EXHIBIT 1005 
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1005
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01797
`
`

`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2006/0062812 A1
`Ross et al.
`(43) Pub. Date:
`Mar. 23, 2006
`
`US 20060062812A1
`
`(54) NOVEL COMPOSITIONS
`
`(30)
`
`Foreign Application Priority Data
`
`(76) Inventors: Calvin Ross, Essex (GB); Clive Booles,
`Essex (GB); Alistair Campbell, Essex
`(GB); Paul William Woodcock, Essex
`(GB); Scott Andrew Davis, Essex (GB)
`
`Mar. 11, 2003 (GB) ....................................... .. 0305579.5
`Dec. 3, 2003 (GB)
`.. 0328023.7
`Sep. 10, 2004 (GB) ....................................... .. 0420173.7
`
`Publication Classi?cation
`
`Correspondence Address:
`SALIWANCHIK LLOYD & SALIWANCHIK
`A PROFESSIONAL ASSOCIATION
`PO BOX 142950
`GAINESVILLE, FL 32614-2950 (US)
`
`(51) Int. Cl.
`(2006.01)
`A61K 31/445
`(2006.01)
`A61K 31/045
`(2006.01)
`A61K 9/00
`(52) US. Cl. ......................... .. 424/400; 514/317; 514/729
`
`(21) Appl. No.:
`
`11/224,383
`
`(57)
`
`ABSTRACT
`
`(22) Filed;
`
`Sep_ 12, 2005
`
`Related US, Application Data
`
`(63) Continuation-in-part of application No. PCT/GB04/
`01037, ?led on Mar. 11, 2004.
`
`Compositions and method are provided, for the treatment of
`pain, e.g. acute breakthrough pain, by means of a systemic,
`non-invasive mode of administration. Speci?cally, the
`invention relates to a sublingual presentation of an opioid
`analgesic, such as fentanyl, or its salts, in amounts that are
`suf?cient to treat the pain.
`
`

`
`Patent Application Publication Mar. 23, 2006 Sheet 1 of 2
`
`US 2006/0062812 A1
`
`Into mixing vessel, add
`Sodium saccharin, ethanol,
`and menthol.
`
`Into separate mixing vessel, add
`citric acid, sodium citrate, and
`sodium hydroxide. Add de-ionised
`water.
`
`Record \Vcights
`
`ll
`
`Mix until complete
`dissolution.
`
`3
`
`Check pH
`
`ll
`
`Adjust pH to pH 8.2 with the
`addition of aqueous sodium
`hydroxide (1M) or citric acid
`
`3
`
`Record \Vcights
`
`3
`
`Mix until complete
`dissolution.
`
`Record \Veight
`
`Mix until complete
`dissolution.
`
`3
`
`Add citrate buffer to
`mixing vessel, continue
`mixing
`
`Fig. 1
`
`

`
`Patent Application Publication Mar. 23, 2006 Sheet 2 0f 2
`
`US 2006/0062812 A1
`
`Check pH
`
`<3
`
`Adjust pH to pll 8.2
`
`ii]
`
`Add remaining water
`
`Filter through a 0.2um
`membrane ?lter
`
`Purgard
`clean
`Air
`bottles and place the
`pumps on the bottles.
`
`Number each unit
`
`Record weights of the
`pumps and bottles
`
`Fig. 2
`
`Pipette 7.084g of the
`formulation into each
`
`Crimp on the pumps
`
`Record weights of the
`pumps and bottles
`
`

`
`US 2006/0062812 A1
`
`Mar. 23, 2006
`
`NOVEL COMPOSITIONS
`
`CROSS-REFERENCE TO EARLIER
`APPLICATION
`
`[0001] This application is a continuation-in-part applica
`tion of International Application PCT/GB04/01037, ?led
`Mar. 11, 2004; Which claims priority to GB 0305579.5, ?led
`Mar. 11, 2003 and GB 0328023.7, ?led Dec. 3, 2003. The
`subject application further claims priority to GB 0420173.7,
`?led Sep. 10, 2004, all of Which are hereby incorporated by
`reference herein in their entirety.
