CN117479950A

CN117479950A - Kappa-opioid receptor agonist implant for treating pruritis

Info

Publication number: CN117479950A
Application number: CN202280042007.2A
Authority: CN
Inventors: K·毕比德瓦尼; M·鲁宾; R·A·帕特尔; S·斯里达兰
Original assignee: Titan Pharmaceuticals Inc
Current assignee: Titan Pharmaceuticals Inc
Priority date: 2021-04-14
Filing date: 2022-04-14
Publication date: 2024-01-30

Abstract

The present disclosure provides compositions, methods, and kits for treating pruritus (itchiness) in an individual. The compositions, methods, and kits are useful for administering an implant comprising a kappa-opioid receptor agonist to an individual, wherein the implant comprises a sustained release composition comprising a kappa-opioid receptor agonist and a biocompatible polymer matrix. Implantation of the device allows for controlled release of the kappa-opioid receptor agonist for an extended period of time. The implant may be subcutaneously implanted in an individual in need of continued treatment with a kappa-opioid agonist to treat and alleviate itch.

Description

Kappa-opioid receptor agonist implant for treating pruritis

Cross Reference to Related Applications

The present application claims priority from U.S. provisional patent application Ser. No. 63/174,958 filed on day 4, 2021 and U.S. provisional patent application Ser. No. 63/213,485 filed on day 22, 2021. The entire contents of said application are incorporated herein by reference.

Technical Field

The present disclosure provides implants (implants) for long-term treatment of pruritis comprising a biocompatible polymer matrix, a kappa-opioid receptor agonist (which may be a peptide), and optionally other therapeutic agents. The biocompatible polymer matrix may be a homogeneous matrix or may include a core (core) polymer material and one or more additional layers.

Background

Itchy (pruritis) or itchy skin (itchy skin) is a common skin disorder that can be caused by a number of local or systemic conditions. Light itching may be treated with over-the-counter medications, such as moisturizing creams or lotions, corticosteroid creams and similar topical treatments, or with topical or oral antihistamines.

Severe or chronic itching or itching not controlled by over-the-counter drugs, require more intensive treatment. Antidepressants such as fluoxetine and phototherapy have been used to treat severe or chronic pruritus. However, such treatments often fail to provide relief. In particular, nearly half of patients undergoing hemodialysis report uremic itching (chronic kidney disease-associated pruritus or CKD-aP), which is often refractory and can last for months or years.

Thus, new therapies are needed to treat itch, such as uremic pruritis (uremic pruritis).

Short peptides have been reported by F.M. Hughes, jr. Et al as potent agonists of kappa-opioid receptors (OpenMed Chem J.2013; 7:16-22) and proposed for use in pain control. International patent application WO 2017/210668 relates to sustained release compositions of kappa-opioid receptor agonists, including the compounds described by Hughes et al.

The present disclosure provides long-term treatment of pruritis with kappa-opioid receptor agonists including kappa-opioid receptor agonist peptides and derivatives of kappa-opioid receptor agonist peptides administered in implants.

Brief description of the invention

The present disclosure provides implants (i.e., implantable drug delivery devices) comprising kappa-opioid receptor agonists (e.g., kappa-opioid receptor agonist peptides). The present disclosure also provides methods of treating itch using the implants.

In some embodiments, the concentration of kappa-opioid receptor agonist in each layer of the implant is designed such that an approximately constant or substantially constant amount of kappa-opioid receptor agonist is released from the implant over a period of time. The period of time may be at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, at least about 21 months, or at least about 24 months.

In some embodiments, the present disclosure provides methods of treating pruritus in an individual comprising administering to the individual an implant comprising a sustained release composition, wherein the sustained release composition comprises a kappa-opioid receptor agonist and a biocompatible polymer matrix, wherein the sustained release composition is configured to release a therapeutically effective amount of the kappa-opioid receptor agonist upon administration. Kappa-opioid receptor agonists may include peptides. Kappa-opioid receptor agonists may include compounds of formula I:

Or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is

Wherein n is an integer from 1 to 4; x is-NR ₂ R ₃ Or (b)R ₁ 、R ₂ 、R ₃ And R is ₄ Each independently is hydrogen, C ₁ -C ₅ Alkyl, C ₁ -C ₅ Substituted alkyl, C ₂ -C ₅ Alkenyl, C ₂ -C ₅ Substituted alkenyl, C ₂ -C ₅ Alkynyl, C ₂ -C ₅ Substituted alkynyl, C ₃ -C ₆ Cycloalkyl, C ₆ -C ₁₀ Aryl, C ₆ -C ₁₀ Substituted aryl or-C ₁ -C ₅ alkyl-C ₆ -C ₁₀ An aryl group; r is R ₇ Is hydrogen, C ₁ -C ₅ Alkyl, C ₁ -C ₅ Substituted alkyl, C ₂ -C ₅ Alkenyl, C ₂ -C ₅ Substituted alkenyl, C ₂ -C ₅ Alkynyl, C ₂ -C ₅ Substituted alkynyl, C ₃ -C ₆ Cycloalkyl, C ₆ -C ₁₀ Aryl, C ₆ -C ₁₀ Substituted aryl, -C ₁ -C ₅ alkyl-C ₆ -C ₁₀ Aryl or-NR ₈ R ₉ ；R ₅ 、R ₆ 、R ₈ And R is ₉ Each independently is hydrogen, C ₁ -C ₅ Alkyl, C ₁ -C ₅ Substituted alkyl, C ₁ -C ₅ Alkenyl, C ₁ -C ₅ Substituted alkenyl, C ₁ -C ₅ Alkynyl, C ₁ -C ₅ Substituted alkynyl, C ₃ -C ₆ Cycloalkyl, C ₆ -C ₁₀ Aryl, C ₆ -C ₁₀ Substituted aryl or-C ₁ -C ₅ alkyl-C ₆ -C ₁₀ An aryl group; or alternatively, R ₅ And R is ₉ Together with the nitrogen atom to which they are attached, form a heterocyclic ring; or alternatively, R ₆ And R is ₉ With nitrogen to which they are attachedTogether, the atoms form a heterocyclic ring.

In some embodiments of formula I, R is:

in some embodiments of formula I, R is:

In some embodiments of formula I, R is:

and the compound of formula (I) is compound a:

in any of the foregoing embodiments, the biocompatible polymer matrix may comprise Ethylene Vinyl Acetate (EVA) copolymer, crosslinked poly (vinyl alcohol), poly (hydroxyethyl methacrylate), acyl substituted cellulose acetate, hydrolyzed olefin vinyl acetate copolymer (hydrolyzed alkylene-vinyl acetate copolymer), polyvinyl chloride, polyvinyl acetate, polyvinyl alkyl ether, polyvinyl fluoride, polycarbonate, polyurethane, polyamide, polysulfone, styrene-acrylonitrile copolymer, crosslinked poly (ethylene oxide), poly (alkylene), poly (vinylimidazole), poly (ester), poly (ethylene terephthalate), polyphosphazene, chlorosulfonated polyolefin, polylactide (PLA), polyglycolide (PGA), polylactic glycolic acid copolymer (PLGA), or a combination thereof.

In any of the foregoing embodiments, the biocompatible polymer matrix may comprise an Ethylene Vinyl Acetate (EVA) copolymer. In some embodiments, the EVA copolymer may comprise from about 20% to about 40% vinyl acetate by total weight of the copolymer. In some embodiments, the EVA copolymer may comprise about 33% vinyl acetate by total weight of the copolymer.

In any of the foregoing embodiments, the kappa-opioid receptor agonist comprises from about 10% to about 85% by weight of the total sustained release composition, for example from about 30% to about 70% by weight of the total sustained release composition.

In any of the foregoing embodiments, the implant may be a rod-like device having a diameter of about 0.5mm to about 10mm and a length of about 0.5cm to about 10 cm.

