JP2018111662A - Everolimus pharmaceutical preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an everolimus pharmaceutical preparation that allows the appearance of a tablet in which the everolimus pharmaceutical preparation is housed to be easily visually confirmed.SOLUTION: The everolimus pharmaceutical preparation is provided that includes: a tablet including everolimus; and a transparent resin-made PTP with the tablet housed therein, preferably, includes: an everolimus pharmaceutical preparation including a tablet including everolimus; and a transparent resin-made PTP with the tablet housed therein, wherein the transparent resin-made PTP and a drying agent are packaged in an aluminum bag.SELECTED DRAWING: None

Description

The present invention relates to everolimus formulations.

Everolimus is an active ingredient of a pharmaceutical having mTOR inhibitory action (see Patent Document 1). A tablet containing everolimus as an active ingredient is approved as a medical drug in Japan as an immunosuppressive agent or an antineoplastic agent (see Non-Patent Documents 1 and 2).

International Publication No. 1994/009010

“Sartican (registered trademark)” package insert, [online], Pharmaceuticals and Medical Devices Agency, [Searched on December 28, 2016], Internet <URL: http: //www.info.pmda. go.jp/downfiles/ph/PDF/300242_3999022F1028_1_10.pdf> “Affinitol (registered trademark) lock” package insert, [online], Pharmaceuticals and Medical Devices Agency, [Searched on December 28, 2016], Internet <URL: http: //www.info.pmda.go .jp / downfiles / ph / PDF / 300242_4291023F1020_1_19.pdf>

However, since the tablets of Non-Patent Documents 1 and 2 are housed in a PTP sheet made of aluminum on both sides, the appearance properties cannot be visually recognized until just before use that is taken out from the PTP sheet.

Accordingly, an object of the present invention is to provide an everolimus preparation that allows easy visual recognition of the appearance of a stored tablet.

As a result of diligent investigation while accumulating trial and error in order to solve the above problems, the present inventors obtained an everolimus preparation obtained by containing a tablet containing everolimus in a PTP having at least one surface made of a transparent resin. It has been found that the appearance of the stored tablet can be easily visually confirmed.

The present inventors have also found that the content of everolimus-related substances may increase in tablets contained in PTP made of transparent resin. And surprisingly, by packaging the everolimus preparation in an aluminum bag together with a desiccant, the inventors have succeeded in reducing the content of everolimus related substances in tablets even under severe conditions. The present invention has been completed based on these findings and successful examples.

Therefore, according to one aspect of the present invention, there is provided an everolimus preparation comprising a tablet containing everolimus and a transparent resin-made PTP containing the tablet.

Preferably, the everolimus preparation of one embodiment of the present invention is formed by packaging the transparent resin PTP in an aluminum bag.

Preferably, the everolimus preparation of one embodiment of the present invention is obtained by packaging the transparent resin PTP and the desiccant in an aluminum bag.

Preferably, in the everolimus preparation of one embodiment of the present invention, the transparent resin-made PTP is moisture-proof PTP, and the tablet is a tablet having a water content of 20% by weight or less.

Preferably, in the everolimus preparation of one embodiment of the present invention, the tablet is a film-coated tablet.

According to the everolimus preparation of one embodiment of the present invention, the appearance of the tablet can be easily visually confirmed at the time of production and use. In addition, according to the everolimus preparation of one preferred embodiment of the present invention, it is possible to store the same while suppressing the generation of everolimus related substances in the tablet as much as the prior art everolimus preparation.

Hereinafter, the everolimus preparation of one embodiment of the present invention will be described in detail. However, the technical scope of the present invention is not limited only to the matters of this item, and the present invention is not limited to various items as long as the object is achieved. Embodiments can be taken.

The everolimus preparation includes at least a tablet containing everolimus and a transparent resin-made PTP containing the tablet.

Everolimus refers to an active ingredient of a pharmaceutical having mTOR inhibitory action.

Everolimus is provided in the form of a tablet containing everolimus (hereinafter also simply referred to as “tablet”). The form of the tablet is not particularly limited, and may be any dosage form such as an uncoated tablet, a film-coated tablet, an orally disintegrating tablet, and a chewable tablet, but it is an uncoated tablet from the viewpoint of ease of production. In view of the fact that various properties can be maintained or masked, film-coated tablets are preferred. In particular, by using a film-coated tablet, it is possible to prevent adverse effects on the tablet due to moisture absorption, light, etc., and to ease the handling difficulty for the user due to the high pharmacological activity of everolimus.

A tablet will not be specifically limited if it contains everolimus, For example, various additives other than everolimus can be contained. Further, the type and amount of the additive are not particularly limited. Examples of the additive include an excipient, a binder, a disintegrant, a stabilizer, a pH adjuster, a fluidizing agent, a surfactant, a colorant, a sweetener, and a lubricant.

