`Rowe
`
`[54] AQUEOUS OPHTHALMIC SPRAYS
`
`[75]
`
`Inventor: Raymond C. Rowe, Congleton, United
`Kingdom
`
`[73] Assignee: Zeneca Limited, London, United
`Kingdom
`
`[21] Appl. No.: 408,971
`
`[22] Filed:
`
`Mar. 23, 1995
`
`[30]
`
`Foreign Application Priority Data
`
`[GB] United Kingdom ................... 9405952
`
`Mar. 25, 1994
`Int. Cl.6
`••••••••••••••••••••••••••••• A61N 1/30; A61M 35/00
`[51]
`[52] U.S. CI ............................. 604/20; 604/289; 604/294;
`604/298; 128/200.14
`[58] Field of Search ..................................... 604/289, 290,
`604/294-302
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`6/1983 Voss et al ..
`4,388,343
`1/1986 Maurice et al. . ................... 6041289 X
`4,564,016
`8/1990 Booth et al ............................. 6041294
`4,952,212
`5,053,000 10/1991 Booth et al ......................... 604/294 X
`5,171,306 12/1992 Vo ........................................... 604/295
`5,368,582 1111994 Bertera ..... ~ .............................. 604/295
`
`FOREIGN PATENT DOCUMENTS
`
`5/1980 European Pat. Off ..
`0011269
`6/1987 European Pat. Off ..
`0224352
`0389665 10/1990 European Pat. Off ..
`0590165
`4/1994 European Pat. Off ..
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US005630793A
`Patent Number:
`Date of Patent:
`
`5,630,793
`May 20, 1997
`
`[11]
`
`[45]
`
`1271341
`8500761
`
`9/1960 France.
`211985 WIPO .
`OTHER PUBLICATIONS
`M. Doring, "Fliissigkeiten mikrofein dosieren", F&M Fein(cid:173)
`werktechnik & Messtechnik, Nov., 1991, pp. 459-463.
`Choi et al, "Generation of controllable monodispersed
`sprays using impulse jet and charging techniques", Review
`of Scientific Instruments, Jun. 1990, pp. 1689-1693.
`"Non-Impact Printing", pp.310,321.
`"Further Applications of Charged Drops" pp. 163-171.
`"Miscellaneous Applications", pp. 204-207.
`Primary Examiner-Sam Rimell
`Assistant Examiner-Robert V. Racunas
`AttorneJ; Agent, or Finn-Cushman Darby & Cushman
`Intellectual Property Group of Pillsbury Madison & Sutro,
`LLP
`[57]
`
`ABSTRACT
`
`A method of administering to the eye a liquid ophthalmic
`formulation, comprising an ophthalmologically acceptable
`liquid and optionally containing an ophthalmologically(cid:173)
`active substance, characterized in that the formulation has a
`viscosity in the range 10-3 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 uniformly-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; and
`spraying apparatus suitable for use in that method.
`
`12 Claims, 1 Drawing Sheet
`
`2
`
`13
`
`Page 1 of 7
`
`SENJU EXHIBIT 2013
`LUPIN v. SENJU
`IPR2015-01097
`
`
`
`U.S. Patent
`
`May 20, 1997
`
`5,630,793
`
`Fig.1.
`
`2
`
`13
`
`6
`
`Fig.2.
`
`0·50
`0·45
`0-40
`0·35
`0·30
`X 0-25
`c::(
`:L 0·20
`~ 0·15
`0·10
`0·05
`0
`- 0· 054---...---r---.----+----,-----r---t---t----+--
`o
`18
`38
`59
`80
`100
`120
`140
`160
`180
`TIME <min)
`
`Page 2 of 7
`
`
`
`5,630,793
`
`1
`AQUEOUS OPHTHALMIC SPRAYS
`
`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
`
`2
`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(cid:173)
`ronmental advantages by the reduced use of non-aqueous
`5 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(cid:173)
`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 ~-adrenoceptor antagonists administered as
`eye-drops can exert a significant cardiovascular effect 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 ophthalmologically(cid:173)
`active substance, characterized in that the formulation has a
`viscosity in the range 10-3 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 uniformly-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(cid:173)
`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 sulphonarnides, for example
`chloramphenicol, sulphacetamide, gentamycin, nystatin,
`acyclovir and idoxuridine;
`
`30
`
`A conventional method of ocular administration of aque(cid:173)
`ous solutions or suspensions comprises the use of eye drops.