`
`FIELD OF THE INVENTION
`
`[0002] This invention relates to formulations of opioid
`analgesics and in particular fentanyl, especially pump spray
`formulations suitable for sublingual delivery.
`
`BACKGROUND OF THE INVENTION
`
`[0003] Opioid analgesics are useful in the treatment of
`pain, such as breakthrough pain. When treating pain, it is
`particularly attractive for the patient to be able to self
`medicate, enabling speci?c pain episodes to be treated, as
`opposed to ongoing treatment When there may be no pain to
`treat. It is highly desirable for the onset of analgesia to occur
`as soon after administration of the opioid analgesic as
`possible, especially Where the patient is self-medicating.
`This not only provides pain relief as soon as possible but it
`can also reduce the risk of overdosage. A delay in the onset
`of the therapeutic effect may prompt the patient to take a
`further dose, With the consequent risk of the serious side
`effects associated With overdosage.
`
`[0004] In the case of breakthrough pain, the onset of pain
`is relatively quick, usually betWeen just a feW seconds and
`10 to 15 minutes, the median being approximately 3 min
`utes. The duration of breakthrough pain episodes tends to be
`anyWhere betWeen 5 minutes and 2 hours, the median being
`betWeen 20 and 60 minutes.
`
`[0005] Thus, for the most effective treatment of pain, and
`in particular, breakthrough pain, the analgesic effect should
`have a rapid onset. What is more, the analgesic effect should
`last for the duration of the pain episode. That said, admin
`istration of a second or further dose may be acceptable,
`provided that these additional doses have a rapid onset of
`effect, so that the pain is not left untreated for too long.
`
`[0006] Fentanyl is a narcotic alkaloid, Which has been
`used for many years as an anaesthetic and an analgesic,
`especially in the treatment of moderate to severe pain.
`Whilst undoubtedly effective for pain relief, and especially
`in the treatment of pain Which is refractive to other treat
`ments, there are a number of issues of clinical management
`associated With the use of fentanyl in therapy.
`
`[0007] Foremost amongst these issues is the potential for
`serious side-effects With fentanyl. It has a much higher
`potency than commonly knoWn narcotics and therefore it is
`necessary to ensure that it is being used Within the estab
`lished therapeutically effective range and to monitor patients
`for evidence of self-medication at greater than the recom
`mended amount. Overdosage With fentanyl can lead to a
`number of undesirable and indeed life-threatening side
`effects, predominantly hypoventilation and respiratory
`depression.
`
`[0008] A number of routes of administration of a medica
`ment can be associated With rapid onset of action. For
`eXample, WO90/07333 describes aerosol formulations of
`fentanyl, Which are adapted for inhalation. HoWever, these
`formulations suffer disadvantages such as their use of
`hydro?uorocarbon propellants and delivery effected by
`metered dose inhalers. In the case of the former, the disad
`vantages include high velocity Which results in “bounce
`back” on administration to the front of the mouth, cold
`sensations on administration and the risk of inhalation; for
`the latter, careful co-ordination of breath and actuation by
`the patient. When metered dose inhalers are used, a signi?
`cant proportion of the delivered dose tends to impact the
`back of the throat from Where it is sWalloWed rather than
`?nding its Way into the bronchial passages. Accordingly, the
`pharmacology of the medication may be unpredictable due
`to poor bioavailability folloWing oral administration or may
`be characterised by a bi-phasic pro?le (fast initial onset as a
`result of the inhaled dose and a sloWer, late effect due to oral
`absorption of fentanyl). Furthermore, manufacture of the
`bulk formulation involves the preparation of large quantities
`of pressurised volatile propellant containing a potent nar
`cotic analgesic. Accordingly, the precautions required to
`ensure safe manufacture are onerous and expensive.
`
`[0009] WO95/31182 describes solution formulations of
`fentanyl in aerosol propellants intended for administration to
`patients by the pulmonary route.
