JP2831131B2 - Base for pharmaceutical film coating and production method thereof - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a high whiteness low polymerization degree cellulose ether which is a base for pharmaceutical film coating, and a method for producing the same.

BACKGROUND ART By applying a film coating to pharmaceutical preparations,
It can mask the bitterness of the formulation, increase the hardness of the formulation, and smooth the surface of the formulation. As a base used for the film coating, a water-soluble low polymerization degree cellulose ether is generally used. Low polymerization degree cellulose ether is a 2% aqueous solution having a viscosity of 20%.
It is a cellulose ether of 20 cSt (centistokes) or less at ℃, and is obtained by depolymerizing cellulose ether having a high degree of polymerization.

The high polymerization degree cellulose ether is obtained by converting purified pulp into alkali cellulose, adding an etherifying agent to the pulp, and reacting it. The cellulose ether having a high degree of polymerization is etherified, purified with hot water, dried, and pulverized to an average particle diameter of about 50 μm. This fine powder is depolymerized. The method of depolymerization is a method using hydrogen chloride gas (JP-B-48-41).
No. 037) and a method of causing hydrogen peroxide to act (Japanese Patent Publication No. Sho 45)
-678 is known.

However, the low-polymerization degree cellulose ether obtained by the above method has a gray or yellowish tint, and when this is used as a base and the preparation is film-coated, the preparation seems to be colored under the influence of the base. For this reason, it has been widely practiced to use a coloring agent in film coating to give a color that makes the preparation look good. However, also in this case, the color of the base influences and the color of the preparation is not clear, and the commercial value of the preparation is impaired. Therefore, the low-polymerization cellulose ether as a base must have high whiteness.

In order to further increase the whiteness of cellulose ether with low polymerization degree, bisulfite ion in aqueous fatty acid alcohol
46-41628) and sulfur dioxide (Japanese Patent Application Laid-Open No. 52-159885) to effect bleaching and decolorization. However, these methods have the disadvantages that the steps are complicated and that sulfur compounds remain in the product as impurities. There is also an attempt to improve whiteness by limiting the amount of water during the reaction (Japanese Patent Laid-Open No. 25101/1987). However, this could not be increased to a certain value.

The present inventors studied what caused the yellow or brown coloring of the cellulose ether having a low polymerization degree. And
Attention was paid to the phenomenon that when a high polymerization degree cellulose ether is subjected to acid hydrolysis, the yellowness of the cellulose ether increases as the viscosity decreases. The yellow index (Yellow Index) was measured using an SM color computer “SM-4” manufactured by Suga Test Instruments Co., Ltd. as a 2% aqueous solution of cellulose ether, and this was used as an index of whiteness.

FIG. 1 shows that three kinds of viscosities (3 cSt,
It is a result of examining the relationship between the absorbance (A) and the wavelength (NM) of ultraviolet rays in a 2% aqueous solution (6 cSt, 500 cSt). In the figure, peaks occur at wavelengths of ultraviolet light of around 230 nm and 280 nm. The lower the viscosity, that is, the lower the degree of polymerization, the larger the peak, and it is expected that many substances which are considered to be the cause of the yellowness exhibiting such a peak are generated.

This material can be extracted from aqueous hydroxypropylmethylcellulose with diethyl ether. Moreover, it was confirmed that the yellowness of the aqueous hydroxypropylmethylcellulose solution after the extraction of this substance was reduced. However, the structure of the substance showing this peak has not been identified yet. This substance probably oxidizes the hydroxyl groups of cellulose,
It is considered that the chromophore was formed as a carbonyl group or a carboxyl group. In this way, it is expected that glucose having a group obtained by oxidative modification of cellulose is cleaved to become a substance which can be extracted with the above-mentioned ether. The yellowness of the aqueous solution of hydroxypropylmethylcellulose as a residue obtained by extracting this substance with ether decreases, but does not return to the yellowness before hydrolysis. Therefore, it is considered that other coloring substances which cannot be extracted with ether remain in the aqueous solution of hydroxypropylmethylcellulose. Therefore, there is a limit in improving whiteness by ether extraction. Furthermore, a separate extraction step is required for producing a low polymerization degree cellulose ether. Therefore, it is not appropriate to add a step of extracting a coloring substance by ether extraction to the extraction step because the production step becomes very complicated.

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a high whiteness and low polymerization degree cellulose ether which can be used as a base for pharmaceutical film coating.

