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United States Patent 19 3,882,228 Boncey et al. 45) May 6, 1975

54 ANAGESC FORMATI(NS lets for Alts ic ('hildren, A (ius to heir Minu 75 live 1 (S. Graham Arthur oncey, ( )wley; facture through Jsc of Atlas Mannitol N.E., ASA Maurice John Hedge, Windsor, Base 3 pp. ( 96()). arties Rae lenderson, figh it is et : ' Mirit in Chew; he hits, 7 Wyclic, all of glitic pp.) July 1963, Drug & Cosmetic industry. 73 Assigice. Aspro-Nicholas, Limited, Slough, l, glicl Irinary furninter She K. Rise Attorney, Agent, or firm Willian. A 11th Iny IDucker 22 le. Nov. 2, 197) 21 Apl. No. 92,284 57 ABSTRA () Foreign Application 'riority Data re-flowing reacily wettable particles coin prise it orc (if spirin substantially clic in passed by . . Nov 28, ') (') intet Kilgol in 582), f() layer can rising a -soluble pharmaceutically ac ceptable cating in a trial having : incling (in f ; it | 5 | J.S. ("I. ... 424/35; 424f 424/32; cast ()5'C', saic citing in laterial including at least 424/44, 424/23) (ne cating agent selected frt in low inclueular weight 5 int. ("...... A6k 9100; At k 27 f()() an inc acils, sugars, sugar lic hols and fixtures 58 Field of Search ...... 424/2 (), (, , , , 2, 35, thereo, and a proccss for preparatt in of such parti 424/44 cles conrises the steps of repring : Suspensin (f aspirin it an aquctus Scution containing the cating 56 References ( 'ited interial, and spray-crying said suspensit, the ingre NIE) SAFES ANS clicits in the suspiciisi in heing inade result in such 4S, 4? 8/84 ' ' ... 424/25) X relative at lounts that the spray-drying Ste) results in $2') 2 | 219t? Style et al. 424/28 () the firinati ) if the articles having the ch: acteris 84.5-4. 1918 .'; a ...... 424/23 () X tics sect frtli, ()'' (ACNS Atlas Pharmaceutical 13 illet in Chewbie Aspirin al 5 (laims, No Drawings 3,882,228 1 2 ANALGESC FORMULATIONS from low molecular weight amino , sugars, sugar alcohols and mixtures thereof. Preferred coating agents This invention relates to aspirin compositions and in to compose or be included in said coating material in particular to aspirin compositions which are readily clude the sugar alcohols, mannitol, inositol and sorbi and completely soluble in water. tol, the amino acids glycine and methionine, the sugars Aspirin preparations intended for dissolution in sucrose and lactose as well as polymeric sugar products water have hitherto been presented in two distinct such as the arabino-galactan polymer sold under the forms, i.e. the so-called "soluble' and “effervescent' trade name "Stractan', and mixtures of such coating forms. Basically these two forms both rely on solubilis agents. The coating material advantageously has a ing the aspirin by forming a water-soluble thereof 10 above 150°C. Preferred coating agents when the preparation is dispersed in water. The two are mannitol, inositol and glycine. forms differ however in the method by which disper The ratio by weight of aspirin to coating material in sion in water is accomplished. the particles of this invention may be as high as 9:1 but The soluble form normally comprises aspirin, cal preferred ratios of aspirin to coating material are from cium , citric and a disintegrating agent 15 about 7: 1 to 1:1. Ratios as low as 1: 10 may however be such as starch. On addition to water, the car used, for example in preparing dispersible aspirin parti bonate and react to form cles for administration to children, but it will readily be which then reacts with the aspirin to form soluble cal appreciated that such low ratios of aspirin to inactive cium aspirin. The amounts of calcium carbonate and coating material are necessarily less economical than is citric acid are only sufficient to convert the aspirin to 20 the case with ratios falling within the preferred range. calcium aspirin and only a small amount of efferves To ensure good dispersibility of the aspirin particles of cence takes place which is not sufficient to quickly dis the present invention, the size of the particles should be integrate the . This is accomplished by the disin such that at least 95 percent by weight should be 150 tegrating agent which, not being water-soluble, results microns or less, and most advantageously 105 microns in a cloudy dispersion being formed. Such soluble tab 25 or less. lets are usually not much larger than conventional non In addition to the foregoing components, the aspirin soluble aspirin tablets and weigh about 600 mg. particles of the invention preferabiy contain a pharma The effervescent form normally comprises aspirin, ceutically acceptable wetting agent and/or a water and citric