JPS60221402A - Preparation of oxycarboxylic acid-type cellulose derivative easily dispersible in water - Google Patents

Abstract

PURPOSE:To obtain the titled derivative having low dusting tendency and excellent redispersibility in water, economically, by preparing an oxycarboxylic acid- type cellulose derivative insoluble in water, separating into solid and liquid from a hydrated solvent solution, pulverizing in wet state, and drying the product. CONSTITUTION:The objective derivative can be produced by preparing a water- insoluble oxycarboxylic acid-type cellulose derivative (e.g. a carboxyalkyl methylcellulose, carboxyalkyl ethylcellulose, etc. having 1-5C alkyl group), separating into solid and liquid from a hydrated solvent solution (e.g. an aqueous solution of a 1-4C alkanol), pulverizing in wet state to <=100mu, preferably <=10mu without drying, and drying the product. USE:Effective for the preparation of a water-based enteric coating liquid.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing easily water-dispersible oxycarboxylic cellulose derivatives. For more details.

Conventional technology concerning a method for providing an easily water-dispersible oxycarboxylic acid type cellulose derivative effective for preparing an aqueous enterostatic coating liquid.Conventional technology When coating solid pharmaceuticals such as granules and tablets with an enteric coating agent. A commonly used method is to dissolve the liquid in a single or mixed solvent such as a halogenated hydrocarbon, alcohol, or ketone and then spray coat it. However, this method requires a large amount of organic solvent to prepare the coating liquid. Not only is it economically disadvantageous because it is difficult to recover the organic solvent, but there are also problems in terms of safety for workers due to the use of large amounts of organic solvents, and safety for users due to residual solvent in the drug. there were.

From this point of view, there has recently been an increasing recognition of the importance of making lIk bath-based coating liquids water-based, and various methods have been proposed. By the way, enteric coating agents are generally polymeric compounds that do not dissolve in water or gastric fluid, but dissolve in septum, and generally have an anionic group. Since such polymer compounds have the property of becoming water-soluble only by forming a salt in an alkaline aqueous solution, the reality is that they cannot simply be made into an aqueous solution.

Therefore, the aqueous coating solution for enteric coating agents having such properties is generally prepared by dispersing fine powder of enteric coating agents pulverized to 100 μm or less in water. Needless to say, it is desirable that the particle size of the enteric coating agent be as small as possible from the viewpoint of water dispersibility during preparation of such a dispersion and film-forming properties of the dispersion.

Various methods of atomization have been proposed in the past. Conventional techniques relating to atomization methods are broadly divided into a method in which a dried product is dry-pulverized using a jet mill or the like, and a physical pulverization method described in, for example, JP-A-55-54881.

However, the method of White (2007) has disadvantages such as the extremely large crushing force during crushing, and the fact that the combined products are made of fine powder, making handling difficult and inconvenient, which is a big problem in practical use. On the other hand, the latter method uses a physical and chemical method, that is, a method of neutralizing the alkaline solution while applying a cutting force, instead of using a dry method using a square or mechanical method. It is a sign that something will happen.

Phosphorizing the interlayer is not an economically advantageous method because it is necessary to significantly lower the solid content concentration during pulverization, and it requires the use of a homogenizer that requires a lot of power. In view of the above situation, the inventors of the present invention sought to solve the shortcomings of the prior art by creating a material that has easy water dispersibility that is advantageous in engineering and effective in preparing a good aqueous enteric coating solution.

Furthermore, as a result of extensive research into a method for producing enteric coating agent powder that produces less powder, we have found that when producing a water-insoluble oxycarboxylic acid type cellulose derivative, the oxycarboxylic conventional cellulose-qm conductor can be used at least partially with water. After solid-liquid separation from the solvent threads containing it, it is wet-pulverized and dried to create a form with little powder that satisfies the purpose.

Furthermore, the present inventors have discovered that it is possible to advantageously obtain a material having easy water dispersibility on an industrial basis, and have completed the present invention.

In this application, the oxycarboxylic acid type cellulose derivative is defined as follows.

