WO2010062908A1 - Disposable self-powered drug delivery device - Google Patents

Abstract

The present invention provides a minimally invasive, disposable, self- powered, patch-like drug delivery device. The device generally comprises a microneedle; a drug reservoir in fluid communication with the microneedle and comprising a drug to be administered; a pressure chamber in gas communication with the drug reservoir and comprising a liquid medium; a trigger for initiating a chemical reaction in the pressure chamber; and a plunger disposed in the drug reservoir, adapted to move unidirectionally in response to a pressure increase in the pressure chamber and to insulate the drug in the drug reservoir from a reactant and/or a product of the chemical reaction. Kits and methods for using the device are also provided.

Description

DISPOSABLE SELF-POWERED DRUG DELIVERY DEVICE

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to Chinese Patent Application No. 200810203610.6 filed on November 28, 2008 and U.S. Provisional Patent Application No. 61/118,987 filed on December 1, 2008, entitled "Disposable Self- Powered Drug Delivery Device," the contents of which are incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

[0002] The present invention generally relates to drug delivery devices and methods of using them, more specifically to disposable, self-powered drug delivery devices that are effective for controlling the rate and extending the duration of drug delivery.

BACKGROUND OF THE INVENTION

[0003] Hypodermal needle injection is the most reliable approach for drug delivery and often the only choice for delivering many therapeutic agents such as macromolecules. However, the use of hypodermal needles is frequently associated with problems such as patient training, patient resistance, safety, and cross- contamination. Thus, alternative approaches to drug delivery have been actively investigated.

[0004] Microneedles are hypodermal mechanical tools that can penetrate the stratum corneum and create drug delivery channels without stimulating underlying pain nerves. (For general reviews, see Prausnitz, M. R., "Microneedles for transdermal drug delivery," Adv. Drug Deliv. Rev. 2004, 56(5):581-7; Vandervoort, J. & Ludwig, A., "Microneedles for transdermal drug delivery: a minireview," Front. Biosci. 2008, 13:1711-5). Microneedle injection or fusion is a minimally invasive drug delivery approach that offers an attractive alternative to hypodermal needle injection. Microneedle injection is usually equally or more effective compared to hypodermal injections, and it effectively overcomes most of the problems associated with hypodermal injections. The minimal invasiveness of microneedle injection directly addresses the problem of patient compliance and renders the needle safer.

[0005] McAllister et al. used a 900 μm hollow glass microneedle to infuse insulin into hairless diabetic rats. (McAllister, D.V., et al., "Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies," Proc. Nat'lAcad. Sci. U.S.A. 2003, 100(24):13755-60). An insulin solution was infused into rats at 10 psi for 30 minutes until a steady reduction of blood glucose level was achieved. A 70% reduction of blood glucose level was observed after five hours of insulin infusion at 14 psi. Dose dependent response was demonstrated.

[0006] Davis et al. tested a hollow microneedle array in hairless diabetic rats. (Davis, S.P., et al., "Hollow metal microneedles for insulin delivery to diabetic rats," IEEE Trans. Biomed. Eng. 2005, 52(5):909-15). The microneedle array consisted of 4 x 4 metal microneedles of 500 μm in length. Insulin was stored in a chamber that was adhered to the animals and diffused into diabetic rats. Glucose level was reduced by 47% four hours after the treatment. Elevated insulin levels were also detected in these animals.

[0007] Due to the small size and limited penetration of the skin surface, hollow microneedle injection is essentially an intradermal administration. It is well established that intradermal injections can enhance immune response and achieve dose sparing effects for many vaccines; therefore, microneedle offers a particularly attractive delivery option for vaccines. {See Mikszta, J.A., et ah, "Protective immunization against inhalational anthrax: a comparison of minimally invasive delivery platforms," J. Infect. Dis. 2005, 191(2):278-88; Alarcon, J.B., et al, "Preclinical evaluation of microneedle technology for intradermal delivery of influenza vaccines," Clin. Vaccine Immunol. 2007, 14(4):375-81).

[0008] Although drug delivery using a microneedle was originally proposed in the early 1970s (see, e.g., U.S. Patent No. 3,964,482), its mass production and commercial applications have remained limited due to significant technical hurdles. One common problem, for example, is drug leakage due to the small size of the microneedle and shallow skin penetration. Additionally, tissue compression caused by the application of the microneedle increases resistance to liquid flow, thereby reducing the delivery rate. (Martanto, W., et al., "Microinfusion using hollow microneedles," Pharm. Res. 2006, 23(l):104-13).

[0009] For example, Davis et al. demonstrated that insertion of a 1080 μm microneedle primarily resulted in skin indentation and only 100-300 μm penetration. In this scenario, the maximal infusion rate was 15 μL/hr. At this rate, it would take several hours o deliver a pharmaceutically effective drug amount. Accordingly, effective application of a microneedle injection system requires a slow, steady and prolonged administration.

[0010] Roxhed et al. attempted to address this problem by using heat expandable beads to drive a microneedle delivery system. (Roxhed, N., et al., "Painless drug delivery through microneedle-based transdermal patches featuring active infusion," IEEE Trans. Biomed. Eng. 2008, 55(3):1063-71). Insulin delivery rates of 2 to 4 μL/hr were observed. The delivery rate was controlled by the amount of beads and by the power input. Notably, the authors observed dye leakage at a rate of 60 μL/hr, consistent with the results reported by Davis et al. Aside from the limited delivery rate, this device required an external power source, which rendered it bulkier and less convenient to use.

[0011] To address some of these problems, Good et al. reported a portable, water-activated micropump based on water absorption by a microbead matrix and the ensuing volume expansion. (Good, B. T., et al., "A water-activated pump for portable microfluidic applications," J Colloid Interface ScL 2007, 305(2):239-49). The expansion ratio may reach as high as 1 : 1000 for some super porous hydrogels. The limitation for this approach is the rapid rate of microbead expansion, which is an inherent property that is difficult to manipulate. For example, Good et al. reported that the volume expansion was complete in seconds after water activation. Accordingly, a high delivery rate of 17 μL/min/mg was observed. Although this rate of delivery may be useful for a number of microfluidic applications, it is not suitable for a microneedle infusion requiring a slower delivery.

[0012] Good et al. further reported another micropump based on a gas generating effervescent reaction. (Good, B. T., et al., "An effervescent reaction micropump for portable microfluidic systems," Lab. Chip 2006, 6(5):659-66). The effervescent reaction uses common reactants such as an alkaline carbonate or bicarbonate and an acid such as citrate. When a carbonate or bicarbonate reacts with an acid, carbon dioxide is released, thereby generating pressure in a closed system. It was shown that the reaction rate could be reduced by using solids with large particle sizes or acids with lower solubility. However, even after optimization, the delivery rate for this system was still on the order of minutes, meaning that it is too fast to be useful for microneedle infusion.

[0013] The combination of a micropump with a microneedle generally represents an attractive delivery approach. A number of patents and patent applications have been reported to use manual pressure, a spring or other means to deliver the drugs, such as, for example, U.S. Patent Nos. 3,964,482, 5,250,023, 5,957,895, 6,503,231, 6,656,147, 6,743,211, 6,780,171, 6,623,457, 6,960,193, 6,939,324, 7,047,070, 6,808,506, 7,083,592, 7,115,108, 7,156,838, 7,250,037, 7,410,476, 7,429,258; U.S. Patent Publication Nos. 2008/0215015; PCT Publication Nos. WO 03/022330, WO 02/002179, WO 03/024507, WO 04/033021, WO 06/054280, WO 06/132602; Chinese Patent No. CN02812823.0; and European Patent Application No. EP1925333. All patent and non-patent references listed herein are hereby incorporated by reference in their entireties.

[0014] Thus, the physical characteristics of a microneedle infusion device mandate that it must be able to provide a slow and sustained drug delivery rate to be effective. In some applications, the delivery rate needs to be on the order of tens of minutes, hours, or even days, which cannot be accomplished using the portable drug delivery devices reported in the art.

[0015] The present invention addresses the shortcomings of many existing drug delivery devices by providing a minimally invasive, portable, self-powered, inexpensive, easy to operate, and flexible drug delivery device that is capable of well-controlled, sustained drug delivery.

SUMMARY OF THE INVENTION

[0016] In one aspect, the present invention provides a minimally invasive, disposable, self-powered, patch-like drug delivery device. The device comprises a microneedle; a drug reservoir in fluid communication with the microneedle and comprising a drug to be administered; a pressure chamber in gas communication with the drug reservoir and comprising a liquid medium; a trigger means for initiating a chemical reaction in the pressure chamber, the trigger means having a first position and a second position, wherein shifting the trigger means from the first position to the second position initiates the chemical reaction; and a plunger disposed in the drug reservoir, adapted to move unidirectionally in response to a pressure increase in the pressure chamber and to insulate the drug in the drug reservoir from a reactant and/or a product of the chemical reaction. In some embodiments, the claimed device is a single use device.

[0017] In another aspect, the present invention provides a method of administering a drug to a subject in need thereof, comprising the steps of providing an embodiment of the present drug delivery device; applying the device to the subject's skin; initiating a chemical reaction in the pressure chamber by shifting the trigger means from the first position to the second position; and maintaining the device on the subject's skin until a therapeutically effective amount of the drug has been delivered to the subject. The rate of drug delivery is controlled by modulating the rate of the chemical reaction in the pressure chamber, which in turn determines the rate at which the driving force is generated. In some embodiments, the chemical reaction is an effervescent (i.e., gas-generating) reaction. The present invention provides methods for controlling the rate of driving force generation by encapsulating or embedding an effervescent reactant in a sustained release matrix. The invention further provides methods for controlling the rate of driving force generation by coupling the effervescent reaction to a second rate-limiting reaction, such as, for example, anhydride hydrolysis.