Examples of the excipient include, but are not limited to, sugar alcohols, saccharides, calcium phosphates, crystalline celluloses, starches, sodium phosphates, and gelatin. The excipients can be used alone or in combination of two or more. Examples of sugar alcohols include, but are not limited to, mannitol, erythritol, xylitol, sorbitol, maltitol, and the like. Sugar alcohols can be used alone or in combination of two or more thereof. Examples of the saccharide include, but are not limited to, glucose, fructose, lactose, sucrose, trehalose, maltose, and oligosaccharide. Saccharides can be used alone or in combination of two or more.

Examples of the binder include ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate copolymer RS, aminoalkyl methacrylate copolymer E, sodium alginate, ethyl cellulose, carrageenan, carboxyvinyl polymer, carboxymethyl ethyl cellulose, agar, copolyvidone, purified shellac, Dextrin, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl starch, hydroxypropylcellulose, vinylpyrrolidone / vinyl acetate copolymer, hypromellose, partially pregelatinized starch, pullulan, pectin, polyvinyl alcohol polyethylene glycol graft copolymer, povidone, polyvinyl alcohol, methacryl Acid copolymer L, METAKU Le acid copolymer LD, methacrylic acid copolymer S, but methylcellulose, and the like, without limitation. A binder can be used individually by 1 type in these or in combination of 2 or more types.

Examples of the disintegrant include, but are not limited to, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, cellulose and derivatives thereof, starch and derivatives thereof, and the like. One of these disintegrants can be used alone, or two or more can be used in combination.

Examples of the stabilizer include dibutylhydroxytoluene, propyl gallate, butylhydroxyanisole, ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, sodium bisulfite, sodium pyrosulfite, citric acid, sodium edetate, and the like. For example, but not limited to. One of these stabilizers can be used alone, or two or more can be used in combination.

Examples of the pH adjuster include citric acid and its salt, phosphoric acid and its salt, carbonic acid and its salt, tartaric acid and its salt, fumaric acid and its salt, acetic acid and its salt, amino acid and its salt, succinic acid and its Examples thereof include, but are not limited to, salts, lactic acid and salts thereof. A pH adjuster can be used individually by 1 type in these or in combination of 2 or more types.

Examples of the fluidizing agent include, but are not limited to, light anhydrous silicic acid, hydrous silicon dioxide, titanium oxide, stearic acid, corn gel, and heavy silicic anhydride. One of these fluidizing agents can be used alone, or two or more can be used in combination.

Examples of the surfactant include phospholipid, glycerin fatty acid ester, polyoxyethylene fatty acid ester, sorbitan fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, sucrose fatty acid ester, lauryl sulfate Examples thereof include, but are not limited to, sodium, polysorbates, sodium hydrogen phosphates, potassium hydrogen phosphates, and the like. One of these surfactants can be used alone, or two or more thereof can be used in combination.

Examples of the colorant include, but are not limited to, iron sesquioxide, yellow sesquioxide, edible yellow No. 5, edible yellow No. 4, aluminum chelate, titanium oxide, and talc. One of these colorants can be used alone, or two or more can be used in combination.

Examples of the sweetener include, but are not limited to, saccharin, aspartame, acesulfame potassium, thaumatin, and sucralose. The sweetener can be used alone or in combination of two or more thereof.

Examples of lubricants include carmellose calcium, carmellose sodium, glycerin, glycerin fatty acid ester, wheat starch, sucrose fatty acid ester, stearyl alcohol, magnesium stearate, cetanol, gelatin, corn starch, potato starch, polyoxyethylene Examples include, but are not limited to, polyoxypropylene glycol, polysorbate, macrogol, glyceryl monostearate, sodium lauryl sulfate, and the like. One of these lubricants can be used alone, or two or more can be used in combination.

Specific examples of the tablet include, in addition to those described in the Examples, 0.25 mg, 0.5 mg and 0.75 mg of Certican (registered trademark) tablets described in Non-Patent Documents 1 and 2, and Affinitol (registered trademark). Examples include, but are not limited to, tablets 2.5 mg and 5 mg.

The tablets are accommodated in a transparent resin PTP. The PTP usually has (1) a mode in which a transparent resin sheet in which a pocket for storing tablets or the like is formed and an aluminum foil to be bonded in a form to cover the pockets for storing tablets or the like, 2) It refers to any one in which two aluminum sheets having pockets for storing tablets or the like are bonded together. The transparent resin-made PTP in the everolimus preparation of one embodiment of the present invention refers to the former (1) PTP. The latter (2) PTP is commonly referred to as double-sided aluminum.

