The present invention relates to needle free injectors, techniques for improving the reliability and manufacturability of needle free injectors, and needle free injectors capable of delivering increased doses.
Many patients are needle-averse or suffer from needle-phobia or have fear of self-administration of a needle-based medical injection. Many patients and/or health-care providers have other difficulties including inability or lack of desire to follow complex instructions, and danger of needle stick injury and cross contamination. Ensuring treatment compliance can be problematic. In addition, it is a problem that patients may need to be trained to self administer an injection, although for some indications the number of injections they would self administer is only a few. In addition, a needle and syringe in general needs to be filled, and for some formulations, dried drug requires reconstitution, which further complicates self administration and reduces compliance. These issues often rule out the possibility of treatment in a home setting, either self treatment or by a relatively un-trained care giver such as a family member. The inability to dose at home can lead to higher costs of therapy, delay in treatment, reduced compliance, reduced comfort, and potential exposure to hospital acquired infections.
A number of biologically-active agents in viscous formulations would benefit from being delivered using the needle-free injector. This group could consist of (but not limited to) anti-inflammatory agents, antibacterial agents, antiparasitic agents, antifungal agents, antiviral agents, anti-neoplastic agents, analgesic agents, anaesthetics, vaccines, central nervous system agents, growth factors, hormones, antihistamines, osteoinductive agents, cardiovascular agents, anti-ulcer agents, bronchodilators, vasodilators, birth control agents and fertility enhancing agents, interferon alpha, growth hormone, osteoporosis drugs including PTH and PTH analogs and fragments, obesity drugs, psychiatric drugs, anti-diabetes, female infertility, AIDS, treatment of growth retardation in children, hepatitis, multiple sclerosis, migraine headaches, and allergic reactions.
An aspect of the invention is a needle-free injector which is comprised of pressurized gas cylinder which gas cylinder is not completely enclosed in the absence of a spool and seal. A spool comprised of a storage seal maintains the glass cylinder in a pressurized state during storage. The injector includes a means for releasing the spool in a manner which releases the pressurized gas into a chamber. A ram is slidably positioned in the chamber in a manner such that the ram is urged forward by released pressure from the gas cylinder. A drug container holds a liquid drug formulation in fluid connection with a drug delivery orifice. When the ram is forced to move by released pressurized gas it causes the liquid formulation to be extruded through the drug delivery orifice in a narrow jet at sufficient speed to puncture human skin and provide for a needle-free injection of the liquid drug formulation.
An aspect of the invention is that the pressurized cylinder need not be punctured due to the presence of the spool valve.
Another aspect of the invention is that the device does not require a spacer to provide an air gap between the nozzle and the injection site on the human skin.
Another aspect of the invention is that the device includes a safety feature such that the device is not accidentally triggered when the cap is removed.
Another aspect of the invention is that the device can provide for subcutaneous injection.
Another aspect of the invention is the screw cap safety feature which when removed does not trigger the device. The cap may be screwed to the drug container to ensure a good seal is maintained. In the absence of some sort of safety device the act of unscrewing the cap if combined with pushing the cap towards the rest of the device could trigger the device. However, the device includes a second set of threads on the cap that engage the cap such that when the cap is unscrewed it is also driven away from the device. This arrangement of the second set of threads on the cap can make it possible to eliminate the need for a safety mechanism such as a block actuated by a lever and makes the device simpler to use.
In one aspect of the invention the spool further comprises an additional seal that seals against loss of the pressurized gas after the gas has been released into the chamber. Further, the spool may be configured such that the pressurized gas holds the spool in a first position by a movable body which blocks motion of the spool prior to releasing the spool.
An aspect of the invention includes a means for releasing the spool so that the spool moves a movable body thereby exposing an end of a spool to a recess into which recess the spool is moved by force applied by the pressurized gas. The moveable body may be moved by the act of pressing the drug delivery orifice of the device against a surface such as human skin.
An aspect of the invention includes an injector configured such that upon releasing the spool a sub-cutaneous injection occurs forcing the liquid drug formulation out of the drug orifice and through the human skin at the injection site.
In one aspect of the invention is provided a needle-free injector which is comprised of a drug capsule containing a liquid drug formulation. The device includes an orifice in the container and the orifice leads to the liquid drug formulation in a fluid connecting manner. A first gas reservoir containing a first pressurized gas at a first pressure is used and the first pressurized gas is in contact with an urges a drug dispensing member forward. Movement of the drug dispensing member is prevented by a trigger mechanism.
