Analgesic formulations

Holder: Idem (71) (74) Agent: Cabinet Pierre Loyer & Fils, 18, rue de Mogador, Paris (9).

(54) Analgesic compositions.

Invention of:

Conventional priority: Patent application filed in Great Britain on November 28, 1969, n. 58.203 / 1969 in the name of the plaintiff.

- · Γ? · Σ j 1 ç ·

42668 the present invention relates to aspirin compositions and, in particular to aspirin compositions easily and completely soluble in water.

aspirin preparations intended to be dissolved in water have so far been presented in two distinct forms: the so-called soluble and "effervescent" forms. Basically, these two forms are each based on the solubilization of aspirin by the formation of one of its water-soluble salts when the preparation is dispersed in water. However, the two forms differ in the method of dispersion in the water. 'water.

the soluble form normally includes aspirin, calcium carbonate, citric acid and a disintegrating agent such as starch "when water is added, calcium carbonate and citric acid react to form calcium citrate which reacts on aspirin to form water-soluble calcium aspirin. the quantities of calcium carbonate and citric acid are only sufficient to transform aspirin into calcium aspirin and there is only a weak effervescence, which is not sufficient to rapidly disintegrate the tablet. This disintegration takes place under the effect of the disintegrating agent which, not being soluble in water, results in the formation of a cloudy dispersion. These soluble tablets are generally not much larger than non-soluble aspirin tablets and weigh approximately 600 mg.

the effervescent form normally includes aspirin, sodium bicarbonate and citric acid and, although it only contains the same amount of aspirin as the soluble form, the weight of the tablet is usually about 3 g. This strong increase in weight is almost entirely due to the presence of an amount of sodium bicarbonate and citric acid sufficient to cause strong effervescence when added to water, so as to disintegrate the tablet and to pass the aspirin in the form of its soluble sodium salt, the effervescent tablets form a perfectly clear solution, which is highly carbonated and contains a high concentration of sodium ions "the subject of the invention is:

- an aspirin composition which disperses easily

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42668 ² 2073431 in water to form a clear solution which carbonates and presents, as a result, a taste, more pleasant than conventional soluble aspirin tablets $

- An aspirin composition forming such a clear solution without having to use a large amount of effervescent couple as in the case of conventional effervescent tablets, which clear solution therefore has a reduced sodium content with the advantage concomitantly restricting daily administration limits less}

a soluble aspirin composition which can be shaped into tablets which are smaller than conventional effervescent tablets or which can contain a much higher proportion of therapeutic substances than in conventional effervescent tablets, without any increase in weight; and

- An aspirin composition which does not agglomerate, easily wettable, suitable for use in aspirin compositions dispersible in water, combined or not with an effervescent couple.

Therefore, there are obtained according to the invention particles of aspirin which do not agglomerate, easily wettable, which comprise an aspirin core practically surrounded by a layer consisting of a pharmaceutically acceptable coating material, having a melting point at least 105 ° C, said coating being composed of or comprising one or more agents chosen from amino acids of low molecular weight, sugars, sugar alcohols and mixtures of these agents. Preferred coating agents for composing or being included in said coating material include sugar alcohols, mannitol, inositol and sorbitol, as amino acids, glycine and methionine, as sugars, suerose and lactose as well as polymeric sweet products such as the arabino-galaetane polymer sold under the trade name of Stractan, and mixtures of these coating agents. The coating material advantageously has a melting point above 150 ° C. Preferred coating agents are mannitol, inositol, and glycine.

The weight ratio of aspirin to the coating material in the particles according to the invention can

42668 ³ 2073431 reach 9: 1, but is preferably between about 7: 1 and 1: l_o However, ratios as low as 1 can be used: 10, for example when preparing dispersible aspirin particles to be administered to children, but it will be readily appreciated that such low ratios of aspirin to inactive coating material are necessarily less cost effective than the ratios used in the preferred interval To ensure good dispersibility of the aspirin particles according to the invention, the particle size must be such that the dimension of at least 95 by weight thereof is less than or equal to 150 microns and, preferably less than or equal to 105 microns.

In addition to the above components, the aspirin particles according to the invention preferably contain a pharmaceutically acceptable wetting agent and / or a water-soluble film-forming agent, which contribute to the formation of said particles and improve their dispersibility in water. 'water.

wetting agents, which may be present in amounts of up to about 5 by weight but preferably less than 1 by weight, based on the total weight of the particle, may be of the cathionic, anionic or nonionic type. As examples of the cathionic type, there may be mentioned quaternary ammonium halides such as benzalconium chloride as examples of the nonionic type, mention may be made of polyoxyethylene mono-oleates, mono-laurates and mono-palmitates and of poly-oxy-ethylene sorbitan, and as examples of the anionic type there may be mentioned the sulfates, sulfonates and sulfo-succinates of alkyl and alkyl-aryl such as sodium dioctyl-sulfosuccinate, sodium lauryl sulfate and sodium dodecyl benzene sulfonate.

