PCT
`
`International Bureau
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 :
`
`(11) International Publication Number:
`
`WO 90/07333
`
`A61K 31/445, 9/12, 9/72
`
`(43) International Publication Date:
`
`12 July 1990 (l2.07.90)
`
`(21) International Application Number:
`
`PCT/GB90/00015
`
`(22) International Filing Date:
`
`4 January 1990 (O4.0l.90)
`
`(74) Agent: BOWMAN, P., A.; Lloyd Wise, Tregear & Co.,
`Norman House, 105-109 Strand, London WC2R OAE
`(GB).
`
`(81) Designated States: AT (European patent), BE (European
`patent), CA, CH (European patent), DE (European pa-
`tent), DK (European patent), ES (European patent), FR
`(European patent), GB (European patent), IT (European
`patent), JP, LU (European patent), NL (European pa-
`tent), SE (European patent), US.
`
`Published
`With international search report.
`
`(30) Priority data:
`8900267.9
`
`6 January 1989 (06.0l.89)
`
`GB
`
`(71) Applicant (for all designated States except US): RIKER LA-
`BORATORIES, INC. [US/US]; 19901 Nordhoff Street,
`Northridge, CA 91324 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only) : PUREWAL, Tarlochan,
`Singh [GB/GB]; 196 Radford Road, Leamington Spa,
`Warwickshire CV31 lLQ (GB). WILKINSON, Anthony
`[GB/GB]; 9 Woodlands Drive, Loughborough, Leices-
`tershire LEl1 3LR (GB). LAMBERT, Alison, Lesley
`[GB/GB];
`1 Goldgarth, Grimsby, South Humberside
`DN32 8QS (GB). SMITH, David, Keith [GB/GB]; 8
`Springfield Close, Loughborough LE1l 3PT (GB).
`DONNELL, David [GB/GB]; Highthorne Cottage,
`Wide Lane, Wymeswold, Leicestershire LEl2 6SE (GB).
`KUEPPER, Anton [DE/DE]; Jupiterstrasse 13, D-4044
`Kaarst 1 (DE).
`
`(54) Title: FENTANYL CONTAINING AEROSOL COMPOSITIONS
`
`(57) Abstract
`
`Fentanyl and physiologically acceptable derivatives thereof dissolved or dispersed in an aerosol propellant to form an aer-
`osol formulation for administration by inhalation.
`
`MYLAN EX 1011, Page 1
`
`MYLAN EX 1011, Page 1
`
`

`
`FOR THE PURPOSES 0F INFORAMTION ONLY
`
`Codes used to identifil States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT‘.
`
`LS
`
`AT
`AU
`BB
`BE
`
`Austria
`Australia
`Barbados
`Belgiim
`Burkina Pam
`Bulgaria
`Benin
`Brazil
`Canada
`Central Afiiaan Republic
`Congo
`Switzerland
`Cameroon
`Germany. Federal Republic of
`Denmark
`
`United Kingdom
`Hungary
`ltaly
`Japan
`Democratic People’s Republic
`of Korea
`Republic of Korea
`Liechtennein
`Sri lanka
`Luxembourg
`Monaco
`
`II
`
`)1
`
`Madagascar
`Mali
`Mauritania
`Malawi
`Netherlands
`Norway
`Romania
`Sudan
`Sweden
`Senegal
`Soviet Union
`Chad
`T050
`United States of America
`
`MG
`ML
`MR
`MW
`NL
`M)
`RD
`
`ES
`
`E
`SV
`SJ
`TD
`TG
`
`MYLAN EX 1011,Page 2
`
`MYLAN EX 1011, Page 2
`
`

`
`W0 90/07333
`
`PCT/GB90/00015
`
`Fentanyl containing aerosol compositions.
`
`This invention relates to analgesic formulations and
`
`in particular to analgesic formulations comprising
`
`fentanyl suitable for administration by inhalation.
`
`Narcotic analgesics are used to relieve moderate to
`
`severe pain, particularly of a visceral origin.‘ The
`
`narcotic analgesics are generally administered by sub-
`
`cutaneous,
`
`intra-muscular or intravenous injection, or
`
`orally in the form of elixirs, tablets (optionally
`
`sublingual) and capsules, or by rectal administration in
`
`the form of suppositories.
`
`In the case of patients who
`
`are hospitalised narcotic analgesics are often
`
`administered in the form of saline drips.
`
`Since the metered dose pressurised inhaler was
`
`introduced in the mid 1950's,
`
`inhalation has become the
`
`most widely used route for delivering bronchodilator drugs
`
`and steroids to the airways of asthmatic patients.
`
`Compared with oral administration of bronchodilators,
`inhalation offers a rapid onset of action and a low
`
`instance of systemic side effects. More recently,
`
`inhalation from a pressurised inhaler has been a route
`
`selected for the administration of other drugs, e.g.,
`
`ergotamine, which are not primarily concerned with
`
`treatment of a bronchial malady.
`
`Various publications, e.g., British Patents Nos.
`
`830426, 837465, 994734 and 2125426: European Patent Nos.
`
`0162239 and W086/04233 which relate to self-propelling
`
`pharmaceutical compositions for administration from
`
`pressurised inhalers disclose the possibility of employing
`
`an analgesic such as morphine, diamorphine and
`
`buprenorphine hydrochloride in such formulations although
`
`there is no disclosure of any specific formulations
`
`containing such analgesics nor any indication of their
`
`efficiency when administered by inhalation.
`
`MYLAhlEX1011,Page3
`
`MYLAN EX 1011, Page 3
`
`

