WO2016137665A1 - Needle-free injectors comprising sound suppression - Google Patents

Abstract

An aspect of the invention is an auto-injector, preferably a needle free injector, that includes a sound suppressor. In some instances, the auto-injectors include an energy source comprising a pressurized gas stored within a chamber, a hole associated with the chamber, e.g., configured to be used for pressurizing the chamber and/or venting gas from the chamber after dosage delivery, and a sound suppressor associated with the hole in a manner sufficient to reduce the sound created during dosage delivery. Aspects of the invention further include sound suppressors themselves, as well as methods of using the devices in delivery of an active agent to a subject, and kits that include devices and/or components thereof, e.g., sound suppressors.

Description

Needle-Free Injectors Comprising Sound Suppression

FIELD OF THE INVENTION

[0001] The present invention relates to delivery of liquid drug formulations

utilizing auto- injection.

BACKGROUND OF THE INVENTION

[0002] For many conditions, injection of an indicated medication can occur at home. Many patients, however, are needle-averse or suffer from needle-phobia, and/or have other difficulties including inability or lack of desire to follow complex instructions, fear of self-administration, and concern related to needle stick injury and cross contamination. Loud or startling sounds made by an injector can cause patient discomfort and/or apprehension. 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 the drug is dried and 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.

[0003] Some issues are particularly acute in the context of elevated viscosity

formulations, including but not limited to controlled release formulations, and formulations of biologic drugs, such as Monoclonal Antibodies (MABs). Elevated viscosity leads to many delivery difficulties, such as high required hand strength for a needle and syringe, long delivery times, and additional pain and fear associated with a large bore needle. Thus there is a need to deliver these compounds without a needle, preferably in a rapid, automated fashion using a system that does not require filling, reconstitution, or other complex procedures. [0004] A dosage form that is easy and fast to self administer can be crucial for acute, debilitating conditions, for example small molecules such at triptans for migraine and cluster headache, or glucagon, a polypeptide for the acute treatment of hypoglycemia. Oral drugs have the advantage that they are easy to self administer. However, many drugs, especially peptide and protein drugs have very limited oral bioavailability, due to digestion and first pass liver metabolism. Additionally, absorption following oral delivery is delayed, with time to peak plasma

concentrations (T_max) of -40 minutes or longer.

[0005] It is known that auto-injectors, and specifically prefilled auto-injectors and needle free injectors, can address the issues above of patient compliance and safety, especially needle-phobia, needle stick injury, cross contamination, low

bioavailability, and delayed onset.

[0006] For needle free injectors, it is important that the design parameters,

including but not limited to the dimensions of the injection orifice or orifices (including but not limited to diameter, length, and cone angle), and the pressure profile in the drug container during delivery, be properly chosen to ensure successful injection. Improper choice of parameters can lead to problems such as wet (incomplete) injection, (see for example U.S. 12/0065615A1, incorporated herein by reference) or at the other extreme too deep, for example intra-muscular, injection.

[0007] Auto-injectors are available using many different types of energy sources, and the energy may be supplied by the user, for example where a spring is manually compressed and latched to temporarily store the energy until it is required to actuate the injector. Alternatively, the injector may be supplied having the energy already stored— for instance by means of a pre-compressed spring

(mechanical or compressed gas), or by a pyrotechnic charge.

[0008] Some injectors are intended for disposal after a single use, whereas others have a re-loadable and/or multi-dose energy storage means and a single or multi- dose medicament cartridge, and there are many combinations to suit particular applications and markets. For the purposes of the present disclosure, the term "actuator" will be used to describe the energy storage and release mechanism, whether or not it is combined with a medicament cartridge. In all cases, it is necessary to arrange for sufficient force throughout the delivery and specifically at the end of the delivery to deliver the entire dose of medicament at the required pressure.

[0009] EP 0 063 341 and EP 0 063 342 disclose a needle-free injector which

includes a piston pump for expelling the liquid to be injected, which is driven by a motor by means of a pressure agent. The liquid container is mounted laterally to the piston pump. The amount of liquid required for an injection is sucked into the pump chamber by way of an inlet passage and a flap check valve when the piston is retracted. As soon as the piston is moved in the direction of the nozzle body the liquid is urged through the outlet passage to the nozzle and expelled. The piston of the piston pump is a solid round piston.

[0010] EP 0 133 471 describes a needle-free vaccination unit which is operated with carbon dioxide under pressure, from a siphon cartridge by way of a special valve.

[0011] EP 0 347 190 discloses a vacuum compressed gas injector in which the depth of penetration of the injected drug can be adjusted by means of the gas pressure and the volume of the drug can be adjusted by way of the piston stroke.

[0012] EP 0 427 457 discloses a needle-free hypodermic syringe which is operated by means of compressed gas by way of a two-stage valve. The injection agent is disposed in an ampoule which is fitted into a protective casing secured to the injector housing. The ampoule is fitted on to the end of the piston rod. Disposed at the other end of the ampoule is the nozzle whose diameter decreases towards the end of the ampoule.

[0013] WO 89/08469 discloses a needle-free injector for one-time use. WO

92/08508 sets forth a needle-free injector which is designed for three injections. The ampoule containing the drug is screwed into one end of the drive unit, with the piston rod being fitted into the open end of the ampoule. At its one end, the ampoule contains the nozzle through which the drug is expelled. A displaceable closure plug is provided approximately at the center of the length of the ampoule. The dose to be injected can be adjusted by changing the depth of the ampoule. The piston rod which projects from the drive unit after actuation of the injector is pushed back by hand. Both units are operated with compressed gas.

