JP2004155657A - Disintegrant - Google Patents

Abstract

The disintegrating agent is characterized in that a hydrogen atom of a hydroxyl group of cellulose is substituted with an alkyl group and / or a hydroxyalkyl group, and the disintegrating agent comprises a crosslinked cellulose ether crosslinked with polyglycidyl ether.
The disintegrant comprising the crosslinked cellulose ether of the present invention has a high swelling ratio, is stable with drugs, and can be produced at low cost.
[Selection diagram] None

Description

＊１ Ｌ−ＨＰＣ＝低置換度ヒドロキシプロピルセルロース，信越化学工業（株）製
【００３３】
【表２】

＊２ 表１の実施例２の架橋セルロースエーテル（ＤＳ＝１．４５、ＭＳ＝０．０２２）
＊３ Ａｃ−Ｄｉ−Ｓｏｌ，旭化成工業社製
＊４ ポリプラスドン，ＩＳＰジャパン社製
【００３４】
【発明の効果】
本発明の架橋セルロースエーテルからなる崩壊剤は、膨潤率が高く、かつ薬物と安定である上、安価に製造することができる。[0001]
TECHNICAL FIELD OF THE INVENTION
TECHNICAL FIELD The present invention relates to a disintegrant using a crosslinked cellulose ether. In particular, in the case of tablets, granules and the like for pharmaceuticals, foods, toiletries, feeds and the like, disintegrants are mixed with a substrate drug or an active ingredient and molded. The present invention relates to a disintegrating agent used in a molding agent that absorbs water and swells to rapidly disintegrate the molding agent, and a useful drug or active ingredient is easily dispersed in water.
[0002]
[Prior art]
According to the Pharmaceutical Excipients Dictionary (1995 supplementary edition, edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo), there are currently 71 types of excipients listed as disintegrants. Among these, low-substituted hydroxypropylcellulose, carmellose calcium (carboxymethylcellulose calcium), croscarmellose sodium (crosslinked carboxymethylcellulose sodium), sodium carboxymethyl starch, partially pregelatinized starch, Crospovidone (crosslinked polyvinylpyrrolidone) and the like. These materials do not normally dissolve in neutral water but swell. Utilizing this property, it is used for disintegrants such as tablets and granules of pharmaceuticals, toiletries, agricultural chemicals and the like. More specific examples of use for pharmaceutical applications include disintegrating agents mixed with binders, lubricants, pigments, fillers, etc. in addition to the active agent, to form tablets under pressure. When the tablet is taken by a person, the tablet comes into contact with the water in the digestive tract, and the disintegrant absorbs the water and disintegrates, so that the other base material is broken apart and the active ingredient is rapidly absorbed.
[0003]
On the other hand, when this disintegrant is not used, the disintegration of the tablet is very slow or the only option is to wait for the components of the tablet to dissolve without disintegration. However, there are many poorly soluble substances in a drug, and the drug cannot be used effectively without the help of a disintegrant. Therefore, disintegrants are very commonly used for pharmaceutical applications.
[0004]
The non-pharmaceutical field includes agricultural chemical formulations. For example, when spraying pesticides on a paddy field, in a small paddy field, air spraying or a spraying machine cannot be used, and it is necessary to spray by hand. In such a case, the finely divided pesticide is generally formed into granules while avoiding scattering by the wind, but once dispersed, the finely divided pesticides are hard to disperse finely and flow out with time. Granules are also used in disinfecting seedlings, but the proportion of active ingredients that actually adhere to the seedlings throughout the rice planting operation is low because they do not disperse. Accordingly, disintegrants are also widely used in this application.
[0005]
Further, in the field of toiletries, it is often observed that a granular detergent in which no disintegrant is used remains dissolved in water, which is an example of disintegrant application. It is also conceivable that a large volume can be covered with a small amount of fish-inspired bait by using a disintegrant and finely dispersing the bait for fishing.
[0006]
Although these disintegrants have many uses as described above, the existing disintegrants listed above each have disadvantages.
[0007]
