WO2015153899A1

WO2015153899A1 - Kits for drug delivery site preparation

Info

Publication number: WO2015153899A1
Application number: PCT/US2015/024116
Authority: WO
Inventors: Andrew Michael Blumenfeld; Brooks M. Boyd; Jeffrey A. Schuster; John Turanin
Original assignee: Zogenix, Inc.
Priority date: 2014-04-02
Filing date: 2015-04-02
Publication date: 2015-10-08
Also published as: WO2015153900A1

Abstract

Apparatuses and methods for preparing an injection site on a target organ for enhanced delivery are described. In one embodiment, a drug delivery device, such as an injector, is supplied in a kit with an applicator for topically applied drugs, including anesthetics, vasodilators, and/or absorption enhancers. The applicator may be combined with another function, such as a needle or orifice cap. In another embodiment, the delivery system is supplied with an alignment ring, gripper, or vacuum cup to ensure the delivery device is in contact with and at the desired angle relative to the target organ, and ensures that the delivery device does not move relative to the delivery site during delivery. Also disclosed are topical applicators and topical formulations.

Description

Kits for Drug Delivery Site Preparation

FIELD OF THE INVENTION

[001] The current invention is directed towards drug delivery systems and kits for

preparing a target delivery site on an organ for drug delivery.

BACKGROUND OF THE INVENTION

[002] Self administration of injectable medications, or administration by a nonprofessional such as a family member, has numerous advantages, including the ability to rapidly and/or regularly self dose medications for conditions such as pain, anaphylaxis, hyperglycemia, etc. without the need for visiting a doctor's office or access to a skilled care giver. Rapid self administration is facilitated by the use of a drug delivery system that is self contained including an on-board power source (e.g. an auto-injector), factory pre-filled, portable, small enough to be carried in a pocket book or glove compartment, single use, and disposable. However, several factors can make self administration problematic. These factors include pain, bleeding, bruising, swelling, cutting, erythema, infection, and/or other local effects at the delivery site, and can lead to fear and patient non-compliance or switching to other delivery methodologies that may not be as effective, such as oral.

[003] Numerous drug delivery systems for self administration or home administration are available, including but not limited to needle and syringe, auto injectors, needle free injectors, pumps, bolus injectors, sprays, infusion systems, gene therapy systems, catheters, and transdermals including active and passive transdermals,

[004] Injection of medications can have many advantages, including rapid onset, high bioavailability, avoidance of first pass metabolism, and low coefficient of variation. Needle free injection has numerous advantages over injection using a needle and syringe, including avoidance of needle stick injury, avoidance of needle phobia, and avoidance of the need for sharps disposal.

[005] Needle free injectors, while addressing some of the issues related to injection with a needle and syringe, have particular requirements to ensure that self administration is easy and comfortable for patients. Among these requirements is the fact that the delivery must occur with the nozzle in contact with (or in some instances such as intra-dermal delivery, at a fixed distance to) the desired injection site on the target organ or skin. Most needle free injectors should be activated with the device perpendicular to the skin or target organ at the desired injection site. Moving the injector during delivery can be problematic and in the worst cases lead to distortion of the injection path in the target organ. At times there can be pain associated with needle free injection. The experience of this pain may be worsened by the expectation on the part of the patient of little or no pain due to the lack of a needle.

[006] Therefore there is a need for a means of preparing the target delivery site on an organ to optimize delivery efficiency and reduce fear and non-compliance.

SUMMARY OF THE INVENTION

[007] An embodiment of the invention includes a dual function, injector device

(preferably a needle-free injector) which is comprised of a first container holding a first formulation comprising a first pharmaceutically active drug in a liquid container, a piston for forcing the first drug from the container at a speed which penetrates skin, a channel leading from the first container to an exit opening, a second container holding a second formulation comprising a second pharmaceutically active drug, generally different from the first pharmaceutically active drug, and an applicator for applying this second drug topically to the surface of a target organ (often the skin) of a human patient wherein the first drug is typically any drug which has a systemic pharmacological effect on a human patient and the second drug is a drug which has a local effect such as decreasing pain, bleeding, swelling, erythema, infection, and bruising wherein the formulation containing the second drug is formulated for topical application and as such is preferably viscous having a viscosity of lOcp or more, 20cp or more, lOOcp or more, 200cp or more wherein the first drug is present in a sufficient amount so as to have a therapeutically desirable effect when injected into a human patient and the second drug is present in a

therapeutically effective amount so as to have a desired topical local effect.

[008] One embodiment of the current invention comprises needle free injector which includes a removable orifice cap that closes the orifice and ensures that the injector contents are maintained in a stable, sterile container closure system. The injector cannot be triggered prior to or during removal of the cap, which also functions as the container and topical applicator for locally active drugs such as vaso-constricting agents, absorption enhancing agents, anesthetic agents, adhesive agents, vacuum sealing agents, cleaning agents, depilatory agents, and/or anti-microbial agents. The cap may include one or more local anesthetic agents and may include additional components to facilitate local absorption, such as an absorption enhancer, a needle, an abrasive, or an array of needles or microneedles. In use, the cap is removed, pressed and/or rubbed against the desired injection site, possibly in combination with squeezing of the cap, and the needle free injection is then applied to the prepared injection site after an optional pre-specified wait time. In a related embodiment, the injector is a needle and syringe which is preferably prefilled, with a similar cap that covers the needle to prevent needle stick and possibly maintains the contents in a stable, sterile manner. Related embodiments may comprise other drug delivery devices such as transdermal devices, pumps, bolus injectors, and catheters.

[009] It is an object of the invention to prepare a site on an organ, preferably skin, for delivery of a drug.

[010] It is an object of the invention to improve delivery efficiency and patient

experience and compliance by reducing or eliminating local drug delivery effects, e.g. local injection effects, including but not limited to pain, bleeding, bruising, swelling, erythema, infection, and injection path distortion.

[011] It is a feature of the invention that it stores and delivers topical drugs and/or surface preparation agents to reduce local delivery effects and prepare a surface for drug delivery.

[012] It is an object of the invention to supply a container for a formulation containing one or more topical drugs and/or surface preparation agents. Preferably the container is factory prefilled with the topical drug(s), and is presented with an overwrap or removable cover that maintains the stability and/or sterility of the formulation.

[013] It is an object of the invention to supply a container for a topical formulation. In one embodiment, the container comprises a rigid or semi-rigid cup containing a compliant material, such as a sponge. The compliant material is contained in the cup in a partially compressed state by a removable and disposable cover or cap. The compliant material is factory infused with the topical formulation. When the cover or cap is removed, the partially compressed compliant material expands, such that it extends beyond the opening in the cup. The cup is then gripped, and the compliant material is pressed or rubbed against a target site on an organ, for example an injection site on skin. Optionally, the cup is semi-rigid, and the pressing or rubbing is combined with squeezing to maximally deliver the infused formulation. After a single delivery, the cup and compliant element are disposed of. [014] It is an object of the invention to prepare a surface for treating or preventing the occurrence of a condition by delivering, preferably injecting, an API. In a preferred embodiment, the condition is a migraine or cluster headache, and the API is a triptan.

[015] It is an object of the invention to constrict the local blood vessels at a drug

delivery site by the application of a vaso-constricting agent.

[016] It is a feature of the invention to reduce pain at a drug delivery site by the topical application of one or more anesthetic agents.

[017] It is a feature of the invention to increase absorption of the topical, local, and/or systemically delivered drug or drugs by the topical application of an absorption enhancing agent.

[018] Preferred additional drugs of the inventions include but are not limited to topical anesthetic agents, including but not limited to benzocaine, lidocaine, tetracaine;

vasoconstricting agents including but not limited to epinephrine, an absorption enhancing agent including but not limited to hyaluronidase, and combinations thereof.

[019] It is a feature of the invention that the application of a vasoconstricting agent in combination with a local anesthetic increases the duration of effect of the anesthetic by constricting the local blood vessels.

[020] It is a further feature of the invention to supply additional, non-injected

compounds including but not limited to additional drugs, adhesives, cleaning agents, antimicrobials, depilatory agents, vacuum sealing agents, and/or other compounds in a convenient package or kit that facilitates storage of the drugs with an injector or other drug delivery device.

[021] It is a further feature of the invention to supply a kit or device which includes a drug delivery device and additional, non-injected compounds including but not limited to additional drugs, adhesives, vacuum sealing agents, cleaning agents, antimicrobials, depilatory agents, absorption enhancing agents, and/or other compounds in a convenient package that facilitates delivery of the additional non-injected compounds.

[022] It is a further feature of the invention to supply the additional compounds in combination to prevent more than one local effect and/or prepare a target organ for delivery, e.g. injection.

[023] It is a further object of the invention to further reduce patient fear, improve

compliance, and eliminate the possibility for needle stick injury and the need for sharps disposal. [024] It is an object of the invention to reduce patient fear, improve compliance, and eliminate the possibility for needle stick injury and the need for sharps disposal by using a needle free injector.

[025] In a particularly preferred embodiment of the invention, the drug delivery system is supplied with a cap, such as a needle cap, catheter cover, transdermal device cover, or a needle free injector orifice cap, that also functions as the container for additional compounds, and is also the applicator for topical application of additional compounds.

[026] It is a further object of the invention to facilitate rapid self administration by using a drug delivery system that is self contained including an on-board power source (i.e. an auto-injector), factory pre-filled, portable, small enough to be carried in a pocket, purse, or glove compartment, single use, and/or disposable.

[027] It is a further object of the invention to ensure that the drug delivery system, preferably an injector, is held in the correct orientation relative to an organ, preferably skin, at the delivery site.

[028] It is a further object of the invention to ensure that an injector is held

perpendicular to the skin at an injection site.

[029] It is a further object of the invention to ensure that a drug delivery or other

medical system, including but not limited to a needled injector, a needle free injector, a transdermal, a pump, a bolus injector, an infusion system, or a catheter does not move relative to the treatment site during treatment.

[030] It is a further object of the invention to ensure that the orifice of a needle free injector is held in contact with the target organ or skin at the injection site.

[031] It is another object of the invention to ensure that the orifice of a needle free injector is held at a desired distance from the skin at the injection site, for example to facilitate intra-dermal injection.

[032] It is a further object of the invention to eliminate the possibility of movement and distortion of the delivery path through the skin or other organ during injection or insertion of a needle.

[033] It is a further object of the invention to ensure that drug delivery from a drug delivery device cannot be initiated unless the drug delivery device is at the correct position, the correct distance from an organ, in contact with an organ, at the correct orientation with respect to an organ, and/or perpendicular with respect to the surface of an organ. Preferably the organ is a patient' s skin. [034] It is a further feature of the invention to supply an injector, preferably a needle free injector, with a separate component that insures that the injector is held at the desired orientation, doesn't move, and is in contact with the skin or at a pre-specified distance from the skin, during injection.

[035] It is a further aspect of the invention to supply a drug delivery device, preferably an injector, more preferably a needle-free injector, with a component that pulls outward and stretches the surface of the target organ, facilitating efficient delivery

[036] In one embodiment of a kit and/or a delivery device, functions selected from a cap, a container for additional, non-injected and/or non-systemically delivered compounds, an applicator for additional, non-injected and/or non-systemically delivered compounds, a component that ensures that the drug delivery device is held at a desired orientation, doesn't move, and is at a pre-specified distance from a target organ or in contact with a target organ, and a component that pulls up and stretches the surface of a target organ, are included in a single part or assembly.