A second gas reservoir containing a second pressurized gas at a second pressure is also present wherein the dispensing member is not urged forward by the second pressurized gas until after it is released by the trigger mechanism.
The invention may be carried out utilizing a pre-filled, self contained, single use, hand-held needle free injector
In a particularly preferred embodiment, the invention is carried out using a needle free injector that is powered by a self contained compressed gas charge, elements of which are described in U.S. Pat. No. 5,891,086 (incorporated by reference in its entirety). This embodiment includes a device for delivering formulations by needle-free injection, for example sub-cutaneously (SC), intra-dermally (ID) or intra-muscularly (IM). An energizer is used in conjunction with a drug cartridge to form a needle-free injector. The cartridge is pre-filled with a liquid to be injected in a subject, the cartridge having at least one liquid outlet and a free piston inward of the liquid outlet in contact with the liquid.
The energizer comprises:
The current invention describes various formulations that can be delivered using a needle-free injector including the injector of U.S. Pat. No. 5,891,086. These formulations active ingredients, and may include various polymers, carriers, etc.
An aspect of the invention is a desirable delivery time, especially for high viscosity formulations. Desirable delivery times may include any delivery times wherein the formulation is successfully delivered. Preferred delivery times include those less than the reaction time of a human, for example less than ˜600 ms, more preferably less than 400 ms, most preferably less than 100 ms per each 0.5 mL of formulation delivered.
Another aspect of the invention is acceptable pain associated with injection
Another aspect of the invention relates to alleviation of fear of needles associated with injection of formulations.
Another aspect of the invention relates to the elimination of the danger of needle stick injury and cross-contamination associated with injection of formulations.
Another aspect of the invention relates to the simplification of preparation associated with injection of formulations, by supplying a pre-filled, single use disposable injector.
Another aspect of the invention relates to the drug release profile associated with injection of high viscosity depot formulation.
Another aspect of the invention is to improve the reliability of needle free injectors.
Another aspect of the invention is to minimize the strains and concomitant deformation and loss of reliability seen in energizer elements exposed during storage to the high forces required for successful needle free injection.
Another aspect of the invention is to minimize the amount of glass forming required to create the drug container of a needle free injector, to minimize the defects in the glass and concomitant glass breakage associated therewith upon pressurization of the drug formulation.
Another aspect of the invention is to eliminate the manufacturing difficulties associated with forming small injection orifices in glass
Another aspect of the invention is to eliminate the possibility of breakage that can occur when the formulation is rapidly pressurized for delivery when a gas bubble is in proximity to an injection orifice formed in glass.
Another aspect of the invention is to improve the manufacturability of needle free injectors.
Another aspect of the invention is to enable delivery of higher doses using needle free injection.
Another aspect of the invention is to enable the use of lower gas pressures for the power source of needle free injectors.
Another aspect of the invention is to provide a needle free injector that is very simple to use, with a simple instruction set and minimal number of steps for preparation and delivery, and requiring only basic manual dexterity and hand strength.
Another aspect of the invention is to provide a needle free injector with safety features that eliminate the possibility of accidental actuation during storage or preparation for delivery.
Another aspect of the invention is to provide a needle free injector with a cover for the injection orifice or orifices that maintains each orifice in a clean and sterile state, and maintains the sterility of the drug formulation, until the device is prepared for delivery.
Another aspect of the invention is to provide a means to ensure that the steps for preparing the injector for delivery must be carried out by the user in the correct order, for example that the orifice cap must be removed prior to, or at the same time as, removal of the safety, to ensure, for example, that the act of removing the cap does not trigger the device.
Another aspect of the invention is the elimination of the need for priming the needle free injector by causing the piercing of a hermetically sealed gas cartridge.
Another aspect of the invention is the elimination of the high variation of pressure with temperature of a power source which is comprised of a pierceable, hermetically sealed CO2 cartridge.
Another aspect of the invention is the elimination of the additional parts and complexity associated with a gas cartridge that must be impaled on a piercing member to release the gas and deliver the medicament from a needle free injector.
These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the formulations and methodology as more fully described below.
The invention is best understood from the following detailed description when read in conjunction with the accompanying drawings. It is emphasized that, according to common practice, the various features of the drawings are not to scale. On the contrary, the dimensions of the various features are arbitrarily expanded or reduced for clarity. Included in the drawings are the following figures:
Before the present formulations and methods are described, it is to be understood that this invention is not limited to particular formulations and methods described, 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 only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.
