EP4704976A1 - Delivery devices for anti-hiv compounds - Google Patents

Abstract

Drug delivery devices comprising a microneedle patch, or microarray patch, having an anti-HIV nucleoside analogue reverse transcriptase translocation inhibitor (e.g., islatravir) are disclosed. The devices can be applied to a subject to prevent or treat HIV infection.

Description

DELIVERY DEVICES FOR ANTLHIV COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/498,907, filed April 28. 2023.

BACKGROUND OF THE INVENTION

[0002] Highly active antiretroviral therapy (HAART) is a method for reducing HIV viral loads, thereby reducing HIV-related morbidity and mortality. Improvements in antiretroviral drugs and broader use of HAART since the mid-1990s have transformed the lives of patients living with HIV through improved efficacy combined with decreased pill burden, toxicity, drug-drug interactions, and drug-food interactions. While life expectancies of those who have achieved immune reconstitution and remain virologically suppressed are now close to baseline, the next frontier of drug products for HIV treatment and prevention will seek to improve patient comfort and convenience to improve adherence and restore a sense of normalcy to patients living with HIV. To this end, some long-acting injectables of antiretrovirals have been developed in order to reduce dosing frequencies, such as CABENUVA®, a once monthly combination of the integrase strand transfer inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor rilpivirine dosed as a crystalline suspension (see A. Leonard, et al. 2022, 18, 17). SUNLENCA®, a long-acting injectable formulation of the HIV-1 capsid inhibitor lenacapavir, has also been recently approved in Europe for once-every-six-month administration (see C. Bernice, et al. Curr Infect Dis Rep 2022, 89).

[0003] These approvals represent significant advances in the field, but challenges to successful implementation and patient acceptance still exist. ViiV Healthcare’s recent CUSTOMIZE study investigated barriers to implementation in US based clinics, including universities, private clinics, and healthcare maintenance organizations, among others. While acceptability was high across multiple types of clinics, some key changes to standard operating practices were pursued to enable treatment administration, including extending clinic hours, purchasing additional refrigerators, and implementing new tracking and reminder systems to enable adherence to monthly appointments. The factor identified as most interfering with patients’ ability to receive injections was injection pain or soreness.

[0004] Research in microneedle technology, including microarray patches (MAPs), since the late 1990s holds promise for reducing or eliminating the pain associated with hypodermic injections through application of arrays of small needles that puncture the skin’s stratum corneum to deliver a therapeutic. The small size of these needles minimizes the degree of interactions with nerve endings in the skin, which results in less pain relative to standard hypodermic injections. While such patches have not yet been marketed (largely due to challenges associated with manufacturing, quality systems, and regulatory processes), successful commercialization and uptake could eventually reduce the amount of healthcare worker intervention in the delivery' of medications through self-administration or administration in local pharmacies. In a global context, MAPs have the potential to enable delivery' to regions with poor cold-chain storage through room temperature stability. However, research involving the use of MAPs has extensively been on the delivery of vaccines.

[0005] Islatravir is a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI) developed for the treatment and prevention of HIV- 1 infection. Islatravir’ s novel structure inhibits reverse transcriptase via multiple mechanisms, resulting in high potency and a high barrier to resistance. Islatravir’ s combination of high potency and slow human clearance makes it a promising low dose, long-acting medication (see Schumann et al.. Lancet HIV 2020, 7, el 64 and US Pat. Pub. No. 2018/0055867, each of which is incorporated by reference herein. [0006] While cabotegravir and rilpivirine have been successfully formulated and coadministered in a MAP, maximal drug loadings were approximately 2.8 mg per 0.36 cm² patch. In order to administer a dose consistent with once monthly CABENUVA" (400 to 900 mg in total), a MAP size of ~50 to 120 cm² would be required (see Moffatt, et al. Pharm Res 2022, which is incorporated by reference herein). Such impractically large MAP sizes are unlikely to be a preferred option for patients living with HIV as it will not only be uncomfortable to wear but would result in difficulty in patch application that could culminate in treatment failure.

Therefore, there is a need to generate a novel microneedle system capable of encapsulating a highly potent antiretroviral agent such as an NRTTI and delivering that agent at therapeutic levels from a reasonable patch size over extended therapeutic durations.

SUMMARY

[0007] Devices and methods for delivering antiretroviral agents using microneedle technology' are provided. These devices and methods may enable self-administration by patients outside of a traditional medical facility. These devices and methods are useful as effective, minimally invasive medicaments for human immunodeficiency virus (HIV) prevention and treatment. [0008] Because the delivery of small molecules via microneedle technology has been a lesser area of focus compared to research into vaccine delivery, with even fewer microneedle technologies targeting long-acting administration, creating the disclosed devices has been challenging. Further complicating this challenge, many approved and investigational antiretroviral agents are not well-suited for reformulation as MAPs, in large part due to insufficient antiviral potency that would result in high dosing requirements. These high dosing requirements typically translate into impractically large MAP sizes that are unlikely to be a preferred option for patients living with HIV.

[0009] Addressing these problems, the disclosed drug delivery devices can encapsulate highly potent antiretroviral agents such as NRTTIs and deliver those agents at therapeutic levels from a reasonable patch size over extended therapeutic durations. The examples of this disclosure demonstrate successful formulation and in vivo delivery of islatravir using long-acting MAPs. They further show that the disclosed patches exhibit excellent needle fidelity, structural integrity, and mechanical strength. In vitro studies demonstrate that the MAPs can penetrate skin up to 580 pm and dissolve within 2 hours, and in rodent models, these dissolving MAPs sustain NRTTI delivery for up to 3 months. Biopharmaceutic modelling demonstrates the potential to achieve multi-month delivery of NRTTI at therapeutic levels with patch sizes measuring approximately 20 cm².

[0010] In some aspects, drug delivery devices comprise a baseplate that has an amount of a first polymer, and a patch. The patch comprises a layer having a first side adhering to the baseplate and a second side opposite to the first side, and a plurality of tips extending from the second side. In addition, the patch comprises a formulation that has an amount of a second polymer, and a suspension of an amount of an anti-HIV nucleoside analogue reverse transcriptase translocation inhibitor (NRTTI). In these aspects, the first side has a surface area of at least 1 square centimeter and at most 60 square centimeters.

[0011] In some embodiments, the first polymer comprises poly (vinylpyrrolidone) (PVP) having a molecular weight of at least 100 kDa and at most 10,000 kDa or at least 500 kDa and at most 3000 kDa. In some embodiments, the poly(vinylpyrrolidone) is at least 50% (w/w) and at most 100% (w/w) or at least 90% (w/w) and at most 98% (w/w) within the baseplate. In some embodiments, the baseplate further comprises glycerol.

[0012] This and other (w/w) percentages mentioned for the drug delivery device, unless specified otherwise, refer to the percentages in the formed (solid) drug delivery device, and not to the solution percentages used in the process before forming the drug delivery device. [0013] In some embodiments, the second polymer is a polymer that dissolves in water, in skin, or both in water and in skin. In some embodiments, the second polymer comprises poly(vinyl alcohol) having a molecular weight of at least 2 kDa and at most 300 kDa or at least 2 kDa and at most 20 kDa. In some embodiments, the poly (vinyl alcohol) is at least 0. 1% (w/w) and at most 40% (w/w) or at least 2% (w/w) and at most 10% (w/w) within the patch.

[0014] In some embodiments, the formulation of the patch further comprises PVP that is at least 0.1% (w/w) and at most 40% (w/w) or at least 2% (w/w) and at most 10% (w/w) within the patch. In some embodiments, said PVP in the formulation of the patch has a molecular weight of at least 5 kDa and at most 300 kDa or at least 40 kDa and at most 80 kDa.

[0015] In some embodiments, the NRTTI is or comprises islatravir. In some embodiments, the suspension further comprises one or more excipients. In some embodiments, the NRTTI is a prodrug of islatravir.

[0016] In some embodiments, the tips have a length dimension of at least 300 micrometers and at most 1300 micrometers or at least 500 micrometers and at most 700 micrometers. In some embodiments, the tips have a maximal width dimension of at least 100 micrometers and at most 600 micrometers or at least 200 micrometers and at most 300 micrometers. In some embodiments, the tips are conical or pyramidal in shape. In some embodiments, the tips are spaced from each other by at least 50 micrometers and at most 600 micrometers or at least 50 micrometers and at most 150 micrometers with respect to their centers. In some embodiments, the tips are uniformly spaced from each other in a regular array configuration.

