JP3212531B2 - Low-substituted hydroxypropylcellulose, low-substituted hydroxypropylcellulose disintegrant and production method thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a low-substituted hydroxypropylcellulose which is added as a disintegrant or a binder to pharmaceutical tablets and the like, a composition containing the same, and a low-substituted hydroxypropylcellulose. It relates to a manufacturing method.

[0002]

2. Description of the Related Art Pharmaceutical tablets and granules are disintegrated by swelling of a disintegrant contained therein. The disintegrants include, for example, low-substituted hydroxypropylcellulose,
Carboxymethylcellulose and its calcium salts, starch and its derivatives. Among them, low-substituted hydroxypropylcellulose is a nonionic disintegrant having little interaction with a drug. The use of low-substituted hydroxypropylcellulose as an additive for pharmaceuticals is disclosed in JP-B-46-42792 and JP-B-57-57.
No.-53100.

[0003] In recent years, tablets have been miniaturized so that they can be easily taken, and the amounts of binders, disintegrants and the like added tend to be suppressed. For this reason, a disintegrant that enhances the disintegration properties of a tablet with a small amount of addition is desired. When low-substituted hydroxypropylcellulose is used, the disintegration time may be too long with a small amount of addition depending on the production method.

[0004]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above-mentioned problems, and it is an object of the present invention to provide a low-substituted hydroxypropyl which can impart excellent disintegrability to tablets and granules even with a small amount of addition. It is an object of the present invention to provide cellulose, a composition containing the same, and a method for producing low-substituted hydroxypropylcellulose.

[0005] In order to achieve the above object, an invention according to claim 1 is a low-substituted hydroxypropylcellulose having a hydroxypropoxyl group content of 5-1.
6% by weight, and the proportion of monosubstituted units substituted by one molecule with hydroxypropyl group in the anhydrous glucose units of cellulose substituted with hydroxypropyl group is 80 mol% or more of the total glucose units substituted. There is a feature. The invention described in claim 2 is a low-substituted hydroxypropylcellulose disintegrant, wherein , of the anhydrous glucose units of cellulose substituted with a hydroxypropyl group, a monosubstituted compound in which only one molecule is substituted with a hydroxypropyl group. ratio, hydroxypropoxyl group content of 80 mol% or more of the total glucose units substituted for
Contains 5 to 16% by weight of a low-substituted hydroxypropylcellulose as a component.

A third aspect of the present invention is the method for producing low-substituted hydroxypropylcellulose according to the first or second aspect, wherein the pulp having a dichloromethane-soluble content of 0.07% by weight or less is used. After impregnating with an aqueous solution of sodium hydroxide to obtain alkali cellulose, this is characterized by reacting the cellulose with 0.2 to 1.0 mol of propylene oxide per anhydrous glucose unit of the cellulose. The invention described in claim 4 is the method for producing low-substituted hydroxypropylcellulose described in claim 3, wherein the α-cellulose content of the pulp is 92% by weight or more.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, low-substituted hydroxypropylcellulose is usually produced by impregnating pulp with sodium hydroxide to obtain alkali cellulose and then reacting with propylene oxide. Propylene oxide adds to the hydroxyl groups of cellulose. Propylene oxide is added in only one mole to the glucose unit, and further added to the same glucose hydroxyl group or the hydroxyl group of the once substituted hydroxypropyl group in a chain manner to produce a plurality of moles of glucose units. Since low-substituted hydroxypropylcellulose has a low degree of substitution, when a plurality of moles of hydroxypropyl groups are added to one glucose unit, there are many unsubstituted glucose units at the same degree of substitution, and the properties of the raw cellulose are reduced. More parts are maintained as they are. Among the anhydrous glucose units of cellulose substituted with a hydroxypropyl group, the ratio of a monosubstituted unit substituted with only one molecule with a hydroxypropyl group is as follows:
When the content is 80 mol% or more of all the substituted glucose units, good disintegration can be obtained even with a low addition amount because the glucose units are uniformly substituted. If this value is less than 80 mol%, the disintegration is poor, probably due to the large number of properties of the raw material cellulose, and a large amount of addition is required.

