Implants

Abstract

The drug delivery implant can include an implant body and a core containing a pharmaceutical agent. The core can be disposed within the implant body extending longitudinally and circumferentially around the core. The implant body can also define an opening that exposes a first surface of the core. Also disclosed is a method for treating a mammal in need of treatment to achieve a desired physiological or pharmacological effect by injecting such a drug delivery implant into the mammal.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 412,678, filed October 3, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] In the treatment of ocular diseases, injections are typically preferred over systemic drug administration because the blood-retinal barrier prevents most drugs from passing from the circulating blood into the eye, and local administration to the eye avoids off-target effects of drugs on other parts of the body. Many ocular diseases require continuous administration of bioactive agents, either lifelong, such as in the treatment of glaucoma or retinal diseases, or over long periods (months), such as after surgery. However, the half-lives of most intravitreal-injected compounds, especially small drug molecules, are relatively short, typically only a few hours. As a result, intravitreal injection treatments typically require frequent administration, which is undesirable due to the associated pain, discomfort, elevated intraocular pressure, intraocular bleeding, increased likelihood of infection, and the possibility of retinal detachment. Therefore, there remains a need for devices and methods that support controlled, sustained, local administration of drugs to the eye.

[0003] There is also a need for injectable, removable, bioerodible sustained-release devices that can maintain steady-state drug concentrations systemically. While there are numerous examples of injectable, bioerodible drug delivery systems that offer nonlinear release (e.g., PLGA, microspheres, liposomes), these typically result in fluctuating plasma levels (initially very high, then exponentially decreasing) and are not easily removable. Alternatively, nonerodible implants (e.g., Jadelle, Norplant) offer reasonable sustained-release kinetics, but upon depletion, the release rate gradually decreases, resulting in a long "tail-off" period, requiring removal of the nonerodible implant when plasma levels fall below the desired range. Summary of the Invention

[0004] In certain embodiments, the present disclosure provides a drug delivery implant shaped and sized for injection. The drug delivery implant can include a core containing a pharmaceutical agent. The drug delivery implant can also include a cylindrical implant body configured to extend longitudinally around and contact the periphery of a longitudinal surface of the core. The implant body can define an opening at a first end of the implant body to expose the first surface of the core. When placed in an aqueous environment, the pharmaceutical agent can diffuse from the first surface of the core through the opening at the first end of the implant body. In some embodiments, the pharmaceutical agent has a solubility of less than about 2 mg / ml.

[0005] In certain embodiments, the present disclosure provides a drug implant comprising a core, which can include a pharmaceutical agent having a solubility of less than about 2 mg / ml.

[0006] In certain embodiments, the present disclosure provides a method for treating a subject in need thereof, comprising implanting an implant according to the present disclosure.

[0007] Numerous further embodiments are provided that may be applied to any aspect of the disclosure described herein.

[0008] In certain embodiments, the release rate of the drug is maintained at a relatively constant level until nearly completely depleted, resulting in a very short "tail-off" period. [Brief explanation of the drawings]

[0009] [Figure 1A] 1 shows a system comprising an implant body and a pharmaceutical-containing core that exhibits a relatively constant release of drug after an initial burst phase. [Figure 1B] 1 shows a system comprising an implant body and a pharmaceutical-containing core that exhibits a relatively constant release of drug after an initial burst phase. [Figure 2] It is shown that the steady-state release is proportional to the surface area of ​​the core. [Figure 3] It shows that the surface area of ​​the core remains substantially constant until the pharmaceutical agent is depleted. [Figure 4] It shows that the release rate of the drug remains substantially constant until depletion. [Figure 5A] This shows that the drug release rate and duration are independent of the implant body composition. The release of K8 (2-Et-AZT) from an implant body containing polyimide (non-erodible) is shown (ID=0.34 mm, length 3.5 mm (n=6), drug loading approximately 350 μg, duration approximately 120 days). [Figure 5B] This shows that the drug release rate and duration are independent of the composition of the implant body. The cumulative amount of K8 released from the PLGA-containing implant body is shown (ID=0.35mm, length 3.5mm (n=4), drug loading approximately 380μg, duration approximately 125 days). [Figure 6A] The release duration of the drug is dependent on the length. A 2.5 mm long tube containing 320 μg of K8 provides sustained release for approximately 60 days (ID=0.37 mm, length 2.5 mm (n=4)). [Figure 6B] The drug release duration is dependent on the length. A 5 mm long tube containing 610 μg of K8 provides sustained release for approximately 220 days (polyimide body (ID=0.37 mm, length 5 mm (n=4)). [Figure 7] Figure 1 shows the cumulative release of K8 from implants (ID = 0.37 mm) compared in vitro and in vivo. [Figure 8] Release of the drug EFdA (Islatravir) from the implant occurs over approximately 100 days. [Figure 9]The release profile of islatravir from the implants over approximately 120 days is shown. The steady-state daily release rate is approximately 75 μg / day, corresponding to a release surface area of ​​3.14 mm. The implants in PLGA tubing (biodegradable) exhibited similar in vitro release profiles to those in polyimide tubing (nondegradable). [Figure 10] The daily release rate of the drug before depletion is shown. The implants exhibited a short tail and were completely depleted within a few days in vitro. [Figure 11] Batch sample results of EFdA plasma concentrations in rats up to one month are shown. DETAILED DESCRIPTION OF THE INVENTION

