CONFECTIONERY DELIVERY SYSTEM FOR PHARMACEUTICALLY ACTIVE SUBSTANCES

Abstract: The invention relates to a confectionery form of matrix suited to contain microcapsules for controlled release of pharmaceutically active substances, of fixed content, which is soluble in the mouth and readily swallowed without chewing, as well as the process for the preparation thereof.

Description: Confectionery delivery system for pharmaceutically active substances The aim of the present invention is to propose a confectionery form of matrix suited to contain micro¬ capsules for controlled release of pharmacologically active substances, of fixed content, which is soluble in the mouth and readily swallowed without chewing, as well as the process for the preparation thereof. Since the microcapsules for controlled release of pharmacologically active substances are not resistant to the high pressures created in the tabletting machines, tablets containing microcapsules for controlled release of pharmaceutically active substances are rarely manu¬ factured. Thus, the most widespread form for the oral ad¬ ministration of microcapsules for controlled release of pharmaceutically active substances are the gelatin cap- sules. However, many patients and particularly children refuse to swallow a medicine in the form of a usual gelatin capsule available in the market. In these patients, the feeling that the capsule -is a foreign body that may make them choke neutralises the mechanism of swallowing. The need consequently exists for the creation of a system of a matrix that would permit the easy oral ad¬ ministration of microcapsules for controlled release of pharmaceutically active substances, which is soluble in the mou€h without chewing. Prior_State-of-the-Art DE-A 336 216 describesa process for coating phar- maceutically active substances for the formation of mi¬ cro capsules which are resitant to the pressures created during tabletting, nevertheless, it imposes considerable limitations in the selection of materials used for said SUBSTITUTE SHEET coating. FR-A 2011960 renders formulated pieces which in¬ clude microcapsules containing pharmaceutically active substances administered orally, nevertheless, it pre- sents the disadvantage that the mixture to be formula¬ ted is exposed to relatively high temperatures for con¬ siderable time, a fact which creates serious risks for alteration or for shortening of the shelf-life of var¬ ious thermolabile pharmaceutical substances. Patent Application EP-0 239983 describesa process which avoids the high temperatures employed in FR-A 2011960 buth which, despite the fact that it makes use of readily melted mixtures, likewise strains, from the thermal point of view, even though to a smaller extent, the pharmaceutically active substances. Patent Application EP-0 227603 grants a confec¬ tionery system for the administration of medicines by means of chewing but likewise strains, from the thermal point of view, the protected pharmaceutically active sub- stances. EP-A 0267160 describes a product which is likewise thermically strained in the course of its processing. In accordance with the present invention, the afore- mentioned problem is solved by addition of the aforemen¬ tioned known per se microcapsules for controlled release of pharmaceutically active substances (see for instance 1) Remington's Pharmaceutical Sciences Handbook, Mack, Publ. Co. New York U.S.A. 18th Edition Pages 1663-1665 2) M. Riag, N. Weiner, F. Martin in H. ieberman, N. Prueger, G. Banker Eds.: Pharmaceutical Dosage Forms - Disperse Systems, Vol. 2 3) Jones D.M., Factors for consideration in fluid bed pro¬ cessing. Pharmaceutical_Technolog i _April_1985 4) Ebert W.R. , Pharm. Tech. I (10): 44, 1977 SUBSTITUTE SHEET 5) Madan P.L., Pharm. Tech. I (10): 68, 1978 6) Jager K.F. et al. "Effort of Material Motion on Agglomeration in the Rotary Fluidized-Bed Granu- lator" Drug Made in Germany, Vol. XXV pp. 61-65 (1982 ) incorporated to the present description by reference) into a suitable low viscosity, fluid confectionery cream system of icecream substitute under stirring, at a tem¬ perature ranging between -1 C and 0 C, and its immediate feeding into a device of continuous or non-continuous operation, for production and kneading of icecream, here it is solidified, under nitrogen bubbling, under pressure, in a matrix for enclosure of microcapsules and it is for¬ mulated, preferably, . in cup-shaped pieces or in icecream borne on a small wooden rod, in certain cases of bulky pharmaceuticals, such as for instance in the case of catharctic plant fibers or of nutritive elements, which are administered in large single doses of up to approxi¬ mately 100 grams, or in the shape of chocolate bars with subdivisions, bonbons, caramels, spheres, sugared pills, cylinders, olives, and in any kind of geomatrical or artistic shape, or colour, confectionery preparations of this sort, of low weight and of small dimensions, for all medicinal products that are usually administered each time in quantities below one gram, at a final temperature of -18 