CA1317883C

CA1317883C - Liquid dosage form for oral administration of a pharmaceutically active substance

Info

Publication number: CA1317883C
Application number: CA000554941A
Authority: CA
Inventors: Kjell Johan Mattsson; Alf Gunnar Martin Nicklasson; Rolf Ivar Sjoqvist
Original assignee: Astra Lakemedel AB
Current assignee: Astra Lakemedel AB
Priority date: 1986-12-22
Filing date: 1987-12-21
Publication date: 1993-05-18
Anticipated expiration: 2010-05-18
Also published as: SE8605515D0; FI875645A; IL86607A; ES2039480T3; HK66396A; FI94923B; DE3785167T2; IE873306L; JP2778030B2; EP0273890B1; NO177177C; ATE87471T1; NO177177B; FI94923C; AU8199187A; DK668787A; NO874960D0; NO874960L; AU609753B2; EP0273890A1

Abstract

Abstract A dosage form for oral administration of a pharmaceutically active substance characterized in that it includes a encapsulated or embedded pharmaceutically active substance in a pharmaceutically acceptable non-aqueous liquid.

Description

~L3~L788~
A 866-1 1987-lO-30 A liquid dosage form for oral administration of a pharrnaceutically actiYe substance _ Description Technical field .
The present invention relates to a liquid dosage form for oral administration containing microspheres or microcapsules of a pharmaceutically active substance which substance has either an unpleasant taste or which substance is unstable in aqueous solution or both.
The present invention also relates to a method of masking unpleasant taste of a pharrnaceutically active substance administered in the form of a solution or suspension and to increase the stability properties of an unstable pharmaceutically active substance administered in the form of a solution or suspension using a non-aqueous liquid carrier.

Background of the Invention .
Many pharmaceutically active substances have a very unpleasant taste, and they are therefore not suited for oral administration in the form of solutions or suspensions. Because the administration by solutions or suspensions is a very suitable one and in some cases the only oral way feasible, (e.g. when a patient can not accept tablets or capsules) the problem is a serious one. Thus, for administration to children and elderly, oral suspensions or solutions may be advantageous. In the former case, taste is very important in order to have a high patient compliance.

The problem o~ rnasking the unpleasant taste of a pharmaceutically active subs~ance in connection with a liquid dosage form for oral adminis-tration and where the substance is microencapsulated has been tackled in different ways.
~"

2 ~ 3 ~ 3 In EP 69097 the combination of a microencapsulated active substance with a basic substance prior to preparing a ready to use aqueous suspension is described.

In EP 101418 the combination of a microencapsulated active substance with a high content of sugar prior to preparing a ready to use aqueous suspension is described.

The object of the present invention is to provide a ready to use so1ution or suspension of a pharmaceutically act;ve substance intended to be administered orally wherein the unpleasant taste of the substance has been masked by combining the principles of microencapsulation and a non-aqueous liquid carrier wherein the encapsulated drug is practically insoluble.
Many pharmaceutically active compounds degrade when dissolved in aqueous or hydrophilic solvents. In order to delay this mechanism, preparations have been formulated where the active compound is reconstituted with water prior to use. In many cases, the suspensions or solutions need to be stored in a cold place. A great improvement would therefore be to have a stable formulation from the manufacturer where the active compound is already suspended in a liquid vehicle. However, when it is not possible to make an ready to use suspension, due to physicochemical reasons, the application of microencapsulation or embedding the active compound in a water repellant micro matrix or a sphere can be used in order to increase the solid state stability. Thus, the microspheres or ~icroeapsules can also be mixed with a granulation for reconstitution which creates a more stable system compared to a conventional granu-lation for reconstitution.
A ~urther object of the invention is therefor to increase the stabilityof a pharmaceutically active substance which is unstable in aqueous or hydrophilic solution or suspension.

A still further object of the invention is to provide controlled release properties of the dosage form according to the invention, thus combining a controlled release with good taste and high stability.