To achieve this object, the formulation film coating base of the present invention is prepared by subjecting a pulp having a copper value of 0.4 g or less to caustic treatment, and purifying the high polymerization degree cellulose ether obtained by adding an etherifying agent with hot water. Is a cellulose ether having a low polymerization degree obtained by depolymerizing a fine powder pulverized by heating and drying.

Another object of the present invention is to provide a method for producing a high whiteness and low polymerization degree cellulose ether which can be used as a base for pharmaceutical film coating.

In order to achieve this object, a method for producing a base material for coating a pharmaceutical film of the present invention comprises subjecting a pulp having a copper value of 0.4 g or less to caustic treatment and adding a high-polymerization degree cellulose ether obtained by adding an etherifying agent to hot water. It is obtained by purifying, drying by heating, and depolymerizing the pulverized fine powder.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the relationship between the viscosity of a 2% aqueous solution of hydroxypropylmethylcellulose and the absorbance of ultraviolet light. FIG. 2 shows a 2% aqueous solution of hydroxypropylmethylcellulose (viscosity 50) produced from different types of pulp.
(CSt) is a graph showing the relationship between the ultraviolet wavelength and the absorbance.

BEST MODE FOR CARRYING OUT THE INVENTION The present inventors have studied the relationship between oxidative modification and yellowness of a cellulose ether having a low degree of polymerization, and have completed the present invention. It can be said that the lower the polymerization degree of cellulose ether, the higher the degree of oxidation modification, and the more the cellulose ether is colored.

Therefore, the present inventors first studied the copper value of pulp as a raw material as a measure of oxidative modification of cellulose ether. The copper value of the pulp indicates the amount of reducing carbonyl groups. The higher the amount of carbonyl groups, that is, the higher the copper value, the higher the degree of oxidation modification of the pulp. Using pulp having a high copper value as a raw material, it was examined whether or not cellulose ether having a high yellowness was produced. Therefore, hydroxypropyl methylcellulose was produced from various pulps having different copper values, and the absorbance of each ultraviolet ray was measured. In addition, the measurement of copper value of pulp is based on JIS P8101 “Test method for dissolved pulp”
And TAPPI T430.

Table 1 below shows the copper values of the three types of pulp A, B, and C, and the wavelength by the 2% aqueous solution (viscosity 500 cSt) of hydroxypropyl methylcellulose produced from each pulp A, B, and C.
It is the result of measuring the absorbance of 200 nm ultraviolet rays.

Pulp A and Pulp B are from Southern Pin
e) is used as raw material, and pulp C is made from cotton linter. Pulp A and pulp B were manufactured by the Kraft method.

Figure 2 shows a 2% aqueous solution of hydroxypropylmethylcellulose obtained from pulp A and pulp C (viscosity 500 cSt)
5 is a graph showing the relationship between the wavelength (NM) of ultraviolet light and the absorbance (A).

As a result, the copper value of the pulp correlates with the absorbance of the produced cellulose ether aqueous solution at an ultraviolet wavelength of 200 nm. It is considered that the absorbance of ultraviolet light having a wavelength of 200 nm indicates a carbonyl group contained in cellulose ether.
From these results, it can be seen that a pulp having a high copper value yields a low-polymerization cellulose ether having a large amount of carbonyl groups, that is, a low-polymerization cellulose ether having a high yellowness. Paradoxically, if a pulp having a low copper value is selected as a raw material, a low polymerization degree cellulose ether having a low yellowness can be produced.

Therefore, as for the cellulose ether having a low polymerization degree used as a base for coating a pharmaceutical film as in the present invention, it is preferable to use pulp having a low copper value as a raw material in order to obtain high whiteness. Specifically, it is preferable to use a pulp having a copper value of 0.4 g or less as a raw material, and a low polymerization degree cellulose ether obtained with a copper value of more than 0.4 g has a large amount of coloring as a base for pharmaceutical film coating and is insufficient. It is.

Production of a high polymerization degree cellulose ether is carried out by mixing an aqueous alkali metal hydroxide solution with wood / cotton pulp (cellulose) as a raw material, adding an alkyl halide and / or an alkylene oxide to the ether, and washing with hot water or the like. Heat and dry.

Furthermore, the present inventors have paid attention to the step of heating and drying a cellulose ether having a high degree of polymerization as a measure of oxidative modification of the cellulose ether. It has also been found that this heating and drying step is related to the yellowness of the cellulose ether having a low degree of polymerization.