[0017] In some embodiments, the first side has a surface area of at least 15 square centimeters and at most 30 square centimeters.

[0018] In some embodiments, the baseplate is removable from the patch 1 to 3 days after the patch is applied to the skin of a subject. In some embodiments, the formulation delivers a sustained amount of the NRTTI to supply a detectable concertation of the NRTTI in the plasma of the subject at least until 1 month after the patch is applied to the skin of the subject. In some embodiments, the device comprises a CMAX that is at least 2-fold lower and at most 50-fold lower or at least 10-fold and at most 50-fold lower after the patch is applied to the skin of a subject as compared to an intramuscular suspension containing the same amount of the NRTTI. In some embodiments, administration of a microarray patch or patches with a total first side surface area less than or equal to 100cm², 60cm². 40cm². or 20cm² is sufficient to deliver an effective amount of the NRTTI to a subject infected with HIV. In some embodiments, the effective amount of the NRTTI is delivered over 1 to 72 hours applied once every 1 to 6 months. In some embodiments, the amount of NRTTI in the patch divided by the first side surface area is at least 0.5 mg per square centimeters and at most 40 mg per square centimeters, at least 2 mg per square centimeters and at most 30 mg per square centimeters, or at least 10 mg per square centimeters and at most 20 mg per square centimeters.

[0019] In some aspects, methods of preventing infection of a subject with HIV comprise applying the drug delivery device of any of the disclosed aspects or embodiments. In some aspects, methods of treating infection of a subject with HIV comprise applying the drug delivery’ device of any of the disclosed aspects or embodiments.

[0020] In some embodiments, the methods further comprise removing the baseplate from the patch 1 to 3 days after the patch is applied to the skin of a subject. In some embodiments, the formulation delivers a sustained amount of the NRTTI to supply a detectable concertation of the NRTTI in the plasma of the subject at least until 1 month after the patch is applied to the skin of the subject. In some embodiments, the methods result in a CMAX that is at least 2-fold lower after the patch is applied to the skin of a subject as compared to an intramuscular suspension containing the same amount of the NRTTI.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figs. 1A-1F show images of microarray patches (MAPs) that contain islatravir. The images of Figures 1A-1C were generated by light microscopy, and the images of Figures 1D-1F were generated by electron microscopy.

[0022] Figs. 2A-2D show characterization of mechanical properties of microarray patches (MAPs) and their ability to puncture porcine skin ex vivo. Fig. 2A shows the quantification of the deformation of microneedle array under 32 N mechanical stress. Fig. 2B shows light microscope image of porcine skin after ex vivo application of islatravir and methylene blue loaded microarray patches (MAPs). Fig. 2C shows optical coherence tomography images of porcine skin immediately after microneedle insertion. Fig. 2D shows optical coherence tomography images of porcine skin 24 hours after microneedle insertion.

[0023] Fig. 3. Islatravir plasma concentrations after dosing a microarray patch (MAP) formulation and an intramuscular (IM) suspension in rats showing dose-normalized plasma concentrations over the 12-week study duration (the line reaching the 12-hour point is for the microneedle formulation).

[0024] Fig. 4. Islatravir plasma concentrations after dosing a microarray patch (MAP) formulation and an intramuscular (IM) suspension in rats showing dose-normalized plasma concentrations over the first 48 hours of the study (the line starting lower at the initial time point is the MAP formulation).

[0025] Fig. 5. Comparison of islatravir plasma concentrations following administration of a microarray patch (MAP) formulation and an intramuscular (IM) suspension in rats showing the fraction of the delivered dose released over the entire study duration (the line reaching the 80-day point is for the MAP formulation).

[0026] Fig. 6. Islatravir pharmacokinetics in minipigs after dosing microneedles with a 24 hour and 48 hour wear time.

[0027] Fig. 7. Delivery efficiency from microarray patches (MAPs) after 24 hour and 48 hour wear time. Delivery efficiency calculated through deconvolution of microarray patches (MAPs) PK with IV PK at timepoints ranging from 24 to 312 hours.

[0028] Fig. 8. Islatravir plasma concentrations after dosing a microarray patch (MAP) formulation and an intramuscular (IM) suspension in minipigs showing dose-normalized plasma concentrations at early timepoints (the line starting lower at the initial time point is the MAP formulation).

[0029] Fig. 9. Predicted human plasma concentrations calculated from dosing 20 cm² microarray patches (MAPs). The calculation was performed by convoluting dose-normalized release rates from rodent and minipig PK with data from clinical PO dosing of islatravir (the line reaching the 12-week point represents the projections from rat). The dashed line is the 85-day Ctrough value observ ed after clinical dosing of an implant containing 62 mg of islatravir.

[0030] Figs. 10A and 10B. Assessment of microarray patch (MAP) mechanical stability after one to three months on station under varying conditions. Needle height reduction shown in Fig. 10A and Insertion depth shown in Fig. 10B.

DETAILED DESCRIPTION

Definitions

[0031] A “patch” is the part of the disclosed drug delivery devices other than the baseplate. The disclosure also uses the terms “microneedle patch” and “microarray patch” (MAP) to refer to the patch. The patch includes tips and a layer.

[0032] The term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable). [0033] The ”C\IAX” (maximum concentration), refers to the highest concentration of drug in the blood measured after a dose. A higher CMAX may be associated with an increased risk of side effects from the drug.

[0034] The “layer’" is the part of the patch that is adjacent to the baseplate. The layer does not need to be separate from the tips; it instead can be part of the same single-piece patch in which base portions of the tips that tie them together are referred to as the “layer” for convenience of terminology. For convenience, the side of the layer facing the baseplate is referred to as the first side, and the side of the layer opposite to the first side is referred to as the second side. The second side ends at a plane where the layer is on average thinnest between the tips; the rest of the patch is the tips.

[0035] The “tips” extend from the layer, away from the baseplate in the drug delivery devices. The Examples also use the term “microneedle tips” to refer to the tips.

[0036] The “length dimension"’ of a tip is the distance between its most distant point from the baseplate and its closest point to the baseplate. The closest point of the tip to the baseplate is on the plane of the second side of the layer.

[0037] The “maximal width dimension” of a tip is its greatest width. For example if the tip is conical, then its maximal width dimension is its diameter on the plane of the second side of the layer.

[0038] When referring to the tips being “spaced from each other” the reference is with respect to their centers — the midpoint along their length dimension.

[0039] The “surface area” of the first side is the two-dimensional area of a theoretical plane that intersects the first side when it is planar. Parts of the disclosure also refer to this as “first side surface area” or “patch surface area.” In contrast, “total surface area” is the sum of the surface areas of one or more patches that are applied to a subject.

[0040] Unless expressly stated to the contrary, all ranges cited herein are inclusive of the recited endpoints and independently combinable. For example, the range of “at least 50% (w/w) and at most 100% (w/w)” is inclusive of the endpoints 50% w/w and 100% w/w. and all intermediate values.

[0041] A “subject” is a human or non-human mammal. In one embodiment, a subject is a human. In another embodiment, a subject is a primate. In another embodiment, a subject is a monkey. In another embodiment, a subject is a chimpanzee. In still another embodiment, a subject is a rhesus monkey. In still another embodiment, a subject is a rodent, such as a rat. [0042] The term “effective amount” as used herein, refers to an amount of compound and/or an additional therapeutic agent, or a composition thereof that is effective in inhibiting HIV replication and in producing the desired therapeutic, ameliorative, inhibitory or preventative effect when administered to a subject suffering from HIV infection or AIDS. In the combination therapies of the present invention, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.

[0043] The terms “treating” or “treatment” as used herein with respect to an HIV viral infection, AIDS or ARC, includes inhibiting the severity of HIV infection or AIDS, e.g., arresting or reducing the development of the HIV infection or AIDS or its clinical symptoms; or relieving the HIV infection or AIDS, e.g., causing regression of the severity' of HIV infection or AIDS or its clinical symptoms.

[0044] The terms “preventing.” or “prophylaxis.” as used herein with respect to an HIV viral infection or AIDS, refers to reducing the likelihood or severity of HIV infection or AIDS.

