Swellable hydrogel microneedles backed by a drug reservoir patch

Abstract

Provided are devices for treating or preventing a disease or condition caused by a virus in a subject and processes of using the devices to deliver a therapeutic to a subject. A device as provided herein includes: a reservoir layer and a microneedle delivery layer, the reservoir layer in contact with the microneedle delivery layer; wherein the reservoir layer includes an active agent, and wherein the reservoir layer is in the form of a pliable glass including the active agent. Also provided are processes of treating or preventing a disease or condition caused by a virus in a subject including applying the device as provided herein to the skin of a subject in need thereof.

Description

SWELLABLE HYDROGEL MICRONEEDLES BACKED BY A DRUG RESERVOIR PATCHCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application depends from and claims priority to U.S. Provisional Application No: 63 / 538,951 filed September 18, 2023, the entire contents of which are incorporated herein by reference.STATEMENT OF GOVERNMENT SUPPORT

[0002] These inventions were made with government support under Grant Nos. R43AI129122-01, R43AI129122-02, R44AI 129122-03, R44AI 129122-04, R44AI129122-05, R44AI129122-06, R44AI129122-07, and R44AI129122-08 awarded by the National Institute of Allergy and Infectious Diseases. The Government has certain rights in the inventions.TECHNICAL FIELD

[0003] The present disclosure generally relates to delivery of antiviral agents.BACKGROUND

[0004] Influenza viruses cause an acute respiratory illness capable of spreading rapidly through communities resulting in about 650,000 deaths worldwide every year due to seasonal epidemics, and even higher mortality during pandemics. Influenza treatments are somewhat ineffective, however, as some influenza strains acquire resistance to the currently marketed therapeutics; the neuraminidase inhibitor (NI) oseltamivir (Tamiflu®), and even the recently approved cap-dependent endonuclease inhibitor baloxavir marboxil (Xofluza®). While zanamivir (ZAN, Relenza®) remains highly active against oseltamivir-resistant influenza strains, it is administered as an oral inhalation powder, which is associated with significant pharmacokinetic variability and is contraindicated in patients with a compromised respiratory system, one of the most vulnerable influenza patient populations.

[0005] As such, there is a clear need for improved mechanisms of delivery of an active agent to a subject independent of whether the active agent is an antiviral agent suitable for use in the treatment of a respiratory infection or has a different mechanism of action.SUMMARY

[0006] The following summary is provided to facilitate an understanding of some of the innovative features unique to the present disclosure and is not intended to be a full description. A full appreciation of the various aspects of the disclosure can be gained by taking the entire specification, claims, drawings, and abstract as a whole.

[0007] Provided are devices for the administration of an active agent to a subject, optionally for treating or preventing a disease or condition caused by a virus in a subject. A device may include a reservoir layer and a microneedle delivery layer, the reservoir layer in contact with the microneedle delivery layer, optionally wherein the reservoir layer includes an active agent, and wherein the reservoir layer is in the form of a pliable glass comprising said active agent. An active agent is optionally an antiviral, optionally zanamivir (ZAN). The microneedle delivery layer optionally includes a swellable polymer, optionally a polymer that will swell upon contact with a fluid and will be capable therein of carrying active agent from the reservoir layer to the skin of a subject. The glass of the reservoir layer optionally further comprises one or more additives. An additive is optionally a sugar (optionally trehalose, or dextran 40), optionally gelatin, optionally HPMC, optionally pullulan, or any combination thereof. Optionally, an additive is present at about 2 wt % to about 50 wt%, optionally about 10 wt% to about 50 wt%, optionally about 20 wt% to about 40 wt%. Optionally, an additive is gelatin present at 20 wt% to 40 wt% by weight. Optionally, a device excludes an additive. The glass of the reservoir layer optionally includes a gelatin at 20 wt% to 40 wt% by weight and trehalose at 10 wt% to 25 wt%. The glass of the reservoir layer optionally includes a PPG at about 10 wt% to about 15 weight percent. The glass of the reservoir layer optionally includes PPG and pullulan and / or a dextran. The pullulan is optionally present at about 35 wt%. The dextran is optionally dextran 40 and is optionally present at about 40 wt%. In any of the devices as provided herein, an active agent is optionally present at 25 wt% or higher, optionally 45 wt% to 65 wt%. The active agent is optionally in the form of an active agent hydrochloride salt. Optionally, the reservoir layer holds a minimum of 100 milligrams of the active agent. In any aspect as provided herein, the device may be configured to release the active agent with a Cmax of 8 hours or less. Optionally, the device is configured to provide sustained release of the active agent over a time of five or more days. The reservoir layer is optionally substantially dry, optionally including less than 10 wt% water, optionally less than 1 wt% water. Optionally, the reservoir layer is configured to maintain the active agent as stable for 30 days or more.Optionally, the pliable glass reservoir layer is configured to not crack under a pressure of 40 N or greater.

[0008] Also provided are processes of treating or preventing a disease or condition caused by a virus in a subject including applying the device of any of the aspects of the foregoing paragraph to the skin of a subject. Optionally, the applying is prior to infection of a subject with the virus. Optionally, applying is following exposure of a subject to said virus, optionally within 48 hours following exposure. Optionally, a virus is an influenza virus.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The aspects set forth in the drawings are illustrative and exemplary in nature and not intended to limit the subject matter defined by the claims. The following detailed description of the illustrative aspects can be understood when read in conjunction with the following drawings.

[0010] FIG. 1 illustrates an exemplary experimental set up and results of diffusion of various formulations of zanamivir (ZAN); where a) is a schematic illustrating the experimental set up for the solute diffusion study in order to evaluate the diffusion kinetics of ZAN across the different hydrogel systems; (b) illustrates a cumulative amount of ZAN hydrate (pg) permeated across different hydrogel systems over 24 hours; (c) illustrates a cumulative percentage of ZAN hydrate (%) permeated across different hydrogel systems over 24 hours; (d) is a cumulative amount of ZAN (pg) permeated using a hydrochloride salt across Gantrez® S-97-PEG 10,000 swollen hydrogel network over 24 h; and (e) illustrates a cumulative percentage of ZAN (%) permeated using a hydrochloride salt across Gantrez® S-97-PEG 10,000 swollen hydrogel network over 24 h. Data points are expressed as means ± SEM, n = 3. Differences were calculated using one-way ANOVA, Tukey’s post hoc test, and deemed significant at where p-value outputs were 0.033(*), 0.002(**), <0.001(***) and <0.0001 (-****)

[0011] FIG. 2 illustrates diffusion of ZAN across a PVDF membrane (Durapore®), where “solution” is straight ZAN HC1 not incorporated into a reservoir, and these are compared with reservoirs from Table 1 of TSRL-3, -10, -21, and -27.

[0012] FIG. 3 illustrates diffusion of ZAN across a PVDF membrane (Durapore®) where TC-668 is TSRL-32 and TC-643 is the same formulation as TSRL-32 but using the hydrate rather than the HC1 salt of ZAN.

[0013] FIG. 4 illustrates physical strength of various microarray patch devices.

[0014] FIG. 5 illustrates: (a) Franz cell set up for testing of dermatomed skin samples; (b) illustrates a cumulative amount of ZAN formulations (mg) permeated across different hydrogel systems over 24 hours; (c) illustrates a cumulative percentage of ZAN hydrate (%) permeated across different hydrogel systems over 24 hours; (d) is the amount of ZAN extracted in various compartments in LYO-1 membranes; (e) is the amount of ZAN extracted in various compartments in LYO-2 membranes, wherein in (d) and (e) the order of data left to right in the graphs is the order as depicted in the legend below the figures.

[0015] FIG. 6 illustrates results from a dose range finding study with steady-state concentrations simulating zero-order ZAN-HC1.

[0016] FIG. 7 illustrates the concentration of ZAN achieved in the plasma or the lung over the course of 50 hours following subcutaneous administration in mice.

[0017] FIG. 8 illustrates preclinical efficacy studies in mice were (a) is an exemplary experimental set; (b) is the survival in each cohort; and (c) is survival based on various dosing.

[0018] FIG. 9 illustrates (a) application of ZAN delivering reservoirs to the skin of rats; (b) plasma levels of ZAN achieved using CarraDres samples or the reservoirs of Table 1 (glass); and (c) achieved parameters.

[0019] FIG. 10 illustrates (a) application of ZAN delivering reservoirs to the skin of rats; (b) plasma levels of ZAN achieved using alginate samples or the reservoirs of Table 1 (glass); and (c) achieved parameters.

[0020] FIG. 11 illustrates physical and performance criteria were met using reservoir samples TSRL-3 and TSRL-27.

[0021] FIG. 12 illustrates results of rat PK during administration of ZAN containing devices using different types of reservoir materials.

[0022] FIG. 13 illustrates (a) the application of hydrogel forming MAP in tandem with drug loaded reservoir near the sternum for in vivo pharmacokinetic study in minipigs; (b) Removal of the intact MAP after 5 days of continuous delivery of ZAN to minipigs with no physiological changes to the site of application; and (c) plasma and lung concentration-time profile of ZAN after MAP-reservoir administration to minipigs. Data are expressed as mean ± SD (n=2-3).DETAILED DESCRIPTION

[0023] Transdermal drug delivery offers a number of improvements over other delivery systems. The drug directly enters the systemic circulation, circumventing absorption and first- pass barriers typical for oral delivery. Transdermal administration avoids skin puncture by syringe needles, eliminating pain and patient visits to a clinician. Transdermal delivery of ZAN, as an example, could allow large numbers of patients to be reached during an influenza outbreak,.

[0024] This disclosure provides, for the first time, the preparation and characterization of a novel drug containing reservoir, optionally loaded with the neuraminidase inhibitor ZAN (as one example), for use in combination with hydrogel-forming microarray patches (MAP(s)) that may be used for a multi-day treatment course following a single patch application. The hydrogel -forming MAP proposed here is positioned to replace the currently used inhaler, and offers the promise of an easier administration to a broader patient population, resulting in better patient compliance. The current system adds tremendous value to the growing need for therapeutics against influenza. The devices and processes provided herein are expected to significantly expand the therapeutic, as well as prophylactic, benefit of active agent / MAP formulations, which can easily be self-administered by patients from the comfort of their home during a subsequent outbreak.

[0025] While this disclosure focuses on administration of zanamivir (ZAN), it is equally appreciated that other active agents can be similarly delivered by the processes and using the devices as provided herein for the treatment or prophylaxis of one of more conditions caused by a virus, optionally one or more enveloped viruses, selected in particular from the group consisting of Arenaviridae, Herpesviridae, Retroviridae, Coronaviridae, Poxviridae, Togaviridae, Flaviviridae, Bunyaviridae, Filoviridae, Orthomyxoviridae, Paramyxoviridae and Rhabdoviridae.