[0010] The implants described herein are suitable for the controlled, sustained release of moderately to lowly soluble or lowly soluble drugs. The drug delivery implant 10 includes a core 12 containing an effective amount of a pharmaceutical agent (e.g., a moderately to lowly soluble or lowly soluble drug). The core 12 is positioned within a cylindrical implant body 14 that is arranged to extend around the core 12 along an axis A1, as shown in FIG. 1 . The implant body 14 defines an opening 16, for example, at a first end 18 of the implant body 14, exposing a first surface 20 of the core 12, as shown in FIG. 1 . When the implant 10 is placed in an aqueous environment, the pharmaceutical agent diffuses from the first surface 20 through the opening 16 at the first end 18 of the implant body 14, as shown in FIGS. 1 and 3 . In certain preferred embodiments, the implant 10 does not include a rate-controlling membrane covering the opening 16, and the first surface is preferably in direct contact with the surrounding environment.

[0011] In certain embodiments, the implant body 14 is impermeable or substantially impermeable to the passage of water and is impermeable or substantially impermeable to the diffusion of pharmaceutical agents within the core, such that release of the pharmaceutical agent occurs solely or primarily through the openings.

[0012] In certain embodiments, the implant body 14 is biodegradable and remains impermeable or substantially impermeable to the diffusion of water and pharmaceutical agents until the pharmaceutical agent within the core is substantially or completely released, after which the implant body 14 biodegrades.

[0013] In certain embodiments, first surface 20 has an initial surface adjacent opening 16, as shown in FIG. 1 . In certain preferred embodiments, first end 18 of implant body 14 is uncapped. For example, when implant 10 is embedded or placed in an aqueous environment, first surface 20 is directly exposed to the aqueous environment across the entire first surface 20. While in the aqueous environment, core 12 dissolves and the pharmaceutical agent diffuses through opening 16, so that the area of ​​the exposed surface remains substantially constant.

[0014] In certain embodiments, the core 12 includes drug particles, and the pharmaceutical agent is present within the drug particles. In certain embodiments, the core includes a pellet (not shown) containing the drug particles and can optionally include a polymeric material (e.g., polyvinyl alcohol) that does not substantially affect the release of the pharmaceutical agent. If present, the polymeric material can maintain the available surface area of ​​the core 12.

[0015] In certain embodiments, core 12 comprises a matrix containing a pharmaceutical agent and a polymeric material, with the pharmaceutical agent dispersed throughout the matrix. When the polymeric material is present in core 12 as part of a matrix or pellet, it is present at less than about 10% w / w of the core, less than about 5% w / w of the core, or less than about 2% w / w of the core. In certain embodiments, the polymeric material is present at about 2.5% w / w of the core. In certain embodiments, the polymeric material does not dissolve in an aqueous environment and maintains the available surface area of ​​core 12. In certain preferred embodiments, the polymeric material does not substantially affect the release rate of the pharmaceutical agent. In certain embodiments, the polymeric material is bioerodible. In certain embodiments, the polymeric material is PVA.

[0016] In certain embodiments, core 12 includes a layer 21 of polymeric material forming a longitudinal surface of core 12, as shown in FIG. 1. In some embodiments, the coating at least partially surrounds core 12 or completely surrounds core 12. In some embodiments, the coating includes a second polymer, e.g., a hydrophilic polymer such as PVA. In certain embodiments, the PVA of the coating has a molecular weight of about 50 KDa to about 300 KDa. In some embodiments, the PVA of the coating has a degree of hydrolysis of about 80% to about 98%.

[0017] For example, core 12 can include a layer 21 of polymeric material located between implant body 14 and the pharmaceutical agent. In certain embodiments, the polymeric material is PVA. In some embodiments, the core includes compressed pellets of pharmaceutical agent that are immersed in a solution of polymeric material (e.g., PVA) to form layer 21 before being inserted into implant body 14. In certain embodiments, core 12 does not include a layer, and the pharmaceutical agent directly contacts implant body 12.

[0018] The implant body 14 surrounds the core 12 and is substantially water-impermeable, as shown in FIG. 1 . In some embodiments, the implant body is non-bioerodible, for example, comprising a polyimide. In some embodiments, the implant body is bioerodible, for example, comprising PLGA, PCL, or PLA. Polymers such as PLGA are available with various erosion rates. Polymers that undergo "bulk" erosion, such as PLGA, are ideal for these systems. In some embodiments, the implant body does not erode until the drug is released.

[0019] The implant body 14 includes a second end 22 spaced from the first end 18, as shown in FIG. 1 . The implant body 14 defines a second opening 24 located at the second end 22 of the implant body 14. In some embodiments, the second end is capped (not shown), exposing only the first surface 20 to the aqueous environment. In preferred embodiments, the cap is impermeable or substantially impermeable. In some embodiments, the cap is constructed of the same material as the implant body 14. In some embodiments, the implant body defines an opening along a longitudinal surface. In some embodiments, both ends of the implant body are capped, and an opening is formed in the wall (i.e., the longitudinal surface) of the implant body through which the agent is released. In some embodiments, the implant body defines one or more openings, e.g., at the first end, the second end, one or more openings along the longitudinal surface, and combinations thereof. In some embodiments, two or more openings on the longitudinal surface expose the surface of the core. In some embodiments, it is preferred that the opening is not covered by a rate-controlling membrane and the exposed surface is in direct contact with the surrounding environment.

