Europäisches Patentamt *EP001303257B1* (19) European Patent Office

Office européen des brevets (11) EP 1 303 257 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: A61K 9/00 of the grant of the patent: 10.08.2005 Bulletin 2005/32 (86) International application number: PCT/EP2001/008688 (21) Application number: 01969530.3 (87) International publication number: (22) Date of filing: 27.07.2001 WO 2002/009666 (07.02.2002 Gazette 2002/06)

(54) Method of preparing a liquid unit dosage form and a kit Verfahren zur Herstellung einer flüssigen Dosierungseinheit und Kit Méthode de préparation d’une unité de dosage liquide et kit

(84) Designated Contracting States: (74) Representative: Jones, Stephen Anthony et al AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU AdamsonJones MC NL PT SE TR BioCity Nottingham Pennyfoot Street (30) Priority: 27.07.2000 GB 0018322 Nottingham NG1 1GF (GB)

(43) Date of publication of application: (56) References cited: 23.04.2003 Bulletin 2003/17 EP-A- 0 247 980 EP-A- 0 552 105 EP-A- 0 597 414 (73) Proprietor: The Boots Company PLC Nottingham, Nottinghamshire NG2 3AA (GB) Remarks: The file contains technical information submitted (72) Inventors: after the application was filed and not included in this • KEATING, David, Anthony specification Nottingham, Nottinghamshire NG2 3AA (GB) • NORMAN, Kurt Nottingham, Nottinghamshire NG2 3AA (GB)

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 303 257 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 1 303 257 B1 2

Description ened, flavoured carrier is contained in a separate con- tainer. Immediately before administration, the iron salt [0001] The present invention relates to pharmaceuti- is transferred to the carrier and mixed therewith. cal compositions. [0006] The present invention provides a method of [0002] In order to make medicines palatable and to 5 preparing a liquid unit dosage form of a medicament or make it easier for patients, for example the aged, infirm medicaments comprising providing a range of first con- or children, who have difficulty in swallowing the usual tainers containing different liquid carriers, providing one solid dosage forms to take their medicine, it has been or more second, sealed containers containing a solid or common practice for formulate medicines as a thick- liquid unit dose of the medicament or medicaments, ened or gelled liquid. This type of medicine is not, how- 10 pouring a quantity of a selected one of the liquid carriers ever, totally satisfactory for several reasons. These in- into a mixing vessel, opening the one or more second, clude: sealed containers, pouring the unit dose of the medica- ment or medicaments from the one or more second con- 1. great care must be taken to ensure that the for- tainers into the mixing vessel, and allowing or causing mulations are stable and that there is no reduction 15 the liquid carrier and the unit dose of medicament or in potency on storage; medicaments to become mixed in the mixing vessel. The medicament is contained as either a single unit 2. the flavouring system will be one chosen by the dose or as several unit doses which can be dispensed manufacturer of the formulation and it may not be separately. acceptable to all patients. Indeed some patients 20 [0007] It is envisaged that a range of liquid carriers may be so deterred by the flavour chosen by the will be available having different flavours or no flavour. manufacturer that they will refuse to take their med- It will therefore be possible to choose the flavour which icines at all; is most acceptable to the patient. By choosing an ac- ceptable tasting carrier, the patient will be more likely to 3. active ingredients found in formulations can 25 take the medicine and so much better patient compli- make the preparation taste unpleasant and bitter; ance can be anticipated. The liquid carrier may contain water and glycerol or sorbitol to provide a satisfactory 4. if the illness being treated is short in duration, mouthfeel. The amount of glycerol or sorbitol may be then the patient may not need all the pharmaceuti- from 5 to 20%, preferably 8 to 15% by volume of the cal composition in the container. The remainder will 30 liquid carrier. A natural or synthetic sweetener may be then either be discarded which is wasteful or will be included. Natural sweeteners include glucose, sucrose stored, often in less-than-ideal conditions until the or maltitol. Artificial sweeteners include saccharin and same illness recurs. By that time the formulation pharmaceutically acceptable salts thereof, acesul- may have degraded so that it is less effective in phame or aspartame. The flavouring may be any of the treating the illness. 35 commercially available flavourings which would be ac- ceptable to the patient. An organic acid, for example cit- 5. combination products can be difficult and lengthy ric acid, may be present as a flavour enhancer. The liq- to develop, in some combination products global uid carrier may be thickened with any of the known phar- acceptability is often not applicable; and maceutically acceptable thickening agents. Suitable 40 thickening agents include starch, sodium carboxyme- 6. pharmacists find it difficult to prescribe combina- thyl cellulose, hydroxypropyl methyl cellulose, microc- tion products. rystalline cellulose, gums (such as tragacanth, acacia, carrageenan and xanthan gums), pectin, gelatin, poly- [0003] EP 552105 discloses a receptacle containing ethyleneglycol and partially neutralised carbomers. Pre- a liquid product provided with a closure lid containing a 45 servatives, such as sodium benzoate, parabens or bro- reservoir of additional liquid. The additional liquid may nopol may be included to ensure that the liquid carrier be added to the liquid product by manual actuation of has an acceptable shelf life. As the liquid carrier does the closure lid which causes the isolating member con- not contain any medicaments the time consuming and taining the reservoir in the lid to rupture. expensive stability trials, which are usually needed dur- [0004] EP 597414 addresses the problem of the in- 50 ing the development of a pharmaceutical composition stability of sennosides as active substances in aqueous to ensure that there are no undesirable interactions be- solutions. It discloses a package comprising a granulate tween any particular medicament and the carrier, are not containing senna extract concentrate and sucrose and required. a bottle containing a liquid carrier. The granulate is shak- [0008] The liquid carrier may be contained in any suit- en with the liquid prior to use. 55 able container made, for example, of glass or synthetic [0005] EP 247980 relates to the problem of the insta- polymeric material. Because the contents of the contain- bility of iron salts in liquid preparations. It discloses that er do not contain any active medicament, there is no the iron salts are stored in one container and a sweet- necessity to have a so-called "child-resistant" closure