At least a portion of the 8 hydroxyl groups per glucose skeleton of cellulose or hydroxyalkylcellulose are carboxyalkyl ether groups (-OCnH, ncO
OH) A cellulose derivative which has been substituted with dibasic carboxylic acid by a half-ester group and an ether group (-0CnH1n+1) and an ester group (-OCR). However, alkyl has 1 to 5 carbon atoms.
n represents an alkyl group of 1 to 5, and R#'i represents an alkyl group having 1 to 5 carbon atoms or a higher fatty acid residue. Oxycarboxylic acid type cellulose derivative! : Cellulose ethers, cellulose esters and cellulose ether esters can be mentioned. The term ether group or ester group refers to an atomic group introduced into cellulose by etherification or esterification of cellulose, and examples of the ester group include acetate, propionate, butyrate, and higher fatty acid ester.

To give more specific examples, examples of oxycarboxylic acid type cellulose derivatives include carboxyalkylalkylcellulose 71 ethers such as carboxymethylethylcellulose, carboxyethylmethylcellulose, carboxypropylmethylcellulose, hydroxyglobil methylcellulose succinate, hydroxypropyl 'Methylcellulose phthalate, acidic succinoyl and r9p phthaloyl fj of hydroxypropyl methylcellulose
Examples include cellulose mixed ether esters such as monomer esters, acidic succinoyl and propionate esters of hydroxypropyl methyl cellulose, and cellulose mixed esters such as cellulose acetate phthalate and cellulose acetate succinate.

Among them, oxycarboxylic acid type cellulose-derived (if water-based - when used as a soluble coating agent,
Particularly preferred are carboxyalkylalkylcelluloses which are highly wood-philic and have excellent hydrolysis resistance. Examples include carboxymethylethylcellulose, carboxyethylethylcellulose, carboxybutylethylcellulose, carboxypropylmethylcellulose, etc.If carboxymethylethylcellulose is used,
A product produced by etherifying carboxymethylcellulose in the presence of a quaternary ammonium salt as a phase transfer catalyst, in particular carboxymethylcellulose is dispersed in advance in an organic solvent that is not freely miscible with an aqueous caustic solution, and then mixed with a caustic alkali and mixed with aqueous caustic alkali. A product obtained by etherification reaction with the addition of a transfer catalyst ethyl halide is preferred because it provides a strong film with uniform distribution of R-substituted ethoxyl groups and less shrinkage.

Next, the production method of the present invention is characterized in that in producing a water-insoluble oxycarboxylic acid type cellulose derivative, the oxycarboxylic acid type cellulose derivative is at least wet-pulverized and then dried. Even if water is added to the dried cellulose derivative and pulverized, it is not possible to achieve the desired properties such as easy water dispersibility. In the present invention.

A solvent system containing at least a portion of water is, for example, an aqueous solution of a lower alkanol of carbon atoms e, l-4.

Examples include organic solvent/water mixed solvent systems such as acetone aqueous solution, and aqueous solutions of basic substances such as ammonia, methylamine, caustic soda, and caustic potash, but are limited to these as long as they dissolve the oxycarboxylic acid type cellulose derivative tl. As a solid-liquid separation method for the zero-order oxycarboxylic acid type cellulose derivative, in the case of an organic solvent/water mixed solvent system such as an aqueous lower alkanol solution, the organic solvent is removed by isobaric distillation. IDI separation is easily possible, and in the case of an aqueous solution of a basic substance such as an aqueous ammonia solution, the precipitate produced by adding an acidic substance that can neutralize the basic substance used can be removed. Separate solid and liquid by filtration or sedimentation.

By the way, it is desirable that the oxycarboxylic acid type cellulose derivative used as an enteric coating agent has various degrees of polymerization depending on its use.

For this reason, there are two methods for producing K: one is to use a cellulose raw material with a degree of polymerization depending on the purpose, and the other is to perform depolymerization in the manufacturing process to achieve the degree of polymerization depending on the purpose.Industrially, the latter method is the depolymerization method. It is practical to adopt

Examples of depolymerization methods include the method previously proposed by the inventors of Tai et al.
No. 5978), that is, there is a method in which an oxycarboxylic acid type cellulose derivative is uniformly dissolved in a solvent system containing at least a portion of water, and then a peroxide is added to depolymerize, but the method is not limited to these. After the depolymerization is completed, the depolymerized nuclear oxycarboxylic acid type cellulose derivative is separated into solid and liquid from the reaction solution, and then wet-pulverized and dried according to the method of the present invention to produce the desired easily water-dispersible oxycarboxylate in an extremely economical manner. It is possible to obtain carboxylic acid type cellulose derivatives.