[0020] In some embodiments, second end 22 is uncapped, and second opening 24 exposes a second surface 26 of core 12 adjacent opening 24, as shown in Figure 1. In some embodiments, the surface area of ​​second surface 26 is substantially the same as the surface area of ​​first surface 20. When placed in an aqueous environment, the pharmaceutical agent can diffuse out of first opening 16 and second opening 24.

[0021] In certain embodiments, the exposed surface area remains relatively constant as the core 12 releases about 10% to about 90%, or about 15% to about 80% of the pharmaceutical agent. In certain embodiments, the exposed surface area remains relatively constant as the core 12 releases up to about 80%, up to about 85%, up to about 90%, up to about 95%, or up to about 99% of the pharmaceutical agent. In certain embodiments, the exposed surface of the core (e.g., first surface 20 or second surface 26) remains substantially constant. For example, the exposed surface area can remain relatively constant as the core releases about 10% to about 90% of the pharmaceutical agent. In certain embodiments, the surface area is about 0.05 mm 2 ~about 0.3mm 2 or approximately 0.06 mm 2 ~about 0.21mm 2 is.

[0022] As the pharmaceutical agent diffuses from opening 16, first surface 20 of core 12 retreats a distance L1 from first opening 16, as shown in the middle and bottom panels of Figure 3. As the pharmaceutical agent diffuses from opening 24, second surface 26 of core 12 retreats a distance L2 from opening 24, as shown in the middle and bottom panels of Figure 3. When in an aqueous environment, L1 is substantially the same as L2. Alternatively, if second surface 26 is capped, L1 is substantially greater than L2 when implant 10 is in an aqueous environment.

[0023] Implant 10 may be implanted for a period and under conditions sufficient to treat the medical condition in question. For example, implant 10 may release pharmaceutical agent for at least 1 month, at least 2 months, at least 3 months, or at least 6 months, or at least 12 months, or at least 24 months. In certain embodiments, implant 10 may be removed before the entire pharmaceutical agent is released, for example, if the subject experiences undesirable side effects.

[0024] When implant 10 is in an aqueous environment (e.g., the vitreous of the eye), the pharmaceutical agent diffuses from core 12 through openings 14 and, optionally, second openings 24. In certain embodiments, the implant releases an initial burst of pharmaceutical agent, followed by a substantially zero-order kinetic release of pharmaceutical agent. The initial burst releases pharmaceutical agent at a rate faster than the rate of the substantially zero-order kinetic release of pharmaceutical agent. In certain embodiments, the substantially zero-order kinetic release occurs over a period of at least about 30 days, at least about 60 days, at least about 90 days, at least about 120 days, at least about 180 days, at least about 210 days, at least 360 days, or at least 720 days.

[0025] In some embodiments of implant 10 disclosed herein, implant 10 provides a drug release rate of about 70 μg / day to about 0.2 μg / day or about 70 μg / day to about 0.5 μg / day.

[0026] The implant body 14 can be sized as needed to accommodate the length required for delivery of the pharmaceutical agent. In certain embodiments, the implant body 14 has a length of about 2 mm to about 10 mm, about 2 mm to about 7 mm, or about 2 mm to about 5 mm. In certain embodiments, the implant body has a diameter of about 0.1 mm to about 0.5 mm, or about 0.1 mm to about 2.0 mm. For delivery, the implant 10 is preferably sized to pass through a needle smaller than a 20-gauge needle (e.g., a 20-30-gauge needle), and even more preferably, to pass through a needle smaller than a 22-gauge needle (e.g., a 22-30-gauge needle). For systemic applications, the implant can be sized to pass through a 12-gauge or 14-gauge needle. It will be understood that the range of needle sizes is exemplary only, and that the systems described herein can be used to manufacture injectable devices for use with needles larger or smaller than those specifically mentioned above. Furthermore, it should be understood that the term "injectable device" or "injectable implant," as used herein, does not strictly refer to a device that is injectable using only the hypodermic needle sizes described above. Rather, the term is intended to be broadly interpreted and may include devices that are administered through an arthroscope, catheter, or other medical instrument. Similarly, the terms "inject" and "injected" are intended to include administration by means other than a hypodermic needle, such as an arthroscope, catheter, or other medical instrument. Thus, the term "needle size" may refer to the size of the incision through which the device is inserted.

[0027] The pharmaceutical agent can have a solubility of less than about 2 mg / ml, preferably less than about 1 mg / ml. In certain preferred embodiments, the pharmaceutical agent is islatravir or K8. In certain embodiments, the pharmaceutical agent has moderate to low solubility. In certain embodiments, "moderate to low solubility" refers to a solubility of less than about 2 mg of compound per ml (in water at a temperature of about 25°C, as measured by the procedure specified in the 1995 USP).