`
`W0 90/07333
`
`PCI‘/GB90/00015
`
`It has now been found that morphine and diamorphine
`
`hydrochloride are considerably less potent when
`administered by inhalation using self-propelling aerosol
`
`compositions than might have been expected from the known
`intravenous dosing data.
`It has also been found that
`
`fentanyl and in particular fentanyl citrate exhibits a
`
`potent, quick acting effect when administered by
`
`inhalation from a self-propelling aerosol formulation.
`Therefore according to the present invention there is
`
`provided an aerosol formulation comprising fentanyl or a
`
`physiologically acceptable derivative thereof dispersed
`
`or dissolved in an aerosol propellant.
`
`The invention also provides a pressurised aerosol
`
`inhaler comprising a container, containing an aerosol
`formulation as defined above, and a valve capable of
`
`dispensing metered doses of the formulation.
`
`The
`
`pressurised aerosol preferably incorporates the means to
`control the dosing frequency from the valve such that not
`
`more than a predetermined maximum number of doses may be
`
`dispensed within a set period of time.
`
`Such a
`
`pressurised inhaler allows the maximum dosage frequency
`
`available to the patient to be pre—set, whilst insuring
`
`the patient cannot receive an overdose.
`
`The inhaler
`
`provides the benefits of on-demand dosing for the patient
`
`with dosage control, and may be used both in hospitals and
`homes without requiring medical personnel to administer
`each dose.
`
`The formulations used in the invention contain T
`
`fentanyl or a derivative thereof either in solution or
`
`suspension in the aerosol propellant system, optionally in
`
`The solvent for fentanyl
`the presence of a cosolvent.
`will generally be present in an amount in the range 5 to
`25% by weight of the composition. The compositions may
`
`additionally comprise one or more surface active agents,
`for example oleic acids, complex esters and ester-ethers,
`e.g., sorbitan trioleate, Span 85, lecithins such as
`
`Epikuron 200, and fluorinated surfactants.
`
`The weight
`
`ratio of surface active agent to fentanyl is generally in
`
`1 MYLAN EX 1011, Page 4
`
`MYLAN EX 1011, Page 4
`
`

`
`W0 90/07333
`
`:
`
`PCI‘/GB90/00015
`
`the range 1 : 100 to 10 : 1.
`
`The concentration of
`
`fentanyl will generally be within the range 0.05 to 5.00%,
`preferably 0.1 to 1.0%, by weight based on the total
`
`composition.
`
`1 A wide range of propellants may be used in the
`
`aerosol formulations of the invention including:
`
`Propellant 11
`
`trichloromonofluoromethane
`
`Propellant 12
`
`dichlorodifluoromethane
`
`Propellant 13
`
`monochlorotrifluoromethane
`
`Propellant 21
`
`dichloromonofluoromethane
`
`Propellant 22
`
`monochlorodifluoromethane
`
`Propellant 113
`
`trichlorotrifluoroethane
`
`Propellant 114
`
`dichlorotetrafluoroethane
`
`Propellant 115
`
`monochloropentafluoroethane
`
`Propellant 134a
`
`1,1,1,2-tetrafluoroethane
`
`Propellant 500
`
`azeotrope of dichlorodifluoromethane
`
`and 1,1-difluoroethane
`In addition to chlorofluorocarbon aerosol propellants
`
`the formulations may contain other propellants, for
`
`example, DME (dimethylether), hydrocarbons and
`
`perfluorocarbons.
`
`One preferred propellant system is disclosed in our
`
`co—pending British Patent Application No. 8828477.3 and
`
`comprises 1,1,1,2-tetrafluoroethane, a surface active
`
`agent and at least one compound having a higher polarity
`
`than 1,1,1,2-tetrafluoroethane. Suitable compounds having
`
`a higher polarity than 1,1,1,2—tetraf1uoroethane include
`
`alcohols, such as ethyl alcohol,
`
`isopropyl alcohol,
`
`propylene glycol, hydrocarbons such as propane, butane,
`
`isobutane, pentane,
`
`isopentane, neopentane, and mixtures
`
`thereof.
`
`The 1,1,1,2-tetrafluoroethane preferably
`
`comprises at least 50% by weight of the formulation,
`
`preferably from 60 to 95% by weight of the formulation.
`
`The weight ratio of 1,1,1,2-tetrafluoroethane to the
`
`compound of higher polarity is generally in the range
`
`50 : 50 to 90: 1, preferably 70 : 30 to 98 : 2, more
`
`preferably 85 : 15 to 95 : 5.
`
`MYLAN EX 1011, Page 5
`
`MYLAN EX 1011, Page 5
`
`

