(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`(10) International Publication Number
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`WO 2004/080382 A2
`(74) Agents: GILL, Sian et al.; Venner, Shipley LLP, 20 Little
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`Britain, London EC1A 7l)I-I (GB).
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`('81) Designated States (unless otherwise indicated, for every
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`TR), OAPI (BF, BJ. CF, CG. CI. CM. GA, GN, GQ, GW.
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`Ml., MR, NE, SN, '1‘D,’1‘G).
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`Published:
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`-* wi/haul inlemationul .i'eztrz:I1 repcirt and to be republislzed
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`upon receipt of that report
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`For 1wo—lelIer codes and other abbreviations, refer to the "Guid—
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`(mce Notes on Codes urzdAbbreviut[an.s " tippeztring at the begin-
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`ning of each regular issue of the PCT Gazette.
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`(19) World Intellectual Property
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`Organization
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`International Bureau
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`(43) International Publication Date
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`23 September 2004 (23.09.2004)
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`(51) International Patent Classificati0n7:
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`A61K
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`(21) International Application Number:
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`PCT/GB2004/001037
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`(22) International Filing Date:
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`11 March 2004 (11.03.2004)
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`(25) Filing Language:
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`(26) Publication Language:
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`English
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`English
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`1
`1 March 2003 (1 1.03.2003)
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`3 December 2003 (03.12.2003)
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`(30) Priority Data:
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`03055795
`03280237
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`Applicant (for all designated States except US): SIRUS
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`PHARIVIACEUTICALS LTD [GB/GB]; 19 Perm Fields,
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`Brixworth Industrial Estate, Brixworth, Northamptonshire
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`NN6 9UA (GB).
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`Inventors; and
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`Inventors/Applicants (for US only): ROSS, Calvin
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`[GB/GB]; Sirus Pharmaceuticals Ltd, 19 Ferro Fields,
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`Brixworth Industrial Estate, Brixworlh, Northamptonshirc
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`NN6 9UA (GB). BOOLES, Clive [GB/GB]; Sirus Phar-
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`maceuticals Ltd, 19 Ferro Fields, Brixworth Industrial
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`Estate, Brixworth, Northamptonshire NN6 9UA (GB).
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`CAIVIPBELL, Alistair [GB/GB]; Sirus Pliarinaceuticals
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`Ltd, 19 Ferro Fields, Brixworth Industrial Estate, Elix-
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`worth, Northamptonshire NN6 9UA (GB).
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`WO2004/080382A2||||1||||l||||HIlllllllllllllllllllllll
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`(54) Title: NOVEL COMPOSITIONS
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`(57) Abstract: This invention relates to fonnulations of fentanyl, especially pump spray formulations suitable for sublingual deliv-
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`ery.
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`Page 1 of 22
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`WO 2004/080382
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`PCT/GB2004/001037
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`Novel Compositions
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`This invention relates to formulations of fentanyl, especially pump spray
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`forinulations suitable for sublingual delivery.
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`Fentanyl is a narcotic alkaloid, which has been used for many years as an anaestlletic
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`and an analgesic, especially in the treatment of moderate to severe pain. \7Vhi1st
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`undoubtedly effective for pain relief, and especially in the treatment of pain which is
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`refractive to other treatments, there are a number of issues of clinical management
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`associated with the use of fentanyl in therapy.
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`Foremost amongst these issues is the potential for serious side effects with fentanyl.
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`It has a much higher potency than commonly known narcotics and therefore it is
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`necessary to ensure that it is being used within the established therapeutically
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`effective range and to monitor patients for evidence of self medication at greater
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`than the recommended amount. Overdosage with fentanyl can lead to a number of
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`undesirable and indeed life—threatening side effects, predominantly hypoventilation
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`and respiratory depression.
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`Due to the nature of the conditions being treated, it is much desired that the onset
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`of analgesia occurs as soon after dosage as is compatible with safety parameters.
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`Furthermore delay in onset of action may prompt the patient to take another dose
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`with consequent risk, as already explained above, of overdosage.
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`A number of routes of administration of a medicament can be associated with rapid
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`onset of action. For example, International Patent Application W090/07333 (Riker
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`Labs) described aerosol formulations of fentanyl, which are adapted for inhalation.
