WO2016149561A1 - Implants sous-cutanés pour la délivrance prolongée de médicaments solubles dans l'eau - Google Patents

Implants sous-cutanés pour la délivrance prolongée de médicaments solubles dans l'eau Download PDF

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Publication number
WO2016149561A1
WO2016149561A1 PCT/US2016/022980 US2016022980W WO2016149561A1 WO 2016149561 A1 WO2016149561 A1 WO 2016149561A1 US 2016022980 W US2016022980 W US 2016022980W WO 2016149561 A1 WO2016149561 A1 WO 2016149561A1
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Prior art keywords
drug
delivery system
sustained release
agents
taf
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PCT/US2016/022980
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English (en)
Inventor
Marc M. Baum
Manjula GUNAWARDANA
John A. Moss
Thomas J. Smith
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Oak Crest Institute Of Science
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Publication of WO2016149561A1 publication Critical patent/WO2016149561A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/31—Somatostatins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0069—Devices for implanting pellets, e.g. markers or solid medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention generally relates to the field of sustained drug delivery.
  • ARV antiretroviral
  • PrEP pre-exposure prophylaxis
  • LA-PrEP Long-acting pre- exposure prophylaxis
  • 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.
  • NRTI nucleoside reverse transcriptase inhibitor
  • TFV NRTI tenofovir
  • 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 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.
  • one or more of the agents are water-soluble compounds having an aqueous solubility greater than 1 mg mL "1 at 20°C.
  • 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).
  • RTI nucleoside reverse transcriptase inhibitor
  • HIV human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • one of the agents is tenofovir alafenamide.
  • 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.
  • one of the agents is a peptide selected from the group consisting of: leuprolide acetate, exenatide acetate, goserelin acetate, and octreotide acetate.
  • 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.
  • 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.
  • 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.
  • the sustained release agent delivery system is implanted into the subject subdermally.
  • 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.
  • 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.
  • virus is HIV.
  • one or more of the agents is a nucleoside reverse transcriptase inhibitor.
  • one or more of the agents is tenofovir alafenamide.
  • 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.
  • the tubing is made of substance selected from the group consisting of: silicone, ethylene vinyl acetate copolymer, polyurethane, and latex, and a combination thereof.
  • 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.
  • 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.
  • sealing includes applying silicone adhesive to the first and/or second ends of the tubing.
  • 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).
  • HIV human immunodeficiency virus
  • one of the agents is tenofovir alafenamide.
  • FIGS 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.
  • PVA polyvinyl alcohol
  • Cross-sections are sliced through the y-z (IB) and x-y planes (1C).
  • FIG. 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.
  • PBMC peripheral blood mononuclear cell
  • 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.
  • FIGS 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.
  • (4B) Actual individual (closed circles) and simulated (dotted line) TAF plasma levels. The dose was 90 ⁇ (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 bea
  • 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).
  • FIGC 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).
  • Constants 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.
  • infectious diseases e.g., a human immunodeficiency virus (HIV) infection, acquired immune deficiency syndrome (AIDS), a herpes
  • HIV includes HIV-1 and HIV-2.
  • agent includes any water-soluble substance, including, but not limited to, any water-soluble drug or prodrug.
  • API active pharmaceutical ingredient, which includes agents described herein.
  • water-soluble is defined as having an aqueous solubility above 1 mg niL "1 at 20°C.
  • 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.
  • 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.
  • the technologies described herein are suitable for the sustained delivery of water-soluble agents, including water-soluble drugs and prodrugs.
  • the device includes a reservoir suitable for containing one or more agents.
  • one or more of the one or more agents includes a water-soluble substance (e.g., a water-soluble drug or prodrug).
  • the walls of the reservoir are formed by a drug- impermeable material (also referred to herein as “drug-impermeable scaffold”).
  • the drag-impermeable scaffold may consist of, consist essentially of, or comprise a drug-impermeable elastomer or polymer.
  • one or more channels are formed in the drag-impermeable scaffold.
  • 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.
  • the drug-impermeable polymer is a biocompatible polymer.
  • 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.
  • the drug-impermeable scaffold could be made to have practically any dimensions and shape suitable for a particular application.