1317~3 Disclosure of the Invention Aqueous suspensions have been used in all prior attempts to tackle the problem of masking unpleasant taste of a liquid oral formulation using a microencapsulated pharmaceut-ically active substance.
It has now been found that the unpleasant taste of a pharmaceutically active compound intended to be administered orally in the form of a solution or a suspension can be masked i~ the active compound which must be microencapsulated or em-bedded in a micromatrix is mixed with a vehicle which consists of a pharmaceutically acceptable non-aqueous liquid, in which the encapsulated drug shows no or extremely low solubility. Hence, it is the combination of a microencapsulated drug and the appli-cation of a non-aqueous liquid carrier which makes this partic-ular invention unique.
Accordingly, it is an aspect of the present invention to provide a liquid dosage form for oral administration of a pharmaceutically active substance comprising a pharmaceutically active substance that is encapsulated and suspended in a pharmaceutically acceptable oil, wherein the active substance is ta~ single wall encapsulated wherein the coating material is selected from the group consisting of carnauba wax, ethylcellulose and a combination of carnauba wax and bees wax or (b) dual wall encapsulated wherein the coating material of the first wall is ethylcellulose and the coating of the second wall iq a combination of carnauba wax and bees wax.

A

-3a- 23~4~ 3 It is also an aspect of the invention to provide a process for the preparation of a liquid dosage form for oral administration of a pharmaceutically active substance comprising a pharmaceutically active substance is encapsulated and suspended in a pharmaceutically acceptable oil, wherein the active substance is (a) single wall encapsulated wherein the coating material is selected from the group consisting of carnauba wax, ethylcellulose and a combination of carnauba wax and bees wax or (b) dual wall encapsulated wherein the coating material of the first wall is ethylcellulose and the coating of the second wall is a combination of carnauba wax and bees wax, wherein the pharmaceutically acceptable substance in encapsulated form is added to gently mixed with the pharmaceutically acceptable oil.
The present invention provides an improved liquid delivery system for active compounds which have an unpleasant taste. It is also advantageous compared to conventional sus-pensions or solutions since it prevents the active compound fromdegrading in the liquid medium. The mechanism behind this phenomenon is first the application of a liquid carrier in which the active compound is not soluble or soluble to a very low extent and secondly the fact that the active compound is micro-encapsulated or embedded in a micromatrix system. Since the active compound is embedded in a micromatrix structure or is microencapsulated the risk for obtaining an unpleasant taste in the mouth due to dilution or washing of the non-aqueous liquid 1~17883 ~3b- 23940-588 is reduced due to a delayed release of the active compound from the matrices or microcapsules in aqueous media. The combination of these two factors is a solid ground for obtaining the above mentioned properties. However, as mentioned above, the appli-cation of micromatrices or microcapsules may also be advantageous for a granulation for aqueous reconstitution in terms of solid state stability before reconstitution.
sy replacing the aqueous vehicle with a non-aqueous vehicle and by microencapsulating or embedding the active com-pound in a matri~ sphere the following advantages are obtained:

.A~

4 13~ ~8~
- The active substance can be prepared in a liquid formulation which is ready to use.
These types of formulations are otherwise normally delivered as a dry powder which has to be mixed with water prior to use. Such a product has relatively bad keeping qualities. Besides, this operation is costly in countries where the pharmacies fullfill them. In countries where the patient himself has to add water the risk of mistakes could not be disregarded. In a manufacturing point of view it is often advantageous to handle a liquid product insteacl of a dry powder and thus avoiding problems in connection with the production environment.

- The formulation of a Inicroencapsulated active substance in a non-aqueous vehicle not only provides masking of an unpleasant taste but affords also enhanced stability. This property is particularly valuable in connection with ccmpounds normally unstable in liquid vehicles, for instance penicillins.

- Furthermore the formulation according to the invention affords controlled release properties to the formulation.
All those pharmaceutical1y active substances which have an unpleasant taste or which are unstable in solution are well suited for use in connection with this invention. Examples of such active substances are Ohemoterapeutics bacampicillin, ampicillin, flucloxacillin, tetra-cycline, dicloxacillin, chloramphenicol, gentamicin, erythromycin, lincomycin, rifampicin, sulphadiazine, sulphamethoxypyridazine, griseofulvine, nitrofurantoine, penicillin V, penicillin G, cephalosporin derivatives.

