JPS5822447B2 - Manufacturing method of sugar-coated tablets - Google Patents

Description

[Detailed description of the invention] The present invention relates to a method for manufacturing sugar-coated tablets.

Traditionally, syrups used in dragee manufacturing have been
An improved method has been proposed.

In other words, generally known syrups are made by blending sucrose with binders such as gum arabic and seratin, but this requires only several days to manufacture sugar-coated tablets (and the resistance of the coating is poor). Weak impact resistance and easily cracks
(1
) A method has been proposed (Japanese Patent Publication No. 44-22316) in which the process is simplified and the production time is shortened by adding a vinyl polymer.

However, method (1) has problems with toxicity to the human body depending on the type of vinyl polymer, the risk of reaction with herbal medicine ingredients, poor film-forming properties, high hygroscopicity of the sugar coating, and discomfort. It has various drawbacks, such as a strong taste.

On the other hand, instead of the gum arabic or gelatin, (2
) A method of improving the disintegrability of the sugar coating layer by using carboxymethylcellulose (Japanese Patent Publication No. 37-14738, JP-A-49-31816); A method using cellulose derivatives (Japanese Patent Publication No. 46-18149, No. 48-32644); (4) discoloration of the surface of the sugar coating (and (ratio) and a method for preventing cracks (Japanese Unexamined Patent Publication No. 108225/1983) have been proposed.

However, since the carboxymethylcellulose used in method (2) is an ionic cellulose derivative, it not only becomes insolubilized in the gastric fluid or reacts with herbal medicine ingredients, but also increases the weight of the sugar-coated tablet. Method (3) has problems with the safety of the organic solvent to the human body and risks of ignition and explosion during handling; Method (4) has disadvantages such as cellulose ether used in it. In terms of compatibility, it is actually worse than gelatin.
For this reason, it is necessary to increase the proportion of water in the syrup, and the syrup has poor storage stability, which may require a longer time to sugar-coat than with conventional methods, and in the case of crude drug ingredients that are sensitive to water. The disadvantage is that it can cause deterioration.

The present invention aims to provide a method for producing sugar-coated tablets that eliminates the drawbacks of such conventional methods, and is based on the general formula A.
R'rnR2n (in the formula, A is a cellulose residue, R1 is a hydroxyethyl group, R2 is a substituted or unsubstituted monovalent hydrocarbon group, m is a positive number, and n is O or a positive number) ) R per anhydroglucose unit
This method is characterized by coating with a syrup containing a cellulose derivative having an average substitutional mole number of 1.0 to 3.5.

The present invention will be explained in detail below.

As a result of various studies on the method of manufacturing sugar-coated tablets using syrup containing non-ionic cellulose ether as a binder, the present invention has developed a method for manufacturing sugar-coated tablets using a cellulose derivative represented by the above-mentioned general formula as a binder. It was completed based on the confirmation that sugar-coated tablets with excellent quality that compensated for the defects could be obtained.

That is, according to the method of the present invention, compared to the conventional method using gelatin, gum arabic, etc. as a binder, it has excellent impact resistance and does not have the disadvantages of taking a long time to disintegrate when left standing. Compared to methods using non-ionic cellulose ethers such as methyl cellulose and hydroxyfuropyl cellulose, it has good compatibility with sucrose, resulting in good syrup uniformity and stability, and strong film strength, which quickly improves impact resistance. At the same time, it prevents water from entering and deterioration of the herbal medicine (and because the amount of water in the syrup is the same as in methods using gelatin and gum arabic, and less than when using methylcellulose, etc., the time required for spray drying etc. is shortened. It also has the advantage of being of equal length, allowing conventional equipment to be applied as is.

Furthermore, there are no problems such as reaction with the main drug or insolubility in gastric juices caused by using ionic cellulose ethers such as carboxymethylcellulose, and there are no problems such as unpleasant taste when using vinyl polymers.

The cellulose derivatives used in the method of the present invention are those represented by the general formula described above, which include those containing only R1 as a substituent and no R2, that is, hydroxyethyl cellulose, and those containing R1 as a substituent and further Hiruulose derivatives in which R2 is present are included.

The above R1 is a hydroxyethyl group, and R2 is an unsubstituted or substituted monovalent hydrocarbon group, and examples of the unsubstituted monovalent hydrocarbon group include a methyl group, an ethyl group, a propyl group, a butyl group, etc. Examples of the substituted-valent hydrocarbon group for the alkyl group include a hydroxypropyl group, a hydroxybutyl group, and a vinyl bond-containing hydrocarbon group.

In addition, two or more different substituents represented by R2 are 1
It also includes being present in a molecule.

