FR2552665A1 - MICROENCAPSULE DRUG IN A SWEET MATRIX - Google Patents

Abstract

AN ORAL-ADMINISTRATIVE MEDICINAL PRODUCT IS PREPARED IN A DOSE FORM WHICH ELIMINATES DISASTERING TASTE AND SENSATION IN THE MOUTH OF THE MEDICINAL PRODUCT AND IS EASILY AND PLEASANTLY INGREDIENT, EVEN BY CHILDREN, BY MICROENCAPSULATION OF THE MEDICINAL PRODUCT AND MICROCAPSULATION OF THE MEDICINAL PRODUCT , SUGAR, PLEASANT TO TASTE, LIKE CHOCOLATE.

Description

The present invention relates to a mode of administration by

  oral drug to children or other people, which is pleasant and completely hides the taste of the drug More particularly, the present invention relates to a form of drug for such administration. Oral medication is one of the most popular methods of administering medication in the body, because it allows the patient to self-medicate. In this area, a pleasant taste is an extremely important factor in the formulation of pharmaceutical forms. L interest of many drugs is greatly reduced due to the unpleasant strong taste of many drug products This is particularly common among products administered to children, but also for adults Many flavors have been used with pharmaceuticals in order to overcome these unpleasant and unpleasant taste problems So it is very common to administer many medicines for children in the form of a scented syrup Unfortunately, the scent simply masks the unpleasant taste in the mouth, but only slightly changes the palatability drug has a particularly bitter taste and even adults reluctantly take it pregnant In many of these cases even syrups

  cannot mask the bitter taste, thus constituting a difficult pharmaceutical problem.

  Among the perfumes used to mask a taste, mention should be made of chocolate. Patents describing the use of chocolate with medicines, for example, are US Pat. Nos. 4,271,142 and 4,327,077 to Puglia et al., N 3,697,641 from Ahrens and N 199 139 from Clark, British patent N 543 309

  of Evans and Australian patent N 7310/32 of Jones et al.

  We also know the vitamins for children, which are coated with chocolate and available on the market; but in such products, some of these vitamins are not enough

  stable Laxatives in chocolate are also well known.

  In all of these products, however, the unpleasant taste is simply masked and the drug products still alter the flavor of the chocolate and the palatability of the drug is not

  significantly improved In addition, there may be stability problems caused by direct contact of the drug with the chocolate.

  In order to allow the release of drugs administered orally into selected portions of the digestive tract, i.e. the stomach or the intestine, pills have been developed in which the drugs are protected by the desired coating A more elaborate pharmaceutical form in this regard, consists of the microencapsulated drug, in which a tablet (or large capsule) contains several hundred tiny capsules (of approximately

  0.5 to 0.8 mm) called microcapsules, containing the drug.

  The type of coating encapsulating the drug is chosen according to the desired medication and the characteristics of

release sought.

  The object of the present invention is to provide a new form of medication for oral administration.

  Another object of the present invention is to provide

  a new form of medication for oral administration, in which the unpleasant taste and sensation of the medication in the mouth is completely eliminated.

  Another object of the present invention is to provide a new form of medicine whose taste appeals very much.

children, as well as adults.

  The present invention also provides a mode of administration of drugs to children, such that the taste of these pleases children.

  These and other objects are obtained in accordance with the present invention, by microencapsulation of the medicament to be administered and coating of the microcapsules in a tender sweet matrix, pleasant to taste like chocolate. The combination of the medicament and the use of a a tender sweet matrix, like chocolate, succeeds both in preventing the unpleasant taste possibly presented by drugs and in overcoming the problem of palatability, which can arise when trying to ingest the drug itself. encap5 sulation will prevent the unpleasant taste of many medicines and the chocolate matrix will overcome the problem of palatability In addition, the encapsulation will prevent the medicine from giving an aftertaste to the chocolate itself, which inevitably happens when the drugs are directly mixed with the chocolate matrix without prior microencapsulation and will avoid a loss of stability of the drug by removing a contact of direct from

this one with chocolate.

  This combination completely eliminates the unpleasant taste of the drugs and the patient will only feel the

  flavor of chocolate or other tender sweet matrix.

  This system is obviously superior to any other method

already existing.

  The sweet and tender matrix used in accordance with the present invention can be any palatable food which can be chewed without chewing and is easily swallowed; it is preferably a confection of sweet taste and easily accepted by children or adults. Although chocolate constitutes the preferred matrix, it is understood that other soft and sweet products can be used as matrix, like fudge (American fondant), marshmallow, peanut butter, locust bean, carob, solid yogurt or even patties of suitable consistency, alone or in combination with other dies The die cannot be hard , like hard candies, because the high pressure which would then be involved during the chewing of this matrix, would break the microcapsules and thus destroy the interest of the present invention Soft chocolate like milk or fondant chocolate, is ideal for this is because it does not have to be chewed much to complete its chewing and, moreover, chocolate with the coated microcapsules can be

  chewed and swallowed without breaking the microcapsules.