First, carmellose calcium (carboxymethylcellulose calcium), croscarmellose sodium (crosslinked carboxymethylcellulose sodium), and sodium carboxymethyl starch are poorly stable with drugs because they are metal salts of cellulosic polymers, that is, ionic. . More specifically, when mixed with aspirin (acetylsalicylic acid), it promotes the decomposition of aspirin, and precipitates crystals of salicylic acid and inactivates pancreatin (amylase-activating enzyme). Crospovidone (cross-linked polyvinylpyrrolidone) has little interaction with drugs, but has high hygroscopicity, which may cause aspirin to decompose when stored in humid places. Partially pregelatinized starch originally has a low swelling ratio, and its disintegration power is inferior to other disintegrants. Low-substituted hydroxypropylcellulose has good stability but slightly lower disintegration power, and it may be necessary to use a large amount of addition depending on the drug.
[0008]
As described above, there has been a demand for a disintegrant that has a high swelling rate and is stable with a drug compared to existing disintegrants.
[0009]
[Patent Document 1]
US Patent No. 3,168,421
[Problems to be solved by the invention]
The present invention has been made in view of the above circumstances, and it is an object of the present invention to provide a disintegrant having a higher swelling rate and being more stable than a conventional disintegrant.
[0011]
Means for Solving the Problems and Embodiments of the Invention
The present inventors have conducted various studies in order to solve the above-described problems, and as a result, in the process of producing a cellulose ether, when introducing an ether group, a crosslinked cellulose ether obtained by performing a crosslinking reaction together has excellent disintegration. The present invention has been found to be an agent, and has led to the present invention.
[0012]
That is, the present invention
(1) a disintegrating agent, wherein a hydrogen atom of a hydroxyl group of cellulose is substituted with an alkyl group and / or a hydroxyalkyl group, and the disintegrating agent comprises a crosslinked cellulose ether crosslinked with polyglycidyl ether;
(2) The crosslinked cellulose ether is obtained by performing a crosslinking reaction with a polyglycidyl ether and a substitution introduction reaction of an alkyl group and / or a hydroxyalkyl group in the same reaction step (1). Disintegrant according to,
(3) The disintegrant according to (1) or (2), wherein the ratio of hydroxyl groups on the glucose unit replaced by the crosslinking reaction is 0.004 to 0.06.
[0013]
Hereinafter, the present invention will be described in more detail.
The disintegrant of the present invention comprises a crosslinked cellulose ether. In this case, the crosslinked cellulose ether has a hydrogen atom of a hydroxyl group of cellulose substituted with an alkyl group and / or a hydroxyalkyl group, and a polyglycidyl ether. In the production of cellulose ether, the cellulose is mixed with an aqueous alkali metal solution, and a crosslinking agent is added simultaneously with an alkylating agent or a hydroxyalkylating agent for introducing an ether substituent. By reacting, the disintegrant can be produced in substantially one step.
[0014]
In order to obtain the desired crosslinked cellulose ether, it is possible to produce the cellulose ether with the ether group introduced in a separate step such as reaction, purification, drying, and if necessary, pulverization, and use it to carry out the crosslinking reaction. However, since the steps are complicated, the steps of reaction, purification, drying, pulverization and the like are duplicated, so that the cost is not completely satisfied.
[0015]
For example, an attempt to crosslink methylcellulose or hydroxypropylcellulose using a crosslinker can be found in U.S. Pat. No. 3,168,421. However, the cellulose ether is converted into an aqueous solution, mixed with a crosslinker, and then crosslinked. This is to obtain an insoluble film, which is different from the present invention.
[0016]