In any of the foregoing embodiments, the implant may be a rod-like device having a diameter of about 2mm to about 3mm and a length of about 2cm to about 4 cm.

In any of the foregoing embodiments, the implant may release from about 0.1mg to about 10mg of kappa-opioid receptor agonist per day.

In any of the foregoing embodiments, the implant may be subcutaneously implanted.

In any of the foregoing embodiments, the implant may comprise a core comprising the sustained release composition, and a first layer comprising a first layer biocompatible polymer matrix surrounding the core.

In any of the foregoing embodiments having a first layer, the first layer biocompatible polymer matrix may comprise ethylene-vinyl acetate (EVA) copolymer, crosslinked poly (vinyl alcohol), poly (hydroxyethyl methacrylate), acyl substituted cellulose acetate, hydrolyzed olefin-vinyl acetate copolymer, polyvinyl chloride, polyvinyl acetate, polyvinyl alkyl ether, polyvinyl fluoride, polycarbonate, polyurethane, polyamide, polysulfone, styrene-acrylonitrile copolymer, crosslinked poly (ethylene oxide), poly (alkylene), poly (vinylimidazole), poly (ester), poly (ethylene terephthalate), polyphosphazene, chlorosulfonated polyolefin, polylactide (PLA), polyglycolide (PGA), polylactic glycolic acid copolymer (PLGA), or a combination thereof.

In any of the foregoing embodiments having a first layer, the first layer biocompatible polymer matrix may comprise an Ethylene Vinyl Acetate (EVA) copolymer. The EVA copolymer of the first layer biocompatible polymer matrix can comprise from about 20% to about 40% vinyl acetate by total weight of the copolymer. The EVA copolymer of the first layer biocompatible polymer matrix can comprise about 33% vinyl acetate by total weight of the copolymer.

In any of the foregoing embodiments, the implant may further comprise one or more additional layers comprising a biocompatible polymer matrix.

In any of the foregoing embodiments comprising a core, a first layer, and optionally one or more additional layers, any of the core, first layer, and one or more additional layers, if present, further comprise one or more other drug substances.

In any of the foregoing embodiments, the implant may remain in the individual for at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, at least about 21 months, or at least about 24 months.

In any of the foregoing embodiments, the concentration of drug substance in the plasma may be approximately constant or substantially constant for at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, at least about 21 months, or at least about 24 months.

In any of the foregoing embodiments, the kappa-opioid receptor agonist may be a compound of formula (I).

In any of the foregoing embodiments, the kappa-opioid receptor agonist may be compound a.

Brief Description of Drawings

Fig. 1 shows plasma concentrations of kappa-opioid receptor agonists for rats with implants having a core consisting of 50% kappa-receptor agonist and 50% ethylene-vinyl acetate (EVA) and a shell surrounding the core consisting of 3% kappa-sheet receptor agonist and 97% EVA.

Figure 2 shows the scratching event of mice after 5 '-guanidyl sodium Qu Yinduo (guanidino naltrindole) (5' -GNTI) administration. The dashed line represents the scratching event for mice using placebo implants or sham surgery (n=7), while the solid line represents the scratching event for mice using implants containing compound a (n=5).

Fig. 3 shows the change in plasma levels of mice over time (solid line) caused by an implant comprising compound a, relative to the change in plasma levels of mice over time (dashed line) caused by subcutaneous injection of compound a.

Figure 4 shows simulated human plasma levels of implants containing compound a relative to CR-845 intravenous bolus.

Figure 5 shows reduced scratching events in mice administered with implants containing compound a relative to control mice.

Detailed Description

The present disclosure provides compositions (i.e., implants), methods, and kits for providing kappa-opioid agonists to an individual.

"drug" and "pharmaceutical substance" are equivalent terms and are used interchangeably.

In one aspect, the implant comprises a sustained release composition comprising a biocompatible polymer matrix and a kappa-opioid receptor agonist, e.g., up to about 5%, up to about 10%, up to about 20%, up to about 25%, up to about 30%, up to about 40%, up to about 50%, up to about 60%, up to about 70%, up to about 80%, or up to about 85% of the kappa-opioid receptor agonist, with the remainder of the sustained release composition comprising the biocompatible polymer matrix.

In some embodiments, the implant comprises a core comprising a biocompatible polymer matrix and a kappa-opioid receptor agonist, and one or more additional layers surrounding the core. In some embodiments, the core is rod-shaped or cylindrical. In some embodiments, the core is rod-shaped or cylindrical and is rounded at either end, that is, the top is covered by a hemisphere, oblate ellipsoid or ellipsoid of substantially the same diameter as the rod-shaped or cylindrical portion of the core. The portion of the implant covering the end of the rod may be substantially 100% polymer, or may comprise the same percentage of polymer and kappa-opioid receptor agonist as in the core of the implant, or may comprise about or at least about 50% polymer and about or at most about 50% kappa-opioid receptor agonist, about or at least about 60% polymer and about or at most about 40% kappa-opioid receptor agonist, about or at least about 70% polymer and about or at most about 30% kappa-opioid receptor agonist, about or at least about 75% polymer and about or at most about 25% kappa-opioid receptor agonist, about or at least about 80% polymer and about or at most about 20% kappa-opioid receptor agonist, about or at least about 85% polymer and about or at most about 15% kappa-opioid receptor agonist, about or at least about 90% polymer and about or at most about 10% kappa-opioid receptor agonist, about or at least about 95% polymer and about or at most about 5% kappa-opioid receptor agonist and about or at most about 98% kappa-opioid receptor agonist, about or at most about or at least about 98% polymer and about or at most about 6% kappa-opioid receptor agonist. In some embodiments, the core extends a majority of the length of the implant. In some embodiments, the core comprises a lower concentration of kappa-opioid receptor agonist than the layer or layers surrounding it. In some embodiments, the core comprises a higher concentration of kappa-opioid receptor agonist than the layer or layers surrounding it. In some embodiments, the core comprises a kappa-opioid receptor agonist and is surrounded by a layer that does not comprise a kappa-opioid receptor agonist.

In some aspects, wherein the implant comprises EVA, the vinyl acetate content is about 33% by weight. The implant typically comprises about 10% to about 85% kappa-opioid receptor agonist, e.g., about 10% to 25% kappa-opioid receptor agonist, about 20% to about 40% kappa-opioid receptor agonist, about 25% to about 75% kappa-opioid receptor agonist, about 30% to about 70% kappa-opioid receptor agonist, or about 40% to about 60% kappa-opioid receptor agonist. In one embodiment, the implant comprises about 50% kappa-opioid receptor agonist.

Another aspect of the present disclosure is a method of delivering a kappa-opioid receptor agonist to an individual in need thereof, the method comprising the step of subcutaneously inserting an implant into the individual, wherein the kappa-opioid receptor agonist is released from the implant into the individual. In some embodiments, an individual in need thereof suffers from itch. In some embodiments, an individual in need thereof suffers from uremic pruritus.

In some embodiments, the individual is a human. In some embodiments, the subject is a mammal, e.g., a primate including a chimpanzee, gorilla, and monkey; domestic animals or pets, including dogs, cats and guinea pigs; experimental animals, such as rats or mice; or animals for agriculture, such as cattle, sheep or pigs.

In one aspect, the implant remains implanted in the subject for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, at least about 21 months, or at least about 24 months.

In another aspect, the concentration of kappa-opioid receptor agonist in each layer of the implant is designed such that a steady state level or an approximately constant level or a substantially constant level of kappa-opioid receptor agonist is released into the individual. In another aspect, the implant provides a steady state level or an approximately constant level or a substantially constant level of kappa opioid receptor agonist in the plasma of the subject.

