EXHIBIT 1003 
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1003
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01797
`
`

`
`(12) UK Patent Application (19) GB (11) 2 399 286 (13) A
`
`(43) Date of A Publication
`
`15.09.2004
`
`0328023.7
`
`03.12.2003
`
`(51)
`
`INT Cl7:
`A61K 9/08 9/12/1 A61P 25/02
`
`(52) UK Cl (Edition W ):
`A5B BJB B180 B5W B513 B54Y B541 B56Y B566 B58Y
`B586 B65X B65Y B66Y B661 B823 B825
`
`(56) Documents Cited:
`EP 0480054 A 1
`
`WO 2002/009707 A 1
`
`(58) Field of Search:
`INT Cl7 A61K, A61P
`Other: CAS-ONLINE, EPODOC, PAJ, TXTE & WPI
`
`(21) Application No:
`
`(22) Date of Filing:
`
`(30) Priority Data:
`(31) 0305579
`
`(32) 11.03.2003
`
`(33) GB
`
`(71) Applicant(s):
`Sirus Pharmaceuticals Ltd
`(Incorporated in the United Kingdom)
`19 Ferro Fields,
`Brixworth Industrial Estate, BRIXWORTH,
`Northamptonshire,
`NN6 9UA,
`United Kingdom
`
`(72)
`
`Inventor(s):
`Calvin John Ross
`Clive Booles
`Alistair Campbell
`
`(74) Agent and/or Address for Service:
`Venner Shipley LLP
`20 Little Britain, LONDON, EC1A 7DH,
`United Kingdom
`
`(54) Abstract Title: Sub-lingual
`
`fentanyl
`
`formulation
`
`formulation comprising (i) fentanyl or pharmaceutically acceptable salt thereof, (ii)
`(57) An pharmaceutical
`water and (iii) a polar organic solvent, wherein the said polar organic solvent
`is available in a sufficient
`amount to enhance the solubility of the fentanyl or salt thereof
`in the water. The resulting solution is for
`use as a sub-lingual spray - preferably delivered by means of a pump spray device.
`
`I\J
`
`Wc.oc.o
`I\J
`00en
`»
`
`Original Printed on Recycled Paper
`
`

`
`1/2
`
`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 Weights
`
`Record Weights
`
`Mix until complete
`dissolution.
`
`Mix until complete
`dissolution.
`
`Add the Fentanyl base
`
`Check pI!
`
`Adjust pH to pH 8.2 with the
`addition of aqueous sodium
`hydroxide (I M) or citric acid
`
`Record Weight
`
`Mix until complete
`dissolution.
`
`to
`Add citrate buffer
`mixing vessel, continue
`rruxmg
`
`Pig. 1
`
`

`
`2/2
`
`Check pH
`
`Adjust pH to pH 8.2
`
`Add remaining water
`
`Filter through a O.2flm
`membrane filter
`
`Purgard
`clean
`Air
`and place
`the
`bottles
`pumps on the bottles.
`
`Number each unit
`
`Record weights of
`pumps and bottles
`
`the
`
`Pipette 7.084g of the
`formulation into each
`
`Pig. 2
`
`Crimp on the pumps
`
`Record weights of
`pumps and bottles
`
`the
`
`

`
`- 1 -
`
`2399286
`
`Novel Compositions
`
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`This invention relates to formulations of fentanyl, especially pump spray
`formulations suitable for sublingual delivery.
`
`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 treatments,
`there are a number of issues of clinical management
`associated with the use of fentanyl in therapy.
`
`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 established therapeutically
`effective range and to monitor patients for evidence of self medication at greater
`than the recommended amount. Overdosage with fentanyl can lead to a number of
`undesirable and indeed life-threatening side effects, predominantly hypoventilation
`and respiratory depression.
`
`Due to the nature of the conditions being treated, it is much desired that the onset
`of analgesia occurs as soon after dosage as is compatible with safety parameters.
`Furthermore delay in onset of action may prompt the patient to take another dose
`with consequent risk, as already explained above, of overdosage.
`
`i\ number of routes of administration of a medicament can be associated with rapid
`onset of action. For example, International Patent Application W090/07333 (Riker
`Labs) described aerosol formulations of fentanyl, which are adapted for inhalation.
`However Riker's formulations suffer disadvantages such as their usc of
`hydrofluorocarbon propellants and delivery effected by metered dose inhalers. In
`the case of the former the disadvantages include high velocity which results in
`'bounce back' on administration to the front of the mouth, cold sensations on
`administration, the risk of inhalation and for the latter, careful co-ordination of
`
`