[0018] In a further aspect, the present invention provides a kit for administering a drug to a subject in need thereof, comprising an embodiment of the present drug delivery device, the drug to be delivered, and one or more additional components such as, for example, printed instructions for using the device, a protective cover for preventing needle damage, a trigger blocker for preventing inadvertent device activation, an adhesive layer for attaching the device to a subject's skin, and/or a pouch for disposing the device after use. In some embodiments, the claimed kit may comprise a single use drug delivery device. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 shows an overview of an embodiment featuring a push pin trigger mechanism. Figure IA shows the device in its resting state; Figure IB shows the device after the removal of the protective cover and the trigger blocker; and Figure 1C shows the device in its activated state.

[0020] Figure 2 shows a bottom view of the embodiment shown in Figure 1. Figure 2A shows the device with the protective cover on; and Figure 2B shows the device with the protective cover removed.

[0021] Figure 3 shows an exploded view of the embodiment shown in Figure 1.

[0022] Figure 4 shows individual components of the drug reservoir of the embodiment shown in Figure 1.

[0023] Figure 5 shows an overview of an alternative embodiment of the present device featuring a twist trigger mechanism.

[0024] Figure 6 shows an exploded view of the embodiment shown in Figure 5.

[0025] Figure 7 shows a prospective view of a twist trigger comprising a panel sealing element.

[0026] Figure 8 shows a prospective view of a twist trigger comprising a half- open chamber.

[0027] Figure 9 shows a prospective view of a twist trigger comprising a fully open chamber.

[0028] Figure 10 shows a top view of an alternative embodiment featuring a push pin trigger mechanism. Figure 1OA shows the device in its resting state; Figure 1OB shows the device with the needle cover and the push pin blocker removed; and Figure 1OC shows the device in its activated state.

[0029] Figure 11 shows an exploded view of the embodiment shown in Figure 10.

[0030] Figure 12 shows a top view of an alternative embodiment featuring a twist trigger mechanism.

[0031] Figure 13 shows an exploded view of the embodiment shown in Figure 12.

[0032] Figure 14 shows an inside view of the twist trigger mechanism and related structures. [0033] Figure 15 shows fluid delivery rates generated by a concept drug delivery device of the present invention in Sprague Dawley rats using benzoic acid encapsulated in different controlled release formulations.

[0034] Figure 16 shows fluid delivery rates generated by a concept drug delivery device of the present invention in Sprague Dawley rats using the hydrolysis of phthalic anhydride, succinic anhydride and poly(sebacic anhydride) as coupled chemical reactions.

[0035] Figure 17 shows fluid delivery rates generated by a concept drug delivery device of the present invention in Sprague Dawley rats using the hydrolysis of single piece phthalic anhydride and powder phthalic anhydride as coupled chemical reactions.

[0036] Figure 18 shows a comparison of blood glucose levels in Sprague Dawley rats subjected to insulin injection by a single bolus ("sc") or by rate- controlled infusion using a concept drug delivery device of the present invention ("Device"). A control group of animals that did not receive insulin is indicated as "Blank".

[0037] Figure 19 shows a time course of insulin delivery to Sprague Dawley rats using a concept drug delivery device of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS A. Definitions

[0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications (published or unpublished), and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are incorporated herein by reference, the definition set forth in this section prevails over the definition that is incorporated herein by reference. [0039] Citation of publications or documents is not intended as an admission that any of such publications or documents are pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.

[0040] As used herein, the singular form "a", "an" and "the" includes plural references unless indicated otherwise.

[0041] As used herein, the term "subject" generally refers to a mammal, including but not limited to a laboratory animal (e.g., mouse, rat, guinea pig, primate), a pet animal (e.g., cat, dog, hamster), a sport animal (horse), a farm animal (e.g., pig, cow, sheep, goat), or a human. In a preferred embodiment, the term "subject" refers to a human.

[0042] As used herein, the term "coupled" or "coupling" refers to either a direct physical contact between two mechanical components or an indirect connection through one or more intermediate members. Such connection may be achieved with the two components and any additional intermediate members being integrally formed as a single unitary body with one another or with the two components and any additional intermediate members being attached to one another. Such connection may be permanent or alternatively may be removable or releasable in nature.

[0043] As used herein, the term "engaged" or "engaging" refers to any mode of mechanical or physical attachment, interlocking, mating, binding, or coupling, such that members that are said to be "engaged" do not come apart or detach from one another without some positive effort, application of energy, or the like. Accordingly, the term "removably engaged" refers to a mechanical or physical attachment that is removable or releasable in nature.

[0044] As used herein, the term "fluid communication" between two or more components refers to a connection, either direct or indirect (e.g., via a connector pipe communication), such that a liquid can flow to and from those components communicating. [0045] As used herein, the term "gas communication" between two or more components refers to a connection, either direct or indirect (e.g., via a connector pipe communication), such that a gas but not a liquid can flow to and from those components communicating.

[0046] As used herein, the term "liquid medium" generally refers to mediums of liquid including, but not limited to aqueous solutions, physiological aqueous solutions, emulsions of the type oil-in- water and suspensions of insoluble salts in an aqueous solution.

[0047] As used herein, the terms "substantially insulate" and "substantially prevent" refer to an arrangement wherein a drug to be administered using a presently disclosed drug delivery device is sufficiently separated from reactive chemical substances (solid, liquid and/or gaseous) so that the drug's safety and efficacy profiles are not significantly affected.

[0048] As used herein, the term "single use device" refers to a device that is intended for just one use, i.e., on a single patient during a single procedure.

[0049] Throughout this disclosure, various aspects of this invention are presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0050] As discussed above, the present invention provides a disposable patch- like device and method for delivering a pre-determined amount of a drug or medication to a subject in need thereof. The delivery device is self-powered and adhered to the skin surface by an adhesive attached to the bottom of the device. Once properly positioned and activated by the user, the device will mix the components of a chemical reaction and generate gas as driving force to deliver the drug or medication stored in the drug reservoir into the subject via one or more microneedle(s). The delivery rate is modulated by controlling the rate of gas generation. Extended delivery times on the order of tens of minutes, hours or longer can be achieved. The commencement of the gas generating reaction and the progression of the infusion can be monitored using a color reagent in the pressure chamber. The completion of delivery may be monitored using by the position of a plunger.

[0051] The present invention can be better understood by reference to the drawings of the enclosed FIGS. 1-14, which represent several illustrative but non- limiting embodiments of the present device.

[0052] Referring to Figures 1-4, one embodiment of the drug delivery device

100 features a push pin mechanism as the trigger means for activating the device, so that the initiation of the drug delivery process can be accomplished in a single step. Figure 1 shows a top view of the drug delivery device 100 featuring the push pin trigger mechanism. Figure IA shows the drug delivery device 100 in its resting state. The needle is protected by the protective cover 112, and the push pin trigger

101 is blocked by a trigger blocker 102. In Figure IB, the protective cover 112 and the trigger blocker 102 are removed, followed by push pin trigger activation as shown in Figure 1C. Figure 2 shows a bottom view of the delivery device 100 protected with protective cover 112 (Figure 2A) and the same device with the protective cover 112 removed (Figure 2B). Figure 3 is an exploded view of the drug delivery device 100 showing individual components of the device. Figure 4 shows individual components of the drug reservoir assembly 110.

[0053] The drug delivery device 100 shown in Figures 1-4 is manufactured in a patch form. In the resting state, the device 100 is covered with the protective cover 112 to prevent drug leakage and accidental needle damage. Once the protective cover 112 is removed, an adhesive layer on the bottom of the housing 111 and the microneedle 11Od are exposed, thereby allowing the patch 100 to adhere and the microneedle 11Od to penetrate a subject's skin surface.

[0054] Alternatively, the drug delivery device 100 can be embedded between a flexible and cloth-like adhesive tape commonly used in bandages to create a softer, more comfortable feeling and a more traditional patch-like format (not shown). [0055] Referring now to Figure 3, the drug delivery device 100 comprises the push pin trigger 101, which is initially blocked by the removable trigger blocker 102 to prevent inadvertent activation. The device is activated by removing the trigger blocker 102 and depressing the push pin trigger 101. The push pin trigger 101 in turn depresses the reactant assembly, which includes a seal 106, a solid plate 107, a solid reactant 108 attached to the solid plate 107, and a sealing membrane 109. The function of the seal 106 and the sealing membrane 109 is to separate the solid reactant 108 from a liquid medium (not shown) contained in a pressure chamber 115. The liquid medium is preferably water or an aqueous buffer that is conducive to successful progression of a desired chemical reaction in the pressure chamber. The liquid medium may or may not comprise one or more of the reactants in a dissolved form. The pressure chamber 115 is connected to the drug reservoir assembly 110 via a connector 116. The liquid medium is retained in the pressure chamber 115 by a gas permeable hydrophobic membrane 118. When the push pin trigger 101 is depressed, it pierces the seal 106 and the sealing membrane 109, thereby allowing contact between the solid reactant 108 and the liquid medium and initiating a pressure generating reaction.

[0056] Referring now to Figure 4, the drug reservoir assembly 110 comprises a drug reservoir HOa having a tubular shape, a microneedle HOd connected to the drug reservoir HOa, a plunger HOb, and a drug filling port 110c. The port HOc is adapted to fill the drug reservoir 110a with a drug to be delivered, and the plunger 110b is used to propel the drug along the drug reservoir HOa. As explained above, the chemical reaction in the pressure chamber 115 usually generates gas, thereby providing a driving force for pushing the plunger HOb along the drug reservoir 110a, which in turn forces the drug in the drug reservoir HOa through the microneedle 11Od and into the subject's skin.

