JPWO2007132718A1 - Solid preparation containing adenosine 5 'triphosphate or a physiologically acceptable salt thereof - Google Patents

Abstract

A solid preparation containing adenosine 5'-triphosphate or a physiologically acceptable salt thereof and having a high active ingredient content even after long-term storage, having a water activity at 25 ° C of 0.28 Aw or less Preferably in the form of tablets, particularly preferably in the form of film-coated tablets.

Description

  The present invention relates to a solid formulation containing a stable adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof. More specifically, the present invention relates to a solid preparation containing adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof excellent in storage stability in which the active ingredient content is highly maintained even after long-term storage.

  Adenosine 5 ′ triphosphate is a compound having a high energy phosphate bond, and releases a large amount of energy when hydrolyzed to adenosine 5 ′ diphosphate and phosphoric acid. In vivo, adenosine 5 ′ triphosphate is mainly used as an energy source for the reaction and is also involved in metabolic reactions as a phosphate donor.

  With regard to the use of adenosine 5'-triphosphate as a pharmaceutical, for example, it may be used as a therapeutic agent for the treatment of sequelae of head trauma, heart failure, stabilization of regulatory function in regulatory eye strain, chronic gastritis with decreased gastrointestinal function, etc. Are known. A composition containing an amount of adenosine triphosphate (ATP) effective for increasing muscle torque and reducing muscle fatigue is also known (Patent Document 1). As what is marketed as a solid formulation containing adenosine 5 'triphosphate, Adephos tablet (Kowa Co., Ltd.), ATP enteric-coated tablet "Daiichi" (Daiichi Pharmaceutical Co., Ltd.), etc. are mentioned, for example.

However, since adenosine 5 'triphosphate is unstable to water and easily decomposes, and the active ingredient content in the preparation decreases with time due to long-term storage, a desiccant such as silica gel is used in the distribution stage. However, since this additional storage means is employed, the manufacturing cost associated with filling with the desiccant increases, or the handling property deteriorates due to refrigeration in the distribution process. . Moreover, there was a possibility that a consumer accidentally swallowed the silica gel as a desiccant. As a method for stabilizing derivatives such as ADP, JP-A-49-87684 discloses a stabilization method characterized by adjusting the water content to 4.0% or less. Stabilization is achieved by adjusting the water content contained in the crystals of the derivative (Example 1 of the same publication), and is not intended to stabilize ATP in the solid preparation.
JP-T-2004-535417 JP 49-87684 A

  An object of the present invention is a solid preparation containing adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof, which is a stable solid preparation whose active ingredient content is highly maintained even after long-term storage. It is to provide.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have determined that the water activity at 25 ° C. is 0.28 Aw or less in a solid preparation containing adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof. By doing so, it was found that a stable solid preparation in which the content of adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof in the solid preparation hardly decreases even after long-term storage can be provided. The present invention has been completed based on the above findings.

That is, the present invention provides a solid preparation containing adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof, and having a water activity at 25 ° C. of 0.28 Aw or less.
According to a preferred embodiment of the present invention, the content of adenosine 5 ′ triphosphate or physiologically acceptable salt thereof in a solid preparation is 1 to 80% by mass relative to the total mass of the solid preparation. The solid preparation in the form of a tablet; and the solid preparation in the form of a film-coated tablet in which water activity is controlled by film coating using a breathable coating machine.

  The solid preparation of the present invention is characterized in that the content of adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof is maintained at a high level even after long-term storage and has excellent storage stability. According to the solid preparation of the present invention, it is possible to avoid an increase in production cost for filling the desiccant and complicated refrigerated storage in the distribution stage, and there is no possibility of accidental ingestion of the desiccant. The solid preparation of the present invention does not cause an appearance change due to swelling during long-term storage, and does not cause adhesion between solid preparations. In the solid preparation of the present invention, as a result of suppressing the expansion after long-term storage, there is an excellent effect that the tablet is not damaged during storage or transportation of the product.

  Adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof used in the solid preparation of the present invention is a known substance and can be easily obtained by those skilled in the art. The kind of physiologically acceptable salt of adenosine 5 ′ triphosphate is not particularly limited, and examples thereof include alkali metal salts such as sodium salt or potassium salt, or alkaline earth metal salts such as magnesium salt or calcium salt. . Of these, adenosine 5 ′ triphosphate disodium is particularly preferred.

  In the present invention, “water activity” means free water in the total water contained in a solid preparation containing adenosine 5 ′ triphosphate and / or a salt thereof (water is classified into bound water or free water from its form. The bound water is strongly bound to the constituents in the solid preparation, whereas free water easily moves and evaporates due to changes in temperature, humidity, etc.). The water activity can be calculated by P / P0, where P is the water vapor pressure in a sealed container at a constant temperature containing the solid preparation and P0 is the vapor pressure of pure water. The water activity of the solid preparation at 25 ° C. can be easily measured by using a known method, and for example, it can be measured by using Aqua Arab CX-3TE (manufactured by Decagon).

  The solid preparation of the present invention has a water activity at 25 ° C. of 0.28 Aw or less, preferably in the range of 0.08 Aw to 0.28 Aw, more preferably in the range of 0.09 Aw to 0.28 Aw, still more preferably 0.10 Aw. It is in the range of ~ 0.28 Aw. In the solid preparation of the present invention having water activity within the above range, the content of the active ingredient adenosine 5 ′ triphosphate or physiologically acceptable salt thereof is highly maintained even after long-term storage, High active ingredient content can be maintained.

  In order to set the water activity of the solid preparation within the above range, for example, the solid preparation may be dried until the water activity at 25 ° C. becomes 0.28 Aw or less. More specifically, for example, the solid preparation is dried by a coating machine such as a pan-type coating machine, an air-flow type coating machine, or a fluidized bed coating machine, and the moisture in the solid preparation is adjusted together with the coating process, or the solid preparation is It is possible to adopt a method such as adjusting to a predetermined water activity by drying in a vacuum dryer or box-type dryer. Alternatively, the solid preparation may be stored with silica gel or the like for a certain period and adjusted to a predetermined water activity. However, the method for adjusting the water activity is not limited to the above specific method, and can be appropriately selected by those skilled in the art.

The form of the solid preparation of the present invention is not particularly limited, and an appropriate form can be selected. For example, solid preparations for oral administration such as tablets, granules, and fine granules are preferred.
The content of adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof in the solid preparation of the present invention is not particularly limited, but is preferably 1 to 80% by weight, for example, based on the total weight of the solid preparation. 5-75 mass% is more preferable, and 2-70 mass% is especially preferable.

  The solid preparation of the present invention may contain other pharmaceutically active ingredients in addition to adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof. Examples of such pharmaceutically active ingredients include caffeine, vitamins, and herbal medicines. These pharmaceutically active ingredients may be blended alone in the solid preparation of the present invention, or two or more kinds may be blended.

  Examples of caffeine include anhydrous caffeine, caffeine, and sodium benzoate caffeine. Examples of vitamins include vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, hesperidin and derivatives thereof, and salts thereof. Herbal medicines include, for example, oxoamidin, maoh, nantenjitsu, scotch, onji, licorice, yellow pepper, red pepper, red pepper, sarcophagus, senega, baimo, fennel, green grass, auren, gadget, chamomile, keihi, gentian, gooh, beast gall (Including yutan), shajin, ginger, sojutsu, clove, chimpi, sandalwood, earth dragon, chiketsu carrot, carrot and the like.

  One or more additives for pharmaceutical preparation may be used for the production of the solid preparation of the present invention containing adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof. Although the kind of additive for a formulation is not specifically limited, For example, an excipient | filler, a binder, a disintegrating agent, or a lubricant etc. can be used.

