HK1005987B - Taste-masked pharmaceutical compositions - Google Patents

Description

The invention relates to flavoured pharmaceutical products for oral use, their manufacture and their use as medicinal products.

The new pharmaceutical preparations of the invention make it possible to administer pharmaceutical active substances with very unpleasant organoleptic properties, such as very poor taste, even in liquid form.

Especially in the elderly and in patients with difficulty in swallowing, the use of larger tablets often causes considerable difficulties and large tablets are also not suitable for children.

Solid forms of medicinal products, such as lacquer tablets, have the advantage of not being felt by the patient, if any, as a distinctive taste of the active substance, but they have the disadvantage of not being divisible without damaging the flavouring coating.

However, individual dosing of the active substance is often essential in geriatrics and paediatrics and can be ensured by the provision of a granular or juice formulation which can be dosed in a variable manner.

It is therefore necessary to provide individually dosable forms of medicinal products for oral use, including unpleasant-tasting active substances, and use as powder or granules for direct application would also be advantageous.

The preparation of a liquid formulation, for example by crushing a tablet and dissolving it in water, is not possible without specific flavour controls due to the extremely poor and long-lasting bitter taste of many antimicrobial active substances. The extremely unpleasant taste is expected to significantly impair patient compliance.

The most unpleasant-tasting active substances in the group of antimicrobials are gyrase inhibitors, especially those of the naphthyridone and quinolone carbonic acid types, in particular ciprofloxacin, norfloxacin, ofloxacin and enoxacin.

In addition to complete taste coverage, it is essential to require rapid and complete release of many active substances in order to ensure bioavailability equivalent to that of tablets. This is problematic because many active substances have an upper small intestinal absorption window and absorption is greatly reduced in the lower intestinal compartments (S. Harder, U. Fuhr, D. Beermann, A.H. Staib, Br. J. Cl. Pharmac. 30, 35 (1990)).

Microencapsulation is itself a widespread technology, not confined to pharmaceutical use (P.B. Deasy; Microencapsulation and related Drug Processes; M. Dekker Inc., N.Y. & Basel, 1984).

In pharmaceutical applications, microencapsulation with insoluble lacquer is a commonly used method to promote drug release, but also to mask flavour. The combination of microencapsulation in the encapsulation is known to result in rapid flavour masking. The EP-A-273 890 encapsulation of Ciprofloxacin is not well known for the rapid release of drug products. However, the use of this method is not known for the preparation of drug products based on the encapsulation of carotenoids or ethanol.

EP-A-101 418 describes the microencapsulation of active substances with hydrocarbons or hydrocarbon-related substances for the purpose of controlled release, flavour masking and stabilization of active substances.

DE-A-3 815 562 describes a process for masking the flavour of pharmaceuticals based on the production of a three-layer wrapper for medicinal products, consisting of fat or fat and polymer.

DE-A-3 816 464 has given rise to another taste-masking process for unpleasant-tasting medicinal substances, also based on the use of lipids.

The tablets formulated with quinolones, in particular norfloxacin, are also known from EP-A-0 189 114, but these are preparations suitable for direct tabletisation (as opposed to the tabletisation of particles of mixture obtained by moist granulation).

EP-A-0 409 254 describes the manufacture of granules/microcapsules intended to ensure a rapid release of the active substance in addition to the flavour mask. The flavour mask is applied with ethyl cellulose lacquer. However, according to the present state of the art, the cores must necessarily contain an explosive, in the range of 35 to 70% relative to the target final weight, in order to achieve the rapid release of the active substance. At explosive levels below 35%, there is no rapid release of the active substance, but rather a delayed release. Compared to the present invention, this form of administration has the disadvantage that, at the same particle volume, less effective particles can be introduced (maximum 40% of the final weight of the active substance) than in the case of the particle used.

The knowledge that lacquer based on poly (meth) acrylic acid and its amino-alkyl esters and/or alkyl esters and ethyl cellulose can be used for the purpose of flavour masking is known from the state of the art.

