WO2016149561A1

WO2016149561A1 - Subdermal implants for the sustained delivery of water-soluble drugs

Info

Publication number: WO2016149561A1
Application number: PCT/US2016/022980
Authority: WO
Inventors: Marc M. Baum; Manjula GUNAWARDANA; John A. Moss; Thomas J. Smith
Original assignee: Oak Crest Institute Of Science
Priority date: 2015-03-17
Filing date: 2016-03-17
Publication date: 2016-09-22

Abstract

In various embodiments, the invention discloses devices, systems and methods for achieving sustained release agent delivery. The methods generally include administering a sustained release agent delivery system to a mammalian organism in need of such treatment at an 5 area wherein release of an effective agent is desired and allowing the effective agent to pass through the device in a controlled manner. In various embodiments, the device consists of a perforated tube of agent-impermeable material (e.g., silicone) containing a core or reservoir of effective agent, with the tube encased in an agent-permeable material that allows the effective agent to pass through the perforations.

Description

SUBDERMAL IMPLANTS FOR THE SUSTAINED DELIVERY OF WATER- SOLUBLE DRUGS FIELD OF THE INVENTION

The present invention generally relates to the field of sustained drug delivery.

BACKGROUND

The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention.

Oral or topical daily administration of antiretroviral (ARV) drugs to HIV-1 negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention, but clinical outcomes have varied widely. Adherence to frequent dosing is burdensome to the user and has emerged as a key factor in explaining the heterogeneous efficacy outcomes of HIV-1 pre-exposure prophylaxis (PrEP) clinical trials. It is well established across different delivery methods that adherence to therapy is inversely related to dosing period. Sustained release or "long-acting" ARV formulations hold significant promise as a means of reducing dosing frequency, thereby increasing the effectiveness of HIV-1 PrEP. Long-acting pre- exposure prophylaxis (LA-PrEP) is an alternative regimen to daily dosing designed to mitigate the above adherence challenges. LA-PrEP primarily has been based on ARV nanoparticles for parenteral administration as injections. Dosing intervals of one month or longer for injectable, long-acting, nanomilled formulations of the integrase strand transfer inhibitor cabotegravir (GSK1265744) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine are undergoing clinical evaluation as possible regimens for HIV-1 therapy and prevention. While these efforts are encouraging, they do not take advantage of the full portfolio of ARV agents currently available, especially drugs from the established nucleoside reverse transcriptase inhibitor (NRTI) mechanistic class.

Five recent clinical trials have demonstrated that vaginal and oral preparations of the NRTI tenofovir (TFV) can be effective in HIV-1 PrEP. A sustained release TFV, therefore, is a desirable addition to the small group of LA-PrEP candidates. Unfortunately, established ARV formulation approaches are not amenable to developing a long acting TFV formulation.

The dosing frequency of long-acting ARV agents is determined by the drug's aqueous solubility, antiviral potency, and systemic clearance kinetics. These criteria severely limit the number of FDA-approved ARV agents suitable for reformulation as nanoparticles. The high aqueous solubilities (> 5 mg mL^"1) of TFV, as well as its prodrugs TFV disoproxil fumarate (TDF) and TFV alafenamide (TAF, GS-7340), make long-acting nanoformulations unfeasible.

There is clearly a need in the art for novel sustained release drug delivery technologies in general, and especially those capable of broadening the number of available agents for HIV-1 LA PrEP.

SUMMARY OF THE INVENTION

In various embodiments, the invention teaches a sustained release agent delivery system that includes an inner agent core including one or more agents; an elongated reservoir impermeable to said one or more agents, wherein the inner agent core is located within the elongated reservoir; one or more delivery channels located orthogonally along the length of the elongated reservoir, wherein the one or more delivery channels are configured to allow the passage of the one or more agents; and one or more polymer membranes permeable to the one or more agents, wherein the one or more polymer membranes cover one or more of the one or more delivery channels and allow for the sustained release of the one or more agents into a subject's body after the agent delivery system is implanted in the subject's body. In some embodiments, one or more of the agents are water-soluble compounds having an aqueous solubility greater than 1 mg mL^"1 at 20°C. In certain embodiments, one or more of the agents are from the nucleoside reverse transcriptase inhibitor ( RTI) mechanistic class used for the prevention and/or treatment of human immunodeficiency virus (HIV) infection and/or acquired immune deficiency syndrome (AIDS). In some embodiments, one of the agents is tenofovir alafenamide. In certain embodiments, one of the one or more agents is an antiviral agent used for the treatment or prevention of one or more viral infections caused by a virus selected from the group consisting of: herpes simplex virus, hepatitis virus, and influenza virus. In some embodiments, one of the agents is a peptide selected from the group consisting of: leuprolide acetate, exenatide acetate, goserelin acetate, and octreotide acetate. In certain embodiments, the elongated reservoir includes walls that include a drug- impermeable polymer selected from the group consisting of silicone, ethylene vinyl acetate copolymer, polyurethane, latex, and combinations thereof. In some embodiments, one or more of the one or more polymer membranes are selected from the group consisting of: polyvinyl alcohol, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, parylene, ethylene vinyl acetate copolymer, and polycaprolactone.

In various embodiments, the invention teaches a method for reducing the likelihood of a subject contracting a viral infection, including: providing a sustained release agent delivery system described above, wherein one or more of the one or more agents of the inner agent core is an antiviral agent; and implanting the sustained release agent delivery system into the subject's body, thereby reducing the likelihood of the subject contracting the viral infection. In some embodiments, the sustained release agent delivery system is implanted into the subject subdermally. In some embodiments, the sustained release agent delivery system is implanted into one or more location in the subject selected from the group consisting of: upper inner or outer arm, inner thigh, back, and combinations thereof. In certain embodiments, the viral infection is caused by a virus selected from the group consisting of: human immunodeficiency virus (HIV), herpes simplex virus (HSV), hepatitis virus, and influenza. In some embodiments, the virus is HIV. In certain embodiments, one or more of the agents is a nucleoside reverse transcriptase inhibitor. In some embodiments, one or more of the agents is tenofovir alafenamide.

In various embodiments, the invention teaches a method for making a sustained release agent delivery system, the method includes: providing a tubing having first and second ends, wherein the tubing is impermeable to the agent; introducing one or more holes along the length of the tubing; sealing the first and second ends of the tubing; coating the tubing with a polymer permeable to the agent; opening at least one end of the tubing; introducing the agent into the tubing through the opened end; and resealing the open end of the tubing. In some embodiments, the tubing is made of substance selected from the group consisting of: silicone, ethylene vinyl acetate copolymer, polyurethane, and latex, and a combination thereof. In certain embodiments, the polymer is selected from the group consisting of: polyvinyl alcohol, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, parylene, ethylene vinyl acetate copolymer, polycaprolacton, and a combination thereof. In some embodiments, the agent is selected from the group consisting of: a nucleoside reverse transcriptase inhibitor, tenofovir alafenamide, emtricitabine, lamivudine, MK-8591 (EFdA), acyclovir, ganciclovir, oseltamivir phosphate, a peptide, leuprolide acetate, exenatide acetate, goserelin acetate, octreotide acetate, and a combination thereof. In certain embodiments, sealing includes applying silicone adhesive to the first and/or second ends of the tubing. In various embodiments, the invention teaches a kit that includes a sustained release agent delivery system described above; and instructions for the use thereof to reduce the likelihood of a subject contracting human immunodeficiency virus (HIV). In some embodiments, one of the agents is tenofovir alafenamide.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments are illustrated in the referenced figures. It is intended that the embodiments and figures disclosed herein are to be considered illustrative rather than restrictive.

Figures 1A-1C depict, in accordance with an embodiment of the invention, a 3D model (1A) and cross-sectional drawings (IB and 1C) of a TAF implant 100. The TAF core 104 inside silicone scaffold 103 with polyvinyl alcohol (PVA) membrane coating 102.

Cross-sections are sliced through the y-z (IB) and x-y planes (1C).

Figure 2 depicts, in accordance with an embodiment of the invention, TAF long acting (LA) implant displays pseudo-zero order (linear) cumulative in vitro release kinetics (mean, n = 6). Solid line corresponds to linear regression (R² = 0.8231) between 4-30 d, resulting in a TAF release rate of 0.92 ± 0.031 mg d^"1.

Figure 3 depicts, in accordance with an embodiment of the invention, subdermal implantation of TAF LA prototype device in beagle dogs maintains sustained drug levels, with low systemic exposure to TAF and TFV with concomitant, efficient peripheral blood mononuclear cell (PBMC) loading with TFV-DP. Pharmacokinetic profiles of plasma TAF (closed circles) and TFV (open circles) and PBMC TFV-diphosphate (TFV-DP (closed diamonds)). Each datapoint represents the mean + standard deviation of four beagle dogs and dotted lines correspond to the median concentrations for each analyte. TFV-DP levels were only measured after Day 20.

Figures 4A and 4B depict, in accordance with an embodiment of the invention, simulation of TAF pharmacokinetics in beagle dogs based on in vitro implant release rates. (4A) Graphical model; C, simulated plasma TAF concentration; V, volume of distribution (6.8 1); CI, clearance (473 J d^"1); AO, amount of drug cleared, Al, amount in the central compartment 1 ; CObs, observed plasma TAF concentration; 57 Rate, zero-order release rate from implant (1.9 μηιοΐ d^'1, 0.92 mg d^"1). (4B) Actual individual (closed circles) and simulated (dotted line) TAF plasma levels. The dose was 90 μιηοΐ (43 mg) and the bioavailability ( ) of the implant was assumed to be 100%. Note linear y-axis. Figure 5 depicts, in accordance with an embodiment of the invention, molar TAF:TFV plasma concentration ratios are stable throughout the 40-day study. Each datapoint represents the mean ± standard deviation of four beagle dogs.

Figures 6A-6C depict, in accordance with an embodiment of the invention, dmg delivery system 200. Fig. 6A depicts a top view of drug delivery system 200, Fig. 6B depicts a cross-section (x-y plane) of drug delivery system 200, in which drug-impermeable elastomer or polymer 203, drug-permeable elastomer or polymer 202, drug core 204, and the interface 201 between dmg core 204 and drug-permeable elastomer or polymer 202 can be seen. Fig, 6C depicts a cross-section (y-z plane) of dmg delivery system 200.

