Analgesic formulations

© Beginning of patent period: 15.Febber 1972 Longest possible duration:

© Issued on: October 25, 1972 © Inventor:

© dependence:

OE 302 533 © Pamphlets considered to delineate the prior art:

GB-PS 889 098 GB-PS 899 900

No. 302533

The invention relates to a process for the preparation of coated Acetylsalicylsäureteilchen by

Contacting particulate acetylsalicylic acid with a coating material in an aqueous one

Carrier.

So far, acetylsalicylic acid preparations, which should be dissolved in water, offered in two basic 5 forms, u.zw. in the so-called soluble and effervescent form. These two forms are based on the fact that the acetylsalicylic acid is converted into a water-soluble salt. However, the two forms differ in the way in which the distribution in water is accomplished.

The soluble form usually contains acetylsalicylic acid, calcium carbonate, citric acid and a disintegrating agent such as starch. Upon addition of water, calcium carbonate and citric acid react to form

Calcium citrate, which then reacts with the acetal salicylic acid to calcium acetylsalicylate. The amounts of calcium carbonate and citric acid are usually only sufficient to convert the acetylsalicylic acid into its calcium salt, and there is only a slight effervescence, which is not sufficient to break the tablet quickly. This is achieved by the disintegrating agent which, even if not water-soluble, causes the formation of a cloudy dispersion. Such soluble tablets are usually not much larger than the usual, non-soluble Acetylsalicylsäuretabletten and weigh about 600 mg.

The effervescent forms usually contain acetylsalicylic acid, sodium bicarbonate and citric acid, and although only the same amount of acetylsalicylic acid as in the soluble form is present, the weight of such a tablet is usually about 3 g. This substantially greater weight is due almost entirely to the presence of sufficient amounts of sodium bicarbonate and citric acid to cause vigorous effervescence as water is added, thus blasting the tablet and converting the acetylsalicylic acid into its soluble sodium salt. Effervescent tablets form a perfectly clear solution which is highly carbonated and has a high concentration of sodium ions.

British Patent Nos. 889, 098 and 899, 900 describe spray-drying processes wherein a particulate material is suspended in a gas stream and then sprayed with a very finely sprayed coating material to form a coating around each suspended particle. It also mentions the coating of acetylsalicylic acid with sugar.

The object of the invention is to provide an acetylsalicylic acid mixture which readily disperses in water and forms a clear solution which carbonates and is therefore more palatable than the usual soluble acetylsalicylic acid tablets. The need to add a larger amount of effervescent and, accordingly, a greater concentration of sodium ions should be avoided so that the daily dose restriction ceases. This also allows a smaller tablet size compared to the effervescent tablets or a much larger Acetylsalicylsäuremenge in a similar sized tablet. According to the invention, it is further intended to obtain an acetylsalicylic acid powder which is free-flowing and readily wettable and which can be used in water-dispersible mixtures, if appropriate also together with an effervescent agent.

Although it has long been known to use sugar as a coating material, it has never been proposed before to coat acetylsalicylic acid alone with a water-soluble sugar. In contrast to the teachings of the above cited patents, according to the process of the present invention, the material of the core is brought into a drying zone 40 together with a coating material in finely divided form, and after drying a core and a layer of the coating material are formed around it. It can easily be seen that the spray-drying process used according to the invention, which can be carried out with a conventional spray-drying plant, is simpler and more economical than spray-drying processes in which the material to be coated must be kept in a fluidized state during the coating process.

The process according to the invention comprises using as coating material a water-soluble, pharmaceutically acceptable substance having a melting point of at least 105 ° C of one or more low molecular weight amino acids, sugars, sugar alcohols or a mixture thereof and preferably a wetting agent and / or a film-forming agent and suspending the particulate acetylsalicylic acid in an aqueous solution of this coating material, after which the suspension thus obtained is spray dried to obtain free flowing, slightly wettable acetylsalicylic acid particles having a core of acetylsalicylic acid and a shell of the coating material, the weight ratio of acetylsalicylic acid to coating material being between 9 x 1 and 1; 10 lies. Preferred coating agents are the sugar alcohols, mannitol, inositol, and sorbitol, the amino acids glycine and methionine, the sugar sucrose and lactose, polymeric sugar products such as arabino-galactan polymers, and mixtures thereof.