The above-mentioned method for producing low-substituted hydroxypropylcellulose in which hydroxypropyl groups are uniformly substituted is characterized in that hydroxyl-soluble pulp having a dichloromethane-soluble content of 0.07% by weight or less, preferably 0.05% by weight or less, is prepared. After being impregnated with an aqueous solution of sodium to form alkali cellulose, 0.2-1.
Including reacting 0 moles of propylene oxide.

[0009] The dichloromethane-soluble matter is measured by extracting the pulp with a Soxhlet extractor using dichloromethane as an extracting agent. Since the dichloromethane extract is mainly composed of water-repellent substances such as resins and oils and fats, if its content exceeds 0.07% by weight, the aqueous sodium hydroxide solution, which is a catalyst for the reaction when producing alkali cellulose, is homogeneous. It is presumed that the hydroxypropyl group is not uniformly substituted during the reaction of propylene oxide because it is less likely to be impregnated.

The hydroxypropoxyl group content of the low-substituted hydroxypropylcellulose is preferably in the range of 5 to 16% by weight, particularly 7 to 13% by weight. The amount of propylene oxide to be adjusted to this range is different depending on the composition and reaction conditions of the alkali cellulose because the reaction efficiency of propylene oxide varies. 0 mol. Hydroxypropoxyl group content is 5% by weight
If it is less than 1, the swelling ratio of hydroxypropylcellulose is low, and disintegration becomes insufficient when used for tablets and the like. If the content exceeds 16% by weight, the hydroxypropylcellulose will eventually become water-soluble.
The average particle diameter is preferably from 5 to 150 μm, particularly preferably from 40 to 1 μm.
A range of 00 μm is desirable. If it is less than 5 μm, the fluidity of hydroxypropylcellulose will be poor. If it exceeds 150 μm, the mixing of hydroxypropylcellulose and the drug becomes uneven.

The α-cellulose content of pulp is JIS P
8101, but preferably 92% by weight or more. The portion other than α-cellulose is a portion that dissolves in an aqueous solution of sodium hydroxide, and because it becomes water-soluble due to hydroxypropylation, if this value is low, the dissolution loss in the washing step increases, and the yield is low. Decrease.
Alkaline cellulose is obtained by immersing a sheet-like pulp in an aqueous sodium hydroxide solution and pressing, or spraying sodium hydroxide on powdered pulp while stirring. Usually, the reaction of propylene oxide is carried out at a temperature of 40 to 80.
C., for 1 to 5 hours, in a pressure-resistant reaction vessel. The resulting low-substituted hydroxypropylcellulose is taken out, neutralized by adding an acid to neutralize free alkali, washed with water, dried and pulverized to obtain a product.

The low-substituted hydroxypropylcellulose composition contains the above-mentioned low-substituted hydroxypropylcellulose as a component and other components such as a drug, an excipient, a binder, a lubricant, and a coloring agent. be able to. According to the present invention, excellent disintegration properties can be imparted even when the types of main drugs are different. This composition is made into granules by granulation, or into tablets as it is or by granulation.

[0013]

Embodiments of the present invention will be described below in detail. In the following examples, unless otherwise specified,% is
It represents% by weight. The dichloromethane solubles in each example,
The method for synthesizing the low-substituted hydroxypropylcellulose, the method for quantifying the substituents, the method for measuring the substituent distribution, and the method for measuring the disintegration time of tablets and granules are as follows.

Dichloromethane soluble matter: 10 g of pulp was placed in a Soxhlet extractor, extracted with dichloromethane for 6 hours, the extract was evaporated on a water bath, further dried at 103 ° C., and determined by the weight of the residue.