2 3 EP 1 303 257 B1 4 on the container. These closures, which are intended to to 800 mg, preferably 200 to 600 mg, most preferably make it difficult for children to open and consume med- 250, 373 or 500 mg. The amount of ketoprofen in a unit icines accidentally, can be difficult for the aged and in- dose may be 25 to 250 mg, preferably 50 to 150 mg, firm to open. The fact that they are not needed is there- most preferably 50 or 100 mg. The amount of fore of significant benefit to this class of patient. 5 in a unit dose may be 20 to 50 mg, preferably 5 to 30 [0009] The one or more second parts of the formula- mg, most preferably 8, 12.5, 16 or 25 mg. If pharmaceu- tion may be a unit dose of the pure medicament in solid tically effective salts of the above compounds are used form or liquid form. This may be combined with other then the amount of salt should be increased to give a pharmaceutical acceptable ingredients. Alternatively a dose of the free medicament corresponding to the fig- multiple dose of the medicament in a solid or liquid form, 10 ures given above. The amount of caffeine in a unit dose this may be pure or combined with other pharmaceutical may be 5 to 200 mg, preferably 10 to 100 mg, most pref- acceptable ingredients. The other pharmaceutically ac- erably 30, 45, 60 or 100 mg. ceptable ingredients may comprise 0.1% to 99.9% of the [0013] Suitable decongestants include ephedrine, unit dose. Suitable other ingredients include taste mask- levomethol, pseudoephedrine preferably as its hydro- ing agents, diluents, binders, lubricants, sweeteners 15 chloride, phenylpropanolamine preferably as its hydro- and flavours. chloride and phenylephrine. [0010] The active medicament may be an analgesic [0014] The amount of ephedrine in a unit dose may or anti-inflammatory, decongestant, cough suppres- be in the range 15-60 mg. The amount of levomethol in sant, expectorant, antihistamine, antiallergy agent, a unit dose may be in the range 0.5-100 mg, preferably agent for treating the gastrointestinal tract (for example 20 0.5-25 mg, most preferably 1, 2, 5, 10 or 25 mg. The antacid, antireflux agent, antiulcer agent, antidiarrhoeal amount of pseudoephedrine preferably as its hydrochlo- agent, laxative or antiemetic), agent to counter motion ride in a unit dose may be in the range 60-120 mg, pref- sickness, antiviral agents, antifungal agents, antibacte- erably 30, 60 or 120 mg. The amount of phenylpropa- rial agents, diuretic agents, antiasthmatic agents, an- nolamine preferably as its hydrochloride in a unit dose timigraine agents, vitamins and/or minerals. 25 may be in the range 5-50 mg, preferably 5-20 mg. The [0011] Suitable analgesics include aspirin, paraceta- amount of phenylephrine in a unit dose may be in the mol (acetaminophen) and non-steroidal anti-inflamma- range 5-25 mg, preferably 5, 10 or 25 mg. tory/analgesics such as diclofenac, indomethacin, [0015] Suitable cough suppressants include bibenzo- mefanamic acid, nabumetone, tolmetin, piroxicam, fel- nium preferably as its bromide, , carbetap- binac, diflunisal, ibuprofen, flurbiprofen, naproxen and 30 entane preferably as its citrate, codeine, dextromethor- ketoprofen or pharmaceutically acceptable salts thereof phan preferably as its hydrobromide, and (for example the sodium or lysine salts) or narcotic an- pholcodeine. algesics such as codeine and pharmaceutically accept- [0016] The amount of in a unit able salts thereof (for example codeine, phosphate or dose may be in the range 20-30 mg. The amount of car- sulphate). Caffeine may be present in analgesic prod- 35 amiphen in a unit dose may be in the range 5-20 mg, ucts to enhance the analgesic effect. preferably 5 or 20 mg. The amount of carbetapentane [0012] The amount of aspirin in a unit dose may be in citrate in a unit dose may be in the range 15-30 mg. The the range 75 to 800 mg, preferably 200-600 mg, most amount of codeine in a unit dose maybe in the range preferably 75, 150, 300, 400 or 600 mg. The amount of 2-50 mg, preferably 5-30mg, most preferably 10 mg. In paracetamol in a unit dose may be 50 to 2000 mg, pref- 40 the present invention pharmaceutically acceptable salts erably 120 to 1000 mg, most preferably 120, 250, 500 of codeine may also be used (for example codeine phos- or 1000 mg. The amount of diclofenac in a unit dose phate or sulphate). The amount of may be 10 to 100 mg, preferably 20 to 80 mg, most pref- hydrobromide in a unit dose may be in the range 15-30 erably 25 or 50 mg. The amount of indomethacin in a mg, preferably 15 or 30 mg. The amount of noscapine unit dose may be in the range 25-75 mg, preferably 25 45 in a unit dose may be in the range 15-30 mg. The amount mg, 50 mg or 75 mg. The amount of mefanamic acid in of pholcodeine in a unit dose may be in the range 2-25 a unit dose may be in the range 250-500 mg, preferably mg, preferably 5 to 20 mg, more preferably 10 to 15 mg. 250 mg or 500 mg. The amount of nabutmetone in a unit [0017] Suitable expectorants include ammonium bi- dose may be in the range 500-1000 mg. The amount of carbonate, , hydrochlo- piroxicam in a unit dose may be in the range 10-40 mg, 50 ride, cocillana , , ipecacuanha, po- preferably 10, 20 or 40 mg. The amount of diflunisal in tassium and pharmaceutically acceptable salts thereof a unit dose may be in the range 250-500 mg, preferably (for example potassium citrate or iodide), potassium 250 mg or 500 mg. The amount of ibuprofen in a unit guaicolsulfonate, squill and hydrate. dose may be in the range 50 to 800 mg, preferably 100 [0018] The amount of ammonium bicarbonate in a to 400 mg, most preferably 100, 200 or 400 mg. The 55 unit dose may be in the range 300-600 mg. The amount amount of flurbiprofen in a unit dose may be 25 to 200 of ammonium chloridein in a unit dose may be in the mg, preferably 50 to 150 mg, most preferably 50 or 100 range 0.3-2 g (300-2000 mg). The amount of bromhex- mg. The amount of naproxen in a unit dose may be 100 ine hydrochloride in a unit dose may be in the range

