Exhibit 1003
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 100
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01799
`
`

`
`(12) UK Patent Application GB 2 399 286 A
`
`(43) Date of A Publication
`
`15.09.2004
`
`(51)
`
`INT CL7:
`A61K 9/08 9/12 ll A61P 25/02
`
`(52) UK CL (Edition W):
`A5B BJB B180 B51Y B513 B54Y B541 B56Y B566 B58Y
`B586 B65X B65Y B66Y B661 B823 B825
`
`(56) Documents Cited:
`EP 0480054 A1
`
`wo 2002/009707 A1
`
`(58) Field of Search:
`CL7
`Other: cAS_oNL|NE' EPODOCI PAJI TX-I-E & WPI
`
`(21) Application No:
`
`(22) Date of Filing:
`
`(30) Priority Data;
`(31) 0305579
`
`0328023.7
`
`03.12.2003
`
`(32) 11.03.2003
`
`(33) GB
`
`(71) App|icant(s)=
`Sirus Pharmaceuticals Ltd
`
`(Incorporated in the United Kingdom)
`19 Ferro Fields,
`BfiXWOI‘th Industrial Estate, BRIXWORTH,
`Northamptonshire, NN6 9UA,
`United Kingdom
`
`(72)
`
`|nventor(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
`
`(57) An pharmaceutical formulation comprising (i) fentanyl or pharmaceutically acceptable salt thereof, (ii)
`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—|ingua| spray — preferably delivered by means of a pump spray device.
`
`V982668289
`
`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 dc-ionised
`water.
`
`Record Weights
`
`Record Weights
`
`Mix until complete
`
`dissolution.
`
`Record Weight
`
`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.
`
`mixing
`
`Add citrate buffer to
`
`mixing vessel, continue
`
`

`
`2/2
`
`Check pH
`
`Adjust pfl to pH 8.2
`
`hI<:1|<:|
`
`Add remaining water
`
`Filter through a 0.2 pm
`membrane filter
`
`Purgard
`clean
`Air
`bottles and place the
`pumps on the bottles.
`
`Record weights of the
`pumps and bottles
`
`Pipette 7.084;; of the
`fotmulation into each
`
`Crimp on the pumps
`
`Record weights of the
`
`pumps and bottles
`
`