  The microcapsules must be small in size to ensure a pleasant and mellow taste. Thus, the dimension must be less than 2 mm in diameter, preferably less than 1 mm in diameter and more advantageously in the range of 10 to 100 microns. The more the microcapsules are small and

  the less likely they are to be noticed by the patient, the more likely they are to escape chewing and to be swallowed essentially intact.

  A very wide range of drugs can be included in the microcapsules used in the present invention. These drugs include antibiotics and other antibacterial agents, analgesics, antihisminics, decongestants, anti-inflammatory agents, antihypertensive agents , hypnotics, painkillers, tranquilizers, alkaloids, diuretics, vasodilators, hormones, vitamins, or other commonly used drugs in an oral dosage form Medications with a particularly bitter taste, such as penicillin, obviously particularly suitable for use

in the present invention.

  Suitable antibiotics include, for example, penicillins, cephalosporins, tetracyclines, chloramphenicol, streptomycins and macrolides. Suitable completely synthetic antibacterial agents such as nitrofurantoin and sulfonimides can be used.

  Suitable anti-inflammatory or analgesic agents include aspirin and acetaminophen. Suitable sphyco30 tropes drugs include methyldopa and guanethidine.

  Suitable diuretic agents are aminophyline and acetazolamide. Suitable anti-bacterial agents include

  benzylpenicillin, phenoxymethylpenicillin, ampicillin 35 and pivaloyloxymethyl or phtalytic esters, amoxy-

  cillin, cloxicillin, dicloxicillin, flucloxicillin, carbenicillin, propicillin, methicillin, cephalxin, cephaloridine, cephaloglycin, cephalothin, tetracycline, oxytetracycline, chlorotetracycline, chlorotetrine5, chlorotetracycline chloramphenicol, sulfathiazole, succinyl sulfathiazone, sulfadimidine, streptamycin, erythromycin, fusidic acid, griseofulvin, kanamycin, lincomycin, spiramycin,

  sulfamethoxy pyrideazine, sulfaphenazole, salicylazo10 sulfapyridine, sulfamethoxazole and trimethoprine.

  Suitable vitamins or nutritional supplements include thiamine, nicotinamide, ascorbic acid, pyrldoxin, riboflavin, tryptophan,

  pantothenates, glycerophosphates and mixtures of these and other vitamins.

  Other drugs include alkofenac, theophylline, hexobendin, xylamide, and O- (4-methoxyphenylcarbomoyl) -3diethylaminopropiophenone oxime

  Any of the microencapsule drugs can normally be used in the form of its conventional salts, hydrates or the like.

  This list is not exhaustive insofar as any drug that can be microencapsulated can be administered

  according to the method of the present invention.

  It is also possible to use in the present invention, a wide range of encapsulation agents and encapsulation methods. The only limitations concerning the encapsulation material lie in that it must be such that the active material constituting the core does not come into contact with chocolate or other matrix during production or storage, must be non-toxic and harmless, must allow the release of material from the core in stomach or gastrointestinal tract and be compatible with the sweet matrix Any capsule material known in the art can be used in the present invention and any microencapsulation method can be used See, for example, microencapsulation methods described by RE Sparks,

  "Microencapsulation", Kirk-Othmer Encyclopedia of Chemical 5 Technology, third edition, volume 15 (1981), pages 470-493.

  It is well known that the microencapsulation material can be chosen for its continuous release properties or for its ability to release a product in a preferred region of the digestive tract (for example, the stomach or the intestine). It is preferred to use a method such that it provides microcapsules of which the largest possible weight percentage is constituted by the active material. For example, US Pat. No. 4,016,254 describes a microencapsulation method according to which the microcapsules produced have an average diameter of 15 100 to 300 μm and include 94% to 99.9% of a drug coated with 0.1 to 6% of a coating agent See also US Patent No. 3,119,742 Any microencapsulation procedure known in the art may be used or discovery in the future, for manufacturing the encapsulated drug useful in the present invention The present invention does not relate to microencapsulation techniques in themselves, but only to the use of mi drug crocapsules

  in a sweet, tender matrix, like chocolate.

