SK3396A3 - Pharmaceutically acceptable composition and preparation method thereof - Google Patents

Abstract

This invention relates to a pharmaceutically acceptable preparation comprising one or more matrix-forming materials in which are entrapped particles which contain at least one beneficial agent.

Description

A pharmaceutically acceptable preparation and a process for its preparation

Technical field

The invention relates to a pharmaceutically acceptable formulation comprising one or more matrix forming substances in which particles containing at least one positive effect agent are retained.

BACKGROUND OF THE INVENTION

Trochisks, also known as lozenges or lozenges, are disc-shaped solids containing the drug in a suitably flavored base. The base may be a hard candied sugar, glycerinated gelatin or a combination of sugar with a mucilaginous substance to make the shape and form stable. These products enter the mouth where they slowly dissolve to release the active ingredient.

The prints can be prepared by an experienced ex tempore manufacturer. The classical method of preparation consists in adding water to the mixture of powdered drug, sugar and resin until a compliant mass is obtained. This mass is shaped into a cylinder and cut into pieces. The thermostable compounds may be formulated into a hard sugar base; such preparations are usually called lozenges. The sugar syrup, with or without a binding agent, is concentrated hot until it becomes a moldable mass, at which time the active substance is added and the mixture is mixed until a homogeneous mass is formed by heat. This warm, homogeneous mass is then formed and, upon cooling, hard sugar is formed. Handmade based on compression is used in the preparation of triplets containing thermolabile ingredients.

The present invention enables advancement in this field by providing a particulate carrier composition, in particular grains, where the original grains can be visible through the matrix forming agent, the excess of the ternary-like product can be monitored at any point after manufacture or packaging.

SUMMARY OF THE INVENTION

The present invention includes a pharmaceutically acceptable formulation comprising at least one pharmaceutically acceptable transparent or semi-transparent solid matrix former in which small particles containing at least one positive acting agent are trapped.

In a further aspect, the present invention relates to a process for the manufacture of these products using injection molding.

DETAILED DESCRIPTION OF THE INVENTION

The final product is a pharmaceutical composition comprising some kind of matrix-forming edible substance in which small particles containing the active substance are trapped. The matrix former is an edible substance that is solid at room temperature and is transparent or semi-transparent to the extent that it allows the user to see some or all of the trapped particles when viewed under normal light conditions with the naked eye. The lozenges and ternary formulations are illustrative of the formulations of the present invention. The composition of the preparations of the tris and lozenges can be found in such literature as e.g. Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co. , Easton, PA, USA, p. 1644-1665 (1990) and Confectionery Production, E. B. Jackson, ed. Van Nostrand Reinhold, New York, p. 245-247 (1990).

For matrix formers, any substances known as edible, solids at room temperature and not plastic or ductile at that temperature, with the possibility of acting as matrices for small particles and allowing the trapped particles to be visible, can be used in these formulations. The matrix may be formed using a single compound, e.g. or a mixture of substances is used. The mixtures may comprise two or more substances from the same class of compounds, such as mixed sugars, or may be a mixture of two or more classes, such as e.g. sugar, wax and polyol. When mixtures are used, they can be used in a manner that allows them to retain their original identity, or can be transformed during manufacture to form a second form representing a combination of subunits into a different chemical entity, which happens during polymerization or crosslinking.

Preferred matrix formers are sugars and edible waxes. Sugars such as sucrose, dextrose, fructose, shorbitol, lysacin and other simple and complex hydrocarbons that can be used in the preparation of lozenges are preferred. Waxes such as white wax, gelatin, carnauba wax, hydrogenated vegetable oils, Labrafils, Compritol 888 ATO, Precirol, polyethylene glycols, beeswax, paraffins, microcrystalline wax, acetylated monoglycerides, cetyl alcohol and glyceryl monostearate. White wax is a particularly preferred matrix former for use in the present invention.

The matrices that can be made according to the invention can be of two types, disintegrating or non-disintegrating. Non-disintegrating matrices can be formed using the hydrophobic matrix forming agents described above. Disintegrating matrices may be formed using a combination of hydrophilic and hydrophobic matrix forming agents; these are represented by the list of substances listed above. The ratio of hydrophobic substances to hydrophilic substances can be adjusted to achieve the desired disintegration time.

In addition to the use of hydrophilic matrix formers, disintegrants such as Ad-Di-Sol, Explotab, pregelatinized starches, crospovidone NF and other substances are known and can be incorporated into the matrix as a fine powder or granules. Any type of particle may be used in this formulation as long as it includes one or more positive effect agents, is stable in the matrix forming agent during manufacture and storage, and has sufficient size and definability in shape and color to be visible in the matrix. The colored beads described above are most preferred.

