JPH0248521A - Film coating method for drug - Google Patents

Abstract

PURPOSE: To advantageously carry out film coating of a gastric acid resistant agent and to simplify cleaning of an apparatus, by suspending a pigment in a coating solution composed of an aqueous polymer dispersion using a specific film-forming material and dissolving a specific amount of xanthan gum in a next step. CONSTITUTION: An agent is coated with a film through a step for suspending a pigment (e.g. talc or titanium dioxide) in a coating solution constituted of an aqueous polymer dispersion using an aqueous latex dispersion composed of a copolymer of ethyl acrylate, methacrylic acid or ethyl acrylate and methyl methacrylate as a film-forming material and a step for dissolving 0.05-0.5% of xanthan gum based on the total amount in the coating solution. Preferably, a mixture of ethyl acrylate and methacrylic acid in a ratio of 1:1, having about 250,000 (relative) molecular weight is used as the polymer dispersion and 0.1-0.2% of xanthan gum is added based on the total of the coating solution.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention uses an aqueous latex dispersion consisting of a copolymer of ethyl acrylate and methacrylic acid, or a copolymer of ethyl acrylate and methyl methacrylate, as a film-forming material. The present invention relates to a method for film coating a drug using a polymer dispersion.

[Conventional technology]

For about ten years now, film coating methods have been increasingly used to replace the classic sugar-based panning method of coating tablets.

Currently, the use of aqueous coating fluids for film coating is considered state of the art.

This method has advantages in terms of productivity, energy utilization, environmental and health protection compared to earlier traditional sugar-based or solvent-based film coating methods.
This can be said to be more preferable.

For aqueous film coating processes, two types of equipment are used to apply the film-forming material:

(1) A film-forming material that dissolves in colloidal form in water;
Among these, coating systems made of various cellulose ethers (eg, hydroxypropylcellulose or hydroxypropylmethylcellulose), polyvinyl alcohol, polyvinylpyrrolidone and its copolymers, polyoxyethylene, and analogs are used.

(2) A coating system consisting of a water-insoluble polymer is used. In this case, the polymer is used in the form of an aqueous latex dispersion.

The aqueous latex polymer dispersion has a size I
It is an emulsion consisting of a shell-forming polymer in the form of ultramicroscopic ellipsoidal latex particles. During film coating, when the water is evaporated, these particles coalesce with each other to form a continuous film.

The aqueous latex dispersion may contain, for example, vinyl acetate monomer,
Using acrylic acid monomer or methacrylic acid monomer,
Prepared by emulsion polymerization.

In addition to so-called true latex dispersions, pseudo-latex dispersions have recently also been used. It is prepared by subsequent dispersion of a polymeric material such as ethylcellulose, cellulose acetate phthalate, or hydroxypropylmethylcellulose phthalate.

If the film-forming material is colloidally dissolved in water, the technical realization of film coating is simpler compared to aqueous latex polymer dispersions. The reason is that the latex polymer particles of the latter dispersion are very prone to flocculation and therefore the coating liquid undergoes irreversible changes.

This is because the polymer precipitates out of the system under the influence of vigorous agitation, pH changes, pigment addition, or temperature changes.

From a practical point of view, condensation of the coating liquid during agitation is a problem because when using conventional coating techniques, the agitation cannot be stopped because the flocculation causes sedimentation of the pigments suspended in the coating liquid. , which raises fundamental questions.

Due to these problems, it is quite difficult to widely implement film coating methods using aqueous latex polymer dispersions. However, the demand for this method is only increasing.

Thus, only water-soluble film coats can of course be prepared by using film-forming materials that are colloidally dissolved in water.

However, in the preparation of an ever-increasing number of sustained-release drugs and gastric acid-resistant drugs, film coating methods using organic solvents are currently predominant.

Film coating methods that require organic solvents are considered hazardous today due to the risk of fire, explosion, health hazards, and environmental pollution.

In view of the above-mentioned problems, it is possible to prepare water-insoluble film coats with certain safety, avoid changes in the composition of the coating liquid due to sedimentation and separation of pigments during coating, and furthermore reduce the cleaning of the equipment. There continues to be a need for film coatings that can reduce the amount of water used, while also eliminating nozzle clogging.

Among the aqueous latex polymer emulsions used for film coating, products prepared by emulsion polymerization using acrylic and methacrylic acid monomers (sold under the trademark Eudragit) are , the most widely used.

