LU86273A1 - COATED DOSAGE FORMS - Google Patents

Description

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BACKGROUND FORMS OF DOSAGE BACKGROUND OF THE INVENTION

The coating of physiologically active substances with polymeric substances is well known. The formulation of suitable coating substances has focused on obtaining final pharmaceutical forms capable of releasing the active ingredients while minimizing the handling problems generally associated with the coated products.

10 DESCRIPTION OF THE INVENTION

It has been found that unique combinations containing a water-dispersible polymer and water-insoluble fillers can be used in coating formulations of physiologically active substances, such as drugs.

In a preferred embodiment, a suspension of kaolin in water is combined with an aqueous dispersion of a copolymer of poly (meth) acrylic esters, for example of "Eudragit E 30 D", to give a coating which reduces the sticky feel inherent in the polymer and which, when dried, gives a coated pharmaceutical form which can release the desired active ingredients for a prolonged period.

Advantages The invention has several advantages over the pharmaceutical forms of the prior art and their methods of preparation.

First, during processing, there is a reduction in the tackiness of the coating substances, which leads to a reduction in problems and a decrease in processing and handling times.

Secondly, the mineral fillers present in the formulations according to the invention increase the water permeability of the coated pharmaceutical forms, this increase is directly proportional to their concentration in the coating formulations. That is, the higher the concentration of kaolin or of other suitable filler, the greater the permeability of the coating after ingestion of the pharmaceutical form. This proportionality makes it possible to somehow adjust the ability of the pharmaceutical form to release the active ingredients.

In addition, the need for one or more hydrophilic film-forming agents, such as, for example, hydropropylmethylcellulose, is avoided. The elimination of these additives leads to savings in time and energy.

Since the fillers used here do not need to be treated, for example by grinding or by contacting processing aids, before their inclusion in the coatings, substantial savings in energy and time are obtained . Untreated kaolin is a particularly preferred filler since it can, in general, be used as received and there is a need for grinding only if the particles cannot be dispersed from substantially uniformly.

Other aspects and advantages of the invention will become apparent on examining the following drawings and the description of the present invention.

DESCRIPTION OF THE INVENTION Pharmaceutical form The invention is centered on a unique combination of water-dispersible polymers and water-insoluble fillers which, when combined in suitable quantities, combine the advantages set out here. .

Polymers

The polymer matrices on which the polymer / filler combinations according to the present invention are based are water-dispersible polymers which do not contain ionizable functional groups in their structures. In other words, the polymers used here are neutral so that they are not affected by the pH gradient prevailing in the gastrointestinal tract. That is to say, for example, that a pH of about 1 to 8 has no effect on the polymers in question. Useful polymers include those which are sold in the form of aqueous dispersions of low viscosity and having the solubility required when used for pharmaceutical coatings. Generally, these are acrylic resins polymerized in '* ·' 3 emulsions produced with the use of one or more alkylesters monomers of acrylic or methacrylic acids. Preferably, these are emulsion polymerization products of (meth) acrylates, the resulting polymers not containing undesirable lonizable groups.

One of the preferred polymers is commercially available under the name "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 of neutral character. Its polymer structure contains structural elements 10 -CH ^ -CRR ^ - in which R represents -H or -CH ^ and R ^ represents -0 (0) 0 ^ or -C (0) 0C2Hg. Its average molecular weight is around 800,000 and its viscosity <50 cp at 20 ° C, as measured with a Brookfield viscometer having an adapter at 6 rpm, according to DAB VII, page 20, under section 31.

Since the polymers have to be mixed with the filler (s) of the invention in an aqueous medium, it is generally preferred that the polymer particles have diameters of the order of 0.01 to 1 mm. Dimensions corresponding to a coagulum content of 500 mg = 0.5¾ maximum are preferred.

In preferred embodiments, one or more top coats are applied to pharmaceutical forms which have been coated with a polymer / filler coating composition. These top coatings contain a hydrophilic substance, for example, Tun or more of hydroxypropyl methylcellulose, polyethylene glycol and the like. Fillers and auxiliary binding agents may also be present.

The charges

The fillers used in the polymer coatings according to the invention are generally substances insoluble in water of mineral character.

Generally, these are mineral substances approved by the FDA, having suitable compatibility with the aqueous polymer dispersions used. The preferred fillers are kaolin, talc and titanium dioxide. Kaolin is the one that is particularly preferred. One can also consider mixtures.

Although the particle size of the filler is not critical, it is generally preferred, for convenience of handling, that it is between about 20 μ (microns) and about) 4 0.001 μ. These particle sizes ensure effective suspension of the filler particles in water or the diluent (s) misci-ble (s) in water before mixing with the polymer component.