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 this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a formulation” includes a plurality of such formulations and reference to “the method” includes reference to one or more methods and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
Active Pharmaceutical Ingredient, API, active drug substance, medicament, or the like: A component of a pharmaceutical formulation that is pharmaceutically active and is delivered for a desired effect.
Actuator: A mechanical device for moving or controlling a mechanism or system. An example of an actuator is a lever that a patient uses to ready an autoinjector for delivery.
Aggregation: formation of linked molecules held together by van der Waals forces or chemical bonds.
AUC: Area under the curve, or the integral, of the plasma concentration of delivered drug over time
Belleville Washers, Belleville Washer Stack, Belleville Spring, or the like: a power source for needle free injection made from a plurality of frustro-conically shaped washers which have a spring characteristic and store power when compressed. The name comes from the inventor, Jullian F. Belleville.
Biodegradable: capable of chemically breaking down or degrading within the body to form nontoxic components. The rate of degradation of a depot can be the same or different from the rate of drug release.
Biologic: A medicinal product created by biological processes (as opposed to chemically). Examples include vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, stem cells, immune globulins, and recombinant therapeutic proteins. Biologics may be isolated from natural sources such as humans, animals, plants, or microorganisms or may be produced by biotechnology methods.
Carbon Dioxide, or CO2: a colorless gas that is odorless at pressures usually found in the atmosphere. CO2 is often used as the power source for needle free injectors. CO2 has the advantages that it is commercially available in pressurized hermetically sealed containers. The CO2 in these containers is liquefied, and thus maintains a relatively constant pressure as the container is depleted (approximately 853 PSI at 70° F.). A disadvantage of CO2 is the relatively large variation of pressure with temperature.
Carrier: a non-active portion of a formulation which may be a liquid and which may act as a solvent for the formulation, or wherein the formulation is suspended. Useful carriers do not adversely interact with the active pharmaceutical ingredient and have properties which allow for delivery by injection, specifically needle free injection. Preferred carriers for injection include water, saline, and mixtures thereof. Other carriers can be used provided that they can be formulated to create a suitable formulation and do not adversely affect the active pharmaceutical ingredient or human tissue.
Centipoise and centistokes: different measurements of viscosity, which are not just different units. Centipoise is a dynamic measurement of viscosity whereas centistoke is a kinematic measurement of viscosity. The conversion from centistoke and centipoise to s.i. units is given below:
Coefficient of Thermal Expansion, Thermal Expansion Coefficient, and the like: The fractional change in size of a material (ΔL/L), per degree C.
Coefficient of Friction: a constant of proportionality relating the normal force between two materials and the frictional force between those materials. Generally friction is considered to be independent of other factors, such as the area of contact. The coefficient of static friction characterizes the frictional force between to materials when at rest. This force is generally what is required to start relative movement. The coefficient of dynamic friction characterizes the frictional force between to materials that are moving relative to one another. In general, the coefficient of static friction is higher than the coefficient of dynamic friction.
Container Closure, Container Closure System, Drug Container, Capsule, and the like: A drug container that is designed to maintain sterility and eliminate the possibility of contamination of the drug formulation. For container closure systems that contain aqueous formulations, the container closure system must also have sufficiently low water vapor transmission rate such that the concentration of the formulation does not change appreciably over the product shelf life. Preferred materials have sufficiently low leachable materials such that they do not comtaminate the formulation during storage. Preferred materials for container closures include glass, more preferably boro-silicate glass, or fluorinated materials such as polytetrafluoroethylene (PTFE).
Container Closure Integrity: The ability of a container closure system to maintain sterility, eliminate the possibility of contamination, and minimize loss of carrier during storage.
CPV trial: a 400 subject trial used to validate the predictive power of the IVIVC of the present invention.
Delivery Phase: A constant or slowly varying formulation pressure during which the bulk of a formulation dose is delivered from a needle-free injector (see
Depot Injection, Depot, and the like: an injection, usually subcutaneous, intravenous, or intramuscular, of a pharmacological agent which releases its active compound in a consistent way over a long period of time. Depot injections may be available as certain forms of a drug, such as decanoate salts or esters. Examples of depot injections include Depo Provera and haloperidol decanoate. Depots can be, but are not always, localized in one spot in the body.
