SK17062000A3 - Effervescent preparations - Google Patents

Abstract

The invention relates to effervescent preparations containing medicaments. According to the invention, preparations of this type are particularly stable in storage if they contain fusible sugar, sugar alcohol and/or a sugar substitute.

Description

METHOD OF MANUFACTURE OF SPARKLING MEDICINES SPARKLING PREPARATIONS

Technical field

The invention relates to a process for the manufacture of medicaments containing effervescent formulations by at least partial melting of the formulation component and the formulations obtainable by the method.

BACKGROUND OF THE INVENTION

Effervescent formulations, such as effervescent powders or effervescent tablets, are in the form of formulations, for example, for active substances with long absorption times or with a tendency to irritate the gastric mucosa, which should alleviate these disadvantageous properties. Medicaments containing effervescent preparations therefore enjoy ever increasing popularity. They are usually produced in 3 to 4 stages, namely

(a) granulating the effervescent component from the carbon dioxide-providing substance and the acidic carbon dioxide-releasing components;

(b) mixing other components (active substances and other excipients),

c) combining the components obtained from steps a) and b) and optionally

d) tabletting the mixture obtained in step c).

Since both the carbon dioxide providing agent and the acid component are unsuitable for direct tabletting, in the past the effervescent components, optionally in combination with the active ingredient, have been subjected to granulation prior to tabletting; see, for example, DE-OS 22 16 072. The stability of the effervescent tablets produced in this way, however, was not as satisfactory as before. In particular, the co-use of buffering agents and flavorings (which mostly consist of many different individual compounds) causes water sensitivity, which leads to coloring, swelling and degradation reactions upon storage. To avoid these adverse reactions, effervescent preparations often occur

31586 / H sealed into metal foils. Although this measure also extends storage stability, it cannot safely prevent the foil wrap from inflating over longer periods of storage.

SUMMARY OF THE INVENTION

It has now surprisingly been found that the stability of medicaments containing effervescent formulations can be increased by a process in which the formulation components are melted.

Accordingly, the present invention provides a process for the manufacture of medicaments containing effervescent formulations from

A. a effervescent additive containing (i) a carbon dioxide-providing substance and (ii) an acid component,

B. a pharmaceutical active substance; and

C. excipients, characterized in that one of the two components A (i), A (ii) and optionally the other components of the effervescent preparation are dispersed in the molten sugar and / or the sugar and / or the sugar substitute; and the resulting mixture is optionally tableted.

The invention includes the fact that optionally one, more or all of the residual components of the effervescent composition are dispersed in the melt.

Preferably, the process is carried out by:

- the melt of component A (i) and / or A (ii) and C) of fusible sugar and / or sugar alcohol and / or of a sugar substitute is ground during or after cooling,

- the milled product is mixed with the active substance B, optionally with the missing component (i) or (ii) of the effervescent preparation A and, if appropriate, other excipients C, and optionally

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the tablet obtained is tableted.

Preferred carbon dioxide providing agents A (i) include alkali metal and alkaline earth metal carbonates and bicarbonates, especially sodium and potassium carbonate and bicarbonate, as well as magnesium and calcium carbonate.

Acidic components A (ii) which serve to release carbon dioxide from the carbon dioxide-providing substance A (i) are all physiologically harmless acids (so-called "edible acids") which are immediately capable of releasing carbon dioxide from component A (i). ); such acids have a first equilibrium exponent of pKs of 1 to 7, preferably 2 to 6 (at 25 ° C). Preferred acid components A (i) include ascorbic acid and polybasic carboxylic acids having 3 to 8 carbon atoms, preferably 4 to 6 carbon atoms and 2 to 6 carboxylic groups per molecule, such as vitamin C, malic acid, citric acid, acid and mixtures thereof.

Suitable pharmaceutical active ingredients C include analgesics such as ibuprofen, ketoprofen, paracetamol and acetylsalicylic acid,

COX-inhibitor _2, as nomesulid, meloxicam, naproxen, and propyphenazon metamizole, antacids such as hydrotalcid, magaldrate, calcium carbonate, antiasthmatics / broncholytics, such as salbutamol, tulobuterol, terbutaline, cromoglicínová acid, theophylline and ketotifen, antibiotics, such as are, for example, quinolones, tetracyclines, cephalosporins, penicillins, macrolides, sulfonamides and polypeptides, psychopharmaceuticals such as benzodiazepines, haloperidol, amitriptyline and carbamazepine, anti-rheumatic drugs such as phenylburazone, indometacin, dicllamicin, diclofenac and piroxicinofenac, glisoxepid.

