Note: Descriptions are shown in the official language in which they were submitted.
WO 96/04947 219 7 711
PCT/GB95/01948
PARTICLE DELIVERY
in our earlier international patent application
= No. WO 94/24263, we disclose a non-invasive drug delivery
system involving the use of a needleless syringe which
= fires light drug-containing particles in controlled doses
into the intact skin or delivers genetic material into
living cells. The syringe described in the earlier
application is constructed as an elongate tubular nozzle,
a rupturable membrane initially closing the passage through
the nozzle adjacent to the upstream end of the nozzle,
particles of a therapeutic agent, particularly a powdered
therapeutic agent, located adjacent to the membrane, and
energizing means for applying to the upstream side of the
membrane a gaseous pressure sufficient to burst the
membrane and produce through the nozzle a supersonic gas
flow in which the particles are entrained.
By appropriate selection of the geometry and Mach
number for the nozzle, which preferably has a convergent
upstream portion, leading through a throat to a cylindrical
or, preferably, divergent downstream portion, it has been
possible to provide a pseudo-steady state, supersonic two
phase flow through the nozzle, in which the particles move
with a velocity close to that of the propelling gas in
which they are entrained. Consequently, a large proportion
of the particles reach the target under quasi-steady flow
conditions and only a small proportion are delivered in
transient flow and carried on the contact surface. This
leads to considerable benefit both in control and in
increased skin or other target penetration and is
surprising in such a transient phenomenon. High speed
photography of the gas/drug jet has confirmed the quasi-
steady flow conditions. Typical photographs of the jet
show the jet lasting for 1.5 milliseconds, with reasonably
homogenous distribution of the drug particles throughout
the jet. The length of time that the jet lasts allows us
to calculate the effective length of the jet and hence its
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volume. This allows us to conclude that the drug particles
are arriving in a continuous flow at the skin surface and
that on average succeeding particles will penetrate in the
same holes as preceding particles, reducing damage and
trauma to the skin. This understanding has led to our
appreciation that the drug dose may be advantageously mixed
with the driving gas in the gas canister. The drug
delivery system can then be considerably simplified as a
rupturable membrane may, in most cases, no longer be
needed. Now the outlet from the chamber may lead directly
to the nozzle via a valve or other means for releasing the
gas. This differentiates our technique from other prior
art, such as EPA-0535005, which relies upon the impact of
a shock wave to accelerate particles, whereas our technique
accelerates them in a flow of gas.
In accordance with the invention, a needleless syringe
is constructed as an elongate nozzle at the upstream end of
which is provided a sealed chamber containing gas at
superatmospheric pressure and particles of a therapeutic
agent, there being means for opening an outlet from the
chamber to release the gas and particles entrained
therewith so that they flow through the nozzle at
supersonic speed. The location of the particles within the
chamber which contains the high pressure gas considerably
simplifies the construction and assembly of the syringe.
The outlet from the chamber may incorporate a
pierceable membrane or a valve, such as a spring-loaded
ball valve, which is pierced or opened by manual
manipulation, such as by movement of two parts of the
syringe relatively to one another.
The chamber may contain a single dose of particles,
and hence sufficient gas for a single shot. Alternatively,
the outlet from the chamber may incorporate a valve which
may be opened and closed a consecutivenumber of times to
deliver a succession of doses of the therapeutic agent.
The time during which the valve is opened may be
automatically controlled by control means, for example
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PCT/GB95/01948
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including a solenoid or stepping motor the valve being
opened for successively longer periods to deliver equal
doses of therapeutic agent in spite of the successively
reducing pressure in the chamber. It will then be
appreciated that by placing the drug in the gas canister,
creating a homogeneous mixing and suspension of the
powdered drug and by using a fast opening metering valve at
the exit of the canister, a multi-shot syringe may be
created, dispensing an infinitely variable, rather than a
unit, dose of drug. By combining the metering valve with
a timing device, the duration of time that the valve is
open for each shot may be controlled. The timer may be
adjusted to take account of the desired dose of drug, the
gas pressure in the reservoir and the drug concentration in
the reservoir (both of which will decrease with each shot).
If the initial values of the drug mass and the gas pressure
in the reservoir are known, then the required duration of
each subsequent shot can be calculated, eg by a
microprocessor, and the timer adjusted accordingly.
Alternatively, when the actual dose is not critical,
for example when the therapeutic agent is an analgesic, the
valve may be opened and closed manually. A degree of
control may then be provided by means of a rupturable
membrane between the valve and the nozzle, the valve being
opened to release sufficient gas and particles into a
rupture chamber upstream of the membrane until the pressure
across the membrane has built up sufficiently for the
membrane to rupture, whereafter the particles, entrained in
the gas, are free to flow from the rupture chamber through
the nozzle to the target. As soon as the operator hears
the membrane burst, he will reclose the valve, for example
by releasing a trigger which holds the valve open against
the spring pressure.
