Method of oral pharmaceutical preparations production

The present invention relates to a process for the manufacture of oral pharmaceutical compositions comprising an encapsulated pharmaceutically active agent.

In the preparation obtained by the process according to the invention, the dissolution of the active substance from the encapsulated form is controlled.

Among alternative forms of orally administered pharmaceutically active agents, the use of a solution or suspension of the active agent in aqueous solution is a form often used in particular in pediatric practice. A dry powder containing the active ingredient and excipients to be dissolved or suspended is called a dry powder to form a mixture.

The product is stored as a dry powder. Prior to administration, the dry powder is dissolved or suspended in an aqueous medium to provide a liquid formulation suitable for oral administration. Optionally, the composition may be prepared at the factory and may be stored for at least two years prior to administration. Pharmaceutically active substances for use in the form of this composition are encapsulated either to mask the aftertaste or to provide controlled release in the body.

To this end, the drugs were coated with polymers or polymers in combination with controlled release plasticizers (> microencapsulation). When applied to granular drugs, this measure leads to retarded dissolution.

The essence of the controlled dissolution method from milkrotobolls is the amount of polymer used to achieve the desired drug profile in blood plasma. This objective can also be achieved by adding water-soluble substances to the coating during coating of the dosage form.

The invention relates to a process for the manufacture of a pharmaceutical composition for oral administration in which the taste of the medicament and / or the mixture with retarded solubility is masked to achieve a delayed release.

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

Drug release from microcapsules is very slow, in the body all drug is released and is available for absorption.

The method of the invention also increases the stability of the drug in the composition.

Accordingly, the present invention provides a process for the manufacture of controlled release oral pharmaceutical formulations with enhanced stability of the active ingredient and masking its unpleasant taste, comprising the active ingredient in a polymer coating and conventional excipients, characterized in that conventional excipients add another substance which is a sugar, oligosaccharide or polysaccharide or a mixture thereof in an amount of 40 to 99% by weight, based on the weight of the whole preparation, wherein either all the ingredients are dry blended and then water is added, or the pre-encapsulated dry substance is mixed with an aqueous solution containing conventional excipients and a sugar, oligosaccharide or polysaccharide or a mixture thereof.

In a preferred embodiment of the process according to the invention, the sugar, oligosaccharide or mixture thereof is added in an amount of 60 to 75% by weight, based on the total composition.

The sugar, oligosaccharide or polysaccharide or mixture thereof is preferably sucrose, glucose, fructose and / or sorbitol.

Sugar or sugar-related substances such as polysaccharides or oligosaccharides such as dextran, disaccharides such as sucrose, maltose, lactose, monosaccharides such as glucose, fructose, galactose, mannose, or xylitol may be used as the release retardant, for example, mannitol, sorbitol, glycerol, glycol, monosaccharide glycosides, or ethylene glycol-derived substances such as polyethylene glycol (commercial names Carbowax and Carbopol).

One or a mixture of two or more thereof may be used for delayed release.

Alternatively, the release controlling agent is encapsulated with the drug in a capsule.

The sugars used according to the invention are, among others, sucrose, glucose, fructose and sorbitol.

Any drug may be used as a pharmaceutically active agent, for example the following:

Chemotherapeutics:

bacampicillin, ampicillin, flucloxacillin, dicloxacillin, chloramphenicol, gentamycin, erythromycin, lincomycin, rifampicin, sulfadiazine, sulfamethoxypyridazine, griseofulvin, nitrofurantoin.

Substances with adrenergic activity and β-receptor stimulators:

ephedrine, terbutaline, theophylline, enprophyline.

Expectorants and antitussives:

ethylmorphine, dextromethorphan, noscapine, bromhexin.

Cardiac glycosides and antiarrhythmics: digitoxin, digoxin, dtspyramide, procainide, tocainide, alprenolol, atenolol, metoprolol, pindolol, propranolol.

Hypotensives:

betanidine, clonidine, guanetidine, methyldopa, reserpine, trimetaphane, hydrolazine, bendropflumatiazide, furosemide, chlorthiazide.

Antihistaminiika:

brompheniramine, chlorocyclizine chlorpheniramine, diphenhydramine, ipromethazine.

Peroráiní antldiabetika:

carbutamide, chlorpropamide, tolazamide, tolbutamide.