  Examples of the excipient include lactose, starches, crystalline cellulose, sucrose, mannitol, light anhydrous silicic acid, hydrogenated oil, and the like. Examples of the binder include hydroxypropyl methylcellulose, hydroxypropylcellulose, gelatin, pregelatinized starch, polyvinyl pyrrolidone, polyvinyl alcohol, pullulan and the like. Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, crospovidone, corn starch, and low-substituted hydroxypropylcellulose. Examples of the lubricant include magnesium stearate and talc.

  The solid preparation of the present invention desirably has a film formed on its surface. As the film-forming polymer, methacrylic acid copolymer L, methacrylic acid copolymer LD, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and the like can be used. When forming a film, blend plasticizers such as triethyl citrate and polyethylene glycol, talc, titanium oxide, yellow iron sesquioxide, iron sesquioxide, legal dyes, light anhydrous silicic acid, hydrous silicon dioxide, etc. You can also. By blending these powders, concealment and light shielding of the solid preparation can be achieved, or the solid preparation can be colored. When the solid preparation is a tablet, it can be further formed into a sugar-coated tablet or a dry-coated tablet after film formation.

  The solid preparation of the present invention can be produced by a known method. For example, in the case of a tablet containing adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof, other pharmaceutically active ingredients or pharmaceutical additives to adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof And granulated by a conventional method, followed by compression molding with a tableting machine. Furthermore, when film-coating a solid preparation, the coating can be performed by a general method such as applying or spraying a coating solution to the solid preparation. In particular, it is convenient and preferable to employ a spray coating method. For example, a film coating is applied to an uncoated tablet containing adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof using a breathable coating machine such as a Doria coater (manufactured by Paulek) or a high coater (manufactured by Freund Sangyo). In this case, the solid preparation of the present invention can be produced by adjusting to a predetermined water activity. When the surface of the solid preparation is required to be glossy, it is preferable to wax with carnauba wax or the like according to a conventional method.

  The solid preparation of the present invention can be administered to a patient for the purpose of prophylaxis and / or treatment for the purpose of expressing the expected efficacy of adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof. For example, as a medicament for the prevention and / or treatment of chronic gastritis associated with sequelae of head trauma, heart failure, or gastrointestinal dysfunction, or as a medicament for stabilization of the regulation function in regulatory eye strain Can do. Further, as disclosed in Japanese Patent Application No. 2005-155319, it can be used as a medicament for recovery from fatigue.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
Example 1
Adenosine 5 ′ triphosphate disodium 600 g, thiamine disulfide 240 g, pyridoxine hydrochloride 240 g, cyanocobalamin 0.6 g, hydroxypropylcellulose 240 g, crystalline cellulose 4034.4 g and carmellose 600 g were mixed, and ethanol 1100 g was added thereto to granulate, After drying and sizing, 45 g of magnesium stearate was added to form granules for tableting. The granules for tableting were compression-molded to obtain a plain tablet of 200 mg (φ8 mm).
In this uncoated tablet, 2400 g of purified water, 410 g of methacrylic acid copolymer LD, 123 g of talc, 61.6 g of triethyl citrate and 5.4 g of titanium oxide were dissolved and dispersed in a film coating solution (Doria Coater DRC-650DS type) The company manufactured a solid preparation of the present invention by adjusting the water activity to 0.28 Aw (25 ° C.) with the above-mentioned air-permeable type coating machine. In addition, the water activity in 25 degreeC was measured using Aqua Arab CX-3TE (made by a Decagon company).

Example 2
Film-coated tablets were obtained in the same manner as in Example 1, and the water activity was adjusted to 0.24 with a vent type coating machine.
Example 3
Film-coated tablets were obtained in the same manner as in Example 1, and the water activity was adjusted to 0.19 with a breathable coating machine.
Example 4
Film-coated tablets were obtained in the same manner as in Example 1, and the water activity was adjusted to 0.15 with a breathable coating machine.
Example 5
Film-coated tablets were obtained in the same manner as in Example 5, and the water activity was adjusted to 0.11.