31586 / H antiallergics / antihistamines such as astemizole, terfenadine, loratadine, clemastine, bamipin and cetirizine, antihypnotics such as etilephrine, norfenephrine and dihydroergotamine mesilate, antitussives such as codeine, anti-knockers, betaphenoline, dextromethorpanpan propranolol, atenolol, metoprolol and prazosin; antihypertensive agents such as calcium antagonists such as nifedipine, nitrendipine, diltiazem, verapamil, felodipine and nimodipine; and carbocistein,

H2-blockers such as ranitidine, famotidine and pirenzepine, local anesthetics such as benzocaine, lidocaine and procain, antiemetics / prokinetics such as metoclopramide, domperidone, meclozin and dimenhydrinate, lipid lowering agents such as pravastatin and fenofibrate, bezafibrate, bezafibrate, bezafibrate, bezafibrate fluvastatin, anti-migraine agents such as caffeine, dihydroergotamine, ergotamine, sumatriptan and pizotifen, sympathomimetics such as pseudoephedrine and pholedrin and vitamins and minerals.

The auxiliaries c) to be at least partially melted in the process according to the invention preferably have, as individual substances and / or in the mixture, a melting point of 30 to 200 ° C, in particular 40 to 160 ° C. Such preferred substances are water-soluble, that is to say, they generally have a water solubility of at least 10 g / l, preferably at least 30 g / l and in particular at least 40 g / l water at 20 ° C.

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Fusible sugars include, for example, monosaccharides such as glucose, mannose, galactose, arabinose, xylose and ribose, and disaccharides such as sucrose, lactose and maltose. Preferred alcoholic sugars C) for the invention include xylitol, mannitol, sorbitol, isomaltitol, lactitol, erythritol, treitol, ribitol, arabitol and dulcitol. Preferred are sugar alcohols as described, for example, in EP 435 450. The term "sugar substitutes" does not include alcoholic sugars within the meaning of the present invention. Preferred sugar substitutes C) are acesulfame, aspartame, saccharin and sodium cyclamate.

Other excipients C) include flavoring agents, sweeteners, lubricants, flow control agents, disintegrants and fillers such as starches and starch derivatives, cellulose and cellulose derivatives and polyethylenes.

The effervescent formulations obtainable according to the present invention may contain components in varying amounts of amounts. Preferred compositions include

A: 5 to 95% by weight, preferably 10 to 80% by weight,

B: 5 to 95% by weight, preferably 40 to 60% by weight; and

C: 1 to 60% by weight, preferably 15 to 30% by weight (sugar, alcohol, sugar substitutes) and optionally 1 to 50% by weight, preferably 5 to 15% by weight, of other excipients.

The effervescent composition a) preferably comprises 3 to 70% by weight of the carbon dioxide-providing substance and 70 to 30% by weight of the acid component, each based on A).

The melt of the effervescent preparation (component A)) and the fusible sugar and / or alcoholic sugar and / or the sugar substitute C) may be produced, for example, by adding the effervescent preparation (component A)) to the melt of the sugar and / or alcohol and / or sugar C) or by melting a mixture of an effervescent preparation (component A)), a sugar and / or alcohol melt and / or a sugar substitute C).

The process of the present invention can also be carried out by bringing all components of the effervescent composition into dispersion into

31586 / H contact with molten sugar and / or sugar and / or sugar substitute, it may be premixing all components and heating together, may be by melting sugar and / or sugar and / or sugar substitute and dispersing the remaining components ( simultaneously or sequentially) in the melt. Of course, mixing forms of the described process variants may also be used.

The melt can be produced by virtually any method:

In this way, it is possible to operate in a heatable stirred vessel without further action. However, it can also be carried out by a melt granulation process such as described in WO 92/6679. A preferred method is melt extrusion, such as described in EP-A 686 392. Conventional single or twin screw extruders can be used for extrusion. In this case, the substances to be used can be added to the extruder via a dosing scale. The temperature in the mass may be 30 ° C to 200 ° C. Depending on the nozzle orifice (preferably 0.5 to 5 mm) and the number of revolutions (preferably 5 to 400 revolutions per minute), the pressure may be 0.2 to 20.0 MPa. The mass flow rate may vary within wide limits, but is preferably 1 to 100 kg / h. The extruded strands are optionally cooled. After grinding, they can be mixed with the active ingredient B) and optionally with other excipients C) and optionally tableted.

