C. and a relative humidity of 75%, 17S, 20-dimethyl-trans-Δ ² -PGA ₁ is substantially in the tablet. Tablets not included or with an overall tablet of 100% with 17S, 20-dimethyl-trans-Δ ² -PGA _{1 not} greater than 5%.