Page 1 of 7
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`SENJU EXHIBIT 2013
`LUPIN v. SENJU
`IPR2015-01100
`
`

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`U.S. Patent
`
`May 20, 1997
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`5,630,793
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`10
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`2
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`\“"‘fiR'u- 3
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`*1
`mg.-;n.!..I_I“.\
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`0
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`18
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`38
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`59
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`80
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`100
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`120
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`140
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`160
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`180
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`TlME(min)
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`005
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`O
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`1
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`AQUEOUS OPHTHALMIC SPRAYS
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`5,630,793
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`2
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`This invention relates to a method of spraying aqueous
`solutions or suspensions to the eye, and apparatus suitable
`for the delivery of such sprays.
`
`BACKGROUND OF THE INVENTION
`
`A conventional method of ocular administration of aque-
`ous solutions or suspensions comprises the use of eye drops.
`This is generally known to have low patient acceptability,
`especially in the young, and it
`is necessary, for
`administration, to incline the recipient’s head towards a
`horizontal position. The administration of a large drop of
`liquid to the eye initiates a blink reflex, which can result in
`a substantial wastage of the applied liquid or suspension by
`drainage either through the tear ducts or onto the skin
`surface. Indeed, it has been reported that if a 30-50 pl drop
`is applied to the eye, the actual volume that remains at the
`target is only 5-7 pl. Therefore, in addition to the low patient
`acceptability, there is a 4—to 10-fold wastage. This leads to
`inefficiency in the use of expensive ingredients and,
`in
`addition,
`the administrator has little control, and is
`uncertain, over the amount of liquid which actually reaches
`the target. This is particularly important if the liquid is a
`solution or suspension of an ophthalmologically-active
`therapeutic substance.
`Another conventional method of ocular administration of
`
`an ophthalmologically-active therapeutic substance com-
`prises the use of an ointment. This similarly has been found
`to have low patient acceptability and, in this method also, a
`substantial wastage of active ingredient can result.
`These problems in the efficient administration of thera-
`peutically active substances to the eye are largely overcome
`in European Patent No. 0 224 352B by generating a spray of
`electrically charged droplets of a liquid formulation com-
`prising an ophthalmologically-active substance and an
`ophthalrnologically-acceptable diluent, for subsequent
`administration to the eye. The formulation has a viscosity in
`the range l0'3 to 1.0 Pa.s at 25° C., and a resistivity in the
`range 10" to 10” ohm.cm at 25° C. The formulation is
`applied to a spray nozzle wherein a sufliciently large elec-
`trical potential relative to earth is applied to the formulation
`fiom a high voltage generator,
`that suflicient electrical
`gradient is produced at the nozzle to atomize the formulation
`as a spray of electrically charged droplets.
`Although such a method allows the delivery to the eye of
`an optimum small volume of a formulation of a therapeutic
`substance, without requiring the recipient’s head to be
`inclined towards the horizontal, it does, however, still have
`some drawbacks. Solutions or suspensions containing more
`than about 50% of water, that is, of lower resistivity than 104
`ohm.crn, cannot be sprayed, and high voltages of 15 kV or
`higher are used. Further, an electrode needs to be in contact
`with the formulation, to achieve the correct voltage for
`atomization, and this could cause cross-contamination prob-
`lems for pharmaceutical formulations. A further disadvan-
`tage is that a formulation containing substantial amounts of
`non-aqueous solvents, which is to be dispensed by this
`method, is likely to be hypertonic, which although accept-
`able for very low volume applications can result in a stinging
`sensation if larger volumes are administered to the eye.