[0028] Examples of compounds with low solubility include immune response modifiers such as cyclosporine A and FK 506, corticosteroids such as dexamethasone, fluocinolone acetonide, and triamcinolone acetonide, antiparasitic agents such as atovaquone and chloroquine, glaucoma treatments such as brimonidine, antibiotics such as erythromycin and ciprofloxacin, differentiation modifiers such as retinoids (e.g., trans-retinoic acid, cis-retinoic acid, and analogs), and antivirals such as islatravir, including high molecular weight (10-mer) antisense compounds with low solubility. anticancer drugs such as ribozyme inhibitors, siRNA molecules, BCNU, methotrexate, regorafenib, axitinib, crenolanib, cabozantinib, gefitinib, erlotinib, sorafenib, sunitinib, dasatinib, nintedanib, ponatinib, linifanib, and afatinib; nonsteroidal anti-inflammatory drugs such as indomethacin, mefenamic acid, and flurbiprofen; and low-solubility derivatives of nucleoside reverse transcriptase inhibitors such as K8.

[0029] Bioerosion of the polymeric materials of the implant body 14, core 12, and coating polymer (e.g., layer 21) may occur due to the slow dissolution of the polymer in aqueous media. Water-soluble polymers compatible with human tissue are known, including, but not limited to, polyvinyl alcohol (PVA), hydroxypropyl cellulose, polyacrylic acid, hydroxypropyl methylcellulose, carboxymethyl cellulose, and hydroxyethyl cellulose. Such polymers are commercially available or can be prepared by methods known in the art. A preferred water-soluble, biocompatible polymer is PVA. Water-soluble PVA has been shown to be nontoxic when used in intraocular implants or intraocular injections (see, e.g., W. Morton Grant, Joel S. Schuman Toxicology of the Eye, 4th ed., Springfield, IL: Charles C. Thomas Pub., Ltd., 1993, Vol. 1, p. 1189).

[0030] The water solubility of a polymer depends on several parameters, including, but not limited to, the molecular weight of the polymer, the degree of crosslinking, the nature and number of pendant groups, and the degree of crystallinity.

[0031] One of the parameters that controls the solubility of PVA is the degree of hydrolysis. PVA is produced by hydrolysis of the pendant acetate groups of polyvinyl acetate precursors. As used herein, "degree of hydrolysis" refers to the mole percentage of pendant alcohol groups relative to the total number of pendant groups present in PVA.

[0032] Another parameter that controls PVA solubility is crystallinity. Highly crystalline PVA samples exhibit low water solubility. The crystallinity of PVA can be increased to a desired level by heating the polymer at a specific temperature for a certain period of time (see, for example, Peter R. Byron, Richard N. Dalby, (1987). Effects of Heat Treatment on the Permeability of Polyvinyl Alcohol Films to a Hydrophilic Solute. Journal of Pharmaceutical Sciences, 76(1), 65-67). Alternatively, the crystallinity of PVA can be increased by subjecting the material to multiple freeze-thaw cycles.

[0033] Suitable matrix and coating polymers should be non-toxic and able to withstand sterilization of the pellets (eg, gamma radiation, electron beam, heat / steam, and / or ethylene oxide gas sterilization) without significant degradation.

[0034] As used herein, "polydispersity index" is a ratio that describes the uniformity of the particle size distribution of a system. A small value, e.g., less than 0.3, indicates a narrow particle size distribution.

[0035] Compounds that can be used in the practice of the present invention should be in a moderately to lowly soluble form, such as a less polar free base or free acid form rather than a salt, and / or a crystalline form rather than a more soluble amorphous form, as necessary to provide the desired release rate. Standard pharmaceutical textbooks can be consulted for procedures for obtaining drugs in moderately to lowly soluble forms.

[0036] A method for treating a mammal to achieve a desired local or systemic physiological or pharmacological effect includes injecting the implant 10 of the present invention into the mammal. Furthermore, one or more of the implants 10 can be administered at once (e.g., in a single injection), or the core can contain multiple agents. Intravitreal injection is a minimally invasive procedure that has become an effective intervention in the management of many ocular diseases. This procedure may include injecting the implant 10 directly into the vitreous cavity of the patient's eye. This procedure avoids anatomical barriers within the eye.

[0037] Intravitreal injectors are disclosed, for example, in the following U.S. Patents: 7,678,078, 8,133,273, 8,287,494, 8,945,214, 9,421,129, 9,693,893, and 9,974,645, each of which is incorporated herein by reference in its entirety.

[0038] The implant 10 of the present invention is particularly suited for direct injection into the eye. In certain embodiments, the implant 10 may be injected near the patient's eye as either an intraocular or periocular injection. For example, the implant 10 may be injected into the vitreous humor or into the anterior chamber. In some embodiments, the implant 10 is administered by intraocular injection (e.g., topical intraocular therapy), intravitreal injection, subretinal injection, suprachoroidal injection, episcleral injection, subtenon injection, retrobulbar injection, or periocular injection.

[0039] The implant 10 of the present invention can be administered, for example, by subcutaneous injection, intratumoral injection, intracranial injection, or intraarticular injection. For example, the implant 10 can be injected under the skin of a patient's arm, leg, or torso. In certain preferred embodiments, the implant 10 containing islatravir can be injected subcutaneously.