[0026] Illustratively, an active agent is an antiviral, antibacterial, antifungal, or other active agent. An active agent is illustratively an antiviral, optionally and anti -influenza agent. An active agent is optionally any active agent that can treat or prevent infection by enveloped viruses, selected in particular from the group consisting of Arenaviridae, Herpesviridae, Retroviridae, Coronaviridae, Poxviridae, Togaviridae, Flaviviridae, Bunyaviridae, Filoviridae, Orthomyxoviridae, Paramyxoviridae and Rhabdoviridae.

[0027] An active agent is optionally an antiviral agent. Illustratively, an antiviral agent is a: neuraminidase inhibitor such as but not limited to oseltamivir, zanamivir, or peramivir; a cap-dependent endonuclease inhibitor such as baloxavir marboxil; or an adamantine such as amantadine or rimantadine. An antiviral is optionally remdesivir. It is appreciated that the processes and devices as used herein may be used for any agent that functions as an antiviral, antibiotic, antifungal, or combination thereof.

[0028] An active agent according to some aspects as provided herein is one that has a desired site of action anywhere in the body, optionally in the lung or portion thereof. In some aspects it was found that transdermal administration of an active agent effectively delivers active agent to the desired site of action for maximal activity without the need for oral or inhalational administration thereby bypassing issues with prior delivery mechanisms, particularly for active agents that are not orally bioavailable and / or for administration to patients that have compromised lung, optionally due to infection.

[0029] As such, provided are processes of treating or preventing infection by an antiviral agent and devices for such administration and / or delivering an active agent to a subject. A process as provided herein includes contacting a subject with a microneedle device with a reservoir as provided herein and comprising one or more active agents with the skin of a subject to thereby direct a level of anti-viral agent to the subject thereby promoting improved efficacious dosing of active agent to a subject optionally suffering from or at risk of a viral infection.

[0030] Provided are devices for delivery of one or more active agents to a subject such as through transdermal delivery. A device is optionally a microneedling (MN) device and includes a reservoir layer and a microneedle delivery layer. A microneedle delivery layer is optionally any such system as found in a microneedling device known in the art, optionally including oneor more swellable polymers. Illustratively, a microneedle device is that described in U. S. Patent Nos: 8,414,548; 9,782,574; 9,549,746; and 10,195,410, among others.

[0031] A device as provided herein also includes a reservoir layer that includes one or more active agents therein. A reservoir layer optionally is in contact, optionally direct contact with a microneedle delivery layer such that an active agent may pass from the reservoir layer into the microneedle delivery layer, optionally upon wetting of the microneedle delivery layer, the reservoir layer, or both. Wetting of the microneedle delivery layer, the reservoir layer, or both is optionally from bodily fluid from a subject upon application of the device and microneedle piercing of the skin, by external or other non- / / / vivo wetting, or a combination thereof. Upon passing to the microneedle delivery layer from the reservoir layer, the active agent may then pass into the epidermis and / or dermis (e.g. upper dermis) of the subject through the microneedle delivery layer for effective subdermal delivery of the active agent to the subject.

[0032] It was found that not all types of reservoir layer material are effective at both storing an active agent and passing the active agent to the microneedle delivery layer. It is desired that an effective reservoir layer satisfy the largest number of effectiveness criteria. Optionally, a reservoir layer satisfies one or more, optionally all of the following: 1) be able to hold the desired drug load (optionally 100 mg or greater); 2) allow the active agent to pass from the reservoir to the microneedle delivery layer, optionally with a minimum retention of active agent (e.g. less than 50% remaining following delivery), have a rapid onset of delivery (e.g. less than 1 hour), optionally reach an in vivo Cmax in less than 8 hours, optionally be capable of sustained delivery for one or more days, optionally 5 days, and be of sufficient physical dimension to be acceptable for wear on the skin of a subject for the desired delivery time; 3) contain only or primarily generally accepted as safe components as the term is understood in the art; 4) be stable for long storage and handling such as providing suitable stability to the active agent itself, be of itself a stable composition, be stable to moisture, excessive heat or cold; and / or 5) be sufficiently pliable to allow for application pressure to the skin without cracking, breaking or deforming in such a way to reduce effective delivery of the active agent. It was found that most, and often all of the desired characteristics are met by the unique reservoir materials used in the devices as provided herein.

[0033] It was found that a reservoir layer that includes, optionally solely includes, a material in the form of a pliable glass, optionally with particular components in particular amounts, suitably satisfied most if not all of the above criteria. A glass, as used herein, is anamorphous solid material, optionally partially or entirely with no crystallinity, and optionally with a water or other solvent content at or below 10 wt%, optionally 5 wt%, optionally 2 wt%, optionally 1 wt%. Glass may be formed by the dehydration or desiccation of a liquid precursor material that may include one or more glass forming agents that serve to prevent crystalline formation upon desiccation. It is appreciated that the active agent, one or more glass forming agents, and one or more additives are present within the structure of the glass itself, and optionally excludes a glass system such as a glass filter membrane with the active agent absorbed into the membrane.

[0034] The term “pliable” as used herein means a glass with sufficient strength to withstand the force necessary to allow a microneedle layer to penetrate the skin of a subject, without the glass layer cracking, breaking or deforming in such a way to reduce effective delivery of the active agent. Pliable optionally does not produce a 25% or greater reduction in force (partial breakage) during a test of up to 40 N using a Lloyd LRX Plus Materials Testing Machine (JLW Instruments, Chicago, IL) using a reservoir layer alone.

[0035] As such, a glass as used in a reservoir layer optionally includes an active agent and one or more additives. An additive may be a compound that forms a glass, or that reduces the formation of crystals upon desiccation and / or densification. Alternatively, an additive may be a compound that imparts one or more desirable characteristics to the glass such as pliability, clarity, dissolution ability, etc. Illustrative examples of an additive include, but are not limited to dimethylsulfoxide, glycerol, sugars, polyalcohols, methylamines, betaines, antifreeze proteins, synthetic anti-nucleating agents, polyvinyl alcohol, cyclohexanetri ols, cyclohexanediols, inorganic salts, organic salts, ionic liquids, gelatin or combinations thereof. In some aspects, an additive is glycerol or a disaccharide. Illustrative examples of a disaccharide additive include sucrose and trehalose. Optionally, a reservoir layer includes one or more additives, optionally 2, 3, 4, or more additives. In some aspects, a reservoir layer excludes an additive.

[0036] An additive may be present in a reservoir layer at a particular concentration so as to import both the desired stability, but also the desired physical characteristics of the reservoir layer.

[0037] An additive is optionally present in the reservoir layer at about 2 wt% to about 50 wt% or any value or range therebetween. Optionally, an additive is present in a reservoir layerat about 10 wt% to about 50 wt%, optionally about 20 wt% to about 40 wt%, optionally about 10 wt% to about 30 wt%, optionally about 20 wt% to about 30 wt%, optionally about 20 wt% to about 25 wt%. An additive is optionally present in a reservoir layer at about 2 wt%, optionally about 2.5 wt%, optionally about 3 wt%, optionally about 4 wt%, optionally about 4.5 wt%, optionally about 5 wt%, optionally about 6 wt%, optionally about 6.5 wt%, optionally about 7 wt%, optionally about 7.5 wt%, optionally about 8 wt%, optionally about 9 wt%, optionally about 10 wt%, optionally about 11 wt%, optionally about 12 wt%, optionally about 13 wt%, optionally about 14 wt%, optionally about 15 wt%, optionally about 15.5 wt%, optionally about 16 wt%, optionally about 17 wt%, optionally about 18 wt%, optionally about 19 wt%, optionally about 20 wt%, optionally about 21 wt%, optionally about 22 wt%, optionally about 23 wt%, optionally about 24 wt%, optionally about 25 wt%, optionally about 26 wt%, optionally about 27 wt%, optionally about 28 wt%, optionally about 29 wt%, optionally about 30 wt%, optionally about 31 wt%, optionally about 32 wt%, optionally about 33 wt%, optionally about 34 wt%, optionally about 35 wt%, optionally about 36 wt%, optionally about 37 wt%, optionally about 38 wt%, optionally about 39 wt%, optionally about 40 wt%, optionally about 41 wt%, optionally about 42 wt%, optionally about 43 wt%, optionally about 44 wt%, optionally about 45 wt%, optionally about 46 wt%, optionally about 47 wt%, optionally about 48 wt%, optionally about 49 wt%, optionally about 50 wt%.

[0038] In some aspects, an additive is a sugar or other material that supports pliability or stability to a glass or acts as an agent to prevent crystal formation in the resulting glass. A sugar is optionally a monosaccharide, disaccharide, or other polysaccharide. Illustrative examples of sugars include but are not limited to sucrose, lactose, glucose, fructose, galactose, trehalose, pullulan, dextrose, alginate, gellan, mannan, agarose, chitosan, and cyclodextrins. Optionally, a sugar or the like is present in a reservoir layer at about 10 wt% to about 50 wt% or any value or range therebetween, optionally about 20 wt% to about 40 wt%, optionally about 12 wt% to about 21 wt%. Optionally, an additive is present at greater than about 10 wt% and no more than about 25 wt%. Optionally, an additive is present at a weight percent of about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21.

[0039] In some aspects, a reservoir layer includes a desiccation additive. A desiccation additive optionally serves to increase the rate at which drying of the reservoir layer material is achieved. In some aspects, a desiccation additive is gelatin. Gelatin, when present, is optionally present at about 20 wt% to about 40 wt%, or any value or range therebetween, optionally about20 wt% to 35 wt%, optionally about 21 wt% to 33 wt%. In some aspects, gelatin is present in a reservoir layer at a weight percent that is about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35.