`
`SUMMARY OF THE INVENTION
`
`The present invention provides accurate dispensing of a
`low volume of a solution or suspension to the eye without
`the above-mentioned drawbacks. In particular the present
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`Page 3 of 7
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`invention allows the dispensing of isotonic solutions, which
`avoids stinging sensations, it allows the use of suspensions
`as well as solutions, and it offers manufacturing and envi-
`romnental advantages by the reduced use of non-aqueous
`solvents. This is achieved by a process which involves the
`production of a colinear stream of uniformly-sized, equally
`spaced droplets of a liquid formulation, using either piezo-
`electric or electromagnetic transducers to cause uniform
`break-up of a jet of the formulation emitted from a nozzle.
`The droplets so produced are initially not electrically
`charged, and charging is accomplished subsequently by
`passing the stream of droplets through a cylindrical charging
`electrode longitudinally positioned so that induced electric
`charges are trapped on the droplets as they pass through the
`cylindrical electrode.
`As indicated above, conventional methods for ocular
`administration lead to wastage of ingredient, for example by
`drainage through the naso-lachrymal duct into the throat,
`and subsequent ingestion into the gastro-intestinal tract,
`whence it can be absorbed systemically and exert undesired
`side-effects. For example, it is well documented in the
`literature that [3-adrenoceptor antagonists administered as
`eye-drops can exert a significant cardiovascular efiect as a
`result of such ingestion into the gastro-intestinal tract.
`The present invention enables accurate targetting of a fine
`spray of electrically charged droplets of a liquid formulation
`to dose just the required amount of an ophthalmologically
`active substance,
`thereby substantially eliminating
`unwanted side-effects.
`
`Thus, according to the invention, there is provided a
`method of administering to the eye a liquid ophthalmic
`formulation, comprising an ophthalmologically acceptable
`liquid ‘and optionally containing an ophthalrnologically-
`active substance, characterized in that the formulation has a
`viscosity in the range 10”?’ to 1.0 Pa.s and a resistivity lower
`than 104 ohm.cm, and that a jet of the formulation is ejected
`towards the eye, from a spray nozzle situated adjacent to a
`piezoelectric or electromagnetic transducer, to form a stream
`of unifonnly-sized, equally spaced, uncharged droplets, the
`stream of uncharged droplets is subsequently directed past a
`charging electrode to induce an electric charge on each
`droplet in the stream, and the charged droplets discharge
`their electric charge by earthing on contact with the eye.
`The method may be carried out in a unit dose mode, by
`charging the nozzle with a unit dose from an external source
`each time it is used, or in multi-dose mode, in which case a
`reservoir of the formulation supplies a unit dose to the spray
`nozzle each time the method is carried out.
`
`The liquid ophthalmic formulation may be a hygiene
`product, for example an eyewash or artificial tears for the
`treatment of dry eye, or a moistening or lubricating product
`for contact lens users, in the form of a conventional, pre-
`dominantly aqueous and essentially isotonic liquid
`preparation, or it may be a product containing an
`ophthalmologically-active substance.
`The ophthalmologically active substances encompassed
`by this invention are any compounds having a pharmaco-
`logical effect on and/or in the eye. Typical of such com-
`pounds are chemotherapeutic agents, compounds to aid
`ocular examination, and compounds to aid surgery, for
`example:
`(a) anti-inflammatory agents, such as prednisolone and other
`corticosteroids;
`(b) antimicrobial drugs, such as antibiotics, antiseptics,
`antivirals, fungicides and sulphonamides, for example
`chlorarnphenicol, sulphacetamide, gentamycin, nystatin,
`acyclovir and idoxmidine;
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`3
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`5,630,793
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`(c) autonomic drugs, such as [5-adrenoceptor antagonists,
`cycloplegics, miotics, mydriatics and vasoconstrictors,
`for example timolol, atenolol, pilocarpine, atropine,
`tropicamide, hyoscine. ephedrine, phenylephrine,
`carbachol, guanethidine and adrenaline;
`(d) local anaesthetics, such a lignocaine or oxybuprocaine;
`(e) diagnostics, such as fluorescein;
`(f) drugs to assist healing of corneal abrasions, such as
`urogastrone and epidermal growth factor (EGF);
`of which (c) is a particularly important group.
