Delivery of particles

The subject of the invention is a needle-free syringe.

From WO-A-92/04439 a needle-free syringe is known for firing dense carrier particles for the genetic transformation of plant cells. In this bioengineering method, dense microprojects, made for example of tungsten or gold, are covered with genetic material and shot into target cells. The microprojectiles are fired with a syringe containing an elongated tubular part with a compressed gas tank connected to it at one end, and an assembly for holding and introducing ejected particles between the ends of the tube and a membrane that closes the passage through the tubular part until it breaks under the influence of applied predetermined gas pressure from the tank, during which particles are ejected through the gas stream from the tubular part. As depicted in this patent, the particles may have been initially immobilized, e.g., electrostatically, on or above the breakable membrane that breaks when the gas flow starts, and which can be the same breakable membrane that breaks, initiating the flow of the gas stream . Alternatively, it is proposed that the particles be injected into the gas stream through a hollow needle.

The object of the invention is to develop a needle-free syringe for non-invasive administration of drugs in the form of light particles at specific doses into intact skin.

Needle-free syringe for percutaneous injection of powdered therapeutic agent, comprising a tubular nozzle, above which is a capsule with powdered therapeutic agent particles, and a drive assembly with an actuating member which, when actuated, delivers these particles through the nozzle from the capsule, according to the invention characterized by the assembly propulsion consists of a tank with compressed gas, located inside the upper cylindrical portion and from the opening mechanism to open this tank to release compressed gas, below which the opening mechanism is a pressure chamber, enclosed within the lower cylindrical portion, and the capsule is sealed between this pressure chamber and the nozzle. The nozzle preferably has an upper tapered section that is connected to the nozzle channel section by means of a constriction.

The capsule is preferably closed by two broken membranes.

The opening mechanism comprises a plunger piston having a head at its lower end, slidingly positioned inside the collar, closing the upper cylindrical part from below and sealed to the collar by means of a ring, and having a button at the upper end.

In a second embodiment of the syringe according to the invention, the opening mechanism comprises a pair of arms protruding downwards on both sides of the upper cylindrical portion and mounted adjacent to their lower ends articulated on pins relative to the upper cylindrical portion ^, and adjacent to their upper ends articulated on the pin relative to the lever having a cam toe, in contact with the upper end of the tank, the neck of this tank is slidably mounted in a seat closing the upper cylindrical part from below and having an upwardly through through projection provided with a channel opening into the chamber.

The nozzle channel section is cylindrical or divergent.

174 974

Below the channel section of the nozzle is a disk that surrounds and projects beyond the lower end of the nozzle.

There is a muffler in the annular space between the disc and the converging section.

The compressed gas tank contains helium.

The capsule contains powdered therapeutic agent particles having a size in the range of 0.1 to 250 pm and a density in the range of 0.1 to 25 g / cm.

The particle size range is from 1 to 50 pm, especially at least 10 pm, and most preferably 10 to 20 pm.

The particle density range is from 0.5 to 2.0 g / cm³.

The capsule preferably contains particles of therapeutic agent with at most a small amount of carrier or solvent by volume, or a powdered stable mixture of drugs that are unstable when mixed in a wet state, especially insulin.

The syringe of the invention may be used for the routine administration of medications such as insulin in the treatment of diabetes. It may also find use in mass immunization programs or for the delivery of slow-release drugs such as analgesics and contraceptives. Syringes of this type can also be used to deliver genetic material to live skin cells for genetic therapy for the stable treatment of diseases such as hemophilia or cutaneous melanoma. Such a syringe can also be used to deliver genetic material to the skin, muscles, blood, lymph, and in the case of minor surgical procedures, to the surfaces of organs.

The use of the syringe of the invention reduces the chances of spreading infectious and autoimmune diseases that are currently transmitted, among others, by reusable needles. Drug delivery through a fluid nozzle causes skin damage and bleeding, and offers no benefit over the needle when it comes to preventing the spread of blood-borne diseases. Therefore, the main benefits of the syringe of the invention include the lack of a needle and less pain, no risk of infection, administration of drugs in a natural solid form, faster and safer use compared to liquid drugs, administered by a syringe with a needle and finally no sharp waste.

The subject of the invention is shown in the embodiment of the drawing, in which fig. 1 is an axial section through a first example of a needle-free syringe according to the invention, fig. 2 - side view of the syringe of fig. 1, fig. 3 - enlarged view of fig. 1; figures 4, 5 and 6 are sections similar to figure 1, but concerning the second, third and fourth examples of the syringe solution according to the invention respectively, figure 7 are a section along line VII-VII in figure 6; and fig. 8 - axial section through the capsule used in the syringes shown.