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`-2 -
`
`breath and actuation by the patient. When metered dose inhalers are used, a
`significant 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 narcotic analgesic. Accordingly the precautions
`required to
`ensure safe manufacture are onerous and expensive.
`
`5
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`10
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`(Aradigm Corp) describes solution formulations of fentanyl in aerosol
`W095/3ll82
`propellants intended for administration to patients by the pulmonary route.
`
`15 W001/97780
`in propellants,
`
`(Pharmasol Ltd) describes solution formulations of fentanyl free base
`typically HFA134a, for sublingual aerosol administration.
`
`20
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`
`WOOO/47203 (MQS Inc) describes formulations of fentanyl citrate for intra-oral
`administration employing oral absorption enhancers.
`
`These prior art formulations of fentanyl employ propellants and also suffer from
`the aforementioned disadvantages.
`
`Certain aqueous formulations of fentanyl for intranasal administration employing
`water and phosphate buffer have been described,
`(Paech, M.J., Lim, C.R., Banks,
`S.L., Rucklidge, M. W. M. & Doherty, D.A. (2003) Anaesthesia 58 (8), 740-744 and
`Lim et al (2003) J Pharm Practice Research 33, 59-63) but 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 formulations of fentanyl employing water and phosphate buffer
`for sublingual administration however these formulations were not advocated for
`use as a spray.
`
`

`
`-3 -
`
`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 consequent
`fast
`onset of effect. A number of ways of administering compositions
`sub lingually 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 lozenge cause increased salivation, which
`facilitates the unwanted swallowing of drug substance. Spray delivery, having low
`volume and ability to target
`the sublingual mucosa,
`largely mitigates this. No
`propellant
`free spray formulations of fentanyl which are adapted for sublingual
`administration have yet been described.
`
`invention to provide a formulation, which avoids or
`It is an aim of the present
`mitigates some or all of the above-mentioned
`disadvantages.
`
`composition is
`Thus according to a first aspect of the invention a pharmaceutical
`provided,
`the composition being a partially pressurised liquid spray formulation,
`which comprises:
`(a)
`fentanyl or a pharmaceutically acceptable salt thereof;
`(b)
`water as carrier; and
`in sufficient amount
`(c)
`a polar organic solvent
`fentanyl or pharmaceutically acceptable salt thereof
`
`to enhance the solubility of the
`in the water.
`
`The formulations of the invention 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.
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`The formulations of the present invention arc also preferably free of any propellant.
`
`Amongst the advantages of these formulations is the fact that by being water based
`they avoid the issues associated with using pressurised hydro fluorocarbon
`propellants as mentioned above. The formulations are partially pressurised and are
`free of propellants such as volatile chlorofluorocarbons (e.g. propellant 12), volatile
`hydrofluoroalkanes (e.g. 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoro-n(cid:173)
`propane) and volatile alkanes (e.g. propane, butane) and other substances which
`have significant vapour pressure at ambient temperature and pressure.
`
`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
`suspensions 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 suspension can be reduced to an extent by shaking the composition
`prior to spraying, some suspensions can settle very rapidly, so that there is still
`potential for variation of active agent content between doses.
`
`20
`
`Furthermore the formulations of the present invention are characterised by good
`long-term physical and chemical stability.
`
`Fentanyl may be employed in the form of a physiologically acceptable salt, which is
`soluble in water together with a polar organic solvent. Examples of suitable salts
`include hydrochloride, chloride, sulphate, tartrate and citrate. Preferably fentanyl is
`employed as the free base.
`
`Preferably the fentanyl or physiologically acceptable salt thereof will be employed in
`the formulation at a concentration of 0.1mg/ ml to 1Omg/ml, preferably 0.5mg/ ml
`to 4.4mg/ml (where weight is expressed as weight of fentanyl free base).
`
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`