acid, and although it soluble film forming agent which assist in the formation contains only the same amount of aspirin as the soluble 30 of said particles and improve the dispersibility thereof form, the weight of the tablet is usually around 3 g. This in water. much increased weight is almost entirely due to the Wetting agents, which may be present in amounts up presence of a quantity of and citric to about 5 percent by weight, but preferably below 1 acid sufficient to cause vigorous effervescence on addi percent by weight, of the total weight of the particle, tion to water so as to disintegrate the tablet and convert 35 may be of the cationic, anionic or nonionic type. Exem the aspirin to its soluble sodium salt form. Effervescent plary of the cationic type are quaternary ammonium tablets form a completely clear solution which is halides such as benzalkonium chloride, exemplary of heavily carbonated and contains a high concentration the nonionic type are polyoxyethylene- and polyoxy of sodium . ethylene sorbitan-monooleates, monolaurates and It is an object of the present invention to provide an 40 monopalmitates, and exemplary of the anionic type are aspirin composition which will readily disperse in water the alkyl and alkyl aryl sulphates, sulphonates and sul to form a clear solution which will be carbonated and phosuccinates such as sodium dioctyl sulphosuccinate, hence more palatable than conventional soluble aspirin sodium lauryl sulphate and dodecylbenzene sulpho tablets. A further object is to provide an aspirin compo nate. sition which will form such a clear solution without the 45 Film forming agents, which may be present in need to use a large quantity of effervescent couple as amounts up to about 10 percent by weight, but prefera in conventional effervescent tablets, which clear solu bly below 1 percent by weight, of the total weight of the tion will therefore have a reduced sodium content with particle, include cellulose derivatives such as hydrox the attendant advantage of having less restriction on yethyl-cellulose, hydroxypropylmethyl cellulose and daily dosage limits. Another object of the present in 50 sodium carboxymethylcellulose, and natural and syn vention is to provide a soluble aspirin composition thetic gums such as soluble starches, dextrin, dextran, which may be formed into smaller tablets than conven gum acacia, gum tragacanth and polyvinylpyrrollidone. tional effervescent tablets or may contain a much in According to a feature of the present invention, there creased therapeutic dosage in a tablet weight no is provided a process for preparing free-flowing parti greater than such conventional effervescent tablets. In 55 cles of the type described above which includes the accordance with another object of the invention, there steps of preparing a of aspirin in an aqueous is provided a free flowing, readily wettable aspirin com solution containing the coating material, and optionally position which is suitable for use in water-dispersible the wetting and/or film forming agents, and spray aspirin formulations whether or not combined with an 60 drying the suspension, the ingredients in the suspension effervescent couple. being made present in such relative amounts that the According to the present invention, therefore, there spray-drying step results in the formation of particles are provided free-flowing, readily wettable aspirin par comprising a core of aspirin substantially encompassed ticles comprising a core of aspirin substantially encom by a layer of the coating material. In accordance with passed by a layer comprising a water-soluble pharma a preferred method of carrying out the process of this ceutically acceptable coating material having a melting 65 invention, the aspirin is suspended in an aqueous solu point of at least 105C, said coating material being tion of the wetting agent and the resultant suspension composed of or including one or more agents selected is converted to a smooth paste by addition of a first por 3,882,228 3 4 tion of a quantity of an of the coating cent compositions are therefore more stable than con material and the film forming agent, the remainder of ventional effervescent compositions. said quantity of solution being added to said paste to The effervescent couple comprises a mixture of a form the suspension, said suspension being fed with pharmacologically acceptable acid and alkali which on continuous agitation to a spray-drying means. The 5 contact with water will react to liberate amount of water used in the preparation of the aspirin causing effervescence and hence dissolution of the suspension is not critical