DosePro, Intraject, '086 system, and the like: a single use, prefilled, disposable, needle free injector currently manufactured by Zogenix corporation. A cartridge is pre-filled with a liquid to be injected in a subject, and having a liquid outlet and a free piston in contact with the liquid The injector comprises an energizer comprising an impact member urged by a compressed gas spring and temporarily restrained until the device is actuated, the impact member being movable in a first direction under the force of the spring to first strike the free piston and then to continue to move the piston in the first direction to expel a dose of liquid through the liquid outlet, the spring providing a built-in energy store and being adapted to move from a higher energy state to a lower energy state, but not vice versa. The energizer may comprise a trigger means to actuate the device, and thus initiate the injection, only when the device is pressed against the skin. Elements and variations of DosePro are described in U.S. Pat. No. 5,891,086 ('086), and additional description, improvements, and variants can be found in U.S. Pat. No. 6,620,135, U.S. Pat. No. 6,554,818, U.S. Pat. No. 6,415,631, U.S. Pat. No. 6,409,032, U.S. Pat. No. 6,280,410, U.S. Pat. No. 6,258,059, U.S. Pat. No. 6,251,091, U.S. Pat. No. 6,216,493, U.S. Pat. No. 6,179,583, U.S. Pat. No. 6,174,304, U.S. Pat. No. 6,149,625, U.S. Pat. No. 6,135,979, U.S. Pat. No. 5,957,886, U.S. Pat. No. 5,891,086, and U.S. Pat. No. 5,480,381, incorporated herein by reference.
Energizer: the mechanical portion of an autoinjector that provides the energy for injection, triggers the device, and ensures the proper pressure profile during delivery. The energizer may contain a safety mechanism that must be set prior to delivery. Note that in some prior art this portion is referred to as the actuator. However here we refer to it as the energizer to avoid confusion with, for example, the safety mechanism actuator.
Excipient: Any substance, including a carrier, added to an active drug substance to permit the mixture to achieve the appropriate physical characteristics necessary for effective delivery of the active drug.
Filter Paper Weight, or FPW: a measure of the amount of injectate left on the skin after a needle free injection event. To measure FPW, the non-injected material is absorbed onto filter paper, the sample is weighed, and the tare weight subtracted. If blood is seen in the sample, this is noted, and in general the results are not used as the blood will cause an overestimate of the FPW. The FPW can be used to correct the VAS, see definition of VAS and example 1.
Formulation, Injectate, and the like: Any liquid, solid, or other state of matter that can be injected. Preferred formulations are liquid formulations, including but not limited to solutions, suspensions including nano-suspensions, emulsions, polymers and gels. Formulations include but are not limited to those containing excipients that are suitable for injection, and contain one or more active pharmaceutical ingredients.
Frustro-conical: Having the shape of a cone whose tip has been truncated by a plane parallel to its base. See Belleville Washers.
Hermetically Sealed Container and the like: a container for pressurized gas used as the power source for needle free injection that is impervious to leakage of the contained gas. Commonly, hermetically sealed containers are formed from deep drawn zinc plated steel and contain pressurized gasses such as nitrogen, or liquefied gasses such as carbon dioxide or nitrous oxide. They are often used in the food service industry for such preparations as soda water or whipped cream, but also find medical applications in areas such as aerosol inhalation (c.f. U.S. Pat. No. 6,981,660) or needle free injection (c.f. us 3.10. U.S. Pat. No. 6,607,510). Usually these containers have a feature that is designed to be pierced to allow the pressurized contents to be accessed.
Immunogenicity: The ability of a substance (an antigen) to provoke an immune response. Aggregated biologic drugs can be immunogenic even when the unaggregated molecule is not immunogenic.
Impact gap, and the like: The width of a gap between an impact member (see ram) and a piston used to create a pressure spike in the formulation. During a needle free delivery event, the impact member is urged across the gap, for example by compressed gas or another energy source, wherein it integrates the work done by the energy source as it travels across the gap, and delivers this energy to the formulation upon impact, creating an early pressure spike. See also “Puncture Phase”.
In vivo (from the Latin for “within the living”): Experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro experiment. In vivo research includes animal testing and human clinical trials. In vivo testing is often preferred over in vitro testing because the results may be more predictive of clinical results
In vitro (from the Latin for “within the glass”): A procedure not in a living organism (see in vivo) but in a controlled environment, such as in a test tube or other laboratory experimental apparatus. In vitro testing is often preferred over in vivo testing due to reduced cost and reduced danger to human and/or animal subjects.