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`- 5 -
`
`Examples of polar organic
`
`solvents
`
`that may be used to enhance
`
`the solubility
`
`of
`
`lower
`include:
`in the water,
`thereof
`salt
`acceptable
`fentanyl, or the physiologically
`(e.g. C2.4 alcohols) such as ethanol;
`lower polyols (e.g. C2_4 polyols) such as
`alcohols
`glycerol and propylene glycol; and polyethylene glycols such as PEG200 and
`PEG400.
`
`Mixtures of the above substances may be used. The preferred polar organic solvent
`is ethanol.
`
`the formulation does not include
`invention,
`In another embodiment of the present
`ethanol.
`Indeed,
`the formulation may be substantially free of any alcohol, or
`completely free of alcohol.
`
`the carrier used is preferably a polyol.
`Where the composition is free of alcohol,
`The preferred polyols include propylene glycol and glycerol.
`
`Generally speaking 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.
`
`is in the range preferably of between 6
`The concentration of polar organic solvent
`and 50%, more preferably 20-45% especially 35-42%.
`
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`Preferably the water meets the USP (US Pharmacopoeia), EP (European
`Pharmacopoeia)
`"Purified Water" standards.
`
`It has also been found that the properties of the claimed formulations may be
`improved by including therein a number of additional
`formulations components.
`
`30
`
`the water in the formulation is present
`Thus, in one embodiment of the invention,
`in the form of an aqueous buffer. The buffer is preferably adapted to stabilise the
`
`

`
`-6 -
`
`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 (e.g.
`nearer pH 6). Example buffer systems include sodium acetate/ acetic acid,
`ammonium acetate/disodium edctate, 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, e.g. a buffer comprising
`citric acid, sodium citrate and sodium hydroxide.
`
`(water or more preferably aqueous
`The concentration of the aqueous component
`buffer) of the formulation of the present
`invention is preferably 50-94%, more
`preferably 55-80%, and especially 58-65%.
`
`in the
`
`It may be desirable to include one or more of the following components
`formulation.
`1) Sweeteners, flavouring or taste-masking agents (to improve patient acceptability),
`for example vanilla, pineapple extract, menthol, saccharin and sodium saccharin.
`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.
`3) Penetration enhancers
`(to improve therapeutic effect), for example menthol.
`4) Mucoadherents
`(in order to increase residency time on the mucosa), for example
`carboxyvinyl polymers, chitosans, polyacrylic acid, gelatin and polyvinyl pyrrolidone.
`5) Preservatives
`(to improve long term resistance to microbial contamination),
`for
`example ethanol, sodium metabisulphite, benzalkonium chloride and Nipas.
`6) Antioxidants,
`for example Alkyl Gallates, Butylated Hydroxyanisole, Butylated
`Hydroxy toluene, Nordihydroguaiaretic
`acid, Tocopherols, Ascorbic acid and
`Sodium metabisulphite.
`for example Magnesium Stearate, Sodium Cctostearyl
`7) Anionic surfactants,
`sulphate, Sodium Lauryl sulphate, Sulphated caster oil, Sodium oleate, Sodium
`stearyl Fumarate and Sodium Tetradecyl Sulphate.
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`for example Glyceryl Monostearate, Macrogol Cetostearyl
`8) Nonionic surfactants,
`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, Oleyl alcohol and
`derivatives.
`9) Foaming agents, for example Alginic Acid and salts, Propylene Glycol Alginate,
`Sodium Lauryl sulphate, Sodium Cetostearyl sulphate, carbomers,
`Hydroxyethylcellulose
`
`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,
`the polar organic solvents such as glycols, especially
`propylene glycol, and the liquid polyethylene glycols, glycerol, methylcellulose,
`hypromellose, hydroxypropylcellulose,
`and many other substituted celluloses.
`
`A versatile component, which improves the acceptability and other properties of the
`formulation,
`is menthol. Menthol, as well as flavouring the formulation, has
`It may also have effect as a penetration enhancer. Preferably
`moisturising effect.
`menthol
`is employed in a concentration range of 0.25% to 7.5%.
`
`in a spray
`is that it is compatible with fentanyl
`One particular advantage of menthol
`formulation unlike peppermint oil (of which menthol
`is one component), which
`causes fentanyl
`to degrade.
`
`the formulation contains a sweetener. The
`In an embodiment of the invention,
`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%.
`
`the
`Preferably the formulation contains saccharin. Surprisingly, we have found that
`longer-term stability of formulations containing saccharin is better than the stability
`of those containing saccharin sodium.
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`
`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.
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`Formulations of the invention are useful in analgesia and in the treatment of pain.
`In a further aspect of the invention, formulations according to the first aspect of
`the invention are provided for use in the treatment of moderate to severe pain. In a
`yet further aspect of the invention, the use of the formulations according to the
`invention in the manufacture of a medicament for analgesia or for the treatment of
`pain is provided.
`In one embodiment, a therapeutically effective amount of a
`formulation for the treatment of pain according to the invention is used.
`
`Formulations according to the invention are preferably packaged as a bulk solution
`containing multiple doses in a pump spray system comprising a sealed container
`fitted with a metering pump. Thus as an aspect of the invention we provide a sealed
`container containing 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) however
`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 tampering, which is an important consideration for narcotic
`substances.
`
`25
`
`In another embodiment, single or multiple use devices comprising a single or
`multiple dose of the formulation of the invention is envisaged.
`
`Preferably the glass container will be coated on the exterior with a suitable moulded
`film of plastic to protect against shattering. For example the film 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
`
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`