Adrenergic ephedrine, terbutaline, theophylline, and betareceptor- enprophylline stimulators Expectorants Ethylmorphine, dextromethorphan, noscapine, and cough bromhexine depressants ~317~3 Heart glucosides Digitoxine, digoxin, dispyramide, procainide, and tocainide, alprenolol, atenolol, metoprolol antiarythmics pindolol, propranolol Blood pressure betanidine, clonidine, guanetidine, methyldopa, depressants reserpine, trimetaphane, hydrolazine, bendro-phlumetiazide, furosemide, chlorotiazide Antihistamines brompheniramine, chlorcyclizine, chlorpheniramine, diphenhydramine, prometazine Peroral carbutamide, chlorpropa~ide, ~olazamide, : antidiabetes tolbutamide Sedatives Hypnotics meprobamate, chlordiazepoxide, diazepam,buspirone, Antidepressants flunitrazepam, nitrazepam, oxazepam, Antipsychotics chloromethiazol, chlorpromazine, fluphenazine, perphenazeine prochloroperazin, haloperidol, lithium, alaproclate, zimeldine, amitryptiline, imipramine, nortriptyline, remoxipride, raclopride ~ Antiepileptics phenytoine, ethotoin, ethosuximide, carbamazepine : 25 Analgetics codeine, morphine, pentazocine, petidine, dextro-Anesthetics propoxyphene, methadone, acetylsalicylic acid, diflunisal, phenazone, phenylbutazon, acetamino-phene, indoMetazine, naproxen, piroxicam, lidocaine, etidocaine Others cimetidine, quinidine, dicoumarine, warfarine, potassium chloride, chloroquine Preferred active substances are remoxipride, raclopride, penicillins, : 35 cephalosporins, alaproclate, buspirone, diazepam and other benso-diazepins.

13~78~

Particularly preferred compounds are remoxipride, acetaminophen, phenoxymethylpenicillin, bacampicillin, bensylpenicillin, flucloxacillin and cephalosporin derivati~es.

The ac~ive substances mentioned above are used in neutral or salt form.

Any salts of the active substances mentioned above can be used, for instance Acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydro-chloride, edetate, edisylate, estolate, esylate9 fumarate, glucep~ate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydra-bamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malte, malea~e, mandelate, mesylate, nlethylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, (embonate), pantothenate, phosphatetdiphosphate, polygalacturo-nate, salicylate, stearate, subacetate, succinate, sulphate, tannate, tartrate, teoclate, triethiodide.
Also the further cationic salts can be used. Suitable cationic salts include the alkali metal, e.g. sodium and potassium, and ammonium salts and salts of amines known in the art to be pharmaceutically acceptable, e.g. glycine, ethylene diamine, choline, diethanolamine, triethanol-amine, octadecylamine, diethylamine, triethylamine, l-amino--2-propanol-2-amino-2-(hydroxymethyl~propane-1,3-diol and 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol.

Coating and matrix materials 3~
The formation of microencapsulated and matrix material is well known in the art and does not form any part of the present invention. Any coating material can be used. The type of coating will be chosen depending on whether only taste masking is desired or whether a controlled release function or a combination of both is desired. The choice of coating will in either case be obvious to the man skilled in the art.

11 ~ll 7~83 Coating and matrix material to be used are, for ;nstance Polymers:

Synthetic polymers of polyvinyl type and copolymers thereof, e.g.
polyvinylchloride, polyvinylacetate9 polyvinylalcohol, polyvinyl-pyrrolidone.

Polyethylene type, e.g. polyethylene, polystyrene.
Polymers of acrylic acid or acrylic acid ester type, e.g.
methylmetacrylate or copolymers of acrylic monomers.

Biopolymers or modified biopoly~ers of cellulose, e.g. ethylcellulose, cellulose acetate phtalate, cellulose acetate, hydroxy propyl cellulose, hydropropylmethyl cellulose, methylcellulose, Na-carboxymethyl cellu-lose.

