Exhibit 1020
`
`Coalition For Affordable Drugs XI LLC
`Exhibit 1020
`Coalition For Affordable Drugs XI LLC v Insys Pharma, Inc.
`IPR2015-01800
`
`

`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2003/0190290 A1
`Ross
`(43) Pub. Date:
`Oct. 9, 2003
`
`US 20030190290A1
`
`(54) PHARMACEUTICAL COMPOSITIONS
`
`Jan. 23, 2001
`
`(GB) ....................................... .. 0101744.1
`
`(75)
`
`IHVGIHOFI C31ViIl ROSS, Hams (GB)
`
`Publication Classification
`
`Correspondence Address:
`MINTZ, LEVIN, COHN, FERRIS, GLOVSKY
`AND POPEO, P.C.
`ONE EINANCIAE CENTER
`BOSTON, MA 02111 (US)
`
`(51)
`
`Int. Cl.7 ........................ ..A61L 9/04; A61K 31/485;
`A6iK 31/445
`
`(52) U.S. Cl.
`
`........................... .. 424/45; 514/282; 514/317
`
`21 A l. N .:
`)
`pp
`°
`(
`(22) PCT Filed:
`
`10312200
`/
`’
`Jun. 22, 2001
`
`(86) PCT NO‘:
`
`PCT/GB01/02761
`
`(30)
`
`Foreign Application priority Data
`
`Jun. 22, 2000
`
`(GB) ....................................... .. 00153601
`
`(57)
`
`ABSTRACT
`
`The present invention relates tocornpositions and dispens-
`ing devices for improved administration of fentanyl and
`other opioid analgesics, such as alfentanil, carfentanil,
`rernifentanil, sufentanil, buprenorphine, morphine, diamor-
`phine, and the like.
`
`

`
`Patent Application Publication
`
`Oct. 9, 2003 Sheet 1 of 3
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`US 2003/0190290 A1
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`

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`Patent Application Publication
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`Oct. 9, 2003 Sheet 2 of 3
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`US 2003/0190290 A1
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`

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`Patent Application Publication
`
`Oct. 9, 2003 Sheet 3 of 3
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`US 2003/0190290 A1
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`FIG. 6
`
`

`
`US 2003/0190290 A1
`
`Oct. 9, 2003
`
`PHARMACEUTICAL COMPOSITIONS
`
`[0001] The present invention relates to compositions and
`dispensing devices for improved administration of fentanyl
`and other opioid analgesics, such as alfentanil, carfentanil,
`remifentanil, sufentanil, buprenorphine, morphine, diamor-
`phine, and the like.
`
`[0002] Opioid analgesics are frequently used for the relief
`of moderate to severe pain, as well as in anaesthesia. The
`present invention relates primarily to the use of fentanyl and
`other opioid analgesics in pain management and in particular
`to the treatment of acute pain or “break-through” pain.
`Ideally, this type of pain relief has rapid onset. Fentanyl and
`other opioid analgesics have rapid effect following admin-
`istration, making them particularly suited for the treatment
`of break-through pain. Nevertheless, onset of their analgesic
`effect can be slowed considerably if there is a delay between
`administration and uptake of the active agent into the blood.
`Such delay means that certain modes of administration are
`unsuitable for treatment requiring rapid onset and are there-
`fore not to be used in the treatment of break-through pain.
`
`consideration when
`[0003] A particularly important
`administering opioid analgesics is that the doses are accu-
`rately controlled and are reproducible. Firstly, it is impera-
`tive that
`the patient does not over-dose. Large doses of
`opioid analgesics may lead to respiratory depression and
`some euphoric activity, which can lead to abuse and depen-
`dency. Secondly,
`it
`is undesirable for the patient
`to be
`provided with a dose which is too small, as such a dose is
`likely to provide inadequate pain-relief.
`
`[0004] Whilst the use of opioid analgesics, and especially
`fentanyl, for the treatment of pain has been proposed in the
`past, an inability to provide accurate and reproducible dos-
`ages severely reduces its actual use in practice.