3 5 EP 1 303 257 B1 6

24-64 mg. The amount of creosote in a unit dose may 12.5 mg. The amount of tripelennamine in the form of be in the range 0.12-0.6 ml. The amount of guaifenesin hydrochloride in a unit dose may be in the range 25-50 in a unit dose may be in the range 100-200 mg, prefer- mg, preferably 25, 37.5 or 50 mg. The amount of tripro- ably 100 mg. The amount of ipecacuanha in a unit dose lidine in the form of hydrochloride in a unit dose may be may be in the range 25-100 mg. The amount of potas- 5 in the range 1-2.5 mg, preferably 1.25-2.5 mg, most sium iodide in a unit dose may be in the range 150-300 preferably 1.25 mg. The amount of cetirizine in a unit mg, preferably 100 mg. The amount of potassium citrate dose may be in the range 5-10 mg, preferably 5 mg or in a unit dose may be in the range 150-300 mg, prefer- 10 mg. The amount of cinnarizine in a unit dose may be ably 100 mg. The amount of potassium guericolsul- in the range of 15-75 mg, preferably 15 mg or 75 mg. fonate in a unit dose may be 80 mg. The amount of squill 10 The amount of mequitazine in a unit dose may be in the in a unit dose may be in the range 60-200 mg. The range 5-10 mg, preferably 5 mg or 10 mg. The amount amount of terpin hydrate in a unit dose may be in the of acrivastine in a unit dose may be 3-20 mg, preferably range 125-600 mg, preferably 300 mg. 5-10 mg, most preferably around 8 mg. [0019] Suitable antihistamines include azatadine or a [0021] Suitable antiallergy agents include astemizole, salt thereof such as the maleate, bromodiphenhy- 15 clemastine or a salt thereof such as the hydrogen fum- dramine or a salt thereof such as the hydrochloride, erate, loratadine, terfenodine. brompheniramine or a salt thereof such as the maleate, [0022] The amount of astemizole in a unit dose may carbinoxamine or a salt thereof such as the maleate, be in the range 0.5-200 mg, preferably 1-100 mg, most chlorpheniramine or a salt thereof such as the maleate, preferably 2, 5, 10, 20 or 40 mg. The amount of clem- cyproheptadine or a salt thereof such as the hydrochlo- 20 astine in the form of its hydrogen fumerate in a unit dose ride, dexbrompheniramine or a salt thereof such as the may be in the range 0.01-200 mg, preferably 0.1-10 mg, maleate, dexchlorpheniramine or a salt thereof such as most preferably 0.2, 0.4, 0.6, 1.2 or 2.4 mg. The amount the maleate, or a salt thereof such as of loratadine in a unit dose may be in the range 0.5-200 the hydrochloride, doxylamine or a salt thereof such as mg, preferably 1-100 mg, most preferably 2, 5, 10, 20 the succinate, phenidamine or a salt thereof such as the 25 or 40 mg. The amount of terfenadine in a unit dose may tartrate, promethazine or a salt thereof such as the hy- be in the range 5-1000 mg, preferably 10-600 mg, most drochloride, pyrilamine or a salt thereof such as the preferably 20, 40, 60, 100 or 200 mg. maleate, pyrilamine or a salt thereof such as the tan- [0023] Suitable antacids include aluminium glycinate, nate, tripelennamine or a salt thereof such as the hydro- aluminium hydroxide gel, aluminium phosphate gel, chloride, tripolidine or a salt thereof such as the hydro- 30 dried aluminium phosphate gel, calcium carbonate, chloride, cetirizine or a salt thereof such as the hydro- charcoal, hydrotalcite, light kaolin, magnesium carbon- chloride, cinnarizine, mequitazine, dcivastine. ate, magnesium hydroxide, magnesium oxide, magne- [0020] The amount of azatadine in the form of maleate sium trisilicate, sodium bicarbonate. in a unit dose may be in the range 1-2 mg, preferably 1 [0024] The amount of aluminium glycinate in a unit mg. The amount of bromodiphenhydramine in the form 35 dose may be in the range 0.1-10 g, preferably 0.1-5g, of hydrochloride in a unit dose may be 3.75 mg. The most preferably 0.2, 0.5, 1 or 2 g. The amount of alu- amount of brompheniramine in the form of maleate in a minium hydroxide gel in a unit dose may be in the range unit dose may be in the range 4-12 mg, preferably 4, 8 1-50 ml, preferably 2-30 ml, most preferably 5, 7.5, 10, or 12 mg. The amount of carbinoxamine in the form of 15 or 30 ml. The amount of aluminium phosphate gel in maleate in a unit dose may be 4 mg. The amount of chlo- 40 a unit dose may be in the range 0.5-100 ml, preferably rpheniramine in the form of maleate in a unit dose may 1-50 ml, most preferably 2, 5, 10, 15 or 30 ml. The be in the range 2-12 mg, preferably 4, 8 or 12 mg. The amount of dried aluminium phosphate gel in a unit dose amount of dexbrompheniramine in the form of maleate may be in the range 50-5000 mg, preferably 100-2000 in a unit dose may be 6 mg. The amount of dexchlorphe- mg, most preferably 200, 400, 800 or 1600 mg. The niramine in the form of maleate in a unit dose may be in 45 amount of calcium carbonate in a unit dose may be in the range of 2-6 mg, preferably 2, 4 or 6 mg. The amount the range 0.1-30 g, preferably 0.5-10 g, most preferably of diphenhydramine in the form of hydrochloride in a unit 0.5, 1, 2 or 5 g. The amount of charcoal in a unit dose dose may be in the range of 12.5 to 200 mg, preferably may be in the range 1-200g, preferably 1-100 g, most 12.5-50 mg, more preferably 12.5, 25 or 50 mg. The preferably 2, 4, 8, 16 or 50 g. The amount of hydrotalcite amount of doxylamine in the form of succinate in a unit 50 in a unit dose may be in the range 0.1-10 g, preferably dose may be in the range 7.5-10 mg, preferably 7.5 or 0.2-5 g, most preferably 0.5, 1 or 2 g. The amount of 10 mg. The amount of phenidamine in the form of tar- light kaolin in a unit dose may be in the range 10 mg- trate in a unit dose may be in the range 5-10 mg, pref- 100 g, preferably 100 mg-75 g, most preferably 1, 10, erably 5 or 10 mg. The amount of promethazine in the 15, 20, 50 or 75 g. The amount of magnesium carbonate form of hydrochloride in a unit dose may be in the range 55 in a unit dose may be in the range 50 mg-10 g, preferably 1.5-6 mg. The amount of pyrilamine in the form of 50 mg-5 g, most preferably 100, 200 or 500 mg. The maleate in a unit dose may be 12.5 mg. The amount of amount of magnesium hydroxide in a unit dose may be pyrilamine in the form of tannate in a unit dose may be in the range 100 mg-10 g, preferably 100 mg-5 g, most