Shellac Gelatin Fats, oils, higher fatty acids and higher alcohols e.g. aluminum rnonostearate, cetylalcohol, hydrogenated beef tallow , hydrogenated castor oil, 12-hydroxysiearyl alcohol, glyceryl mono- or dipalmitate, glyceryl mono- di-, or tristearate, myristyl alcohol, stearic acid, stearyl alcohol.

Polyethyleneglycols Waxes e.g. bees wax, carnauba wax, Japan wax, paraff;n, synthetic wax, spermaceti.

Sugars and sugar alcohols e.g. mannitol, sorbitol, sucrose, xylitol, glucose, maltose.

:L3~7883 The microcapsules or micromatrices useful for the present invention can be prepared by any of several acknow7edge of rnicroencapsulation processes or microsphere or matrix production processes including pan coating, prilling, extrusion and spheronization, fluid bed processes, spray drying, spray chilling coacervation and other processes.

Microspheres, microcapsules or matrix beads in the size range of 10-1000 microns are suitable for being suspended in the liquid carrier.
Preferably, the size range of 50-150 ~m are used since this size range is small enough in order to give a smooth appearance in the mouth ~hich is especially important ~or pediatric formulations. This size range can easily be obtained by means of e.g. spray chilling or spray drying and these processes are also suitable for generating controlled release microcapsules in the same size range. The size range of 50-150 ~m is lS also preferred because of the low risk of crushing the spheres bet~eenthe teeth after administration as it might be for larger beads.

Any combinations of the above mentioned polymers, fats and waxes can be used for encapsulation purposes, viz, different polymers can be Mixed, a polymer can be mixed with a fat or wax etc.

The encapsulation of the drug can be achieved in the form of micro-capsules, but the encapsulation is not restricted to the micro size.

Microcapsules :
Microcapsules are defined as a solid or a liquid core enclosed in a coating. The coating may also be referred to as the wall or shell.
Various types of microcapsule structures can be obtained depending on the manufacturing process, e.g. mononuclear spherical, multinuclear spherical, multinuclear irregular, encapsulated mononuclear capsules, dual-walled microcapsules etc. When no distinct coating and core region can be observed, the analogous terms are microparticles, microspheres, micromatrices or microbeads (c.f. multinuclear microcapsules above). The microcapsules usual1y have a particle size between 1 and 2000 ~m. The preferred size range for this invention is 50-lS0 ~m.

~L7'~83 The microcapsules referred to in the present invention can thus be designed as micromatrices, overcoated micromatrices or overcoated ho~ogeneous microsphere cores.

~b~
Non-aqueous vehicle is a pharmaceutically acceptable non-aqueous liquid such as a pharmaceutically acceptable oil, e.g. hydrogenated coconut oil, such as Miglyol~ and Viscoleo~ , coconut oil, peanut oil, sesame oil, corn oil.

Emulsifying agents (super active agents) to be used are for instance:

- bile salts or derlvatives thereof - propyl gallat - sorbiton fatty acid esters - polyoxyethylene sorbiton fatty acid esters - polyoxyethylene sorbitol esters - polyoxyethylene acids - polyoxyethylenel alcohols - polyoxyethylene adduct not otherwise classified - mono and diglycerides - polyoxyethylene glyceryl fatty acid e~ters - fusidic acid derivatives - sodium lauryl sulphate Preferréd embodiments ______~
A preferred embodiment of the present invention is obtained when remoxipride is encapsulated in carnauba wax and mixed with a vehicle consisting of hydrogenated coconut oil.
Other preferred embodiments are obtained when ~6~

~317~83 -9a~ 23940-588 phenoxymethyl penicillin (penicillin V), bacampicillin, bensyl-penicillin, flucloxacillin or acetaminophen are encapsulated in carnauba wax and mixed with a vehicle consisting of hydrogenated coconut oil.

,,, ,~ , i, . .

' ~3~83 Still other preferred embodiments are obtained when the active substance is encapsulated in either carnauba wax and beeswax or in ethyl cellulose, carnauba wax and bees wax and mixed with a vehicle consisting o~ hydrogenated coconut oil.

