Exhibit 1005
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1005
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01800
`
`

`
`(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
`Dec. 3, 2003
`Sep. 10, 2004
`
`(GB) ....................................... .. 0305579.5
`
`(GB)
`03280237
`(GB) ....................................... .. 0420173.7
`
`Publication Classification
`
`Correspondence Address:
`SALIWANCHIK LLOYD & SALIWANCHIK
`A PROFESSIONAL ASSOCIATION
`PO BOX 142950
`GAINESVILLE, FL 32614-2950 (US)
`
`(51)
`
`1111- C1-
`(200601)
`A61K 31/445
`(2006-01)
`1461K 31/045
`(2006.01)
`A61K 9/00
`(52) U.S. Cl.
`......................... .. 424/400; 514/317; 514/729
`
`(21) Appl. No.:
`
`11/224,383
`
`(22) Filed:
`
`Sep. 12, 2005
`
`Related U.S. Application Data
`
`(63) Continuation-in-part of application No. PCT/GB04/
`01037, filed on Mar. 11, 2004.
`
`(57)
`
`ABSTRACT
`
`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. Specifically,
`the
`invention relates to a sublingual presentation of an opioid
`analgesic, such as fcntanyl, or its salts, in amounts that are
`suflicient to treat the pain.
`
`

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

`
`Patent Application Publication Mar. 23, 2006 Sheet 2 of 2
`
`US 2006/0062812 A1
`
`Check pl-I
`
`Adjust pH to pll 8.2
`
`Add remaining water
`
`Filter through a 0.2pm
`membrane filter
`
`
`
`Purgard
`clean
`Air
`and place the
`bottles
`pumps on the bottles.
`
`Number each unit
`
`Record weights of the
`pumps and bottles
`
`2
`
`Pipette 7.08-1g 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, filed
`Mar. 11, 2004; which claims priority to GB 0305579.5, filed
`Mar. 11, 2003 and GB 0328023.7, filed Dec. 3, 2003. The
`subject application further claims priority to GB 0420173.7,
`filed Sep. 10, 2004, all of which are hereby incorporated by
`reference herein in their entirety.
`
`FIELD OF TIIE 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 specific 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.
`
`In the case of breakthrough pain, the onset of pain
`[0004]
`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, W090/07333 describes aerosol formulations of
`fentanyl, which are adapted for inhalation. However, these
`formulations suffer disadvantages such as their use of
`hydrofluorocarbon 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 signifi-
`cant proportion of the delivered dose tends to impact the
`back of the throat from where it is swallowed rather than
`
`finding 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 profile (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] W001/97780 describes solution formulations of
`fentanyl free base in propellants, typically HFA134a, for
`sublingual acrosol 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 s11bling11al administration, but these formulations are not
`advocated for use as a spray.
`
`It is well known that the application of carefully
`[0013]
`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
`
`In the past, spray devices, including pump sprays,
`[0014]
`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 finely spread over the sublingual
`nucosa in order for them to be properly absorbed. When
`hey are concentrated at
`a small area of the sublingual
`mucosa, absorption is reduced.
`
`It is an aim of the present invention to provide a
`:0015]
`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-
`ation preferably exhibits improved performance compared
`o 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 elfect, together with an advantageous
`aharmacokinetic response and drug plasma profile which
`will avoid the disadvantages associated with the fast onset
`observed when opioid analgesics are administered intrave-
`lously.
`
`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
`aroblems associated with other formulations, and can avoid
`he use of propellants.
`
`:0018] According to the invention, a pharmaceutical com-
`aosition, preferably a partially pressurised liquid spray for-
`nulation, comprises:
`
`(a) fentanyl or a pharmaceutically acceptable
`[0019]
`salt thereof;
`
`[0020]
`
`(b) water as carrier; and
`
`(c) a polar organic solvent in sufficient amount to
`[0021]
`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. Specifically, the invention relates to a sub-
`
`lingual presentation of an opioid analgesic, such as fentanyl,
`or its salts, in amounts that are sufficient 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 profile suitable to
`achieve optimal pain relief over the duration of symptoms
`with minimized side-effects.
