JP2560381B2 - Sugar coating liquid, sugar coating layer and method for forming the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a sugar coating liquid, a sugar coating layer, and a sugar coating layer used for sugar coating of solid preparations represented by solids such as fine granules, granules and tablets in the field of food or medicine. Regarding the forming method.

2. Description of the Related Art Generally, for example, sucrose sugar-coating liquid is not harmful to the human body, and the sugar-coating layer formed by this is uniform, and further, the force from the internal plain tablet and the external force It is required to have excellent strength against impact and to have good disintegration in body fluids. In order to meet this purpose, the strength of the sugar coating layer has been conventionally improved by adding a binder such as gelatin, gum arabic powder, polyvinylpyrrolidone, or carboxymethylcellulose to a sugar coating solution for sugar coating. So far, gelatin, gum arabic powder and the like have been widely used as binders for sugar-coated layers because they are safe and can be obtained at a relatively low cost.
However, these binders have problems such as discoloration of the surface of the sugar-coated tablet with time and change of disintegration time. In addition, there is an unstable supply-demand balance depending on the season, as represented by the end of gum arabic.

Under such circumstances, a polysaccharide (pullulan) obtained by culturing black yeast from corn starch as a raw material is used as a binding agent in the sugar coating layer as a binding agent capable of ensuring a large amount and stable quality. This is proposed in JP-A-59-219220. However, when pullulan is used alone as a binder in a sucrose sugar coating solution, the viscosity of the solution increases, so the addition rate is limited, and as a result of the increase in viscosity, uniform sugar coating is performed during sugar coating operation. The liquid requires warming to form the layer. Further, although the sugar coating layer formed is relatively uniform, its strength against impact is not sufficient. As a method for solving the weakness of the sugar-coated layer against impact, for example, JP-A-62-178525 proposes a method in which polyvinylpyrrolidone is added to pullulan and both components are used as a binder. However, the viscosity of the liquid does not show a sufficient reduction effect, and it is necessary to warm the sugar coating liquid during the sugar coating operation as in the case of pullulan alone.

In addition, when compound drugs are compounded into one prescription, some drugs may be added to the sugar coating layer for stabilization due to compounding changes of the drugs. For example, water-soluble flusultiamine hydrochloride, which has a strong odor, has a strong odor when added to sucrose sugar coating solution and heated, resulting in bad conditions during work.Therefore, use flusultiamine hydrochloride powder as a spraying agent. ing. However, when it is added in the form of powder, there are known drawbacks such as increased loss due to scattering during the process and contamination of the working environment. Therefore, it is often added to the bare tablet itself. In this case, the fact that the odor can be reduced by blending cyclodextrin is described in, for example, JP-A-61-61
Although it is proposed in JP-A-257923, the ratio of α-cyclodextrin to flusultiamine is as large as 5 times.

On the other hand, the finding of adding cyclodextrin to a coating agent is found in JP-A-61-129138, and it is proposed that the addition of cyclodextrin prevents sublimation of a sublimable drug, but it is odorous in the same solution. It does not coexist with a tightly water-soluble drug, but it prevents the sublimation of a sublimable drug from a bare tablet by cyclodextrin added to the coating agent.

Means for Solving the Problems The inventors of the present invention have conducted extensive studies for the purpose of practical application of a sucrose sugar coating solution using pullulan as a binder, and by adding cyclodextrin thereto, I found that I could solve all the problems at once. That is, the viscosity of the pullulan-containing sugar coating liquid is reduced by further mixing cyclodextrin with the sucrose sugar coating liquid having pullulan as a binder, which facilitates the liquid coating of the sugar coating liquid at room temperature and also reduces the viscosity. As a result, the solid component ratio in the sugar coating liquid can be increased, so that the operation time can be shortened, and the addition amount of pullulan can be increased if necessary. Furthermore, even if a drug with a strong odor is added to the sugar coating solution, it is possible to prevent the generation of the odor, and to prevent the loss and the pollution of the working environment due to the scattering when the powder is sprayed. It was also found that the formed sugar-coated layer is homogeneous and smooth, and a sugar-coated tablet excellent in impact resistance can be obtained.