but it must be sufficient to composition throughout the water and carbonation of allow the suspension to be fed to the spray-drier. Since the resultant solution. Suitable acids, which may be all the water must be removed in the spray-drier, it will used singly or in combination, include particularly cit be clear that an unnecessarily large amount of water 10 ric acid, fumaric acid, , malic acid and tar should also be avoided. Generally therefore, it has been taric acid as well as mono-alkali metal thereof. found that the process of the present invention can be Suitable alkalis include particularly ammonium, alkali most satisfactorily operated when the weight of water metal and alkaline earth metal and bicar used in preparation of the suspension of aspirin is from bonates and mixtures thereof, particularly sodium and about 1 to 5 times the weight of the total content 15 potassium carbonate or bicarbonate. of the suspension. In accordance with another feature of the present in The spray drier may be of conventional type vention, all or a part of the particles of an acidic com equipped with a suitable centrifugal atomiser orjet ca ponent of the effervescent couple has its properties pable of ejecting droplets of the suspension into a cur modified by the formation on the surface thereof of a rent of hot gas, normally air. The inlet temperature of water-soluble coating such that the coated acid parti the spray-drier may range from about 125 to 300°C, cles are substantially stable in the presence of an alkali and is preferably from about 50 to 300°C, depending component of the effervescent couple until the compo on the coating agent present in the suspension, whilst sition is dispersed into water whereupon the coating is the outlet temperature will normally be from about 50 25 dissolved leaving the acid free to react with the alkali to 180°C. In order to obtain the most useful suspension component. Suitable coatings include water-soluble for spray-drying, it is preferred that the aspirin for use materials such as pharmaceutically acceptable natural in that suspension should have a particle size of from or synthetic gums, sugar or sugar alcohols, for example 10 to 300 microns and most advantageously 70 percent polyvinylpyrrollidone, sucrose, lactose or mannitol, as by weight of the aspirin should have a particle size less 30 well as coatings comprising an alkali or alkaline earth than 75 microns. metal salt of the acid. Coatings with a pharmacolog The free-flowing, readily wettable powder obtained by the foregoing process may be used in the prepara ically acceptable water-soluble material may be tion of water-dispersible or soluble aspirin powders or achieved by conventional means. The salt coating may tablets. It is however particularly suited to be combined 35 be formed by reacting the acid in a semi-dried state with an effervescent couple to form an effervescent with a suitable alkali or alkaline earth metal salt, the powder or tablet. Using the aspirin particles of the pres acid being reacted with a less than stoichiometric pro ent invention, such effervescent preparations will nor portion of the salt, and thereafter drying the resultant mally contain half or less than half the quantity of effer product. Alternatively the coating may be formed by vescent couple used in conventional effervescent aspi- 40 mixing the acid in a semi-dissolved state with a salt rin tablets or can contain double or more than double composition in water obtained by reacting the acid with the weight of active ingredient without weighing more a less than stoichiometric proportion of a suitable alkali than conventional effervescent aspirin tablets. Accord or alkaline earth metal salt and thereafter drying the ingly, a feature of the present invention is the provision resultant product. All or a part of the alkali component of effervescent compositions, preferably tablets, com- 45 of the effervescent couple may be similarly treated. As prising the free-flowing readily wettable aspirin parti mentioned previously, the coated aspirin particles of cles of the present invention and an effervescent cou the present invention may be used in the preparation of ple, the ratio by weight of the aspirin to the total weight pharmaceutical compositions, particularly those in of the composition being greater thann l:8 and prefera tended to be dispersed in water. Such compositions will bly between 1:6 and 1:3. Since in conventional effer 50 normally comprise the free-flowing readily wettable as vescent aspirin tablets that ratio is 1:10 or even less, it pirin particles and a pharmaceutically acceptable car can readily be