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 codeine 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.