The process of the present invention preferably uses neither water nor the conditions of treatment of the volatile organic solvent, i.e., it is preferably operated in the absence of water and solvents. In other words, it is not operated as described in DE-OS 22 16 072 or Acta Pharm. Suec., 24, (2), 84, 1987, Drug Dev. Ind. Pharm., 13, (9-11), 1891-1913 (1987) and Drug Dev. Ind. Pharm., 14, (13), 1791-98, 1988.

The process of the present invention may be carried out continuously or discontinuously.

According to the process of the present invention, components A (i) and / or A (ii) and optionally other components of the effervescent agent are dispersed in the melt sugar, the alcohol sugar or the sugar substitute C), i.e.

31586 / H, the fusible component C) forms a matrix into which component A (i) and / or A (ii) and optionally other components of the effervescent composition are incorporated.

The subject of the present invention is furthermore effervescent formulations

A. an effervescent preparation containing (i) a carbon dioxide-providing substance and (ii) acid components,

B. a pharmaceutical active ingredient; and

C. excipients, characterized in that the excipients C comprise fusible sugar and / or sugar alcohol and / or a sugar substitute and component A (i) and / or A (ii) is dispersed in a fusible sugar matrix, and and / or sugar substitutes and / or sugar substitutes.

DETAILED DESCRIPTION OF THE INVENTION

The percentages in the following examples always refer to weight.

Example 1

Effervescent composition from separately extruded components A (i) and A (ii)

Extrudate I

Mix mannitol and sodium bicarbonate in the ratio shown in the following table. The mixture was treated with the twin-screw extruder (Leistriz Micro 27 / 40D) at a rotational speed of 30 min ^-1 and the nozzle diameter of 1 mm. The nozzles are arranged around the outer diameter of the worms. The temperature in the mixing zone and the nozzles is 80 ° C. The extrudate is cooled with a cooling bath and then ground using an oscillating screen.

Extrudate II

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Mannitol, citric acid and sodium citrate are mixed, extruded and further processed as above.

table

Extrudate i Extrudate II mannitol 60% 60% sodium bicarbonate 40% citric acid 6,7% sodium citrate 33.3%

Based on a single dose, 125 mg of extrudate I, 150 mg of extrudate II are mixed with 50 mg of acetylsalicylic acid, 5 mg of aspartame and 30 mg of orange flavor and filled into a sachet.

Example 2

Analogously to Example 1 is extruded extrudate I and extrudate II at 70 ° C and a nozzle diameter of 0.8 mm and a rotational speed of 26 rpm ^{the first} The ratios are shown in the following table.

table

Extrudate I Extrudate II xylitol 60% 60% sodium bicarbonate 40% citric acid 40%

Based on a single dose, 125 mg of extrudate I, 150 mg of extrudate II are mixed with 500 mg of acetylsalicylic acid, 5 mg of saccharin and 30 mg of mandarin flavor and filled into a sachet.

Example 3

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Analogously to Example 2 was extruded extrudate I and extrudate II at 60 and nozzles with a diameter of 1 mm and the number of revolutions 35 rpm ^first The ratios are shown in the following table.

table

Extrudate I Extrudate II xylitol 30% 30% sodium bicarbonate 70% citric acid 70%

Based on a single dose, 125 mg of extrudates I and II are mixed with 150 mg of ascorbic acid and 2.5 mg of chlorpheniramine hydrogen maleate and filled into a sachet.

Example 4

Analogously to Example 2 was extruded extrudate I and extrudate II at 60 and nozzles with a diameter of 2 mm and the speed of 35 rpm ^{the first} The ratios are shown in the following table.

table

Extrudate I Extrudate II isomalt 60% xylitol 60% potassium bicarbonate 40% ascorbic acid 40%

Based on a single dose, 125 mg of extrudate I, 250 mg of extrudate II are mixed with 500 mg of acetylsalicylic acid, 5 mg of saccharin, 2 mg of aspartame and 30 mg of orange flavor and filled into a sachet.