`
`- 9 -
`
`product. Coatings include polymers and lacquers but also silicone dioxide can be
`used to line the inside of the container with an unreactive coating.
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`
`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.
`
`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
`communication with the bulk formulation by means of a dip-tube.
`
`15
`
`Example metering pumps are those manufactured by Valois and illustrated in
`International Patent Application No. WOOl/66089.
`
`20
`
`25
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`30
`
`The metering pump is preferably a non-venting type with a dip tube. Such non(cid:173)
`venting metering pumps may have, for example, a 100111metering chamber capacity.
`The materials of construction include polypropylene and polyethylene. 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 preferably be adopted.
`
`Preferably the actuator will be 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.
`
`Typically a patient is treated by administration sublingually of 1 to 4 actuations, e.g.
`1 or 2 actuations from the spray pump. Another advantage of sublingual spray
`delivery is the ability to easily titrate patients by 1 or 2 doses as required by a single
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`

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`- 10 -
`
`actuation.
`
`This is not
`
`the case with other
`
`forms of drug delivery (patches,
`
`lozenges,
`
`tablets,
`
`suppositories).
`
`and filled
`certain formulations
`for preparing
`One of the possible methods
`containers according to the invention is shown in the figures, for illustrative
`purposes.
`
`Figure 1 is a flow-chart showing the first stage of the method of preparing a
`formulation comprising 400f.!gfentanyl.
`
`Figure 2 is a flow-chart showing the second stage of the method.
`
`Other formulations of the invention may be prepared by analogous methods, or
`methods known to a skilled person.
`
`Weight percentage values given herein are expressed as w/w.
`
`The formulations and products of the invention have better physical and chemical
`stability, are more environmentally friendly, are more conveniently or safely
`administered to patients, are more conveniently or safely manufactured,
`are more
`economical
`to manufacture, or have other advantages relative to prior art
`formulations and products.
`
`The invention will now be illustrated by reference to the following examples:
`
`General
`Citrate buffer when employed contained:
`Citric acid
`2.0 %
`Sodium citrate
`1.0 %
`Sodium Hydroxide
`1.0%
`water: to 100%
`pH 8.2 (adjusted with NaOH).
`
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`- 11 -
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`Example
`
`1
`
`Formulation
`
`(per container):
`
`O.0280g
`Fentanyl base
`O.0177g
`Saccharin
`2.8336g
`Absolute ethanol
`O.0531g
`Menthol
`Citrate buffer
`4.1516g
`The target dose is 400ll-gper actuation.
`
`Example 2
`Formulation (per container):
`O.0280g
`Fentanyl base
`O.0198g (equivalent
`Saccharin sodium
`2.8336g
`Absolute ethanol
`O.0531g
`Menthol
`Citrate buffer
`4.1516g
`The target dose is 400ll-gper actuation of lOOll-1.
`
`to O.0177g saccharin)
`
`Example 3
`Formulation (per container):
`O.0280g
`Fentanyl base
`O.0177g
`Saccharin
`Absolute ethanol
`2.8336g
`Citrate buffer
`4.2047g
`The target dose is 400ll-gper actuation of lOOll-1.
`
`Example 4
`Formulation (per container):
`O.0280g
`Fentanyl base
`O.0198g (equivalent
`Saccharin sodium
`Absolute ethanol
`2.8336g
`
`to O.0177g saccharin)
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`- 12 -
`
`Water
`
`4.2026g
`
`The target dose is 400llg per actuation
`
`of 100111.
`
`5
`Example
`Formulation (per container):
`0.0140g
`Fentanyl base
`0.0198g (equivalent
`Saccharin sodium
`2.8336g
`Absolute ethanol
`Menthol
`0.OS31g
`Citrate buffer
`4.16S6g
`The target dose is 200llg per actuation of 100111.
`
`to O.Ol77g saccharin)
`
`Packaging of formulations
`The example formulations may be packaged into a suitable coated glass container
`and fitted with a suitable non-venting metered dose pump. An actuator suitable for
`sublingual delivery may be fitted.
`
`Test data
`The formulation of Example 1 was subjected to the following tests.
`Units were placed on stability storage at SoC, 2soC/60% RH, 30°C/6S% RI-Iand
`40°C/7S% RH. For each test 3 replicates were assessed.
`
`a) Appearance (including clarity).
`Observation be made and the results recorded.
`
`b) Mean Weight of Expelled Dose (Shot weight)
`Each unit will be weighed before and after test sprays. From these
`measurements, mean shot weight will be calculated by difference calculation
`c) pH
`pH is measured on a single unit at each time point at each condition. The
`unit is opened under controlled conditions and the pH measured by use of a
`pH meter.
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`- 13 -
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`Products
`d) Degradation
`A sample of the formulation
`
`from each unit was taken and examined for
`
`degradation
`
`products by HPLC assay. The result was recorded as 'none',
`
`<0.1 % (no identification)
`
`or percentage
`
`of identified degradant.
`
`5
`
`The results were as follows:
`
`Test
`(Specification)
`Appearance
`(clear,
`no particles,
`colourless)
`Shotweight
`(90 - 110mg)
`pH (7.7 - 8.7)
`Degradation
`product A
`Degradation
`product B
`
`Condition A Condition B
`
`Condition C
`
`Condition D
`
`Pass
`
`Pass
`
`Pass
`
`8.2
`ND
`
`ND
`
`Pass
`
`8.2
`ND
`
`ND
`
`Pass
`
`Pass
`
`8.2
`ND
`
`ND
`
`Pass
`
`Pass
`
`8.2
`<0.1%
`
`0.1-0.15%
`
`The formulation of Example 2 was subjected to the same tests, with the following
`results:
`
`10
`
`Test
`Appearance
`(clear,
`no particles,
`colourless)
`Shotweight
`190 - 11 Omg)
`pH (7.7 - 8.7)
`Degradation
`product A
`Degradation
`product B
`
`Condition A Condition B
`Pass
`Pass
`
`Condition C
`Pass
`
`Condition D
`Pass
`
`Pass
`
`8.3
`ND
`
`NO
`
`Pass
`
`8.3
`NO
`
`ND
`
`Pass
`
`8.3
`NO
`
`ND
`
`Pass
`
`8.3
`<0.1%
`
`<0.1%
`
`Condition A: 2-8"C, ambient humidity
`Condition B: 25"C, 60% relative humidity
`
`