Figure 7A depicts, in accordance with an embodiment of the invention, a cross- section (along the long axis) of tube-shaped dmg deliver}' system 300, in which drug- impermeable elastomer or polymer 303, drug-permeable elastomer or polymer 305, drug- permeable elastomer or polymer coating 302, dmg core 304, and the interface 301 between drug core 304 and drug-permeable elastomer or polymer 305 can be seen. Fig. 7B depicts, in accordance with an embodiment of the invention, a cross-section (along the long axis) of tube-shaped dmg delivery system 500, in which drug-impermeable elastomer or polymer 503, drug-permeable elastomer or polymer 505, drug-permeable elastomer or polymer coating 502, and drug core 504 can be seen.

Figure 8A depicts, in accordance with an embodiment of the invention, a top view of tube-shaped drug delivery system 600, in which drug-permeable elastomer or polymer 605 and drug-impermeable elastomer or polymer 602 can be seen. Fig. 8B depicts, in accordance with an embodiment of the invention, a top view of tube-shaped dmg delivery system 700, in which drug-permeable elastomer or polymer 705 and drug-impermeable elastomer or polymer coating 702 can be seen.

Figures 9A depicts, in accordance with an embodiment of the invention, a cross- section (along the short axis) of tube-shaped dmg delivery system 400, in which drug- permeable polymer or elastomer 405, drug-impermeable polymer or elastomer 403, dmg core 404, and the interface 401 between dmg core 404 and drug-permeable elastomer or polymer 405 can be seen. Fig. 9B depicts, in accordance with an embodiment of the invention, a cross section (along the short axis) of tube-shaped drug delivery system 300 (describe above). Fig. 9C depicts, in accordance with an embodiment of the invention, a cross-section (along the short axis) of tube-shaped drug deliver}' system 100 (described above). Fig, 9D depicts, in accordance with an embodiment of the invention, a cross-section of tube-shaped drug delivery system 200 (described above).

DESCRIPTION OF THE INVENTION

All references cited herein are incorporated by reference in their entirety as though fully set forth. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Allen et al, Remington: The Science and Practice of Pharmacy 22^nd ed., Pharmaceutical Press (September 15, 2012); Hornyak et al, Introduction to Nanoscience and Nanotechnology, CRC Press (2008); Singleton and Sainsbury, Dictionary of Microbiology and Molecular Biology 3^rd ed., revised ed., J. Wiley & Sons (New York, NY 2006); Smith, March 's Advanced Organic Chemistry Reactions, Mechanisms and Structure 7^th ed., J. Wiley & Sons (New York, NY 2013); and Singleton, Dictionary of DNA and Genome Technology 3^rd ed, Wiley -Blackwell (November 28, 2012), provide one skilled in the art with a general guide to many of the terms used in the present application.

One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. Indeed, the present invention is in no way limited to the methods and materials described. For purposes of the present invention, certain terms are defined below.

"Conditions" and "disease conditions," include, but are not limited to, conditions that can be treated or prevented through the use of one or more agents administered through a sustained release agent delivery device. These conditions may include, but are in no way limited to, infectious diseases (e.g., a human immunodeficiency virus (HIV) infection, acquired immune deficiency syndrome (AIDS), a herpes simplex virus (HSV) infection, a hepatitis virus infection, an influenza infection, and tuberculosis), conditions treatable with leuprolide (e.g., anemia caused by bleeding from uterine leiomyomas (fibroid tumors in the uterus), cancer of the prostate, and central precocious puberty), diabetes (including but not limited to types treatable with exenatide), autoimmune diseases, CNS conditions, and analogous conditions in non-human mammals. In addition, the invention includes the administration of biologies, such as proteins and peptides, for the treatment or prevention of a variety of disorders such as diabetes, endometriosis, etc.

As used herein, the term "HIV" includes HIV-1 and HIV-2. As used herein, the term "agent" includes any water-soluble substance, including, but not limited to, any water-soluble drug or prodrug.

As used herein, the term "API" means active pharmaceutical ingredient, which includes agents described herein.

As used herein, "water-soluble" is defined as having an aqueous solubility above 1 mg niL^"1 at 20°C.

The terms "drug deliver}' system" and "implant" are used interchangeably herein, unless otherwise indicated.

"Mammal," as used herein, refers to any member of the class Mammalia, including, without limitation, humans and nonhuman primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domesticated mammals, such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs, and the like. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be included within the scope of this term.

With the foregoing background in mind, in various embodiments, the invention teaches devices, systems and methods for treating, preventing, reducing the likelihood of having, reducing the severity of and/or slowing the progression of a condition in a subject. In various embodiments, the technologies described herein are suitable for the sustained delivery of water-soluble agents, including water-soluble drugs and prodrugs.

Devices and systems of the invention

Various embodiments of the present invention teach an implantable device (also referred to herein as "sustained release agent deliver}' device") that can be used to facilitate the sustained release of one or more agents. In certain embodiments, the device includes a reservoir suitable for containing one or more agents. In some embodiments, one or more of the one or more agents includes a water-soluble substance (e.g., a water-soluble drug or prodrug). In certain embodiments, the walls of the reservoir are formed by a drug- impermeable material (also referred to herein as "drug-impermeable scaffold"). In some embodiments, the drag-impermeable scaffold may consist of, consist essentially of, or comprise a drug-impermeable elastomer or polymer. In some embodiments, one or more channels are formed in the drag-impermeable scaffold. In certain embodiments, one end of one or more channels terminates in the inside of the reservoir, while the other end is covered by one or more drug-permeable membrane. In certain embodiments, the drug-impermeable polymer is a biocompatible polymer. In some embodiments, the biocompatible polymer can include, but is in no way limited to one or more of polydimethylsiloxane (silicone), ethyl ene- co-vinyl acetate copolymer, polyurethane, latex, poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), and combinations thereof. One of skill in the art would readily appreciate that the drug-impermeable scaffold could be made to have practically any dimensions and shape suitable for a particular application. Merely by way of example, if the reservoir is cylindrical (e.g., as depicted in Fig. I), the length of the scaffold or inner reservoir may be about 1-10 mm, 10-20 mm, 20-30 mm, 30-40 mm, 40-50 mm, 50-60 mm, 60-70 mm, 70-80 mm, 80-90 mm, 90-100 mm, or more than 100 mm. The inner diameter of the reservoir may similarly be of any practical length for a particular application. In certain embodiments, if the shape of the reservoir is cylindrical (e.g., as depicted in Fig. 1), the inner diameter of the scaffold or reservoir may be about 1-2 mm, 2-3 mm, 3-4 mm, 4-5 mm, 5-6 mm, 6-7 mm, 7-8 mm, 8-9 mm, or 9-10 mm, or more, or a combination thereof. In some embodiments, the inner diameter of the scaffold or reservoir may vary across the length of the device. In some embodiments, if the shape of the reservoir is cylindrical (e.g., as depicted in Fig. 1), the outer diameter of the drug-impermeable scaffold or inner reservoir may be about 1-2 mm, 2-3 mm, 3-4 mm, 4-5 mm, 5-6 mm, 6-7 mm, 7-8 mm, 8-9 mm, or 9-10 mm, or more, or a combination thereof. In certain embodiments, the outer diameter of the drug- impermeable scaffold or inner reservoir may vary along the length of the device. In various embodiments, the number of channels (also referred to herein as delivery channels) or holes described above may be about 1-10, 10-20, 20-30, 30-40, 40-50, or more than 50. In some embodiments, the diameter of the deliver}' channels or holes may be about 0.01-0.1 mm, 0, 1- 0.2 mm, 0.2-0.5 mm, 0.5-1 mm, 1-2 mm, 2-5 mm, 5-10 mm, or greater, or a combination thereof. In some embodiments, one or more of the one or more drug-permeable membranes may comprise, consist of, or consist essentially of one or more drug-permeable polymers. Merely by way of example, one or more biocompatible polymers may be used for one or more of the one or more drug-permeable membranes. Examples of biocompatible polymers include, but are in no way limited to, polyvinyl alcohol (PVA), polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, parylene, ethylene vinyl acetate copolymer, and polycaproiactone. In some embodiments, one or more of the one or more drug-permeable membranes include PVA. In certain embodiments, a thickness of one or more of the one or more drug-permeable membranes located at the end of one or more channels may be 1-10 μηι, 10-20 μηι, 20-30 μηι, 30-40 μιη, 40-50 μιη, 50-60 μηι, 60-70 μηι, 70-80 μηι, 80-90 μηι, 90-100 μηι, or more than 100 μτη. In certain embodiments in which more than one channel is included in the device, two or more channels may terminate in drug-permeable membranes of different thickness and/or different compositions. In some embodiments, the device may have drug-permeable membranes of different thicknesses covering different channels of different regions of the device. For example, one half (or some other portion) of the device may include one or more channels that terminate in a drag-permeable membrane of a first thickness and/or composition, while another half (or some other portion) of the device may include one or more channels that terminate in a permeable membrane of a second thickness and/or composition. In certain embodiments, one or more of the one or more channels terminate in, are filled with, or are partially filled with more than one layer of any drug- permeable membrane described herein.

In certain embodiments, the invention teaches a sustained release agent delivery system that includes a sustained release agent deliver}' device described herein and one or more agents (e.g., drugs) in its reservoir. In some embodiments, one or more of the one or more agents are water-soluble. In certain embodiments, one or more of the one or more agents are a drug or prodrug. In some embodiments, one or more of the one or more agents include a water-soluble drug. Non-limiting examples of water-soluble drugs that could be included in the reservoir of the agent delivery system include tenofovir alafenamide (TAF), acyclovir, ganciclovir, oseltamivir phosphate, peptides, proteins, analogs of any of the aforementioned substances, or combinations of any of the aforementioned substances. In some embodiments, a drug included in the reservoir is tenofovir alafenamide (TAF). Non- limiting examples of peptides that may be included in the drag deliver}' system include, but are in no way limited to, leuprolide acetate, exenatide acetate, goserelin acetate, and octreotide acetate. In certain embodiments of the invention, an agent contained in the reservoir includes a drag from the nucleoside reverse transcriptase inhibitor (NRTI) mechanistic class.