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`However Riker’s formulations suffer disadvantages such as their use of
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`hydrofluorocarbon propellants and delivery effected by metered dose inhalers. In
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`the case of the former the disadvantages include high velocity which results in
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`administration, the risk of inhalation and for the latter, careful co-ordination of
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`Page 2 of 22
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`PCT/GB2004/001037
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`breath and actuation by the patient. When metered dose inhalers are used, a
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`significant proportion of the delivered dose tends to impact the back of the throat
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`from where it is swallowed rather than finding its way into the bronchial passages.
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`Accordingly, the pharmacology of the medication may be unpredictable due to poor
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`bioavailability following oral administration or may be characterised by a bi~phasic
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`profile (fast initial onset as a result of the inhaled dose and a slower, late effect due
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`to oral absorption of fentanyl). Furthermore, manufacture of the bulk formulation
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`involves the preparation of large quantities of pressurised volatile propellant
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`containing a potent narcotic analgesic. Accordingly the precautions required to
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`ensure safe manufacture are onerous and expensive.
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`W095/31182 (Aradigm. Corp) describes solution formulations of fentanyl in aerosol
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`propellants intended for administration to patients by the pulmonary route.
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`W001 /97780 (Pharmasol Ltd) describes solution formulations of fentanyl free base
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`in propellants, typically I-IF.A134a, for sublingual aerosol administration.
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`W000/47203 (MQS Inc) describes formulations of fentanyl citrate for intra—ora1
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`administration employing oral absorption enhancers.
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`These prior art formulations of fentanyl employ propellants and also suffer from
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`the aforementioned disadvantages.
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`Certain aqueous formulations of fentanyl for intranasal administration employing
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`water and phosphate buffer have been described, (Paech, M.]., Lim, C.B., Banks,
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`S.L., Rucklidge, M. W. M. (Sc Doherty, D.A. (2003) Anaesthesia 58 (8), 740-744 and
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`Lim et al (2003) J Pharm Practice Research 33, 59-63) but such formulations can
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`suffer problems of nasal irritation associated with medium to long term usage via
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`this route which is undesirable.
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`\Weinberg et al (1988) Clin Pharmacol Therap 44
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`335-342 discloses formulations of fentanyl employing water and phosphate buffer
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`for sublingual administration however these formulations were not advocated for
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`1.156 as Z. SPI2.y.
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`Page 3 of 22
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`wo 2004/080382
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`PCT/GB2004/001037
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`It is well known that the application of carefully chosen medicaments to the
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`sublingual mucosa offers a route of administration which is capable of resulting in
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`very rapid transmission of medicament to the bloodstream with consequent fast
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`onset of effect. A number of ways of administering ComposiLi011s sublingually are
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`known. For example, tablets or liquids may be held under the tongue prior to
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`-swallowing. Another method is spray delivery. Of these various types of sublingual
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`adminis tration, spray delivery is preferred as it does not involve holding the
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`composition under the tongue for an extended period of time as, for example, witl1
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`a lozenge and it reduces the amount of material which is swallowed (and may enter
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`the blood stream in a delayed manner via the gastrointestinal tract). Pharmaceutical
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`compositions, for example a fentanyl lozenge cause increased salivation, which
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`facilitates the unwanted swallowing of drug substance. Spray delivery, having low
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`volume and ability to target the sublingual mucosa, largely mitigates this. No
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`propellant free spray formulations of fentanyl which are adapted for sublingual
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`administration have yet been described.
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`It is an aim of the present invention to provide a formulation, which avoids or
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`mitigates some or all of the above-mentioned disadvantages.
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`Thus according to a first aspect of the invention a pharmaceutical composition is
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`provided, the composition being a partially pressurised liquid spray formulation,
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`which comprises:
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`fentanyl or a pharmaceutically acceptable salt thereof;
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`water as carrier; and
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`a polar organic solvent in sufficient amount to enhance the solubility of the
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`fentanyl or pharmaceutically acceptable salt thereof in the water.