Example 6 (comparative example)
Film-coated tablets were obtained in the same manner as in Example 1, and the water activity was adjusted to 0.37 with a vent type coating machine.
Example 7 (comparative example)
Film-coated tablets were obtained in the same manner as in Example 1, and the water activity was adjusted to 0.29 with a breathable coating machine.

Test Example 1: Residual rate of adenosine 5′-triphosphate disodium 100 tablets each obtained in Examples 1 to 7 were placed in a No. 5 standard bottle and sealed, and then stored at 60 ° C. for one month. The content of disodium adenosine 5 ′ triphosphate after storage was measured by HPLC, and the residual ratio from the initial was calculated.
Test Example 2: Appearance Change Rate Each of the tablets obtained in Examples 1 to 7 was put into a No. 5 standard bottle and sealed, and then stored at 60 ° C. for one month to calculate the appearance change rate. The appearance change rate was obtained from the following equation.
Appearance change rate (%) = (Tablet thickness after one month at 60 ° C.−Initial tablet thickness) / Initial tablet thickness × 100 (%)
Test Example 3: Degree of Adhesion Each of the tablets obtained in Examples 1 to 7 was placed in a No. 5 standard bottle and sealed, and then stored at 60 ° C. for one month to evaluate the degree of adhesion of the tablets. The following criteria were applied for the evaluation.
2: Strong adhesion 1: Mild adhesion 0: No adhesion observed Table 1 shows the results of Test Examples 1 to 3.

  Compared to the tablets of Examples 6 and 7 where the water activity at 25 ° C is 0.37 and 0.29 Aw (comparative examples), the tablets of Examples 1 to 5 whose water activity at 25 ° C is 0.28 Aw or less are 60 Even after storage at 1 ° C. for 1 month, the residual ratio of adenosine 5′-triphosphate is remarkably high, and the content of adenosine 5′-triphosphate or its physiologically acceptable salt is sufficiently high even after long-term storage. It was maintained. Moreover, in the tablets of Examples 1 to 5, swelling and adhesion of the tablets were remarkably suppressed.

Example 8
Adenosine 5 ′ disodium triphosphate 600 g, thiamine disulfide 240 g, pyridoxine hydrochloride 240 g, riboflavin 15 g, cyanocobalamin 0.6 g, hydroxypropylcellulose 240 g, hydrogenated oil 300 g, crystalline cellulose 3719.4 g, carmellose 600 g were mixed with ethanol. 1000 g was added, granulated, dried and sized, and 45 g of magnesium stearate was added thereto to form granules for tableting. The granules for tableting were compression-molded to obtain a plain tablet of 200 mg (φ8 mm).
In this uncoated tablet, 2400 g of purified water, 410.1 g of methacrylic acid copolymer LD, 123 g of talc, 61.5 g of triethyl citrate, 5.4 g of titanium oxide and 0.9 g of yellow iron sesquioxide were dissolved and dispersed in a film coating solution. A tablet coating machine (Doria Coater DRC-650DS model, POWREC Co., Ltd.) makes one tablet 220 mg film-coated tablet, and the water activity is adjusted to 0.22 Aw (25 ° C.) with the above-described air-permeable type coating machine to obtain the solid preparation of the present invention. It was.

  The solid preparation of the present invention is characterized in that the content of adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof is maintained at a high level even after long-term storage and has excellent storage stability.

Claims (4)

A solid preparation containing adenosine 5 ′ triphosphate or a physiologically acceptable salt thereof, wherein the water activity at 25 ° C. is 0.28 Aw or less. The solid preparation according to claim 1, wherein the content of adenosine 5'-triphosphate or a physiologically acceptable salt thereof in the solid preparation is 1 to 80% by mass relative to the total mass of the solid preparation. The solid preparation according to claim 1 or 2, which is in the form of a tablet. The solid preparation according to claim 3, which is in the form of a film-coated tablet whose water activity is adjusted by film coating using a breathable coating machine.