WO2018085318A2 - Self-contained syringe for dissolution and administration of drugs - Google Patents

Abstract

The invention provides a mixing syringe adapted for the storage of a two- component medicament in unmixed form. One of the components is a liquid, which is maintained in a separate, collapsible compartment until just prior to administration, while the other component, which may be solid or liquid, is stored within the syringe body. The act of partially withdrawing the plunger from the syringe creates a partial vacuum within the syringe body, and atmospheric pressure forces the liquid from the collapsible compartment through a one-way valve and into the syringe body. The combined medicament is then injected by use of the syringe in the usual manner.

Description

SELF-CONTAINED SYRINGE FOR DISSOLUTION AND

ADMINISTRATION OF DRUGS

RELATED APPLICATIONS

Priority is claimed to US Provisional Application No. 62/416, 139 filed November 1, 2016.

FIELD OF THE INVENTION

The invention relates to hypodermic syringes, in particular mixing syringes, which are adapted to store a drug composition and the solvent necessary for its administration.

BACKGROUND

Many injectable solutions or suspensions of pharmaceuticals, particularly biologies, have insufficient stability to allow for prolonged storage prior to use.

Such drugs must be transported and stored under refrigerated conditions, or in dry form, typically as a lyophilized powder. Lyophilization, while it can be an effective solution to the stability problem, requires that medical personnel prepare an injectable solution or suspension from the dry powder, at the time of use. This involves the removal of the solvent - typically water or saline - from one vial, injection of the solvent into a second glass vial containing the dry pharmaceutical, and shaking or swirling the vial until a solution is obtained, followed by withdrawal of the solution back into the syringe, and then injection into the patient or into an IV line. This is time consuming, and it requires that at least one additional component, such a sterile saline or water for injection, be available, along with appropriate syringes and needles and appropriately trained personnel. While not a problem in a modern hospital, the availability of refrigerated storage, or the elements needed for reconstitution of lyophilized drugs, is not guaranteed at remote health facilities in undeveloped areas, refugee camps, and military field hospitals.

Furthermore, the additional operations introduce opportunities for errors, waste, and for the inadvertent loss of sterility. The quantity of sterile saline in a bottle or vial is rarely the precise amount required, and the unused portion is either discarded, or used for further preparations, a practice that introduces risks of infection associated with multiple punctures with multiple needles.

There is therefore a need for disposable, prefilled syringe systems that contain all needed components in the correct amounts, and that permit the components to be readily mixed under sterile conditions at the time of use. As a result of this need, a large number of such "mixing syringe" systems have been designed, but none has received widespread acceptance, and the use of sterile saline withdrawn from a separate bottle or vial is still almost universally employed.

In one class of designs, the plunger of an outer syringe is formed by a second concentric syringe, the barrel of which contains saline or some other fluid component of the medicament. In place of a hypodermic needle, the inner syringe is provided with a check valve. In use, the plunger of the inner syringe is depressed, expelling the fluid through the check valve into the outer syringe, which contains the dry powder component. The check valve prevents the fluid from re-entering the barrel of the inner syringe. After dissolution or suspension is complete, the inner syringe is used as the plunger of the outer syringe, to expel the contents through a hypodermic needle.

Examples of such systems are described in U.S. Patent Nos. 3,678,931 and 3,682, 174 (Cohen), 3,685,514 (Cheney), 4,405,317 (Case) and 4,464,174 (Ennis), all of which are incorporated herein by reference for the purpose of disclosing suitable check valve designs. These systems are complex and difficult to manufacture, and are accordingly costly.

In another type of system, a single barrel and plunger are employed, and the liquid and dry powder components are contained in separate chambers within the barrel, separated by sliding seals. Depression of the plunger presses the seal between the chambers against a needle, so as to cause a puncture. The liquid component is then expelled from the first chamber, through the needle, and into the second chamber, where it dissolves or suspends the dry powder component. Further depression of the plunger forces the sliding seal into the syringe, expelling the contents through a hypodermic needle. Examples of such systems are shown in U.S. Patent Nos.

3,785,379 (Cohen), 4,055, 177 (Cohen) and 4,059,109 (Tischlinger).

U.S. Patent No. 4,060,082 (Lindberg et al.) discloses a system which consists of two syringes in series. The liquid contents of the first syringe are injected through an elastomeric sliding seal into the barrel of the second syringe where the dry powder is contained. The first syringe is removed, and a plunger is fitted to the sliding seal, creating a syringe containing the desired solution or suspension. The system is long and somewhat unwieldy, and it requires the expense of two syringes, plus their connections, in order to effect a single injection.