`[0010] WO01/97780 describes solution formulations of
`fentanyl free base in propellants, typically HFA134a, for
`sublingual aerosol administration.
`[0011] WO00/47203 describes formulations of fentanyl
`citrate for intra-oral administration employing oral absorp
`tion enhancers.
`
`[0012] Certain aqueous formulations of fentanyl for intra
`nasal administration employing Water and phosphate buffer
`have been described; see Paech, M. J., Lim, C. B., Banks, S.
`L., Rucklidge, M. W. M. & Doherty, D. A. (2003) Anaes
`thesia 58 (8), 740-744, and Lim et al (2003) J Pharm Practice
`Research 33, 59-63. Such formulations can suffer problems
`of nasal irritation associated With medium to long term
`usage via this route Which is undesirable. Weinberg et al
`(1988) Clin Pharmacol Therap 44 335-342, discloses for
`mulations of fentanyl employing Water and phosphate buffer
`for sublingual administration, but these formulations are not
`advocated for use as a spray.
`
`[0013] It is Well knoWn that the application of carefully
`chosen medicaments to the sublingual mucosa offers a route
`of administration Which is capable of resulting in very rapid
`transmission of medicament to the bloodstream With con
`sequent fast onset of effect. A number of Ways of adminis
`tering compositions sublingually are knoWn. For eXample,
`tablets or liquids may be held under the tongue prior to
`sWalloWing. Another method is spray delivery. Of these
`various types of sublingual administration, spray delivery is
`preferred as it does not involve holding the composition
`under the tongue for an extended period of time as, for
`eXample, With a loZenge, and it reduces the amount of
`material Which is sWalloWed (and may enter the blood
`stream in a delayed manner via the gastrointestinal tract).
`Pharmaceutical compositions, for eXample a fentanyl lOZ
`enge, cause increased salivation, Which facilitates the
`unWanted sWalloWing of drug substance.
`
`

`
`US 2006/0062812 A1
`
`Mar. 23, 2006
`
`[0014] In the past, spray devices, including pump sprays,
`have been proposed for sublingual administration. However,
`their effect has not been properly optimised. In order to
`reduce the amount of the dispensed composition Which fails
`to contact the sublingual mucosa, the compositions tend to
`be dispensed in a focussed manner, so that the sublingual
`spray devices have a tendency to administer the composi
`tions to a relatively small part of the sublingual mucosa. This
`means that the composition is effectively concentrated in the
`relatively small area, Which sloWs doWn absorption and also
`means that some of the composition may not be absorbed,
`but rather may be Washed aWay by saliva and sWalloWed.
`This is a particular problem in the case of lipophilic opioid
`analgesics such as fentanyl. It has been shoWn that the
`lipophilic drugs need to be ?nely spread over the sublingual
`mucosa in order for them to be properly absorbed. When
`they are concentrated at a small area of the sublingual
`mucosa, absorption is reduced.
`
`[0015] It is an aim of the present invention to provide a
`formulation, Which avoids or mitigates some or all of the
`above-mentioned disadvantages.
`[0016] Another aim of the present invention is to provide
`a presentation of an opioid analgesic for treating pain, and
`in particular breakthrough pain, Wherein the opioid analge
`sic is administered via the sublingual route and the presen
`tation preferably eXhibits improved performance compared
`to knoWn opioid analgesic compositions, including those
`Which may be administered sublingually and intravenously.
`In particular, it is an aim of the invention to provide fast
`onset of therapeutic effect, together With an advantageous
`pharmacokinetic response and drug plasma pro?le Which
`Will avoid the disadvantages associated With the fast onset
`observed When opioid analgesics are administered intrave
`nously.
`
`SUMMARY OF THE INVENTION
`
`[0017] The present invention is based at least in part on the
`understanding that spray delivery, having loW volume and
`ability to target the sublingual mucosa, largely mitigates
`problems associated With other formulations, and can avoid
`the use of propellants.