`
`W0 90/07333
`
`a
`
`_
`
`T
`
`PCI‘/GB90/00015
`
`In an alternative system the fentanyl or derivative,
`
`thereof in the form of a finely divided solid is coated
`with a dry coating of a perfluorinated surface-active
`
`dispersing agent and thereafter mixed with an aerosol
`
`propellant.
`
`Such systems are disclosed generally in U.S.
`
`The preferred propellant for such
`Patent No. 4,352,789.
`formulation is 1,1,1,2-tetrafluoroethane, preferably with
`
`an adjuvant having a polarity equal to or lower than the
`
`polarity of 1,1,1,2-tetrafluoroethane.
`
`Suitable adjuvants having a polarity equal to or
`
`lower than Propellant 134a include perfluorinated organic
`
`compounds such as perfluorinated alkanes and cycloalkanes.
`
`Specific examples of adjuvants include perfluoropropane,
`
`perfluorobutane, perfluorocyclobutane, perfluoropentane,
`
`perfluorohexane, perfluorotributylamine,
`
`aperfluoromethylcyclohexane and perfluorodecalin.
`
`Such
`
`compositions generally comprise from 0.001 to 20% by
`weight of finely—divided solid fentanyl coated with a
`
`perfluorinated surface-active dispersing agent which
`
`constitutes at least 0.001%, normally 0.001 to 50%,
`
`preferably 0.001 to 20% by weight of the coated solid
`
`material, and suspended in an aerosol propellant
`comprising l,l,l,2-tetrafluoroethane and an adjuvantz
`
`having a polarity equal to or lower than that of l,l,l,2—
`
`tetrafluoroethane.
`
`0
`
`The perfluorinated surface-active dispersing agents
`
`(hereinafter referred to as "perfluorinated surfactants"
`
`or "surfactants") are substantially insoluble in the
`
`propellant.a This insolubility is due to the relatively
`
`ionic character of one end of the surfactant molecule.
`
`This ionic group is compatible with the solid powdered
`
`material and enables the surfactant to wet the solid
`
`material. Although the perfluorinated surfactant is
`
`insoluble in the propellant, when coated on the solid
`material,
`the outermost perfluorinated groups of the
`
`surfactant allow the solid coated material to be dispersed
`
`in the propellant due to the compatibility between the
`
`perfluorinated groups and the propellant.
`
`MYLAhlEX1011,Page6
`
`MYLAN EX 1011, Page 6
`
`

`
`WO 90/07333
`
`PCT/GB90/00015
`
`Perfluorinated surfactants most useful in the
`
`compositions of the present invention include
`perfluorinated alcohol phosphate esters and their salts;
`
`perfluorinated sulfonamide alcohol phosphate esters and
`
`their salts; perfluorinated alkyl sulfonamide alkylene
`
`quaternary ammonium salts; N,N-(carboxyl-substituted
`
`lower alkyl) perfluorinated alkyl sulfonamides;
`
`and
`
`mixtures thereof.
`
`By "perfluorinated" it is meant that
`
`the surfactant contains at least one perfluorinated alkyl
`
`group. Particularly preferred perfluorinated alcohol
`
`phosphate esters are the free acids of the diethanolamine
`
`salts of mono- and bis(lH,1H,2H,2H-perfluoroalkyl)
`
`phosphates.
`The phosphate salts, available under the
`trade name "Zonyl RP" from E. I Dupont de Nemours and
`
`Company, Wilmington, Del., are converted to the
`
`corresponding free acids.
`
`Preferred perfluorinated sulfonamide alcohol
`
`phosphate esters are described in U.S. Patent No.
`
`3,094,547, and have the general formula:
`
`0 l
`
`l
`[RfSO2N(R)R'O]mP(OH)3_m
`1
`
`in which;
`
`R is hydrogen or an alkyl group having from 1 to
`
`about 12, preferably from 1 to 6, carbon atoms;
`
`R‘
`
`is an
`
`alkylene bridging group containing 2 to about 12 carbon
`
`atoms, preferably from 2 to 8 carbon atoms; Rf is a
`
`perfluorinated radical selected from perfluoroaliphatic
`
`groups of general formula CnF2n+1 or
`
`perfluorocycloaliphatic groups of general formula
`
`CnF2n-1 in which;
`
`n is an integer from 1 to 18,
`
`preferably from 6 to 12, and m is an integer from 1 to 3.
`
`Although the mono-, di— and triesters are useful,
`
`the diester is most readily available commercially.
`
`Particularly preferred perfluorinated sulfanomide alcohol
`
`phosphate esters and salts of these include perfluoro-n-
`
`octyl-N—ethylsulfonamidoethyl phosphate, bis(perfluoro-n-
`
`octyl-N-ethylsulfonamidoethyl)phosphate,
`
`the ammonium
`
`MYLAhlEX1011,Page7
`
`MYLAN EX 1011, Page 7
`
`