As the hydroxyethylcellulose, it is preferable to use a cellulose in which the number of substituted moles of hydroxyethyl groups is on average 1.0 to 3.5 mol, preferably 1.4 to 3.0 mol, per anhydroglucose unit of cellulose.

When R2 is present in addition to R1 as a substituent, cellulose derivatives include hydroxyethylmethylcellulose, hydroxyethylethylcellulose, hydroxyethylhydroxypropylcellulose, hydroxyethylhydroxybutylcellulose, and hydroxyethylhydroxyfurobylmethylcellulose. Celluloses having three or more substituents such as hydroxyethyl groups, and those substituted with various vinyl bond-containing hydrocarbon groups in addition to the human heptoxyethyl group can also be used, but the number of substituted moles per anhydroglucose unit of cellulose is hydroxyethyl The groups are the same as in the case of hydrodiethylcellulose, and the substituents other than the hydroxyethyl group vary depending on the type of substituent, but the amount is preferably 1.0 mol or less, and the amount of substituents other than the hydroxyethyl group is preferably 1.0 mol or less. When there are two or more kinds of substituents, the preferable range is that the sum of the substituents is 1.0 mol or less.

This is because it is related to the compatibility of the hydroxyethyl cellulose with sucrose, and the compatibility generally worsens as the number of moles of substituents other than the hydroxyethyl group increases.

On the other hand, the degree of polymerization of hydroxyethylcellulose and other cellulose derivatives is preferably lower from the viewpoint of compatibility with sucrose and sugar-coating operation, but on the other hand, it is preferable from the viewpoint of the impact resistance of the coating of sugar-coated tablets and the absorption into the body when taken. It is not desirable if the value is too low.

From these points, the viscosity of a 2% aqueous solution at 20°C is 2~
A range of 100 centipoise, preferably 5 to 50 centipoise, gives good results.

A commonly used method is used to produce sugar-coated tablets, but when producing syrup using at least one of hydroxyethyl cellulose and other cellulose derivatives as a binder, the amount of these binders can be small. The smaller the amount, the better from the point of view of cost and additives, but if it is too small, it will cause problems in terms of film strength, etc.
If it is too much, it will cause problems in terms of sugar coating operation and compatibility with sucrose, so it should be 1.5 to 50% by weight based on sucrose.
It is preferably in the range of 3 to 30% by weight (and preferably in the range of 1 to 30% by weight, preferably 2 to 20% by weight based on the entire syrup system).The above composition is mainly used as a sub-coating liquid. When used as a protective coating or smoothing liquid, it may be used in a smaller amount than the above-mentioned preferred range.

In the syrup composition, binders other than the cellulose derivatives mentioned above can also be used in combination as long as they do not impair the advantages of the present invention, and plasticizers such as precipitated calcium carbonate, titanium dioxide, talc, polyethylene glycol, and glycerin can also be used. In addition, various pigments may be used in order to omit the coloring step in some cases.

Of course, there is no problem in using a mixture of disintegrants such as precipitated calcium carbonate, talc, and low-substituted hydroxyflobil cellulose as a dispersing agent.

Furthermore, the amount of water used for syrup varies depending on the coating equipment, method, active ingredient, etc., but in general it is natural that less water is better, but considering the stability and uniformity of the syrup, at least It is necessary to have a saturated solution composition or higher, and it is also possible to use sugars other than sucrose such as glucose and mannitol.
It is not possible to make general regulations.

Although most of the conventionally used apparatuses can be used for producing the sugar coating, preferable results can be obtained by producing it with a fully automatic pan or the like which is commonly used these days.

The cellulose derivative used in the present invention can be produced by a commonly used method, but it is natural that a product produced by a more uniform reaction will yield more favorable results. In some cases, the products prepared by the above method do not give preferable results within the range of substituents of the present invention.

Examples of the production of hydroxyethyl cellulose used in the present invention are as follows.

Wood pulp with a degree of polymerization of 600 was ground into a fine powder of 100 mesh passes, and while stirring, it was mixed with Inflovir alcohol in an amount of 10 times the weight of the pulp in a stainless steel autoclave, and was mixed with 0.3% by weight of cellulose.
Add 50% concentration of 4 parts by weight to make alkaline cellulose and add ethylene oxide according to the desired replacement amount.
After reacting at 5° C. to 55° C. for 4 hours or more and cooling, the alkali in the crude hydroxyethyl cellulose slurry produced was neutralized with an acid, and then washed with an aqueous acetone solution, dried, and pulverized to obtain hydroxyethyl cellulose.

In addition, other cellulose derivatives can be obtained by the same method as above, but the reaction temperature, reaction time, etc. are naturally different because etherifying agents such as dichloromethyl, chloroethyl, and propylene oxide are reacted in addition to ethylene oxide. Depending on whether ethylene oxide and other etherifying agents are reacted simultaneously or separately, not only the reaction conditions but also the conditions for subsequent washing, drying, pulverization, etc. will vary.

