JPH06100602A - Solid oral preparation and production thereof - Google Patents

Abstract

PURPOSE:To obtain the title preparation in which the unpleasant taste of a drug has been masked without decreasing bioavailability, by mixing the drug with a specific starch. CONSTITUTION:This preparation comprises a drug having an unpleasant taste (e.g. sulpyrine) and a modified starch having a cold-water-soluble content of 40% or lower and a degree of swelling of 3-15ml/g (e.g. partially gelatinized starch). It can be produced preferably by adding an aqueous solution of the drug to a powder containing the starch, followed by mixing.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an oral solid preparation in which an unpleasant taste is masked by blending a drug having an unpleasant taste with a specific processed starch, and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Masking the unpleasant taste of drugs is important from the standpoint of facilitating drug administration and enhancing drug compliance. Conventionally, as a masking method, a method of applying a film coating using a polymer base (for example, Japanese Patent Laid-Open No. 1-100116),
A method of mixing a polymer base with a drug to form a matrix structure (for example, JP-A-63-150220), and a method for adding a sweetener such as sucrose, saccharin, aspartame (for example, JP-A-2-96526). Etc.

[0003]

However, in the method shown in (1), since the unpleasant taste masking is achieved by suppressing the elution of the drug in the mouth by the polymer base, at the same time, the drug in the body is There is a problem that the dissolution property is also hindered and the bioavailability is reduced. Also,
There were also problems such as an increase in the number of coating steps and the need for organic solvents. In the method shown below, the unpleasant taste threshold of the drug was extremely low, and the masking effect was insufficient.

[0004]

Means and Actions for Solving the Problems As a result of intensive studies, the inventors of the present invention described above by blending a modified starch having a cold water-soluble content of 40% or less and a swelling volume of 3 to 15 ml / g. The present invention has been completed by solving the above problem. That is, the present invention masks the unpleasant taste, which is characterized by containing a drug having an unpleasant taste and a modified starch having a cold water-soluble content of 40% or less and a swelling volume of 3 to 15 ml / g. An oral solid preparation and an aqueous solution of a drug having an unpleasant taste are contained in a cold water soluble content of 40% or less and a swelling volume of 3 to
The present invention relates to a method for producing an oral solid preparation having an unpleasant taste masked, which is characterized in that the solid preparation is added to and mixed with a powder containing 15 ml / g of modified starch.

The oral solid preparation of the present invention is characterized by having a high effect of masking the unpleasant taste of the drug in the mouth by blending a specific processed starch, but especially for suppressing the dissolution rate. There is no problem that it is not necessary to add a molecular base and that the swelling modified starch is added to prevent dissolution of the drug in the body and reduce bioavailability. In addition, the drug as an aqueous solution,
By mixing with a powder containing the processed starch having a high swelling property in water, the drug easily penetrates into the particles of the processed starch, so that the masking effect is further enhanced. In addition, there is also an advantage that it can be easily carried out because an oral solid preparation can be produced by using a granulating machine used for usual preparations without requiring a coating machine.

The present invention will be described in detail below. The unpleasant taste of the drug in the present invention means bitterness, sourness and astringency, but bitterness is often a problem in oral solid preparations. Drugs having a bitter taste include sulpiline, metoclopramide hydrochloride, promethazine hydrochloride, chlorpromazine hydrochloride, diltiazem hydrochloride, dibekacin sulfate,
Guanetidine sulfate, salbutamol sulfate, naphazoline nitrate, alimemazine tartrate, propantheline bromide, calcium pantothenate, aminophylline, chloramphenicol, nicotinic acid amide, vitamin B1, vitamin B
Examples thereof include, but are not limited to, diphosphates, vitamin B6 and vitamin B12. Also, a mixture of these may be used. Since the drug is used as an aqueous solution, it needs to be dissolved in water and is related to the compounding amount of the drug.
The solubility in ml of water is preferably 0.1 g or more, particularly preferably 1 g or more.