`
`[0018] According to the invention, a pharmaceutical com
`position, preferably a partially pressurised liquid spray for
`mulation, comprises:
`[0019] (a) fentanyl or a pharmaceutically acceptable
`salt thereof;
`
`[0020] (b) Water as carrier; and
`[0021] (c) a polar organic solvent in suf?cient amount to
`enhance the solubility of the fentanyl or pharmaceuti
`cally acceptable salt thereof in the Water.
`
`[0022] The formulations of the invention may be used in
`analgesia and for the treatment of pain. They are preferably
`administered sublingually as a spray. The formulations are
`Well tolerated When administered to the sensitive sublingual
`mucosa and the sublingual spray administration Will result in
`rapid onset of the therapeutic effect of the fentanyl.
`[0023] The present invention also provides a pharmaceu
`tical composition for use in the treatment of acute break
`through pain by means of a systemic, non-invasive mode of
`administration. Speci?cally, the invention relates to a sub
`
`lingual presentation of an opioid analgesic, such as fentanyl,
`or its salts, in amounts that are suf?cient to treat the acute
`pain. Advantageously, the presentation of the opioid anal
`gesic provides a rapid onset of action, as Well as a pharma
`cokinetic response and drug plasma pro?le suitable to
`achieve optimal pain relief over the duration of symptoms
`With minimiZed side-effects.
`
`[0024] The invention also relates to a speci?c drug for
`mulation, dispensed using a metered pump action spray
`Which is speci?cally designed for delivery via the sublingual
`route. This affords signi?cant improvements and advantages
`in terms of plasma bioavailability and pharmacokinetic
`pro?le compared to similar, but non-optimised, propellant
`driven aerosol formulations. These bene?ts relate in particu
`lar to:
`
`i) a faster rate of onset of effect;
`
`[0025]
`[0026]
`[0027] iii) a faster TmaX.
`
`ii) a faster rate of offset of effect; and
`
`[0028] According to a further aspect of the invention, an
`opioid analgesic pharmaceutical composition provides an
`opioid analgesic plasma concentration of 250 pg/ml Within
`a period of no more than 2 hours, folloWing sublingual
`administration using a pump spray dispensing device. The
`opioid analgesic is preferably fentanyl.
`
`[0029] Amongst the advantages of these formulations is
`the fact that, by being Water-based, they avoid the issues
`associated With using pressurised hydro?uorocarbon propel
`lants as mentioned above. The formulations may be partially
`pressurised and are free of propellants such as volatile
`chloro?uorocarbons (e.g. propellant 12), volatile hydro?uo
`roalkanes (e.g. 1,1,1,2-tetra?uoroethane or 1,1,1,2,3,3,3
`hepta?uoro-n-propane) and volatile alkanes (e.g. propane or
`butane) and other substances Which have signi?cant vapour
`pressure at ambient temperature and pressure.
`
`[0030] Furthermore the formulations of the present inven
`tion are characterised by good long-term physical and
`chemical stability.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0031] FIG. 1 is a ?oW-chart shoWing the ?rst stage of a
`method of preparing a formulation comprising 400 pg
`fentanyl.
`
`[0032] FIG. 2 is a ?oW-chart shoWing the second stage of
`the method.
`
`DESCRIPTION OF THE INVENTION
`
`[0033] The present invention provides a sublingual pre
`sentation of an opioid analgesic, such as fentanyl, Which
`enables pain relief to be achieved very rapidly folloWing
`administration of the drug.
`
`[0034] In one embodiment of the present invention, the
`formulation is a solution, rather than a suspension. Whilst it
`is possible to spray a suspension, the fact that most suspen
`sions settle means that the amount of active agent included
`in the dispensed dose Will be variable and this can be highly
`undesirable. Although the effect of the settling of the sus
`pension can be reduced to an eXtent by shaking the compo
`
`

`
`US 2006/0062812 A1
`
`Mar. 23, 2006
`
`sition prior to spraying, some suspensions can settle very
`rapidly, so that there is still potential for variation of active
`agent content betWeen doses.