[0040] In some aspects, a reservoir layer includes an additive that is a polymer. A polymer is optionally alginate, HPMC, PPG, isosorbide (e.g. PolySorb), pullulan, dextran, or a combination thereof. A polymer, when present, is optionally present at about 2 wt% to about 40 wt%, or any value or range therebetween, optionally about 20 wt% to about 35 wt%, optionally about 25 wt% to about 40 wt%. In some aspects, a polymer is present in a reservoir layer at about 2 wt%, optionally about 2.5 wt%, optionally about 3 wt%, optionally about 4 wt%, optionally about 4.5 wt%, optionally about 5 wt%, optionally about 6 wt%, optionally about 6.5 wt%, optionally about 7 wt%, optionally about 7.5 wt%, optionally about 8 wt%, optionally about 9 wt%, optionally about 10 wt%, optionally about 11 wt%, optionally about 12 wt%, optionally about 13 wt%, optionally about 14 wt%, optionally about 15 wt%, optionally about 15.5 wt%, optionally about 16 wt%, optionally about 17 wt%, optionally about 18 wt%, optionally about 19 wt%, optionally about 20 wt%, optionally about 21 wt%, optionally about 22 wt%, optionally about 23 wt%, optionally about 24 wt%, optionally about 25 wt%, optionally about 26 wt%, optionally about 27 wt%, optionally about 28 wt%, optionally about 29 wt%, optionally about 30 wt%, optionally about 31 wt%, optionally about 32 wt%, optionally about 33 wt%, optionally about 34 wt%, optionally about 35 wt%, optionally about 36 wt%, optionally about 37 wt%, optionally about 38 wt%, optionally about 39 wt%, optionally about 40 wt%, optionally about 41 wt%, optionally about 42 wt%, optionally about 43 wt%, optionally about 44 wt%, optionally about 45 wt%, optionally about 46 wt%, optionally about 47 wt%, optionally about 48 wt%, optionally about 49 wt%, optionally about 50 wt%.

[0041] Optionally, an additive is pullulan wherein the pullulan is optionally present at about 30 wt%, optionally about 31 wt%, optionally about 32 wt%, optionally about 33 wt%, optionally about 34 wt%, optionally about 35 wt%, optionally about 36 wt%, optionally about 37 wt%, optionally about 38 wt%, optionally about 39 wt%, optionally about 40 wt%, optionally about 41 wt%, optionally about 42 wt%, optionally about 43 wt%, optionally about 44 wt%, optionally about 45 wt%, optionally about 46 wt%, optionally about 47 wt%, optionally about 48 wt%, optionally about 49 wt%, optionally about 50 wt%.

[0042] Optionally, an additive is a dextran, optionally a dextran with a molecular weight of about 40 kDa. The dextran is optionally present at about 30 wt%, optionally about 31 wt%, optionally about 32 wt%, optionally about 33 wt%, optionally about 34 wt%, optionally about 35 wt%, optionally about 36 wt%, optionally about 37 wt%, optionally about 38 wt%, optionally about 39 wt%, optionally about 40 wt%, optionally about 41 wt%, optionally about 42 wt%, optionally about 43 wt%, optionally about 44 wt%, optionally about 45 wt%, optionally about 46 wt%, optionally about 47 wt%, optionally about 48 wt%, optionally about 49 wt%, optionally about 50 wt%.

[0043] Optionally, an additive is HPMC. HPMC when present is optionally present at about 2 wt% to about 20 wt%. Optionally, HPMC is present at about 2 wt%, optionally about 2.5 wt%, optionally about 3 wt%, optionally about 4 wt%, optionally about 4.5 wt%, optionally about 5 wt%, optionally about 6 wt%, optionally about 6.5 wt%, optionally about 7 wt%, optionally about 7.5 wt%, optionally about 8 wt%, optionally about 9 wt%, optionally about 10 wt%, optionally about 11 wt%, optionally about 12 wt%, optionally about 13 wt%, optionally about 14 wt%, optionally about 15 wt%, optionally about 15.5 wt%, optionally about 16 wt%, optionally about 17 wt%, optionally about 18 wt%, optionally about 19 wt%, optionally about 20 wt%.

[0044] Optionally, an additive is PPG. PPG when present is optionally present at about 2 wt% to about 20 wt%. Optionally, PPG is present at about 2 wt%, optionally about 2.5 wt%, optionally about 3 wt%, optionally about 4 wt%, optionally about 4.5 wt%, optionally about 5 wt%, optionally about 6 wt%, optionally about 6.5 wt%, optionally about 7 wt%, optionally about 7.5 wt%, optionally about 8 wt%, optionally about 9 wt%, optionally about 10 wt%, optionally about 11 wt%, optionally about 12 wt%, optionally about 13 wt%, optionally about 14 wt%, optionally about 15 wt%, optionally about 15.5 wt%, optionally about 16 wt%, optionally about 17 wt%, optionally about 18 wt%, optionally about 19 wt%, optionally about 20 wt%.

[0045] Optionally, a reservoir includes two polymer additives. Optionally, a reservoir includes both PPG and pullulan. Optionally, the PPG is present at about 2 wt% to about 20 wt%. Optionally, PPG is present at about 2 wt%, optionally about 2.5 wt%, optionally about 3 wt%, optionally about 4 wt%, optionally about 4.5 wt%, optionally about 5 wt%, optionally about 6 wt%, optionally about 6.5 wt%, optionally about 7 wt%, optionally about 7.5 wt%, optionally about 8 wt%, optionally about 9 wt%, optionally about 10 wt%, optionally about 11wt%, optionally about 12 wt%, optionally about 13 wt%, optionally about 14 wt%, optionally about 15 wt%, optionally about 15.5 wt%, optionally about 16 wt%, optionally about 17 wt%, optionally about 18 wt%, optionally about 19 wt%, optionally about 20 wt%. Optionally, the pullulan is present at about 30 wt%, optionally about 31 wt%, optionally about 32 wt%, optionally about 33 wt%, optionally about 34 wt%, optionally about 35 wt%, optionally about36 wt%, optionally about 37 wt%, optionally about 38 wt%, optionally about 39 wt%, optionally about 40 wt%, optionally about 41 wt%, optionally about 42 wt%, optionally about43 wt%, optionally about 44 wt%, optionally about 45 wt%, optionally about 46 wt%, optionally about 47 wt%, optionally about 48 wt%, optionally about 49 wt%, optionally about 50 wt%.

[0046] Optionally, a reservoir includes both PPG and a dextran, optionally dextran 40. Optionally, the PPG is present at about 2 wt% to about 20 wt%. Optionally, PPG is present at about 2 wt%, optionally about 2.5 wt%, optionally about 3 wt%, optionally about 4 wt%, optionally about 4.5 wt%, optionally about 5 wt%, optionally about 6 wt%, optionally about6.5 wt%, optionally about 7 wt%, optionally about 7.5 wt%, optionally about 8 wt%, optionally about 9 wt%, optionally about 10 wt%, optionally about 11 wt%, optionally about 12 wt%, optionally about 13 wt%, optionally about 14 wt%, optionally about 15 wt%, optionally about15.5 wt%, optionally about 16 wt%, optionally about 17 wt%, optionally about 18 wt%, optionally about 19 wt%, optionally about 20 wt%. The dextran is optionally present at about 30 wt%, optionally about 31 wt%, optionally about 32 wt%, optionally about 33 wt%, optionally about 34 wt%, optionally about 35 wt%, optionally about 36 wt%, optionally about37 wt%, optionally about 38 wt%, optionally about 39 wt%, optionally about 40 wt%, optionally about 41 wt%, optionally about 42 wt%, optionally about 43 wt%, optionally about44 wt%, optionally about 45 wt%, optionally about 46 wt%, optionally about 47 wt%, optionally about 48 wt%, optionally about 49 wt%, optionally about 50 wt%.

[0047] One or more active agents are included in the glass of the reservoir layer. Optionally, one active agent is included in the reservoir layer. Optionally, 2, 3, or more active agents are included in the reservoir layer. An active agent, or the total of all active agents, is optionally present in the glass of the reservoir layer at a concentration of about 50 wt% or higher, optionally about 55 wt% or higher, optionally about 60 wt% or higher, optionally about 65 wt% or higher, optionally about 70 wt% or higher, optionally about 75 wt% or higher.

[0048] An active agent is optionally present in the reservoir layer or specifically in the glass of the reservoir layer at a desired concentration, optionally that may be delivered over the desired treatment time. Optionally, an active agent is present in the reservoir layer or specifically in the glass of the reservoir layer at 100 milligrams to 500 milligrams. Optionally, an active agent is present in the reservoir layer or specifically in the glass of the reservoir layer at 1 mg or greater, optionally 10 mg or greater, optionally 50 mg or greater, optionally 100 mg or greater, optionally 125 mg or greater, optionally 150 mg or greater, optionally 175 mg or greater, optionally 200 mg or greater, optionally 250 mg or greater, optionally 300 mg or greater, optionally 400 mg or greater, optionally 500 mg or greater.

[0049] An active agent retention within a reservoir layer following delivery to a subject is optionally 50% of the original amount presented or less. Optionally, an active agent retention within a reservoir layer following delivery to a subject is optionally equal to or less than 50%, 40%, 30%, 20%, 15%, or 10% of the original amount held in the reservoir layer.

[0050] An active agent is optionally in the form of a salt of an active agent. In particular aspects, an active agent is in the form of an acid salt of an active agent, optionally a hydrochloride (HC1) salt form. An active agent is optionally not in the form of a hydrate.

[0051] A reservoir layer is optionally formed by combining an aqueous solution or suspension of active agent and one or more additives, and allowing the system to dry to a water content of about 10 wt% or less, optionally about 5 wt% or less, optionally about 1 wt% or less. During desiccation, the presence of the additive(s) prevents crystallization of the material thereby promoting glass formation. It is appreciated that in some aspects, a glass is free of any crystal formation. In some aspects, however, some level of crystal formation is inevitable such that some crystal regions may be present in the glass, but are acceptable as long as the presence of the crystal regions do not detract from the desired pliability of the glass or negatively impact the reconstitution of the active agent or other delivery characteristic of the active agent. In some aspects, desiccation is performed under vacuum such as in vitrification processes as known in the art. Optionally, forming a reservoir layer includes stirring or other agitation. Optionally, forming a reservoir layer includes heating the material during desiccation, or optionally excluding application of heat through an external heat source. In other aspects, formation of the reservoir layer includes simple air desiccation of the material over time to produce the resulting pliable glass.

[0052] A device as provided herein may include a reservoir with physical dimensions and / or pliability characteristics so as to be applied to the skin without introducing an unacceptable number of fractures or other defects into the device or reservoir upon application. As such, a reservoir as provided herein has a thickness. A thickness is optionally measured at a central point within the reservoir. In aspects where a reservoir is produced by drying in a chamber, a meniscus may form in the device shape. A thickness as measured herein is optionally at or near the center point of such a reservoir. A thickness or a reservoir is optionally about 1 mm to about 3.5 mm, or any value or range therebetween. Optionally, a thickness is less than about 3.5 mm. Optionally, a thickness is less than about 2 mm. Optionally, a thickness is about 1.25 mm to about 2.3 mm. Optionally, a thickness is about 1.25 mm. to 2.3 mm. Optionally a thickness is about 1.4 mm to about 3.25 mm.