[0014] WO 93/03779 discloses a needle-free injector with a two-part housing and a liquid container which is fitted laterally to the unit. The drive spring for the piston is stressed by means of a drive motor. The spring is released as soon as the two parts of the housing are displaced relative to each other by pressing the nozzle against the injection location. Respective valves are provided in the intake passage for the liquid and in the outlet of the metering chamber.

[0015] WO 95/03844 discloses a further needle-free injector. It includes a liquid- filled cartridge which at one end includes a nozzle through which the liquid is expelled. At the other end the cartridge is closed by a cap-type piston which can be pushed into the cartridge. A piston which is loaded by a pre-stressed spring, after release of the spring, displaces the cap-type piston into the cartridge by a predetermined distance, with the amount of liquid to be injected being expelled in that case. The spring is triggered as soon as the nozzle is pressed sufficiently firmly against the injection location. This injector is intended for one-time or repeated use. The cartridge is arranged in front of the spring-loaded piston and is a fixed component of the injector. The position of the piston of the injector which is intended for a plurality of uses is displaced after each use by a distance in a direction towards the nozzle. The piston and the drive spring cannot be reset. The pre stressing of the spring is initially sufficiently great to expel the entire amount of liquid in the cartridge all at once. The spring can only be stressed again if the injector is dismantled and the drive portion of the injector assembled with a fresh, completely filled cartridge.

[0016] U.S. patent No. 5,891,086 describes a needle-free injector, combining an actuator and a medicament cartridge. The 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 actuator comprising an impact member urged by a spring and temporarily restrained by a latch means, 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 actuator may comprise trigger means to operate the said latch, and thus initiate the injection, only when a predetermined contact force is achieved between the liquid outlet of the said cartridge and the subject.

[0017] In U.S. Pat. No. 3,859,996, Mizzy discloses a controlled leak method to ensure that the injector orifice is placed correctly at the required pressure on the subject's skin at the correct normal to the skin attitude. When placement conditions are met, controlled leak is sealed off by contact pressure on the subject's skin, the pressure within the injector control circuit rises until a pressure sensitive pilot valve opens to admit high pressure gas to drive the piston and inject the medicament.

[0018] In WO Patent 82/02835, Cohen and Ep-A-347190 Finger, disclose a

method to improve the seal between the orifice and the skin and prevent relative movement between each. This method is to employ a vacuum device to suck the epidermis directly and firmly onto the discharge orifice. The discharge orifice is positioned normal to the skin surface in order to suck the epidermis into the orifice. This method for injection of the medicament into the skin and the injector mechanism are different and do not apply to the present invention because of its unique ampoule design.

[0019] In U.S. Pat. No. 3,859,996 Mizzy discloses a pressure sensitive sleeve on the injector which is placed on the subject, whereby operation of the injector is prevented from operating until the correct contact pressure between orifice and the skin is achieved. The basic aim is to stretch the epidermis over the discharge orifice and apply the pressurized medicament at a rate which is higher than the epidermis will deform away from the orifice.

[0020] In U.S. Pat. No. 5,480,381, T. Weston discloses a means of pressuring the medicament at a sufficiently high rate to pierce the epidermis before it has time to deform away from the orifice. In addition, the device directly senses that the pressure of the discharge orifice on the subject's epidermis is at a predetermined value to permit operation of the injector. The device is based on a cam and cam follower mechanism for mechanical sequencing, and contains a chamber provided with a liquid outlet for expelling the liquid, and an impact member, to expel the liquid. [0021] In U.S. Pat. No. 5,891,086, T. Weston describes a needle-free injector that contains a chamber that is pre-filled with a pressurized gas which exerts a constant force on an impact member in order to strike components of a cartridge and expulse a dose of medicament. This device contains an adjustment knob which sets the dose and the impact gap, and uses direct contact pressure sensing to initiate the injection. Further examples and improvements to this needle-free injector are found in US6620135, US6554818, US6415631, US6409032, US6280410, US6258059, US6251091, US6216493, US6179583, US6174304, US6149625, US6135979, US5957886, US5891086, and US5480381, incorporated herein by reference.

[0022] Prior art auto-injectors that utilize a pressurized gas as the energy source for the injection may contain a means for venting the gas after the injection is completed. This can be effectively done by the placement of a venting hole that is exposed to the pressurized gas when a delivery element is urged past the hold by the pressurized gas. This venting of the gas can create a noise that is startling to the patient, and which may cause trepidation and lack of compliance with prescribed therapy. Thus there is a need for a means for suppressing the sound made when the gas is vented.

[0023] Prior art sound suppressors are porous elements that slow the flow of gas and

reduce sound waves. However porous elements can be difficult and expensive to manufacture, can be difficult to clean, and may harbor microbial and other contamination.

[0024] Prior art sound suppressors may be used with needle free injectors that vent

pressurized gas in a way that entrains drug containing particles for delivery. These sound suppressors may also function to contain stray particles. In these types of systems, the need to entrain the particles in a gas jet that is of sufficient velocity to inject the particles can lead to very high levels of noise. The fact that the gas is directed toward the injection site can lead to elevated gas pressures and can cause recoil of the skin and/or the device. Repeated use can lead to drug build up, reducing the effectiveness of the gas venting and sound suppression. The requirements for a large area and high porosity of the sound suppressor can render this component difficult to manufacture. SUMMARY

[0025] An aspect of the invention is an auto-injector, preferably a needle free

injector, that includes a sound suppressor. The auto-injector of the current invention includes an energy source comprising a pressurized gas stored over the shelf life of the auto-injector within a gas chamber, a hole associated with the gas chamber, preferably in the side of the gas chamber configured for example to be used for pressurizing the chamber prior to delivery and/or venting gas from the chamber after delivery of the dose, and a sound suppressor associated with the hole configured to reduce the sound created during, or preferably substantially simultaneously with the completion of, injection. The pressurized gas is vented in a way whereby it does not contact the drug formulation. Aspects of the invention further include sound suppressors themselves, as well as methods of using the devices in delivery of an active agent to a subject, and kits that include devices and/or components thereof, e.g., sound suppressors.