As film-forming agents which may be present in amounts of up to $ 10 by weight but preferably less than 1% by weight, relative to the total weight of the particle, mention should be made of cellulose derivatives such as 1 hydroxyethyl cellulose, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose, and natural and synthetic gums such as soluble starches, dextrin, dextran, acacia gum, tragacanth and polyvinylpyrrolidone ·.

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One of the objects of the invention is to provide a process for preparing particles which do not agglomerate of the type described above which comprises the stages consisting in preparing a suspension of aspirin in an aqueous solution containing the coating material, and optionally the wetting agents and / or film-forming agents, and to be dried by atomizing the suspension, by ensuring the presence of the ingredients in the suspension in relative amounts such that the drying and atomization stage results in the formation of particles comprising an aspirin core substantially coated with a layer of coating material. According to a preferred procedure for implementing the method according to the invention, the aspirin is suspended in an aqueous solution of wetting agent and the suspension obtained is transformed into a smooth paste by addition of a first portion of an amount of aqueous solution of coating material and film-forming agent, the remainder of said amount of solution being added to said paste to form the suspension, said suspension being sent with continuous stirring to a spray dryer. The amount of water used to prepare the aspirin suspension is not essential, but it must be sufficient to allow the suspension to be sent to the spray dryer. Since all the water has to be drained into the spray dryer, it is clear that a large amount of unnecessary water can also be avoided. In general, therefore, it has been found that the method according to the invention can be carried out satisfactorily by using, during the preparation of the aspirin suspension, a weight of water of between approximately 1 and 5 times the weight of the total solids content of the suspension.

The dryer-atomizer can be of the conventional type, provided with a suitable atomizer or centrifugal nozzle, capable of sending droplets of suspension in a stream of hot gas, normally air. The inlet temperature of the spray dryer can be between about 125 and 300^oC and is preferably between about 150 and 3 0 ° C, depending on the coating agent present in the suspension, while the outlet temperature is normally between about 50 and 180 ° C. To obtain the lapLus suspension useful for drying and atomizing, it is preferable that the aspirin to be used in this suspension i

7042668 5 ₂₀₇₃43t has a particle size dimension between 10 and 300 microns and, more advantageously, $ 70 by weight of the aspirin must have a particle size dimension of less than 75 microns.

The powder which does not agglomerate, easily wettable, obtained by the above process, can be used to prepare powders or aspirin tablets dispersible in water or soluble. It is however particularly suitable for being combined with an effervescent couple to form an effervescent powder or an effervescent tablet. Using aspirin particles according to the invention, these effervescent preparations normally contain half or less than half the amount of effervescent couple used in conventional effervescent aspirin tablets, or can contain twice or more than twice as much. weight of active ingredient, without weighing more than conventional effervescent aspirin tablets. Consequently, a characteristic of the invention resides in the fact that it provides effervescent compositions, preferably effervescent tablets, comprising the aspirin particles which do not agglomerate, easily wettable, according to the invention and a couple effervescent, the weight ratio of the aspirin to the total weight of the composition being greater than 1: 8 and preferably between 1: 6 and 1: 3. Because, in conventional effervescent aspirin tablets, this ratio is equal to or even less than 1: 10, it is clear that considerable savings can be made by using coated aspirin particles according to the invention, not only as regards the savings which can be attributed to the reduction in the amounts of effervescent couple, but also as regards the packaging costs caused by the much smaller size of the tablets, due to the use of these coated particles. For example, a conventional effervescent aspirin tablet containing 300 mg of aspirin normally weighs from 3 to 3.6 g, while an effervescent aspirin tablet according to the invention containing coated aspirin particles which equivalent to 300 mg of aspirin, may weigh only about 1.1 to 1.3 g. Another advantage of the use of the coated particles according to the invention in effervescent compositions lies in the fact that the coating prevents the inter^{70 42668 6} 2073431 action of aspirin and an alkaline constituent of the couple before dispersion in water. These effervescent compositions are therefore more stable than conventional effervescent compositions.

The effervescent couple comprises a mixture of pharmaceutically acceptable acid and alkali which react, on contact with water, to release carbon dioxide, causing effervescence and, consequently, dissolution of the composition in all the water and carbonation of the solution obtained. As suitable acids which can be used separately or in combination, mention is made in particular of citric acid, fumaric acid, adipic acid, malic acid and tartaric acid, as well as their mono-alkaline salts. As suitable alkalis, consideration is given in particular to alkaline and alkaline-earth and ammonium carbonates and bicarbonates, and mixtures thereof, in particular sodium and potassium carbonate or bicarbonate.