Depending on the composition and solubility of the monomers, these polymers include the following.

Monomer Abbreviation: Methacrylic acid MAS Methyl methacrylate MMA Ethyl acrylate
The trade name, composition, and solubility of the EA trimethylammonium ethyl methacrylate chloride TAM latex copolymer dispersion are shown below.

Eudragit L 300 Poly (MAA-E
A) Eudragit soluble at pH 5.5 or higher
EN 30D poly(EA-MMA) insoluble,
Hydrophobic Eudragit R5300 Poly(EA-MM
A-TAM) Insoluble, poorly permeable Eudragit R
L 300 Poly(EA-MMS-TAM) Insoluble, easily permeable A number of technical reports on film coating with the above dispersions have been published by Roehm, West Germany.
Pharma GmbH (Roehm Pharn)
+aGmbH), but none of the problems mentioned above regarding latex polymer dispersions are completely solved.

In this technical process, polyoxyethylene, polyvinylpyrrolidone or hydroxypropylmethylcellulose are used to suppress the settling and separation of pigments
Acta Phar+s, Technol, ) 32.1
Page 46 (1936); [Practice of lacquer-Pan
ning) J, Seam 1 Pharma GmbH (
Published by Wistelstadt, West Germany, pages 64-74 (1983)].

The coach ink solution containing the pigment described in the above-mentioned publication must be constantly stirred during the coating process, but vigorous stirring is not possible.

This agitation prevents the sedimentation and separation of the turbid pigment in the bottle containing the coating liquid.
It is not possible to stabilize the coating liquid to 1@ turbidity within the length of several meters.

This causes the pigment to settle in the pipeline or at the nozzle, clogging the atomization orifice and making cleaning the equipment more difficult.

Because of this pigment deposit, the mill must be cleaned frequently after each production batch.

The reason for this is that particles that accumulate on the feed pump and then reach the orifice of the nozzle and stick therein cause a clogging phenomenon when starting the next coating.

The above observation is one of the recently published literature.

Practical course of lacquer coating (Pra(:ti)
calCourse in Lacquer Coat
ing) J page 144 (1986), the following observation is made.

This means that if pigments or other solid materials are suspended in the lacquer dispersion to suppress settling separation, the coating liquid must be constantly stirred during coating. This has since been reported on the use of film coatings and has also been confirmed by the experience of Lehm Pharma GmbH.

For the same reason, the pipeline leading to the nozzle should be as short as possible.

[Problem to be solved by the invention]

Hitherto, the above-mentioned 1jtJ problems in coating with aqueous pigment dispersions have not been solved.

The aim of the invention is to develop a film coating method. More specifically, it is the sedimentation separation of the pigments dispersed in the coating liquid.

It can also be suppressed by using an aqueous latex polymer dispersion for film formation, which allows the composition of the coating solution to remain unchanged during the coating process, eliminates the clogging phenomenon of the pulverizer, and makes it easier to clean the equipment. An object of the present invention is to provide a film coating method using a coating liquid that can further simplify the process.

[Means to solve the problem]

While conducting research to increase the stability of pigment suspensions prepared using aqueous polymer dispersions, copolymers of ethyl acrylate and methacrylic acid or ethyl acrylate and methyl methacrylate (trademarked under Eudragit) were used. In contrast, the stability of pigment suspensions containing
It has been found that the inclusion of 0.05-0.5%, preferably 0.1-0.2% xanthan gum is completely ensured.

Due to the above facts, the present invention provides an aqueous latex dispersion formed by using an aqueous latex dispersion comprising a copolymer of ethyl acrylate and methacrylic acid or a copolymer of ethyl acrylate and methyl methacrylate as a film-forming material. This invention relates to a method for coating a drug with a film.

The method comprises the steps of suspending a pigment, preferably talc, titanium dioxide, particularly preferably a metal-free organic pigment, in a coating liquid consisting of an aqueous polymer dispersion; 0.05~ of weight
and dissolving 0.5% xanthancam.

Xanthan gum is a natural polysaccharide produced by Xanthomonas campestris. Similar to cellulose, the backbone structure of xanthan gum is composed of β-1,4-glucan, whose side chains have mannose acetate, mannose, and glucuronic acid. What is the average molecular weight of xanthan gum?

Millions of daltons.

