CH661663A5 - DOSAGE FOR DRUGS IN MICROCAPSULES WITH SUESSER MATRIX. - Google Patents

Description

The invention relates to a manner in which medication can be administered orally to children or others in a convenient manner so that the taste of the medication is completely obscured. In particular, the invention relates to a form of medicament which permits such an application.

Oral administration is one of the most common methods of administering drugs to the body because it allows the patient to self-medicate. With this dosage form, the pleasant taste is an extremely important factor in the packaging of pharmaceutical dosage forms. Because of the very unpleasant taste of many drugs, the value of many drugs is significantly reduced. This is particularly common with funds for children, but also applies to adults. To overcome these problems of unpleasant and bad taste, numerous flavorings have been used in pharmaceuticals. It is very common to give medicinal products to children as flavored syrups. Unfortunately, the flavoring only masks the unpleasant taste in the mouth, but has very little effect on the actual taste. A number of medicines have a particularly bitter taste and even adults are reluctant to take them. In many such cases, even syrups cannot mask the bitter taste, which is a difficult pharmaceutical problem.

Chocolate is one of the flavoring agents used for masking. Examples of patents in which chocolate is used in connection with medicaments include U.S. Patents 4,271,142 and 15,432,777, 3,697,641 and 199,139, and British Patents 543,309 and AU Patent 7310 / 32. Vitamin supplements for children that are encased in chocolate are also known and on the market, but some of the vitamins are not sufficiently stable in these products. Laxatives in chocolate 20 lade are also well known. In all, however, the unpleasant taste is only masked and the medication still affects the smell and taste of chocolate and the pleasant taste of the medicine is not significantly improved. In addition, stability problems can arise from the direct contact of the drug with the chocolate.

To allow the release of orally administered drugs within selected parts of the digestive tract, i.e. in the stomach or intestinal area, pills 30 were developed in which the medication is protected with a desired coating. A more recent pharmaceutical form for this purpose are microencapsulated drugs, where a tablet (or large capsule) contains several hundred small (about 0.5-0.8 mm large) capsules (called microcapsules 35), which in turn contain the drug. The type of coating that encapsulates the drug is selected depending on the medication desired and the desired release.

The aim of the invention is a new form of medication 40 for oral administration, further a new form of medication for oral administration, completely eliminating the unpleasant taste and mouthfeel of the medicament, and the provision of a new form of medication which is suitable for both Children as well as for 45 adults is very tasty. Another goal is to enable the administration of medication for children in such a way that it is tasty for the child, that is to say the use of the new pharmaceutical form, in particular for children.

These and other goals are achieved according to the invention by introducing the active ingredient to be administered into microcapsules and embedding the microcapsules in a soft, sweet, tasty matrix, such as chocolate. The combination of the encapsulation of the drug or drug and the use of the soft, sweet matrix, such as chocolate, achieves both the goal of preventing the unpleasant taste that the drug can have and of overcoming the taste problems that may arise if you try to take the medicine yourself. Encapsulation prevents the unpleasant taste that many medicines have, and the chocolate matrix serves as a way to overcome the problem of ingestion. In addition, the encapsulation prevents the drug from causing a flavor change in the chocolate itself, which inevitably occurs when drugs are mixed directly with a chocolate matrix without first being housed in microcapsules, and it also prevents loss of stability.

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lity of the drug by switching off the direct contact of the drug with the chocolate.

This combination completely eliminates the unpleasant taste of the medication and the patient only tastes the chocolate or the other sweet, soft matrix. Obviously, this system is superior to other existing methods.

As the soft, sweet matrix according to the invention, any savory food can be used that can be kneaded or eaten and swallowed easily without substantial chewing, preferably a pack that has a sweet taste and is easily accepted by children and adults. Although chocolate is the preferred matrix, it should be noted that other soft, sweet matrices, such as fudge (crumbly soft caramel *), marshmallow (foam confectionery with mostly tough, elastic consistency *), peanut butter, locust bean or locust bean gum, solid yoghurt or even bakery products from suitable Consistency as a matrix can be used alone or in combination with other matrices. The matrix is not intended to be hard, like hard confectionery, since the strong pressure that would be required to chew such a matrix would break the microcapsules and thus destroy the purpose of the invention. A soft chocolate such as sweet or milk chocolate is ideal for this purpose, since no substantial chewing is required to completely knead the chocolate and the embedded microcapsules can be chewed and swallowed without breaking.

