Abstract:
A needleless syringe particle delivery system is provided. The needleless syringe has an elongate nozzle that is connected at its upstream end to a sealed chamber. The sealed chamber contains gas at super-atmospheric pressure and particles of a therapeutic agent. Upon release of the gas from the sealed chamber, a flow is formed which entrains the particles and allows the particles to pass through the nozzle at supersonic speed for subsequent delivery to a target surface.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
   This application is a continuation-in-part of International Patent Application Number PCT/GB95/01948, filed Aug. 17, 1995, designating the United States, from which priority is claimed pursuant to 35 U.S.C. §365(c). 

   TECHNICAL FIELD 
   The present invention relates generally to a needleless syringe for use in delivery of particles of a therapeutic agent to a target surface. More particularly, the invention pertains to a needleless syringe system that includes a sealed chamber containing particles of a therapeutic agent and a gas at super-atmospheric pressure. 
   BACKGROUND OF THE INVENTION 
   In commonly-owned U.S. application Ser. No. 08/474,367, a non-invasive delivery system is described that entails the use of a needleless syringe. The syringe is used for transdermal delivery of powdered therapeutic compounds and compositions to skin, muscle, blood or lymph. The syringe can also be used in conjunction with surgery to deliver therapeutics to organ surfaces, solid tumors and/or to surgical cavities (e.g., tumor beds or cavities after tumor resection). 
   The needleless syringe is constructed a s an elongate tubular nozzle, having a rupturable membrane initially closing the passage through the nozzle adjacent to the upstream end of the nozzle. Particles of a powdered therapeutic agent are located adjacent to the membrane. The therapeutic agent is delivered using an energizing means which applies a gaseous pressure to the upstream side of the membrane that is sufficient to burst the membrane, thereby producing a supersonic gas flow through the nozzle in which the particles are entrained. 
   SUMMARY OF THE INVENTION 
   Recent studies have shown that, by the appropriate selection of the geometry and Mach number for the nozzle in the needleless syringe described in U.S. application Ser. No. 08/474,367, it is possible to provide a pseudo-steady state, supersonic, two-phase flow through the nozzle. Particles that are disposed within this multi-phasic flow travel with a velocity close to that of the propelling gas in which they are entrained. The selected geometry for the nozzle preferably has a convergent upstream portion, leading through a throat to a cylindrical or, preferably, divergent downstream portion. 
   Consequently, a large proportion of the particles containing the therapeutic agent 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/particle 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 particles throughout the jet. The length of time that the jet lasts allows one to calculate the effective length of the jet and hence its volume. Thus, one is able to conclude that the particles containing the therapeutic agent are arriving in a continuous flow at the target skin or mucosal surface, and, 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 the appreciation that the dose delivered by the needleless syringe delivery system may advantageously be mixed with the driving gas in the gas canister. The delivery system can then be considerably simplified as a rupturable membrane may, in most cases, no longer be needed. In particular, the outlet from the chamber may lead directly to the nozzle via a valve or other means for releasing the gas. This differentiates the invention from previous devices, such as those described in EPA-0535005, which generally rely upon the impact of a shock wave to accelerate particles toward a target surface, whereas the present invention accelerates particles toward a target surface within 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. A means is provided for rapidly opening an outlet from the chamber to release the driving gas in a flow, allowing particles of the therapeutic agent, entrained within the gas flow, to exit the chamber and pass through the nozzle with a velocity approaching the supersonic speeds of the driving gas flow. Locating particles of the therapeutic agent within the chamber, which also contains the driving gas under high pressure, considerably simplifies the construction, assembly, and use, of the present needleless syringe. 
   The outlet from the chamber may incorporate a pierceable membrane or a valve, such as a spring-loaded ball valve, which is actuated by either mechanical means or by manual manipulation, for example, by movement of two parts of the syringe relative to each other. 
   The chamber may contain a single dose of particles, and hence sufficient gas for delivery of a single administration of a therapeutic agent. Alternatively, the outlet from the chamber may incorporate a valve which can be opened and closed a consecutive number of times to deliver a succession of doses of therapeutic agent. The time during which the valve is opened may be automatically controlled by control means, for example, means entailing the combination of a solenoid or stepping motor to actuate the valve into an open position 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 therapeutic agent and driving gas within the chamber, creating a homogeneous mixing and suspension of the powdered therapeutic agent, and by using a fast opening metering valve at the exit of the chamber, a multi-shot syringe can be provided which dispenses an infinitely variable, rather than a fixed unit, dosage of the agent. By combining the metering valve with a timing device, the duration of time that the valve is open for each administration may be controlled. The timer can also be adjusted to take account of the desired dose of the therapeutic agent, the gas pressure in the reservoir, and the agent concentration within the reservoir, both of which will decrease with each successive administration. If the initial values of the mass of therapeutic agent, and the gas pressure in the chamber, are known, the required duration of each subsequent administration can be calculated, e.g., by a microprocessor, and the timer adjusted accordingly. 