`Suitably,
`the ophthalmologically active substance is
`present in the formulation in a concentration range of from
`about 0.1% to about 20%, and preferably from about 5% to
`about 10%, but
`the required concentration depends,
`naturally, upon the potency of the particular active substance
`being used.
`A resistivity lower than 104 ohm.cm for the liquid oph-
`thalmic formulation is achieved by making it predominantly
`aqueous, although a small proportion of non-aqueous
`liquids, up to about 20%, may also be incorporated. Suitable
`such non-aqueous liquids are, for example, glycerol, propy-
`lene glycol, polyethylene glycol of average molecular
`weight up to about 600, and dimethyl isosorbide.
`The viscosity of the formulation may be adjusted to
`within the required range by the addition of viscolysers, for
`example hydroxyethylcellulose, hydroxypropylcellulose,
`carboxymethylcellutose, hydroxypropylmethylcellulose,
`methylcellulose, polyvinyl alcohol, polyethylene glycol,
`dextran or polyvinylpyrrolidone.
`The tonicity of the formulation may be adjusted into the
`range tolerated by the eye, for example tonicity equivalent
`to 0.2—1.4% w/v sodium chloride, by the addition of a
`tonicity modifier. A preferred range of tonicity is equivalent
`to from 0.6—1.0% w/v sodium chloride, and especially
`preferred are solutions having a tonicity as close as possible
`to 0.9% w/v sodium chloride. A suitable tonicity modifier is,
`for example, sodium chloride itself. The addition of sodium
`chloride as a tonicity modifier also has the effect of lowering
`the resistivity of the formulation.
`The formulation may also contain a preservative, for
`example benzalkonium chloride, chlorhexidine acetate, phe-
`nylmercuric acetate, phenylrnercuric nitrate,
`thiomersal,
`chlorbutol. benzyl alcohol or p-hydroxybenzoates.
`The formulation may also contain a pH buffer salt, to
`maintain the pH of the formulation at an optimum to
`minimize chemical degradation, to increase comfort for the
`user, and to enhance therapeutic effect. Suitable such buffer
`salts are, for example, borate buffer (boric acid/borax),
`phosphate buffer (sodium hydrogen phosphate/sodium
`phosphate) and citrate bufl’er (citric acid/sodiurn citrate).
`Several drugs used in ophthalmic formulations oxidize on
`exposure to air, with loss of potency, and the formulation
`may therefore advantageously contain an antioxidant, for
`example sodium metabisulfite for acid formulations, or
`sodium sulfite for alkaline formulations.
`
`A chelating agent, for example disodium edetate, may
`also be included, to remove traces of heavy metals, where
`the presence of such impurities catalyses the breakdown of
`the drug. Disodium edetate also has the effect of enhancing
`the activity of certain preservatives, and the concentration of
`benzalkonium chloride, for example. may be reduced when
`disodium edetate is also present in the formulation.
`According to a further feature of the invention there is
`provided an apparatus for carrying out the method described
`above. The invention thus provides spraying apparatus for
`dispensing a liquid formulation to the eye, as described
`above, which comprises:
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`(i) at least one spray nozzle having an outlet of sufficiently
`small cross section to be capable of retaining an appro-
`priate amount of a liquid formulation, by surface tension;
`(ii) means to supply an appropriate measured volume of a
`liquid formulation to the spray nozzle;
`(iii) means to eject a measured volume of liquid formulation
`from the spray nozzle as a jet;
`(iv) means for exciting the jet ofliquid formulation emitted
`from the spray nozzle to form a stream of droplets of
`liquid formulation;
`(v) a charging electrode spaced co-axially in front of the
`spray nozzle, and so spaced that the stream of droplets,
`immediately they are formed, are within the charging field
`of the electrode; and
`(vi) means for applying a voltage to the electrode.