C. It is evident for the experts in the Art that, when, in certain cases, it is necessary to effect an even better homogenising of the microcapsules whitin the confectionery matrix, the formulated product may be recycled to the kneading department of the facility and subjected, once again, to the production process. Futhermore, it is obvious that provision may be made, in the facilities for production and kneading of the ice¬ cream, to have the scrapers of the cooling surfaces shorter and bearing soft elastic extremities on their edges, in SUBSTITUTE SHEET order to avoid the creation of high pressures between the metal surface, which could eventually bring about the destruction of the coatings of the microcapsules. Of course, during the blowing of the nitrogen, the main¬ tenance of the highest possible temperatures ensures, in the best possible manner, the protection of the coatings of the microcapsules. Nevertheless, even at the temperature of -18 C, there still exists, within the solid confectionery ma¬ trix that is so formed, a small quantity of water (A.W. Farall, Engineering for Dairy and Food Products, page 300) which contains dissolved amounts of sugar, glu¬ cose, milk salts, etc. and which has not solidified. In the long run, this constitutes a risk in keeping intact the totality of the microcapsules containing the active substance of the catharcfcic plant fibres etc. The inventors have also solved the aforementioned problem in the following manner. The capsules and the water soluble plant fibres are rendered provisionally water-proof, at low temperatures below zero, before their addition to the binding confectionery mixture which creates the matrix that consists of the principle solid phase of the icecream, the possibly minimal aforementioned eutetic still liquid phase and the abundant gaseous phase of the enclosed nitrogen. The provisional water-prrofing is car- ried out inside a rotating, inclined with respect to the vertical axis, special container designed for the coat¬ ing of tablets or microcapsules (coating-drum), by coat¬ ing with an adequate amount of edible vegetal oil, such as for instances peanut oil, sesame oil, olive oil, palm oil, etc., which is added at a very slow rate in small doses, in the form of spray produced under very large pressure, and subsequently by blowing cool air at a temperature sufficiently lower than that of the metling point of the corresponding oil, in order to obtain the SUBSTITUTE SHEET polishing of the microcapsules (microspherules) . The coated microcapsules are transferred immediately to the stock container, under stirring, and are added to the aforementioned cream mixture which is likewise at a temperature of approximately 0 C to -1 C. It is ob- vious for teh experts in the Art that the water-proof microcapsules, instead of being added in the stirred stock container of the cream of the icecream substitute, in their totality and in a precisely fixed ratio, may be fed into a special capsule-filling machine and dispensed with dosimetric accuracy into the corresponding forming moulds of the aforementioned geometrically shaped for¬ mulations between two or more superposed layers of ice¬ cream substitute in the form of a sandwich. Alternatively, it may be possible to use, for the polishing process, an- hydrous molten cooking milk butter, working under the same conditions of cooling. If so desired, the microcapsules may be polished prior to the aforementioned provisional water-proofing by means of a mixture of synthetic waxes, on condition that the melting point of the latter is below 3o C- It is understood that other, known by the experts in the Art, pharmacologically accepted hydrophobic substances may also be employed for the aforementioned provisional water¬ proofing, at low temperatures below zero, of the confec- tionery matrix enclosing the microcapsules, on condition that said substances melt instantaneously at the temp¬ erature of the mouth, such as for instance liquid pa¬ raffin or mixtures thereof. The quantity of wax employed is controlled by the special expert in such a matter that, in association with the amount of solidified vegetal oil, it ensures the better water-proofing of the microcapsules (spherules) containing the pharmaceutically active sub¬ stance. The weight of the vegetal oils or butter and waxes SUBSTITUTE SHEET used for the water-proofing of the microcapsules ranges between 0.5% and 20% of the weight of the micrcen- capsulated pharmacautically active substances and pre¬ ferably between 7% and 18%. The content of the microcapsules within the con¬ fectionery matrix ranges between o.l% and 60%, prefer¬ ably between 6% and 30%, and most preferably between 8% and 20% by weight. The limits within which the contents of the various components of the aforementioned matrix of confectionery composition, which is, as far as its taste is concerned, an icecream substitute richer or poorer in calories, may vary, are indicated below. Water-proof microcapsules of pharmaceutically active substance 0.1 - 25% milk powder FAO/WHO 1 - 18% sugar USP 