U.S. Patent No. 4,116,240 (Guiney) discloses a syringe in which the powder component of the medicament is stored in a compartment within the plunger seal. Depression of the plunger generates hydraulic pressure sufficient to cause an internal lid to pop off, exposing the compartment to the liquid in the main chamber of the syringe. There is no provision for returning the lid to its original position, so as to close off the powder storage compartment prior to injection, and the lid itself remains loose within the syringe chamber; these shortcomings are likely to prevent complete discharge of the syringe contents.

U.S. Patent No. 3,659,749 (Schwartz) describes a single syringe, with a hollow plunger which contains the liquid component. The hollow is fitted with a sliding seal at the rear, and a check valve or frangible seal at the forward end.

Withdrawal of the plunger from the syringe barrel generates a vacuum, which draws the liquid out past the valve or seal and into the syringe barrel, where it mixes with the powder component. The sliding seal follows the liquid down through the hollow plunger. After the solution or suspension is obtained, the plunger is depressed, and the contents are expelled through a hypodermic needle. The design is compact and offers ease of use, but it is mechanically complex. US 3,659,749 is incorporated herein by reference, for the purpose of disclosing suitable check valve and frangible seal designs. Another liquid-in-plunger design is that of U.S. Patent No. 5,779,668 (Grabenkort), employing a needle and septum between the chambers.

U.S. Patent No. 4,861,335 (Reynolds) discloses a syringe having a collapsible chamber within the plunger, within which the liquid components is stored. Partial depression of the plunger causes a double-ended needle to pierce both the chamber and the plunger seal, and subsequent withdrawal of the plunger creates a vacuum in the syringe barrel, drawing the liquid out through the needle. The chamber collapses under atmospheric pressure as the liquid is drawn out. The needle is affixed to a mount having spiral threads, so that rotating the plunger causes withdrawal of the needle from the plunger seal, leaving the syringe ready for use. An optional "nonreturn valve" for preventing back-flow is mentioned, but it is not relied upon to maintain separation between the components. The retracting needle of this design provides a conceptually simple alternative to the check valves of the prior art, but the mechanism required to retract the needle renders the design mechanically complex, and the ease of use of the syringe is compromised by the several steps needed to pierce the seals, transfer the liquid, and withdraw the needle.

There remains a need for a two-component mixing syringe that is inexpensive to manufacture and easy to use.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a mixing syringe system for the administration of two-component medicaments, within which pre-measured aliquots of a liquid component, and a dry powder or second liquid component, are stored in separate compartments. In use, operation of the syringe causes the two components to be combined, and the resulting solution or suspension can then be injected. The invention provides a mixing syringe that is mechanically simple and easy to operate.

According to the invention, a syringe for the mixing and administration of a medicament having two components is provided. The syringe of the invention comprises a barrel having a substantially closed end bearing a needle mount, a plunger stem movable within the barrel; a sliding plunger seal affixed to the plunger stem and sliding within the barrel, having a front face and a rear face, a syringe chamber defined by the substantially closed end of the barrel, the barrel, and the front face of the sliding plunger seal, a collapsible bladder positioned behind and attached to the rear face of the plunger seal; and a fluid channel transiting the plunger seal and providing a fluid connection between the interior of the bladder and the syringe chamber. Prior to use of the syringe, the flow of liquid through the fluid channel is prevented by a check valve.

A liquid component of the medicament can be stored in the bladder until required for use, and the second component, which may be a powder or a liquid, may be stored in the syringe chamber. In use, the hypodermic needle or the needle mount is initially sealed off from the atmosphere, and the plunger stem is partially withdrawn from the barrel, the attached plunger seal moving with the stem and sliding within the barrel so that a partial vacuum is induced in the syringe chamber. The pressure differential between the bladder and the syringe chamber causes the check valve to open, and the liquid component is forced, by atmospheric pressure on the collapsible bladder, into admixture with the second component stored in the syringe chamber.

After suitable agitation to effect the mixing of the components and the dissolution or suspension of the medicament, the needle mount or needle is unsealed, and a hypodermic needle, if it is not already present, is fitted to the needle mount in communication with the previously closed syringe chamber. The plunger is moved inwardly to eject the contents of the syringe through a hypodermic needle, in the usual manner of using a hypodermic syringe.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an isometric exploded view of a syringe in accordance with one embodiment of the invention.