EP-A-0 312 340 also applies to the selection of the paint component. It describes retardant formulations of poorly water-soluble active substances with the addition of the carbomers auxiliary. In contrast, the present invention teaches fast-release formulations in which, for the manufacture of the coating, such lacquer is used as is known in the art for the manufacture of retardant formulations which, with the worst aqueous active form (base form), lead to the fastest release rates with simultaneous film masking.

EP-A-0 295 941 describes orally applicable liquid suspensions with a non-water-based oil base, where the suspended active substance is released with delay.

EP-378 137 describes water-dispersible medicinal products that allow the oral application of active substances with organoleptically unfavourable properties in liquid form. The active substance is first applied to sugar beets, which are then coated with a film. Relatively low-dose substances such as pinaverium bromide, metoclopramide and salbutamol are called medicinal products. Polymers are water-insoluble substances such as shellac and ethyl cellulose, which are combined with substances that are soluble below pH 5.

EP-A-212 641 describes flavour-masking compounds consisting of a polymer matrix of medicinal products containing the active substance. According to the application, the polymer used is a copolymer of methacrylic acid and its methyl ester (®Eudragite S 100). The matrix dissociates in a medium with a pH of none of 4, and the active substance is released into this medium.

®Eudragit S 100 is used, according to the manufacturer's instructions, for the manufacture of gastric acid-resistant, intestinal acid-soluble lacquer.

The microencapsulation of norfloxacin to reduce side effects such as stomach irritation and haemorrhage is described by Esmat E. Zein-El-Dien (Pharm. Ind. 53, 87 (1991)).

The full flavour masking required for the claimed antimicrobials, combined with rapid release, cannot be achieved by the methods of the state of the art so far generally known.

In general, antimicrobial agents are structures that contain acidic or basic functional groups or, at the same time, e.g. carbonic acid groups and amines in the molecule (betaine). Typically, one or the best water-soluble form of these agents is used to ensure rapid release of the active substance. For organic carbonic acids, these are generally their alkaline or alkaline salts, or for betaines, their carbonic acid salts or acid salts (e.g. hydrochlorides).

Err1:Expecting ',' delimiter: line 1 column 684 (char 683)

By definition, the anhydrates of the active substance ciprofloxacin contain less than 5% water in the basic form in the microcapsule formulation of the invention, in particular less than 3.0% water in the form of crystal water or other water adducts.

The invention is thus directed at pharmaceutical products containing active substances which are flavoured by microencapsulation, as defined in claim 1.

The microcapsules of the invention are manufactured as follows:

Err1:Expecting ',' delimiter: line 1 column 105 (char 104)

As binders to increase the mechanical strength of the microgranulate, substances such as acacia gum, alginic acid and alginate, carboxymethylcellulose, ethylcellulose, gelatine, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, xanthan gum, pectin, traganth, microcrystalline cellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, sodium carymethylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl salts, gum arabic, sorbitol, starch (vinyl, corn, carotene), sacchlorophenol, sorbitol, rizol, mannitol, agar, are used. Agar is a mineral oil, which is used in the manufacture of 25 to 10% of carboxylic acid, agar, carboxylic acid, carboxylic acid, carboxylic acid, carboxylic acid, carboxylic acid, carboxylic acid, carboxylic acid, carboxylic acid, carboxylic acid, carboxylic acid, carboxylic acid, carboxylic acid, carboxylic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbolic acid, carbo

The microcapsules used in accordance with the invention are produced by coating the microgranular cores in suitable apparatus with the coating of the invention.

The coating of the micro-granules is applied to the cores, which provides a complete coverage of the surface of the granules. The coating composition for the micro-encapsulation must be chosen in such a way as to ensure sufficient permeability to aqueous media and a rapid release of the active substance. The composition and thickness of the coating ensure that the micro-capsules are dissolved after passing through the sensitive area but that the active substance is released in time before passing through the absorption site. Therefore, coatings that cause over-expansion resistant to gastric juice and allow the active substance to be released into the intestinal tract after the gastric secretion are not suitable.