In vivo/in vitro correlation, IVIVC, and the like: a model, preferably a mathematical model, that predicts in vivo performance based on in vitro measurements, design parameters, and the like. A predictive IVIVC allows the predictive value of in vivo measurements without the need for expensive and potentially dangerous human or animal clinical trials. An IVIVC is preferably based on a meta-analysis of several clinical, preferably human, trials utilizing different configurations of a drug, drug delivery technology, or other medical device technology. For the sake of this discussion, and IVIVC can be taken to mean a model that predicts in vivo injection performance of a needle free injector based on injector design parameters and bench measurements of performance.
Jet Test, Jet Tester, Jet Test Method, and the like: a laboratory apparatus that measures the force on a transducer when impinged upon by the liquid jet during a simulated drug delivery event. Using these data the formulation pressure over time can be calculated. The Jet Test is often conducting simultaneously with the Strain Gauge test.
Needle free Injector, Needle-less injector, Jet Injector, and the like: a drug delivery system which delivers a subcutaneous, intramuscular, or intradermal injection without the use of a hypodermic needle. Injection is achieved by creating at least one high velocity liquid jet with sufficient velocity to penetrate the skin, stratum subcutaneum, or muscle to the desired depth. Needle free injection systems include, but are not limited to, the DosePro® system manufactured by Zogenix Corporation, the Bioject® 2000, Iject or Vitaject devices manufactured by Bioject Medical Technologies, Incorporated, the Mediject VISION and Mediject VALEO devices manufactured by Antares, the PenJet device manufactured by Visionary Medical, the CrossJect device manufactured by Crossject, the MiniJect device manufactured by Biovalve, the Implaject device manufactured by Caretek Medical, the PowderJect device manufactured by AlgoRx, the J-tip device manufactured by National Medical Products, the AdvantaJet manufactured by Activa Systems, the Injex 30 device manufactured by Injex-Equidyne, and the Mhi-500 device manufactured by Medical House Products.
Piston: a component of a needle free injector that under force from an energy source drives liquid formulation out of an orifice to achieve a needle free injection. In a preferred embodiment, the needle free injector is prefilled with formulation, and the piston then becomes a drug contact surface of the container-closure system. In a particularly preferred embodiment, the piston has the additional function of transmitting energy from an impact member to the formulation to create a pressure spike, see “Puncture Phase”. Preferably, the piston comprises PTFE.
Polytetrafluoroethylene, PTFE, Teflon, and the like: a synthetic fluoropolymer of tetrafluoroethylene. PTFE is most well known by the DuPont brand name Teflon. PTFE is a high molecular weight fluorocarbon solid, consisting wholly of carbon and fluorine. PTFE has one of the lowest coefficients of friction against any solid. PTFE has also been shown to be an acceptable drug contact surface for many drug formulations.
Prophylaxis: The administration of a drug used to prevent the occurrence or development of an adverse condition or medical disorder.
Puncture Phase, Initial Pressure Spike, and the like: An initial spike in pressure in the formulation in a needle-free injector that creates a jet with sufficient energy to drill to the desired depth into or through the skin (see
Ram, impact member, and the like: a component that when exposed to a pressure is urged forward across an air space (see “impact gap”) before striking a drug delivery piston. The work done by the expanding gas as the ram traverses the impact gap is essentially all delivered to the formulation when the ram strikes the piston, creating a pressure spike (see “puncture phase”) that creates a hole in the skin to the desired depth, for example the subcutaneum. The pressurized gas then drives the ram and piston forward, delivering the formulation through the hole and into the desired tissue.
Resilient: returning to the original form or position after being bent, compressed, or stretched
Specific gravity: The ratio of a compound's density to that of water.
Spool Valve: a valve wherein the pressure of the needle-free injector pressurized gas power source urges a gas blocking component forward, but motion of the gas blocking component is inhibited by an additional device element. When the additional device component is removed, preferably due to relative movement of the additional device component when the needle-free injector is pressed against the skin of a patient, the gas blocking component is allowed to move forward, exposing a gas exit port that allows the pressurized gas to flow to a drug delivery mechanism, causing drug delivery. In one embodiment, the “balanced spool valve”, the proximal and distal ends of the gas blocking component are exposed to the power source pressure, and expose surfaces of different areas to the pressurized gas, allowing the actuation force to be tuned, and potentially optimizing and/or minimizing the frictional force on the additional device component that blocks movement of the gas blocking component.