After drying, the water content of the high polymerization degree cellulose ether is reduced to 1
-5% by weight is required. 1% water by weight
If it is less than 5%, the whiteness deteriorates. If it exceeds 5% by weight, the rate of subsequent depolymerization is low, and the productivity is lowered, which is not practical. Further, it is necessary that the water content is not less than 1% by weight even in the drying and drying step. Even if the water content is once less than 1% by weight and the water content is adjusted again to 1 to 5% by weight, the whiteness of the cellulose ether having a low polymerization degree obtained by depolymerizing it is not improved.

Upon drying, it is preferable to maintain the temperature of the product to be dried (the temperature of the cellulose ether having a high degree of polymerization) at 40 to 80 ° C. If the temperature is lower than 40 ° C., the drying time becomes longer and the productivity is reduced. If the temperature exceeds 80 ° C., the whiteness of the cellulose ether after depolymerization becomes poor. Further, the atmosphere in which the high polymerization degree cellulose ether is brought into contact with the dryer, such as jackets and tubes, and the atmosphere circulating in the machine for drying is preferably 100 ° C. or lower. If the temperature is higher than this, even if the product temperature is 80 ° C. or lower, there is a possibility that the product is locally heated and the whiteness of the final product is reduced.

This drying may be performed in air, but is preferably performed in an inert gas such as nitrogen or under reduced pressure such that oxygen gas is substantially absent.

As the drying method, a tray-type dryer, a fluidized-bed dryer, a stirring-type dryer, and a tube-type dryer can be used as in the related art.

After the drying is completed, the high polymerization degree cellulose ether is ground to a predetermined size.

Furthermore, the present inventors focused on the time of the pulverization step as a measure of the oxidative modification of cellulose ether. The high polymerization degree cellulose ether is finely pulverized to an average particle diameter of about 50 μm, so that it is easy to handle and has good solubility, and good handling in hydrolysis (fluidity of powder) can be obtained. However, when the pulverization time is long, the cellulose ether having a high polymerization degree is easily oxidized and modified by oxygen. Incidentally, a pole mill is generally used as the crusher.

Using a ball mill, the time required to grind hydroxypropylmethylcellulose to a particle size of about 50 μm, the ultraviolet absorption of the ground hydroxypropylmethylcellulose, and the low polymerization after depolymerizing the ground hydroxypropylmethylcellulose The relationship between hydroxypropyl methylcellulose and the yellowness was examined. As a result, as the grinding time increases, the absorption of the hydroxyl group at the wavelength of 200 nm of the oxidized and modified glucose hydroxyl group and the carboxyl group at the wavelength of 200 nm increases, and it can be confirmed that the yellow degree of the low polymerization degree hydroxypropyl methylcellulose also increases. Was. Therefore, oxidative modification of the cellulose ether can be avoided by shortening the grinding time.

An impact crusher is suitable as a crusher capable of crushing in a short time, and a crusher having a time required for crushing to a particle diameter of about 50 μm within 1 minute is preferable. The impact crusher is constituted by an impact plate attached to an outer periphery of a high-speed rotating blade disposed in a grinding chamber, or a combination of a high-speed rotating impact plate and a blade. The pulverized raw material is sent into the pulverizing chamber, and pulverized by collision between the pulverized material and an impact plate or between pulverized materials moving at high speed.

Examples of the impact crusher include a turbo mill (manufactured by Turbo Kogyo), PPSR (manufactured by Balman), ACM (manufactured by Hosokawa Micron), and a Victory mill (manufactured by Hosokawa Micron). Further, a jet mill (manufactured by Nippon Pneumatics Co., Ltd.) for fixing the impact plate and crushing the raw material by crushing the raw material with high-pressure gas is also included. These impact crushers have a crushing time of less than one minute, and some can be crushed in a few seconds.

The high polymerization degree cellulose ether pulverized to an average particle size of 50 μm is depolymerized by a known method to be a low polymerization degree cellulose ether having improved whiteness.

The yellowness of the low polymerization degree cellulose ether obtained by depolymerizing the cellulose ether finely pulverized by these impact grinders and the low polymerization degree cellulose ether obtained by depolymerization without pulverization are as follows. It was the same.

In the present invention, the raw material pulp is subjected to a caustic treatment, and a high polymerization degree cellulose ether obtained by adding an etherifying agent is 20 ° C.
Has a viscosity of 20 cSt or more, preferably tens to hundreds of cSt, including methylcellulose,
Examples thereof include alkyl and hydroxyalkyl cellulose such as hydroxymethylcellulose and hydroxyethylcellulose, and hydroxyalkylalkylcellulose such as hydroxypropylmethylcellulose and hydroxybutylmethylcellulose.