Naturally, if the oxycarboxylic acid type cellulose derivative with a polymerization degree suitable for the purpose is available, the core oxycarboxylic acid type cellulose derivative is uniformly dissolved in the solvent system specified in the present invention, and then subjected to depolymerization treatment. It goes without saying that it is better to subject the product to wet pulverization after solid-liquid separation without carrying out this step.

Next, as the grinding device used in the wet grinding step of the present invention, conventionally known wet grinding machines such as a ball mill, attritor, disper mill, colloid mill, and camera mill can be used, but are limited thereto. It's not a thing.

Father, 1 yen The solid content concentration during 1-type pulverization varies depending on the type of pulverizer used and the target particle size of the pulverized product, but it is usually 50% or less.

In particular, it is preferably 80% or less. Similarly, particle deformation during wet grinding affects the water dispersibility of the product after drying, and hence the film forming properties, so it is desirable to make it as small as possible, but it is usually less than 100 microns, preferably less than 10 microns.

The drying of the pulverized product thus obtained can be carried out by conventional methods such as ventilation drying, vacuum drying, spray drying, freeze drying, etc. Drying can be easily carried out by heating and dehydrating the slurry beforehand. Since the enteric property is affected, it is desirable to process the process at a low temperature and in a short time as much as possible until a dry product is obtained after wet grinding.

Effects of the Invention (1) The okiku power obtained by carrying out the method according to the above (6)) The soft-boiled special loin loin derivative does not undergo secondary aggregation due to water acting as a binder in the drying process after wet grinding. occurs and remains granular or lumpy even after drying,
It does not suffer from the problem of dusting, which is one of the disadvantages of dry grinding methods such as jet mills, and has excellent redispersibility in water.

That is, (1) by carrying out the present invention, the drawbacks of the prior art can be overcome, and (7) it is possible to easily provide easily water-dispersible oxycarboxylic acid type cellulose derivatives by an economically advantageous method, and the industrial use thereof can be improved. Kaoru and Oru are extremely large.

By carrying out the present invention! There are no particular restrictions on the method for preparing the enteric coating liquid by dispersing the oxycarboxylic acid type cellulose derivative in water to form an aqueous system.

At the request of my father, I used hydroxypropyl methylcellulose, an emulsifier, to further improve the dispersion stability and film-forming properties of the water-based coating liquid.

Human α-xyglobil cellulose, water-soluble film forming agents such as polyvinyl alcohol, polyethylene glycol, ethylene glycol, lJ acetin.

Plasticizers such as various glycerin fatty acid esters.

An alkali metal salt of an acid having an acid dissociation constant a (pKa) of 8 or more at 25 pe C, a coloring agent such as a lichen dye, etc. can be added during or after dispersion.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples.

In the following examples, the terms ``part'' and ``kita'' refer to ``heiyakubu daiji'' and ``jubutsu kata,'' unless they are limited to males, and the various measured values were obtained by the following methods.

1) Dissolve the viscosity sample in an ethanol/water mixed solvent (80/20), adjust the 5% solubility, and measure using a B-type viscometer at a rotor rotation speed of 8 Or, p, m, and 250°C. This is what I did.

2) Minimum film forming temperature (hereinafter abbreviated as M, F, T): 0.294 parts of sodium citrate, 0.017 parts of citric acid, emulsifier (trade name: Twee 780, manufactured by Kao Atlas Co., Ltd.) 0
．． 05 parts, 2% hydroxypropyl methylcellulose (
Product name T O-5R.

Shin-Etsu Jigaku Kogyo Co., Ltd.) water-soluble '/$5 parts, 3 parts of plasticizer (trade name MGK, manufactured by Nikko Chemical Co., Ltd.) and 10 parts of a sample classified into 70 to 16 meshes were mixed with 10 parts of water.
Using a homo mixer (manufactured by Tokushu Kika Kogyo Co., Ltd.) with 6.6 parts, the mixture was dissolved to emulsified and dispersed at very high temperature. Then, the dispersion was filtered through a 70 sieve sieve and the P solution was used to prepare M, F, and T solutions according to a conventional method.