Spring: a mechanism capable of storing energy for use in propelling the medicament in the syringe into and through the patient's skin and into body, wherein the force provided by the energy store is proportional to a displacement. This mechanism may be mechanical, e.g. compressible metal component such as a coil spring or Belleville washer stack. Preferably, the mechanism is a compressed gas spring in which the energy is stored, and when released the gas expands.
Stiff: having a high elastic modulus or low compressibility. In this case, a material that is able to transmit impact energy effectively through it medium.
Strain Gauge Test, Strain Gauge Method, and the like: A method of measuring the formulation pressure during an in vitro delivery event, wherein a strain gauge is attached to the formulation container, calibrated for formulation pressure, and then used to measure the pressure profile over time of the formulation. The Strain Gauge Test is generally conducted in parallel with a Jet Test.
Subcutaneous tissue, stratum subcutaneum, hypodermis, hypoderm, or superficial fascia, and the like: A layer of tissue that lies immediately below the dermis of skin, consisting primarily of loose connective tissue and lobules of fat. The stratum subcutaneum is the target of a subcutaneous injection.
Visual Assessment Score, VAS, and the like: A semi-quantitative method of scoring needle free injections on a scale of 0-4, based on observation. Any injection scored as a 0, 1 or 2 is termed unsuccessful (see “wet injection”, below), while a 3 or 4 is a successful injection. Injection scores are defined as follows:
0=100% splash back of injectate, not even a hole in the epidermis
1=hole in the epidermis but very little, if any penetration of injectate
2=some penetration of injectate (˜5% and <90%)
3=˜90 and <95% penetration of injectate
4=˜95% penetration of injectate
Water Vapor Transmission Rate (WVTR)) is the steady state rate at which water vapor permeates through a material. Values are expressed in g/100 in2/24 hr in US standard units and g/m2/24 hr in metric units.
Wet injection: an unsuccessful needle free injection, whereby more than 10% of the injectate does not penetrate to the stratum subcutaneum. A related definition is an injection with a Visual Assessment Score (VAS) of less than 3.
The current invention is related to improvements to pre-filled needle free injectors to improve reliability, safety, and manufacturability.
One embodiment of the invention is shown in
One improvement is to gas cylinder 20. As compared to other devices, gas cylinder 20 is larger in diameter and less deeply drawn. This allows a larger volume, and thus less change in pressure as delivery progresses. At the same time, it easier to manufacture, being less deeply drawn than the gas cylinder in, for example, the device described in '086. Preferably gas cylinder 20 is deep drawn aluminum, although other fabrication techniques including but not limited to impact extrusion, die casting, or machining may be used. As shown in
The gas in gas cylinder 20 is contained during storage, and released upon triggering of the device, by spool valve 21. Unlike some prior art devices, spool valve 21 is functionally separate from the component that converts the pressure of the gas in gas cylinder 20 into the energy required to cause needle-free injection, in this embodiment ram 12. This allows the forces that spool valve 21 is subjected to during storage to be significantly less than those that ram 12 would be subjected to were it exposed to the pressurized gas during storage, due to the large differences in area exposed to the pressurized gas. This greatly minimizes the possibility of deformation and creep, and thereby reduces the possibility of premature firing or lack of firing. These issues can be exacerbated by high temperatures seen during storage or accelerated pharmaceutical stability. This aspect of the invention can remove a potential need for a device priming step that overcomes these issues.
The functioning of spool valve 21 is as follows. When the device is held by its case (not shown) and injection orifice or orifices 27 are pressed against the patient's skin at the intended injection site, sliding body 15 moves downward. This exposes spool 17 to spool retaining cage 18, which in turn allows spool 17 to move to the left as shown in
Valve block 19 is preferably machined aluminum, but may be made by methods including but not limited to die casting, and may be combined with gas cylinder 20 and/or ram cylinder 13.
Prior art devices, such as that described in U.S. Pat. No. 6,607,510 ('510), have a hermetically sealed gas cartridge wherein the device is “primed” by impaling the cartridge on a piercing element to release the gas. In the invention disclosed in '510, an orifice cap is removed and then screwed into the opposite end of the device, forcing the hermetically sealed gas cartridge onto the piercing element. As such, any additional valve components do not require a perfect seal, such as an O-ring seal, and no such seal is disclosed in '510. However, in the embodiment described here, the spool valve is the primary seal that keeps the pressurized gas from leaking during storage, and thus requires additional sealing elements 24 and 25 in spool 17 (see
Spool retaining cage 18 is preferably stamped, but alternatives include but are not limited to die casting or injection molded polymers or metals.