In some embodiments, one or more of the one or more channels includes a segment of wicking material (e.g., silk or biocompatible polymer suture, or biocompatible hydrogel material) that passes through the impermeable polymer scaffold. In some embodiments, the walls of one or more of the one or more channels is coated with a layer of wicking material (e.g., biocompatible hydrogel polymer). Methods of treatment and prevention

In various embodiments, the invention teaches a method for reducing the likelihood of a subject contracting a viral infection. In some embodiments, the method includes (1) providing one or more sustained release agent delivery systems described herein, wherein one or more of the one or more agents in the reservoir (also referred to herein as "drug core") of one or more of the systems is an antiviral agent; and (2) implanting one or more of the sustained release agent delivery systems into the subject's body, thereby reducing the likelihood of the subject contracting the viral infection. In some embodiments, the sustained release agent delivery system is implanted into the subject subdermally. In certain embodiments, the sustained release agent delivery system is implanted into one or more location in the subject that may include, but is in no way limited to, upper arm (inner or outer), inner thigh, back, abdomen and combinations thereof. In some embodiments, the viral infection is caused by a virus that may include, but is in no way limited to, HIV, herpes simplex virus (HSV), a hepatitis virus, and influenza. In certain embodiments, the virus is HIV. In certain embodiments, one or more of the agents is an antiviral agent useful for treating the target viral infection. In certain embodiments one or more of the agents is a nucleoside reverse transcriptase inhibitor (NRTI). In certain embodiments one or more of the agents is from another mechanistic class targeting HIV. In some embodiments, one of the agents is tenofovir alafenamide (TAF). In some embodiments, the drug core further includes one or more admixed excipients, which may include, but are in no way limited to one or more of any of the following categories of substances: binders, disintegrants, anti -adherents, lubricants, glidants, pH modifiers, antioxidants and preservants. In some embodiments, the binders and/or disintegrants may include, but are in no way limited to, starches, gelatins, carboxymethylcellulose, croscarmellose sodium, methyl cellulose, ethyl cellulose, hydroxy methyl cellulose, hydroxy ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl ethyl cellulose, hydroxypropylmethyl cellulose, macrocrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, sodium starch glycolate, lactose, sucrose, glucose, glycogen, propylene glycol, glycerol, sorbitol, polysorbates, and colloidal silicon dioxide. In certain embodiments, the anti-adherents or lubricants may include, but are in no way limited to, magnesium stearate, stearic acid, sodium stearyl fumarate, and sodium behenate. In some embodiments, the glidants may include, but are in no way limited to, fumed silica, talc, and magnesium carbonate. In some embodiments, the pH modifiers may include, but are in no way limited to, citric acid, lactic acid, and gluconic acid. In some embodiments, the antioxidants and preservants may include, but are in no way limited to ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisoie (BHA), cysteine, methionine, vitamin A, vitamin E, sodium benzoate, and parabens. In certain embodiments, one or more of the sustained release agent delivery systems (also referred to herein as "implants") are implanted in a subject and allowed to remain implanted in the subject for 1-730 days or more. In some embodiments, the one or more implants remain in the subject for 30-700 days, 60-670 days, 90-640 days, 120-610 days, 150-580 days, 180-550 days, 210-520 days, 240-490 days, 270-460 days, 300-430 days, 330-400 days, or 360-370 days. In some embodiments, when one or more implants are used, two or more implants are removed after different periods of time. In some embodiments, the one or more implants are loaded with an amount of TAP such that implantation of the one or more implants results in a total dose (including all of the implants) of 0.05-10 mg/day. In some embodiments, the total dose of TAF is 0.05-10 mg/day, or 0.5-2 mg/day, or 2-4 mg/day, or 4-6 mg/day, or 6-8 mg/day, or 8-10 mg/day. In some embodiments, each of the one or more implants includes 20-500 nig of TAF. In some embodiments, each of the one or more implants includes 50-100 mg of TAF. In some embodiments of the invention, each of the one or more implants includes 20-500 mg, 30-400 mg, 40-300 mg, or 50-200 mg of TAF. In various embodiments, the total daily drug dose ranges and amount of drug per implant for other drugs, aside from TAF, are the same as those for TAF^'. In some embodiments, the dimensions of one or more of the implants include any of the dimensions of the devices described herein. In some embodiments, the number of implants introduced into the subject for treating a condition (including but not limited to a condition caused by a virus) is 1-12. In some embodiments, the number of implants introduced into the subject when using TAF in the drug core is 1-12. In certain embodiments, when the method is for reducing the likelihood of an individual becoming infected with HIV, the method further includes administering one or more additional dmgs known to be effective in treating or preventing HIV. In some embodiments, the one or more additional drugs are administered orally, parenterally, through subdermal implantation, or by any other route of administration known to be effective for treating or preventing HIV. Merely by way of non-limiting examples, additional drugs that may be administered may include TAF, the integrase inhibitor cabotegravir, the NRTI emtricitabine, the NRTI lamivudine (3TC), the nucleoside reverse transcriptase translocaton inhibitor MK-8591 (EFdA), and other anti retroviral agents with high potencies and aqueous solubilities. In some embodiments, the subject treated according to the inventive methods described above has a high risk of contracting HIV. In some embodiments, that subject is treated with at least one implant containing TAF. In some embodiments, the subject is a child. In some embodiments, the subject is an adolescent. In some embodiments, the subject is an adult.

In various embodiments, the invention teaches a method for treating a subject who has been infected with a virus described herein by administering one or more drug delivery system described herein. In some embodiments, the virus is HIV. In some embodiments, the subject has been diagnosed with AIDS. In some embodiments, the virus is one of the hepatitis viruses. In some embodiments, the virus is HSV, In various embodiments, the method includes implanting one or more sustained release agent delivery systems ("implants") described herein into the body of the subject. In some embodiments, the drug core of one or more of the implants includes one or more drugs useful for treating the specific viral infection. In some embodiments, the drug core of one or more of the implants includes one or more drugs useful for the treatment of HIV, which may include, but are in no way limited to TAF, the integrase inhibitor cabotegravir, the RTI emtricitabine, the RTI lamivudine (3TC), the nucleoside reverse transcriptase translocaton inhibitor MK-859I (EFdA), and other anti retroviral agents with high potencies and aqueous solubilities. In some embodiments, the drug core further includes one or more admixed excipients, which may include, but are in no way limited to any of the admixed excipients described herein. In some embodiments, one or more of the implants that includes one or more drugs are implanted subdermaliy. In some embodiments, one or more of the implants are positioned subdermaily in one or both arms of the individual. In certain embodiments, the one or more implants are allowed to remain implanted in the individual for 1 -730 days or more. In some embodiments, the implants remain implanted for 30-700 days. 60-670 days, 90-640 days, 120-610 days, 150-580 days, 180-550 days, 210-520 days, 240-490 days, 270-460 days, 300-430 days, 330- 400 days, or 360-370 days. In some embodiments, when one or more implants are used, two or more implants are removed after different durations of implantation. In some embodiments, the one or more implants are loaded with an amount of TAF such that implantation results in a total dose (from all combined implants) of 0.05-10 mg/day. In some embodiments, the total dose of TAF is 0.05-10 mg/day, or 0.5-2 mg/day, or 2-4 mg/day, or 4- 6 mg/day, or 6-8 mg/day, or 8-10 mg/day. In some embodiments each of the one or more implants includes 20-500 mg of TAF. In some embodiments, each of the one or more implants includes 50-100 mg of TAF. In some embodiments of the invention, each of the one or more implants includes 20-500 mg, 30-400 mg, 40-300 mg, or 50-200 mg of TAF. In some embodiments one or more of the implants contain one or more of th e mtegra se inhibitor cabotegravir, the NRTI emtricitabine, the NRTI lamivudine (3TC), the nucleoside reverse transcriptase translocaton inhibitor MK-8591 (EFdA), and other antiretroviral agents with high potencies and aqueous solubilities. In some embodiments, the total daily dosage ranges and drug amounts per implant for the drugs provided in addition to or instead of TAF are the same as those listed above for TAF. In certain embodiments, the method for treating a subject who has been infected with HIV further includes administering one or more additional drugs known to be effective in treating an HIV infection. In some embodiments, the additional drugs are administered orally, parenterally, through subdermal implantation, or by any other route of administration known to be effective. Merely by way of non-limiting examples, one or more additional drugs that may be administered may include, but are in no way limited to, TAF, the integrase inhibitor cabotegravir, the NRTI emtricitabine, the NRTI lamivudine (3TC), and the nucleoside reverse transcriptase translocaton inhibitor MK-8591 (EFdA). In some embodiments, one or more of the additional drugs described above may also be present in one or more of the implants implanted into the individual.

In some embodiments each type of drug included in the one or more implants for treating a viral condition is released at a total dose (i.e. dose from all implants together) of 0.05-10 mg/day. In some embodiments any of the drugs included (when included alone or in combination) may be included in amount of 20-500 mg, 30-400 mg, 40-300 mg, or 50-200 mg per implant. In some embodiments, the number of implants introduced into the individual is 1-12. In some embodiments, the number of implants introduced into the individual is 1-12, 3-9, 4-8, 5-7, or 6. In some embodiments, the number of implants introduced into the individual is 2 groups (i.e., at different locations) of 6 (12 total implants).

Although certain non-limiting examples of dosing are described above, the pharmaceutical compositions according to the invention may generally be delivered in a therapeutically or prophylactically effective amount. The precise therapeutically or prophylactically effective amount is that amount of the composition that will yield the most effective results in terms of efficacy of treatment or prevention in a given subject. This amount will vary depending upon a variety of factors, including but not limited to the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration. One skilled in the clinical and pharmacological arts will be able to determine a therapeutically effective amount through routine experimentation, for instance, by monitoring a subject's response to administration of a compound and adjusting the dosage accordingly. For additional guidance, see Remington: The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).

Methods of manufacture

Integration of various implant device and system features

The drug deliver' devices and systems described herein can be manufactured in a number of sequential steps. In some embodiments, one step is fabricating the implant drug- impermeable scaffold. In some embodiments, this involves manufacturing a drug- impermeable, tubular device with one or more delivery channels that are holes, slots, or sections of the tubular device terminating in or otherwise containing a permeable material to allow diffusion of one or more drug out of the lumen ("drug core") of the scaffold. In some embodiments, a drug-permeable polymer coating is applied to the drug-impermeable scaffold such that it covers the delivery channels and serves as a rate-controlling membrane across which the drug diffuses out of the drug containing scaffold interi or and into the sub-dermal space. In certain embodiments, one or more drug is packed into the lumen. The daig can be packed as a powder using methods known to those skilled in the art of pharmaceutical capsule preparation using a tamp filling process on a machine based on a dosating disk design. This method uses a tamping dosator device that consists of one or more tamping pins or fingers that repeatedly press a metered amount of powdered drug or drug/excipient mixture into a hole in a rotating dosator disk, sequentially building up a plug of powder of predetermined size (mass, volume) in the hole. The dosating disk is them rotated so that the hole containing powder is positioned above the implant lumen, and the powder plug is pressed into the implant lumen with an ejector pin. Each implant may be filled with one or more plugs from the dosator. A machine using a dosating nozzle design that works similarly and is known to those skilled in the art of pharmaceutical capsule preparation may be used to fill the implant lumen instead of a dosating disk design machine. Alternatively, the drug can be compressed into pellets with or without suitable excipients using methods known to those skilled in the art of pharmaceutical tablet formulation. In some embodiments, compressed pellets are inserted into the scaffold interior as a stack of cylindrical pellets similar to a roll of Lifesavers® candy. In some embodiments, the end of the scaffold is sealed with a room- temperature curing silicone adhesive (for silicone implants), or by thermal sealing of the tubular scaffold (thermoplastic implants, i.e. polyurethane). In certain embodiments, the drug-permeable polymer is incorporated into the implant scaffold as a linear stripe, spiral stripe, or discrete patches instead of as a polymer overcoat.