The syringe of the invention shown in Figs. 1 to 3 is about 18 cm long and is positioned so that it can be held in the palm of the hand with the thumb resting on the upper end. It comprises an upper cylindrical portion 10 having a gas container 11. The upper end of the cylindrical part 10 is closed by an end plug 12 which has a hanging flange 13. The lower end of the cylindrical part 10 is closed by an integral end wall 14 formed by an outwardly projecting threaded flange 15. The plunger piston 16 has an upper extension 17 and a lower head 18, which slide in flanges 13 and 15, respectively. The upward movement of the piston is limited by the abutment of the upper end of the extension 17 on the arm 19 in the end plug 12. The plunger 16 can be moved down from this position through the stroke corresponding to the gap 20 shown in Fig. 1, obtained by the downward pressure on the button 21 fixed at the upper end of the plunger piston 16. During this stroke, the widening 17 tightly contacts the flange 13 by means of the circular ring 22. In the upper position of the plunger piston 16, the head 18 tightly contacts the flange 15 due to the circular ring 23 which seals the tank 11, but when the plunger piston 16 moves downwards, this sealing ring 23 extends from the lower end of the flange 15, thereby creating an outlet 'from the tank 11 in the gap between the head 18 and the flange 15.

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The bottom cylindrical part 10 is bolted to the bottom cylindrical part 24 containing the compression chamber 25. The bottom cylindrical part 24 is fitted with a nozzle 26. Between the upper end of the nozzle 26 and the lower side of the annular rib 27 is sealed integrally formed with the cylindrical part 24 capsule 28 , containing the injected particles. Capsule 28 is sealed to nozzle 26 and ribs 27 with circular rings 29 and 30, hollowed out in nozzle 26 and capsule 28, respectively.

As shown in Figure 8, the capsule 28 comprises a ring 31 having a truncated inner circumference surrounding the compartment 32 containing the injected particles. The top of this compartment 32 is closed by a relatively weak membrane "Mylar" and the bottom is closed by a stronger membrane 34 of the same type. Membranes 33, 34 can be tightly attached to the upper and lower walls of the ring 31 by squeezing between the nozzle 26 and the rib 27, however, it is recommended that they be attached hot to the edge of the ring 31, so that the capsule 28 is an independent sealed unit. Membrane 34 may be wrinkled at the bottom, as shown by the dashed line, to further ensure that all particles are transferred from the compartment 32 when the membranes 33, 34 break during use. The ring 31 can be divided into two parts by a weak membrane between these parts so as to provide two separate compartments.

The passage through the nozzle 26 has an upper, tapered portion 35 (downstream of the flow) leading through the constriction 36 to the channel section 37 having a cylindrical or divergent shape. The tapered portion 35 is an extension of the inner shape of the truncated ring cone 31. The nozzle 26 is surrounded by a tubular portion forming a disc rim 38 and a cylindrical portion of the damper 39 made of two halves divided by a longitudinal plane. The upper ends of these two halves are held in position due to the overlap of the annular flange 41 and the corresponding groove. The inner surface of the cylindrical portion of the muffler 39 has integrally formed numerous axially spaced, radially projecting inwardly flanges 40. The outer surface of the nozzle 26 adapts to them due to a series of radially projecting outer flanges 41, each of which is arranged axially at an equal distance between the respective adjacent orifice pair 40. The outer diameter of the flanges 41 is slightly larger than the internal diameter of the flanges 40. In the cylindrical portion of the muffler 39, an exhaust ring 42 is formed.

The cylindrical part 10 should be reusable and is preferably made of metal or plastic. The parts bolted to the bottom of the cylindrical part 10 are made mainly of plastics and constitute waste after one use. In an alternative embodiment, the entire syringe is made of plastic, is supplied in a sterile package and is waste after a single use.

In use, the reservoir 11 in the cylindrical portion 10 is filled with a gas such as helium under pressure, by screwing the supply cord onto the flange 15 and releasing the plunger 16 so that the reservoir is filled with a gas stream flowing up around the widening 18. When the button is released 21, then the plunger piston 16 retracts, sealing the reservoir 11, because the supply pressure acts on the bottom side of the widening 18.