The microcapsules should be small in size to enable easy and pleasant consumption. For example, the size should be less than 2 mm in diameter, preferably less than 1 mm in diameter, in particular in the range from 10 to 100 μm. The smaller the microcapsules, the less easily they will be noticed by the patient and the less likely they will be chewed but swallowed intact.

A very wide range of medicaments is suitable for inclusion in the microcapsules used according to the invention. Such drugs include antibiotics and other antibacterial agents, analgesics, antihistamines, laxatives, anti-inflammatory agents, antihypertensive agents, hypnotics, sedatives, tranquilizers, alkaloids, diuretics, vasodilators, hormones, vitamins or any other medication that is commonly used in oral Dosage form is administered. Those with a particularly bitter taste, such as penicillin, are of course particularly suitable for use in the present invention.

Suitable antibiotics include penicillins, cephalosporins, tetracyclines, chloramphenicol, streptomycins and macrolides. Suitable fully synthetic antibacterial agents include nitrofurantoin and the sulfonimides. Suitable anti-inflammatory or analgesic agents include aspirin and acetaminophen. Suitable psychotropic drugs include methyldopa and guanethidine. Suitable diuretics include aminophy-lin and acetazolamide.

Antibacterial agents include benzylpenicillin, phenoxymethylpenicillin, ampicillin and its pivaloyloxy methyl or phthalate esters, amoxycillin, cloxicillin, diclo-xicillin, flucloxicillin, carbenicillin, propicillin, methicillin, cephalecyclinin, cephalogininin, cephalogininin, cephalogininin, cephalogininin, cephalogininin, cephalogininin, cephaloginin, cephaloginin, cephaloginin, cephaloginin, cephaloginin, cephalogin Neomycin, chloramphenicol, sulfathiazole, succinylsulfathiazole, sulfadimidine, streptomycin, erythromycin, fusidic acid, griseofulvin, kanamycin, lincomycin, spiramycin,

* see Dr. Oetker "Food and Nutrition", Ceres-Verlag. Rudolf-August Oetker KG, Bielefeld, 2nd edition, 1983.

Sulfamethoxypyrideazine, sulfaphenazole, salicylazosulfapyridine, sulfamethoxazole and trimethoprin.

Suitable vitamins or nutritional supplements include thiamine, niodtinamide, ascorbic acid, pyridoxine, ri-boflavin, tryptophan, pantothenates, glycerophosphates and mixtures of these and other vitamins.

Other drugs include alcofenac, theophylline, hexobendine, xylamide and 0- (4-methoxyphenyl-carbamoyl) -3-diethyl-aminopropiophenone oxime.

Usually, all drugs that are to be placed in microcapsules can be considered their usual salts. Hydrates or the like can be used.

This list is not intended to be exhaustive, since any medicament that can be placed in microcapsules can be administered in the form of the present invention.

A wide range of encapsulants and encapsulation methods can be used in accordance with the invention. The only limitation on the encapsulation material is that it must be such that the active core material does not come into contact with the chocolate or other matrix during manufacture or storage; it must be non-toxic and harmless, it must release the core material in the stomach or gastrointestinal tract, and it must be compatible with the sweet matrix. Any encapsulation material known in the art can be used in accordance with the invention, as can any method of microencapsulation. For example referred to the methods of microencapsulation, which are described in Sparks, R.E., "Microencapsulation", Kirk-Othmar Encyclopedia of Chemical Technology, 3rd edition, vol. 15 (1981), pages 470-493. As is known, the microencapsulation material can be selected so that there is a delayed release or a release in a preferred area of the digestive tract (e.g. stomach or intestine). A method is preferably chosen such that the highest possible percentage of the microcapsules is the active substance. For example, U.S. Patent No. 4,016,254 shows a method for microencapsulation, wherein the microcapsules have an average diameter of 100 µm to 300 µm and contain 94-99.9% of a medicament that is covered by 0.1-6% coating agent is. See also U.S. Patent 3,119,742. Thus, any microencapsulation method can be used to make the encapsulated medicament for use in the invention. The invention does not relate to the operation of microencapsulation as such, but only to the use of medicament microcapsules in a sweet, soft matrix, such as chocolate.