4 7 EP 1 303 257 B1 8 preferably 100, 250, 500 or 750 mg. The amount of mag- the range 1-200 mg, preferably 2-100 mg, most prefer- nesium oxide in a unit dose may be in the range 100 ably 2-5, 5, 10, 20 or 50 mg. The amount of aloin in a mg-10 g, preferably 100 mg-5 g, most preferably 100, unit dose may be in the range 1-200 mg, preferably 250, 500 or 750 mg. The amount of sodium bicarbonate 2-100 mg, most preferably 5, 10, 15 or 30 mg. The in a unit dose may be in the range 0.1-50 g, preferably 5 amount of bisacodyl in a unit dose may be in the range 0.5-25 g, most preferably 0.5, 1, 2, 5 or 10 g. 0.1-100 mg, preferably 0.5-50 mg, most preferably 1, 2, [0025] Suitable antireflux agents include simethicone 5, 10 or 20 mg. The amount of ispaghula husk in a unit and sodium alginate. dose may be in the range 100 mg-50 g, preferably 500 [0026] The amount of simethicone in a unit dose may mg-25 g, most preferably 1, 2, 3, 5 or 10 g. The amount be in the range 5-1000 mg, preferably 10-500 mg, most 10 of lactulose in a unit dose may be in the range 100 mg- preferably 25, 40, 50, 60, 100 or 200 mg. The amount 50 g, preferably 500 mg-30 g, most preferably 1, 2, 5, of sodium alginate in a unit dose may be in the range 10 or 15 g. The amount of phenolphthalein in a unit dose 50 mg-10 g, preferably 75 mg-5 g, most preferably 100, may be in the range 1-5000 mg, preferably 5-4000 mg, 250, 500 or 1 g. most preferably 7.5, 15, 30, 60, 100, 200 or 300 mg. The [0027] Suitable antiulcer agents include bismuth sub- 15 amount of senna extract (including sennosides A+B) in salicylate, H2 receptor antagonists such as cimetidine, a unit dose may be in the range 0.5-100 mg, preferably famotidine, ranitidine and nizatidine and proton pump 1-50 mg, most preferably 2.5, 5, 7.5, 10, 15 or 30 mg. inhibitors such as omeprazole, pantoprazole and lanso- [0033] Suitable antiemetics include dimenhydrinate, prazole. metoclopromide or a salt thereof such as the hydrochlo- [0028] The amount of bismuth subsalicylate in a unit 20 ride, domperidone or a salt thereof such as the maleate, dose may be in the range 250-2000 mg, preferably buclizine, cyclizine, prochlorperazine or a salt thereof 50-1500 mg, most preferably 75, 150, 300, 600 or 1000 such as the maleate, ipecacuanha, squill. mg. The amount of cimetidine in a unit dose may be in [0034] The amount of ipecacuanha in a unit dose may the range 10 mg-5 g, preferably 50 mg-2 g, most pref- be in the range 25-100 mg. The amount of squill in a unit erably 100, 200 or 400 mg. The amount of famotidine in 25 dose may be in the range 60-200 mg. The amount of a unit dose may be in the range 10-80 mg, preferably domperidone may be in the range 5-50 mg, preferably 20 or 40 mg. The amount of ranitidine in a unit dose may 5, 10, 15, 20, 25, 30, 40 or 50 mg. The amount of bu- be in the range 100-600 mg, preferably 300-600 mg, clizine in a unit dose may be in the range 2-100 mg, pref- most preferably 300 or 600 mg. The amount of nizatidine erably 5-50 mg, more preferably 6.25, 13.5, 25, prefer- in a unit dose may be 50 to 500 mg, preferably 100 to 30 ably 5-50 mg, more preferably 6.25, 13.5, 25 or 50 mg. 400 mg, more preferably 150 to 300 mg. The amount of The amount of cyclizine in a unit dose may be in the omeprazole in a unit dose may be 5 to 50 mg, preferably range 1-50 mg, preferably 2-30 mg, more preferably 5, 10 to 40 mg, more preferably 10, 20 or 40 mg. The 7.5, 10, 15, 20 or 25 mg. The amount of metoclopromide amount of pantoprazole in a unit dose may be 10 to 50 in a unit dose may be in the range 2-30 mg, preferably mg, preferably 15 to 45 mg, more preferably 20 to 40 35 5, 10, 15 or 30 mg. The amount of dimenhydrinate in a mg. The amount of lansoprazole in a unit dose may be unit dose may be in the range 5-50 mg, preferably 25 5 to 50 mg, preferably 10 to 40 mg, more preferably 15 mg. The amount of prochlorperazine in a unit dose may or 30 mg. be in the range 3-25 mg, preferably 3 mg or 5 mg. If [0029] Suitable antidiarrhoeal agents include lopera- pharmaceutically effective salts of the above com- mide or a salt thereof, such as the hydrochloride, meth- 40 pounds are used then the amount of salt should be in- ylcellulose, diphenoxylate and morphine or a salt there- creased to give a dose of the free medicament corre- of, such as the hydrochloride. sponding to the figures given above. [0030] The amount of loperamide in the for of its hy- [0035] Suitable agents to counter motion sickness in- drochloride in a unit dose may be in the range 0.1-50 clude cinnarizine, dimenhydrinate, hyoscine or a salt mg, preferably 0.5-20 mg, most preferably 1, 2, 4 or 8 45 thereof such as the hydrobromide and meclozine or a mg. The amount of methylcellulose in a unit dose may salt thereof such as the hydrochloride. be in the range 20 mg-5 g, preferably 50 mg-4 g, most [0036] The amount of cinnarizine in a unit dose may preferably 100, 200, 500 mg, 1 or 2 g. The amount of be in the range 0.5-200 mg, preferably 1-100 mg, most diphenoxylate in the for of its hydrochloride in a unit dose preferably 5, 10, 20, 40 or 60 mg. The amount of dimen- may be 1-10 mg, preferably 2-5 mg, more preferably 2.5 50 hydrinate in a unit dose may be in the range 1-500 mg, mg. The amount of morphine in the for of its hydrochlo- preferably 5-300 mg, most preferably 10, 20, 50, 100 or ride in a unit dose may be in the range 20-4000 µg, pref- 250 mg. The amount of hyoscine hydrobromide in a unit erably 50-2000µg, most preferably 100, 200, 400, 800 dose may be in the range 0.01-1 mg, preferably 0.05-0.5 or 1600 µg. mg, most preferably 0.05, 0.1, 0.2, 0.3 or 0.5 mg. The [0031] Suitable laxatives include agar, aloin, bisa- 55 amount of meclozine hydrochloride in a unit dose may codyl, ispaghula husk, lactulose, phenolphthalein and be in the range 0.5-200 mg, preferably 1-100 mg, more senna extract (including sennosides A + B). preferably 2, 5, 10, 20 or 40 mg. [0032] The amount of agar in a unit dose may be in [0037] Suitable antiviral agents include aciclovir. The