The use of aqueous paint suspensions is preferable for environmental and occupational safety reasons.

As film formers for the manufacture of lacquers for the manufacture of microcapsules, a number of substances are used individually, such as acacia gum, acrylic acid polymers and copolymers (polyacrylamide, polyacryl dextrane, polyalkylcyanoacrylate, polymethyl methacrylate), agar agar, agarose, albumin, alginic acid and alginate, carboxyvinyl polymers, cellulose derivatives such as cellulose acids, polyamides (nylon 6-10, polyadipyl-L-lysine, polyterephthalamide, polyetherethylene, L-lysine), polyethylene, polyethylene, polyethylene, polyethylene glycol, polyethylene oxide, polyethylene oxide, polyethylene oxide, polyethylene oxide, and copolymers, some of which are only available in the form of anions.

The coating layer can be applied in conventional coating equipment, such as a powder coating machine using the Wurster process.

However, the products of the invention can only be prepared with microcapsules for which neutral methyl and/or ethyl ester compounds of polymethyl acrylic acid (®Eudragit NE 30 D, Röhm, Darmstadt) and/or quaternary ammonium compounds of polymethyl acrylic acid (®Eudragit RL 30 D, ®Eudragit RS 30 D, Röhm, Darmstadt) and ethyl cellulose (®Aquacoat, FMC Corp.) are used as film formers. These lacquers, which are not water-soluble in themselves, can be combined with water-soluble polymers to increase permeability, which provide a pore formation in the paint layer. Water-soluble pore formers include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextran, dextrin, cyclodextrin, polyethylene glycols, polyalcohols, polyvinyl pyrrolidone, starch and starch hydrolysates such as modified starch types (glutathized starch, STA-RX 1 500, celutab, maltodextrin), and carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier carrier

The preferred combination of water-insoluble and water-soluble components is a mixture of ®Eudragite NE 30 D and hydroxypropylmethylcellulose, which, by means of suitable mixtures of these substances, e.g. in the ratio 100/20 to 100/50, preferably 100/20 to 100/40 and preferably 100/40, has been used to achieve optimal flavour coverage and rapid and complete release of the active substance from microcapsules in the pH range 1 to 4,5.

Even other paints specifically recommended in the literature for flavour masking, such as ®Eudragite E 12.5, did not produce the desired results in terms of flavour masking and release behaviour. Thus, in view of EP-A-378 137, the use of ®Eudragite E 12.5 for flavour masking might seem appropriate. Surprisingly, however, it was found that, for example, the combination of ®Eudragite NE 30 D with HPMC produces the best flavour masking while at the same time good release of active substance at pH 1 and 4.5.

Furthermore, the addition of a plasticizer may be necessary for film formation, which is a substance that facilitates film formation and increases the elasticity and mechanical stability of the paint.

The use of such plasticizers may include diethylphthalate, acetyltributyl citrate, glycerol, diethylsebacate, dimethylphthalate, dibutylphthalate, tributyl citrate, butyl stearate, polyethylene glycols with different chain lengths, glycerol monostearate, triacetin, castor oil and other native and synthetic oils, triethyl citrate, acetyltributyl citrate, 1,2-propylene glycol, acetylated fatty acid glycerides and polyoxyethylene-polyoxypropylene polymers.

The incorporation of surfactants into the coating helps to spread the dispersion of the coating onto the solid particles during the microencapsulation process and improves the wettability of the microcapsules.

