JP2003095928A - Sugar-coated preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a sugar-coated preparation which is excellent in storage stability of a water-unstable drug and in which the elution delay is prevented with time, and further preserves the storage stability of the water-unstable drug, and To provide a method for preventing elution delay. SOLUTION: An uncoated tablet containing a water-unstable drug is HL
A sugar-coated preparation, which is protected by a composition for protection containing B containing 10 or more surfactants, and coated with a sugar-coated composition containing succinated gelatin.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a sugar-coated preparation which is excellent in storage stability of a water-labile drug and which is prevented from delaying elution of the sugar-coated preparation with time. The present invention also relates to a method for ensuring the storage stability of a water-labile drug in a sugar-coated preparation and preventing the elution delay of the sugar-coated preparation over time.

[0002]

2. Description of the Related Art For tablets containing a water-labile drug as a main ingredient, a tablet which can prevent the water-labile drug from decomposing and can be stored in a good condition for a long period of time is required. On the other hand, considering the case where tablets are taken, tablets that can be eluted at an appropriate elution time are required. Elution takes time,
Further, it is not desirable that the elution amount is small with respect to the elapsed time. Therefore, a tablet that can well store a water-unstable drug and prevent elution delay with time is preferable.

Inventions for preventing the elution delay of sugar-coated preparations over time are disclosed in JP-A-51-35414 and JP-A-63-63.
No. 126821 and the like. In particular,
JP-A-51-35414 discloses a sugar-coated preparation produced by using a composition for sugar coating containing acid-treated gelatin, and JP-A-63-126821 discloses sucrose, pullulan, gelatin and a low molecular weight product. Sugar-coated preparations produced using a composition for sugar coating containing gelatin are described. Then, it is attempted to suppress the elution time delay with time by including gelatin in the sugar coating composition. However, the sugar-coated preparations described in both publications do not have a protective layer, and when these sugar-coated preparations contain a water-unstable drug as a main ingredient in uncoated tablets, the water content of the sugar-coating liquid reaches uncoated tablets. There is a problem that the water-labile drug is decomposed.

Therefore, in order to secure the storage stability of the water-labile drug, it is conceivable that a plain tablet containing the water-labile drug is protected and further sugar-coated to obtain a sugar-coated preparation. However, although the general sugar-coated preparation thus obtained can considerably suppress the decomposition of the water-labile drug, it causes a delayed elution with time.

No preparation has yet been obtained which can favorably store a water-labile drug and prevent elution delay with time.

From the above points, the storage stability of a water-labile drug is excellent, and particularly, it can be stored well under a high temperature or high humidity environment for a long period of time, and the results regarding the dissolution property such as the dissolution time and the dissolution amount are improved. In particular, it has been desired to provide a preparation capable of preventing the dissolution delay with time.

[0007]

The present invention has been made from the above point of view, and is intended for a preparation containing a water-labile drug, particularly a sugar-coated preparation, which is excellent in storage stability of the water-labile drug and is stable over time. An object of the present invention is to provide a sugar-coated drug product in which a typical dissolution delay is prevented, and to provide a method for preventing the dissolution delay of a water-labile drug while keeping the storage stability.

[0008]

Means for Solving the Problems As a result of intensive studies in consideration of the above points, the present inventors have found that a plain tablet containing a water-labile drug is protected with a surfactant having an HLB of 10 or more. It is possible to prevent the elution delay with time while maintaining the storage stability of the water-labile drug by sugar-coating with a sugar coating composition liquid containing succinated gelatin after protection with the composition liquid for coating. The present invention has been completed and the present invention has been completed.

That is, the present invention is as follows. (1) HLB is 10 in a plain tablet containing a water-labile drug.
A sugar-coated preparation, which has been protected with the above-mentioned composition composition for protecting containing a surfactant and further sugar-coated with the composition solution for sugar coating containing succinated gelatin. (2) The sugar-coated preparation according to (1), wherein the water-labile drug is methylmethionine sulfonium chloride or cysteine. (3) HLB is 10 in a plain tablet containing a water-labile drug.
Storage stability of the water-labile drug in sugar-coated preparations by applying sugar-coating with a liquid composition containing succinated gelatin after protection with the liquid composition containing a surfactant described above. A method for preventing elution delay, which prevents the elution delay of a sugar-coated preparation with the lapse of time. (4) The method for preventing dissolution delay according to (3), wherein the water-labile drug is methylmethionine sulfonium chloride or cysteine.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below.