Sedatives, hypnotics, antidepressants:

hexobarbital, pentobarbital, phenobarbital, meprobamate, chlordiazepoxide, diazepam, flunitrazepam, nitrazepam, oxazepam, chlormethiazole, chlonpromazine, flufenazine, perfenazine, prochloriperazine, haloperidol, lithium, alaproklat, zimeldine,.

amitryptiline, imiipramine, nortriptyline.

Antiepileptics:

phenytoin, ethotoin, ethosuximide, kanbamezepine.

Analgesics, anesthetics:

codeine, morphine, pentazocine, petidine, dextropropoxyphene, methadone, acetylsalicylic acid, diflunisal, phenazone, phenylbutazone, acetaminophen, hidometazine, naproxen, piroxicam, lidocaine, etidocaine.

Next:

cimetidine, quinidine, dicoumarin, warfarin, potassium chloride, chloroquine.

A preferred compound is bacampicillin hydrochloride (1'-ethoxycarbonyloxyethyl-6- [D (-) -2-amino-2-phenylacetamido) -penicillanic acid hydrochloride), other epimeric forms, and the racemic form of baicampicillin hydrochloride.

Other preferred compounds are:

theophylline, neprophylline and erythromycin.

Said medicaments may be used in neutral or salt form.

The following salts can be used from these drugs:

acetate, benzenesulfonate, benzoate, hydrogen carbonate, hydrogen tartrate, bromide, calcium acetate, camsylate, carbonate, chloride, citrate, dihydrochloride,

77S3 adetate, edisylate, estolate, esylate, fumarate, gluceiptate, gluconate, glutamate, glycolylarsenilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, methylbromate, mesylate, maleate, maleate, maleate, maleate, maleate, maleate , methylnitrate, methylsulfate, muconate, napsylate, nitrate, pampate (ombonate), panthotenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theoclate, triethiodide.

Cationic salts can also be used. Suitable cationic salts include alkali metal such as sodium and potassium, and ammonium and amine salts known in the art, pharmaceutically acceptable , such as:

glycine, ethylenediamine, 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.

Encapsulation of the drug can be accomplished in the form of microcapsules, but encapsulation is not limited by micro size. .

Upholstery material

Polymers:

Synthetic polyvinyl type polymers, for example polyvinyl chloride, polyvinyl acetate, polyvinyl alcohol.

Of the polyethylene type, for example polyethylene, polystyrene.

Polymers of acrylic acid or of the acrylic or methacrylic ester type, for example methyl methacrylate or copolymers of acrylic monomers.

Biopolymers or modified cellulose biopolymers, for example ethylcellulose, cellulose phthalate acetate.

The polymers may be water-insoluble, acid- or alkali-soluble and mixed with plasticizers or other fillers and a water-soluble biopolymer such as hydroxypropylcellulose.

As such, optionally in combination, fats and oils, waxes, higher fatty acids and alcohols or polyhydric alcohols may also be used.

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

In another embodiment of the invention, the BAPC is encapsulated in an acid-soluble polymer such as Eudragit E 100 and sucrose is used as a retarder to prepare a dry powder for the composition, which is then dissolved in water to form the composition.

In another embodiment of the invention, theophylline is encapsulated in a microcapsule of ethylcellulose and sorbitol is used as a retarder to prepare a dry powder for the composition, which is then dissolved in water to form the composition.

In another embodiment of the invention, acetylsalicylic acid is encapsulated in a cellulose phthalate acetate capsule and sucrose is used as a retardant, to form a dry powder for the mixture, which is then dissolved in water to form the mixture.

The release controlling agent is mixed with the other ingredients and the drug microcapsules are added to the dry powder and mixed in a conventional mixer. This dry powder is then filled into vials in a filling machine. Water is then added, either by the consumer or by the pharmacy, to dissolve the release controlling agent.

Alternatively, a solution of the release controlling agent and other components is prepared. The drug microcapsules can then be added either to this solution and then filled into vials ready for use, or the drug microcapsules can be filled into a separate container and added to the solution by the consumer or pharmacy before use.

<img file="CS257769B2_D0001.tif" />

Release studies

Release studies have been conducted to demonstrate that the microcapsules will not release any significant amount of drug into the retarder, causing off-flavor in contact with water, degradation or loss to fulfill the controlled release function.

The microcapsules were added to the retardant solution of the invention. The amount of drug released from the microcapsules was analyzed. This is called escape. The samples were in some cases stored for up to 80 days at room temperature. The retarder was analyzed spectrophotometrically. The result is given as the percentage of release, which is the amount of substance that is in solution divided by the initial amount of encapsulated drug.