[0026] It is an object of the invention to provide a sound suppressor for a needle free injector that reduces the sound created by the venting gas by 5 db or more, preferably by 7db or more, more preferably by 10 db or more, relative to the sound created in the absence of the sound suppressor.

[0027] It is a further object of the invention to improve compliance with therapy by reducing the level of sound created by gas venting from a needle free injector, thereby reducing the amount of trepidation felt by the patient, and the propensity to startle the patient, during or immediately after an injection.

[0028] It is an object of the invention to reduce the rate at which gas is vented from a gas chamber and thereby reduce the associated sound. The duration of the venting of gas is greater than 2 times, preferably more than 5 times, more preferably more than 10 times, and most preferably about 20 times or more than the duration of gas venting in the absence of the sound suppressor.

[0029] It is an object of the invention to delay the venting of the gas so it does not occur during the injection.

[0030] It is an advantage of the invention that the sound suppressor is non-porous,

rendering it simpler and less expensive to manufacture, easier to clean, and less likely to harbor microbial and other contaminants. [0031] It is an advantage of the invention that the sound suppressor and the vented gas do not contact the formulation and drug, eliminating the possibility of drug contamination and blockage of the sound suppressor.

[0032] It is an object of the invention to supply an auto-injector comprising an energy source comprising a pressurized gas stored within a gas chamber prior to actuation of the autoinjector, preferably over the shelf life of the auto-injector, wherein the gas chamber comprises a hole, said hole being configured for venting the gas from the gas chamber after dose delivery; and a sound suppressor in contact with the gas chamber, which sound suppressor is associated with the hole in a manner sufficient to reduce sound produced during use.

[0033] It is an object of the invention to supply an autoinjector with a sound suppressor, wherein the magnitude of sound reduction is 5 dB or more as compared to a control with no sound suppression.

[0034] It is an object of the invention to supply an autoinjector with a sound suppressor,, wherein the magnitude of the sound reduction is 10 dB or more.

[0035] It is an object of the invention to supply an autoinjector with a sound suppressor, wherein the magnitude of sound reduction is about 7 dB.

[0036] It is an object of the invention to supply an autoinjector with a sound suppressor, wherein the gas chamber is substantially in the shape of a right circular cylinder, and the sound suppressor is in the form of a toroid with a bore substantially in the shape of a right circular cylinder, which bore encircles and is in contact with the gas chamber.

[0037] It is an object of the invention to supply an autoinjector with a sound suppressor, wherein the toroid is fabricated of a material that comprises an ingredient to increase lubricity.

[0038] It is an object of the invention to supply an autoinjector with a sound suppressor, wherein the bore has a diameter which is between about 0 mm and about 0.24 mm less than the outside diameter of the gas chamber.

[0039] It is an object of the invention to supply an autoinjector with a sound suppressor, wherein the bore has a diameter which is about 0.11 mm less than the outside diameter of the gas chamber.

[0040] It is an object of the invention to supply an autoinjector with a sound suppressor, wherein the sound suppressor comprises a material chosen from a metal, a glass, a polymer, or a ceramic, preferably wherein the material is a polymer selected from polycarbonate, PET, Acetal, or Nylon, more preferably wherein the polymer is lubricated PET, preferably wherein the polymer comprises a uniformly dispersed solid lubricant

[0041] It is an object of the invention to supply an autoinjector with a sound suppressor, comprising a needle free injector

[0042] It is an object of the invention to supply an autoinjector with a sound suppressor as described above, wherein the hole has a diameter greater than 0.01"

[0043] It is an object of the invention to supply an autoinjector with a sound suppressor as described above, wherein the hole has a length less than 0.04"

[0044] It is an object of the invention to supply an autoinjector with a sound suppressor as described above, further comprising a dispensing member inserted into an end of the gas chamber, wherein the dispensing member is not inserted into the hole, wherein the dispensing member comprises a seal which seals the pressurized gas in the gas chamber, wherein when the auto-injector is actuated, the dispensing member moves in a first direction whereby the seal moves past the hole whereupon the pressurized gas vents through the hole

[0045] An auto-injector which may be in the form of a needle-free injector device is disclosed and is comprised of various components as described herein along with a sound suppressor which is structured and positioned relative to the injector components in a manner which reduces the sound which the injector produces when formulation is forced out of the injector. The injector includes an energy source which may be comprised of pressurized gas contained within a gas chamber. The injector includes a hole which is associated with that chamber which hole is configured relative to the chamber to allow pressurizing the gas in the chamber and venting gas from the chamber immediately after the delivery process.

[0046] The auto-injector or needle-free injection device of the invention may

include the specific components shown within Figure 1 and specifically will include a sound suppressor which is positioned over an exit opening used for venting pressurized gas following delivery of formulation from the device. The sound suppressor is preferably in the form of a toroid, with an inner bore preferably substantially in the form of a right circular cylinder, with the edges rounded or having a chamfer. Preferably, the sound suppressor is installed on a device similar to that shown in figure 1 wherein the cylindrical bore encircles a chamber containing pressurized gas, which chamber is itself substantially in the form of a right circular cylinder. The sound suppressor fabricated with materials that increase lubricity and reduce friction and may be comprised in part of metal, glass, polymeric materials or ceramics, and preferably contains uniformly dispersed solid lubricant. The cylindrical bore may have an inner diameter which corresponds to the outer diameter of the gas chamber and may be slightly smaller than the outer diameter of the gas chamber such as 0.01 to 0.15 mm less than the outer diameter of the gas chamber so that the sound suppressor can be tightly fit around the gas chamber and thereby act to suppress sound when the device is used.

