CZ6696A3 - Preparation suitable for pharmaceutical application and process for preparing 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 composition suitable for pharmaceutical use and a process for its manufacture

Technical field

The invention relates to solid, transparent or semitransparent, pharmaceutically acceptable compositions (pills, lozenges) comprising one or more matrix-forming materials in which small particles containing at least one beneficial agent are retained. Such a form avoids the confusion of particles and their active agent and makes the compositions more resistant to damage and unmistakable.

BACKGROUND OF THE INVENTION

Pills, also known as lozenges or tablets, are disc-shaped solids containing the therapeutic agent in a suitably flavored base. The base may be a hard sugar candy, glycerinated gelatin, or a combination of sugar with a sufficient amount of vegetable slime to provide shape or form stability. These products are placed in the mouth where they slowly dissolve and release the active agent.

Pills can be prepared according to the recipe (magistraliter) by a trained and authorized person. The classic method is to add water to a mixture of powdered drug, sugar and gum until a greasy mass is obtained. This mass is formed into a roller and pieces are cut from the stick. The thermostable compounds may be formed into a hard sugar base; These compositions are usually called lozenges. The sugar syrup, with or without the binder, is thickened until it becomes a supple mass, at which point the active ingredient is added and the mixture is kneaded while warm to form a homogeneous mass. This warm mass is then treated in a mold to form a product that is cooled to form a hard candy. Production,

AND

- 2 based on compression, was used to prepare pills containing heat-labile ingredients. ^{J ~}

The present invention provides an advantage in the art by providing a pellet-like composition as a carrier for particulate matter, in particular a bead, through which the bead-like state can be maintained by the matrix-forming material. In addition, the integrity of the product, the pill, can be maintained at any time after manufacture and packaging.

and

SUMMARY OF THE INVENTION

The present invention encompasses a pharmaceutically acceptable composition comprising at least one pharmaceutically acceptable transparent or semitransparent solid matrix forming matrix in which small particles containing at least one beneficial agent are retained.

A second aspect of the invention is a method of making such articles using farm-casting (shaping).

The resulting product is a pharmaceutical composition comprising a type of edible matrix-forming material in which small particles that contain or contain the active agent are trapped. The matrix forming material is a certain edible material that is a solid at ambient temperature and is transparent or semitransparent to a degree no higher than to allow the user to see some or all of the trapped particles when viewed with the naked eye under normal light conditions. The lozenge and pill compositions are illustrative of the compositions which are included within the scope of the invention. The composition of lozenges and pills can be found in such texts as, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Co., Easton, PA, USA on pages 1644-1665 (1990) and Sugar Confectionery.

- 3 Manufacture, E, B. Jackson, edited by Van Nostrand Reinhold, New York, on pages 245-247 ”(Τ9'δΓ0 ') 7

With respect to matrix-forming materials, any materials known in the art that are edible, solid at ambient temperature, are not plastic or ductile at such temperature, are able to serve as a matrix for small particles and allow to see trapped particles may be used in such formulations. The matrix may be formed using a single compound, for example a wax or sugar, or a mixture of substances may be used. The compositions may contain two or more substances belonging to the same class of compounds, such as mixed sugars, or may be mixtures of compounds from two or more classes, such as mixtures of sugar, wax and polyol.

If mixtures are used, they can be used in a manner that allows the constituents to retain their original identity, or they can be converted into another form of association during the manufacturing process _. subunits to form a different chemical entity that occurs during polymerization or crosslinking.

Preferred matrix forming materials are sugars and ₅ waxes. Sugars such as sucrose, dextrose, fructose are preferred. sorbitol, lycaquine and other simple and complex sugars that can be used to form lozenges. The waxes include white wax, geluciruses, carnauba wax. hydrogenated vegetable oils, Lábrafily, Compritol 888 ATO, Preciroi. polyethylene glycols, beeswax, paraffins, microcrystalline wax, acetylated monoglycerides, cetyl alcohol and glycerol monostearate. A particularly preferred matrix forming agent is a white wax for use in the present invention.

The matrices that can be formed using the present invention can be of two types, disintegrating or non-disintegrating.

Non-decaying matrices can be formed using the hydrophobic matrix-forming materials described above. Crumbling

The 4 matrices may be formed using a combination of hydrophilic and hydrotropic matrices, as described above in the above list of materials. The ratio of hydrophobic and hydrophilic materials can be adjusted to obtain the desired decomposition time.

In addition to the use of hydrophilic matrix-forming materials, disintegrants in the form of a fine powder or spheres known in the art such as Ad-Di-Sol, Explotab, pregelatinized starches, crospovidone NF and others can also be added to the matrix materials.

Any kind of particle may be used in the composition, provided that they contain or include one or more beneficial agents, are stable in the matrix-forming material during manufacture and storage, and have a sufficient size and definition in shape and color such that they are visible in the matrix. Most preferred are colored beads as described below.