The term positive agent is any compound or substance that affects the mammal equally or differently when used as prescribed and for the intended purpose. For example, a drug is a positive effect agent within the meaning of this definition. However, there are numerous other compounds that may have a subjective or objective positive effect on the consumer, which is also included within the meaning of the term. For example, an antacid or anti-flugelant may have a positive effect when used in the treatment of digestive disorders. Breath freshener is a positive effect for many people both subjectively and objectively. Nutritional agents such as vitamins, minerals, or amino acid adjuvants are positive for those in need of a dietary supplement. The flavoring and sweetening agents have a subjective positive effect and are also a source of energy and thus are also included. These examples illustrate only a few of the many types of substances that are included under the term positive agents. Others are known in the art in practice.

Drugs and drug delivery are of greatest concern here. The term drug as used in its broadest sense means any agent that has a pharmacological effect on the user and which can be administered by particles using SGC technology as described above. Any solid or liquid form of the drug may be used provided that it can be incorporated into the particle, as is true of any compound that contains a positive effect agent within the intentions of the invention. Both lipophilic and hydrophilic drugs can be used. Medicines for the treatment of cough, cold and allergic symptoms are of greatest concern. They include: antihistamines, anti-inflammatory drugs, analgesics, antipyretics, nasal decongestants, expectorants, sedatives when used as cough and cold medicines, and the like. Most preferred are phenylpropanolamine hydrochloride, caramifene edizylate, acetaminophen, acetosalicylic acid or other non-steroidal anti-inflammatory drug, pseudoephrine hydrochloride, dextromethorphan hydrobromide and chlorpheniramine maleic acid.

As regards particle size, the basic criterion is that the particles are visible to the naked eye through the matrix under normal illumination. The size of the beads in the pocket may be different. Preferably, the beads have a diameter of about 149 to 1190 microns. Most preferably, the particle size is between 420 to 840 microns (about 20 to 40 mesh). The particle size may vary in a given formulation or particles of different close ranges may be processed in confectionery and these end products may be mixed to allow the selection of preparations with different particle sizes.

The particles may contain the active ingredient alone or, more often, the active ingredient is coated with a protective layer that may or may not affect the rate of dissolution of the particles and the release of the active ingredient. Particle formation from the active ingredient itself is primarily shaped from the raw material in different ways, usually mechanically. The coating may represent protection of the undiluted compound. Sometimes it is necessary to coat the particles for functional and anesthetic reasons. There are a number of methods for coating particles. For example, the auctioning is a well established technology that provides a base pellet. The improved approach involves the formation of a core and then one or more layers of core shell are added. If the grains are differently coated, i. if some have a thinner coating layer and any particles with different coating thicknesses are introduced into the capsule, the drug may be released for a longer period of time. This technology was introduced by R. H. Blyth in US Patent 2,738,303. There is described a therapeutic composition in a single dosage form prepared from small grains (sugar pellets), screened, placed on a coating pan moistened with syrup, then treated with a 80:20 mixture of dextroamphetamine sulfate and calcium sulfate dihydrate, then dried. This procedure was repeated several times to apply the drug to the fine grain; it is then treated with talc to form a core pellet. These pellets are further treated with a wax-and-fat coating solution 1 or more times to form pellets with one or more fat layers surrounding the pellet core. Recent developments include placing an osmotic wall around the pellet core and formulation where the drug dissolves in the particles of the material that makes up the wall and passes through it for water exposure. Reference to such particles can be found in the literature, for example, in US Patent 4,434,153; significant parts are supported by citations. See also U.S. Patent 4,961,932, which provides a basic list of patents that relate to small or small pills and dosage forms containing them.

The particles may be prepared as monochromatic or of different coloration, if desired. Colorants and shades may be of any kind, as long as they are non-toxic or have no adverse or detrimental effect on the user. For example, the blue particle may be ready for use with transparent white wax lozenges. Or, red, white and blue beads could be incorporated into the sorbitol base to provide aesthetically pleasing lozenges.

The stability of the particles as compared to the stability of the active substance is another factor to be considered. The particles must remain chemically and physically stable under the conditions of production of the fingertips. Furthermore, the particle and the matrix must not undergo any kind of chemical or physical interaction in production. It is not possible to identify or define all conditions or combinations that could lead to particle-matrix interactions. Particle shells known to be soluble in core sorbitol or syrup should not be used in the formation of coated grains where the matrix-forming agent is sugars.

The stability of the positive agent is taken into account as is, with any formulation, not exclusively with these formulations. There is no simple recipe for the preparation of a substance that will not be chemically degradable. Each preparation must be weighed on a case-by-case basis; depending on the experience of the person skilled in the art.