Methods of fabricating implant scaffold and release polymer coating

In certain embodiments, the drug-impermeable polymer tubing is extruded, and the delivery channel (s) are formed by a post-extrusion process off of the extrusion line. In some embodiments, the post-extrusion process may include, but is in no way limited to, punching or laser drilling.

In some embodiments, the drug-impermeable polymer tubing is extruded and the delivery channei(s) are formed by an extrusion line process. In some embodiments, the extrusion line process may include, but is in no way limited to, punching, laser drilling, or a transitional extrusion process. In some embodiments, extrusion and/or hole/channel formation may be accomplished according to any of the methods described in U.S. Patent Nos. 6,394, 141; 5,945,052; 5,549,579; and 5,511,965, all of which are hereby incorporated herein by reference in their entirety as though fully set forth.

In certain embodiments, a drug-permeable polymer coating is extruded on a tube made of drug-impermeable material, in which one or more channels have been formed by a post-extrusion process or extrusion line process, as described above.

In certain embodiments, a single co-extrusion process is used to form a tube that includes drug-impermeable polymer material, as well as one or more sections of drug- permeable polymer material (e.g., stripes, longitudinal bands, spiral bands, or other arrangements of permeable polymer areas). In certain embodiments, the resulting tube may be coated with an additional layer of drug-permeable polymer as described herein.

Drug-permeable polymer manufacturing methods

In certain embodiments, a drug-permeable polymer is applied to the device by dip or spray coating a pre-formed implant (any implant described above - e.g., an implant with one or more channels formed as described above). In some embodiments, a drug-permeable polymer coating is extruded on a pre-formed drug-impermeable polymer tube in which one or more channels have been formed.

In some embodiments, drug-permeable polymer stripes or otherwise shaped segments are integrated with (i.e. co-extruded with) sections of drug-impermeable polymer sections to form a single tube with one or more drug-permeable polymer and drag-impermeable polymer sections.

In some embodiments, a drug-permeable coating is extruded on a pre-formed drug- impermeable/drug-permeable tubing (e.g., a tubing formed by co-extrusion as described above).

Thermal processing of drug-permeable polymer to impart desired sustained release properties

In some embodiments, a PVA polymer coating can be applied by multi-step thermal dehydration (nucleophilic substitution inducing cross-linking via ether groups followed by elimination of water to form double bonds), which imparts chemical characteristics that lead to advantageous active pharmaceutical ingredient ("API") drug release from the device/implant.

In certain embodiments, all implant fabrication and thermal processing is performed prior to API (i.e., drug) introduction, making the manufacturing process amenable to use with thermally sensitive APIs, including but in no way limited to peptides, antibodies, nucleic acids, and the like.

Radio-opaque labeling of implants

In various embodiments, one or more radio-opaque materials are incorporated into the elastomer matrix (i .e. drug-impermeable polymer). The radio-opaque material can be integrated in the form of one or more band, or other shape, or dispersed throughout drug- impermeable polymer.

Methods for forming delivery channels

One or more deliver channels of the systems and devices described herein may be formed in any number of ways, including but not limited to, by mechanical punching or drilling using a bit consisting of a thin-walled tube sharpened along the circumference of one end and rotated to penetrate one of both walls of the extruded or otherwise formed tubular implant scaffold.

In certain embodiments, one or more delivery channels of the systems and devices are formed by using a laser drilling process. In certain embodiments, a focused laser beam of a wavelength suitable for ablation of drug-impermeable polymer material is focused on the scaffold wail to remove material and form a delivery channel. The channel may be circular in cross section, or an oblong, slot-shaped cross section, or any other desirable shape. The channel may be formed by focusing the laser in a fixed position for a time suitable to completely penetrate the polymer, or by moving the beam along the polymer scaffold to form a larger circular or other shaped cut-out (slot) by trepanning.

In some embodiments, one or more deliver}' channels may be formed during the extaision process. In certain embodiments, the tubular extrusion profile may be interrupted during the extrusion process to form voids in the extrusion wall that serve as delivery channels.

Kits of the invention

In various embodiments, the present invention teaches a kit for treating a subject for whom it is desired to treat or prevent a condition that can be treated or prevented with a sustained release agent delivery device or system, as described herein. In some embodiments, the present invention teaches a kit for treating a subject who has an HIV infection. In some embodiments, the present invention teaches a kit for treating a subject who has been diagnosed with AIDS. In some embodiments, the present invention teaches a kit for reducing the likelihood of a subject contracting HIV. In some embodiments, the kit consists of, or consists essentially of, or comprises: one or more sustained release agent delivery device or system described herein; and instructions for using the sustained release agent delivery device or system to treat or prevent a condition in a subject. In some embodiments, the condition is any condition described herein. In some embodiments, the condition is HIV. In various embodiments, one, two, three, or more of the same or different types of sustained release drug delivery devices or systems described herein are provided in the kit.

In various embodiments, the kit is an assemblage of materials or components, including at least one of the inventive sustained release drug delivery systems or devices. In one embodiment, the kit consists of, or consists essentially of, or comprises a sustained release drug delivery device or system described herein.

The exact nature of the components configured in the inventive kit depends on its intended purpose. In one embodiment, the kit is configured particularly for the purpose of treating or preventing a condition in mammalian subjects. In another embodiment, the kit is configured particularly for the purpose of treating human subjects. In further embodiments, the kit is configured for veterinary applications, treating subjects such as, but not limited to, farm animals, domestic animals, and laboratory animals.

Instructions for use may be included in the kit. "Instructions for use" typically include a tangible expression describing the technique to be employed in using the components of the kit to affect a desired outcome. Optionally, the kit also contains other useful components, such as, containers, instruments used to perform implantation of the devices and systems described herein, syringes, scalpels, bandaging materials or other useful paraphernalia as will be readily recognized by those of skill in the art.

The components are typically contained in suitable packaging material(s). As employed herein, the phrase "packaging material" refers to one or more physical structures used to house the contents of the kit, such as the inventive devices, systems, accompanying instruments, and the like. The packaging material is constructed by well-known methods, preferably to provide a sterile, contaminant-free environment. As used herein, the term "package" refers to a suitable solid matrix or material such as glass, plastic, paper, foil, and the like, capable of holding the individual kit components. The packaging material generally has an external label which indicates the contents and/or purpose of the kit and/or its components.

The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way.

EXAMPLES

Example 1

Drug characteristic considerations for HIV treatments

By way of additional background concerning HIV-related treatments, long-acting

TFV formulations must overcome the drug's low potency and high aqueous solubility, while taking advantage of its slow systemic clearance kinetics. To demonstrate antiviral activity against HIV-1, TFV must undergo in vivo phosphorylation to the active moiety, TFV diphosphate (TFV-DP) in cells supporting HIV-1 replication. Because TFV-DP is ionized and trapped intracellularly, it persists with a longer half-life than the parent drug in plasma. The intracellular half-life of TFV-DP in peripheral blood mononuclear cells (PBMCs) of healthy individuals was estimated at 48 h. The prodrug TAF (EC₅₀ 5 nM) is 1,000 times more potent than TFV and 10 times more potent than the prodrug TDF, making TAF a good choice as the TFV moiety in the development of a long-acting formulation. Oral TAF also leads to lower plasma TFV exposure than oral TDF, a favorable characteristic for long-term safety.

Materials

Tenofovir alafenamide (TAF) was provided by Gilead Sciences, Inc. (Foster City,

CA). Polyvinyl alcohol (PVA) with a mean molecular weight (Mw) 85,000-124,000 kD (98- 99% hydrolyzed) was obtained from Sigma-Aldrich (St. Louis, MO). Tenofovir, [adenine- ¹³C₅]-(TFV-¹³C₅) was obtained from Moravek Biochemicals, Inc. (Brea, CA) and maraviroc- D₆ (MVC-D₆) was obtained from Santa Cruz Biotechnology, Inc. (Dallas, TX). All other reagents were obtained from Sigma-Aldrich, unless otherwise noted.

Formulation of TAF Long Acting (TAF LA) subdermal implant

Sections (40 mm length) of medical-grade platinum cured silicone tubing (721048, Harvard Apparatus, Holliston, MA, 1.5 mm ID x 1.9 mm OD) were plasma-etched using a Model PDC-32G plasma cleaner (Harrick Plasma, Ithaca, NY) at a medium RF setting for 3 min. Fourteen delivery channels (1.0 mm diameter) per implant were mechanically punched (Fig. 1) using a punching device consisting of a section of 1.0 mm OD steel tubing with one end sharpened to a knife edge along the entire circumference. Channels were oriented such that the punching device perforated both walls of the implant tubing at 7 locations spaced along the longitudinal axis of the implant, creating 14 channels. Both open ends were sealed using silicone adhesive (MED3-4213, NuSil Technology LLC, Carpinteria, CA). The sealed segments were dip coated in 5% (wt/wt) PVA solution, air-dried overnight at room temperature (25°C), and dip-coated a second time with 10% (wt/wt) PVA solution, followed by another round of drying. The silicone plug at one end of the segments was removed and a metal pin inserted, followed by thermal processing in an oven at 190°C for 4.75 h in air. The stainless steel pins were removed, and the devices were packed with TAF. The open end was re-sealed with silicone adhesive. The implants were dried overnight at room temperature and the exterior was cleaned with an applicator wetted with 1 ^χ phosphate-buffered saline solution (PBS, Thermo Fisher Scientific, Inc., Hudson, H). The PVA membrane thickness was determined by sectioning the implant in the y-z plane (Fig. IB) and imaging the membrane thickness using an inspection microscope. In vitro release kinetics measurements.