FIG. 2 is a perspective view of the collapsible bladder of Fig. 1.

FIG. 3 is a cut-away side view of the plunger, bladder, plunger seal, and flap valve assembly of Fig. 1.

FIG. 4 is a transparent view of a sleeve valve used in an alternative

embodiment of the invention.

DETAILED DESCRIPTION OF PREFERRED EMBODFMENTS

As used herein, the term "needle mount" refers to the portion of a syringe at the closed end of the barrel that is adapted for affixing a hypodermic needle to the syringe. By way of example, the needle mount may be a bore, into which the needle may be permanently cemented, or it may be a fitting such as a Luer taper or Luer lock, as is commonly used in the art, to which a needle may be reversibly affixed.

The syringe of the invention comprises a syringe barrel bearing a needle or needle mount at a first end, a plunger stem movable within the barrel, and a sliding plunger seal affixed to the plunger stem and movable within the barrel. The plunger seal has a front face and a rear face, and is transited by a fluid channel. A syringe chamber is defined by the first end of the barrel, the barrel, and the front face of the sliding plunger seal, and contains one of the two components of the medicament. A collapsible bladder is positioned behind the rear face of the plunger seal, with the interior of the bladder in fluid communication with the fluid channel. A check valve is disposed in or on the plunger seal, and regulates fluid communication between the fluid channel and the syringe chamber.

One or more collapsible bladders are positioned behind, and in some embodiments are directly attached to, the plunger seal, and lie generally alongside the plunger stem, for example in syringes where the plunger stem has an cross- or X- shaped cross-section. In some embodiments, where the plunger stem is a substantially hollow cylinder, a single bladder may lie in a cavity within the plunger stem. The bladder is formed at least in part from a flexible, preferably elastomeric and substantially water-impervious polymer, preferably a nitrile, urethane, or silicone rubber. Flexible, non-elastomeric polymers may be employed, particularly if the bladder takes the form of a pouch or is otherwise capable of collapse by folding rather than deformation, and laminates can be employed if specific barrier properties are desired.

The shape and structure of the bladder is not critical, so long as it is readily collapsed by atmospheric pressure so as to permit the contents of the bladder to be expelled into the syringe chamber. The bladder may, for example, take the form of a cylindrical or balloon-like structure, or it may have a pillow- or envelope-like form, as is known for example in the field of pouches for intravenous fluids. Bellows folds may be incorporated to ensure substantially complete collapse and ejection of the contents under atmospheric pressure. The bladder may incorporate rigid components, such as flat, parallel plates joined at their peripheries by flexible walls, and in some embodiments, a rigid component of the bladder may be integral with the plunger structure.

A fluid channel, interrupted by a check valve, transits the plunger seal and provides a fluid connection between the interior of the bladder and the syringe chamber. The channel may take the form of a simple bore through the plunger seal, or it may comprise a metal or polymer tube, in part or in its entirety. Such a tube may extend past the rear face of the plunger seal, and in such embodiments the bladder may be directly attached to the distal end of the tube. In certain embodiments, the tube may be integral with the bladder. The tube may extend past the front face of the plunger seal, and the check valve in such embodiments may be attached to the protruding portion of the tube. It is however preferable that there be minimal protrusions from the front face of the plunger seal, as such protrusions could prevent complete dispensing of the mixed medicament. In embodiments having a plurality of bladders, each bladder may have its own tube and check valve assembly.

Alternatively, the bladder tubes may merge into a single fluid channel, served by a single check valve.

The flow of liquid through the fluid channel is prevented by a check valve when the syringe is not in use, and when the syringe is being used to inject the medicament. The check valve is oriented and adapted to open and permit liquid to pass from the bladder into the syringe chamber only in the presence of a net positive hydraulic pressure from within the bladder. In the absence of a net positive hydraulic pressure from within the bladder, the check valve prevents the flow of liquid through the fluid channel. The hydraulic pressure is generally atmospheric pressure, transferred through the bladder to liquid side of the valve. Prior to operation of the syringe, this is countered by atmospheric pressure on the dry side of the valve, and there is zero net pressure, thereby allowing the valve to remain closed. The valve, when under no net pressure, is either biased toward its closed conformation, and/or is sealed against liquid flow with a sealant material.