In the device described in '086, the ram is a right circular cylinder, with the ram and perpendicular details described above. Because it is of constant and relatively small cross sectional area, the gas pressure required to create the desired formulation pressure and puncture phase pressure are quite large, creating issues around component deformation and gas leakage. To reduce the gas pressure, the pressurized gas in the embodiment of the current invention shown in
Ram 12 and ram head 14 are preferably machined from a single piece of aluminum, but alternatively may be a single cold formed piece, machined from separate parts, diecast magnesium or zinc, or an over-molded polymer head on a machined shaft. Preferably ram 12 is inserted into ram guide 11 after filling of the pressurized gas and after any leak checking and after ram cylinder 13 is attached to valve block 19, but alternatively may be assembled prior to filling if ram seal 26 is a one way valve or may be inserted into ram cylinder 13 prior to ram cylinder 13 being attached to valve block 19.
In order that ram 12 remain in place as assembled to maintain the required impact gap, ram 12 must be held either by a feature that breaks away under the force of the pressurized gas, or held in place by a frictional force that is strong enough to hold ram 12 during handling and storage but is small compared to the force of the pressurized gas bearing on ram head 14. One embodiment of this, shown in
Ram guide 11 is preferably a zinc or aluminum die casting, although other solutions include but are not limited to injection molded polymers or metals or machined steel or aluminum. Ram head 14 is guided by ram cylinder 13, and preferably ram cylinder 13 is fabricated from stock tubing, although other solutions include but are not limited to deep drawn or impact extruded, injection molded polymer, machined including machined as part of valve block 19, die cast, or extruded. Preferably ram cylinder 13 is stock tubing with swaged ends, welded to valve block 19 and attached to ram guide 11 with a crimp ring 10. Alternatives include but are not limited to welding to ram guidell and/or crimping to valve block 19.
Ram 12 is guided by ram guide 11 to strike and then drive piston 8 to deliver liquid drug formulation 28 contained within the drug container defined and closed by piston 8, capsule 6, nozzle 5, and rubber seal 4. Capsule 6 is reinforced by capsule sleeve 7, which also serves to hold nozzle 5 in contact with capsule 6 in those embodiments of the invention wherein nozzle 5 is a separate part, as shown in
Capsule sleeve 7 is preferably an injection molded plastic component, but other solutions are possible, including but not limited to a steel stamping or zinc or magnesium die casting. Capsule sleeve 7 is preferably screwed onto ram guide 11, but may also be attached with a crimp ring or by other attachment methods. Capsule sleeve 7 also has additional features that allow attachment of cap 1 (see below).
The body of drug capsule 6 is preferably glass, more preferably borosilicate glass. In one embodiment, the sides of capsule 6 are simple sections of glass tubing, also known as “cane”. In this embodiment, nozzle 5 is a separate part held in place by capsule sleeve 7. This embodiment has the advantages of ease of fabrication and also has the advantage of allowing a continuous taper from the inlet of nozzle 5 to injection orifice or orifices 27, which allows for better liquid flow characteristics. Preferably, nozzle 5 is machined from a polymer, more preferably from Polytetrafluoroethylene (PTFE). Other embodiments utilize other polymers or metals and may be injection molded, die cast, machined, stamped, or utilize any other fabrication technique. Optionally, nozzle 5 may incorporate a metal support collar to minimize distortion of injection orifice 27 upon pressurization. Capsule 6 and capsule sleeve 7 are preferably assembled by inserting the optional support collar, then optional nozzle 5, and finally capsule 6 into capsule sleeve 7 with an interference fit. Injection orifice or orifices 27 are preferably machined, but may also be fabricated by a method selected from but not limited to e-beam, laser drilling, or liquid jet cutting. Optionally, the quality of an orifice created by any of the above means may be improved by an etching step, including but not limited to chemical etching, or plasma etching, or by rotating the part as an orifice is created.
