Pharmaceutical mixture

The present invention is concerned with an oral pharmaceutical preparation containing an microencapsulated pharmaceutically active substance. More specifically the preparation is a dry powder for mixture or said dry powder dissolved in an aqueous solution.

The object of the invention is to provide a preparation wherein the dissolution of the active substance from the microencapsulation is controlled, which is a ready-to-use pharmaceutical suspension with controlled release of active substance including masking of bad taste and stability increasing of active substance characterized in that it contains a microencapsulated active substance combined outside the encapsulation with 60-99% (weight/weight) of the ready-to-use suspension, preferably 60-75%, of a release controlling substance which is a carbohydrate selected from polysaccharides, oligosaccharides, disaccharides and monosaccharides or a carbohydrate-related compound selected from the group consisting of mannitol, sorbitol, glycerol, glycol, a glycoside of a monosaccharide and a substance derived from ethyleneglycol or a mixture of such compounds.

Background art

Among alternative forms of orally administering pharmaceutically active substances the use of a solution or a suspension of the active principle in an aqueous solution is a form often seen in pediatric use. This preparation is called a mixture. The dry powder including the active principle and adjuvants which is to be dissolved or suspended is called dry powder for mixture.

The preparation is stored as a dry powder. Before administration the dry powder is dissolved or suspended in an aqueous solution giving rise to a liquid formulation for oral administration-a mixture. Alternatively the mixture can be prepared in the factor and stored at least for two years prior to administration. Pharmaceutically active substances for use in mixtures have been encapsulated either to mask bad taste or to control the release in the body.

Hitherto medicins have been coated with polymers or with polymers in combination with plasticizers to control drug release (microencapsulation). Applied on granulates of a drug it retards the rate of dissolution.

The main way to control drug dissolution from microcapsules is the amount of polymer applied, in order to obtain the expected plasma profile of the drug. This can also be obtained by adding water soluble substances to the coat during the coating process.

Disclosure of the invention

The present invention provides a mixture, wherein bad taste of the drug is masked and/or it provides a mixture with retarded dissolution to obtain slow release effect.

The mixture is obtained either by suspending the dry powder in an aqueous solution or by suspending the microcapsules in a solution of the release controlling substance.

The drug release from the microcapsules within the mixture, here called leakage, is very low, but in the body the drug is released from the microcapsules and available for absorption.

This invention also provides for increased drug stability in the mixture.

This result is obtained by adding to the microencapsulated active substance and customary adjuvants a release-controlling substance (sink).

As sink can be used a carbohydrate or a carbohydrate-related compound, for instance a poly- or an oligosaccharide such as dextrane; a disaccharide such as saccharose, maltose or lactose; a monosaccharide such as glucose, fructose, galactose, mannose or xylitol; a carbohydrate-related compound such as mannitol, sorbitol, glycerol, glycol, a glycoside of a monosaccharide or a substance derived from ethyleneglycol for instance polyethyleneglycol (trade names Carbowaxes@ and Carbopoles^O).

As sink one or a mixture of two or more of the mentioned substances can be used.

The amount of sink should be between 60% and 99% (weight/weight), preferably 60-75% (weight/ weight) of the entire preparation, that is of the ready to use suspension for oral administration (the mixture).

Sugars that can be used according to the invention are among others sucrose, glucose, fructose and sorbitol.

As pharmaceutically active substance any drug can be used, for instance any one of the following:

Chemotherapeutics: bacampicillin, ampicillin, flucloxacillin, tetracycline, dicloxacillin, chloramphenicol, gentamicin, erythromycin, lincomycin, rifampicin, sulphadiazine, sulphamethoxypyradazine, griseofulvine, nitrofurantoine.

Adrenergis and beta-receptor-stimulators: ephedrine, terbutaline, theophylline, enprophylline.

Expectorants and cough depressants: Ethylmorphine, dextromethorphan, noscapine, bromhexine.

Heartglucosides and antiarythymics: Digitoxine, digoxin, dispyramide, procainide, tocainide, alprenolol, atenolol, metoprolol, pindolol, propranolol.

Blood pressure depressants: betanidine, clonidine, guanetidine, methyldopa, reserpine trimetaphane, hydrolazine, bendropphlumetiazide, furosemide, chlorotiazide.

Antihistamines: brompheniramine, chlorcyclizine, chlorpheniramine, diphenhydramine, prometazine.

Peroral antidiabetes: carbutamide, chlorpropamide, tolazamide, tolbutamide.

Sedatives, hypnotics, antidepressants: hexobarbital, pentobarbital, phenobarbital, meprobamate, chlordiazepoxide, diazepam, flunitrazepam, nitrazepam, oxazepam, chlormethiazol, chlorpromazine, fluphenazine, perphenazine, prochlorperazin, haloperidol, lithium, alaproclate, zimeldine, amitryptiline, imipramine, nortripthyline.

