HUT73666A - Matrix-entrapped beadlet preparation containing perls - Google Patents

Description

PUBLICATION LITERATURE

Matrix pharmaceutical formulation containing beads

The present invention relates to solid, transparent or semi-transparent pharmaceutically acceptable formulations (tablets, lozenges) containing one or more matrix-forming agents in which small particles of at least one beneficial agent are present. With this design, the particles and the active ingredient remain unchanged and the formulations are more tangible.

Tablets, which may also be referred to as lozenges, are disk-shaped solid products containing the active compound in a suitably flavored base. The base material may be hard sugar, glyceride gelatin, or a combination of sugar with an appropriate adhesive to form stable formulations. These formulations are placed in the mouth where they slowly dissolve and

83166-3072-SZŐ-wood the drug is released.

Tablets can be prepared rapidly in known manner. In one method, water is added to a mixture of the powdered active ingredient, sugar, and rubber to give a plastic mass. This mass is turned into rolls and cut into pieces. Heat-resistant compounds can be prepared on a hard sugar base, and such compositions are commonly referred to as lozenges. The sugar syrup is concentrated with or without a binder under heat until it becomes a plastic mass, the active ingredient is then added and the mixture is kneaded into a homogeneous mass. The resulting hot mass is then processed into a mold of appropriate shape, and the resulting product is cooled to give a hard sugar material. Tablets containing thermosensitive components are manufactured by compression.

The present invention has advantages over the described products and processes in that a tablet-like formulation is used as a carrier for the production of particles, particularly beads, wherein the matrix-forming material exhibits the natural state of the beads while preserving the integrity of the tablet-like products.

SUMMARY OF THE INVENTION The present invention relates to pharmaceutically acceptable compositions comprising at least one pharmaceutically acceptable transparent or semi-transparent solid matrix-forming agent in which small particles containing at least one beneficial agent are present.

The present invention relates to these products

- 3 injection molding.

The finished product is a pharmaceutical composition comprising a matrix-forming edible material containing small particles of the active ingredient. The matrix-forming material is an edible material that is solid at room temperature and transparent or semi-transparent to the extent that the particles are visible to the naked eye under normal light conditions. The compositions of the invention may be in the form of tablets or lozenges. Knowledge of its composition can be found, for example, in Remington Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, PA, USA 1664-1665 (1990) and Radiation Confectionery Manufacture, Ε. B. Jackson, Ed. Nostrand Reinhold, New York, pp. 245-247 (1990).

As a matrix-forming material, any known material which is edible, solid at room temperature, non-plastic or extensible at this temperature, can act as a matrix for small particles, and the particles contained therein can be used. The matrix may be formed using a compound such as wax or sugar or a mixture of different materials. The mixtures may contain one or more compounds of the same type, such as mixed sugars, or mixtures of two or more types of compounds, such as sugars, waxes and polyols. If mixtures are used, they are processed so that they retain their original structure or are transformed into a secondary form during the processing process, ie they are chemically modified, for example · ·

- or curing these materials.

Preferred matrix forming agents are sugars and edible waxes. Sucrose, dextrose, fructose, sorbitol, lycosin and other simple or complex carbohydrates which are useful in the preparation of tablets are preferred as sugars. Waxes include, for example, white wax, gelucir, carnauba wax, hydrogenated vegetable oil, Labrafil, Compritol 888 ATO, Precirol, polyethylene glycols, beeswax, paraffins, microcrystalline wax, acetylated monoglycerides, cetyl alcohol and glyceryl monostearate. A particularly preferred matrix forming agent in the present invention is white wax.

The matrices of the present invention can be of two types, disintegrating or non-disintegrating. Non-disintegrating matrices are prepared from the hydrophilic matrix forming materials described above. Disintegrating matrices may be prepared using a combination of hydrophilic and hydrophobic matrix-forming materials, such as those listed above. The ratio of hydrophobic to hydrophilic materials can be adjusted to achieve the desired disintegration time.

In addition to hydrophilic matrix forming agents, disintegrating agents such as Ad-Di-Sol, Explotab, pregelatinized starches, crospovidone NF and other materials may be incorporated into the matrix in the form of fine powders or beads.

Any particle containing one or more beneficial substances, stable in the matrix forming material during manufacture and storage, and of sufficient size, shape and color to be visible in the matrix may be used in the composition. Particularly preferred are the tinted colored beads known later in the art.