The remainder of the syringe is normally delivered in an airtight, sterile container with the capsule 28 in place and through a nozzle 26 filled with a light gas such as helium at substantially equal atmospheric pressure, which is closed by a film 43 removably attached to the underside of the nozzle 26 and having free episode 44. This part is bolted to the cylindrical part 10.

To make the injection, the wider end of the disc 38 is applied to the patient's skin and, after removing the film 43 by pulling the free section 44, the button 21 is released. The gas released from the reservoir 11 into the chamber 25 creates a pressure in the chamber sufficient to break the membranes 33 and 34 and allowing gas to pass through the nozzle 26, with the particles entrained therein, into the patient's skin. The shock wave reflected from the patient's skin goes up through the labyrinth between the nozzle 26 and the surrounding silencer 39, through the winding path between the orifices 40 and 41 and finally out through the opening 42, which elements reduce the sound of the gas released.

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The gas load in tank 11 should be enough to make five or ten injections, although the current prototype allows only one injection to be made, before the tank needs to be refilled. After the injection, disposable items attached to the bottom of the cylindrical part 10 become waste. However, in some situations, the nozzle is not unscrewed from the lower cylindrical portion 24, and a new capsule 28 is attached just before a new injection is made. If the tank 11 will contain enough gas for several injections, it is recommended that the plunger piston 16 be spring-loaded upwards so that the lower end of the tank 11 closes when the button 21 is released just after firing from the syringe.

Figure 4 shows a modified syringe solution in which the upper cylindrical portion 10 has an open upper end and its lower end is attached to the connector 45, which is screwed to the upper end of the lower cylindrical part 24. The connector 45 has a socket with a circular ring 46, in which enters tightly adhering to the socket, neck 47 on a metal tank 48 containing compressed gas, such as helium, which is loosely placed in the cylindrical portion 10. The bottom wall of the coupling 45 is provided with a projection 49 through which a passage 50 opens that opens into the pressure chamber 25. Two arms 51, running downwards on opposite sides of the cylindrical part 10, are attached with pins 52, near their lower ends, to the cylindrical part 10 and a pin 53, near their upper ends, to a lever 54, which has a cam nose 55 attached so that it enters the upper end of the reservoir 48. The neck 47 of the tank 48 includes a spring valve that opens under the effect of internal pressure on the neck from the hollow projection 49 when the lever 54 rotates clockwise as shown in Fig. 4, pushing the tank 48 deeper into the seat 45.

The parts below the chamber 25 are only schematically shown in Fig. 4, but they may include any elements such as the stop / silencer and foil seal shown in Figs. 1 to 3. The operation of this syringe is analogous to that of the syringe shown in Fig. 1, since the chamber 25 is compressed before injection, releasing gas from the reservoir 48 into the chamber 25 by means of the lever 54. In this case some or all of the parts may be disposable.

In the first two embodiments, a semi-permeable membrane that filters out any bacteria or foreign matter from the gas source can be attached at its edge to the cylindrical part 24, e.g. between two parts that are threaded and run through the interior of part 24 above the capsule 28 .

Figure 5 shows a modification of the first embodiment of the syringe. The main difference is that the cylindrical part 24 is longer and provided with a piston 56 which is sealed to the inner wall of the cylindrical part 24 by a circular ring 57. The piston is trapped in the cylindrical part 24 by overlapping the annular edge 58.

In this case, the chamber 25 may be pre-filled with gas, such as helium, at atmospheric pressure, preferably 2-4 bar, but possibly as high as 10 bar.

In use, the button 21 is pressed to force the piston 56 downwards a short distance in the cylindrical part 24, after which the gas released from the tank 11 enters the cylindrical part 24 behind the piston 56 and forces it to hit the chamber 25 and the pressure between piston 56 and capsule 28 is enough to break the capsule. In this example, it was intended that the cylindrical portion 24 was separated from the cylindrical portion 10 so that it was exchangeable with the piston 56.

The syringe shown in Figures 6 and 7 has disposable parts that are similar to those in the syringe of Figure 5 except that the piston 56 has a slightly different shape and includes a poppet valve 59 through which the chamber 25 can be pre-filled with gas under pressure greater than atmospheric. In this case, the upper cylindrical portion 10 includes a sliding plunger 60 having an annular guide end 61, attached to overlap the piston 56 enclosing the poppet valve 59. Plunger 60 is initially in position

174 974 an advanced, counter-acting pair of parallel, helically coiled compression springs 62, thanks to the plate with an opening 63, which slides sideways at the upper end of the cylindrical part 10 and enters an additional annular groove at the upper end of the core 64, which is screwed into the widening 65 at the upper end of plunger 60 and thus constitutes an extension of this piston. Springs 62 operate between the widening 65 and the edge on the insert 66 in the cylindrical portion. Plate 63 with a hole moves sideways thanks to finger lever 67.