[0040] These methods of administration and preparation techniques are well known to those skilled in the art and are described in Remington's Pharmaceutical Sciences.

[0041] The presently disclosed subject matter is illustrated throughout this description by specific, but non-limiting, examples. The examples may include compilations of data representative of data collected at various times during the course of development and experimentation related to the invention. Each example is provided by way of explanation of the disclosure, and is not intended to limit the disclosure. Indeed, it will be apparent to those skilled in the art that various modifications and variations can be made to the teachings of the present disclosure without departing from the scope of the disclosure. For example, features illustrated or described as part of one embodiment may be used on another embodiment to yield still a further embodiment.

[0042] All references to singular features or limitations in this disclosure are intended to include the corresponding plural features or limitations, and vice versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made.

[0043] All combinations of method or process steps used herein can be performed in any order unless otherwise specified by the context in which the referenced combination occurs or unless something to the contrary is clearly implied.

[0044] In one aspect, the present disclosure relates to an implant 10 shaped and sized for injection and consisting of a plurality of drug particles compressed into essentially a pellet, wherein the drug has a solubility in water of less than about 100 μg / mL at about 23° C. In a preferred embodiment, the implant 10 does not include a polymer matrix or polymer coating.

[0045] In some embodiments of the implant 10 disclosed herein, the device has a maximum dimension of about 1 mm to about 30 mm or about 1 mm to about 10 mm. The implant 10 can have an aspect ratio of about 1.5 to about 25.

[0046] In certain embodiments, the present disclosure relates to a method for treating a mammal to obtain a desired physiological or pharmacological effect, comprising administering a drug delivery device to a mammal in need of such treatment.

[0047] Specific embodiments of the present invention are described herein. Naturally, variations, modifications, alterations, and substitutions of equivalents to those embodiments will be apparent to those skilled in the art upon reading the foregoing description. Skilled artisans can employ such variations, modifications, alterations, and substitutions of equivalents as appropriate, and may thus practice the invention otherwise than as specifically described herein. Those skilled in the art will readily recognize a variety of non-critical parameters that can be changed, modified, or altered to yield essentially similar results. Accordingly, this invention includes 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 invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0048] definition Although the terms used herein are believed to be well understood by those of ordinary skill in the art, certain definitions are provided to facilitate description of the presently disclosed subject matter.

[0049] Unless otherwise defined, all 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.

[0050] As used herein, all abbreviations for protecting groups and compounds are consistent with their common usage, recognized abbreviations, or the IUPAC-IUB Biochemical Nomenclature Commission (see (1972) Biochemistry, 11(9), 1726-1732), unless otherwise specified.

[0051] Following long-standing patent law convention, the terms "a," "an," and "the" as used in this application (including the claims) refer to "one or more." Thus, for example, a reference to a "cell" includes a plurality of such cells, and the like. Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth, used in the specification and claims should be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.

[0052] As used herein, the term "about," when referring to a value or amount of mass, weight, time, volume, concentration, or percentage, is intended to encompass, in some embodiments, a variation of ±20%, in some embodiments, ±10%, in some embodiments, ±5%, in some embodiments, ±1%, in some embodiments, ±0.5%, and in some embodiments, ±0.1% from the specified amount, as appropriate for carrying out the disclosed methods. As used herein, ranges may be expressed as from one particular value that is "about" and / or to another particular value that is "about." It is also understood that there are several values ​​disclosed herein, and that each value is also disclosed herein as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It is also understood that each unit between two particular units is disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. "Treating" a condition or patient refers to taking measures to achieve beneficial or desired results, including clinical results. As used herein, and as well understood in the art, "treatment" is an approach for achieving beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, whether detectable or undetectable, reduction in the extent of disease, stabilization of the disease state (i.e., not worsening), prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or total). "Treatment" can also mean prolonging survival compared to expected survival if not receiving treatment.

[0053] With respect to administration of a formulation, the term "administration" refers to any method of providing a composition and / or pharmaceutical composition thereof to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, intravitreal administration, including via an intravitreal continuous implant, intracameral (inside the anterior chamber) administration, suprachoroidal injection, subretinal administration, subconjunctival injection, sub-Tenon administration, periocular administration, transcleral drug delivery, and the like. Administration can be continuous or intermittent. In various embodiments, the formulation can be administered therapeutically, i.e., administered to treat an existing disease or condition. In further various embodiments, the formulation can be administered prophylactically, i.e., administered for the prevention of a disease or condition.

[0054] The term "prevention," when used in reference to a condition such as local recurrence (e.g., pain), a disease such as cancer, a complex syndrome such as heart failure, or any other medical condition, is art-recognized and well understood in the art and includes administration of a composition that reduces the frequency of, or delays the onset of, symptoms of, a medical condition in a subject compared to subjects not administered the composition. Thus, cancer prevention, by way of example, includes reducing the number of detectable cancerous growths in a population of patients receiving prophylactic treatment compared to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population relative to an untreated control population, by a statistically and / or clinically significant amount.