Still another preferred embodiment is obtained when ~he active substance is encapsulated in either cannauba wax, bees wax, cannauba wax and bees wax or ethyl cellulose and mixed wi~h a vehicle consisting of hydro-genated coconut oil and a suitable emulsifying agent, e.g. bile salts.
The preparation is preferably made by adding the solid powders (i.e, flavouring agents and sugars) to the fluid component by mixing until a homogenious suspension is obtained. Finally the microcapsules are added and gently mixed. The suspension can then be added to glass or plastic bottles. In some cases, a thickening agen~ is preferable to prevent a too rapid sedimentation of the suspended particles (e.g. a1uminum monostearate, stearic acid, bees wax etc.) Best mode of carring out the invention .
Example 1 Remoxipride substance with a particle size less than 10 ~m was suspended in a carnauba wax melt at 100C. The slurry was spray chilled into microspheres with a diameter between 50 and 125 ~rll.

Remoxipride microspheres consist of:

Remoxipride hydrochloride monohydrate 40 %
Carnauba wax 60 %

Composition of an oral suspension:

Remoxipride microcapsules 13.5 g Sodium bicarbonate 0.84 9 Caramel flavour 0.50 9 Sucrose powder 35.50 9 Hydrogenated coconut oil 60.00 9 11 3~7~83 In a beaker the oil was added and the sucrose powder was added in small portions while stirring vigorously. Sodium bicarbonate and the flavouring component were added and finally the remoxipride micro capsules were added. The resulting product was a free flowing swspension with a nice appearance.

The taste of this product was judged by 10 people and was compared to an aqueous solution with the same concentration of remoxipride. The people was asked to judge if the product was acceptable from a taste point of view compared to the plain remoxipride solution.

Results:

Acceptable Not acceptable The composition according to ex 110 0 Remoxipride aqueous solution 0 10 The invented product was superior to a non taste masked aqueous product.
Thus the invented product has a very high degree of taste masking as the plain solution has a very bitter taste, which was the main comment from the test panel for the plain remoxipride solution.

Example 2 A suspension according to the present invention, containing remoxipride micromatrices (40 % remoxipride and 60 % wall material) was filled in no. 1 hard gelatin capsules. The capsules were administered to two male beagle dogs, and plasma was collected. As reference a solution of remoxipride was used. The dose of the oil suspension (the invented product) was 215 ,umol and the solution was 250 ,umol of remoxipride. The plasma concentrations of remoxipride were analyzed with a high pressure liquid chromatography method.

~ 31~83 The maximum plasma concentration obtained (Cmax) and the extent of bioavailability (AUC) are shown in the Table.

The C~nax reflects the highest c~ncentration of the drug. A drug th~t absorbs rapidly reaches a higher Cmax-value than if it absorbs slowly.
The area under the plasma concentration vs. time curve (AUC) reflects the amount of the drug that has been absorbed during the experimental period.

Results:

Cmax AUC
,u~nol/l pmolxh/l Dog 1 Dog 2 Dog 1 Dog 2 The invented product 10.5 9.4 72 56 Remoxipride solution 11.9 11.2 72 58 It can easily be seen that the invented product is bioequivalent to a plain solution of remoxipride. As a matter of fact, if corrections are made for the dosing difference the invented product has 9 and 4 percent better bioavailability in the two dogs respectively. Thus, the taste rnasking efforts have no negative effect upon the biopharmaceutical properties of the drug.

Exarnple 3 3~
Controlled release microcapsules were prepared by means of spray chilling. The particles consisted of 16 % remoxipride hydrochloride monohydrate and 84 % carnauba waxibees wax. Particles with a size between 53 and 105 ~rn were collected and used for further experiments.
The release rate of remoxipride from the microcapsules in water at 37Cis given below:

~311 7~3 Percent (%) remoxipride released lh2h 4h 6h 8h S
The controlled release microcapsules were added to an oil formulation.

Composition:

Remoxipride controlled release microcapsules described above: 8.3 9 Caramel flavour0.5 g Peppermint oil0.5 9 Sucrose powder41.0 9 Hydrogenated coconut oil 60.0 g Caramel ~lavour, peppermint oil and sucrose powder were added to the oil and mixed vigorously. Then the controlled release microcapsules were added and gently mixed. The resulting product has thus controlled release properties and it is also taste masked.