The coating material preferably has a melting point above 150 ° C. Particularly preferred coating agents are mannitol, inositol and glycine.

The weight ratio of acetylsalicylic acid to coating material in the particles of the invention is preferably between 7: 1 and 1: 1. Even low ratios, such as 1:10, can be used, for example, to prepare dispersible children's acetylsalicylic acid particles, but such lower ratios of acetylsalicylic acid to inactive Plating material necessarily less economical than it

- 3 No. 302533 is the case for the preferred ranges.

In order to ensure good dispersibility of the acetylsalicylic acid particles prepared according to the invention, the particle size should be such that at least 95% by weight has a size of 150μ or less and preferably of 105μ or less. In addition to the components already mentioned, the acetylsalicylic acid particles according to the invention preferably also contain a pharmaceutically acceptable wetting agent and / or a water-soluble film-forming agent, which facilitate the formation of the particles and improve their dispersibility in water.

Wetting agents which may be present in amounts of up to 5% by weight but preferably less than 1% by weight, based in each case on the total weight of the particles, may be of the cationic, anionic or nonionic type. Exemplary of the cationic type are quaternary ammonium halides such as benzalkonium chloride, examples of the nonionic type are polyoxyethylene and polyoxyethylene sorbitan monooleate, monolaurates and monopalmitates, and exemplified by the anionic type are alkylaryl sulfates, sulfinates and sulfosuccinates such as sodium dioctyl sulfosuccinate, sodium lauryl sulfate and dodecyl benzene sulfonate.

Film forming agents, which may be present in amounts up to 10% by weight, but preferably up to 1% by weight, include cellulose derivatives such as hydroxyethyl cellulose, hydroxypropylmethyl cellulose and sodium carboxymethyl cellulose, and natural and synthetic adhesives such as soluble starches, dextrin, dextran, gum acacia , Gum tragacanth and polyvinylpyrrolidone.

According to a preferred embodiment of the method, the acetylsalicylic acid is in an aqueous

Solution of the wetting agent suspended and the resulting suspension is processed by addition of a first portion of an aqueous solution of the coating material and the film former to a smooth paste, and then the remainder of said solution is added to the paste to form a suspension. The suspension is then introduced with constant stirring into a system for spray drying.

The amount of water used to prepare the acetylsalicylic acid suspension is not critical, but it must be sufficient to allow processing in a spray dryer. Since all the water in the spray dryer must be removed, of course, an excessive amount of water is to be avoided. It has been found that in general the process according to the invention can best be carried out when the weight of the water for the preparation of the suspension is about 1 to 5 times the total solids content of the suspension.

The spray dryer may be of the usual type, equipped with a suitable centrifugal atomizer or nozzle, which ejects the droplets of the suspension into a hot gas stream, usually air. The inlet temperature of the spray dryer may be between 125 and 300 ° C, preferably between 150 and 300 ° C, depending on the coating agent present in the suspension, while the outlet temperature is normally between 50 and 180 ° C. To obtain the most suitable suspension for spray-drying , acetylsalicylic acid having a particle size of 100 to 300μ is preferably used in the suspension, and it is particularly preferred when 70% of the salicylic acid particles are less than 75μ in size.

The free-flowing, readily wettable powder obtained by the process described above can be used to prepare water-dispersible or soluble acetylsalicylic acid powders or tablets. However, it is particularly suitable for combination with an effervescent to form an effervescent powder or effervescent tablet. Using the Acetylsalicylsäureteilchen invention produced such effervescent preparations usually contain about half or less than half of effervescent compared to the amount contained in the usual effervescent acetylsalicylic acid tablets, but they can also twice as much or more of the active substance at the same weight as in the usual effervescent tablets included.

In conventional effervescent acetylsalicylic acid tablets, the weight ratio of acetylic acid to the total weight of the mixture is 1:10 or even lower. In contrast, using the inventively prepared material, this ratio can be greater than 1 x 8 and preferably between 1: 6 and 1: 3. By applying the invention, therefore, a substantial cost saving is possible, not only by the saving of effervescent, but also by lower packaging costs, since smaller tablets are possible by the beschich50 teten particles. For example, a standard effervescent tablet containing 300 mg of acetylsalicylic acid will normally weigh 3 to 3.6 g, whereas an effervescent tablet of the type described herein may weigh about 1.1 to 1.3 g with 300 mg of acetylsalicylic acid.