The sugar-coated preparation of the present invention contains a succinated gelatin after the uncoated tablet containing the water-labile drug is protected with a protecting composition composition containing a surfactant having an HLB of 10 or more. It is obtained by sugar coating with a composition liquid for sugar coating.

In the present invention, the water-labile drug means a drug which is decomposed by absorbing water. For example, methylmethionine sulfonium chloride, amino acids (aspartic acid and cysteine, etc.), various vitamins (vitamin E, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin A, vitamin D, vitamin C, nicotinic acid amide, vitamin P) And its derivatives, etc.), crude drugs (hops, yochinin, senburi, roto extract, garlic, oak, carrots, oxoamidin, etc.) and enzymes (starch digestive enzymes, protein digestive enzymes,
Fat digestive enzymes, fibrin digestive enzymes, etc.) and the like.
When these drugs absorb water and start to decompose, they give off an offensive odor, cause discoloration, or decrease in content.

The content of the water-labile drug in the sugar-coated preparation of the present invention is preferably 1 to 30% by weight, more preferably 3 to 20% by weight, particularly preferably 5 to 15% by weight, based on the total amount of the preparation. Is.

In the present invention, HLB is a hydrophilic-lipophilic balance and represents a ratio of hydrophilicity and lipophilicity. HLB in the present invention is represented by the following formula using the Davis cardinal number.

HLB = 7 + Σ (group number of hydrophilic group) + Σ (group number of new oil group) The HLB value of the surfactant contained in the composition for protection application in the sugar-coated preparation of the present invention is preferably 10 or more, more preferably Is 12.5 or more, and particularly preferably 15 or more.

Examples of the surfactant having HLB of 10 or more in the sugar-coated preparation of the present invention include polyethylene glycol monostearate (40EO) (HLB = 17.5) and polyethylene glycol monostearate (45EO) (HLB = 1).
8.0), polyethylene glycol monostearate (55
EO) (HLB = 18.0), polyethylene glycol monostearate (25EO) (HLB = 15.0), polyethylene glycol monostearate (10EO) (HLB = 11.0) and polyethylene glycol monolaurate (10EO) (HLB = 12.
Polyethylene glycol fatty acid ester such as 5), polyoxyethylene (21) lauryl ether (HLB = 19.0), polyoxyethylene (25) lauryl ether (HLB = 19.5), polyoxyethylene (9) lauryl ether (HLB = 14.5) And polyoxyethylene (4.2) lauryl ether (HLB = 11.
Polyoxyethylene alkyl ethers such as 5), monococonut oil fatty acid polyoxyethylene (20) sorbitan (HLB = 1
6.9), polyoxyethylene (20) sorbitan monopalmitate (HLB = 15.6), polyoxyethylene (20) sorbitan monostearate (HLB = 14.9), polyoxyethylene (20) sorbitan monooleate (HLB = 15.0) And polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan monoisostearate (HLB = 15.0).

The amount of the surfactant having HLB of 10 or more in the sugar-coated preparation of the present invention is 0.3 to 10% based on the total amount of the preparation.
It is preferably 2% by weight, more preferably 0.5 to 1.5% by weight.

In the present invention, the succinated gelatin is an aqueous solution thereof (a total of 20 g of succinated gelatin is obtained by adding water to 3 g of succinated gelatin).
It shall be 0 g. PH of 5.5) to 6.5) and the substitution degree of succinic acid of 95% or more are preferably used. Also, succinated gelatin can be produced by using a method of reacting succinic anhydride with gelatin generally obtained by alkali treatment.

The content of succinated gelatin in the sugar-coated preparation of the present invention is preferably 0.1 to 2% by weight, more preferably 0.2 to 1.5% by weight, based on the total amount of the preparation.
It is particularly preferably 0.3 to 1% by weight. Further, the sugar-coating layer (layer formed by using the composition liquid for sugar-coating coating described later) is preferably 0.2 to 4% by weight, more preferably 0.4 to 3% by weight, and particularly preferably. It is 0.6 to 2% by weight.