8) Undispersed rate The dispersion dispersed by the method in 2) is passed through a 70 soussieve sieve to ensure that it contains no more than 70 sosocieties. Me,
This value was used to calculate the undispersed rate.

Enteric Coating Test a) '1 Preparation of Refurbishment 1 Microcrystalline cellulose (trade name: Avicel, manufactured by Nokazai Kogyo Co., Ltd.) Disintegrating excipient for direct compression (trade name: Perfiller, manufactured by Freund) (manufactured by Kakashi Co., Ltd.) - 1/1 mixture was directly compressed into tablets with a tablet size of about 200 liters and a diameter of 8 ml.

Next, the tablets were coated with an 8% aqueous solution of TC-5R (7) using an automatic film coating device (FM-1f type, Freund Sankuri Co., Ltd. V) according to a conventional method. It was covered with a film and subjected to a coating test.

b) Preparation of coating liquid The aqueous dispersion obtained by the preparation method of the M, F, T, and minute liquids prepared for measurement in Section 2) and P1 was subjected to a coating test.

C) Coating test Automatic film coating equipment ()・Ecoater mini type, manufactured by Freund Sangyo Co., Ltd.).

The above tablet 0.85 was charged with 4'e, and the coating dispersion was sprayed at a liquid volume of about 52y//min to cover the uncoated tablet with a coating film of about 12%.

During this time, the coating pan is rotating (approximately 32 r
pm) Drying at 80-85°C.

After coating the specified amount, use dry air for 20 minutes.
Dry for a minute. The enteric properties of the obtained coated tablets were evaluated according to the disintegration test method described in the Japanese Pharmacopoeia (10th revision).Reference Example Degree of substitution of carboxymethyl group: 0.48. Solution viscosity characteristics (
Ratio of viscosity at rotor rotation speed 6 and 80) η6/
η,,o=1.050. CMC84 with a horizontal content of 5.6%
, 71 was dispersed in 8\20 of toluene in an autoclave and kept at a temperature of 80 to 40°C with 48% water i...! After adding 71.1 liters of an aqueous solution of sodium chloride, 51.1 F of sodium monoxide flake water was added under force and stirred at 85 to 45°C for 10 minutes to thoroughly form a slurry.

Next, ethyl ethyl tetraethylammonium chloride 841 and 2042 was added and allowed to react at 115±5° C. at 10 degrees. The reaction system is a good slurry from beginning to end.
It was Hara.

The finished IN of the cold thick portion was recovered by distillation, and about 2,002 liters of water was added thereto, and the PL of the system was adjusted to about 1 with 12N (plic acid), and further washed with water to obtain CMEC.The solution viscosity was 84 cps, and the infiltration viscosity was 80. Ocps * Ethoxyl group has a chivalry of 2.01. Carboxymethyl group replacement VO, CMEC of 48 is enshrined.

Example 1 Carboxymethyl group substitution # (hereinafter abbreviated as DS) 048,
Ethoxyl group DS2.01. 50 parts of carboxymethylethyl cellulose (hereinafter abbreviated as CMEC) with a viscosity W of 80.0 cps was dispersed in 606.7 p+ of water (then 25%
864 parts of aqueous ammonia and 1.66 parts of caustic soda were added and completely dissolved at room temperature. After dissolving, raise the temperature to 50°C.
Add 2.5 parts of 0% hydrogen peroxide solution and heat at 50-55°C.
．． Stirred for 5 hours.

Next, after cooling to room temperature and adding 10 parts of soypropyl alcohol, 8.6N sulfuric acid was added until the system temperature reached 3.0 to precipitate the solid content, and then heated to 80°C and heated to 50% at the same temperature. Hold for minutes. Next, it is suction filtered using a Nutsche filter when hot, and thoroughly washed with warm water at 70°C to 80°C to obtain particles with a particle size of 1.
A wet CMEC of ˜2IIII11 with a water content of 50T was obtained.