A further advantage of the use of coated particles produced in accordance with the invention in effervescent mixtures is that the coating prevents the acetylsalicylic acid and the alkali component of the effervescent from influencing each other before being dispersed in water. Such effervescent mixtures are therefore more stable than the usual effervescent mixtures.

The effervescent agent consists of a mixture of a pharmacologically acceptable acid and an alkali which upon contact with water to release CO₂ react, causing an effervescence and, associated therewith, a solution of the mixture in the entire water and a carbonation of the resulting solution.

Suitable acids, which can be used individually or in combination, are in particular citric acid,

Nr.302533

Fumaric acid, adipic acid, maleic acid and tartaric acid and their monoalkali salts. Suitable alkalis include in particular ammonium, AlkaE and alkaline earth carbonates and bicarbonates and mixtures thereof, in particular sodium and KaEumcarbonat or bicarbonate.

According to another embodiment of the invention, some or all of the acid compound in the effervescent is modified in properties by forming a water-soluble coating on its surface so that the coated acid particles are substantially stable in the presence of an alkali component until the mixture melts in Water is dispersed, whereupon the coating is dissolved and the acid is released, so that it can react with the alkaEschen component.

Suitable coatings include water soluble materials such as pharmacologically acceptable natural or synthetic gums, sugars or sugar alcohols, e.g. As polyvinylpyrrolidone, lactose or mannitol, and

AlkaE or alkaline earth salts of acid.

Coatings of a pharmacologically acceptable, water soluble material can be obtained according to the standard procedures. The coatings of salts can be formed by reaction of the acid in semi-dried state with a suitable AlkaE or alkaline earth metal salt, the acid being reacted with less than the stoichiometric amount of salt, and subsequent drying. The coating may also be prepared by mixing the acid in semi-dissolved state with a salt mixture in water prepared by reacting the acid with a less than stoichiometric amount of a suitable alkali or alkaline earth salt, and drying the product.

Part or all of the alkaline component of the effervescent can be treated in a similar manner.

As already mentioned, the AcetylsaEcylsäureteilchen prepared according to the invention can be used for the preparation of pharmaceutical preparations, in particular of those which are dispersed in water so. Such mixtures will normally contain the free-flowing, readily-wettable acetyl-acylic acid particles and a pharmaceutically acceptable carrier therefor. The carrier may act as a diluent and be solid, semi-solid or liquid.

Examples of carriers are sachets and capsules. Possible diluents are starch, sorbitol, sucrose, SyrupB.P., acacia, tragacanth, stearate, talc, methyl and propyl p-hydroxybenzoates and sweeteners. The effervescent agents mentioned above are also included in the term diluent. In effervescent mixtures, only water-soluble diluents are usually used, and these are usually only the effervescent and a sweetener, in particular saccharin, cyclamic acid, an AlkaE salt of these compounds or a mixture thereof.

The following examples are intended to explain the invention in more detail.

Example 1; Free flowing acetylacetic acid particles were prepared from the following mixture:

Mannitol 1000 g

Acetylsaecylic acid 3000 g

Polyvinylpyrrolidone θ. 5 g

Sodium di (2-ethylhexyl) sulfosuccinate 0.5 g

The mannitol was dissolved in 6 liters of water. Polyvinylpyrrolidone and sulfosuccinate were each in their own accord

100 ml of hot water dissolved. The mannitol and polyvinylpyrrolidone solutions were mixed and diluted to 10 liters with water. The acetylsalicylic acid was screened through a 0.4 mm mesh screen to remove hard aggregates (thereby 75% of the sieved material had a particle size below 70μ), and then with the sulfosuccinate solution and 2 liters of the mannitol-polyvinylpyrrolidone solution Forming a smooth paste mixed. The paste was then thoroughly mixed with the remainder of the mannitol solution and, while continuously stirred, was pumped into a spray dryer having a central atomizer at 24,000 rpm.