The transparent resin used for the PTP made of transparent resin is not particularly limited as long as it is transparent enough to see the tablet contained in the pocket. For example, polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride, polystyrene And polyethylene terephthalate and copolymers thereof. Of these, polypropylene and polyvinyl chloride are preferred.

The aluminum foil to be bonded in the form of covering the pocket used for the transparent resin PTP is not particularly limited as long as it is generally used as PTP. For example, it can be purchased from Taketomo, Toyo Aluminum, UACJ, etc. Aluminum foil that can be used.

The everolimus preparation of one aspect of the present invention includes (A) an embodiment in which a transparent resin PTP containing a tablet containing everolimus is packaged in an aluminum bag in order to improve the light stability of the tablet containing everolimus (B) It is preferable to employ an embodiment in which a tablet containing everolimus is a film-coated tablet. Of course, both of the above aspects (A) and (B) may be used in combination.

The aluminum bag in the above aspect (A) is not particularly limited as long as it improves the light stability of tablets containing everolimus. For example, the aluminum bag has an aluminum pillow and an aluminum opening having a re-sealable chuck. And so on. Needless to say, as the aluminum constituting the bag, a resin film on which aluminum is vapor-deposited is generally used.

When aluminum bags are used, in order to suppress the degradation of everolimus due to moisture, a desiccant such as silica gel or zeolite may be enclosed in the aluminum bag together with PTP made of transparent resin containing tablets containing everolimus. preferable. Examples of the silica gel include, but are not limited to, those that can be purchased from Fuji Gel Sangyo Co., Ltd., Yamanin Pharmaceutical Co., Ltd., Marutani Processing Machine Co., etc. Examples of the zeolite include, but are not limited to, those that can be purchased from Tokai Chemical Industries, Yamanin Pharmaceutical Co., Cosmo Bio Co., etc.

When packaging a transparent resin PTP containing everolimus-containing tablets in an aluminum pillow, moisture-proof PTP can be selected in order to suppress degradation of everolimus due to moisture after the aluminum pillow is opened. As the moisture-proof PTP, TAS (registered trademark) series manufactured by Taisei Corporation, Super Foil (registered trademark) and Vinyl foil (registered trademark) series manufactured by Mitsubishi Plastics, Sumilite (registered trademark) series manufactured by Sumitomo Bakelite Co., Ltd., medical manufactured by ZACROS Examples thereof include, but are not limited to, PTP sheets (using Honeywell's Aclar (registered trademark)).

When moisture-proof PTP is adopted as the PTP made of transparent resin, the moisture of the tablet itself is not evaporated from the inside of the PTP pocket, and therefore, the moisture may promote the hydrolysis of everolimus. In order to prevent such a possibility, the tablet is dried until, for example, the water content is 20% by weight or less, preferably 15% by weight or less, more preferably 10% by weight or more preferably 5% by weight or less. It is desirable that The method of drying the tablet is not particularly limited, and examples thereof include air drying, drying by heating, drying with a desiccant such as silica gel and zeolite, etc., but it suppresses the generation of everolimus related substances and shortens the production time. From the viewpoint, drying with a desiccant such as silica gel and zeolite is preferable.

On the other hand, when the tablet containing everolimus is used as the film-coated tablet as the above-mentioned embodiment (B), the coating agent used is a photoprotective agent such as titanium oxide, iron sesquioxide, yellow iron sesquioxide or the like as commonly known. As long as the light stability of the active ingredient (everolimus) in the tablet to be coated (core tablet) can be ensured by including the other ingredients (mainly the coating substrate, etc.), it is particularly limited. Is not to be done. Examples of the coating substrate include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone ethyl acrylate, methyl methacrylate copolymer dispersion, hydroxypropyl methyl cellulose acetate succinate, and methacrylic acid copolymer. It is not limited to these.

The degree of stability of the everolimus-containing tablet in the everolimus preparation of one embodiment of the present invention is not particularly limited. For example, after storage at a temperature of 50 ° C. and harsh conditions such as the humidity for 7 to 14 days, It is preferable that the content of the related substance of everolimus measured is approximately the same as that of a tablet containing everolimus contained in double-sided aluminum PTP stored under the same conditions.

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples, and the present invention can take various modes as long as the problems of the present invention can be solved. it can.

[Example 1]
As Example 1, an everolimus-containing tablet (plain tablet) having the formulation shown in Table 1 was produced, and the tablet was stored as a transparent resin PTP in a polypropylene PTP sheet (transparent polypropylene on the surface, aluminum on the back). Thus, an everolimus preparation was produced. Specifically, an everolimus preparation was produced according to the following description.