[0053] A device as provided herein optionally includes a reservoir with sufficient pliability to allow for application pressure to the skin without cracking, breaking or deforming in such a way to reduce effective delivery of the active agent. Optionally, a pliable glass is one that does not crack, break or otherwise reduce the ability to transfer active agent to the microneedle delivery layer following standard thumb pressure applying the device to the skin. Pliability is optionally measured by force testing, optionally using a Lloyd LRX Plus Materials Testing Machine (JLW Instruments, Chicago, IL). A reservoir optionally has a pliability that does not produce a fracture (force reduction to 1 N or less during test) up to a force of 40 N. Optionally, a reservoir has a pliability that does not produce a 25% or greater reduction in force (partial breakage) during a test of up to 40 N.

[0054] A reservoir layer is in active agent communication with a microneedle delivery layer or a device is configured to put the reservoir layer in active agent communication with the microneedle delivery layer upon application to the skin of a subject. Optionally, the reservoir layer is contacting, optionally directly contacting, a microneedle delivery layer such that upon rehydration of the reservoir layer, active agent is able to be transmitted into the microneedle delivery layer for subsequent delivery to the skin of a subject.

[0055] A microneedle delivery layer is optionally formed by applying a material to a mold and polymerizing the material to form the microneedle delivery layer. Polymers suitable for a microneedle delivery layer optionally include swellable polymers. Illustratively, a polymer is the free acid form of the copolymer of methyl vinyl ether and maleic anhydride (sold as Gantrez™ S-97 BF polymer) in combination with polyethylene glycol (PEG, optionally10,000 Da). Other polymers may be used as is known in the art optionally polyvinyl alcohol along or in combination with a sugar as described herein. Optionally, a polymer is a combination of poly(methylvinylether / maleic acid), esters thereof and poly (methyl / vinyl ether / maleic anhydride).

[0056] The microneedle delivery layer is optionally formed by applying a material to a mold and allowing the material to polymerize or otherwise dry in the mold so as to form the microneedle delivery layer.

[0057] The microneedle delivery layer is optionally then contacted with a reservoir layer to form the device. Optionally, a microneedle delivery layer is contacted to a reservoir layer and the two are packaged in a single use package that is sufficient to substantially protect the device from contact with moisture until use. A peelable film may be removed from the package to retrieve the device for application to a subject.

[0058] Also as provided herein are processes of treating or preventing a disease or condition in a subject, optionally a disease or condition caused by a virus or other pathogenic agent. A process includes applying the device as provided herein to the skin of a subject for a treatment time. Optionally, a device may be applied to the skin of a subject prior to infection or onset of a disease or condition. Optionally, a device may be applied to the skin of a subject following infection or onset of a disease or condition, optionally within 48 hours following exposure or onset or one or more symptoms of a disease or condition.

[0059] It is appreciated that the active agents of this disclosure are optionally formulated for administration to a human individual. However, it is appreciated that the active agents of this disclosure and method of treatment may be indicated in non-human applications as well. Thus, an active agent is advantageously administered to a subject that is a human or a non- human organism such as a rodent, bovine, equine, avian, canine, feline, or other such species. As used herein, the terms “subject” and “patient” are synonymous and refer to a human or non- human animal, optionally a mammal including non-primates such as cows, pigs, horses, goats, sheep, cats, dogs, avian species and rodents; a non-human primate such as monkeys, chimpanzees, and apes; and a human, also optionally denoted specifically as a “human subject”.

[0060] Variable dosing regimens are operative in the method of prevention or treatment as provided herein. While single dose treatment is effective in producing therapeutic effects, it isnoted that longer courses of treatment such as several days to weeks have previously been shown to be efficacious in drug therapy (Beck et al., Human Gene Therapy, 6: 1525-30 (1995). The exact dose of active agent required is appreciated to vary from subject to subject, depending on the age, weight and general condition of the subject, the severity of the disease being treated, the particular pharmaceutical species, the mode of administration, and the like. An appropriate dose is readily determined by one of ordinary skill in the art using only routine experimentation given the teachings herein. Generally, total dosage is in the range of about 0.1 to 7 mg / kg, optionally 0.5 to 20 mg / kg, optionally 1 to 15 mg / kg, optionally 1 to 10 mg / kg. optionally 1 to 5 mg / kg, about 2 to about 5 mg / kg, or about 2 to about 4 mg / kg where the amount of active agent is delivered at a substantially consistent rate over 1 to 10 days, optionally 3 to 7 days, optionally 5 days. In some aspects a dosage is substantially consistent for the duration of administration of the device as provided herein. Substantially consistent delivery is optionally one where upon reaching a desired plasma or epithelial lining fluid (ELF) concentration, optionally the Cmax, the concentration of active agent is at or above the 50% inhibitory concentration for an active agent target virus, optionally at or above the 90% inhibitory concentration of the active agent target virus, but not so high so as to produce toxicity in the subject during delivery time. Optionally, substantially consistent is a delivery that produces a plasma or tissue concentration from 8 hours after device application to 120 hours following device application that remains at or above the IC50 for the particular active agent, optionally between 10 to 100-fold above the IC50 for the particular active agent.

[0061] Various aspects of the present disclosure are illustrated by the following nonlimiting examples. The examples are for illustrative purposes and are not a limitation on any practice of the present disclosure. It will be understood that variations and modifications can be made without departing from the spirit and scope of the invention. Reagents illustrated herein are commercially available, and a person of ordinary skill in the art readily understands where such reagents may be obtained.EXAMPLES

[0062] Production of microneedle delivery device.

[0063] For the production of microneedle patches for both in vitro and in vivo release studies, microneedle molds are filled with the prepared polymer and submitted to 60 psi of positive pressure for 20 minutes. Once removed from positive pressure, the molds are transferred to a drying oven at 40 °C for 48-72 hrs. Microneedle arrays are then removed fromthe molds, excess polymer is removed, and the arrays are cross-linked at 80 °C for about 1 hour. Post cross-linking, MN arrays are stored in a desiccator until use.

[0064] General process for preparing reservoirs:

[0065] Reservoir layers TSRL-X were formed by using a dilute ZAN-HC1 solution at a concentration to provide the desired volume of liquid. Prior to bringing the solution to final volume, various excipients (if included) were added to the solution in the final dried glass percentages shown in Table 1 below. Trehalose (if used) was added, and stirred until homogenous. Once dissolved, other additives (e.g. gelatin, alginate, pullulan, dextran (e.g. dextran 40 with average mol. wt. 40,000), glycerol, hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), polypropylene glycol (PPG), isosorbide (PolySorb™) were added slowly to prevent clumping. Finally, the appropriate volume or water was added and the solution was stirred for 10 minutes.

[0066] The above created solutions were pipetted into a silicone tray with cylindrical holes (13 mm diameter, 5-14 mm depth) and weighed. The molds containing solution were then left to dry at room temperature for 72-96 hours, at which point the dried reservoir was removed from the mold. In some examples, the solution was heated to 40 °C and / or stirred during the drying time. Following drying, masses were taken of each reservoir after removal.

[0067] Reservoir TSRL-32

[0068] Reservoir layer TSRL-32 was formed by adding to 326 mg of water to 0.0264 g of Zanamivir Hydrate in a vial and the mixture was stirred rapidly. To this suspension was added 137 mg of 6N HC1 and 54 mg of polypropylene glycol (PPG). The mixture was stirred until all the solids dissolved. To the solution was added 215 mg of Dextran 40. Water was added to bring the volume to 1 mL with stirring until all the solids were dissolved. Then the mixture was allowed to stand to let the bubbles dissipate. The solution was then dispensed into the appropriate size mold for drying. Drying was at 27 degrees with 10% relative humidity for up to 72 hours.

[0069] Reservoirs TSRL-8 and TSRL-9:

[0070] Reservoir layers LYO-1 (TSRL-8) and LYO-2 (TSRL-9) in the form of wafers were prepared by mixing weighed drug (or above prepared ZAN-HC1), gelatin, trehalose and deionized water, as detailed in the Table 1, using the SpeedMixer™ (GermanEngineering, Hauschild & Co. KG, Hamm, Germany) at 3,500 rpm for 3 minutes (min). Approximately 100 mg of each formulation was cast into an open-ended cylindrical mold (diameter 8 mm, depth 4 mm). Prior to the lyophilization process, the cast formulations were frozen at -80 °C for 3 h.Next, the formulations were lyophilized in a freeze dryer (Virtis™ Advantage XL-70, SP Scientific, Warminster PA, USA) for 24 h, following a cycle of primary drying for 13 h at -40 °C, secondary drying for 11 h at 25 °C and vacuum pressure maintained at 50 mTorr throughout the cycle.

[0071] Example TSRL-6 in Table 1 was prepared by adding 400 pL of ZAN HC1 solution to a tin foil cup (1.2 cm x 1.2 cm), and left to dry at ambient conditions overnight, at which point the foil was trimmed down to the base of the glass.

[0072] The above created solutions were pipetted into a silicone tray with cylindrical holes (13 mm diameter, 5-14 mm depth) and weighed. The molds containing solution were then left to dry at room temperature for 72-96 hours, at which point the dried reservoir was removed from the mold. In some examples, the solution was heated to 40 °C and / or stirred during the drying time. Following drying, masses were taken of each reservoir after removal.

[0073] Table 1 : The weight percent (wt%) composition of exemplary reservoirs. (Unless indicated all reservoirs were 1.2 cm2.)1= larger surface area reservoir of 3.1 cm2

[0074] CarraDres Reservoirs:

[0075] For the production of the CarraDres™ reservoir which is used as a comparator for the examples in Table 1, a dilute HC1 solution of ZAN was made by mixing 408 microliters (pL) of concentrated HC1 with 1 mL of deionized water. 1.71 g of Zanamivir hydrate was weighed directly into a tared 25 mL graduated cylinder, along with 3 mL of water. This was kept on an ice bath for 10 minutes along with all of the dilute HC1 solution. The dilute acid solution was pipetted in its entirety into the Zanamivir solution slowly and dropwise, allowing the suspension to remain cool during addition. After addition, the vial containing the dilute HC1 was washed with two (2) 250 pL aliquots of water, adding the aliquots to the Zanamivir HC1 solution after vortexing. The solution was continually stirred at room temperature until drug appears fully dissolved. While stirring, 120 pL of benzyl alcohol was added to the solution. Once the benzyl alcohol has dissolved into solution, 5.262 mL of water is added to bring the concentration of Zanamivir HC1 to 150 mg / mL. After the last addition of water, the solution was stirred for 5 minutes.