The amount of microcapsules introduced into a single unit dose depends on the desired dosage of the active substance in question which is to be administered. For example, 200 mg easily in the form of microcapsules and dispersed in a unit dose of the size of a bite of the matrix in such a way that this amount is practically imperceptible to the people eating the matrix. The maximum amount of microcapsules that can be introduced into the matrix depends to a large extent on the size of the microcapsules and the smaller the microcapsules, the greater the amount that can be introduced without being perceived when the matrix is ingested by the person concerned. In the case of extremely small microcapsules of the order of magnitude, e.g. In carbon-free copy papers, it is easily conceivable that quantities of up to 50% or even more can be used without adversely affecting the consistency of the matrix. If e.g. B. the chocolate piece dose is very low, then the unit dose

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amount of active ingredient in very small microcapsules is 500 mg in 1 g chocolate. Such a large filling is, however, not a preferred embodiment, since a considerable breakage of the microcapsules during chewing seems almost inevitable. The filling should therefore preferably not exceed about 25-30% of the weight of the matrix and particularly advantageously it is less than 10% depending on the average dose of the active ingredient to be administered and the desired size of the unit dose of the matrix. A dose of the matrix which is practically the size of a bite usually amounts to about 1 to 15 g, depending on the density of the matrix.

If the matrix is chocolate, the microcapsules are preferably incorporated into the chocolate during its original manufacturing process. For example, sweet chocolate and milk chocolate obtained by mixing cocoa butter, sugar, chocolate liquid and, in the case of milk chocolate, milk or milk solids. These components are brought to a fine particle size and then subjected to the treatment known as “conching”, which is a kneading process in which chocolate is slowly mixed and moisture and volatile acids are slowly released while the remaining chocolate paste is smoothed . The conching temperatures for sweet chocolate are usually in the range of 55-85 ° C and for milk chocolate 45-55 ° C. Aromas and flavors, emulsifiers and the like are usually added during the conching process. The most suitable time for adding the microcapsules used according to the invention in the course of chocolate production is therefore also during the conching process. Care must of course be taken to ensure that there is sufficient mixing in order to achieve a practically homogeneous distribution of the microcapsules, so that there is an exact amount of active ingredient in each calculated unit of weight of the chocolate.

Following the conching process, the product is standardized, annealed and shaped in the usual known manner.

The microcapsules need not be added during the conching process, but can be added in any suitable process step during chocolate production or in such a way that the finished chocolate is taken, melted, mixed with microcapsules, mixed until homogeneous and then again is deformed.

Of course, the manner in which the microcapsules are added to the chocolate or other soft, sweet matrix is not critical and any method can be used, provided that a practically homogeneous distribution of the microcapsules is achieved.

example 1

The microcapsules used in this example were the drug "Contac", manufacturer Menley & James Laboratory (a Smith-Kline company). Each capsule contained 600 microcapsules, each about 0.5-0.8 mm in diameter. The microcapsules were produced by the so-called pan coating process. Each capsule, i.e. 600 microcapsules each contained 75 mg of phenylpropanolamine hydrochloride and 8 mg of chlorpheniramine maleate.

The 600 microcapsules of a Contac capsule were embedded in chocolate by first placing a commercially available chocolate bar in an aluminum pan container

Melt heated (50 ° C) and then the microcapsules were added and mixed until a homogeneous distribution of the capsules in the chocolate matrix was achieved, which took about 3 minutes. The chocolate was immediately chilled and molded into a unit dose of approximately 32 x 20 x 9 mm.

When chewing this chocolate, no taste of the drug was detectable, in contrast to a strong, unpleasant taste that was perceived when the capsules were chewed without the chocolate. In addition, there was practically no grainy feeling when chewing the chocolate pieces.

A sample of this chocolate was stored for more than 1 month at room temperature and then visually inspected and the stability of the drug was analyzed by mass spectroscopy. After one month there was no change in the shape or number of embedded microcapsules and 100% of them could be recovered from the chocolate matrix. The mass-20 spectrometric analysis of the embedded encapsulated drug showed results identical to that of a control sample (i.e., original microcapsules stored in a commercially available package). The embedding of the microcapsules in the chocolate matrix therefore had no effect whatsoever on the stability or the chemical or physical state of the active substances present in the microcapsules.

Example 2

30 The microcapsules used in this example were the drug “Sudafed, S.A.”, manufacturer Burroughs Wellcome Co. .. Each capsule contained about 300 microcapsules (diameter 0.6-0.9 mm). Each large capsule contained 120 mg pseudoephedrine hydrochloride. These 35 microcapsules were embedded in a single ordinary chocolate unit following the procedure described in Example 1. When chewing and swallowing these chocolate tablets, there was no unpleasant taste of the medicine.