The low-polymerized cellulose ether obtained by depolymerizing the high-polymerized cellulose ether preferably has a 2% aqueous solution viscosity of 20 cSt or less at 20 ° C., and corresponds to the high-polymerized cellulose ether such as methyl cellulose, hydroxymethyl cellulose, or hydroxyethyl cellulose. Examples of such alkyl and hydroxyalkylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, and other hydroxyalkylalkylcellulose.

Hereinafter, specific embodiments of the present invention will be described with reference to examples, but the present invention is not limited to these examples.

Example 1 300 g of wood pulp was impregnated with 730 g of a 49% aqueous sodium hydroxide solution and charged in a 5-liter autoclave. Into this, 474 g of methyl chloride, 160 g of propylene oxide
And reacted at 50-85 ° C. for 4 hours. Wash the obtained hydroxypropyl methylcellulose with 20 hot water,
It was dehydrated to a water content of 50% by weight. This was put into a stirring type drier, and the temperature of the wall and the drying air was set to 90 ° C. and dried for 2 hours. During this time, the temperature of the dried product was a maximum of 70 ° C. The water content after drying was 2.0% by weight. This was pulverized with an impact pulverizer to obtain a highly polymerized hydroxypropylmethylcellulose having a viscosity of 400 cSt of a 2% aqueous solution at 20 ° C.

This high degree of polymerization hydroxypropyl methylcellulose
0.5% by weight of hydrogen chloride was added as an aqueous solution and mixed with stirring so that the total water content was 5% by weight with respect to the high polymerization degree hydroxypropyl methylcellulose. 70 ° C
After depolymerization for 2 hours, the viscosity of a 2% aqueous solution at 20 ° C. was 6 cSt to obtain low polymerization degree hydroxypropyl methylcellulose.

This 2% aqueous solution is used for SM color computer "SM-4"
The yellowness was measured by Suga Test Instruments Co., Ltd. and found to be YI = 10. This YI value was used as an index of whiteness.

Comparative Example 1 After obtaining 50% by weight hydrous hydroxypropyl methylcellulose in the same manner as in Example 1, the wall temperature of the dryer was 120 ° C.
It was dried in air at a hot air temperature of 90 ° C. for 1.5 hours. During this time, the product temperature was a maximum of 85 ° C., and the moisture content at the end was 0.5% by weight.
The obtained high polymerization degree hydroxypropyl methylcellulose was depolymerized by the same method as in Example 1. Then, a low-polymerization degree hydroxypropyl methylcellulose having a 2% aqueous solution viscosity of 6 cSt at 20 ° C. was obtained. This was measured for yellowness in the same manner as in Example 1, and YI = 13.

Example 2 A 50% by weight hydrous hydroxypropyl methylcellulose was obtained in the same manner as in Example 1, and then dried for 1 hour in a dryer having a wall temperature of 120 ° C and a hot air temperature of 90 ° C. During this time, the product temperature was up to 70 ° C., and the moisture content at the end was 2.0% by weight. The obtained high polymerization degree hydroxypropyl methylcellulose was depolymerized by the same method as in Example 1. Then, a low-polymerization degree hydroxypropyl methylcellulose in which the viscosity of a 2% aqueous solution at 20 ° C. was 6 cSt was obtained. When the yellowness was measured in the same manner as in Example 1, YI = 11.

Example 3 A 50% by weight aqueous hydroxypropylmethylcellulose was obtained in the same manner as in Example 1, and then dried for 2 hours in a dryer having a wall temperature of 90 ° C. and a nitrogen gas temperature of 90 ° C. in the apparatus. During this time, the product temperature was up to 70 ° C., and the moisture content at the end was 2.0% by weight.
The obtained high polymerization degree hydroxypropyl methylcellulose was depolymerized by the same method as in Example 1. Then, a low-polymerization degree hydroxypropyl methylcellulose having a 2% aqueous solution viscosity of 6 cSt at 20 ° C. was obtained. When the yellowness was measured in the same manner as in Example 1, YI = 9.