`
`2399286
`
`Novel Compositions
`
`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 conse uent risk, as alread ex lained above of overdosa re.
`Cl
`Y
`»
`Es
`
`A number of routes of administration of a medicament can be associated with rapid
`
`onset of action. For example, International Patent Application \X/O90/07333 (Riker
`
`Labs) described aerosol formulations of fentanyl, which are adapted for inhalation.
`
`However Riker’s formulations suffer disadvantages such as their use 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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`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.
`
`W095/31182 (Aradigm Corp) describes solution formulations of fentanyl in aerosol
`
`propellants intended for administration to patients by the pulmonary route.
`
`W001/97780 (Pharmasol Ltd) describes solution formulations of fentanyl free base
`
`in propellants, typically HFA134a, for sublingual aerosol administration.
`
`W000/47203 (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._]., Lim, C.B., 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 ct 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.
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`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 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 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.
`
`It is an aim of the present invention to provide a formulation, which avoids or
`
`mitigates some or all of the above—mentioned disadvantages.
`
`Thus according to a first aspect of the invention a pharmaceutical composition is
`
`provided, the composition being a partially pressurised liquid spray formulation,
`
`which comprises:
`
`(a)
`
`(b)
`
`(C)
`
`fentanyl or a pharmaceutically acceptable salt thereof;
`
`water as carrier; and
`
`a polar organic solvent in sufficient amount to enhance the solubility of the
`
`fentanyl or pharmaceutically acceptable salt thereof 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 are 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 hydrofluorocarbon
`
`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. l,1,1,2—tetrafluoroethane and 1,1,1,2,3,3,3—heptafluoro—n—
`
`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.
`
`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 10mg/ml, preferably 0.5mg/ml
`
`to 4.4mg/ml (where weight is expressed as weight of fentanyl free base).
`
`10
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`Examples of polar organic solvents that may be used to enhance the solubility of
`
`fentanyl, or the physiologically acceptable salt thereof in the water, include: lower
`
`alcohols (e.g. C_,__4 alcohols) such as ethanol; lower polyols (e.g. C“ polyols) such as
`
`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.
`
`70
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`I5
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`20
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`25
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`30
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`In another embodiment of the present invention, the formulation does not include
`
`ethanol. Indeed, the formulation may be substantially free of any alcohol, or
`
`completely free of alcohol.
`
`Where the composition is free of alcohol, the carrier used is preferably a polyol.
`
`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.
`
`The concentration of polar organic solvent is in the range preferably of between 6
`
`and 50%, more preferably 20-45% especially 35-42°/o.
`
`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.
`
`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 (e.g.
`
`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, e.g. a buffer comprising
`
`citric acid, sodium citrate and sodium hydroxide.
`
`The concentration of the aqueous component (water or more preferably aqueous
`
`buffer) of the formulation of the present invention is preferably 50-94%, more
`
`preferably 55-80%, and especially 58-65%.
`
`It may be desirable to include one or more of the following components in the
`
`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
`
`Hydroxytoluene, Nordihydroguaiaretic acid, Tocopherols, Ascorbic acid and
`
`Sodium mctabisulphite.
`
`7) Anionic surfactants, for example Magnesium Stearate, Sodium Cetostearyl
`
`sulphate, Sodium Lauryl sulphate, Sulphated caster oil, Sodium oleate, Sodium
`
`stearyl Fumarate and Sodium Tetraclecyl Sulphate.
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`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, 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
`
`moisturising effect.
`
`It may also have effect as a penetration enhancer. Preferably
`
`menthol is employed in a concentration range of 0.25% to 7.5%.
`
`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.
`
`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—O.5°/o, e.g. around 0.28%.
`
`Preferably the formulation contains saccharin. Surprisingly, we have found that the
`
`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.
`
`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.
`
`In another embodiment, single or multiple use devices comprising a single or
`
`multi
`
`le dose of the formulation of the invention is envisa ed.
`29
`
`P
`
`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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`product. Coatings include polymers and lacquers but also silicone dioxide can be
`
`used to line the inside of the container with an unreactive coating.
`
`Another as ect of the invention is a metered dose dis ensin s stem com risin a
`P
`P
`g Y
`P
`8
`
`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.
`
`Example metering pumps are those manufactured by Valois and illustrated in
`
`International Patent Application No. W001/66089.
`
`The metering pump is preferably a non—venting type with a dip tube. Such non-
`
`venting metering pumps may have, for example, a 100ul metering 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 titratc patients by 1 or 2 doses as required by a single
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`_10-
`
`actuation. This is not the case with other forms of drug delivery (patches, lozenges,
`
`tablets, suppositories).
`
`One of the possible methods for preparing certain formulations and filled
`
`containers according to the invention is shown in the figures, for illustrative
`
`PUIPOSCS.
`
`Figure 1 is a flow—chart showing the first stage of the method of preparing a
`
`formulation comprising 400ug fentanyl.
`
`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
`
`meth()ds 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
`
`Sodium citrate
`
`2.0 ‘V0
`
`1.0 °/o
`
`Sodium Hydroxide
`
`1.0%
`
`water: to 100°/o
`
`pH 8.2 (adjusted with NaOH).
`
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`-11-
`
`Example 1
`
`Formulation (per container):
`
`Fentanyl base
`
`Saccharin
`
`Absolute ethanol
`
`Menthol
`
`Citrate buffer
`
`0.0280g
`
`0.0l77g
`
`2.8336g
`
`0.0531g
`
`4.1516g
`
`The target dose is 400pg per actuation.
`
`10
`
`Example 2
`
`Formulation (per container):
`
`Fentanyl base
`
`0.0280g
`
`Saccharin sodium
`
`0.0198g (equivalent to 0.0177g saccharin)
`
`75
`
`Absolute ethanol
`
`Menthol
`
`Citrate buffer
`
`2.8336g
`
`0.0531g
`
`4.1516g
`
`The target dose is 400ug per actuation of 100ul.
`
`20
`
`Example 3
`
`Formulation (per container):
`
`Fentanyl base
`
`Saccharin
`
`Absolute ethanol
`
`25
`
`Citrate buffer
`
`0.0280g
`
`0.0177g
`
`2.8336g
`
`4.2047g
`
`The target dose is 400ug per actuation of 1001.11.
`
`Example 4
`
`Formulation (per container):
`
`30
`
`Fcntanyl base
`
`().0280g
`
`Saccharin sodium
`
`0.0198g (equivalent to 0.0177g saccharin)
`
`Absolute ethanol
`
`2.8336g
`
`