[0047] An aspect of the invention is an auto-injector which may be in the form of a needle-free injector for injecting a medication into a patient through the skin. The auto-injector may be powered by a gas chamber and include a piston. The auto- injector includes a vent hole for venting gas out of the device following the delivery of a dose formulation. The vent hole is surrounded by a sound suppressor which is positioned relative to the vent hole in a manner so as to reduce any sound generated by gas exiting the vent hole. The sound suppressor maybe in the form of a toroid with a bore in a shape of a right circular cylinder. The bore encircles and contacts a surface of the injector device at the vent hole with the center of the vent hole at the center of the bore.

[0048] In an aspect of the invention, the injector device includes a gas chamber with a diameter of about 4 mm to about 8 mm and a bore with an inner bore diameter of about 4 mm to about 8 mm with all of the dimensions being ± 20%, ±10%, ±1%.

[0049] The injector device may have a gas chamber diameter of 6.16 ±0.093 mm with an inner bore diameter of 6.01±0.03 mm.

[0050] The sound suppressor may be structured so as to have external ribs with a height of 1 mm ± 0.2 mm. The sound suppressor component may be comprised of a variety of materials which may include a uniformly dispersed lubricant which lubricant may be included on the material surface making up the sound suppressor or dispersed throughout the sound suppressor material.

[0051] Another aspect of the invention is a method of drug delivery using a needle- free injector as described herein, wherein the sound of the actuation of the device due to gas exiting a vent hole of the device is suppressed by a structured sound suppressor which is shaped and comprised so as to reduce sound which suppressor may be a toroid with a bore in the shape of a right circular cylinder.

[0052] The auto-injector or needle-free injector device as described above includes multiple embodiments. For example, additional embodiments are described individually below noting that those individual embodiments can be combined in different manners so as to obtain multiple different configurations of the injector device.

[0053] The auto-injector as described above wherein the magnitude of sound

reduction is 5 dB or more as compared to a control with no sound suppression.

[0054] The auto-injector as described above wherein the magnitude of the sound reduction is 10 dB or more.

[0055] The auto-injector as described above wherein the magnitude of sound

reduction is about 7 dB.

[0056] The auto-injector as described above wherein the gas chamber is

substantially in the shape of a right circular cylinder, and the sound suppressor is in the form of a toroid which encircles the gas chamber.

[0057] The auto-injector as described above wherein the toroid is fabricated of a material that comprises an ingredient to increase lubricity.

[0058] The auto-injector as described above wherein the toroid has an inner

diameter which is between about 0 mm and about 0.15 mm less than the outside diameter of the gas chamber.

[0059] The auto-injector as described above wherein the toroid has an inner

diameter which is about 0.11 mm less than the outside diameter of the gas chamber.

[0060] The auto-injector as described above wherein the sound suppressor

comprises a material chosen from a metal, a glass, a polymer, or a ceramic.

[0061] The auto-injector as described above wherein the material is a polymer.

[0062] The auto-injector as described above wherein the polymer is selected from polycarbonate, Polyethylene terephthalate (PET), Acetal, or Nylon.

[0063] The auto-injector as described above wherein the polymer is selected from lubricated PET, Acetal C, Nylon 6, or Nylon 66.

[0064] The auto-injector as described above wherein the polymer is lubricated PET, preferably PET-P [0065] the autoinjector as described above, wherein the sound suppressor is non-porous

[0066] The auto-injector as described above with a property of the sound

suppressor chosen from;

[0067] a. an inner bore diameter of about 4 mm to 8 mm,

[0068] b. an outside diameter of about 8 mm to 12 mm

[0069] c. an external rib with a height between 0.4 and 1.6 mm,

[0070] d. a length of about 3.5 mm to 5.5 mm

[0071] e. a wall thickness between 0.4 and 3 mm.

[0072] The auto-injector as described above wherein the gas chamber has an outer diameter of about 4 mm to about 8 mm.

[0073] The auto-injector as described above wherein the properties of the sound suppressor are chosen from:

[0074] a. an inner diameter of 6.05 ± 0.03 mm,

[0075] b. an outside diameter of 10 ± 0.2 mm

[0076] c. an external rib with a height of 1 ± 0.2 mm

[0077] d. a length of 4.57 ± 0.10 mm

[0078] e. a wall thickness of 1.02 ± 0.05 mm.

[0079] The auto-injector as described above wherein the gas chamber has an outer diameter of 6.160 ± 0.093 mm.

[0080] The auto-injector as described above comprising a needle free injector.

[0081] A sound suppressor wherein the sound suppressor is as described above.

[0082] A method of delivering a dose of an active agent to a human or animal subject comprising using an auto-injector as described above.

[0083] A method of reducing the sound produced by an autoinjector, comprising adding the sound suppressor to the auto-injector as described above.

[0084] A method of increasing compliance with a therapy, the method comprising reducing the sound made by the auto-injector through the use of the sound suppressor as described above.

[0085] A kit comprising an auto-injector as described above and a sound suppressor as described above.

[0086] The auto-injector as described above wherein the polymer, which is

preferably lubricated PET, comprises a uniformly dispersed solid lubricant. BRIEF DESCRIPTION OF THE DRAWINGS

[0087] 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:

[0088] Fig. 1 is a cut-away view of one embodiment of the invention, a needle free

injector that includes a sound suppressor.

[0089] Fig. 2 provides a depiction of an embodiment of a sound suppressor.

[0090] Fig. 2a provides a depiction of the top view of the sound suppressor of Fig. 2.