[0057] In addition to the structural elements described above, the device 100 also comprises a housing that includes a top portion 103 and a bottom portion 113. The top and bottom housing portions 103 and 113 comprise interlocking elements 105 and 111, respectively, which work in concert to maintain the housing sealed under pressure. Referring to Figure 2B, the bottom housing portion 113 further comprises an opening 114 to accommodate the microneedle 11Od and another opening to accommodate the filling port 110c of the drug reservoir assembly.

[0058] The drug delivery status of the drug delivery device 100 may be monitored in several ways. The initiation of the delivery is indicated by a color change in the pressure chamber 115 caused by a color reagent (e.g., a pH-sensitive dye), which may be co-formulated with the solid reactant 108. Thus, a contact between the solid reactant and the liquid medium will also result in a contact between the color reagent and the liquid medium. Since the liquid medium will usually have a neutral or somewhat basic initial pH, the contact between the color reagent and the liquid medium will usually result in a color change (e.g., clear to purple). As the contact between the solid reactant and the liquid medium gradually reduces the pH in the pressure chamber, another color change will take place (e.g., purple to yellow), which is indicative of the drug delivery status. When the drug reservoir 110a has been emptied and the plunger 110b has traveled all the way toward the microneedle 11Od, a magnifying view window 104 will permit a visual inspection of the plunger 110b. The plunger 110b may be colored to facilitate a visual inspection and verification of the drug delivery completion. Thus, the delivery process may be visually monitored at every stage from initiation through completion.

[0059] As explained above, the protective cover 112 is used to protect the microneedle and to ensure its sterility before the device is used. Once the drug delivery is complete, the protective cover 112 may be replaced as a safety measure to prevent injury and to ensure proper disposal. In a preferred embodiment, the present drug delivery device is a disposable, single-use device.

[0060] Referring to Figures 5-9, a drug delivery device 200 features a twist trigger mechanism as the trigger means for initiating the drug delivery process. Figure 5 shows a top view of the device 200 featuring the twist trigger mechanism. Figure 6 is an exploded view of the device 200 showing individual components of the device.

[0061] The device 200 shown in Figures 5-9 is a drug delivery device in a patch form. Similar to the device 100 described above, the device 200 is covered with a protective cover 212 to prevent drug leakage and inadvertent needle damage. The application of the device is accomplished by removing the protective cover 212, applying the patch to a subject's skin, and allowing the microneedle to penetrate the skin surface.

[0062] Referring to Figure 6, the device 200 differs from the device 100 described above in that it comprises a pressure chamber having two partitions 210 and 211 connected to a drug reservoir 207 via a connector 215. A liquid medium is retained in the pressure chamber partition 211 by a gas-permeable hydrophobic membrane 208. The liquid medium is preferably water or an aqueous buffer that is conducive to successful progression of a desired chemical reaction in the pressure chamber. The liquid medium may or may not comprise one or more of the reactants in a dissolved form. In the resting state, the pressure chamber partitions 210 and 211 are separated from each other by a twist trigger 206. The device 200 is activated by using a wrench 201 to rotate the twist trigger 206, which creates an opening between the pressure chamber partitions 210 and 211, thereby allowing contact between the solid reactants and the liquid medium contained in the partitions 210 and 211, respectively.

[0063] As pointed out above, the main difference between the push pin trigger embodiment and the twist trigger embodiment is the mechanism of activation. Referring to Figure 6, the twist trigger 206 separates the pressure chamber partitions 210 and 211 in the resting state and creates a large opening between the partitions 210 and 211 once the trigger is rotated using the wrench 201.

[0064] Figure 7 shows an alternative twist trigger embodiment 217 comprising a panel 218 for separating the partitions 210 and 211, which requires a 90° turn for activation.

[0065] Figure 8 shows another alternative twist trigger embodiment 219 comprising a half-open chamber 220 that contains one or more solid reactant(s) (not shown). In the resting state, the contents of the chamber 220 are insulated from a liquid medium and/or reactant contained in the pressure chamber 210/211. Rotating the trigger 219 using the wrench 201 exposes the solid contents of the chamber 220 to the pressure chamber 210/211, thereby permitting contact between the reactant contained in the chamber 220 and the liquid medium and/or reactant contained in the pressure chamber 210/211. [0066] Figure 9 is an enlarged view of the twist trigger 206 shown in Figure 6. In contrast to the twist trigger 219 shown in Figure 8, the twist trigger 206 features a fully open chamber 221 that does not contain any reactants. As discussed above, the role of the chamber 221 is to serve as a conduit between the pressure chamber partitions 210 and 211 when the trigger 206 is rotated using the wrench 201.

[0067] The drug reservoir assembly 207 is similar to the drug reservoir assembly 110 shown in Figure 4 and described above. A chemical reaction in the pressure chamber 211/210 usually generates a gas product that is the driving force for pushing a plunger along the drug reservoir, which in turn forces a drug in the drug reservoir through the microneedle and into the subject's skin. The status of delivery can be monitored using a magnifying view window 202 in essentially the same fashion as described above for the device embodiment 100.

[0068] In addition to the structural elements described above, the device 200 also comprises a pressure chamber seal 205 and a housing that includes a top portion 204 and a bottom portion 214. The top and bottom housing portions 204 and 214 comprise interlocking elements 203 and 216, respectively, which work in concert to maintain the housing sealed under pressure. The bottom housing portion 214 further comprises an opening 213 to accommodate the microneedle 11Od and another opening 209 to accommodate the filling port 110c of the drug reservoir assembly.

[0069] Referring to Figures 10 and 11, an alternative drug delivery device 300 features a push pin trigger mechanism as the trigger means for activating the drug delivery process. Figure 10 shows a top view of the device 300 featuring the push pin trigger mechanism 301. In the resting state (Figure 10A), the microneedle 310 is covered by a protective cover 311 to prevent drug leakage and accidental needle damage, and inadvertent activation is prevented by a trigger blocker 302. In Figure 1OB, the trigger blocker 302 and the protective cover 311 are removed to expose an adhesive layer on the bottom of the housing 312 and the microneedle 310, and to allow the device 300 to adhere to a subject's skin surface. In Figure 1OC, the push pin trigger 301 is depressed and the device is activated to cause the microneedle 310 to penetrate the skin surface. Figure 11 is an exploded view of the device 300 featuring the push pin trigger mechanism 301. [0070] As discussed above, before activation, the push pin trigger 301 is locked in place using the removable trigger blocker 302 to prevent inadvertent activation of the device. The device 300 is activated by removing the protective cover 311 and the trigger barrier 302 and depressing the push pin trigger 301. Depressing the push pin trigger 301 breaks a sealing membrane 305 that separates a liquid medium contained in a pressure chamber (not shown) disposed inside a top housing portion 304 from a solid reactant 306. The pressure chamber is separated from a drug reservoir 312 by a membrane 307. The liquid medium is preferably water or an aqueous buffer that is conducive to successful progression of a desired chemical reaction in the pressure chamber. The liquid medium may or may not comprise one or more of the reactants in a dissolved form. A chemical reaction in the pressure chamber generates a gas product that imposes pressure on the membrane 307, which in turn forces a drug in the drug reservoir 312 into the subject's skin through the microneedle 310. In some embodiments, the membrane 307 may be a static, flexible membrane that becomes deformed in response to a pressure increase in the pressure chamber. In other embodiments, the membrane 307 may be a mobile, rigid plunger that travels toward the microneedle 310 in response to a pressure increase in the pressure chamber.

[0071] In addition to the structural elements described above, the device 300 also comprises a push pin seal 303 and a bottom housing portion 308, which in turn comprises an opening 309 to accommodate the microneedle 310.

[0072] The initiation of the drug delivery process may be monitored by a color change in the pressure chamber caused by a color reagent (e.g., a pH-sensitive dye) co-formulated with the solid reactant 306. Thus, a contact between the solid reactant and the liquid medium will also result in a contact between the color reagent and the liquid medium. Since the liquid medium will initially have a neutral or weakly basic pH, the contact between the color reagent and the liquid medium will usually result in a color change (e.g., clear to purple). As the contact between the solid reactant and the liquid medium gradually reduces the pH in the pressure chamber, another color change will take place (e.g., purple to yellow), which is indicative of the drug delivery status. Accordingly, both the initiation and progression of the drug delivery may be tracked by monitoring various color changes in the pressure chamber. [0073] As explained above, the protective cover 311 is used to protect the microneedle 310 from damage and to ensure its sterility before the device is used. Once the drug delivery is complete, the protective cover 311 may be replaced as a safety measure to prevent injury and to ensure proper disposal. In a preferred embodiment, the present drug delivery device is a disposable, single-use device.

[0074] Referring to Figures 12-14, an alternative drug delivery device 400 features a twist trigger mechanism 403 as the trigger means for initiating the drug delivery process. Figure 12 shows a top view of the device 400 featuring the twist trigger 403. Figure 13 is an exploded view of the device 400 featuring the twist trigger 403 showing individual components of the device. Figure 14 shows an inside view of the twist trigger 403 and related structures.

[0075] The device 400 shown in Figures 12-14 is a drug delivery device in a patch form. In the resting state, the device 400 is covered with a protective cover 408 to prevent drug leakage and inadvertent microneedle damage. The device 400 is activated by removing the protective cover 408 and exposing a microneedle 407 and an adhesive layer on the bottom housing portion 405, which allows the device to adhere to a subject's skin and the microneedle 407 to penetrate the skin surface. As shown on Figure 13, the bottom housing portion 405 comprises an opening 406 to accommodate the microneedle 407.