`This is generally known to have low patient acceptability, 10
`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 15
`drainage either through the tear ducts or onto the skin
`surface. Indeed, it has been reported that if a 30-50 J.1l drop
`is applied to the eye, the actual volume that remains at the
`target is only 5-7 J.Il. Therefore, in addition to the low patient
`acceptability, there is a 4-to 10-fold wastage. This leads to 20
`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 25
`therapeutic substance.
`Another conventional method of ocular administration of
`an ophthalmologically-active therapeutic substance com(cid:173)
`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(cid:173)
`peutically active substances to the eye are largely overcome
`in European Patent No. 0 224 352B by generating a spray of 35
`electrically charged droplets of a liquid formulation com(cid:173)
`prising an ophthalmologically-active substance and an
`ophthalmologically-acceptable diluent, for subsequent
`administration to the eye. The formulation has a viscosity in
`the range 10-3 to 1.0 Pa.s at 25° C., and a resistivity in the 40
`range Hf to 1012 ohm.cm at 25° C. The formulation is
`applied to a spray nozzle wherein a sufficiently large elec(cid:173)
`trical potential relative to earth is applied to the formulation
`from a high voltage generator, that sufficient electrical
`gradient is produced at the nozzle to atomize the formulation 45
`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 50
`some drawbacks. Solutions or suspensions containing more
`than about 50% of water, that is, oflower resistivity than 104
`ohm.cm, 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 55
`atomization, and this could cause cross-contamination prob(cid:173)
`lems for pharmaceutical formulations. A further disadvan(cid:173)
`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- 60
`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 65
`low volume of a solution or suspension to the eye without
`the above-mentioned drawbacks. In particular the present
`
`Page 3 of 7
`
`
`
`5,630,793
`
`3
`(c) autonomic drugs, such as ~-adrenoceptor antagonists,
`cycloplegics, miotics, mydriatics and vasoconstrictors,
`for example timolol, atenolol, pilocarpine, atropine,
`tropicarnide, 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(cid:173)
`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(cid:173)
`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(cid:173)
`nylmercuric acetate, phenylmercuric 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 buffer (citric acid/sodium 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 metabisuliite for acid formulations, or
`sodium suliite 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:
`
`5
`
`10
`
`4
`(i) at least one spray nozzle having an outlet of sufficiently
`small cross section to be capable of retaining an appro(cid:173)
`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 of liquid 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
`15 (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
`20 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
`25 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
`30 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-
`35 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
`40 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(cid:173)
`turbed at a wavelength equal to 9.016 times the radius of the
`45 spray nozzle, so that, for example, for a nozzle of approxi(cid:173)
`mately 100 J.llll diameter, frequencies of 1-200kHz, pref(cid:173)
`erably 50-150kHz, are required.
`The charging electrode which is spaced co-axially in front
`of the spray nozzle conveniently takes the form of a cylinder
`so 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
`55 to acquire an electrical charge. As indicated above, for
`efficient 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
`60 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
`65 charged within the duration of the charging electrode pulse,
`which will typically be 2-4 )JS. It can be shown mathemati(cid:173)
`cally that, for a given geometry, the charge on the droplets
`
`Page 4 of 7
`
`
`
`5,630,793
`
`5
`is determined solely by the voltage applied to the charging
`electrode. For droplets of approximately 100 J.1II1 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 5
`sub-harmonic of it Resistivities for the liquid formulation of
`less than 104 olun.cm, and preferably in the range of 102 to
`103 olun.cm, are required in order for the droplets to become
`fully charged.
`Generally, in the apparatus of this invention, at least the 10
`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 15
`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 20
`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.
`
`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
`sufficient pressure 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(cid:173)
`lation is broken up to produce a colin ear 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:
`
`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.
`
`25
`
`30
`
`35
`
`DEI'All..ED DESCRIPTION OF THE
`PREFERRED EMBODIM:ENTS
`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 40
`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 45
`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 50
`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(cid:173)
`tral orifice of the transducer, by a tight push fit, to cooperate 55
`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(cid:173)
`trolled through the frequency control unit 11.