[037] It is a feature of the invention to supply an injector, preferably a needle free

injector, with an attached component that ensures that the injector is held at the desired orientation, doesn't move, and is in contact with the skin or at a pre-specified distance from the skin, during injection.

[038] It is a further feature of the invention to supply a needle free injector with an attached component that readies the skin for injection, including but not limited to stretching the skin, lifting the skin, forcing the skin to be in contact with the needle free injector orifice, forcing the skin to be largely perpendicular to the axis of the orifice, and ensuring that the skin does not move relative to the orifice.

[039] It is a feature of the invention to supply an injector with an attached or separate component or alignment ring that largely surrounds an orifice or needle, and thereby ensures that the injector is held in the correct orientation during injection. The area of contact of the alignment ring with the target organ may be of any shape. Preferably the area of contact is cirucular, with an injection orifice or needle or arrays thereof substantially centered on the circle. However, other shapes may be used, including but not limited to squares, pentagons, hexagons, etc. The alignment ring may also comprise a plurality of extensions extending radially from the drug delivery device. Any number of extensions can be used, although it is preferred that there be more than two extensions to maintain the orientation of the device about any rotation axis. Preferably there are three or more extensions, more preferably 4 extensions.

[040] It is a feature of the invention to supply an injector with an attached or separate component that includes an adhesive and/or a vacuum sealing medium, whereby when the component is placed against the skin, it removably adheres to the skin, and thereby ensures that the injector does not move during delivery.

[041] It is a further object of an embodiment of the invention to supply an injector with an attached or separate component that does not allow the patient to see the injection site, needle free injector orifice, the act of inserting a needle. Preferably, the patient cannot tell if the injector is needled or needle free.

[042] It is an object of the invention to reduce patient anxiety and fear, and

increase patient comfort and compliance, by supplying a drug delivery device with a separate or attached component that does not allow the patient to see, for

example, the needle or catheter of a drug delivery device, does not allow the patient to see the orifice of a needle free injector, does not allow the patient to see the delivery site, and/or does not allow the patient to see the insertion of the needle, catheter, or the like.

[043] It is a feature of the invention to supply an injector with an attached moveable or deformable component that mechanically grips the skin, and pulls and stretches the skin, ensuring that the skin is prepared for the injection and that the injector does not move during delivery. In a preferred embodiment, the injector is a needle-free injector, and the component also ensures that the skin is in contact with an injection orifice.

[044] In a preferred embodiment of the invention, the drug delivery device is a needle free injector with one or more injection orifices, that is triggered by pressing the orifice or orifices against the skin of a human or animal patient.

[045] In one embodiment, the drug delivery system is supplied as a kit with a separate alignment component or "alignment ring" that is adhered to the skin prior to delivery, contained in a package with an instruction for use and a label. Subsequently, the injector is inserted into the alignment component to a desired depth, and the formulation is delivered. The alignment ring ensures that the injector is held at a predetermined angle to and at a predetermined distance from the target organ or skin, preferably perpendicularly, and additionally ensures that that the injector does not move relative to the skin surface during injection. [046] In the embodiment where the drug delivery system is a needle free injector, the orifice end of the injector is inserted into and through the alignment ring until the orifice is pressed against the target organ or skin, or (for example for an intra-dermal injection) held at a fixed distance from the target organ or skin. Preferably, the force of the orifice being pressed against the target organ or skin actuates the trigger. Alternatively, for example for an intradermal injection, the device being pressed against the spacer triggers the device.

[047] In the embodiment where the injector is needled, the alignment ring in

combination with the length of the needle can set the depth of injection, for example for an injection chosen from an intra-dermal, sub-cutaneous, intra- venous, or intra-muscular injection.

[048] The alignment ring can also have features that interact with mating features such as actuators on the injector. In this way, when the injector is inserted into the alignment ring to the proper depth, the feature on the alignment ring and injector can enable the injector for triggering or delivery, trigger the injector in the embodiment where the injector is an auto-injector, insert a retractable needle, expose the orifice of a needle free injector, etc.

[049] The alignment ring embodiment preferably comprises an adhesive that holds the alignment ring in the desired location on the skin or target organ. In a preferred embodiment, the adhesive is pre-applied to the alignment ring. The adhesive may be a two sided adhesive tape which is dye cut and factory applied to the alignment ring, with the outer adhesive layer covered, for example by a release liner. The release liner may be removed, for example via an exposed tab, prior to adhering the alignment ring to the target injection site. Alternatively, the release liner may be attached to the device packaging or to another component, and the act of removing the alignment ring from its packaging or another component removes the release liner. Alternatively, the adhesive may be a high viscosity liquid adhesive that is factory applied to the alignment ring and covered by a protective sheet or cap. In yet another embodiment, the kit contains a separate applicator for an adhesive that is applied to the target injection site or to the alignment ring immediately prior to placement of the alignment ring. Preferably, the applicator is a cap for the drug delivery system, for example an orifice cap, needle or catheter cap, or a cover for a transdermal skin contact area. [050] In one embodiment, adhesive is contained in a second formulation which optionally comprises one or more APIs for the reduction of local effects. In yet another embodiment, the alignment ring contains one or APIs for the reduction of local effects in the central region of the alignment ring into which the injector and optional needle is inserted. In these embodiments, the alignment ring is adhered to the desired delivery site for a wait time that is sufficient to allow the APIs to take effect, and then the drug delivery system is inserted and the first formulation is delivered.

[051] In another preferred embodiment, the injector is supplied with an attached

alignment ring that functions as a vacuum cup which surrounds one or more injection orifices or needles, and a vacuum source. The vacuum source may be separate from the injector, and pneumatically attached to the injector, for example via flexible tubing. Preferably, the vacuum source is contained within the injector, and most preferably the vacuum source is actuated by the person giving the injection, for example via a lever, preferably via a thumb actuated lever. In a preferred embodiment, the vacuum source is actuated by the act of pressing the injector against the desired delivery site. The vacuum cup utilizes the vacuum to seal to the desired injection site, ensuring that the injector cannot move during the injection. In addition, the vacuum cup act as an alignment ring and ensures that the injection occurs at a preferred angle to the skin at the desired injection site, preferably perpendicularly. This is accomplished both by the vacuum drawing the skin into the vacuum cup and against the orifice or orifices, and by the vacuum cup being large enough that the injector itself is held at the desired angle to the skin. Preferably, the triggering of the device is interlocked to the vacuum, ensuring that the device can only be triggered when the vacuum cup is in sealing contact with the skin. More preferably, the vacuum itself actuates the device trigger. In a particularly preferred embodiment, the injector is an auto-injector that is powered by a compressed gas that is contained within the injector, and the vacuum actuates a valve, preferably a spool valve, which releases the compressed gas, causing the auto-injector to deliver.

[052] Although the invention can be carried out through any route and method of

delivery that facilitates the desired delivery kinetics and drug dynamics, such as oral, buccal, nasal, pulmonary, rectal, vaginal, transdermal, ocular, or parenteral, including intra-muscular, intra-dermal, sub-cutaneous, intra- arterial, or intravenous, or direct delivery to an organ, it is preferably not oral, more preferably nasal, pulmonary, buccal, or parenteral. In a particularly preferred embodiment the delivery is intra-dermal injection, intra-muscular injection, or most preferably subcutaneous injection, and in the most preferred embodiment, the formulation is delivered by needle free injection via the sub-cutaneous route.

[053] Most preferably, the invention is carried out utilizing a pre-filled, self

contained, compact, portable needle free auto-injector.

[054] 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 as described in U.S. Patent No. 5,891,086 (incorporated by reference in its entirety). 5,891,086 describes a device for delivering formulations, including viscous formulations, by needle-free injection for SC, ID or IM, but not limited to these applications. An actuator for use in conjunction with a cartridge to form a needle- free injector, the cartridge being pre-filled with a liquid to be injected in a subject, the cartridge having a liquid outlet and a free piston inward of the liquid outlet in contact with the liquid, said actuator comprising:

(a) a housing having a forward portion adapted to be connected with the cartridge;

(b) impact member mounted within said housing inward of the forward portion so as to be movable from a first position toward the forward portion to strike the free piston when a cartridge is connected and to continue to move the free piston toward the liquid outlet whereby a dose of the liquid is expelled through the liquid outlet in the cartridge;

(c) a chamber within said housing pre-filled with pressurized gas and connected with said impact member such that said pressurized gas is constantly in communication with and constantly exerts a force on said impact member to normally urge said impact member toward the liquid outlet; and

(d) a latch within said housing which engages said impact member to prevent movement of the impact member toward the forward portion in response to said force exerted by said pressurized gas, and being mounted to be movable out of engagement with said impact member to a firing position, in which said latch permits such movement.

[055] The current invention describes various formulations that can be delivered using a needle-free injector including the injector of 5,891,086. These formulations contain active ingredients, and may include various polymers, carriers, etc. [056] Additional preferred embodiments of the needle free injector can be found in WO 2012/096889 Al

[057] Another preferred embodiment is the needle free injector with multi-use actuator as described in US patents 7,281,502, 7,351,220, and 7,814,871

[058] An aspect of the invention is a desirable delivery time of high viscosity formulations.

[059] Another aspect of the invention is acceptable pain associated with injection

[060] Another aspect of the invention relates to alleviation of fear of needles

associated with injection of migraine formulations.

[061] Another aspect of the invention relates to the elimination of the danger of needle stick injury and cross-contamination associated with injection of migraine formulations.

[062] 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.

[063] Another aspect of the invention relates to the drug release profile associated with injection of high viscosity depot formulation, especially surface eroding systems.

[064] The invention includes many aspects including topical applicators, drug delivery systems, and methods of treating humans or animals by applying topical formulations and injecting therapeutic formulations. A kit aspect of the invention may comprise a needle free injector which comprises a first container holding a first formulation and a second container holding a second formulation. The first formulation is generally comprised of a pharmaceutically active drug which has systemic activity and the second formulation is generally comprised of a second pharmaceutically active drug different from the first drug which has a local topical effect. The device may include a topical applicator configured to deliver the second formulation to the surface of an organ such as the patient' s skin and may also include a package which includes all of the components. In some variations the containers are preloaded with a desired formulation and the entire device is disposable. In other variations the containers are preloaded and can be dispensed and replaced with a new container for further use with the delivery device. [065] One embodiment of the invention is a dual function needle free injector device which is comprised of two different container which hold two different drug formulations wherein one formulation is for systemic delivery to treat a patient and the second formulation is for topical application. The topical formulation may be an anesthetic alone or with other drugs which have other topical effects. The device such as the needle free injector may be connected to an alignment ring which makes it possible for the patient to correctly align the drug delivery device such as the needle free injector with the patient's skin. The alignment ring may include adhesive and may be positioned such that the needle-free injector will fire the drug formulation through the skin at an angle of approximately 90° + 10°.

[066] 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.

BRIEF DESCRIPTION OF THE DRAWINGS

[067] 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:

[068] Fig. 1 shows an embodiment of the injector of the current invention, with a cap/applicator attached.

[069] Fig. 2a shows an embodiment of the cap/applicator of the current invention.

[070] Fig. 2b shows a cross sectional view of the cap/applicator of Fig. 2a.

[071] Fig. 2c shows the cap/applicator of Fig. 2a in use.

[072] Fig. 3 shows one embodiment of the alignment ring of the current invention.