[0076] CarraDres™ sheets (hydrogel wound dressing material) was cut into squares of 0.75 x 0.75 cm. Each square was placed into a pre-weighed scintillation vial, and then the vial was weighed again. 2 mL of Zanamivir HC1 solution as produced above (150 mg / ml) was added to each container, and an additional weight was taken. All containers were stored refrigerated. After ~48 hours, each square was removed from the solution, each side was gently blotted with a Kimwipe, and then weighed just prior to use. A final weight of the container with remaining solution was taken following removal of the square.

[0077] Example 2: Physical testing parameters

[0078] The reservoirs of Table 1 were subjected to testing for the ability to withstand the rigors of handling and application to the skin of a subject without fracture or degradation. Reservoirs made with different excipients and prepared under either ambient temperature, heating to 40 °C or shaking at ambient temperature during drying were placed meniscus down on the sample plate. A 500 N maximum load cell was used with a 1.5 cm diameter probe to apply force to the reservoir. The stop load was set at 40 N, and the probe was lowered at a rate of 0.100 mm / s.

[0079] The first point after which the detected force reduced by 25% or greater was considered a partial breakage and recorded. Subsequent partial breakages were not recorded. A failure was recorded as the highest force after which there was a reduction of force to less than 1 N, at which point the instrument automatically reset and did not proceed with testing. Results are illustrated in Table 2. Generally the data is the average of 3 samples with one exception with an n=l (marked with a *).

[0080] Table 2:

[0081] It was noted that TSRL-27 (dried without heat) was highly pliable and able to be substantially folded completely without fracture or cracking and then return to the original form demonstrating excellent pliability. Similar lack of fracture is expected for TSRL-28 as well.

[0082] Example 3: In vitro diffusion analyses

[0083] To determine the diffusion of various formulations of ZAN, side-by-side diffusion cells (PermeGear, Hellertown PA, USA) were utilized to determine drug permeation across the hydrogel film, as previously described in Q. K. Anjani, et al., European Journal of Pharmaceutics and Biopharmaceutics, 2021, 158:294-312. Initially, hydrogel films were preswollen in phosphate buffered saline (PBS) (pH 7.4). After 24 hours, the films were then cut into a circle shape with diameter of 9 mm2to be placed between the receiver and donor compartments. 3 ml of drug solution (1 mg / ml) and PBS (pH 7.4) were filled into the donor and receiver compartments, respectively. At pre-determined time intervals, an aliquot (3 mL) from the receiver solution was taken and replaced with the same amount of fresh PBS (pH 7.4). All the samples obtained were analyzed using a validated of high-performance liquid chromatography (HPLC) method. The composition and dissolution rates for various reservoirs are shown in FIG. lb and FIG. 1c.

[0084] To test if the Zanamivir free base or Zanamivir HC1 salts could be used interchangeably, LYO-1 and LYO-2 membranes (Table 1) were each prepared with the ZAN- free base and the ZAN-HC1. With respect to the type of ZAN salts, LYO-2 reservoirs displayed a higher drug content (pg) relative to LYO-1. LYO reservoirs fabricated from ZAN HC1 displayed a significantly faster ( / ?<0.05) dissolution time relative to ZAN hydrate.

[0085] The reservoirs of Table 1 were also subjected to in vitro diffusion analyses to determine if the reservoirs met the desired criteria of rapid release of the drug and if the results of the LYO wafers could be improved. For these studies, the Teledyne Hanson Phoenix DB-6 Dry Heat Diffusion system was prepared by pre-heating the block to 32 °C and filling all cells with receptor medium (phosphate buffered saline pH 7.4). The Durapore membrane was placed between the clamped pieces atop the system wherein the respective reservoir was placed on top. Cells were stirred at 600 rpm.

[0086] 500 pL was sampled from each cell at 0, 0.25, 0.5, 1, 2, 4, 6, 8, and up to 24 hour time points. Generally there was little change after 8 hours. Cell sampling necks were stoppered before and after sampling. Samples were stored at 4 °C until analysis. Immediately after collection, 500 pL of receptor medium, PBS (32 °C) was injected back into the cell. Samples were analyzed using LC-MS / MS with results illustrated in FIGs. 2 and 3.

[0087] As is illustrated in FIG. 2, all of the TSRL reservoirs rapidly diffused ZAN-HC1 to a greater degree than the CarraDres membrane samples. TSRL-3 reached full release of ZAN- HC1 within 1 hour, TSRL-10 reached full release within two hours and TSRL-27 reached fullrelease by 4 hours, whereas the CarraDres material required as much as 8 hours to full release ofZAN HCl.

[0088] In FIG. 3 TSRL-32 is shown along with the TSRL-32 hydrate. Permeation is 100% in 24 hours for TSRL-32 which is the HC1 salt of Zanamivir but the hydrate permeates slower and only reaches 84% after 24 hours. TSRL-32 meets all the in vitro criteria for an ideal reservoir for the delivery of Zanamivir via microneedles

[0089] Example 4: Preparation of microarray patch (MAP) devices

[0090] The MAP devices were prepared from a hydrogel formulation consisting of a solution of 30 wt% of Gantrez™ S-97 BF polymer (the free acid form of the copolymer of methyl vinyl ether and maleic anhydride) and polyethylene glycol (PEG, MW = 10,000). The Gantrez-PEG solution was added on top of laser-ablated silicon MN templates (Blueacre Technology Ltd, Dundalk, Ireland), and positive pressure was applied to form the MAP. The needles were then dried in the mold at 40 °C. After 48 hours, the MAPs were removed from the molds, optionally trimmed, and thermally cross-linked at 80 °C for 24 hours. The final MAPs were packaged with a desiccant to prevent premature hydration.

[0091] The M APs were assessed for their physical strength by determining their ability to reproducibly penetrate multiple layers of polyolefin film (e.g. Parafilm ®M) as shown in FIG. 4(a) and (b). All MAPs were attached to the bottom of the probe of the Lloyd LRX Plus® (Ametek® Instruments, Largo, FL, USA) with double sided foam tape and inserted into six layers of polyolefin film at a rate of 0.1 mm / s until a force of 40 N was reached (equivalent to standard thumb pressure for application to the skin of a subject), where it was held for 30 seconds. Penetration was measured by depth, with each layer of film measuring ~160 micrometers (pm). Upon application, respective film layers were separated and observed microscopically to evaluate the pore uniformity as a function of penetration depth. It can be seen in FIG. 4(b) that the hydrogel forming MAP resulted in complete insertion into the first polyolefin film layer, as evident by the absence of any error bars. In addition, the average penetration depth was measured at 450 pm, with a high degree of reproducibility (CV<15%). This would suggest that the hydrogel forming MAP would be capable of breaching the outermost layer of the skin, the stratum corneum. in a consistent and reproducible fashion. It is expected that this would permit intradermal insertion of the MAP for the delivery of active agent such as ZAN into and across the skin with a low degree of variability.

[0092] The needles from the fabricated MAPs are sharp enough to pierce the skin as shown in FIG. 4(c), but once hydrated through exposure to dermal interstitial fluid, the polymer swells, resulting in the formation of a continuous hydrogel network. Upon swelling, this type ofhydrogel forming MAP is inherently self-disabling. This provides a safeguard mechanism to healthcare workers and caretakers, who might assist patients with drug administration, by preventing accidental needle reinsertion, which will ultimately mitigate the risk of sharps injury and transmission of blood borne infection. The swelling kinetics of the MAP (% water uptake over time) is shown in FIG. 4(d). It can be seen that the MAP doubled in weight in 2 hours, and reached maximum swelling capacity of approximately 800% within 4 hours. The degree of swelling that takes place upon skin application is understood to be sufficient to result in the formation of a continuous aqueous hydrogel conduit to deliver drug molecules from the dry reservoir into and across the skin.

[0093] Example 5: In vitro permeation studies

[0094] Using ex vivo dermatomed neonatal porcine skin, a permeation study was conducted using a Franz cell set up (Permergear, Hellertown PA, USA) substantially as illustrated in FIG. 5(a). The dermatomed skin samples were collected from stillborn piglets within 24 hours postmortem. Skin samples were stored at - 20°C prior to use. When assembling the Franz cells, skin sample was secured to the donor compartment using cyanoacrylate glue. PBS (pH 7.4) buffer was added into the receiver compartment and was thermostatically regulated at 37 ± 1 °C under stirring at 600 rpm. Hydrogel -forming MAPs were applied to the porcine skin via manual pressure for 30 s. Subsequently, a ZAN-loaded reservoir was added on top of the patch. The Franz cells set up is completed by meticulously securing the donor compartment with the receiver compartment using a metal clamp. In order to obviate the MAP from swelling out of the skin, a stainless-steel cylindrical weight (15.0 grams (g)) was then placed on top of the reservoir. Polyolefin film (Parafilm® M) was used to seal the sampling arm of the Franz cells to mitigate unwanted evaporation of the receiver solution. Throughout the permeation study, 200 pL of the receiver media was sampled and replaced with the equal volume of fresh PBS at predetermined time points. The collected receiver media was centrifuged at 14,000 rpm for 15 mins. The supernatant was collected for HPLC analysis. Where necessary, samples and external standards were diluted in PBS (pH 7.4).

[0095] Drug quantification was performed using HPLC (Agilent technologies 1220 infinity UK Ltd, Stockport, UK) equipped with Agilent degasser, binary pump, auto standard injector and UV detector. Analysis of the drug was carried out using a Spherisorb® ODS1 column (150 mm x 4.6 mm internal diameter, 5 micrometer (pm) particle size) (Waters, Dublin, Ireland) with the flow rate of 1 milliliter per minute (mL / min) at ambient temperature. The mobile phase used was deionized water and acetonitrile at a ratio of 95:5 v / v. The injection volume was 20microliters (pL) and the UV detector was set at 210 nanometers (nm). Chromatograms were analyzed using the Agilent ChemStation® Software B.02.01. The International Council of Harmonisation (ICH) 2005 guidelines were followed as a reference to assess all the analytical methods.

[0096] Statistical analysis was performed using graphing and analysis software sold as GraphPad Prism® version 8.0 (GraphPad Software, San Diego, California, USA). All experimental results were presented as means ± standard deviation (SD) unless otherwise stated. An unpaired t-test was used for the comparison of two cohorts. One-way analysis of variance (ANOVA) was used for the comparison of multiple cohorts. In all cases, p<0.05 used to denote statistical significance, where - value outputs were 0.033(*), 0.002(**), <0.001(***) and <0.0001 (****).

[0097] As can be seen from FIG. 5(b) and (c), the total ZAN delivered into and across the skin increases over the course of 24 hours. It was apparent that LYO wafers manufactured from ZAN HC1 resulted in a higher ZAN permeation across the skin and into the receiver compartment ( / ?<0.05). It should be noted that LYO-1 HC1 resulted in an overall more rapid and higher ZAN delivery ( / ?<0.05) across the skin within the first 8 hours. However, formulation LYO-2 HC1 resulted in a higher delivery (mg) of ZAN over the course of 24 hours (FIG. 4(c)).