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`The formulations of the invention are preferably administered sublingually as a
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`spray. The formulations are well tolerated when administered to the sensitive
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`sublingual mucosa and the sublingual spray administration will result in rapid onset
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`of the therapeutic effect of the fentanyl.
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`Page 4 of 22
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`WO 2004/080382
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`PCT/GB2004/001037
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`The formulations of the present invention are also preferably free of any propellant.
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`Amonorst the advantages of these formulations is the fact that by being water based
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`they avoid the issues associated with using pressurised hydrofluorocarbon
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`propellants as mentioned above. The formulations are partially pressurised and are
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`free of propellants such as volatile chlorofluorocarbons (e.g. propellant 12), volatile
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`hydrofluoroalkanes (e.g. 1_,l,l,2-tetrafluoroethane and 1,1,1,2,3,3,3—l1eptafluoro-n-
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`propane) and volatile alkanes (e.g. propane, butane) and other substances which
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`have significant vapour pressure at ambient temperature and pressure.
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`In one embodiment of the present invention, the formulation is a solution, rather
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`than a suspension. Wliilst it is possible to spray a suspension, the fact that most
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`suspensions settle means that the amount of active agent included in the dispensed
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`dose will be variable and this can be highly undesirable. Although the effect of the
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`settling of the suspension can be reduced to an extent by shaking the composition
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`prior to spraying, some suspensions can settle very rapidly, so that there is still
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`potential for variation of active agent content between doses.
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`Furthermore the formulations of the present invention are characterised by good
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`long—term physical and chemical stability.
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`Fentanyl may be employed in the form of a physiologically acceptable salt, which is
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`soluble in water together with a polar organic solvent. Examples of suitable salts
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`include hydrochloride, chloride, sulphate, tartrate and citrate. Preferably fentanyl is
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`employed as the free base.
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`Preferably the fentanyl or physiologically acceptable salt thereof will be employed in
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`the formulation at a concentration of 0.111-lg/ml to 10mg/ml, preferably 0.5mg/ml
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`to 4.4mg/ ml (where weight is expressed as weight of fentanyl free base).
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`Page 5 of 22
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`

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`WO 2004/080382
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`PCT/GB2004/001037
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`Examples of polar organic solvents that may be used to enhance the solubility of
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`fentanyl, or the physiologically acceptable salt thereof in the water, include: lower
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`alcohols (e.g. CH alcohols) such as ethanol; lower polyols (e.g. CM polyols) such as
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`glycerol and propylene glycol; and polyethylene glycols such as PEGZOO and
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`PEG400.
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`Mixtures of the above substances may be used. The preferred polar organic solvent
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`is ethanol.
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`In another embodiment of the present invention, the formulation does not include
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`ethanol. Indeed, the formulation may be substantially free of any alcohol, or
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`completely free of alcohol.
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`Wliere the composition is free of alcohol, the carrier used is preferably a polyol.
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`The preferred polyols include propylene glycol and glycerol.
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`Generally speaking it will be desired to employ the least amount of polar organic
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`solvent necessary (or a modest excess over that necessary) to adequately solubilise
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`the fentanyl, or physiologically acceptable salt thereof, and such that the fentanyl
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`remains in solution under the conditions of likely usage or exposure.
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`The concentration of polar organic solvent is in the range preferably of between 6
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`and 50%, more preferably 20-45% especially 35-42%.
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`Preferably the water meets the USP (US Pharmacopoeia), EP (European
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`Pharmacopoeia) "Purified Water" standards.
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`It has also been found that the properties of the claimed formulations may be
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`improved by including therein a number of additional formulations components.
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`Thus, in one embodiment of the invention, the water in the formulation is present
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`in the form of an aqueous buffer. The buffer is preferably adapted to stabilise the
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`Page 6 of 22
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`

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`VVO 2004/080382
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`PCT/GB2004/001037
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`pH of the formulation at pH 7.4 to 8.5, preferably at pH 8.0 to 8.5, more preferably
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`at 8.1 to 8.3, or around 8.2. At higher pH values we have found evidence that the
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`bioavailability of the formulation is improved relative to lower pH values (e.g.