[073] Fig. 4 shows one embodiment of the vacuum cup and vacuum source

equipped injector of the current invention.

[074] Fig. 5a shows a cross section of the spool valve vacuum trigger of the

embodiment of Fig. 4.

[075] Fig. 5b shows the cross section of Fig. 5a after triggering. [076] Fig. 6a shows an embodiment of the topical applicator of the current

invention.

[077] Fig. 6b shows the embodiment of Fig. 6b after removal of a cover.

[078] Fig. 7 shows another embodiment of the vacuum cup and vacuum source

equipped injector of the current invention, wherein the vacuum is created via the act of pressing the injector against a desired injection site.

[079] Fig. 8 shows another embodiment of the current injection, with a

deformable or moveable alignment ring that grips and raises the surface of the target organ at the desired injection site.

[080] Figure 8b shows the embodiment of figure 8 after pressing against the

surface of the target organ and actuating the alignment ring.

DETAILED DESCRIPTION OF THE INVENTION

[081] 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.

[082] 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.

[083] 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.

[084] 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.

[085] 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

[086] 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.

[087] Actuator: A mechanical device for moving or controlling a mechanism or

system. An example of actuators include a lever that a user uses to ready a drug delivery system for delivery, a lever that creates a vacuum, a lever and linkage designed to operate a deformable or movable alignment ring, or a button, lever, or the like that is used to trigger delivery from a drug delivery system. An actuator may be actuated directly by a user, or may be actuated by relative movement of two components of a drug delivery system or kit, such as insertion of an injector into an alignment ring. An actuator may actuate a component of a drug delivery device directly through a linkage or push rod or the like, or it may act indirectly, for example by generating a vacuum that acts on a vacuum cup and/or a trigger mechanism. Alternatively, an actuator can refer to the mechanical portion of an auto-injector that comprises an energy store, an optional safety that must be set prior to delivery, a trigger for the device, and components that ensure the proper pressure profile during delivery. [088] Ambient Pressure: The pressure of the atmosphere surrounding an injector during an injection. Ambient pressure can vary, for example with elevation and weather.

[089] API: Active Pharmaceutical Ingredient or drug

[090] Applicator, Topical Applicator, and the like: A component which serves as a delivery system, and preferably as a container closure system, for a formulation which is applied to the surface of an organ, preferably the skin. The formulation may contain APIs, such as vasodilators, local anesthetics, and/or anti-microbials, and may also contain other ingredients, such as absorption enhancers, adhesives, vacuum sealing agents, depilatory agents, cleaning agents, and the like. The topical applicator may be supplied as a standalone product, but is preferably supplied as part of a kit which includes a drug delivery system. In a particularly preferred embodiment, the topical applicator comprises a cap for a drug delivery system, for example an orifice cap, a needle or catheter cap, or a cover for the skin contact area of a transdermal system. The applicator is preferably supplied with a cover or overwrap that maintains the stability and/or sterility of the contained formulation. The applicator cover or overwrap may be removed by the user prior to use as a separate step. Preferably the act of removing the applicator from a kit, a package, or another component such as a drug delivery system removes the cover. Preferably the cover or overwrap comprises one or more polymers, including but not limited to include polyethylene, polyester, nylon, cyclic olefin copolymer, and polychlorotrifluoroethylene, and may comprise one or metals including aluminum., In a preferred embodiment, the formulation is applied to a desired delivery site by rubbing or pressing the applicator on the desired site site, optionally while extruding the second formulation by or after squeezing the applicator container, manipulating an actuator such as a depressing a plunger, pressing a button, moving a switch or actuating a lever, etc. or a combination thereof

[091] AUC: Area under the curve, or the integral, of the plasma concentration of delivered drug over time.

[092] Auto-Injector: an injector for delivery a formulation containing an active pharmaceutical ingredient, wherein the energy for the delivery is supplied by the injector rather than being sourced by the patient or a care giver during delivery. An Auto-Injector will have a trigger for releasing the energy and initiating drug delivery, and optionally will have a safety mechanism and/or a mechanism for setting the delivered dose. The trigger can be, for example, a push button, but the auto-injector is preferably designed so that it cannot be triggered unless it is pressed against the desired injection site, for example by pressing it against the desired injection site or by ensuring a vacuum is present indicating that the device is sealed to the injection site. Auto-injectors may be single use or multi use, and fixed dose or variable dose. Preferred auto-injectors prefilled, compact, portable, fixed dose, single use disposable needle free injectors. Other preferred embodiments include multiuse actuators with multi-dose drug reservoirs, or more preferably, with removable, single dose disposable drug reservoirs. Preferred energy sources include pressurized gas or combustible materials, but may also include mechanical springs or chemical or electro-chemical sources such as batteries or pyrotechnic charges.

[093] Bayonet Fitting: a mechanism for removably attaching two components in a way similar to how a bayonet is attached to a rifle. In general, one of the components has a pin, and the other has a mating slot or groove which has a right angle bend. To separate the components, both are gripped, rotated relative to each other, and then pulled apart.

[094] Bolus Injector: a drug delivery device that delivers an infusion of a drug over a longer period than would be comfortable using a needle and syringe. Bolus injectors are similar to pumps, but in general require shorter delivery times than pumps. Bolus injectors generally have a needle or catheter, but may be needle free or transdermal. Bolus injectors can deliver through a tube such as an infusion set, or may attach directly to the skin. Preferably bolus injectors deliver over a time greater than 1 minute, greater than 5 minutes, greater than 10 minutes, or greater than 30 minutes. Preferably bolus injector deliver over a time less than 5 hours, preferably less than 3 hours, more preferably less than 1 hour.

[095] Cap: a component that covers a component of a drug delivery system.

Preferably the covered component contains the route through which the API is delivered to the target organ. For example, the cap may cover the needle of a needled injector, a catheter, the skin contact surface of a transdermal, the microneedles of a microneedle array, or preferably one or more orifices of a needle free injector. Caps preferably maintain sterility and stability of prefilled formulations, and minimize water vapor transmission rate. Caps minimize needle stick injury when used with needled injectors, and keep the orifices of needle free injectors free of dust and other contaminants that can impact jet formation.

Preferably the injector is an auto-injector with a trigger, and the trigger is interlocked to the cap to ensure that the cap is removed before delivery can be initiated. Preferably the device has features that ensure that the removal of the cap cannot cause the device to trigger. This is especially important for needle free injectors that are triggered by pressing the orifice against the desired injection site. Preferably, the cap also comprises a container closure system and/or applicator for a second, non injected, topically applied formulation (see "Topical Applicator"). Preferably the second formulation is indicated to reduce local effects, including but not limited to bleeding, erythema, infection, bruising, pain, and/or swelling. The second formulation contains APIs including but not limited to vaso-constricting agents, absorption enhancing agents, one or more local anesthetic agents, and mixtures thereof. In a preferred embodiment, the cap also functions as an applicator for the second formulation, whereby the second formulation is applied to a desired injection site by rubbing the cap on the desired injection site, optionally while extruding the second formulation by squeezing the cap, manipulating an actuator such as a plunger or lever, etc. The cap may also contain other, preferably liquid, compounds, including but not limited to adhesives and/or vacuum sealing media.

[096] Catheter: a tube that can be inserted into a body to perform a medical

procedure, such as administration of medications or other fluids, drainage, angioplasty, angiography, ablation, measurement of pressure, in vitro fertilization, hemodialysis, etc.

[097] Cluster headache: Cluster headaches are extremely painful, piercing,

unilateral headaches with a duration of 15 minutes to three hours. The unilateral property may shift from one side of the head to the other between events, or rarely may shift during a cluster headache event. Other symptoms may include ptosis (drooping eyelid), conjunctival injection (red-eye), lacrimation (tearing), rhinorrhea (runny nose), restlessness and pacing, and, less commonly, facial blushing, swelling, sweating, and/or aversion to bright lights and loud noise. Cluster headaches often recur regularly, at the same time of day each day, or a week later. [098] Compliance: Adherence to a prescribed therapy, including performing an injection according to instructions. Compliance is improved by limiting local effects, and by supplying a injector that is easy to use and doesn't cause fear and anxiety, such as due to needle phobia. Compliance is improved through the use of an injector, preferably an auto-injector, more preferably a needle free injector, which has properties selected from being prefilled, self contained, prefilled, portable, single use, and disposable.

[099] Container Closure, Container Closure System, and the like: A drug

container that is designed to maintain sterility, stability, 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. Preferably container closure systems include at least one substantially transparent material to allow for inspection of the formulation. Preferred materials for container closures include glass, more preferably borosilicate glass, substantially clear polymers with low water vapor transmission rates including but not limited to cyclo-olefin polymer and copolymers, or fluorinated materials such as polytetrafluoroethylene (PTFE).

[0100] 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.

[0101] Delivery Phase: A constant or slowly varying formulation pressure during which the bulk of a formulation dose is delivered from a needle-free injector. 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.

[0102] Depot Injection, Depot, and like terms: An injection, usually subcutaneous, intravenous, intradermal, 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.

[0103] Energy source: a component of a drug delivery system, preferably of an

actuator of an auto-injector, that supplies the energy required for the delivery.

Preferred energy sources include mechanical springs, compressed gas, electrical storage such as batteries, and chemically based energy sources including but not limited to pyrotechnic compounds and combustible compounds including but not limited to Butane and Propane. Particularly preferred energy sources are

compressed nitrogen, compressed air, butane, and propane.

[0104] Formulation, Injectate, and the like: Any liquid, solid, or other state of

matter that can be injected and contains one or more APIs. Preferred formulations are liquid formulations, including but not limited 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. See also "Topical Formulation".

[0105] Injection: Delivery of a liquid formulation to a target tissue under pressure

by way of a needle or high velocity liquid jet. While injections can be used to deliver formulations to any tissue, preferred injections go through the skin

(including but not limited to sub-cutaneous, intra- venous, or intra-muscular

injections) or into the skin (intra-dermal injections).

[0106] Injector: A device for implementing an injection.

[0107] Local effect: an unintended effect of an injection. Local effects include but are not limited to pain, swelling, erythema, bruising, and distortion of the injection pathway.

[0108] Migraine: A neurological disease with many symptoms, the most predominant of which is headache. The headache is often one-sided and pulsating lasts from hours to days, and is often accompanied by nausea and vomiting, a heightened sensitivity to bright lights and noise, and other symptoms. Approximately one third of people who experience migraine get a preceding aura. Migraine may be distinguished from other headache conditions by: 5 or more attacks without aura, or two or more attacks with aura, 4 hours to 3 days in duration, 2 or more of - unilateral location, pulsating quality, moderate to severe pain, aggravation by or avoidance of routine physical activity, and 1 or more accompanying symptoms - nausea and/or vomiting, photophobia, photophobia. Although many examples are given in terms of migraine, it will be understood that the present invention may be applied to other conditions, for example cluster headache, pain, epilepsy, psychosis, hypoglycemia, panic, vaccination, diabetes, counter terrorism, autoimmune disorders, rheumatoid arthritis, lupus, schleradoma, chrones disease, neurological disorders, Alzheimers, multiple sclerosis, psoriasis, growth retardation in children, hepatitis, AIDS, infertility, ulcer, obesity, athsma, COPD, pulmonary fibrosis, osteoporosis, and allergic reactions. A number of biologic ally- active agents would benefit from being delivered using the current invention. 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, bronchodilators, vasodilators, birth control agents and fertility enhancing agents, interferon alpha, growth hormone, and PTH and PTH analogs and fragments

[0109] Multidose, reusable, and the like: Containing enough formulation for and capable of delivering more than one dose, or capable of being refilled. Multidose injectors may deliver a single, pre-determined dose, or may allow for the selection of a dose.