`
`W0 90/07333
`
`PCI‘/GB90/00015
`
`6
`
`salt of bis(perfluoro-n-octyl-N-ethyl-sulfonamidoethyl)
`
`phosphate, bis(perfluorodecyl-N-ethylsulfonamidoethyl)
`
`phosphate and bis(perfluorohexyl-N-ethylsulfonamidoethyl)
`phosphate.
`The above named preferred surfactants are of
`
`particular use in medicinal aerosol compositions due to
`
`their non—irritating and non-toxic nature.
`
`The preferred perfluorinated alkyl sulfonamide
`alkylene quaternary ammonium salt for use in the
`
`preparation of aerosol medicaments according to the
`
`present invention is N,N-dimethyl-N-decyl-N-(perfluoro-n-
`
`octylsulfonamidopropyl)ammonium bromide.
`
`A preferred N,N-bis(carboxyl-substituted lower
`
`alkyl)perf1uorinated alkyl sulfonamide for use with
`
`medicaments in aerosol compositions of the present
`
`invention is N,N-bis(4-carboxyl-n-buty1perfluoro-n-
`
`octylsulfonamide).
`
`The perfluorinated surfactant constitutes at least
`
`0.001% and generally up to 50%, usually up to 20%,
`desirably between 0.1 and 5%, and preferably, for
`medicinal purposes, between 0.1 and 1% by weight of the
`
`solid material to be suspended. However, the minimum
`
`amount of perfluorinated surfactant required is dependent
`
`upon the concentration of solid material present.
`
`For
`
`best results,
`
`the concentration of perfluorinated
`
`surface-active agent is kept at a minimum as it may tend
`
`to increase the droplet size of the aerosol particles.
`
`The particle size of the powder should desirably be
`
`no greater than 100nm diameter, since larger particles may
`
`tend to agglomerate, separate from the suspension and may
`
`clog the valve or orifice of the container. Preferably
`
`the particle size should be less than 25pm in diameter.
`
`Desirably the particle size of the finely—divided solid
`
`powder should for physiological reasons be less than 25pm
`
`and preferably less than about 10um in diameter. The
`
`‘W
`
`particle size of the powder for inhalation therapy should
`preferably be in the range 2 to 10 microns.
`
`MYLAhlEX1011,Page8
`
`MYLAN EX 1011, Page 8
`
`

`
`W0 90/07333
`
`.
`
`PCI‘/GB90/00015
`
`The finely-divided solid material may constitute up
`
`to about 20% by weight of the total composition.
`
`Desirably it shall constitute up to 10%, generally up to
`
`5% and preferably up to 3%, by weight of the total
`
`composition.
`
`The minimum concentration of the solid
`
`material is governed by its specific activity and in the
`
`case of highly active material can be as low as 0.001% by
`
`weight of the total composition although a concentration
`
`of 0.01% is preferred.
`
`It is also possible to coat finely divided solid
`
`fentanyl or derivatives thereof with non-perfluorinated
`
`surface-active agents in similar manner and thereafter mix
`
`with a wide range of aerosol propellants. Propellant 134a
`
`is preferred because of its ozone friendly properties.
`
`other propellant systems which may be employed
`
`include mixtures of aerosol propellants. General
`
`concentration ranges for specific propellants which may be
`employed in admixtures are as follows:
`
`Propellant ll
`
`Propellant 12
`
`Propellant 22
`
`:
`
`:
`
`:
`
`15 to 25% by weight
`
`50 to 90% by weight
`
`5 to 50% by weight
`
`The aerosol formulations of the invention are
`
`preferably used in a pressurised aerosol inhaler
`
`comprising a container and a valve capable of dispensing
`
`doses of the formulation,
`
`in which the inhaler
`
`additionally comprises means to control the dosing
`
`frequency from the valve.
`
`The control means preferably comprises an electronic
`
`timing device associated with means to prevent actuation
`
`of the valve of the pressurised aerosol inhaler such that
`
`the inhaler may be disabled until the end of a controlled
`
`period of time during which a pre—set maximum number of
`
`doses have been dispensed.
`
`The electronic time control of
`
`the dosing frequency can take either of the following
`forms:
`
`MYLAhlEX1011,Page9
`
`MYLAN EX 1011, Page 9
`
`

`
`W0 90/07333
`
`PC'I‘/GB90/00015
`
`(i)
`
`The patient can take from 1 to 'N' doses at the start
`
`of the control period 'T'. The clock starts when the
`first dose is dispensed:
`the patient then has a shorter
`
`period 't' to take further doses up to 'N'.
`The device
`then locks out for the remainder of the control period
`IT! .
`
`(ii) The patient can take up to 'N' doses during the
`
`whole of the control period.
`
`The clock starts at the
`
`first dose in a new control period.
`
`Option (ii) is the preferred dosage-control mode for
`
`most situations.
`
`The control period,
`
`'T', and the
`
`maximum number of doses 'N' can be either factory pre—set
`
`or adjustable by medical or nursing staff.
`
`The inhaler
`
`device may have provision for internal adjustment of these
`
`control parameters. Alternatively,
`
`the controls may be
`
`positioned externally using one-way rotary switches which
`
`allow only increase of time 'T' and reduction of the
`maximum number of doses 'N' to prevent overdosage. The
`
`parameters may be set to ensure a sufficient time has
`elapsed for a dose to take effect before the patient may
`take a further dose.
`A further control feature which may be incorporated
`in the device is a locking mechanism designed to effect
`
`permanent disablement of the device after the label—claim
`
`number of doses has been dispensed,
`
`thus allowing precise
`
`control of the number of doses available from each aerosol
`
`container.
`
`A further feature which may be incorporated into the
`
`inhaler device is a liquid crystal display which may
`
`display a variety of information, for example:
`
`(a)
`
`the balance of the label—claim number of doses
`
`remaining in the aerosol canister,
`
`(b)
`
`the time remaining in the current control period,
`
`1-)
`
`and,
`
`(c)
`
`the number of available doses remaining in the
`
`current control period.
`
`MYLAhlEX1011,Page1O
`
`MYLAN EX 1011, Page 10
`
`