Initially, when the plunger 60 is raised and extended and the piston 56 is at the upper end of the chamber 25, a stop at the lower end of the syringe is applied as previously described to the patient's skin. Lowering the lever 67 releases the core 64 and the plunger 60, which further drives the piston 56 until the pressure in the chamber 25 is not sufficient to break the membranes of the capsule 28.

In each of these examples, the geometry through the nozzle 26 and the geometry of the disk 38 are important, and the following parameters are typical for a nozzle with a nominal speed of 2 mach. The tapered portion 35 is 10 mm long and tapers from a diameter of 6 mm to a diameter of throat 36 1.5 mm. The divergent part 37 is 50 mm long, and the diameter in intervals of 5 mm from the throat 36 down to the outlet end of the nozzle are 1.74, 1.95, 2.03, 2.10, 2.16, 2.19, respectively, 2.20, 2.21, 2.22 and 2.23. Shield 38 has a length along the 30 mm axis and extends from an upper diameter of 12 mm to 30 mm.

The solution of the syringes shown in Figs. 5 to 7 can be modified for laboratory use by using in the wall of the cylindrical part 24 an inlet gate connected to a source of e.g. helium, through which gas can be pumped into the chamber 25 between injections to an initial pressure of 2-4 bar. In this case, it is not necessary to dispose of the lower parts of the syringe after each injection, and they do not have to be delivered in assembled form immediately. Thus, the cylindrical portion 10 may have a rigid structure and may be held still. The particle material can be sandwiched between the membranes 33, 34 of the sealed capsule 28 between the cylindrical portion 10 and the nozzle 26. However, in laboratory conditions, one membrane may be sufficient to dispense the particle material from the top of the cylindrical portion 10, before attaching the piston 56 to the top of the cylindrical portion 10, and before increasing the pressure inside the cylinder through the inlet gate. The propellant gas is then released to lower the piston 56.

The syringe driving assembly may comprise a chamber located above the membrane, preferably in the syringe holder, and a assembly for controlled raising of gas pressure in the chamber, in which case the assembly for increasing pressure in the chamber may comprise a source of compressed gas connected to the chamber by, for example, tight coupling or through the bleed valve. Alternatively, the syringe is a complete, portable unit and contains its own compressed gas tank, which can be refilled several times.

Typical practical operating parameters are: diaphragm rupture pressure between 20 and 75 atmospheres in a pressure chamber with a volume between 1 and 5 ml, producing a supersonic shock wave at speeds between 1 and 8 waves, preferably between 1 and 3 waves.

The gas / particle velocity exiting the nozzle, and hence the penetration depth depends on the diaphragm rupture pressure, but, given the short duration of the phenomenon, experiments have shown that this velocity also critically depends on the nozzle geometry. This is useful because it allows you to control the penetration depth by replacing the nozzle instead of changing the thickness of the membrane. Preferably, the nozzle should have a converging top leading through the throat to a cylindrical or preferably divergent bottom. The upper part allows placing a tightly closed dose of therapeutic agent in a wider part, and the supersonic shock wave arises in the throat. The divergence of the lower part significantly affects the speed of the gas, which expands at a pseudostationary supersonic speed. Increasing this pseudo-stationary speed causes an increase in the depth of penetration of the particles, which is peculiar to the phenomenon that is considered to be essentially short-lived. The divergent part also seems to transform the momentary flow at the moment of the diaphragm rupture into smooth flow at the exit of the nozzle, which unifies the path

174 974 particles to the target. In addition, divergence of the nozzle results in even distribution of particles at the target application site.

In one series of experiments using helium over the membrane, only changing the rupture pressure of the membrane, the permeation into a homogeneous target medium was measured. The fracture pressures of 42, 61 and 100 atmospheres gave penetration depths of 38, 50 and 70 units, respectively. However, similar experiments in which only the internal geometry of the divergent part was changed also gave different permeation values. Namely, three nozzles of the same length and diameter of the exit but with geometrically different interiors, selected so as to produce the numbers of machs 1, 2 and 3 under theoretical steady state conditions, gave penetration depths to the target of 15, 21 and 34 units, respectively.