[0110] Needle-Free Injector, Needle-Less Injector, Jet Injector, and the like: an

injector that does not use a needle, pilot projectile, or other mechanical device to puncture the skin and deliver the formulation, but instead creates a high velocity liquid jet of formulation that is capable of puncturing the target tissue, usually the skin. Needle free injectors generally utilize a power source to pressurize a liquid formulation, forcing it out of one or more orifices to create a high velocity jet.

Preferably the pressurization comprises a low pressure precompression to compress any contained gas in the formulation, a high pressure spike (the "puncture phase") that creates a hole in the target tissue, and a lower pressure "delivery phase" during which the majority of the formulation is delivered. Preferred needle free injectors are prefilled, self contained, single use, and portable.

[0111] Piston: a moveable component that seals one end of a preferably cylindrical container. Pistons are generally used to pressurize material in a container and/or move material in or out of a container. An example of a piston is the drug delivery piston of an injector, for example a needle-free injector that under force from an energy source drives liquid formulation out of an orifice to achieve injection. In a preferred embodiment, the injector is a needle free injector which 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. Another example of a piston is a retractable element that can be used to create a partial vacuum, preferably in order to hold a drug delivery device in place on the surface of a target organ, pull the surface of the target organ into contact with or proximity to an injection orifice, needle or other delivery

component, and/or trigger a drug delivery device.

[0112] Portable: capable of being easily transported, for example, in a pocket, purse, or glove compartment. Portable injectors preferably have no linear dimension (length, width, or height) greater than 25 cm, preferably no linear dimension greater than 20 cm, more preferably no linear dimension greater than 15 cm. Portable injectors preferably weigh less than 1 kg, preferably less than 0.5 kg, more preferably less than 0.25 kg, most preferably less than 0.1 kg. Preferred portable injectors are self contained, prefilled, and single use.

[0113] Prefilled: Prefilled injectors are injectors wherein the formulation is filled into the injector before delivery to an end user, for example by a manufacturer, pharmacy, physician, or the like. Similarly, prefilled drug capsules are filled prior to delivery to an end user, and may be installed on a multi-dose injector by the end user. Pre-filled injectors or capsules specifically do not require filling at the point of use by the patient or a care giver. Preferred pre-filled injectors are self contained, single use, and portable.

[0114] Pressure, gas pressure, air pressure, atmospheric pressure, and the like: The

force per unit area exerted by a gas on a surface. Pressure can be measured in units of Pascal (Pa), which is a Newton per square meter. Standard atmospheric

pressure at sea level is 1.01325 xlO⁵ Pa, or one atmosphere (atm).

[0115] 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 an organ such as 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 (see "delivery phase"), in order that the formation of the hole is stopped prior to the injection becoming a painful intra-muscular injection.

[0116] Pump: a drug delivery device that deliver a formulation at a controlled rate.

Pumps usually deliver through a needle or catheter, but may be needle free or transdermal. The formulation may be delivered through a tubing set, or may attach directly to the skin, sometimes referred to as a "patch pump". Pumps may be somewhat large hospital devices mounted for example on a pole. Preferred pumps are small, discrete and portable. One preferred type of pump is an insulin pump for treatment of diabetes. Pumps may deliver at a preset constant average rate, and/or may have a bolussing feature that allows a single relatively large dose to be

delivered, for example by a diabetic before meal time.

[0117] Release liner: a cover for an adhesive surface that will adhere to the

adhesive, maintaining its adhesive properties and keeping it clean during storage.

A release liner has a contact surface coated with a release agent with low surface energy that allows it to release from the adhesive, leaving the adhesive intact.

Preferred materials include Kraft paper such as super calendared, clay coated, or machine glazed or machine finished Kraft paper, or polymer films, and may

comprise polyvinyl alcohol, polyester, polypropylene, cyclic olefin copolymer, and/or polychlorotrifluoroethylene, and may comprise one or metals including aluminum.

[0118] Self-Contained: containing some or all of the components, materials, energy sources, vacuum sources, etc. that are required for injection. Self contained injectors specifically do not require an external source of energy, such as mains power, or an external source of vacuum. While a self contained injector may require filling with drug formulation prior to delivery, preferred self contained injectors are pre-filled or allow installation of a pre-filled drug capsule. Preferred self-contained injectors are portable. Self contained injectors may be single dose or multi-dose. Preferred multi-dose injectors contain enough energy that the energy source does not have to be re-filled or recharged for the useful lifetime of the device.

[0119] Single dose, single dose disposable, single use, and the like: only capable of being used for the delivery of 1 dose. Preferred single dose injectors are prefilled, self contained, and portable. [0120] Spool Valve: a valve with a channel and an object movably disposed in the channel (a "spool"), wherein the spool in one position allows a flow, and in another position blocks a flow. Spool valves differ from other valves such as needle or gate valves in that the seal is created by the body of the spool, not around the end of a needle or gate. Spool valves differ from rotary valves such as ball valves in that the when the seal is released the flow occurs around the outside and not through the spool. Spool valves preferably comprise a seal, more preferably, two, three, or more seals. The spool can be any shape, but is preferably substantially a right circular cylinder, with features on the circumference, for example to seat seals or features that allow airflow. Preferably the shape of the spool is sufficiently close to shape of the channel that the seals are maintained in sealing contact with the inside walls of the channel. Preferably the spool valve of the current invention is configured such that prior to triggering, both ends of the spool communicate with air spaces that are substantially at ambient pressure, and portion of the circumference displaced from both ends is in communication with an air space at a pressure significantly elevated above ambient pressure. The airspaces at ambient pressure may communicate with the outside environment in order to maintain the pressure substantially at ambient pressure, and said communication may be a lead designed to be large relative to any leak from the high pressure source through the spool valve seals, and large enough to substantially maintain the pressure at ambient during any changes in ambient pressure due to weather, temperature change, or altitude change, but small enough to maintain the pressure when the spool valve is actuated and the high pressure material is released.

[0121] 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 mechanism obeys Hooke's law, i.e. 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.

[0122] Alignment Ring: A component of a drug delivery system or kit which has a

central bore into which a delivery portion of a drug delivery system is inserted or attached, and a radial flange with a face that contacts an organ, preferably skin, around a desired drug delivery site. The bore of the alignment ring and/or the direction in which the drug is delivered is at a fixed angle to the face, preferably substantially perpendicular to the face, to ensure that the delivery happens at a pre-specified angle. In one embodiment, the face is adhered to the target organ for example prior to the insertion of the delivery portion of the drug delivery system by the use of an adhesive, or by the use of a partial vacuum. In another embodiment, the alignment ring is movable or deformable, and the motion grips the surface of the target organ, holding the drug delivery device in place, and/or pulling the surface of the target organ toward the drug delivery device, for example onto a needle or in contact with or at a predetermined distance from an orifice, microneedle array or other transdermal source. Although the Alignment Ring is called a ring, and preferably the shape of the contact area on the target organ is round, it should be noted that any shape of the bore is acceptable, including but not limited to squares, triangles, pentagons, hexagons, or more complex shapes including extensions or legs, preferably three, four or more, as long as it engages an outside surface or feature on the drug delivery system and controls the angle of the drug delivery system relative to the target organ and/or keeps the drug delivery system fixed relative to the target organ during delivery. The Alignment Ring will surround enough of the drug delivery device to maintain the fixed angle and/or position relative to the target organ, and preferably encircles the drug delivery device. Preferably the alignment ring encircles the device and injection site in such a way that the patient cannot see the injection site, needle, catheter, needle free injection orifice, etc, and cannot see the act of inerting a needle, catheter, and the like, in order to reduce patient fear and anxiety, and improve patient comfort and compliance. Preferably the alignment ring engages a portion of the outside surface of the drug delivery device, but other embodiments are possible, such as ribs that engage the surface along lines, or ribs that engage slots in the surface of the drug delivery device, or similarly ribs on the drug delivery device that engage an inside surface or slots in the alignment ring. The alignment ring may have additional features that interact with the triggering mechanism of the drug delivery device, for example causing the device to trigger only when the alignment ring is in contact, including sealing contact, with the surface of the target organ, a predetermined contact force with the surface of the target organ is achieved, and/or a predetermined distance of the drug delivery device from the target organ, including zero distance, is achieved.

Topical Application: delivery of a formulation, usually liquid, to the surface of an organ, preferably the skin, usually for local effect. Topical formulation: a formulation for topical application. Topical formulations are preferably liquid, and preferably have elevated viscosity, such as 5 or more, 10 or more, 50 or more, 100 or more, 500 or more, 1000 or more, 5000 or more, or 10,000 or more cP or cS. Topical formulations may contain one or more active ingredients such as vasodilators, local anesthetics, and/or anti-microbials, and/or may contain other topical surface preparation agents, such as absorption enhancers, adhesives, vacuum sealing agents, depilatory agents, cleaning agents, and the like. Topical Formulations may comprise one or more local anesthetics, including but not limited to Benzocaine, Chloroprocaine, Cocaine,

Cyclomethycaine, Dimethocaine, Larocaine, Piperocaine, Propoxycaine, Procaine, Novocaine, Proparacaine, Tetracaine, Amethocaine, Lidocaine, Articaine,

Bupivacaine, Cinchocaine, Dibucaine, Etidocaine, Levobupivacaine, Lidocaine, Lignocaine, Mepivacaine, Prilocaine, Ropivacaine, Trimecaine, and/or

combinations, conjugates, prodrugs, or fragments thereof. Topical formulations may comprise one or more vasoconstricting agents, including by not limited to Epinephrine, 251-NBOMe, Amphetamine, AMT, Antihistamine, Caffeine, Cocaine, DOM, LSA, Methylphenidate, Mephedrone, Oxymetazoline, Phenylephrine, Propylhexedrine, Pseudoephedrine, Tetrahydrozoline hydrochloride, and/or combinations, conjugates, prodrugs, or fragments thereof. Topical formulations may comprise one or more absorption and/or dispersion enhancing agents, including but not limited to Hyaluronic Acid, Chitosan, an Alkylsaccharide, A Surfactant, Laureth Benzote, Laureth acetate, and/or combinations, conjugates, prodrugs, or fragments thereof. Topical formulations may comprise one or more anti-microbials, including but not limited to an anti-bacterial such as a penicillin, a cephalosporin, a polymyxin, a rifamycin, a lipiarmycin, a quinolone, a sulfonamide, a macrolide, a lincosamide, a tetracycline, an aminoglycoside, a cyclic lipopeptide, a glycylcycline, a oxazolidinone, and/or a lipiarmycin; Anti-fungals including an Imidazole, a triazole, a thiazole, an allylamine, an echinocandin, benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, polygodial, tolnaftate, undecylenic acid and/or crystal violet; an anti-viral; and/or an anti-parasitic.

Preferred active pharmaceutical agents in Topical Formulations include but are not limited to Benzocaine, Lidocaine, Tetracaine, Hyaluronic Acid, Epinephrine, and/or combinations, conjugates, prodrugs, or fragments thereof. [0125] Transdermal: Delivery of a formulation or API by absorption or diffusion through the skin, or a drug delivery system for achieving delivery by absorption or diffusion through the skin. The absorption of the drug may be passive, or may be enhanced by the use of electric current, micro-needle arrays, sound, radio frequency and other electromagnetic power, lasers, permeation enhancers, heat, etc. Injection, and specifically needle free injection, although often used to deliver formulation through the skin, is specifically not considered to be transdermal delivery.