`
`W0 90/07333
`
`.
`
`PCT/GB90/00015
`
`Suitable inhaler devices are shown in the
`
`accompanying drawings in which:
`I Figure 1 represents a diagram of an inhaler, and,
`
`Figure 2 represents a block diagram of an electrical
`
`circuit for use in the inhaler of Figure 1.
`
`Referring to Figures 1 and 3 of the accompanying
`
`drawings,
`
`the inhalation devices comprise a housing 2
`
`accommodating an aerosol container 4 having a dispensing
`
`valve 6.
`
`The aerosol container 4 is mounted vertically
`
`with the outlet valve 6 positioned within a nozzle block
`
`8.
`
`The housing 2 has a mouthpiece 10 which may be adapted
`
`by the provision of a nasal adaptor if the medicament is
`
`to be administered via the nose.
`
`In use,
`
`the patient
`
`inhales via the mouthpiece 10,
`
`initiating movement of the
`
`container relative to the valve, causing a dose of
`
`medicament to be fired from the valve,
`
`through the nozzle
`
`block,
`into the mouthpiece, and thence into the lungs as
`the patient inhales.
`
`In the inhaler shown in Figure 1,
`
`the start of
`
`inhalation is sensed by a precision-moulded triggering
`
`mechanism which responds to an inhalation flow rate of
`
`about 30 litres/minute.
`
`The triggering mechanism
`
`comprises a vane 20 associated with a locking device
`
`acting on the nozzle block 8, allowing actuation of the
`
`aerosol device only during inhalation. Examples of such
`
`arrangements are disclosed in European Patent No.
`
`0l47028B.
`
`Force is first applied to the aerosol container
`
`by the manual raising of cocking lever 22. However, when
`
`the device is locked—out by the control means the cocking
`
`force will not facilitate actuation of the valve since
`
`movement of the vane of the triggering mechanism is
`
`blocked by lever 24.
`
`When doses are available to the patient,
`
`the control
`
`means causes operation of the solenoid 26, causing lever
`
`28 to be pushed forwards and its hooked end to engage
`
`within an aperture in lever 24. When cocking lever 22 is
`
`then raised,
`
`levers 28 and 24 are also raised, so freeing
`
`the triggering mechanism for operation.
`
`Inhalation will
`
`MYLAhlEX1011,Page11
`
`MYLAN EX 1011, Page 11
`
`

`
`W0 90/07333
`
`T
`
`PCI‘/GB90/00015
`
`10
`
`then move the vane, freeing the nozzle block and allowing
`
`the cocking force to move the container relative to the
`
`thereby firing the aerosol valve and delivering a
`valve,
`dose of medicament.
`
`The electronic circuitry is illustrated in
`
`diagrammatical form in Figure 2 and comprises an
`
`integrated circuit incorporating a clock regulated by a
`
`separate quartz crystal oscillator. The bi-stable d.c.
`
`solenoid is controlled via a power switch comprising field
`
`effect transistors (F.E.T's). The circuit includes a
`
`control switch for selecting the control period 'T',
`
`the
`
`A liquid
`dosage period 't' and the number of doses ‘N’.
`crystal display is provided to display one or more types
`
`of information defined herein before.
`
`The electronic
`
`circuitry may readily be reduced to a chip and printed
`
`circuit board for accommodation within the device as shown
`
`at 13.
`
`A battery 15 provides the necessary power.
`
`The
`
`liquid crystal display may be positioned at any suitable
`place on the housing.
`
`The entire inhalation device may be compacted and the
`
`outer dimensions of the housing may be of the order of
`
`90 mm x 60 mm x 30 mm.
`
`T
`
`The inhaler may be provided in either a disposable or
`re-usable form.
`In the former case the device is
`
`completely sealed to prevent access to the aerosol
`
`canister.
`
`In the latter, it is openable but has a
`
`locking mechanism to prevent unauthorised opening. This
`
`lock may be either mechanical or take the form of a code-
`
`operated electronic lock integrated with the device's
`
`electronic circuitry.
`
`The invention.will now be illustrated by the
`
`following examples.
`
`The fentanyl citrate employed in the Examples
`
`[contained 64% of the anhydrous base.
`
`7!
`
`MYLAhlEX1011,Page12
`
`MYLAN EX 1011, Page 12
`
`