`
`[0005] The aim of the present invention is, therefore, to
`ensure that accurate and reproducible doses of formulations
`comprising opioid analgesics are administered to a patient.
`This is achieved by a combination of two features. Firstly, a
`mode of administration is selected which not only provides
`rapid absorption of a dispensed dose into the blood stream,
`but also provides absorption of a predictable amount of the
`dispensed opioid analgesic into the blood stream. Secondly,
`a formulation is provided which can be dispensed so that an
`accurate and reproducible amount of the opioid analgesic is
`present in each dispensed dose.
`
`invention is particularly concerned
`[0006] The present
`with providing patient-controlled analgesia, where the
`patients self-administer the drug in response to the pain they
`are experiencing. This can reduce the period of time during
`which the patient’s pain goes untreated. Ideally, for such
`self-pain management to be effective, the drugs must be
`available to the patient in such a way that they can be easily
`and safely administered.
`
`[0007] A number of methods of administering fentanyl
`and other opioids are know, each having disadvantages
`which mean that the doses administered can be unpredict-
`able and inaccurate. The known methods of administration
`
`include injection, inhalation (lung delivery), oral adminis-
`tration and transdermal absorption (using patches).
`
`for
`is known,
`[0008] Oral administration of fentanyl
`example in the form of tablets, lozenges or elixirs and the
`
`like. Whilst this mode of administration is undoubtedly very
`convenient and easy for the patient, the active agent fentanyl
`is only slowly absorbed into the blood stream via the
`gastrointestinal tract and the onset of the drug’s effect is
`therefore delayed. The drug also undergoes
`first-pass
`metabolism in the liver when administered orally. Further-
`more, patients requiring break-through pain relief frequently
`drift in and out of consciousness and so administration of the
`
`analgesic in the form of a tablet or lozenge will therefore
`pose a risk of choking, making constant supervision of the
`patient essential.
`
`[0009] Transdermal patches for the delivery of fentanyl
`are also known. They rely upon a gradual absorption of the
`active agent through the skin and have been designed for
`rate-controlled drug delivery, that is slow release over a long
`period of time. Transdermal patches provide a convenient
`mode of delivery for opioid analgesics over an extended
`period of time. Opioid analgesics were previously consid-
`ered unsuitable for providing analgesic effect over a pro-
`longed period of time because they exhibit rapid onset and
`have a relatively short period of analgesic effect. Despite the
`benefits of transdermal patches, the slow administration is
`clearly not suited to treatment of break-through pain, where
`immediate relief is desired. Transdermal patches have also
`been found to cause irritation in some patients. Studies have
`also shown that transdermal patches occasionally result in
`unexpectedly increased absorption and therefore severe tox-
`icity.
`
`Injection is obviously one mode of administration
`[0010]
`which will allow rapid onset of fentanyl and other opioid
`analgesics. However, injections are painful, especially when
`regular administration is required. It can also be difficult for
`patients to inject themselves, especially if weak or lacking
`co-ordination, often making it necessary for someone other
`than the patient to perform the administration. This clearly
`reduces the patient’s own control over the dosage level.
`
`[0011] An alternative means of administering fentanyl
`which provides rapid onset of the physiological effect is lung
`delivery by inhalation. Fentanyl aerosol compositions are
`known for inhalation, for example, using metered dose
`inhalers. Such inhalers represent a simple and portable
`means of providing on-demand dosing. The metered dose
`inhalers may be provided with safety mechanisms to ensure
`that the patient cannot administer too much drug over a
`certain period,
`thereby reducing the risk of an overdose.
`Aerosol compositions for inhalation are disclosed in WO90/
`07333 and WO95/31182. The compositions disclosed con-
`tain fentanyl or fentanyl derivatives, either in solution or
`suspension in the aerosol propellant system, optionally in
`the presence of a cosolvent.
