GB2170210A - Coating composition for dosage forms - Google Patents

Abstract

The coating of dosage forms with aqueous polymeric compositions containing specified polymers and water-insoluble fillers results in reduced tackiness and sustained release in the body. The polymers are of esters of acrylic acid or methacrylic acid and contain no ionizable functional groups.

Description

SPECIFICATION Coating compositions for dosage forms This invention relates to coating compositions for sustained release dosage forms.

The coating of physiologically-active substances with polymeric materials is well-known. The formulation of suitable coating materials has centered on obtaining suitable release properties for the final dosage form while minimizing the handling problems generally associated with coated products.

According to one aspect of the present invention, there is provided a coating composition, suitable for coating sustained release dosage forms, which composition comprises or consists essentially of: (a) a water-dispersible polymer of an ester of acrylic acid or methacrylic acid, which polymer contains no ionizable functional groups; (b) a water-insoluble filler; and (c) water.

The present invention resides in the discovery that unique combinations containing a waterdispersible polymer and water-insoluble fillers can be employed effectively in coating formulations for physiologically-active substances, e.g. drugs.

In a preferred embodiment of the foregoing aspect of the present invention, a suspension of kaolin in water is combined with an aqueous dispersion of a copolymer of poly(meth) acrylic esters, e.g. that known as "Eudragit E 30 D", to produce a coating which reduces the inherent tackiness of the polymer and which, once dried, yields a coated dosage form having desirable sustained release properties.

The present invention also provides dosage forms coated with a coating composition in accordance with the first-mentioned aspect.

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

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

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

In addition, the need for one or more hydrophilic film-formers, e.g. hydroxypropylmethyl cellulose, is obviated, although such film-formers can nonetheless be used if desired. The elimination of these additives results in time and energy savings.

Since the fillers used in the coating compositions of the present invention need not be treated, e.g. by milling or contracting with processing aids, prior to their inclusion in the coatings, substantial energy and time saving may be achieved. Untreated kaolin is highly preferred as a filler since it can generally be used as received, needing milling only if the particles cannot be substantially uniformly dispersed.

Another aspect of the present invention provides a process for reducing the tackiness of an aqueous polymeric conmposition when applied to solid dosage forms, which comprise employing in that composition as the sole polymeric component, a water-dispersible polymer of an ester of acrylic acid or methacrylic acid.

A further aspect of the present invention provides a process for increasing the water-permeability of a coated dosage form, which comprises employing, as the sole polymeric component of the coating composition, a water-dispersible polymer of an ester of acrylic acid or methacrylic acid, which polymer contains no ionizable functional groups.

A yet further aspect of the present invention provides a process for decreasing the number of handling problems associated with applying a polymeric coating to a dosage form, comprising applying to the coated dosage form an overcoat containing a water-soluble hydrophilic polymer.

The polymeric matrices on which the polymer/filler combinations of the first aspect of the present invention are based are water-dispersible polymers containing no ionizable functional groups in their backbones. In other words, the polymers useful herein are neutral so that they are not affected by the pH gradient which prevails in the gastrointestinal tract. Thus, a pH of from 1 to 8 will not affect these polymers.

Useful polymers include those sold as aqueous dispersions having low viscosity and the requisite soiubility when applied in pharmaceutical coatings. Generally, they are emulsion polymerized acrylic resins produced using one or more monomeric alkyl esters of acrylic or methacrylic acids. Preferably, they are emulsion polymerization products of (meth)acrylates, the resultant polymers containing no undesirable ionizable groups.

One preferred polymer is commercially available as "Eudragit E 30 D." This product is available from Rohn Pharma GmbH of Darmstadt, Federal Republic of Germany. "Eudragit E 30 D" is an aqueous dispersion of an acrylic resin which is neutral in character. Its polymeric structure contains units of structure -CH2-CRR'-, wherein R is -H or -CH3 and R1 is -C(O)OCH3 or -C(O)OC2Hs. It has an average molecular weight of about 800,000 and a viscosity of t50 cp at 20"C, as measured with a Brookfield viscometer with adapter 6 r.p.m., according to DAB VII, page 20, subsection 31.

As the polymers are to be admixed with the filler(s), in an aqueous environment, to produce the coating compositions of the present invention, it is generally preferred that the polymer particles have diameters of the order of 0.01 to 1 mm. Sizes corresponding to a coagulum content of 500 mg=0.5% maximum are preferred.

In optional embodiments, one or more overcoat may be applied to the dosage forms which have been coated with a polymer/filler coating composition according to the present invention.

These overcoats can contain a hydrophilic material, e.g. one or more of hydroxypropylmethyl cellulose polyethylene glycol and the like. Fillers and auxiliary binders can be present in the overcoat.

The fillers employed in the coating compositions of the present invention are generally waterinsoluble materials of an inorganic character.

Generally, they are FDA-approved inorganic substances having suitable compatibility with the aqueous polymer dispersions being used. Preferred fillers are kaolin, talc and titanium dioxide.

Kaolin is highly preferred. Mixtures are operable.