Xanthan gum is used in the pharmaceutical industry as a carrier for sustained release tablets and to increase the stability of pharmaceutical suspensions. Therefore, the use of xanthan gum ensures the stability of suspensions consisting of aqueous latex polymer dispersions, which is in contrast to other suspension stabilizers used in the pharmaceutical industry, such as polyvinylpyrrolidone. , hydroxypropyl methylcellulose, or polyoxyethylene).

Those skilled in the art are aware that the stability of suspensions is influenced by complex interactions between the dispersed particles and the dispersion medium (surface tension, adsorption, interfacial charge, etc.) . Therefore, the stability of the dispersion cannot be predicted.

This is especially true when the suspension contains both solid particles and highly agglomerated Latinx polymer particles. Therefore, when preparing a stable suspended FA solution, it is necessary to find the optimal stabilizer depending on each case.

The above fact is supported by our experience that xanthan gum cannot be used for the suspension stability of any aqueous Eudragit dispersion.

Our h31? According to N.
Preference is given to the use in the case of aqueous EudraHit EN 30D dispersions consisting of polymers. However, xanthan gum causes copolymer coagulation.

Therefore, in addition to ethyl acrylate and methyl methacrylate rl-Jat, aqueous Eudragit containing 2.5% by weight or 5% by weight of trimethylammonium ethyl methacrylate chloride monomer, respectively.
R3300 dispersion, and Eudragit RL 3
(lf) In the case of dispersions, xanthan gum cannot be used to increase suspension stability.

According to a preferred embodiment of the process according to the invention, a 1:1 mixture of ethyl acrylate and methacrylic acid, a copolymer with a (relative) molecular weight of about 250,000, is used as the polymer dispersion and the coating 0.1 to 0.0 of the total weight of the liquid.
Adding 2% xanthan gum.

According to another preferred embodiment of the process according to the invention, ethyl acrylate monomer and methyl methacrylate monomer
An aqueous latex dispersion consisting of a copolymer having a ratio of 1:1 to 1:1.5 and a (relative) molecular weight of about 800,000 is used as the aqueous polymer dispersion, and 0.0. Adding 1-0.2% xanthan gum.

Add xanthan gum as follows.

The xanthan gum is dissolved in water, the pigment is suspended in the resulting colloidal solution, and finally this pigment suspension is mixed with the latex dispersion of the copolymer.

The stability of the coating suspension prepared as described above is very good and even after standing for 24 hours, ti
Sedimentation separation of i material is hardly observed.

During coating, therefore, stirring of the coating suspension obtained is unnecessary and, moreover, no pigment deposition occurs in the pipeline of the coating apparatus.

Therefore, the stable coating suspension prepared according to the invention does not cause problems when coating films with latex dispersions of aqueous acrylic acid/methacrylic acid copolymers.

The nozzles do not become clogged, and there is no need for troublesome cleaning in continuous batch mills when producing the same product.

Not stirring the coating suspension improves the stability of the latex copolymer dispersion against coagulation. When coating with acrylic acid/methacrylic acid copolymer dispersions, it is therefore not necessary to readjust the mill pipeline by means of additional technical operations in order to minimize the length.

Preventing pigment deposition improves the color consistency of various manufacturing batches.

Since the amount of xanthan gum required to ensure the stability of the suspension is extremely small compared to the amount of polymeric material used to form the coating, the permeability and solubility of the resulting coating remain unchanged. .

Therefore, when preparing gastric acid-resistant drugs or sustained-release drugs, there is no need to thicken the film coat. however.

If relatively large amounts of water-soluble suspension aid materials (eg, polyvinylpyrrolidone or hydroxypropyl methylcellulose) are used, relatively thick film coats are required.

〔Example〕

Hereinafter, the present invention will be explained in detail based on preferred embodiments.

However, these Examples do not limit the present invention.

Example 1 Comparison of Suspension Stability of Coating Liquids 10 g of talc, which had been micronized to ZOam or less particles (measured by a microscope) using a Fryma J80 air jet mill, was mixed with Ultra Teurax (Ult
raTurrrax) MG45 type homogenizing device to suspend in each of the following solutions.

(1) 90ml of ion-exchanged water ('2) 0 xanthan gum in 90ml of ion-exchanged water
．． (3) A solution containing 1.0 g of polyoxyethylene 6000 in 90 ml of ion-exchanged water (4) A solution containing 25 in 1.0 g of polyvinylpyrrolidone in 90 ml of ion-exchanged water (5) A liquid Eud containing 1.0 g of Avicel RC981 in 90ff11 of ion-exchanged water.
Add 50 ml of ragit L 30D dispersion to each of the above suspensions and stir it for 10 minutes using a laboratory stirrer at 60 rp+s before pouring into a graduated cylinder.