  • 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.
  • the shape of the reservoir is cylindrical (e.g., as depicted in Fig.
  • 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.
  • the outer diameter of the drug- impermeable scaffold or inner reservoir may vary along the length of the device.
  • 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.
  • 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.
  • 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.
  • one or more biocompatible polymers may be used for one or more of the one or more drug-permeable membranes.
  • 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.
  • PVA polyvinyl alcohol
  • one or more of the one or more drug-permeable membranes include PVA.
  • 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 ⁇ , 10-20 ⁇ , 20-30 ⁇ , 30-40 ⁇ , 40-50 ⁇ , 50-60 ⁇ , 60-70 ⁇ , 70-80 ⁇ , 80-90 ⁇ , 90-100 ⁇ , or more than 100 ⁇ .
  • two or more channels may terminate in drug-permeable membranes of different thickness and/or different compositions.
  • the device may have drug-permeable membranes of different thicknesses covering different channels of different regions of the device.
  • 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.
  • 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.
  • agents e.g., drugs
  • one or more of the one or more agents are water-soluble.
  • one or more of the one or more agents are a drug or prodrug.
  • 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.
  • a drug included in the reservoir is tenofovir alafenamide (TAF).
  • TAF tenofovir alafenamide
  • 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.
  • an agent contained in the reservoir includes a drag from the nucleoside reverse transcriptase inhibitor (NRTI) mechanistic class.
  • NRTI nucleoside reverse transcriptase inhibitor
  • 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.
  • 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).
  • the invention teaches a method for reducing the likelihood of a subject contracting a viral infection.
  • 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.
  • the sustained release agent delivery system is implanted into the subject subdermally.
  • 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.
  • 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.
  • the virus is HIV.
  • one or more of the agents is an antiviral agent useful for treating the target viral infection.
  • one or more of the agents is a nucleoside reverse transcriptase inhibitor (NRTI).
  • NRTI nucleoside reverse transcriptase inhibitor
  • one or more of the agents is from another mechanistic class targeting HIV.
  • one of the agents is tenofovir alafenamide (TAF).
  • 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.
  • 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.
  • the anti-adherents or lubricants may include, but are in no way limited to, magnesium stearate, stearic acid, sodium stearyl fumarate, and sodium behenate.
  • the glidants may include, but are in no way limited to, fumed silica, talc, and magnesium carbonate.
  • the pH modifiers may include, but are in no way limited to, citric acid, lactic acid, and gluconic acid.
  • 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.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisoie
  • cysteine cysteine
  • methionine methionine
  • vitamin A vitamin E
  • sodium benzoate sodium benzoate
  • parabens parabens.
  • one or more of the sustained release agent delivery systems are implanted in a subject and allowed to remain implanted in the subject for 1-730 days or more.
  • 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.
  • two or more implants are removed after different periods of time.
  • 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.
  • 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.
  • each of the one or more implants includes 20-500 nig of TAF.
  • each of the one or more implants includes 50-100 mg of TAF.
  • each of the one or more implants includes 20-500 mg, 30-400 mg, 40-300 mg, or 50-200 mg of TAF.
  • 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 ' .
  • the dimensions of one or more of the implants include any of the dimensions of the devices described herein.
  • the number of implants introduced into the subject for treating a condition is 1-12.
  • the number of implants introduced into the subject when using TAF in the drug core is 1-12.
  • the method 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.
  • 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.
  • 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.
  • the subject treated according to the inventive methods described above has a high risk of contracting HIV.
  • that subject is treated with at least one implant containing TAF.
  • the subject is a child.
  • the subject is an adolescent.
  • the subject is an adult.
  • 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.
  • the virus is HIV.
  • the subject has been diagnosed with AIDS.
  • the virus is one of the hepatitis viruses.
  • the virus is HSV.
  • the method includes implanting one or more sustained release agent delivery systems ("implants") described herein into the body of the subject.
  • the drug core of one or more of the implants includes one or more drugs useful for treating the specific viral infection.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • each of the one or more implants includes 20-500 mg of TAF.
  • each of the one or more implants includes 50-100 mg of TAF.