Structure of the Invention The present invention relates to a method for forming a sugar-coating layer, characterized in that (1) a sugar-coating solution containing pullulan and cyclodextrin and (2) a sugar-coating solution containing pullulan and cyclodextrin are used to coat a solid material with sugar. 3) A sugar coating layer containing pullulan and cyclodextrin.

The pullulan used in the present invention is a water-soluble viscous polysaccharide in which maltotriose (those in which 3 molecules of glucose are bound by α-1,4) are regularly linearly linked by α-1,6. This product is usually produced extracellularly by culturing Aureobasidium pullulanes using starch, particularly corn starch, as a raw material. Pullulan obtained from such a culture broth is an amorphous, amorphous white powder and is listed in the Japanese Pharmacopoeia Standard (1986 version). It is known that pullulan has a molecular weight of 10,000 to 5,000,000, but any molecular weight can be used in the present invention. Further, in the present invention, a water-soluble pullulan derivative such as pullulan ester or pullulan ether can be used.

On the other hand, as the cyclodextrin used in the sugar coating liquid of the present invention, microorganisms specific to starch [eg, Bacillus
Macerans amylase (Bacillus macerans amylas
In addition to various cyclodextrins obtained by acting the cyclodextrin-forming enzyme produced by e)], various cyclodextrin derivatives and copolymers are used. Examples of the cyclodextrin include α (degree of polymerization 6),
Those with β (degree of polymerization 7) and γ (degree of polymerization 8) are used [Pharmacia Vol.16, No1 (1980), Pharmaceutical Journal Vol.10.
1, (10) 857-873 (1981), JP-A-53-3123]. As the cyclodextrin derivative or copolymer that can be used as the cyclodextrin in the present invention,
For example, tri-O-methylcyclodextrin [Chemical Pharmaceutical Bulletin (Chemical
& Pharmaceutical Bulletin) Volume 28, 1552-1558 (19
80)], di-O-methylcyclodextrin [Industrial Bulletin, No. 6452, published on March 28, 1983], triaminocyclodextrin [Angewandte Chemie International Edition in English (Angewandte Chemie : International Edition in E
nglish), Vol. 19, 344-362 (1980)], and ethylated β-cyclodextrin [J.Pharm.Sci.Vo.
l.76, No8, 660-661 (1987)] and the like.

In the present invention, α-, β-, γ-cyclodextrin,
Further, one kind of the cyclodextrin derivative and the copolymer or two or more kinds thereof may be mixed and used at an appropriate ratio.

The sugar coating liquid containing the above two components in the present invention is an aqueous solution of a saccharide capable of forming a layer, usually sucrose, and pullulan and cyclodextrin are mixed with sucrose to be dissolved in water or prepared beforehand. Add to sucrose sugar coating liquid. The amount of pullulan blended is 0.5 to 5 of the solid components in the sugar coating solution.
% By weight. The cyclodextrin is used in an amount of usually 0.1 to 30% by weight, preferably 0.5 to 30% by weight, based on the solid components in the sugar coating solution. In the case of α-cyclodextrin, the range of 0.5 to 20% by weight is particularly preferable. In this case, addition of 0.1 wt% or less has little effect of reducing the viscosity of the sugar coating solution using pullulan as a binder, and addition of 30 wt% or more of cyclodextrin having low solubility, for example, β-cyclodextrin. Causes recrystallization and the like in the sucrose sugar-coating liquid due to temperature change and the like, and is not preferable for always obtaining a homogeneous sucrose sugar-coating liquid. Further, it is possible to achieve the purpose of deodorizing a drug having a strong odor in the range of 0.1 to 30% by weight.