While it is allowed to stand, observe the height of the talc layer that settles to the bottom of the graduated cylinder.

The results are summarized in the following table.

(Left below) (time) (1) (2) (3)
(4) (5)1 35an Om
m 30mm 30mm 2
0nn2 34m+++ Oom 2
8mm 28nn 20nwn3 3
0mm O-0-25n 251111
2011111124 30mm 2m
m 25g+ 25ffn 20+m
+ As is clear from the measurement data, in contrast to sample (2) containing 0.1% xanthan gum, the stability of the talc-based suspension is significantly lower in film coating with an aqueous IEudragit dispersion or in pharmaceutical The ability to stabilize suspensions cannot be achieved with conventionally used suspension stabilizers [polyoxyethylene, polyvinylpyrrolidone, Avicel RC581 (sodium carboxymethyl cellulose attached to microcrystalline cellulose)]. .

A low value after 1 hour signifies a shrinkage phenomenon of the suspension, which makes it difficult to push the sediment out of the pipeline of the coating device.

Sharp! fp9 2 Film coating using a coating solution containing xanthan gum or polyvinyl pyrochloride A. After attaching a Wurstar 6" film coating device to a Glatt WSGS flow device, 1 kg of biconvex tablets with a diameter of 6 rm were coated. The weight of each tablet is 80 cm, and each tablet contains cetastine as the active ingredient. Mix 1 g of xanthan gum with 175 ml of ion-exchanged water, and mix the mixed solution with 1 g of xanthan gum. , to swell or dissolve, 2
Leave it for 4 hours.

11) Transfer the solution obtained in (I) to a bottle of an experimental homogenizing device (Model: 302), add 19 g of talc micronized as described in Experimental Example 1, and 35% aqueous dimethylpolymer. After adding 8 g of siloxane dispersion,
The mixture is homogenized by stirring at 000 rpm.

■) 201g of aqueous Eudragit L 30D dispersion
was added to the S suspension obtained in (■), and the mixture was filled with ion-exchanged water to make 450 g. suspension,
Stir at 60 rpm using a laboratory stirrer and then use without stirring for coating.

(B) Polyvinylpyrrolidone (Kollidon) containing polyvinylpyrrolidone (Kollidon) as a suspension stabilizer in place of 5% Corchine xanthan gum
) A coating liquid is prepared as described in (A) except that 5 g is used.

Film coating is performed based on the following conditions.

Incoming air temperature: 80°C Coating liquid feed stream 1: 15 m1/min Atomized air pressure 1.5 bar Coating time:
30 minutes actual *Observation (A) Toyosuke of coating liquid containing xanthan gum (method according to the present invention) There was no precipitation of talc from the coating liquid even without stirring during the coating process.

There were no solid deposits in the pipeline during the coating process. The pipeline was cleaned simply by washing it with water.

There were no solid deposits on the nozzle. The nozzle was cleaned just by rinsing it with water.

Resistance of coated granules to stomach acid.

As a result of an investigation based on the regulations of the United States Pharmacopoeia (USP) XXI (dissolution test conducted at 37'C for 2 hours in a buffer solution of ρ old, 2), no dissolution of the active ingredient was observed. B) Examination of coating sputum containing polyvinylpyrrolidone (standard example) Despite continuous stirring (experimental stirrer, 60 rpm), during the coating process, the coating liquid contained
A deposited layer of 2-3ffI11 of talc formed towards the bottom of the container.

During the coating process, approximately 1/4 of the pipe cross-section has sediment that can only be removed by mechanical cleaning.
It was piled up.

Since the coating time was relatively short, 30 minutes, there was no clogging of the nozzle, but the talc sediment attached to the nozzle could not be removed without disassembling the entire nozzle.

The resistance of the coated granules to stomach acid is determined by USP
As a result of the investigation based on the provisions of XI, it was found that artificial gastric fluid (pH 1
The amount of the active ingredient eluted into the buffer solution (2) was 5-8% in 2 hours. This can be explained by the reduced impermeability of the coating to water due to the relatively large amount of polyvinylpyrrolidone used.