In vitro release studies were designed to mimic sink conditions and were carried out as follows. The implants were placed in dissolution medium (100 ml) consisting of l x PBS with 0.01% NaN₃ added to prevent microbial growth. The vessels were agitated in an orbital shaker at 25 ± 2°C and 72 rpm. Aliquots (150 μΐ) were removed at predetermined time points and were analyzed by UV absorption spectroscopy { _max = 262 nm), using a SpectraMax® Plus Absorbance Microplate Reader (Molecular Devices, Sunnyvale, CA), to determine the TAF concentration using a ten-point standard curve.

Animals

The pharmacokinetic and preliminary safety animal study was carried out at MPI

Research, Inc. (Mattawan, MI). Animals were handled in strict accordance with the Guide for the Care and Use of Laboratory Animals, under approved internal Institutional Animal Care and Use Committee protocols using MPI Research Standard Operating Procedures. Male beagle dogs (Canis lupus familiaris, n = 4) between the ages of ca. 13 and 19 months were used in the study. Animals were housed under standard conditions, had ad libitum access to water and a standard laboratory diet, and were between 9.2 and 12.4 kg at the time of implantation.

Implantation procedure

The animals were fasted overnight prior to implantation and through at least 1 h post implantation. The anesthetized animal was placed in ventral recumbency on the surgical table and prepped for sterile surgery using chlorhexidine scrub and solution. A running medial lateral skin incision (1 cm) was made, 2 cm to the side of the vertebral column in the dorsal scapular region. Within the incision line, a subcutaneous pocket (ca. 5 cm ^χ 2 cm) was made by blunt dissection for placement of the TAF LA implant using a hemostat or forceps to pull the implant into the pocket cranial to caudal. Following implantation the subcutaneous incisions were closed with absorbable sutures and the incisions were closed with staples. Assessment of toxicity

Toxicity was evaluated by clinical observations, cageside observations (twice daily), and body weight (at least weekly). Plasma and PBMC sample collection

Blood was collected from the jugular vein at the following predetermined time points post implantation: 2, 24, 48, 96, 144, 240, 336, 504, 672, 840, and 936 h. Whole blood samples for PBMC isolation and analysis were only collected between 504 and 936 h. Blood (3 mL) for plasma was collected into tubes containing K₂EDTA as the anticoagulant and maintained on wet ice before being processed for plasma by centrifugation at 2-8°C. Plasma samples were stored and transported frozen at -60 to -90°C. For PBMC isolation, blood (3 mL) was collected into Vacutainer® CPT™ Cell Preparation Tubes (Becton, Dickinson and Company, Franklin Lakes, NJ) using sodium citrate as the anticoagulant and processed according to the manufacturer's instructions. The layer containing the PBMCs was transferred into a 15 ml tube and brought to a final volume of 14-15 ml with l x Dulbecco's phosphate buffered saline (DPBS). The suspension was centrifuged at 550 g for 6 min, the supernatant decanted, and the pellet resuspended in l x DPBS (final volume of 14-15 ml). The suspension was subjected to another round of centrifugation and resuspension of the pellet in 1 x DPBS (final volume of 14-15 ml). The suspension was centrifuged at 550 g for 6 min and the pellet incubated in Red Blood Cell Lysis Buffer (eBioscience, San Diego, CA, 5 mL) for 5 min at room temperature and protected from light. The mixture was resuspended in l x DPBS (final volume of 14-15 ml) and centrifuged at 550 g for 6 min. The supernatant was decanted, the resulting pellet resuspended in l x DPBS (1 mL), and transferred into a cryopreservation vial. An aliquot of the suspension was used to count viable PBMCs using a hemocytometer. The number of PBMCs collected per 3 mL whole blood sample (mean ± SD) was 4.8 ± 2.1 x l0⁶ cells. The remaining suspension was centrifuged at 550 g for 6 min and the supernatant decanted. The cell pellet was lysed using cold (2-8°C) 70% (vol/vol) methanol (0.5 ml), followed by freezing to -50 to -90°C. Quantification of TAF and TF V plasma concentrations

Dog plasma samples were purified and analyzed separately for TAF and TFV. Plasma samples were thawed on ice and two 100 μΐ aliquots were dispensed into separate 96- well plates, along a minimum of six standards and a minimum of three quality controls in accordance with FDA guidelines. Samples were spiked with 10 μΐ of internal standard (IS) solution (1 μg ml^"1 MVC-D₆ for TAF and 1 μg ml^"1 TFV-¹³C₅ for TFV). For TAF, sample purification was carried out in a 96-well format using a protein and phospholipid removal system (Phree, Phenomenex, Inc., Torrance, CA) according to the manufacturer's instructions. For TFV, sample purification was carried out in a 96-well using a mixed-mode anion exchange and reversed-phase copolymeric sorbent system (Oasis MAX,Waters Corporation, Milford, MA) according to the manufacturer's instructions. The purified samples were dried in vacuo using a SpeedVac concentrator system (Savant SC210A Plus, Thermo Fisher Scientific, Inc.) and were reconstituted in 0.1% (vol/vol) formic acid in water (200 μΐ for TAF; 100 μΐ for TFV) prior to analysis. The concentration of TAF was measured at Oak Crest by LC-MS/MS using an UPLC system consisting of a model G1367A well-plate autosampler and a model G1312A binary pump (1200 Series, Agilent Technologies, Santa Clara, CA) interfaced to an API 3000 triple quadrupole tandem mass spectrometer (AB Sciex, Framingham, MA) with a Turbo Ion Spray electrospray ionization source. An Agilent Zorbax Eclipse XDB-C18 Rapid Resolution column (2.1 x 50 mm; 3.5 μπι) controlled at 40°C was the stationary phase. The following gradient program was used (A, 0.1% vol/vol formic acid in water; B, 0.1% vol/vol formic acid in acetonitrile): 0.25 min 100% A; 0.25 min ramp from 100:0 A:B to 95:5 A:B; 1.5 min ramp from 95:5 A:B to 70:30 A:B; 1.5 min hold at 70:30 A:B; 1.5 min ramp from 70:30 A:B to 95:5 A:B; 0.5 min ramp from 95:5 A:B to 100:0 A:B resulting in a total run time of 5.5 min, with a TAF retention time of 3.5 min. The measured transition ions, m/z, under ESI+ ionization mode were: TAF, parent 477.0 amu, product, 270.0 amu; MVC-D₆ (IS), parent 520.7 amu, product, 280.6 amu.

The concentration of TFV was measured by LC-MS/MS using the above instrumentation and stationary phase. The following gradient program was used (A, 0.1% vol/vol formic acid in water; B, 0.1% vol/vol formic acid in acetonitrile): 0.25 min ramp from 100:0 A:B to 95:5 A:B; 0.5 min ramp from 95:5 A:B to 100:0 A:B; 0.25 min hold at 100:0 A:B resulting in a total run time of 1.0 min, with a TFV retention time of 0.2 min. The measured transition ions, m/z, under ESI+ ionization mode were: TFV, parent 288.1 amu, product, 176.2 amu; TFV-¹³C₅ (IS), parent 293.1 amu, product, 181.2 amu.

Both methods used seven-point standard curves (1-100 ng ml^"1 TAF, 10-1000 ng ml^"1

TFV) prepared in blank plasma and showed linearity in excess of an R² value of 0.98. The lower limits of quantification (LLQ) for TAF and TFV in plasma were 0.5 ng ml^"1 (1 nM) and 5 ng ml^"1 (17 nM), respectively. Three separately prepared quality control samples were analyzed at the beginning and end of each sample set to ensure accuracy and precision within 20%, in accordance with FDA bioanalytical validation criteria.

Quantification of PBMC TFV-DP concentrations

The concentration of TFV-DP in PBMCs was measured at Johns Hopkins University using established methods that met FDA bioanalytical validation criteria. The analytical measuring range of the assay was 50.0-1,500 fmol/sample. TFV-DP measurements exceeding the upper limit of quantitation (ULQ) were diluted and reanalyzed. Results were converted to fmol/10⁶ cells based on the lysate specific number of PBMCs present in the sample. Intracellular concentrations were calculated assuming a mean volume of 0.2 μ1/10⁶ PBMCs in order to maintain consistency with prior reports.

Used implant residual drug analysis

Residual drug in used implants was extracted with 23 50% (vol/vol) aqueous methanol and the concentration of TAF and TFV measured by high-performance liquid chromatography (FIPLC) with UV detection (1100 Series, Agilent Technologies). A Phenomenex (Torrance, CA) Atlantis-C18 column (2.1 x 100 mm; 5 μιη) controlled at 30°C was used as the stationary phase. The following gradient program was used (A, 1.0% vol/vol acetic acid and 3.0% vol/vol acetonitrile in water; B, acetonitrile): 2 min 100% A; 2 min ramp from 100:0 A:B to 75:25 A:B; 2 min hold at 75:25 A:B; 2 min ramp from 75:25 A:B to 100:0 A:B; 3 min hold at 100:0. The detection wavelength was 260 nm and the retention times were 9.46 min (TAF) and 1.13 min (TFV). The method run times were 11 min.

Pharmacokinetic data analyses

Noncompartmental analyses (NCA) were performed in Phoenix software (version 6.4,

Pharsight Corporation, Sunnyvale, CA) using literature plasma TAF concentration versus time plots following oral TAF administration (5 mg kg^"1, F 8.6 ± 0.8%) in beagle dogs (see Babusis et al., 2013. Mechanism for Effective Lymphoid Cell and Tissue Loading Following Oral Administration of Nucleotide Prodrug GS-7340. Mol. Pharmaceut. 10:459-466, which is hereby incorporated herein by reference in its entirety as though fully set forth). The NCA was used to determine volume of distribution (V) and clearance (CI) for use in the simulation. The systemic parameters determined in the NCA, along with the in vitro implant release rates, were used to simulate plasma TAF concentration versus time plots in Phoenix software (Fig. 4). All parameters are defined as part of Fig. 4 and the implant dosage form was assumed to have a 100% TAF bioavailability.

Statistical analysis

Dataset group statistics and plots were carried out using GraphPad Prism (version 6.02; GraphPad Software, Inc., La Jolla, CA). Statistical significance was defined at a P value of < 0.05.