In the sugar coating liquid of the present invention, a base used for formulating a conventional coating liquid, such as a bulking agent (for example, talc, calcium hydrogen phosphate, precipitated calcium carbonate, calcium sulfate, kaolin, lactose, starch, crystalline cellulose, etc.), Binders (eg gum arabic powder, polyvinylpyrrolidone, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose etc.), colorants (eg tar dyes, caramel, red iron oxide etc.), lubrication (eg propylene oxide-ethylene oxide copolymer, polyethylene glycol etc.) ), A hiding agent (such as titanium oxide), etc., may be appropriately mixed,
The blending amount of pullulan, cyclodextrin, etc. is determined by the solid components including these fillers. The blending amount of these bases can be appropriately determined according to the purpose. The concentration of the syrup solution used as the stock solution [sucrose / (sucrose + water)] is, for example, 40 to 75% by weight, usually 55 to 70% by weight.

The sugar coating layer containing vullan and cyclodextrin of the present invention is formed by coating the above-mentioned sugar coating solution containing pullulan and cyclodextrin on a solid substance, for example, a solid preparation such as a bare tablet (coating). be able to. The sugar-coating liquid of the present invention is sugar-coated on a solid material through a conventional coating process using a conventional sugar-coating device. In this step, a method of spraying a spraying agent such as talc may be adopted. For example, in order to form a sugar coating layer on a bare tablet, pouring of a sugar coating solution and drying are repeated by a conventional method. In the case of sugar-coated tablets, usually, syrup solution finishing and wax glazing are further performed to form sugar-coated tablets.
In the case of the present invention, by lowering the viscosity of the sucrose sugar coating solution, and by adding a drug to the sucrose sugar coating solution, the injection and drying of the sucrose sugar coating solution can be carried out continuously, as in a commonly known film coating. It is possible to apply. Further, it is a solid preparation smaller than a bare tablet, which has been conventionally difficult to be coated with sugar coating due to a decrease in viscosity of the sugar coating solution.
For example, sugar coating can be applied to granules, fine granules, pills and the like.

Hereinafter, the present invention will be described more specifically with reference to examples.

Examples Example 1 An example of the preparation method and prescription of the sucrose sugar coating solution of the present invention is shown.
The preparation method is as follows: The specified amounts of pullulan and sucrose in Table-1 were roughly mixed, added to water and dissolved by heating at about 85 ° C, and then the specified amounts of talc and α-cyclodextrin (α-CyD) were stirred. Machine dispersed and dissolved.

Example 2 An example of the preparation method and prescription of the sucrose sugar coating liquid of the present invention is shown.
The preparation method is as follows: The specified amounts of pullulan and sucrose shown in Table-2 were roughly mixed, added to water and dissolved by heating at about 85 ° C, and then the specified amount of fursultiamine hydrochloride (TTFD · HCL), talc and hydrochloric acid. 0.5 mol of α-cyclodextrin (α-CyD) with respect to fursultiamine was dispersed and dissolved with a stirrer.

Example 3 A sugar-coated tablet according to the present invention is manufactured by using 635 g (12700) of a plain tablet containing lactose and starch as main components (lactose: starch = 7: 3).
Tablets and uncoated tablets (weight: 50 mg) were placed in a 12-inch coating pan, and the uncoated tablets were sugar-coated with the sucrose sugar-coating solution of Example 1 (Table-1) (kneading). During this kneading, the sucrose sugar coating liquid was not heated and the liquid temperature was operated at 23 to 28 ° C. After that, a syrup solution (67% sucrose aqueous solution) was used for finishing, and then waxing was applied for polishing. The obtained sugar-coated tablet had a smooth and uniform sugar-coated layer.

 The coating conditions are as shown in Table 3 below.

Example 4 In the production of sugar coating of granules in the present invention, the granules containing lactose, starch and crystalline cellulose as the main components (lactose: starch: crystalline cellulose = 5: 4: 1) were applied by a centrifugal fluidized coating apparatus (CF apparatus). , CF-360, manufactured by Freund)
Add 00 g, heat the sucrose sugar coating solution of Example 2 (Table-2) to 60 ° C., spray talc at 10 g / min while spraying at a solution rate of 25 ml / min, and coat 20% of the granules. did. The obtained coated granules were vacuum dried at 40 ° C. for 16 hours, and 12 to 32 mesh granules were obtained using a round sieve.