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`nearer pH 6). Example buffer systems include sodium acetate/acetic acid,
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`ammonium acetate/disodium edetate, boric acid/ sodium hydroxide,
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`orthophosphoric acid/ sodium hydroxide, sodium hydrogen carbonate/ sodium
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`carbonate, disodium hydrogen orrhophosphate/ citric acid (taken from the British
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`Pharmacopoeia). The preference is use of a citrate buffer, e.g. a buffer comprising
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`citric acid, sodium citrate and sodium hydroxide.
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`The concentration of the aqueous component (water or more preferably aqueous
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`buffer) of the formulation of the present invention is preferably 50-94%, more
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`preferably 55-80%, and especially 58-65%.
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`It may be desirable to include one or more of the following components in the
`formulation.
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`* 1) Sweeteners, flavouring or taste—1nasking agents (to improve patient acceptability),
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`for example vanilla, pineapple extract, menthol, saccharin and sodium saccharin.
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`2) Moisturising agents (to improve patient comfort and overcome the drying
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`tendency of ethanol and other polar organic solvents), for example pineapple
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`extract, lanolin, polypropylene glycol, and polyethylene glycol.
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`3) Penetration enhancers (to improve therapeutic effect), for example menthol.
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`4-) Mucoadherents (in order to increase residency time on the mucosa), for example
`carboxyvinyl polymers, chitosans, polyacrylic acid, gelatin and polyvinyl pyrrolidone.
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`5) Preservanves (to improve long term resistance to microbial contamination), for
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`example ethanol, sodium metabisulphite, benzalkonium chloride and Nipas.
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`6) Antioxidants, for example Alkyl Gallates, Butylated Hydroxyanisole, Butylated
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`Hydroxytoluene, Nordihydroguaiaretic acid, Tocopherols, Ascorbic acid and
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`Sodium metabisulphite.
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`7) Anionic surfactants, for example Magnesium Stearate, Sodium Cetostearyl
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`sulphate, Sodium Lauryl sulphate, Sulphated caster oil, Sodium oleate, Sodium
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`stearyl Fumarate and Sodium Tetradecyl Sulphate.
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`Page 7 of 22
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`

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`WO 2004/080382
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`PCT/GB2004/001037
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`8) Nonionic surfactants, for example Glyceryl Monostearate, Macrogol Cetostearyl
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`Ethers, Poloxamers, Polyoxyl Stearates, Polysorbates, Sorbitan Esters, Sucrose
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`Esters, Tyloxapol, Propylene Glycol Monostearate, Quillaia, Polyoxyl Caster Oils,
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`Nonoxinols, Lecithins and derivatives, Oleic acid and derivatives, Oleyl alcohol and
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`derivatives.
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`9) Foaming agents, for example Alginic Acid and salts, Propylene Glycol Alginate,
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`Sodium Lauryl sulphate, Sodium Cetostearyl sulphate, earl:-omers,
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`Hydroxyethylcellulose
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`Some of the components proposed above may already be included in the
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`composition of the present invention for other purposes. Suitable moisturising
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`agents include, for example, the polar organic solvents such as glycols, especially
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`propylene glycol, and the liquid polyethylene glycols, glycerol, methylcellulose,
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`hypromellose, hydroxypropylcellulose, and many other substituted celluloses.
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`A versatile component, which improves the acceptability and other properties of the
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`formulation, is menthol. Menthol, as well as flavouring the formulation, has
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`moisturising effect. It may also have effect as a penetration enhancer. Preferably
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`menthol is employed in a concentration range of 0.25% to 7.5%.
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`One particular advantage of menthol is that it is compatible with fentanyl in a spray
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`formulation unlike peppermint oil (of which menthol is one component), which
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`causes fentanyl to degrade.
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`In an embodiment of the invention, the formulation contains a sweetener. The
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`preferred sweetener is saccharin or a physiologically acceptable salt thereof such as
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`saccharin sodium. Preferably the concentration of sodium saccharin or
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`physiologically acceptable salt thereof is around 0.1-0.5”/o, e.g. around 0.28%.
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`Preferably the formulation contains saccharin. Surprisingly, We have found that the
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`longer—term stability of formulations containing saccharin is better than the stability
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`of those containing saccharin sodium.