5 9 EP 1 303 257 B1 10 amount of aciclovir in a unit dose may be in the range lose, polymethacrylates, powdered cellulose, pregelat- 100 to 1000 mg, preferably 200 to 800 mg. inised starch, silicified microcrystalline cellulose, sodi- [0038] Suitable antifungal agents include fluconazole um chloride, starch, sucrose, sugar, talc, xylitol. One or and terbinafine. The amount of fluconazole in a unit more diluents may be used. The amount of diluent may dose may be in the range 50-200 mg, preferably 50 mg 5 be in the range 10-98% w/w. or 200 mg. The amount of terbinafine may be in the [0049] Suitable binders include acacia, alginic acid, range 250-500 mg, preferably 250 mg. carboxymethylcellulose, cellulose, dextrin, ethylcellu- [0039] Suitable antibacterial agents include erythro- lose, gelatin, glucose, guar gum, hydrogenated vegeta- mycin and fusidic acid and salts thereof such as the so- ble oil, hydroxyethylcellulose, hydroxypropylmethylcel- dium salt. The amount of erythromycin in a unit dose 10 lulose, liquid glucose, magnesium aluminium silicate, may be in the range 125-500 mg, preferably 125 mg, maltodextrin, methylcellulose, polyethylene oxide, 250 mg or 500 mg. The amount of fusidic acid in a unit polymethacrylates, povidone, sodium alginate, starch, dose may be in the range 250-500 mg, preferably 250 vegetable oil and zein. One or more binders may be mg. used. The amount of binder may be in the range 10-50% [0040] Suitable diuretics include frusemide. The 15 w/w. amount of frusemide in a unit dose may be in the range [0050] Suitable lubricants include calcium stearate, 20-80 mg, preferably 20, 40 or 80 mg. canola oil, glyceryl palmitostearate, hydrogenated veg- [0041] Suitable anti-asthmatic agents include keto- etable oil, magnesium stearate, mineral oil, poloxamer, tifen. The amount of ketotifen in a unit dose may be in polyethylene glycol, polyvinyl alcohol, sodium ben- the range 1-4 mg, preferably 1 mg or 2 mg. 20 zoate, sodium lauryl sulphate, sodium stearyl fumarate, [0042] Suitable anti-migraine agents include su- stearic acid, talc and zinc stearate. One or more lubri- matriptan. The amount of sumatriptan in a unit dose may cants may be used. The lubricant may be in the range be in the range 20-100 mg, preferably 20, 50 or 100 mg. 0.01-10% w/w. [0043] Suitable vitamins include A, B1, B2, B3, B5, [0051] The granules may be formed by methods B6, B12, C, D, E, folic acid, biotin, and K. Suitable min- 25 known by the skilled man for example wet granulation erals include calcium, phosphorus, iron, magnesium, or dry granulation. zinc, iodine, copper, chloride, chromium, manganese, [0052] The one or more second part of the pharma- molybdenum, nickel, potassium, selenium, boron, tin ceutical compositions of the present invention may be and vanadium. contained in a sealed container(s) prior to use. The [0044] The medicament may be taste masked to fur- 30 sealed container may be any suitable container such as ther improve the taste profile of the pharmaceutical com- a sachet, pouch, ampoule or capsule made from a ma- position. The medicament may be taste masked using terial which is compatible with the medicament and any methods known in the art for example adding taste other ingredients which are present. The sealed con- masking ingredients such as ethylcellulose, hydroxy- tainer should be easy to open to enable all its contents propylmethylcellulose, methylethylcellulose, hydroxy- 35 to be poured from the container. propylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, [0053] The first and one or more secondn parts of the mono glycerides, diglycerides, stearic acid, palmitic ac- pharmaceutical composition of the present invention are id, gelatin, hydrogenated cotton seed oil and more gen- kept separate until just before use. When the patient re- erally any food grade polymer, starch, wax or fat. The quires a unit dose of the medicament to be administered taste masking agents may be used singly or in combi- 40 the two parts of the pharmaceutical composition are nation. mixed and swallowed by the patient. To mix the parts, a [0045] Preferably the unit dose of medicament is suitable quantity of the liquid carrier is poured into a mix- granulated optionally with other excipients. The other ing vessel. The exact quantity of liquid carrier is not crit- excipients may include taste masking agents, sweeten- ical but is envisaged that an amount between 10 and 50 ers, flavours, diluents, binders, lubricants. 45 ml, preferably 15 to 30 ml will be used. The mixing vessel [0046] Suitable sweeteners include acesulfame K, may be provided with markings indicating the suggested sodium saccharin, aspartame, sucrose. The amount of quantities but this is not essential. The sealed container sweetener may be in the range 0.001% to 0.1%. holding the unit dose of medicament is then opened and [0047] Suitable flavours are available commercially the contents are poured into the liquid carrier. The liquid and the flavour may be enhanced by the addition of an 50 carrier and the contents of the sealed container should acid such as citric acid, ascorbic acid, tartaric acid. then be mixed in any suitable manner for example by [0048] Suitable diluents include calcium phosphate stirring or shaking. The preferred method of mixing is by (anhydrous and dihydrate), calcium sulphate, car- shaking. To facilitate this the mixing vessel may be pro- boxymethylcellulose calcium, cellulose acetate, vided with a removable lid which when fitted to the mix- dexrates, dextrin, dextrose, fructose, glyceryl palmito- 55 ing vessel seals the mixing vessel enabling the vessel stearate, hydrogenated vegetable oil, kaolin, lactitol, to be shaken to distribute the unit dose of medicament lactose, magnesium carbonate, magnesium oxide, throughout the liquid carrier. It is envisaged that the maltitol, maltodextrin, maltose, microcrystalline cellu- mixed contents of the mixing vessel will be ingested by