[0098] Based on the results in FIGs. 5(d) and (e), it can be seen that ZAN HC1 reservoirs resulted in both higher cumulative drug permeation and delivery efficiency relative to ZAN Hydrate. This suggests that changing the salt of the drug did improve the delivery efficiency, but this did not mitigate the interaction of the drug with the hydrogel, resulting in some drug still being retained within the hydrogel network of the MAP at 24 hours. In the case of LYO-1 HC1, there is a higher drug loading within the wafer relative to LYO-1 Hydrate which in turn resulted in a higher amount (pg) of ZAN being delivered and entrapped within the hydrogel forming MAP. At higher drug loading as seen in LYO-2, however, the amount entrapped within the hydrogel forming MAP was relatively similar p> 0.05). Indeed, the amount of drug entrapped within the hydrogel system may be viewed as drug-loss from the 24-hour permeation study. However, should this system be viewed from a long-term application (e.g., over the course of 5 days), the amount of ZAN entrapped within the hydrogel would continue to diffuse into the skin over the treatment course thus leading to longer term total delivery.

[0099] Similar results to the LYO-2 HC1 studies should be achieved using the remaining ZAN-HC1 containing reservoirs as illustrated in Table 1 with excellent drug extraction fromeach reservoir producing excellent transfer to the microneedle portion of the device and subsequent transfer to the test skin samples.

[0100] Example 6: Evaluation of zero order ZAN delivery in in Hollow-Fiber- Infection Model (HEIM)

[0101] MDCK cells were mixed with oseltamivir-resistant A / HongKong / 2369 / 20009 (A / HK-H275Y) (H1N1 pdm) virus strain at a multiplicity of infection (MOI) of 10'6and inoculated into hollow fiber cartridges. Medium containing various concentrations of ZAN- HC1 was circulated through the HF cartridges in a continuous loop and was sampled daily. Viral supernatants were clarified via centrifugation and frozen at -80 °C prior to quantification by plaque assay on MDCK cells.

[0102] Results from a dose range finding study with steady-state concentrations simulating zero-order ZAN-HC1 input demonstrated that at plasma levels as low as 10 ng / mL ZAN reduced viral replication up to 48 hours (FIG. 6). The maximum virus suppression was achieved with a continuous infusion of 1000 ng / mL, which was similar to the effect observed at 2800 ng / mL, the concentration equivalent to the 24 hour AUC associated with 600 mg BID ZAN administered intravenously in humans. Viral suppression at 100 ng / mL was similar to that achieved at 1000 ng / mL. As such, in some aspects, a target range for ZAN MAP delivery in humans is optionally 200-300 ng / mL over a 5-day treatment course.

[0103] Example 7: Pharmacokinetics (PK) of ZAN via subcutaneous delivery

[0104] Prelclinical delivery of ZAN using MAPs as provided herein was studied in mice and rats. For PK determinations the mouse model proved to be too small of an animal for the required MAP size application. PK studies were alternatively performed in mice with subcutaneous (SC) administration to assess if ZAN levels in the lung remained above the IC50 over a long enough period that efficacy could be expected with BID SC dosing. Tests were performed over the course of 48 hours. Male CFW mice (n=4) were dosed with 30 mg / kg dose of Zanamivir HC1. Plasma and lung samples were obtained at 0, 5, 15, and 30 minutes, and 1, 2, 4, 8, 24, and 48 hours post dose.

[0105] Plasma samples were analyzed by LC-MS / MS. Plasma standards, QCs and study samples (300 pL) were diluted with 300 pL of ZAN Internal Standard solution (500 ng / mL in 4% phosphoric acid in water) and then processed by solid phase extraction using Waters Oasis MCX 1 cc (30 mg) LP Extraction Cartridges. LC-MS / MS (Shimadzu 8050 massspec, Shimadzu Nexera X2 HPLC) was performed after elution form a Kinetex C8 column with a 0.1% Formic acid in water: acetonitrile gradient. ZAN was monitored at two transitions (333.2^60.2; 333.2— >121.05), as well as the internal standard ZAN -13C,15N2(336.2^63.2;336.2^121.05). The method was suitable for measuring ZAN in mouse and rat plasma over a concentration range of 10 to 5,000 ng / mL and in pig plasma over a concentration range of 50 to 50,000 ng / ml with a %RE<15% and %CV<15%.

[0106] Lung tissue was analyzed by combining lung tissue (150 milligrams (mg)) with water (300 pl) containing Zanamivir internal standard solution at 333 ng / ml, and homogenized using a Bullet Blender set at speed 10 for 4 minutes. Samples were then centrifuged and 250 pl supernatant was combined with 350 pl 4% phosphoric acid and then processed and analyzed as described above. The method was suitable for measuring ZAN in lung tissue over a concentration range of 10 to 2,000 ng / ml with a revised accuracy criteria of %RE<20%.

[0107] Quantification of ZAN in epithelial lining fluid (ELF) was performed using bronchoaveolar lavage (BALF) samples collected from both rats and pigs. Samples were filtered using a 0.2 micron filter and analyzed using the LC / MS / MS method described above over a concentration range of 1.5 to 1,500 ng / ml with a %RE<20% and %CV<20%.

[0108] The samples filtered for ZAN quantification were also analyzed for urea concentration. Filtered pig samples were further diluted 10-fold with water prior to analysis. Standards, QCs and samples were analyzed by LC-MS / MS (Shimadzu 8050 massspec, Shimadzu Nexera X2 HPLC), after elution form a Kinetex C18 column with an isocratic 90: 10 ratio of 0.1% Formic acid in water: 0.1% Formic acid in acetonitrile. Urea was monitored at two transitions (61.1^-41.1; 61.1 ^>18.2). The method was suitable for measuring urea in BALF over a concentration range of 10 to 10,000 ng / mL in both rat and pig BALF with a %RE<20% and %CV<20%. Serum samples were collected from both rats and pigs and analyzed for urea concentration via standard clinical pathology assays at the University of Michigan (rats) and Charles River Laboratories (pigs). ZAN concentration in ELF was determined using the following equation: CELF=CBALF X (Ureaserum / UreaBALF).

[0109] After SC administration of ZAN at 30 mg / kg in mice, plasma levels peaked at 15 min and fell below the detection limit by 8 hours, while lung concentrations remained ~60-fold above the IC50 at 48 hours post dose (Fig. 7). The concentration-time profile of ZAN in plasma and lungs revealed a significantly prolonged half-life of ZAN in the lung (ti / 2 = 30.0 hours).

[0110] For preclinical efficacy studies, doses of ZAN were chosen based on the above results. In the dose-response study, female BALB / c mice (n=10) were assigned to seven cohorts including placebo, two controls (ribavirin and oseltamivir) and four treatment groups with ZAN. Mice were inoculated intranasally with a lethal dose of pandemic influenza A / Hong Kong / 2369 / 2009 (H1N1) oseltamivir-resistant virus four hours after the first dose and treatedBID for five days according to the treatment schedule summarized in FIG. 8(a). Animals were observed for weight loss and mortality for 21 days. The table in FIG. 8(b) shows the study design and animal survival in each cohort.

[0111] As expected, the majority of mice died in the placebo group, and all in the oseltamivir group. Ribavirin, as the positive control, protected mice completely, and the 100 mg / kg / day dose of ZAN protected 9 out of 10 mice. Surviving animals in the lower dose groups regained their weight upon recovery. While our initial expectation had been that we would also see some degree of protection at the 30 mg / kg dose of ZAN, further review of the potency data against the A / Hong Kong / 2369 / 2009 (HINlpdm) strain suggest that ZAN’s ECso (0.36 pM) translates to 120 ng / ml

[0027] . With twice per day dosing at 15 mg / kg, ZAN likely fell below this target concentration in the lung tissue between 4 and 8 hours post-dose.

[0112] We subsequently conducted a dose-regimen study at 100 mg / kg / day SC BID for 5 days, QD for 5 days, and every other day or every third day, again including oseltamivir at 100 mg / kg / day and ribavirin at 75 mg / kg / day as the negative and positive control, respectively. Survival graphs are shown in FIG. 8(c). All surviving animals regained their weight upon recovery. Daily QD dosing showed the best protection, with 80% of mice surviving. Protection progressively declined with less frequent dosing, and all animals died when only a single dose was given. Thus, paired with the efficacy driver being AUC above the IC50 for a ZAN MN, these data strongly support that a single dose administration of the ZAN MN formulation can lead to complete protection of influenza infection in humans. While continuous infusion of ZAN was not feasible in mice, the favorable pharmacokinetic and distribution into the epithelial lung lining fluid (ELF), as well as the PK / PD modeling and HFIM data, further support that with continuous, MAP-enabled delivery optimized therapeutic outcomes can be achieved.

[0113] Example 8: Pharmacokinetic (PK) characterization of ZAN transdermal delivery in mice and rats

[0114] The ZAN MN product (TSRL-066) with a 150 mg reservoir loading dose was applied topically to rats (n=4) as schematically illustrated in FIG. 9(a). Both Carradres™ (CD hydrogel) and dry reservoirs of Table 1 were evaluated. The ZAN MN product size used was 1 cm2. The treatment site (lateral anterior dorsal surface) was shaved and treated with depilatory cream 24 hours prior to application; and cleaned with 70% ethanol just prior to application. Foam rings were adhered to the skin, and MN & ZAN reservoir applied in the middle of the rings. MN and ZAN reservoirs were covered with Scotchpak®, Tegaderm™, and kinesiologytape to keep the dose in place. At study termination, ZAN MN patches were removed, and no visible signs of irritation were noted. Blood samples were collected over a 72-hour period, and lung lavage samples were collected at 0.5, 1, 2, 4 (separate cohorts) and 72 hours post dose. Samples were analyzed by LC / MS / MS (LOQ = 10 ng / mL) for ZAN concentration. Bronchoalveolar lavage (BAL) samples were then taken by making a small incision into the trachea and flushing 5 ml (2 ml for group 13) of water into the lungs and then withdrawing the water back into the syringe. All BAL samples were frozen at -80° C within 1 hour of collection. Pharmacokinetic parameters estimates are calculated from the concentration-time profiles using the WinNonLin Non-compartmental Analysis program, version 8.1.0.3530.