Method for synthesizing low-substituted hydroxypropylcellulose: Pulp was immersed in an aqueous solution of 49% by weight of sodium hydroxide and pressed to obtain alkali cellulose having 24 to 25% by weight of sodium hydroxide. 100 parts by weight of this alkali cellulose was charged into a reactor, and nitrogen gas replacement was performed. After the replacement, 9.0 parts by weight of propylene oxide (0.5 mol per anhydroglucose unit of cellulose) is charged into the reactor, and the mixture is reacted with stirring at 40 ° C. for 1 hour, 50 ° C. for 1 hour, and 70 ° C. for 1 hour. As a result, 109 parts by weight of a reaction product was obtained. This reaction product was charged into 2000 parts by weight of hot water at 95 ° C. containing an equivalent amount of acetic acid and sodium hydroxide to neutralize and dehydrate. After washing the dehydrated product with hot water of 90 ° C,
The sample was dehydrated, dried, pulverized with a vibration mill, and sieved with a sieve having an opening of 75 μm to obtain a sample. Substituent quantification method: Measured according to the method of the Japanese Pharmacopoeia.

Measuring method of substituent distribution: 3 g of a sample and dimethyl sulfoxide (DMSO) were placed in a separable flask.
256 ml was added and stirred at 60 ° C. for 30 minutes. After cooling,
12 ml of a 30 w / v% DMSO solution of sulfur dioxide and 6 ml of diethylamine were added, and the mixture was stirred to dissolve the sample.
Then, 36 g of sodium hydroxide powder was added, stirred for 2 hours, and left overnight. To this, 50 ml of methyl iodide was added dropwise while stirring, and 1 hour at room temperature and 30 minutes at 40 ° C.
The methylation reaction was carried out at 50 ° C. for 30 minutes and at 60 ° C. for 4 hours. The reaction solution was poured into hot water to precipitate a reaction product, neutralized with concentrated hydrochloric acid, filtered, washed with hot water, and dried in vacuum.

To 50 mg of the dried product, 3 ml of a 2M aqueous trifluoroacetic acid solution was added, and the mixture was sealed and hydrolyzed at 120 ° C. for 3 hours. Furthermore, after concentrating this to 1 ml, 1 ml of a 30% sulfuric acid aqueous solution was added, and the mixture was hydrolyzed at 120 ° C. for 30 minutes.
After cooling, barium carbonate was added for neutralization, and methanol 3m
The mixture was shaken, allowed to stand, and filtered. To the filtrate was added 100 μl of a 15% aqueous solution of sodium borohydride in 0.2 M sodium hydroxide, and the mixture was stirred at room temperature for 1 hour for reduction.
To this, 100 μl of acetic acid was added, and the mixture was concentrated at 100 ° C. to just before drying. After adding 3 ml of methanol with stirring,
The operation of evaporating was repeated 5 times to remove boron. 2 ml of pyridine and 0.1 ml of acetic anhydride were added thereto, and
Acetylation was performed at 0 ° C. for 3 hours to obtain a test solution.

The test solution was quantified for various methyl, methoxypropyl, and glucitol acetates by gas chromatography under the following conditions. I asked. Apparatus: 5890 SERIES II (Hewlett-Packard) Detector: Flame ionization detector Column: 5% phenylmethyl silicone 0.2 mmφ
× 25m Initial temperature: 170 ° C Heating rate: 2.5 ° C / min

Method for measuring disintegration time of tablets: Based on calcium hydrogen phosphate (Rikamit U-100, manufactured by Kyowa Chemical Industry Co., Ltd.), 2 parts by weight of sample Nos. 1 to 3 and 98 parts by weight of calcium hydrogen phosphate were used. A composition for direct compression was prepared with a mixing ratio of 0.5 parts by weight of magnesium stearate. This was pressed with a KT-2 tablet press (Okada Seisakusho)
Tableting with a tableting pressure of 0.6 tons, diameter 9 mm, weight 30
0 mg tablets were obtained, and the disintegration time was measured according to the method of the Japanese Pharmacopoeia.