Anti-HIV Compounds and Their Suspensions

[0045] In some aspects, the drug delivery devices disclosed herein comprise anti-HIV compounds, for example within a formulation that forms the microarray patches. In some embodiments, the anti-HIV compounds are anti-HIV nucleoside analogue reverse transcriptase translocation inhibitors (NRTTIs).

[0046] In some embodiments, the NRTTI has the following structure:

[0047] In some embodiments, the NRTTI is or comprises 4^,-ethynyl-2-fluoro-2'- deoxyadenosine (i.e., EFdA). In some embodiments, the NRTTI is or comprises (2R,3S,5R)-5-(6- amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol. In some embodiments, the NRTTI is or comprises any one of the compounds disclosed in US Pat. No. 7,339,053, which is incorporated herein by reference in its entirety.

[0048] In some embodiments, the NRTTI is or comprises islatravir. In some embodiments, the NRTTI is or comprises a prodrug or another form of islatravir (e.g., islatravir triphosphate, islatravir monohydrate).

[0049] In some embodiments, the anti-HIV compounds is or comprises any of those agents listed in Table A.

Table A: Antiviral Agents for Preventing HIV Infection or AIDS

El = entry inhibitor; FI = fusion inhibitor; Ini = integrase inhibitor; inSTI = integrase strand transfer inhibitor, PI = protease inhibitor; nRTI = nucleoside reverse transcriptase inhibitor; nnRTI = non-nucleoside reverse transcriptase inhibitor; CI = capsid inhibitor.

[0050] Some of the drugs listed in the table can be used in a salt form, e.g., abacavir sulfate, delavirdine mesylate, indinavir sulfate, atazanavir sulfate, nelfmavir mesylate, saquinavir mesylate.

[0051] In some embodiments, the additional therapeutic agent is an HIV capsid inhibitor. In some embodiments, the additional therapeutic agent is lenacapavir (Sunlenca®). The structure and method of action of lenacapavir is discussed in US Publication No. 2018/0051005. published February 22, 2018, which is herein incorporated by reference in its entirety. In some embodiments, the additional therapeutic agent is capsid inhibitor GS-CA1 (see Vidal, et al. Long-acting capsid inhibitor protects macaques from repeat SHIV challenges. Nature 601, 612- 616 (2022), herein incorporated by reference in its entirety).

[0052] In some embodiments, the additional therapeutic agent is ulonivirine, an nRTI that is described in International Publication No. WO 2014/058747, which is herein incorporated by reference in its entirety⁷. Ulonivirine is 3-chloro-5-((6-oxo-l-((6-oxo-5-(trifluoromethyl)-l,6- dihydropyridazin-3-yl)methyl)-4-(trifluoromethyl)-l,6-dihydropyrimidin-5-yl)oxy)benzonitrile. [0053] In some embodiments, the additional therapeutic agent is doravirine, an nnRTI described in International Publication No. WO 2011/120133, which is herein incorporated by reference in its entirety.

[0054] Once the antiviral agent is formulated according to the disclosed methods (e.g., detailed in Example 1), it forms a suspension within the formulation.

Patch Formulations, Baseplate Compositions, and Device Structures

[0055] In some aspects, the drug delivery' devices comprise a baseplate and a patch.

[0056] In some embodiments, the baseplate and the patch are made from the same composition. In some embodiments, the baseplate and the patch are made from different compositions. [0057] In some embodiments, the baseplate has an amount of a first polymer. In some embodiments, the first polymer is poly(vinylpyrrolidone) (PVP). In some embodiments, PVP has a molecular weight of 100-10,000 kDa, 200-8000 kDa, 300-6000 kDa, 400-4000 kDa, or 500- 3000 kDa. In some embodiments, PVP has a molecular weight of about 100, about 200, about 300, about 400, about 500. about 600, about 700, about 800, about 900. about 1000, about 1500. about 2000, about 2500, about 3000, about 3500, about 4000, about 4500, about 5000, about 5500, about 6000, about 6500, about 7000, about 7500, about 8000, about 8500, about 9000, about 9500, or about 10000 kDa. In some embodiments, PVP has a molecular weight of 100, 200, 300. 400, 500, 600, 700, 800. 900, 1000, 1500. 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, or 10000 kDa. In some embodiments, PVP is 50-100, 90-100, 90-99, or 90-98% (w/w) within the baseplate. This and other (w/w) percentages, unless specified otherwise, refer to the percentages in the formed (solid) drug delivery device, and not to the solution percentages used before forming the drug delivery device. In some embodiments. PVP is 50. 51, 52, 53, 54, 55, 56, 57, 58, 59, 60. 61. 62. 63. 64. 65. 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% (w/w) within the baseplate. In some embodiments, the baseplate further comprises glycerol. In some embodiments, the first polymer is polyethylene glycol, a polyacrylamide, polyacrylic acid, gelatin, hyaluronic acid, or polyvinyl alcohol.

[0058] In some embodiments, the patch comprises a layer and a plurality of tips. In some embodiments, the layer and the tips are formed as a single-piece patch, and have the same formulation. The side of the layer facing the baseplate is referred to as its first side, and its side facing away from the baseplate is referred to as its second side. The tips extend from the second side of the layer (i.e., away from the baseplate).

[0059] In some embodiments, the patch comprises a formulation that has a second polymer. In some embodiments, the second polymer is a polymer that dissolves in water, in skin, or both in water and in skin. In some embodiments, the second polymer is poly(vinyl alcohol) (PVA). In some embodiments, PVA has a molecular weight of 2-300, 2-200, 2-100. 2-75. 2-50. 2-40. 2-30, or 2-20 kDa. In some embodiments, PVA has a molecular weight of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,

105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195,

200, 205. 210, 215, 220, 225, 230. 235, 240, 245, 250, 255, 260, 265. 270, 275, 280, 285, 290.

295, or 300 kDa. In some embodiments, PVA is 0.1-40, 0.5-30, 1-20, or 2-10% (w/w) within the patch. In some embodiments, PVA is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3. 3.5. 4, 4.5, 5. 5.5. 6, 6.5. 7. 7.5, 8, 8.5. 9. 9.5, 10, 12, 14. 16. 18. 20. 22. 24. 26. 28. 30, 32, 34, 36, 38, or 40% (w/w) within the patch.

[0060] In some embodiments, the formulation of the patch further comprises PVP. In some of these embodiments, PVP has a molecular weight of 2-300, 2-200, 2-100, 2-75, 2-50, 2-40, 2-30, or 2-20 kDa. In some of these embodiments, PVP has a molecular weight of 2. 3, 4, 5, 6. 7, 8, 9.

10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295. or 300 kDa. In some embodiments, PVP is 0. 1-40, 0.5-30, 1-20, or 2-10% (w/w) within the patch. In some embodiments, PVP is 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40% (w/w) within the patch.

[0061] In some embodiments, the microarray patch formulation is fabricated using a dissolving polymer (as opposed to a hydrogel or biodegradable polymer). The patch backing (i.e.. baseplate) can be removed after a period of approximately one day to a few days (e.g., 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90 hours), which eliminates the need to “wear” the patch over the entire treatment duration.

[0062] In some embodiments, the patch comprises a formulation that has one or more polymers selected from polyethylene glycol, polyacrylamides, polyacrylic acid, gelatin, hyaluronic acid, polyvinyl alcohol, and polyvinyl pyrrolidone.

[0063] In some embodiments, the formulation of the patch also comprises a suspension of an amount of an anti-HIV nucleoside analogue reverse transcriptase translocation inhibitor

(NRTTI). The NRTTI. in some embodiments, is any one of the compounds disclosed in X\\s Anti- HIV Compounds and Their Suspensions section. In some embodiments, the NRTTI is or comprises islatravir.