[0091] Fig. 2b provides a cross sectional view through the centroid of the sound

suppressor of Fig. 2.

[0092] Fig. 2c provides a detail view of the circled area of Figure 2b.

[0093] Fig. 3 is a graph showing differences in observed sound levels with and without a sound suppressor using an actuator of a preferred embodiment of the auto-injector.

[0094] Fig. 4 provides a cross-sectional schematic view of a preferred embodiment of the gas chamber.

DETAILED DESCRIPTION

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

DEFINITIONS

[00100] 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.

[00101] 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 auto-injector for delivery. Alternatively, an actuator can refer to the mechanical portion of an auto-injector that comprises an energy store, and may include a safety that must be set prior to delivery, a trigger for the device, and ensures the proper pressure profile during delivery.

[00102] Aggregation: formation of linked molecules held together by

hydrophobic interactions, Van der Waals forces or chemical bonds.

[00103] AUC: Area under the curve, or the integral, of the plasma

concentration of delivered drug over time

[00104] Auto-injector: an injector for delivery a formulation containing an active pharmaceutical ingredient, wherein the energy for the delivery is contained in the injector, rather than being supplied by the patient or a care giver during delivery. An auto-injector will have a trigger for initiating the injection. The trigger can be, for example, a push button, but the auto-injector is preferably triggered by pressing it against the desired injection site. Preferred auto-injectors are needle free injectors.

[00105] 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.

[00106] Biologic: A medicinal products 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. Biologies may be isolated from natural sources such as humans, animals, plants, or microorganisms - or may be produced by biotechnology methods.

[00107] Bulk erosion :The rate of water penetration into the depot exceeds the rate at which the depot is eroded (i.e. transformed into water soluble products)— leading to an erosion process that occurs throughout the entire volume of the depot— characteristic of most hydrophilic polymers used in drug delivery currently.

[00108] 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.

[00109] Centipoise and centistokes: different measurements of viscosity, which are not just different units. Centipoise is a dynamic measurement of viscosity whereas centistokes is a kinematic measurement of viscosity. The conversion from centistokes and centipoise to S.I. units is given below:

lcS = 0.000 lm²/s lcP = 0.001Ns/m²

[00110] Coefficient of Thermal Expansion, Thermal Expansion Coefficient, and the like: The fractional change in size of a material (AL/L), per degree C.

[00111] 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 two 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.

[00112] Container Closure, Container Closure System, 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 liquid formulations, the container closure system must also have sufficiently low 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 contaminate the formulation during storage. Preferred materials for container closures include glass, more preferably boro-silicate glass, or fluorinated materials such as polytetrafluoroethylene (PTFE).

[00113] 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.

[00114] CPV trial: a 400 subject trial used to validate the predictive power of the IVIVC of the present invention. [00115] 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 Figure 2). In a preferred embodiment of the current invention, the desired injection is a subcutaneous injection. This in general requires a previous, higher pressure phase (see "puncture phase") wherein the hole through which the injectate is delivered is formed.

[00116] 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.

[00117] DosePro, or Intraject: 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 has a liquid outlet and a free piston in contact with the liquid, the actuator comprising a dispensing member urged forward by compressed gas and temporarily restrained until the device is actuated, the dispensing member being movable in a first direction under the force of the gas 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 gas 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 compressed gas is stored in a gas chamber in the form of a right circular cylinder which is closed on one end and open on the other end. The dispensing member comprises a seal. The gas chamber comprises a hole in the side wall of the gas chamber. During manufacture, the gas chamber is pressurized though the hole, and subsequently the dispensing member is forced into the gas chamber in a second direction opposite the first direction such that the seal moves past the hole, sealing the gas chamber and preventing the pressurized gas from escaping through the hole. When the device is actuated, the dispensing member moves in the first direction until the seal moves past hole and exposes the hole to the pressurized gas, venting the pressurized gas from the gas chamber. The actuator 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. Patent No. 5,891,086, and additional description, improvements, and variants can be found in US6620135, US6554818, US6415631, US6409032, US6280410, US6258059, US6251091, US6216493, US6179583, US6174304, US6149625, US6135979, US5957886, US5891086, and US5480381, incorporated herein by reference. Although many delivery systems and techniques may be used with the current invention, DosePro is the preferred method.

[00118] 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.

[00119] 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 Excipient that are suitable for injection, and contain one or more active pharmaceutical ingredients.

[00120] 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.

[00121] Impact gap, slap-hammer distance, and the like: The width of a gap between an impact member and a piston used to create a slap hammer effect, i.e. 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".

[00122] 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 invito 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

[00123] 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.

[00124] 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.

[00125] Jet Test, Jet Tester, Jet Test Method, and the like: a benchtop 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.

[00126] 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. [00127] 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.

[00128] 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.

[00129] Porous: a material property of containing a plurality of minute spaces or holes that allow gas to flow through.

[00130] Prophylaxis: The administration of a drug used to prevent the occurrence or development of an adverse condition or medical disorder.

[00131] 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. In a preferred embodiment of the invention, the injection is a subcutaneous injection. In order to achieve an efficient, reproducible subcutaneous injection, it is important that the jet be sufficiently energetic to drill down to the subcutaneum. However, it is then important that the bulk of the formulation be delivered at a lower pressure, in order that the formation of the hole is stopped prior to the injection becoming a painful intra-muscular injection.

[00132] Skinfold Thickness is a measure of the amount of subcutaneous fat,

obtained by inserting a fold of skin into the jaws of a caliper. The skinfolds are generally measured on the upper arm, thigh or upper abdomen of a human patient.

[00133] Surface Erosion: The rate of water penetration into a depot is slower than the rate at which the depot is eroded— the depot erodes from the surface before water has penetrated the entire volume of the device.