`In one embodiment of this invention, the means to supply
`an appropriate measured volume of a liquid formulation is
`provided by a metered valve or syringe-pump of the type
`used for multi-dose administration of insulin, to control the
`passage of the liquid formulation from a reservoir in the
`apparatus,
`to the spray nozzle. Alternatively, accurately
`measured low volumes can be supplied to the apparatus by
`placing the spray nozzle in the liquid formulation and
`drawing in the required volume by pipette action, for
`example by using a piston in a syringe.
`In a preferred aspect of this invention, we have found that
`the best spraying results are achieved using a modification of
`the previous apparatus,
`in which the spray nozzle is
`demountable from the apparatus. In use the required volume
`of formulation is placed in the demounted spray nozzle,
`which is then located on the spraying apparatus in any
`convenient manner, such as by screwing or by friction-fit on
`an appropriate receiving member. In this way,
`the low
`volume of formulation is measured in any convenient man-
`ner prior to use.
`Piston action can also be used as the means to eject a
`measured volume of liquid formulation from the spray
`nozzle as a jet.
`The means for exciting the jet of liquid formulation
`emitted from the spray nozzle to form a stream of droplets
`of liquid formulation may, for example, a piezoelectric or an
`electromagnetic transducer. For optimum droplet
`generation, the jet of liquid formulation needs to be per-
`turbed at a wavelength equal to 9.016 times the radius of the
`spray nozzle, so that, for example, for a nozzle of approxi-
`mately 100 um diameter, frequencies of 1-200 kHz, pref-
`erably 50-150 kHz, are required.
`The charging electrode which is spaced co—axially in front
`of the spray nozzle conveniently takes the form of a cylinder
`or annulus, co-axial with the spray nozzle, charged to a
`suitable positive or negative potential, but it may also be in
`the form of separate elements of any suitable form, located
`around the axis of the nozzle, and with a space between,
`through which the stream of droplets can be directed in order
`to acquire an elecnical charge. As indicated above, for
`eflicient use of the formulation, that is, so that all of the
`active ingredient reaches the treatment site, it is necessary
`that each droplet in the stream becomes electrically charged
`as soon as it is formed from the jet, so the charging electrode
`must be located in front of the nozzle so that immediately a
`droplet is formed, it is within the charging field of the
`charging electrode.
`The resistivity of the liquid formulation must be chosen to
`be low enough to ensure that the droplets become fully
`charged within the duration of the charging electrode pulse,
`which will typically be 2-4 us. It can be shown mathemati-
`cally that, for a given geometry, the charge on the droplets
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`5,630,793
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`5
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`is determined solely by the voltage applied to the charging
`electrode. For droplets of approximately 100 mm diameter,
`charging voltages in the range of about 0.1 to about 1000 V
`are suitable, modulated at the same frequency as the drop
`generation rate, that is, the transducer frequency, or some
`sub—harmonic of it. Resistivities for the liquid formulation of
`less than 104 ohm.cm, and preferably in the range of 10’ to
`103 ohm. cm, are required in order for the droplets to become
`fully charged
`Generally, in the apparatus of this invention, at least the
`spray nozzle is suitable to be hand-held when in use, and
`comprises one or two spray nozzles, depending upon
`whether it is desired to treat eyes separately or concurrently.
`Conveniently, the voltage required to charge the charging
`electrode is provided by a battery powered voltage
`generator, housed in hand-held apparatus.
`In another
`embodiment, the voltage can be generated in a remote pack,
`and supplied by an electrical connection to a hand-held
`spraying apparatus. In another embodiment, the reservoir
`supplying the formulation to the spray nozzle may be remote
`from the hand-held spray nozzle, and connected thereto by
`appropriate flexible tubing. In another embodiment, both the
`voltage generator and the reservoir may be remote from the
`hand-held spray nozzle.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`A particular embodiment will now be described, by way
`of example only, with reference to FIG. 1, which is a
`schematic view illustrating the principal components of one
`form of the apparatus.