[0064] In some embodiments, the formulation or suspension further comprises one or more excipients. The excipients, in some embodiments, include any that have been used in FDA- approved products. In some embodiments, the excipients comprise acacia, acetone sodium bisulfate, alum, aluminum hydroxide, aluminum phosphate, ammonium acetate, arginine, ascorbate, ascorbyl palmitate, benzyl alcohol, calcium carbonate, calcium phosphate hydroxide, carboxymethyl cellulose, castor oil, cellulose, chitosan, chrlorbutanol, citrate buffer, citric acid, collagen, cottonseed oil, cresol, cyclodextrin, cysteine, dextran, dextrose, DNA, EDTA, EDTA, fats, Freund's complete adjuvant, Freund's incomplete adjuvant, fructose, galactose, gelatin, glucose, glycine, histidine, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hyaluronic acid, IL-1, IL- 12, IL-2, killed Bordetella pertussis, lactose, Lecithin, magnesium stearate, maltitol, mannitol, methionine, methyl paraben, methylcellulose, Mycobacterium bovis, paraffin oil, phenol. Pluronic F-68, polyethylene glycol, polyglycolic acid, polylactic acid, polylactive co- glycolic acid, Polysorbate 20, Polysorbate 80. polyvinyl alcohol, polyvinylpyrrolidone, potassium phosphate, propyl paraben, Quil A, raffinose, selenium, serum albumin, silica, sodium carbonate, sodium carboxymethyl cellulose, sodium chloride, sodium citrate, sodium citrate, sodium hydroxide, sodium phosphate, Sorbitantrioleate, sorbitol, squalene, sucrose, talc, thimerosal. toxoids, trehalose, Tris acetate, Tris base-65, Tris HC1-65, vitamins, or xylitol.

[0065] In some embodiments, the tips have a length dimension of 300-1300, 300-1000, 400- 900, or 500-700 micrometers. In some embodiments, the tips have a length dimension of about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1000, about 1050, about 1100. about 1150, about 1200, about 1250. or about 1300 micrometers. In some embodiments, the tips have a length dimension of 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, or 1300 micrometers. In some embodiments, the tips have a maximal width dimension of 100-600, 100-500, 150-400, or 200-300 micrometers. In some embodiments, the tips have a maximal width dimension of 100. 120, 140, 160, 180, 200. 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 420, 440, 460, 480, 500, 520, 540, 560, 580, or 600 micrometers. In some embodiments, the tips are conical or pyramidal in shape. In some embodiments, the tips are spaced from each other by 50-600, 50-500, 50-400, 50-300, 50-200, or 50-150 micrometers. . In some embodiments, the tips are spaced from each other by about 50, about 75. about 100. about 125, about 150, about 175. about 200. about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 425, about 450, about 475, about 500, about 525, about 550, about 575, or about 600 micrometers. In some embodiments, the tips are spaced from each other by 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375. 400, 425, 450. 475, 500. 525, 550, 575, or 600 micrometers. In some embodiments, the tips are uniformly spaced from each other in a regular array configuration.

[0066] In some embodiments, the first side has a surface area of 1-60, 2-50, 5-40, 10-30, or 15- 30 square centimeters. In some embodiments, the first side has a surface area of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. 17. 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31. 32. 33. 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 square centimeters. [0067] In some embodiments, the amount of NRTTI in the patch divided by the first side surface area is 0.5-40, 1-30, 2-30, or 10-20 mg per square centimeters. In some embodiments, the amount of NRTTI in the patch divided by the first side surface area is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4,

4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5. 15. 15.5, 16. 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5. 21. 21.5. 22. 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26,

26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 31.5, 32, 32.5, 33, 33.5, 34, 34.5, 35, 35.5, 36,

36.5, 37, 37.5, 38, 38.5, 39, 39.5, or 40 mg per square centimeters. As an example, when the first side surface area is 20 square centimeters, and the amount of NRTTI in the patch divided by the first side surface area is 16 mg per square centimeters, that means the total amount of NRTTI in the patch is 320 mg (since 320/20 = 16).

Methods and Uses

[0068] In some aspects, methods of preventing infection of a subject with HIV comprise applying any of the disclosed the drug delivery devices to the skin of a subject. In some aspects, methods of treating infection of a subject with HIV comprise applying any of the disclosed drug delivery devices to the skin of a subject.

[0069] Any of the disclosed the drug delivery devices may be applied to the skin of a subject to achieve prophylaxis against HIV infection. In some aspects, any of the disclosed the drug delivery devices may be used in pre-exposure prophylaxis (PrEP). In some aspects, any of the disclosed the drug delivery devices may be used in post-exposure prophylaxis (PEP).

[0070] In some methods, the baseplate is removed from the patch 1 to 3 days after the patch is applied to the skin of a subject. In some methods, the formulation delivers a sustained amount of the NRTTI to supply a detectable concentration of the NRTTI in the plasma of the subject at least until 1 month after the patch is applied to the skin of the subject. In some methods, the application results in a relative CMAX of the NRTTI as compared to a CMAX from the application of an intramuscular suspension containing the same amount of the NRTTI, that is 2-50, 2-40, 2- 30. 2-20. 2-10. or 2-5-fold lower. For example, if the CMAX from the application of an intramuscular suspension containing the same amount of the NRTTI is 0.2 per liter, then a 2-fold lower CMAX from the application of the disclosed drug delivery devices would be 0. 1 per liter and a 4-fold lower CMAX from the application of the disclosed drug delivery devices would be 0.05 per liter.

[0071] In some embodiments, the microarray patch formulation enables sustained delivery of the therapeutic (i.e., the NRTTI). Slow dissolution of the microarray patch within the skin enables circulating levels of drug to be detected in plasma at >3 months, even for drugs with short preclinical half-lives.

[0072] In some embodiments, the microarray patch formulation reduces burst release relative to other delivery' techniques (such as intramuscular suspensions, subcutaneous suspensions, and oral tablets), which improves therapeutic margins relative to toxicological concerns related to counts of CD4+ T cells and/or total lymphocytes.

[0073] In some embodiments, the combination of the microneedle formulation, the potency and pharmacokinetics of the molecule, and the drug delivery' efficiency of the microneedle system enables therapeutically relevant dose levels to be delivered in a microarray patch measuring between 1 and 5 in².

[0074] In some methods, the administration of a microarray' patch or patches with a total first side surface area less than or equal to 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 cm² is sufficient to deliver an effective amount of the NRTTI to a subject infected with HIV. In some methods, the effective amount of the NRTTI is delivered over 1 to 72 hours applied once every 1 to 6 months.

[0075] In some embodiments, the microarray patch or patches are applied by the patient, without a need for a physician or other clinician.

EXAMPLES

[0076] The following examples are provided to promote a further understanding of the invention.

Example 1: Preparation of Microarray Patch Formulations Containing Islatravir

[0077] To fabricate the first layer of the microarray patch (the tips), islatravir was mixed with aqueous PVA 9-10 kDa and PVP k29 in varying ratios according to Table 1. The formulations were mixed at 3000 rpm for 3 min using a SpeedMixer™ DAC 150. 1 FVZ-K (GermanEngineering, Hauschild & Co. KG, Hamm, Germany). Following initial mixing, deionized water was then added to decrease viscosity of the gel and formulations were subjected to a further cycle of mixing at 3000 rpm for 3 min. The homogenized aqueous polymer-drug containing blend was then added to microneedle (MN) molds, which were placed in a pressure tank and subjected to 5 bars of positive pressure for 3 min (Protima®, TUV Rheinlad, Koln, Germany) to fill the microprojection cavities. Following this, excess formulation was then removed from the mold surface with a clean spatula. Formulations containing MN molds were then replaced in the positive pressure chamber and subjected to a further 5 bar pressure for 30 min, to allow the formulations to dry in the microprojection cavities under pressure. A silicone elastomer ring was then applied to the outer surface of the MN mold with the application of PVA 9-10 kDa (40% w/w) acting as a temporary adhesive. The formulations were air dried at 19°C for 24 hours.

[0078] Once the system dried, and to fabricate the baseplate layer, 850 pL of baseplate formulation was applied on top of the tip formulation within the MN mold, centrifuged at 3500 rpm for 15 min then air-dried for 12 h until the baseplate formed a flexible consistency. The microarray patch with baseplate was then placed on level surface at 37.5° C for a further 24 h to ensure complete drying. Five formulations Fl, F2, F3, F4, and F5 were prepared in this manner. [0079] The opaque drug containing layer was localized to the pyramidal section of the obelisk micro-projections of the microneedles, while a flat and clean baseplate made up the base of the microneedle projections. NRTTI drug loading decreased from formulation Fl to formulation F5, consistent with the decreasing amount of islatravir cast into the needle tips of the PDMS molds. A maximal total drug load of ~5.8 mg was encapsulated into a 16 x 16 MAP for formulation F 1 with an overall patch size of 0.36 cm², which is the size of a postage stamp.