According to another characteristic of the invention, all or part of the particles of an acid component of the effervescent couple sees its properties modified by the formation on its surface of a water-soluble coating, such as the acid particles coated are practically stable in the presence of an alkaline component of the effervescent couple, until the composition is dispersed in water, whereupon the coating dissolves, leaving the free acid to react on the alkaline component. Suitable coatings are water soluble materials such as pharmaceutically acceptable natural or synthetic gums, sugar and sugar alcohols, for example polyvinyl-pyrrolidone sucrose, lactose, or mannitol, as well as coatings consisting of an alkaline or alkaline earth salt of the acid.

Coatings can be made with a pharmaceutically acceptable water-soluble material by conventional means. The salt coating can be formed by reacting the acid in a semi-dry state on an appropriate alkaline or alkaline earth salt, reacting the acid on an amount of salt less than the amount corresponding to the stoichiometric proportions, then drying the product obtained. The coating can also be formed by mixing the acid in a

42668 ⁷_2073431 semi-dissolved state with a salt-in-water composition obtained by reacting the acid with an amount less than that corresponding to the stoeohiimetric proportions of an appropriate alkaline or alkaline earth salt, then drying the product obtainedUoOn can be treated analogous to all or part of the alkaline component of the effervescent couple "As mentioned above, the aspirin particles coated according to the invention can be used to prepare pharmaceutical compositions, in particular those intended to be dispersed in water. These compositions normally include the easily wettable aspirin particles which do not agglomerate and a pharmaceutically acceptable support for these particles, the support can serve as a vehicle or diluent for said particles and can be solid, semi-liquid or liquid. As examples of support acting as vehicles for aspirin particles, we can say sachets and capsules. Examples of diluents are starch, lactose, mannitol, sorbitol, sucrose, BP syrup, acacia gum, tragacanth, stearates, talc, methyl and propyl p-hydroxybenzoates and sweetening agents, the expression diluents ”also embraces the effervescent couples mentioned above. In these effervescent compositions, normally only water-soluble diluents are used and it is common, in these compositions, that the only diluents are an effervescent couple and a sweetening agent, in particular a compound or a mixture of compound (s ) Ghoisis among saccharin, cyclamic acid or an alkaline salt of these compounds "the invention is described in more detail in the nonlimiting examples which follow"

Example 1

Coated aspirin particles which do not agglomerate are prepared as follows:

Mannitol 1,000 g

Aspirin 3,000 g

Polyvinyl-pyrrolidone 6.5 g

Di- (2-ethylhexyl) -sulfosuccinate.

sodium '0.5 ga

Distilled water qs

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The mannitol is dissolved in water (6 liters). Polyvinyl-pyrrolidone, like suifosuccinate, is dissolved in hot water (100 ml) * The mannitol and polyvinyl-pyrrolidone solutions are mixed and diluted to ten liters with water. aspirin through a 0.387 mm mesh screen to remove hard aggregates (75% by weight of sieved material having a particle size less than 70 microns), then mixed with the suifosuccinate solution and. 2 liters of the mixture of mannitol and polyvinyl-pyrrolidone solutions to form a smooth paste. "The paste is thoroughly mixed with the rest of the mannitol solution and, while constantly stirring, it is discharged into a dry sprayer fitted with a central atomizer rotating at 24,000 revolutions per minute. The aspirin solution is atomized in a current of hot air passing through the dryer-atomizer, the inlet and outlet temperatures of the air being respectively equal to 200 ° C. and 100 ° 0, 98% are passed through. by weight of the dry aspirin particles, coated, which do not agglomerate through a sieve of 0.152 mm mesh, that is to say of a particle size less than 150 microns. Analysis of the particles passed through a sieve shows that approximately 99% by weight of the particles are less than 105 microns and approximately 93% by weight less than 75 microns.