In another preferred embodiment, drug capsule 6 does not have a separate nozzle 5, but instead is formed from a single piece of glass into which injection orifice or orifices 27 are fabricated. While this configuration has certain disadvantages relative to machinability, forming of the injection orifice, and breakage upon pressurization of formulation 28, it has the advantage of being developed and proven, for example in the '086 device. As with capsule 6 with separate polymer nozzle 5 embodiment above, this embodiment is assembled by inserting glass capsule 6 into capsule sleeve 7 with an interference fit. In this embodiment, injection orifice or orifices 27 are preferably laser drilled, more preferably UV laser drilled, most preferably excimer laser drilled, but may also be fabricated by a method selected from but not limited to e-beam, machining, or liquid jet cutting. Optionally, the quality and centering of orifice 27 may be improved by rotating capsule 6 while fabricating the hole. Also optionally, the quality of orifice or orifices 27 created by any of the above means may be improved by an etching step, including but not limited to chemical etching or plasma etching.
Piston 8 is preferably machined from PTFE. This has certain advantages, including the lubricious properties of PTFE, the fact that PTFE is non-reactive and thus an excellent drug contact surface, and also that PTFE is a material which is substantially non-resilient when subjected to a slowly applied force but is highly resilient when subjected to a rapidly applied force, (c.f. U.S. Pat. No. 5,891,086) allowing it to be slowly inserted into glass capsule 6 with a very tight interference fit, but allowing it to still transmit the bulk of the energy of impact of ram 12 to formulation 28 almost instantaneously.
To maintain sterility of formulation 28, limit water vapor transmission, and keep orifice or orifices 27 free of foreign debris, injection orifice or orifices 27 are preferably covered with rubber seal 4. Rubber seal 4 is attached to cap 1 through a rotating element, spin cap 3. Spin cap 3 prevents strain in and concomitant leakage from rubber seal 4 that may arise as rubber seal 4 is rotationally seated onto nozzle 5 by screwing cap 1 onto threads that are part of capsule sleeve 7.
While it is preferred that cap 1 be removed by unscrewing from threads as shown in
To ensure that the device is not accidentally triggered during storage, transport, or removal of cap 1, safety mechanism 9 is included. Safety mechanism 9 blocks the movement of the case relative to the internal components, and thus prevents triggering of the device. In the embodiment shown in
In yet another embodiment of the device, there is no separate safety mechanism 9. Instead, cap 1 is threaded to both case 2 and capsule sleeve 7, in such a way that when it is screwed on, it bottoms out by firmly pressing the rubber seal 4 against nozzle 5 sealing the injection orifice. The threads on the case bias cap 1 and capsule sleeve 7 and therefore the internal components downward (where downward is as shown in
The case (not shown) is preferably a injection molded plastic clam shell assembly, preferably attached to the interior components by friction fit, although other methods of attachment, including but not limited to a snap fit, adhesives, or friction weld may be used. Preferably ram guide 11 has features that prevent the rotation of the internal components relative to the case, but alternatives include but are not limited to features on ram cylinder 13, valve block 19, features on sliding body 15, or features on capsule sleeve 7. Similarly, the case is preferably designed to interact with ram cylinder 13 to linearly guide the internal components relative to the case when injection orifice or orifices 27 are pressed against the skin, but alternatives include but are not limited to interaction with valve block 19, sliding body 15, or features on capsule sleeve 7. In addition, a reactive polymer, or more preferably a viscous or kilopoise grease is preferably included between ram cylinder 13 and the case, or alternatively between ram cylinder 13 and sliding body 15. This has numerous advantages, including
Other methods of maintaining a minimum acceptable trigger force, maintaining skin stretch, and avoiding accidental triggering include, but are not limited to a spring or a detente between the internal components and the case. Other methods of minimizing accidental triggering include but are not limited to a retractable guard, similar to those used to prevent needle stick injury from a needle syringe.
In the ball bearing trigger embodiment shown in
In the embodiment shown in
Also shown in
In the embodiment shown in
Also shown in
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.
In example 1, a test was performed on a laboratory prototype with the important energizer features of the system shown in
In example 2, a test was performed with a laboratory apparatus as described in example 1, but utilizing a 0.5 mL glass formulation capsule identical to that used in the '086 device. The results of this test are shown in
In example 3, a test was performed on a laboratory prototype (see
The instant invention is shown and described herein in a manner which is considered to be the most practical and preferred embodiments. It is recognized, however, that departures may be made therefrom which are within the scope of the invention and that obvious modifications will occur to one skilled in the art upon reading this disclosure.
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/US12/20654 | 1/9/2012 | WO | 00 | 3/22/2016 |
Number | Date | Country | |
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61431325 | Jan 2011 | US |