Usually, grinding or other treatment of the feed is not necessary. However, when the packaging or storage of the filler has caused agglomeration of the filler particles, minimum grinding of the particles, in an aqueous medium or not or in another suitable medium, may be beneficial for the final mixture of the polymer components. and charge.

10 The plaintiff does not intend to be bound by any particular theory as to the action of the charges. It appears, however, that "fillers function as processing enhancers and coating permeability modifiers by virtue of their limited power to swell with water and their bulk density. After the coatings have dried, the filler particles, which are dispersed throughout the entire coating or film, allow the formation of pores or channels at the interface of the particles and the polymer. These pores or channels are believed to function as orifices through which body fluid (s) can "extract" small amounts of the coated drug or other physiologically active substance.

The polymeric coatings according to the invention contain (based on a dry weight), about 5 to about 95% by weight, preferably about 15 to about 75% by weight of polymer and about 5 to about 80% by weight, preferably between about 10 and about 60% by weight of filler. When an aqueous diluent is present, it generally constitutes the complement to 100% of the coating.

Although plasticizers, solvents, dyes, etc. are not necessary ingredients, they can be used when desired. For example, additional amounts of titanium dioxide may be present to improve the color of the final product. Generally, however, only the aqueous diluent, the polymer and the filler need be present in the coatings according to the present invention.

35 Physiologically active substance

The physiologically active substrate which serves as a substance for the coatings of the invention can be one or more of a whole series of substances. Although the drugs are the preferred ones, it can also be vitamins, placebo and the like. Mixtures of these substances can be used. When the active component of the final product is a drug, it is generally a solid substance with sufficient affinity for gastrointestinal fluids which must be absorbed by the body once it is brought into contact with these. fluids. Suitable drugs include anti-infective agents, phenols and their derivatives, sulfonamides, sulfones, surfactants, chelating agents, anti-malarial agents, antibiotics, central nervous system depressants, stimulants, adrenergic agents, cholinergic agents, autonomous blocking agents, diuretics, cardiovascular agents, local anesthetics, histamine and antihistamine agents, analgesic agents, antitussive agents, steroids, carbohydrates, amino-15 acids, proteins, enzymes, hormones, antiemetic agents, cognition enhancers and the like. A preferred group of drugs includes pseudoephedrine and theophylline. Mixtures of these drugs can be used.

The active component of the pharmaceutical forms according to the invention generally represents from about 0 to about 95% by weight, preferably from about 5 to about 90% by weight, of the total composition (dry weight), this depending on administration of the drug.

Substrates

The coatings according to the invention can be used to cover a whole series of solid substrates. Although lozenges or active ingredient cores are the preferred substrates, other forms can be treated. Dragees, cachets, powders, granules and other forms in which the physiologically active component may be presented may also be considered. The presence of carriers and other conventional ingredients can be tolerated in the active component of the drug. However, care should be taken to exclude both degradable, water soluble and / or volatile ingredients from the substrate and coating. This exclusion must ensure a long shelf life of the final products.

Suitable devices for coating active substrates include coating basins, fluid bed devices and the like. In general, any device suitable for applying water-based coating to solid substrates can be used.

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EXAMPLES

Preparation of lozenges:

Pellet seeds composed of sugar and starch are placed in a preheated chamber of a centrifugal granulator. A hydroxypropylcellulose binder solution is sprayed onto the seeds while simultaneously introducing a sieved powder each containing diphenhydramine hydrochloride, pseudoephedrine hydrochloride and theophylline at a suitable speed. Once the pellets are prepared, they are left to dry in the oven at 45 ° for 24 hours. The sieved fraction 12-18 is selected and transferred to plastic bags.

Coating procedure:

Diphenhydramine hydrochloride, pseudoephedrine and theophylline tablets are coated with mixtures of kaolin and a dispersion of Eudragit® E 30 D. The preparation of coating formulations involves the formation of a suspension of untreated kaolin using a magnetic stirrer, which suspension is then intimately mixed with the desired amount of polymer dispersion. The pellets (weighing 300 g) are initially slowly coated with the coating formulations shown in Table I in fluid bed equipment, i.e., a device, at about 1.0 ml per minute until their weight is increased by approximately 3¾. They are then dried for 30 minutes using fluidizing air while they are still in the chamber. The coating is then resumed at higher speed. The formulation is stirred throughout the coating process. The coated pellets are transferred to a paper lined tray and air dried. Kaolin is used as received, but can also be passed through a ball mill if necessary. L Eudragit 30 E 30 D is filtered through a fine sieve (120 mesh) before use, in order to remove solid particles or scraps of film. Dissolution:

In vitro dissolution studies are performed using the USP dissolution apparatus II at 37 ° and 75 rpm. The dissolution media are water, gastric simulated juice (without enzyme) and / or intestinal fluid. The samples are removed and the dissolving medium is replaced automatically at pre-selected time intervals ► 7. A drug release test is conducted spectrophotometrically 3 258 nm.