[0126] Triptan: Tryptamine based drugs used for the treatment of migraine and cluster headaches. They are 5-HT1 (serotonin) receptor agonists. They bind to 5- HT1B and 5-HT1D receptors in blood vessels, causing constriction and subsequent inhibition of pro-inflammatory neuropeptide release. Additionally they act on serotonin receptors in nerve endings, decreasing the release of several peptides, including CGRP and Substance P. Triptans include but are not limited to sumatriptan (Imitrex, Imigran), rizatriptan (Maxalt), naratriptan (Amerge,

Naramig), zolmitriptan (Zomig), eletriptan (Relpax), almotriptan (Axert,

Almogran), and frovatriptan (Frova, Migard). The term triptan is also meant to include other forms such as salts, esters, active fragments, analogues and other forms of these drugs, as well as Tryptamine based drugs that may be developed in the future

[0127] Vacuum, Partial Vacuum, and the like: a reduction in gas pressure relative to the surrounding ambient air.

[0128] Vacuum cup: a device or type of alignment ring attached to an injector that uses a supplied vacuum to seal a drug delivery device to the skin, and thereby ensure that the injector does not move and is held at a predetermined angle, preferably perpendicularly, to the target organ or skin. Preferably, the vacuum cup pulls the skin into the cup, holding it against or at a fixed distance to one or more orifices, microneedle arrays, transdermal sources, or pulls the skin onto a needle or catheter, and stretches and tensions the skin to prepare it for, for example, needle free injection. Preferred vacuum pressures are less than 100 kPa, preferably less than 75 kPa, more preferably less than 50 kPa. Preferably the injector comprises an actuator with a trigger, and the trigger is interlocked to the vacuum in the vacuum cup, ensuring that the device cannot trigger unless the vacuum cup is sealed to the target organ or skin and a pre-determined vacuum is applied. Still more preferably, the vacuum directly actuates the trigger. The applied vacuum is less than ambient pressure, preferably less than 90% of ambient pressure, more preferably less than 75% of ambient pressure, more preferably less than 50% of ambient pressure.

[0129] 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.

INVENTION IN GENERAL

[0130] Figure 1 shows one embodiment of the current invention which is a needle free, self contained, portable, prefilled, single use, and disposable auto-injector. Although the example given is of a needle free injector, the invention can be applied to any medical device that requires a cap, and requires the topical application of a substance to prepare a treatment site on skin or another organ. Preferably, the medical device is a drug delivery system, and the treatment site is a delivery site. These drug delivery systems include but are not limited to needles, catheters, pumps, infusion system, bolus injectors, passive transdermals such as patches, and active transdermals including but not limited to transdermals enhanced by radio frequency, lasers and other light sources, heat, sound, electrical current, etc. Other devices that do not deliver drugs may include sensors, stimulators, surgical tools and the like.

[0131] In the embodiment of Figure 1, needle free injector 1 is equipped with actuator

11, first formulation reservoir 10 which contains a first formulation and is sealed by a piston, injection orifice or orifices 8, and cap/applicator 6. Actuator 11 includes a source of power for supplying the energy needed to the injection. The source of power can be any compact portable power source including but not limited to batteries, a mechanical spring, or a pyrotechnic or combustion source. Preferably, the source of power is a gas container which holds a pressurized gas. Actuator 11 also includes a trigger to release the power from the power source, a safety mechanism to ensure the injector is not triggered prematurely, and a transmission mechanism that creates the desired pressure profile as a function of time in the first formulation reservoir. Preferably the transmission mechanism includes a ram which is initially separated from the piston by an air gap. The pressurized gas acts directly on the ram, and the piston acts directly on the first formulation. [0132] Actuator 11, first formulation reservoir 10, and cap/applicator 6 may be filled, charged, and assembled in a factor setting and delivered to a customer substantially as shown as a single use disposable unit. Alternatively, actuator 11 maybe a muli-use component. In this embodiment, first formulation reservoir 10 and cap/applicator 6 are factory filled and assembled as a single unit to be attached to actuator 11 prior to use.

[0133] To ready needle free injector 1 for delivery, cap/applicator 6 is removed.

Cap/applicator 6 can be removably attached to injector 1 in many ways, including but not limited to screw off, a bayonet fitting, snap off, twist off, or pull off.

[0134] Needle free injector 1 can be triggered by many means, including but not limited to pushing a button or actuating a lever or a slide. Preferably needle free injector 1 is triggered by pushing nozzle 8 against the desired injection site, i.e. a target organ or the skin. To prevent the injector from triggering during manufacturing, transport, storage, and while removing cap/applicator 6, injector 1 is supplied with a safety mechanism. In the embodiment of figure 1 , the safety mechanism is put in the ready to fire state by rotating lever 3 around axis 2. Lever 3 comprises tip 4 which is captured under a lip of cap/applicator 6, ensuring that the injector cannot be placed in the ready to fire state until after cap/applicator 6 is removed.

[0135] In another preferred embodiment, injector 1 is triggered by pressing injection orifice 8 against the desired injection site, and does not include lever 3. In this embodiment, cap/applicator 6 is attached to drug reservoir 10 via a first set of threads. Injector 1 including reservoir 8 is at least partially surrounded by a housing, which the user grips during delivery. Cap/applicator 6 is also attached to a housing (not shown) via a second set of threads. The first set of threads and the second set of threads are configured such that the act of removing cap/applicator 6 by unscrewing it biases drug reservoir relative to the casing in a direction opposite that required to trigger the device, i.e. downward when in the orientation shown in Fig. 1. This prevents the possibility of the act of removing cap/applicator 6 causing injector 1 to trigger.

[0136] In order to keep the first formulation in the first formulation reservoir 10 sterile, stable, and to prevent water vapor transmission, nozzle 8 is covered by cap/applicator 6. Orifice seal 23 as shown in Figure 2b comprises a suitable sealing material, which is preferably a compliant material. Additional preferred properties for orifice seal 23 are low WVTR, low leachables, high dimensional stability (low creep), and compatibility with drug formulations including small molecule and large molecule (peptide and protein) formulations. Preferably, cap/applicator 6 is removed by unscrewing, and orifice seal 23 may be supplied with an optional rotating mechanism to avoid stress and concomitant loss of seal when cap/applicator 6 is installed.

[0137] Cap/applicator 6 includes second formulation 22 in reservoir 5. Second

formulation 22 preferably has one or more APIs which are indicated for avoiding local effects including but not limited to pain, bleeding, swelling, erythema, infection, and bruising, and is formulated for topical application. Alternatively or in addition, second formulation reservoir 5 may contain non-active ingredients, including but not limited to adhesives, vacuum sealing agents, cleaning agents, and/or depilatory agents.

[0138] Second formulation 22 may comprise a local anesthetic, including but not limited to Benzocaine, Chloroprocaine, Cocaine, Cyclomethycaine, Dimethocaine, Larocaine, Piperocaine, Propoxycaine, Procaine, Novocaine, Proparacaine,

Tetracaine, Amethocaine, Lidocaine, Articaine, Bupivacaine, Cinchocaine,

Dibucaine, Etidocaine, Levobupivacaine, Lidocaine, Lignocaine, Mepivacaine, Prilocaine, Ropivacaine, Trimecaine, and/or combinations, conjugates, prodrugs, or fragments thereof.

[0139] Second formulation 22 may comprise a vasoconstricting agent, including by not limited to Epinephrine, 251-NBOMe, Amphetamine, AMT, Antihistamine, Caffeine, Cocaine, DOM, LSA, Methylphenidate, Mephedrone, Oxymetazoline, Phenylephrine, Propylhexedrine, Pseudoephedrine, Tetrahydrozoline

hydrochloride, and/or combinations, conjugates, prodrugs, or fragments thereof.

[0140] Second formulation 22 may comprise an absorption and/or dispersion

enhancing agent, including but not limited to Hyaluronic Acid, Chitosan, an

Alkylsaccharide, A Surfactant, Laureth Benzote, Laureth acetate, and/or

combinations, conjugates, prodrugs, or fragments thereof.

[0141] Second formulation 22 may contain an anti-microbial, including but not

limited to an anti -bacterial such as a penicillin, a cephalosporin, a polymyxin, a rifamycin, a lipiarmycin, a quinolone, a sulfonamide, a macrolide, a lincosamide, a tetracycline, an aminoglycoside, a cyclic lipopeptide, a glycylcycline, a

oxazolidinone, and/or a lipiarmycin; Anti-fungals including an Imidazole, a triazole, a thiazole, an allylamine, an echinocandin, benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, polygodial, tolnaftate, undecylenic acid and/or crystal violet; an anti- viral; and/or an anti-parasitic.

[0142] Preferred active pharmaceutical agents in second formulation 22 include but are not limited to Benzocaine, Lidocaine, Tetracaine, Hyaluronic Acid,

Epinephrine, and/or combinations, conjugates, prodrugs, or fragments thereof.

[0143] Although as shown in figures 1 and 2 cap/applicator 6 has a single second formulation reservoir 5, the cap may contain multiple reservoirs 5 containing multiple formulations 22 and/or surface preparation compounds. In this way non- compatible compounds can be stored in a stable manner.

[0144] Cap/applicator 6 may include one or more nozzles 7 for the delivery of second formulation 22 in second formulation reservoir 5. In order to keep second formulation 22 contained within second formulation reservoir 5 after removal of cap/applicator 6 from injector 1 but before the topical application of second formulation 22, and to avoid leaking or dripping, second formulation 22 preferably has elevated viscosity of greater than 10 cP, preferably greater than 100 cP, more preferably greater than 1000 cP. Alternatively or in addition, nozzle 7 comprises a material or coating which is hydrophobic, lipophobic, or has similar properties to avoid wicking of the second formulation. A coating may be applied by many methods, including but not limited to plasma coating. Alternatively nozzle 7 may be fabricated such that the exit is normally closed, and second formulation 22 must be pressurized to open the end of nozzle 7 and extrude second formulation 22. In a preferred embodiment, second formulation 22 and nozzle 7 have 2 or more of the above properties to avoid leaking and dripping.

[0145] Nozzle 7 may have a cover (not shown) that is used to maintain container closure integrity, which cover is removed by the user immediately prior to the topical application of second formulation 22. For example the cover may be a release liner that is adhered to the exterior of cap/applicator 6 and covers nozzle 7. Preferred release liners may include multiple layers, including but not limited to a polymer layer and a metallic layer. Preferred polymers include polyethylene, polyester, nylon, cyclic olefin copolymer, and polychlorotrifluoroethylene, and metals include aluminum. In a preferred embodiment, nozzle 7 does not have a separate cover, but is sealed to the outside of drug reservoir 10 as shown in figure 1 to maintain container closure integrity of second formulation reservoir 5 during storage.

[0146] Nozzle or Nozzles 7 and injection orifice 8 can in general be in any location, although in general they cannot be aligned, in order to avoid mixing of the first and second formulations. In a preferred embodiment, orifice 8 is on the central axis of injector 1, and nozzle 7 is displaced from the central axis of injector 1. In a preferred embodiment, there are multiple nozzles 7, including 2, 3, 4, 5, 6, or more, arrayed in a circle or circles centered on the central axis of injector 1 and on injection orifice 8.

