JPH01197432A - Solution for forming sugar layers, sugar layer and formation thereof - Google Patents

Abstract

PURPOSE:To obtain a solution for forming sugar-coated layers, by adding cyclodextrin to a sucrose solution for sugar coating to facilitate the application of the solution at room temperature with the viscosity reduced and enable the increase in the solid content. CONSTITUTION:An aqueous solution of a saccharide which can form layers, usually sucrose is combined with pullulan and cyclodextrin. The amount of pullulan is 0.5-5wt.%, and cyclodextrin is 0.1-30%, preferably 0.5-30% (0.5-20wt.% in case of alpha-cyclodextrin), respectively. The solution is applied to solid products according to the usual coating process using a conventional sugar-coating machine to give sugar-coated tablets having a smooth and high shock-resistant coating layer.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to sugar-coating liquids, sugar-coating layers and their Regarding the formation method.

BACKGROUND OF THE INVENTION In general, for example, sucrose coating liquid is not only harmless to the human body, but also the sugar coating layer formed by it is uniform and has an internal layer. ! l! It is required to have excellent strength against force from the lock and external impact, and to have good disintegration properties in body fluids. To meet this objective, it has been conventionally attempted to improve the strength of the sugar coating layer by adding binders such as gelatin, gum arabic powder, polyvinylpyrrolidone, and carboquine methylcellulose to the sucrose coating solution for sugar coating. Until now, gelatin and gum arabic powder have been frequently used as binders for sugar coating layers because they are safe and can be prepared manually at relatively low cost. However, these binders have problems such as causing the surface of the sugar-coated tablet to change color over time and changing the disintegration time. Furthermore, there are some products, such as gum arabic powder, whose supply and demand balance is unstable depending on the season.

Under these circumstances, a polysaccharide (pullulan) obtained by culturing black yeast using corn starch as a raw material is used as a binder in the sugar coating layer as a binder that can be obtained in large quantities and with stable quality. This is proposed in Japanese Patent Laid-Open No. 59-219220. However, when pullulan is used alone as a binder in a sucrose coating solution, the viscosity of the solution increases, so there is a limit to its addition rate. The liquid must be heated to form a layer. The glycocalyx layer that is further formed is
Despite being relatively uniform, its impact strength is not sufficient. As a method for solving this weak impact strength of the sugar coating layer, for example, Japanese Patent Laid-Open No. 62-178525 proposes a method in which polyvinylpyrrolidone is added to pullulan and both components are used as a binder. However, it does not show a sufficient effect of reducing the viscosity of the liquid.
As with pullulan alone, it is necessary to heat the sugar coating solution during sugar coating operations.

Furthermore, when compounding multiple drugs into one formulation, some of the drugs may be added to the sugar coating layer to stabilize the formulation because the combination of these drugs changes. For example, when fursultiamine hydrochloride, which is water-soluble and has a strong odor, is added to the sucrose coating solution, the odor becomes strong and creates poor working conditions, so powdered fursuldiamine hydrochloride is used as a dispersing agent. There is.

However, when it is added in powder form, it is known to have drawbacks such as increased loss due to scattering during the process and contamination of the working environment. Therefore, it is often added to the plain tablet itself. In this case, it is possible to reduce the odor by adding cyclodextrin.
As proposed in Japanese Patent No. 7923, the ratio of α-cyclodextrin to fursuldiamine is five times as large.

On the other hand, the knowledge of adding cyclodextrin to the coating material is found in JP-A-61-129138, and it is proposed that the addition of cyclodextrin prevents sublimation of sublimable drugs. It is not intended to be used together with harsh water-soluble drugs, but rather, the cyclodextrin added to the coating material prevents the sublimation of sublimable drugs from the plain tablets.