While the particle size of the filler is not crucial, it is generally preferred, for ease of handling, that it lie between 20 u (microns) and 0.001 u. These particle sizes ensure efficient suspension of the filler particles in water or water-miscible diluent(s) prior to admixture with the polymeric component.

Milling or other treatment of the filler is not usually required. However, when packaging or storage of the filler has caused agglomeration of filler particles, minimal milling of the particles, in the presence or absence of aqueous or other suitable media, may be beneficial to the ultimate combining of polymer and filler components.

The applicants do not intend to be bound by any particular theory as to the action of the fillers. However, the fillers appear to function as processing enhancers and permeability modifiers in the coating by virtue of their limited water swellability and bulk. After the coatings dry, the filler particles, which are dispersed throughout the coating or film, aid in the formation of pores or channels at the interface of the particles and the polymer. It is believed that these pores or channels function as openings through which the body fluid(s) can "leach out" small quantities of the coated drug or other physiologically active substance.

The polymeric coatings of the present invention preferably contain, on a dry basis, from 5 to 95% by weight, more preferably from 15 to 75% by weight, of polymer and from 5 to 80% by weight, more preferably from 10 to 60% by weight, of filler. When an aqueous diluent is present, it will generally comprise the balance of the coating.

Preferably, the coating composition contains from 2 to 30% by weight of the water-dispersible polymer, from 2 to 30% by weight of the water-insoluble filler, and the balance water.

While plasticizers, solvents and colourants are not necessary ingredients, they may be used when desired. For example, additional quantities of titanium dioxide may be present to improve the colour of the final product. Generally, however, only the aqueous diluent, the polymer and the filler need be present in the coating compositions of the present invention.

The physiologically active substance which serves as the substrate, or as a component of the substrate, to be covered by the coating of the present invention may be one or more of a wide variety of materials. While drugs are preferred, they may also be vitamins, placebos, and the like. Mixtures of such substances can be used. When the active component of the final product is a drug, it is generally a solid substance having sufficient affinity for gastrointestinal fluids to be absorbed by the body once it is contacted with those fluids.Suitable drugs include antiinfective agents, phenols and their derivatives, sulfonamides, sulfones, surfactants, chelating agents, antimalarials, antibiotics, central nervous system depressants, stimulants, adrenergic agents, cholinergic agents, autonomic blocking agents, diuretics, cardiovascular agents, local anesthetics, histaminic and antihistamic agents, analgesic agents, antitussive agents, steroids, carbohydrates, amino acids, proteins, enzymes, hormones, antiemetic agents, cognition activators, and the like. One preferred group of drugs include pseudoephedrine and theophylline.

Mixtures of drugs can be used.

The active component of the dosage forms coated in accordance with the present invention will generally comprise about 0 to 95% by weight, preferably from 5 to 90% by weight, of the total composition on a dry weight basis, depending upon the dosage of the drug.

The coating compositions of the present invention can be used to cover a wide variety of solid substrates. While pellets or cores of active substances are the preferred substrates, other forms can be treated. Tablets, capsules, powders, granules and other forms into which the physiologically active component may be shaped are also operable. The presence in the sub strate of carriers and other conventional ingredients, in addition to the active component of the drug, can be tolerated. Care should be exercised, however, to exclude degradable, water-soluble, and/or volatile ingredients from both the substrate and the coating. Such exclusion will help assure long shelf life for the final products.

Suitable devices for coating the active substrates include coating pans, fluided bed devices and the like. In general, those devices suited to the application of water-based coatings to solid substrates can be used.

Examples Pellet Preparation: Non-pareil seeds composed of sugar and starch were placed in a prewarmed chamber of a centrifugal granulator. A binder solution of hydroxypropylcellulose was sprayed onto the seeds while simultaneously a meshed powder of each of diphenhydramine hydrochloride, pseudoephedrine HCI and theophylline was fed at an appropriate rate. Once the pellets were made, they were allowed to dry in an oven at 45" for 24 hours. The 12-18 mesh fraction was screened and transferred to plastic bags.

Coating Procedure: Diphenhydramine hydrochloride, pseudoephedrine and theophylline pellets were coated with mixtures of kaolin and Eudragit6 E 30 D dispersion. The preparation of the coating formulations involved formation of a suspension of untreated kaolin using a magnetic stirrer followed by intimate mixing of the suspension with the desired quantity of the polymeric dispersion. The pellets (300 gm in weight) were initially coated with the coating formulations set out in Table I slowly in fluidized bed equipment, i.e., a device, at about 1.0 ml per minute until their weight was increased by approximately 3%. They were then dried for 30 minutes using the fluidizing air while still in the chamber. Coating was then resumed at a faster rate. The formulation was stirred throughout the coating process. The coated pellets were transferred to a paperlined tray and dried under air.Kaolin was used as received but can also be ball-milled if necessary. Eudragit2 > E 30 D was filtered through a fine sieve (120 mesh) before use in order to remove solid or film particles.