[0076] Referring now to Figure 14, the twist trigger 403 comprises a half-open chamber 411 to accommodate one or more solid reactant(s) (not shown). In the resting state, the opening of chamber 411 is blocked by a sealing panel 410, which insulates the contents of the chamber 411 from a liquid medium contained in a pressure chamber (not shown) disposed in a top housing portion 402. The liquid medium is preferably water or an aqueous buffer that is conducive to successful progression of a desired chemical reaction in the pressure chamber. The liquid medium may or may not comprise one or more of the reactants in a dissolved form. The device is activated by rotating the twist trigger 403 using a wrench 401 to expose the solid reactant inside the chamber 411 to the liquid medium inside the pressure chamber. The pressure chamber is separated from a drug reservoir 409 by a membrane 404. A chemical reaction in the pressure chamber usually generates a gas product that imposes pressure on the membrane 404, which in turn forces a drug in the drug reservoir 409 into the subject's skin through the microneedle 407. In some embodiments, the membrane 404 may be a static, flexible membrane that becomes deformed in response to a pressure increase in the pressure chamber. In other embodiments, the membrane 404 may be a mobile, rigid plunger that travels toward the microneedle 407 in response to a pressure increase in the pressure chamber.

[0077] The initiation of the drug delivery process may be monitored by a color change in the pressure chamber caused by a color reagent (e.g., a pH-sensitive dye) co-formulated with the solid reactant contained in the chamber 411 of the twist trigger 403. Thus, a contact between the solid reactant and the liquid medium will also result in a contact between the color reagent and the liquid medium. Since the liquid medium will initially have a neutral or weakly basic pH, the contact between the color reagent and the liquid medium will usually result in a color change (e.g., clear to purple). As the contact between the solid reactant and the liquid medium gradually reduces the pH in the pressure chamber, another color change will take place (e.g., purple to yellow), which is indicative of the drug delivery status. Accordingly, both the initiation and progression of the drug delivery may be tracked by monitoring various color changes in the pressure chamber.

[0078] As explained above, the protective cover 408 is used to protect the microneedle 407 from damage and to ensure its sterility before the device is used. Once the drug delivery is complete, the protective cover 408 may be replaced as a safety measure to prevent injury and to ensure proper disposal. In a preferred embodiment, the present drug delivery device is a disposable, single-use device.

B. Microneedle

[0079] The microneedle assembly comprises at least one hollow microneedle fixed on a surface and connected to the drug reservoir. When administering a drug, the microneedle assembly preferably makes contact with a subject's skin and penetrates the outer layer of the skin.

[0080] At least one microneedle is needed for drug administration, similar to the hypodermal needle injection. In some embodiments, an array of microneedles may be used, said array comprising 2, 3, 4, 5 or more microneedles, which can increase the absorption area, facilitate a faster delivery, or allow a larger volume of drugs to be delivered within a set time period.

[0081] The length of the microneedle may depend on the specific applications. For subcutaneous injection or infusion, the length of the microneedle is preferably more than about 3-5 mm. For intradermal injection of infusion, the length of the microneedle is preferably less than about 2 mm, or less than about 1 mm, or less than about 0.5 mm. There is no limitation on the width and shape of the microneedle. Smaller gauge needles such as gauge 31 to 36 are generally preferred since they tend to reduce pain sensation and tissue damage compared to larger needles.

[0082] The microneedle may be made from any suitable materials, such as, for example, stainless steel, silica, glass, titanium, plastics like polycarbonate or polypropylene, and natural or synthetic polymers. It is understood, however, that this list is not meant to be exhaustive and that other suitable microneedle materials may be used equally effectively.

C. Drug Reservoir

[0083] A drug to be delivered is stored in a special compartment that is in liquid communication with the microneedle assembly and is in gas communication with the pressure chamber. In some embodiments, the drug reservoir and the pressure chamber are separated by a mobile, air-tight membrane or plunger that can travel along the drug reservoir under pressure to force the drug in the drug contained in the reservoir through the microneedle and into the subject's skin.

[0084] In some embodiments, the drug reservoir may have a cylindrical or tubular shape. In some embodiments, the drug reservoir may have a conical design at the end connected to the microneedle assembly in order to reduce dead volume.

[0085] In some embodiments, the length of the drug reservoir is significantly larger than its internal diameter. In some embodiments, the drug reservoir is a tubular structure with the ratio of length to internal diameter ranging from about 2:1 to about 1000:1, more preferably from about 10:1 to about 500:1. The length and diameter of the reservoir will usually depend on the volume of the drug to be delivered. The long tubular drug reservoirs allow a tighter control of drug delivery rate because the plunger needs to travel a longer distance in order to expel the same drug volume compared to reservoirs wherein the ratio of length to internal diameter is less than or equal to 1. In addition, the driving force required to expel the drug is significantly reduced due to the small contact surface area between the reservoir and plunger. The less the internal diameter of the drug reservoir, the more accurate the drug delivery rate. In some embodiments, the internal diameter of the drug reservoir may range from about 0.2 mm to about 5 mm, more preferably from about 1 mm to about 3 mm. In some embodiments, the volume of the drug reservoir may range from about 10 μL to about 10 ml, more preferably from 100 μL to about 2 ml, which can satisfy the requirements of most injectable drug formulations.

[0086] In some embodiments, a large volume of drug infusion can be achieved with the use of the present device by expanding the drug reservoir and the pressure mechanism accordingly. The resulting device can provide a portable and controlled delivery of a large volume of medication, and therefore it may be used for additional clinical applications such as intravenous drug infusion.

[0087] In some embodiments, the drug reservoir and the pressure chamber are separated by a gas-permeable hydrophobic membrane. The gas-permeable hydrophobic membrane prevents the solution phase reactant from entering the drug reservoir while allowing the passage of gas into the drug reservoir at a rate that depends on the structure of the membrane. The rate of gas passage depends on physicochemical characteristics of the membrane such as pore size and surface chemistry. Materials that may be used to fabricate this type of membrane include plastic polymers such as, for example, fluoropolymers (e.g., DuPont Teflon®), polyethylene, and polypropylene. The gas-permeable hydrophobic membrane can be used to modulate the transfer of pressure from the pressure chamber to the drug reservoir in order to facilitate a steady, well-controlled delivery.

[0088] In some embodiments, two or more drug reservoirs can be incorporated into the same drug delivery device to facilitate a simultaneous delivery of two or more drugs without the need to formulate them together. The two or more drug reservoirs may be coupled to the same pressure chamber to achieve similar delivery profiles. Alternatively, each drug reservoir may be coupled to its own pressure chamber if different delivery rates are desired for the drugs in the two or more drug reservoirs. For example, pramlintide may be used in combination with insulin to treat diabetes. Currently, a patient has to inject both insulin and pramlintide separately. A dual drug reservoir design of the present drug delivery device allows co-administration of insulin and pramlintide in a single operation without the need to co-formulate the two drugs.

D. Driving Force

[0089] In some embodiments, the driving force is generated by a gas generating chemical reaction such as, for example, an effervescent reaction. As discussed above, the drug reservoir is connected via a plunger or a membrane to a pressure chamber, in which the effervescent reactants and medium are stored. The pressure generating compartment consists of two separate parts in which the effervescent couples and/or aqueous medium are stored until the trigger mechanism is activated and an effervescent reaction is initiated.

[0090] The traditional effervescent reactants typically include a carbonate salt and an acid. The carbonate salt is preferably an alkaline carbonate or bicarbonate, or a combination thereof. The commonly used acids include but are not limited to acetic acid, malic acid, citric acid, butyric acid, caproic acid, ascorbic acid, tartaric acid, caprylic acid, capric acid, lauric acid, benzoic acid, phenylacetic acid, benzoylaminoacetic acid, acetyl salicylic acid, salicylic acid, and various combinations thereof.

[0091] When used in a drug delivery system, the traditional effervescent reaction is usually intended to facilitate dissolution or mixing of a drug formulation and is often completed in a short period of time. The generation of carbon dioxide can pressurize the pressure chamber and plunger or membrane to expel the drug via a needle assembly.

[0092] Since microneedle infusion requires a steady and prolonged infusion, the traditional fast effervescent reaction is not suitable. Even after using large particle size reactants and less soluble benzoate as reported by Davis et al, the short time frame of this reaction is not compatible with microneedle infusion. [0093] The present invention provides several approaches to extend the reaction time to be more compatible with the physiological requirements of a microneedle infusion.

[0094] In some embodiments, the rate of gas generation is modulated by embedding or encapsulating the effervescent reactants in a controlled release matrix. The effervescent reactants can be embedded together or separately. The controlled release matrix allows gradual and sustained release of the effervescent reactants, thereby facilitating slow and steady pressure generation.

[0095] Materials that may be used effectively to formulate the sustained release matrix include both hydrophilic and hydrophobic compounds commonly used in the controlled or sustained release formulations, see reviews. The materials to form sustained release matrix include both biodegradable and non-biodegradable materials, including but not limit to, poly(methyl methacrylate), poly(ethylene terephthalate), poly(dimethylsiloxane), poly(tetrafluoroethylene), polyethylene, polyurethane, polyesters such as poly(glycolic acid), poly(lactic acid), or copolymer poly(lactic glycolic acid), poly(caprolactone), block or multiblock co-polymers of polyesters such as poly(ether esters) like polydioxanone, poly(ester carbonates), poly(ester amide), poly(ester urethanes), poly(ortho esters), polyanhydrides, poly(alkyl cyanoacrylates), poly(amino acids), polyphosphazenes, polyphosphoesters, polysaccharides, cellulose, starch, alginic acid, hyaluronic acid, chitin, chitosan, proteins, collagen, gelatin, Polyhydroxyalkanoates, Poly(γ-glutamic Acid), polyethylene glycol, polyvinyl alcohol, PVP, ethyl cellulose, hydroyxpropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, Eudrgit polymers, cellulose acetate phthalate, cellulose acetate trimelliate, polyvinyl acetate phthalate, hydroxy propyl methylcellulose phthalate, pectin, dextran, cyclodextrin, guar gum, inulin, chondroitin sulfate, locust bean gum, wax, and their derivatives, salts, block or multi-block co-polymers where applicable.