The type of gas is not critical. Relatively cheap gases such as helium, nitrogen and carbon dioxide are suitable for this purpose. The gas released to the upper side of the membrane to break it should be sterile, as it will be part of a gas stream carrying particles through the nozzle to the patient's skin or other destination. Helium is useful for this because it is available in an inert, sterile form.

There is another benefit of using helium to rupture the membrane. It is believed that most of the particles move on the contact surface between the "upper and lower" gas, which are initially separated by a membrane, this contact surface located just behind the shock wave. The lighter the gas released above the membrane is, the higher the shock wave velocity (and contact surface) will be in the nozzle at a given pressure difference across the membrane during its cracking and the given nozzle geometry. Hence, if light gas is used, the desired shockwave velocity can be achieved with a smaller pressure difference assuming that the film will burst at such a pressure difference. Generally, therefore, the gas released to the upper surface of the membrane to break it should be lighter than air.

The velocity of the shockwave in the nozzle is the higher the lighter the gas is in the nozzle. The use of at least partial vacuum has been suggested, but it is difficult to achieve and maintain in practice. Therefore, to reduce even more the required diaphragm rupture pressure to achieve the desired shockwave velocity (and contact surface) in the nozzle, it is recommended that the inside of the nozzle below the membrane contains a gas such as helium, which is lighter than air, at a pressure substantially equal to atmospheric , the gas being sealed with an easily removable seal, such as a removable plug, cap or tear foil, at the bottom end of the nozzle. In use, this seal would be removed just before use of the syringe so that the gas would have little time to diffuse out of the nozzle before being shot out of the syringe.

The seal at the lower end of the nozzle also has the additional advantage that it remains sterile, so that there is only a minimal chance of some foreign bodies entering the nozzle after, for example, opening the sterile package, and before firing from the syringe, because then such foreign bodies in the inevitable way would be entrained by the gas stream carrying the drug particles to the patient's skin.

The source of the particles should contain a well-defined dose of the drug and be put on as a sterile kit. Absolute sterility should be sought and, as a consequence, it should be assumed that at least a set of tubular nozzle and remains of a source of particles and a broken membrane, and perhaps also a compression chamber, will be disposable and will be replaced with a new set from a sealed, sterile package. It is quite advantageous if the entire syringe, including the drive mechanism, compression chamber, nozzle, membrane and particles will be disposable and that all residues will be waste. Such a disposable set should be manufactured in the cheapest possible way, primarily from plastics. Alternatively, the syringe may easily be disassembled into two parts, namely a disposable lower portion, including at least a sterile nozzle, membrane and particles, and an upper portion, including a portion of the drive assembly. However, in this particular arrangement, the gas source and its coupling to the compression chamber will not be interchangeable due to the construction of relatively expensive metal parts. Because the bare end and internal surfaces of these parts connect

174 974 with the inside of the compression chamber, and therefore, when the drug is administered with the interior of the tubular nozzle, there is a risk of contamination by bacteria and other contaminants that settle on the non-replaceable parts.

Therefore, it is recommended that the upper end of the chamber be closed with a sterile battery, such as a semi-permeable membrane that passes gas, but not bacteria. Alternatively, the chamber may be cylindrical and the sterile barrier will be a piston, as well as a piston displacement assembly in the cylindrical chamber to re-compress the gas. The piston displacement assembly may be a source of compressed gas discharged onto the top of the piston. In this way, the syringe may be a stand-alone, portable unit containing. its own compressed gas tank, as well as a valve that can be opened manually to expose the piston to gas pressure. Alternatively, the piston displacement assembly may include a spring that is positioned so that it can be tensioned and released manually to displace the piston.

The use of a piston makes it possible to provide an initially predetermined volume of gas at a predetermined pressure, which can be slowly increased by moving the piston along the cylindrical chamber until the pressure in the chamber is sufficient to rupture the film and discharge particles. The amount of gas that passes through the tubular part is therefore precisely determined and causes little noise after firing. The overall volume necessary to increase the gas pressure from 20 to 40 bar can be minimized, which is sufficient to break the membrane, provided that the helium or other gas in the cylindrical chamber is pre-compressed above atmospheric pressure, preferably up to 2 bar, before the piston moves. Similarly, to avoid creating a "dead space" between the leading end of the piston and the diaphragm when it bulges away from the piston just before fracture, the piston surface should preferably be convex so that it can get closer to the center of the diaphragm.