As net agents, substances such as sodium lauryl sulphate (USP), polysorbate (20, 40, 60, 80, 65, 61, 85, 21), poloxamers (ethylene oxide-propylene oxide block copolymers) of different HLB values, lecithins, oleic acid and oleic acid salts, sorbitanic esters (span 20, 40, 60, 80, 85), propylene glycol monosterate and monolaurate, glycerol monosterate and monooleate, Brij types (PEG-ether), polyoxyethylene polyoxyethylene polyoxyethylene (PEG-10-ether, PEG-20-ether, etc.), polyoxyethylene polyoxyethylene (PEG-ether), Cacophonyl-methyl esters of different concentrations, and/or resin (PEG-40-ethylene oxide, PEG-40-ethylene oxide, PEG-ethylene oxide, PEG-ethylene oxide, and/or diisoxyethylene oxide, respectively), are used.

To reduce or avoid adhesion or adhesion of particles during the microencapsulation process, anti-adhesive agents should be added, such as magnesium stearate, calcium stearate, calcium benate, talcum, colloidal silica, stearic acid, precirol (mixture of mono-, di- and triterpene palmitic and stearic acid with glycerol), hydrated cotton seed oil, hydrated castor oil and polyethylene glycol of various molecular weights.

Quantities of 0,1-90%, and in particular of 5-40%, are preferred.

The coating may also contain dyes.

The microcapsules can be coated with a polishing layer which not only serves to beautify the appearance but also constitutes an important functional unit of the microcapsules of the invention: by placing a final layer over the actual coating, a direct interaction between an oily juice component, for example, and the flavour coating is prevented. In particular, when using a water-soluble or at least hydrophilic polishing layer, direct contact of an oily juice carrier with the microcapsule coating and a delay in release caused by oil/lacquer interactions are prevented.

Polishes are suitable for polyethylene glycols of different molecular weights or mixtures thereof, talc, surfactants (Brij types, Myrj types, glycerol monostearate, poloxamers), fatty alcohols (stearyl, cetyl, lauryl and myristyl alcohol and mixtures thereof) and preferably polyethylene glycols with molecular weights of 3000 to 20 000.

The polishing layer is applied after the micro-granules have been painted.

Err1:Expecting ',' delimiter: line 1 column 237 (char 236)

The microcapsules of the invention described herein result in excellent taste masking and the very rapid release of the active substance required for pharmacokinetic reasons. At least 70-80% of the encapsulated active substance can be dissolved within 15-30 min. This requirement is met for both highly acidic (pH 1) and less acidic (pH 4,5) pH media in the in vitro test. This result represents the excellent bioavailability of the active substance formulated in accordance with the invention.

Surprisingly, it was found that Complete flavour masking and the rapid release of active substance required to ensure high bioavailability can be achieved by microencapsulation of the active substance with the excipients of the invention,using the betaine form (base form of the active substance) as the active substance.In addition to complete flavour masking,a rapid release of active substance can be ensured if the base form of the active substance, ciprofloxacin betaine, can be used for microencapsulation.A rapid release can be ensured when using an appropriate lacquer formula and lacquer order,both in the strongly salicylic acid and in the weakly salicylic acid (Hp 1 and 4,5) forms.The specific lacquer form of the active substance can be used in the form of a free-flowing lacquer,which is not possible to achieve in the presence of a soluble base,which is either in the form of a free-flowing lacquer or in the form of a liquid which is not soluble in the active substance.

Err1:Expecting ',' delimiter: line 1 column 480 (char 479)

The use of the microcapsules is essential to produce a juice formulation based on an oily juice base of the invention that meets the release requirements described in the high and low acid release environments (Figures 2-5).

The bioavailability of a representative formulation of the invention is similar to that of a rapid-release tablet formulation (Figure 6).

A rapid release of the active substance can also be achieved by the use of an explosive, depending on the state of the art. However, a disadvantage compared with explosive-free formulations is that significantly higher amounts of coating must be applied to the explosive-containing microcapsule cores containing the unpleasantly tasting active substance in order to ensure a taste-covering microencapsulation at all.

The object of the invention is also to control the rate of release by means of the moisture content of the microcapsules: by adjusting the water content, e.g. of the ciprofloxacin microcapsules, to the anhydrate level of the basic form of the active substance, a considerable acceleration of release can be achieved, which makes the use of a conventional explosive, which is unfavourable for the economy of the process, unnecessary.