6 11 EP 1 303 257 B1 12 the patient soon after mixing. Because of this there will 5. The present invention makes it easy to give com- be no time for any adverse interaction between the med- binations of medicaments which are specifically di- icament and any of the excipients used in the liquid car- rected at the symptoms of any particular patient, by rier as can sometimes occur in the prior art liquid com- mixing the liquid carrier with unit doses of more than positions on storage. 5 one medicament. In the known liquid compositions [0054] A further aspect of the present invention also containing combinations of medicaments is select- provides a kit of parts for preparing a liquid unit dosage ed by the manufacturer and it may not be the com- form of a medicament or medicaments comprising a bination which is actually needed by any particular range of first containers containing differently flavoured patient. liquid carriers, one or more second sealed containers 10 containing a solid or liquid unit dose of the medicament 6. Taste will improve due to the bitterness of active or medicaments and a separate mixing vessel into ingredients being suppressed by tastemasking, which a quantity of selected liquid carrier and the unit therefore having a positive effect on the overall dose of the medicament or medicaments can be intro- taste of the formulation. duced and mixed. Preferably the mixing vessel is pro- 15 vided with a lid which seals the container enabling the 7. The present invention avoids the present unde- liquid carrier and the unit dose of medicament to be sirable practice of storing a number of partly used mixed by shaking the sealed mixing vessel. The mixed liquid compositions which will be used again if the pharmaceutical composition may then be ingested by illness recurs. Using the present invention, any un- the patient from the mixing vessel. 20 consumed liquid carrier can be used to treat a dif- [0055] The pharmaceutical compositions of the ferent illness by mixing into the liquid carrier a dif- present invention described herein have several advan- ferent solid unit dose of medicament. tages over the known liquid dosage forms. [0056] The invention will be illustrated by the following 1. Because the liquid carrier and the second or more 25 Examples which are given by way of example only. part incorporating the medicament are mixed imme- diately prior to administration, there can be no in- Example 1  Sugar-free liquid carrier teractions between the medicament and any of the excipients as sometimes occurs in the known com- [0057] positions on storage because the medicament and 30 excipients are in contact for long periods of time. Ingredient % weight or v/v Because of this possible instability of the known compositions, each one of them must be subjected to time consuming and expensive stability testing. Glycerol 10 v In the present invention each flavoured variety of 35 Maltitol solution 30 v the liquid carrier must be tested but only once. Sodium benzoate 0.2 w There is no requirement to test the liquid carrier eve- Citric acid 0.2 w ry time a composition containing a new medicament Acesulfame K 0.025 w is required. Sodium saccharin 0.0125 w 40 Liquid flavour 0.1 v 2. The medicaments are stored in separate contain- Purified water to 100 v ers in solid or liquid form. The possibility of interac- tions with other excipients in the known liquid com- [0058] The liquid carrier uses the sweetness and positions does not occur with the present invention. mouthfeel of glycerol and maltitol to give a good mouth- The contents of the container must, of course, un- 45 feel taste. Thickener systems may be used to give a dergo stability testing but this will be much simpler thicker syrup. than testing the known liquid compositions.