`FIG. 2 illustrate mydriatic response measurements.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`
`Referring to FIG. 1, there is a body member 1 of a suitable
`size to be hand-held. On one wall of the body member 1
`there is mounted a guide 2 in the form of a short tube, the
`diameter of which approximates to the size of the eye to be
`treated. In the portion of the wall of the body member 1
`which lies within the guide tube 2 there is positioned
`centrally the outlet 3 of a narrow bore tube 4 which at its
`other end broadens to provide a wider bore section 5,
`positioned in a side wall of the body member 1, and in which
`a spring-loaded piston 6 can operate. Located in the wall of
`the body member 1, and disposed around the outlet 3 of the
`narrow bore tube 4 in an annular manner is a piezoelectric
`or electromagnetic transducer 7, which is powered through
`electrical connections 8 and 9 from a voltage generator 10
`via a frequency control unit 11, both of which are housed
`within the body member 1. A demountable nozzle 12 is
`provided which is capable of being detached from the
`apparatus in order to be charged with the formulation to be
`administered, and then re-attached securely within the cen-
`tral orifice of the transducer, by a tight push fit, to cooperate
`with the outlet 3 of the narrow bore tube 4. Within the guide
`tube 2, adjacent to the transducer 7 and separated therefrom
`by a small distance, is an annular or cylindrical charging
`electrode 13, located co-axially with the transducer 7, and
`electrically insulated from the other parts of the apparatus.
`The charging electrode 13 is charged to suitable positive or
`negative potential through an electrical connection 14 from
`the voltage generator 10, and its pulse frequency is con-
`trolled through the frequency control unit 11.
`In use,
`the demountable nozzle 12 is filled with the
`appropriate volume of the formulation to be administered,
`the apparatus is held in the hand, and the guide tube is
`
`’
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`6
`positioned directed towards the eye to be treated, and a short
`distance therefrom. The voltage generator 10 is switched on,
`to activate the transducer 7 and the charging electrode 13.
`The piston 6 is then depressed against its spring, to create
`suflicient pres sure within the narrow bore tube 4 to expel the
`liquid formulation from the nozzle 12, through the central
`orifice of the transducer 7, whereby the jet of liquid formu-
`lation is broken up to produce a colinear stream of uniformly
`sized, equally spaced, uncharged droplets. The stream of
`droplets then passes through the bore of the annular charging
`electrode 13, where each droplet acquires an electric charge.
`The frequency control unit 11 is pre-adjusted to ensure that
`the voltage on the charge electrode is varied at the same
`frequency as, or a greater frequency than, that at which the
`droplets are produced, so that each droplet is individually
`electrically charged. The charged droplets then continue
`towards the eye to be treated, where they discharge their
`electric charge at the first earthed surface they encounter,
`namely the tissue of the eyeball, to give the eyeball an even
`coating of the formulation, without sensation.
`
`The invention will now be illustrated, but not limited, by
`the following Example:
`
`EXAMPLE 1
`
`Ephedrine hydrochloride (0.25 mg) was formulated as a
`5% solution in physiological saline, radiolabelled with
`approximately 0.8 Gbq of 99”’I‘c-DTPA complex. This for-
`mulation was sprayed, from apparatus essentially as here-
`inbefore described in this specification, onto one eye of each
`of 6 New Zealand white rabbits, according to the following
`procedure:
`
`The test animals were acclimatised to the experimental
`conditions, by exposure to constant
`light intensity and
`minimal distractions, for 20 minutes. They were then placed
`in restraining boxes which were positioned approximately
`30-40 cm in front of a camera (Pentax ME Super 35 mm
`camera fitted with an SMC Pentax 50 mm lens and 2X
`
`converter) set up on a tripod. A scale of known magnitude
`was placed next to, and in the same plane as, the pupil, prior
`to photographs being taken.