10 - 18% lecithin USP 2 - 4% casein USP 0.5 - 4% vegetal gum USP 0.1 - 1% synthetic sweetener USP adequate amount flavour USP adequate amount colorant USP adequate amount water USP, sufficient quantity up to 100%. Without excluding the normal usage of air for the swelling (overrun) of the aforementioned icecream sub¬ stitute, the use of nitrogen or of any other inert gas is considered preferable for the better maintenance of the matrix. In the present description, the percentage of swel- ling (overrun) of the icecream is determined by the fol¬ lowing quotient: litres_of_final_voll™e_of_icecream_-_l mixture_x_100 litres of initial mixture SUBSTITUTE SHEET The aforementioned nitrogen is introduced into the mass of the solidified and kneaded icecream under pressure of up to 5 atmosphere from a nitrogen steel container. The swelling (overrun) of the liquid initial con- fectionery mixture used may range from 30% up to 200% (volume/volume), preferably from 50% up to 150%, and is most preferably checked at 100% (volume/volume) which gives a smoother texture, in the mouth, to the cream of the icecream which, at the temperature of the mouth, following a short stay therein, melts without having to be chewed. The aforementioned formulated pieces may even¬ tually be coated with one of the usual coatings such as chocolate, sugar, wafer or other from the confectionery point of view acceptable material or combination of ma¬ terials, and may also bear subdividing scores. The afore¬ mentioned coating is carried out in accordances with the well known technology in the manufacture of icecream, chocolate and caramels, in well known per se automatic machines (see for example: 1) Arthur W. Farall, Engineering for Dairy and Food Pro¬ ducts, John Wiley and Sons Inc. pages 297-332, New York and London 2) Chocolate, Cocoa and Confectionery : Science and Tech¬ nology, 2nd Edition, AVI Publishing Co. Inc., Westport, Conn. (1950) 3) Icecream, 4th Edition (1986) AVI Publishing Co. Inc., which are incorporated herein by reference). Prior to the application of the coating, the fin¬ ished product that has been formulated in the proper ma¬ trix is frozen eventually below its storage temperature of approximately -20 C, at temperatures of -30 C up to even -60 C, in order to enable even the outer surface of SUBSTITUTESHEET the icecream that will come in contact with the pos¬ sibly slightly warmer sugar-syrup of chocolate-syrup not to be subjected to any thermal strain whatsoever, not even instantaneous. The abolition of the need for chewing brought about by this system for administration of pharmaceu¬ tically active substances eliminates the risk for application of great pressure, by the teeth, on the coatings of the active substances, which cause damage to said coatings and undesirable early release of the active substances into the mouth as well as the sense of unpleasant taste. Furthermore, it is known, from the principles of physical chemistry, that a storage tem¬ perature of the preparation of the present invention, which is 40 C up to 80 C lower than that of the am- 4 bient temperature, slows down by a multiple of 10 up o to 10 approximately the rate of the reactions leading to the oxidation and the aging of the product. Further¬ more, the enclosure of 100% up to 200%, by volume, of nitrogen in the preparation, in association with the favourable influence of the low temperature on the suspension of all chemical, physicochemical or micro- bial alteration processes, significantly lengthens the shelf life of the preparation. Besides, in aco- cordance with Vant' Hoff's Law, a reduction of 10 C in the temperature doubles or tribles the preservation properties. It is obvious that, apart from the ice¬ cream composition proposed above, any composition of commercial ice-cream or ice-lolly may likewise be used for the purpose of the present invention. The aforementioned formulated pieces may also be formulated within receptors made of composite sheet with layers of paper, plastic and/or metal, and be closed her¬ metically. In accordance with the well known pharmaco- technical practice formanufacture of dosage forms, the SUBSTITUTE SHEET dimensions and the weight of the various formulations indicated above are determined in such a manner that, depending on the nature and on the content of the phar¬ maceutically active substance contained therein, said formulations are administered once up to three times daily to cover the needs of an adult patient of body weight 70 Kg. water^groof_ crocagsules_for_controlled_release^^hich ™SY_^ _l-;§ -^_i2_-=-} _E-i--:§ --:-=_--:SY S--:i22 In the present description, the term microcapsules for controlled release of pharmaceutically active sub- stances includes, apart from the totality of the cap¬ sules of enteric or gastric release which are known in the Art, also the microcapsules whose only aim is the simple masking of the taste of the pharmaceutically ac¬ tive substance which they encapsulate until the latter pass through the mouth. Furthermore, in the present description, the term microspherules and