The moisture content of the microcapsules can be adjusted in different ways: The microgranules to be coated can be adjusted to the desired moisture content before the painting process and, if necessary, subjected to additional night drying to the anhydrate stage after the painting process.

Microgranules which are lacquered without special pre-drying and may initially have a water content of up to 30% by weight can be adjusted to the desired water content (anhydrate level of the basic active substance) by drying after the micro-encapsulation process.

Oil-based juice (multi-dose form)

It is not possible to provide an aqueous finished juice formulation as the lacquer coating of the microcapsules becomes permeable after some time in the aqueous environment, so it is advantageous to choose a non-wet dispersion medium for the microcapsules.

Oily dispersion media such as almond oil, peanut oil, olive oil, poppy oil, peanut oil, cotton seed oil, soybean oil, corn oil, ethyl oleate, oleoleate, isopropyl myristat and isopropyl palmitate are suitable, medium chain triglycerides are particularly suitable due to their neutral taste and favorable viscosity.

The liquid auxiliaries which can be combined with the oily media mentioned above may include ethanol, glycerol, propylene glycol, polyethylene glycol, 1,3-butanol, benzyl alcohol, diethylene glycol and triethylene glycol, among others.

The use of emulsifiers is also advantageous. Oily juice formulations are sensitive to moisture. Even small amounts of water lead to significant viscosity increases which can make it difficult or impossible to control the release of the original liquid formulation from the container. Emulsifiers increase the water tolerance of an oily formulation and facilitate the use of the microcapsules when incorporated into the oily carrier liquid. They also reduce the viscosity of the suspensions. The substances described above can be used as net agents.

Furthermore, combinations of lecithin with W/O emulsifiers such as sorbitol fatty acid ester types, fatty alcohols and glycerol mono- and di-fatty acid esters are particularly suitable to reduce the sensitivity to water of oil juices containing higher amounts of sugars or sugar substitutes in addition to active substance microcapsules.

As additives to increase density and thus stabilize suspension, sucrose, mannitide, sorbitol, xylite, fructose, glucose, lactose and other sugars and sugar substitutes are preferably suitable. The concentration in the oil juice is between 5-70%, preferably between 15-60%, and especially between 20-40%. These substances must be present in the oil juice in very fine particle sizes (medium particle size about 1-50 μm, preferably between 3-20 μm). This is achieved either by applying oily substances or by homogenising the open suspension base by moisture digestion.

Surprisingly, it was found that the best physical stability for oily suspension juices can be achieved when sucrose is used.

The use of antioxidants to protect oil-bearing media includes α-, β-, γ-, δ-tocopherol, ascorbyl palmitate, ascorbyl stearate, L-cysteine, thiodipropionic acid, thiomyl lactic acid, thioglycolic acid, monothioglycerol, propyl gallate, butyl hydroxyanisol, butyl hydroxytoluol, etc.

The antimicrobial excipients may include phenol, kresol (o-, p-, m-), p-chlor-m- kresol, benzyl alcohol, phenylethylic alcohol, phenoxyethyl alcohol, chlorbutanol, p-hydroxybenzoic acid methyl ester, -ethyl ester, -propyl ester, -butyl ester, benzalkonium chloride and other quaternary ammonium compounds, chlorhexidine diacetate and -digluconate, phenyl mercury compounds, thiomersal, benzoic acid and its salts, sorbic acid and its salts, ethanol, 1,2-propylene glycol, glycerin, 2-bromobromide-propan-1,3'-propan-1,3'-propan, 2,4-dihydrochloric acid and 2,4-dihydrochloric acid-24, in concentrated solutions.

To increase the stability of sedimentation, viscosity-enhancing substances such as colloidal silica, bentonite, etc. can be used further.

Flavourings, sweeteners and colours may also be added.

The containers in which the suspensions are filled may be made of glass or plastic, for example, and may contain substances which give the contents special protection, e.g. protection against light.