`
`- 14 -
`
`Condition C: 30DC, 60% relative humidity
`Condition D: 40°C, 75% relative humidity
`
`5
`
`Appearance: all samples were clear and colourless with no particles.
`Shotweight: all samples were within target.
`pH: stable (8.2-8.3).
`Moisture content: acceptable.
`Degradation products A and B: none detected.
`
`10
`
`From the test results, it was concluded that the tested formulations of the invention
`demonstrate excellent physical and chemical stability.
`
`

`
`- 15 -
`
`Claims
`
`5
`
`1.
`liquid spray formulation, comprising:
`A pharmaceutical
`(a)
`fentanyl or a pharmaceutically acceptable salt thereof;
`water as carrier; and
`(b)
`to enhance the solubility of the
`in sufficient amount
`a polar organic solvent
`(c)
`fentanyl or pharmaceutically acceptable salt thereof in the water.
`
`A formulation according to claim 1 wherein fentanyl is present as the free
`
`2.
`base.
`
`10
`
`A formulation according to claim 1 or claim 2, wherein the formulation is
`3.
`partially pressurised,
`
`4.
`A formulation according to anyone of the preceding claims, wherein the
`fentanyl, or a pharmaceutically acceptable salt thereof,
`is present at a concentration
`of 0.1-10 mg/ml.
`
`A formulation according to anyone of the preceding claims wherein the
`5.
`polar organic solvent is selected from ethanol, propylene glycol, glycerol or
`polyethylene glycol and mixtures thereof.
`
`A formulation according to claim 5 wherein the polar organic solvent is
`6.
`ethanol.
`
`A formulation according to anyone of the preceding claims wherein the
`7.
`polar organic solvent is present
`in an amount of 6-50% w/w.
`
`15
`
`20
`
`25
`
`8.
`present
`
`A formulation according to claim 7 wherein the polar organic solvent
`in an amount of 35-42% w/w.
`
`is
`
`30
`
`