25 parts of water was added to 050 parts of this wet CME, and the mixture was wet-milled using a ball mill until the average particle size was 80 μm. It was then dried at 70° C. in a double-air dryer. The dry product was obtained as a lump. This lump was crushed into 70 to 16 mesh pieces and was depolymerized into a low viscosity product with a viscosity of 12.6 cρS without any powder.

The M, F, T, of this dispersion in water according to the nitrometric method is below 27°C, the undispersed rate is 0.0%, and the dispersibility and film forming properties are excellent. showed good results.

In addition, when tablets coated with 12% of this product were subjected to a disintegration test according to the 10th revised Japanese Pharmacopoeia according to the coating test method, there was no change in the test with the first liquid, and the disintegration test with the second liquid took 8 to 10 minutes. It was revealed that the product completely disintegrated and became a good water-based enteric coating agent.

Example 2 50 parts of water was added to 50 parts of depolymerized CMEC with a particle size of 1 to 2 and a water content of 50% obtained in Example 1, and mycolloid (
(manufactured by Tokushu Kika Kogyo Co., Ltd.) until the average particle size was 10μ. Then in a 9-air dryer at 70°C.
C of the lumps dried and depolymerized to a viscosity of 12,5 cps.
I got MBC. This material was crushed into 70 to 16 meshes and dispersed in water according to the M, F, T measurement method.
% and showed good results in terms of dispersibility and film-forming properties.

In addition, when a tablet coated with 12% crystal was subjected to a disintegration test according to the Japanese Pharmacopoeia Revised by the Deshi in accordance with the coating test method, there was no change in the test according to Part 1F. 4
．． In a two-liquid test, it was found that Honjima completely disintegrated in 7 to 11 minutes, making it a good water-based enteric coating agent.

Comparative Example 1 The depolymerized CMEC obtained in Example 1 with a particle size of 1 to 2 particles and a moisture content of 50% was dried at 70°C using a ventilation dryer without wet pulverization, and the resulting agglomerates were dried. MF after being crushed and classified into 70 to 16 pieces.

T, MP of the dispersion in water according to the measurement method, T.

The temperature was 70° C. or higher, and the undispersed rate was 18%, indicating that both dispersibility and film-forming properties were insufficient.

Example 3 Carboxymethyl group DS0.42. Ethoxyl group DS2
．． 80 parts of 0MEC with lO, viscosity 18.1 cps
% aqueous methanol solution.

After complete dissolution, methanol was distilled and recovered at normal pressure until the temperature in the system reached 98° C. to precipitate CMEC.

This material was suctioned and filtered using a hot Nunoche, and further 70
Thoroughly wash with warm water of ~80"C and wet CME with a moisture content of 54.
I got a C.

50 parts of water was added to 50 parts of this wet "CMEo" and wet milled using a ball mill until the average particle size was 20μ.Then, it was dried in a dryer at 70°C to obtain a lumpy mass of CMBCf.
:Obtained.

This material was crushed into 70 to 16 mesh pieces, M and F.

T, M of the dispersion dispersed in water according to the measurement method, F,
T.

The temperature was 32°C, the undispersed rate was 0.2%, and the dispersibility and film-forming properties showed good results.

In addition, when a tablet coated with 12% Honjima was subjected to a disintegration test according to the Japanese Pharmacopoeia (Deshi Revised) according to the coating test method, there was no change in the test with the first liquid, and it completely disintegrated in 7 to 9 minutes in the test with the second liquid. It has become clear that Honjima is a good water-based enteric coating agent.

Comparative Example 2 A 0MEC agglomerate treated in the same manner as in Example 8 except that it was dried without wet pulverization in Example 8 was crushed into 70 to 16 mesh pieces and classified, followed by M, F, T, M, F, T, of the dispersion liquid dispersed in water according to the measurement method.
The temperature was 70° C. or higher, and the undispersed rate was 27%, indicating that both dispersibility and film-forming properties were insufficient.

Example 4 50 parts of water was added to 50 parts of depolymerized 0MEC with a water content of 50% from the gourd with a particle size of 1 to 2 obtained in Example 1.

Wet pulverization was performed using a vibrating mill (manufactured by Chuo Jikoki Shoji Co., Ltd., model B-1) until the average particle size was 4.0 μm. Thereafter, the mixture was heated to 80° C. and filtered under suction using a hot Nutsche filter to obtain a 0MEC cake with a solid content of 58%.