Antiepileptics: phenytoine, ethotoin, ethosuximide, carbamazepine.

Analgetics, anesthetics: codeine, morphine, pentazocine, petidine, dextropropoxyphene, methadone, acetylsalicylic acid, diflunisal, phenazone, phenylbutazon, acetaminophene, indometazine, naproxen, piroxicam, lidocaine, etidocaine.

Others: cimetidine, quinidine, dicoumarine, warfarine, potassium chloride, chloroquine.

The preferred drug is bacampicillin hydrochloride (1'-ethoxycarbonyloxyethyl 6-[D(-)-2-amino-2-phenylacetamidol]-penicillanate hydrochloride), other epimeric forms and the racemic form of bacampicillin hydrochloride.

Other preferred drugs are theophylline, enprophylline and erythromycine.

The drugs mentioned above are used in neutral or salt form.

The following salts of the drugs mentioned above can be used: <ul id="ul0001" list-style="none"><li>Acetate, benzenesulfone, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, clycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methytnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulphate, tannate, tartrate, teoclate, triethiodide.</li></ul>

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, triethanolamine, octadecylamine, diethylamine, triethylamine, 1-amino-2-propanol-2-amino-2-(hydroxymethyl)propane-1,3-diol and 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol.

Coating material

Polymers: <ul id="ul0002" list-style="none"><li>Synthetic polymers of polyvinyl type, e.g. polyvinylchloride, polyvinylacetate, polyvinylalcohol.</li></ul>

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 biopolymers of cellulose, e.g. ethylcellulose, cellulose acetate phtalate.

The polymer can be water insoluble, acid soluble or alkaline soluble and mixed with plasticizer or other filler and water soluble modified biopolymer, e.g. hydroxy-propyl-cellulose.

Also fats and oils, wax, higher fatty acids, higher alcohols or polyhydric alcohols can be used as such or in combination.

In one embodiment of the invention bacampicillin hydrochloride (BAPC) is encapsulated in an insoluble, microporous polymer, such as ethyl cellulose and sucrose is used as sink to make a dry powder for mixture, which is then dissolved in water to make a mixture.

In another embodiment of the invention BAPC is encapsulated in a polymer soluble in acid, such as Eudragit^@ E 100 and sucrose is used as sink to make a dry powder for mixture, which is then dissolved in water to make a mixture.

In a further embodiment of the invention theophylline is microencapsulated in a shell of ethyl cellulose and sorbitol is used to sink to make a dry powder for mixture, which is then dissolved in water to make a mixture.

In a further embodiment of the invention acetylsalcylic acid is encapsulated in a shell of cellulose acetate phtalate and sucrose is used as sink to make a dry powder for mixture, which is then dissolved in water to make a mixture.

A release controlling substance is mixed with other constituents and microcapsules of the drug are added to this dry powder and mixed in a conventional blender. This dry powder is then added to bottles in a filling machine. Water is then added, by the customer or at the pharmacy, to dissolve the release controlling substance.

Alternatively, a solution of the release controlling substance and other consittuents is prepared. The microcapsules of the drug can then be added either to this solution and then filled into bottles ready to use, or the microcapsules of the drug can be filled into a separate container and be added by the customer or the pharmacy to the solution prior to use.

Best mode of carrying out the invention

Leakage studies

Leakage studies were carried out in order to show that the microcapsules will not release any significant amount of the drug into the sink causing bad taste in contact with water, causing degradation or losing its ability to work as controlled release formulation.

Microcapsules were added to sink solution according to the invention. The amount of drug which had been released from the microcapsules was analyzed. This is called leakage. The samples were in some instances stored up to 80 days at room temperature. The sink was analyzed spectrophotometrically. The result is given in percent leakage which is the amount of the drug which is in solution divided by the initial amount of microencapsulated drug.

In order to demonstrate the effect of the release controlling substance the release studies were also performed in water. Microcapsules were placed in a beaker and water was added. The stirring rate was 30 rpm and the amount of release was calculated as described above.

Example 1

25.8 g of pharmaceutical mixture contains

<tables id="tabl0001" num="0001"><img file="EP0101418B1_D0001.tif" /></tables>Fructose was dissolved in water before the microcapsules were added.

The mixture contains 67.5% release controlling substances. <tables id="tabl0002" num="0002"><img file="EP0101418B1_D0002.tif" /></tables>

Example 2

31.3 g of pharmaceutical mixture contains:

<tables id="tabl0003" num="0003"><img file="EP0101418B1_D0003.tif" /></tables>The two mixtures were prepared according to Example 1.

The mixture contain a) 75% b) 72% release controlling substance. <tables id="tabl0004" num="0004"><img file="EP0101418B1_D0004.tif" /></tables>

Example 3

31.3 g of pharmaceutical mixture contains: <tables id="tabl0005" num="0005"><img file="EP0101418B1_D0005.tif" /></tables>The three mixtures were prepared according to Example 1.