[0096] The matrix formulated with these materials allows gradual and sustained release of the compounds embedded in the matrix. The time frame for release can vary from minutes, hours, days, weeks, and months, depending on the specific composition of the matrix. [0097] In general, hydrophilic polymers produce faster release and a shorter delivery time, while hydrophobic polymers such as ethyl cellulose yield more sustained release kinetics. The desired release kinetics can be adjusted by using different combinations of the polymer mixture. For example, a matrix containing 30% ethyl cellulose, 10% hydroxyl propylcellulose, 20% glycerol, and 40% benzoate generated gas pressure for about 60 minutes. In contrast, a matrix containing 35% ethyl cellulose, 35% PEG-400, 12% triacetin, and 18% benzoate was shown to generate gas pressure for over 12 hours.

[0098] The controlled release matrix can be in the form of a membrane, patch, disc, sphere, particle, capsule, rod, pellet, powder, or any other form. The matrix may contain a plasticizer to ensure uniformity, a stabilizer to keep the formulation stable, and an excipient to modulate release of the embedded compounds.

[0099] In some embodiments, the rate of pressure generation can be controlled and modulated by the solubility of the effervescent reactants. For example, insoluble carbonate salts with cations such as calcium, magnesium, or zinc often have limited use in the traditional effervescent reaction. However, the insoluble carbonate salts offer an alternative approach for sustained release of the carbonate species and an extended reaction time.

[0100] In some embodiments, the rate of pressure generation may be controlled by coupling a secondary chemical reaction with the effervescent reaction. The purpose of the coupled reaction is to generate one or more reactant(s) required for the effervescent reaction to take place. Thus, the rate of the coupled reaction will ultimately determine the rate at which one or more effervescent reactant(s) become available to participate in the pressure generating effervescent reaction.

[0101] In some embodiments, the coupled chemical reaction is ester hydrolysis, which produces an alcohol and an acid. The rate of ester hydrolysis can vary up to 10³ fold depending on the ester species and reaction conditions. Accordingly, the rate of formation of an acid species can be controlled by selecting a suitable ester and hydrolysis conditions to achieve a desired rate of pressure generation.

[0102] In some embodiments, the coupled chemical reaction to generate the acid species is anhydride and polyanhydride hydrolysis. An anhydride reacts with the hydroxyl group in water or alcohol to form an acid, which subsequently serves as a reactant in an effervescent reaction. The hydrolysis rate of an anhydride varies greatly depending on the structure of the corresponding acid, which offers a particularly useful tool for controlling the rate of acid formation and ultimately the drug delivery rate. In some embodiments, the anhydride hydrolysis reaction may be selected from phthalic anhydride hydrolysis, poly(sebacic anhydride) hydrolysis, succinic anhydride hydrolysis, or a combination thereof.

[0103] In addition, the hydrolysis rate of an anhydride also depends on the surface area of the anhydride and the concentration of bicarbonate. A larger anhydride surface area will usually result in a faster hydrolysis and a faster delivery rate, while a smaller anhydride surface area will usually result in an extended reaction time and a significantly slower delivery rate.

[0104] Polyanhydrides are commonly used in controlled release formulations as a biodegradable matrix. Polyanhydrides contain a hydrophobic core and a water labile linkage; consequently, degradation of polyanhydrides is a surface eroding process. Polyanhydride-based controlled release matrices often manifest zero-order kinetics. This type of kinetics is particularly attractive in a coupled reaction since the hydrolysis of polyanhydrides will result in a steady production of acid species. In the present invention, the hydrolysis of a polyanhydride matrix yields a steady supply of acid to participate in the effervescent reaction. The rate of polyanhydride hydrolysis may vary from days to weeks depending on the acid species. Therefore, a polyanhydride hydrolysis-coupled effervescent reaction can be used to generate a steady and sustained pressure.

E. Trigger Mechanism

[0105] The present drug delivery device is designed for drug administration using a built-in pressure mechanism driven by an effervescent reaction. In a typical embodiment, a mechanical trigger may be used to initiate contact between an aqueous medium and effervescent reactants. The aqueous medium may be water alone, an acid solution or a carbonate solution.

[0106] In some embodiments, the aqueous medium and effervescent reactants are separated by a thin membrane, which can be penetrated by a physical object such as, for example, a sharp pin. In other embodiments, contact between the aqueous medium and effervescent reactants may be initiated by a twist trigger to connect chambers containing individual reactants.

[0107] The present invention is designed to be an inexpensive, portable, and self-powered drug delivery device. Accordingly, the use of an external power source is generally discouraged. However, it should be noted that battery-triggered activation can be readily adopted to work with the present device and may be considered as a functional equivalent. For example, a battery operated valve may be employed as the trigger mechanism. Alternatively, an electrically induced melting of a membrane may also be used to achieve the same result. Various combinations of the different trigger types described above are also contemplated within the present invention. F. Status Indicator

[0108] In some embodiments, progress of the pressure-generating reaction may be monitored by incorporating a color reagent into the device. There are many suitable color reagents, such as, for example, pH sensitive dyes. For instance, a pH sensitive dye such as phenol red can be placed in the same chamber with an acid- releasing solid matrix. Upon initial contact with an aqueous medium or a carbonate solution having a neutral or basic pH, the dye will render the solution red or purple, marking initiation of the pressure generating reaction.

[0109] As acid is gradually released from the matrix, it reacts with carbonate, forming carbon dioxide and reducing the pH of the liquid medium in the reaction chamber. The pH reduction may be manifested by a change from red or purple to pale yellow, indicating successful progression of the drug administration. If, on the other hand, the solution in the reaction chamber remains red or purple, it may serve as a warning that the pressure generating reaction is not progressing as expected and therefore drug delivery may be incomplete.

[0110] In some embodiments, the position of the plunger may serve as an indicator of successful completion of drug delivery. To this end, the device may comprise a translucent window disposed in its housing proximal to the microneedle assembly, to allow a patient or clinician to visually track the position of the plunger toward the end of drug administration to confirm that the entire content of the drug reservoir has been delivered to the patient. G. Plunger

[0111] As discussed above, in some embodiments, a plunger may be used as a physical barrier for separating a drug in the drug reservoir from the gas produced by the chemical reaction in the pressure chamber and as a mechanical means for moving the drug along the drug reservoir in a unidirectional fashion.

[0112] In some embodiments, the plunger may be in the form of a sphere to ensure air-tightness during travelling in the tubing-like drug reservoir. The plunger may also be colored to serve as an indicator of successful completion of drug delivery. In other embodiments, the plunger may also be in the form of a flexible or rigid planar membrane. The plunger preferably should be made from a chemically inert material that does not produce a significant friction with the drug reservoir walls. In some embodiments, the plunger may be made from ceramics or polymers such as, for example, fluoropolymers (e.g., DuPont Teflon®) and other non-stick materials.

H. Therapeutic Agents

[0113] In some embodiments, the drugs to be delivered using the present drug delivery devices may comprise those drugs that are usually delivered using a hypodermal injection system. The drugs to be delivered using the present drug delivery devices may further comprise drugs that are delivered via the transdermal route, drugs that undergo extensive first-pass metabolism, drugs that cause significant gastrointestinal or hepatic side effects, drugs that benefit from pharmacokinetic modulation, or drugs that have poor absorption.

[0114] In some embodiments, the drugs to be delivered may comprise a small molecular drug selected from the group consisting of an androgen, an estrogen, a testosterone, a nitroglycerine, a nicotine, an anti-hypertension drug, an aciclovir, an alprazolam, an aspirin, an aldosterone, an atenolol, an azithromycin, an AZT, a penicillin, a bacitracin, a benzyl-penicillin, a caffeine, a candoxatril, a captopril, a carbamazepine, a chloramphenicol, a cimitidine, a clonidine, a cephalosporin, a cyclosporine, a haloperidol, a desipramine, a dexmethasone, a danazol, a diazepam, a diclofenac, a diltiazem, a diclofenac, a ketorolac, a doxorubicin, an epinephrine, an enalapril-maleate, an erythromycin, a clindamycin, a famotidine, a felodipine, a fluorouracil, a flurbiprofen, a furosemide, a hydrochlorthiazide, an isoxicam, an isoproterenol, an ibuprofen, an imipramine, an itraconazole, a labetalol, a lisinopril, a methotrexate, a metoprolol-tartarate, a nadolol, a naloxone, a nortriptylene, an omeprazol, a phenytoin, a piroxcam, a prazosin, a prostaglandin, a macrolide, a methylprednisolone, a progesterone, a medroxyprogesterone, a monobactams, an aztreonam, a propanolol, a quinidine, a ranitidine, a scopolamine, a tenidap, a terfenadine, a trovafloxacin, a valproic, a vinblastine, a ziprasidone, a rapamycin, a ketoconazole, , a steroid, a hydrocortizone, a prednisone, a triamcinalone, a ketoprofen, a naproxen, a nefidipine, a prostaglandin, an alprostadil, and a misoprostol, a riboflavin, a levodopa, a furosemide, a fentanyl, a lidocaine, a selegiline, a tetracaine, a rotigotine, a methylphenidate, an estrodiol, a nortriptyline, a propranolol, an organic nitrate, a megestrol, a buprenorphine, a morphine, a meglumine antimoniate, a lisuride, a granisetron, a bupropion, a methulglucamine, a perospirone, a phenserine, a tulobutanol, an enalaprilate, an atenolol, a cimetidine, a ranitidine, a terbutaline, a meloprolol, a L-dopa, a benzerazide, a phenylalanine, an antipyrine, their salts, analogs, and derivatives.