The sealed chamber containing the gas under pressure
and the particles may be supplied as a separate unit to be
united, at the time of use, with another part of the
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syringe incorporating the tubular nozzle, and possibly also
a diaphragm-piercing or valve-opening device.
One slight disadvantage with the earlier syringe, in
which gas pressure was used to burst the rupturable
membrane, was the difficulty in ensuring that the full
prescribed dose of particles was delivered in the gas flow,
without any remaining in the proximity of the remnants of
the burst membrane. With the new syringe, this
disadvantage can be overcome if the particles are initially
located in one or more open ended passageways within the
chamber, and arranged such that upon opening of the outlet
and release of the compressed gas, at least some of this
gas sweeps through the passageway(s) and thus entrains
substantially all the particles within the passageway(s).
The particles may be initially retained in the passageways
under gravity, or electrostatically, or by means of weak
membranes closing the ends of the passageways until
ruptured by the release of pressure. Another solution
involves making the particles of drug to be so small as to
remain suspended in the gas for a few seconds when agitated
but big enough so.as to not enter the skin cells and reduce
bio-availability. On the contrary, the drug particles
occupy extra-cellular space and hence diffuse readily into
the systemic circulation. Particle diameters of between
10-20 m are preferable. A ball bearing may be placed
inside the gas canister to help homogenous distribution of
the drug upon shaking, prior to firing.
Study of the drug jet and its arrival at the target
surface has further led to the appreciation that the jet
dimensions are important and affect the concentration of
drug per unit volume of target skin. By increasing the
volume of driver gas one may lengthen the duration of the
jet and increase the dosage of drug that may be delivered,
subject to the limitation of drug concentration that is
viable in the skin. For a given concentration, dosage
delivered may also be increased by increasing target skin
area. This may be achieved by increasing the diameter of
WO 96/04947 219 7 711 PCT/GB95101948
the throat of the nozzle, whilst maintaining constant the
ratio of inlet and exit diameters. Target diameter may
also be increased by increasing the spacing distance of the
nozzle exit from the target.
5 In other respects, for example in the use of a
spacer/silencer at the downstream end of the nozzle, in the
nozzle geometry, in the type of particle which may be
delivered, and in the type and pressure of gas to be used,
reference is made to the earlier application.
Some examples of syringes constructed in accordance
with the present invention are illustrated diagrammatically
in the accompanying drawings, in which:
Figure 1 is an axial section through a first example;
Figure 2 is a side elevation of the first example;
Figures 3 and 4 correspond to Figures 1 and 2 but show
a second example;
Figures 5 and 6 show, to an enlarged scale, parts of
Figures 3 and 4;
Figures 7 and 8 correspond to Figures 5 and 6 but show
a third example;
Figures 9 and 10 correspond to Figures 1 and 2 but
show a fourth example;
Figure 11 is a diagrammatic axial view of a canister;
Figure 12 is a section taken on the XII-XII in Figure
11;
Figure 13 is an exploded view of another example;
Figure 14 is an enlargement of part of Figure 13; and,
Figure 15 is a view of a further example.
The syringe shown in Figures 1 and 2 is almost
identical to the syringe shown in Figures 1 to 3 of the
earlier application WO 94/24263, in having an upper barrel
portion 13 containing a sealed reservoir or chamber 14 and
coupled by screw threads via a lower barrel portion 15 to
a nozzle 16 associated with a spacer 17 and silencer 18.
An outlet 19 in the bottom of the chamber 14 is closed by
a valve element 20 on the end of a plunger 21 which is
depressible=by a button 22. The syringe differs from that
R'096/04947 2197711 PCT/GB95/01948
6
in the earlier application in not having at the top,
upstream end of the nozzle 16 a capsule consisting of two
rupturable membranes between which the particles of
therapeutic agent are isolated. Instead, these particles
23 are located within the chamber 14. When the particles
are to be delivered, the button 22 is depressed thereby
moving the sealed carrying part of the element 20
downwardly out of the outlet 19, and releasing the
compressed gas and particles in the chamber 14 to flow at
supersonic speed through the nozzle 16 to a target
positioned beyond the spacer 17.
The syringe shown in Figures 3 to 6 differs from that
shown in Figures 1 and 2 in that the chamber 14 is provided
within a canister 24 which is slidable within a sleeve 25
corresponding to the upper barrel portion 13 in the first
example. An outlet 19A is closed by a valve consisting of
a ball closure element 26 which is urged onto a seating 27
by a helically coiled compression spring 28. Within the
lower barrel portion 15A there is provided an upwardly
projecting spigot 29 which can enter the outlet 19A and,
when the upper end of the canister 24 is pressed downwardly
into the upper barrel portion 25, displaces the ball
closure element 26 from its seat and allows sudden release
of the gas and particles which are contained within the
chamber 14. The valve may be reclosed, for multi shot use
by releasing the pressure on the canister.