`
`wo 90/07333
`
`PCI‘/GB90/00015
`
`11
`
`Example 1
`
`The following formulations were prepared:
`.
`can
`
`Fentanyl citrate
`
`0.0031
`
`.
`
`can
`
`0.0031
`
`spa'n 85
`
`0.0069 (0.1%)
`
`0.0343 (0.5%)
`
`Ethanol
`
`(21%w/w)
`
`Propellant 12
`
`Total
`
`Fentanyl citrate
`
`Span 85
`
`Epikuron 200
`
`Propellant 11
`
`Propellant 12
`
`Total
`
`1.4417
`
`5.4183
`
`6.87
`
`0.075
`
`0.658
`
`—
`
`7.504
`
`24.714
`
`32.951
`
`1.4143
`
`5.4183
`
`6.87
`
`0.075
`
`—
`
`0.600
`
`7.504
`
`24.773
`
`32.952
`
`All formulations were filled into glass bottles equipped
`with non-metering valves.
`
`The formulation containing Epikuron 200 formed a
`
`solution.
`
`The following suspension formulations were prepared:
`
`Example 2
`
`0.5%Span 0.4%Span 0.2%Span 0.1%Span
`
`ggcan
`
`ggcan
`
`ggcan
`
`ggcan
`
`Fentanyl citrate
`
`0.0748
`
`0.0748
`
`0.0748
`
`0.0748
`
`Span 85
`
`0.1648
`
`0.1318
`
`0.0659
`
`0.0330
`
`Propellant 11
`
`7.9998
`
`8.0314
`
`8.0973
`
`8.1302
`
`Propellant 12
`
`24.7140
`
`24.7140 24.7140 24.7140
`
`Total
`
`32.9534
`
`32.952
`
`32.952
`
`32.952
`
`The formulations were filled into glass bottles fitted
`
`with non—metering valves.
`
`Suspension formulations having
`
`a high Span content exhibited a reduced tendency to
`
`agglomerate compared with formulations having a lower
`
`Span content.
`
`MYLAhlEX1011,Page13
`
`MYLAN EX 1011, Page 13
`
`

`
`W0 90/07333
`
`-
`
`PCI‘/GB90/00015
`
`0
`
`12
`
`Example 3
`
`The following suspension formulation was prepared:
`A
`can
`
`Fentanyl citrate
`
`spa'n 85
`
`Propellant 11
`
`Propellant 12 0
`
`Total
`
`0.0187
`
`0.0412
`
`1.9996
`
`6.1785
`
`8.2380
`
`The formulation was filled into 5ml plain aluminium vials
`
`fitted with 50 ul valves using a 2 stage pressure fitting
`
`in which the non-volatile components were admixed and
`
`introduced into the vial,
`
`the valve crimped in place and
`
`the volatile propellant introduced into the vial through
`
`the valve under pressure.
`
`Dosage can be varied by varying the valve size as
`
`follows:
`
`T
`
`Valve Size
`
`Dose Per Shot
`
`25ul
`
`Soul
`
`63ul
`
`looul
`
`0
`
`Example 4
`
`50uge
`
`looug
`
`126ug
`
`200pg
`
`—Formulations were calculated for a delivery of 100ug of
`
`base per shot when a Soul valve was fitted, and for a
`fill weight of 16g.
`The suspensions were filled into
`
`polyethylene terephthalate bottles to allow the
`
`appearance of the gross formulation to be studied. All
`units were prepared by two—stage pressure filling.
`
`The following stable suspensions contained Propellant
`
`134a and ethanol in a weight ratio of 90 : 10.
`
`0.1% wgw Span 85
`
`mg/ml
`
`Fentanyl citrate
`
`3.1250.
`
`Span 85
`
`Ethanol
`
`1.1610
`
`115.6714"
`
`Propellant 134a
`
`1041.0426
`
`Total
`
`ll6l.0OO0
`
`MYLAhlEX1011,Page14
`
`MYLAN EX 1011, Page 14
`
`

`
`WO 90/07333
`
`PCI‘/GB90/00015
`
`13
`
`0.3% w[w Sgan 85
`
`Fentanyl citrate
`
`Span 85
`
`Ethanol
`
`Propellant 134a
`
`Total
`
`mg/ml
`
`3.1250
`
`3.4830
`
`115.4392
`
`1038.9528
`
`1161.0000
`
`0.5% wgw Sgan 85
`
`Fentanyl citrate
`
`Span 85
`
`Ethanol
`
`Propellant 134a
`
`Total
`
`mg/ml
`
`3.1250
`
`5.8050
`
`115.2070
`
`l036.8630
`
`ll6l.0000
`
`0.01% wgw Sgan 85
`
`Fentanyl citrate
`
`Span 85
`
`Ethanol
`
`Propellant 134a
`
`Total
`
`0.02% wgw Span 85
`
`Fentanyl citrate
`
`Span 35
`
`Ethanol
`
`Propellant 134a
`
`Total
`
`mg/ml
`
`3.1250
`
`0.1161
`
`115.7759
`
`lO4l.9830
`
`1161.0000
`
`mg/ml
`
`3.1250
`
`0.2322
`
`115.7643
`
`lO41.8785
`
`1161.0000
`
`MYLAhlEX1011,Page15
`
`MYLAN EX 1011, Page 15
`
`