In any of the embodiments disclosed herein, the core can comprise a polymer such as ethylene vinyl acetate mixed with a radiopaque compound. In some embodiments, the radiopaque compound is barium sulfate. In some embodiments, the radiopaque compound is bismuth subcarbonate, bismuth trioxide, or tungsten. The inclusion of radiopaque compounds allows for positioning and visualization of the implant in the body by X-ray or ultrasound imaging.

In one embodiment, the present disclosure provides a rod-shaped core comprising a polymer that is substantially free of drug substances. The core is surrounded by a monolayer comprising a polymer and a kappa-opioid receptor agonist. In one embodiment of this type, the length of the rod is about 2cm to about 3cm, for example about 2.6cm, and the diameter is about 2mm to about 3mm; the monolayer has a thickness of about 0.5mm to about 1mm and the core has a diameter of about 0.5mm to about 2mm. In one embodiment, both the core and the monolayer comprise the same polymer, such as Ethylene Vinyl Acetate (EVA). In some embodiments, the core comprises a polymer, such as Ethylene Vinyl Acetate (EVA); the layers comprise different polymers, for example bioerodible (bio-erodible) polymers such as PLGA. The monolayer comprises from about 10% to about 85% kappa-opioid receptor agonist.

In one embodiment, the present disclosure provides a rod-shaped core comprising a polymer that is substantially free of drug substances. The core is surrounded by two layers comprising a polymer and a drug substance, wherein at least one of the layers comprises a kappa-opioid receptor agonist. In one embodiment of this type, the length of the rod is about 2cm to about 3cm, for example about 2.6cm, and the diameter is about 2mm to about 5mm; each layer has a thickness of about 0.5mm to about 1mm and the core has a diameter of about 0.5mm to about 2mm. In one embodiment, the core and both layers comprise the same polymer, such as Ethylene Vinyl Acetate (EVA). In some embodiments, the core comprises a polymer, such as Ethylene Vinyl Acetate (EVA); the layers comprise different polymers, for example bioerodible polymers such as PLGA. Both layers contain a drug substance, which may be the same substance in each layer or may be different substances in each layer, e.g. the substances are independently selected from other kappa-opioid receptor agonists, mu-opioid receptor antagonists, mixed mu-opioid receptor agonists/antagonists such as buprenorphine, delta-opioid receptor agonists, delta-opioid receptor antagonists, anti-inflammatory agents and steroids. At least one of the layers independently comprises from about 10% to about 85% of a kappa-opioid receptor agonist. In one embodiment, both layers contain kappa-opioid receptor agonist and the outermost layer comprises a lower concentration of kappa-opioid receptor agonist than the innermost layer; for example, the outermost layer comprises from about 10% to about 90% kappa-opioid receptor agonist, and the innermost layer comprises from about 10% to about 90% kappa-opioid receptor agonist, wherein the outermost layer comprises a lower concentration of kappa-opioid receptor agonist than the innermost layer.

In one embodiment, the present disclosure provides a rod-shaped core comprising a polymer that is substantially free of drug substances. The core is surrounded by three layers comprising a polymer and a drug substance, wherein at least one of the layers comprises a kappa-opioid receptor agonist. In one embodiment of the type shown, the rod has a length of about 2cm to about 3cm, for example about 2.6cm, and a diameter of about 3mm to about 7mm; each layer has a thickness of about 0.5mm to about 1mm and the core has a diameter of about 0.5mm to about 2mm. In one embodiment, the core and all layers comprise the same polymer, such as Ethylene Vinyl Acetate (EVA). In some embodiments, the core comprises a polymer, such as Ethylene Vinyl Acetate (EVA); the layers comprise different polymers, for example bioerodible polymers such as PLGA. All layers contain a drug substance, the drug substance in each layer may be the same substance, the drug substance in each layer may be a different substance, or the drug substances in two layers are the same and the third layer is different, provided that at least one layer contains a kappa-opioid receptor agonist. Other pharmaceutical substances that may be used in the layer include, for example, compounds independently selected from other kappa-opioid receptor agonists, mu-opioid receptor antagonists, mixed mu-opioid receptor agonists/antagonists such as buprenorphine, delta-opioid receptor agonists, delta-opioid receptor antagonists, anti-inflammatory agents, and steroids. The layers may independently comprise about 10% to about 90% of the drug substance. In one embodiment, each layer contains the same drug substance, but the drug substance concentration is different for each layer, such that the average concentration of drug substance in each layer decreases with increasing distance from the core. Thus, the outermost layer comprises about 10% to about 90% of the drug substance, while the middle layer comprises about 10% to about 90% of the drug substance, and the innermost layer comprises about 10% to about 90% of the drug substance, provided that the outer layer has a lower concentration of drug substance than the middle layer, while the inner layer (adjacent the core) has a higher concentration of drug substance than the middle layer. In one such embodiment, the drug substance in all three layers is a kappa-opioid receptor agonist.

In one embodiment, the present disclosure provides a rod-shaped core comprising a polymer that is substantially free of drug substances. The core is surrounded by four layers comprising a polymer and a drug substance, wherein at least one of the layers comprises a kappa-opioid receptor agonist. In one embodiment of the type, the length of the rod is about 2cm to about 3cm, for example about 2.6cm, and the diameter is about 4mm to about 9mm; each layer has a thickness of about 0.5mm to about 1mm and the core has a thickness of about 0.5mm to about 1mm. In one embodiment, the core and all layers comprise the same polymer, such as Ethylene Vinyl Acetate (EVA). In some embodiments, the core comprises a polymer, such as Ethylene Vinyl Acetate (EVA); the layers comprise different polymers, for example bioerodible polymers such as PLGA. All of the layers comprise a drug substance, provided that at least one of the layers comprises a kappa-opioid receptor agonist. Other pharmaceutical substances that may be used in the layer include, for example, substances selected from the group consisting of other kappa-opioid receptor agonists, mu-opioid receptor antagonists, mixed mu-opioid receptor agonists/antagonists such as buprenorphine, delta-opioid receptor agonists, delta-opioid receptor antagonists, anti-inflammatory agents, and steroids. The layers may independently comprise about 10% to about 90% of the drug substance. In one embodiment, each layer contains the same drug substance, but the drug substance concentration is different for each layer, such that the average concentration of drug substance in each layer decreases with increasing distance from the core. Thus, the outermost layer comprises from about 10% to about 90% drug substance, the second outermost layer comprises from about 10% to about 90% drug substance, the third outermost layer comprises from about 10% to about 90% drug substance, and the innermost layer (adjacent the core) comprises from about 10% to about 90% drug substance, provided that the outermost layer has a lower concentration of drug substance than the second outermost layer, the second outermost layer has a lower concentration of drug substance than the third outermost layer, and the third outermost layer has a lower concentration of drug substance than the innermost layer (adjacent the core). In one such embodiment, the drug substance in all four layers is a kappa-opioid receptor agonist.

In one embodiment, the present disclosure provides a rod-shaped core comprising a polymer that is substantially free of drug substances. The core is surrounded by five layers comprising a polymer and a drug substance, wherein at least one of the layers comprises a kappa-opioid receptor agonist. In one embodiment of the type, the length of the rod is about 2cm to about 3cm, for example about 2.6cm, and the diameter is about 5mm to about 10mm; each layer has a thickness of about 0.5mm to about 1mm and the core has a thickness of about 0.5mm to about 1mm. In one embodiment, the core and all layers comprise the same polymer, such as Ethylene Vinyl Acetate (EVA). In some embodiments, the core comprises a polymer, such as Ethylene Vinyl Acetate (EVA); the layers comprise different polymers, for example bioerodible polymers such as PLGA. All of the layers comprise a drug substance, provided that at least one of the layers comprises a kappa-opioid receptor agonist. Other pharmaceutical substances that may be used in the layer include, for example, substances independently selected from the group consisting of other kappa-opioid receptor agonists, mu-opioid receptor antagonists, mixed mu-opioid receptor agonists/antagonists such as buprenorphine, delta-opioid receptor agonists, delta-opioid receptor antagonists, anti-inflammatory agents, and steroids. The layers may independently comprise about 10% to about 90% of the drug substance. In one embodiment, the layers contain the same drug substance, but the drug substance concentrations of the layers are different such that the average concentration of drug substance in each layer decreases with increasing distance from the core. Thus, the outermost layer comprises about 10% to about 90% drug substance, the second outermost layer comprises about 10% to about 90% drug substance, the third outermost layer comprises about 10% to about 90% drug substance, and the innermost layer (adjacent the core) comprises about 10% to about 90% drug substance, provided that the outermost layer has a lower concentration of drug substance than the second outermost layer, the second outermost layer has a lower concentration of drug substance than the third outermost layer, the third outermost layer has a lower concentration of drug substance than the fourth outermost layer, and the fourth outermost layer has a lower concentration of drug substance than the innermost layer (adjacent the core). In one such embodiment, the drug substance in all five layers is a kappa-opioid receptor agonist.