[0147] Cap/applicator 6 may optionally comprise a mechanism (not shown) to

enhance the local absorption of APIs in second formulation 22, including but not limited to mechanical enhancement using a needles or needles, micro-needle arrays, brushes including wire brushes, or abrasives.

[0148] Cap/applicator 6 may optionally comprise a mechanism (not shown) to

enhance the local absorption of APIs in second formulation 22 by directing energy toward the desired delivery site. Preferred forms of energy include but are not limited to heat, vibration including sound, subsonic sound, and ultrasound, pressure, stretching, electric voltage and/or current, and/or electromagnetic radiation including radio waves, millimeter waves, infra-red, visible, ultra-violet, x-rays, or gamma rays. In this embodiment, cap/applicator 6 preferably comprises a self contained power source and a mechanism for releasing the energy.

[0149] Figure 2 shows the operation of the embodiment of cap/applicator 6 of

Figure 1. Figure 2a shows cap/applicator 6 after removal from injector 1. Figure 2b shows a cross section of cap/applicator 6, including second formulation 22 contained within second formulation reservoir 5, and side walls 21. Figure 2c shows the topical application of second formulation 22 using cap/applicator 6 of the current invention.

[0150] The usage of injector 1 and cap/applicator 6 of this embodiment of the

current invention is as follows. Cap/applicator 6 is removed from injector 1 by an action chosen from a list including but not limited to snapping it off, pulling it off, twisting it off, twisting followed by pulling, or preferably by unscrewing. An optional cover (not shown) is removed and discarded. This exposes orifice 8 and nozzle or nozzles 7. The user selects a site, preferably an injection site, on organ 29, which is preferably skin. Holding cap/applicator 6 by walls 21 using thumb 27 and finger 28, the open end of cap/applicator 6 is applied to the selected site on organ 29, and walls 21 are pressed inwardly. This creates an elevated pressure in second formulation 22, forcing it out of nozzle 7. Cap/applicator 6 is optionally moved laterally across the surface of organ 29, spreading second formulation 22 over a desired area. After second formulation 22 is applied, cap applicator 6 is discarded. Other means of delivering second formulation 22 may be used, including but not limited to pressing an actuator such as a plunger, pushrod, lever, or the like.

[0151] The user then waits a prescribed amount of time, for example to allow one or more APIs in second formulation 22 to take effect, to allow an adhesive to cure, etc. The prescribed wait time may be 0 seconds (i.e. no wait time) but is preferably 30 seconds or more, more preferably 1 minute or more, 5 minutes or more, or about 10 minutes.

[0152] After the prescribed wait time, optional lever 3 is rotated to put injector 1 in the ready state.

[0153] Injection orifice 8 is then pressed against the desired injection site until injector 1 triggers.

[0154] Injector 1 (or in the embodiment where actuator 11 is a multi-use

component, first formulation reservoir 10, which is detached by the user) is then discarded, and the injection site is cleaned, treated, bandaged, and/or pressure is applied as required.

[0155] Figure 3 shows an additional embodiment that may be combined with the embodiment shown in Figures 1 and 2. In this embodiment, injector 1 is supplied as part of a kit that also includes alignment component or "alignment ring" 31. Alignment ring 31 can be of any shape, but is preferably round in cross section. Some or all of the shape of interior region 35 of alignment ring 31 preferably matches some or all of the exterior shape of injector 1. Alignment ring 31 is placed in contact with organ 28, preferably skin, at a desired delivery site, and optionally held in place using adhesive 32. Alignment ring 31 comprises radial extension 33. Radial extension 33 supplies a surface or face with which to adhere alignment ring 31 to target organ 28. In addition, radial extension 33 serves to ensure that wall 34 of alignment ring 31 holds the central axis of injector 1 and/or orifice 8 at a fixed angle to the surface of organ 28, preferably perpendicular to organ 28 as shown in figure 3. In this way alignment ring 31 ensures that injector 1 is held at the correct orientation to organ 28 and does not move relative to organ 28, eliminating the possibility of distortion of the injection path into or through organ 28 and ensuring that the injection is to the desired depth in or through organ 28. Preferably alignment ring 31 is configured in such a way that it substantially encircles the delivery site and/or component of the injector, for example a needle, catheter, injection orifice, and the like, such that the patient cannot see it during the delivery process, thereby reducing patient anxiety and fear, and improving patient comfort and compliance. In a particularly preferred embodiment, the injector is a needled injector, and the patient cannot see the needle or the act of insertion of the needle into the target organ.

Adhesive 32 may be supplied separately from alignment ring 31, for example as a liquid with an applicator, or as an adhesive tape. In one preferred embodiment, the adhesive is contained in and applied using the cap/applicator described above and shown in figures 1 and 2. More preferably, the adhesive is a double sided adhesive tape which is fabricated, for example die cut, to cover some or all of the front face of radial extension 33 of alignment ring 31, is factory adhered to the front face, and is supplied with a release liner that is removed prior to applying alignment ring 31 to organ 28. The release liner may cover front opening 36, and is preferably the same shape as adhesive 32 to facilitate fabrication, possibly with the addition of a tab or other feature that extends beyond adhesive 32 to facilitate removal. Alternatively, the release liner may be attached to or comprise packaging, and removal of alignment ring 31 from the packaging removes the release liner. Adhesive 32 may also contain one or more APIs for the reduction of local effects, including but not limited to pain, bleeding, swelling, infection, bruising, and/or erythema. In one embodiment, the adhesive is only applied to the front face of radial extension 33, and not in front opening 36 of central bore 35 of alignment ring 32, leaving opening 36, through which the injection occurs, clear of adhesive. In an alternative embodiment, adhesive 32 covers front opening 36, and the injection occurs through adhesive 32. This embodiment is preferred in those embodiments that include an API in the adhesive that is preferably applied directly to the injection site. In an alternative embodiment, adhesive 32 does not cover front opening 36, but front opening 36 is filled with a second formulation in a form including but not limited to a liquid, gel, powder, solid, or gas.

[0157] Alignment ring 31 and injector 1 may be supplied together as part of a kit, with optional components selected from labels, cleaning swabs or cloths, instructions including written instructions, audio instructions, and/or video instructions, dosing logs, dosing reminders, timers, razors, adhesives, second drug formulation containers and applicators, bandages, etc, and the kit and or components may be packaged in one or more boxes, overwraps, secondary packages, or tertiary packages. Alternatively or in addition, instructions may be supplied by an external electronic device, including but not limited to a smart phone, tablet, computer, wrist watch, or eye glasses. The packaging may also be used to hold the injector, alignment ring, and/or other components after use until they can be safely disposed of, for example in a sharps container when the injector comprises a needle. In the embodiment where adhesive 32 or other components such as a topical formulation applicator have a release liner, the release liner may be attached to the packaging, and the act of removing them from the packaging also removes the release liner, for example exposing adhesive 32.

[0158] By way of an example, alignment ring 31 and injector 1 may be used as follows. Alignment ring 31 is removed from its packaging, and a release liner is removed, exposing adhesive 32. Adhesive 32 is pressed onto target organ 28, preferably the skin of a human or animal patient, with opening 36 surrounding the target injection site. If required, the user waits for a specified wait time, for example for adhesive 32 to cure or for an API in adhesive 32 to take effect. A cap is removed from injector 1, and injector 1 is optionally placed in a ready to inject state, for example by rotating optional lever 3. Injector 1 is then placed in central bore 35 of alignment ring 31 and injection orifice 8 is pressed against organ 28, triggering injector 1. Injector 1 is then disposed of, and alignment ring 31 is removed from organ 28 and disposed of.

[0159] Many alternative embodiments are possible. Alignment ring 31 may be supplied attached to injector 1, and function as the cap for orifice 8. Alignment ring 31 may comprise features that interface and actuate mating features on injector 1. These mating features may be a safety mechanism that only allows injector 1 to be triggered if inserted in alignment ring 31. Similarly, the mating features may directly actuate the trigger of injector 1, for example when orifice 8 is at a

predetermined distance, preferably in contact with, organ 28 or when injector 1 is pressed into alignment ring 31 or against target organ 28 with a predetermined force. The kit may contain multiple injectors 1, which may contain the same or different formulations. While alignment ring 31 is preferably single use and

disposable, it can also be multi-use.

[0160] Alignment ring 31 may be fabricated by many methods, including but not limited to injected molding, machining, lithography, or 3D printing. Alignment ring 31 can be fabricated using many materials, including but not limited to polymers, metals or glasses. Preferably alignment ring 31 is an injected molded polymer part. Preferred polymers include but are not limited to polycarbonates, nylons, poly ethylenes, polypropolenes, polyolefins, polyvinylchlorides, and ethylene vinyl acetates.

[0161] Figure 4 shows another embodiment of the invention. In this embodiment, drug delivery device 1 is a needle free injector that is powered by compressed gas source 109. Compressed gas source 109 is sealed by, and when the injector 1 is triggered, gas in compressed gas source 109 is released by a spool valve comprising spool 105. Injector 1 comprises vacuum source 104.

[0162] In the embodiment of Figure 4, injector 1 comprises vacuum cup 108. Vacuum cup 108 extends radially from injector 1, and when pressed against an organ of a user, preferably skin, vacuum cup 108 acts as an alignment ring, ensuring that injector 1 is held at a preferred angle relative to the organ. As shown in Figure 4, vacuum cup 108 ensures that injector 1 is held perpendicular to the surface of the target organ, but may be modified to ensure that injector 1 is at any angle relative to the target organ appropriate to the type of injector, desired depth of injection, active pharmaceutical ingredients, and/or target organ.

[0163] To create a partial vacuum, the user actuates lever 101, which compresses spring 102 and moves piston 103 which is sealed by seal 114. Seal 114 can be any type of seal but is preferably selected from an o-ring seal, an overmolded polymer seal, and a grease seal, or combinations thereof. Vacuum source 104 communicates with spool 105 and vacuum cup 108 via vacuum plenum 106. Spool 105 is optionally held in place by safety 107, which is connected to piston 103 or lever 101, and moves upward when lever 101 is actuated, presenting a path for spool 105 to move toward or into vacuum plenum 106. [0164] When vacuum is applied to vacuum cup 108 when it is pressed against the target organ, the applied vacuum pulls the surface of the target organ, preferably skin, into vacuum cup and to a fixed distance from, preferably tightly against, injection orifice 8. This ensures that the target organ is stretched in the region of orifice 8 and preferably in contact with orifice 8 to ensure a successful needle free injection. This also obviates the need to prepare the target organ, for example skin, by pinching a fold of the surface for injection. The applied vacuum also ensures that injector 1 does not move during injection, reducing the possibility of distortion of the injection path. As described below, the injector trigger preferably requires the vacuum to be present in vacuum cup 108 in order to trigger the device, preventing premature firing and further reducing the possibility of injection path distortion. Preferably the front surface of vacuum cup 108 is somewhat non-planar, so that the device cannot be triggered by pressing against a flat, non-compliant surface like a table top.