Example 4 Dual-walled controlled release microcapsules were prepared by means of spray drying and spray chilling. The microcapsule core consisted of remoxipride hydrochloride monohydrate and ethyl cellulose. The cores were then overcoated with carnauba wax and bees wax, respectively.
Particles with a size between 50 and 150 ~m were collected and used for further experiments. The fihal content of remoxipride hydrochloride monohydrate was found to be 16 X.

The release rate of remoxipride from the microcapsules in water at 37C is given below:

~31~883 .
Percent (%) remoxipride released 2h 4h 6h 8h lOh 15h 20h 24h .

:
10 The controlled release microcapsules were added to an oil formulation.
Composition:

Dual-walled remoxipride controlled release 1~ microcapsules 15.6 9 Caramel flavour 0.5 9 Peppermint oil 0.5 9 Sucrose powder 35.4 9 Hydrogenated coconut oil 60.0 9 Caramel flavour, peppermint oil and sucrose powder was added to the oil and mixed vigorously. Then the controlled release microcapsules were added and gently mixed. The resulting product has controlled release properties and it is also taste masked.

Example 5 Phenoxymethyl penicillin -K microcapsules consist of Phenoxymethyl penicillin -K 40 %
Carnauba wax 60 %

The penicillin powder with a particle size less than 10 ~m was suspended in a carnauba wax melt at 105C. The slurry was spray chilled into microspheres with a diameter between 50 and 125 ,um.

~317~
Composition of an oral suspensiQn:

Phenoxymethyl penicillin -K
microcapsules 11.6 Lemon flavour 0.42 9 Strawberry flavour 0.70 9 Maltol 0.28 9 Sucrose powder 30.4 g Hydrogenated coconut oil 56.5 9 ~ The taste of this product was judged by seven people and was cornpared to : . a phenoxymethyl penicillin~l-K suspension on the market with the same ~ dosage strength (K~VEPENI~ 50 m~/nll). The table summarizes the taste ; scores obtained where 0 denotes a very bad taste and 100 denotes a perfect taste.

, : Subject no. New suspension Market suspension 2~

j 4 78 31 _ x 87.6 63.9 The data demonstrate a much better acceptance for the new type of suspension of phenoxymethyl penicillin -K. Also, the taste profile is more irregular for the rnarket suspension and Inore uniform for the ne one which shows that the new suspension has a much better taste in general.

~7 `Al,~.~f~d~

~3~7~83 Example 6 Bacampicillin hydrochloride substance with a particle size less than 10 ~m was suspended in a carnauba wax melt at 100C. The slurry was spray chilled into microcapsules with a diameter between 50 and 125 ~m.

Bacampicillin hydrochloride microcapsules consis1; of Bacampicillin hydrochloride 25 ~, Carnauba wax 75 X

Composition of an oral suspension Bacampicillin microcapsules 14.14 g Strawberry flavour 1.30 g Lemon flavour 0.69 9 Maltol 0.29 9 Sucrose powder 25.08 g Hydrogenated coconut oil 58.51 9 Example 7 Bacampicillin hydrochloride substance with a particle size less than 10 ~m was suspended in a carnauba wax melt at 100C. The slurry was spray chilled into microcapsules with a diameter between 50 and 125 ~m.

Bacampicillin hydrochloride microcapsules consist of Bacampicillin hydrochloride 40 Carnauba wax 60 %

Co~position of an oral suspension Bacampicillin microcapsules 8.81 9 Strawberry flavour 1.30 g Lemon flavour 0.69 9 Sucrose powder 20.00 9 Hydrogenated coconut oil 58.51 9 17 ~3~83 Example 8 Phenoxymethyl pencillin -K substance with a particle size less than 10 ~m was suspended in a carnauba wax melt at 100C. The slurry was spray chilled into microcapsules with a diameter between 50 and 125 ,um.