When the syringe is used in a drug delivery clinic, the tubular nozzle, diaphragm, particles, cylindrical chamber, drive assembly and plunger assembly will be enclosed in a sterile, sealed package and become waste after use. In an alternative solution, including replaceable and non-replaceable parts, it will be possible to avoid contamination of the piston displacement assembly, whether in the form of a spring, a hand pin or a source of compressed fluid behind the piston, due to the fact that the piston maintains the insulating barrier of the reusable parts during the administration of the medicine. above the piston from inside the disposable part below the piston.

The disposable set should be made at the lowest possible cost, in particular from plastics. Because during feeding, high pressure will build up in the chamber, tending to push the chamber walls away, with the risk of gas leaking out of the piston, so the chamber wall should be made of hard engineering plastic. Alternatively, the chamber can be enclosed in a hard shell to which it fits tightly. This cover can be reusable.

Another application for a new syringe is the laboratory delivery of genetic material to living cells for their genetic transformation. In this case, assuming relatively sterile conditions in the laboratory, it does not appear necessary to pre-place disposable parts under sterile conditions, it may be sufficient to assemble the syringe in the laboratory, for example with components comprising a separate (if possible - for single use) tubular nozzle and a cylindrical chamber that can be separated to replace the broken diaphragm, as well as a separate component piston, inserted into the chamber after applying genetic material to the membrane.

Various assemblies described in WO-A-92/04439 may be used to arrange the particles prior to rupture of the membrane, provided the particles are made of very dense metal and / or for the genetic transformation of plant cells, in which case the number of particles, who achieve the goal is not a critical factor. However, this device is not suitable for powdered medications because the medicament-containing particles are so light that they are difficult to immobilize before firing, they must be delivered at the prescribed dose and must be sterile prior to administration. That is why it is recommended

174 974 that the powdered medicament particles are sandwiched between two breakable membranes extending across the interior of the nozzle.

One of the two auxiliary membranes, and in principle both can form the main breakable membrane, the crack of which initiates the flow of gas. Alternatively, the membrane may be located above or below the main breakable membrane in any convenient position along the nozzle.

The main diaphragm and the secondary diaphragms can be permanently fixed in a disposable syringe or in a disposable part of the syringe, or they can be fixed by the edges between the joined parts of the nozzle, for example between the twisted sections.

It is recommended that the edges of the membranes are sealed directly along their edges, so as to form a common bag or capsule containing the particles, or indirectly, for example by tightly fastening to the opposite axial sides of the ring between them. In both cases, the edges of the sealed capsule can be clamped between separate parts of the nozzle.

A sachet, capsule or other sealed unit may include three or more membranes to provide a plurality of separate compartments containing various powdered medicaments to be injected together to provide drug mixtures that otherwise would react adversely even when dry. Such unit may be used as a sterile kit and may contain a well-defined dose of medicine. By placing it so that it ruptures when the diaphragm ruptures, you can ensure that the medicine is available at the right dose and exactly when it is needed. A particular advantage of the new technique for injecting dry powdered medications is that it can be used to administer stable mixtures of medications that are not stable when mixed in solution.

The sealed capsule contains a predefined dose of medication and it is important that substantially all of this dose is delivered to the patient's skin. Therefore, it is important that virtually no particle is trapped between the membranes, adhering to their edges after rupture. For this reason, at least one of the membranes should be slightly wrinkled to ensure sufficient separation to place most of the particles radially inward relative to the edges of the membranes.

One would expect that the closer the nozzle is to the patient's skin, the greater the depth of penetration of the particles will be. Although this is true when reducing distances from several tens of millimeters, experiments show that there is some optimal distance for maximum penetration, which decreases when the nozzle is further brought closer to the skin, probably due to the reflection of the shock wave overlapping the contact surface.

It is therefore desirable to provide a spacer at the lower outlet end of the nozzle in order to ensure an absolute separation of the nozzle from the patient's skin by a distance of 35 mm, preferably from 5 to 15 mm. Another desirable effect of providing such separation of the nozzle from the patient's skin is to allow the stream leaving the nozzle to expand radially outward and, consequently, to cause particles to hit the patient's skin surface, much larger than the cross-sectional area of ​​the nozzle. For example, if the nozzle at the lower end has an outlet aperture with a diameter of about 2.5 mm, the desired jet distribution will cause it to hit substantially uniformly on a patient's skin surface with a diameter of 20-30 mm. Consequently, it is recommended that the spacer be a tubular rim sufficiently wide and of a shape that does not prevent expansion of the gas-entrained drug-entrained particles leaving the nozzle outlet during use on a surface of at least five and preferably at least ten times the outlet surface at the level of the lower end of the disc, that is where the disc will press on the patient's skin during use.