In order to demonstrate the effect of the release controlling agent, release studies have been performed in water. The microcapsules were placed in a beaker and water was added. It was stirred at 30 rpm and the amount of release was calculated as above.

Example 1

100 ALIGN! g of dry powder contains:

<td>Bacampicillin hydrochloride as microcapsules of ethylcellulose (70% drug) sodium bicarbonate mannitol sucrose</td><td>5.61 g 0.83 g 9,35 g 83.1 g</td>

<td colspan="2">Sodium bicarbonate, mannitol, and sucrose were premixed before the microcapsules were added. Final mixing was performed in a beaker. The mixture contains 46 w / w%. percent of the release controlling substance.</td>

<td>5 ml of water was added</td><td>4.81 g of powder.</td>

<td rowspan="2">Time (days)</td><td>Relaxation</td>

<td> (%)</td>

<td> 1</td><td> 0,5</td>

<td> 2</td><td> 0,9</td>

<td> 4</td><td> 1,1</td>

<td> 7</td><td> 1,3</td>

<td> 10 ·</td><td> 1,2</td>

<td>Mercury titration</td><td>the method was</td>

<td>in this case, the chihuahuas were analyzed.</td><td>release of</td>

<td>Time (days)</td><td>Release to water (%)</td>

<td> 0,042</td><td> 60</td>

<td> 0,084</td><td> 90</td>

Example 2

25.8 g of the pharmaceutical composition contains:

Bacampicillin hydrochloride in the form of microcapsules of Eudraigit E 100 (64%) 0.80g Fructose 18.75g Water 6.25g

Before addition of the microcapsules, fructose was dissolved in water. The mixture contains 67.5% release controlling agent.

Time (days) Release (%)

<td> 2</td><td></td><td> &lt; 0,2</td>

<td>Time (hours)</td><td></td><td>Release to water (%)</td>

<td> 0,008</td><td></td><td> 50</td>

<td> 0,05</td><td></td><td> 90</td>

<td>Example 3</td><td></td><td></td>

<td colspan="2">31.3 g of the pharmaceutical composition</td><td>contains:</td>

<td colspan="2">theophylline as microcapsules of ethylcellulose (72% drug)</td><td>0.05 g</td>

<td>rfructose</td><td></td><td>23.44 g</td>

<td>^and (water</td><td></td><td>7.82 g</td>

<td>ísorbit</td><td></td><td>20,94 g</td>

<td>^b (water</td><td></td><td>7.82 g</td>

<td colspan="3">Both mixtures were prepared according to the example</td>

<td> 2.</td><td></td><td></td>

<td colspan="3">Mixtures contain a) 75%, b) 72%</td>

<td>dici release.</td><td></td><td></td>

<td>Time</td><td>Relaxation</td><td></td>

<td>(days)</td><td> (%)</td><td></td>

<td></td><td>and)</td><td>(b)</td>

<td> 1</td><td> &lt; 0,2</td><td> 0,7</td>

<td> 3</td><td> &lt; 0,2</td><td></td>

<td> 5</td><td> &lt; 0,2</td><td> ' —</td>

<td> 7</td><td> «' 0,2</td><td> —</td>

<td> 10</td><td> &lt; 0,2</td><td> —</td>

<td>Time (days)</td><td></td><td>Release to water (%)</td>

0,21 50

0,33 90

Example 4

Example 5

31.3 g of the pharmaceutical composition contains:

theophylline as microcapsules of ethylcellulose (72% of the drug) 0.05g isaccharose 9.38g ^and (sorblt 9.38g isaccharose 9.38g ³ (glycerin 9.38g (glucose 9.38g) ^C Vructose 9.38g water 12.5g

All three mixtures were prepared according to Example 2.

The compositions contain 60% release controlling agents.

<td>Time</td><td>and)</td><td>Release (%) b)</td><td>C)</td>

<td> 1</td><td> 0,20</td><td> 0,20</td><td> 0,26</td>

<td> 2</td><td> 0,31</td><td> 0,35</td><td> 0,28</td>

<td> 5</td><td> 0,65</td><td> 0,82</td><td> 0,49</td>

<td> 9</td><td> 1,15</td><td> 1,77</td><td> 0,90</td>

75.1 g pharmaceutical composition contains: acetylsalicylic acid as microcapsules (69% drug) phthalate acetate cellulose 0.100 g sucrose 48.75 g phosphate buffer (pH 7.0) 26.25 g

Sucrose was dissolved in phosphate buffer. Microcapsules were then added.