The composition of the microcapsules used for the oil-juice formula, in particular the quality of the active substance and its hydrate level, as well as the film composition and lacquer content, are crucial for the quality of such a preparation.The required rapid release of the active substance can surprisingly be obtained if the basic form of the active substance is present in the microcapsules suspended in the oil-juice as an anhydrate, whereas recipes with microcapsules with a higher water content, such as the dihydrate level, produce an unacceptably slow release of the active substance.

It was further established that, for example, microcapsules containing ®Eudragit 12.5, ®Eudragit RL 30, ®Eudragit RS 30 D and/or ethyl cellulose and e.g. HPMC and magnesium stearate or talcum as lacquering components are particularly suitable for Ciprofloxacin oils. However, microcapsules containing a mixture of ®Eudragit NE 30 D and HP and magnesium stearate as lacquering components are particularly preferable: this lacquering composition has surprisingly produced a taste-masking stable formula.

Err1:Expecting ',' delimiter: line 1 column 160 (char 159)

Err1:Expecting ',' delimiter: line 1 column 55 (char 54)

For example, glass bottles or bags made of suitable plastic or metal foil may be used as packaging material for the separately packaged microcapsules.

Zusammensetzungen von den Wirkstoff in Betain-Form enthaltenden Mikrogranulaten zur Herstellung von Mikrokapseln
Beispiel	1 mit PVP 25	2 ohne PVP 25	3 Vergleichsbeispiel mit Sprengmittel
Ciprofloxacin (-Betain)	10,00	10,00	10,00
PVP 25	0,70	-	0,70
Ac-Di-Sol	-	-	1,00
Herstellung	Feuchtgranulation	Feuchtgranulation	Feuchtgranulation
	Wirbelschichtsprühgranulation	-	Wirbelschichtsprühgranulation

Zusammensetzung von den Wirkstoff in Hydrochlorid-Form enthaltenden Mikrokapseln mit ®Eudragit NE 30 D / HPMC-Lacken (Vergleichsbeispiele)
Beispiel	4	5	6
®Eudragit NE 30 D / HPMC oder MC=	100/10	100//20	100/20
Lackauftragsmenge (theoret.)	40%	15%	40%
Ciprofloxacin-HCl	1470,00	1470,00	1470,00
PVP 25	30,0	30,0	30,0
®Eudragit NE 30 D (Trockensubstanz)	469,2	159,4	425,2
HPMC 3 cp	-	32,0	85,3
Tylose MH 300	46,8	-	-
Magnesiumstearat	84,0	32,0	85,3
Tween 20	4,2	1,6	4,2

Zusammensetzung von den Wirkstoff in Hydrochlorid-Form enthaltenden Mikrokapseln mit ®Eudragit NE 30 D / HPMC-Lacken (Vergleichsbeispiele)
Beispiel	7	8	9	10	11
®Eudragit NE 30 D / HPMC oder MC=	100/30	100/30	100/40	100/40	100/40
Lackauftragsmenge (theoret.)	20 %	30 %	50 %	60 %	80 %
Ciprofloxacin-HCl	1470,00	1470,00	1470,00	1470,00	1470,00
PVP 25	30,0	30,0	30,0	30,0	30,0
®Eudragit NE 30 D (Trockensubstanz)	201,9	302,9	468,75	562,5	750,0
HPMC 3 cp	60,7	91,0	187,50	225,0	300,0
Magnesiumstearat	35,4	53,1	93,75	112,5	150,0
Tween 20	2,1	3,1	5,25	6,3	8,4

Zusammensetzung von den Wirkstoff in Hydrochlorid-Form enthaltenden Mikrokapseln mit ®Eudragit NE 30 D / HPMC-Lacken (Vergleichsbeispiele)
Beispiel	12	13
®Eudragit RL 30 D / Triethylcitrat=	100/10	100/20
Lackauftragsmenge (theoret.)	50 %	60 %
Ciprofloxacin-HCl	1470,00	1470,00
Maisstärke feucht	30,00	30,00
®Eudragit RL 30 D (Trockensubstanz)	387,55	442,80
Triethylcitrat	39,00	88,65
Talkum	323,25	368,55

