JP2000007585A - Moisture-resistant solid preparation and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a moisture-resistant solid preparation excellent in moistureproofness and handleability under pharmaceutical manufacturing process and excellent in preservability as well, and to provide a method for producing the preparation. SOLUTION: This solid preparation is such one as to comprise a hygroscopic bulk, a coating agent comprising an oil ingredient such as animal/vegetable fat-and-oil, fat and hydrocarbon oil and wax, and a preparation stock. This solid preparation has a relative room temperature moisture absorption of <=65% and relative accelerated moisture absorption of <=80%. The other objective method for producing the above solid preparation comprises heating a mixture of a hygroscopic bulk, a coating agent as mentioned above, a preparation stock, and a solvent followed by molding the mixture and then drying the mixture thus molded.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a moisture-resistant solid preparation and a method for producing the same, and more particularly, to a specific coating, which is suppressed in hygroscopicity, and which can be used during production, use or storage. The present invention relates to a moisture-resistant solid preparation excellent in stability and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, various drug substances have been used in pharmaceutical preparations. Among these drug substances, a preparation prepared from a hygroscopic drug substance powder having hygroscopicity is used in the air during storage or opening. There was a risk of deterioration due to the absorption of water. Conventionally, such problems have been addressed by sugar coating or film coating of the preparations, and in tablets, the hygroscopicity has been improved by coating with PTP or the like.

[0003]

However, such a conventional method for improving hygroscopicity is not suitable for fine granules and granules having a large surface area, and they are sealed and packaged at the time of formulation. However, there is a problem that the hygroscopicity cannot be suppressed during storage or during use or during storage.

[0004] Under such circumstances, various attempts have been made to prevent hygroscopicity of fine granules and granules containing a hygroscopic drug substance powder, but none of them have been satisfactory. Also, in the case of PTP packaging, if a tablet containing a hygroscopic drug substance powder is stored for a long period of time, the prevention of moisture absorption becomes extremely inadequate and it is still unsatisfactory, and the development of an appropriate moisture-proof technology has been desired.

[0005] The present invention has been made in view of such problems of the prior art, and has as its object to provide excellent moisture proofing and handling properties at the time of formulation, and also have a good storage stability. An object of the present invention is to provide an excellent moisture-resistant solid preparation and a method for producing the same.

[0006]

The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, have performed infiltration / coating using a specific oil and brazing material, and using such oil and brazing material. The inventors have found that the above-mentioned problems can be solved by using the treated moisture-resistant drug substance powder composition, and have completed the present invention.

That is, the moisture-resistant solid preparation of the present invention is a coating agent containing a drug substance powder having hygroscopicity and at least one oil component and wax component selected from the group consisting of animal and vegetable oils, fats and hydrocarbon oils. And a raw material for the preparation, characterized in that the relative room temperature moisture absorption is 60% or less and the relative accelerated moisture absorption is 80% or less.

Further, in the method for producing a moisture-resistant solid preparation of the present invention, the above-mentioned moisture-absorbing drug substance powder, the above-mentioned coating agent, the above-mentioned raw material for the preparation and a solvent are mixed in producing the above-mentioned moisture-resistant solid preparation. And then heated, then molded and dried.

Further, according to another method for producing a moisture-resistant solid preparation of the present invention, in producing the above-mentioned moisture-resistant solid preparation, the moisture-absorbing drug substance powder is coated with the coating agent, A composition is prepared in advance, and then the obtained moisture-resistant drug substance powder composition, the drug substance and the solvent are mixed, molded, and then dried.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the moisture-resistant solid preparation of the present invention will be described in detail. As mentioned above, this solid formulation
A drug substance powder having hygroscopicity, a coating agent, and a drug substance containing, specifically, granules containing these components,
Fine granules, tablets and pills. Here, the hygroscopic drug substance powder targeted by the present invention is not particularly limited as long as it has hygroscopicity, but ginger syrup, pancreatin, dextran sodium sulfate, liver hydrolyzate, Examples include citric acid, ascorbic acid or potassium bitartrate and any mixtures thereof.

The present invention is particularly effective for the above-mentioned hygroscopic drug substance powders having high hygroscopicity. Specifically, the present invention relates to a drug substance powder having a room temperature moisture absorption of 10 to 50%. It is suitable for. Examples of such highly hygroscopic drug substance powder include ginger syrup, pancreatin, sodium dextran sulfate or liver hydrolyzate, and any mixture thereof.