   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 of therapeutic agent 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 surface. Upon hearing the membrane burst, the operator of the device can close the valve, for example, by releasing a trigger which holds the valve open against a tensioning means, such as spring pressure. 
   Sealed chambers, which contain a driving gas under pressure and particles of a selected therapeutic agent, can be supplied as a separate unit from the rest of the needleless syringe device. At the time of use, a sealed chamber is attached to the syringe which includes the tubular nozzle, and, possibly, a diaphragm-piercing or valve-opening means. 
   One slight disadvantage with the needleless syringe described in U.S. application Ser. No. 08/474,367, wherein gas pressure is used to burst the rupturable membrane, is the possibility of having less than the entire prescribed dose of particles of the therapeutic agent delivered within the gas flow, for example, if a portion of the particles are retained in the proximity of the remnants of the burst membrane. With the present invention, 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, electrostatically, or by means of weak membranes closing the ends of the passageways until ruptured by the release of pressure. 
   Another embodiment entails the provision of very small particles of a powdered therapeutic agent which are small enough to remain suspended in the gas for a few seconds when agitated, but big enough to prevent their direct entry into cells in the targeted surface, thereby reducing the bio-availability of the agent. In this regard, it is preferred that the particles of the therapeutic agent delivered with the present devices occupy extra-cellular space and hence diffuse readily into the systemic circulation. Particle diameters of between 10-20 μm are preferable. A ball bearing may be placed inside the gas canister to help provide a homogenous distribution of the particles of the therapeutic agent upon shaking, prior to their administration. 
   Study of the jet released from the present devices, and its arrival at the target surface, has further led to the appreciation that the jet dimensions are important and affect the concentration of therapeutic agent delivered per unit volume of target skin or mucosa. By increasing the volume of the driving gas, one may lengthen the duration of the jet and increase the dosage of agent that is delivered, subject to limitations particular to the selected therapeutic agent. For a given concentration, delivered dosages may also be increased by increasing the targeted surface area. This can be achieved by increasing the diameter of the throat of the nozzle, while maintaining the ratio of inlet and exit diameters constant. Target diameter may also be increased by increasing the spacing distance of the nozzle exit from the target. 
   Reference is made to U.S. application Ser. No. 08/474,367 for other aspects of the needleless syringe, for example, the use of a spacer/silencer at the downstream end of the nozzle, various alternative nozzle geometries, types of therapeutic agent particles which may be delivered, and the composition, and pressure, of the driving gas to be used. 

   
     BRIEF DESCRIPTION OF THE FIGURES 
     Some examples of syringes constructed in accordance with the present invention are illustrated diagrammatically in the accompanying drawings, in which: 
       FIG. 1  is an axial section through a first embodiment of the invention; 
       FIG. 2  is a side elevation of the embodiment of  FIG. 1 ; 
       FIGS. 3 and 4  correspond to  FIGS. 1 and 2 , showing a second embodiment of the invention; 
       FIGS. 5 and 6  are exploded views of portions of the second embodiment of the invention depicted in  FIGS. 3 and 4 ; 
       FIGS. 7 and 8  show an alternative embodiment of the device of  FIGS. 3-6 ; 
       FIGS. 9 and 10  show yet another alternative embodiment of the device depicted in  FIGS. 3-6 ; 
       FIG. 11  is a diagrammatic axial view of a canister for use with the devices of the invention; 
       FIG. 12  is a section taken along XII—XII in  FIG. 11 ; 
       FIG. 13  is an exploded view of a third embodiment of the invention; 
       FIG. 14  is an enlarged view of a portion of the device of  FIG. 13 ; and, 
       FIG. 15  is a pictorial representation of a still further embodiment of the invention. 
   

   DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
   Before describing the present invention in detail, it is to be understood that this invention is not limited to particular pharmaceutical formulations or process parameters as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting. 
   All publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety. 
   It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a therapeutic agent” includes a mixture of two or more such agents, reference to “a gas” includes mixtures of two or more gases, and the like. 
   A. Definitions 
   Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. The following terms are intended to be defined as indicated below. 