Means for Solving the Problems The present inventors have been conducting intensive research with the aim of commercializing a sucrose coating solution using pullulan as a binder, and found that by adding cyclodextrin to it, the above-mentioned I found a way to solve the problems all at once. That is,
By further adding cyclodextrin to the sucrose coating solution containing pullulan as a binder, the viscosity of the pullulan-containing sugar coating solution is reduced, which makes it easier to apply the sugar coating solution at room temperature, and by reducing the viscosity. Since it is possible to increase the solid component ratio in the sugar coating solution, the operation time can be shortened, and if necessary, the amount of pullulan added can be increased. Furthermore, even if a chemical with a strong odor is added to the sucrose coating solution, the generation of the odor can be prevented, and loss and contamination of the working environment due to scattering that would occur when spraying as a powder can be prevented. Furthermore, it has been found that it is possible to obtain sugar-coated tablets in which the formed sugar-coated layer is homogeneous and smooth, and also has excellent impact resistance.

Structure of the Invention The present invention provides a method for forming a sugar-coating layer, characterized in that a solid substance is sugar-coated with (1) a sugar-coating liquid containing pullulan and cyclodextrin; (2) a sugar-coating liquid containing pullulan and cyclodextrin; 3) A glycocalyx layer containing pullulan and cyclodextrin.

The pullulan used in the present invention is
Maltotriose (three molecules of glucose linked together with α-1,4 bonds) is a water-soluble sticky polysaccharide in which α-1,6 bonds are regularly arranged in a linear manner. This product is usually made from starch, especially corn starch, and is made from Aureobasidium pullulans.
It is produced extracellularly by culturing the bacteria. Pullulan obtained from such a culture solution is an amorphous white powder and is listed in the Pharmacotopic Ingredient Standards (1986 edition). The molecular weight of pullulan is to, oo
Although molecular weights ranging from 0 to 5,000,000 are known, any molecular weight can be used in the present invention. Further, in the present invention, water-soluble pullulan derivatives such as pullulan ester and pullulan ether can be used.

On the other hand, the cyclodextrin used in the sugar-coating solution of the present invention may contain specific microorganisms [e.g., Bacillus macerans amylase].
In addition to various cyclodextrins obtained by the action of a cyclodextrin-forming enzyme produced by N.s. amylase), various cyclodextrin derivatives and copolymers are used. Examples of the cyclodextrin include α (degree of polymerization 6), β (degree of polymerization 7), and γ (degree of polymerization 8).
) Norano is used [)7) Lemanoa Vol.
l 6, Nol (1980), Pharmaceutical Journal Vol.

101, (10) 857-873 (1981), JP-A-53-3123]. Examples of cyclodextrin derivatives and copolymers that can be used as the cyclodextrin in the present invention include tri-methylcyclodextrin [chemical/pharmaceutical
Bulletin (Chemical & Pharmaceu
Technical Bulletin) Volume 28.

+552-1558 (1980)], G-O-medyl cyclodextrin [see Sangyo Jiho, No. 6452, published March 28, 1980], triaminone clodextrin [Angevante Hemi-International.
Edition in Ingrid x (Angewa
ndte Chemie: International
alEdition in English), Vol. 19, 344-362 (1980)] and ethylated β-cyclodextrin [J, Phar
m, Sci, Mol.

76, No. 8, 660-661 (1987)].

In the present invention, one or more of α-1β-1γ-cyclodextrin, cyclodextrin derivatives and copolymers, or a mixture of two or more thereof in an appropriate ratio can be used.

The sugar coating solution containing the above two components in the present invention is an aqueous solution of sugars capable of forming a layer, usually sucrose, and pullulan and cyclodextrin are mixed with sucrose and dissolved in water or prepared in advance. Add to sucrose coating solution. The formulation m of pullulan is 0.5 to 5 of the solid component in the sucrose coating solution.
Weight%.

The amount of cyclodextrin added is usually 0.1 to 30% by weight, preferably 0.5 to 30% by weight of the solid components in the sucrose coating solution.
30% by weight is used. In the case of α-cyclodextrin, the range of 0.5 to 20% by weight is particularly preferred. In this case, if the addition amount is less than 0.1% by weight, the effect of lowering the viscosity of the sucrose coating solution using pullulan as a binder is small, and if the addition amount is more than 30% by weight, in the case of cyclodextrin with low solubility, for example, β- Cyclodextrin causes recrystallization in the sucrose coating solution due to changes in temperature, etc., and is not preferable in order to always obtain a homogeneous sucrose coating solution. Moreover, the purpose of deodorizing a drug with a strong odor can also be achieved with a range of 0.1 to 30% by weight.