`
`[0035] Fentanyl may be employed in the form of a physi
`ologically acceptable salt, Which is soluble in Water together
`With a polar organic solvent. Examples of suitable salts
`include hydrochloride, chloride, sulphate, tartrate and cit
`rate. Preferably fentanyl is employed as the free base. It Will
`nevertheless be understood that the buffer may provide some
`salt.
`[0036] Preferably the fentanyl or physiologically accept
`able salt thereof Will be employed in the formulation at a
`concentration of 0.1 mg/ml to 10 mg/ml, preferably 0.5
`mg/ml to 4.4 mg/ml (Where Weight is expressed as Weight of
`fentanyl free base). More preferably, fentanyl or physiologi
`cally acceptable salt thereof Will be employed in the com
`position at a concentration of 0.1 mg/ml to 10 mg/ml,
`preferably 0.5 mg/ml to 4.4 mg/ml (Where Weight is
`expressed as Weight of fentanyl free base).
`[0037] Examples of polar organic solvents that may be
`used to enhance the solubility of fentanyl, or the physiologi
`cally acceptable salt thereof in the Water, include: loWer
`alcohols (e.g. C2_4 alcohols) such as ethanol; loWer polyols
`(e.g. C2_4 polyols) such as glycerol and propylene glycol;
`and polyethylene glycols such as PEG200 and PEG400.
`
`[0038] Mixtures of the above substances may be used. The
`preferred polar organic solvent is ethanol.
`[0039] In another embodiment of the present invention,
`the formulation does not include ethanol. Indeed, the for
`mulation may be substantially free of any alcohol, or com
`pletely free of alcohol.
`[0040] Where the composition is free of alcohol, the
`carrier used is preferably a polyol. The preferred polyols
`include propylene glycol and glycerol.
`[0041] Generally it Will be desired to employ the least
`amount of polar organic solvent necessary (or a modest
`excess over that necessary) to adequately solubilise the
`fentanyl, or physiologically acceptable salt thereof, and such
`that the fentanyl remains in solution under the conditions of
`likely usage or exposure.
`[0042] The concentration of polar organic solvent is in the
`range preferably of betWeen 6 and 50%, more preferably
`20-45% especially 35-42%.
`[0043] Preferably the Water meets the USP (US Pharma
`copoeia) or EP (European Pharmacopoeia) “Puri?ed Water”
`standards.
`
`[0044] It has also been found that the properties of the
`claimed formulations may be improved by including therein
`one or more additional components.
`
`[0045] Thus, in one embodiment of the invention, the
`Water in the formulation is present in the form of an aqueous
`buffer. The buffer is preferably adapted to stabilise the pH of
`the formulation at pH 7.4 to 8.5, preferably at pH 8.0 to 8.5,
`more preferably at 8.1 to 8.3, or around 8.2. At higher pH
`values We have found evidence that the bioavailability of the
`formulation is improved relative to loWer pH values (eg
`nearer pH 6). Example buffer systems include sodium
`acetate/acetic acid, ammonium acetate/disodium edetate,
`boric acid/sodium hydroxide, orthophosphoric acid/sodium
`
`hydroxide, sodium hydrogen carbonate/sodium carbonate,
`disodium hydrogen orthophosphate/citric acid (taken from
`the British Pharmacopoeia). The preference is use of a
`citrate buffer, eg a buffer comprising citric acid, sodium
`citrate and sodium hydroxide.
`
`[0046] The concentration of the aqueous component
`(Water or more preferably aqueous buffer) of the formulation
`of the present invention is preferably 50-94%, more prefer
`ably 55-80%, and especially 58-65%.
`
`[0047] It may be desirable to include one or more of the
`folloWing components in the formulation.
`[0048] 1) SWeeteners, ?avouring or taste-masking agents
`(to improve patient acceptability), for example vanilla, pine
`apple extract, menthol, saccharin and sodium saccharin.
`[0049] 2) Moisturising agents (to improve patient comfort
`and overcome the drying tendency of ethanol and other polar
`organic solvents), for example pineapple extract, lanolin,
`polypropylene glycol, and polyethylene glycol.
`[0050] 3) Penetration enhancers (to improve therapeutic
`effect), for example menthol.