[0115] Plasma concentrations exceeding ZAN IC50 levels for influenza virus isolates (>1.4 ng / mL) were achieved with the both the CD as well as the dry ZAN HC1 glass reservoir as early as 15 min post administration (FIG. 9(b)). For the carradres samples, the concentrations continued to increase until 24 hours post administration, at which time steady state was achieved and maintained through 72 hours post administration. As expected, MAP-enabled delivery of ZAN in the carradres resulted in ELF concentrations of 351 ng / ml at the 30 min time point with much higher levels achieved with the glass reservoirs. By four hours the carradres ELF levels had increased to 2056 ng / ml, and steady-state levels were maintained through the 72 hour time point, now in equilibrium with the plasma concentrations. At 72 hours both the carradres and the glass reservoirs produced plasma and ELF levels above the therapeutic target concentrations. Without being limited to one particular theory, it was believed that initial lung levels would likely exceed plasma levels, since transdermal application ZAN is distributed to the lung capillary system first and undergoes lung “clearance”, which is highly desirable, since ZAN is an extracellular target in the lung. The very rapid onset and magnitude of ZAN appearing in ELF adds further strength to this delivery approach of ZAN for treatment and prevention of influenza disease.

[0116] Delivery with the dry reservoir samples of Table 1 results in even higher initial concentrations in both plasma and ELF that slowly declined over the treatment course, but remained within the target range through the last point evaluated, 72 hours (FIG. 9(b) “glass” illustrating results obtained with devices with reservoir example TSRL 6). The dry reservoirs successfully delivered target plasma and ELF concentrations within 30 min of MAP application. However, some prior dry reservoirs that may have glass-like properties are quite brittle and break easily when removed from the foil liners and under pressure. Evaluations of ZAN-loaded alginate thin-films (representing reservoir example TSRL-7 in Table 1) at a 50 mg dose and LYO-1 Hyd wafers at a 9.5 mg dose also showed successful delivery of ZAN wellabove the IC50 starting at 15 min post patch administration, and maintaining steady-state levels through the three-day study duration. Further, administration of the LYO-2 HC1 formulation with a loading dose of 45 mg resulted in attaining Cmax (4929 ng / ml) by 8 hours, with efficacious levels maintained through the end of the study (FIG. 10). As illustrated in FIG. 11, devices with reservoir examples TSRL-3 and TSRL-27 both met the physical and performance criteria in the rat pharmacokinetic study with TSRL-27 plasma concentrations exceeding the IC50 for 90 hrs.

[0117] These results clearly demonstrate that efficacious ZAN levels in the lung can be achieved with transdermal delivery via the ZAN-MN device and concentrations in ELF are maintained over 72 hours at levels where maximal effect was observed in the HFIM and provide a single dose drug / device product that delivers ZAN continuously over 5 days.

[0118] In FIG. 12 the glass (TSRL-6), the alginate (TSRL-7), the pullulan (TSRL-31) and the dextran 40 with ZAN HC1 (TSRL-32) and ZAN hydrate are compared in another rat PK experiment. Once again, the ZAN hydrate gave the lowest plasma levels. The pullulan gave high initial levels but dropped below the desired levels by 48 hours. The Dextran 40 HC1 (TSRL-32) showed excellent initial delivery of ZAN with delivery continuing for 144 hours.

[0119] Example 9: Studies of ZAN-MP delivery in minipigs

[0120] A 3 -day pilot study in Gottingen Minipigs (n=2) was performed to ensure that the data generated in rats could be effectively translated to the minipigs. The definitive 5-day study was designed to assess the PK of ZAN in plasma and broncheoalveolar samples over the treatment course postulated in the target product profile. The same study techniques were used as for the mice and rats. Animals were fasted overnight prior to administration of Telazol for each phase. Prior to dose administration, all animals were administered Telazol for sedation during the dosing and removal procedures with a single intramuscular injection of a dose level of 1-6 mg / kg. Isoflurane was administered to effect by inhalation to animal undergoing broncheoalveolar lavage (Group 3, main study).

[0121] During the pilot study, both Carradres™ and dry reservoirs of TSRL-6 as in Table 1 were evaluated. The hair was clipped from the ventral surface on the day prior to dosing. On the day of dosing, the exposure site was cleaned with 70% isopropyl alcohol just prior to application. A foam support was adhered around the treatment area with tissue adhesive (Vetbond or similar). The MAP was secured to the skin within the area of the foam support (4 MAPs / animal in the treatment site). Each MAP was pressed firmly against the skin for 30 seconds. For Group 1, the gel loaded reservoir (drug- soaked hydrogel -150 mg) was applied to each array. For Group 2, 20 pL of water and the film reservoir (-150 mg) were applied toeach MAP, and a foam insert was applied to cover the arrays. The exposure site and foam support were covered with ScotchPak and Tegaderm. Kinesiology tape was used to further secure the array and a JET undershirt jacket was placed on the animals. Plasma samples were collected at 0.5, 2, 8, 24, and 72 hours post-application.

[0122] The results from the pilot study underscore the similar profiles for both the CarraDres™ as well as the dry drug reservoir formulation with plasma levels well above the IC50 at the earliest sampling time point at 30 min (FIG. 13).

[0123] MAPs with Carradres™ reservoirs were further studied in the main study arm (Group 3) and applied as described above. Dosing occurred while the animals were sedated for pre-dose BALF collections. For the BALF collection animals were anesthetized per SOP and intubated for sample collection. The animals were placed into a recumbent position and the appropriately sized bronchoscope was passed through the endotracheal tube using a double swivel connector into an appropriate airway. For each time point, a maximum of 4 mL / kg was used to lavage the selected lobar bronchus with warmed saline. After the saline wash, gentle suction was applied to collect the sample for analysis. After collections at 2, 8, 24, and 72 hours, the animals were allowed to recover normally and were returned to their cages. Blood samples were collected pre-dose, and at approximately 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours post dose, and the BALF samples were collected pre-dose, and at approximately 0.5, 2, 8, 24, and 72 hour post-dose.

[0124] During the 5-day study, plasma was sampled more frequently, and ELF was obtained at three time points during the first eight hours. During ELF sampling pigs are anesthetized and we attribute the associated reduction in blood flow to the decline of the plasma and ELF levels after an initial peak at 1-2 hours (FIG. 13(c)). After 24 hours levels had recovered to the initial concentrations, and ZAN was delivered continuously through the end of the study (120 hours). The MAP was removed completely intact and the clinical observations showed no signs of skin irritation (FIG. 13(b)).

[0125] These results demonstrate for the first time that the MAP formulation of ZAN as provided herein is able to deliver the drug across the skin and reach target steady-state exposure levels in plasma and ELF that are orders of magnitude above the IC50 and maintained over the entire treatment course of five days. Furthermore, initial studies with a dry reservoirs of Table 1 demonstrated an even more desirable concentration-time profile, with peak levels being reached rapidly after administration and maintained with a long half-life over multiple days. This represents an exciting new therapeutic strategy for the treatment of influenza, especiallyfor patients with preexisting respiratory conditions, and could prove useful for prophylaxis in a large number of high-risk patients and in the general population.LISTING OF ADDITIONAL EXEMPLARY ASPECTS

[0126] Aspect 1. A device for treating or preventing a disease or condition caused by a virus in a subject comprising: a reservoir layer and a microneedle delivery layer, said reservoir layer in contact with said microneedle delivery layer; wherein said reservoir layer comprises an active agent, and wherein said reservoir layer is in the form of a pliable glass comprising said active agent.

[0127] Aspect 2. The device of aspect 1, wherein said active agent is an antiviral.

[0128] Aspect 3. The device of aspects 1 or 2, wherein said active agent is zanamivir.

[0129] Aspect 4. The device of any Aspect as provided herein, wherein said delivery layer comprises a swellable polymer.

[0130] Aspect 5. The device of any Aspect as provided herein, wherein said glass further comprises one or more additives.

[0131] Aspect 6. The device of Aspect 5, wherein said additive comprises a sugar.

[0132] Aspect 7. The device of Aspect 6, wherein said sugar is trehalose.

[0133] Aspect 8. The device of any of Aspects 5-7, wherein said additive is present at 10 wt% to 50 wt%, optionally 20 wt% to 40 wt%.

[0134] Aspect 9. The device of Aspect 5, wherein said additive is a gelatin.

[0135] Aspect 10. The device of Aspect 9, wherein said gelatin is present at 20 wt% to 40 wt% by weight.

[0136] Aspect 11. The device of any of Aspects 1-4, wherein said reservoir excludes an additive.

[0137] Aspect 12. The device of any one of Aspects 1-11, wherein said glass comprises a gelatin at 20 wt% to 40 wt% by weight and trehalose at 10 wt% to 25 wt%.

[0138] Aspect 13. The device of any one of Aspects 1-11, wherein said glass comprises a polypropylene glycol (PPG) at 10 wt% to 15 weight percent.

[0139] Aspect 14. The device of Aspect 13 further comprising pullulan at about 35 wt%.

[0140] Aspect 15. The device of Aspect 13, further comprising dextran 40 at about 40 wt%.

[0141] Aspect 16. The device of any Aspect as provided herein, wherein said active agent is present at 25 wt% or higher, optionally 45 wt% to 65 wt%.

[0142] Aspect 17. The device of any Aspect as provided herein, wherein said active agent is in the form of an active agent hydrochloride salt.

[0143] Aspect 18. The device of any Aspect as provided herein, wherein said reservoir layer holds a minimum of 250 milligrams of said active agent.

[0144] Aspect 19. The device of any Aspect as provided herein, wherein said device is configured to release said active agent with a Cmax of 8 hours or less.

[0145] Aspect 20. The device of any Aspect as provided herein, wherein said device is configured to provide sustained release of said active agent over a time of five or more days.

[0146] Aspect 21. The device of any Aspect as provided herein, wherein said reservoir layer comprises less than 10 wt% water, optionally less than 1 wt% water.

[0147] Aspect 22. The device of any Aspect as provided herein, wherein said reservoir layer is configured to maintain said active agent as stable for 30 days or more.

[0148] Aspect 23. The device of any Aspect as provided herein, wherein said reservoir layer is configured to not crack under a pressure of 40 N or greater.

[0149] Aspect 24. The device of any of Aspects 1-23 in any combination.

[0150] Aspect 25. A process of treating or preventing a disease or condition caused by a virus in a subject comprising: applying the device of any one of claims 1-24 to the skin of a subject.

[0151] Aspect 26. The process of Aspect 25, wherein said applying is prior to infection of a subject with said virus.

[0152] Aspect 27. The process of Aspect 25, wherein said applying is following exposure of a subject to said virus, optionally within 48 hours following exposure.