The mixture contains 65% release controlling agent.

Time (days) Release (%) .1 3,5

Time (days) Release into phosphate buffer. PH 7.0 (%)

0,008 50

0,017 90

Time (days) Water release (%)

0,21

0,33

Example 6

Bacampicillin hydrochloride as microcapsules of ethyl-

<td>cellulose (70% drug)</td><td> 0,27</td><td> 0,27</td><td> 0,27</td>

<td>sodium bicarbonate</td><td> 0,40</td><td> 0,40</td><td> —</td>

<td>manit</td><td> 0,45 </td><td> —</td><td> —</td>

<td>sucrose</td><td> 4,0</td><td> —</td><td> —</td>

<td>water</td><td> 5,0</td><td> 5,0</td><td> 5,0</td>

Example 7

The mixtures were prepared according to Example 1.

Mixture a) contains 44% release controlling agent.

The release from the microcapsules into water was the same as in Example 1.

Four different microcapsules coated with ethylcellulose were suspended in sorbitol dissolved in water as follows:

Release time (° / o) (days) abc

0,5

0,9

1,1

1,3

1,2

100 ALIGN! microcapsules with orbit water

50.0 mg

45,1 g

19,3 g

The compositions contain 70% release controlling agent.

<td colspan="2" rowspan="2">Microcapsules</td><td colspan="2">Release to sorbitol</td><td colspan="2">Release into water</td>

<td> (%)</td><td>(days)</td><td> (%)</td><td>(h)</td>

<td>KCl</td><td> (86)*</td><td> 16</td><td> 21</td><td> 56</td><td> 3</td>

<td>paracetaminophen</td><td> (91)*</td><td> 19</td><td> 21</td><td> 35</td><td> 1</td>

<td>f lukloxacillin</td><td> (89)*</td><td> 20</td><td> 1</td><td> 90</td><td> 0,5</td>

<td>Penicillin V</td><td> (83)*</td><td> 10</td><td> 1</td><td> 80</td><td> 1</td>

К salt

Explanatory notes:

* active ingredient content in microcapsules

Example 8

0.2 g microcapsules with theophylline according to example 3 were suspended in various sugar solutions.

<td>Release-controlling substance</td><td></td><td colspan="2">Release (%) Time (days)</td><td></td>

<td>° / o (w / w)</td><td></td><td></td><td></td><td></td>

<td>xylit</td><td> 55</td><td> 13</td><td> 80</td><td></td>

<td>glucose</td><td> 50</td><td> 17</td><td> 40</td><td></td>

<td>sorbit</td><td> 70</td><td> 3</td><td> 80</td><td></td>

<td>fructose.</td><td> 75</td><td> 3</td><td> 80</td><td></td>

<td>fructose-α-xylite</td><td> 19-41</td><td> 10</td><td> 80</td><td></td>

<td>fructose-xylite</td><td> 28-28</td><td> 6</td><td> 80</td><td></td>

<td>fructose-xyht</td><td> 56-14</td><td> 4</td><td> 80</td><td></td>

<td colspan="2">In this way, it is possible to reduce</td><td>Time (days)</td><td colspan="2">Relaxation</td>

<td>at a few percent ipo</td><td>almost three</td><td></td><td> (%)</td><td></td>

<td colspan="2">months of storage at room temperature.</td><td> -----------------------</td><td></td><td> —</td>

<td></td><td></td><td> 12</td><td> 2,7</td><td></td>

<td>Example 9</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Time (days)</td><td colspan="2">Relaxation</td>

<td>65.4 g of the pharmaceutical composition</td><td>include:</td><td></td><td colspan="2">into water (%)</td>

<td>microcapsules with theophylline</td><td></td><td> 0,25</td><td> 28</td><td></td>

<td>coated with wax (52% of drug)</td><td>1 1,0 g</td><td></td><td></td><td></td>

<td>sorbit</td><td>45,1 g</td><td>Example 11</td><td></td><td></td>

<td>water</td><td>19,3 g</td><td colspan="2">27.15 g of the pharmaceutical composition contains:</td><td></td>

<td colspan="2">The mixture was prepared according to Example 3.</td><td>ethylcellulose coated micro-</td><td></td><td></td>