`
`WO 90/07333 5
`
`PCT/GB90/00015
`
`14
`
`0.05% wzw Span 35
`
`Fentanyl citrate
`
`Span 85
`
`Ethanol
`
`Propellant 134a
`
`Total
`
`mg/ml
`
`3.1250
`
`0.5805
`
`115.7294
`
`1041.5651
`
`1161.0000
`
`Example 5
`
`The following stable suspensions were prepared as in
`
`Example 4 and contained Propellant 134a and n-Pentane in
`10.
`
`a ratio of 90 :
`
`0.1% w(w Span 85
`
`Fentanyl citrate
`
`Span 85
`
`Pentane
`
`mg/ml
`
`3.1250
`
`1.1610
`
`115.6714
`
`Propellant 134a
`
`104l.04265
`
`Total
`
`0
`
`ll61.0000
`
`0.3% wgw Span 85
`
`Fentanylpcitrate
`
`Span 85
`
`mg/ml
`
`3.1250
`
`3.4830
`
`Pentane
`
`_
`
`Propellant 134a
`
`Total
`
`115.4392
`
`1038.9528
`
`1161.0000
`
`0.5% wgw Span 85
`
`Fentanyl citratep
`
`Span 85
`
`Pentane
`
`Propellant 134a
`
`Total
`
`mg/ml
`
`3.1250
`
`5
`
`5.8050
`
`115.2070
`1036.8630
`
`1l61.0000’
`
`MYLAhlEX1011,Page16
`
`vi
`
`’.I.-
`
`M
`
`MYLAN EX 1011, Page 16
`
`

`
`WO 90/07333
`
`PCT/GB90/00015
`
`15
`
`Example 6
`
`The following suspensions were prepared as in Example 4
`
`and contained Propellant 134a and Propellant 11 in a
`ration of 95 : 5.
`
`0.1% wgw Span 85
`
`Fentanyl citrate
`
`Span 85
`
`mg/ml
`
`3.1250
`
`1.1610
`
`Propellant 11
`
`Propellant 134a
`
`Total
`
`57.8357
`
`lO98.8783
`
`1161.0000
`
`0.2% wgw Span 85
`
`Fentanyl citrate
`
`Span 85
`
`mg/ml
`
`3.1250
`
`2.3220
`
`Propellant 11
`Propellant 134a
`Total
`
`57.7776
`
`lO97.7754
`
`ll61.0000
`
`Example 7
`
`Fentanyl citrate formulations of the invention were
`
`compared with morphine sulphate, morphine base and
`
`diamorphine hydrochloride formulations presented as
`
`metered-dose inhalation aerosols in various single-dose
`
`and repeat-dose experiments in rodent and non-rodent
`
`species.
`
`The comparative formulations were as follows.
`can
`
`Diamorphine HCI
`
`0.063 (10% drug overage)
`
`Span 85 (20% of drug)
`
`Propellant 11
`
`Propellant 12
`
`Total
`
`0.013
`
`1.640
`
`5.145
`
`6.860
`
`MYLAhlEX1011,Page17
`
`MYLAN EX 1011, Page 17
`
`

`
`W0 90/07333
`
`PCTIGB90/00015
`
`.0»:
`
`Morphine Sulphate
`
`Span 85
`Propellant 11
`
`Propellant 12
`
`Total
`
`Morphine base
`
`Span 85
`
`Propellant 11
`
`Propellant 12
`
`Total
`
`16
`
`0.147
`
`0.034
`1.534
`
`5.145
`
`6 . 860
`
`0 . 1200
`
`0.0412
`
`1.8983
`
`6.1785
`
`4
`
`8.2380
`
`Each formulation was filled into 5ml vials equipped with
`
`Sopl dispensing valves.
`
`Rodent Inhalation Exposure Procedure
`
`The system consisted of an aluminium cylindrical
`chamber of approximately 41.5 litre volume.
`It was
`fitted with a flat top which supported an electrically
`
`driven mechanism, capable of actuating up to six inverted
`
`metered-dose inhaler (MDI) aerosol cans simultaneously.
`
`The duration and frequency of operation was controlled by
`
`a time switch.
`
`The MDI can nozzles opened directly into the
`
`T
`
`exposure chamber where the administered aerosol dose was
`
`mixed and dispersed by a regulated constant supply of
`clean dry air.i An extract duct at the base of the
`
`chamber was connected via a filter to a vacuum system.
`
`The pressure within the chamber was maintained just below
`
`atmospheric pressure.
`
`p
`
`MDI cans were selected, weighed and inverted in the
`template of the actuating mechanism.
`The ram mechanism
`
`was positioned to cover the bases of the cans so that
`teach downward stroke of the ram would actuate the cans
`
`causing them to fire simultaneously into the exposure
`chamber.
`5
`
`MYLAhlEX1011,Page18
`
`MYLAN EX 1011, Page 18
`
`