The present inventors have studied how low-cost a cross-linked cellulose ether can be manufactured by employing a simple manufacturing process.As a result, the introduction of the ether group and the cross-linking reaction were achieved in substantially the same process. I found what I can do. In this case, preferably, after the base cellulose is mixed with an aqueous alkali metal hydroxide solution serving as a reaction catalyst, both of the ether group introduction and crosslinking reactions are carried out in the same reactor. More specifically, the etherification reaction and the cross-linking reaction may be carried out by adding a polyglycidyl ether to the catalyzed cellulose to cause a cross-linking reaction, and then using the same reactor and adding an etherifying agent to carry out the etherification reaction. Alternatively, after the etherification reaction is terminated, a crosslinking agent may be added to cause a crosslinking reaction. However, in order to complete both reactions in the shortest time, it is most preferable to add the etherifying agent and the crosslinking agent at about the same time to carry out the reaction.
[0017]
Here, as the cellulose, since cellulose itself is widely produced in nature, it is not particularly limited, but if dare to be exemplified, cotton, cotton linter, a bulk or a sheet obtained by refining wood, that is, Pulp.
[0018]
Examples of the aqueous alkali metal hydroxide solution include aqueous solutions of potassium hydroxide, lithium hydroxide and the like, and sodium hydroxide is advantageous in terms of cost.
[0019]
Examples of the etherifying agent for alkylation include methyl halides such as methyl chloride and ethyl chloride, and ethyl halides. Examples of the etherifying agent for hydroxyalkylation include ethylene oxide and propylene oxide. Examples of the cellulose ether obtained by an etherification reaction using such an etherifying agent include alkyl cellulose such as methyl cellulose, hydroxyalkyl cellulose such as hydroxyethyl cellulose and hydroxypropyl cellulose, hydroxyethyl methyl cellulose, and hydroxyalkyl alkyl such as hydroxypropyl methyl cellulose. Cellulose is mentioned.
[0020]
The amount of the etherifying agent to be added is not particularly limited. However, if the amount is too small, the crystal structure of cellulose is not sufficiently broken, and there is a possibility that the absorbability may be reduced. The average number of hydroxyl groups substituted with methoxyl groups per glucose unit of cellulose (Degree of Substitution) (hereinafter abbreviated as "DS") is preferably about 1.0 to 2.2. In the case of hydroxyalkyl cellulose as an example, the degree of hydroxyalkyl group substitution (average number of hydroxyalkyl groups added per glucose unit of cellulose (Molecular Substitution); hereinafter, abbreviated as “MS”) is 0.1 to 1. About 0 is preferable.
[0021]
As a cross-linking agent, polyglycidyl ether is used to make the final product nonionic.
[0022]
Examples of the polyglycidyl ether include ethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, and polypropylene glycol diglycidyl ether. Such a polyglycidyl ether is nonionic when the epoxy functional groups at both ends are bonded to a hydroxyl group in a cellulose or a hydroxyl group in a hydroxyalkyl group, or when only one of the epoxy groups is bonded. The fact that it is nonionic is less likely to cause an interaction with the drug when used as a disintegrant.
[0023]
As described above, polyglycidyl ether has two epoxy groups and is introduced into a hydroxyl group of cellulose. However, both epoxy groups do not always react with hydroxyl groups, and only one of them may be introduced into cellulose. The degree of MS substitution assuming that two epoxy groups have completely reacted with the cellulose is preferably 0.004 to 0.06, particularly preferably 0.01 to 0.04. When the amount is less than this range, crosslinking is not sufficient, and the cellulose ether partially dissolves and exhibits viscosity, so that water penetration is hindered, and it may not function effectively as a disintegrant. If it exceeds this range, the crosslinks are so dense that they do not easily swell and may not be cost-effective.
When the amount of polyglycidyl ether to be added is small, it may be added by diluting it with an etherifying agent, water, or an organic solvent that does not interfere with the reaction.
[0024]
As the reaction conditions for the etherification reaction and the cross-linking reaction, it is preferable to carry out the reaction at 30 to 120 ° C, particularly 40 to 100 ° C. The reaction time is not particularly limited, but is usually 2 to 8 hours.
[0025]