appreciated that considerable cost sav rier therefor. The carrier may serve as a vehicle or dilu ings may be made using the coated aspirin particles of ent therefor and may be solid, semi-solid or liquid. Ex the present invention, not only in terms of the savings emplary of carriers acting as vehicles for the aspirin attributable to reduced quantities of effervescent cou 55 particles are sachets and capsules. Examplary of dilu ple but also in packaging costs due to the much smaller ents are starch, lactose, mannitol, sorbitol, sucrose, tablet size resulting from using these coated particles. syrup B.P., gum acacia, gum tragacanth, stearates, , As an example a conventional effervescent aspirin tab methyl and propyl p-hydroxybenzoates and sweeteners. let containing 300 mg. of aspirin will normally weigh The effervescent couples referred to above are also in from about 3 to 3.6 g. whilst an effervescent aspirin 60 cluded within the term diluents. In effervescent compo tablet of the present invention containing coated aspi sitions, only water-soluble diluents will normally be rin particles equivalent to 300 mg. of aspirin can weigh used and commonly in such compositions the only dilu as little as about 1. to 1.3 g. A further advantage of the ents will be an effervescent couple and a sweetener, use of the coated particles of the present invention in particularly one or a mixture of saccharin, cyclamic effervescent compositions is that the coating prevents 65 acid, or an alkali metal salt thereof. interaction of the aspirin and the alkali component of The following Examples will further illustrate the the couple prior to dispersion in water. Such efferves present invention: 3,882,228 S 6 coating particles through a 100 mesh B.S.S. screen, it EXAMPLE 1 was found that 98 percent by weight of the particles Free flowing coated aspirin particles were prepared were less than 90 microns. as follows: EXAMPLE 4 Aspirin particles were prepared as in Example ex Mannito 1000 g. Aspirin 3000 g. cept that the mannitol was replaced by sorbitol (700 g.) Polyvinylpyrrollidone 6.5 g. and lactose (300 g.) Sodium di(2-ethylhexyl)sulphosuccinate 0.5 g. Distilled water C.S. O EXAMPLE 5 The mannitol was dissolved in water (6 litres). The Effervescent tablets were made to the following for polyvinylpyrrollidone and the sulphosuccinate were mula by conventional methods: each dissolved in hot water (00 ml.). The mannitol and polyvinylpyrrollidone solutions were mixed and di mig. ?tablet luted to 10 litres with water. The aspirin was sieved 5 *Aspirin particles (from Example 1) 400 mg. through a 40 mesh B.S.S. screen to remove hard aggre Citric acid 450 mg. gates (75 percent by weight of sieved material having Sodium bicarbonate 495 mg. a particle size less than 70 microns) and then mixed Sodiurn saccharin 2 mg. with the sulphosuccinate solution and 2 litres of the Total 1347 mg. mannitol/polyvinylpyrrollidone solutions to form a 20 "the aspirin particles from Example i were analysed and found to contain 300 mg. smooth paste. The paste was then thoroughly mixed of aspirin in a total weight of particles of just under 400 mg. For convenience the weight was brought up to 400 mg. by addition of mann it. The increased with the remainder of the mannitol solution and, whilst percentage of aspirin in the coated particles over that which could theoretically be being continuously agitated, was pumped to a spray prescnt can be accounted for by a slight loss of coating agent due to idherance to the walls of the spray-drier drier fitted with a central atomiser revolving at 24,000 25 r.p.m. The aspirin solution was atomised into a current The dissolution time in water of the effervescent aspi of hot air passing through the drier, the inlet and outlet rin tablets of this Example was between 60 and 90 sec., temperature of the air being 200°C. and 100°C. respec that is to say the same as conventional effervescent tab tively. 98 percent by weight of the resultant dry, free lets containing 300 mg. of aspirin. The latter tablets flowing coated aspirin particles passed through a 100 30 mesh B.S.S. screen, i.e. had a size less than 150 mi however normally weigh at least 3 g. and accordingly crons. Analysis of the sieved particles showed that ap are much larger than the tablets of this Example. Signif proximately 99 percent by weight were less than 105 icant savings in packaging costs and, even allowing for microns and approximately 93 percent by weight were the cost of preparing the aspirin particles, in raw less than 75 microns. material costs can therefore be achieved using the aspi 35 rin particles of the present invention. Furthermore, EXAMPLE 