The expression "unpleasant taste is masked" in the present invention means that the taste is not felt during 30 seconds in the mouth after being taken. Even if the formulation is contained in the mouth and an unpleasant taste is felt after 30 seconds have passed, there is no practical problem because it is usually after swallowing. The processed starch used in the present invention has a cold water-soluble content of 40% or less, preferably 10% or less, and a swelling volume of 3 to 15 ml / g. 4 soluble in cold water
When it exceeds 0%, when the solid preparation is put in the mouth, it becomes pasty and easily stays in the mouth, or it becomes easy to wet with water and the dissolution of the drug is accelerated, so that the bitterness is easily felt.
In addition, when the amount of solubles in cold water is large, there is a problem that the granules are likely to become large particles and it is difficult to control the particle size of the granules because the paste effect is produced when the drug aqueous solution is added. Further, if the swelling volume is less than 3 ml / g, the penetration of the drug into the particles of the processed starch is restricted, which is not preferable. Also,
The use of modified starch having a swelling volume of more than 15 ml / g is not preferable because the solid preparation absorbs saliva in the mouth and easily adheres to the palate.

The processed starch may be one having the above-mentioned properties. For example, the processed starch obtained by alpha-converting the starch and then cooling it to partly convert it into beta (Japanese Patent Laid-Open No. 56-56).
92751, hereinafter referred to as "beta starch"),
Processed starch obtained by adding water to corn starch and then mechanically pregelatinizing it by grinding (JP-B-46
No. 21471, hereinafter referred to as "pregelatinized starch") and cereal starch species such as corn starch, rice starch, wheat starch and the like in the presence of water, and dried without destroying the outer shell thin film structure. There is a substantially non-birefringent processed starch (Japanese Patent Publication No. 59-47600, hereinafter referred to as "partially pregelatinized starch") which substantially preserves the outer thin film structure of raw starch.

Of these, partially pregelatinized starch is most suitable for the present invention. The partially pregelatinized starch has a particle size distribution substantially free of a sieve fraction of 60 Tyler mesh or more, and its surface has an uneven structure having deep wrinkles similar to the surface of the cerebrum. The drug having a bitter taste is not only supported inside the partially pregelatinized starch particles having a high swelling property in water in the state of an aqueous solution, but also on the wrinkled portion of this surface, so The effect is the highest compared to the modified starch of. In addition, since the cold water soluble content is as low as 10% or less, when mixed with an aqueous solution of a drug, the liquid does not easily thicken and the liquid easily penetrates into the starch particles, which has the advantage of increasing the amount of the drug loaded. is there. At the same time, there is an advantage that it is easy to control the particle size of the product.

The method for producing the oral solid preparation of the present invention will be described. A drug aqueous solution was prepared by dissolving a drug having an unpleasant taste in water, and the cold water soluble content was 40% or less and the swelling volume was 3%.
~ 15 ml / g to the powder containing modified starch,
After mixing or granulating to obtain a desired particle size, it is dried to obtain a granulated product. As the granulator, it is possible to use a machine which is generally used in the preparation, but in particular, a granulation product such as a mixing stirrer, a high speed stirrer, a tumbling fluidized bed granulator, an extrusion granulator, etc. It is preferable to use a machine that is relatively sheared. If necessary, the granulated product is crushed or sieved to obtain granules, fine particles, and powders. Further, it may be formed into a tablet form by tableting.

The reason for using the drug aqueous solution is that when water is added after mixing the drug with the modified starch, the water is absorbed by the modified starch before the drug is dissolved, so that the drug is sufficiently supported on the modified starch. Because it is not done. The effect is higher when the drug is completely dissolved, but even if the drug is not completely dissolved, it may be dissolved in 70 to 80% depending on the kind of the drug, the compounding amount and the like. It is advantageous to increase the concentration of the aqueous solution up to near the solubility of the drug, because the ratio of the drug to the processed starch can be increased. Further, a binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc., and a water-soluble substance such as sucrose, lactose etc. may be added to the aqueous drug solution. Also, a solvent miscible with water such as ethanol or acetone may be added, but if the amount is increased, the swelling property of the processed starch is reduced and the amount of the drug carried inside the processed starch is decreased. Should be. A solvent such as methylene chloride or ethyl ether, which is miscible with water in a small amount, may be added within a miscible range.