This material was dried in a ventilation dryer at 70"C to a viscosity of 12.
Massive CMEC depolymerized to 4 cps was obtained.

Crush this into 70 to 16 meshes, M, F, T
.

M, F, T, of the dispersion liquid dispersed in water according to the measurement method.
is below 27°C, and the amount of undispersed matter is 0.0%, indicating good dispersibility.

Good results were shown in both film-forming properties and film-forming properties.

Also, the coating wk is #19. When the tablets coated with pepper were tested using the Japanese Pharmacopoeia of Deshi Kosei, there was no change in the test using the first liquid, and when the test using the 2vP test, they completely disintegrated in 8 to 12 minutes, indicating that Honjima is a good water-based enteric coating agent. It became clear that this would happen.

Example 5 Carboxyethyl group DS 0.50. Ethoxyl group DS
1.81. 30% using carboxyethyl ethyl cellulose (hereinafter abbreviated as CEEC) 50s with a viscosity of 68 cps
The depolymerization treatment was carried out in the same manner as in Example 1 except that the hydrogen peroxide solution was changed to 5 parts. Next, the process was carried out in the same manner as in Example 1 except that 5 parts of isopropyl alcohol was added to obtain wet CEEC having a grain size of about 0.5 to 1 and a water content of 52%.

Add 50 parts of water to 50 parts of this wet CEEC, and use Mycolloider (manufactured by Tokushu Kika Kogyo Co., Ltd.) to obtain an average particle size l
Wet grinding was carried out until it became Oμ. Then, using a spray dryer (manufactured by Okawara Kakoki Co., Ltd.), hot air was heated at a temperature of 150°C.
and dried to obtain a granular product.

The viscosity of the obtained granular C'DEC is 1B, 7 cps.
MF, T
, M, F of the dispersion dispersed in water according to the measurement method.

T was 27° C. or less, and the undispersed matter was 0.0, indicating good dispersibility and film-forming properties.

In addition, according to the coating test method, tablets coated with 12% of this product were subjected to a disintegration test according to the Japanese Pharmacopoeia Revised by Deshi, and there was no change in the test with the first liquid, but it completely disintegrated in 10 to 12 minutes in the test with the second liquid. It became clear that this product was a good water-based coating agent.

Example 6 M
The same procedure as in Example 1 was repeated except that the polymerization step was omitted and the amount of isopropyl alcohol added was changed to 5 parts to obtain wet hydroxypropyl methyl cellulose phthalate having a particle size of 2 to 8 particles and a water content of 48%.

50 parts of water was added to 50 parts of this wet hydroxyglobil methylcellulose phthalate and wet milled using a ball mill until the average particle size was 80 μm.

Thereafter, it was dried in the same manner as in Example 1 using a 2-air dryer to obtain a dried block. (Viscosity 14.1 cps) After crushing this lump into 70 to 16 meshes, MP,
T, M of the dispersion dispersed in water according to the measurement method, F,
T is 88°C, the undispersed rate is about 0.5%, and 2
Good results were shown in terms of dispersibility and film-forming properties.

In addition, according to the coating test method, tablets coated with 12% of this product were subjected to a disintegration test according to the Japanese Pharmacopoeia Revised by Deshi, and there was no change in the test with the first liquid, and the disintegration was completely completed in 8 to 11 minutes in the test with the second liquid. It was revealed that the product disintegrated and became a good aqueous enteric coating.

Patent applicant: Kojin Co., Ltd.

Claims (1)

[Claims] 1. Easy water dispersibility characterized by producing a water-insoluble oxycarboxylic acid star cellulose derivative and separating it into solid and liquid from a water-containing solvent system, which is wet-pulverized without prior drying and then dried. Method for producing oxycarboxylic acid hot cellulose derivative 2 Oxycarboxylic acid type cellulose 0 conductor is carboxyalkyl methyl cellulose or carboxyalkyl methylcellulose
A method for producing an easily water-dispersible carbon/carboxylic acid disk cellulose rust conductor according to claim 1, wherein the conductor is ethyl cellulose. However, alkyl refers to an alkyl having 1 to 5 carbon atoms.