Measurement method of disintegration time of granules: 95 parts by weight of phenacetin (manufactured by Yamamoto Chemical Co., Ltd.) and 5 parts by weight of Sample Nos. 1 to 3 were mixed in a kneader, and kneaded after adding 27 parts by weight of water. Granulation was performed using a 5-inch cylindrical extruder with a 0.6 mmφ screen. This is dried and granulated, 3
A granule of 55 to 710 μm was obtained, and the disintegration time was measured according to the method of the Japanese Pharmacopoeia.

[0021]Example 1 96.1% α-cellulose content and soluble in dichloromethane
Is low-substituted hydroxypro using 0.01% pulp.
Pill cellulose was synthesized and dried pulp
The yield was 95%. The obtained powder was used as sample No. 1.
Quantification of substituents, distribution of substituents, disintegration of tablets and granules
The decay time was measured and the results are shown in Table 1. Example 2 α-cellulose content is 94.5% and dichloromethane soluble
To dry pulp using 0.05% pulp
-Substituted hydroxypropyl cellulose with 93% yield
I got The obtained powder was designated as Sample No. 2, and was the same as in Example 1.
The same tests were performed, and the results are shown in Table 1.

COMPARATIVE EXAMPLE 1 Using pulp having an α-cellulose content of 95.2% and a dichloromethane-soluble content of 0.08%, low-substituted hydroxypropylcellulose was obtained with a yield of 94% based on dried pulp. The powder obtained was used as Sample No. 3, and the same test as in Example 1 was performed. The results are shown in Table 1. Comparative Example 2 Low-substituted hydroxypropylcellulose was synthesized from pulp having an α-cellulose content of 89.7% and a dichloromethane-soluble content of 0.01%. The yield based on the dried pulp was 84%. .

[0023]

[Table 1]

The tablets and granules of Examples 1 and 2 are shorter in disintegration time than the tablets and granules of Comparative Example 1, and are superior in disintegration. This is because, as can be seen from the ratio of each substituted product in Table 1, the ratio of the monosubstituted low-substituted hydroxypropyl cellulose in Examples 1 and 2 is 80 mol% or more.

[0025]

According to the present invention, there is provided a low-substituted hydroxypropylcellulose which imparts excellent disintegrability only by being slightly added to tablets or granules.
Tablets or granules in which this was blended, because the proportion of hydroxypropylcellulose contained was reduced,
In particular, tablets are made smaller and easier to take.

Continuation of the front page (72) Inventor Mitsuyoshi Oshima 28-1, Nishifukushima, Oku-ku, Nukujuku-mura, Niigata Pref. (58) Field surveyed (Int.Cl. ⁷ , DB name) C08B 11/08 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. The proportion of a monosubstituted unit in which only one molecule is substituted with a hydroxypropyl group among the anhydroglucose units of cellulose substituted with a hydroxypropyl group is 80 mol% or more of all the substituted glucose units. The hydroxypropoxyl group content is 5 to 16 times
Low substituted hydroxypropylcellulose in % by weight . 2. The proportion of monosubstituted units substituted by one molecule with a hydroxypropyl group among the anhydroglucose units of cellulose substituted with a hydroxypropyl group is at least 80 mol% of all the substituted glucose units. Hydroxy
A low-substituted hydroxypropylcellulose disintegrating agent characterized by comprising a low-substituted hydroxypropylcellulose having a cipropoxyl group content of 5 to 16% by weight as a component. 3. The method for producing a low-substituted hydroxypropylcellulose according to claim 1 or 2,
A pulp having a dichloromethane-soluble content of 0.07% by weight or less is impregnated with an aqueous solution of sodium hydroxide to obtain alkali cellulose, which is then reacted with 0.2 to 1.0 mol of propylene oxide per anhydrous glucose unit of cellulose. A method for producing low-substituted hydroxypropylcellulose, comprising: 4. The pulp having an α-cellulose content of 92
The method for producing low-substituted hydroxypropylcellulose according to claim 3, wherein the amount is not less than% by weight.