The term beneficial agent means any substance or material that acts in a mammal in a particular way when consumed for its intended use in a prescribed manner. For example, a drug is a beneficial agent for the purposes for which it is intended. However, there are a number of other compounds that may have an objective or subjective beneficial effect on the user and should be included within the meaning of the term. For example, an antacid (acid neutralizing agent) or anti-flatulent agent can have a beneficial effect when used to treat digestive problems. A breath freshener provides both objective and subjective benefits in many people. Nutritional agents such as vitamins, minerals, or amino acid supplements are also beneficial for those in need of supplementing their diet. Flavors and sweeteners provide a subjective benefit as well as an energy source and can also be included. However, these examples illustrate only a few of the many different types of substances that are considered to belong to

- 5 range of term beneficial Reagent. Others will be apparent to those skilled in the art.

Drugs and their dosage are of great importance here. The term medicament is used in the broadest sense and includes any agent that exerts a pharmacological effect on the user and which can be administered by means of particles using the technique described herein. Any solid or liquid form of the drug may be used, provided that it can be manufactured in particulate form, as is true of any compound that constitutes a beneficial agent for the purposes of this invention. Both fat and water-soluble drugs can be used. The greatest interest is given to medicines for, treatment of cough, colds (rhinitis) and allergic symptoms. They include antihistamines; medicines for the treatment of inflammation, pain and fever; nasal congestion reducing agents; expectorants (expectorants); sedatives used in cough and cold medicines and the like. Most preferred are phenylpropanolamine hydrochloride, caramiphene edisylate, acetaminophen, aspirin or other non-steroidal anti-inflammatory agents, pseudoephrine hydrochloride, dextromethorphan hydrobromide, and chlorpheniramine maleate.

Regarding the particle size, the essential aspect will be the formation of particles in a size such that they are visible to the naked eye under normal light conditions. The size of the beads may vary in each given capsule. Balls having a diameter of about 149 to 1190 μππ will be preferred. A preferred particle size is in the range of about 420 to 840 gm. The particle size may vary in a given formulation, or particles of different narrow ranges may be combined and these end products mixed to provide a choice of compositions with different particle sizes.

The beads may comprise the agent itself, or, more often, the agent may be covered with a protective layer that may or may not

Affect the rate of dissolution of the particle and the release of the active ingredient.

the beads of the reagent itself are mostly constituted by a mass to form the raw material by certain means, usually mechanical. Some kind of coating may be added to protect the clean particle. More frequent is the case when the particles will be covered by a cover for functional and aesthetic reasons. There are many ways of coating particles. A well known technique is

...... for example, a mastic coating providing a base tablet. A more complex approach is to create the core and add one or more layers of its shells. If the cores are coated differently, ie some have a thicker coating, any particles with different coating thicknesses are filled into one capsule and the drug can be released over an extended period of time. This technology was introduced by RH Blyth in U.S. Patent 2,738,303. It discloses a beneficial composition in the form of a dosage unit prepared from unpaired, unitary embryonic nuclei (sugar tablets), screened, placed in a coating pan moistened in a syrup, then treated with a 80:20 mixture of dextroamphetamine sulfate and calcium sulfate dihydrate and then dried. This procedure was repeated several times to incorporate the drug onto the non-parental germ nucleus. this is treated with talc to form a core tablet. These tablets were then treated one or more times with a wax-fat coating solution to form tablets with one or more fat layers surrounding the core tablet. Further developments include placing an osmotic wall around the core tablet and means wherein the drug is dissolved in the particle wall material and permeates the wall outside upon contact with water. References to such particles can be found in the literature, for example, in U.S. Patent 4,434,153; the corresponding parts are incorporated herein by reference. See also U.S. Patent 4,961,932, containing a basic list of patents relating to small or small pills and dosage forms containing them.

The particles may be prepared in one color or, if desired, in different colors. Dyes or mordant dyes of any kind

- 7 may be used provided they are not toxic or do not have an inappropriate or harmful effect on the user. For example, a particle may be prepared for use with a transparent white wax lozenge. Another possibility is to incorporate red, white and blue beads into the sorbitol base to provide an aesthetically pleasing lozenge.

Another factor to consider when forming beads is the stability of the beads as compared to the stability of the agent. The beads must remain chemically and physically stable under the conditions used to manufacture the pills. Moreover, once produced, the particles and matrix must undergo some kind of chemical or physical interaction. It is not possible to determine or determine all the conditions or combinations that may lead to interactions between the particles and the matrix. However, coatings of particles known to be soluble in tsorbitol or corn syrup should not be used to form coated beads when it is envisaged to use these sugars as matrix forming agents.

It is also necessary to consider the stability of the beneficial agent in conjunction with any formulation, not just these formulations. There is no simple recipe for forming a product that will not chemically decompose. Each means must be determined on a case-by-case basis, which is within the skill of the art.