`
`[0012] However, there are some disadvantages associated
`with lung delivery. Inhalation of known formulations has
`been found to cause a pronounced and involuntary cough,
`possibly due to irritation of the trachea and lungs by the
`active agent
`in the composition. A further disadvantage
`associated with inhalation is that it requires patient coordi-
`nation to properly draw the composition into the lungs. This
`means that failure to properly coordinate spraying the com-
`position and inhaling may lead to only part of the dose
`reaching the lungs and being taken up. Additionally, the
`inhalation mode of administration also relies upon the
`patient’s ability to inhale deeply and this can pose a problem
`
`

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`US 2003/0190290 A1
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`Oct. 9, 2003
`
`where the patient is weak or a smoker, for example. The
`patency of the patient’s airways is clearly also an important
`factor. Consequently, it is difficult to guarantee a predictable
`or consistent dose when administering the opioid formula-
`tion by inhalation.
`
`It is probably as a result of the abovementioned
`[0013]
`problems associated with aerosol inhalation that no form of
`fentanyl lung delivery has been marketed to date.
`
`[0014] The applicants have found that the disadvantages
`experienced when using the known methods of administra-
`tion discussed above may be overcome when fentanyl or
`other opioid analgesics are administered sublingually, pref-
`erably as an aerosol spray. Sublingual delivery of a phar-
`maceutically active agent results in fast uptake. The active
`agent is administered to the oral and sublingual mucosa,
`from which it
`is rapidly absorbed into the bloodstream.
`Sublingual delivery also avoids first-pass metabolism of the
`active agent.
`
`[0015] Sublingual spray delivery is preferred over other
`types of sublingual delivery such as tablets, lozenges and
`liquids, as the amount of the active agent which is acciden-
`tally swallowed and therefore is not immediately effective is
`significantly reduced. Additionally, the spray administration
`can result
`in even faster absorption of the active agent
`through the sublingual mucosa.
`
`[0016] The sublingual spray mode of delivery does not
`suffer from the disadvantages discussed above in connection
`with inhalation. Rather, the amount of the dispensed dose
`which actually enters the blood stream can be accurately
`predicted, as only a small proportion of the dispensed dose
`will be “lost”, i.e. will not be absorbed through the sublin-
`gual mucosa.
`
`[0017] Sublingual delivery of fentanyl and other opioid
`analgesics is clearly an attractive method of administration.
`For example, spraying the composition under the tongue is
`painless and much more suitable for self-administration for
`the majority of patients than injection. Furthermore, unlike
`lung delivery by inhalation, sublingual delivery does not
`cause irritation of the trachea and lungs and there is no
`attendant cough. A further advantage of sublingual delivery
`over lung delivery by inhalation is that there is no require-
`ment for patient co-ordination or the ability to inhale deeply,
`the sprayed dose merely has to be directed under the tongue.
`
`formulations comprising fentanyl and
`[0018] Aerosol
`other opioid analgesics are known in the prior art for
`administration by inhalation. The formulations disclosed
`generally comprise an opioid salt, a propellant and a solvent.
`As opioid salts are not soluble in propellants and are also not
`soluble in commonly used solvents, such as ethanol, these
`formulations are suspensions.
`
`disadvantages
`have
`formulations
`[0019] Suspension
`which result in dispensed doses containing an unpredictable
`amount of the opioid analgesic, thereby rendering them
`unsuitable for providing the desired accurate and reproduc-
`ible doses.
`
`[0020] Opioid salts are soluble in water. However, aque-
`ous solutions are not suitable for the purposes of the present
`invention, as they would require the inclusion of preserva-
`tives, which is undesirable in a pharmaceutical preparation.
`
`Indeed, aqueous pharmaceutical solutions are generally
`avoided because of their frequent instability.
`
`In order for an accurate and reproducible amount of
`[0021]
`the opioid analgesic to be dispensed in a single dose, the
`opioid must be uniformly distributed throughout the formu-
`lation. If the formulation is a suspension, the opioid will not
`be uniformly distributed.