`
`- 16 -
`
`9.
`
`A formulation
`
`according
`
`to anyone
`
`of the preceding
`
`claims wherein the
`
`formulation
`
`is buffered.
`
`A formulation
`10.
`citrate buffer.
`
`5
`
`according
`
`to claim 9 wherein
`
`the formulation
`
`is buffered with
`
`A formulation according to anyone of the preceding claims wherein the
`11.
`formulation has pH between 7.4 and 8.5.
`
`10
`
`12.
`8.2.
`
`A formulation according to claim 11 wherein the formulation has pH around
`
`A formulation according to anyone of the preceding claims which contains a
`13.
`sweetener.
`
`15
`
`20
`
`14.
`
`A formulation according to claim 13 wherein the sweetener is saccharin.
`
`A formulation according to claim 13, wherein the sweetener
`15.
`sodium.
`
`is saccharin
`
`A formulation according to anyone of the preceding claims which contains
`16.
`menthol.
`
`A formulation according to anyone of the preceding claims for sublingual
`17.
`administration as a spray.
`
`25
`
`A formulation according to anyone of the preceding claims, for use in
`18.
`treating pain or as a method of analgesia.
`
`30
`
`A formulation according to claim 18 wherein the formulation is administered
`19.
`sublingually as a spray.
`
`

`
`- 17 -
`
`20.
`
`Use of a formulation
`
`according
`
`to anyone
`
`of claims 1 to 17 in the
`
`manufacture
`
`of a medicament
`
`for analgesia or for the treatment
`
`of pain.
`
`A use according
`21.
`sublingually as a spray.
`
`.5
`
`to claim 20 wherein
`
`the formulation
`
`is administered
`
`A sealed container containing a plurality of doses of a formulation according
`22.
`to anyone of claims 1 to 17.
`
`10
`
`23.
`
`A container according to claim 22, which is made out of glass.
`
`A metered dose dispensing system comprising a sealed container according
`24.
`to claim 22 or claim 23 fitted with a metering pump, an actuator and a channelling
`device.
`
`15
`
`20
`
`A metered dose dispensing system according to claim 24 containing a
`25.
`metering chamber which is adapted for dispensation with the container
`in the
`upright orientation and wherein the metering chamber is in communication with the
`formulation by means of a dip-tube.
`
`A metered dose dispensing system according to claim 24 or claim 25 adapted
`26.
`for sublingual administration of the formulation as a spray.
`
`

`
`INVESTOR
`
`IN PEOPLE
`
`Application No:
`Claims searched:
`
`GB0328023.7
`1-26
`
`Examiner:
`Date of search:
`
`Dr Bill Thomson
`15 April 2004
`
`Patents Act 1977: Search Report under Section 17
`
`Documents considered to be relevant:
`Identity of document and passage or figure of particular reference
`Category Relevant
`to claims
`
`X
`
`X
`
`1, 5-8 and EP 0480054 Al
`- See whole document,
`(MORIMOTO)
`16 at least
`page 4, line 4 and Example 8
`
`in particular page 3, line 37 -
`
`1 and 5 at WO 02/009707 Al
`(NYCOMED DANMARK AIS) - See whole document,
`least
`page 3, line 34 - page 4, line 18 and Examples 2 and 3
`
`in particular
`
`Categories:
`X Documentindicatinglack of novelty or inventive
`step
`Y Documentindicatinglack of inventive step if
`combinedwithone or more other documentsof
`same category.
`& Member of the same patent family
`
`A Document indicatingtechnologicalbackground and/or state
`of the art.
`Document publishedon or after the declared priority date
`but before the filing date of this invention.
`
`P
`
`E
`
`Patent documentpublishedon or after, but with priority date
`earlier than, the filing date of this application.
`
`Field of Search:
`Searchof GB, EP, WO & US patent documentsclassified in the followingareas of the UKCw :
`
`Worldwidesearch of patent documentsclassified in the followin areas of the IPC07
`A61K; A61P
`The followin online and other databaseshave been used in the re aration of this search re ort
`CAS-ONLINE, EPODOC, PAJ, TXTE & WPI
`
`An Executive Agency of the Department of Trade and Industry