  The amount of microcapsules to be loaded in a single unit dose will depend on the dose of the pharmaceutical product to be administered. For example, a dose of 200 mg can easily be put into microcapsules and dispersed in a unit dose of matrix of the size of a bite, so that those who eat the matrix will hardly perceive this dose The maximum loading of microcapsules in the matrix will be largely dependent on the size of the microcapsules; the smaller the microcapsules and the greater the quantity that can be loaded without being noticed during ingestion of the matrix In the case of very small microcapsules, for example of the order of the size of the particles used in duplicating papers without carbon, it is conceivable that amounts of up to 50% or even more could be used without harming the consistency of the matrix For example, if the dose of chocolate pieces is very small, a unit dose of drug included in very small microcapsules, can be 500 mg in 1 g of chocolate However, We do not prefer such a large loading, because it is then practically inevitable to have a notable rupture of the microcapsules during chewing However, the loading should preferably not exceed about 25 to 30% of the weight of the matrix and it should more preferably be less than 10%, depending on the average dose of the particular drug. area to be administered and the desired size for the unit dose of matrix A dose of matrix having substantially the size of a mouthful will generally be about

  1 to 15 g, depending on the density of the matrix.

  When the matrix is chocolate, the microcapsules are preferably added to the chocolate, during its initial production process. For example, dark chocolate and milk chocolate are made by mixing cocoa butter, sugar, liqueur chocolate and, in the case of milk chocolate, milk or milk solids These elements are then refined to a small particle size and then subjected to kneading Kneading is a kneading process in which one mixes slowly chocolate by letting moisture and volatile acids go away while smoothing the remaining chocolate paste

  kneading for fondant chocolate are generally in the range of 55 to 85 C and 45 to 55 C for milk chocolate.

  It is conventional to add perfumes, emulsifiers, etc. during mixing. Thus, the most appropriate time to add the microcapsules of the present invention is during mixing. Obviously, care must be taken to ensure sufficient mixing in order to obtain a distribution. practically homogeneous microcapsules, so that there can be a precise amount of drugs in any

given unit weight of chocolate.

  The product is standardized, softened and molded according to well known methods, following kneading. It is not necessary to add the microcapsules during the kneading, but they can be introduced at any suitable stage of the production of the chocolate or else, the finished chocolate can be taken, melted, the microcapsules added to it, mix until homogeneous and mold it

again.

  It should be understood that the mode of addition of the microcapsules in chocolate or another sweet, tender matrix is not critical and that any procedure can be used as long as a distribution is obtained.

  practically homogeneous microcapsules.

  In addition to the foregoing provisions, the invention also comprises other provisions, which will emerge from the

description which follows.

  The invention will be better understood using the complement

  of description which will follow, and which refers to examples

  for implementing the process which is the subject of the present invention.

  It should be understood, however, that these examples of implementation are given only by way of illustration of the subject of the invention, of which they do not constitute

no way a limitation.

Example 1

  The microcapsules used in this example are those of the industrial drug "Contac" manufactured by the Menley 30 and James Laboratory (Smith Kline Company) Each capsule contains 600 microcapsules each having a diameter of approximately

  0.5 to 0.8 mm The microcapsules are prepared by coating. Each capsule (that is to say 600 microcapsules) contains 75 mg of phenylpropanolamine hydrochloride and 8 mg of chlorpheniramine maleate.

  The 600 microcapsules of a "Contac" capsule are coated in chocolate, by heating a square of commercial chocolate, until melting (50 C) in an aluminum container, then adding and mixing the microcapsules until obtaining a homogeneous distribution of the capsules in the chocolate matrix, which takes approximately 3 minutes. Then the chocolate is immediately cooled and

  mold in one unit measuring approximately 32 x 20 x 9 mm.

  When this chocolate is chewed, no drug taste is observed compared to the pronounced taste noted during the chewing of the capsules in the absence of chocolate. In addition, one does not at all have the impression of eating granules

  when you chew the chocolate pieces.

  A sample of this chocolate was kept for one month at room temperature and observed by eye, then the stability of the drug was determined by mass spectroscopic analysis. After one month, there was no change in the form or in the number of coated microcapsules and 100% of these could be recovered from the chocolate matrix Mass spectrometric analysis of the coated encapsulated drug was found to be identical to that of a control sample (i.e., initial microcapsules stored in industrial packaging) Thus, the introduction of the microcapsules into the chocolate matrix did not alter the stability of the product

  chemical, or the physical state of the drugs in the microcapsules.

Example 2

  The microcapsules used in this example are those of the industrial drug "Sudafed, S A" manufactured by Burroughs Wellcome Co Each capsule contains approximately

  300 microcapsules (diameter 0.6 to 0.9 mm) Each large capsule contains 120 mg of pseudoephedrine hydrochloride.

  These microcapsules are coated in a single unit of

  usual chocolate, as described in Example 1.

  When you chew and swallow the chocolate tablet, you

  detected no unpleasant drug taste.