[00134] Specific gravity: The ratio of a compound's density to that of water. [00135] 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.

[00136] 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.

[00137] 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.

[00138] Successful Injection: an injection in which 90% or greater of the intended

injection volume is delivered through the skin into the subcutaneous tissue.

[00139] Toroid: a volume created by rotation of a surface about an axis. A toroid is a preferred shape for the sound suppressor of the current invention. Preferred toroids are of substantially rectangular cross section, more preferably with the addition of a raised rib on the outside surface.

[00140] 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. The visual assessment is calibrated by weighing the amount of injectate left on the skin, see "Filter Paper Weight" definition above. 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% to < 90%)

3 = >90% to < 95% penetration of injectate

4 = > about 95% penetration of injectate [00141] 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.

[00142] 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.

INVENTION IN GENERAL

[00143] The use of a prefilled injector has many benefits over a standard needle and syringe, including:

• No need to draw formulation into the syringe prior to use

• Fewer steps

• Simpler instructions

• Minimal amount of equipment required (especially important for acute indications wherein the injector must be carried around by the user.)

• Fast administration

• Improved patient compliance

• Improved disease outcomes.

[00144] Prefilled auto-injectors have additional advantages in that the energy for the

delivery comes from the device rather than the patient or caregiver that is administering the medication. This can be very important, for example, in the delivery of high viscosity formulations that require high hand strength, long delivery times, and large needle gauges, when delivered utilizing a standard needle and syringe.

[00145] A preferred embodiment of the auto-injector is the needle-free injector. Needle- free injectors are preferred because of:

• No danger of needle stick injury and related exposure to disease

• No needle phobia

• Small diameter liquid jets result in little or no pain sensation

• No requirement for sharps disposal

• Very short flow path (as compared to a hypodermic needle) that reduces viscous losses and enables delivery of high viscosity formulations. [00146] In one embodiment, the needle free injector includes an impact member that is separated from a piston, which piston is in contact with a liquid drug formulation. When the device is triggered (preferably by pressing against the target skin region), energy from a compressed gas power source is transferred to the impact member as work done by the gas in expansion as the impact member traverses the gap. This creates a pressure spike in the formulation when the impact member strikes the piston. This pressure spike forces the formulation through one or more nozzles or orifices, and creates a very energetic liquid jet that creates a hole in the epidermis to the desired depth, preferably the subcutaneum (the "puncture phase"). The pressurized gas then continues to urge the impact member, and thus the piston, forward, delivering the formulation through the hole and into the subcutaneous tissue (the "delivery phase") at a lower pressure that holds the hole open and delivers the dose, but does not continue increasing the depth of the hole. In this way, a repeatable subcutaneous injection is achieved while avoiding a painful intra-muscular injection. Control of the size of the gap, the force on the impact member, the dimensions and shape of the orifice or orifices, and potentially the mass of the impact member can all influence the rate of successful injection and the amount of injectate delivered.

[00147] Of interest are needle-free injectors that include the DosePro technology, as described in U.S. Patent No. 5,891,086, and additional description and improvements can be found in US6620135, US6554818, US6415631, US6409032, US6280410,

US6258059, US6251091, US6216493, US6179583, US6174304, US6149625,

US6135979, US5957886, US5891086, and US5480381.

[00148] As summarized above, aspects of the invention include needle free injectors comprising a hole associated with the gas chamber and a sound suppressor

associated with the hole. The sound suppressor component and associated

manufacturing processes were developed to decrease the sound of the DosePro drug delivery system without otherwise affecting system performance or human factors such as usability.

[00149] The sound suppressor can be fabricated by any means available, including

but not limited to machining, injection molding, or 3-D printing. In a preferred embodiment the sound suppressor is machined. The fabrication technique and material chosen must be able to achieve sufficient tolerances such that the installation force is minimized and the sound suppression is maintained over the shelf life of the system.

[00150] Many different materials may be utilized for the sound suppressor, including but not limited to metals, glasses, polymers, or ceramics. Preferably the material is a polymer, preferably chosen from polycarbonate, polyethylene terephthalate (PET), Acetal, or Nylon, more preferably lubricated PET, Acetal C, Nylon 6, or Nylon 66. In a particularly preferred embodiment, the sound suppressor is fabricated from PET, preferably PET-P, containing a uniformly dispersed solid lubricant (lubricated PET). Lubricated PET has many advantages, including enhanced wear, inertness, low coefficient of friction, high strength, high wear resistance, high service temperatures, precise machineability, low rate of stress relaxation (creep) and resistance to acidity. Lubricated PET excels under high pressure, high velocity, and metal to plastic mating surfaces. These properties are important to maintain noise suppression over the shelf life of the product, and to minimize installation force.

[00151] A preferred embodiment of the invention utilizing a preferred sound

suppressor and the DosePro device is shown schematically in FIG. 1. In the embodiment of FIG. 1, the injection force is provided by a compressed gas contained in gas chamber 130. Gas chamber 130 is in the form of a cylinder which is closed at its upper end and which contains gas, typically air, under a pressure which is typically in the range 5.5 MPa (800 psi) to 20.7 MPa (3000 psi). The cylinder houses ram 111. The end of ram 111 has a frustoconical portion 131 and flange 132 between which is situated O-ring seal 133. Prior to use, ram 111 is held in the illustrated position by latch 108 engaging in a groove in the ram, the upper surface of the groove forming cam surface 109. In the position shown in FIG. 1 latch 108 is unable to move leftwards, because it bears against the inner wall of sleeve 102.