The sugar-coating liquid of the present invention contains bases used in the formulation of conventional sugar-coating liquids, such as fillers (such as talc, calcium hydrogen phosphate, precipitated calcium carbonate, mu, sulfuric acid, kaolin, lactose, starch, crystalline cellulose). etc.), binder (
For example, gum arabic powder, polyvinylpyrrolidone, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc.), coloring agents (for example, tar pigment, caramel, red iron, etc.), lubricants (for example, propylene oxide-ethylene oxide copolymer,
Polyethylene glycol, etc.), masking agents (for example, titanium oxide, etc.), etc. may be appropriately blended, and the amount of pullulan, cyclodextrin, etc. to be blended is determined depending on the solid components including these fillers. The amount of these bases to be blended can be determined as appropriate depending on the purpose. The concentration of the syrup liquid used as the stock solution [sucrose/(sucrose+water)] is, for example, 440 to 75% by weight, usually 55 to 70% by weight.

The sugar-coating layer containing pullulan and cyclodextrin of the present invention is formed by coating a solid substance, for example, a solid preparation such as a bare tablet, with the above-mentioned sugar-coating liquid containing pullulan and cyclodextrin. be able to. The sugar coating solution of the present invention can be prepared using a conventional sugar coating equipment.
The solid material is coated with sugar through the usual coating process. In this step, a method of spraying a dispersing agent such as talc may be adopted. For example, to form a sugar coating layer on a plain tablet, the addition of a sugar coating solution and drying are repeated in a conventional manner. In the case of sugar-coated tablets, they are usually further finished with a syrup solution and polished with wax to become sugar-coated tablets. In the case of the present invention, by lowering the viscosity of the sucrose coating solution and adding a drug to the sucrose coating solution, the addition and drying of the sucrose coating solution can be performed continuously, as in conventional known film coating. It is possible to apply Furthermore, it is a solid preparation smaller than a plain tablet, which has traditionally been difficult to coat with a sugar coating due to the reduced viscosity of the sucrose coating. For example, granules, fine granules, gunpowder, etc. can also be coated with sugar.

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Examples Example 1 An example of the preparation method and formulation of the sucrose coating solution of the present invention will be described. The preparation method is to roughly mix the specified amounts of pullulan and sucrose in Table 1, then add them to water and dissolve by heating at approximately 85°C. Then, add the specified amounts of talc and α-cyclodextrin (α-CyD) using a stirrer. Dispersed and dissolved.

Table 1 = Prescription Example 2 of Sucrose Coating Solution An example of the preparation method and formulation of the sucrose coating solution of the present invention is shown. The preparation method is to roughly mix the prescribed amounts of pullulan and sucrose in Table 2, add them to water and dissolve them by heating at approximately 85°C, then add the prescribed amounts of fursuldiamine hydrochloride (TTFD・IIcL), talc, and fursululan hydrochloride. 0.5 mol of α-cyclodextrin (α-CYD) based on thiamine was dispersed and dissolved using a stirrer.

Table 2: Prescription example 3 of sucrose sugar-coated liquid In the production of sugar-coated tablets in the present invention, 635 g (12
700 tablets (uncoated tablet type i: 50 mg) were placed in a 12-inch coating pan, and the uncoated tablets were sugar-coated using the sucrose sugar coating solution of Example 1 (Table 1) (kneading process). For this kneading process, the temperature of the liquid was 23 to 28 without heating the coating liquid in a shower oven.
It was operated at 6C. After that, it was finished using a syrup solution (67% aqueous solution of ci-sugar), and then waxed and polished.

The obtained sugar-coated tablet had a smooth and uniform sugar-coated layer.

The coating conditions are as shown in Table 3 below.