[0165] Preferably the volume of vacuum plenum 106 and vacuum cup 108 (when sealed to the target organ) is minimized. This allows for minimization of the required travel of lever 101. It also allows for the minimization of the area of vacuum piston 103, minimizing the force that must be applied to lever 101, Preferably the combined volume of vacuum plenum 106 and vacuum cup 108 is less than 20 cc, more preferably less than 10 cc, still preferably less than 5 cc, most preferably less than 3 cc. Preferably the required force on lever 101 is less than 50N, more preferably less than 25N, still more preferably less than 10N, most preferably about 5N or less. Preferably vacuum plenum 106 is fabricated of tubing with the minimum diameter that will not substantially impede the flow of air from vacuum cup 108 to vacuum source 104. Preferably the inside diameter of the tubing is less than 10 mm, preferably less than 5 mm, more preferably less than 2.5 mm, most preferably about 1 mm or less.

[0166] The seal of vacuum cup 108 to the target organ is optionally improved by

including a sealing medium between the edge of vacuum cup 108 and the target organ. The sealing medium can be any medium that improves the seal and is acceptable for contact with the target organ, including but not limited to greases, petroleum jellies, emollients, lotions, moisturizers, gels, ultrasound coupling media, and the like. The sealing medium is preferably of elevated viscosity, preferably more than 10 cP, more preferably more than 100 cP, most preferably more than 1000 cP. The sealing medium may be contained within vacuum cup 108 and is covered by the orifice cap (not shown) prior to use. Preferably, the sealing medium is packaged in and applied with a cap/applicator as previously described. Alternatively or in addition, the seal may be provided by the properties and material of vacuum cup 108, for example making it flexible, or may be provided by an additional component around the rim, preferably over- molded onto the rim, that is compliant and provides a good seal, for example a rubber component.

[0167] In the embodiment of Figure 4, vacuum cup 108, vacuum source 104, vacuum plenum 106 and injector 1 are preferably integrated at a factory and form a unified drug delivery system that is self contained, portable, prefilled, single use, and disposable. In another embodiment, injector 1 is prefilled, single use, and disposable, and vacuum cup 108, vacuum source 104, and vacuum plenum 106 form a separate, multi-use device into which injector 1 is installed prior to use. In yet another embodiment, vacuum cup 108, vacuum source 104, vacuum plenum 106 and injector 1 are integrated into a durable, multi-dose device, which is either filled prior to use by filling drug reservoir 113 or replacing drug reservoir 113, or wherein drug reservoir 113 contains multiple doses. In another preferred embodiment, vacuum cup 108, drug reservoir 113, and piston 112 are a factory integrated and filled single use disposable component that is attached to the other components of injector 1, which are multi-use, prior to delivery.

[0168] Although shown in figure 4 is the embodiment where injector 1 is a needle free injector, injector 1 can be replaced by any type of drug delivery device that requires controlled placement relative to a target organ, including but not limited to needled injectors, catheters, transdermal systems, gene therapy delivery systems, pumps, bolus injectors, and the like. In one preferred alternate embodiment, injector 1 is a needled injector or pump with a retractable needle or catheter, and when lever 101 is actuated, more preferably only when there is a predermined partial vacuum in vacuum cup 108, the needle or catheter is inserted and delivery commenced.

[0169] For most applications, lever 101 will return to its initial position when released under the urging of spring 102. This allows for an immediate additional attempt if a seal of vacuum cup 108 to the target organ is not achieved, whereby the user removes vacuum cup 108 from the target organ, releases lever 101, repositions vacuum cup 108 against the target organ, and again actuates lever 101. However, there are some applications that require an extended duration delivery of more than 10 second, preferably more than 1 minute, more preferably more than 5 minutes. These applications include but are not limited to high volume infusions, high viscosity formulations, and formulations that because of irritation or other local effects at the delivery site need to be delivered slowly. Preferred high volume and/or high viscosity formulations include protein formulations, peptide formulations, high concentration low molecular weight formulations, sustained release formulations including depots, and other controlled release formulations. For extended duration deliveries, it will be preferable for lever 101 have a feature such as a detente to lock it in place in the actuated position. In a particularly preferred

embodiment, the detente or other locking mechanism is not active unless a predetermined partial vacuum is achieved.

[0170] Figure 5a shows a detailed view of the spool valve. In the embodiment of figure

5a, spool 105 has three seals, preferably o-ring seals: first seal 136, second seal 137, and third seal 130. Stop 141 limits the travel of spool 105 when injector 1 is triggered.

[0171] First seal 136 isolates volume 135 from the high pressure gas of compressed gas source 109, which communicates with spool 105 in the region between first seal 136 and second seal 137 via gas conduit 133. It is important that volume 135 be maintained at ambient pressure so that there is no net force on spool 105 until a partial vacuum exists in vacuum plenum 106. Accomplish this, volume 135 communicates with the ambient air via leak 134. The size of leak 134 is chosen such that it is larger than any leak through seal 136, and is large enough that volume 135 is largely maintained at ambient pressure during any changes in weather, temperature, or altitude. The size of leak 134 is small enough that no appreciable loss of pressurized gas occurs when injector 1 is triggered. Preferably leak 134 is non-sealingly covered, for example by injector casing 138, so that leak 134 does not become obstructed.

[0172] Second seal 137 isolates headspace 139 from the high pressure gas of compressed gas source 109, which communicates with spool 105 in the region between first seal 136 and second seal 137 via gas conduit 133. It is important that headspace 139 be maintained at ambient pressure so that there is no net force on ram head 110 until injector 1 is triggered. To accomplish this, headspace 139 communicates with the ambient air via leak 131. The size of leak 131 is chosen such that it is larger than any leak through seal 137, and is large enough that headspace 139 is largely maintained at ambient pressure during any changes in weather, temperature, or altitude. The size of leak 131 is small enough that no appreciable loss of pressurized gas occurs when injector 1 is triggered. [0173] Third seal 130 ensures that headspace 139 does not communicate with vacuum plenum 106 so that vacuum source 104 does not have to evacuate head space 139. In somewhat different embodiment, head space 139 is small enough that it can be easily evacuated by vacuum source 104 without appreciably changing the amount of travel required of lever 101. Third seal 130 is eliminated, as is leak 131. In the embodiment without third seal 130, upon triggering of injector 1 spool 105 preferably travels far enough that second seal 137 traverses conduit 132, sealing the now pressurized gas of headspace 139 from vacuum plenum 106.

[0174] The operation of injector 1 of the embodiment of figures 4 and 5 is as follows:

The user removes a cap (not shown) that covers orifice 8. The cap may be a simple cover for orifice 8 and an optional sealing medium (not shown) that has been previously applied to vacuum cup 108, but preferably is cap/applicator 6 as described relative to Figures 1 - 2. Optionally the user applies a second formulation using cap applicator 6, discards cap/applicator 6, and waits for a pre-specified wait time. Preferably, cap/applicator 6 contains a vacuum sealing medium to ensure a good seal of vacuum cup 108 to the surface of a target organ.

[0175] Injector 1 is then gripped between the fingers and palm near the top in such a way that the thumb extensibly contacts lever 101. Vacuum cup 108 is placed in contact with the target organ, preferably the skin, and the thumb is extended, actuating lever 101. The actuation of lever 101 causes vacuum piston 103 to move upward, drawing air from vacuum plenum 106 and simultaneously translating safety 107. If vacuum cup 108 is in sealing contact with the target organ, a partial vacuum is created in vacuum plenum 106 and vacuum cup 108. The partial vacuum in vacuum cup 108 pulls the skin up into firm contact with injection orifice 8 and stretches the skin, preparing it for injection. When the partial vacuum falls below a predetermined pressure, the force on spool 105 exceed the static friction due to first seal 136, second seal 137 and optional third seal 130, and spool 105 begins to move. The frictional force now drops to the lower kinetic frictional force, and spool 105 now rapidly moves to its maximum extent of travel where it contacts stop 141, accompanied by a sound that lets the user know that injector 1 has triggered. Figure 5b shows the spool valve in this post triggered state, and shows flow path 140 whereby the pressurized gas from gas reservoir 109 flows into headspace 139 from high pressure inlet 133 to conduit 132. This flow pressurizes headspace 139, creating a force on ram head 110 of ram 111. Under the urging of this force, ram 111 moves downward and strikes piston 112. This causes a pressure spike in formulation 113, forcing a portion of formulation 113 out of injection orifice 8 and forming a hole into the target organ to a predetermined depth. Under the continued urging of the pressurized gas, the remainder of formulation 113 is delivered out of orifice 8 and through the previously formed hole.

[0176] In the case where a sufficient seal is not created between vacuum cup 108 and the target organ, air flows into vacuum cup 108 to replace air that is drawn into vacuum source 104, and the pressure in vacuum plenum 106 remains sufficiently close to ambient pressure that there is substantially zero net force on spool 105, and injector 1 does not trigger. As there is no associated sound, the user knows that they must try again. The user moves cup 108 out of contact with the target organ, releases lever 101 (or in the case of a detente on lever 101, pulls lever 101 down to release the detente) and the above steps starting with the placement of vacuum cup 108 against the target organ are repeated.

[0177] Another embodiment of the topical drug applicator is shown in Fig. 6. Cup 200 and cover 202 contain the topical drug formulation, which is infused into compliant, absorbent element 201, which is preferably a sponge. To use the topical drug applicator of this embodiment, the user grips cup 200 with one hand and then bends tab 203 until it separates from cup 200. This is the state shown in 203. The user then peels off and disposes of cover 202. Drug infused compliant element 201 then expands to extend outside cup 200, as shown in Fig. 6b. The user then presses and/or rubs the now exposed compliant element 201 against a desired site on a target organ or skin. The pressing and/or rubbing is optionally combined with squeezing of cup 200, much as is shown in Fig. 2c. At this point the topical applicator is disposed of.

[0178] The topical applicator of Fig. 6 may be a standalone item, or may be supplied as a multiplicity of identical applicator in a box, bag, or other package, with instructions for use and additional information that may comprise an expiry date, drug contents, drug strength(s). Preferably the topical applicator of Fig. 6 is supplied as part of a kit with a drug delivery device, preferably an injector, and additional items as described above and below. The topical applicator of Fig. 6 may be combined with additional functionality, for example a cap for drug delivery device, including but not limited to a needle cap or an orifice cap. In another embodiment, cover 202 is attached to another component, for example a drug delivery device or a package, and the act of detaching the topical applicator from the other component also removes cover 202. [0179] Figure 7 shows another embodiment of the invention, related to that shown in figure 4. This embodiment, similarly to that shown in figure 4, comprises drug delivery device 1 powered by compressed gas source 109, a spool valve comprising spool 105, vacuum source 104, vacuum cup 108, injection orifice 8, and vacuum plenum 106.

[0180] In place of lever 101, the embodiment of figure 7 comprises movable housing 116 which is connected to piston 103 via push rod 115. In use the user grips movable housing 116 and presses vacuum cup 108 and orifice 8 against the desired injection site. When vacuum cup 108 is firmly seated against the target organ, additional user force will cause movable housing 116 to move downward relative to drug delivery device 1. This downward movement causes push rod 115 to push piston 103 downward against return spring 102, creating a partial vacuum in the volume of vacuum source 104 above piston 103, vacuum plenum 106 and vacuum cup 108 if and only if vacuum cup 108 is sealed to the surface of the target organ. If a seal is not achieved as indicated by the lack of sound, the user removes vacuum cup 108 from the surface of the target organ, and return spring 102 returns piston 103, push rod 115, and moveable housing 116 back to their original position relative to drug delivery device 1, and the process is repeated. Damping medium 117 is provided between moveable housing 116 and a component locked rigidly to drug delivery device 1 (shown here as vacuum plenum 106) in order to avoid recoil of drug delivery device 1 when it is triggered. Any suitable damping mechanism can be used, preferably damping or kilopoise grease. The system may include a trigger safety mechanism (not shown) similar to safety 107 shown in figure 4, with an aperture into which spool 105 can move when the safety moves downward. The additional details of the operation are the same as in Figure 4 as described above.