The blending ratio of the processed starch in the powder varies depending on the dosage form, the blending amount of the drug, etc., but is approximately 2
It is effective if the content is 0% or more. If 50% or more of modified starch is blended, the effect is further enhanced. However, the method of first mixing or granulating the drug aqueous solution and the modified starch only, and then adding other additives as necessary is It is most effective in that the drug loading is sufficiently carried out. When the compounding amount of the drug is small in this method, the compounding ratio of the processed starch in the powder may be 20% or less as long as the ratio of the drug to the processed starch described later is appropriate. As other additives, commonly used additives such as starches such as corn starch, sugars such as sucrose and lactose, cellulose derivatives such as crystalline cellulose and low-substituted hydroxypropylcellulose are used.

The ratio of the drug to the modified starch is determined by the amount of drug to be administered, the solubility of the drug, the weight of the preparation and the like, but it is preferably about 1/100 to 5/1. 5
When it is / 1 or more, the masking effect of unpleasant taste is almost lost. It is particularly preferably about 1/100 to 2/1. The granules, tablets, etc. obtained by this method may be further coated with a polymer base in order to completely mask the unpleasant taste. In comparison, the amount used can be considerably reduced. Of course, this does not apply to coatings provided for the purpose of preventing moisture absorption and aesthetics.

[0014]

EXAMPLES The present invention will be described below with reference to examples. The evaluation methods of the processed starch and the oral solid preparation are as follows. << Processed Starch >>-Cold water soluble content (%) To 297 ml of pure water at 25 ° C, 3 g of a sample (in terms of dry matter) was added, and the mixture was stirred at 1500 rpm for 2 minutes using an ace homogenizer (manufactured by Nippon Seiki Co., Ltd.). Next, the obtained suspension is filtered using a filter paper. Take 30 ml of the filtrate and
Dry to constant weight at 05 ° C. 1000 residue weight
The value obtained by doubling and dividing by the weight of the sample used is the cold water-soluble component.

Swelling volume (ml / g) 5 g of a sample is added to about 80 ml of pure water at 25 ° C. and dispersed using a magnetic stirrer. Dispersion with stopper 10
Put in a 0 ml measuring cylinder, add pure water to make 100 ml. After sealing and leaving still for 24 hours, the swollen sample volume is divided by 5 to obtain the swollen volume. << Oral solid preparation >> ・ Sensory test for bitterness The oral solid preparation (about 250 mg) is contained in the mouth, and it is represented by the time until the bitterness is felt.

[0016]

Example 1 Pure water and sulpirin were mixed at a weight ratio of 1: 1 to prepare an aqueous sulpirin solution. Partially pregelatinized starch made from corn starch (Asahi Kasei Co., Ltd.)
Product name PCS <registered trademark>, abbreviated as PCS hereinafter. Cold water soluble content 2.2%, swelling volume 8.6 ml / g) 200 g
And 100 g of an aqueous solution of sulpirin were mixed in a Shinagawa universal mixer (manufactured by Sanei Seisakusho Co., Ltd.) and then crushed by a flash mill (manufactured by Fuji Paudal Co., Ltd.). The granulated product was dried at 40 ° C for one day and then sieved to obtain a granule. As a result of the bitterness sensory test, this granule did not feel bitterness even after 30 seconds.

[0017]

Example 2 Rice starch having a water content of 50% was heated to 100 ° C. to be gelatinized, then cooled at 5 ° C. for about 2 hours, partially converted into beta, dried and pulverized to obtain beta. Granules were obtained in the same manner as in Example 1 except that modified starch (soluble in cold water 6.0%, swelling volume 5.5 ml / g) was used.
As a result of the bitterness sensory test, this granule did not feel bitterness even after 30 seconds.

[0018]

Example 3 Pregelatinized starch made from corn starch (manufactured by Colorcon Co., Ltd., trade name Starch 1500,
Granules were obtained in the same manner as in Example 1 except that 21.0% of cold water soluble matter and swelling volume of 9.2 ml / g) were used.
As a result of the bitterness sensory test, this granule did not feel bitterness even after 30 seconds.