The obtained coated granules did not have a peculiar odor of fursultiamine hydrochloride during the production or in the products. In addition, the sucrose sugar coating solution did not have the specific odor of fursultiamine hydrochloride.

Experimental Example Experimental Example 1 Pullulan (3.2% relative to sucrose) and sucrose-immobilized sucrose sugar coating liquid were prepared, and the viscosity thereof was investigated.

 The method for preparing the sucrose sugar coating solution was in accordance with Example 1.

The viscosity was measured by keeping the temperature of the sucrose sugar coating solution constant with a BL type viscometer. In addition, the subsequent method of measuring the viscosity,
This method was applied.

The studied prescriptions and the results are shown in Table-4. As is apparent from the table, a dramatic decrease in viscosity was confirmed by the addition of α-cyclodextrin (α-CyD).

That is, as in the formulations (i) and (iii) of the present invention, α-
When 5,10% of cyclodextrin was added and the solid component concentration was made constant by adjusting the amount of talc, the viscosity at 20 ° C was lower than the viscosity at 60 ° C in the control formulation. Therefore, the operation of heating to 60 ° C. was unnecessary, and the sucrose sugar coating liquid coating could be carried out at room temperature. Furthermore, in the case of the formulation (ii) in which 5% of α-cyclodextrin was added to the control formulation, the viscosity was lower than that of the control formulation, although the solid component concentration was increased by about 4%. Also,
In the formulation (iv) containing 10% of α-cyclodextrin, the solid component concentration was increased by about 7%. When the temperature of the sucrose sugar coating solution was controlled at 60 ° C, the viscosity was about the same as that of the control formulation and coating was possible.

Experimental Example 2 Pullulan (3.2% with respect to sucrose), polyvinylpyrrolidone (PVP, 2.4% with respect to sucrose), sucrose and purified water were fixed to prepare a sugar coating liquid, and its viscosity was investigated.

 The sucrose sugar coating solution was prepared according to Example 1.

Cyclodextrin used α- and β-, and the amount of talc was reduced according to the amount added. α-Cyclodextrin (α-CyD) is 0.5, 1, 5, 10, 20, and 30%, and β-
Cyclodextrin (β-CyD) is 1, 5, 10, 20, and 30
The addition rate was%.

As typical examples of formulations, Table 5 shows formulations without addition of cyclodextrin (control formulation) and with addition of 1% of α- and β-cyclodextrin. In other formulations, the amount of talc added is varied in accordance with the addition rate of cyclodextrin to keep the solid component concentration constant. Also, the syrup concentration is
It is fixed at 61.2%.

The viscosity measurement results are shown in Table-6. Addition of α-cyclodextrin was found to have a viscosity decreasing effect in the range of 0.5 to 20%. Addition of β-cyclodextrin was found to have an effect of decreasing the viscosity at 5 to 30%.

Experimental Example 3 A sucrose sugar coating solution was prepared by fixing pullulan (3% to sucrose) and sucrose and purified water, and fursultiamine hydrochloride (TTFD / HCL) was added as a odor-tightening agent to form a sugar coating. It was dissolved in a liquid and cyclodextrin was further added to investigate its deodorizing effect.

 The sucrose sugar coating solution was prepared according to Example 2.

As cyclodextrin, α- and β-cyclodextrin (α-CyD and β-CyD) were used, and 0.5 was added to fursultiamine hydrochloride in a molar ratio. Further, the weight correction by the addition of cyclodextrin was performed on talc in the same formulation.

Table 7 shows the formulation of the sugar coating liquid, the viscosity, and the odor of fursultiamine hydrochloride generated from the sugar coating liquid. As is clear from the table, the remarkable deodorizing effect of fursultiamine hydrochloride was confirmed by the addition of cyclodextrin.

Claims (3)

(57) [Claims] 1. A sugar coating liquid containing pullulan and cyclodextrin. 2. A method for forming a sugar coating layer, which comprises coating a solid material with a sugar coating solution containing pullulan and cyclodextrin. 3. A sugar coating layer containing pullulan and cyclodextrin.