To formulate the sugar-coated preparation of the present invention, a usual preparation method can be used. For example, an uncoated tablet is protected with a composition liquid for protection by using an automatic coating device or a coating pan to form a protected tablet, and then a composition liquid for sugar coating (also referred to as a composition liquid for sugar coating) is coated with sugar. It can be made into a sugar-coated tablet. Here, the protecting is a step performed before the sugar coating step, and is a step performed for the purpose of suppressing permeation of water used in the sugar coating step into the plain tablets. For example, a waterproof film is applied to the surface of the plain tablet in advance.

In addition to the above-mentioned surfactant having an HLB of 10 or more, other components can be added to the composition liquid for protecting used when carrying out the protecting. Other components include various additives that are acceptable as pharmaceutical additives and that can be orally administered. These additives are
If desired, a plurality of types can be used in combination. As such an additive, for example, a water-soluble polymer,
The above-mentioned HLB is less than 10 surfactants, other coating agents and the like.

Examples of the water-soluble polymer include cellulose ether polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose 2910 and methylcellulose, vinyl polymers such as polyvinyl alcohol and polyvinylpyrrolidone, and glycol polymers such as polyethylene glycol. An acrylic acid-based polymer such as a methacrylic acid copolymer can be used.

As the surfactants (surfactants having a HLB of less than 10) other than the above-mentioned 10 or more surfactants, for example, glyceryl monostearate, glyceryl monooleate, glyceryl monomyristate, etc. may be used. You can

As other coating agents, for example, ethyl cellulose, hydrogenated oil, refined shellac and talc can be used.

Next, in addition to the succinated gelatin, other components can be added to the composition coating composition for sugar coating used in the sugar coating step. Other components include various additives that are acceptable as pharmaceutical additives and that can be orally administered. These additives can be used in combination of two or more kinds as desired. Examples of such additives include colorants, sugar coating agents and brightening agents.

As the colorant, for example, various food dyes,
Tar pigments and ferric sesquioxide can be used.

As the sugar coating agent, for example, precipitated calcium carbonate, purified sucrose, sucrose, sodium hydrogenphosphate, talc, gum arabic, gum arabic powder, gelatin, pullulan, titanium oxide and the like can be used.

As the brightening agent, for example, carnauba wax and fish scale foil can be used.

Furthermore, various optional ingredients which are acceptable as pharmaceutical additives and which can be administered orally can be added to the plain tablet of the sugar-coated preparation of the present invention as desired. As such additives, for example, excipients, binders, disintegrants, lubricants and the like can be added as desired.

As the excipient, for example, lactose, starch, crystalline cellulose, sucrose, D-mannitol, light anhydrous silicic acid, calcium hydrogen phosphate and the like can be used.

As the binder, for example, hydroxypropylmethyl cellulose 2910, pregelatinized starch, polyvinylpyrrolidone, pullulan and the like can be used.

As the disintegrant, for example, crospovidone, hydroxypropyl starch, carmellose, carmellose calcium, croscarmellose sodium, corn starch and the like can be used.

As the lubricant, for example, magnesium stearate, sodium stearyl fumarate, talc and the like can be used.

The sugar-coated preparation of the present invention can be formulated into sugar-coated tablets, sugar-coated granules and the like.

[0035]

EXAMPLES The present invention will be specifically described below with reference to examples. <Production Example> Methylmethionine sulfonium chloride 1
000g, Polyvinylpyrrolidone 300g, Lactose 600
g, corn starch 1550 g, and carmellose calcium 500 g, kneading and granulating after adding ethanol 600 mL, and then drying and sizing, and adding magnesium stearate 50 g to the tablet machine (Kikusui Seisakusho Collect 1
9 TU) was compression-molded to produce 40,000 plain tablets each having 100 mg. This is an uncoated tablet.

Table 1 summarizes the above-mentioned charged amount and the compounding amount per tablet.

[0037]

[Table 1]

[0038]