`
`[0024] The invention also relates to a specific drug for-
`mulation, dispensed using a metered pump action spray
`which is specifically designed for delivery via the sublingual
`route. This affords significant improvements and advantages
`in terms of plasma bioavailability and pharmacokinetic
`profile compared to similar, but non-optimised, propellant-
`driven aerosol formulations. These benefits relate in particu-
`lar to:
`
`[0025]
`
`i) a faster rate of onset of elfect;
`
`[0026]
`
`ii) a faster rate of offset of effect; and
`
`[0027]
`
`iii) a faster Tmax.
`
`[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 hydrofluorocarbon propel-
`lants as mentioned above. The formulations may be partially
`pressurised and are free of propellants such as volatile
`chlorofluorocarbons (e.g. propellant 12), volatile hydrofluo-
`roalkanes (e.g. 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-
`heptafluoro-n-propane) and volatile alkanes (e.g. propane or
`butane) and other substances which have significant 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 flow-chart showing the first stage of a
`method of preparing a formulation comprising 400 ,ug
`fentanyl.
`
`[0032] FIG. 2 is a flow-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.
`
`In one embodiment of the present invention, the
`[0034]
`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
`areferred polar organic solvent is ethanol.
`
`In another embodiment of the present invention,
`[0039]
`he formulation does not include ethanol. Indeed, the for-
`mulation may be substantially free of any alcohol, or com-
`aletely free of alcohol.
`
`the
`[0040] Where the composition is free of alcohol,
`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
`hat the fentanyl remains in solution under the conditions of
`likely usage or exposure.
`
`[0042] The concentration of polar organic solvent is in the
`ange 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) “Purified Water”
`standards.
`
`It has also been found that the properties of the
`[0044]
`claimed formulations may be improved by including therein
`one or more additional components.
`
`the
`in one embodiment of the invention,
`[0045] Thus,
`water in the formulation is present in the form of an aqueous
`Juffer. The buffer is preferably adapted to stabilise the pH of
`he formulation at pH 7.4 to 8.5, preferably at pH 8.0 to 8.5,
`nore 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 (e.g.
`1earer pH 6). Example buffer systems include sodium
`acetate/acetic acid, ammonium acetate/disodium edetate,
`I)OI‘lC 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, e.g. a buffer comprising citric acid, sodium
`citrate and sodium hydroxide.
`
`the aqueous component
`[0046] The concentration of
`(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%.
`
`It may be desirable to include one or more of the
`[0047]
`following components in the formulation.
`
`l) Sweeteners, flavouring or taste-masking agents
`[0048]
`(to improve patient acceptability), for example vanilla, pine-
`apple extract, menthol, saccharin and sodium saccharin.
`
`2) Moisturising agents (to improve patient comfort
`[0049]
`and overcome the drying tendency of ethanol and other polar
`organic solvents), for example pineapple extract, lanolin,
`polypropylene glycol, and polyethylene glycol.
`
`3) Penetration enhancers (to improve therapeutic
`[0050]
`effect), for example menthol.
`
`4) Mucoadherents (in order to increase residency
`[0051]
`time on the mucosa), for example carboxyvinyl polymers,
`chitosans, polyacrylic acid, gelatin and polyvinyl pyrroli-
`done.
`
`5) Preservatives (to improve long term resistance to
`[0052]
`microbial contamination), for example ethanol, sodium met-
`abisulphite, benzalkonium chloride and Nipas.
`
`6) Antioxidants, for example alkyl gallates, buty-
`[0053]
`lated hydroxyanisole, butylated hydroxytoluene, nordihy-
`droguaiaretic acid, tocopherols, ascorbic acid and sodium
`metabisulphite.