[0181] Figure 8 shows another embodiment of the invention, related to that shown in figure 4. This embodiment, similarly to that shown in figure 4, comprises drug delivery device 1 powered by compressed gas source 109, a spool valve comprising spool 105, and injection orifice 8.

[0182] Alignment ring 108 now has the ability to grip the surface of the target organ, and deform, rotate, or otherwise move in order to create an injection platform on the surface of target organ 29, pulling the desired injection site on target organ 29 into proximity or preferably contact with orifice 8. In this way it is ensured that target organ 29 is prepared for delivery by pulling up and stretching the surface of target organ 29, bringing the target injection site on organ 29 into proximity or contact with orifice 8, and ensuring that the target injection site does not move during the injection. Alignment ring 108 is moved by any suitable means. In the embodiment shown in figure 8, alignment ring 108 is deformed by pressing on lever 101, preferably with the thumb while gripping drug delivery device 1 with the fingers. As shown in figure 8b, when the lever is pressed, it moves down, compressing return spring 102, and actuating push rod 115, which in turns acts upon alignment ring 108. After delivery, return spring 102 returns lever 101, push rod 115, and alignment ring 108 back to their original position relative to drug delivery device 1. Triggering of the embodiment of figure 8 (not shown) can be achieved by any suitable means, such as a mechanical link to lever 101. Preferably, drug delivery device 1 includes features that ensure that triggering only occurs when the target injection site on organ 29 is in proximity or contact with orifice 8. This can be achieved by any suitable means, including but not limited to directly sensing the position of organ 29 with respect to orifice 8 or including additional components that ensure that the triggering only occurs when a predetermined compressive force on push rod 115 is achieved at the correct position of alignment ring 108. In a preferred embodiment, the vacuum features shown in figures 4 or 7 and described above are combined with the embodiment of figure 8, and the device is configured to trigger only when a predetermined vacuum is achieved.

Alignment ring 108 can be constructed of any suitable material or materials. In one embodiment, alignment ring 108 is substantially rigid, and includes features such as a hinge or hinges that allow for the deformation shown in figure 8b. Alternatively cup 108 may be fabricated of a compliant material and is elastically deformed. The edges of cup 108 are fabricated of a material and in a shape that is capable of gripping the surface of the target organ, and if required, creating a vacuum seal. This material may be used for the entirety of alignment ring 108, which may then function similarly to a suction cup, or may be a different material that is, for example, over-molded onto the body of alignment ring 108. Element 115 is shown as a push rod. In an alternate embodiment, element 115 may take the form of a cylinder which encircles drug delivery device 1, and contacts alignment ring 108 substantially in a circle.

Any of the above embodiments are optionally packaged in a kit which may contain components selected from a delivery device, a first drug formulation containing one or more systemically active drugs, labels, a topical drug applicator, a second drug formulation containing one or more topical drugs and/or surface preparation agents, an alignment ring, cleaning swabs or cloths, instructions including written instructions, pictures, audio instructions, and/or video instructions, a dosing log, a dosing reminder, a timer, a compliance monitor, a razor, an adhesive, a bandage, etc. The kit may contain a plurality of any of the components. The kit and or components may be packaged in one or more containers, boxes, overwraps, secondary packages, or tertiary packages. The drug delivery device is preferably an injector, more preferably an auto-injector, still more preferably a needle free injector, most preferably a prefilled, single use disposable, portable, compact, self contained needle free auto-injector. The first and/or second drug formulation(s) may be separately packaged in a container, and then inserted, injected, or otherwise loaded into or attached to the drug delivery device prior to use, with or without its container. Preferably, the first drug formulation is factory loaded into the drug delivery device. The second drug formulation may be separately packaged and then applied to the topical drug applicator by the user prior to delivery. Preferably, the second drug formulation is factory packaged in the topical drug applicator, which includes a cover or overwrap that ensures the stability and sterility of the topical drug formulation. The topical drug applicator may be separate from the drug delivery system. Preferably the topical drug applicator is attached to the injector; more preferably has an additional function, most preferably also functions as a cap or cover for the drug delivery device. In a particularly preferred embodiment, the kit contains a factory prefilled, single use disposable, self contained, portable, needle free auto-injector, and the topical drug applicator also functions as the orifice cap for the needle free injector. In another preferred embodiment, the first drug formulation, first drug formulation container, second formulation, cap/applicator, and piston are supplied separately as a factory prefilled and assembled single use disposable component, to be attached to a multi-use actuator prior to use.

[0184] 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.

[0185] 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. A drug delivery kit, comprising:

a first container holding a first formulation comprising a first pharmaceutically active drug;

a second container holding a second formulation comprising a topical formulation comprising one or more of:

a second pharmaceutically active drug different from the first pharmaceutically active drug;

a topical surface preparation agent;

a topical applicator configured to deliver the second formulation to a surface of an organ of a patient;

a drug delivery system configured to deliver the first formulation beyond the surface of the organ of the patient; and

a package containing the first container, the second container, the topical applicator and the drug delivery system.

2. The kit of claim 1, wherein the topical applicator is configured to possess an additional functionality selected from the group consisting of a cap, a cover, an alignment ring, and a vacuum cup.

3. The kit of claim 2, wherein:

the drug delivery device is a needle-free injector;

the topical applicator is removably attached to the needle-free injector;

the topical applicator additional functionality is a cap for an injection orifice, and removal of the topical applicator exposes the injection orifice; and

further wherein removal of the topical applicator exposes nozzles for application of the topical formulation.

4. The kit of claim 3, wherein the nozzles are comprised of a material whereby nozzle surfaces possess a property selected from the group consisting of:

hydrophobic, and lipophobic.

5. The kit of claim 1, wherein the topical applicator is removably attached to a component selected from the group consisting of the drug delivery system, and the package.

6. The kit of claim 1 wherein the topical applicator comprises a cover and removal of the cover exposes a compliant element which is infused with the topical formulation, and wherein exposing the compliant element allows the compliant element to expand outside of a cup.

7. The kit of any of any of the preceding claims, further comprising:

an alignment ring configured to accomplish a function selected from the group consisting of:

ensuring that the drug delivery system is at a predetermined angle to a surface; ensuring that the drug delivery system is substantially perpendicular to a surface; ensuring that the drug delivery system cannot move during delivery of the first formulation;

ensuring that a surface is at a predetermined fixed distance to a component of the drug delivery system;

ensuring that a surface is in contact with a component of the drug delivery system; ensuring that a surface is stretched at a site of delivery of the first formulation; ensuring that the alignment ring is in sealing contact with a surface before the drug delivery system triggers.

8. The kit or topical applicator of any of any of claims 1- 6 or 14 - 16, wherein the topical formulation is comprised of a compound selected from the group consisting of a vaso- constricting agent, an absorption enhancing agent, an anesthetic agent, an adhesive agent, a cleaning agent, a depilatory agent, an anti-microbial agent, a vacuum sealing agent, and mixtures thereof.

9. The kit or topical applicator of claim 8, wherein the topical formulation comprises a component selected from an adhesive, a vacuum sealing agent, a cleaning agent, a depilatory agent, a local anesthetic, Benzocaine, Chloroprocaine, Cocaine, Cyclomethycaine, Dimethocaine, Larocaine, Piperocaine, Propoxycaine, Procaine,

Novocaine, Proparacaine, Tetracaine, Amethocaine, Lidocaine, Articaine, Bupivacaine, Cinchocaine, Dibucaine, Etidocaine, Levobupivacaine, Lidocaine, Lignocaine,

Mepivacaine, Prilocaine, Ropivacaine, Trimecaine, a vasoconstricting agent, Epinephrine, 251-NBOMe, Amphetamine, AMT, Antihistamine, Caffeine, Cocaine, DOM, LSA,

Methylphenidate, Mephedrone, Oxymetazoline, Phenylephrine, Propylhexedrine,

Pseudoephedrine, Tetrahydrozoline hydrochloride, an absorption enhancing agent, a dispersion enhancing agent, Hyaluronic Acid, Chitosan, an alkylsaccharide, A Surfactant, Laureth Benzote, Laureth acetate, an anti-microbial, an anti-bacterial, a penicillin, a

cephalosporin, a polymyxin, a rifamycin, a lipiarmycin, a quinolone, a sulfonamide, a macrolide, a lincosamide, a tetracycline, an aminoglycoside, a cyclic lipopeptide, a

glycylcycline, a oxazolidinone, a lipiarmycin; an anti-fungal, Imidazole, a triazole, a thiazole, an allylamine, an echinocandin, benzoic acid, ciclopirox, flucytosine,

griseofulvin, haloprogin, polygodial, tolnaftate, undecylenic acid crystal violet; an antiviral; an anti-parasitic, and combinations, conjugates, prodrugs, or fragments thereof.

10. The kit of claim 9, wherein the drug delivery system is selected from the group consisting of:

a needle-free injector;

a needled injector;

an auto-injector;

a catheter;

a passive transdermal system;

an active transdermal system;

a gene therapy delivery system;

a pump;

a bolus injector; and

an infusion system.

11. The kit of claim 10, wherein the surface comprises the skin of a human.

12. The kit of claim 10, wherein the drug delivery system is a needle free injector comprising an injection orifice, and wherein the topical applicator comprises a cap which covers and seals an injection orifice of the injector, and wherein the topical formulation comprises a drug selected from the group consisting of benzocaine, lidocaine, tetracaine, epinephrine, hyaluronidase, and combinations thereof.

13. The kit of claim 12, wherein the needle free injector comprises a factory filled first formulation container and a second formulation container, wherein the injector is self contained, portable, single use, and disposable.

14. The kit of claim 12, wherein the needle free injector comprises a multi-use actuator and a plurality of factory filled first formulation containers and second formulation containser,wherein each of the first formulation containers is attached to one of the second containers which is configured as a topical applicator that is factory filled with topical formulation.

15. The drug delivery system of claim 9, wherein the second formulation has a viscosity of 10 cS or more.

16. The drug delivery system of claim 15, wherein the second formulation has a viscosity of 100 cS or more

17. The kit or topical applicator of claim 9, wherein the topical applicator is configured to apply the topical formulation via an action selected from the group consisting of:

pressing the topical applicator against a surface,

rubbing the topical applicator against a surface,

squeezing the topical applicator,

pressing a button,

moving a switch,

depressing a plunger,

actuating a lever, and

a combination thereof.

18. A dual function needle-free injector device, comprising:

a first container holding a first formulation comprising a first pharmaceutically active drug in a liquid carrier;

a piston for forcing the first drug from the first container at a speed which penetrates skin;

a channel leading from the first container to an exit opening; a second container holding a second formulation comprising a second drug, different from the first drug; and

a topical applicator for applying the second drug topically to skin.

19. The device of claim 18 comprising an injection orifice, wherein the topical applicator comprises a cap which covers and seals the injection orifice.

20. The device of claim 19, wherein the second drug is selected from the group consisting of benzocaine, lidocaine, tetracaine, epinephrine, hyaluronidase, and combinations thereof.