Further, in the present specification, "moisture absorption at room temperature"
The term means the rate of weight increase (%) when the target drug substance powder or solid preparation is left for 10 to 45 days under the conditions of laboratory temperature and humidity. Further, the "relative room temperature moisture absorption rate" is represented by the following formula (room temperature moisture absorption rate of a drug substance powder or solid preparation subjected to moisture resistance treatment) / (moisture absorption rate of the drug substance powder or solid preparation) x 100 ... Value (%).

Next, the coating agent contains an oil component consisting of animal and vegetable fats and oils, fats or hydrocarbon oils and any mixture thereof, and a wax component. Such oil is not particularly limited, and various animal oils, for example, various whale oils, horse oil, tallow, lard and sheep fat, and various fish oils, sardine oil, saury oil, squid oil, herring oil And sea animal oil, various vegetable oils, soybean oil, rapeseed oil,
Peanut oil, camellia oil, corn oil, cottonseed oil, olive oil, safflower oil, sesame oil, safflower oil, palm oil, coconut oil, etc., and various hydrocarbon oils can be mentioned. Particularly preferred are camellia oil and olive oil. Can be. In addition, it is desirable that these oils are those generally recognized as additives for internal medicines due to the formulation.

[0014] On the other hand, the solder is not particularly limited, and various kinds of waxes and waxes can be used. Specifically, sugar cane wax, wood wax, cocoa butter, spermaceti, beeswax, fluid Examples thereof include paraffin and synthetic triglyceride. Among them, cocoa butter and beeswax can be particularly preferably used. In addition, it is desirable that these brazing components, as well as the above-mentioned oil components, are those generally recognized as additives for internal medicines.

Next, the above-mentioned raw materials for the preparation include various additives usually used for the preparation of the preparation, for example, excipients, disintegrants, binders, lubricants and flavors. In the present invention, these pharmaceutical raw materials are not particularly limited, but various kinds of sugars such as lactose, silicic anhydride and calcium carbonate as excipients, various kinds of cellulose and calcium carboxymethylcellulose (CMC) as disintegrants, Hydroxypropylcellulose is preferably used as the agent, and magnesium stearate is preferably used as the lubricant.

The moisture-resistant solid preparation of the present invention can contain additives other than the above-mentioned components. Examples of such additives include antioxidants such as vitamin E and food additives. Or a coloring agent recognized by the Japanese Pharmacopoeia.

The moisture-resistant solid preparation of the present invention has a relative room temperature moisture absorption of 65% or less and a relative accelerated moisture absorption of 80% or less.
% Or less. Typically, granules have a relative room temperature moisture absorption of 65% or less and a relative accelerated moisture absorption of 80% or less, and tablets have a relative room temperature moisture absorption of 60% or less and a relative accelerated moisture absorption of 75%. It is as follows.

Here, "accelerated moisture absorption rate" means the rate of weight increase (%) when the target drug substance powder or solid preparation is allowed to stand at about 40 ° C. and 75% relative humidity for 10 to 45 days. Shall mean. The “relative accelerated moisture absorption rate” is represented by the following formula (accelerated moisture absorption rate of drug substance powder or solid preparation subjected to moisture resistance treatment) / (accelerated moisture absorption rate of the drug substance powder or solid preparation) × 100. It means the expressed value (%).

As described above, the moisture-resistant solid preparation of the present invention comprises:
It has a predetermined relative room temperature moisture absorption rate and a relative accelerated moisture absorption rate, and is excellent not only in moisture resistance but also in storage stability and ease of handling. The amount of each of the above components is not particularly limited as long as the relative room temperature moisture absorption and the relative accelerated moisture absorption are satisfied, but typically, the amount of the hygroscopic drug substance powder is 100 parts by weight. On the other hand, the coating agent may be blended in a proportion of 10 to 60 parts by weight, and the drug substance in a proportion of 100 to 9000 parts by weight. In addition, a more preferable formulation is that the hygroscopic drug substance powder is 20 to 4 times.
0 parts by weight, 5 to 10 parts by weight of the coating agent, and 50 to 70 parts by weight of the drug substance.

If the amount of the coating agent is less than 10 parts by weight based on 100 parts by weight of the hygroscopic drug substance powder, the moisture-proof effect becomes insufficient, and if it exceeds 60 parts by weight, oil may ooze out of the obtained preparation. Yes, not preferred.