A beneficial agent is any compound or substance which, after ingestion in the prescribed manner, has any effect on the mammal. Thus, for example, according to the said definition, an active ingredient is a beneficial agent. Many other compounds can form beneficial compounds for the user and are also included within the definition given. For example, an antacid or antigen may have a beneficial effect when used in the case of indigestion. An air freshener gives many people an objective or subjective benefit. Foods, such as vitamins, minerals, or amino acids, are beneficial substances for individuals who need to take such a diet. Flavorings and sweeteners may also be beneficial substances. Also included are energy-related materials. These examples illustrate some of the various substances which are considered to be beneficial substances according to the present invention. Others are known to those skilled in the art.

The active ingredients and the systems providing the active ingredient are of great importance. The term active ingredient is used in its widest sense and includes any agent which is therapeutically active on the user and can be applied by soft gelatin capsule technology using the particles described above. Any solid or liquid active ingredient can be used, provided that it can be converted to a particulate material, and this applies to any compound that is beneficial to the invention. Both lipid soluble and water soluble active compounds can be used. Particularly important are the active ingredients used for cough, cold and allergic symptoms. These include antihistamines, anti-inflammatory drugs, pain and fever drugs, nasal decongestants, expectorants, tranquilizers used in coughs and colds. Particularly preferred are phenylpropanolamine hydrochloride, caramifene, edisylate, acetaminophen, aspirin and other non-steroidal anti-inflammatory agents, pseudoephrine hydrochloride, dextromethorphan hydrobromide and chlorpheniramine maleate.

The particle size is such that the particles can be seen through the matrix under normal light conditions by the naked eye. The size of the beads may vary within a given capsule. The beads are preferably about 149-1190 microns in diameter. Particularly preferably, the particle size is about 420-840 microns (about 20-40 mesh). The particle size may vary within a single formulation, or different narrow particle size particles may be processed together, and the resulting end products are mixed to form different particle size formulations.

The beads may contain the pure active ingredient, which is very common. The active ingredient may be coated with a protective layer, which may affect the dissolution of the particle and release of the active ingredient. Beads of pure active ingredient are generally prepared by molding the raw material by mechanical means. The pure

a coating may be used to protect the conjunctiva. Very often, particles are coated with both functional and aesthetic considerations. There are many ways to include particles. By evaporation, for example, basic pellets are obtained. In a more complex process, a core is formed and then coated with one or more layers. By coating the 'cores' in different ways, i.e., the thickness of the coating layer, and placing these particles of different thicknesses in a capsule, the active ingredient is released over a longer period of time. Such a process is described in USP 2,737,303. It describes the preparation of dosage units prepared from non-parental seeds (sugar pellets), which are sieved, coated in a container, moistened with syrup, and then treated with dextro-amphetamine sulfate and calcium sulfate dihydrate. They are treated with a 20% mixture and then dried. The process is repeated several times to form the active ingredient on the non-parental nucleus. The system is then treated with talc to give the seed pellet. These pellets are then treated once or more with a coating solution consisting of wax and fat to form one or more fatty layers around the core pellet. Subsequent improvements have resulted in the formation of an osmotic wall around the core pellet and formulations where the active ingredient is dissolved in the particle wall-forming material and released into the surrounding environment by the action of water. Such particles are described in the literature, for example, in USP 4,434,153. USP 4,961,932 discloses patents describing small or small pills and dosage forms containing them.

The particles can be produced in a single color or, if desired, in different colors. Any paint or varnish that is non-toxic or has no adverse side-effects for the consumer may be used. Blue particles can be prepared, for example, with a clear white wax solution. Red, white and blue beads can be incorporated into a sorbitol base to provide tablets that are aesthetically pleasing.

The stability of the particles in relation to the stability of the active substance must be taken into account. The particles must be chemically and physically stable under the conditions used in the preparation of the tablets. The particle and the matrix must not undergo chemical or physical reaction after processing. Not all circumstances or combinations that result in particle-matrix interactions can be said. Granular coatings made with sorbitol or cereal syrup are not suitable for the production of coated beads where sugars are matrix forming agents.

Also important is the stability of the beneficial agent, alone or in any formulation, not just the formulation of the invention. A simple recipe cannot be given to produce products that are not chemically degraded. For each formulation, the aforementioned properties should be investigated separately and are known to those skilled in the art.

There is no need for any limitation in the process according to the invention. For example, tabs ♦ · ·· * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · forming a sugar base by mixing the ingredients and cooking the mixture with or without mixing to obtain a tablet. A portion of the resulting mixture, which was kept at elevated temperature to maintain its liquid state, is used as a diluent. The particles are added to the liquid air with stirring to give a dispersion. The material thus obtained is poured into a suitable tool, where it is cooled and then packaged.

