JPS61176536A - Coated dosage form - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The coating of physiologically active substances with polymeric substances is well known. The formulation of a suitable coating material is centered on obtaining adequate release properties of the final dosage form while minimizing the handling problems normally associated with coated products. .

It has been discovered that unique combinations containing water-dispersible polymers and water-insoluble fillers can be used in coating formulations for physiologically active substances such as drugs.

In a preferred embodiment, the inherent tackiness of the polymer is reduced and the desired sustained release properties are achieved when dry.
A suspension of kaolin in water is combined with a copolymer of poly(meth)acrylic esters, such as 1-Eudra
git) Combine with E 30 D''.

The present invention has several advantages over prior art dosage forms and methods of making them.

First, during processing, the tackiness of the coating material is reduced, resulting in fewer problems and shorter processing and handling times.

Second, the inorganic fillers present in the formulations of the invention increase the water permeability of the coated dosage form in direct proportion to the presence of fillers in the coated formulation. That is, the greater the concentration of kaolin or other suitable filler, the greater the permeability of the coating after the dosage form has been ingested. This proportion makes it possible to adjust the release properties of the dosage form to some extent.

Additionally, the need for one or more hydrophilic film-forming agents such as hydropropyl methylcellulose is eliminated. Removal of these additives saves time and energy.

Substantial energy and time savings are achieved since the fillers used do not have to be treated, for example by milling or contact with processing aids, prior to inclusion in the coating formulation. Untreated kaolin is highly suitable as a filler because it is generally available as available and requires milling only if the particles cannot be substantially uniformly dispersed.

Other aspects and advantages of the invention will become apparent from the accompanying drawings and the description below.

The present invention is directed to unique combinations of water-dispersible polymers and water-insoluble fillers that when combined in appropriate amounts provide the benefits described herein.

The polymeric substrate upon which the polymer/filler combination of the present invention is based is a water-dispersible polymer that does not contain ionizable functional groups in its backbone. In other words, the polymers useful in the present invention are neutral so that they are unaffected by the monotonous gradients that prevail in the gastrointestinal tract. That is, about 1 to about 8... has no effect on the polymer of the present invention.

Useful polymers include those sold as aqueous dispersions that have low viscosity and the necessary solubility when applied in pharmaceutical coatings.

Generally, these polymers are emulsion polymerized acrylic resins produced using 1m or more monomeric alkyl esters of acrylic or methacrylic acid.

Preferably, these polymers are emulsion polymerization products (meth)
As an acrylate, the resulting nonapolymer does not contain undesirable ionizable groups.

One suitable polymer is “Eudraji” Il!830D.
1 Eudrazito R30D'' is a neutral aqueous dispersion of acrylic acid resin. Its polymer structure is -CH2
-CRRI- (in the formula, R is -H or -CH3, and R1 is 10(0)OCH3 or -C(0)OC2H)
5) structural unit. It has a viscosity of <500p at 20C as measured on a Brookfield viscometer with an adapter (6r, p-m,) and a
, ooo (DAB ■, 20th
page, subsection 31).

Since the polymer is mixed with the filler of the invention in an aqueous environment, it is generally preferred that the polymer particles have a diameter in the range .alpha.01 to 1.mu. 5ooη=0, a size corresponding to a coagulum content of 5% maximum is preferred.

In some embodiments, 14 or more overcoats are applied to the use form coated with the polymer/filler coating composition. These overcoats contain hydrophilic materials such as one or more of hydroxypropyl methylcellulose, polyethylene glycol, and the like. Fillers and auxiliary binders can be used.

The fillers used in the polymeric coatings of the present invention are generally inorganic, water-insoluble materials.

Generally, these are FDA-approved inorganic materials that have suitable compatibility with the aqueous polymer dispersions used. Suitable fillers are kaolin, talc and titanium dioxide.

Kaolin is highly suitable. Mixtures may also be used.

Although the particle size of the filler is not critical, it is generally preferred to be between about 20 microns and about 0.001 microns for ease of handling. These particle sizes allow for effective suspension of the filler particles in water or a water-miscible diluent prior to mixing with the polymeric components.

Milling or other processing of fillers is usually not necessary.

However, if packaging or storage of the filler causes agglomeration of the filler particles, the particles should be minimized in the presence or absence of an aqueous or other suitable medium for final mixing of the polymer and filler components. It is advantageous to have a mill ring.