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`Page 8 of 22
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`

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`WO 2004/080382
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`PCT/GB2004/001037
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`It has been discovered that it is not generally necessary to include a preservative in
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`the formulation when ethanol is present due to its preservative qualities.
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`Formulations of the invention are useful in analgesia and in the treatment of pain.
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`In a further aspect of the invention, formulations according to the first aspect of
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`the invention are provided for use in the treatment of moderate to severe pain. In a
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`yet further aspect of the invention, the use of the formulations according to the
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`invention in the manufacture of a medicament for analgesia or for the treatment of
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`pain is provided. In one embodiment, a therapeutically effective amount of a
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`formulation for the treatment of pain according to the invention is used.
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`Formulations according to the invention are preferably packaged as a bulk solution
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`containing multiple doses in a pump spray system comprising a sealed container
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`fitted with a metering pump. Thus as an aspect of the invention we provide a sealed
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`container containing a plurality of doses of a formulation according to the
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`invention. The container will preferably contain between 20 to 200 doses. Example
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`containers are those made out of plastics, glass and metal (e.g. aluminium) however
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`glass containers are preferred. Glass containers have the advantage that the
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`contents of the container can be seen (i.e. it is possible to determine visually when
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`the contents are about to run out). Furthermore glass containers are less
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`susceptible to tampering, which is an important consideration for narcotic
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`substances.
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`In another embodiment, single or multiple use devices comprising a single or
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`multiple dose of the formulation of the invention is envisaged.
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`Preferably the glass container will be coated on the exterior with a suitable moulded
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`film of plastic to protect against shattering. For example the film may be of
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`polypropylene. The material may be coloured and contain a UV absorber.
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`Optionally, the interior of the containers can be coated to enhance stability of the
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`Page 9 of 22
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`

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`WO 2004/080382
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`PCT/GB2004/001037
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`product. Coatings include polymers and lacquers but also silicone dioxide can be
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`used to line the inside of the container with an unreactive coating.
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`3 Y
`.~_-»
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`Another as ect of the invention is a metered dose dis ensin s stem com risino a
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`sealed contailler containing a formulation of the invention fitted with a metering
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`pump, an actuator and a channelling device. The metered dose dispensing system is
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`preferably adapted for sublingual administration.
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`Suitable metering pumps include those adapted for dispensation with the container
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`in the upright or inverted orientation. Preferably the metering chamber is adapted
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`for dispensation with the container in the upright orientation since this facilitates
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`administration under the tongue. Accordingly the metering chamber will be in
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`communication with the bulk formulation by means of a dip—tube.
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`Example metering pumps are those manufactured by Valois and illustrated in
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`~ International Patent Application No. W001/66089.
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`The metering pump is preferably a non—venting type with a dip tube. Such non-
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`venting metering pumps may have, for example, a 100ul metering chamber capacity.
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`The materials of construction include polypropylene and polyethylene. Suitable
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`sealing materials, e.g. thermoplastic crimp gaskets suitable for the purpose will be
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`In addition, a suitable aluminium ferrule purposely designed for
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`crimping on to glass containers may suitably be employed. Suitable grade stainless
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`employed.
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`steel springs will preferably be adopted.
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`Preferably the actuator will be designed to deliver a sublingually effective dose. The
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`package may be further enhanced by the fitting of a lock—out system to promote
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`compliance by patients.
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`Typically a patient is treated by administration sublingually of 1 to 4 actuations, e.g.
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`1 or 2 actuations from the spray pump. Another advantage of sublingual spray
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`delivery is the ability to easily titrate patients by 1 or 2 doses as required by a single
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`Page 10 of 22
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`WO 2004/080382
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`PCT/CB2004/001037
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`actuatioil. This is not the case with other forms of drug delivery (patches, lozenges,
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`tablets, suppositories).
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`One of the possible methods for preparing certain formulations and filled
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`containers according to the invention is shown in the figures, for illustrative
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`purposes.
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`Figure 1 is a flow—chart showing the first stage of the method of preparing a
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`formulation Coinprising 400p.g fentanyl.
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`Figure 2 is a flow-chart showing the second stage of the method.