`It
`is well known to agitate a
`suspension formulation prior to dispensing,
`in order to
`disperse the suspended active agent. However, rapid cream-
`ing, settling or flocculation after such agitation are common
`sources of dose irreproducibility in suspension formulations.
`
`the opioid analgesic
`in a solution,
`In contrast,
`[0022]
`would be uniformly dispersed, leading to the same amount
`of opioid always being present in a given volume of the
`formulation.
`
`[0023] A fiirther problem associated with the use of an
`aerosol suspension formulation is that the formulation is
`significantly more likely to clog the nozzle of the dispensing
`device than a solution is. Such clogging can, once again,
`render it very unlikely that accurate and reproducible doses
`are dispensed.
`
`In contrast, to the opioid analgesic salts, the free
`[0024]
`base form of opioid analgesics are soluble in conventional
`propellants. Thus, formulations comprising an opioid anal-
`gesic free base will be solutions.
`
`In accordance with a first aspect of the present
`[0025]
`invention, a pharmaceutical composition is provided com-
`prising a solution of an opioid analgesic and a propellant, for
`sublingual administration. The opioid analgesic may be
`selected from fentanyl, alfentanil, carfentanil, remifentanil,
`sufentanil, buprenorphine, morphine, and diamorphine.
`
`In a preferred embodiment of the invention, the
`[0026]
`opioid analgesic is in the free base form. Preferably, the
`opioid is fentanyl free base.
`
`In another preferred embodiment, the composition
`[0027]
`is a solution which is substantially free of water. The
`concentration of water in the composition should be less
`than 0.25% and is preferably less than 0.15%.
`
`[0028] The propellant may be, for example, 1,1,1,2-tet-
`rafluoroethane (HFC-134a), 1,1,1,2,3,3,3-heptafluoropro-
`pane (HFC-227) or a combination thereof. An alternative
`propellant which may be used is butane.
`
`frequently
`aerosol compositions
`In the past,
`[0029]
`included one or more chlorofluorocarbon as a propellant,
`dichloro-difluoromethane being commonly used. It is well
`documented that chlorofluorocarbons are implicated in the
`depletion of the ozone layer and their production, therefore,
`is being phased out. 1,1,1,2-tetrafluoroethane (HFC-134a)
`and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) are signifi-
`cantly less harmful to the ozone layer and they are of low
`toxicity and of suitable vapour pressure for use as aerosol
`propellants, making then suitable for use in pharmaceutical
`aerosols. An additional benefit is that HFC-134a and HFC-
`
`227 can be used in combination with many pharmaceutically
`active agents, without causing any degradation to them or
`reducing their physiological activity. They are also not
`flammable.
`
`the composition
`In a preferred embodiment,
`[0030]
`according to the first aspect of the invention comprises
`
`

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`US 2003/0190290 A1
`
`Oct. 9, 2003
`
`between 50 and 99% w/w HFC-134a or HFC-227. More
`preferably, the amount of propellant is between 75 and 95%
`w/w.
`
`the
`the composition may comprise just
`[0031] Whilst
`active agent and propellant, the propellant will evaporate
`upon spraying and the active agent will therefore have no
`other constituent to “hold it in place” at
`the sublingual
`mucosa. It is essential that the active agent remain in contact
`with the sublingual mucosa for long enough to allow absorp-
`tion. It is therefore preferable for the composition of the
`present invention to include a carrier. In a preferred embodi-
`ment of the invention, the carrier is a lower alkyl (C1-C4)
`alcohol, a polyol, or a (poly) alkoxy derivative. In embodi-
`ments,
`the carrier is a C1-C4 alkyl alcohol or a lanolin
`alcohol and, preferably, is ethanol or isopropyl alcohol. The
`most preferred alcohol is ethanol. The carrier does not act as
`a solvent or co-solvent.
`
`[0032] The preferred polyols include propylene glycol and
`glycerol and the preferred (poly) alkoxy derivatives include
`polyalkoxy alcohols, in particular 2-(2-ethoxyethoxy) etha-
`nol (available under the Trademark Transcutol®).