[0080] Microarray patches (MAPs) that contain islatravir were imaged using light microscopy (Fig. 1 panels A-C) and scanning electron microscopy (SEM) (Fig. 1, panels D-F). Specifically, morphology was visualized using a stereo microscope (Leica EZ4 D, Leica Microsystems. Milton Keynes, UK) and SEM (Tabletop Microscope TM3030, Hitachi, Krefeld, Germany). SEM images of samples w ere recorded at an accelerating voltage of 15 kV under vacuum. To quantify the amount of encapsulated islatravir, each patch w as separately added to 5 mL deionized water and subjected to sonication for 3 hours to ensure complete dissolution of the polymer. The suspension was then mixed with 5 mL of methanol and sonicated for 3 hours to ensure complete dissolution of drug. The mixture w as appropriately diluted before high- performance liquid chromatography (HPLC) analysis.

Table 1. Islatravir Containing Microneedle Tip and Baseplate Formulations Fl through F5. The composition of the formulation in solution and composition of solids are included below.

Example 2: Mechanical Testing of Islatravir Containing Microneedle Formulations and Confirmation of Ex Vivo Skin Insertion

[0081] A texture analyzer was used to determine mechanical and insertion properties of the islatravir microarray patches (MAPs). The MAP was attached to a probe and moved downward at 0.5 mm/s to compress the microneedles against a flat aluminum surface. A force of 32 N (analogous to the force exerted by manual thumb pressure during skin application) was applied for 30 s before the probe was moved upward again. The length of individual needles in the microneedle (MN) arrays was measured before and after compression and the percentage reduction of MN heights w as calculated and reported (Fig. 2, panel A).

[0082] To demonstrate the ability of islatravir microarray patches (MAPs) to insert into the skin, microneedles were applied to full-thickness neonatal porcine skin using thumb pressure applied to the back of the patch (Fig. 2, panel B). Full-thickness neonatal porcine skins were obtained from stillborn piglets within 24 h post-mortem and stored at -20 °C until use. Prior to the experiment, the skins were allowed to thaw and equilibrate to room temperature by immersion in PBS (pH 7.4).

[0083] A light microscope was used to visualize the penetration of islatravir and methylene blue microarray patches (MAPs). The needle insertion and dissolution within the skin was monitored using an EX-101 optical coherence tomography (OCT) microscope (Michelson Diagnostics Ltd.. Kent, UK) (see Fig. 2. panels C and D). These images were then processed and analyzed to study the exact length of microneedle insertion using Imaged® (National Institutes of Health, Bethesda MD, USA). In addition, the mechanical properties of the patches were evaluated using a TA-TX2 Texture Analyzer (TA) (Stable Microsystems, Haslemere, UK) as previously described. The patch was attached to a probe and moved downward at a test speed of 0.5 mm/s to compress the patch against a flat aluminum surface. A force of 32 N was applied to the patch for 30 s. The length of individual microneedles was measured before and after compression and the percentage reduction of microneedle heights w as calculated and reported. [0084] In situ visualization using OCT indicated that the drug-loaded layers of the needle tips of formulations Fl and F2 were fully embedded into the skin (Fig. 2, panels C and D). This would suggest that when the patches are applied to the skin, the base layer should dissolve and embed the drug containing layer into the skin, forming micro-depots for sustained drug release.

Example 3: Quantification of Microneedle Drug Loading and Ex Vivo Drug Delivery Efficiency from Islatravir Containing Microneedles

[0085] To determine the amount of islatravir loaded into each microarray patch (MAP), a single MAP measuring 0.6 cm x 0.6 cm (a surface area of 0.36 cm²) was added to 5 mL deionized water and subjected to water bath sonication for 3 hours to ensure complete dissolution of polymer. The suspension was added to 5 mL of methanol and sonicated for 3 hours to ensure complete dissolution of drug. A 100 pL aliquot was added to 900 pL of methanol, vortexed for 10 min and filtered using PTFE syringe filter 0.45 pm, to obtain sample with a total dilution of 100X. A 0.5 mL aliquot was assayed by HPLC according to the parameters in Table 2.

Table 2. HPLC Method for Quantification of Islatravir in Microarray Patches

[0086] A skin dissolution study was performed to characterize the dissolution time course after insertion into ex vivo neonatal porcine skin over a 24-hour period. MAPs were manually inserted into neonatal porcine skin tissue using thumb pressure for 30 secs. To avoid dislodging the patch from the skin surface, a cylindrical stainless steel metal weight of approximately 15 g was placed on the top of the MAP. The samples w ere placed in a thermostatically controlled chamber (Genlab incubator, Genlab Ltd., Cheshire, UK) set at 37°C and were analyzed at 2, 6 and 24 hours by carefully removing the patch off the skin. MAPs and the skin samples were examined under a stereo microscope. The drug deposition of the formulations was evaluated using a Franz cell setup (PermeGear, Inc., Hellertown, PA, USA). [0087] Each of the microarray patch (MAP) formulations described in Table 1 were inserted into ex vivo porcine skin tissue (stratum corneum side) using manual thumb pressure for 30 seconds. The porcine skin containing the MAP was then applied to the donor chamber of a Franz cell apparatus. The receptor compartment of the Franz cell was filled with degassed phosphate buffered saline (PBS) at a pH of 7.4, covered with a thermal water jacket to maintain receiver temperature at 37°C and stirred using a stir bar at 600 rpm. After a period of 24 hours, the skin was removed from the Franz cell and homogenized. Homogenization was performed by placing the skin into a 2 mL Eppendorf tube containing two stainless steel beads and adding 0.5 mL of HPLC water prior to 15 minutes of homogenization at 50 rpm. 1 mL of 100% MeOH was added and then the mixture was homogenized for an additional 15 minutes at 50 rpm using Tissue Lyser LT (Qiagen Ltd., Manchester, UK). After the second homogenization step, an additional 3.5 mL of methanol was added to form a final mixture in a 15 mL Falcon tube. The mixture was sonicated for one hour. After sonication, 200 uL of the mixture was removed and added to 1800 uL of diluent (20:80 acetonitrile: water).

[0088] The samples were vortexed and filtered through 0.45 pm PTFE filter into HPLC vials prior to assaying by HPLC. With regards to the receptor compartment, 12 ml of the receptor fluid was collected and diluted with 8 ml of methanol. The samples were vortexed for 1 minute. Next 2 ml of the mixture was transferred into an Eppendorf tube and centrifuge at 14000 rpm for 15 mins. The supernatant was then collected for HPLC analysis. The total mass of drug recovered from homogenization was added to the mass of drug within the receptor compartment of the Franz cell to determine how much drug had been delivered from the microarray patches (MAPs) into the skin. This total quantity was divided by the amount of islatravir initially present within the patch to calculate delivery efficiency, shown in Table 3.

[0089] Quantification of islatravir was carried out using a reversed-phase Agilent HPLC system (Agilent Technologies 1220 Infinity compact LC series, Agilent Technologies UK Ltd, Stockport, UK) coupled with a UV detector. The analysis and separation were conducted on an XBridge* C18 column with a particle size of 3.5 pm, an internal diameter of 4.6 mm, and a length of 150 mm (Waters, Dublin, Ireland). The samples were eluted with a mobile phase mixture composed of 0.1% v/v phosphoric acid and acetonitrile at a flow rate of 1 mL/min. The analysis was carried out at 30°C with a 20 pL injection volume over a 10-minute period. Table 3. Quantification of islatravir loading in small and large patches and delivery to porcine skin ex vivo

[0090] Formulation Fl, which has the highest drug load of the series, also resulted in the highest amount of islatravir administered into and across the skin with up to 2.48 mg of the drug being delivered. Thus, Fl exhibited the highest delivery efficiency at 46.7%. In contrast. F2-F4 resulted in approximately 0.8- 1.2 mg of islatravir being delivered into and across the skin. Nevertheless, formulations F2-F4 exhibited a delivery efficiency of approximately 25-37%. Lastly, F5 which has the lowest drug loading had the lowest amount of drug being delivered with only 0.5 mg of the compound being delivered. With respect to all formulations, the delivery efficiency of these formulations was rather similar and not statistically different to one another (p > 0.05). Guided by this in vitro delivery data in tandem with the drug loading data for the patches, formulation Fl was selected for further evaluation in vivo along with stability testing. In order to support large animal studies, islatravir-loaded dissolving patches were scaled up from a size of 0.36 cm² containing 256 microneedles to a size of 1.76 cm² containing 1110 microneedles, thereby increasing in the number of microneedles per patch by approximately four-fold and the patch area by approximately 4.5-fold. Table 3 includes data corresponding to the use of formulation Fl in a large patch.