[00152] The lower end of gas chamber 130 has an outwardly directed flange 130a, which enables the cylinder to be held by crimping flange 130a beneath outwardly directed flange 140a at the upper end of coupling 140. The sleeve 102 is formed of upper sleeve portion 102a within which the cylinder is situated, and lower sleeve portion 102b. Sleeve portion 102b is connected to the coupling by interengaging screw threads 141 formed on the inner and outer walls of the sleeve portion 102b and coupling 140 respectively.

[00153] The injector contains medicament cartridge 103 which has piston 104

slidingly and sealingly located therein, in contact with medicament 105. As considered from the upper end of FIG. 1 , the piston may comprise a cylindrical portion, a larger diameter cylindrical sealing portion, and a frusto-conical portion. Cartridge 103 has discharge orifice 106. Orifice 106 is sealed by resilient seal 134 which is held in place by seal carrier 135. Seal carrier 135 is connected to lower sleeve portion 102b by frangible joint 136.

[00154] As a precaution against accidental firing, removable block 137 is provided at the lower part of upper sleeve portion 102a. The lower edge of block 137 bears against ring 142 which is bonded to the exterior surface of coupling 140 or (not shown) formed integrally therewith. The function of ring 142 is to prevent downward movement of sleeve portion 102a relative to coupling 140, for so long as block 137 is present. Accordingly, ring 142 need not extend completely around the periphery of the coupling, and could be replaced by one or more separate elements.

[00155] Annular space 138 is formed in the inside wall of sleeve 102, where the sleeve is adjacent to gas chamber 130, and the space is filled with a damping grease (indicated diagrammatically by a succession of black bands), so that the grease is in intimate contact both with sleeve 102 and cylinder 130.

[00156] When the embodiment of FIG. 1 is to be operated, the user snaps off seal carrier 135 at frangible joint 136, which takes seal 134 with it and exposes orifice 106. The user then removes block 137, and grasping upper sleeve portion 102a urges the orifice against the substrate (e.g. the user's own skin) which is to be injected. This moves upper sleeve portion 102a downwardly, with respect to the lower sleeve portion 102b. This brings aperture 139 in the wall of upper sleeve portion 102a into alignment with latch 108, which is thus able to move sideways into aperture 139 under the influence of the force of the gas within gas chamber 130 acting on latch 108 via cam surface 109 formed in ram 111. The injector is thus caused to fire. As a precaution, in case latch 108 fails to move under the influence of cam surface 109, auxiliary cam surface 143 is provided on the inside of the sleeve portion 102a. The resulting recoil is damped by damping grease. [00157] Accidental firing during the assembly process is a real possibility. Firstly, immediately prior to installation of upper sleeve portion 102a there is a stage in which the partially assembled device has a period of quarantine to check for gas leaks. Secondly, during installation of upper sleeve portion 102a the device will be subjected to numerous forces and vibration arising from the assembly equipment. Even after installation of upper sleeve portion 102a, the assembly stresses arising as the cartridge is installed may be sufficient to cause accidental firing, despite the presence of block 137.

[00158] To deal with this problem the device has a safety mechanism. In the

illustrated embodiment this is provided by forming the slot in the ram not only with cam surface 109 but also with locking surface 109a which extends perpendicular to the axis of the ram and is located radially inwardly of cam surface 109 and engages latch portion 108a. To enable the combination of cam surface 109 and locking surface 109a to be used in the intended manner, upper sleeve portion 102a is provided with opening 144 which extends therethrough at a location which, prior to the device being fired, is aligned with the end of the latch 108 remote from the slot in the ram.

[00159] Gas chamber 130 is substantially in the shape of a right circular cylinder, and venting hole 150 is in the side of gas chamber 130. The vent hole has a diameter greater than 0.005" in diameter, preferably greater than 0.010", more preferably greater than 0.020", most preferably about 0.6 mm. The length of the vent hole is less than 0.08", preferably less than 0.04", more preferably less than 0.03", most preferably about 0.58 mm. After the auto-injector is triggered, pressurized gas in gas chamber 130 forces ram 111 to move downward. Ram 111 comprises gas seal or seals 133, preferably an 0-ring, to contain the pressurized gas. Substantially simultaneously with the end of the dose delivery, gas seal 133 moves beyond venting hole 150, placing the venting hole in fluid communication with the pressurized gas. Sound suppressor 151 is installed with an interference fit around gas chamber 130, substantially covering venting hole 150. Because the sound suppressor is fitted over an existing component, gas chamber 130, and located within an existing space inside the DosePro device, no changes to other components are necessary. The installed position and physical size of the sound suppressor allow unimpeded movement of other components during device actuation, allowing actuation by the same mechanism as shown in figure 1 and described above.

[00160] Fig. 2 shows a preferred embodiment of sound suppressor 151. Sound

suppressor 151 is in the form of a rectangular toroid with a central bore in the form of a right circular cylinder. Rib 201 is an added feature on the outside surface of sound suppressor 151 to improve the strength and creep resistance of sound suppressor 151 and provide an adequate engagement surface for an assembly tool while minimizing the amount of material required and any potential for interference with other actuator components. In another embodiment, rib 201 is not included, and thickness 205 (see figure 2c) is increased to provide the necessary strength and engagement surface.

[00161] Fig. 2a shows a top view of sound suppressor 151. Inside diameter 202

must be held to tight tolerances due to the competing requirements of low

installation force and maintainance of sound suppression. Inside diameter 202 is between about 1 and about 46 mm, preferably between about 3 and about 16 mm, more preferably between about 4 and about 8 mm, most preferably about 6.05 ± 0.03mm.