microcapsules is used indiscriminately and alternatively for practicles of dimensions ranging from a few tenths of a micrometer up to 5000 micrometers, preferably up to 1000 micrometers and more preferably up to 500 micrometers. Moreover, the term artistic shape includes all forms that are an artistic model of, for instance, a fruit or an animal or an object, etc., such as for example children's toys. Only few of the numerous classes of pharmaceutical products that may be converted into microcapsules for controlled release and used for the production of con¬ fectionery preparations, in accordance with the present invention, are listed below: SUBSTITUTESHEET 1. Anti-inflammatory substances 2. Factors for dilatation of the coronary artery 3. Tranquillizers 4. Nutrient additives 5. Diuretics 6. Pharmaceuticals against migraine 7. Pharmaceuticals against angina pectoris 8. Expectorants 9. Antipyretics 10. Anti-cholesterinemic and anti-lipidemic agents 11. Anti-arrhythmics 12. Ion-exchange resins 13. Inorganic supplements such as potassium chloride, calcium carbonate, magnesium oxide and other salts of alkaline metals and of alkaline-earth metals 14. Laxatives 15. Vitamins 16. Compounds for the binding of the acids of the stomach 17. Antitussives 18. Antihistaminics 19. Various alkaloids 20. Decongestives As well as mixtures of microcapsules including chemically interacting incompatible with one another pharmaceuticals such as vitamin C and calcium carbonate or cholestyramine and potassium chloride. For the better understanding of the present in¬ vention, two examples of its execution are given below, which, however, do not limit its scope Example_l Composition_of_an_ice-cream_substitute Water-proof microcapsules of pharmaceutically active substance 1000 g SUBSTITUTE SHEET Milk powder FAO/WHO 470 g Sacharose USP 1500 g Lecithin USP 180 g Casein USP 50 g Glucose USP 180 g Vegetal gum USP 10 g Synthetic sweetener USP adequate amount Flavour USP adequate amount Colorant USP adequate amount Water USP sufficient quantity up to 10000 g Following complete dissolution of all the above mentioned excipients under stirring and eventual slight warming, they are transferred to the special continuous- operation machine for production of ice-cream, in the cream feeding vessel. The mixture is cooled to a temperature slightly below zero, and, under vigorous stirring, the pharmaceu¬ tically active substance is added all at once, starting at the same time the production of the ice-cream and its swelling by 100% by means of nitrogen blown from a steel container. The above product is filled into recipients made of composite sheet and the formulated pieces are kkeepptt aatt aa tteemmppeerraattuurree ooff --440 C with excellent results as regards their preservation. Examgle_2 Comgosition_of_commercial_ice-cream Water-proof microcapsules of pharmaceutically active substance Fresh milk Saccharose Milk cream Egg yolks Glucose 0.15 Kg SUBSTITUTE SHEET Alpigen Super 0.05 Kg Couantreau 0.03 Kg half a teaspoonful of vanilla Proceed as in case of example 1, with the only difference that the formulated pieces of ice-cream are of the wellknown shape and dimensions of ice-cream coa¬ ted with chocolate that is held by means of a small wooden rod, or of ice-cream that is filled in cups of different sizes. Note: In working in accordance with the process indi¬ cated in example 1, for the same amount of microcapsules, we used, instead of the aforementioned synthesis of com¬ mercial ice-cream, a synthesis of commercial ice-lolly made of fruit juices, with equally satisfactory results. SUBSTITUTE SHEET

Claims: Claims 1. Process for the preparation of a confectionery formulation consisting of well known per se microcap- sules for controlled release of pharmaceutically active substances enclosed within a matrix. , characterised in that in the vessel of its preparation, the pharmaceutically acceptable binding mixture of ice-cream substitute used for the formulation is liquid at a temperature of -1°C up to 0 C under which is effected, under appropriate stirring, the addition to the latter and the homogeneous dispersion of the provisionally water-proof microcapsules, in a precise predertmined ratio, and in that the composi- tion and viscosity are appropriate for its rapid solidi¬ fication within an appropriate equipment for production, kneading and formulation of ice-cream, with the simulta¬ neous enclosure, under pressure, within the mass of approximately 100% nitrogen by volume (volume/volume) or of some other inert gas. by final cooling to approxima¬ tely -20 C, for the creation of a formulation of ice-cream of a variety of geometrical or artistic shapes or colours, made up of elementary "trihasic particles" which are a mixture of a principal solid phase of ice-cream, a pos- sibly minimal liquid phase of a solution of sugar and milk salts, and an abudant gaseous nitrogen phase, as well as of the aforementioned microcapsules, which, when warm¬ ed inside the mouth, given the impression of a smooth pleasant texture and taste of ice-cream cream that melts in a very short time without being chewed, avoiding the risk of damage of the microcapsules caused by chewing or previous warming thereof during the production process of the confectionery formulation. 