Hydroxyethylcellulose and other cellulose derivatives obtained in this manner were analyzed for the number of moles substituted by known methods such as the Seisel method, Morgan method, or modified methods thereof, and a 2% by weight aqueous solution was analyzed. Next, reference examples and examples are given below where the viscosity is measured.

Reference Examples Various cellulose derivatives and various cellulose derivatives as comparative examples were used to prepare 1% by weight aqueous solutions for each, and while the solution 1001 was placed in a beaker and stirred with a stirrer, a separately prepared 65% by weight solution was added. The amount of the sucrose aqueous solution required to separate the white turbidity by adding the sugar aqueous solution was measured.

All liquids used in the measurements were conducted at 20°C and relative humidity of 80%.

However, the abbreviations used in the table are as follows.

M, S,: Average number of moles of substituents per anhydroglucose trophic position cps: Centipoise (2% aqueous solution dust) HEC: Hydroxyethylcellulose HEMC: Hydroxyethylmethylcellulose HEE
C: Hydroxyethyl ethylcellulose HEHPC: Hydroxyethylhydroxyfuropylcellulose HEHBC: Hydroxyethylhydroxybutylcellulose MC: Methylcellulose HPMC: Hydroxyfuropylmethylcellulose HPC
：Hydroxyfurobylcellulose and other substituents）・・・・・・・・・Methyl group (2)・・・・・・・・・Ethyl group (3)・−
......Hydroxyethyl group (4)°°"°
゛°°°′°゛Hydroxybutyl group example Automatic coating pan FM-2 type (manufactured by Freund Sangyo)
1 kg of bare tablets with an average weight of 150 m9 were added to 90 m2 of water.
Cellulose derivative (indicated by the sample plate) 1
A sub-coating solution in which 00P was dissolved and then sucrose 1000@ was dissolved, and precipitated carbonic acid Luciuno, 7501
, a dusting agent well mixed with 20 g of talc, each in a weight ratio of 1
Sugar coating was performed until the average weight of the tablets was 2202.

Next, dissolve 22 grams of cellulose derivative in 294 grams of water, then dissolve 545 grams of sucrose, and then apply a smoothing liquid in which 1517 grams of precipitated calcium carbonate and 82 grams of titanium dioxide are dispersed until the average weight of the tablets is 260 cubic meters.

Further, in water 3507, 649 g of sucrose was dissolved and 1 titanium dioxide was dispersed, and the average weight of the tablet was 300 m9.
Finally, using a solution of 60g of carnauba wax and 40g of beeswax dissolved in 900y of carbon tetrachloride, the wax solid content is 0.1% by weight based on the tablet.
Polishing was carried out until the white sugar-coated tablets were obtained.

As a comparative example, Zab coating liquid (~880 g of water, 607 g of gelatin, 160 g of gum arabic, 90 g of sucrose)
0g dissolved and used, and HE as a smoothing liquid.
Dragee-coated tablets were made in the same manner as above except that gelatin was used instead of CO.

Table 2 shows the results of measuring the strength and disintegration time of the white sugar-coated tablets thus obtained, as well as visual observation.

Claims (1)

[Claims] 1 General formula AR1mR2n (in the formula, A is a cellulose residue, R1 is a hydroxyethyl group, R2 is a substituted or unsubstituted monovalent hydrocarbon group, m is a positive number, and n is 0 or a positive number) and the average number of substituted moles of R1 per anhydroglucose unit is 1.0 to 3.5. . 2. The method according to claim 1, wherein the average number of moles of R1 substituted per anhydroglucose unit is 1.4 to 3.0. 3. The method according to claim 1, wherein the average number of moles of R2 substituted per anhydroglucose unit is 0 to 1.0. 4 When cellulose derivative is made into a 2% aqueous solution, 2 to 1
The method according to claim 1, which exhibits a viscosity of 0.00 centipoise (20° C.). 5 When the cellulose derivative is made into a 2% aqueous solution, 5 to 5
The method according to claim 1, which exhibits a viscosity of 0 centipoise (20°C). 6. The method according to claim 1, wherein the content of cellulose derivative in the syrup is 1 to 30% by weight. 7. The method according to claim 1, wherein the cellulose derivative content of Shiro Ruff Oki is 2 to 20% by weight. 8. The method according to claim 1, wherein the amount of cellulose derivative relative to sugar in the syrup is 1.5 to 50% by weight. 9. The method according to claim 1, wherein the amount of cellulose derivative relative to sugars in the syrup is 3 to 30% by weight.