200 mg of hypromellose was dispersed in a solution of 51 mg of everolimus (containing 2 wt% of dibutylhydroxytoluene) in 0.19 mL of ethanol. Then, methanol was evaporated from the dispersion by drying the obtained dispersion for 30 minutes with a dryer. The obtained solid was sized in a mortar to obtain everolimus solid solution.

Lactose hydrate 1314.9 mg, crospovidone 378.5 mg, and magnesium stearate 9.1 mg were added to 190 mg of the obtained everolimus solid solution and mixed. The obtained mixture was tableted with a tableting machine at a tableting pressure of 8 kN to produce 125.0 mg everolimus-containing tablets (plain tablets).

The everolimus preparation tablet was manufactured by accommodating the obtained everolimus containing tablet in transparent resin-made PTP using a blister packaging machine. Furthermore, the obtained everolimus preparation was packaged in an aluminum pillow using a pillow packaging machine together with silica gel as a desiccant.

[Comparative Example 1]
Ten tablets of Affinitol (registered trademark) 2.5 mg PTP product (double-sided aluminum) were used as the everolimus preparation of Comparative Example 1.

[Experimental example 1: Confirmation of appearance]
About the everolimus formulation of Example 1, the appearance property of the tablet accommodated at the time of manufacture or use can be visually recognized because the surface of the PTP sheet is a transparent resin. However, in the everolimus preparation of Comparative Example 1, since the PTP sheet was aluminum on both sides, the appearance properties of the contained tablets could not be visually recognized.

[Experimental Example 2: Measurement of related substances]
With respect to the everolimus preparation of Example 1 and the everolimus preparation of Comparative Example 1 that were pillow-wrapped, the content of everolimus-related substances under severe conditions was measured. Specifically, after both were stored for 0 days, 7 days, and 14 days under conditions of a temperature of 50 ° C. and a normal humidity, the contents of everolimus related substances were measured using 3 tablets at each measurement point. did. The content of related substances was measured under the conditions described in Table 2 below using HPLC.

The results of measuring the content of everolimus related substances are shown in Table 3. The everolimus preparation of Example 1 was able to ensure the same or lower stability as the everolimus preparation of Comparative Example 1 even though each tablet was contained in a transparent resin PTP sheet.

[Example 2]
As Example 2, Everolimus was used in the same manner as in Example 1 except that moisture-proof PTP (the surface was a medical PTP sheet manufactured by ZACROS (using Aclar (registered trademark) of Honeywell) and the back was aluminum) was used. An everolimus preparation containing the containing tablet in a PTP sheet was produced. The obtained everolimus preparation was packaged in an aluminum pillow using a pillow packaging machine together with silica gel as a desiccant.

The everolimus preparation of Example 2 packaged in an aluminum pillow was stored for 14 days under the conditions of a temperature of 25 ° C. and a humidity of 90% RH, and then the content of an everolimus related substance in the tablet Was measured and found to be as low as 1.08 wt%. From this result, it was found that the everolimus preparation can be stably stored by using moisture-proof PTP.

[Example 3]
As Example 3, an everolimus preparation in which the everolimus-containing tablet was housed in a PTP sheet was produced in the same manner as in Example 1 except that the everolimus-containing tablet was a film-coated tablet. Film-coated tablets are obtained by coating 400 g (3,200 tablets) of everolimus-containing tablets (plain tablets) by a spray-drying method using a coating agent containing 16 g of polyvinyl alcohol, 12.8 g of talc and 3.2 g of titanium oxide. Manufactured. The obtained everolimus preparation was packaged in an aluminum pillow using a pillow packaging machine together with silica gel as a desiccant.

The everolimus preparation of Example 3 was stored for 7 days under the same conditions as in Experimental Example 2 and the content of everolimus related substance in the tablet was measured. As a result, it was almost the same as that of the everolimus preparation of Example 1. Of everolimus related substances (0.93 wt%). From this result, it was found that the amount of related substances did not increase even when film-coated with everolimus-containing tablets.

Since the everolimus preparation of one embodiment of the present invention can easily visually recognize the appearance of the contained tablet at the time of manufacture and use, the quality of the appearance is excellent in industrial productivity. It contributes as a safe everolimus preparation that can be secured.

Claims (5)

An everolimus preparation comprising a tablet containing everolimus and a transparent resin-made PTP containing the tablet. The everolimus preparation according to claim 1, wherein the everolimus preparation is formed by packaging the transparent resin PTP in an aluminum bag. The everolimus preparation according to claim 1, wherein the everolimus preparation is formed by packaging the transparent resin PTP and a desiccant in an aluminum bag. The everolimus preparation according to any one of claims 1 to 3, wherein the transparent resin-made PTP is moisture-proof PTP, and the tablet is a tablet having a water content of 20% by weight or less. The everolimus preparation according to any one of claims 1 to 4, wherein the tablet is a film-coated tablet.