`
`7) Anionic surfactants, for example magnesium
`[0054]
`stearate, sodium cetostearyl sulphate, sodium lauryl sul-
`phate, sulphated castor oil, sodium oleate, sodium stearyl
`fumarate and sodium tetradecyl sulphate.
`
`for example glyceryl
`8) Nonionic surfactants,
`[0055]
`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.
`
`9) Foaming agents, for example alginic acid and
`[0056]
`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 flavouring 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.
`
`Z0059] One particular advantage of menthol is that it is
`compatible with fentanyl
`in a spray formulation unlike
`aeppermint oil (of which menthol is one component), which
`causes fentanyl to degrade.
`
`In an embodiment of the invention, the formulation
`Z0060]
`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
`hysiologically acceptable salt thereof is around 01-05%,
`e.g. around 0.28%.
`
`Z0061] Preferably the formulation contains saccharin. Sur-
`wrisingly, we have found that the longer-term stability of
`formulations containing saccharin is better than the stability
`of those containing saccharin sodium.
`
`is not generally
`it
`It has been discovered that
`Z0062]
`iecessary to include a preservative in the formulation when
`ethanol is present due to its preservative qualities.
`
`Z0063] Formulations of the invention are useful in anal-
`gesia and in the treatment of pain, e.g. the treatment of
`noderate to severe pain, acute pain and cancer or other
`Jreakthrough pain. A therapeutically effective amount of a
`formulation for the treatment of pain according to the
`invention may be used.
`
`Z0064] 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 fittcd
`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-
`Jering, which is an important consideration for narcotic
`substances.
`
`Z0065] Preferably the glass container is coated on the
`exterior with a suitable moulded film of plastics material, to
`arotcct against shattcring. For example, the film may be of
`aolypropylene. 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
`aolymers and lacquers but also silicone dioxide can be used
`0 line the inside of the container with an unreactive coating.
`
`In another embodiment, single or multiple use
`Z0066]
`devices comprising a single or multiple dose of the formu-
`lation of the invention are envisaged.
`
`Z0067] The compositions of the invention are preferably
`dispensed using a pump spray device. Preferably, the pump
`consists of a metering chamber allied with efficient precom-
`ression 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,
`he 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 specifically 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 floor 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 fitted 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, e.g.
`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 fitting 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 50 141 of
`he composition upon a single actuation of the device and
`his volume will be administered in a localised fashion,
`contacting just a relatively small portion of the sublingual
`nucosa.
`In contrast,
`in a preferred embodiment of the
`wresent invention, a volume of 100 ,u.l is administered in a
`single actuation of the pump spray device, and this dose can
`3e applied to the majority of the area of the sublingual
`nucosa.
`
`:0078] Administration of the opioid analgesic composition
`as a fine layer covering the majority of the sublingual area,
`according to the present invention, will lead to faster absorp-
`ion (and therefore a faster onset of the therapeutic effect)
`and will result in a greater proportion of the formulation
`Jeing 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
`han 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
`aain-relieving effect, a plasma concentration of between 250
`3g/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
`3e provided within no more than 30 minutes of s11blingual
`administration, preferably within no more than 15 minutes.
`:008l] The present invention may achieve equivalent effi-
`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 elfect 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 sidc-cffccts.
`
`[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 Infinity),
`of no less than 60% that of intravenous administration,
`preferably no less than 65% of intravenous administration,
`more preferably no less than 70% of intravenous adminis-
`tration. Alternative sublingual aerosol presentations typi-
`cally demonstrate lower bioavailability than this and it has
`been disclosed that the bioavailability of other oral trans-
`mucosal formulations presented in different delivery sys-
`tems may be as low as 50% (MicroMedex HEALTHCARE
`Services 2001; Volume 108).
`
`[0083] The increased bioavailability means that smaller
`doses can be administered whilst still achieving the same
`plasma concentrations and therapeutic effect, as a