In other embodiments, the disclosed implants may include additional layers, each of which has a drug concentration that decreases with increasing distance from the core, in a manner similar to that described above.

In any of the above embodiments, one or more of the layers may be non-bioerodible. In any of the above embodiments, all of the layers may be non-bioerodible. In any of the above embodiments, the core may be non-bioerodible. In any of the above embodiments, one or more of the core and the layers may be non-bioerodible, provided that there is no non-bioerodible material outside the bioerodible layer or the bioerodible core (i.e., if the implant has any bioerodible layer, any other layer outside the layer must be bioerodible; likewise, if the implant has any non-bioerodible layer, any bioerodible layer is outside the layer, that is, the bioerodible layer is farther from the core than any non-bioerodible layer.

In any of the above embodiments, one or more of the layers may be bioerodible. In any of the above embodiments, all of the layers may be bioerodible, while the core is non-bioerodible. In any of the above embodiments, each of the core and the one or more layers is bioerodible.

In any of the above embodiments, one or more of the layers may comprise a mixture of bioerodible polymer and non-bioerodible polymer. The mixture may be mixed together before extrusion into the same layer. Alternatively, the mixture may be co-extruded into the same layer as the layer is formed. In various embodiments, the ratio of bioerodible polymer to non-bioerodible polymer in the mixed layer may be about 10% bioerodible and 90% non-bioerodible, about 20% bioerodible and 80% non-bioerodible, about 25% bioerodible and 75% non-bioerodible, about 30% bioerodible and 70% non-bioerodible, about 33% bioerodible and 67% non-bioerodible, about 40% bioerodible and 60% non-bioerodible, about 50% bioerodible and 50% non-bioerodible, about 60% bioerodible and 40% non-bioerodible, about 67% bioerodible and 33% non-bioerodible, about 70% bioerodible and 30% non-bioerodible, about 75% bioerodible and 25% non-bioerodible, about 80% bioerodible and 20% non-bioerodible, or about 90% bioerodible and 10% non-bioerodible. In one embodiment, the bioerodible polymer is selected from any of the bioerodible polymers described elsewhere in this specification. In one embodiment, the non-bioerodible polymer is selected from any of the non-bioerodible polymers described elsewhere in this specification. In any of the foregoing embodiments of the hybrid layer, the bioerodible polymer can be PLGA. In any of the foregoing embodiments of the hybrid layer, the non-bioerodible polymer can be EVA. In any of the foregoing embodiments of the hybrid layer, the bioerodible polymer can be PLGA and the non-bioerodible polymer can be EVA. When a layer of a mixture comprising bioerodible and non-bioerodible polymers is used, any layer external to the mixed layer is bioerodible or mixed bioerodible/non-bioerodible.

In one embodiment, the present disclosure provides a rod-shaped core comprising a polymer that is substantially free of drug substances. The core is surrounded by two layers comprising a polymer and a drug substance, provided that at least one layer comprises a kappa-opioid agonist. In one embodiment of the type, the length of the rod is about 2cm to about 3cm, for example about 2.6cm, and the diameter is about 2mm to about 5mm; each layer has a thickness of about 0.5mm to about 1mm and the core has a diameter of about 0.5mm to about 2mm. In one embodiment, the core and all layers comprise the same polymer, such as Ethylene Vinyl Acetate (EVA). In some embodiments, the core comprises a polymer, such as Ethylene Vinyl Acetate (EVA); the layers comprise different polymers, such as bioerodible polymers, e.g., PLGA, and each layer comprises the same bioerodible polymer. Both layers comprise a drug substance, provided that at least one of the layers comprises a kappa-opioid receptor agonist. Other pharmaceutical substances that may be used in the layer include, for example, substances independently selected from the group consisting of other kappa-opioid receptor agonists, mu-opioid receptor antagonists, mixed mu-opioid receptor agonists/antagonists such as buprenorphine, delta-opioid receptor agonists, delta-opioid receptor antagonists, anti-inflammatory agents, and steroids. In one embodiment, both layers contain the same drug substance, and the outermost layer contains a higher concentration of drug substance than the innermost layer; for example, the outermost layer comprises about 10% to about 90% drug substance, and the innermost layer comprises about 10% to about 90% drug substance, wherein the outermost layer comprises a higher concentration of drug substance than the innermost layer. In one such embodiment, the drug substance in both layers is a kappa-opioid receptor agonist. Optionally, this embodiment may comprise other layers comprising a polymer and a drug substance; in this case, the outermost layer contains the highest concentration of drug substance, and each of the more inner layers contains a lower level of drug. The arrangement allows the drug to be released into the individual at a high initial rate over a period of time, resulting in a higher initial serum or systemic level of the drug, followed by a decrease in the release rate over time, which results in a lower subsequent serum or systemic drug level, which gradually decreases over a period of time. In some embodiments, wherein the outermost layer also comprises the highest concentration of drug, the further inner layer may comprise approximately equal concentrations of drug but all lower than the outermost layer. This will allow for an initial high rate of release of the drug into the individual over a period of time, resulting in a higher initial serum or systemic level of the drug, followed by a lower substantially steady-state level of the drug over a period of time.

In other embodiments, the disclosed implants may comprise other layers, each layer containing an increasing concentration of drug with increasing distance from the core.

In one embodiment, the present disclosure provides a rod-shaped core comprising a polymer that is substantially free of drug substances. The core is surrounded by a monolayer comprising a polymer and a kappa-opioid receptor agonist. Finally, the monolayer is surrounded by a layer of a substantially pure drug substance, optionally a kappa-opioid receptor agonist. In one embodiment of that type, the length of the rod is about 2cm to about 3cm, for example about 2.6cm, and the diameter is about 2mm to about 3mm; the thickness of the monolayer is about 0.5mm to about 1mm and the diameter of the core is about 0.5mm to about 2mm, while the thickness of the pure drug layer is determined by the amount of pure drug to be used. In one embodiment, the core and monolayer both comprise the same polymer, such as Ethylene Vinyl Acetate (EVA). In some embodiments, the core comprises a polymer, such as Ethylene Vinyl Acetate (EVA); the layers comprise different polymers, such as bioerodible polymers such as PLGA. The monolayer comprises from about 10% to about 90% kappa-opioid receptor agonist. The pure drug layer comprises about 100% of a drug substance independently selected from, for example, kappa-opioid receptor agonists, mu-opioid receptor antagonists, mixed mu-opioid receptor agonists/antagonists such as buprenorphine, delta-opioid receptor agonists, delta-opioid receptor antagonists, anti-inflammatory agents, and steroids. In one embodiment, the drug substance in both the monolayer and the pure drug layer is a kappa-opioid receptor agonist.

In further embodiments, the disclosed implants may include additional layers, each layer having an increasing concentration of drug substance with increasing distance from the core, with a layer of substantially pure drug substance on the exterior of the implant. The arrangement allows for an initial high rate of drug release into the individual over a period of time, resulting in a higher initial serum or systemic drug level.