Example 1 400 g of hardened oil and glyceryl monostearate (trade name: Nikkor MGS) were added to the plain tablets obtained in the production example.
-B [Nikko Chemical]) (HLB = 4) 100 g and polyethylene glycol monostearate (40EO) (Brand name: Nikkor MYS-40 [Nikko Chemical]) (HLB = 1
7.5) A solution of 100 g dissolved in 600 mL of ethanol, and 200 g of talc in a coating pan (Kikusui Seisakusho 12
Inch type) is used to spray or spray on uncoated tablets, 120 mg per tablet (uncoated tablet 100 mg, protect layer 20 mg)
Protected lock of. Subsequently, 660 g of white sugar and succinated gelatin (trade name:
60 mg of succinated gelatin [manufactured by Nippi Gelatin Industry Co., Ltd.], 280 g of gum arabic, 1100 g of precipitated calcium carbonate and 1100 g of talc were sprayed using a sugar coating composition liquid prepared by dissolving or dispersing in 600 mL of purified water. , Protect layer 20m
g, a sugar-coated layer (80 mg), and then further coated with white sugar 1
740 g, succinated gelatin 20 g and titanium oxide 24
250 mg per tablet was sprayed using a composition coating composition for sugar coating in which 0 g was dissolved or dispersed in 900 mL of purified water.
(Uncoated tablet 100 mg, protect layer 20 mg, sugar coating layer 80
mg, further coated sugar-coated layer 50 mg) to obtain a sugar-coated tablet.

Table 2 shows a summary of the charged amount and the compounded amount per tablet described in Example 1. Table 2 also shows the charged amount and the compounding amount per tablet described in each of the comparative examples below.

[0040]

[Table 2]

[0041]

Comparative Example 1 400 g of hardened oil, 100 g of glyceryl monostearate (HLB = 4) and polyethylene glycol monostearate (40EO) (HLB = 1
7.5) A solution of 100 g dissolved in 600 mL of ethanol, and 200 g of talc in a coating pan (Kikusui Seisakusho 12
Inch type) was used to spray or disperse the uncoated tablets into 120 mg protective lock tablets. Subsequently, 660 g of white sugar, 60 g of gelatin (trade name: gelatin E1 [manufactured by Nippi Gelatin Industry Co., Ltd.], 280 g of gum arabic, 1100 g of precipitated calcium carbonate and 1100 g of talc were dissolved or dispersed in 600 mL of purified water in the resulting protected tablet. After spraying with the composition liquid for coating to prepare 200 mg sugar-coated tablets per tablet, white sugar 1740 was further added.
g, gelatin E1 (20 g) and titanium oxide (240 g) were dissolved or dispersed in purified water (900 mL) and sprayed to obtain a sugar-coated tablet (250 mg per tablet).

[0042]

Comparative Example 2 A solution of 400 g of hardened oil and 200 g of glyceryl monostearate (HLB = 4) dissolved in 600 mL of ethanol, and 200 g of talc in a coating pan (Kikusui Seisakusho 12-inch type) were applied to the plain tablets obtained in the Production Example. Using it, it was sprayed or sprayed on plain tablets to give 120 mg / tablet lock tablets. Then, in the obtained lock lock,
660 g of white sugar, 60 g of succinated gelatin (trade name: succinated gelatin [Nippi Gelatin Industry]), 280 g of gum arabic, 1100 g of precipitated calcium carbonate and 1 talc
200 g per tablet by spraying with a composition coating composition for sugar coating in which 100 g is dissolved or dispersed in 600 mL of purified water.
g sugar-coated tablet, 1740 g of sucrose, 20 g of succinated gelatin and 240 g of titanium oxide are further added to 900 g of purified water.
The composition coating solution for sugar coating dissolved or dispersed in mL was sprayed to obtain a sugar-coated tablet of 250 mg per tablet.

[0043]

Comparative Example 3 825 g of sucrose, 75 g of succinated gelatin (trade name: succinated gelatin [manufactured by Nippi Gelatin Industries]), 350 g of gum arabic, 1300 g of precipitated calcium carbonate and 1450 g of talc were added to purified water in the plain tablet obtained in the Production Example. 200 mg per tablet was sprayed using the composition coating composition for sugar coating dissolved or dispersed in 750 mL (100 m of uncoated tablets)
g, sugar-coated layer 100 mg) to give a sugar-coated tablet, and then 1740 g of sucrose, 20 g of succinated gelatin and titanium oxide 2
250 mg per tablet was sprayed using a composition coating composition for sugar coating in which 40 g was dissolved or dispersed in 900 mL of purified water.
A sugar-coated tablet (uncoated tablet 100 mg, sugar-coated layer 100 mg, and further coated sugar-coated layer 50 mg) was obtained. <Evaluation Test and Results> Regarding the tablets obtained in Example 1 and Comparative Examples 1 to 3, tablets immediately after production and after being stored for 2 weeks under the condition of 50 ° C. were used as experimental objects. Immediately after production and after storage for 2 weeks at 50 ° C (in Table 1, "5
After 0 ° C.-2 W ”. ) For each tablet,
The amount of elution of methylmethionine sulfonium chloride, the main drug, after 60 minutes, the lag time, and the content of methylmethionine sulfonium chloride, the main drug, were measured by the following methods.