The mixtures contain 60% of release controlling substances. <tables id="tabl0006" num="0006"><img file="EP0101418B1_D0006.tif" /></tables>

Example 4

75.1 g of pharmaceutical mixture contains:

<tables id="tabl0007" num="0007"><img file="EP0101418B1_D0007.tif" /></tables>Sucrose was dissolved in the phosphate buffer. The microcapsules were then added.

The mixture contains 65% release controlling substance. <tables id="tabl0008" num="0008"><img file="EP0101418B1_D0008.tif" /></tables>

Example 5

<tables id="tabl0009" num="0009"><img file="EP0101418B1_D0009.tif" /></tables><tables id="tabl0010" num="0010"><img file="EP0101418B1_D0010.tif" /></tables>

Example 6

Four different microcapsules coated with ethylcellulose were suspended in sorbitol dissolved in water according to following composition. <tables id="tabl0011" num="0011"><img file="EP0101418B1_D0011.tif" /></tables>

The mixture contain 70% release controlling substance. <tables id="tabl0012" num="0012"><img file="EP0101418B1_D0012.tif" /></tables>

Example 7

0.2 g theophyllin microcapsules according to Example 2 were suspended in different sugar solutions.

<tables id="tabl0013" num="0013"><img file="EP0101418B1_D0013.tif" /></tables>

It is thus possible to restrict the leakage in the mixture to only a few percent after almost three months storage in room temperature.

Example 8

65.4 g of pharmaceutical mixture contains:

<tables id="tabl0014" num="0014"><img file="EP0101418B1_D0014.tif" /></tables>The mixture was prepared according to Example 2.

The mixture contains 69% release controlling substance. <tables id="tabl0015" num="0015"><img file="EP0101418B1_D0015.tif" /></tables>

Example 9

26.31 g of pharmaceutical mixture contains

<tables id="tabl0016" num="0016"><img file="EP0101418B1_D0016.tif" /></tables>The mixture was prepared according to Example 2

The mixture contains 70% release controlling substance. <tables id="tabl0017" num="0017"><img file="EP0101418B1_D0017.tif" /></tables>

Example 10

27.15 g of pharmaceutical mixture contains:

<tables id="tabl0018" num="0018"><img file="EP0101418B1_D0018.tif" /></tables>Polyethyleneglycol was mixed with water and the microcapsules were added.

The mixture contains 75% release controlling substance. <tables id="tabl0019" num="0019"><img file="EP0101418B1_D0019.tif" /></tables>

The release in water, see Example 2.

Example 11

13.877 g of pharmaceutical mixture contains:

<tables id="tabl0020" num="0020"><img file="EP0101418B1_D0020.tif" /></tables>The microcapsules were added to a solution of fructose in water.

The mixture contains 71 % release controlling substance. <tables id="tabl0021" num="0021"><img file="EP0101418B1_D0021.tif" /></tables>

Release studies

Microcapsules were suspended in 75% release controlling substance solution and after two or three days storage the microcapsules were filtered off and the release of the drug was measured. The microcapsules were placed in a beaker containing either simulated gastric fluid or simulated intestinal fluid at 37°C in order to simulate the in vivo situation. The stirring rate was 30 rpm. Samples were withdrawn after certain time points and those were analyzed for drug content spectrophotometrically.

The results show time to obtain 50, 70 and 90 percent release of the total amount of microencapsulated drug. <tables id="tabl0022" num="0022"><img file="EP0101418B1_D0022.tif" /></tables><tables id="tabl0023" num="0023"><img file="EP0101418B1_D0023.tif" /></tables><tables id="tabl0024" num="0024"><img file="EP0101418B1_D0024.tif" /></tables>

Microcapsule compositions as in Examples 6, 8 and 10. <tables id="tabl0025" num="0025"><img file="EP0101418B1_D0025.tif" /></tables>

Release studies have also been carried out on the compositions in Example 7. The release rate was performed according to USP XX (method II paddle) 100 rpm in 900 ml 37° water.

The release rate is expressed as percent released per hour. The initial release rate was 12%/h. <tables id="tabl0026" num="0026"><img file="EP0101418B1_D0026.tif" /></tables>

The influence on storage time of the microcapsules in the different sink solution is negligible.

Stability studies

Microcapsule suspensions were prepared with sink solutions according to the invention. The suspensions were stored and the drug content was measured with HPLC analysis as a selective and precise method. <tables id="tabl0027" num="0027"><img file="EP0101418B1_D0027.tif" /></tables><tables id="tabl0028" num="0028"><img file="EP0101418B1_D0028.tif" /></tables>

The results imply that mixtures according to the invention has an improving effect on the stability of drugs.