`
`[0033] Further preferred (poly)alkoxy derivatives include
`polyoxyalkyl ethers and esters, such as polyoxyethylene
`ethers or esters. The preferred polyoxyethylene ethers and
`esters are polyoxyethylene alkyl ethers, polyoxyethylene
`castor oil derivatives, polyoxyethylene sorbitan fatty acid
`esters and polyoxyethylene stearates.
`
`[0034] The preferred fatty acid alkyl esters are ethyl
`oleate,
`isopropyl myristate and isopropyl palmitate. The
`preferred polyalkylene glycol is polyethylene glycol.
`
`In preferred embodiments, the inventive composi-
`[0035]
`tion can comprise up to 50% or, preferably, 25% w/w carrier.
`More preferred embodiments include between 3% and 15%
`w/w, or between 4 and 10% w/w carrier. The pharmaceutical
`compositions can comprise between 50% and 99% w/w,
`preferably between 75% and 99% w/w, and, more prefer-
`ably, between 88% and 95% w/w HFC-134a or HFC-227.
`
`In further embodiments, compositions used in the
`[0036]
`present invention can comprise a plurality of different car-
`riers.
`
`[0037] Further excipients can be included in the compo-
`sitions employed in the present invention. For example,
`neutral oils as well as surfactants (the latter for aiding the
`smooth operation of the valve), as are well known to those
`skilled in the art, may be included.
`
`[0038] Thus, in further preferred embodiments, composi-
`tions employed in the invention can comprise an organic
`surfactant. The preferred organic surfactant is oleyl alcohol,
`although others can be employed, including sorbitan tri-
`oleate, sorbitan mono-oleate, sorbitan monolaurate, poly-
`oxyethylene (20) sorbitan monolaurate, polyoxyethylene
`(20) sorbitan mono-oleate, natural lecithin, oleyl polyox-
`ytheylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl
`polyoxyethylene (4) ether, block copolymers of oxyethylene
`and oxypropylene, oleic acid, synthetic lecithin, diethylene
`glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, iso-
`propyl myristate, glyceryl mono-oleate, glyceryl monostear-
`ate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol,
`cetyl pyridinium chloride, olive oil, glyceryl monolaurate,
`corn oil, cotton seed oil or sunflower seed oil.
`
`It is preferable to include a flavouring oil in a
`[0039]
`composition to be delivered sublingually, in order to mask
`the unpleasant taste of the combination of propellant and
`opioid analgesic. The preferred flavouring oil is peppermint
`oil, although it is clear that other flavour oils may be used,
`according to preference.
`
`[0040] The inclusion of the flavouring oil is also beneficial
`as it serves to lubricate the valve of the dispensing device,
`thereby helping its smooth and reliable operation. Thus,
`inclusion of the flavouring oil obviates the need for the
`composition to include an additional lubricant.
`
`[0041] Furthermore, a volatile oil, such as peppermint oil,
`acts as a penetration enhancer when included in a compo-
`sition for aerosol sublingual delivery, thereby increasing the
`absorption of the active agent at the sublingual mucosa and
`making the administration more effective. Thus, inclusion of
`a volatile flavouring oil will further obviate the need for the
`composition to include an additional penetration enhancer.
`
`In a particularly preferred embodiment of the
`[0042]
`invention, the composition a solution of fentanyl free base,
`ethanol as a carrier, and HFC-134a as a propellant.
`
`[0043] According to a further preferred embodiment, the
`compositions of the present invention comprise opioid anal-
`gesics in combination with other pharmaceutically active
`agents. For example, the muscular rigidity, which may be
`experienced upon administration of
`fentanyl, may be
`antagonised by co-administration of a muscle relaxant, such
`as naxalone. Similarly, the respiratory depression which may
`be associated with the administration of opioid analgesics
`may be countered by administering an additional active
`agent.