[0115] In some embodiments, the drugs to be delivered may comprise a macromolecule selected from the group consisting of a protein, a peptide, a polysaccharide, a nucleic acid, a lipid, a carbohydrate or any combination thereof.

[0116] In some embodiments, the protein drug to be delivered is selected from the group consisting of an anti -thrombin, an albumin, an alpha- 1 -proteinase inhibitor, an antihemophilic factor, a coagulation factor, an antibody, an anti-CD20 antibody, an anti-CD52 antibody, an anti-CD33 immunotoxin, a DNase, an erythropoietin, a factor IX, a factor VII, a factor VIII, a follicle stimulating hormone, a granulocyte colony-stimulating factor (G-CSF), a pegylated G-CSF, a galactosidase alpha or beta, a glucagon, a glucocerebrosidase, a granulocyte- macrophage colony-stimulating factor (GM-CSF), a chorionic gonadotropin, a hepatitis B antigen, a hepatitis B surface antigen, a hepatitis B core antigen, a hepatitis B envelopment antigen, a hepatitis C antigen, a hirudin, an anti-HER-2 antibody, an anti-IgE antibody, an anti-IL-2 receptor antibody, an insulin, an insulin glargine, an insulin NPH, an insulin Lente, an insulin aspart, an insulin lispro, an interferon, a pegylated interferon, an interferon alpha or alpha 2a or alpha 2b or consensus, an interferon beta or beta- Ia or beta- Ib or betaser, an interferon gamma, a interleukin-2, a interleukin-11, a interleukin-12, a luteinizing hormone, a nesiritide, an osteogenic protein- 1, an osteogeneic protein-2, a lyme vaccine, a platelet derived growth factor, an anti-platelet antibody, an anti-RSV antibody, a somatotropin, an anti-tumor necrosis factor (TNF) antibody, a TNF receptor-Fc fusion protein, a tissue plasminogen activator (tPA), a TNK-tPA, a thyroid stimulating hormone (TSH), a fibrinolytic enzyme, a thrombolytic enzyme, an adenosine deaminase, a pegylated adenosine deaminase, an anistreplase, an asparaginase, a collagenase, a streptokinase, a sucrase, a urokinase, an aprotinin, a botulinum toxin, a fibroblast growth factor, a vascular endothelia growth factor, and a venom. The proteins may be produced by recombinant technology, chemical synthesis or extracted from biological sources. The proteins also include the mutants and modified analogs or derivatives. The origin of the proteins may be from human or other species.

[0117] In some embodiments, the peptide drug to be delivered is selected from the group consisting of an ACTH, an anti-angiogenic peptide, an adamtsostatin, an adiponectin, an adipokinetic hormone, an deiponutrin, an adipose desnutrin, an adrenomedullin, an agouti-related protein, an alarin, an allatostatin, an amelogenin, a calcitonin, an amylin, an amyloid, an agiopoietin, an angiotensin, an anorexigenic peptide, an anti-inflammatory peptide, an anti-diuretic factor, an anti-microbial peptide, an apelin, an apidaecin, a RGD peptide, an atrial natriuretic peptide, an atriopeptin, an auriculin, an autotaxin, a bombesin, a bombinakinin, a bradykinin, a brain natriuretic peptide, a brain-derived neutrophic factor, a brevinin, a C-peptide, a caspase inhibitor, a pancreatic peptide, a buccalin, a bursin, a C-type natriuretic peptide, a brain natriuretic peptide, a calcitonin related peptide, a calcitonin receptor stimulating peptide, a calmodulin, a CART, a cartilostatin, a casomokinin, a casomorphin, a catestatin, a cathepsin, a cecropin, a cerebellin, a chemerin, a chelocystokinin, a chromogranin, a ciliary neutrophic factor, a conantokin, a conopressin, a conotoxin, a copeptin,a cortical androgen stimulating hormone, a corticotropin release factor, a cortistatin, a coupling factor, a defensin, a delta sleep inducing peptide, a dermorphin, a vasopressin, a desamino-vasopressin, a diuretic hormone, a dynorphin, an endokinin, an endomorphin, an endorphin, an endostatin, an endothelin, an enkephalin, an enterostatin, an exendin, an exendin-4, an erythropoietic peptide, an epithelia growth factor, a fat targeted peptide, a galanin, a gastric inhibitory peptide, a gastrin, a gastrin releasing peptide, a ghrelin, a glucagon, a glucagon-like peptide, a glutathione derivative, a gluten exorphin, a growth hormone releasing factor, a GM-CSF inhibitory peptide, a growth hormone peptide, a guanylin, a HIV peptide, a helodemine, a hemokinin, a HCV peptide, a HBV peptide, a HSV peptide, a Herpes virus peptide, a hirudin, a hydra peptide, an insulin-like growth factor, a hydrin, an intermedin, a kassinin, a keratinocyte growth factor, a kinetensin, a kininogen, a kisspeptin, a kyotorphin, a laminin peptide, a leptin peptide, a leucokinin, a leucopyrokinin, a leupeptin, a luteinizing hormone releasing hormone (LHRH), a lymphokine, a melanin concentrating hormone and its inhibitor, a melanocyte stimulating hormone releasing inhibitor, a melanotropin- potentiating factor, a morphine modulating neuropeptide, a MSH, a neoendorphin, a nesfatin, a neurokinin, a neuromedin, a neutropeptide Y, a neurotensin, a neutrotrophic factor, a nociceptin, an obestatin, an opioid receptor antagonist, an orexin, an osteocalcin, an oxytocin, a pancreastatin, a peptide YY, a physalaemin- like peptide, a secretin, a somatostatin, a sperm-activating peptide, a substance P, a syndyphalin, a thrombospondin, a thymopoietin, a thymosin, a thyrotropin-releasing hormone, a transforming growth factor, a tuftsin, a tumor necrosis factor antagonist or related peptide, a usrechistachykinin, a urocortin, a urotensin antagonist, a valorphin, , a vasotocin, a VIP, a, xenopsin or related peptide. The peptides may be produced by recombinant technology, chemical synthesis or extracted from biological sources. The peptides may also include mutants, modified analogs or derivatives of the corresponding wild-type molecule. The peptides to be delivered may be derived from human cell or from other any species.

[0118] In some embodiments, the biological active macromolecule to be delivered is a vaccine that can confer on a recipient active or passive immunization against pathogens and/or conditions selected from the group consisting of an adenovirus, anthrax, BCG, botulinum, cholera, diphtheria tetanus, pertussis, haemophilus B, hepatitis A, hepatitis B, influenza, encephalitis, measles, mumps, rubella, meningococcal, plague, tuberculosis, pneumococcus, polio, rabies, rotavirus, rubella, smallpox, tetanus toxoid, typhoid, varicella, yellow fever, human papilloma virus (HPV), Lyme disease, meningitis, bacterial antigens and any combination thereof.

[0119] In some embodiments, the biologically active macromolecule to be delivered is an allergen selected from the group consisting of house dust mice, animal dander, molds, pollens, ragweed, latex, vespid venoms and insect-derived allergens, and any combinations thereof.

[0120] The biological active macromolecules listed above may comprise a family of related molecules, including the wild type molecule with a native sequence and structure, analogs with modified structure or sequence, and chemically or biologically modified analogs.

[0121] For example, as used herein, the term "GLP-I agonist" refers to compounds that which fully or partially activate the human GLP-I receptor. Glucagon-like peptide 1 (GLP-I) is released from the L-cells in the intestine and serves to augment the insulin response after oral intake of glucose or fat. The term includes GLP-I peptides, as well as variants, analogs, and derivatives thereof. For example, GLP-I peptides comprise the wild type glucagon-like peptide, truncations, elongations, mutations, or other variations thereof. The term includes analogs such as ZPlOA or BIM-51077, a GLP-I or its analog conjugated to polyethylene glycol, a GLP-I or its analog fused with albumin such as albugon, or chemically conjugated to the albumin such as liraglutide or CJC-1131. Similarly, extendin-4 (also called exenatide) is a GLP-I agonist, and its and its analogs are thus included in the term "GLP-I agonist." Exenatide, exenatide analogs such as those reported in U.S. Patent No. 7,329,646, and long-acting conjugates such as CJC-1134, are all glucagon-like peptides, and/or derivatives thereof. It is not possible to exhaust all the analogs and the scope of this present invention is not limited to the list provided above.

I. Pharmaceutical Formulations

[0122] In some embodiments, the present drug delivery devices may be used to deliver drugs in liquid form. Aqueous and non-aqueous solutions, suspensions, emulsions, gels and creams are all suitable pharmaceutical formulations that may be delivered using the present devices. When desired, formulations adapted to yield sustained release of the active compound may be employed.

[0123] Solutions and suspensions may be aqueous, for example, prepared from water alone (e.g., sterile or pyrogen-free water) or from a combination of water with a physiologically acceptable co-solvent (e.g., ethanol, propylene glycol or polyethylene glycols such as PEG 400).