Example 2

Coated aspirin particles are prepared which do not agglomerate, according to the same process as in Example 1, but using the following ingredients:

<td>Aspirin</td><td> 3.000</td>

<td>Wisteria</td><td> 3.000</td>

<td>Sodium-carhoxymethyl-cellulo'se</td><td> 25</td>

<td>Polyoxyethylene monolaurate-</td><td></td>

<td>sorbitan</td><td> 5</td>

<td>Distilled water</td><td> 12</td>

The particles obtained have a particle size distribution similar to that obtained in Example l_e

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Example 3

Coated aspirin particles are prepared which do not agglomerate as follows:

Aspirin 4,500 g Inositol 500 g Acacia gum 50 g Sodium lauryl sulfate 15 g Distilled water q_es₀

Dissolve inositol, acacia gum and sodium lauryl-swjlfate in water (5 liters). The aspirin (particle size from 10 to 150 microns) is added to the solution obtained, with vigorous stirring, and the solution is diluted to 10 liters, with water. While stirring constantly, the aspirin suspension is discharged into the rotating atomizer (at 30,000 revolutions per minute) of a dryer-atomizer. The inlet and outlet temperatures of the spray dryer are 230 ° 0 and 120 ° 0 respectively. After initial sieving of the coated particles through a screen or sieve of 0.152 mm, · it is found that 98%&gt; by weight of the particles have a particle size less than 90 microns.

Example 4

Aspirin particles are prepared as in Example 1, except that the mannitol is replaced by sorbitol (700 g) and lactose (300 g).

Example 5

Tablets are produced, effervescent to obtain the following composition, by conventional methods:

<td>* Aspirin particles (from Example 1)</td><td> 400</td><td>mg</td>

<td>Citric acid</td><td> 450</td><td>mg</td>

<td>Sodium bicarbonate</td><td> 495</td><td>mg</td>

<td>Saccharin-sodium</td><td> 2</td><td>mg</td>

<td>Total:</td><td> 347</td><td>mg</td>

* We analyze the aspirin particles from Example 1 and find that they contain 300 mg of aspirin for a total weight of particles just below 400 mg. For convenience, the weight is reduced to 400 mg by addition of mannitol. The increase in percentage of aspirin in the coated particles, compared to that which could theoretically be present, can be attributed to a slight loss

42668 coating agent, due to adhesion to the walls of an atomizer. the duration of dissolution in water of the effervescent aspirin tablets of this example is between 60 and 90 s, that is to say is the same as for the conventional effervescent tablets containing 300 mg of aspirin. The latter tablets normally weigh, however, at least 3 g and are, therefore, much larger than the tablets in this example.

We can therefore achieve significant savings in packaging costs and, even taking into account the cost of manufacturing the aspirin particles, in the costs inherent in the raw material, by using the aspirin particles according to the invention. In addition, since the daily dose of effervescent aspirin tablets is normally restricted, so that the absorption of sodium ion does not exceed about 200,000 equivalents (10 conventional tablets contain a total of 3.0 g aspirin), an increased amount of aspirin can be obtained with the tablets of this example, where the sodium ion content barely exceeds 8,000 equivalents: This means that up to, for example, 24 aspirin tablets containing 7.2 g aspirin per day can be administered, a significant dose increase over what could be obtained with the tablets. classic effervescent aspirin.

<td> -</td><td>Example 6 We make tablets</td><td>sparkling</td>

<td>to get</td><td>the following composition, by;</td><td>standard processes</td>

<td>sics:</td><td></td><td>Mg / tablet</td>

<td>D</td><td>Particles of aspirin (from the ex-</td><td></td>

<td> 2)</td><td>pie 2) Malic acid (coated)</td><td>600 mg 500 mg</td>

<td> 3)</td><td>Sodium bicarbonate</td><td>510 mg</td>

<td> 4)</td><td>Sodium carbonate (treated)</td><td>35 mg</td>

<td> 5)</td><td>Saccharin-sodium</td><td>5 mg</td>

<td></td><td>Total:</td><td>1,650 mg</td>

Ingredient 1 is obtained by taking a weight of aspirin particles containing, according to the analysis, 300 mg of aspirin and increasing it to 600 mg by addition of glycine.

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Ingredient 2 is obtained by mixing 10 kilograms of malignant acid in the semi-dissolved state with a composition of sodinm malate in water obtained from 8 kilograms of malignant acid and 2 kilograms of hydroxide. sodium. Continue to mix for 5 minutes and dry the mixture to obtain malignant acid finely coated with sodium malate₀

Ingredient 4 is obtained by heating anhydrous sodinm carbonate at 170 ° C. for 3 hours, sounds empty._at

In examples 5 and 6 above, the coated aspirin particles according to the invention constitute the nneqne therapeutic ingredient. However, the aspirin particles according to the invention can be used, in total or partial replacement of non aspirin -processed in other types of aspirin compositions, including formulations containing therapeutic ingredients in addition to aspirin, such as codeine, caffeine, phenacetin, paraeetamol, phenylephrine, chloropheniramine, amphetamine, dexamphetamine, allobarbitone, amylobarbitone, bntobarbitone, phenobarbitone, meprobamate, phenolphthalein, methocarbamol, vitamin G, vitamin E and dihydrocodeine.

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