<td colspan="2">The mixture contains 69% of the release controlling agents.</td><td>capsules containing theophylline</td><td></td><td></td>

<td>vání.</td><td></td><td> (72 %)</td><td> 0,15</td><td>G</td>

<td></td><td></td><td>polyethylene glycol</td><td></td><td></td>

<td>Time (days)</td><td>Relaxation</td><td>(Canbonax 400)</td><td> 20,25</td><td>G</td>

<td></td><td> (%)</td><td>water</td><td> 6,75</td><td>G</td>

<td> 22</td><td> 0,7</td><td colspan="2">The polyethylene glycol was mixed with water</td><td>and</td>

<td></td><td></td><td>microcapsules were added.</td><td></td><td></td>

<td>Time (days)</td><td>Relaxation</td><td colspan="3">The mixture contains 75%</td>

<td></td><td>into water (%)</td><td>vání.</td><td></td><td></td>

0,5 19

Example 10

26.31 g of the pharmaceutical composition contains: wax-coated microcapsules with prochloiperazine (3.4% of the drug) 10.0 mg sorblt 18.0g water '8.3g

The mixture was prepared according to Example 3.

The mixture contains 70% release controlling agents.

Time (days) Release (%)

152,4

Release to water, see Example 3.

Example 12

13.877 g of pharmaceutical composition contains: erythromycin in microcapsules coated with cellulose phthalate acetate (57% drug) 0.877g fructose 9.75g water 3.25g

The microcapsules were added to a solution of sucrose in water.

The mixture contains 71% release controlling agent.

<td>Time (days)</td><td></td><td>Relaxation (%)</td>

<td> 10</td><td></td><td> &lt; 1</td>

<td>Time (days)</td><td></td><td>Release to water (%)</td>

<td> 0,25</td><td></td><td> 46</td>

Release studies

The microcapsules were suspended in a solution containing 75% release controlling agent, and after two to three days of storage, the microcapsules were filtered and drug release was evaluated. The microcapsules were placed in a beaker containing either artificial gastric fluid or artificial intestinal fluid at 37 ° C to mimic the situation in vivo. The stirring speed was 30 rpm. After some time samples were taken and analyzed spectrophotometrically for drug content.

The results show the time to obtain 50, 70 and 90% release of the total encapsulated drug.

Microcapsules with theophylline

Artificial gastric fluid Artificial intestinal fluid

<td rowspan="2">% (%)</td><td colspan="2">(clock)</td><td colspan="2">(clock)</td>

<td>original</td><td>storage 3 days</td><td>original</td><td>Storage 2 days</td>

<td> 50</td><td> 4,2</td><td> 4,4</td><td> 3,7</td><td> 4,4</td>

<td> 70</td><td> 5,7</td><td> 5,8</td><td> 5,5</td><td> 6,6</td>

<td> 90</td><td> 6,2</td><td> 6,4</td><td> 7,5</td><td> 8,3</td>

Acetylsalicylic acid

<td rowspan="2">Release (%)</td><td colspan="2">Artificial gastric fluid (clock)</td><td colspan="2">Artificial intestinal fluid (clock)</td>

<td>original</td><td>storage 2 days</td><td>original</td><td>storage 2 days</td>

<td> 50</td><td></td><td></td><td> 0,14</td><td> 0,21</td>

<td> 70</td><td></td><td></td><td> 0,22</td><td> 0,21</td>

<td> 90</td><td></td><td></td><td> 0,3</td><td> 0,5</td>

<td>1 h</td><td> 12 %</td><td> 8 %</td><td></td><td></td>

<td>2 h</td><td> 25 %</td><td> 15 %</td><td></td><td></td>

Bacampicillin hydrochloride microcapsules from Eudragit E 100

Relax- Artificial gastric fluid (hours) (%) original storage days

Artificial intestinal fluid (hours) original storage days

<td> 50</td><td> '0,4</td><td> 0,8</td><td> 1,5</td><td> 3,0</td>

<td> 70</td><td> 0,5</td><td> 0,9</td><td> 1,8</td><td> 3,7</td>

<td> 90</td><td> 0,7</td><td> 1,0</td><td> 2,5</td><td> 5,0</td>

Microcapsule composition as in Examples 7, 9 and 11.