[0124] Such solutions or suspensions may further contain other excipients, for example preservatives (e.g., benzalkonium chloride), solubilizing agents/surfactants such as polysorbates (e.g., Tween 80, Span 80, benzalkonium chloride), buffering agents, isotonicity-adjusting agents (for example sodium chloride), and viscosity enhancers. Suspensions may further contain suspending agents (e.g., macrocrystalline cellulose and carboxymethyl cellulose sodium).

[0125] Aqueous suspensions may contain drugs in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium hydroxyl carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents.

[0126] Oily suspensions may be formulated by suspending the drug in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. These compositions may be preserved by including an anti-oxidant such as ascorbic acid. [0127] The pharmaceutical compositions that can be used with the delivery device of the present invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil (e.g., olive oil or arachis oil), a mineral oil (e.g., liquid paraffin) or a mixture thereof. Suitable emulsifying agents may include naturally-occurring gums (e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides (e.g., soy bean, lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate) and condensation products of the partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsions may further contain one or more sweetening and/or flavoring agent(s).

H. Methods of Use

[0128] In a further aspect, the present invention provides a method of administering a drug comprising the steps of applying one of the present drug delivery devices to a subject's skin surface, activating the trigger mechanism, and maintaining the device on the subject's skin until a therapeutically effective amount of the drug has been delivered to the subject. The present devices may be applied by hand or using a special device applicator.

[0129] In some embodiments, the present drug delivery may be used for injection or infusion via intra-dermal, subcutaneous, intra-muscular, intravenous, or other routes. For example, intravenous infusions often require a dripping device and restrict physical movement of the patients. The present devices can be readily adapted as portable intravenous infusion devices by expanding the drug reservoir and pressure chamber accordingly. The infusion volume and infusion rate can be adjusted, thus allowing the patients to move about freely with the present device.

[0130] One of the critical challenges associated with microneedle application is the tissue compression created when a microneedle is applied, which severely limits the drug delivery rate. Microneedle retraction may partially alleviate this problem. In some embodiments, the microneedle may be applied to penetrate the skin at an angle to reduce the extent of tissue compression. In some embodiments, a lateral force may be applied to the patch to enable microneedle penetration. The larger the angle, the more lateral and less direct force is needed. [0131] Although the present drug delivery device is generally intended to be minimally invasive by employing a microneedle, the extended delivery time is a critical feature for facilitating the delivery of certain drugs regardless of the type of needle used. For example, basal insulin supplement, an essential treatment to control basal blood glucose levels for diabetic patients, requires a steady delivery rate and a prolonged delivery time. The present device may be readily adapted to deliver basal insulin formulations using small gauge needles. Although this modification may render the device somewhat more invasive, it still provides significant advantages, such as a tightly controlled delivery rate to improve efficacy and reduce adverse side effects.

I. Kits

[0132] In yet another aspect, the present invention provides a kit comprising an embodiment of the presently disclosed drug delivery device. In some embodiments, the kit may comprise a device that has been pre-filled with a drug to be administered. In other embodiments, a drug to be administered may be provided in a separate container or tube in the solid or lyophilized (freeze-dried) form, so that it can be dissolved or reconstituted in a liquid medium and introduced into the device immediately prior to administration.

[0133] In addition to the drug delivery device and the drug to be delivered, the kit may optionally comprise additional components such as, for example, printed instructions for using the device, a protective cover for preventing needle damage, a trigger blocker for preventing inadvertent device activation, an adhesive layer for attaching the device to a subject's skin, and/or a pouch for disposing the device after use. In some embodiments, the kit may be intended for single use and therefore may comprise a single use drug delivery device.

EXAMPLES

[0134] The following examples are included for illustrative purposes and are not intended to limit the scope of current invention. Although gas pressure is used as the driving force in the exemplary embodiments described below, it is noted that the driving force may also be generated using alternative chemical, mechanical, electrical, and/or biological means.

EXAMPLE 1 Sustained Infusion Using a Controlled Release Matrix in Rats

[0135] To control the rate of delivery, an effervescent reactant can be encapsulated in a controlled release matrix to provide for a gradual supply of the reactant for the effervescent reaction. The effect of the controlled release matrix was demonstrated in a concept device of the present invention.

[0136] An infusion catheter connected to a 31 gauge needle was filled with 470 μL of water and connected to a 1 ml syringe having 6.0 mg of solid benzoic acid or benzoic acid equivalent in a controlled release matrix attached to the plunger. The phthalic anhydride was either in the form of a fine powder prepared using an 80 mesh screen, or in the form of a single piece. The needle was placed subcutaneously in male Sprague Dawley rats (-200 g body weight) under anesthesia (1 ml of 20% urethane i.p.), and infusion was initiated by drawing 0.2 ml of a saturated sodium bicarbonate (NaHCO₃) solution into the syringe, thereby contacting the NaHCO₃ with the phthalic anhydride. The amount of solution remaining in the catheter was measured at different time points to determine the rates of infusion.

[0137] To formulate the controlled release matrix, benzoic acid, ethyl cellulose (EC), triacetin and hydroxyl propylcellulose (HPC) were dissolved completely in ethanol and plated on a Petri dish to evaporate the solvent and form a membrane matrix. The different benzoic acid formulations and the corresponding times required for infusing 100 μL of water (T_1O0) are shown in Table 1 below. The time- volume plot for the same benzoic acid formulations is shown in Figure 15.

Table 1: Effect of controlled release matrix on the rate of infusion.

[0138] This study shows that the rate of infusion was high when pure benzoic acid was used, with delivery being complete within several minutes. The infusion rate was significantly reduced, and delivery time markedly extended, when benzoic acid was encapsulated in a controlled release matrix. This study also shows that the time of delivery can be extended to tens of minutes or even several hours by adjusting various formulation parameters in the controlled release matrix.

EXAMPLE 2 Sustained Infusion Based on Anhydride Hydrolysis

[0139] This example demonstrates that the rate of delivery depends significantly on the chemical nature of the effervescent reactant. For instance, anhydride hydrolysis represents one type of chemical reaction that can be used for the sustained release of different acid species. The effect of anhydride hydrolysis on the rate of delivery was demonstrated in a concept drug delivery device of the present invention.

[0140] An infusion catheter connected to a 31 gauge needle was filled with 470 μL of water and connected to a 1 ml syringe having 5.4 mg of solid succinic anhydride, 8.0 mg of solid phthalic anhydride, or 10 mg solid poly(sebacic anhydride) attached to the plunger. The needle was placed subcutaneously in male Sprague Dawley rats (-200 g body weight) under anesthesia (1 ml of 20% urethane i.p.), and infusion was initiated by drawing 0.2 ml of a saturated sodium bicarbonate (NaHCO₃) solution into the syringe, thereby contacting the NaHCO₃ with the anhydrides. The amount of solution remaining in the catheter was measured at different time points to determine the rates of infusion. [0141] The effect of the different anhydride species on the rate of delivery is shown in Figure 16, and the corresponding times required for infusing 100 μL of water (Tioo) are shown in Table 2 below.

Table 2: Effect of anhydride species on the rate of infusion

[0142] This study shows that the infusion rate can be modulated significantly by employing different anhydrides. The reaction with succinic anhydride facilitates complete fluid delivery on the order of minutes, whereas phthalic anhydride and poly(sebacic anhydride) were shown to prolong the duration of delivery to several hours or even days.

EXAMPLE 3 Effect of Anhydride Formulation on Rate of Delivery

[0143] This example demonstrates that the time of delivery can be extended by reducing the surface area of solid phthalic anhydride in a concept drug delivery device of the present invention.

[0144] An infusion catheter connected to a 31 gauge needle was filled with 470 μL of water and connected to a 1 ml syringe having 8.0 mg of solid phthalic anhydride attached to the plunger. The phthalic anhydride was either in the form of a fine powder prepared using an 80 mesh screen, or in the form of a single piece. The needle was placed subcutaneously in male Sprague Dawley rats (-200 g body weight) under anesthesia (1 ml of 20% urethane i.p.), and infusion was initiated by drawing 0.2 ml of a saturated sodium bicarbonate (NaHCO₃) solution into the syringe, thereby contacting the NaHCO₃ with the phthalic anhydride. The amount of solution remaining in the catheter was measured at different time points to determine the rates of infusion. [0145] The effect of phthalic anhydride formulation on the rate of infusion is shown in Figure 17, and the corresponding times required for infusing 100 μL of water (T_1Oo) are shown in Table 3 below.

Table 3: Effect of anhydride formulation (i.e., surface area) on the rate of infusion.

[0146] The reaction of sodium bicarbonate with phthalic anhydride in powder form having a large surface area resulted in a shorter time of delivery, whereas using a phthalic anhydride preparation with a smaller surface area resulted in a significantly longer time of delivery. This study shows that the rate of infusion can be modulated by controlling the surface area of a solid anhydride preparation.

EXAMPLE 4 Insulin Delivery in Rats by Rate Controlled Infusion

[0147] This example demonstrates successful rate controlled delivery of biologically active insulin in rats using a concept drug delivery device of the present invention.

[0148] Ten male Sprague Dawley rats (-200 g body weight) were fasted for 4 hours and divided into three groups. The "Device" group consisted of 4 animals. An infusion catheter connected to a 31 gauge needle was filled with 100 μL of 0.6U insulin solution in 0.0 IN HCl. The infusion catheter was then connected to a 1 ml syringe having 8.0 mg of solid phthalic anhydride attached to the plunger. The phthalic anhydride was in the form of a fine powder prepared using an 80 mesh screen. The needle was inserted subcutaneously into the backs of the animals under anesthesia (1 ml of 20% urethane i.p.), and infusion was initiated by drawing 0.2 ml of 30 mg/ml sodium bicarbonate (NaHCO₃) solution into the syringe, thereby contacting the NaHCO₃ with the phthalic anhydride. The amount of solution remaining in the catheter was measured at different time points to determine the rates of infusion.