The elution amount and lag time after 60 minutes were as follows: Japanese Pharmacopoeia No. 13 Pharmacopeia Dissolution Test Method No. 2 (purified water 900 mL,
The paddle rotation speed was 50 rpm). The elution amount after 60 minutes is a measurement of the total amount of methylmethionine sulfonium chloride eluted after 60 minutes from the start of the test. The lag time is the time required until 1.25 mg or more of methylmethionine sulfonium chloride is eluted (the shorter the time is, the more preferable in this preparation).
Is measured. In addition, the main drug content is a measurement of the content of methylmethionine sulfonium chloride per tablet.

Table 3 shows the measurement results.

[0046]

[Table 3] From these results, in the sugar-coated preparation of Example 1 of the present invention, methylmethionine sulfonium chloride was stored favorably for a long time (stored for 2 weeks under the condition of 50 ° C.), and the dissolution property after further storage for a long time (lag time And the amount of elution over time)
It was confirmed that also showed a good result.

On the other hand, it was confirmed from the results of the elution amount and the lag time that the dissolution property after storage for 2 weeks under the condition of 50 ° C. was decreased when the succinated gelatin was not added to the composition composition for sugar coating. Further, the elution lag time of tablets immediately after production is extended. Similarly, polyethylene glycol monostearate (40E
It was confirmed from the results of the elution amount and the lag time that the dissolution property after storage for 2 weeks under the condition of 50 ° C. was decreased when O) was not added. Further, the elution lag time of tablets immediately after production is extended. Further, when the protection was not applied, the stability of the main drug was extremely deteriorated.

As described above, a plain tablet containing a water-labile drug is protected with a protective composition composition containing a surfactant having an HLB of 10 or more, and then a sugar coating composition solution containing succinated gelatin. It was confirmed that by coating with sugar coating, the storage stability of the water-labile drug can be retained, and the elution delay with time after storage for a further period can be prevented.

[0049]

INDUSTRIAL APPLICABILITY According to the present invention, a sugar-coated preparation having excellent storage stability of a water-labile drug and preventing the elution delay with time, and a storage stability of the water-labile drug while maintaining the storage stability It was possible to provide a method for preventing the elution delay.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Masato Ozaki             332-1 Ohno Nitta, Fuji City, Shizuoka Prefecture (72) Inventor Hirotada Ogawa             20-14 Suzukawanishimachi, Fuji City, Shizuoka Prefecture (72) Inventor Niichiro Takano             1-3-1-302 Mitojima, Fuji City, Shizuoka Prefecture (72) Inventor Shinichiro Kobayashi             332-1 Ohno-Nitta, Fuji City, Shizuoka Prefecture (72) Inventor Makoto Sasaki             935-101 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture (72) Inventor Yukari Hagiwara             14-21 Matsubarahonmachi, Ito City, Shizuoka Prefecture F-term (reference) 4C076 AA43 BB01 CC21 DD25H                       DD28H DD41 DD46H DD67                       DD67H EE16 EE23H EE30                       EE32 EE38 EE42H EE52H                       EE58H FF21 FF31 FF63                 4C206 AA01 AA02 JA26 JA27 MA03                       MA05 MA11 MA28 MA55 MA72                       NA03 ZC21

Claims (4)

[Claims] 1. An HL for a plain tablet containing a water-labile drug.
A sugar-coated preparation, which has been protected with a composition liquid for protection containing a surfactant having a B of 10 or more, and further coated with a composition liquid for sugar coating containing succinated gelatin. 2. The sugar-coated preparation according to claim 1, wherein the water-labile drug is methylmethionine sulfonium chloride or cysteine. 3. An uncoated tablet containing a water-labile drug, HL
After B is protected with a composition liquid for protection containing a surfactant of 10 or more, it is coated with a composition liquid for sugar coating containing succinated gelatin to form a water-unstable drug in a sugar coating preparation. A method for preventing elution delay, which prevents elution delay of a sugar-coated preparation with time while maintaining storage stability. 4. The method for preventing dissolution delay according to claim 3, wherein the water-labile drug is methylmethionine sulfonium chloride or cysteine.