Next, a method for producing the moisture-resistant solid preparation of the present invention will be described. This moisture-resistant solid preparation was heated while mixing the above-mentioned hygroscopic drug substance powder, coating agent, drug substance and other additives and a solvent as required at the above-mentioned predetermined mixing ratio, and kneaded sufficiently. Thereafter, it can be obtained by molding and then drying. Further, the moisture-resistant tablet according to the present invention is obtained by tableting the thus obtained granules or granules as a raw material.

In this production method, the solvent is added in order to realize homogeneous mixing when preparing a mixture of the drug substance powder and the coating agent, and to facilitate the subsequent molding. Examples of such a solvent include water and organic solvents, specifically, water, various alcohols, ethers, ketones, esters, and the like, and a mixed solvent thereof. Particularly, acetone and isopropyl alcohol are preferable. Can be used. The addition amount can be appropriately changed depending on the type of the solvent, the intended moisture resistance, the dosage form, and the like, but the weight ratio is 1: 2 to 1: 1 (solvent: mixture)
It is preferable that

The heating temperature of the mixture of the drug substance powder, the coating agent, the drug substance and the like is desirably not lower than the melting temperature of the coating agent and lower than the decomposition / degradation temperature of the hygroscopic drug substance powder. The reason for this is that, in order to improve the moisture resistance, it is preferable that the coating agent coats the drug substance powder through a permeation / infiltration state, and for this purpose, it is desirable that the mixture containing the coating agent is sufficiently melted. However, if it becomes higher than the decomposition or alteration temperature of the drug substance powder, the intended medicinal effect may not be obtained,
Not preferred.

Specifically, the above-mentioned heating temperature can be appropriately selected depending on the type of the drug substance powder and the coating agent, but is typically about 40 to 110 ° C., preferably about 6 ° C.
The temperature may be 5 to 100 ° C, more preferably about 65 to 80 ° C. When the heating temperature is lower than 65 ° C., the mixture containing the coating agent may be separated into layers, and the drug substance powder may not be sufficiently infiltrated.

The molding of the mixture obtained as described above
For example, it can be performed by an extrusion granulator, and the obtained granules can be dried at a high temperature, a normal temperature, and a low temperature, and can be performed by, for example, a blow dryer. In addition, tableting of the obtained granular material or granule preparation can be performed using a known tableting machine such as a single-shot tableting machine or a rotary tableting machine, using a lubricant such as magnesium stearate, 1 to
It can be carried out at a compression pressure of 5 t / cm ² .

Next, another method for producing the solid preparation of the present invention will be described. In this production method, first, a hygroscopic drug substance powder is infiltrated and covered with the above-mentioned coating agent to prepare a moisture-resistant drug substance powder composition. Then, this moisture-resistant drug substance powder composition is mixed with the above-mentioned drug substance and, if necessary, a solvent, and kneaded.
The moisture-resistant solid preparation of the present invention can be obtained by molding and drying.

The above-mentioned moisture-resistant drug substance powder composition has a form in which the hygroscopic drug substance powder is coated with a coating agent, and the coating simply covers the drug substance powder along its surface. Not only that, but rather, the coating agent is intended to cover the surface with the drug substance slightly penetrating into the bulk of the drug substance. Such a coating penetrating into the bulk of the drug substance can significantly improve the moisture resistance of the hygroscopic drug substance powder.

The moisture-resistant drug substance powder composition typically contains 100 parts by weight of a hygroscopic drug substance powder and 10 to 60 parts by weight of a coating agent. In the present production method, heating is not required, and the amount of the solvent is the same as in the above-mentioned production method.

[0029]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.

(Example 1) [Preparation of granule] 600 g of liver hydrolyzate, 135 g of a coating agent containing vegetable oil and wax, and 30 g
A moisture-resistant drug substance powder composition containing the following antioxidant and 30 g of silicic anhydride as an excipient was prepared. Subsequently, an excipient 14 containing lactose and silicic anhydride was added to 795 g of the moisture-resistant drug substance powder composition.
55 g, 450 g of hydroxypropylcellulose as a binder, and 300 g of a disintegrant containing cellulose and CMC calcium were added and mixed, and 2,000 ml of an alcohol solvent was added and kneaded. The obtained kneaded product was molded by an extrusion granulator, dried by blast drying, and then sized to obtain a moisture-resistant granule of this example.