`
`W0 90/0733-3
`
`.
`
`PCI‘/GB90/00015
`
`17
`
`Each rodent was held in an individual,
`
`tapered,
`
`polycarbonate restraint tube, fitted onto the exposure
`chamber and sealed by means of a push fit through a
`
`rubber '0' ring. Only the animal's nose was exposed to
`
`the test atmosphere.
`
`Animals were observed both during and following
`
`dosing for clinical signs of drug effect.
`
`Non-Rodent Inhalation Exposure Procedure
`
`Inhalation dosing to Beagle dogs was performed using
`
`a dosing apparatus, comprising a mouthpiece, face mask,
`
`and modified MDI.
`
`The mouthpiece was located inside the
`
`animal's mouth on top of the tongue, and the face mask,
`
`incorporating the mouthpiece, sealed around the dog's
`
`snout by means of a rubber sleeve.
`
`The mask was
`
`connected via a one-way flap valve and exhaust tube to an
`
`extract system.
`
`The modified MDI was attached by a push
`
`fit connection to the distal end of the mouthpiece.
`When assembled and fitted to the dog the animals‘
`
`respiratory cycle was clearly indicated by the movement
`
`of the one-way flap valve.
`
`The MDI can was actuated
`
`manually in the normal way, by downward pressure at a
`
`time to coincide with inspiration.
`
`Non-Rodent Intranasal Exposure Procedure
`
`Animals were dosed by direct application of the test
`
`material into each nostril by means of an adaptor fitted
`
`to the MDI.
`
`Rodents
`
`Results
`
`Fentanyl citrate in formulation of Example 3
`
`Single Exposure Period
`
`Using six cans firing at six shots per minute for a
`
`single-exposure period between three and ten minutes,
`
`the
`
`animals showed gradual sedation and eventually exhibited
`
`marked narcosis by ten minutes.
`
`MYLAhlEX1011,Page19
`
`MYLAN EX 1011, Page 19
`
`

`
`VVT)90/07333
`
`PCI‘IGB90/00015
`
`18
`
`Multiple exposure period
`
`Using six cans firing at six shots per minute for
`three ten minute exposures daily for up to five days,
`
`marked narcosis or sedation was observed for all animals
`for up to two hours post exposure (see Table 1).
`Diamorphine hydrochloride
`T
`T
`
`Using six cans firing at six shots per minute for a
`
`single-exposure period between ten and fifteen minutes,
`
`no overt pharmacological effects were noted. Animals
`
`showed a slight reduction in respiratory rate during
`
`exposure and slight.salivation following exposure for a
`
`short time. Post exposure animals were slightly
`subdued.
`
`Mopphine sulphatef
`
`Animals were exposed to an atmosphere generated from
`
`six cans actuated at a rate of six shots per minute for a
`
`period of ten or sixty minutes. There was no observable
`effect seen in the behaviour of the animals following the
`
`ten minute exposure. During the second exposure,
`
`the
`
`rate of respiration dropped and following exposure the
`animals appeared to be very slightly subdued and easily
`startled.
`
`Non-Rodent
`
`fFentanyl citrate in Formulation of Example 3
`
`Single exposure
`
`Administration of test material was performed, by
`
`the inhalation and intranasal routes. Doses
`
`administered ranged from 8 to 25 actuations per session
`
`for the inhalation administration and from 5 to 35
`
`actuations per session for the intranasal route of
`
`administration. Following inhalation, fentanyl citrate
`
`caused rapid and marked sedation with the effect lasting
`
`for at least one hour at high doses.
`
`similar
`
`observations were seen following intranasal
`
`administrationi
`
`N3
`
`‘Lfl
`
`(Pl
`
`MYLAhlEX1011,Page2O
`
`MYLAN EX 1011, Page 20
`
`

`
`W0 90/07333
`
`p PCI‘/GB90/00015
`
`19
`
`Multiple—exposure period
`
`Animals were treated with a nominal dose of
`0.1§mg.kg fentanyl three times daily over a five day
`
`period.
`
`To achieve the correct dose, animals were
`
`weighed daily, and the body weight used to calculate the
`
`requisite number of metered dose aerosol actuations to be
`
`administered.
`
`(Results are shown in Table 2).
`
`Diamorphine hydrochloride
`
`A
`
`A nominal dose of 30mg diamorphine hydrochloride
`
`administered by the inhalation route caused sedation in 1
`
`out of 2 dogs. However, subsequent administration of the
`
`high dose formulation at similar or higher nominal doses,
`
`failed to produce signs of sedation in either animal.
`
`In
`
`subsequent experiments a nominal dose of
`
`8 - 9 mg/Kg
`
`diamorphine hydrochloride administered intranasally, was
`
`capable of producing a marked degree of sedation in dogs
`
`whilst a nominal dose of 10 - 13 mg/Kg administered over
`three sessions caused a constant state of sedation
`
`throughout the whole do