[0153] Aspect 28. The process of any of Aspects 25-27, wherein said virus is an influenza virus.REFERENCE LIST[1] C. Paules, K. Subbarao, Lancet 2017, 390, 697.[2] Influenza (Seasonal).[3] A. D. luliano, K. M. Roguski, H. H. Chang, D. J. Muscatello, R. Palekar, S. Tempia, C. Cohen, J. M. Gran, D. Schanzer, B. J. Cowling, P. Wu, J. Kyncl, L. W. Ang, M. Park, M. Redlberger-Fritz, H. Yu, L. Espenhain, A. Krishnan, G. Emukule, L. van Asten, S. Pereira da Silva, S. Aungkulanon, U. Buchholz, M. A. Widdowson, J. S. Bresee, E. Azziz-Baumgartner, P. Y. Cheng, F. Dawood, I. Foppa, S. Olsen, M. Haber, C. Jeffers, C. R. MacIntyre, A. T. Newall, J. G. Wood, M. Kundi, T. Popow-Kraupp, M. Ahmed, M. Rahman, F. Marinho, C. V. Sotomayor Proschle, N. Vergara Mallegas, F. Luzhao, L. Sa, J. Barbosa-Ramirez, D. M. Sanchez, L. A. Gomez, X. B. Vargas, a. B. Acosta Herrera, M. J. Llanes, T. K. Fischer, T. G. Krause, K. Molbak, J. Nielsen, R. Trebbien, A. Bruno, J. Ojeda, H. Ramos, M. an der Heiden, L. del Carmen Castillo Signor, C. E. Serrano, R. Bhardwaj, M. Chadha, V. Narayan, S. Kosen, M. Bromberg, A. Glatman-Freedman, Z. Kaufman, Y. Arima, K. Oishi, S. Chaves, B. Nyawanda, R. A. Al-Jarallah, P. A. Kuri-Morales, C. R. Matus, M. E. J. Corona, A. Burmaa, O. Darmaa, M. Obtel, I. Cherkaoui, C. C. van den Wijngaard, W. van der Hoek, M.Baker, D. Bandaranayake, A. Bissielo, S. Huang, L. Lopez, C. Newbern, E. Flem, G. M. Groneng, S. Hauge, F. G. de Cosio, Y. de Molto, L. M. Castillo, M. A. Cabello, M. von Horoch, J. Medina Osis, A. Machado, B. Nunes, A. P. Rodrigues, E. Rodrigues, C. Calomfirescu, E. Lupulescu, R. Popescu, O. Popovici, D. Bogdanovic, M. Kostic, K. Lazarevic, Z. Milosevic, B. Tiodorovic, M. Chen, J. Cutter, V. Lee, R. Lin, S. Ma, A. L. Cohen, F. Treurnicht, W. J. Kim, C. Delgado-Sanz, S. de mateo Ontanon, A. Larrauri, I. L. Leon, F. Vallejo, R. Bom, C. Junker, D. Koch, J. H. Chuang, W. T. Huang, H. W. Kuo, Y. C. Tsai, K. Bundham charoen, M. Chittaganpitch, H. K. Green, R. Pebody, N. Goni, H.Chiparelli, L. Brammer, D. Mustaquim, Lancet 2018, 391, 1285.[4] NIAID Emerging Infectious Diseases / Pathogens | NIH: National Institute of Allergy and Infectious Diseases, .[5] S. S. Wong, R. J. Webby, Clin Microbiol Rev 2013, 26, 476.[6] C. I. Paules, S. G. Sullivan, K. Subbarao, A. S. Fauci, Vir England Journal of Medicine 2018, 378, 7.[7] H.-N. Gao, H.-Z. Lu, B. Cao, B. Du, H. Shang, J.-H. Gan, S.-H. Lu, Y.-D. Yang, Q. Fang, Y.-Z. Shen, X.-M. Xi, Q. Gu, X.-M. Zhou, H.-P. Qu, Z. Yan, F.-M. Li, W. Zhao, Z.-C. Gao, G.-F. Wang, L.-X. Ruan, W.-H. Wang, J. Ye, H.-F. Cao, X.-W. Li, W.-H. Zhang, X.-C. Fang, J. He, W.-F. Liang, J. Xie, M. Zeng, X.-Z. Wu, J. Li, Q. Xia, Z.-C. Jin, Q. Chen, C. Tang, Z.-Y. Zhang, B.-M. Hou, Z.-X. Feng, J.-F. Sheng, N.-S. Zhong, L.-J. Li, H. Gao, H. Lu, J. Gan, S. Lu, N Engl J Med 2Q13, 368, 2277.[8] R. Gao, B. Cao, Y. Hu, Z. Feng, D. Wang, W. Hu, J. Chen, Z. Jie, H. Qiu, K. Xu, X. Xu, H. Lu, W. Zhu, Z. Gao, N. Xiang, Y. Shen, Z. He, Y. Gu, Z. Zhang, Y. Yang, X. Zhao, L. Zhou, X. Li, S. Zou, Y. Zhang, X. Li, L. Yang, J. Guo, J. Dong, Q. Li, L. Dong, Y. Zhu, T. Bai, S. Wang, P. Hao, W. Yang, Y. Zhang, J. Han, H. Yu, D. Li, G. F. Gao, G. Wu, Y. Wang, Z. Yuan, Y. Shu, N Engl J Med2 3, 368, 1888.[9] D. M. Morens, J. K. Taubenberger, A. S. Fauci, N Engl J Med 2013, 368, 2345.

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[0034] ICH, 2005, pp. 1070-1072.

[0154] The foregoing description of particular aspect(s) is merely exemplary in nature and is in no way intended to limit the scope of the claims, their application, or uses, which may, of course, vary. The claims are described with relation to the non-limiting definitions and terminology included herein. These definitions and terminology are not designed to function as a limitation on the scope or practice of the claims but are presented for illustrative and descriptive purposes only. While the processes or compositions are described as an order of individual steps or using specific materials, it is appreciated that steps or materials may be interchangeable such that the description may include multiple parts or steps arranged in many ways as is readily appreciated by one of skill in the art.

[0155] It will be understood that, although the terms “first,” “second,” “third” etc. may be used herein to describe various elements, components, regions, layers, and / or sections, these elements, components, regions, layers, and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer, or section from another element, component, region, layer, or section. Thus, “a first element,” “component,” “region,” “layer,” or “section” discussed below could be termed a second (or other) element, component, region, layer, or section without departing from the teachings herein.

[0156] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms “a,” “an,” and “the” are intended to include the plural forms, including “at least one,” unless the content clearly indicates otherwise. “Or” means “and / or.” As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items. It will be further understood that the terms “comprises” and / or “comprising,” or “includes” and / or “including” when used in this specification, specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of oneor more other features, regions, integers, steps, operations, elements, components, and / or groups thereof. The term “or a combination thereof’ means a combination including at least one of the foregoing elements.

[0157] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. It will be further understood that terms such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0158] Specific embodiments of the prodrug are described herein. It should be understood that the devices and reservoirs of this disclosure may be embodied in different forms and should not be construed as limited to the specific embodiments set forth in this disclosure.

[0159] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. It will be further understood that terms such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and the present disclosure, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0160] Various modifications of the present invention, in addition to those shown and described herein, will be apparent to those skilled in the art of the above description. Such modifications are also intended to fall within the scope of the appended claims.

[0161] It is appreciated that all reagents are obtainable by sources known in the art unless otherwise specified.

[0162] Patents, publications, and applications mentioned in the specification are indicative of the levels of those skilled in the art to which the invention pertains. These patents, publications, and applications are incorporated herein by reference to the same extent as if each individual patent, publication, or application was specifically and individually incorporated herein by reference.

[0163] The foregoing description is illustrative of particular embodiments of the invention, but is not meant to be a limitation upon the practice thereof.

[0164] We claim:

Claims

CLAIMS1. A device for treating or preventing a disease or condition caused by a virus in a subject comprising: a reservoir layer and a microneedle delivery layer, said reservoir layer in contact with said microneedle delivery layer; wherein said reservoir layer comprises an active agent, and wherein said reservoir layer is in the form of a pliable glass comprising said active agent.

2. The device of claim 1, wherein said active agent is an antiviral.

3. The device of claim 1, wherein said active agent is zanamivir.

4. The device of claim 1, wherein said microneedle delivery layer comprises a swellable polymer.

5. The device of claim 1, wherein said glass further comprises one or more additives.

6. The device of claim 5, wherein said additive comprises a sugar.

7. The device of claim 6, wherein said sugar is trehalose or dextran 40.

8. The device of claim 1, wherein said additive is present at 10 wt% to 50 wt%, optionally 20 wt% to 40 wt%.

9. The device of claim 1, wherein said additive is a gelatin.

10. The device of claim 9, wherein said gelatin is present at 20 wt% to 40 wt% by weight.

11. The device of claim 1, wherein said reservoir excludes an additive.

12. The device of any one of claims 1-11, wherein said glass comprises a gelatin at 20 wt% to 40 wt% by weight and trehalose at 10 wt% to 25 wt%.

13. The device of any one of claims 1-11, wherein said glass comprises a PPG at 10 wt% to 15 weight percent.

14. The device of claim 13 further comprising pullulan at about 35 wt%.

15. The device of claim 13, further comprising dextran 40 at about 40 wt%.

16. The device of any one of claims 1-11, wherein said active agent is present at25 wt% or higher, optionally 45 wt% to 65 wt%.

17. The device of any one of claims 1-11, wherein said active agent is in the form of an active agent hydrochloride salt.

18. The device of any one of claims 1-11, wherein said reservoir layer holds a minimum of 100 milligrams of said active agent.

19. The device of any one of claims 1-11, wherein said device is configured to release said active agent with a Cmax of 8 hours or less.

20. The device of any one of claims 1-11, wherein said device is configured to provide sustained release of said active agent over a time of five or more days.

21. The device of any one of claims 1-11, wherein said reservoir layer comprises less than 10 wt% water, optionally less than 1 wt% water.

22. The device of any one of claims 1-11, wherein said reservoir layer is configured to maintain said active agent as stable for 30 days or more.

23. The device of any one of claims 1-11, wherein said reservoir layer is configured to not crack under a pressure of 40 N or greater.

24. The device substantially as described herein.

25. A process of treating or preventing a disease or condition caused by a virus in a subject comprising: applying the device of any one of claims 1-11 to the skin of a subject.

26. The process of claim 25, wherein said applying is prior to infection of a subject with said virus.

27. The process of claim 25, wherein said applying is following exposure of a subject to said virus, optionally within 48 hours following exposure.

28. The process of claim 25, wherein said virus is an influenza virus.

29. The process of claim 28, wherein the active agent is zanamivir.

30. The process of claim 25, wherein the virus is an influenza virus, the active agent is zanamivir, and the reservoir layer includes PPG and pullulan and / or a PPG and dextran.

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