`In use, the demountable nozzle 12 is filled with the 65
`appropriate volume of the formulation to be administered,
`the apparatus is held in the hand, and the guide tube is
`
`EXAMPLE 1
`
`Ephedrine hydrochloride (0.25 mg) was formulated as a
`5% solution in physiological saline, radiolabelled with
`approximately 0.8 Gbq of 99"'Tc-DTPA complex. This for(cid:173)
`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 em 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 1/1s second, using IS0400 film (Kodak Gold
`400). Photographs were taken 5 minutes prior to dosing of
`the ephedrine formulation, in order to allow determination
`of baseline (control) pupil diameters. The ephedrine formu(cid:173)
`lation (5 j.tl) was then administered to the eye as a pulse of
`charged droplets generated from the apparatus of the inven(cid:173)
`tion described above, and photographs taken at intervals
`over the next 3 hours.
`
`Pupil diameters were determined from the developed
`colour prints (approximately 15x10 em) using an electronic
`micrometer (Digimatic Caliper, Mitutoyo Corp., Japan).
`Absolute pupil diameters were established by comparing the
`60 pupil diameter with the known scale on the photographs.
`From these measurements, the maximum response ratio was
`determined from the relationship:
`
`RRmax=(pupil diameter at time t)-( average pupil diameter at time
`to) (average pupil diameter at time to)
`
`Page 5 of 7
`
`
`
`7
`The following results were obtained:
`
`5,630,793
`
`8
`
`RRmax
`
`Animal
`No.
`
`Tune (min)
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Mean
`
`0
`18
`38
`59
`80
`102
`120
`140
`160
`180
`
`0.00
`0.09
`0.24
`0.35
`0.14
`0.11
`0.13
`0.11
`0.10
`0.04
`
`0.00
`0.03
`-0.15
`0.29
`-0.05
`-0.07
`-0.06
`-0.11
`-0.12
`-0.14
`
`0.00
`0.11
`0.15
`0.09
`0.03
`0.01
`0.13
`0.02
`0.11
`-0.02
`
`0.00
`0.40
`0.48
`0.52
`0.18
`0.15
`0.01
`0.25
`0.15
`0.26
`
`-0.04
`0.17
`0.13
`0.15
`-0.16
`0.02
`0.05
`-0.02
`-0.14
`-0.11
`
`0.00
`0.11
`0.11
`0.15
`0.10
`0.02
`-0.03
`
`-0.08
`-0.12
`
`*= standard deviation.
`
`-0.01
`0.15
`0.16
`0.25
`0.04
`0.04
`0.04
`0.05
`0.00
`-0.02
`
`20
`
`sn•
`
`0.01
`0.13
`0.20
`0.16
`0.13
`0.08
`0.08
`0.13
`0.13
`0.14
`
`35
`
`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 aninlals, and a continuing effect
`up to 80 minutes in some animals, after the administration
`of only 5 j.tl of the ephedrine formulation by the method of 25
`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(cid:173)
`mulation to the surface of the eye. said method comprising 30
`the steps of:
`providing a spray nozzle having a liquid outlet in prox(cid:173)
`imity to but spaced from said surface, said nozzle being
`situated adjacent to a piezoelectric or electromagnetic
`transducer;
`providing to said nozzle said liquid ophthalmic formula(cid:173)
`tion comprising an ophthalmologically-acceptable liq(cid:173)
`uid having a viscosity in the range 10-3 to 1.0 Pa.s and
`a resistivity lower than 104 ohm.cm;
`ejecting a jet of said formulation from said spray nozzle
`towards said surface, forming a stream of uniformly(cid:173)
`sized, equally spaced, uncharged droplets by means of
`said transducer; and
`causing said droplets, upon formation, to pass through the 45
`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(cid:173)
`inflammatory 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- 65
`sured volume of a liquid formulation by surface ten-
`sion;
`
`means to supply said measured volume of liquid formu(cid:173)
`lation to said spray nozzle;
`means to eject said measured volume of liquid formula(cid:173)
`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 surface, 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
`40 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-
`50 electric or electromagnetic transducer is adapted to excite
`the liquid jet formulation at a frequency of 1-200kHz.
`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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`5,630,793
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`9
`wall substantially coaxial with and in open communi(cid:173)
`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 detachably attached to said body member within 10
`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;
`
`5
`
`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 annular 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(cid:173)
`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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