Examples 4 and 5 and Comparative Examples 2 to 4 Examples 4 and 5 and Comparative Examples 2 to 4 were prepared using hydroxypropyl methylcellulose (29% methoxy group) using pulp having a copper value shown in Table 2 as follows. , Hydroxypropyl group 9%). First, a purified pulp was impregnated with a 50% by weight aqueous solution of sodium hydroxide to prepare alkali cellulose having 34% by weight of sodium hydroxide. Methyl chloride is equimolar to sodium hydroxide and propylene oxide is
1.50 moles were charged and charged in a pressure vessel. After etherification at 50 to 90 ° C. for 4 hours, the reaction was completed and purified with hot water. Thereafter, drying was performed under the conditions of each drying step shown in Table 2. After drying, each hydroxypropyl methylcellulose containing water shown in the same table was obtained.

Each of the hydroxypropyl methylcellulose obtained above was finely pulverized with each of the pulverizers shown in Table 2 to an average particle diameter of 50 μm. Each grinding time is described in the same table. The viscosity of a 2% aqueous solution of milled hydroxypropylmethylcellulose was 500 cSt at 20 ° C. To this high polymerization degree hydroxypropylmethylcellulose, 12% hydrochloric acid was added in an amount of 0.0030 parts by weight based on the hydroxypropylmethylcellulose to depolymerize. The viscosity of the 2% aqueous solution after the depolymerization was 6 cSt, and the yellowness of each of the low-polymerized hydroxypropylmethylcellulose was measured.

Next, a 6% aqueous solution was prepared for each sample of low polymerization degree cellulose ether. The diameter of this aqueous solution is 8mm,
A white tablet mainly composed of lactose and corn starch weighing 200 mg per tablet was coated with 8 mg per tablet. 1.5 kg of coated white tablets in total
Met. Coating is pan coating equipment FM-2
(Freund Sangyo Co., Ltd.). The coated tablets were measured for yellowness using the SM color computer described above. The results are shown in Table 2. 40 ° C, RH
(Relative Humidity) One tablet at 75% atmosphere
After standing for a month, the yellowness was measured. Its yellowness is also second
It is shown in the table.

INDUSTRIAL APPLICABILITY The low-polymerized cellulose ether provided by the present invention is remarkably excellent in whiteness as compared with that produced by the prior art. Further, when this is used as a base for coating a pharmaceutical film, it has become possible to produce a medical preparation which is superior in whiteness and clearer when colored. Further, the production method of the present invention does not require bleaching and can easily and inexpensively obtain a low-polymerized cellulose ether having high whiteness without leaving any impurities.

────────────────────────────────────────────────── ─── front page of the continuation (72) inventor Nakamura Shinichiro medium Niigata Prefecture kubiki County Kubiki village Oaza west Fukushima 28 address -1 Shin-Etsu Chemical Co., Ltd. synthesis technology research house (58) investigated the field (Int.Cl. ⁶ , DB name) A61K 47/38

Claims (8)

(57) [Claims] 1. A pulp having a copper value of 0.4 g or less is subjected to caustic treatment, and a cellulose ether having a high degree of polymerization obtained by adding an etherifying agent is purified by hot water, dried by heating, and depolymerized to a fine powder. A base for pharmaceutical film coating comprising the cellulose ether having a low polymerization degree obtained by the above method. 2. The cellulose ether having a low degree of polymerization at 20 ° C.
2. The base for a pharmaceutical film coating according to claim 1, wherein the viscosity of the 2% aqueous solution is 20 cSt or less. 3. The low polymerization degree cellulose ether is methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
The base for coating a pharmaceutical film according to claim 1, wherein the base is a low-polymerization-degree cellulose ether selected from hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, and hydroxybutylmethylcellulose. 4. A pulp having a copper value of 0.4 g or less is subjected to caustic treatment, and a cellulose ether having a high degree of polymerization obtained by adding an etherifying agent is purified with hot water, dried by heating, and depolymerized to a fine powder. A method for producing a pharmaceutical film coating base comprising the low polymerization degree cellulose ether obtained as described above. 5. The pharmaceutical film coating according to claim 4, wherein the atmosphere for the heating and drying is maintained at 100 ° C. or lower, and the temperature of the high polymerization degree cellulose ether is maintained at 40 to 80 ° C. Method for manufacturing bases. 6. The method according to claim 4, wherein the heat drying is performed in an inert gas or an oxygen-deficient atmosphere. 7. The method according to claim 4, wherein the water content of the cellulose ether having a high polymerization degree is reduced to 1 to 5% by weight by heating and drying. 8. The method according to claim 4, wherein the pulverization is performed using an impact pulverizer, and the pulverization time is within 1 minute.