`[0051] 4) Mucoadherents (in order to increase residency
`time on the mucosa), for example carboxyvinyl polymers,
`chitosans, polyacrylic acid, gelatin and polyvinyl pyrroli
`done.
`
`[0052] 5) Preservatives (to improve long term resistance to
`microbial contamination), for example ethanol, sodium met
`abisulphite, benZalkonium chloride and Nipas.
`[0053] 6) Antioxidants, for example alkyl gallates, buty
`lated hydroxyanisole, butylated hydroxytoluene, nordihy
`droguaiaretic acid, tocopherols, ascorbic acid and sodium
`metabisulphite.
`[0054] 7) Anionic surfactants, for example magnesium
`stearate, sodium cetostearyl sulphate, sodium lauryl sul
`phate, sulphated castor oil, sodium oleate, sodium stearyl
`fumarate and sodium tetradecyl sulphate.
`[0055] 8) Nonionic surfactants, for example glyceryl
`monostearate, macrogol cetostearyl ethers, poloxamers,
`polyoxyl stearates, polysorbates, sorbitan esters, sucrose
`esters, tyloxapol, propylene glycol monostearate, quillaia,
`polyoxyl caster oils, nonoxinols, lecithins and derivatives,
`oleic acid and derivatives, and oleyl alcohol and derivatives.
`[0056] 9) Foaming agents, for example alginic acid and
`salts, propylene glycol alginate, sodium lauryl sulphate,
`sodium cetostearyl sulphate, carbomers and hydroxyethyl
`cellulose.
`
`[0057] Some of the components proposed above may
`already be included in the composition of the present
`invention for other purposes. Suitable moisturising agents
`include, for example, polar organic solvents such as glycols,
`especially propylene glycol, and liquid polyethylene gly
`cols, glycerol, methylcellulose, hypromellose, hydroxypro
`pylcellulose, and many other substituted celluloses.
`
`[0058] Aversatile component, Which improves the accept
`ability and other properties of the formulation, is menthol.
`Menthol, as Well as ?avouring the formulation, has a mois
`turising effect. It may also have effect, depending on its
`concentration, as a penetration enhancer. Preferably menthol
`
`

`
`US 2006/0062812 A1
`
`Mar. 23, 2006
`
`is employed in a concentration range of 0.25% to 7.5%,
`although it may be yet lower.
`[0059] One particular advantage of menthol is that it is
`compatible With fentanyl in a spray formulation unlike
`peppermint oil (of Which menthol is one component), Which
`causes fentanyl to degrade.
`
`[0060] In an embodiment of the invention, the formulation
`contains a sWeetener. The preferred sWeetener is saccharin
`or a physiologically acceptable salt thereof such as saccharin
`sodium. Preferably the concentration of sodium saccharin or
`physiologically acceptable salt thereof is around 0.1-0.5%,
`e.g. around 0.28%.
`
`[0061] Preferably the formulation contains saccharin. Sur
`prisingly, We have found that the longer-term stability of
`formulations containing saccharin is better than the stability
`of those containing saccharin sodium.
`
`[0062] It has been discovered that it is not generally
`necessary to include a preservative in the formulation When
`ethanol is present due to its preservative qualities.
`
`[0063] Formulations of the invention are useful in anal
`gesia and in the treatment of pain, eg the treatment of
`moderate to severe pain, acute pain and cancer or other
`breakthrough pain. A therapeutically effective amount of a
`formulation for the treatment of pain according to the
`invention may be used.
`
`[0064] Formulations according to the invention are pref
`erably packaged as a bulk solution containing multiple doses
`in a pump spray system comprising a sealed container ?tted
`With a metering pump. Thus a sealed container may contain
`a plurality of doses of a formulation according to the
`invention. The container Will preferably contain betWeen 20
`to 200 doses. Example containers are those made out of
`plastics, glass and metal (e.g. aluminium); glass containers
`are preferred. Glass containers have the advantage that the
`contents of the container can be seen (i.e. it is possible to
`determine visually When the contents are about to run out).