Phenoxymethyl penicillin -K microcapsules consist of Phenoxymethyl penicillin -K 40 %
Carnauba wax 60 %

Composition of an oral suspension Phenoxymethyl penicillin microcapsules 15.63 9 Strawberry flavour 0.35 9 Lemon flavour 0.15 g Sucrose powder 61.91 9 Hydrogenated coconut oil 70.00 9 The stability of this product was investigated during storage at 25C
and 37C for four months. The table shows the assayed quantity of degradation product (mg penicilloic acid/g suspension).

Storage Time 25C 37C

0 0.20 mg~g 0.20 mg/g 4 months 0.45 mg/g 0.60 mg/g ;

The result in the table shows that the invented formulation of phenoxymethylpenicillin -K is very stable. An increase of only 0.4 mg/g of penicilloic acid is obtained after 4 months' storage at an accelerated storage condition (37C). This corresponds only to about 1%
in relation to the phenoxymethylpenicillin -K concentration in the ; suspension.

~3~L78~3 Example 9 Bensylpenicillin -K substance with a particle size less than 10 ,um was suspended in a carnauba wax melt at 100C. The slurry was spray chilled into microcapsules with a diameter between 50 and 125 ,um.

Bensylpenicillin -K microcapsules consist of Bensylpenicillin -K 40 %
Carnauba wax 60 %

Composition of an oral suspension Bensylpenicillin -K microcapsules 11.6 9 Lemon flavour 2.2 g Strawberry flavour 2.8 9 Sucrose powder 41.1 9 Hydrogenated coconut oil 54.7 9 Example 10 Flucloxacillin -Na substance with a particle size less than 10 ,um was suspended in a carnauba wax melt at 100C. The slurry was spray chilled into microcapsules with a diameter between S0 and 125 ,um.
: 25 Flucloxacillin -Na microcapsules consist of Flucloxacillin -Na 36 %
Carnauba wax 64 %
Composition of an oral suspension Flucloxacillin -Na microcapsules 6.41 9 Strawberry flavour 1.32 9 : 35 Lemon flavour 0.70 9 Maltol 0.26 9 Sucrose powder 31.95 9 Hydrogenated coconut oil 59.34 9 '9 ~L317~8~

Example 11 1.0 9 of polyisobutylene was dissolved in 200 ml of cyclohexane under stirring and heating up to 80C. After the polyisobutylene was dissolved 1.0 9 of ethylcellulose was dissolved. To the cyclohexane solution 2.Q g of Remoxipride hydrochloride monohydrate powder was suspended. Under stirring and controlled cooling, the resulting coated particles were collected and filtered off. The coated particles, or microcapsules, were washed with coo1 cyclohexane and then air-dried.
Composition:

Microcapsules described above 2.0 9 Butterschotch flavour 0.1 9 Sodiumbicarbonate 0.1 9 Sucrose powder 3.0 9 Peanut oil 8.0 9 The microcapsules, flavour, sodium bicarbonate and sucrose were added to the peanut oil and gently mixed. The resulting oral suspension was not tasting any bitterness of remoxipride.

Claims

1. A liquid dosage form for oral administration of a pharmaceutically active substance comprising a pharmaceutically active substance that is encapsulated and suspended in a pharmaceutically acceptable oil, wherein the active substance is (a) single wall encapsulated wherein the coating material is selected from the group consisting of carnauba wax, ethylcellulose and a combination of carnauba wax and bees wax or (b) dual wall encapsulated wherein the coating material of the first wall is ethylcellulose and the coating of the second wall is a combination of carnauba wax and bees wax.

2. A liquid dosage form according to claim 1, wherein the pharmaceutically acceptable oil is hydrogenated cocounut oil.

3. A liquid dosage form according to claim 1, wherein the pharmaceutically active substance is encapsulated in carnauba wax.

4. A liquid dosage form according to claim 1, wherein the pharmaceutically active substance is encapsulated in carnauba wax and bees wax.

5. A liquid dosage form according to claim 1, wherein the pharmaceutically active substance is encapsulated in ethyl-cellulose, carnauba wax and bees wax.