Results

Physical characteristics of the TAF LA implant

The physical characteristics of the sustained release TAF implant are presented in Table 1 and Figure 1. The orange-brown color of the implant (Table 1) is the result of dehydration of the PVA backbone during thermal processing, leading to the formation of conjugated double bonds. In vitro cumulative release profiles (Fig. 2, Table 1) exhibited burst-free, sustained release with zero-order (linear) kinetics over 30 d. Residual drug analysis on the used implants showed that ca. 80% of the TAF payload was delivered over the 40-d study: residual TAF, 0.85 ± 0.81 mg (mean ± SD). Only traces of TFV (mean 0.13 mg) were detectable. The TAF implant in vitro dissolution rate (K_d 0.92 mg d^"1, Table 1) was not statistically significantly different (P 0.1859, two-tailed unpaired t test with Welch's correction) from the in vivo release rate (K_a 1.07 mg d^"1, Table 1).

Table 1 - Physical characteristics of long-acting TAF implant used in the dog study.

Physical characteristic TAF LA implant

Appearance orange-brown

Drug loading (mg, mean ± standard 42.9 ± 0.3

deviation)

Outer diameter, OD (mm) 1.9

Length (mm) 40

Number of delivery channels 14

Diameter of delivery channels (mm) 1.0

PVA content (% wt/wt) 7.3 Membrane thickness (μηι) 31.2 ± 3.8

In vitro release rate (rng d^'1) 0,92 (0.86-0.98)^a

In vivo release rate (mg d^"' ) 1.07 (1.04-1.1 Of

a95% confidence level

Toxicity

No adverse events related to treatment with the test article were noted during the course of the study. Overall, there were no significant abnormalities and the majority of clinical observations noted were considered to be incidental, procedure-related, or common findings for animals of this species. Lack of appetite was noted on Day 3 for all animals and correlated with minimal/no body weight gain for the majority of the animals through Day 21. The loss of appetite appeared to be transient, however, with higher body weights noted for all animals on Day 40 compared to body weight values on Day -1. The incision sites appeared healthy on Days 2-9 following surgery and the staples/sutures were removed on Day 8. There was no clinical evidence of inflammation at the implantation sites. Two animals were placed under veterinary consultation while on study for an open incision site (Animal Number 102, Day 13) and mild erythema in both ears (Animal Number 104, Day 29).

Pharmacokinetics of sustained release TAF in dogs

Dog plasma TAF and TFV concentration versus time plots following a single subcutaneous dose are shown in Fig. 3, superimposed with TFV-DP PBMC concentrations on Day 20-40. For TFV-DP measurements below the LLQ, but above the limit of detection, the concentration was set to 25 fmol/sample. Only one TFV-DP measurement (Day 39) met this criterion (Table 2) and led to a concentration of 32 fmol/10⁶ cells (PBMC count for the sample was 3.1 >< 10⁶ cells, 0.25 ml volume analyzed, resulting in a total of 0.78 lO⁶ cells analyzed). One measurement exceeded the ULQ (Day 21), but there was insufficient sample remaining to dilute and reanalyze, so this sample was omitted from the analysis. The TAF implants maintained sustained plasma levels of TAF and TFV as well as PBMC TFV-DP concentrations for 40 d (Fig. 3). The molar TAF:TFV plasma concentration ratio (median ± SD, 0.047 ± 0.024 for Dl-40) was stable throughout the study (Fig. 5). These data, along with residual drug analysis, strongly suggest that TAF is stable in the implant for at least 40 d in vivo. The short TAF plasma half-life in dogs (92 min) suggests that if significant prodrug hydrolysis were occurring in the implant, the TAF:TFV plasma concentration ratios would decrease significantly over the course of the study. The magnitude of the TAF:TFV ratio, i.e., high plasma TFV levels relative to TAF in paired samples, suggests that TAF metabolism to TFV could occur in vivo, possibly via intracellular dephosphorylation of TFV- DP and transporter-mediated efflux of TFV into blood, in agreement with prior reports. A summary of drug concentrations is presented in Table 2. Median PBMC TFV-DP concentrations of 511.8 fmol/10⁶ cells, an underestimate as the ULQ sample was omitted from the analysis, were observed over the first 35 days, before dipping on Day 40 as the implant drug reservoir was being depleted (Fig. 3). A lowering of the daily TAF release rate after 35 d also was observed in vitro (Fig. 2), consistent with drug depletion from the implant.

Table 2 Summary of TAF, TFV, TFV-DP concentrations from the dog study (n=4)

Analyte, matrix³ n % above LLOQ Median (IQR^C)

TAF, plasma 44 100%

ng ml^-1 0.85 (0.60-1.50) nM 1.8 (1.3-3.2)

TFV, plasma 44 98%

ng mi ^! 15.0 (8.8-23.3) nM 52,2 (30.5-81.0)

TFV-DP, PBMCs 16 94%

fmol/ 0⁵ cells 179.2 (128.2-616.7) nM 895.8 (640.9-3,083) ^aAU values correspond to time points with the implant in place

bProportion of samples that contained quantifiable drug levels

interquartile rang, between first (25^th percentile) and third (75^th percentile) quartiles

Simulation of plasma 1 TAF levels

A PK model (Fig. 4A) based on systemic parameters derived by NCA of published data from oral TAF administration in beagle dogs and the measured in vitro TAF release rates was used to simulate the corresponding TAF plasma levels a priori (Fig. 4B). The purpose of this exercise was not to model the in vivo TAF PKs, but to predict TAF exposure purely based on in vitro release rates and literature PK data. Based on this simple approach, the analysis afforded reasonable agreement between simulated and measured values, despite the short TAF plasma half-life in dogs and the low observed concentrations. The lower observed levels after Day 30 likely are due to drug depletion from the implant, resulting in a change in release kinetics from zero order to first order (Fig. 2).

Discussion

The primary objectives of the current study were to develop a sustained release TAF implant and to evaluate the PK and preliminary safety of the device in dogs. The results are discussed below with an emphasis on HIV-1 prophylaxis, although a similar device could be used in the treatment of HIV-1/AIDS, as described herein. Pharmacokinetics and preliminary safety of TAF implant prototype in dogs: implications to HIV-1 PrEP

In HIV-1 PrEP, unlike treatment of HIV-1/AIDS, there is no biomarker of ARV drug effect in susceptible, uninfected individuals to guide product development. Randomized clinical trials (RCTs) for PrEP based on TFV preparations have used sparse sampling of plasma, PBMCs, or cervicovaginal fluid to correlate measured drug levels (PK) with the primary pharmacodynamic (PD) endpoint: HIV-1 seroconversion. For systemic PrEP, TFV- DP concentration in PBMCs represents an accepted metric for estimating threshold protective drug levels. In iPrEX -an RCT where HIV-negative men who have sex with men took a 1 daily oral combination of TDF and emtricitabine (FTC)- HIV-1 protection was 92% in participants moderately adhering to the regimen, as determined by plasma TFV levels. A post hoc analysis found that a PBMC TFV-DP concentration of 16 fmol/10⁶ cells was associated with 90% protection (see Anderson et al., iPrEx Study T. 2012. Emtricitabine- tenofovir Concentrations and Pre-exposure Prophylaxis Efficacy in Men Who Have Sex with Men. Sci Transl. Med. 4: 151ral25, which is hereby incorporated herein by reference in its entirety as though fully set forth). It should be noted that, unlike in the experiments reported above, the iPrEX RCT used cryopreserved PBMCs, which leads to 33-67% loss of TFV-DP. A more conservative EC₉₀ therefore lies in the 24-48 fmol/10⁶ cells range. In the experiments reported herein, a subcutaneous implant delivering TAF at a rate of 1.07 ± 0.02 mg d^"1 for 40 d in beagle dogs maintained median PBMC TFV-DP levels of 512 fmol/10⁶ cells over the first 35 d. This achieved median concentration is 11-32 times higher than the protective target from iPrEX (corresponding to a TFV-DP concentration range of 48-16 fmol/10⁶ cells). Simple allometric scaling (see West GB, Brown JH. 2005. The Origin of Allometric Scaling Laws in Biology from Genomes to Ecosystems: Towards a Quantitative Unifying Theory of Biological Structure and Organization. J. Exp. Biol. 208: 1575-1592; and Sharma V, McNeill JH. 2009. To Scale or not to Scale: the Principles of Dose Extrapolation. Br. J. Pharmacol. 157:907-921, both of which are hereby incorporated herein by reference in their entirety as though fully set forth) (exponent 0.75) from beagle dogs (mean weight 10.8 kg) to humans (70 kg) affords a preliminary, lower target daily TAF release rate of 0.14 mg d^"1 to maintain a median TFV-DP PBMC concentration of 16 fmol/10⁶ cells. The concentration of PBMCs in beagle dog whole blood (mean 1.6^χ 10⁶ cells/mL, SD 0.7>< 10⁶ cells/mL) was comparable to typical values for HIV-negative humans. A one-year implant therefore would need to contain at least 52 mg TAF, a feasible quantity for an implant with practical physical dimensions.

Novel implant design for the sustained delivery of water-soluble drugs.

A sustained release formulation of TAF has not been previously reported. The implant utilized in the experiments described above consists of a drug-filled, PVA-coated silicone cylinder with orthogonal delivery channels (Fig. 1). The number and cross-sectional diameter of the channels, coupled with the physiochemical properties of the outer polymer membrane determine the implant release rate. The degrees of freedom allow the drug release rate to be tuned over a wide range, even for water-soluble drugs such as NRTIs. The release rate is not influenced by implant drug loading, as in matrix systems where the drug is dispersed in the polymer. The silicone shell is impermeable and all drug release is through the PVA-coated delivery channels, which linearize drug release. The implant architecture also has the benefit of protecting the drug core from chemical degradation, as evidenced by the in vivo stability of the TAF depot over 40 d. Controlled and sustained release is independent of the implant shell material, thereby offering flexibility in polymer choices, which can be important for large scale production. The successful development of candidates for LA-PrEP in HIV-1 prevention will require devices that are safe, effective, well tolerated, and affordable. The TAF implant described here was designed with these criteria in mind and afforded burst-free, linear TAF release (Fig. 2), a significant advantage over injectable long-acting ARV nanoformulations. One year TAF implant

The geometry and size of the TAF implant is based on three widely used contraceptive implants. The Norplant® subcutaneous contraceptive implant first approved in 1983 (Finland) consisted of six individual tubular silicone capsules (2.4 mm O.D. x 34 mm long), each containing 36 mg levonorgestrel (LNG). Approved in 1996, the Norplant II (Jadelle®) implant consists of two silicone rods (2.5 mm O.D. x 43 mm long), each with 75 mg LNG dispersed in the elastomer. The Implanon/Nexplanon devices are single rods (2 mm dia. x 40 mm length) containing 68 mg etonogestrel dispersed in ethylene vinyl acetate. These dimensions are identical to the prototype TAF implant used in the dog study described above. All three implant types are inserted sub-dermally on the inside of the upper arm by making a small incision and using an insertion device consisting of a hollow needle and trochanter for placement. Multiple, individual rods (e.g., Norplant and Jadelle) are implanted in a fan-shaped pattern. The devices also are easily replaced. Insertion/removal of the proposed TAF implants could follow identical methods to those used successfully to insert/remove millions of these contraceptive implants.