`
`In accordance with a second aspect of the present
`[0044]
`invention, devices are provided for sublingually delivery of
`the opioid analgesic compositions according to the first
`aspect of the invention. These devices can assist dispensing
`of accurate and reproducible doses, and/or can assist direc-
`tion of the dispensed dose to the sublingual area, to ensure
`that as mush of the dispensed dose as possible is absorbed
`through the sublingual mucosa.
`
`[0045] Devices for administering metered aerosol doses of
`pharmaceutical preparations are well known in the art, and
`include devices with inverted valves and upright valves.
`Devices with inverted valves are preferred, as the volumes
`of pharmaceutical composition that they dispense are more
`accurate and consistent. Examples of suitable upright valve
`devices for dispensing the pharmaceutical compositions
`described herein are readily available from Bespak PLC of
`Bergen Way, Kings Lynn, Norfolk PE30 2JJ, United King-
`dom.
`
`[0046] Devices with upright valves include those dis-
`closed in WO 92/11190, U.S. Pat. No. 4,819,834 and U.S.
`Pat. No. 4,407,481. Many of these devices include metering
`valves having components formed from plastic materials,
`such as the valves available from Bespak PLC of Bergen
`Way, Kings Lynn, Norfolk PE30 2JJ, United Kingdom, in
`which the valve core, metering chamber and some other
`structural components are formed from plastic materials.
`The plastic materials currently used for forming these struc-
`tural parts in valves employed with many chlorofluorocar-
`bon containing compositions include certain acetal co-poly-
`mers.
`
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`US 2003/0190290 A1
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`Oct. 9, 2003
`
`[0047] Although the plastics employed to manufacture
`metering valves, including the aforementioned acetal co-
`polymers, have also been found to be stable in the presence
`of HFC-134a alone, the applicants, to their surprise, have
`determined that many of these plastics materials can be
`caused to swell in the presence of compositions which
`include certain carriers or active agent solubilising co-
`solvents with HFC-134a. When such swelling takes place in
`a valve, the fit of mutually slidable components, such as
`metering chambers and valve cores, is adversely effected
`and they can bind together or become loose, causing the
`valve to leak or cease functioning altogether. It
`is very
`important to avoid this problem in connection with the
`present invention.
`
`[0048] This problem has now been solved by using a
`device for providing pharmaceutical doses comprising a
`container, filled with a pharmaceutical composition accord-
`ing to the first aspect of the invention, and valve means
`arranged for delivering aerosol doses of said pharmaceutical
`composition to the exterior of the container, wherein at least
`a portion of the device is formed from a polyester. Prefer-
`ably,
`the valve means includes at least one component
`formed from a polyester, which component, more prefer-
`ably, is a metering chamber and/or a valve core.
`
`In further embodiments, the container comprises a
`[0049]
`polyester and, preferably, consists of metal lined with a
`polyester. The canister cap can also be so formed.
`
`[0050] Apart from allowing the aforementioned swelling
`problem to be solved, an advantage of this aspect of the
`present
`invention is that use of expensive metal valve
`components can be avoided.
`
`[0051] The preferred polyesters are polyalkylene benzene
`dicarboxylates, more preferably polyalkylene terephthalates
`and, most preferably, a polybutylene terephthalate.
`
`[0052] Such materials, preferably, have a density of about
`1.3g/cm3 and a water absorption of about 0.6% (23° C.
`saturation). The polyesters, also, are preferably partially
`crystalline in nature and have a crystalline melting range of
`220-225° C.
`
`[0053] Examples of suitable polybutylene terephthalates
`include those available under the Trademark Celanex® from
`
`Hoechst UK Limited, Walton Manner, Milton Keynes,
`Bucks MK7 7AJ, United Kingdom. Particularly preferred
`are Celanex® 2500 and Celanex® X 500/2.
`
`In another preferred embodiment of the present
`[0054]
`invention, the dispensing device has a bespoke mouthpiece,
`the mouthpiece being adapted to channel and direct
`the
`composition according to the first aspect of the invention
`from an orifice of the device, towards the sublingual area of
`the patient. Such a mouthpiece could be used in conjunction
`with a conventional spray device, such as one of the types
`discussed above.