In one aspect, the present disclosure provides an implant for delivering a kappa-opioid receptor agonist comprising the substance and a biocompatible polymer matrix. The drug is encapsulated in a matrix and the implant is subcutaneously implanted in a mammal, such as a dog or cat or a human. The drug substance is continuously released from the implant through the pores open at the surface of the matrix over a sustained period of time. After any initial burst of drug, the drug is delivered, for example, at a rate of at least about 0.1mg per day, typically from about 0.1mg to about 5mg per day. In some embodiments, the drug release rate is about 0.01mg per day, 0.02mg per day, 0.03mg per day, 0.04mg per day, 0.05mg per day, or 0.1mg per day. In some embodiments, the drug release rate is from about 0.1mg to about 0.5mg per day, from about 0.5mg to about 1.0mg per day, from about 1.0mg to about 3.0mg per day, or from about 3.0mg to about 5.0mg per day.

The rate of drug release is determined by the size and other physical parameters of the implant, the location of the implant, and the concentration of drug in the various layers of the implant, and can be adjusted to provide the desired dosage depending on the individual's disease, physical condition, and body weight or body surface area.

Kappa-opioid receptor agonists

In any of the embodiments of the implants, sustained release compositions, or methods disclosed herein, the kappa-opioid receptor agonist may be a compound of formula (I):

as defined herein.

In preferred embodiments, in any of the embodiments of the implants, sustained release compositions, or methods disclosed herein, the kappa-opioid receptor agonist may be compound a:

or a pharmaceutically acceptable salt or stereoisomer thereof.

Preparation of the implant

In some embodiments, the implant may be produced by an extrusion process. The drug substance may be prepared by milling (e.g., ball milling, impact milling), spray drying, solvent precipitation, screening, or other methods or combinations of methods known in the art for preparing fine particles. The drug may be combined with a polymer, which is also prepared as fine particles. The mixed mixture may be extruded, for example, by a Microtruder screw extruder (model RCP-025,Randcastle Extrusion Systems,Cedar Grove,NJ) or by other extrusion devices known in the industry. The extrusion diameter as well as the temperature, pressure and other parameters may be suitably controlled for each drug.

When EVA is used as the biocompatible polymer matrix, the implant may be produced using an extrusion process in which ground EVA is mixed with kappa-opioid receptor agonist, melted, and extruded into a rod-like structure. The shaft is cut into individual implants of the desired length and packaged and sterilized prior to use.

Other methods of encapsulating therapeutic compounds in implantable polymeric, non-erodable matrices are well known to those skilled in the art. Such methods include, for example, solvent casting (see, for example, U.S. Pat. nos. 4,883,666, 5,114,719 and 5,601,835). Depending on the desired shape, size, kappa-opioid receptor agonist loading and release kinetics for a particular type of individual or clinical indication, one skilled in the art will be readily able to determine the appropriate method of preparing the implant.

In some embodiments, a core comprising a polymer may be formed, for example, by extrusion, and then coated with one or more layers comprising the polymer and drug by dip coating or spray coating methods. Solvent evaporation techniques can be used to mix the polymer and drug in a solvent. The solution comprising the polymer, drug and solvent may then be applied to the surface of the core by dipping or spraying. The resulting composition then undergoes a drying process in which the solvent is evaporated and the polymeric material forms a film or layer on the core along with the drug dispersed therein. This step may be repeated with various solutions of the same or different concentrations of drug and polymer to deposit additional layers on the composition. Implants comprising multiple layers may be produced by any combination of extrusion and coating, as known in the art.

The extrudate may be extruded horizontally and collected for further processing. The extrudate may be cut to a desired length, for example, from about 1cm to about 3cm. The extrudate can then be washed in any solvent in which the drug is dissolved, then dried and packaged.

Examples of implantable polymeric devices for continuous drug release are described, for example, in U.S. patent No. 4,883,666;5,114,719;5,601,835;10,111,830; and 10,123,971; and U.S. patent application publication No. 2021/0007973 to Patel et al, which is useful for delivering kappa-opioid receptor agonists.

Implants having multiple layers may be produced by coextrusion methods known in the art, such as by the methods disclosed in U.S. patent No. 5,063,018 (for producing catheters having lumens) or U.S. patent nos. 4,832,589, 4,379,117, 3,880,691 and 3,337,665. Multi-manifold dies, such as multi-manifold dies that are co-extruded with an infeed block, are known in the art for producing multi-layer materials.

Kappa-opioid receptor agonists disclosed herein, such as compound a, may be administered in a hetero-implant, such as those disclosed in U.S. patent nos. 10,111,830 and 10,123,971. The implant comprises a rod-shaped core comprising a core polymer material, wherein the core does not comprise a drug substance. The core polymer material may be Ethylene Vinyl Acetate (EVA). The core may have a diameter of about 0.5mm to about 3.5mm. The implant also includes a first layer containing a first layer of drug substance surrounding the core. Optionally, the implant further comprises one or more additional layers, wherein each of the one or more additional layers comprises an independently selected further drug substance. The first layer may comprise EVA. The one or more additional layers may comprise EVA. The first layer may comprise a kappa opioid receptor agonist disclosed herein, e.g., compound a, or any one or more of the one or more additional layers may comprise a kappa opioid receptor agonist disclosed herein, e.g., compound a.

Kappa opioid receptor agonists disclosed herein (e.g., compound a) may be administered in implants comprising a core and a porogenic shell, such as the implants disclosed in U.S. patent application publication No. US 2021/0007973. The implant comprises a core comprising a first polymeric material and a core drug substance; and a shell comprising a second polymeric material and a porogen material. The porogen material may be removed from the shell leaving pores of defined size in the shell. The porogen material may comprise particles having an average diameter of 1 micron to 300 microns, for example particles having an average diameter of 1 micron to 50 microns. The pore former material may be selected from alkyl cellulose, hydroxyalkyl cellulose, ethyl cellulose, methyl cellulose, hydroxymethyl cellulose, fatty acids, stearic acid, palmitic acid, myristic acid, linoleic acid, biocompatible salts, sodium chloride, calcium chloride, sodium phosphate, benzoic acid, citric acid, polyvinylpyrrolidone (PVP). Salts of the above acids, such as sodium or potassium salts, may also be used.

Physical parameters of the implant

In some embodiments, the implant comprises a dimension of about 0.5mm to about 7mm in diameter. In some embodiments, the implant is about 0.5cm to 10cm in length. In some embodiments, the implant is about 1cm to about 3cm in length. In some embodiments, the implant is about 2cm to about 3cm in length. In some embodiments, the implant is about 2.6cm in length. In some embodiments, the implant has a diameter of about 1mm to about 4mm. In some embodiments, the implant has a diameter of about 1mm to about 3mm. In some embodiments, the implant has a diameter of about 2mm to about 3mm. In some embodiments, the implant has a diameter of about 2.4mm. In some embodiments, the implant has a diameter of about 1mm to about 2mm. In some embodiments, the implant has a diameter of about 1.5mm. In some embodiments, the implant comprises dimensions of about 2.4mm in overall diameter and about 2.6cm in overall length. In some embodiments, the implant is about 1.5mm in diameter. In some embodiments, the implant comprises dimensions of about 1.5mm in overall diameter and about 2.6cm in overall length.

In some embodiments, the core comprising the biocompatible polymeric matrix or the biocompatible polymeric matrix and the drug, the first layer, and any additional layers each independently have a diameter or thickness of about 0.5mm to about 5mm. In one embodiment, the core and layer are each independently from about 0.5mm to about 3.5mm. In some embodiments, the core and layer are each independently from about 0.5mm to about 2mm. In some embodiments, the core and layer are each independently from about 1mm to about 2mm. The thickness or diameter of the core may vary with the thickness of the layers. If multiple layers are present, each layer may have the same thickness as the other layers, or each layer may have a different thickness than the other layers, or some layers may have the same thickness as the other layers while some layers may have a different thickness than the other layers. The "thickness" of a layer refers to the distance between the start point of the layer and the end point of the layer measured from the center of the implant; for example, for a cylindrical implant with a regular annular layer, the layer starting 2mm from the center and ending 3.5mm from the center has a thickness of 1.5 mm.