[0091] As indicated in Table 3, the larger patch was able to insert the drug-containing tips into the dermal layer of the skin. The large patch successfully delivered 8.8 mg of islatravir into the skin, corresponding to a delivery efficiency of 34.5%, as measured using the Franz diffusion cell apparatus. Delivery efficiency dropped slightly relative to the smaller patches, as can be expected based on the lower penetration depth. Nevertheless, the total amount delivered increased substantially relative to the smaller patches (approximately 2.5-fold), enabling progression into minipig studies using the larger patch sizes (see Example 6). Example 4: Quantification of In Vivo Drug Delivery Efficiency from Islatravir Containing Microneedles in rats

[0092] To quantify in vivo drug delivery, four islatravir microarray patches (MAPs) were applied to Sprague Dawley rat skin for a period of 24 hours prior to removal. Two different islatravir MAP formulations - formulation Fl and formulation F2 - were tested. Blood plasma samples were collected from the tail vein at 1, 5, 24, 29 and 48 hours, prior to sacrificing the animal and resecting the skin at the site of the injection. Islatravir was quantified in the plasma by LC-MS. In order to determine how much drug was released from the patch into systemic administration, blood plasma concentration data was deconvoluted against islatravir IV PK in rats utilizing Phoenix 64 WinNonLin (Build 8.1.0.3530, Certara, Princeton, New Jersey), to quantify the total islatravir concentrations in plasma and skin tissues.

[0093] The samples underwent fortification with stable-isotope labelled internal standards and underwent salt-assisted liquid-liquid extraction using 1 M ammonium acetate at pH 5 and acetonitrile. Subsequently, the processed samples were chromatographed using reversed-phase chromatography employing a gradient elution involving water with 0.2 mM ammonium fluoride and methanol. Detection was performed on a Sciex (Framingham, MA, USA) API 6500+ triple quadrupole mass spectrometer by monitoring precursor to product ion combinations in multiple reaction monitoring (MRM) mode. For skin tissue analysis, a homogenization process was employed. The entire skin sample was weighed and transferred to a 15 mL polypropylene centrifuge tube, followed by the addition of 19X volume of 70/30 methanol-water, assuming a density of 1 g/mL (20 times dilution). Four 5/32” stainless steel beads were then added, and the tube was capped and sealed using Parafilm®. Subsequently, the tubes underwent homogenization for 5 minutes at maximum RPM (1750 rpm) using a SPEX (Cole-Parmer, Metuchen. NJ, USA) Geno/Grinder. This process was repeated for an additional 5 minutes. Analysis of the homogenate samples involved the fortification of sample aliquots with stable labelled internal standards, followed by precipitation with acetonitrile before injection. The LC-MS/MS conditions used for skin tissue analysis remained consistent with those used for plasma analysis. [0094] The percentage of total drug delivered to the skin was calculated by dividing the total amount of drug recovered from skin homogenization by the total amount of drug present in the microarray patches (MAPs). Similarly, the percentage of total drug delivered to the plasma was calculated by dividing the amount of drug in plasma calculated through deconvolution by the total amount of drug in all four patches applied to the animal. Projected total in vivo delivery from all four patches was calculated by multiplying the projected amount encapsulated in four patches with the in vivo percent delivered (sum of percent to skin and percent to plasma) (Table 4).

Table 4. In vivo drug delivery efficiency after application of islatravir MAP formulation Fl and F2 to female Sprague Dawley rats

Example 5: In Vivo Rodent Pharmacokinetics After Administration of Microarray Patch Application

[0095] To evaluate in vivo pharmacokinetics, a 90 mg/mL islatravir suspension and four islatravir microarray patches (MAPs) were administered to Sprague Dawley rats for a period of 24 hours. MAPs were removed from the rat skin after 24 hours of wear time and all animal plasma was assayed to determine islatravir concentration for a period of three months (or until plasma levels were below the lower limit of quantitation).

[0096] To quantify the fraction of administered drug released into the bloodstream, blood plasma concentration data was deconvoluted against IV PK. The total amount of drug released into systemic circulation at a given timepoint was divided by the total administered dose (6.3mg for the intramuscular suspension) or the total amount of drug delivered to the animal from the MAPs (2.32 mg calculated as a sum of plasma + skin concentrations as described in Example 4) to calculate fraction released. Blood plasma concentration in mg/L was divided by the above doses to calculate a dose normalized plasma concentration utilized to compare achievable pharmacokinetic profiles from these systems.

[0097] Results demonstrated prolonged delivery of islatravir from the MAP formulation as compared to the intramuscular suspension (Fig. 3), with compound detectable in plasma of all six rats for at least three months after MAP delivery’, compared to ~4 days from the intramuscular suspension (Fig. 5). As shown in Fig. 5, intramuscular injection of islatravir showed significantly higher drug delivery efficiency, with 100% of dosed islatravir detected in plasma within 24 hours. Rapid burst release can be expected given the high solubility of islatravir in aqueous media. In contrast, as shown in Figs. 4 and 5, the MAP formulation demonstrated more sustained release over the 3-month period, with a significant decrease in the dose-normalized CMAX by approximately 10-fold, from 0.157 L'¹ for the intramuscular suspension to 0.015 L ¹ for the MAP formulation. Early timepoints were characterized by a degree of burst release which resulted in high plasma concentrations at timepoints prior to one week followed by a comparably more consistent plasma levels over the remainder of the study (Fig. 4). Pseudo-steady state release rates were approximately 10 pg/day. This sustained release supports the notion that microneedle tips successfully deposit into skin and release drug through slow dissolution of the microneedle tip in the skin over time.

[0098] Rat studies were carried out in a climate-controlled room where temperature was maintained between 20°C and 23°C and relative humidity was in the range of 44%-57% Islatravir microparticles were suspended in a vehicle containing a combination of sodium carboxymethylcellulose, polysorbate 80 and sucrose and dosed to the quadricep at a 70 L injection volume and 90mg/mL active concentration. Female Sprague Dawley rats (Charles River Laboratories, Harlow, UK), 8-10 weeks of age, were acclimatized to the animal house conditions for a week prior to the experiment. The dorsal hair of the rats for the microarray patch (MAP) treated cohort was removed one day prior to the experiment using electric hair clippers (Remington Co.. London, UK) followed by depilatory cream (Boots Smooth Care hair removal ream sensitive, Boots, Nottingham, UK) under gaseous anesthetic (2-4% isofluorane in oxygen). Following this, rats were left for a 24 hours period to allow their skin to recover, and to ensure the complete restoration of the skin’s barrier function before MAP application. On the following day, rats were sedated again followed by the administration of MAPs using firm thumb pressure. Prior to their application, MAPs were initially secured inside Microfoam™ adhesive frames.

Afterwards, Tegaderm™ film was placed on top of the MAPs and kinesiology tape was eventually wrapped around the back of the rats to hold the MAPs firmly in place for 24 hours. Rats after MAP treatment were housed individually for 24 hours following post-application to ensure that the MAPs remained in place. Each rat in this study received four MAPs with the composition corresponding to Formulation FL MAPs were removed from rodent skin after 24 hours. In one study, blood plasma concentration was assessed over a three-month study period. Blood samples were collected into 1.5 mL EDTA microtubes over the course of the study via tail vein bleeds. To separate the plasma from the rest of the blood components, samples taken from rats were centrifuged immediately at 2,200 g for 10 minutes at 4°C. The obtained supernatants were then transferred into their respective labelled microtubes and stored in a -20°C freezer until further analysis. Example 6: In Vivo Minipig Pharmacokinetics After Administration of Microarray Patch Application

[0099] Islatravir microarray patches (MAPs) underwent further evaluation in minipigs to collect extensive animal data for insights into their potential performance in humans. Minipigs are commonly used as a model for transdermal drug delivery due to the similarities in skin thickness and composition with humans.

