Note: Descriptions are shown in the official language in which they were submitted.
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WO 95126236 PCT/GB95100643
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TITLE: AQU80US OPIiTIiALMIC 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.
A conventional method of ocular administration of aqueous
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 30-501 drop is applied to the
eye, the actual volume that remains at the target is only 5-7u1.
Therefore, in addition to the low patient acceptability, there is a 4-
to l0-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 i~ortant 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 comprises 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
therapeutically 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 comprising an
ophthalmologically-active aubstaace and an ophthalmologically-
acceptable diluent, for subsequent administration to the eye. The
formulation has a viscosity in the range 10 3 to l.OPa.s at 25°C, and
a resistivity in the range 104 to 1012ohm.cm at 25°C. The formulation
is applied to a spray nozzle wherein a sufficiently large electrical
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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 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 104ohm.cm, cannot be sprayed, and high voltages of
lSkV 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 problems for pharmaceutical
formulations. A further disadvantage 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 acceptable
for very low volume applications can result in a stinging sensation if
larger volumes are administered to the eye.
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 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 environmental 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
piezoelectric 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
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through the naso-lachrymal duct into the t'.~.roat, and subsequent
:_ngestion into the gastro-intestinal tract, whence it can be absorbed
systemically and exert Lndesired side-effects. For example, it is
we'_1 documented in the literature r_::at p-adrenoceptcr 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
apray of electrically charged droplets of a liquid for:mulaticn to dose
just the required amount cf an ophthalmologically active substance,
thereby substantially eliminating unwanted side-effects.
Thus, according to the invention, there is provided a method
of administering a liquid ophthalmic formulation, comprising an
ophthalmologically acceptable liquid optionally cantaining an
ophthalmologically-active substance, to t'.~.e eye as electrical'_y
charged droplets which discharge their electric change by earthing on
contact with the eye, characterized in that the formulation has a
viscosity in the range 10-3 to l.OPa.s and a resistivity lower than
7.04ohm.cm, and that a jet of the formulation is ejected towards the
eye, from a spray nozzle sitiated adjacent to a piezoeieca ric or
electromagnetic transducer, to form a stream of uniformly-sized,
equally spaced, uncharged droplets, the stream of u.~.charged droplets
is subsequently directed past a charging electrode to induce an
electric charge on each drop.Let in the stream.
The method may be ~~arried opt 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 !:ygie.~.e product,
for example an eyewash or art ificial tears for the treatment of dry
eye, or a moistening or lubricating product for contact lens users, in
t:he form of a conventional, ;predominantly aqueous and essentially
isotonic liquid preparation, or it may be a product containing an
ophthalmologically-active suostance.
The ophthalmologically active substances encompassed by this
invention are any compounds having a pharmacological effect en and/or
.-, .., _ _, ~ . ~ -
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in the eye. Typical of such compounds are chemotherapeutic agents,
compounds to aid ocular examination, and compounds to a.id surgery, for
example:
(a) anti-inflammatory agents, such as prednisolone and other
corticosteroids;
(b) antimicrobial 3rugs, such as antibiotics, antiseptics,
antivirals, fungicides and sulphonamides, for example chloramphenicol,
sulphacetamide, gentamycin, nystatin, acyclovir and idoxuridine;
(c) autonomic drugs, such as f3-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'k to about 10%, but the required
concentration depends, naturally, upon the potency of the particular
active substance being used.
A resistivity lower than 104ohm.cm for the liquid ophthalmic
formulation is achieved by making it predominantly ac~;~eous, although a
small proportion of non-aqueous liquids, up to about 2.0%, may also be
incorporated. Suitable such non-aqueous liquids are, fo:r example,
glycerol, propylene glycol, polyethylene glycol of average molecular
weight up to about 600, and dimethyl isosorbide.
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The viscosity of: the formulation may be adjusted to within
the required range by the addition of viscolysers, for example
hydroxyethylcellulose, hydroxypropylcellulose, carbo;cymethylcellulose,
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 it.se.lf. 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, phenylm.ercuric acetate,
phenylmercuric nitrate, thiomersal, chlorbutol, benzyl c3lcOhU1 or
p-hydroxybenzoates.
The formulation may also contain a pH buffer salt, to
maintain the pH of the formulation at an optimum to minimize chemica l
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
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.
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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:
(i) at least one spray nozzle having an outlet of sufficiently small cross
section to be
capable of retaining an appropriate 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) a piezoelectric or electromagnetic transducer 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
~hargin~ field of the
electrode; and
(vi) means for applying a voltage to the electrode;
wherein at least the spray nozzle is suitable to be hand held when in use.
In one embodiment of this invention, the means to supply an appropriate
measured volume of a liquid formulation is provided by a metered va.l~~e or
syringe-pump of
the type used for mufti-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 t:he 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
nnanner, such as by screwinj or by frietion-tit on an appropriate receivin;z
member. In this
way, the low
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volume of formulation is measured in any convenie.~.t manner prior to
use.