Although the implant may be interpreted as having a core and one or more layers that are cylindrical or annular in cross-section, it should be understood that the cross-section of the core and one or more layers may be elliptical, polygonal, star-shaped, irregular, or of uneven thickness.

In some embodiments, each layer containing a polymer and a drug may comprise a different polymer or mixture thereof, and a different drug or mixture thereof.

Drug release

The release of the drug from the implant depends on the dissolution rate and passive diffusion through the polymer matrix. Thus, the surface area of the implant determines the release rate. The release mechanism of the drug from the polymeric material also depends on the nature of the polymer and the drug. The drug diffuses through the polymer into the surrounding tissue and body fluids. For erodable or bioerodible polymers, release can also occur through degradation or erosion of the polymer. Degradation or erosion of the polymer may occur by hydrolysis, enzymatic degradation, or other processes.

Drug release rates are also affected by implant cleaning prior to insertion into an individual. The irrigated implant maintains a more stable release rate after insertion; unwashed implants may exhibit significantly higher burst release immediately after implantation. Burst release can be detrimental to an individual because local or systemic drug concentrations rapidly rise from zero to potentially supratherapeutic levels. The initial burst may also unnecessarily deplete the drug depot and shorten the duration of the release period. The implant may be washed with any solvent in which the drug is dissolved, such as water, ethanol, isopropanol, and the like. After washing, it may be dried to remove the solvent. After drying, packaging and sterilizing can be carried out.

In some cases, an initial high dose of drug is required, and in such cases, the cleaning of the implant may be omitted in order to provide an initial burst as a loading dose. In certain embodiments of the implant, a layer of substantially pure drug substance is placed outside the implant for enhanced loading dose (initial dose).

In a non-limiting example, the extruded implant may be cut into implants of appropriate length, such as 2.6cm. The extrudate may optionally be washed, for example with 95% ethanol at room temperature for 30 minutes, to remove surface agents. The washed implant may be dried (e.g., air dried at room temperature for 30min, then forced air dried at 40 ℃ for 1 hour, then vacuum dried at 30 ℃ for 24 hours) to remove residual ethanol. The implant can be placed in a moisture-proof foil pouch, heat sealed, and then sterilized using gamma radiation (2.9-3.1 Mrads).

In some embodiments, the implant provides an approximately constant level of drug in the subject's or individual's plasma over a period of time. In one embodiment, the approximately constant drug level does not vary by more than about ±30% over 1 day, 1 week, 1 month, 3 months, 6 months, or 9 months as compared to the mean or average plasma level over the time period. In some embodiments, the approximately constant level of the drug does not vary by more than about ±20% over 1 day, 1 week, 1 month, 3 months, 6 months, or 9 months as compared to the mean or average plasma level over the period of time. In some embodiments, the approximately constant level of the drug does not vary by more than about ±10% over 1 day, 1 week, 1 month, 3 months, 6 months, or 9 months as compared to the mean or average plasma level over the period of time. By "approximately constant release rate" is meant that an approximately constant level of drug substance is released from the implant over a period of time, e.g. 1 day, 1 week, 1 month, 3 months, 6 months or 9 months. In some embodiments, the approximately constant release rate does not vary by more than about ±30%, 20% or ±10% of the mean or mean release over the indicated period of time. To achieve steady state plasma levels, an approximately constant release rate is preferred. Average or mean release may be calculated from week 1 after implantation to exclude the initial burst period.

By "substantially constant" is meant that the concentration of the drug in the plasma is within about 3 standard deviations, within about 2 standard deviations, or preferably within about 1 standard deviation of the mean plasma level over an extended period of about 80%. The measurement of plasma levels may be performed hourly, twice daily, twice weekly, biweekly, monthly, or at any other periodic interval to determine the average plasma level. For example, if the average plasma level of a drug sampled at weekly intervals is 2.0ng/ml and one standard deviation of the measurements is + -0.1 ng/ml, then for a measurement of about 80%, plasma levels falling within about + -0.3 ng/ml, about + -0.2 ng/ml, or preferably about + -0.1 ng/ml are considered substantially constant. By "extended time" is meant from about 3 months to about 1 year or more, such as at least about 3 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months, or about 24 months or more. Mean plasma levels may be calculated from the first week after implantation to exclude the initial burst.

In embodiments where an initial burst or initial loading dose is desired (e.g., embodiments where excess drug substance is not washed away from the surface of the implant, or embodiments where the implant is surrounded by a layer of pure drug), the period of time during which the initial burst or initial loading dose occurs is excluded from calculation of a steady state plasma level or steady state release rate, an approximately constant plasma level or approximately constant release rate, or an approximately constant plasma level or substantially constant release rate. The initial burst period or initial loading dose period ends when the release rate or plasma level falls within the steady state, approximately constant, or substantially constant range described above.

The implants disclosed herein show a particularly good release rate of compound a (a hydrophilic small peptide). Delivery of hydrophilic agents from implants can be difficult because rapid release of the contents can occur when implants containing hydrophilic agents are contacted with aqueous interstitial fluid in the body. Furthermore, long-term administration of therapeutic peptides is challenging due to the rapid breakdown of small peptides by peptidases and proteases in the circulation. Peptide drugs tend to have a relatively short half-life in the circulation, typically on the order of a few hours. As shown in example 1, the disclosed implants provide controlled release, producing sustained and significant plasma levels of compound a in the rat body 2000 hours (about 83 days or nearly three months) after implantation. As presently disclosed, achieving controlled release of hydrophilic peptide drugs in the blood for nearly three months is an important outcome. In view of the results, the disclosed implants may provide important benefits to individuals with pruritus in need of long-term treatment.

Drug delivery kinetics

Drug delivery may have controlled release over the lifetime of the implant. If a laminate implant comprising a core and one or more layers is used, varying the concentration of kappa-opioid receptor agonist in the core and/or different layers may be employed to adjust the drug delivery rate over time. In one embodiment, the implant exhibits a generally linear release of the kappa-opioid receptor agonist over time. In some embodiments, the release of the kappa-opioid receptor agonist from the implant is approximately constant or substantially constant over the lifetime of the implant or over a specified time period of the lifetime of the implant. In an implant having a core containing a kappa opioid receptor agonist and at least one layer, the agonist is released from the implant layer by layer from the outermost layer to the innermost layer. However, each layer has a smaller diameter and surface area than the layer that is outside. Thus, the more interior layers need to have a higher concentration of kappa-opioid receptor agonist than the more exterior layers to maintain a substantially constant or substantially constant rate of agonist release. In some embodiments, the concentration of kappa-opioid receptor agonist may be designed layer by layer to produce different agonist release rates. For example, if each layer contains the same or lower kappa-opioid receptor agonist concentration as the adjacent outer layer, this will result in a gradual decrease in the agonist delivery rate. Layer-by-layer modulation of the concentration of kappa-opioid receptor agonist may also produce a slow rise in agonist delivery over the lifetime of the implant or a specific period of the lifetime of the implant. Alternating layers of relatively high and low concentrations of kappa-opioid receptor agonist may produce a pulse rate of agonist delivery that rises and falls over time.

In one embodiment, more than one implant may be inserted into a subject to achieve a desired level of drug concentration in plasma. Drug delivery levels are preferably within the therapeutic range of the drug and below levels that may cause toxicity. In one embodiment, the implant may contain multiple drugs. In one embodiment, multiple drugs are integrated into the implant and released layer by layer to maintain steady state levels of each drug throughout the duration of the implant. In some embodiments, the drugs are distributed layer by layer at different concentrations such that drug delivery may occur in a wavy fashion, releasing a higher dose of one drug followed by a higher dose of another drug over time.