`
`The animals were allowed to settle, and photographs were
`taken at f12 and 1/15 second, using ISO400 film (Kodak Gold
`400). Photographs were taken 5 minutes prior to closing of
`the ephedrine formulation, in order to allow determination
`of baseline (control) pupil diameters. The ephedrine formu-
`lation (5 pl) was then administered to the eye as a pulse of
`charged droplets generated from the apparatus of the inven-
`tion described above, and photographs taken at intervals
`over the next 3 hours.
`
`Pupil diameters were determined from the developed
`colour prints (approximately 15x10 cm) using an electronic
`micrometer (Digimatic Caliper, Mitutoyo Corp., Japan).
`Absolute pupil diameters were established by comparing the
`pupil diameter with the known scale on the photographs.
`From these measurements, the maximum response ratio was
`determined from the relationship:
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`RR,,,,,,,=(pupil diameter at time t)—(average pupil diameter at time
`to) (average pupil diameter at time to)
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`5,630,793
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`The following results were obtained:
`
`
`RRma.x
`
`Animal
`
` No.
`
`
`
`
`
`
`
`
`
`
`
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`
`
`
`2 3 4 5 6 Mean1Time (min) SD”
`0
`0.00
`0.00
`0.00
`0.00
`-0.04
`0.00
`-0.01
`0.01
`18
`0.09
`0.03
`0.11
`0.40
`0.17
`0.11
`0.15
`0.13
`38
`0.24
`-0.15
`0.15
`0.48
`0.13
`0.11
`0.16
`0.20
`59
`0.35
`0.29
`0.09
`0.52
`0.15
`0.15
`0.25
`0.16
`80
`0.14
`-0.05
`0.03
`0.18
`-0.16
`0.10
`0.04
`0.13
`102
`0.11
`-0.07
`0.01
`0.15
`0.02
`0.02
`0.04
`0.08
`120
`0.13
`-0.06
`0.13
`0.01
`0.05
`-0.03
`0.04
`0.08
`140
`0.11
`-0.11
`0.02
`0.25
`-0.02
`—
`0.05
`0.13
`160
`0.10
`-0.12
`0.11
`0.15
`-0.14
`-0.08
`0.00
`0.13
`180
`0.04
`-0.14
`-0.02
`0.26
`-0.11
`-0.12
`-0.02
`0.14
`
`*= standard deviation
`
`These results are presented graphically in FIG. 2, and show
`a marked mydriatic response in the measurements taken at
`18. 38 and 59 minutes in all animals, and a continuing effect
`up to 80 minutes in some animals, after the administration
`of only 5 pl of the ephedrine formulation by the method of
`this invention, which is a much lower volume than that
`normally required with conventional modes of application.
`I claim:
`
`1. A method for administering a liquid ophthalmic for-
`mulation to the surface of the eye. said method comprising
`the steps of:
`providing a spray nozzle having a liquid outlet in prox-
`imity to but spaced from said surface. said nozzle being
`situated adjacent to a piezoelectric or electromagnetic
`transducer;
`
`providing to said nozzle said liquid ophthahnic formula-
`tion comprising an ophthalmologically-acceptable liq-
`uid having a viscosity in the range 104 to 1.0 Pa.s and
`a resistivity lower than 104 ohrn.cm;
`ejecting a jet of said formulation from said spray nozzle
`towards said surface, forming a stream of uniformly-
`sized, equally spaced, uncharged droplets by means of
`said transducer; and
`
`causing said droplets, upon formation, to pass through the
`charging field of a charging electrode, thereby inducing
`an electric charge on each droplet before contacting
`said surface; whereby the charged droplets discharge
`their electric charge by earthing on contact with the
`surface of said eye.
`2. A method as claimed in claim 1 wherein the liquid
`ophthalmic formulation is a hygiene product.
`3. A method as claimed in claim 1 wherein the liquid
`ophthalmic formulation is a product containing an
`ophthalmologically-active substance.
`4. A method as claimed in claim 3 wherein the
`ophthalmologically-active substance is selected from anti-
`inflarnmatory agents, antimicrobial drugs, autonomic drugs,
`local anaesthetics, diagnostics and drugs to assist the healing
`of corneal abrasions.