The term "check valve", as used herein, may refer to a check valve of any known design. Suitable examples include, but are not limited to, ball check valves, poppet valves, tilting disc and flap (clapper) valves, and umbrella, duckbill and cross- slit valves. Flap, duckbill and cross-slit valves are preferred, for their simplicity and long-term reliability. Suitable valves are commercially available, for example from Minivalve International B.V., Oldenzaall The Netherlands. The design disclosed by A. Hickerson et al, Sens. Actuators A: Phys. 2013 203:76-81, referred to herein as a "sleeve valve", is also particularly suitable.

Flap, duckbill and cross-slit valves may be formed directly in, and be integral with, the elastomeric material of the plunger seal, or they may be separately manufactured and inserted into the fluid channel of the plunger seal. A flap valve may take the form of a disc covering the opening of the fluid channel, as shown in the drawings. The disk can be of any water-impermeable material. The disk is

permanently affixed at at least one point to the plunger seal, or is retained by a cage, so that it serves as a check valve against reverse flow of fluid from the syringe chamber back into the bladder.

In certain embodiments, the fluid channel narrows as it approaches the front face of the plunger seal, and a terminal portion of the fluid channel is not a bore but rather a slit cut through the plunger seal. In these embodiments, the body of the plunger seal serves as a duckbill or cross-slit check valve. As discussed further below, the interior walls of the slit may be sealed with a sealant or adhesive to enhance the barrier function of the check valve.

In some applications of the invention, the check valve must be capable of maintaining a dry environment in the syringe chamber, so as to preserve lyophilized, moisture-sensitive material, in the presence of an aqueous solution stored in the bladder. This requires an essentially impermeable barrier between the bladder and the syringe chamber, and the check valve design should be chosen accordingly. For devices intended to have a long (e.g., multi-year) shelf life, even the molecular diffusion of water molecules past the check valve must be kept to a minimum. As an aid to effective long-term containment of moisture, a film of sealant material may be present on mutually engaged surfaces of the check valve. The sealant will typically be a highly hydrophobic material, for which there is a substantial energy barrier to penetration by water molecules. The sealant will preferably be viscous enough to ensure that it does not flow away, and remains in place for an extended period of time. Suitable materials include hydrocarbon greases such as those sold under the mark APIEZON™, and fluoroether (e.g. KRYTOX™) or fluorosilicone

(e.g. MOLYKOTE™) greases.

Most check valves rely on a closing force that biases the elements of the valve into the closed position; the valve opens when this closing force is overcome by the hydraulic pressure exerted by the restrained fluid. As the valve of the present invention is intended to open only once, the closing force may be augmented, or even replaced, by a frangible seal, created by a sealant or adhesive. By way of example, the flap valve illustrated in the drawings can be cemented into place with an epoxy resin, or held closed by a viscous grease. The greater the diameter of the flap, the longer the path is for water molecules to diffuse through the sealant or adhesive. The strength of the bond between the adhesive and the flap and/or plunger seal will be such that the valve can be opened by atmospheric pressure. The wide variety of sealants and adhesives, and the wide range of materials suitable for the flap and plunger seal, provide the practitioner with an extensive range of options.

The syringe barrel is preferably transparent or at least translucent, and may be of any standard design, and is typically formed from glass or plastic. A circular cross- section, while not required, is most commonly employed.

The component stored within the syringe chamber may be a lyophilized powder, or a crystalline or amorphous solid, or a liquid. In most applications of the invention, it will be a dry solid. The solid is preferably processed into a form that is rapidly soluble; in general this will involve transformation into a finely divided state. Adjuncts and excipients may be employed, as is well-known in the art, to enhance dissolution rates, prevent aggregation, and improve the handling characteristics of the solid component. The solid may be stored as a loose powder, or it may be pressed into tablets, spheres, or other solid forms in the interest of consistent dispensing during manufacturing.

Turning now to the drawings, Fig. 1 illustrates the components of the invention in an exploded format, for an embodiment having a single bladder. Shown in part is the syringe body 1 having a male Luer tip 11 for needle attachment. The first end of the syringe barrel is illustrated, while the second, distal end has been omitted in the interest of compact illustration. Mounted to the plunger 3 is the bladder 5. Bladder 5 is provided with an exit tube 6 which extends through the end of the plunger and into the fluid channel 7 which transits the plunger seal 2. Not shown is the water-tight connection between tube 6 and the channel 7. On the front face of plunger seal 2 is flap 4, which when in full contact with the front face of plunger seal 2 occludes the fluid channel 7. Flap 4 functions as a flap-type check valve when pinned, at a point on its perimeter, to the front face of plunger seal 2. Flap 4 may be pinned by any suitable means, such as stapling, riveting, or spot-welding. Flap 4 may optionally be retained by a surrounding cage (not shown). Fig. 2 is a perspective view of bladder 5 and exit tube 6. In this particular embodiment, the bladder is a cylinder with hemispherical ends.