The AcetylsaEcylsäurelösung was sprayed into a hot air stream, which was preceded by a dryer and its inlet and outlet temperature was 200 and 100 ° C. 98% by weight of the resulting dry free-acid acetylacetic acid particles had a particle size of less than 150μ. An analysis of the sieved

Particles showed that about 99% by weight was less than 105μ and about 93% by weight was less than 75μ.

Example 2; Following the same procedure as in Example 1, a free-flowing acetyl-acylic acid mixture was prepared from the following components;

<td>AcetylsaEcylsäure</td><td>3000 g</td>

<td>glycine</td><td>3000 g</td>

<td>NatriumcarboxymethylceEulose</td><td>25 g</td>

<td>Polyoxyäthylensorbitanmonolaurat</td><td>⁵ G</td>

<td>DestilEertes water</td><td>12 1.</td>

Nr.302533

The particles obtained had a size distribution similar to that obtained according to Example 1.

Example 3: A free-flowing acetylsalicylic acid preparation was prepared as follows.

<td></td><td>acetylsalicylic acid inositol</td><td>4500 g 500 g</td>

<td>5</td><td>acacia</td><td>50 g</td>

<td></td><td>sodium lauryl sulfate</td><td>15 g</td>

Inositol, acacia and sodium lauryl sulfate were dissolved in 5 liters of water. The acetylsalicylic acid (particle size 10 to 150μ) was added with vigorous stirring to the resulting solution, and the solution was diluted to 10 liters with water. With constant stirring, the acetylsalicylic acid suspension was pumped into the atomizer (30,000 rpm) of a spray drier. The inlet and outlet temperatures of the spray drier were 230 and 120 ° C. After sieving the particles through a 0.15 mm mesh sieve, it was found that 98% of the particles had a particle size below 90μ.

Example 4: Acetylsalicylic acid particles were prepared as in Example 1, except that mannitol was replaced by sorbitol (700 g) and lactose (300 g).

From the following mixture effervescent tablets were prepared by the usual methods:

mg / tablet

Acetylsalicylic acid particles prepared according to Example 1 400

Citric acid 450

Sodium bicarbonate 495

Sodium acarin 2 total 1347.

The acetylsalicylic acid particles of Example 1 were analyzed and it was found that 300 mg of acetylsalicylic acid gave a total weight of coated particles of just under 400 mg. By adding 25 mannitol, for the sake of greater simplicity, a weight of exactly 400 mg was set. The slightly larger amount of acetylsalicylic acid compared to the theoretically achievable can be explained by the fact that coating agent is lost to a slight extent because of the adhesion to the walls of the spray dryer.

The dissolution time for the effervescent tablets prepared by this method was 60 to 90 seconds, ie as much as in the conventional effervescent tablets with 300 mg acetylsalicylic acid. However, the latter normally have a weight of at least 3 g and are accordingly much larger than the tablets of this example. Substantial savings in packaging costs and raw material costs are therefore possible using the invention. In addition, the daily dose of effervescent tablets is normally limited so that no more than 200 milliequivalents of sodium ions are taken (content of 10 conventional tablets containing 3.0 g of acetylsalicylic acid) whereas the effervescent tablets prepared here increase the daily dose can, as a tablet contains only about 8 milliequivalent of sodium ions. That is, it can be taken up to 24 tablets with a total content of acetylsalicylic acid of 7.2 g, which is a significant increase over the previously achievable for effervescent doses.

In addition, effervescent tablets were prepared from the following batch by the usual methods:

<td>Acetylsalicylic acid particles of Example 2</td><td>mg / tablet 600</td>

<td>Malic acid (coated)</td><td>500</td>

<td>sodium bicarbonate</td><td>510</td>

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

<td>sodium</td><td>5</td>

a total of 1650.

Ingredient (1) was obtained by mixing an amount of acetylsalicylic acid particles, which was analyzed for their content of acetylsalicylic acid and contained 300 mg of acetylsalicylic acid, with 300 mg of glycine.

Ingredient (2) was obtained by mixing 10 kg of malic acid in a semi-dissolved state with a sodium malate solution in water of 8 kg of malic acid and 2 kg of sodium hydroxide. It was mixed for a further 5 minutes and the mixture was dried to yield malic acid which was thinly coated with sodium malate.

Nr.302533

Ingredient (4) was obtained by heating anhydrous sodium carbonate at 170 ° C for 3 hours under vacuum.