Zusammensetzung von den Wirkstoff in Hydrochlorid-Form enthaltenden Mikrokapseln mit ®Eudragit E 12,5 (Vergleichsbeispiele)
Beispiel	14
Lackauftragsmenge (theoret.)	50%
Ciprofloxacin-HCl	1470,00
Maisstärke feucht	30,00
®Eudragit E 12,5 (Trockensubstanz)	409,50
Mikrokristalline Cellulose	170,25
Magnesiumstearat	170,25

Zusammensetzung von den Wirkstoff in Betain-Form enthaltenden Mikrokapseln mit ®Eudragit NE 30 D / HPMC-Lacken
Beispiel	15	16	17	18	19
®Eudragit NE 30 D / HPMC=	100/10	100/20	100/20	100/20	100/30
Lackauftragsmenge (theoret.)	20%	15 %	20%	25%	20%
Ciprofloxacin	10,000	10,000	10,000	10,000	10,000
PVP 25	0,700	0,700	0,700	0,700	0,700
	1,660	1,138	1,517	1,897	1,440
HPMC 3 cp	0,167	0,228	0,304	0,380	0,432
Magnesiumstearat	0,298	0,228	0,304	0,380	0,252
Tween 20	0,015	0,012	0,015	0,019	0,015

Zusammensetzung von den Wirkstoff in Betain-Form enthaltenden Mikrokapseln mit ®Eudragit NE 30 D / HPMC-Lacken
Beispiel	20	21	22	23	24
®Eudragit NE 30 D / HPMC=	100/40	100/40	100/40	100/40	100/40
Lackauftragsmenge (theoret.)	20%	35%	40%	50%	60%
Ciprofloxacin	10,000	10,000	10,000	10,000	10,000
PVP 25	0,700	0,700	0,700	0,700	0,700
®Eudragit NE 30 D (Trockensubstanz)	1,328	2,324	2,656	3,320	3,984
HPMC 3 cp	0,531	0,929	1,062	1,328	1,593
Magnesiumstearat	0,265	0,464	0,530	0,662	0,795
Tween 20	0,015	0,026	0,030	0,038	0,045

Zusammensetzung von den Wirkstoff in Betain-Form enthaltenden Mikrokapseln mit ®Eudragit NE 30 D / HPMC-Lacken und Polierschicht
Beispiel	25
®Eudragit NE 30 D / HPMC=	100/40
Lackauftragsmenge (theoret.)	20 %
Ciprofloxacin	10,000
PVP 25	0,700
®Eudragit NE 30 D (Trockensubstanz)	1,328
HPMC 3 cp	0,531
Magnesiumstearat	0,265
Tween 20	0,015
PEG 6000	0,642

Zusammensetzung von den Wirkstoff in Betain-Form enthaltenden Mikrokapseln mit ®Eudragit NE 30 D / HPMC-Lacken (Vergleichsbeispiele mit Sprengmittel-Zusatz)
Beispiel	26	27
®Eudragit NE 30 D / HPMC=	100/30	100/30
Lackauftragsmenge (theoret.)	60 %	60 %
Ciprofloxacin	10,000	10,000
PVP 25	0,700	0,700
Ac-Di-Sol	1,000	1,000
®Eudragit NE 30 D (Trockensubstanz)	4,725	4,725
HPMC 3 cp	1,419	1,419
Magnesiumstearat	0,828	0,828
Tween 20	0,048	0,048
PEG 6000	-	0,936

Zusammensetzung von den Wirkstoff in Betain-Form enthaltenden Mikrokapseln mit ®Eudragit RL 30 D-Lacken
Beispiel	28	29
®Eudragit RL 30 D / Triethylcitrat =	100/20	100/10
Lackauftragsmenge (theoret.)	50%	60%
Ciprofloxacin	10,000	10,000
PVP 25	0,700	0,700
®Eudragit RL 30 D (Trockensubstanz)	2,638	3,320
Talkum gesiebt	2,188	2,760
Triethylcitrat	0,525	0,340