[Measurement of Moisture Absorption Rate of Granules at Room Temperature] 1 g of the moisture-resistant granules obtained as described above was placed in a glass bottle, left open in a laboratory with the bottle open, and taken out with time to determine the change in weight. It was measured. The rate of weight increase was calculated based on the measured values, and this value was defined as the room temperature moisture absorption of the granules of this example. In addition,
The moisture absorption at room temperature of the granules of Comparative Example 1 described below was measured and found to be 45%.
The relative room temperature moisture absorption rate was calculated from the above equation with the value on the day as 100, and the obtained results are shown in Table 1.

[Measurement of Accelerated Moisture Absorption Rate of Granules] 1 g of the moisture-resistant granules of this example were placed in a small polyethylene bag, the small bag was sealed by heat sealing, and its weight was measured. Next, the sachet containing the granules was filled with a saturated saline solution under the eye plate,
It was allowed to stand in a desiccator maintained at 0 ° C. and a relative humidity of 75%, taken out with time, and the change in weight was measured. The rate of weight increase was calculated based on the measured values, and this value was used as the accelerated moisture absorption rate of the moisture-resistant granules. In addition, the accelerated moisture absorption of the granule of Comparative Example 1 described later was measured, and the relative accelerated moisture absorption was calculated from the above formula with the value on the 45th day as 100, and the obtained results are shown in Table 2.

(Comparative Example 1) [Production of Control Granule and Measurement of Moisture Absorption] A bulk drug substance composition was prepared in the same manner as in Example 1 except that the coating agent was not subjected to moisture resistance treatment. 795 g of the composition was subjected to the same formulation treatment as in Example 1 to obtain a granule of this example. The same operation as in Example 1 was performed to measure the accelerated moisture absorption and the room temperature moisture absorption, and the obtained results are shown in Tables 1 and 2.

[0034]

[Table 1]

[0035]

[Table 2]

(Example 2) [Preparation of tablet] A moisture-resistant drug substance containing 1040 g of the liver hydrolyzate, 115 g of the above coating agent, 25 g of an antioxidant, and 320 g of an excipient containing starch and calcium carbonate. 1500 g of a powder composition was prepared. This drug substance powder composition 15
500g excipient containing lactose and calcium carbonate
Then, 250 g of the above binder, 50 g of a disintegrant containing CMC calcium and talc were added and mixed, and 1700 ml of an alcoholic solvent was added and kneaded, followed by granulation to obtain granules. Thereafter, the granules were blown dry, added with 50 g of magnesium stearate as a lubricant, mixed, and compressed at a compression pressure of 2.5 t / cm ^{2 to form} a tablet having a diameter of 10 t / cm ^2.
Thus, an R-type uncoated tablet of this example having a thickness of 5.5 mm and a thickness of 5.5 mm was obtained.

[Measurement of room temperature absorption of tablets] The same operation as in the case of the granules shown in Example 1 was repeated except that the obtained 4 uncoated tablets were used. Was calculated. However, the measurement period was 15 days. Further, the relative room temperature absorption rate was calculated from the above formula with the value on the 15th day of the tablet of Comparative Example 2 described later as 100, and the obtained results are shown in Table 3.

[Measurement of Accelerated Absorption Rate of Tablet] The same operation as in the case of the granules shown in Example 1 was repeated, except that the above-mentioned four uncoated tablets were placed in an opened glass bottle. The accelerated moisture absorption was calculated. However, the measurement period was set to 15 days.
In addition, as described above, the relative accelerated moisture absorption was calculated for the tablet of Comparative Example 2 described below, and the obtained results are shown in Table 4.

Comparative Example 2 Production of Control Tablet and Measurement of Moisture Absorption Instead of the moisture-resistant drug substance powder composition, 1040 g of liver hydrolyzate and starch 150 were used.
g and the same operation as in Example 2 except that the drug substance powder composition containing 310 g of calcium carbonate was used to obtain a tablet of this example. The room temperature absorption rate and the accelerated absorption rate were measured in the same manner as in Example 2, and the obtained results are shown in Tables 3 and 4.

[0040]

[Table 3]

[0041]

[Table 4]

(Example 3) [Preparation of granule] The components of the moisture-resistant drug substance powder composition of Example 1 were mixed in the same composition, and 600 ml of a solvent was added to the mixture and heated to 70 ° C. It was stirred and dispersed. Next, an excipient, a binder and a disintegrant having the same components and the same composition as in Example 1 were added, mixed, and further kneaded by adding 1400 ml of a solvent. Do the operation,
A moisture-resistant granule of this example was obtained. As in Example 1, the room temperature moisture absorption and the accelerated moisture absorption were measured between Comparative Example 3 described below,
The obtained results are shown in Tables 5 and 6.