2. Process in accordance with claim 1, characterised in that, prior to their addition to the confectionery SUBSTITUTESHEET binding mixture, the microcapsules containing the pharmaceutically active substance are rendered provisionally water-proof inside a revolving special vessel used for the coating oftablets (coating-drum) by coating with a sufficient quantity of edible plant oil such as for instance peanut oil or sesame oil or olive oil or palm oil, etc., which is added at a very slow rate, in small portions, as a spray that is pro¬ duced under very high pressure, and subsequently by blowing a cool air at a temperature sufficiently lower than the melting point of the corresponding oil, in order to obtain the polishing of the microcapsules fol¬ lowing solidification of the oil, and in that they are immediately transferred into the vessel of the ice-cream production machine, under stirring for their mixing with the liquid cream at a temperature of approximately 0 C up to -1 C. 3. Process in accordance with claims 1 and 2 charac- terised in that, prior to their being rendered water¬ proof by means of vegetal oil and in order to complete their water-proofing, the microcapsules are polished eventually by means of a suitable layer of readily melt¬ ing mixture of synthetic waxes or other pharmaceutically acceptable hydrphobic materials whose melting point is below 30 c, such as for instance liquid paraffin or mix¬ ture thereof. 4. Process in accordance with claims 1 - 3 characterised in that air may be used instead of nitrogen or any other inert gas for the swelling of the formulation. 5. Process in accordance with claims 1 to 3 or 4 cha¬ racterised in that the formed pieces of various geome- trical or artistic shapes or colours and dimensions are coated with a fine layer of chocolate and/or caramel or SUBSTITUTE SHEET wafer or other suitable confectionery coating or com¬ bination thereof. 6. Process in accordance with any one of claims 1 to 5 characterised in that the formed piece bears subdividing scores, such as those, for instance, borne on chocolates available in the market. 7. Process in accordance with any one of claims 1 to 6 characterised in that the formed piece is a sandwich of microcapsules within two or more layers of ice-cream substitute hermetically packaged inside a thin-walled recipient consisting of a composite sheet with layers of paper, plastic and/or metal. 8. Process in accordance with any one of claims 1 to 7 characterised in that the formed pieces are stored for a long time at approximately -40 C and for daily or weekly consumption at approximately -20 C. o o 9. New, stored at -18 C up to -40 C, formed confectionery, solid system for oral administration of well known per se microcapsules or microspherules for the controlled release of pharmaceutically active substances of all kinds in ac- cordance with any of claims 1 - 8, characterised in that its texture and taste are those of ice-cream and in that it is offered as a formed piece of the composition in¬ dicated below, richer or poorer in calories. Water-proof microcapsules of pharmaceutically active substances milk powder FAO/WHO saccharose USP lecithin USP casein USP glucose USP vegetal gum USP SUBSTITUTE SHEET synthetic sweetener USP adequate amount flavor USP adequate amount colorant USP adequate amount water USP sufficient quantity up to 100% 10. New confectionery formulation in accordance with any one of claims 1 - 8 characterised in that it has, as binding matrix material, any composition of commercial ice-cream. 11. New confectionery formulation in accordance with any one of claims 1 - 8 characterised in that it has, as bind¬ ing matrix material, any composition of commercial ice- lolly. 12. New confectionery formulation in accordance with any one of claims 1 - 11 in which the active substance is a medicinal product selected from the group consisting of anti-inflammatory substances, factor for dilatation of the coronary artery, tranquillizers,nutritive additives diurectics, medicines against migraine, anti-asthmatics, expectorants, antipyretics, anticholesterinemic and anti- lipidemic agents, anti-arrhythmics, ion-exchange resins, inorganic supplements such as potassium chloride, calcium carbonate, magnesium oxide and other salts of alkaline metals or alkaline-earth metals, laxatives, vitamins, compounds binding the acids of the stomach, antitussives, antihistaminics, various alkaloids, and decongestives, contained in a formulation in provisionally water-proof, cooled microcapsules for controlled release, in a content of 0.1 - 25% by weight. SUBSTITUTE SHEET

Inventors: KONTOS ANGELOS G, KONTOS GEORGIOS C, KONTOS, ANGELOS, G., KONTOS, GEORGIOS, C.
Applicants: KONTOS ANGELOS G, KONTOS GEORGIOS C, KONTOS, ANGELOS, G., KONTOS, GEORGIOS, C.
Application year: 1993
Main classification: A61K9
IPC codes: A23G9, A61J3, A61K9