   The term “transdermal” delivery captures both transdermal (or “percutaneous”) and transmucosal administration, i.e., delivery by passage of a therapeutic agent through the skin or mucosal tissue. See, e.g.,  Transdermal Drug Delivery: Developmental Issues and Research Initiatives , Hadgraft and Guy (eds.), Marcel Dekker, Inc., (1989);  Controlled Drug Delivery: Fundamentals and Applications , Robinson and Lee (eds.), Marcel Dekker Inc., (1987); and  Transdermal Delivery of Drugs , Vols. 1-3, Kydonieus and Berner (eds.), CRC Press, (1987). Aspects of the invention which are described herein in the context of “transdermal” delivery, unless otherwise specified, are meant to apply to both transdermal and transmucosal delivery. That is, the compositions, systems, and methods of the invention, unless explicitly stated otherwise, should be presumed to be equally applicable to transdermal and transmucosal modes of delivery. 
   As used herein, the terms “therapeutic agent” and/or “particles of a therapeutic agent” intend any compound or composition of matter which, when administered to an organism (human or animal) induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. More particularly, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; local and general anesthetics; anorexics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antihistamines; anti-inflammatory agents; antinauseants; antineoplastics; antipruritics; antipsychotics; antipyretics; antispasmodics; cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics); antihypertensives; diuretics; vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins peptides and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like). 
   Particles of a therapeutic agent, alone or in combination with other drugs or agents, are typically prepared as pharmaceutical compositions which can contain one or more added materials such as carriers, vehicles, and/or excipients. “Carriers,” “vehicles” and “excipients” generally refer to substantially inert materials which are nontoxic and do not interact with other components of the composition in a deleterious manner. These materials can be used to increase the amount of solids in particulate pharmaceutical compositions. Examples of suitable carriers include water, silicone, gelatin, waxes, and like materials. Examples of normally employed “excipients,” include pharmaceutical grades of dextrose, sucrose, lactose, trehalose, mannitol, sorbitol, inositol, dextran, starch, cellulose, sodium or calcium phosphates, calcium sulfate, citric acid, tartaric acid, glycine, high molecular weight polyethylene glycols (PEG), and combinations thereof. In addition, it may be desirable to include a charged lipid and/or detergent in the pharmaceutical compositions. Such materials can be used as stabilizers, anti-oxidants, or used to reduce the possibility of local irritation at the site of administration. Suitable charged lipids include, without limitation, phosphatidylcholines (lecithin), and the like. Detergents will typically be a nonionic, anionic, cationic or amphoteric surfactant. Examples of suitable surfactants include, for example, Tergitol® and Triton® surfactants (Union Carbide Chemicals and Plastics, Danbury, Conn.), polyoxyethylenesorbitans, e.g., TWEEN® surfactants (Atlas Chemical Industries, Wilmington, Del.), polyoxyethylene ethers, e.g., Brij, pharmaceutically acceptable fatty acid esters, e.g., lauryl sulfate and salts thereof (SDS), and like materials. 
   “Gene delivery” refers to methods or systems for reliably inserting foreign nucleotide sequences, either DNA or RNA, into host cells. Such methods can result in expression of non-integrated transferred nucleotide sequences, extrachromosomal replication and expression of transferred replicons (e.g., episomes), or integration of transferred genetic material into the genomic DNA of host cells. 
   By “vector” is meant any genetic element, such as a plasmid, phage, transposon, cosmid, chromosome, virus, virion, etc., which is capable of replication when associated with the proper control elements and which can transfer gene sequences between cells. 
   B. General Methods 
   One embodiment of the needleless syringe of the present invention is shown in  FIGS. 1 and 2 . The needleless syringe has an upper barrel portion  13  containing a sealed reservoir or chamber  14 . The barrel portion  13  is coupled via a lower barrel portion  15  to a nozzle  16  which can be associated with a spacer  17  and silencer  18 . The barrel portion  13  can be coupled to the lower barrel portion by screw threads, or the like. An outlet  19  in the bottom of the chamber  14  is in communication with a release means  20 , which is arranged at a chamber-nozzle interface. The release means  20  can comprise any suitable element, such as a valve or the like, which is capable of controlling communication between the chamber  14  and the nozzle  16  via the lower barrel portion  15 . The release means can be actuated between open and closed positions by any suitable means, for example, by the action of a plunger  21  which is depressible by a button  22 . In the embodiment depicted in  FIGS. 1-2 , the release means  20  comprises a valve. 
   Particles  23  of a powdered therapeutic agent are located within the chamber  14 . When the particles are to be delivered to a target surface, the button  22  is depressed to move a sealed carrying part of the valve downwardly and out of the outlet  19  to actuate the valve into an open position. Opening of the valve releases the compressed gas in a supersonic gas flow, wherein the gas flow contains particles from the chamber  14  which pass through the nozzle  16  for delivery to a target surface positioned beyond the spacer  17 . 