Example 3

Microcapsules of aspirin coated with a hydrolyzed protein (gelatin) and having an average diameter of 1.7-2.0 n, each microcapsule containing 99% aspirin, were prepared according to the method described in Example 59 of the US patent 4 016 254 described procedure. 40.4 g of these microcapsules were added to 1 kg of milk chocolate during the conching process stage of the process for producing this chocolate. After mixing until homogeneous, the chocolate was standardized and tempered, in the usual known manner, after which it was poured into molds, to produce unit doses of approximately 5 g each. Each 55 units contained microcapsules containing 200 mg aspirin. The chocolate units could be chewed and swallowed without an unpleasant aspirin taste.

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Example 4

Aspirin microcapsules encased in hydroxyphenylmethyl cellulose were made using an all-metal, conical Uni-65 Glatt 4 "sausage apparatus. The average size of the aspirin microcapsules was 80-180 (i and each microcapsule contained 93% aspirin and 7% wrapping material.

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A similar coating was carried out under the same conditions using cellulose acetyl phthalate as the wrapping material.

The microcapsules produced as stated were embedded in chocolate (100 mg encapsulated material per 1.5 g chocolate) according to the procedure described in Example 1. When chewing and swallowing the chocolate tablets obtained, no unpleasant taste of the drug was perceived.

Example 5

Acetaminophen was encapsulated in 2.4% ethyl cellulose (Ethocel) and 1.0% hydroxypropyl methyl cellulose phthalate (HP 50). This coating was carried out in an Aeromatic Strea-I fluid bed device. The average size of the microcapsules obtained was 80-120 [im. The microcapsules were embedded in chocolate (100 mg encapsulated material per 1.5 g chocolate) according to the procedure described in Example 1. When chewing and swallowing these chocolate tablets, there was no unpleasant taste of the drug.

Examples 6-13

The following drugs, each in an encapsulated form, approximately 500-600 nm in diameter, were embedded in 1.5 g of chocolate in the unit dose shown in the table below. In any case, there was no unpleasant taste after the drug when the chocolate formulation was chewed and swallowed.

Example No. Active ingredient unit dosage

6

Theophylline

200 mg

7

Chlorpromazine

75 mg

hydrochloride

8th

Chlorpheniramine maleate

8 mg

9

Erythromycin

250 mg

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Iron (II) sulfate

167 mg

heptahydrate

11

Nitroglycerin

2.5 mg

12

Papaverine hydrochloride

150 mg

13

niacin

250 mg

Based on the above explanation of preferred embodiments, numerous modifications within the scope of the invention are of course available to the person skilled in the art.

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Claims (10)

661 663 2nd PATENT CLAIMS 1. Dosage form for the oral administration of active pharmaceutical substances, characterized in that that the active substance is embedded in microcapsules in a soft, sweet, tasty matrix. 2. Dosage form according to claim 1, characterized in that there is a sufficient amount of microencapsulated active substance in this matrix to give a unit dose of this active substance in each unit the size of a bite of this matrix. 3. Dosage form according to claim 1, characterized in that the soft, sweet-tasting matrix is sufficiently soft to chew it without the need for strong chewing movements. 4. Dosage form according to claim 1, characterized in that chocolate, fudge, marshmallow, peanut butter, locust beans (kernel flour) or solid yogurt is used as the matrix. 5. Dosage form according to claim 1, characterized in that the matrix is chocolate. 6. Dosage form according to claim 1, characterized in that the matrix is sweet chocolate or milk chocolate. 7. Dosage form according to claim 1, characterized in that the active ingredient is an antibacterial, analgesic, antihistamine, laxative, anti-inflammatory, antihypertensive, hypnotic, sedative, tranquilizer, alkaloid, diuretic, vasodilator, hormone or vitamin. 8. Dosage form according to claim 1, characterized in that the microcapsules of the active ingredient have a diameter of less than 1 mm, preferably from 10 to 100 µm. 9. Dosage form according to claim 1, characterized in that the active ingredient is encapsulated in a material which prevents the active ingredient from coming into contact with the matrix during production and storage of the embedding matrix before use, is non-toxic and harmless and Release of the active substance in the stomach or gastrointestinal tract allowed after ingestion. 10. A process for the preparation of a dosage form for the oral administration of a pharmaceutical active ingredient, characterized in that the active ingredient is introduced into microcapsules and the microencapsulated active ingredient is embedded in a soft, sweet, tasty matrix.