`Furthermore, glass containers are less susceptible to tam
`pering, Which is an important consideration for narcotic
`substances.
`
`[0065] Preferably the glass container is coated on the
`exterior With a suitable moulded ?lm of plastics material, to
`protect against shattering. For example, the ?lm may be of
`polypropylene. The material may be coloured and contain a
`UV absorber. Optionally, the interior of the containers can be
`coated to enhance stability of the product. Coatings include
`polymers and lacquers but also silicone dioxide can be used
`to line the inside of the container With an unreactive coating.
`
`[0066] In another embodiment, single or multiple use
`devices comprising a single or multiple dose of the formu
`lation of the invention are envisaged.
`
`[0067] The compositions of the invention are preferably
`dispensed using a pump spray device. Preferably, the pump
`consists of a metering chamber allied With ef?cient precom
`pression qualities giving a high level of accuracy. Preferably,
`only pumps Which are non-venting and are able to pass
`severe bacteriological challenge tests should be used. Suit
`able pumps include VALOIS VP7 series pumps. Preferably,
`the pump spray device comprising a composition of the
`invention is capable of administering a metered dose of the
`composition to the sublingual mucosa.
`
`[0068] Also preferably, the pump spray device has fea
`tures Which are speci?cally adapted for improved sublingual
`delivery, as discussed in greater detail beloW.
`[0069] When the composition is administered to the sub
`lingual mucosa using such a device, the opioid analgesic has
`a surprisingly rapid onset of action. In addition, increased
`bioavailability is observed, compared to that observed When
`opioid analgesic formulations are administered sublingually
`using other means (such as tablets, loZenges or elixirs) or
`devices (such as pressurised meter dose inhaler or other
`propellant-driven spray devices).
`[0070] When the compositions of the present invention are
`dispensed using a pump spray device, the composition Will
`be dispensed at a much sloWer speed than is observed When
`compositions are dispensed using propellant-driven aerosol
`devices. Firstly, this Will reduce the impact the composition
`has on the sublingual area, thereby reducing the pain Which
`the high velocity impact can cause. This Will also avoid the
`additional salivation Which may be caused by the high
`velocity impact of a liquid on the sublingual mucosa. Such
`additional salivation can cause the administered composi
`tion to be Washed aWay from the sublingual mucosa, pre
`venting its absorption. Secondly, the reduced velocity of the
`compositions of the present invention can reduce the ten
`dency of the dispensed compositions to form a cloud or mist
`Which contacts areas other than the sublingual area Within
`the mouth.
`[0071] The oral mucosa can be distinguished according to
`important regions in the oral cavity; the ?oor of the mouth
`(sublingual), the buccal mucosa and the inner side of the
`lips. The sublingual mucosa is relatively permeable, giving
`rapid absorption of selected drug formulations. HoWever the
`buccal mucosa is considerably less permeable and, there
`fore, not able to give rapid absorption. In an important
`embodiment of the present invention, the composition is
`administered to the majority of the area of the sublingual
`mucosa, preferably the composition is administered to more
`than 50, 60, 70, 80, 90, 95 or 98% of the area of the
`sublingual mucosa. This is possible When the composition is
`dispensed using a pump spray device at relatively sloW
`speeds, as discussed above, and When a large enough volume
`of the composition is being dispensed for the desired exten
`sive coverage.
`[0072] Another aspect of the invention is a metered dose
`dispensing system comprising a sealed container containing
`a formulation of the invention ?tted With a metering pump,
`an actuator and a channelling device. The metered dose
`dispensing system is preferably adapted for sublingual
`administration. Commercially available pump spray devices
`can be obtained from a limited number of suitable providers,
`such as, for example, Valois Pharmaceutical Division, Route
`des Falaises, 27100 Le Vaudreuil, France, and Bespak
`Europe Limited, Bergen Way, King’s Lynn, Norfolk, PE30
`2]], United Kingdom.