Example 2  Liquid carrier containing sugar 3. The patient can choose the flavour of the liquid carrier for his or her medicine which is acceptable 50 [0059] to him or her. This will improve patient compliance with the dosing regime. Ingredient % weight or v/v 4. The amount of wastage is reduced as the liquid Glycerol 10 v carrier can be stored until it is needed again for use 55 Liquid sugar demin 40 v with a different medicament to treat different symp- Sodium benzoate 0.2 w toms in the patient. Citric acid 0.2 w

7 13 EP 1 303 257 B1 14

(continued) Example 5

Ingredient % weight or v/v [0067] Liquid flavour 0.1 v Purified water to 100 v 5 Ingredient mg/sachet Taste masked aspirin 375 [0060] The base uses the sweetness and mouth-feel Xylitol 190 of glycerol and liquid sugar to give a good mouth-feel. Total 565 Thickener systems may be used to give a thicker syrup. 10 [0068] Taste masked aspirin is 80% aspirin, 20% ethyl Example 3 cellulose as the taste masking agent. Therefore sachet contains 300 mg of the active ingredient. [0061] [0069] The powdered taste masked medicament is 15 sealed within a sachet. When the medicament is to be Ingredient mg/sachet administered to the patient, the contents of the sachet Taste masked paracetamol 555.55 are added to a quantity (preferably 5 to 30 ml) of the Total 555.55 liquid carrier of either Example 1 or Example 2 and mixed by shaking. The resulting liquid dosage form is 20 then taken by the patients. [0062] Tastemasked paracetamol is calculated as be- ing 90% of paracetamol and 10% of ethyl cellulose as Example 6 the taste masking ingredient. Therefore the actual dose of paracetamol is 500 mg. [0070] [0063] The powdered taste masked medicament is 25 sealed within a sachet. When the medicament is to be administered to the patient, the contents of the sachet Ingredient mg/sachet are added to a quantity (preferably 5 to 30 ml) of the Taste masked paracetamol 277.8 liquid carrier of either Example 1 or Example 2 and Lactose 222.2 mixed by shaking. The resulting liquid dosage form is 30 Total 500 then taken by the patients.

[0071] Taste masked paracetamol is 90% paraceta- Example 4 mol, 10% ethyl cellulose as the taste masking agent. Therefore a sachet contains 250 mg of the active ingre- [0064] 35 dient. [0072] The powdered taste masked medicament is Ingredient mg/sachet sealed within a sachet. When the medicament is to be Taste masked ibuprofen 285.71 administered to the patient, the contents of the sachet Xylitol 274.29 are added to a quantity (preferably 5 to 30 ml) of the Total 560 40 liquid carrier of either Example 1 or Example 2 and mixed by shaking. The resulting liquid dosage form is then taken by the patients. [0065] Taste masked ibuprofen is based on 70% of ibuprofen and 30% mono and diglycerides of fatty acids Example 7 as the taste masking ingredient. Therefore the actual 45 dose of ibuprofen is 200 mg. [0073] The efficacy of the compositions of the present [0066] The powdered taste masked medicament is invention were demonstrated in the following way. The sealed within a sachet. When the medicament is to be formulation of Example 6 was mixed with the sugar free administered to the patient, the contents of the sachet liquid carrier of Example 1 and an expert panel were are added to a quantity (preferably 5 to 30 ml) of the 50 asked to compare the taste with that of a widely-used liquid carrier of either Example 1 or Example 2 and paediatric pain relief oral suspension containing para- mixed by shaking. The resulting liquid dosage form is cetamol. 87% of the panel preferred the taste of the then taken by the patients. composition according to the present application.

55 Claims

1. A method of preparing a liquid unit dosage form of

8 15 EP 1 303 257 B1 16

a medicament or medicaments comprising; the mixing vessel allowing the contents to be mixed by shaking the sealed vessel. providing a range of first containers containing different liquid carriers, providing one or more second, sealed contain- 5 Patentansprüche ers containing a solid or liquid unit dose of the medicament or medicaments, 1. Ein Verfahren zur Herstellung einer flüssigen Do- pouring a quantity of a selected one of the liquid sierungseinheit einer Mischung eines Medikaments carriers into a mixing vessel, opening the one oder von Medikamenten, welches umfasst: or more second, sealed containers, 10 Zur-Verfügung-Stellung einer Reihe von ersten Be- pouring the unit dose of the medicament or hältern, die verschiedene Flüssigkeitsträger bein- medicaments from the one or more second halten, containers into the mixing vessel, and Zur-Verfügung-Stellung eines oder mehrerer zwei- allowing or causing the liquid carrier and the ter dicht verschlossener Behälter, die eine feste unit dose of medicament or medicaments to be- 15 oder flüssige Dosierungseinheit des Medikaments come mixed in the mixing vessel. oder von Medikamenten beinhalten, Ausgießen einer Menge eines ausgewählten Flüs- 2. A method as claimed in Claim 1 in which the liquid sigkeitsträgers in ein Mischgefäß, carrier comprises water, glycerol and/or sorbitol, Öffnen des einen oder der mehreren zweiten dicht and optionally a natural or synthetic sweetener and/ 20 verschlossenen Behälter, Ausgießen der Dosie- or thickening agent. rungseinheit des Medikaments oder der Medika- mente von dem einen oder den mehreren zweiten 3. A method as claimed in Claim 1 or Claim 2, wherein Behältern in das Mischgefäß, und the liquid carrier comprises a patient-acceptable fla- Gestatten und Veranlassen des Flüssigkeitsträgers vouring and optionally an organic acid flavouring 25 und der Dosierungseinheit des Medikaments oder enhancer. der Medikamente, in dem Mischgefäß vermischt zu werden. 4. A method as claimed in any one of claims 1 to 3, wherein the mixing vessel is provided with a lid 2. Ein Verfahren nach Anspruch 1, bei dem der Flüs- which seals the mixing vessel allowing the contents 30 sigkeitsträger Wasser, Glycerol bzw. Sorbitol und to be mixed by shaking the sealed vessel. optional einen natürlichen oder synthetischen Zuk- keraustauschstoff bzw. ein Verdickungsmittel um- 5. A kit of parts for preparing a liquid unit dosage form fasst. of a medicament or medicaments , the kit compris- ing; 35 3. Ein Verfahren nach nach Anspruch 1 oder Anspruch 2, wobei der Flüssigkeitsträger einen für den Pati- a range of first containers containing differently enten angenehmen aromatischen Geschmacks- flavoured liquid carriers, stoff und optional einen auf einer organischen Säu- one or more second, sealed containers con- re basierenden Geschmacksverstärker umfasst. taining a solid or liquid unit dose of the medica- 40 ment or medicaments, and 4. Ein Verfahren nach einem der Ansprüche 1 bis 3, a separate mixing vessel into which a quantity wobei das Mischgefäß mit einem Deckel ausgestat- of selected liquid carrier and the unit dose of tet ist, der das Mischgefäß dicht verschließt, wobei the medicament or medicaments can be intro- es den Inhalten gestattet wird, durch Schütteln des duced and mixed. 45 dicht verschlossenen Gefäßes vermischt zu wer- den. 6. A kit as claimed in Claim 5 in which the liquid carrier comprises water, glycerol and/or sorbitol, and op- 5. Ein Set von Teilen zur Herstellung einer flüssigen tionally a natural or synthetic sweetener and/or Dosierungseinheit einer Mischung eines Medika- thickening agent. 50 ments oder von Medikamenten, wobei das Set um- fasst; 7. A kit as claimed in Claim 5 or Claim 6, wherein the eine Reihe von ersten Behältern, die Flüssigkeits- liquid carrier comprises a patient-acceptable fla- träger mit verschiedenen Geschmacksrichtungen vouring and optionally an organic acid flavouring beinhalten, enhancer. 55 ein oder mehrere zweite dicht verschlossene Be- hälter, die eine feste oder flüssige Dosierungsein- 8. A kit as claimed in any one of claims 5 to 7, wherein heit des Medikaments oder von Medikamenten be- the mixing vessel is provided with a lid which seals inhalten, und