The desired products can also be produced by injection molding. This is particularly effective when waxes are used as matrix forming agents. The heated mixture of wax and particles is passed through an injection molding machine, the equipment tool being filled with the agent, and the product is cooled during the manufacturing process. In addition, premixed streams of room temperature materials can be processed by melting under reduced pressure, so that no cooling step is required. As a third alternative, the matrix-forming material is mixed with the flow of particles, then the mixture is introduced into a mixer and then injected into a mold to form the final product. Other injection molding techniques may be used in accordance with the present invention.

The final product can be packaged without any special handling instructions. Consideration should be given to standard measures such as the exclusion of moisture or ultraviolet light. Preferably, the product is packaged in such a way that the consumer can see the contents of the matrix and the particles before opening the package. According to the present invention, the product is packaged in an opaque container or a coated container.

According to the invention, the composition can be in any form. The tablets and lozenges may be uniform in shape, such as oval, circular, triangular or multi-faceted. Geometric shapes can also be used. Shapes that express real or imagined people or objects can also be produced, especially when using injection molding technology. Design and shape are limited by the manufacturer's imagination.

The following examples illustrate the invention without limiting it.

EXAMPLES

Example 1

Production of wax matrix cups containing beads

An appropriate amount of white wax is introduced into a glass cup and heated on an oil bath using a hot plate until the wax melts. Beads from Central Pharmaceuticals, Inc. of Seymour, Indiana are poured into the molten wax and mixed with a spatula to form a homogeneous suspension. The molten wax / pearl suspension is carefully poured into a mold, allowed to cool, and hard cups are formed. These cups are then pressed out of the mold.

The active ingredient in the beads is 12.0 mg of chlorfeneramine maleate and 75.0 mg of phenylpropanolamine hydrochloride. The beads are coated in various ways such that some of the beads release the active ingredient immediately and the other beads delayed release at various times within 12 hours.

Example 2

Preparation of pure tablet-matrix cups containing beads

Prototypes of pure tablet-matrix cups containing beads are prepared as follows.

A 96: 4 mixture of the desired amount of sorbitol (70% solution) and lycazine was transferred to a steam jacketed cooking apparatus and cooked until the water evaporated. The vessel is then vacuum-treated and cooking is continued until no bubble appears in the liquid sugar dispersion. The resulting molten curled paste is placed in a stainless steel vessel and stored in a drying oven at 110 ° C. The desired amount of sugary stock is transferred to a glass mixer and mixed with a mechanical stirrer. Beads from Central Pharmaceuticals, Inc. of Seymour, Indiana are poured into the sugar mass and mixed into a homogeneous suspension. Some crystal sorbitol (Neosorb) was inoculated with the sugar base / pearl suspension and carefully poured into molds. The molds were placed in a 40 ° C oven and allowed to cool to give hard cups. These cups are pressed out of the mold.

The active ingredient in the beads is 12.0 mg of chlorfeneramine • «· ·.

12 lax and 75.0 mg phenylpropanolamine hydrochloride. The beads are coated in various ways such that some of the beads release the active ingredient immediately and the other beads delayed release at various times within 12 hours.

· 9 · 9 · · · ··· «· V · ♦ ·· * ··« ·· ·

- 13 Patent claims

Claims (9)

Claims A pharmaceutically acceptable composition comprising at least one pharmaceutically acceptable transparent or semi-transparent solid matrix-forming agent in which small particles containing at least one beneficial agent are present. The composition of claim 1, wherein the matrix forming agent is wax or edible sugar and the particles are beads of about 149 to about 1190 microns in diameter. The composition of claim 2, wherein the beneficial agent is an active ingredient. The composition according to claim 3, wherein the beads release the active ingredient in a delayed or immediate manner and containing medicaments for the treatment of cough, cold and / or allergy symptoms. The composition of claim 1, wherein the beads release the active ingredient delayed or immediate release and contain a medicament for treating cough, cold and / or allergic symptoms. 6. A process for the preparation of a composition according to claim 1, characterized in that injection molding is used. The process of claim 6, wherein the matrix forming material is wax. The method of claim 7, wherein the composition comprises disintegrating or non-disintegrating beads. The method of claim 7, wherein the composition comprises at least one wax as a matrix-forming agent and the particles are beads of delayed or immediate release beads containing a medicament for treating cough, cold and / or allergic symptoms. For the notifier, the agent is: ilcuó IL.