With respect to manufacture, there are no limitations on the usual practice of the present invention. For example, lozenges are usually prepared by preparing a candy base by combining ingredients and boiling the mixture, with or without stirring, to form a feedstock from which lozenges will be prepared. Thereafter, the portion of this mixture which is maintained at elevated temperature to still be fluid is used as a diluent; the particles are added with stirring to the liquid mixture to form a dispersion. This material is poured into molds, cooled and packaged.

Another possibility is that the products can be manufactured by injection molding processes. This approach is ^; Especially suitable, waxes are used as matrix forming agents. The heated mixture of wax and particles is passed through the injection molding apparatus in such a way as to fill the mold and allow for cooling of the product during the production cycle. Alternatively, the premix mixture at ambient temperature is pressurized to form. removing the cooling step. A third possibility is that the feed stock to form the matrix may be mixed with the feed stock flow, passed through the mixer, and injected into the mold to form the final product. Other injection molding processes are considered to be within the scope of the present invention.

The end product can be packaged without special precautions. The usual considerations, such as the need to exclude moisture or ultraviolet light, should be taken into account. If such a package of product is preferred that would allow the consumer to see the contents and particles in the matrix prior to opening the package, the invention may be practiced in connection with packaging the product in a transparent container or outer wrapper.

Any form or shape may be used in the present invention. The pills or lozenges may be oval, square, rectangular, or have a multifaceted shape. Geometric forms can be used. Shapes that represent persons or things, whether real or imaginary, may also be prepared, particularly when using injection molding techniques. The shape and form are limited only by the imagination of the skilled person.

The following examples are intended to illustrate the invention. They are not to be construed as limiting the invention in any way.

- 9 Examples of the Invention

Example 1

Preparation of hard tablets containing beads in a wax matrix

The required amount of white wax was placed in a glass beaker and heated in an oil bath until the wax melted, using a hot plate. The beads, obtained from Central Pharmaceuticals, Inc, Seymour, Indiana, were poured into molten wax and mixed with a spatula to obtain a homogeneous suspension. The molten wax and bead suspension was carefully poured into molds and allowed to cool and form hard tablets (tablets consisting of a hard soluble outer layer surrounding the drug). These tablets were then knocked out of the molds.

The active ingredients in the beads were chlorpheneramine maleate (12.0 g) and phenylpropanolamine-HCl (75.0 mg). These beads were unevenly coated, so that some beads released the active ingredients immediately and others at several time points over a 12 hour period.

Example 2

Preparation of hard tablets containing beads in clear lozenge matrix

Prototypes of hard paste matrix tablets containing beads were prepared as follows:

The required amount of a 96: 4 mixture of sorbitol (70% solution) and lysine was added to the steam jacket and boiled until all the water had evaporated. A vacuum was then set in the vessel and boiling continued until all of the liquid candy dispersion had disappeared.

- 10 bubbles. This molten candy was emptied into a stainless steel container and stored in an oven at a temperature of 11o ~ ^e G. The required amount of candy base (base) was transferred into a glass beaker and placed under a mechanical stirrer. The beads, obtained from Central Pharmaceuticals, Inc, Seymour, Indiana, were poured into a candy base and blended to obtain a homogeneous suspension. The candy base suspension of the beads was inoculated with several crystals of sorbitol (Neosorb) and carefully poured into molds. The molds were placed in an oven at 40 ° C and allowed to cool and form hard tablets. These were then knocked out of the molds.

The active ingredients in the beads were chlorpheneramine maleate (12.0 g) α-phenylpropanolamine-HCl (75.0 mg). These beads were unevenly coated, so that some beads released the active ingredients immediately and others at several time points over a 12 hour period.

Represented by:

Claims (8)

A composition suitable for pharmaceutical use comprising at least one pharmaceutically acceptable, transparent or semitransparent solid matrix forming matrix in which small particles containing at least one beneficial agent are retained. A composition suitable for pharmaceutical use according to claim 1, wherein the matrix forming agent is wax or edible sugar and said particles are spheres having a diameter of about 149 to 1190 microns. A composition suitable for pharmaceutical use according to claim 2, wherein the beneficial agent is a medicament. Composition for pharmaceutical use according to claim 3, characterized in that the beads are beads released over time, or immediate release beads containing medicaments for the treatment of cough, rhinitis and / or allergic symptoms. A composition suitable for pharmaceutical use according to claim 1, characterized in that the beads are beads released over time, or beads released immediately, containing medicaments for the treatment of cough, rhinitis and / or allergic symptoms. 6. A method of making a composition according to claim 1, comprising the use of injection molding. 7. The method of claim 6, wherein the matrix forming agent is a wax. 8. A method according to claim 7, characterized in that The composition comprises beads that are disintegrating or non-gnawing. ^~: ~ ~ -------- 9. The method of claim 7, and you z'n No Ujica t in that the composition comprises at least one wax as the matrix-forming, and the particles are beadlets comprising released over time, or beads, released immediately, containing medicaments for the treatment of cough, rhinitis and / or allergic symptoms.