6.0 kg of biconvex tablets with a diameter of 8 mm are weighed and placed into a Blatt GC type apparatus with a kettle jacket between the holes. Each tablet weighs 200 square meters and contains pancreatin as the active ingredient.

Prepare the coating liquid as follows.

(A) Coating of xanthan gum 4.2 g of xanthan gum is mixed with 1100 g of ion-exchanged water, left to swell for 2 hours, and then 108 g of talc and 22 g of titanium dioxide are added. The suspension is stirred for 10 minutes with a laboratory stirrer and then homogenized twice using a Fryma MZ80 colloid mill fitted with a geared disc.

■) Fabric softener Citroflex 2 (Citrofl
ex) (diethyl citrate) 65.0g, Eudr
After addition to the dispersion of agit LaO2, the mixture is stirred for 2 hours at 60 rpm in a laboratory stirrer.

III) 26.0 g of a 23% aqueous antifoam silicone emulsion of type SEZ are diluted with 50.0 ml of water.

Pour the above three mixtures into a 4 liter container.
Stir for 15 minutes using a laboratory stirrer.

(B) The method described in (A) except that xanthan gum is not added to the suspension of coachine 1 (1) that does not contain xanthan gum, and talc and titanium dioxide are suspended only in ion-exchanged water. Prepare the coating liquid according to the procedure.

Film coating is carried out under the following conditions.

Kettle rotation speed: 15-18/win Supply flow rate: 14
Resistance/mjn Micronization pressure = 2.8 bar Temperature of incoming air: 50°C Temperature of particle bed: 42°C Coating time = 2.5 hours! LfL (Example according to the invention) During the 2.5 hour coating time, without continuing to stir the coating liquid during the coating process.
No solids were deposited in the container.

No solids were deposited in the pipeline during the coating process. The pipeline was cleaned by washing with water at the end of the coating.

No solid matter adhered to the nozzle. The nozzle was cleaned by washing with water.

Resistance of coated granules to stomach acid is USP X
Conforms to the provisions of XI.

(B) In the case of a coating liquid that does not contain xanthan gum (standard example) Despite continuous stirring at 1100 rpm using an experimental stirrer, a thickness of 3 to 4 ni was obtained from the coating liquid.
A layer of n solids formed on the bottom edge of the container.

During the coating process, the pipeline has deposits that can only be removed by mechanical cleaning, at approximately 17 mm in cross-section.
3 deposited.

After about 100 minutes of work, the nozzle became clogged, and it was impossible to clean it without disassembling the whole thing. At the end of the coating process (ie, after an additional 50 minutes of micronization), a significant amount of solids was also observed deposited on the nozzle.

Resistance of coated granules to stomach acid is USP X
It meets the requirements of XI.

The coating power of the coating was weakened by the titanium dioxide and talc deposited in the coating equipment pipeline. Regarding the color of the coating, the color of the film-coated tablet prepared using the coating liquid containing xanthan gum was not white.

Basis - Value - The xanthan gum used in the coating solution ensures the cloud stability of the pigment suspended in the coating solution.

The implementation of the coating is therefore considerably simpler, the composition of the coating liquid remains unchanged (no solids are deposited) and, moreover, the resistance of the coating to gastric acid is not adversely affected.

Claims (5)

[Claims] (1) A method of film coating a drug with an aqueous polymer dispersion using an aqueous latex dispersion consisting of a copolymer of ethyl acrylate and methacrylic acid or a copolymer of ethyl acrylate and methyl methacrylate as a film-forming material. suspending the pigment in a coating liquid consisting of an aqueous polymer dispersion;
% of xanthan gum. (2) The film coating method according to claim (1), wherein the pigment is talc or titanium dioxide. (3) The film coating method according to claim (1), wherein the pigment is a metal-free organic pigment. (4) As an aqueous polymer dispersion, a 1:1 mixture of ethyl acrylate and methacrylic acid with a (relative) molecular weight of approximately 2
50,000 copolymer and adding xanthan gum in an amount of 0.1 to 0.2% of the total weight of the coating liquid. (5) As an aqueous polymer dispersion, 1.5:1 to 1:1 of ethyl acrylate monomer and methyl methacrylate monomer
．． 5, with a (relative) molecular weight of approximately 800,000, and the addition of 0.1 to 0.2% of xanthan gum based on the total weight of the coating liquid. The film coating method according to item (1).