  • each of the one or more implants includes 20-500 mg, 30-400 mg, 40-300 mg, or 50-200 mg of TAF.
  • 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.
  • 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.
  • 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.
  • the additional drugs are administered orally, parenterally, through subdermal implantation, or by any other route of administration known to be effective.
  • 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).
  • one or more of the additional drugs described above may also be present in one or more of the implants implanted into the individual.
  • 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.
  • any of the drugs included may be included in amount of 20-500 mg, 30-400 mg, 40-300 mg, or 50-200 mg per implant.
  • 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).
  • 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 step is fabricating the implant drug- impermeable scaffold.
  • 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.
  • 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.
  • 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.
  • 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.
  • compressed pellets are inserted into the scaffold interior as a stack of cylindrical pellets similar to a roll of Lifesavers® candy.
  • 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).
  • 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.
  • the drug-impermeable polymer tubing is extruded, and the delivery channel (s) are formed by a post-extrusion process off of the extrusion line.
  • the post-extrusion process may include, but is in no way limited to, punching or laser drilling.
  • the drug-impermeable polymer tubing is extruded and the delivery channei(s) are formed by an extrusion line process.
  • the extrusion line process may include, but is in no way limited to, punching, laser drilling, or a transitional extrusion process.
  • 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.
  • 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.
  • 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).
  • the resulting tube may be coated with an additional layer of drug-permeable polymer as described herein.
  • 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).
  • a drug-permeable polymer coating is extruded on a pre-formed drug-impermeable polymer tube in which one or more channels have been formed.
  • 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.
  • 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).
  • 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.
  • thermal dehydration nucleophilic substitution inducing cross-linking via ether groups followed by elimination of water to form double bonds
  • 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.
  • 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.
  • 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.
  • one or more delivery channels of the systems and devices are formed by using a laser drilling process.
  • 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.
  • one or more deliver ⁇ ' channels may be formed during the extaision process.
  • the tubular extrusion profile may be interrupted during the extrusion process to form voids in the extrusion wall that serve as delivery channels.
  • 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.
  • the present invention teaches a kit for treating a subject who has an HIV infection.
  • the present invention teaches a kit for treating a subject who has been diagnosed with AIDS.
  • the present invention teaches a kit for reducing the likelihood of a subject contracting HIV.
  • 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.
  • the condition is any condition described herein.
  • the condition is HIV.
  • 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.
  • the kit is an assemblage of materials or components, including at least one of the inventive sustained release drug delivery systems or devices.
  • the kit consists of, or consists essentially of, or comprises a sustained release drug delivery device or system described herein.
  • the kit is configured particularly for the purpose of treating or preventing a condition in mammalian subjects.
  • the kit is configured particularly for the purpose of treating human subjects.
  • 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.
  • 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.
  • 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.
  • packaging 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.
  • TFV formulations must overcome the drug's low potency and high aqueous solubility, while taking advantage of its slow systemic clearance kinetics.
  • TFV TFV diphosphate
  • TFV-DP TFV diphosphate
  • the prodrug TAF (EC 50 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.
  • TAF Tenofovir alafenamide
  • 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- 13 C 5 ]-(TFV- 13 C 5 ) was obtained from Moravek Biochemicals, Inc. (Brea, CA) and maraviroc- D 6 (MVC-D 6 ) was obtained from Santa Cruz Biotechnology, Inc. (Dallas, TX). All other reagents were obtained from Sigma-Aldrich, unless otherwise noted.
  • TAF LA TAF Long Acting
  • 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 ⁇ phosphate-buffered saline solution (PBS, Thermo Fisher Scientific, Inc., Hudson, H).
  • PBS phosphate-buffered saline solution
  • 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.
  • 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.
  • a subcutaneous pocket (ca. 5 cm ⁇ 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.
  • the subcutaneous incisions were closed with absorbable sutures and the incisions were closed with staples.
  • 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 K 2 EDTA 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.
  • PBMC isolation blood (3 mL) was collected into Vacutainer® CPTTM 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).
  • DPBS Dulbecco's phosphate buffered saline
  • 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.
  • Dog plasma samples were purified and analyzed separately for TAF and TFV.