Example 3

  Microcapsules of aspirin coated with hydrolyzed protein (gelatin) having an average diameter of 1.7 to 2.0;, each containing 99% of aspirin, are prepared according to the method which is described in Example 59 of US Pat. N 4,016,254 40.4 g of these microcapsules were added to 1 kg of milk chocolate during the kneading stage of its production. After mixing until homogeneous, the chocolate is standardized and softened in the conventional manner, then poured in molds to produce units of about 5 g each. Each unit contains microcapsules which include 200 mg of aspirin. The chocolate units can be chewed and swallowed without detecting the unpleasant taste of aspirin.

Example 4

  Preparing aspirin microcapsules coated with hydroxyphenylmethylcellulose using the Uni20 Glatt 4 "Wurster conical, all metal device The medium size

  of aspirin microcapsules is 80-180 p and each microcapsule contains 93% aspirin and 7% coating.

  A similar coating was made in the same

  conditions using cellulose acetylphthalate as the coating material.

  The microcapsules thus prepared are coated in

  chocolate (100 mg of encapsulated material per 1.5 g of chocolate) according to the method which is described in Example 1 When the chocolate tablet is chewed and swallowed, no unpleasant taste of the drug is detected.

Example 5

  Acetaminophen was encapsulated in 2.4% ethylcellulose (Ethocel) and 1.0% hydroxypropylmethylcellulose phthalate (HP 50) This coating is produced in an Aeromatic Strea-I fluidized bed apparatus The medium size of microcapsules thus obtained, is 80-120 p. The microcapsules are coated in chocolate (100 mg of encapsulated material per 1.5 g of chocolate) as described in Example 1 When the chocolate tablet is chewed and swallowed, no unpleasant taste of the drug is detected. Examples 6 to 13 The following drugs, each encapsulated in elements of approximately 500 to 600 μm in diameter, are coated in quantities of 1.5 g of chocolate, according to the unit doses

  No unpleasant drug taste was detected in any case, while the chocolate formulation was chewed and swallowed.

  Example N Active ingredient Unit dose 6 Theophylline 200 mg 7 Chlorpromazine hydrochloride 75 mg 8 Chlorpheniramine maleate 8 mg 9 Erythromycin 250 mg 10 Ferrous sulphate heptahydrate 167 mg 11 Nitroglycerin 2.5 mg 12 Papaverine hydrochloride 150 mg 13 Niacin 250 mg It follows from the above, the invention is in no way limited to those of its modes of implementation, embodiment and application which have just been described in a more explicit manner; on the contrary, it embraces all the variants which may come to mind of the technician in the field, without departing from the framework, or the scope, of the present invention.

Claims (9)

  1 Dosage form for the oral administration of a pharmaceutical active principle, characterized in that it comprises a pharmaceutical active principle coated in a sweet matrix, tender and pleasant to taste.   2 dosage form according to claim 1, characterized in that the matrix contains a sufficient amount of microencapsulated active ingredient to provide a unit dose of the active ingredient in each unit of the matrix 10 having the size of a bite.   3 dosage form according to claim 1, characterized in that the tender, sweet, pleasant-tasting matrix is sufficiently tender to allow its chewing without   that a notable chewing is necessary.   4 dosage form according to claim 1, characterized in that the matrix is chosen from the group formed by chocolate, fondant, marshmallow, butter   peanuts, carob and solid yogurt.   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 dark chocolate or milk chocolate.   7 dosage form according to claim 1, characterized in that the active principle is an anti-bacterial agent, an analgesic, an antihistamine agent, a decongestant, an anti-inflammatory agent, an anti-hypertensive agent a hypnotic agent, a sedative , a tranquilizer, a   alkaloid, diuretic, vasodilator, hormone or vitamin.   8 dosage form according to claim 1, characterized in that the microcapsules of active ingredient have a diameter of at least 1 mm.   9 Galenic form according to claim 1, characterized in that the microcapsules of active principle have a   diameter of about 10 to 100 microns.   Dosage form according to claim 1, characterized in that the active principle is encapsulated in a material which prevents the active principle from coming into contact with the matrix during the production and storage of the coated matrix before use, which is non -toxic and harmless and allows the release of the active ingredient in the stomach or the gastrointestinal tract after ingestion. 11 Application of the dosage form according to one   any one of claims 1 to 10 to the oral administration of a pharmaceutical active ingredient devoid of an unpleasant taste or a bad sensation in the mouth.   12 Application of the dosage form according to any one of claims 1 to 10 to administration oral in pediatrics.   13 Process for producing a useful dosage form   for the oral administration of a pharmaceutical active principle according to any one of claims 1 to 10, carac20 terized in that it comprises:   the microencapsulation of the active principle, and the coating of the active principle microencapsulated in a matrix   tender, sweet and pleasant to the taste.