2 since the daily dosage of effervescent aspirin tablets is Free flowing coated aspirin particles were prepared normally restricted so that the sodium intake will by the same method as Example 1 but using the follow not exceed about 200 mille equivalents ( 10 conven ing ingredients: tional tablets containing a total of 3.0 g. aspirin), an in 40 creased daily dosage of aspirin can be obtained with the tablets of this Example since the sodium ion content is Aspirin 3000 g. Glycine 3000 g. just under 8 mille equivalents. That is to say up to 24 Sodium carboxymethylcellulose 25 g. tablets containing 7.2 g of aspirin may be administered Polyoxyethylene sorbitan monolaurate 5 g. daily, a significant increase in dosage over that hitherto Distilled water 2 litres 45 obtainable with conventional effervescent aspirin tab The resultant particles had a size distribution similar lets. to that obtained in Example 1. EXAMPLE 6 EXAMPLE 3 Effervescent tablets were made to the following for Free flowing coated aspirin particles were prepared mula by conventional methods: as follows: mgitablet Aspirin 450 g. 55 ) Aspirin particles (from Example 2) O) ng sitol 500 g. 2) Malic acid (coated) 500 ing, Gum acacia 50 g. 3) Sodium bicarbonate 51() ring. Sodium lauryl sulphate 5 g. 4) (treated) 35 ng Distilled witer (.S. 5) Sodium saccharin s ng. Total 1650 ng. The inositol, gum acacia and sodium lauryl Sulphate were dissolved in water (5 litres). The aspirin (particle 60 size 10 to 150 microns) was added to the resultant solu Ingredient ( 1) was obtained by taking a weight of as tion with vigorous stirring and the solution was diluted pirin particles shown by analysis to contain 300 mg. as with water to 10 litres. With continuous agitation, the pirin and making up to 600 mg. by addition of glycine. aspirin suspension was pumped to the atomiser wheel 65 Ingredient (2) was obtained by mixing 10 kilos of (revolving at 30,000 r. p.m.) of a spray-drier. The inlet malic acid in a semi-dissolved state with a sodium ma and outlet temperatures of the spray-drier were 230°C. late composition in water obtained from 8 kilos of and 20°C. respectively. After initial screening of the malic acid and 2 kilos of sodium hydroxide. Mixing was 3,882,228 7 8 continued for 5 minutes and the mixture was dried to agent; and up to ten percent by weight of a film forming give malic acid finely coated with sodium malate. agent selected from hydroxy ethyl cellulose, hydroxy Ingredient (4) was obtained by heating anhydrous so propyl methyl cellulose, sodium carboxy methyl cellu dium carbonate at 170°C. for 3 hours under vaccuum. lose, starches, dextrin, dextran, gum acacia, gum tragi In the foregoing Examples 5 and 6, the coated aspirin canth and poly vinyl pyrrolidone. particles of the present invention constitute the sole 2. Pharmaceutical compositions comprising the free therapeutic ingredient. However, the aspirin particles flowing readily wettable aspirin particles claimed in of this invention can be used in whole or part replace claim 1, and a pharmaceutically acceptable carrier ment of untreated aspirin in other types of aspirin for therefor. mulations, including formulations containing therapeu O 3. Free-flowing readily wettable aspirin particles, as tic ingredients additional to aspirin, such as codeine, claimed in claim 1, wherein the coating material in caffeine, phenacetin, paracetamol, phenylephrine, cludes mannitol. chlorpheniramine, amphetamine, dexamphetamine, 4. Free-flowing readily wettable aspirin particles, as allobarbitone, amylobarbitone, butobarbitone, pheno claimed in claim 1, wherein the coating material in barbitone, meprobamate, phenolphthalein, methocar 15 cludes glycine. bamol, vitamin C, vitamin K and dihydrocodeine. 5. Free-flowing readily wettable aspirin particles, as We claim: claimed in claim 1, exhibiting the following physical 1. Free flowing readily wetable coated aspirin parti properties: cles, of which at least 95 percent by weight are not i. the melting point of the coating material being more than 150 microns, comprising: one part of aspirin 20 above 15OC to one to one ninth part of a coating agent comprising ii. the ratio by weight of aspirin to coating material at least one ingredient selected from glycine, methio being from about 7:1 to about 1:1 nine, sucrose, lactose, arabino galactan sugar products, iii. at least 95 percent by weight of the particles being mannitol, inositol and sorbitol; said coating agent also not greater in size than 105 microns. comprising up to five percent by weight of a wetting 25 sk sk sk k k

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