6. A liquid dosage form according to claim 1, wherein the active substance is remoxipride.

7. A liquid dosage form according to claim 6 wherein the remoxipride is encapsulated in carnauba wax.

8. A liquid dosage form according to claim 6 or 7 wherein the pharmaceutically acceptable oil is hydrogenated coconut oil.

9. A liquid dosage form according to claim 1, wherein the active substance is selected from the group consisting of bacampicillin, penicillin V, bensylpenicillin and flucloxacillin or pharmaceutically acceptable salts thereof.

10. A liquid dosage form according to claim 1 wherein the active substance is acetominophen or a pharmaceutically acceptable salt thereof.

11. A liquid dosage form according to claim 9 or 10 wherein the active substance is encapsulated in carnauba wax and the pharmaceutically acceptable oil is hydrogenated coconut oil.

12. A process for the preparation of a liquid dosage form for oral administration of a pharmaceutically active sub-stance comprising a pharmaceutically active substance that is encapsulated and suspended in a pharmaceutically acceptable oil, wherein the active substance is (a) single wall encapsulated wherein the coating material is selected from the group consisting of carnauba wax, ethylcellulose and a combination of carnauba wax and bees wax or (b) dual wall encapsulated wherein the coating material of the first wall is ethylcellulose and the coating of the second wall is a combination of carnauba wax and bees wax, wherein the pharmaceutically acceptable substance in encapsulated form is added to and gently mixed with the pharmaceutically acceptable oil.

13. A process of claim 12 wherein solid adjuvants are added to the pharmaceutically acceptable oil and mixed therewith until a homogeneous suspension is obtained, whereafter the pharmaceutically active substance in encapsulated form is added and gently mixed with the suspension.

14. A method of obtaining taste masking/controlled release/improved stability in a liquid oral formulation of a pharmaceutically active substance wherein the pharmaceutically active substance in microencapsulated form is added to a vehicle consisting of a pharmaceutically acceptable oil, wherein the active substance is (a) single wall encapsulated wherein the coating material is selected from the group consisting of carnauba wax, ethylcellulose and a combination of carnauba wax and bees wax or (b) dual wall encapsulated wherein the coating material of the first wall is ethylcellulose and the coating of the second wall is a combination of carnauba wax and beeswax.

15. An oral pharmaceutical dosage form comprising an encapsulated pharmaceutically active substance and a pharmaceu-tically acceptable non-aqueous liquid wherein the active substance is encapsulated in a coating, selected from the group consisting of ethylcellulose, carnauba wax and a combination of carnauba wax and beeswax which coating is applied by spray drying and spray chilling in a solvent system which does not contain a halogenated solvent.

16. An oral pharmaceutical dosage form comprising an encapsulated pharmaceutically active substance and a pharmaceu-tically acceptable non-aqueous liquid wherein the active substance is encapsulated in a first coating of ethylcellulose which is then coated with a second coating comprising a combination of carnauba wax and beeswax, the encapsulation being effected by spray drying and spray chilling, in a solvent system which does not contain a halogenated solvent.

17. A dosage form according to claim 15 or 16 wherein the active substance is remoxipride.

18. A dosage form according to claim 15 or 16 wherein the active substance is selected from the group consisting of bacampicillin, penicillin V, benzylpenicillin and flucloxacillin.

19. An oral pharmaceutical dosage form according to claim 15 or 16, wherein the non-aqueous liquid is a pharmaceutically acceptable oil.

20. An oral pharmaceutical dosage form according to claim 19 wherein the pharmaceutically acceptable oil is hydrogenated coconut oil.

21. A process for the preparation of an oral pharmaceutical dosage form comprising adding solid adjuvants to a non-aqueous liquid, mixing the adjuvants and the non-aqueous liquid until a homogeneous suspension is obtained, and adding a pharmaceutically active substance encapsulated in a coating, selected from the group consisting of ethylcellulose, carnauba wax and a combination of carnauba wax and beeswax which is applied by spray drying and spray chilling in a solvent system which does not contain a halogenated solvent in the encapsulation procedure.

22. A process according to claim 21 wherein the active substance is encapsulated in a first coating of ethylcellulose and a second coating comprising a combination of carnauba wax and beeswax.