Conclusion

The long-acting TAF implants described herein could be used for HIV-1 prophylaxis in vulnerable populations. Sustained release TAF delivery could improve drug adherence and reduce transmission compared to daily oral dosing. A TAF implant also could be used as part of a highly active antiretroviral therapy (HAART) regimen for the treatment of HIV- 1/AIDS. Example 2

As described herein, in various embodiments, the implant can include a solid drug core (and can include admixed excipients) encased in a cylinder-shaped elastomer (e.g., silicone) sheath with delivery channels mechanically punched in the longitudinal axis (Fig. 1). As the daig does not diffuse through the elastomer, any biocompatible polymer could be employed. Both ends of the cylinder are sealed. The entire drug-filled device is surrounded by a PVA membrane that has been heat-treated to impart the desired physicochemical properties (see Byron PR, Dalby RN. Effects of Heat Treatment on the Permeability of Polyvinyl Alcohol Films to a Hydrophilic Solute, J Pharml Sci, 1987;76(l):65-7; and Petrova NV et al., Effect of Microwave Irradiation on the Cross-linking of Polyvinyl Alcohol. Russ J Appl Chem. 2005;78(7): 1 158-61, both of which are hereby incorporated herein by reference in their entirety as though fully set forth). The dimensions of the implant are determined by the target drug and excipient loading. The daily drug (e.g., TAF) release rate is driven by a number of factors: (1) number and cross-sectional diameter of delivery channels (in one example 14 delivery channels, each 1 mm diameter were employed); (2) thickness and thermal processing conditions of outer PVA membrane (in one example the PVA membrane was heat-treated for 4.75 h at 190°C) and (3) physiochemical properties of the daig solid core (e.g. TAF - which, like other drugs, may include solubilizing excipients), drug particle size and crystallinity, and chemical form (e.g., for TAF either as the free-base (TAF, solubility 5.23 mg mL-1, 11.0 mM) or the hemifumarate salt (TAF₂, solubility 19.9 mg ml/¹, 37.2 niM)). As was demonstrated by Byron and Dalby (Byron PR, Dalby R . 1987. Effects of heat treatment on the permeability of polyvinyl alcohol films to a hydrophilic solute. J Pharm Sci 76:65-67.) thermal processing changes permeability of hydrophilic solutes probably by cross linking and dehydration of the polymer. The higher the temperature and the longer the duration of treatment, the greater the reduction in permeability.

Once implanted subdermally, the subcutaneous fluids diffuse across the outer PVA membrane(s) of the drug implant and through the delivery channei(s) to form a saturated drug (e.g., TAF) solution inside the cylinder core. The concentration gradient formed across the PVA membrane (e.g., for TAF, saturated drug solution within the core to ca. 3 ng ml/¹ TAF steady state plasma concentrations for a 1 mg d^"1 device) drives diffusion of the drug through the delivery channel(s) and into the subcutaneous fluid, resulting in zero order (linear) release. The zero order release gives way to first order kinetics when ca. 80% of the drag payload has been delivered (Fig 2) guiding the specification of device drug content to > 30% the total mass targeted for delivery. By tailoring the three design parameters described above, the delivery rate may be precisely controlled over two orders of magnitude, a flexibility that has been exploited in TAF implant development to dial in the target 1 mg d^"1 rate used in the dog study, but which could also be exploited for delivering other water- soluble drugs.

Implants for dose-ranging PK-PD can be developed for additional animal species based on the configurations and criteria in Table 3. An implant for humans can likewise be made. For a device delivering TAF, the implant TAF loading required to maintain the target delivery rate and, hence, TFV-DP steady state PBMC concentration for the required duration determines the implant geometry, defined by the O.D., I.D., and length of each implant and the number of rods required (Table 3). A human target of 0.14 mg d^"1 TAF could be maintained for 1 year using a 2.4 mm O.D. ^χ 40 mm length single-rod implant. A human dose of 1 mg d^"1 would only require an implant configuration of four rods, compared to six rods for Norplant, due to the advantageous features of the design described herein. In various embodiments, additional implants could be used, as described herein above.

Table 3 - Example implant design criteria and characteristics

Subdermal drug implant, fabrication considerations

A silicone tube segment is cut to length, a metal pin inserted for support, and one end sealed with medical-grade liquid silicone resin (LSR). Delivery channels are punched radially along the tube length (1-20 per device) and the outer tube surface is treated in a plasma cleaner to enhance polymer adhesion. The device is dip-coated with PVA and heat- treated to form the release membrane that covers the entire silicone surface and the delivery channels (Fig. 1). The pin is removed and implant core is filled manually with one or more drug. For example, with 99+% TAF or TAF₂ with 0.1 -1% magnesium stearate added as a lubricant using a modified tamp dosator method, which involves a tamping dosator device that consists of one or more tamping pins or fingers that repeatedly press a metered amount of powdered drug or drug/excipient mixture into a hole in a rotating dosator disk, sequentially building up a plug of powder of pre-determined size (mass, volume) in the hole. The dosating disk is then rotated so that the hole containing powder is positioned above the implant lumen, and the powder plug is pressed into the implant lumen with an ejector pin. Each implant may be filled with one or more plugs from the dosator. A machine using a dosating nozzle design that works similarly and is known to those skilled in the art of pharmaceutical capsule preparation may be used to fill the implant lumen instead of a dosating disk design machine. The open end of the device is then sealed with LSR. As in Nexplanon, barium sulfate, a radiopaque salt, can be incorporated into the implant elastomer to allow its placement and position to be determined by X-ray imaging. Custom silicone extrusion can be used to fabricate scaffolds to target dimensions. In order to modulate performance of the device, certain extrusion methods and post-extrusion cutting and delivery channel drilling can be implemented, as described herein above.

When using TAF, the in vitro TAF release rate (as shown in Fig. 2) can be determined by placing implants in jars containing 100 mL 1 x PBS (pH 7,2) with shaking at 30 RPM and 37°C. Aliquots can be removed at predetermined time points and analyzed by UV spectroscopy (X max 262 nm) or HPLC to determine the TAF concentration in the release medium. The compendial LISP Type 4 (flow-through) dissolution apparatus is recommended for release testing of implants, however, for devices with I month to >1 year sustained delivery, Type 4 ceil geometry and flow rates are not appropriate. The following parameters can be iteratively modified to achieve the target in vitro release rates: delivery channel size; number of channels per device; outer device PVA coating thickness and thermal processing conditions; and number of individual implant segments. Example 3

Numerous devices, systems and methods are described herein. The following descriptions include certain non-limiting examples of devices and systems of the invention that can be used in conjunction with the inventive methods described herein. Each pattern (i.e., dots, diagonal lines, shading, no shading, etc.) depicted in various sections of the referenced figures indicates a particular type of material (e.g., drug) or material characteristic (e.g., drug-permeable or drug-impermeable).

Figs. 1A-1C depict, in accordance with an embodiment of the invention, drug delivery system 100 with drug core (e.g., TAF) 104. Drug delivery system 100 includes drug delivery channels/windows 101 and drug-permeable polymer (e.g., PVA) membrane 102. Drug deliver}' system 100 further includes drug-impermeable polymer (e.g., silicone) scaffold 103. Once subdermally implanted into a subject, body fluids interact with drug core 104, and drug passes through channels 101 and drug-permeable polymer membrane 102, and then into the body of the subject. Fig. 1 A depicts drug core 104 within drug delivery system 100. Fig. I B depicts a cross-section (y-z plane) of drug delivery system 100, Fig, 1C depicts a cross- section (x-z plane) of drug delivery system 100. Drug-permeable polymer membrane 102 is applied by dip coating or spraying drug-impermeable polymer (e.g., silicone) scaffold 103 with a drug-permeable polymer after channels 101 have been introduced by any method described herein. Figs. 6A-6C depict, in accordance with an embodiment of the invention, drug delivery system 200, in which drug-permeable membrane 202 (e.g, PVA) has been applied by extaiding, dip coating, or spraying on top of drug-impermeable polymer (e.g., silicone) scaffold 203 after channels 201 have been introduced by any method described herein. Fig. 6A depicts the top surface of drug delivery system 200, in which the outlines of the channels 201 are shown to indicate location. Fig. 6B depicts a cross-section (x-z plane) of drug delivery system 200, in which drug-permeable polymer 202, drug-impermeable polymer scaffold 203, drug core 204, and interface 201 between drug core 204 and drug-permeable polymer 202 can be seen. Fig. 6C depicts a cross-section (y-z plane) of drug delivery system 200. Drug delivery system 200 can be formed by extruding, dip coating, or spraying a drug- permeable membrane 202 over a drug-impermeable polymer scaffold (e.g. silicone) 203 in which delivery channels 201 have been formed. Although the delivery channels shown in Fig. 6B are filled with drug-permeable membrane 202, in other embodiments, the delivery channels may also be partially-filled, or not filled (i.e. where the drug-permeable membrane stretches across one or more channels, as shown in Fig. 1).

Fig. 7A depicts, in accordance with an embodiment of the invention, a cross-section (x-z plane) of drug deliver' system 300, in which sections of drug-permeable polymer 305 are situated between sections of drug-impermeable polymer scaffold 303. Drug delivery system 300 further includes drug-permeable polymer coating 302. When drug delivery system 300 is implanted subdermally into a subject's body, drug 304 passes through drug- permeable polymer 305 at interface 301, then through drug-permeable polymer coating 302, and finally the drug is released into the subject's body. Drug delivery system 300 can be formed by extruding a single tube which has drug-impermeable polymer sections 303 as well as drug-permeable polymer sections 305. A layer of drug-permeable polymer 302 can then be applied to the tube by dip coating or spraying, or by extruding directly over the tube. Alternatively, a device similar to drug delivery system 300 could be manufactured without drug-permeable coating 302.

Fig. 7B depicts, in accordance with an embodiment of the invention, a cross-section (x-z plane) of drug delivery system 500, which includes a section of drug-permeable polymer 505. Drug-impermeable polymer scaffold 503, drag-permeable polymer coating 502, and packed drag core 504 can also be seen in Fig. 7B. Drug-impermeable polymer scaffold 503 and drug-permeable polymer section 505 can be extruded as a single tube. A layer of drug- permeable polymer 502 can then be applied to the tube by dip coating or spraying, or by extruding directly over the tube. Alternatively, a device similar to drug delivery system 500 could be manufactured without drug-permeable polymer coating 502.