[0149] The "sc" (subcutaneous) and "Blank" groups consisted of 3 animals each. In the "sc" group, the animals were anesthetized in the same manner as those in the "Device" group and then given an insulin bolus (200 μL of 0.6U insulin solution in 0.0 IN HCl) subcutaneously. In the "Blank" group, the animals were anesthetized in the same manner as those in the "Device" and "sc" groups, but no insulin was administered. Tail vein blood was withdrawn from each animal at regular time intervals, and blood glucose was measured using a OneTouch Ultra glucometer.

[0150] Figure 18 shows the blood glucose levels in all three groups at various time points. Figure 19 shows a time course of insulin delivery to the animals of the "Device" group. This study shows that biologically active insulin can be administered effectively to laboratory animals using a concept drug delivery device of the present invention. A 100 μL volume of an insulin solution was delivered subcutaneously in 40-60 minutes and resulted in a significant blood glucose reduction comparable to that produced by a bolus of insulin. Comparable bioavailability was observed for the subcutaneous bolus injection and infusion using the concept drug delivery device.

Claims

1. A device for administering a drug to a subject, the device comprising: a) a microneedle; b) a drug reservoir enclosed in a housing, the drug reservoir being in fluid communication with the microneedle and comprising a drug to be administered; c) a pressure chamber enclosed in the housing, the pressure chamber being in gas communication with the drug reservoir and comprising a liquid medium; d) a trigger means for initiating a chemical reaction in the pressure chamber, the trigger means having a first position and a second position, such that shifting the trigger means from the first position to the second position initiates the chemical reaction in the pressure chamber; and e) a plunger disposed in the drug reservoir, the plunger being adapted to move unidirectionally in response to a pressure increase in the pressure chamber and to substantially insulate the drug in the drug reservoir from a reactant and/or a product of the chemical reaction.

2. The device of claim 1, further comprising a protective cover removably engaged to the housing and adapted to prevent needle damage.

3. The device of claim 1 or 2, further comprising an adhesive layer disposed on a bottom surface of the housing and adapted for attaching the device to the subject's skin.

4. The device of any of the preceding claims, further comprising a gas- permeable membrane adapted to substantially prevent the liquid medium from entering the drug reservoir.

5. The device of any of the preceding claims, wherein the drug reservoir has a cylindrical shape.

6. The device of claim 5, wherein the drug reservoir has a ratio of length to internal diameter ranging from about 2:1 to about 1000:1.

7. The device of any of any of the preceding claims, further comprising a connector adapted for coupling the drug reservoir to the pressure chamber.

8. The device of any of the preceding claims, wherein the drug reservoir comprises a port adapted for filling the drug reservoir with the drug to be delivered.

9. The device of any of the preceding claims, wherein the trigger means is selected from a group consisting of a push-pin mechanism, a twist mechanism, a battery-operated electric valve, a heating mechanism, and a combination thereof.

10. The device of any of the preceding claims, further comprising a trigger blocker adapted to maintain the trigger means in the first position and prevent the trigger means from moving to the second position.

11. The device of any of the preceding claims, further comprising a solid reactant assembly disposed in the housing, the solid reactant assembly comprising a solid reactant attached to a solid support and a sealing membrane adapted to insulate the solid reactant from the liquid medium.

12. The device of any of the preceding claims, wherein the pressure chamber comprises a first partition comprising a liquid medium and a second partition comprising a reactant.

13. The device of claim 12, wherein the first and second partitions of the pressure chamber are completely insulated from each other when the trigger means is in the first position, and are in fluid communication with each other when the trigger means is in the second position.

14. The device of any of the preceding claims, further comprising an indicator adapted for monitoring initiation, progression and/or completion of the chemical reaction in the pressure chamber.

15. The device of claim 14, wherein the indicator is a color reagent.

16. The device of claim 15, wherein the color reagent is a pH sensitive dye.

17. The device of any of the preceding claims, further comprising a translucent window adapted for monitoring the plunger's movement along the drug reservoir.

18. The device of any of the preceding claims, wherein the chemical reaction is an effervescent reaction.

19. The device of claim 18, wherein the effervescent reaction generates carbon dioxide.

20. The device of claim 19, wherein the carbon dioxide generating reaction is a reaction between an acid and a carbonate salt.

21. The device of claim 20, wherein the carbonate salt is selected from the group consisting of a carbonate, a bicarbonate, and a combination thereof.

22. The device of claim 20 or 21 , wherein the acid is selected from the group consisting of acetic acid, malic acid, citric acid, butyric acid, caproic acid, ascorbic acid, tartaric acid, caprylic acid, capric acid, lauric acid, benzoic acid, phenylacetic acid, benzoylaminoacetic acid, salicylic acid, acetyl salicylic acid, and a combination thereof.

23. The device of any of claims 20-22, wherein the acid is generated by a coupled chemical reaction.

24. The device of claim 23, wherein the coupled chemical reaction is selected from the group consisting of an ester hydrolysis, an anhydride hydrolysis, a polyanhydride hydrolysis, and a combination thereof.

25. The device of claim 24, wherein the anhydride hydrolysis reaction rate is modulated by reducing the anhydride's surface area.

26. The device of claim 24 or 25, wherein the anhydride hydrolysis is selected from the group consisting of phthalic anhydride hydrolysis, poly(sebacic anhydride) hydrolysis, succinic anhydride hydrolysis and a combination thereof.

27. The device of any of claims 11 -26, wherein the rate of the chemical reaction is modulated by reducing the solid reactant's dissolution rate.

28. The device of claim 27, wherein the reduction of the solid reactant's dissolution rate is accomplished by embedding or encapsulating the solid reactant in a controlled release matrix.

29. The device of claim 28, wherein the controlled release matrix comprises ethyl cellulose, triacetin, and hydroxyl propylcellulose.

30. A device for administering at least two drugs to a subject, the device comprising: a) a first and second microneedles; b) a first drug reservoir enclosed in a housing, the first drug reservoir being in fluid communication with the first microneedle and comprising a first drug to be administered; c) a second drug reservoir enclosed in the housing, the second drug reservoir being in fluid communication with the second microneedle and comprising a second drug to be delivered; d) a first pressure chamber enclosed in the housing, the first pressure chamber being in gas communication with the first drug reservoir and comprising a first liquid medium; e) a second pressure chamber enclosed in the housing, the second pressure chamber being in gas communication with the second pressure chamber and comprising a second liquid medium; f) a trigger means for initiating a first chemical reaction in the first pressure chamber and a second chemical reaction in the second pressure chamber, the trigger means having a first position and a second position, such that shifting the trigger means from the first position to the second position initiates the first and second chemical reactions in the first and second pressure chambers; and g) plungers disposed in each of the first and second drug reservoirs, the plungers being adapted to move unidirectionally in response to pressure increases in the first and second pressure chambers and to substantially insulate the first and second drugs in the first and second drug reservoirs from reactants and/or products of the first and second chemical reactions.

31. The device of claim 30, wherein the first drug is the same as or different from the second drug.

32. The device of claim 30 or 31 , wherein the first liquid medium is the same as or different from the second liquid medium.

33. The device of any of claims 30-32, wherein the first chemical reaction is the same as or different from the second chemical reaction.

34. The device of any of claims 30-33, further comprising a first solid reactant assembly disposed in the housing, the first solid reactant assembly comprising a first solid reactant attached to a first solid support and a first sealing membrane configured to insulate the first solid reactant from the first liquid medium.

35. The device of claim 34, further comprising a second solid reactant assembly disposed in the housing, the second solid reactant assembly comprising a second solid reactant attached to a second solid support and a second sealing membrane configured to insulate the second solid reactant from the second liquid medium.

36. The device of claim 35, wherein the first solid reactant is the same as or different from the second solid reactant.

37. The device of any of the preceding claims, wherein the device is a single use device.

38. A method of administering a drug to a subject, comprising the steps of: a) providing the device of any of claims 1-29 and 37; b) applying the device to the subject's skin; c) initiating the chemical reaction in the pressure chamber by shifting the trigger means from the first position to the second position; and d) maintaining the device on the subject's skin until a therapeutically effective amount of the drug has been delivered to the subject.

39. A method of administering two drugs to a subject, comprising the steps of: a) providing the device of any of claims 30-37; b) applying the device to the subject's skin; c) initiating the first and second chemical reactions in the first and second pressure chambers by shifting the trigger means from the first position to the second position; and d) maintaining the device on the subject's skin until a therapeutically effective amount of the two drugs has been delivered to the subject.

40. The method of claim 38 or 39, further comprising the step of removing a protective cover prior to applying the device to the subject's skin.

41. The method of any of claims 38-40, further comprising the step of removing a trigger blocker prior to shifting the trigger means from the first position to the second position.

42. The method of any of claims 38-41 , wherein drug delivery is accomplished via a route of administration selected from the group consisting of intradermal, subcutaneous, intramuscular, and intravenous administration.

43. A kit comprising the device of any of claims 1-37 and printed instructions for using the device.

44. The kit of claim 43, further comprising a protective cover for preventing needle damage.

45. The kit of claim 43 or 44, further comprising a trigger blocker for preventing inadvertent device activation.

46. The kit of any of claims 43-45, further comprising an adhesive layer for attaching the device to the subject's skin.

47. The kit of any of claims 43-46, wherein the kit comprises a single use device.