Comparative Example 3 Production of Control Granules and Measurement of Moisture Absorption The same operation as in Example 3 was repeated except that a mixture containing 600 g of the liver hydrolyzate and 195 g of silicic anhydride was used. A granule of this example was obtained. The room temperature absorption rate and the accelerated absorption rate of the obtained granules were measured, and the obtained results are shown in Tables 5 and 6.

[0044]

[Table 5]

[0045]

[Table 6]

(Microscopic Observation of the Granules of Example 3 and Comparative Example 3) The granules prepared using the granules of Example 3, ie, the drug substance powder treated with the coating agent, and the untreated granules of Comparative Example 3 The surface of the granule was magnified 50 times and observed under a microscope, and the results are shown in FIGS. 1 and 2, respectively. As a result, on the surface of the granule of Comparative Example 3 shown in FIG. 2, many yellow-brown particles due to the drug substance powder were found, and many hygroscopic drug substance powders were exposed without being covered. Do you get it. In contrast, no yellow-brown particles were observed on the surface of the granule of Example 3 shown in FIG.
It can be seen that the whole granule is slightly yellow and the hygroscopic drug substance powder is not exposed.

The results of the above-mentioned moisture absorption test are presumed to be caused by this phenomenon, and the results of Example 3 belonging to the scope of the present invention were obtained.
In the granules of Comparative Example 3, the drug substance powder was uniformly dispersed and provided with a sufficient moisture-resistant coating throughout, and showed good moisture resistance. It is presumed that the dispersion was insufficient and that the drug substance powder was agglomerated to some extent, which also reduced the moisture resistance.

[0048]

As described above, according to the present invention, it is possible to perform infiltration / coating using a specific oil component and a brazing component, and to provide a moisture-resistant drug substance powder composition treated with such an oil component and a brazing component. Thus, it is possible to provide a moisture-resistant solid preparation which is excellent in moisture-proof property and handleability at the time of formulation and excellent in storage stability, and a method for producing the same.

[Brief description of the drawings]

FIG. 1 is a micrograph of granules according to the moisture-resistant solid preparation of the present invention.

FIG. 2 is a micrograph of a granule that has not been subjected to a moisture resistance treatment.

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Claims (8)

[Claims] 1. A drug substance powder having hygroscopicity, an animal and vegetable oil and fat,
A solid preparation comprising a coating agent containing at least one oil component and a wax component selected from the group consisting of fats and hydrocarbon oils, and a raw material for preparation, wherein the relative room temperature moisture absorption is 65% or less, A moisture-resistant solid preparation having an accelerated moisture absorption of 80% or less. 2. The method according to claim 1, wherein the hygroscopic drug substance powder is at least one selected from the group consisting of ginger syrup, pancreatin, dextran sulfate sodium, and liver hydrolyzate. The solid preparation according to the above. 3. The composition according to claim 1, wherein the coating agent is contained in a proportion of 10 to 60 parts by weight and the drug substance is contained in a proportion of 100 to 9000 parts by weight based on 100 parts by weight of the hygroscopic drug substance powder. Or the moisture-resistant solid preparation according to 2. 4. In producing the moisture-resistant solid preparation according to any one of claims 1 to 3, mixing the hygroscopic drug substance powder, the coating agent, the preparation raw material, and a solvent. And heating, then molding and drying. 5. The method for producing a moisture-resistant solid preparation according to claim 4, wherein the heating is performed at a temperature equal to or higher than the melting temperature of the coating agent and lower than the decomposition temperature of the hygroscopic drug substance powder. 6. In producing the moisture-resistant solid preparation according to any one of claims 1 to 3, the hygroscopic drug substance powder is coated with the coating agent to form a moisture-resistant drug substance powder composition. Is prepared in advance, and then the obtained moisture-resistant drug substance powder composition, the above-mentioned drug substance and the above-mentioned solvent are mixed, molded, and then dried to produce a moisture-resistant solid drug product. Method. 7. The moisture-resistant drug substance powder composition comprises 10 to 60 parts by weight of the hygroscopic drug substance powder with respect to 100 parts by weight of the coating agent. A method for producing the moisture-resistant solid preparation according to the above. 8. The weight ratio of the total amount of the hygroscopic drug substance powder, coating agent and drug substance to the solvent is 2: 1 to 1.
The method for producing a moisture-resistant solid preparation according to any one of claims 4 to 7, wherein the ratio is 1: 1.