The spacer may be associated with a sound suppressor, such as cotton wool. A perforated spacer can provide a suitable embossing effect. It is recommended that the tubular disc ensuring separation is not perforated and that the silencer is placed in the annular space inside the barrel surrounding the nozzle in order to absorb the shock wave reflected from the patient's skin through the spacer disc. The silencer may have a labyrinth construction and provide e.g. a winding path between overlapping annular flanges extending radially outward from the nozzle surface and radially inwardly from the barrel, this path leading to at least one outlet to the atmosphere through the barrel wall. This has proven to be extremely effective at suppressing the sound that is produced when the diaphragm breaks and the shock wave leaves the nozzle, bringing particles into contact with the patient's skin.

Preliminary experiments have confirmed the effectiveness of the syringe according to the invention, especially in the percutaneous range of powdered drug injections. The theoretical model assumes that the skin behaves as a medium of resistance very similar to water. Thus, at low Reynolds numbers, resistance applies to Stokes law, but at higher Reynolds numbers, the resistance factor is constant. Evidence of this behavior of resistance on a smooth sphere in a homogeneous medium, such as water, is given in BS Massey's Fluid Mechanics (Van Nostrand). Calculations show that adequate penetration, e.g. between 100 and 500 mm under the skin, is possible using powdered drug particles that are not large enough to damage the skin cells, using gas velocity e.g. 1 up to 8 waves, preferably 1 to 3 waves, which are relatively easy to obtain when the breakable membrane breaks. Penetration depends on the particle size, i.e. the nominal diameter of the particles assuming that the particles are essentially spherical, on the density of the particles, the initial velocity at impact on the skin, as well as on the density and kinematic viscosity of the skin. Different penetration depths depend on tissue, e.g. the epidermis or muscle to which the particles are to be delivered, in order to obtain the optimal therapeutic effect, so the parameters determining penetration should be appropriately selected.

The following example explains the usefulness of a needle-free syringe according to the invention.

Example. Eight healthy, white male rats (Wistar, mean weight: 250 g) were anesthetized with an injection of 0.25 ml Sagatal (barbital pentathol sodium, 60 mg / ml). Everyone's fur was removed in the abdominal region using commercially available depilatory cream (Immac). Animals 1 to 4 were then injected with 0.1 mg of bovine insulin (powder form, Sigma) using a needle-free syringe of the invention as shown in Figure 1. Animals 5 and 6 were injected with 1 mg bovine insulin (powder form) under identical conditions. The mean insulin particle size was about 10 gm and the administration speed was 750 m / s. For comparison, animals 7 and 8 were injected with 0.1 mg insulin dissolved in 0.9% NaCl, using a conventional syringe, through a needle.

Prior to the injection (for control purposes), a blood sample was taken from each of the animals used in the experiment, followed by four hours after the injection. In each case, 3 drops of blood (about 50 g) were taken from the animal's tail and mixed with 2 g of heparin to prevent clotting. This mixture was then mixed with 100 g 6% perchloric acid to stop glucose metabolism. The mixture was centrifuged and glucose concentration was determined in the supernatant.

Glucose levels (BGL) for animals 1 to 6 are given in the table below:

<td rowspan="2">Animal</td><td colspan="2">BGL (mM)</td>

<td>0 hours</td><td>4 hours</td>

<td> 1</td><td> 5,30</td><td> 2,22</td>

<td> 2</td><td> 5,40</td><td> 1,29</td>

<td> 3</td><td> 7,22</td><td> 1,51</td>

<td> 4</td><td> 5,64</td><td> 2,87</td>

<td> 5</td><td> 5,07</td><td> 0,91</td>

<td> 6</td><td> 5,36</td><td> 2,63</td>

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The results of animals 7 and 8 showed BGL values ​​2.2-3.3 mM and 2.0-2.4 mM after 1 and 2 hours, respectively. These results show that insulin was given by needle-free injection in an amount sufficient to produce a significant therapeutic effect and that the level of this therapeutic effect appears to be comparable to that obtained after a conventional injection with a syringe needle. Comparison of these results after 4 hours with other results shows that the reduction of working pressure (from 65 bar to 40 bar) and reduction of insulin load (from 1.0 mg to 0.1 mg) does not give significant differences in BGL. This is extremely important for three reasons:

- first, reducing the operating pressure reduces the structural requirements for a possible mass production clinical device design;

- secondly, reducing working pressure ensures that any undesirable effects that could occur in the skin are eliminated; and

- thirdly, reducing the drug load proves that this mode of administration is highly efficient, ensuring the sufficiency of the bioavailability associated with this technique of administration.