  • Plasma samples were thawed on ice and two 100 ⁇ 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 ⁇ of internal standard (IS) solution (1 ⁇ g ml "1 MVC-D 6 for TAF and 1 ⁇ g ml "1 TFV- 13 C 5 for TFV).
  • IS internal standard
  • 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.
  • 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 ⁇ for TAF; 100 ⁇ 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.
  • 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-D 6 (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- 13 C 5 (IS), parent 293.1 amu, product, 181.2 amu.
  • TFV TFV
  • 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.
  • TFV-DP 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/10 6 cells based on the lysate specific number of PBMCs present in the sample. Intracellular concentrations were calculated assuming a mean volume of 0.2 ⁇ 1/10 6 PBMCs in order to maintain consistency with prior reports.
  • 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).
  • FRPLC high-performance liquid chromatography
  • 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.
  • NCA Noncompartmental analyses
  • the physical characteristics of the sustained release TAF implant are presented in Table 1 and Figure 1.
  • Table 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.
  • Fig. 2, Table 1 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.
  • Fig. 3 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.
  • 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/10 6 cells (PBMC count for the sample was 3.1 > ⁇ 10 6 cells, 0.25 ml volume analyzed, resulting in a total of 0.78 lO 6 cells analyzed).
  • 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 was stable throughout the study (Fig. 5).
  • a AU values correspond to time points with the implant in place
  • 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.
  • 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).
  • 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.
  • PK measured drug levels
  • PD primary pharmacodynamic
  • TFV- DP concentration in PBMCs represents an accepted metric for estimating threshold protective drug levels.
  • 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.
  • 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).
  • 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.
  • 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.
  • HAART highly active antiretroviral therapy
  • 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.
  • 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 (TAF 2 , solubility 19.9 mg ml/ 1 , 37.2 niM)).
  • TAF free-base
  • TAF 2 solubility 19.9 mg ml/ 1 , 37.2 niM
  • 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.
  • a saturated drug e.g., TAF
  • 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
  • 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.
  • 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.
  • 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. ⁇ 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.
  • additional implants could be used, as described herein above.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • drug core 104 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.
  • 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.
  • drug-impermeable polymer e.g., silicone
  • FIG. 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • SLA stereolithography-based photopolymerization method
  • 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.
  • CLIP continuous liquid interface production
  • 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.

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Abstract

Dans divers modes de réalisation, l'invention concerne des dispositifs, des systèmes et des procédés permettant la délivrance d'un agent à libération prolongée. Les procédés comprennent généralement l'administration d'un système de délivrance d'un agent à libération prolongée à un organisme d'un mammifère nécessitant un tel traitement, dans une zone où la libération d'un agent efficace est souhaitée et permettant ensuite à l'agent efficace de passer à travers le dispositif d'une manière contrôlée. Dans divers modes de réalisation, le dispositif est constitué d'un tube perforé de matériau imperméable à l'agent (par exemple, de la silicone) contenant un noyau ou réservoir d'agent efficace, avec le tube enfermé dans un matériau perméable à l'agent qui permet à l'agent actif de passer à travers les perforations.