We do not intend to be bound by any particular theory of filler action. However, fillers appear to act as processing enhancers and permeability modifiers in coatings due to their limited water swellability and bulk. After the coating dries, the filler particles dispersed in the coating or film assist in the formation of pores or channels at the particle-polymer interface. These pores or grooves function as openings through which body fluids can leach out small amounts of coated drugs or other physiologically active substances.

The polymer coatings of the present invention contain, on a dry basis, about 5-95% by weight polymer, preferably about 15-75% by weight, and about 5-80% filler, preferably about 10-60% by weight. do. If an aqueous diluent is present, it generally consists of the remainder of the coating.

Warming agents, solvents, colorants, etc. are not required ingredients, but they can be used if desired. for example,·
Additional amounts of titanium dioxide may be used to improve the color of the final product.

However, it is generally necessary that only aqueous diluents, polymers and fillers be present in the coatings of the present invention.

Physiologically active substrates as materials coated according to the invention include a wide variety of materials of 1 m or more. Although drugs are preferred, these may also be vitamins, placebos, etc. Mixtures of such substances may also be used. When the active ingredient of the final product is a drug, it is generally a solid substance that has sufficient affinity for gastrointestinal fluids to be absorbed by the body when it comes into contact with gastrointestinal fluids. Suitable agents include anti-infectives, phenols and their derivatives, sulfonamides, sulfones,
surfactants, chelating agents, antimalarial agents, antibiotics, central nervous system depressants, stimulants, adrenergic agents, cholinergic agents, autonomic neuroleptics, diuretics, cardiovascular agents, local anesthetics, histamines and antihistamines, analgesics, antitussives, steroids, carbohydrates, amino acids, proteins, enzymes,
Includes hormones, antiemetics, cognitive activators, etc. One preferred group of drugs is pseudoephedrine and theophylline. Mixtures of drugs can also be used.

The active ingredients of the dosage forms of the invention generally comprise from about 0 to 95%, preferably from about 5 to 90%, by weight of the total composition on a dry weight basis, depending on the dosage of the drug.

The coatings of the present invention can be used to coat a wide variety of solid substrates.

Although the core is the preferred substrate for the active agent, other forms can also be used.

Tablets, capsules, powders, granules and other forms containing physiologically active ingredients can also be used.

The presence of carriers and other conventional ingredients in the active ingredient of the drug is permissible. However, care must be taken to exclude degradable, water-soluble and/or volatile components from substrates and coatings. Such exclusions help ensure a long shelf life of the final product.

Suitable equipment for coating the active substrate includes coating pans, fluidized bed equipment, and the like. Generally, any equipment suitable for applying water-based coating formulations to solid substrates can be used.

An example is a let formulation. Non-barrel seeds consisting of sugar and starch are placed in a pre-warmed chamber of a centrifugal granulator. The mesh-treated powders of diphenhydramine hydrochloride, sinidoephedrine HCA, and theophylline are fed at appropriate rates while at the same time the binder solution of hydroxypropyl cellulose is spread over the seeds. Once the pellets are formed, they are dried in an oven at 45° C. for 24 hours. Select a fraction of 12-18 meshes and transfer to a plastic bag.

Coating Process Diphenhydramine hydrochloride, pseudoephedrine and theophylline pellets are coated with a mixture of kaolin and Eudrazito E30D dispersion. The production of the coating formulation consists of forming a suspension of untreated kaolin using a magnetic stirrer and then intimately mixing this suspension with the desired amount of polymer dispersion. (30 C1 by weight) is first gradually coated with the coating formulation described in Table 1 in a fluidized bed apparatus at a rate of about to-per minute until the weight increases by about 3 hours. The coating is left indoors and dried for 30 minutes using flowing air.

Coating is then started again at a more rapid rate. The formulation is stirred during this coating operation. Transfer the coated Kubo Red to a paper plate and dry under air. Kaolin was used as received, but can be ball milled if necessary. Ooid 2sito■E30
D is filtered through a fine sieve (B20 mesh) before use to remove solids or film particles.

Dissolution In vitro dissolution studies were performed using a vsp dissolution apparatus at 37C and 75 rpm. The dissolution medium is water,
Mimics (without enzymes) gastric and/or intestinal fluids. At preselected time intervals, samples are removed and the dissolution medium is automatically replaced. Released drug testing was performed spectrophotometrically at 258 nm.