TABLE I

Coating formulations 5 Drug E 30 D (g) kaolin (g) water (g). diphenhydramine hydrochloride ... 200 20 180. pseudoephedrine hydrochloride ... 200 40 427. theophylline ...................... 200 60 540 EXAMPLE 1 10 Diphenhydramine hydrochloride tablets produced as described above and having a final coating weight of 20¾ by weight are compared with diphenhydramine hydrochloride pellets provided with a second coating to determine the release rates.

The second coated pellets are prepared by subjecting the single coated pellets to further coating by a second coating formulation. This second coating contains hydroxypropylmethylcellulose and is applied so as to obtain a final coating weight of 2% by weight.

The results of these release studies conducted, in accordance with the dissolution procedure described above, are shown in Table II.

TABLE II

Release data of active ingredient from diphenhydramine hydrochloride tablets with and without second coating

Release time in ¾ hours with coating without coating 0.5 4 3 1 9 8 30 2 33 33 4 56 56 6 69 69 8 77 77 10 82 82 35 12 85 85

Drawings

FIG. I represents a release curve (obtained by reporting the percentage of active principle released cumulative as a function of * f 8 time) for the pseudoephedrine, that is to say its hydrochloride, in each of the fluids indicated. The pellets are prepared and the dissolution studies are carried out as described above.

Figures II to VI are produced using the coatings, the coating levels and the respective dissolution media indicated above.

As these examples and the figures 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. Figure II shows the variations in the release rate as a function of the kaolin / resin ratio.

Optimally, a second or higher coating can be applied to minimize handling problems. For example, the soft lumps often observed when storing coated pellets at room temperature are removed by applying a second water-soluble coating. The second coating, which is composed of less than 2% by weight of hydroxypropyl methylcellulose, does not affect the speed or the amount of drug release in any way.

The speed of release of the active principle from the pharmaceutical forms prepared using the coatings according to the present invention can be adjusted by varying parameters such as the concentration of the filler (see FIG. IV) and the level of coating or its thickness ( see figure III). For example, the amount of kaolin or other filler in the coating formulation can be increased to the point where the integrity of the film is lost and immediate release of the drug occurs.

Likewise, a coating layer of insignificant thickness would be an ineffective barrier to release. Generally, coating thicknesses corresponding to an overall coating / active ingredient (i.e. coating / drug) ratio of about 2 to about 98% are desirable. Preferably, a coating / drug ratio of the order of 10 to 90% is used, this depending on the drug and on the physico-chemical characteristics of the drug.

Reasonable variations such as those which may appear to the skilled artisan can be applied without departing from the spirit of the invention.

Claims (7)

1. A coating composition for sustained release pharmaceutical forms which consists essentially of: (a) a water dispersible poly (meth) acrylic ester polymer, this polymer not containing ionizable functional groups ·, (b ) a filler insoluble in water; and (c) water. 2. The coating composition according to claim 1, which contains about 2 to about 30¾ by weight of (a), about 2 to about 10¾ 30 by weight of (b), the balance to 100¾ being water. 3. Coating composition according to claim 2, in which (b) is chosen from the group consisting of: kaolin, talc, titanium dioxide and their mixtures. 4. The coating composition of claim 2, wherein (b) is kaolin. 5. Pharmaceutical form coated with the composition according to claim 1. 6. Pharmaceutical form coated with the composition according to claim 3. 7. Pharmaceutical form coated with the composition according to claim 4. 8. A method of reducing the tackiness of aqueous polymeric compositions applied to solid pharmaceutical forms which consists in using in these compositions as sole polymer component, a polymer of (meth) acrylic ester dispersible in water. 9. The method as claimed in claim 8, in which the compositions also contain a water-insoluble filler chosen from the group consisting of: kaolin, talc, titanium dioxide and their mixtures. 10.- A method of increasing the water permeability of a coated pharmaceutical form which consists in using as the only polymer component of the coating composition, a water-dispersible polymer consisting of poly (meth) acrylic ester , this polymer not containing ionizable functional groups. 11. A method according to claim 10, in which the compositions also contain a filler insoluble in water chosen from the group consisting of: kaolin, talc, titanium dioxide and their mixtures.