Table 3; Coating Condition Example 4 In the production of sugar coating for granules in the present invention, granules containing lactose, starch, and cellulose as the main components (lactose/starch; crystalline cellulose - 5:4:1) are centrifuged. 2000 g of the sucrose coating solution of Example 2 (Table 2) was placed in a fluidized coating device (CF device, CF-360, manufactured by Freund), heated to 60°C, and sprayed at a liquid rate of 25 g/min. At the same time, 10g of talc was sprinkled over 7 minutes to coat 20% of the granules. The obtained coated granules were rotated at 40°.
C2 It was vacuum dried for 16 hours and granules of 12 to 32 meshes were obtained using a round surface.

The obtained coated granules did not have a particular odor of fursultiamine hydrochloride both during manufacture and as a finished product.

Also, the sucrose coating solution did not have the specific odor of fursultiamine hydrochloride.

Experimental Example 1 Pullulan (3.2% based on sucrose) and a sucrose sugar coating solution in which sucrose was fixed were prepared and their viscosity was investigated.

The method for preparing the sucrose coating solution was the same as in Example 1.

The viscosity was measured using a BL viscometer while keeping the temperature of the sucrose coating solution constant. The viscosity measurement method below is as follows:
I used this method.

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

That is, when 5.10% α-noclodextrin is added as in the formulations (i) and (ii) of the present invention, and the solid component concentration is kept constant by adjusting the amount of talc, the concentration at 60°C in the control formulation is The viscosity at 20°C was lower than the viscosity. Therefore, the operation of heating to 60° C. was no longer necessary, and sucrose coating could be performed at room temperature.

Furthermore, in the case of formulation (11) in which 5% α-cyclodextrin was added to the control formulation, the viscosity was lower than that of the control formulation, even though the solid component concentration increased by about 4%.

In addition, a formulation containing 10% α-cyclodextrin (
In iv), the solid component concentration increased by about 7%. If the temperature of the sucrose coating solution was controlled at 60°C, the viscosity was comparable to that of the control formulation, and coating was possible.

Experimental Example 2 A sugar coating solution was prepared by fixing pullulan (3.2% based on sucrose), polyvinylpyrrolidone (PVP, 2.4% based on sucrose), sucrose and purified water, and its viscosity was determined. investigated.

The sucrose coating solution was prepared in accordance with Example 1.

α- and β-cyclodextrins were used, and the amount of talc was reduced according to the amount added. α-Cyclodextrin (
α-CyD) are 0.5, 1.5, 10°20, and 3
0%, and β-cyclodextrin (β-CyD) is 1, 5, 10, 20. and 30% addition rate.

As representative examples of formulations, Table 5 shows a formulation without the addition of cyclodextrin (control formulation) and a formulation with the addition of 1% α- and β-cyclodextrin. Other formulations vary the amount of talc added in conjunction with the rate of cyclodextrin addition, keeping the solid component concentration constant. Also, the syrup liquid concentration is 6
It is fixed at 1.2%.

The viscosity measurement results are shown in Table 6. Addition of α-cyclodextrin was found to have a viscosity reducing effect in the range of 0.5 to 20%. Addition of β-cyclodextrin
%, the effect of reducing viscosity was observed.

Table-5 Nibruran, PVP and cyclodextrin (
Typical formulation example) The unit is %, and the value in parentheses indicates per solution.

Table 6: Viscosity measurement results (liquid temperature 25°C) Experimental example 3 Pullulan (3% based on sucrose) and a sucrose sugar-coating solution in which sucrose and purified water were fixed were prepared and used as a strong-smelling drug. , fursultiamine hydrochloride (TTFD.HCL) was added and dissolved in the sugar coating solution, and cyclodextrin was further added to investigate its deodorizing effect.

The preparation of the sucrose coating was learned from Example 2.

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

Table 7 shows the formulation of the sugar coating solution, its viscosity, and the odor of fursultiamine hydrochloride generated from the sugar coating solution. As is clear from the table, a remarkable deodorizing effect of fursuldiamine hydrochloride was observed when cyclodextrin was added.

Table-7 Hydrochloric acid units by dichlordextrin are %, ()
Figures inside indicate per solution.

Claims (3)

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