Fig. 8A depicts, in accordance with an embodiment of the invention, the top surface of tube-shaped drug delivery system 600. Drug delivery system 600 includes a band of drug- permeable polymer 605 integrated between sections of drug-impermeable elastomer or polymer coating 602. By varying the size and thickness of each of the drug-permeable sections, the rate of drug release of the inner drug core (not depicted) can be 'tuned.'

Fig. 8B depicts, in accordance with an embodiment of the invention, the top surface of tube-shaped drug delivery system 700. Drug delivery system 700 includes rectangular sections of drug-permeable polymer 705 integrated within drug-impermeable polymer coating 702. By varying the surface area and thickness of each drug-permeable section, the rate of drug release of the inner drug core (not depicted) can be 'tuned.'

Figs. 9A-9D depict, in accordance with various embodiments of the invention, cross- sections of various drag delivery systems. Fig. 9A depicts a cross-section (along the short axis) of tube-shaped drug delivery system 400. Drug delivery system 400 includes sections of drag-permeable polymer 405 situated between sections of drag-impermeable polymer 403, Drug core 404 is also depicted. Drug-permeable polymer sections 405 can be extruded together with drug -impermeable polymer sections 403, thereby forming a single tube that can be loaded with drag core 404 in any manner described herein. Interface 401 between drug core 404 and drug-permeable polymer 405 can also be seen. Fig. 9B depicts a cross-section (along the short axis) of drug deliver' system 300 described above. Fig. 9C depicts a cross- section (along the short axis) of drug delivery system 100 described above. Fig. 9D depicts a cross-section (along the short axis) of drag deliver}' system 200 described above.

Example 4

In addition to extrusion, implant scaffolds consisting of a tubular lumen of the dimensions described here and containing pre-formed delivery channels may be fabricated using additive manufacturing techniques. These additive techniques allow for complex, nonsymmetrical three-dimensional structures to be fabricated using 3D printing devices and methods known to those skilled in the art. One preferred method is extrusion deposition 3D printing, whereby the implant scaffold is fabricated by deposition of sequential layers of polymer that are melted and deposited from an extrusion nozzle that moves in two- dimensions. In this method, a three dimensional computer model of the implant scaffold design is converted or sliced into a series of two dimensional layers, and a 3D printer fabricates the device by applying polymer material by extrusion or spraying in a layer by- layer fashion to recreate the three dimensional structure. A second preferred method is 3D printing using a stereolithography-based photopolymerization method (SLA) whereby the two-dimensional layers are deposited in the desired pattern and photopolymerized to build up the three dimensional structure. A third preferred method is 3D printing using selective laser sintering whereby a polymer powder is melted using a laser beam that is scanned two- dimensionaliy in the desired pattern to sequentially form layers that reproduce the desired three-dimensional structure.

A preferred method of additive manufacturing that avoids sequential layer deposition to form the three-dimensional structure is to use continuous liquid interface production (CLIP), a technique recently developed by CarbonSD. In CLIP, three dimensional objects are built from a fast, continuous flow of liquid resin that is continuously polymerized to form a monolithic structure with the desired geometry using UV light under controlled oxygen conditions. The CLIP process is capable of producing solid parts that are drawn out of the resin at rates of hundreds of mm per hour. Implant scaffolds containing complex geometries may be formed using CLIP from a variety of materials including polyurethane and silicone.

The various methods and techniques described above provide a number of ways to carry out the invention. Of course, it is to be understood that not necessarily all objectives or advantages described can be achieved in accordance with any particular embodiment described herein. Thus, for example, those skilled in the art will recognize that the methods can be performed in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objectives or advantages as taught or suggested herein. A variety of alternatives are mentioned herein. It is to be understood that some preferred embodiments specifically include one, another, or several features, while others specifically exclude one, another, or several features, while still others mitigate a particular feature by inclusion of one, another, or several advantageous features.

Furthermore, the skilled artisan will recognize the applicability of various features from different embodiments. Similarly, the various elements, features and steps discussed above, as well as other known equivalents for each such element, feature or step, can be employed in various combinations by one of ordinary skill in this art to perform methods in accordance with the principles described herein. Among the various elements, features, and steps some will be specifically included and others specifically excluded in diverse embodiments.

Although the application has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the embodiments of the application extend beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and modifications and equivalents thereof.

In some embodiments, the terms "a" and "an" and "the" and similar references used in the context of describing a particular embodiment of the application (especially in the context of certain of the following claims) can be construed to cover both the singular and the plural. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (for example, "such as") provided with respect to certain embodiments herein is intended merely to better illuminate the application and does not pose a limitation on the scope of the application otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application.

Preferred embodiments of this application are described herein, including the best mode known to the inventors for carrying out the application. Variations on those preferred embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. It is contemplated that skilled artisans can employ such variations as appropriate, and the application can be practiced otherwise than specifically described herein. Accordingly, many embodiments of this application include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the application unless otherwise indicated herein or otherwise clearly contradicted by context.

All patents, patent applications, publications of patent applications, and other material, such as articles, books, specifications, publications, documents, things, and/or the like, referenced herein are hereby incorporated herein by this reference in their entirety for all purposes, excepting any prosecution file history associated with same, any of same that is inconsistent with or in conflict with the present document, or any of same that may have a limiting affect as to the broadest scope of the claims now or later associated with the present document. By way of example, should there be any inconsistency or conflict between the description, definition, and/or the use of a term associated with any of the incorporated material and that associated with the present document, the description, definition, and/or the use of the term in the present document shall prevail.

In closing, it is to be understood that the embodiments of the application disclosed herein are illustrative of the principles of the embodiments of the application. Other modifications that can be employed can be within the scope of the application. Thus, by way of example, but not of limitation, alternative configurations of the embodiments of the application can be utilized in accordance with the teachings herein. Accordingly, embodiments of the present application are not limited to that precisely as shown and described.

Claims

CLAIMS What is claimed is:

1. A sustained release agent delivery system comprising:

an inner agent core comprising one or more agents;

an elongated reservoir impermeable to said one or more agents, wherein the inner agent core is located within the elongated reservoir;

one or more delivery channels located orthogonally along the length of the elongated reservoir, wherein the one or more delivery channels are configured to allow the passage of the one or more agents; and

one or more polymer membranes permeable to the one or more agents, wherein the one or more polymer membranes cover one or more of the one or more delivery channels and allow for the sustained release of the one or more agents into a subject's body after the agent delivery system is implanted in the subject's body.

2. The sustained release agent delivery system of claim 1, wherein one or more of the agents are water-soluble compounds having an aqueous solubility greater than 1 mg mL^"1 at 20°C.

3. The sustained release agent delivery system of claim 1, wherein one or more of the agents are from the nucleoside reverse transcriptase inhibitor ( RTI) mechanistic class used for the prevention and/or treatment of human immunodeficiency virus (HIV) infection and/or acquired immune deficiency syndrome (AIDS).

4. The sustained release agent delivery system of claim 1, wherein one of the agents is tenofovir alafenamide.

5. The sustained release agent delivery system of claim 1, wherein one of the one or more agents is an antiviral agent used for the treatment or prevention of one or more viral infections caused by a virus selected from the group consisting of: herpes simplex virus, hepatitis virus, and influenza virus.

6. The sustained release agent delivery system of claim 1, wherein one of the agents is a peptide selected from the group consisting of: leuprolide acetate, exenatide acetate, goserelin acetate, and octreotide acetate.

7. The sustained release agent delivery system of claim 1, wherein the elongated reservoir comprises walls that comprise a drug-impermeable polymer selected from the group consisting of silicone, ethylene vinyl acetate copolymer, polyurethane, latex, and combinations thereof.

8. The sustained release agent delivery system of claim 1, wherein one or more of the one or more polymer membranes are selected from the group consisting of: polyvinyl alcohol, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, parylene, ethylene vinyl acetate copolymer, and polycaprolactone.

9. A method for reducing the likelihood of a subject contracting a viral infection, comprising: providing the sustained release agent delivery system of claim 1, wherein one or more of the one or more agents of the inner agent core is an antiviral agent; and

implanting the sustained release agent delivery system into the subject's body, thereby reducing the likelihood of the subject contracting the viral infection.

10. The method of claim 9, wherein the sustained release agent delivery system is implanted into the subject subdermally.

11. The method of claim 10, wherein the sustained release agent delivery system is implanted into one or more location in the subject selected from the group consisting of: upper inner or outer arm, inner thigh, back, and combinations thereof.

12. The method of claim 11, wherein the viral infection is caused by a virus selected from the group consisting of: human immunodeficiency virus (HIV), herpes simplex virus (HSV), hepatitis virus, and influenza.

13. The method of claim 12, wherein the virus is HIV.

14. The method of claim 13, wherein one or more of the agents is a nucleoside reverse transcriptase inhibitor.

15. The method of claim 13, wherein one or more of the agents is tenofovir alafenamide.

16. A method for making a sustained release agent delivery system, the method comprising: providing a tubing having first and second ends, wherein the tubing is impermeable to the agent;

introducing one or more holes along the length of the tubing;

sealing the first and second ends of the tubing;

coating the tubing with a polymer permeable to the agent;

opening at least one end of the tubing;

introducing the agent into the tubing through the opened end; and

resealing the open end of the tubing.

17. The method of claim 16, wherein the tubing is made of substance selected from the group consisting of: silicone, ethylene vinyl acetate copolymer, polyurethane, and latex, and a combination thereof.

18. The method of claim 16, wherein the polymer is selected from the group consisting of: polyvinyl alcohol, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, parylene, ethylene vinyl acetate copolymer, polycaprolacton, and a combination thereof.

19. The method of claim 16, wherein the agent is selected from the group consisting of: a nucleoside reverse transcriptase inhibitor, tenofovir alafenamide, emtricitabine, lamivudine, MK-8591 (EFdA), acyclovir, ganciclovir, oseltamivir phosphate, a peptide, leuprolide acetate, exenatide acetate, goserelin acetate, octreotide acetate, and a combination thereof.

20. The method of claim 16, wherein sealing comprises applying silicone adhesive to the first and/or second ends of the tubing.

21. A kit comprising

the sustained release agent delivery system of claim 3; and

instructions for the use thereof to reduce the likelihood of a subject contracting human immunodeficiency virus (HIV). The kit of claim 21, wherein one of the agents is tenofovir alafenamide.