<td> ..</td><td> ' ·«,·</td><td></td><td> 257789</td><td></td>

<td></td><td> 17 ^J</td><td></td><td></td><td></td>

<td colspan="2" rowspan="2">Microcapsules</td><td colspan="5">Release into water initial storage</td>

<td> (%)</td><td>(h)</td><td>(days)</td><td> (%]</td><td>(h)</td>

<td>KC1</td><td></td><td> 56</td><td> 3</td><td> 14</td><td> 53</td><td> 3</td>

<td>Penicillin salt V</td><td>and)</td><td> 35</td><td> 1</td><td> 14</td><td> 48</td><td> 1</td>

<td>paracetaiminofen</td><td></td><td> 80</td><td> 1</td><td> 3</td><td> 81</td><td> 1</td>

<td>theoylin coated with wax</td><td>(lb)</td><td> 19</td><td> 12</td><td> 25</td><td> 17</td><td> 12</td>

<td>theophylline .coated ethylcellulose</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>lózou</td><td>C)</td><td> 46</td><td> 6</td><td> 6</td><td> 50</td><td> 6</td>

a) according to Example 7

b) according to Example 9

c) according to Example 11

The release studies were also performed on the formulations in Example 8. The release rate was monitored according to USP XX (Method II) 100 rpm in · 900 mL water at 37 ° C.

The release rate is expressed as the release rate per hour. The initial release rate was 12% / h.

Release Control Agent Release Rate Time (days) (° / o / h)

<td>xylit</td><td> 9,9</td><td colspan="2"> 80</td>

<td>glucose</td><td> 9,7</td><td> 40</td><td></td>

<td>sorbit</td><td> 11,7</td><td> 80</td><td></td>

<td>fructose</td><td> 11,8</td><td> 80</td><td></td>

<td>fructose-xylite (19-41)</td><td> 10,5</td><td> 80</td><td></td>

<td>fructose-xylite (38-28)</td><td> 11,9</td><td> 80</td><td></td>

<td>fructose-xylite (56-14)</td><td> 11,9</td><td> 80</td><td></td>

<td>Influence on the storage time of microcapsules in</td><td></td><td>sucrose</td><td> 8,32</td>

<td>different solutions with retarders is neglected-</td><td></td><td>water</td><td> 4,48</td>

<td>telný. Stability study Microcapsule suspensions were prepared with</td><td></td><td>(e) Bacampicillin, HCl, microcapsules coated with ethyl-</td><td>grams G</td>

<td>retardant solutions according to the invention. Sus-</td><td></td><td>cellulose (72 ° / o drugs)</td><td> 0,36</td>

<td>pensions were stored and drug content was</td><td></td><td>fructose</td><td> 9,6</td>

<td>evaluated by HPLC analysis as selective a</td><td></td><td>water</td><td> 3,2</td>

<td>the exact method.</td><td></td><td>(f) acetylsalicylic acid;</td><td></td>

<td>Mixtures.</td><td></td><td>microcapsules coated with cellulose phthalate acetate</td><td></td>

<td></td><td></td><td>(69% drug)</td><td> 0,72</td>

<td>Mixtures not according to the invention</td><td></td><td>sucrose</td><td> 8,32</td>

<td></td><td></td><td>citrate buffer pH 3</td><td> 4,48</td>

<td>1a) according to Example 6b</td><td></td><td>(g) erythromycin, microcapsules</td><td></td>

<td>(b) according to Example 6c</td><td></td><td>phthalate acetate coated</td><td></td>

<td>c) according to example 6a</td><td></td><td>cellulose (87% drug)</td><td> 8,32</td>

<td>d) Bakamplcllin HCl micro-</td><td></td><td>phosphate buffer pH 7.0</td><td> 4,48</td>

capsules coated with ethylcellulose (72% drug) 0.36

<td>Mixture</td><td>time (days)</td><td>Storage conditions temperature (° C)</td><td>Intact drug (%)</td>

<td>and</td><td> 1</td><td> 25</td><td> 2</td>

<td>b</td><td> 1</td><td> 25</td><td> 60</td>

<td>C</td><td> 10</td><td> 25</td><td> 91</td>

<td>d</td><td> 7</td><td> 25</td><td> 83</td>

<td>E</td><td> 7</td><td> 25</td><td> 89</td>

<td>F</td><td> 30</td><td> 50</td><td> 70</td>

<td>G</td><td> 30</td><td> 50</td><td> 82</td>

<td>Explanatory notes:</td><td></td><td></td><td></td>

<td>* initial quantity</td><td>untouched</td><td>drug was 100%.</td><td></td>

The results show that the compositions of the invention improve drug stability.