PCT/US2016/022980 2015-03-17 2016-03-17 Implants sous-cutanés pour la délivrance prolongée de médicaments solubles dans l'eau WO2016149561A1 (fr)

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US20180235900A1 (en) * 2017-02-06 2018-08-23 Research Triangle Institute Subcutaneous reservoir device and method of manufacture
WO2018175237A1 (fr) * 2017-03-23 2018-09-27 Particle Sciences, Inc. Dispositif d'administration de médicament implantable et amovible
EP3454868A4 (fr) * 2016-05-12 2019-12-18 Merck Sharp & Dohme Corp. Système d'administration de médicaments pour l'administration d'agents antiviraux
WO2020081622A1 (fr) * 2018-10-16 2020-04-23 Research Triangle Institute Dispositif de réservoir biodégradable sous-cutané
US10912933B2 (en) 2014-08-19 2021-02-09 The Regents Of The University Of California Implants for localized drug delivery and methods of use thereof
EP3609508A4 (fr) * 2017-04-10 2021-02-10 Merck Sharp & Dohme Corp. Système d'administration de médicament pour l'administration d'agents antiviraux
WO2021071974A1 (fr) * 2019-10-07 2021-04-15 Oak Crest Institute Of Science Dispositif d'administration de médicament pouvant être implanté par voie orale
WO2021207329A1 (fr) * 2020-04-07 2021-10-14 Research Triangle Institute Formulations multi-médicaments pour dispositif de réservoir sous-cutané biodégradable
US11173291B2 (en) 2020-03-20 2021-11-16 The Regents Of The University Of California Implantable drug delivery devices for localized drug delivery
CN114209807A (zh) * 2022-01-13 2022-03-22 南京昂谷医药科技有限公司 戈舍瑞林植入剂制剂及其制备方法
US11338119B2 (en) 2020-03-20 2022-05-24 The Regents Of The University Of California Implantable drug delivery devices for localized drug delivery
US11344526B2 (en) 2020-03-20 2022-05-31 The Regents Of The University Of California Implantable drug delivery devices for localized drug delivery
WO2022160022A1 (fr) * 2021-01-29 2022-08-04 Luiz Peracchi Edson Implant sous-cutané réabsorbable de longue durée à libération prolongée de substance pharmacologiquement active pré-concentrée en polymère pour le traitement du diabète de type 2 et procédé
US11793814B2 (en) 2019-01-25 2023-10-24 Brown University Compositions and methods for treating, preventing or reversing age associated inflammation and disorders
US11890438B1 (en) 2019-09-12 2024-02-06 Cochlear Limited Therapeutic substance delivery

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US11918770B2 (en) 2014-08-19 2024-03-05 The Regents Of The University Of California Implants for localized drug delivery and methods of use thereof
US10912933B2 (en) 2014-08-19 2021-02-09 The Regents Of The University Of California Implants for localized drug delivery and methods of use thereof
US11324935B2 (en) 2014-08-19 2022-05-10 The Regents Of The University Of California Implants for localized drug delivery and methods of use thereof
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EP3454868A4 (fr) * 2016-05-12 2019-12-18 Merck Sharp & Dohme Corp. Système d'administration de médicaments pour l'administration d'agents antiviraux
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EP3609508A4 (fr) * 2017-04-10 2021-02-10 Merck Sharp & Dohme Corp. Système d'administration de médicament pour l'administration d'agents antiviraux
US11419817B2 (en) 2017-04-10 2022-08-23 Merck Sharp & Dohme Llc Drug delivery system for the delivery of antiviral agents
WO2020081622A1 (fr) * 2018-10-16 2020-04-23 Research Triangle Institute Dispositif de réservoir biodégradable sous-cutané
US11793814B2 (en) 2019-01-25 2023-10-24 Brown University Compositions and methods for treating, preventing or reversing age associated inflammation and disorders
US11890438B1 (en) 2019-09-12 2024-02-06 Cochlear Limited Therapeutic substance delivery
WO2021071974A1 (fr) * 2019-10-07 2021-04-15 Oak Crest Institute Of Science Dispositif d'administration de médicament pouvant être implanté par voie orale
US11173291B2 (en) 2020-03-20 2021-11-16 The Regents Of The University Of California Implantable drug delivery devices for localized drug delivery
US11338119B2 (en) 2020-03-20 2022-05-24 The Regents Of The University Of California Implantable drug delivery devices for localized drug delivery
US11344526B2 (en) 2020-03-20 2022-05-31 The Regents Of The University Of California Implantable drug delivery devices for localized drug delivery
WO2021207329A1 (fr) * 2020-04-07 2021-10-14 Research Triangle Institute Formulations multi-médicaments pour dispositif de réservoir sous-cutané biodégradable
WO2022160022A1 (fr) * 2021-01-29 2022-08-04 Luiz Peracchi Edson Implant sous-cutané réabsorbable de longue durée à libération prolongée de substance pharmacologiquement active pré-concentrée en polymère pour le traitement du diabète de type 2 et procédé
CN114209807A (zh) * 2022-01-13 2022-03-22 南京昂谷医药科技有限公司 戈舍瑞林植入剂制剂及其制备方法

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