`
`_
`
`_
`
`Water
`
`4.2026g
`
`The target dose is 400ug per actuation of 100p1.
`
`Example 5
`
`Formulation (per container):
`
`Fentanyl base
`
`0.0l40g
`
`Saccharin sodium
`
`0.0198g (equivalent to 0.0177g saccharin)
`
`Absolute ethanol
`
`2.8336g
`
`Menthol
`
`0.053lg
`
`Citrate buffer
`
`4.1656g
`
`The target dose is 200ug per actuation of 100ul.
`
`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 5°C, 25°C/60°/o RH, 30°C/65"/o RH and
`
`40°C/75% RH. For each test 3 replicates were assessed.
`
`a) Appearance (including clarity).
`
`Observation l)e 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.
`
`I0
`
`75
`
`20
`
`25
`
`30
`
`

`
`-13-
`
`(1) Degradation Products
`
`A sample of the formulation from each unit was taken and examined for
`
`degradation products by HPLC assay. The result was recorded as ‘none’,
`
`<O.1°/o (no identification) or percentage of identified degradant.
`
`The results were as follows:
`
`Test
`
`
`(Specification)
`
`Condition A
`
`Pass
`
`Pass
`
`Condition c
`
`Pass
`
`Condition D
`
`Pass
`
`
`
`Appearance
`(clear,
`no particles,
`colourless
`
`
`
`
`
`
`
`
`90 - 110m)
`
`8.
`
`roduct A
`
`roduct B
`
`
`
`
`
`
`
`The formulation ofllxarnple 2 was subjected to the same tests, with the following
`
`70
`
`results:
`
`Appearance
`(clear,
`no particles,
`colourless
`
`C
`
`Pass
`
`°°“‘““°“B
`
`
`Pass
`
`
`
`Pass
`
`Pass
`
`Pass
`
`Pass
`
`Qhotweight
`90 110m)
`.
`8.3
`P“‘”‘87>_
`Degradation
`ND
`ND
`ND
`<O.1%
`roduct A
`
`Pass
`
`Pass
`
`Degradation
`roduct B
`
`ND
`
`ND
`
`
`
`ND
`
`<0.1°/o
`
`
`
`
`
`
`
`
`
`
`Condition A: 2—8"C, ambient humidity
`
`Condition B: 25"C, 60% relative humidity
`
`

`
`-14-
`
`Condition C: 30°C, 60% relative humidity
`
`Condition D: 4-0"C, 75°/o relative humidity
`
`Appearance: all samples were clear and colourless with no particles.
`
`Shotweight: all samples were within target.
`
`pl-l: stable (8.2—8.3).
`
`Moisture content: acceptable.
`
`Degradation products A and B: none detected.
`
`70
`
`From the test results, it was concluded that the tested formulations of the invention
`
`demonstrate excellent physical and chemical stability.
`
`

`
`-15-
`
`Claims
`
`1.
`
`(a)
`
`(b)
`
`(c)
`
`A pharmaceutical liquid spray formulation, comprising:
`
`fentanyl or a pharmaceutically acceptable salt thereof;
`
`water as carrier; and
`
`a polar organic solvent in sufficient amount to enhance the solubility of the
`
`fentanyl or pharmaceutically acceptable salt thereof in the water.
`
`2.
`
`A formulation according to claim 1 wherein fentanyl is present as the free
`
`70
`
`base.
`
`3.
`
`A formulation according to claim 1 or claim 2, wherein the formulation is
`
`partially pressurised.
`
`4.
`
`A formulation according to any one of the preceding claims, wherein the
`
`fentanyl, or a pharmaceutically acceptable salt thereof, is present at a concentration
`
`of 0.1 -10 mg/ml.
`
`5.
`
`A formulation according to any one of the preceding claims wherein the
`
`polar organic solvent is selected from ethanol, propylene glycol, glycerol or
`
`polyethylene glycol and mixtures thereof.
`
`6.
`
`A formulation according to claim 5 wherein the polar organic solvent is
`
`ethanol.
`
`7.
`
`A formulation according to any one of the preceding claims wherein the
`
`polar organic solvent is present in an amount of 6-50"/o w/w.
`n
`
`8.
`
`A formulation according to claim 7 wherein the polar organic solvent is
`
`present in an amount of 35-42% w/w.
`
`75
`
`20
`
`25
`
`.30
`
`