Table 1 Theophylline 200 60 540 cases
1 Diphenhydramine hydrochloride pellets prepared as described above with a final coating weight of 20% by weight were compared to overcoated diphenhydramine hydrochloride pellets for release rate.

Overcoated pellets were produced by additionally coating a single layer coated pellet with an overcoat formulation. The overcoat contains hydroxypropyl methyl cellulose and 2% by weight
applied to give a final coating weight of .

The results of the release study conducted by the dissolution procedure described above were
As shown in Table n.

Kn table 0.5 4
3 As these examples and the accompanying figures demonstrate, the rate of drug release from the dosage form is directly proportional to the kaolin to polymer ratio in the final film or coating. Figure 2 shows
Changes in kaolin/resin ratio versus release rate are shown.

Optimally, a second coating or overcoat can be applied to minimize handling problems. For example, the soft lumps often observed when storing coated pellets at room temperature are eliminated by applying a water-soluble overcoat. An overcoat of less than 2 weight hydroxypropyl methylcellulose does not affect the rate or extent of drug release in any way.

The release rate of dosage forms made using the coatings of the present invention depends on the filler concentration (see Figure 4),
The thickness and coating level can be adjusted by varying parameters such as thickness (see Figure 3). For example, the amount of kaolin or other filler in the coating formulation can be increased to the point where film integrity is lost and direct drug release occurs.

Similarly, coating layers of negligible thickness may not pose an obstacle to release. Generally, a coating thickness corresponding to a total coating/active ingredient (eg, coating/drug) ratio of about 2 to 98 inches is desired. Preferably, coating/drug ratios ranging from 10 to 90 are used, depending on the dosage and physicochemical properties of the drug.

Reasonable modifications made by those skilled in the art do not depart from the scope of the invention.

[Brief explanation of the drawing]

FIG. 1 shows the release curves (obtained by plotting the cumulative release vs. time) for pseudoephedrine or hydrochloride in each of the dissolution media described above. Figures 2-6 are obtained using each of the coatings, coating levels and dissolution media described above. ◆ Figure in water, 2 hours (hrs, 1) Release curve of theophylline in water %B and o22% coating ■ 3.1. ◇3.2.
, 09%, 9% (two dissolution media) time (hrs
,) in? fl revenge r: N7Ln and Dohumin's release song green (2-
WIH'noQFig, 6 FT5 (hrs,
1◇Pseudo-social masturbation

Claims (1)

[Scope of Claims] 1) A water-dispersible poly(meth)acrylic acid ester polymer essentially containing (a) no ionizable functional groups, (
A coating composition for sustained release dosage forms consisting of b) a water-insoluble filler and (c) water. 2) about 2-30% by weight of (a) above; about 2-30% by weight;
The coating composition according to item 1 above, comprising (b) above and residual water (remainder). 3) The coating composition of clause 2, wherein (b) is selected from the group consisting of kaolin, talc, titanium dioxide and mixtures thereof. 4) The coating composition according to item 2 above, wherein (b) is kaolin. 5) A dosage form coated with the composition of item 1 above. 6) A dosage form coated with the composition according to item 3 above. 7) A dosage form coated with the composition of item 4 above. 8) Reducing the stickiness of aqueous polymeric compositions when applied to solid dosage forms comprising the use of a water-dispersible (meth)acrylate ester polymer as the only polymeric component in the composition. Method. 9) The method of claim 8, wherein the composition also contains a water-insoluble filler selected from the group consisting of kaolin, talc, titanium dioxide and mixtures thereof. 10) Water permeability of a coated dosage form consisting of using a water-dispersible polymeric (meth)acrylate ester polymer that does not contain ionizable functional groups as the only polymeric component of the coating composition. How to increase. 11) The method of claim 10, wherein the composition also contains a water-insoluble filler selected from the group consisting of kaolin, talc, titanium dioxide, and mixtures thereof. 12) A method of reducing the numerous handling problems associated with applying a polymer coating to a dosage form comprising applying an overcoat containing a water-soluble hydrophilic polymer. 13) The method according to item 12, wherein the hydrophilic polymer is selected from the group consisting of hydroxypropylmethylcellulose, polyethylene glycol, and mixtures thereof.