The modification shown in Figures 7 and 8 differs from
that of the Figures 3 to 6 example only in that a thumb
piece 28 is pivotally mounted in the top of the barrel
portion 25 by means of a lug on the thumb piece engaging an
aperture 30 in the barrel portion. Depression of the thumb
piece forces the bulb 24 downwards within the barrel
portion 25 and provides a mechanical advantage which
facilitates movement of the ball closure element against
the high pressure within the chamber 14.
Figures 9 and 10 show an alternative way of forcing
the canister 24 downwardly to open the ball valve. In this
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example a cylindrical shroud 31 is slipped down over the
canister 24 and its lower end 32 slides on the lower barrel
portion 15A. Downward pressure on the closed upper end of
the shroud 31 forces the canister 24 downwards to open the
valve.
The pressure containing parts of the syringe will
usually be made of metal, but may also be made of a rigid
engineering plastics material, such as a polycarbonate. A
canister 24A made of such plastics material is shown in
Figures 11 and 12. The body of the canister is made in two
parts 33 and 34 which are fused or welded together. The
canister contains an insert 35 consisting of a number of
parallel cylindrical passageways 36. Upon assembly, the
canister is filled with high pressure gas and the particles
of therapeutic agent are located within the passageways 36.
An outlet 37 of the canister may be fitted with a ball
valve such as in the previous examples, or closed by means
of a pierceable diaphragm which is sufficiently strong to
contain the internal gas pressure but which may be readily
breached by a needle, which may be hollow, when the
canister is moved relatively to the needle.
Figures 13 and 14 show a multi dose syringe which
comprises a canister 38 containing compressed gas and
particles of therapeutic agent, together with an agitator,
such as a metal ball. Prior to discharge, the canister is
shaken so that the particles are suspended in the gas and
entrained by the gas when it is released.
Screwed into the lid of the canister is a valve
housing 39 containing a valve chamber having a lower side
passage 41 leading down into the canister 38 into which it
opens, and an upper side passage 42 into which is screwed
a nozzle assembly 43 consisting of a rupture chamber 44 and
a nozzle 45 separated by a rupturable membrane 46. A
plunger 47 extends into the valve chamber 40 and carries an
0 sealing ring 48. The plunger is urged upwardly by a
helically coil compression spring 49 so that the ring 48 is
above the side passage 41. When the plunger 47 is
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depressed against the action of the spring, by downward
displacement of an L-shaped lever 50, which is pivoted to
the valve housing 39, the ring 48 rides to below the
passage 41, allowing the escape of a suspension of the
particles in the conveying gas from the canister 38 and
into the rupture chamber 44. When the pressure in the
chamber 44 has built up sufficiently, the membrane 46
bursts and the particles, entrained in a supersonic gas
flow, are ejected through the nozzle 45. The lever 50 is
conveniently manipulated by grasping the canister 38 in the
palm of the user's hand, and depressing the free end of the
lever with the thumb. As soon as the user hears the
membrane burst, the lever 50 can be released, so that the
plunger 47 is raised under the action of the spring 49,
effectively reclosing the valve ready for a subsequent
shot, prior to which the membrane 46 will need to be
replaced, for example by unscrewing the nozzle 45 from the
part of the assembly 43 containing the rupture chamber 44.
The system shown in Figure 15 differs from that of
Figure 13 and 14 in that the canister 38 of gas and
particles is connected to the nozzle 45 via tubing 50,
which may be rigid or flexible, containing a pressure
regulator 51 and a pressure indicator 52, and a valve 53.
The valve is a fast acting valve which is controlled by a
solenoid or stepping motor 54 under the control of a micro
processor 55, which is connected to the control 54 by an
umbilical 56. In this example the valve 53 is opened
according to the timing programme of the micro processor
55, for a predetermined time to cause the required dose to
be ejected through the nozzle 45. The micro processor will
be programmed not only with the required dose but with the
initial pressure in the canister 38 and the concentration
of particles of therapeutic agent, so that the required
dose can be repeated irrespective of reducing pressure in
the canister 38.
Typically, in each of the illustrated examples, the
gas provided in the chamber 14 may be helium at a pressure
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of the order of 40 to 80 bar. The nozzle may be of
convergent/divergent, or convergent/cylindrical form with
a length of between 50 and 100, preferably 60mm, and a
throat diameter of between 1 and 10, preferably between 1.5
and 5mm. With appropriate gas pressure, particles having
a diameter of 10-40Am will be accelerated through the
nozzle to velocities of between Mach 1 and 3.