Once manufacture is complete, there are no limitations of the invention in practice. For example, Lozenges are commonly produced by preparing a sugar base in combination with ingredients and cooking the mixture, with or without stirring, to form a feedstock from which the lozenges are prepared. Then, the portion of this mixture which is maintained at elevated temperature to remain liquid is used as a solvent; the particles are added to the liquid mixture with stirring to form a dispersion. This material is then poured into a mold, cooled and packaged.

Alternatively, the products may be manufactured by injecting molding techniques. This approach is particularly useful when waxes are used as matrix forming agents. The heated mixture and particles are passed through an injection molding apparatus in a manner such as filling a mold that allows the product to cool during manufacture. Or, the premixed stream at room temperature under pressure is introduced into the molds to avoid the cooling step. As a third alternative, the matrix-forming material feedstock mixed with the particulate stream feedstock is passaged through a mixing apparatus and injected into the mold to form the final product. Other injecting molding methods are also within the meaning of the invention.

The resulting product can be packaged without special handling instructions. Usual measures, such as the need to exclude moisture or UV radiation, should be taken into account. While it is preferred that the contents and particles in the matrix be visible to the consumer before opening the package, in accordance with the invention, the product could also be packaged in opaque containers or overpacks.

Any form or shape can be used according to the invention. The prints or lozenges may be of uniform shape, such as oval, square, rectangular or multifaceted. Geometric forms can be used. Shapes representing characters or objects, whether real or fictional, may be prepared, especially when injection molding techniques are used. The shape and form depend only on the imagination of the manufacturer.

The following examples serve to illustrate the invention. They do not limit the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of wax matrix heads containing grains

The required amount of white wax was placed in a glass cup and heated in an oil bath on a hot plate until the wax melted. Grains obtained from Central Pharmaceuticals, Inc. Seymour, Indiana, was poured into the melted wax and mixed with a spatula to obtain a homogeneous suspension. The melted wax / grain suspension was carefully poured into molds, allowed to cool to form hard heads. These heads were then removed from the mold.

The active ingredients in the beads were chlorpheneramine maleate 12.0 mg and phenylpropanolamine hydrochloride 75.00 mg. These beads were coated differently so that some beads release the active ingredients immediately and some at several time intervals for 12 hours.

Example 2

Preparation of clear lozeng matrix heads containing beads

The prototypes of the clear lozeng matrix granules containing the beads were prepared as follows:

The required amount of a 96: 4 mixture of sorbitol (70% solution) and lysine was added to a steam jacket cooker and boiled until the water was evaporated. Vacuum was then applied to the vessel and boiling continued until all the bubbles in the liquid sugar dispersion had disappeared. The molten sugar mass was filled into a steel container and stored in a thermostate at 110 C. The required amount of sugar base was transferred to a glass container and placed under a mechanical mixer. Grains obtained from Central Pharmaceuticals, Inc. Seymour, Indiana was poured into the sugar base and mixed until a homogeneous suspension was formed. The sugar base / grain suspension was seeded with a few crystals of sorbitol (Neosorb) and was carefully poured into the mold. The molds are placed on a heater at 40 ^e C, allowed to cool and form hard head. These heads were then removed from the molds.

The active ingredients in the beads were chlorpheniramine maleate 12.0 mg and phenylpropanolamine hydrochloride 75.0 mg. These beads were coated differently so that some beads release the active ingredients immediately and some at several time intervals for 12 hours.

Claims (9)

PATENT CLAIMS What is claimed is: 1. A pharmaceutically acceptable composition comprising at least one pharmaceutically acceptable transparent or semitransparent solid matrix former in which small particles containing at least one active agent are retained. The composition of claim 1, wherein the matrix former is wax or edible sugar and said particles are granules having a diameter of between about 149 to 1190 microns. The formulation of claim 2, wherein the active agent is a medicament. Composition according to claim 3, characterized in that the grains are gradually or immediately released and contain medicaments for the treatment of cough, cold and / or 1 allergic symptoms. ' Composition according to claim 1, characterized in that the grains are gradually or immediately released and contain medicaments for the treatment of cough, cold and / or allergic symptoms. 6. A method of making a composition according to claim 1, which comprises injection molding. The method of claim 6, wherein the matrix former is wax. The method of claim 7, wherein the composition comprises beads that are disintegrating or non-disintegrating. The method of claim 7, wherein the composition comprises at least one wax as a matrix former, and the particles are granules comprising sustained or immediate release granules comprising medicaments for treating cough, cold and / or allergic symptoms.