The implant may be designed to provide a stable concentration of drug in the plasma. The implant may be designed such that the concentration of drug produced in the plasma remains substantially constant for an extended period of time. The implant may be designed such that the concentration of drug produced in the plasma remains approximately constant over an extended period of time.

In another aspect, the present disclosure provides an implant for treating itch comprising a kappa-opioid receptor agonist and a biocompatible polymer matrix, wherein when the implant is subcutaneously implanted in a mammal, the kappa-opioid receptor agonist is sustained in vivo released for a period of time by passing through pores opening to the surface of the matrix at a steady state rate.

In some embodiments, the implant is configured to release about 0.01mg of the kappa-opioid receptor agonist per day. In some embodiments, the implant is configured to release at least about 0.01mg per day, such as about 0.01mg to about 5mg per day, about 0.01mg to about 4mg per day, about 0.01mg to about 3mg per day, about 0.01mg to about 2mg per day, about 0.01mg to about 1mg per day, about 0.01mg to about 0.5mg per day, about 0.01mg to about 0.25mg per day, about 0.01mg to about 0.1mg per day, about 0.01mg to about 0.05mg per day, about 0.01mg to about 0.02mg per day of kappa-opioid receptor agonist.

In some embodiments, the implant is configured to release about 0.05mg of the kappa-opioid receptor agonist per day. In some embodiments, the implant is configured to release at least about 0.05mg per day, such as about 0.05mg to about 5mg per day, about 0.05mg to about 4mg per day, about 0.05mg to about 3mg per day, about 0.05mg to about 2mg per day, about 0.05mg to about 1mg per day, about 0.05mg to about 0.5mg per day, about 0.05mg to about 0.25mg per day, or about 0.05mg to about 0.1mg per day of the kappa-opioid receptor agonist.

In some embodiments, the implant is configured to release about 0.1mg of the kappa-opioid receptor agonist per day. In some embodiments, the implant is configured to release at least about 0.1mg per day, such as about 0.1mg to about 5mg per day, about 0.1mg to about 4mg per day, about 0.1mg to about 3mg per day, about 0.1mg to about 2mg per day, about 0.1mg to about 1mg per day, about 0.1mg to about 0.5mg per day, about 0.1mg to about 0.25mg per day, or about 0.1mg to about 0.2mg per day of the kappa-opioid receptor agonist.

In some embodiments, the approximate rate of release of the kappa-opioid receptor agonist is about 0.01 mg/day, 0.02 mg/day, 0.03 mg/day, 0.04 mg/day, 0.05 mg/day, 0.75 mg/day, 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, about 0.4 mg/day, about 0.5 mg/day, about 0.6 mg/day, about 0.7 mg/day, about 0.8 mg/day, about 0.9 mg/day, or about 1.0 mg/day.

When subcutaneously implanted, the implants disclosed herein continuously release kappa-opioid receptor agonist at a pseudo or near zero order release rate for an extended period of time. In some embodiments, the initial burst of kappa-opioid receptor agonist released in vivo after implantation is reduced or minimized by pre-washing the implant to remove surface kappa-opioid receptor agonist prior to implantation. The pre-wash may be performed in any solution in which the kappa-opioid receptor agonist is soluble, for example in ethanol for 30 minutes. The release rate may be altered by changing the kappa-opioid receptor agonist loading percentage, the porosity of the matrix, the structure of the implant or the hydrophobicity of the matrix, or by adding a hydrophobic coating on the exterior of the implant. The implant can deliver kappa-opioid receptor agonists without the need for external medical devices such as intravenous tubing or pumps.

Exemplary polymers

In some embodiments, the implant may comprise a single biocompatible polymer matrix material mixed with a kappa-opioid receptor agonist. In some embodiments, the implant may be heterogeneous, that is, the implant may comprise multiple layers comprising different compositions. For example, the implant may comprise a core comprising a core biocompatible polymer matrix surrounded by one or more layers comprising a layer biocompatible polymer matrix. At least one of the core and one or more layers further comprises a kappa-opioid receptor agonist. Optionally, at least one of the core and one or more layers may comprise one or more drug substances. The one or more drug substances may be disposed in the core or in the same layer as the kappa-opioid receptor agonist, or may be in a different location than the kappa-opioid receptor agonist. That is, the other drug substance or substances may be in either the core or any of the surrounding layer or layers, whether the kappa-opioid receptor agonist is in the core or in the surrounding layer or layers.

The core and layer biocompatible polymer matrices may be the same or different. The core or any layer may also comprise a mixture of two or more biocompatible polymers; the core and the layers may comprise different polymer mixtures.

As used herein, "polymer" or "polymeric material" refers to a macromolecule comprising repeating monomer units or comonomer units. The polymer may be bioerodible or non-bioerodible. The polymer may be a homopolymer, a copolymer, a terpolymer, or may contain three or more monomers.

Exemplary polymers useful in preparing the implant include: acrylic resins (acrylic), agarose, alginate and combinations thereof, cellulose ethers, collagen, copolymers containing poly (ethylene glycol) and polybutylene terephthalate segments (PEG/PBT) (PolyActive (TM)), copolymers of poly (lactic acid) and glycolic acid, copolymers thereof with poly (ethylene glycol), derivatives and mixtures thereof, dextran, dextrose, elastin, epoxides, ethylene-vinyl acetate (EVA copolymers), fluoropolymers, gelatin, hydroxypropyl methylcellulose, maleic anhydride copolymers, methylcellulose and ethylcellulose, water insoluble cellulose acetate, water insoluble chitosan, water insoluble hydroxyethyl cellulose, water insoluble hydroxypropyl cellulose, peptides, PLLA-polyglycolic acid (PGA) copolymers (also known as poly-L-lactic-co-glycolic acid or PLGA), poly (L-lactic acid), poly (2-ethoxyethyl methacrylate), poly (2-hydroxyethyl methacrylate), poly (2-methoxyethyl acrylate), poly (2-methoxyethyl methacrylate), poly (acrylamide), poly (hydroxy-L-lactone), poly (phenylic acid), poly (D-caprolactone), poly (phenylglyoxylic acid), poly (D-phenylglyoxylic acid) Poly (D, L-lactide) (PLA), poly (D, L-lactide-co-caprolactone) (PLA/PCL) and poly (glycolide-co-caprolactone) (PGA/PCL), poly (D, L-lactide-co-glycolide) (PLA/PGA), poly (ether urethane urea) (poly (etherurethane urea)), poly (ethyl glutamate-co-glutamate), poly (ethylene carbonate), poly (ethylene glycol), poly (ethylene-co-vinyl alcohol), poly (glutamate), poly (glutamic acid-co-ethyl glutamate), poly (glycolic acid), poly (glycolide-co-trimethylene carbonate) (PGA/PTMC), poly (hydroxypropyl methacrylamide), poly (iminocarbonate), poly (leucine-co-hydroxyethylglutamine), poly (L-lactide-co-D, L-lactide) (PLLA/PLA), poly (L-lactide-co-glycolide) (PLLA/PGA), poly (lysine), poly (orthoesters), poly (oxaamides), poly (oxaesters), poly (phosphazenes), poly (phosphate) (poly (phospho esters)), poly (phospho) (poly (phosphoesters)), poly (propylene carbonate), poly (propylene glycol), poly (pyrrole), poly (t-butoxycarbonyl methyl glutamate), poly (tetramethylene glycol) (poly (tetramethylene glycol)), poly (trimethylene carbonate), poly (urea), poly (urethane-urea), poly (vinyl alcohol-co-vinyl acetate), poly (vinylpyrrolidone) (PVP), poly [ (97.5% dimethyl-trimethylene carbonate) -co- (2.5% trimethylene carbonate) ], polyacrylic acid, polyoxyalkylene, polyamide, polycaprolactone (PCL) -poly (hydroxybutyrate-co-hydroxypentanoate) copolymer (PHBV), polycaprolactone (PCL), polycaprolactone co-polybutyl acrylate, poly (alpha-hydroxy acid/alpha-amino acid) (polypepeptides), polydioxanone (PDS), polyester, polyethylene glycol, polyethylene oxide (PEO), polyethylene terephthalate (PGA), poly [ (97.5% dimethyl-trimethylene carbonate) -co- (2.5% trimethylene carbonate), polyacrylic acid, polyoxyalkylene, polyamide, poly (L-glycolic acid) and copolymers thereof such as poly (PLL-hydroxybutyrate) Poly (PHBV), poly (hydroxybutyrate) co-hydroxybutyrate) Poly (PET), polyurethane, silicone, tyrosine derived polyacrylate, tyrosine derived polycarbonate, tyrosine derived polyurethane, tyrosine derived polyphosphate, carbamate, and combinations, derivatives, and mixtures thereof.