`
`the dispensing
`the mouthpiece of
`[0055] Preferably,
`device is angled in relation to the main body of the device,
`so that the mouthpiece directs the dispensed composition to
`the sublingual mucosa when the device is activated whilst
`held in the normal position for use.
`
`[0056] Such a mouthpiece could be used in conjunction
`with devices having either an upright or an inverted valve.
`
`In a preferred embodiment, the device has an inverted valve,
`such devices generally being capable of dispensing accurate
`volumes of composition.
`
`In a further preferred embodiment, the mouthpiece
`[0057]
`for directing the dispensed composition to the sublingual
`area is part of a housing in which the main body, including
`the container, of the spray device is held. The mouthpiece
`could be rigidly fixed with respect to the housing, or the
`connection between the housing and the mouthpiece could
`be flexible, allowing the angle of the mouthpiece relative to
`the main body of the device to be adjusted.
`
`In a further embodiment, the mouthpiece is shaped
`[0058]
`in such a way that it assists directional dispensing of the
`composition to the sublingual area of the mouth.
`
`[0059] Preferably, the mouthpiece is long enough to allow
`the opening of the mouthpiece to sit under the tongue when
`the composition is dispensed. This will reduce the amount of
`composition being dispensed to parts of the oral cavity other
`than the sublingual area. Even more preferably, for greater
`comfort and greater ease of use, the mouthpiece is also a
`slim shape, fitting comfortably under the tongue or being
`comfortably held to direct the spray towards the sublingual
`area.
`
`[0060] Additionally, the mouthpiece may also be shaped
`in such a way that it discourages the spread of the dispensed
`composition after it leaves the mouthpiece. When a com-
`position is dispensed by a conventional spray device it will
`generally spread, forming a cloud. This is undesirable where
`a small area of the oral cavity is to be targeted. In a preferred
`embodiment, the mouthpiece opening is no larger than the
`average size of the sublingual area. This means that, despite
`some degree of spreading of the dispensed composition after
`it has left the mouthpiece, the spread will be limited to
`ensure that the area of the oral cavity contacted by the
`dispensed composition will correspond generally to the
`sublingual area, provided the composition is dispensed in
`the correct direction.
`
`It is also advantageous for the dispensing device to
`[0061]
`be adapted to reduce or control the velocity at which the
`dispensed composition leaves the device. This will help to
`ensure that the composition comes into contact with the
`sublingual mucosa and stays in contact for long enough for
`the pharmaceutically active agent
`to be absorbed. Such
`control may be provided, to an extent, by the shape of the
`mouthpiece of the dispensing device.
`
`[0062] Thus, in a possible embodiment, the mouthpiece of
`the spray device has a cross-sectional area which first
`gradually increases, and then decreases. The resultant
`“duckbill” shape may both control
`the velocity of the
`dispensed composition and limit its spread. It is clear that a
`variety of mouthpiece shapes may be used to reduce the
`velocity of the dispensed composition.
`
`In another preferred embodiment, the velocity with
`[0063]
`which the composition is dispensed is also reduced by
`providing the device with a plurality of orifices through
`which the composition is released. The provision of more
`than one orifice will
`reduce the force with which the
`
`dispensed composition is released from the main body of the
`device, thereby reducing its exit velocity. The more orifices
`through which the composition is dispensed, the slower the
`velocity of the substance dispensed.
`
`

`
`US 2003/0190290 A1
`
`Oct. 9, 2003
`
`In a yet more preferred embodiment, in a device
`[0064]
`having a plurality of orifices these orifices may be shaped
`and positioned to be directional, preferably serving to direct
`the individual jets of dispensed composition toward on
`another, to avoid unnecessary and undesirable spreading of
`the composition around the oral cavity.
`
`[0065] Most preferably, the orifices are directed so that jets
`of dispensed composition converge at a point which is
`approximately the same distance from the nozzle of the
`device as the sublingual area will be from the nozzle when
`the device is used. Thus, the composition should contact a
`relatively small area, avoiding wastage caused by the com-
`position being dispensed to areas other than the sublingual
`mucosa.