`
`-16-
`
`9.
`
`A formulation according to any one of the preceding claims wherein the
`
`formulation is buffered.
`
`10.
`
`A formulation according to claim 9 wherein the formulation is buffered with
`
`citrate buffer.
`
`11.
`
`A formulation according to any one of the preceding claims wherein the
`
`formulation has pH between 7.4 and 8.5.
`
`A formulation according to claim 11 wherein the formulation has pH around
`
`12.
`
`8.2.
`
`13.
`
`A formulation according to any one of the preceding claims which contains a
`
`sweetener.
`
`14.
`
`A formulation according to claim 13 wherein the sweetener is saccharin.
`
`15.
`
`A formulation according to claim 13, wherein the sweetener is saccharin
`
`sodium.
`
`16.
`
`A formulation according to any one of the preceding claims which contains
`
`menthol.
`
`17.
`
`A formulation according to any one of the preceding claims for sublingual
`
`administration as a spray.
`
`18.
`
`A formulation according to any one of the preceding claims, for use in
`
`treating pain or as a method of analgesia.
`
`19.
`
`A formulation according to claim 18 wherein the formulation is administered
`
`sublingually as a spray.
`
`70
`
`75
`
`20
`
`25
`
`30
`
`

`
`-17-
`
`20.
`
`Use of a formulation according to any one of claims 1 to 17 in the
`
`manufacture of a medicament for analgesia or for the treatment of pain.
`
`21.
`
`A use according to claim 20 wherein the formulation is administered
`
`sublingually as a spray.
`
`22.
`
`A sealed container containing a plurality of doses of a formulation according
`
`to any one of claims 1 to 17.
`
`23.
`
`A container according to claim 22, which is made out of glass.
`
`24.
`
`A metered dose dispensing system comprising a sealed container according
`
`to claim 22 or claim 23 fitted with a metering pump, an actuator and a channelling
`
`device.
`
`25.
`
`A metered dose dispensing system according to claim 24 containing a
`
`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.
`
`26.
`
`A metered dose dispensing system according to claim 24 or claim 25 adapted
`
`for sublingual administration of the formulation as a spray.
`
`70
`
`75
`
`20
`
`

`
`
`
`03'
`
`'4?‘
`
`;
`5 Patent
`3% Office 3:
`[CWT
`“P9 é
`
`o '1“
`
`{c‘E
`,.A,,
`INVESTOR IN PEOPLE
`
`Application No:
`
`GB0328023.7
`
`Examiner:
`
`Dr Bill Thomson
`
`Claims searched:
`
`1-26
`
`Date of search:
`
`15 April 2004
`
`Patents Act 1977: Search Report under Section 17
`
`Documents considered to be relevant:
`
`16 at least
`
`(MORIMOTO) - See whole document, in particular page 3, line 37 —
`page 4, line 4 and Example 8
`
`page 3, line 34 - page 4, line 18 and Examples 2 and 3
`
`1 and 5 at W0 02/009707 A1
`
`(NYCOMED DANMARK A/S) - See whole document, in particular
`
`Cate ories:
`Document indicating lack of novelty or inventive
`step
`Y Document indicating lack of inventive step if
`combined with one or more other documents of
`same category.
`
`
`Patent document published on or after, but with priority date
`E
`& Member of the same patent family
`
`
`earlier than, the film date of this a u lication.
`
`
`
`
`
`
`Document indicating technological background and/or state
`of the art.
`Document published on or after the declared priority date
`but before the filing date of this invention.
`
`
`
`P
`
`
`
`
`
`Field of Search:
`
`Search of GB, EP, W0 & US patent documents classified in the following areas of the UKCW 2
` :
`Worldwide search of patent documents classified in the following areas of the IPCO7
`A61K; A61P
`The followin online and other databases have been used in the rearation of this search re ort
`
`CAS—ONLINE, EPODOC, PAJ, TXTE & WPI
`
`An Executive Agency of the Department of Trade and lndusuy