[0019]

Comparative Example 1 A bitterness sensory test was conducted using 50 mg of bulk sulpirin powder, and a bitterness was felt after 2 seconds.

[0020]

[Comparative Example 2] Corn starch (manufactured by Nitto Kagaku Co., Ltd., cold water soluble content 0.4%, swelling volume 1.8 ml / g) was used as PCS.
A granule was obtained by the same procedure as in Example 1 except that it was used instead of. As a result of a bitterness sensory test, this granule felt bitterness after 4 seconds.

[0021]

Comparative Example 3 Potato starch having a water content of 35% was subjected to heat milling 3 times with a roll mill, dried with a hot air drier, and then crushed with a bantam mill to obtain processed starch (cold water soluble component 4
Granules were obtained in the same manner as in Example 1 except that 8.0% and a swelling volume of 16.5 ml / g) were used. As a result of the bitterness sensory test, this granule felt a bitter taste after 12 seconds.

[0022]

Comparative Example 4 200 g of PCS and 50 g of bulk sulpirin powder were lightly mixed in a mortar, and then a bitter sensory test was conducted. As a result, a bitterness was felt after 3 seconds. Further, this mixture was put in a mixing stirrer, 60 g of pure water was added and mixed, and dried to prepare granules. As a result of a bitterness sensory test, this granule felt a bitter taste after 8 seconds.

[0023]

Example 4 450 g of an aqueous solution of sulpirin was mixed in the same manner as in Example 1, 200 g of lactose was further added and mixed, and the same procedure as in Example 1 was carried out to obtain a granule. As a result of the bitterness sensory test, this granule did not feel bitterness even after 30 seconds.

[0024]

Example 5 Of 200 g of PCS, 100 g of crystalline cellulose (Avicel <registered trademark> P manufactured by Asahi Kasei Kogyo Co., Ltd.)
H-101) was replaced, and the same operation as in Example 1 was carried out to obtain granules. As a result of the bitterness sensory test, this granule did not feel bitterness even after 30 seconds.

[0025]

Example 6 A drug aqueous solution containing diltiazem hydrochloride 10% and hydroxypropyl cellulose (L type) 2% was prepared. Next, 150 g of PCS was charged into a tumbling type fluidized bed granulator (Freund Sangyo Co., Ltd., Spiraflow-Mini), and hot drug air of 60 ° C. was sent to the aqueous solution for stirring while stirring.
0 g was added, the mixture was granulated, dried, and sieved. As a result of the bitterness sensory test, this granule did not feel bitterness even after 30 seconds.

[0026]

Example 7 An aqueous drug solution containing 20% calcium pantothenate and 2% hydroxypropylcellulose (L type) was prepared. Next, 1 kg of PCS was charged into a high-speed stirring granulator (FS-10 manufactured by Fukae Industry Co., Ltd.) and stirred,
1 kg of the drug aqueous solution was added, and the mixture was granulated, dried, and sieved.
As a result of the bitterness sensory test, this granule did not feel bitterness even after 30 seconds.

[0027]

EFFECT OF THE INVENTION A powder containing an aqueous drug solution having an unpleasant taste and a processed starch having a specified physical property of having a cold water-soluble content of 40% or less and a swelling volume of 3 to 15 ml / g is usually prepared. By mixing with a granulator used in the manufacture of pharmaceuticals, an oral solid preparation in which the unpleasant taste is effectively masked can be obtained. Compared with the conventional coating method, the process is shorter and the operation is easier, so that it can be easily performed. Further, there is no problem of deterioration of bioavailability, which is seen in the coating method.

Claims (2)

[Claims] 1. An oral masked unpleasant taste, comprising a drug having an unpleasant taste and a modified starch having a cold water-soluble content of 40% or less and a swelling volume of 3 to 15 ml / g. Solid formulation. 2. An aqueous solution of a drug having an unpleasant taste is added to and mixed with a powder containing processed starch having a cold water-soluble content of 40% or less and a swelling volume of 3 to 15 ml / g. A method for producing an oral solid preparation in which an unpleasant taste is masked.