[0100] In order to determine the drug delivery⁷ efficiency and pharmacokinetics from administration of islatravir MAPs, 16 male naive 13 to 14 week old Gottingen minipigs weighing between 7 and 11 kg were obtained from Ellegaard Gottingen Minipigs A/S. Techniques for application of MAPs were equivalent to those described for rats, above, with removal of patches after a 24 hour wear time for one arm and after a 48 hour wear time for another arm. Ten large islatravir-loaded MAPs, or a single 90mg/mL islatravir suspension, were administered to each minipig (with each patch applied to the abdominal skin along the ribcage). MAPs were removed from the skin after 24 or 48 hours of wear time and all animal plasma was assayed to determine islatravir concentration. In the 24-hour arm, islatravir was detected in minipig plasma during the entire 24-hour application, but no additional compound was found in the plasma after this period (Fig. 6)

[0101] Blood samples of 0.5 ml volume were collected from the animals and centrifuged (1500 g, 10 minutes, 4°C) to prepare plasma for analysis. Skin samples (dose site area) were excised from the animals. LC-MS/MS analysis was employed to determine the concentrations of minipig plasma and skin. For plasma, a 0.05 mL aliquot was used, establishing a lower limit of quantitation of 0.030 ng/mL and a dynamic range from 0.030 to 40 ng/mL. Processed samples were chromatographed on a Waters (Milford, MA, USA) HSS T3 C18 column (50 x 3.0 mm, 2.5 pm) employing gradient elution with a mixture of water and methanol containing 0.1% propionic acid. Detection was carried out on a Sciex API 6500 triple quadrupole mass spectrometer, monitoring precursor to product ion combinations in MRM mode. Skin tissue analysis involved a homogenization process. The skin sample's entire weight was transferred to a 15 mL polypropylene centrifuge tube, followed by the addition of 19x volume of 70/30 methanol -water (assuming a density of 1 g/mL, resulting in a 20x dilution). Stainless steel beads were included, and the tube was capped and sealed with Parafilm®. The tubes were homogenized using a SPEX (Cole-Parmer, Metuchen, NJ) Geno/Grinder for two cycles of 5 minutes at maximum rpm (1750 rpm). Using a 0.01 mL aliquot, the lower limit of quantitation for skin samples was determined to be 1.13 ng/mL, with a dynamic range from 1.13 to 1500 ng/mL. After fortifying sample aliquots wi th stable labelled internal standards, homogenate samples were precipitated with acetonitrile before injection. LC-MS/MS conditions matched those used for minipig plasma analysis.

[0102] In the 24-hour arm, islatravir was detected in plasma for at least 5 days in all animals, with some circulating levels detected in one minipig for up to 20 days (Fig. 7). To quantify the fraction of administered drug released into the bloodstream, blood plasma concentration data was deconvoluted against IV PK. Delivery efficiency was calculated by dividing the total administered dose (15 mg for the intramuscular suspension and 255 mg for the MAPs) by the amount of drug detectable in plasma over the first 13 days. The delivery efficiency from the 24- hour patches was less than 1% for all animals. Extending the patch wear time to 48 hours increased the overall delivery efficiency, varying from 6% to 57% among the four animals in the study (Fig. 7). Blood plasma concentration in mg/L was divided by the above doses to calculate a dose normalized plasma concentration utilized to compare achievable pharmacokinetic profiles from microneedle and intramuscular administration. The MAP formulation was show n to reduce the dose-normalized CMAX by approximately 6-fold, from 22 mL'¹ for the intramuscular suspension to 3.6 mL'¹ for the microneedle formulation (Fig. 8).

Example 7: Efficacious Human Patch Size Projections from Rodent and Minipig PK

[0103] The extraordinary potential of islatravir as a long-acting medication is associated with its extended clearance in humans (R. P. Matthews et al. Clin Transl Sci, 2021, 14, 1935, which is incorporated by reference herein). Therefore, in order to predict achievable treatment durations resulting from MAP administration, dose-normalized release rates resulting from administration of MAPs in rats and in minipigs were convoluted with modelled islatravir IV PK in humans in Phoenix 64 WinNonLin. Dose-normalized human plasma concentrations were then multiplied by a 322 mg dose to calculate predicted plasma concentrations after dosing microarray patches (MAPs) with a total surface area of 20 cm² and compared against a 0.1 nM plasma concentration target, which has previously been demonstrated to be consistent with greater than a one-log reduction in plasma HIV1-RNA.

[0104] As shown in Fig. 9, projections from rat were demonstrated to be consistent with over three months of efficacy, whereas projections from minipig were consistent with at least one month of efficacy. Drug loading per unit surface area w as assumed to be equivalent to small Fl patches (see Table 3) with percent delivery equivalent to that of the smaller patch size. The dashed line in Fig. 9 is the 85-day Ctrough value observed after clinical dosing of an implant containing 62 mg of islatravir; such levels are consistent with exceeding the 0.05 pmol islatravir triphosphate concentration per 10⁶ PBMC cells associated with efficacy. Therefore, dosing

MAPs with a total surface area of 20 cm² is consistent with projected clinical efficacy in humans.

Example 8: Microarray Patch Stability Evaluation

[0105] The stability of the islatravir-loaded microarray patch (MAP) formulations was evaluated over a three-month period at a number of different conditions (Table SI), ranging from refrigerated in pouch under ambient humidity through 40°C and 75% relative humidity out of pouch. In particular, the stability was evaluated in terms of needle height reduction, ex vivo skin insertion, crystallinity, and drug content over time after storing samples at 25°C/RH 65% and 40°C/RH 75% in the stability chamber (Binder GmBH, Tuttlingen, Germany) and 2-8°C/ambient humidity in the fridge. Samples were analyzed at each predetermined time point (30, 60 and 90 days). Full-thickness neonatal porcine skins were obtained from stillborn piglets and allowed to thaw and equilibrate as described above.

[0106] Islatravir loaded MAPs were inserted into full thickness ex vivo neonatal porcine skin using thumb pressure (32 N) applied to the back of the patch. A light microscope was used to visualize the penetration of MAPs. The needle insertion and dissolution within the skin was monitored using an EX-101 optical coherence tomography (OCT) microscope (Michelson Diagnostics Ltd.. Kent, UK). These images were then processed and analyzed to study the exact length of microneedle insertion using the software I mage J" (National Institutes of Health, Bethesda MD, USA).

[0107] In addition, the mechanical properties of the MAPs were evaluated using a TA-TX2 Texture Analyser (TA) (Stable Microsystems. Haslemere, UK) as previously described [1,2], The MAP was attached to a probe and moved downward at a test speed of 0.5 mm/s to compress the microneedle (MN) against a flat aluminum surface. A force of 32 N was applied to the patch for 30 s. The length of individual needles in the MN arrays was measured before and after compression and the percentage reduction of MN heights was calculated and reported (Fig. 10, panel A).

[0108] No changes in the chemical composition/impurity profile of the drug were observed over this three-month study. Likewise, no changes in the X-ray diffraction pattern of the drug were observed, indicating that the drug remained crystalline throughout the study (data not shown).

[0109] It was observed that, regardless of the storage condition and duration, all evaluated MAPs displayed no significant changes (p > 0.05) in needle height reduction. All displayed an average height reduction between 4-6%. Previous studies on dissolving MAPs have indicated that MAPs displaying a height reduction of less than 10% would possess sufficient mechanical robustness to pierce and puncture the skin upon application (see, e.g, Q. K. Anjani, et al. Drug Deliv Transl Res 2023). This was further validated by a skin insertion study (Fig. 10B) that showed all the MAPs, regardless of the storage condition and duration, were able to puncture the skin (as visualized using OCT imaging). This is the ideal intradermal depth needed for the formulation to be deposited in order for the drug to dissolve from the depot into the dermal microcapillaries before reaching systemic circulation (see, e.g., A. H. Sabri, et al., Adv Drug Deliv Rev 2020, 153. 195).