Piston action can also be used as the means to eject a
measured vol~.i.~~e of .:iquid formulation from the svray nozzle as a jet.
The means for exciting the jet of liquid for:nulaticn emitted
from the spray nozzle to form a stream of droplets ef liquid
formulation is a piezoelectr:.c or an electromagnetic transducer. For
optimum droplet generation, the jet of liquid formulation needs to be
perturbed at a wavelength equal to 9.016 times the radius of the spray
nozzle, so that, fcr example, for a nozzle of approximately 100um
diameter, frequencies of 1-200k!-lz, pref=_rably 50-'~SOkH.., are required.
The charging electrode which is spaced co-axvally in front
of the spray nozzle ccnveniently takes the form cf a cylinder or
annulus, co-axial with the spray nczzle, charged to a suitable
positive or negative potential, but it may also be in the 'orm of
separate elements of any suitable form, located around the axis of the
nozzle, and with a space between, through which =he stream of droplets
can be directed in order to acquire an electrical charge. As
indicated above, for efficient use of the formulation, that is, so
that all cf the active i.~.gred~ent reaches the treatment: site, it is
necessary that each droplet in the stream becomes e'_ecT~r~cally c:~.arged
as soon as it is formed from the jet, so the cha:ging electrode oust
be located in front of the nozzle so that immediately a droplet is
formed, it is within the charging field ef the charging electrode.
The resistivity of the liquid formulatin must be chosen to
be low enough to ensure that the droplets become fully charged within
the duration of the charging electrode pulse, which wi.'.1 typically be
2-4us. It can be shown mathematically that, for a given geomet=y, the
charge cn the droplets is determined solely by the volt:age app~.v2d to
the charging electrode. For droplets of approximately 100~;,m diameter,
charging voltages in the range of about 0.1 to abort 1000V 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 :L04ohm.cm, and
preferably in the range of 102 to 103ohm.cm, are required in order for
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droplets to become fully charged. -
Generally the apparatus of this invention 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.
A particular embodiment will now be described, by way of example only, with
reference to Figure l, which is a schematic view illustrating the principal
components of one
farm of the apparatus.
Referring to Figure 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
SeCtlOn J,
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
cutlet 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 1 l, both of which are housed within the body member L.
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 central 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 ?, adjacent to the transducer
7 and
v:i
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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 t:he voltage
generator l0, and its pulse frequency is controlled through the
frequency control unit 11.
In use, the demountable nozzle 12 is fillec3 with the
appropriate volume of the formulation to be administered, the
apparatus is held in the hand, and the guide tube is positioned
directed towards the eye t.o 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 formulation 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 indiv:i.dually 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:
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Example 1
Lphedrine hydrcchlcride (0.25mg) was formulated as a 5~
solution in physiolcgical saline, radio'_abelled with approximately
0.8Gbq of 9~mTC-DTP~1 temp'-ex. This fcrmulation was strayed, from
apparatus essentially as hereinbefere described in this; specification,
ontc one eye of each of 6 New Zealand white rabbits, according to the
following procedure:
The test animals were acclimatised tc the experimental
cord=dons, by exposure to constant ly'.~.t inte~azwy a.~.d :nirimal
distractions, for 20 minutes. They wer= then placed is restraining
boxes which were positioned aporoxima_e'y 30-40cm in front of a camera
(Pe~a ax ME Super 35mm camera fitted with an SMC Pentax 50mm lens and
2x converter) set up en a tripod. A scale of known magnitude was
;,
pla~~d next to, and in the same plane as, the pup-_, p::icr to
photographs being taken.
The animals were allowed to settle, and photographs were
taken at f12 and 1/15 second,, using IS0~00 film (Kodak Gold NCO).
Photographs were taken 5 minutes prior to dosing of the er~hedrine
fors~ulation, in order to allow determination of baseli:.~.e (control)
pupil diameters. The ephedrine formulation (5u1) was then
a,dm'_-:istered to the eye as a pulse of c~:arged droplats generated from
t:he apparatus of the invention described above, and photo>graphs taken
at i_~.tervals over the next 3 hours.
Pupil diameters were dete..~.nined from the developed colour
pri~ts (approximately 15xi0cm) using an electronic micrometer
(Digimatic Caliper, Mitutoyo Corp., Japan). Absolute pupi.i diameters
were established by comparing the pupil diameter with the known scale
<:n the photographs. From these measurements, the maximum response
r_at~o was determined from the relationship:
'~Rma x
(auoil diameter at time t) -~ (average pupil diameter at time t0)
(average pupil diameter at time t0)
The following results were obtained:
'~~I,~w. .. . . .J~~ _ _. a
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RF'tmax
Animal
o. 1 2 4 5 6 M an SD*
Time
(min)
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 O.OB
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.
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These results are presented graphically in Figure 2, and show a marked
mydriatic response in the measurements taken at 18, 38 and 59 minutes
W all animals, and a continuing effect up to 80 minutes in some
animals, after the administration of only 5~.1 of the ephedrine
formulation by the method of this invention, which is a much lower
~~olume than that normally required with conventional modes of
application.