[0055] As used herein, the terms "effective amount," "effective dosage," "sufficient amount," "effective amount," "therapeutically effective amount," or grammatical equivalents thereof, mean a dosage sufficient to produce a desired result, alleviate or in some way relieve the symptoms, or halt or reverse the progression of the condition, and provide a subjective relief or objectively identifiable improvement in symptoms noted by a clinician or other qualified observer. Improvement in the symptoms of a particular condition by administration of a pharmaceutical composition described herein refers to any relief that may be associated with administration of the pharmaceutical composition, whether permanent, temporary, sustained, or transient.

[0056] The term "subject" can refer to a human or non-human subject (e.g., primates, horses, pigs, rabbits, dogs, sheep, goats, cows, cats, guinea pigs, rodents, and non-mammals). The term "subject" does not denote a particular age or sex. Thus, it is intended to encompass adult and newborn subjects, as well as fetuses, regardless of gender. The term "subject" includes human and veterinary subjects.

[0057] The term "sustained release" refers to a drug-containing formulation or dosage form, such as an implant, that slowly releases a pharmaceutical agent over an extended period of time.

[0058] As used herein, "substantially impermeable" refers to inhibiting diffusion by at least one, two, or preferably at least three orders of magnitude.

[0059] As used herein, "bioeroded" or "bioerosion" refers to the gradual breakdown or breakdown of a solid structure or material into its molecular components over a period of time in a biological system by one or more physical or chemical processes, such as, for example, dissolution by solubilization, emulsion formation, or micelle formation.

[0060] Incorporation by Reference All publications and patents mentioned herein are incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0061] The presently disclosed subject matter is further illustrated by the following specific, but non-limiting, examples, which may include compilations of data representative of data collected at various times during the course of development and experimentation related to the present invention. [Example]

[0062] Example 1 Polyimide (MicroLumen) tubing was obtained, cut to a 10 cm length, and attached to the end of a syringe. Separately, a large amount of the drug K8 (the synthesis of K8 is described in US20180044327, published February 15, 2018, and incorporated herein by reference in its entirety) was melted on a heating pad and injected into the polyimide tubing. After cooling, the tubing was cut to length (e.g., 2.5 mm, 5 mm, etc.). A similar approach can be used to create K8 implants using PLGA tubing (Biogeneral).

[0063] The implants exhibit a steady release of the substance as shown in FIGS. 1B and 2 and as illustrated in FIG. [Table 1]

[0064] Example 2 Polyimide (MicroLumen) tubing was obtained, cut to a 10 cm length, and attached to the end of a syringe. Separately, a large amount of the drug K8 (the synthesis of K8 is described in US20180044327, published February 15, 2018, and incorporated herein by reference in its entirety) was melted on a heating pad and injected into the polyimide tubing. After cooling, the tubing was cut to length (e.g., 2.5 mm, 5 mm, etc.). A similar approach can be used to create K8 implants using PLGA tubing (Biogeneral).

[0065] Figures 5A-B show 100% release of K8 from two similar implants. As can be seen, after an initial burst, release continues at a relatively constant rate until the drug is fully released. The two implants consist of a K8 core (i.e., no other material) within a polyimide tubing (non-erodible) or a PLGA tubing (bioerodible).

[0066] The duration of the steady-state phase of drug release is governed by the length of the tube, but is not directly proportional to the length (because the initial burst is the same regardless of the length of the tube). Figures 6A-B show that a 2.5 mm long tube containing 320 μg of drug provides sustained release for approximately 60 days, and a 5 mm long tube containing 610 μg of drug provides sustained release for approximately 220 days.

[0067] In the above experiments, the in vitro release was measured by immersing the implants in PBS solution (pH 7.4) at 37°C. Samples were taken periodically and analyzed by HPLC, and the entire medium was periodically replaced to maintain a sink condition. The graph shows the cumulative release versus time.

[0068] Release rates were determined in vivo by injecting the implants into the vitreous of rabbits. Animals were sacrificed on days 28, 56, and 120, and the eyes were enucleated for analysis. Vitreous and drug concentrations were measured, and the amount of residual drug in the implant was determined (Table 2). The amount of drug released into the eye was calculated (initial amount of drug in the implant minus the amount of residual drug). Figure 7 plots the cumulative in vitro release versus the actual in vivo release, demonstrating excellent correlation between in vitro and in vivo. [Table 2]

[0069] After the drug is released, the implant body can be completely eroded. Polymers such as PLGA are available with a variety of erosion rates. Polymers that undergo "bulk" erosion, such as PLGA, are ideal for these systems.

[0070] Example 3 EFdA (Islatravir) was mixed with an equal weight of a 5% aqueous solution of polyvinyl alcohol (EMD Chemicals), wet-granulated, and dried. The particles were then compressed in a 2 mm tablet die to form 24 mg pellets (containing 4% PVA). The pellets were immersed in a 5% PVA solution and inserted into 2 mm diameter polyimide tubing. The dried implants were then heated at 105 °C for 2 hours. These implants were fully released over approximately 100 days, following the same pattern as the much smaller K8 implants, with an initial burst followed by a more constant release until complete depletion (Figure 8). As the implants depleted, the release rate decreased very rapidly, similar to the K8 implants (Figure 4).