[00162] Fig. 2b shows a cross sectional view of sound suppressor 151. Outside

diameter 203 is between about 3 and about 50 mm, preferably between about 5 and about 20 mm, more preferably between about 8 and about 12 mm, most preferably about 10 ± 0.2 mm. Rib 201 has a height between about 0.1 and about 10 mm, preferably between about 0.5 and about 5 mm, more preferably between about 0.8 and about 2 mm, most preferably about 1 ± 0.2 mm. Length 204 is between about 1 and about 20 mm, preferably between about 3 and about 10 mm, more preferably between about 3.5 and about 5.5 mm, most preferably about 4.57 ± 0.10 mm.

[00163] Fig. 2c shows a detail of the cross section of Fig. 2b. The thickness 205 is between about 0.1 and about 10 mm, preferably between about 0.5 and about 5 mm, more preferably between about 0.8 and about 2 mm, most preferably about 1.02 ± 0.05 mm.

[00164] The addition of sound suppressor 151 to a gas powered auto-injector actuator preferably reduces the sound associated with venting of the gas by about 5 db or more, preferably by about 7 db or more, more preferably by about 10 db or more. [00165] Figure 4 shows a preferred embodiment of gas chamber 130, including venting hole 150. Gas chamber 130 is preferably substantially in the shape of a right circular cylinder. Gas chamber 130 can be fabricated from any of a number of materials, including but not limited to metals, polymers, glasses, or ceramics. Preferably gas chamber 130 is fabricated from a metal, more preferably aluminum, most preferably an alloy comprising aluminum. Gas chamber 130 may be fabricated by any means, including but not limited to molding, machining, drawing, stamping, or 3D printing. Outside diameter 402 is between 1 and 46 mm, preferably between 3 and 16 mm, more preferably between 4 and 8 mm, most preferably 6.160 ± 0.0.093 mm.

[00166] Gas chamber 130 and sound suppressor 151 are preferably designed with an

interference fit, i.e. inside diameter 202 of sound suppressor 151 is preferably slightly less than outside diameter 402 of gas chamber 130. The amount of interference should be sufficient to ensure adequate sound suppression and maintain the location of sound suppressor 151 relative to gas chamber 130 during handling and shipping of the device, while allowing sound suppressor 151 to be pressed onto gas chamber 130 with an acceptably low force. The interference (difference in diameters) is preferably between about 0 and about 1 mm, more preferably between about 0 and about 0.24 mm, most preferably between about 0.02 and about 0.2 mm. In a particularly preferred

embodiment, the interference fit is approximately 0.11 mm.

EXAMPLES

[00167] 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. EXAMPLE 1

[00168] Sound suppressor 151 was added to DosePro as shown in Fig. 1. Sound

suppressor 151 was machined from lubricated PET as described above.

[00169] The sound suppressor was effective in reducing sound upon actuation

without impacting device performance. A comparison of the sound traces for typical unsuppressed and sound suppressed DosePro actuators is shown in Fig. 3.

With the sound suppressor installed, the "click" associated with actuation is still present with a comparable sound pressure level, but the sound associated with gas exhaust has been substantially reduced. The venting noise associated with the sound suppressed version is an average of 7 dB quieter (in terms of total sound energy) than the unsuppressed DosePro actuator.

[00170] 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.

[00171] 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.

Claims

CLAIMS What is claimed is:

1. An auto-injector, comprising:

an energy source comprising a gas chamber holding a pressurized gas prior to actuation; a vent hole in the chamber which vent hole allows for venting the gas from the gas chamber following delivery of a dose of formulation from the auto-injector; and

a sound suppressor in contact with the gas chamber, which sound suppressor is configured relative to the vent hole so as to reduce sound generated from gas exiting the vent hole.

2. The auto-injector of claim 1, wherein the gas chamber is a right circular cylinder, and the sound suppressor is a toroid with a bore in the shape of a right circular cylinder, which bore encircles and contacts a surface of the gas chamber at the vent hole.

3. The auto-injector of claim 2, wherein the gas chamber has a diameter of about 4 mm to about 8 mm and the bore has an inner bore diameter of about 4 mm to about 8 mm.

4. The auto-injector of claim 3, wherein the gas chamber has a diameter of 6.160 ± 0.093 mm and the bore has an inner bore diameter of 6.05 ± 0.03 mm.

5. The auto-injector of claim 4, wherein the sound suppressor has an external rib with a height of 1 ± 0.2 mm

6. The auto-injector of claim 2, wherein the sound suppressor is fabricated of a material that comprises a uniformly dispersed lubricant.

7. The auto-injector of claim 6, wherein the bore has a diameter which is between about 0 mm and about 0.24 mm less than the outside diameter of the gas chamber.

8. The auto-injector of claim 7, wherein the bore has a diameter which is about 0.11 mm less than the outside diameter of the gas chamber.

9. The auto-injector of any of claims 1 to 6, wherein the sound suppressor comprises a material selected from the group consisting of a metal, a glass, a polymer, and a ceramic.

10. The auto-injector of claim 9, wherein the material is a polymer selected from the group consisting of a polycarbonate, PET, Acetal, and Nylon.

11. The auto-injector of claim 10, wherein the polymer is lubricated PET.

12. The auto-injector of claim 10, wherein the polymer comprises a uniformly dispersed solid lubricant.

13. The auto-injector of any of the preceding claims, wherein the auto-injector is a needle free injector

14. The auto-injector of any of claims 1 - 12, wherein the vent hole has a diameter greater than 0.01" and a length of less than 0.04".

15. The auto-injector of claim 13, further comprising:

a dispensing member inserted into an end of the gas chamber;

wherein the dispensing member is not inserted into the vent hole and comprises a seal which seals the pressurized gas in the gas chamber; and

wherein when the auto-injector is actuated, the dispensing member moves in a first direction whereby the seal moves past the vent hole whereupon the pressurized gas vents through the vent hole.