Fig. 3 is a partially cut-away side view of the plunger assembly. Plunger seal 2 is attached to the end of plunger 3, with flap 4 affixed to the front surface so as to occlude fluid channel 7 (not shown). Bladder 5 may be mounted to plunger 3 by any suitable means, such as via clips, a weld or an adhesive bond. Alternatively, bladder 5 may rely on exit tube 6 as its sole means of attachment to the plunger. 3. Exit tube 6 penetrates the front end of plunger 3 and is seated within fluid channel 7 with a watertight seal. The water-tight seal may rely on friction, i.e. on a tight fit of exit tube 6 within the fluid channel 6, given that plunger seal 2 is made of an elastomer and will inherently tend to form such a seal. Optionally, water-tightness can be enhanced by the presence of grease, adhesive, and/or a layer of a different, preferably hydrophobic elastomer between the contacting surfaces. Mechanical means, such as O-rings, may be employed as well.

Fig. 4 is a transparency view of a sleeve valve. Exit tube 6 is capped with end- cap 8, and features a cut out side aperture 9. Sleeve 10 is a closely-fitting elastomeric cylinder, which in its closed state seals off aperture 9. In use, hydraulic pressure exerted by the fluid within exit tube 6 causes sleeve 10 to expand in diameter, until a flow path is created between the outer surface of tube 6 and the inner surface of sleeve 10. Fluid escapes through side aperture 9 only for as long as the internal pressure is sufficient to maintain the flow path. When the pressure drops, the stretched sleeve 10 relaxes, contracts, and closes off the aperture 9, thereby preventing back- flow through the valve.

In use, with Luer tip 11 temporarily capped, withdrawal of plunger 3 from the syringe barrel creates a partial vacuum in the syringe chamber, decreasing the atmospheric pressure on the outer surface of flap 4 (or sleeve 10). Bladder 5, meanwhile, remains subject to full atmospheric pressure, and this pressure is transferred via the contained fluid to the inner surface of flap 4 (or sleeve 10). The differential in pressure causes flap 4 to be displaced (or sleeve 10 to expand), and fluid flows out of the bladder 5 through the exit tube 6, past flap 4 (or sleeve 10), and into the syringe chamber. Bladder 5 collapses as its contents are forced out. When fluid transfer is complete, the syringe is shaken to ensure dissolution of the dry component, a needle is affixed to Luer tip 11, and the contents injected in the usual manner. Depressing the plunger 3, in the course of injecting the contents of the syringe, creates a pressure differential which causes flap 4 (or sleeve 10) to close, preventing the movement of fluid back into the bladder 5. The same method of operation applies to alternative embodiments having different check valve designs.

The examples and drawings provided herein are intended to be illustrative, and the scope of the invention should be understood to encompass all of the variations and substitutions that would be obvious to one of skill in the art.

Claims

CLAIMS I claim:

1. A syringe for the mixing and administration of a medicament having solid and liquid components, comprising:

(a) a syringe barrel bearing a needle or needle mount at a first end;

(b) a plunger stem movable within the barrel;

(c) a sliding plunger seal affixed to the plunger stem and movable within the barrel, having a front face and a rear face and transited by a fluid channel;

(d) a syringe chamber defined by the first end of the barrel, the barrel, and the front face of the sliding plunger seal;

(e) one or more collapsible bladders positioned behind the rear face of the plunger seal, the interior of the bladder being in fluid communication the fluid channel; and

(f) a check valve disposed so as to regulate fluid communication between the fluid channel and the syringe chamber;

wherein opening the check valve permits flow of liquid from the one or more bladders through the fluid channel and into the syringe chamber; and

wherein the check valve is openable by atmospheric pressure exerted on the one or more bladders as the plunger stem is partly withdrawn from the syringe barrel.

2. The syringe according to claim 1, wherein the check valve is a flap valve.

3. The syringe according to claim 1, wherein the check valve is a duckbill valve.

4. The syringe according to claim 1, wherein the check valve is a cross slit valve.

5. The syringe according to claim 1, wherein the check valve is a sleeve valve.

6. The syringe according to claim 1, wherein the one or more bladders is a flexible pouch.

7. The syringe according to claim 1, wherein the one or more bladders is an

elastomer balloon.