[0071] Similar EFdA implants (2 mm diameter, 5% PVA, heated at 105°C) were tested for release in buffer without first encasing them in polyimide tubing. The implants released EFdA completely and degraded within 7 days.

[0072] At the low concentrations used, PVA does not significantly slow the release of EFdA or provide physical stability; however, when the EFdA / PVA implant is placed in a tube, the matrix keeps the EFdA within the tube, thereby ensuring that the surface area available for dissolution is maintained.

[0073] Example 4 - EFdA Implants - In Vitro Release Implants were typically placed in 1–10 ml of phosphate-buffered saline (pH 7.4) in microcentrifuge tubes or capped test tubes. These were placed in a 37°C water bath. Daily samples were removed and replaced with fresh buffer for analysis by HPLC. The entire buffer was periodically replaced to maintain sink conditions. A graph of cumulative release versus time was plotted to determine the release rate (Figure 9). To determine the tail-off period, the release rate was measured until the release rate fell below the detection level. The daily release rate was then plotted against the previous day to determine the daily release rate before exhaustion (Figure 10). The x-axis represents the number of days before termination, i.e., -1, -2, etc. This was necessary because a simple average would result in an erroneous assessment if implants exhausted on different days. As a somewhat tragic example, if 10 people died (over a hypothetical 10-day period) and their temperatures were measured, the average temperature of the group would suggest a steady decline in body temperature over the last 10 days of their lives. Measuring each individual's temperature for the 10 days before death would likely yield different results. The developed EFdA implant is a compressed pellet inserted into an impermeable tube, open at both ends. Implants in PLGA tubing (biodegradable) showed similar in vitro release characteristics to implants in polyimide tubing (nondegradable). Emission surface area is 3.14mm 2 The daily release rate at steady state is approximately 75 μg / day (FIG. 9). After a short burst effect, in vitro release is relatively constant (Figure 9), and with this type of device, release remains nearly constant until the device is completely depleted, at which point release decreases very rapidly (Figure 10). The implants exhibited short tails and were completely depleted within a few days in vitro (Figure 10). With a 1.5mm diameter implant that is releasable at both ends, a 5mm length can last for 3 months, and a 13mm length can last for 12 months.

[0074] Example 5 - EFdA Implants in Rats Test Plan: In this study, two different sizes of EFdA implants (in PLGA tubes) will be tested: Implant #1: * Short-term implant with a target release period of 3 months. - This test group shows a tail effect in as short a period as three months. Implant #2: Potential clinical dose implant with targeted release over 12 months. This study demonstrates PK and tail effects over the long term of 12 months. Blood samples will be collected on a scheduled basis and analyzed for EFdA plasma concentrations to assess: Burst Effect Steady-state kinetics of release by measuring plasma levels (and residual drug content of explanted devices) Tail effect 12-month PLGA tube integrity [Table 3] [Table 4]

[0075] Batch sample results (Figure 11): 1. There was an initial burst on the first day and continued to decrease over the first week. Plasma concentrations stabilized from days 7 to 30, with EFdA concentrations ranging from 4 to 6 ng / ml. 2. Although the long-term implant contained more than twice as much drug and had a much larger total surface area (including the sides of the tube), the short and long implants had similar plasma concentrations. This was because the ends of the tubes in both implants were the same diameter, allowing for easy diffusion and the same release rate. 3. Administration proceeded smoothly and observations showed that the animals tolerated the drug well. 4. A bioanalytical method for EFdA in rat plasma was established.

[0076] The study demonstrates the benefits of the new implant: 1) The release rate is relatively constant after a short burst effect. 2) The release rate can be controlled (in this case by controlling the diameter of the tube) 3) Emissions remain relatively constant until the device is fully depleted (no tail-off effect) 4) By inference, duration is easily controlled (by changing the length) 5) By inference, these implants are very easy to manufacture because they do not require the application of a rate-limiting membrane to the end of the tube (and the membrane would require a difficult manufacturing process, as one would need to ensure that the membrane is of a reproducible thickness and that the manufacturing process needs to be validated).

Claims

1. 1. A drug delivery implant shaped and sized for injection, said implant comprising: a core containing a pharmaceutical product; a cylindrical implant body configured to extend longitudinally around and contact a longitudinal surface of the core, the implant body defining an opening disposed on the longitudinal surface of the implant body exposing a first surface of the core; When the implant is placed in an aqueous environment, the pharmaceutical agent diffuses from the first surface of the core through the openings in the implant body. The implant.

2. The implant of claim 1 , wherein two or more openings on the longitudinal surface expose a surface of the core.

3. 1. A drug delivery implant shaped and sized for injection, said implant comprising: a core containing a pharmaceutical product; a cylindrical implant body configured to extend longitudinally around and contact a longitudinal surface of the core, the implant body defining an opening at a first end thereof exposing the first surface of the core; When the implant is placed in an aqueous environment, the pharmaceutical agent diffuses from the first surface of the core through the opening at the first end of the implant body. The implant.

4. The implant of any one of claims 1 to 3, wherein the pharmaceutical agent has a solubility of less than about 2 mg / ml.