In the present invention, the crosslinked cellulose ether thus obtained is used as a disintegrant, and the method of use is the same as that of the conventional disintegrant. Specifically, when a molding agent such as a tablet or a granule is obtained in medicines, agricultural chemicals, foods, toiletries, feeds, and the like, it is used instead of or together with a conventional disintegrant.
[0026]
The disintegrant of the present invention absorbs water when it comes into contact with water and swells, whereby the above-mentioned molding agent easily and rapidly disintegrates.
[0027]
【Example】
Hereinafter, the present invention will be described specifically with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. In the following examples, parts are parts by weight.
[0028]
[Examples and Comparative Examples]
250 g of cotton linter pulp was charged into an internal stirring type autoclave having an internal volume of 5 L, and the pressure was reduced to -98 kPa. Next, 300 g of 50% by weight sodium hydroxide was added and stirred for 10 minutes. As a crosslinking agent, ethylene glycol diglycidyl ether (molecular weight 174.2 g / mol) diluted with acetone to a total of 30 g was added, and further 200 g of methyl chloride was added, and the temperature was further raised to 90 ° C. at 60 to 70 ° C. for 2 hours. Warm and maintain temperature for 30 minutes to complete the reaction. After purging the internal residual gas, the crude reaction product was purified with hot water, dried, treated and sized with a pulverizer equipped with a screen having an opening of 0.5 mm to obtain a sample.
[0029]
The following Table 1 shows the physical properties of six types of samples prepared by changing the amount of the cross-linking agent added by the above method. In addition, the MS substitution degree of ethylene glycol diglycidyl ether is a value on the assumption that it is completely crosslinked, that is, both epoxy groups are bonded to cellulose.
[0030]
The swelling characteristics were as follows. A tablet consisting of a mixed powder of 100 mg of a sample and 400 mg of alumina was prepared in a cylinder with a diameter of 15 mm and a tableting pressure of 55 MPa, and an upper punch with a water pipe was placed so as to be in contact with the tablet. The swelling ratio was calculated from the tablet thickness after one minute by the following formula. Further, the tablet after the test was taken out, and the swelling state and the permeation state of water (whether or not water permeated to the lower part of the tablet) were visually observed. Table 1 shows the results.
Swelling ratio (%) = [(Tablet thickness after swelling / Tablet thickness before swelling) -1] × 100
[0031]
The stability was as follows. Using aspirin and vitamin C as drugs, a mixed powder having the following formulation was directly pressed to form tablets of 8 mmφ, 225 mg / tablet. This was placed in a sealed glass container, stored at 50 ° C. for 3 months, and visually observed.
(1) Aspirin 8 parts of aspirin powder, 2 parts of disintegrant, 0.5 part of stearic acid (2) Vitamin C
8 parts of granular vitamin C (VC97, manufactured by Takeda Pharmaceutical Co., Ltd.), 2 parts of swelling agent, 0.5 part of magnesium stearate
[Table 1]

* 1 L-HPC = low-substituted hydroxypropyl cellulose, manufactured by Shin-Etsu Chemical Co., Ltd.
[Table 2]

* 2 Crosslinked cellulose ether of Example 2 in Table 1 (DS = 1.45, MS = 0.022)
* 3 Ac-Di-Sol, manufactured by Asahi Kasei Corporation * 4 Polyplasdon, manufactured by ISP Japan [0034]
【The invention's effect】
The disintegrant comprising the crosslinked cellulose ether of the present invention has a high swelling ratio, is stable with drugs, and can be produced at low cost.

Claims (3)

A disintegrating agent comprising a crosslinked cellulose ether in which a hydrogen atom of a hydroxyl group of cellulose is substituted with an alkyl group and / or a hydroxyalkyl group, and which is crosslinked with polyglycidyl ether. 2. The disintegration according to claim 1, wherein the crosslinked cellulose ether is obtained by performing a crosslinking reaction with a polyglycidyl ether and a substitution introduction reaction of an alkyl group and / or a hydroxyalkyl group in the same reaction step. Agent. 3. The disintegrant according to claim 1, wherein the ratio of hydroxyl groups on the glucose unit replaced by the crosslinking reaction is 0.004 to 0.06.