9 17 EP 1 303 257 B1 18

ein gesondertes Mischgefäß, in das eine Menge ei- 4. Une méthode selon n'importe laquelle des revendi- nes ausgewählten Flüssigkeitsträgers und eine Do- cations allant de 1 à 3, dans laquelle le réservoir de sierungseinheit eines Medikaments oder von Medi- mélange est fourni avec un couvercle qui ferme le kamenten zugeführt werden kann und dort ver- réservoir de mélange permettant au contenu d'être mischt werden kann. 5 secoué et mélangé par le réservoir hermétique.

6. Ein Set nach Anspruch 5, bei dem der Flüssigkeits- 5. Un jeu d'éléments servant à préparer une unité de träger Wasser, Glycerol bzw. Sorbitol und optional dosage sous forme liquide d'un ou de plusieurs mé- einen natürlichen oder synthetischen Zuckeraus- dicaments, le jeu comprenant : tauschstoff bzw. ein Verdickungsmittel umfasst. 10 une première série de récipients contenant des 7. Ein Set nach Anspruch 5 oder Anspruch 6, wobei porteurs liquides aux différentes saveurs ; der Flüssigkeitsträger einen für den Patienten an- un ou plusieurs deuxièmes récipients herméti- genehmen aromatischen Geschmacksstoff und op- ques contenant une unité de dosage solide ou tional einen auf einer organischen Säure basieren- 15 liquide du ou des médicament(s), et den Geschmacksverstärker umfasst. un réservoir de mélange indépendant dans le- quel il est possible d'introduire et de mélanger 8. Ein Set nach einem der Ansprüche 5 bis 7, wobei un porteur liquide sélectionné et une unité de das Mischgefäß mit einem Deckel ausgestattet ist, dosage du ou des médicament(s). der das Mischgefäß dicht verschließt, wobei es den 20 Inhalten gestattet wird, durch Schütteln des dicht 6. Un jeu selon la revendication 5 dans lequel le por- verschlossenen Gefäßes vermischt zu werden. teur liquide comprend de l'eau, du glycérol et/ou du sorbitol, et, de manière facultative, un édulcorant naturel ou synthétique et/ou un agent épaississant. Revendications 25 7. Un jeu selon la revendication 5 ou la revendication 1. Une méthode de préparation pour une unité de do- 6, dans lequel le porteur liquide comprend un aro- sage sous forme liquide d'un ou de plusieurs médi- matisant acceptable par le patient et, de manière caments consistant : facultative, un acide organique exhausteur de goût. 30 en une première série de récipients contenant 8. Un jeu selon n'importe laquelle des revendications différents porteurs liquides, allant de 5 à 7, dans lequel le réservoir de mélange en un ou plusieurs deuxièmes récipients her- est fourni avec un couvercle qui ferme le réservoir métiques contenant une unité de dosage solide de mélange permettant au contenu d'être secoué ou liquide du ou des médicament(s), 35 et mélangé par le réservoir hermétique. à verser une quantité de porteur liquide sélec- tionné dans un réservoir de mélange, à ouvrir le ou les seconds récipients herméti- ques, à verser l'unité de dosage du ou des médica- 40 ments depuis le ou les deuxièmes récipients dans le réservoir de mélange, et à permettre ou à faire en sorte que le porteur liquide et l'unité de dosage du médicament ou des médicaments se mélangent à l'intérieur du 45 réservoir.

2. Une méthode selon la revendication 1, dans laquel- le le porteur liquide comprend de l'eau, du glycérol et/ou du sorbitol, et, de manière facultative, un édul- 50 corant naturel ou synthétique et/ou un agent épais- sissant.

3. Une méthode selon la revendication 1 ou la reven- dication 2, dans laquelle le porteur liquide com- 55 prend un aromatisant acceptable par le patient et, de manière facultative, un acide organique exhaus- teur de goût.

10