`
`5. Apparatus for treating an eye by administering a
`measured volume of a liquid ophthalmic formulation to the
`surface of said eye, comprising:
`at least one spray nozzle having a liquid outlet having an
`interior cross section adapted to retain therein a mea-
`sured volume of a liquid formulation by srnface ten-
`sron;
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`means to supply said measured volume of liquid formu-
`lation to said spray nozzle;
`means to eject said measured volume of liquid formula-
`tion from said spray nozzle outlet as a jet;
`a piezoelectric or electromagnetic transducer adapted to
`excite said jet of liquid formulation to form a stream of
`droplets of said liquid formulation;
`a charging electrode spaced co-axially in front of said
`spray nozzle outlet and adapted so that said droplets,
`upon formation, are charged by said electrode; and
`means to apply a voltage to said electrode; said apparatus
`being adapted, when said nozzle outlet is in a spaced
`relationship with said surface, to direct said droplets
`toward said stnface, and to permit said charged droplets
`to discharge their electric charge by earthing on contact
`with the surface of said eye.
`6. Apparatus as claimed in claim 5 wherein the measured
`volume of the formulation is supplied to the nozzle by a
`metered valve or syringe pump.
`7. Apparatus as claimed in claim 5 wherein the measured
`volume of the formulation is supplied by drawing into the
`nozzle the required amount from an external source by
`pipette action.
`8. Apparatus as claimed in claim 5 where the measured
`volume of the formulation is contained in a demountable
`spray nozzle which is locatable on an appropriate receiving
`member in the apparatus.
`9. Apparatus as claimed in claim 5 wherein the piezo-
`electric or electromagnetic transducer is adapted to excite
`the liquid jet formulation at a frequency of 1-200 kHz.
`10. Apparatus as claimed in claim 5 wherein the charging
`electrode is in the form of a cylinder or annulus charged to
`a voltage of between 0.1 and 1000 v.
`11. Apparatus as claimed in claim 5 wherein at least the
`spray nozzle is suitable to be hand-held when in use.
`12. Apparatus for treating an eye by administering a
`measured volume of a liquid ophthalmic formulation to the
`surface of said eye, said apparatus comprising:
`a body member, of a suitable size to be hand-held in use,
`having a tubular guide with one end thereof mounted
`on a first exterior wall of said body member, the other
`end of said guide being open and having a diameter
`approximating to the size of the eye surface to be
`treated;
`
`a narrow bore tube positioned in said body member and
`having an outlet end extending through said exterior
`
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`Page 6 of 7
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`
`9
`
`10
`
`5,630,793
`
`wall substantially coaxial with and in open communi-
`cation with said guide, said tube having an inlet end in
`open communication with a wider bore tubular section
`having a spring—loaded piston, located in and operable
`from a second exterior wall of said body member;
`an annular piezoelectric or electromagnetic transducer
`attached to said body member, and having a central
`orifice, coaxial with and in open communication with
`the outlet end of said tube and with said guide;
`a nozzle dctachably attached to said body member within
`the central orifice of said transducer, coaxial with and
`in communication with said tube outlet, said nozzle
`being adapted to be detached from said body member
`in order to be charged with the formulation to be
`administered and then re-attached thereto;
`
`10
`
`a voltage generator adapted to power said transducer
`through electrical connections via a frequency control
`unit, said generator and control unit being positioned
`within said body member; and
`an~annula.r charging electrode located within the tubular
`guide, having a central opening coaxial with the central
`orifice of said transducer, said electrode being in a
`spaced relationship with said transducer and electri-
`cally insulated said body member,
`tubular nozzle,
`transducer and nozzle, and said electrode being adapted
`to receive a positive or negative electrical charge from
`said voltage generator with said charge having a pulse
`frequency controlled through said frequency control
`unit.
`
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