`[0073] Suitable metering pumps include those adapted for
`dispensation With the container in the upright or inverted
`orientation. Preferably the metering chamber is adapted for
`dispensation With the container in the upright orientation
`since this facilitates administration under the tongue.
`Accordingly the metering chamber Will be in communica
`tion With the bulk formulation by means of a dip-tube.
`[0074] Example metering pumps are those manufactured
`by Valois and illustrated in WO01/66089.
`
`

`
`US 2006/0062812 A1
`
`Mar. 23, 2006
`
`[0075] The metering pump is preferably a non-venting
`type With a dip tube. Such non-venting metering pumps may
`have, for example, a 100 pl metering chamber capacity. The
`materials of construction include polypropylene and poly
`ethylene. Suitable sealing materials, eg thermoplastic
`crimp gaskets suitable for the purpose Will be employed. In
`addition, a suitable aluminium ferrule purposely designed
`for crimping on to glass containers may suitably be
`employed. Suitable grade stainless steel springs Will pref
`erably be adopted.
`[0076] Preferably the actuator is designed to deliver a
`sublingually effective dose. The package may be further
`enhanced by the ?tting of a lock-out system to promote
`compliance by patients.
`[0077] Astandard spray device used for sublingual admin
`istration Will generally dispense a volume of about 50 pl of
`the composition upon a single actuation of the device and
`this volume Will be administered in a localised fashion,
`contacting just a relatively small portion of the sublingual
`mucosa. In contrast, in a preferred embodiment of the
`present invention, a volume of 100 pl is administered in a
`single actuation of the pump spray device, and this dose can
`be applied to the majority of the area of the sublingual
`mucosa.
`[0078] Administration of the opioid analgesic composition
`as a ?ne layer covering the majority of the sublingual area,
`according to the present invention, Will lead to faster absorp
`tion (and therefore a faster onset of the therapeutic effect)
`and Will result in a greater proportion of the formulation
`being absorbed and therefore having a therapeutic effect (i.e.
`greater bioavailability).
`[0079] In one embodiment of the invention, the relief of
`acute pain is experienced very shortly after administration of
`a dose of opioid analgesic, such as fentanyl. Preferably, the
`composition has a time-to-onset-of-action of less than 30
`minutes, less than 15 minutes, less than 10 minutes or less
`than 5 minutes, folloWing sublingual spray administration.
`[0080] Thus, compared to the knoWn propellant-driven
`systems, it has been found that the pump action spray system
`of the present invention provides therapeutic plasma levels
`in a shorter time. In order for the opioid analgesic to have a
`pain-relieving effect, a plasma concentration of betWeen 250
`pg/ml and 2 ng/ml is required. The therapeutically effective
`concentrations vary betWeen patients and it is therefore
`generally necessary to titrate. According to the present
`invention, a plasma concentration of at least 250 pg/ml may
`be provided Within no more than 30 minutes of sublingual
`administration, preferably Within no more than 15 minutes.
`[0081] The present invention may achieve equivalent ef?
`cacious pain relief at loWer maXimum plasma concentrations
`compared With those observed as a result of intravenous
`administration and this, in turn, results in loWer incidence of
`adverse side-effects. When an opioid analgesic is adminis
`tered intravenously, the plasma concentration Will rapidly
`peak, generally at a level Which far eXceeds What is neces
`sary for the desired therapeutic effect. These high plasma
`peaks are frequently associated With severe side-effects.
`What is more, in order to obtain a therapeutic effect of
`adequate duration, it is often necessary to administer larger
`doses of opioid analgesics intravenously than is necessary
`When they are administered according to the present inven
`tion. The administration of these larger doses can also lead
`to adverse side-effects.
`
`[0082] As mentioned above, the present invention also
`provides increased bioavailability of the opioid analgesic. In
`one embodiment of the invention, the compositions of the
`invention, or the pump spray devices comprising the com
`positions, provide, upon administration, a bioavailability, as
`determined by AUCinf (Area Under the Curve to In?nity),
`of no less than 60% that of intravenous administration,
`preferably no less than 65% of intravenous administration,
`more preferably no less than 70% of intravenou