Discussion

[0110] As described above, dissolvable islatravir MAPs were formulated at up to 87% total solid loading and successfully penetrated skin, as evidenced by ex vivo porcine skin tissue testing, an in vivo study in rats, and an in vivo study in minipigs. In contrast to similar efforts to deliver less potent antiretrovirals with MAP technology, this effort demonstrates proof of concept for extended (e.g., one month or longer) delivery at efficacious levels within a reasonable patch surface area of 20 cm², which is equivalent to the surface area of approximately three US quarters. The stability of the formulated MAPs is consistent with storage at 25°C and 40°C, indicating that these devices have the potential to address challenges with cold chain storage, which often limits access in low resource settings. These data support the potential of long-acting MAP technology in HIV treatment and prevention. If successful, such a technology' could have a dramatic effect on the global burden of HIV by improving overall patient adherence to medication, increasing the number of at-risk individuals interested in pursuing HIV PreP, and/or expanding access to lower middle-income countries where refrigeration and access to medical personnel is limited.

Claims

CLAIMS What is claimed is:

1. A drug deliver)’ device comprising: a baseplate that has an amount of a first polymer; and a patch comprising a layer having a first side adhering to the baseplate and a second side opposite to the first side; and a plurality' of tips extending from the second side, wherein the patch comprises a formulation that has an amount of a second polymer; and a suspension of an amount of an anti-HIV nucleoside analogue reverse transcriptase translocation inhibitor (NRTTI), wherein said first side has a surface area of at least 1 square centimeter and at most 60 square centimeters.

2. The drug delivery device of claim 1. wherein the first polymer comprises poly(vinylpyrrolidone) having a molecular weight of at least 100 kDa and at most 10,000 kDa.

3. The drug delivery' device of claim 1, wherein the first polymer comprises poly(vinylpyrrolidone) having a molecular weight of at least 500 kDa and at most 3000 kDa.

4. The drug delivery' device of claim 2 or 3, wherein said poly(vinylpyrrolidone) is at least 50% (w/w) and at most 100% (w/w) within the baseplate.

5. The drug delivery device of claim 2 or 3, wherein said poly(vinylpyrrolidone) is at least 90% (w/w) and at most 98% (w/w) within the baseplate.

6. The drug delivery device of any one of claims 1 to 5, wherein the baseplate further comprises glycerol.

7. The drug delivery' device of any one of claims 1 to 6, wherein the second polymer is a polymer that dissolves in water.

8. The drug delivery device of any one of claims 1 to 6, wherein the second polymer is a polymer that dissolves in skin.

9. The drug delivery’ device of any one of claims 1 to 6, wherein the second polymer comprises poly(vinyl alcohol) having a molecular weight of at least 2 kDa and at most 300 kDa.

10. The drug delivery’ device of any one of claims 1 to 6, wherein the second polymer comprises poly(vinyl alcohol) having a molecular weight of at least 2 kDa and at most 20 kDa.

11. The drug delivery device of claim 9 or 10, wherein said poly(vinyl alcohol) is at least 0.1% (w/w) and at most 40% (w/w) within the patch.

12. The drug delivery device of claim 9 or 10. wherein said poly(vinyl alcohol) is at least 2% (w/w) and at most 10% (w/w) within the patch.

13. The drug delivery’ device of any one of claims 9 to 12, wherein said formulation of the patch further comprises poly(vinylpyrrolidone) that is at least 0. 1% (w/w) and at most 40% (w/w) within the patch.

14. The drug delivery device of any one of claims 9 to 12, wherein said formulation of the patch further comprises poly (vinylpyrrolidone) that is at least 2% (w/w) and at most 10% (w/w) within the patch.

15. The drug delivery' device of claim 13 or 14, wherein said poly(vinylpyrrolidone) within the patch has a molecular weight of at least 5 kDa and at most 300 kDa.

16. The drug delivery' device of any one of claims 1 to 15, wherein the NRTTI is islatravir.

17. The drug delivery device of any one of claims 1 to 16, wherein the tips have a length dimension of at least 300 micrometers and at most 1300 micrometers.

18. The drug delivery' device of any one of claims 1 to 16, wherein the tips have a length dimension of at least 500 micrometers and at most 700 micrometers.

19. The drug delivery' device of any one of claims 1 to 18, wherein the tips have a maximal width dimension of at least 100 micrometers and at most 600 micrometers.

20. The drug delivery device of any one of claims 1 to 18, wherein the tips have a maximal width dimension of at least 200 micrometers and at most 300 micrometers.

21. The drug delivery’ device of any one of claims 1 to 20, wherein the tips are conical or pyramidal in shape.

22. The drug delivery’ device of any one of claims 1 to 21, wherein the tips are spaced from each other by at least 50 micrometers and at most 600 micrometers with respect to their centers.

23. The drug delivery device of any one of claims 1 to 21, wherein the tips are spaced from each other by at least 50 micrometers and at most 150 micrometers with respect to their centers.

24. The drug delivery device of claim 22 or 23, wherein the tips are uniformly spaced from each other in a regular array configuration.

25. The drug delivery’ device of any one of claims 1 to 24, wherein said first side has a surface area of at least 15 square centimeters and at most 30 square centimeters.

26. The drug delivery’ device of any one of claims 1 to 25, wherein the baseplate is removable from the patch 1 to 3 days after the patch is applied to the skin of a subject.

27. The drug delivery device of any one of claims 1 to 26, wherein the formulation delivers a sustained amount of the NRTTI to supply a detectable concentration of the NRTTI in the plasma of a subject at least until 1 month after the patch is applied to the skin of the subject.

28. The drug delivery device of any one of claims 1 to 27, wherein application of the patch to the skin of a subject results in a CMAX of the NRTTI that is at least 2-fold low er as compared to administration of an intramuscular suspension containing the same amount of the NRTTI.

29. The drug delivery device of any one of claims 1 to 27, wherein application of the patch to the skin of a subject results in a CMAX of the NRTTI that is at least 10-fold and at most 50-fold lower as compared to administration of an intramuscular suspension containing the same amount of the NRTTI.

30. The drug delivery’ device of any one of claims 1 to 29, w herein administration of the patch or multiple patches with a total first side surface area less than or equal to 100cm² is sufficient to deliver an effective amount of the NRTTI to a subject infected w ith HIV.

31. The drug delivery device of any one of claims 1 to 29, wherein administration of the patch or multiple patches with a total first side surface area less than or equal to 60cm² is sufficient to deliver an effective amount of the NRTTI to a subject infected with HIV.

32. The drug delivery device of any one of claims 1 to 29, wherein administration of the patch or multiple patches with a total first side surface area less than or equal to 40cm² is sufficient to deliver an effective amount of the NRTTI to a subject infected with HIV.

33. The drug delivery device of any one of claims I to 29, wherein administration of the patch or multiple patches with a total first side surface area less than or equal to 20cm² is sufficient to deliver an effective amount of the NRTTI to a subject infected with HIV.

34. The drug delivery device of any one of claims 30 to 33, wherein said effective amount of the NRTTI is delivered over 1 to 72 hours applied once every 1 to 6 months.

35. The drug delivery' device of any one of claims 1 to 34, wherein the amount of NRTTI in the patch divided by the first side surface area is at least 0.5 mg per square centimeters and at most 40 mg per square centimeters.

36. The drug delivery' device of any one of claims 1 to 34, wherein the amount of NRTTI in the patch divided by the first side surface area is at least 2 mg per square centimeters and at most 30 mg per square centimeters.

37. The drug delivery' device of any one of claims 1 to 34, wherein the amount of NRTTI in the patch divided by the first side surface area is at least 10 mg per square centimeters and at most 20 mg per square centimeters.

38. A method of preventing infection of a subject with HIV, the method comprising applying the drug delivery device of any one of claims 1 to 37 to the subject.

39. A method of treating infection of a subject with HIV, the method comprising applying the drug delivery device of any one of claims 1 to 37 to the skin of the subject.

40. The method of claim 38 or 39, the method further comprising removing the baseplate from the patch 1 to 3 days after the patch is applied to the skin of the subject.

41. The method of any one of claims 38 to 40. wherein the formulation delivers a sustained amount of the NRTTI to supply a detectable concentration of the NRTTI in the plasma of the subject at least until 1 month after the patch is applied to the skin of the subject.

42. The method of any one of claims 38 to 41. wherein the device results in a CMAX of the NRTTI that is at least 2-fold lower after the patch is applied to the skin of a subject as compared to an intramuscular suspension containing the same amount of the NRTTI.