In a first embodiment of the method of the invention, insulin particles with a nominal diameter of 10 gm were injected at an initial speed of 750 m / s into the skin. Assuming that the insulin particles have a density close to the density of the skin, i.e. about 1, and that the kinematic viscosity of the skin is equal to the assumption of water viscosity at 10^_6m²/ s, the depth of penetration of particles inside the skin is about 200 gm. To achieve greater permeability, the particle size can be increased to 20 mm, and the initial speed to 1500 m / s, in which case the penetration depth will increase to about 480 gm.

In a second example of using the method of the invention, not for transdermal injection, but for the genetic transformation of cells, for example, for injection of tungsten DNA-coated carrier particles into corn cells, comparable tissue penetration would require a reduction in particle size to allow their density to increase. Thus, if such coated particles with a nominal diameter of 1 gm and a density of 20 are injected into corn cells at a speed of 500 m / s, the penetration depth is about 200 gm. In general, a new injection method for intradermal injection from a powdered drug can be used for particles between 0.1 and 250gm, preferably between 1 and 50 gm, and most preferably between 10 and 20 gm. The particles usually have a density in the range between 0.1 and 25 g / cm³, but for transdermal injections from powdered medications, they should have a density in the range between 0.5 and 2.0 g / cm 3, and most preferably substantially 1.0 g / cm. Injection rates may be from 200 to 2500 (or even up to 3000 and more) m / s, however, for transdermal drug injections, this speed should be between 500 and 1500 m / s, and most preferably between 750 and 1000 m / s.

The powdered therapeutic agent is usually ground and sieved to obtain a suitable diameter. Alternatively, the particles may be fine spherical casings with a diameter of, for example, up to 100 gm, in which solid or liquid drugs may be contained. If the casing has controllable permeability, this may be an additional means of slowly releasing the drug after it has been delivered. It may be necessary to incorporate a substantially inert carrier into the particles to achieve adequate penetration, especially if the therapeutic agent is potent or has a low density. The carrier may be mixed with the therapeutic agent or coating casings may also be used. The dose required will depend on the amount and concentration of the therapeutic agent and the number of particles in one injection.

Another aspect of achieving suitable particle penetration parameters in the method of the invention is the selection of the dimensions, mass and initial velocity of the particles to give them the angular momentum density, i.e. the angular momentum of the particle divided by the anterior surface area of ​​the particle, in the range from 2 to 10, and preferably from 4 to 7 kg / s / m. It is desirable to control angular momentum density to achieve controlled administration, which is different from the type of tissue. In the first example of the use of the method mentioned above, which is injected at a speed of 750 m / s with powdered insulin having a particle size of 10 gm, a density of angular momentum is 5 kg / s / m. In the second example, regarding the injection of tungsten DNA-coated carrier particles into corn cells, particles with a nominal diameter of 1 pm and a speed of 500 m / s have an angular density of 6-7 kg / s / m.

A characteristic of the method of actuating the syringe according to the invention is that the penetration depth can be precisely controlled, thus ensuring specific delivery to the desired place. Thus, for example, permeation can be chosen as less than 1 mm for intradermal active agent, 1-2 mm for subcutaneous active agent, and 10 mm or more for active agent for intramuscular administration. The therapeutic agent itself can also be selected accordingly. Examples of therapeutic agents that can be used are viruses and proteins for immunization purposes, analgesics such as ibuprofen, hormones such as human growth hormone, and drugs such as insulin or calcitonin. The therapeutic agent can be administered without any carrier, solvent or other density increasing agent. In some cases, e.g. A carrier may be used to provide particles of a particular size containing a highly active therapeutic agent, however, the amount will typically be much less than in conventional pharmaceutical mixtures, e.g. less than 75%, and often less than 50% of the volume of the particles. For example, insulin and calcitonin will usually be administered subcutaneously. HGH (Human Growth Hormone) can be administered subcutaneously or, less frequently, intramuscularly . Immunogens of hepatitis A, meningitis and BCG can be administered intramuscularly, subcutaneously and intradermally.

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