5. The implant of any one of claims 1 to 3, wherein the pharmaceutical agent has a solubility of less than about 1 mg / ml.

6. The implant of any one of claims 3 to 5, wherein the first surface of the core has an initial surface area adjacent the opening.

7. 7. The implant of any one of claims 1 to 6, wherein the exposed surface area of ​​the core remains substantially constant as the core dissolves and the pharmaceutical agent diffuses through the openings.

8. 8. The implant of claim 7, wherein the exposed surface area remains relatively constant as the core releases about 10% to about 90% of the pharmaceutical agent.

9. The implant of any one of claims 1 to 8, wherein the core comprises drug particles, and the pharmaceutical agent is present within the drug particles.

10. 10. The implant of claim 9, wherein the core comprises a pellet containing the drug particles and, optionally, a polymeric material.

11. The implant of any one of claims 1 to 10, wherein the core comprises a matrix comprising the pharmaceutical agent and a polymeric material.

12. 12. The implant of claim 11, wherein the polymeric material is present at less than about 10% w / w of the core.

13. 12. The implant of claim 11, wherein the polymeric material is present at less than about 5% w / w of the core.

14. 12. The implant of claim 11, wherein the polymeric material is present at less than about 2% w / w of the core.

15. The implant of any one of claims 11 to 14, wherein the polymeric material does not substantially affect the release rate of the pharmaceutical agent.

16. The implant of any one of claims 11 to 15, wherein the polymeric material is PVA.

17. The implant of any one of claims 1 to 16, wherein the pharmaceutical agent is islatravir or K8.

18. An implant according to any one of claims 1 to 17, wherein the core comprises a layer of PVA forming the longitudinal surface of the core.

19. The implant of any one of claims 1 to 18, wherein the implant body is substantially impermeable to water.

20. The implant of any one of claims 1 to 19, wherein the implant body comprises polyimide.

21. The implant according to any one of claims 1 to 18, wherein the implant body is biodegradable.

22. 22. The implant of claim 21, wherein the implant body comprises PLGA, PCL, or PLA, preferably PLGA.

23. 23. The implant of any one of claims 1 to 22, wherein the implant body defines a second opening at a second end of the implant body, the second opening exposing a second surface of the core.

24. The implant of any one of claims 1 to 23, wherein the implant body has a length of about 1 mm to about 30 mm.

25. The implant of any one of claims 1 to 3, wherein the implant body has a length of about 2 mm to about 7 mm.

26. The implant of any one of claims 1 to 23, wherein the implant body has a length of about 2 mm to about 5 mm.

27. The implant of any one of claims 1 to 26, wherein the implant body has a diameter of about 0.1 mm to about 0.5 mm.

28. The implant of any one of claims 1 to 26, wherein the implant body has a diameter of about 0.1 mm to about 2 mm.

29. 29. The implant of any one of claims 1 to 28, wherein when the implant is placed in an aqueous environment, the implant releases an initial burst of the pharmaceutical agent followed by a substantially zero order kinetic release of the pharmaceutical agent, the initial burst releasing the pharmaceutical agent at a rate that is faster than the rate of the substantially zero order kinetic release of the pharmaceutical agent.

30. 30. The implant of claim 29, wherein the substantially zero order kinetic release occurs over a period of at least about 30 days.

31. 30. The implant of claim 29, wherein the substantially zero order kinetic release occurs over a period of at least about 60 days.

32. 30. The implant of claim 29, wherein the substantially zero order kinetic release occurs over a period of at least about 90 days.

33. 30. The implant of claim 29, wherein the substantially zero-order kinetic release occurs over a period of at least about 120 days.

34. 30. The implant of claim 29, wherein the substantially zero order kinetic release occurs over a period of at least about 180 days.

35. 30. The implant of claim 29, wherein the substantially zero order kinetic release occurs over a period of at least about 210 days.

36. 30. The implant of claim 29, wherein the substantially zero order kinetic release occurs over a period of at least about 360 days.

37. 30. The implant of claim 29, wherein the substantially zero order kinetic release occurs over a period of at least about 720 days.

38. 1. A drug implant comprising a core, said core comprising a pharmaceutical agent having a solubility of less than about 2 mg / ml.

39. 39. The drug implant of claim 38, wherein the core comprises a polymer present at less than about 5 wt% of the core.

40. 39. The implant of claim 38, wherein the pharmaceutical agent has a solubility of less than about 1 mg / ml.

41. 40. The implant of claim 38 or 39, wherein the pharmaceutical agent has a solubility of about 0.2 to 0.7 mg / ml.

42. 40. The implant of claim 38 or 39, wherein the pharmaceutical agent is K8 or islatravir.

43. A method for treating a subject in need thereof, comprising implanting an implant according to any one of claims 1 to 42.

44. 44. The method of claim 43, wherein implanting comprises administering the implant using an intraocular syringe.

45. 44. The method of claim 43, wherein implanting comprises administering the implant by intraocular injection, e.g., intravitreal injection, subretinal injection, episcleral injection, subtenon injection, retrobulbar injection, or periocular injection.

46. 44. The method of claim 43, wherein implanting comprises administering the implant by subcutaneous injection, intratumoral injection, intracranial injection, or intraarticular injection.

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