   The syringe shown in  FIGS. 3-6  differs from the embodiment of  FIGS. 1 and 2  in that the chamber  14  is provided by a canister  24  which is slidable within a sleeve  25  corresponding to the upper barrel portion  13  in the first example. An outlet  19 A is closed by a valve which can be actuated between open and closed positions to allow or prevent the passage of the contents of chamber  14  to other, downstream, portions of the needleless syringe. In the particular embodiment depicted in  FIGS. 3 and 4 , the valve is actuated by a ball closure element  26  which is urged onto a seating  27  by a helically coiled compression spring  28 . Within a lower barrel portion  15 A of the syringe, there is provided a projection  29  which is sized to enter the outlet  19 A. When the upper end of the canister  24  is pressed downwardly into the upper barrel portion  25 , the projection  29  serves to displace the ball closure element  26  from its seat, thereby allowing sudden release of gas and particles contained within the chamber  14 . The valve may be reclosed, for example, when the syringe is used for multiple administrations of a therapeutic agent from the chamber, by releasing the pressure applied to the upper end of the canister and allowing the ball closure to return to it&#39;s seated position. 
   Another embodiment of the invention is shown in  FIGS. 7 and 8 . This embodiment is substantially similar to the device depicted in  FIGS. 3  to  6 ; however, the ball closure element  26  is moved between open and closed positions by movement of a thumb piece  68  that is pivotally mounted in the top of the barrel portion  25 . More particularly, the thumb piece  68  is mounted by means of a lug which engages an aperture  30  in the barrel portion of the syringe device. Depression of the thumb piece forces the canister  24  downwards within the sleeve  25 , thereby providing a mechanical advantage which facilitates movement of the ball closure element  26  against the high pressure within the chamber  14  to displace it from its seat, allowing release of the gas and particles contained within the chamber  14 . 
   The ball closure element  26  can also be actuated by way of a modified housing. Referring now to  FIGS. 9 and 10 , an alternative means for urging the canister  24  downwardly in the syringe to open the ball valve is shown. In this example a cylindrical shroud  31  fits over the canister  24 . The shroud is constructed to slide relative to the rest of the syringe such that an open lower end  32  of the shroud slides over the lower barrel portion  15 A. 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 polymeric material, for example, a polycarbonate. A canister  24 A made of such a polymeric material is shown in  FIGS. 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 substantially 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 relative to the needle. 
   A number of alternative canister configurations can be used with the present needleless syringes without departing from the spirit of the invention. For example, alternative canister configurations can be provided having means for disaggregating particles of the therapeutic agent to provide a more homogenous suspension of particles within the released gas flow. Any irregular interior surface feature within the canisters  24  and/or  24 A can be used in this manner to agitate and/or disaggregate particles as they exit the canister. Such features include, but are not limited to, one or more baffles, retaining tubes, or like structures, formed on the interior surface of the canister. In the alternative, a series of features can be used to force the gas and particles along a tortuous path when exiting the canister. For example, a helical or otherwise spiral feature can be used to impart a spin on the exiting gas and particles as they exit the canister. Also, a moveable feature, such as a propeller, can be arranged adjacent to the outlet  37  of the canister. As the exiting gas flows through the outlet, the propeller blades are caused to spin, thereby helping to disaggregate particles contained within the gas flow. 
   The canisters  24  and/or  24 A can also have a sealing membrane arranged over the outlet  37 . The membrane can be used to maintain a sterile barrier about the outlet, such as in applications where the canisters are handled separately from the rest of the syringe up until the time the therapeutic agent is to be delivered. 
   In another embodiment of the invention, a needleless syringe is provided that is capable of delivering multiple doses of a therapeutic agent. Referring now to  FIGS. 13 and 14 , a multi-dose syringe is shown which comprises a canister  38 , containing compressed gas, particles of therapeutic agent, and 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. 
   Attached to the lid of the canister is a valve housing, generally indicated at  39 , that contains a valve chamber having a lower side passage  41  which communicates with the canister  38  into which it opens, and an upper side passage  42  to which is attached a nozzle assembly  43 . The nozzle assembly comprises a rupture chamber  44  and a nozzle  45  separated by a rupturable membrane  46 . The assembly further includes a plunger  47 , that extends into the valve chamber  40 . A sealing O-ring  48 , arranged adjacent to one end of the plunger maintains a seal between the plunger and the walls of the valve chamber  40 . The plunger is urged upwardly by a compression spring  49  so that the O-ring  48  is maintained above the side passage  41 . 