`
`In a preferred embodiment of the invention, the
`[0066]
`orifices of the device are further adapted to dispense par-
`ticles of a particular size, thereby optimising absorption
`across the sublingual mucosa.
`
`[0067] Some examples of devices for sublingual delivery
`of opioid analgesics will now be described, by way of
`example only, and with reference to the following drawings.
`
`[0068] FIG. 1 is a cross sectional View of an embodiment
`of a device in accordance with the invention.
`
`[0069] FIG. 2 is a cross sectional View of an embodiment
`of a housing, including a mouthpiece, for an inverted valve
`device, in accordance with the present invention.
`
`[0070] FIG. 3 is a view of the underside of the housing
`shown in FIG. 2.
`
`[0071] FIG. 4 is a perspective View of the housing shown
`in FIG. 2.
`
`[0072] FIG. 5 is a view down the mouthpiece of the
`housing shown in FIG. 2, the housing containing a spray
`device with a nozzle having three orifices.
`
`[0073] FIG. 6 is a side View of a device with an upright
`valve, and a mouthpiece according to the present invention.
`
`[0074] FIG. 7 is a perspective view of the device shown
`in FIG. 6, wherein the spray device is being activated by
`downward pressure on the top of the device.
`
`[0075] The device 1, shown in FIG. 1, comprises a
`substantially cylindrical canister 2 sealed with a cap 3. Both
`the canister 2 and the cap 3 may be manufactured from a
`variety of materials. The canister and cap may be lined with
`a polyester (such as Celanex® 2500) or a lacquer (not
`shown).
`
`[0076] A valve body moulding 4 comprises a cylindrical
`portion 5, which defines a metering chamber 6 and a stepped
`flange portion 7, and is formed by injection moulding from
`Celanex® 2500. The stepped flange portion 7 defines a first
`and outwardly facing annular seat 8 and a second, inwardly
`facing annular seat 9. The first annular seat 8 accommodates
`an annular sealing ring 10 and the second annular seat 9
`accommodates a first sealing washer 11. The first sealing
`washer 11 is located so as to cooperate with the cylindrical
`portion 5 of the valve body moulding 4, in defining the
`metering chamber 6.
`
`[0077] A base 12 of the cylindrical portion 5 of the valve
`body moulding 4 completes the boundary to the metering
`chamber 6 and provides a seat for a second sealing washer
`13.
`
`[0078] The sealing ring 10 and the first and second sealing
`washers 11 and 13 can be formed from a butyl rubber,
`neoprene or one of the elastomers disclosed for such pur-
`poses in WO 92/11190.
`
`[0079] An elongate, substantially cylindrical and partially
`hollow valve core 14 is slidably located within the first and
`second sealing washers 11 and 13 and extends through an
`orifice 15, defined in the base 12. The valve core 14 is
`formed by injection moulding from Celanex® 2500.
`
`[0080] Astepped inlet passage 16 communicates between
`a first end 17 of the valve core 14 and an inlet orifice 18,
`formed through the side of the valve core 14. In a likewise
`manner, an outlet passage 19 communicates between the
`second end 20 of the valve core 14 and an outlet orifice 21
`
`formed through the side of the valve core 14. An annular
`flange 22 extends radially outwardly from the valve core 14
`between the inlet and outlet orifices 18 and 21 and adjacent
`to the outlet orifice 21.
`
`[0081] A stainless steel compression coil spring 23 acts
`between the annular flange 22 and the second sealing washer
`13, urging the annular flange 22 into contact with the first
`sealing washer 11, such that the outlet orifice 21 lies inside
`the first sealing washer 11 and is thereby isolated from the
`metering chamber 6. In this position, as shown in FIG. 1, the
`inlet orifice 18 is located within the metering chamber 6. A
`flexible tube 24 is engaged within the stepped inlet passage
`16 and extends from the valve core 14 to the