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`Other formulations of the invention may be prepared by analogous methods, or
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`methods known to a skilled person.
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`Weight percentage values given herein are expressed as W/W.
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`The formulations and products of the invention have better physical and chemical '
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`stability, are more environmentally friendly, are more conveniently or safely
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`administered to patients, are more conveniently or safely manufactured, are more
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`economical to manufacture, or have other advantages relative to prior art
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`formulations and products.
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`The invention will now be illustrated by reference to the following examples:
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`Gifiitl
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`Citrate buffer when employed contained:
`Citric acid
`2.0 %
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`Sodium citrate
`1.0 °/o
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`Sodium Hydroxide
`water: to 100%
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`1.0%
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`pH 8.2 (adjusted with NaOH).
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`Page 11 of 22
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`WO 2004/080382
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`pCT/GB2004/00-[037
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`Example 1
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`Formulation (per container):
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`Fentanyl base
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`Saccliarin
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`0.0280g
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`0.01 77g
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`Absolute ethanol
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`2.8336g
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`Menthol
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`Citrate buffer
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`0.053lg
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`4.1 51 6g
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`The target dose is 400 ug per actuation.
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`Example 2
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`Formulation (per container):
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`Fentanyl base
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`0.0280g
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`Sacchatin sodium
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`0.0198g (equivalent to 0.0177g sacclmrin)
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`Absolute ethanol
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`Z.8336g
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`Menthol
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`Citrate buffer
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`0.0531g
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`4.1516g
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`The target dose is 400ug per actuation of l0O[..Ll.
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`Example 3
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`Formulation (per container):
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`Fentanyl base
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`Saccharin
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`0.0280g
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`0.0177g
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`Absolute ethanol
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`2.8336g
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`Citrate buffet
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`_
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`4.2047g
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`The target dose is 400tLg pet actuation of100pLl.
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`Example 4
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`Formulation (pet containex)‘.
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`Fentanyl base.
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`Saccharin sodium
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`0.02805;
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`0.0198g (equivalent to 0.017"/g saccharin)
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`Absolute ethanol
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`Z.8336g
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`Page 12 of 22
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`WO 2004/080382
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`PCT/GB2004/001037
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`Water
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`4-.2026g
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`The target dose is 400ug per actuation of 100ul.
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`Exarnple 5
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`Formulation (per container):
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`Fentanyl base
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`0.0l40g
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`Saccharin sodium
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`0.0198g (equivalent to 0.0177g saccharin)
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`Absolute ethanol
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`2.8336g
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`Menthol
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`Citrate buffer
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`0.0531g
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`4.1 656g
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`The target dose is 2O0[.Lg per actuation of 100ul.
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`Packaging of formulations
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`The example formulations may be packaged into a suitable coated glass container
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`and fitted with a suitable n0n—venting metered dose pump. An actuator suitable for
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`sublingual delivery may be fitted.
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`Test data
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`The formulation of Example 1 was subjected to the following tests.
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`Units were placed on stability storage at 5°C, 25°C /50% RH, 30°C/65% RH and
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`40°C/75°/o RH. For each test 3 replicates were assessed.
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`21) Appearance (including clarity).
`Observation be made and the results recorded.
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`b) Mean \X/eight of Expelled Dose (Shot weight)
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`Each unit will be weighed before and after test sprays. From these
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`measurements, mean shot weight will be calculated by difference calculation
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`pH
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`pH is measured on a single unit at each tjrne point at each condition. The
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`unit is opened under controlled conditions and the pH measured by use of a
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`pH meter.
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`Page 13 of 22
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`VVO 2004/080382
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`PCT/GB2004/001037
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`cl) Degradation Products
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`A sample of the formulation from each unit was taken and examined for
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`degradation products by HPLC assay. The result was recorded as ‘none’,
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`<O.l°/o (no identification) or percentage ofidentified degradant.
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`The results were as follows:
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`Test
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`Condition A Condition 13
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`Condition C
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`Condition D
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`(Specification)
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`Appearance
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`(clear,
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`no particles,
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`colourless)
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`Shotweight
`90 — 110m )
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`pH (7.7 — 8.7)
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`Degradation
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`roduct A
`Degradation
`roduct B
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