Zusammensetzung von den Wirkstoff in Betain-Form enthaltenden Mikrokapseln mit ®Eudragit RL 30 D-Lacken (Vergleichsbeispiele mit Sprengmittel-Zusatz)
Beispiel	30	31
®Eudragit RL 30 D / Triethylcitrat=	100/20	100/20
Lackauftragsmenge (theoret.)	60%	60%
Ciprofloxacin	10,000	10,000
PVP 25	0,700	0,700
Ac-Di-Sol	1,000	1,000
	3,460	3,460
Talkum gesiebt	2,870	2,870
Triethylcitrat	0,690	0,690
PEG 6000	-	0,936

Beispiel gemäß der Erfindung Ciprofloxacin Mikrokapseln in Ölsaft-Formulierung (Angaben zur Herstellung von 140 ml Ciprofloxacin Saft 5% m/v)
Ciprofloxacin	7,000
Polyvinylpyrrolidon 25	0,490
®Eudragit NE 30 D	2,257
HPMC 3 cp	0,910
Magnesiumstearat	0,455
Tween 20	0,018
Miglyol 812	98,214
Saccharose mikrofein	39,025
Lipoid S 75	1,405
Erdbeeraroma	0,156
Mikrokapseln: ®Eudragit NE 30 D / HPMC = 100/40; Lackauftrag 48,6 %.

Claims (5)

1. Pharmaceutical compositions containing active ingredients which are flavour-masked by microencapsulation having rapid release of active ingredient and high bioavailability, characterized in that the microencapsulated active ingredient is ciprofloxacin-betaine containing less than 5%, in particular less than 3.0%, of water in the form of water of crystallization or other water adducts and the capsule wall consists of a coating of water-insoluble neutral methyl and/or ethyl ester compounds or quaternary ammonium compounds of polymethacrylic acid or mixtures thereof or ethylcellulose and which can optionally contain additional water-soluble polymers, plasticizers, wetting agents and other customary auxiliaries, and the pharmaceutical compositions are formulated as an oily juice.
2. Pharmaceutical compositions according to Claim 1, characterized in that the capsule wall consists of a coating which contains neutral methyl and/or ethyl ester compounds of polymethacrylic acid (®Eudragit NE 30 D, Röhm, Darmstadt), and/or quaternary ammonium compounds of polymethacrylic acid (®Eudragit RL 30 D, ®Eudragit RS 30 D) or ethylcellulose and triethyl citrate and, if appropriate, hydroxypropylmethylcellulose as film formers.
3. Pharmaceutical compositions according to Claims 1 and 2, characterized in that the capsule wall consists of a coating containing a mixture of 100 parts by weight of neutral methyl- and/or ethyl ester compounds of polymethacrylic acid (®Eudragit NE 30) and 20 to 50 parts by weight of hydroxypropylmethylcellulose and, if appropriate, customary auxiliaries.
4. Pharmaceutical compositions according to Claims 1 to 3, characterized in that the microcapsules have a size of 10 to 800 µm.
5. Processes for the preparation of pharmaceutical compositions according to Claims 1 to 4, characterized in that the ciprofloxacin-betaine is granulated in moist form, then the moisture content of the active ingredient is optionally adjusted by drying to 0 to 30% by weight, the microgranules thus obtained are coated with a coating based on neutral methyl and/or ethyl ester compounds or quaternary ammonium compounds of polymethacrylic acid and ethylcellulose, which coating can optionally contain water-soluble polymers, plasticizers, wetting agents and other customary auxiliaries, then the desired moisture content of the active ingredient ciprofloxacin-betaine is optionally adjusted by drying, the microcapsules thus obtained are optionally polished and are formulated as an oily juice.