Dissolution: In vitro dissolution studies were carried out using the USP dissolution apparatus II at 37 and 75 rpm. The dissolution media were water, simulated (without enzymes) gastric fluid and/or intestinal fluid. Samples were withdrawn and dissolution medium replaced automatically at preselected time intervals. Assay of the released drug was conducted spectrophotometrically at 258 nm.

Table I Coating Formulations Drug E 30 D (gm) Kaolin (gm) Water (gm) Diphenhydramine 200 20 180 hydrochioride Pseudoephedrine 200 40 427 hydrochloride Theophylline 200 60 540 Example 1 Diphenhydramine hydrochloride pellets produced as described above and having a final coating weight of 20 wt% were compared to overcoated diphenhydramine hydrochloride pellets for release rates.

The overcoated pellets were prepared by subjecting the singly coated pellets to an additional coating with an overcoat formulation. That overcoat contained hydroxypropylmethylcellulose and was applied to give a final coating weight of 2 wt%.

The results of the release studies, which were conducted in accordance with the dissolution procedure described above, are given in Table II.

Table It Release Data of Diphenhydramine Hydrochloride Pellets With and Without an Overcoat Percent Release Time (hrs.) With Overcoat Without Overcoat 0.5 4 3 1 9 8 2 33 33 4 56 56 6 69 69 8 77 77 10 82 82 12 85 85 Drawings Figure I represents a release curve (derived by plotting cumulative percent released versus time) for pseudoephedrine, i.e., hydrochloride in each of the fluids indicated. The pellets were prepared and the dissolution studies were carried out as described above.

Figures II thorough VI were derived using the respective coatings, coating levels and dissolution media indicated thereon.

As these examples and the drawings indicate, the rate of drug release from the dosage form is directly proportional to the ratio of kaolin to polymer in the final film or coating. Fig. II shows changes in kaolin/resin ratio vs. release rate.

Optimally, a second coating or overcoat can be applied in order to minimize handling problems. For example, the soft lumps that are often observed when coated pellets were stored at room temperature were eliminated by applying a water-soluble overcoat. The overcoat, which was composed of less than 2% by weight of hydroxypropylmethylcellulose, did not in any way affect the rate or extent of drug release.

The release rate for dosage forms made using the instant coatings can be adjusted by varying such parameters as filler concentration (see Fig. IV) and coating level or thickness (see Fig. III).

For example, the amount of kaolin or other filler in the coating formulation can be increased to the point that film integrity is lost and immediate drug release occurs.

Likewise, a coating layer of insignificant thickness would be an inefficient barrier to release.

Generally coating thicknesses corresponding to an overall coating/active component (e.g., coating/drug) ratio of about 2 to about 98% are desirable. Preferably, a coating/drug ratio on the order of 10 to 90% is used depending on dose and physical chemical characteristics of the drug.

Reasonable variations, such as those which would occur to a skilled artisan, can be made herein without departing from the scope of the invention.

Claims (14)

1. A coating composition, suitable for coating sustained release dosage forms, which composition comprises or consists essentially of: (a) a water-dispersible polymer of an ester of acrylic acid or methacrylic acid, which polymer contains no ionizable functional groups; (b) a water-insoluble filler; and (c) water.

2. A coating composition according to Claim 1, which contains from 2 to 30% by weight of the water-dispensible polymer, from 2 to 30% by weight of the water-insoluble filler, and the balance water.

3. A coating composition according to Claim 1 or 2, wherein the water-insoluble filler is kaolin, talc, titanium dioxide, or a mixture thereof.

4. A coating composition according to Claim 3, wherein the water-insoluble filler is kaolin.

5. A coating composition according to any preceding claim, wherein the ester of acrylic acid or methacrylic acid is an alkyl ester.

6. A coating composition according to Claim 5, wherein the alkyl ester is the methyl or ethyl ester.

7. A coating composition according to any preceding claim, wherein the water-dispersible polymer is the sole polymeric component of the coating composition.

8. A dosage form coated with a coating composition according to any preceding claim.

9. A process for reducing the tackiness of an aqueous polymeric composition when applied to solid dosage forms, which comprise employing in that composition as the sole polymeric component, a water-dispersible polymer of an ester of acrylic acid or methacrylic acid.

10. A process according to Claim 9, wherein the coating composition also contains a waterinsoluble filler selected from kaolin, talc, titanium dioxide, and mixtures thereof.

11. A process for increasing the water-permeability of a coated dosage form, which comprises employing, as the sole polymeric component of the coating composition, a water-dispersible polymer of an ester of acrylic acid or methacrylic acid, which polymer contains no ionizable functional groups.

12. A process according to Claim 11, wherein the composition also contains a waterinsoluble filler selected from kaolin, talc, titanium dioxide, and mixtures thereof.

13. A process for decreasing the number of handling problems associated with applying a polymeric coating to a dosage form, comprising applying to the coated dosage form an overcoating containing a water-soluble hydrophilic polymer.

14. A process according to Claim 13, wherein the hydrophilic polymer is selected from hydroxypropylmethylcellulose, polyethylene glycol, and mixtures thereof.