   In order to actuate the device, the plunger  47  is depressed against the action of the compression spring  49  by the downward displacement of an L-shaped lever  50 , which is pivotally connected to the valve housing  39 . The downward displacement of the lever causes the O-ring  48  to move below the passage  41 , thereby allowing release of a suspension of particles of the therapeutic agent and conveying gas from the canister  38  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 toward a target surface through the nozzle  45 . The lever  50  can be manipulated by grasping the canister  38  in the palm of an operator&#39;s hand, and depressing the free end of the lever. As soon as the operator hears the membrane burst, the lever  50  can be released, so that the plunger  47  is returned to its closed position under the action of the spring  49 , effectively reclosing the valve. Before the next injection is delivered from the device, the membrane  46  can be replaced, for example by detaching the nozzle  45  from the nozzle assembly  43  to access the membrane. 
   Referring now to  FIG. 15 , another multidose needleless syringe system is shown. The system shown in  FIG. 15  differs from the system of  FIGS. 13 and 14  in that the canister  38 , which contains the driving gas and the particles of the therapeutic agent, is not directly attached to the nozzle  45 . Instead, an assembly comprising the nozzle communicates with the canister via a canister-nozzle interface, which can include tubing  50 , which may be rigid or flexible. In the embodiment of  FIG. 15 , the interface also includes a pressure regulator  51 , a pressure indicator  52 , and a control valve  53 , which are respectively used to regulate a desired pressure within the system, and to deliver doses of the therapeutic agent from the canister  38 . The valve can be any suitable fast acting valve, and is generally controlled by a solenoid or stepping motor  54  which can be under the control of a micro-processor  55 . In the particular embodiment depicted in  FIG. 15 , the micro-processor is connected to the control  54  by an umbilical  56 . In this example the valve  53  is opened for a predetermined time according to a timing program supplied by the micro-processor  55 , thereby allowing a selected dose of the therapeutic agent to be ejected through the nozzle  45 . The micro-processor can be programmed with dosage parameters, such as information regarding one or more desired dosages, the initial pressure of gas contained within the canister  38  and the original concentration of the particles of therapeutic agent within the gas. In this manner, a selected dose can be repeatedly delivered from the device, irrespective of a concomitant reduction in the gas pressure within the canister  38 . 
   Typically, in each of the illustrated examples, the gas provided in the chamber  14 , or within the canisters  24 ,  24 A, or  38 , may be helium at a pressure of the order of 40 to 80 bar. However, any other suitable delivery gas may be used. The nozzles  16  or  45  may be of convergent/divergent, or convergent/cylindrical form with a length of between 50 and 100 mm, preferably 60 mm, and a throat diameter of between 1 and 10 mm, preferably between 1.5 and 5 mm. 
   The needleless syringes of the present invention can be used for transdermal delivery of powdered therapeutic compounds and compositions, for delivery of genetic material into living cells (e.g., gene therapy or nucleic acid vaccination), both in vivo and ex vivo, and for the delivery of biopharmaceuticals to skin, muscle, blood or lymph. The syringes can also be used in conjunction with surgery to deliver therapeutic agents, drugs, immunogens, and/or biologics to organ surfaces, solid tumors and/or to surgical cavities (e.g., tumor beds or cavities after tumor resection). In theory, practically any agent that can be prepared in a substantially solid, particulate form can be safely and easily delivered using the present devices. 
   Delivery of therapeutic agents from the above-described needleless syringe systems is practiced with particles having an approximate size generally ranging from 0.1 to 250 μm. For drug delivery, the optimal particle size is usually at least about 10 to 15 μm (the size of a typical cell). For gene delivery, the optimal particle size is generally substantially smaller than 10 μm. Particles larger than about 250 μm can also be delivered from the devices, with the upper limitation being the point at which the size of the particles would cause untoward damage to the skin cells. The actual distance which the delivered particles will penetrate a target surface depends upon particle size (e.g., the nominal particle diameter assuming a roughly spherical particle geometry), particle density, the initial velocity at which the particle impacts the surface, and the density and kinematic viscosity of the targeted skin or mucosal tissue. In this regard, optimal particle densities for use in needleless injection generally range between about 0.1 and 25 g/cm 3 , preferably between about 0.9 and 1.5 g/cm 3 , and injection velocities generally range between about 200 and 3,000 m/sec. With appropriate gas pressure, particles of a therapeutic agent having an average diameter of 10-70 μm are accelerated through the nozzle at velocities approaching the supersonic speeds of the driving gas flow. 
   Accordingly, novel needleless syringe delivery systems and methods for using the same are disclosed. Although preferred embodiments of the subject invention have been described in some detail, it is understood that obvious variations can be made without departing from the spirit and the scope of the invention as defined by the appended claims.