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Example 5

Analogously to Example 1 is extruded extrudate I and extrudate II at 60 and nozzles with a diameter of 1 mm and the number of revolutions 35 rpm ^first The ratios are shown in the following table.

table

Extrudate I Extrudate II mannitol 60% potassium bicarbonate 20% calcium carbonate 20% ascorbic acid 40%

Based on a single dose, 1500 mg of extrudate I, 750 mg of extrudate II are mixed with 5 mg of aspartame and 10 mg of currant flavor and filled into a sachet.

Example 6

Preparation with only one extruded component, namely A (ii)

The ratios are shown in the following table.

table

Extrudate II from pr. 2 1200 mg famotidine 10 mg sodium bicarbonate 400 mg sodium carbonate 100 mg magnesium stearate 20 mg

Analogously to Example 1, only the acid component and the alkaline effervescent component are extruded and the active ingredient admixed thereto. Magnesium stearate is then mixed. This mixture is compressed into an effervescent tablet.

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Example 7

Joint extrusion of A (i) and A (ii)

Xylitol 60% sodium citrate 14% sodium bicarbonate 23% citric acid 3%

Method of production:

A) extrusion analogously to Example 1; 1, or

B) xylitol is melted at a temperature of about 120 ° C and the components are gradually added and mixed. After cooling, the melt is ground.

Based on a single dose, 600 mg of the extrudate obtained is mixed with 200 mg of acetylcysteine and 10 mg of lemon flavor. The resulting powder mixture is filled into a sachet.

Example 8

A mixture of 54% xylitol, 6% pseudoephedrine, 14% sodium citrate, 23% sodium bicarbonate, and 3% citric acid was extruded analogously to Example 1. The extrudate was ground and filled.

Comparison of stability of ASS-containing effervescent formulations

Determination of the salicylic acid (SAS) degradation product after 3 months storage at 25 ° C in a vapor-tight package.

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Feeling. Contents SAS SAS content after 3 months ASS effervescent granules, flavored * 0.02% 1,61% ASS-effervescent granulate (extruded), flavored ** 0,04% 0,18% ASS effervescent tablet, flavored * 0.3% 1,83% ASS effervescent tablet, non-flavored ** 0,17% 0.8%

the granulate is produced by the prior art technology (comparative experiment) according to the invention.

Claims (7)

PATENT CLAIMS A process for the manufacture of medicaments containing effervescent formulations from A. a effervescent additive containing (i) a carbon dioxide-providing substance and (ii) an acid component, B. a pharmaceutical active ingredient; and C. an excipient, characterized in that one of the two components A (i), A (ii) and optionally the other components of the effervescent preparation are dispersed in the molten C) sugar and / or the sugar sugar and / or the sugar substitute and the resulting mixture is optionally tableted. Method according to claim 1, characterized in that it is: - the melt of component A (i) and / or A (ii) and C) of fusible sugar and / or sugar and / or sugar substitute is ground during or after cooling, - the comminuted product is mixed with the active substance B, optionally with the missing component (i) or (ii) of the effervescent preparation A and, if appropriate, other excipients C, and optionally the tablet obtained is tableted. Method according to claim 1, characterized in that an extruder is used for melting. The method according to claim 1, characterized in that the pharmaceutical active substance B is selected from the group consisting of analgesics, antacids, antiasthmatics / broncholytics, antibiotics, psychopharmaceuticals, antidiabetics, antiallergics / antihistamines, antihypotonics, antitussive / laxance, expander, laxance, expiratory, expiratory, expiratory, expiratory, expiratory, expiratory, -blockers, local anesthetics, 31586 / H antiemetics / prokinetics, lipid lowering agents, anti-migraine agents, sympathomimetics, vitamins and minerals. The process according to claim 1, wherein the melt temperature is 30 ° C to 200 ° C. The process of claim 1, wherein the melt temperature is 40 ° C to 160 ° C. 7. Effervescent agent of A. an effervescent preparation containing (i) a carbon dioxide-providing substance and (ii) acid components, B. pharmaceutical active substances; and C. excipients, characterized in that the excipients C comprise fusible sugar and / or sugar alcohol and / or a sugar substitute and component A (i) and / or A (ii) is dispersed in a fusible sugar matrix and / or an alcoholic sugar and / or a sugar substitute.