Exemplary erodable or bioerodible polymers useful in preparing the implant include polyamides, aliphatic polycarbonates, polyalkylcyanoacrylates, polyalkylene oxalates, polyanhydrides, polycarboxylic acids, polyesters, poly (hydroxybutyrates), polyimides, poly (iminocarbonates), polycaprolactone (PCL), poly-D, L-lactic acid (DL-PLA), polydioxanone, poly (glycolic acid), poly-L-lactic acid (L-PLA), poly-L-lactic acid-co-glycolic acid (PLGA), polyorthoesters, polyphosphazenes and polyphosphoesters, poly (trimethylene carbonate), and derivatives and mixtures thereof. The polymer may also be formed from a material selected from the group consisting of cellulose esters, polybutylene terephthalate, polycarbonate, polyester, polyetheretherketone, polyethylene-co-tetrafluoroethylene, polymethyl methacrylate, polyolefin, polypropylene, polysulfone, polytetrafluoroethylene, polyurethane, polyvinylchloride, polyvinylidene fluoride, silicone, and derivatives and combinations thereof.

Other representative examples of polymers for implants include, but are not limited to, ABS resins, acrylic polymers and copolymers, acrylonitrile-styrene copolymers, alkyd resins and carboxymethyl cellulose, as well as ethylene-vinyl acetate copolymers, cellophane, cellulose butyrate, cellulose acetate, cellulose ethers, cellulose nitrate, cellulose propionate, copolymers of vinyl monomers with olefins, ethylene-methyl methacrylate copolymers, epoxy resins, ethylene-vinyl alcohol copolymers (commonly known as EVOH or trade name EVAL), poly (glycerol sebacate), poly (glycolic acid-co-trimethylene carbonate), poly (hydroxybutyrate-co-valerate), poly (hydroxyvalerate), poly (lactide-co-glycolide), poly (propylene fumarate), poly (trimethylene carbonate), polyacrylonitrile, polyamides such as nylon 66 and polycaprolactam, polycarbonates, polycyanoacrylates, polydioxanone, polyesters, polyethers, polyimides, and ethylene-alpha-olefin copolymers, polyoxymethylene, polyphosphate urethanes, polyvinyl aromatics, polyvinyl esters such as poly (ethylene), poly (ethylene oxide), poly (ethylene ether such as poly (ethylene ether acetate), poly (ethylene ether) such as poly (ethylene ether acetate Polyvinylidene halides such as polyvinylidene fluoride-based homopolymers or copolymers (e.g., polyvinylidene fluoride (PVDF) or poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-co-HFP) and polyvinylidene chloride) commercially available under the trade names Solef (TM) or Kynar (TM), rayon-triacetate, silicones, halogenated ethylene polymers and copolymers such as polyvinyl chloride, copolymers of the polymers with poly (ethylene glycol) (PEG), or combinations thereof.

In some embodiments, the polymer may be a copolymer of poly (lactic acid) and glycolic acid, poly (anhydride), poly (D, L-lactic acid), poly (D, L-lactide-co-glycolide), poly (ethylene carbonate), poly (glycolic acid), poly (glycolide), poly (L-lactic acid), poly (L-lactide-co-glycolide), poly (orthoester), poly (oxaamides), poly (oxaesters), poly (phosphazene), poly (phosphate), poly (propylene carbonate), poly (trimethylene carbonate), poly (tyrosine derived iminocarbonates), poly (arylates of tyrosine derivatives), copolymers of these polymers with polyethylene glycol (PEG), or combinations thereof.

Examples of non-bioerodible polymers useful in the implants of the invention include poly (ethylene-co-vinyl acetate)

(EVA), polyvinyl alcohol, and polyurethanes, such as polycarbonate-based polyurethanes.

A preferred polymer for the implant is Ethyl Vinyl Acetate (EVA).

In some embodiments, where the implant comprises EVA or where the implant comprises a core comprising EVA and one or more additional layers, the vinyl acetate content may be from about 2 wt% to about 40 wt%, from about 10 wt% to about 35 wt%, from about 30 wt% to about 35 wt%, or about 33 wt%.

The EVA-kappa-opioid receptor agonist mixture of the first layer of the implant typically comprises about 10% to about 85%, e.g., about or at least about 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80% or 85% kappa-opioid receptor agonist, e.g., about 25% to about 50% kappa-opioid receptor agonist or about 50% to about 75% kappa-opioid receptor agonist. In one embodiment, the EVA-kappa-opioid receptor agonist blend of the first layer of the implant comprises about 50% kappa-opioid receptor agonist and about 50% EVA. In some embodiments, the EVA-kappa-opioid receptor agonist blend of the first layer of the implant comprises about 66.7% kappa-opioid receptor agonist and about 33.3% EVA. In some embodiments, the EVA-kappa-opioid receptor agonist blend of the first layer of the implant comprises about 75% kappa-opioid receptor agonist and about 25% EVA. In various embodiments, the duration of kappa-opioid receptor agonist release is from about 3 months to about 1 year or more, for example at least about 3 months, 6 months, 9 months, or 12 months.

The core or any layer of the implant may comprise a single type of polymer or a mixture of two or more polymers. A mixture of the two polymers can modulate the release rate of the drug. It is desirable to care for the release of a therapeutically effective amount of a drug from an implant over a substantial period of time. U.S. Pat. No. 6,258,121 to Yang et al discloses a method of varying the release rate by mixing two polymers of different release rates and incorporating them into a monolayer; this technique may also reduce burst release of the drug after implantation.

Where appropriate, a kappa-opioid receptor agonist impermeable coating is placed over at least a portion of the implant to further modulate the release rate. In appropriate cases, the implant does not contain any coating impermeable to kappa-opioid receptor agonists.

Exemplary other drug substances

As used herein, a "drug" or "drug substance" is any bioactive agent or other substance that has therapeutic value in a living organism. Other pharmaceutical substances may be included in the implant containing kappa-opioid receptor agonists. Such other drugs include other kappa-opioid receptor agonists, mu-opioid receptor antagonists, mixed mu-opioid receptor agonists/antagonists such as buprenorphine, delta-opioid receptor agonists, delta-opioid receptor antagonists, anti-inflammatory agents, and steroids.

In some embodiments, the other drug substance is independently selected from buprenorphine and fentanyl.

Insertion and removal of implants

In one method of the present disclosure, the implant is applied by subcutaneous implantation and is preferably placed in the interstitial space between the skin and muscle layers. In various embodiments, the implant is subcutaneously implanted at a site selected from the group consisting of the upper arm, the scapula region, the back, the legs, and the abdomen. Prior to implantation, the individual may be lightly anesthetized, such as with isoflurane or other anesthetic agents known in the art, and/or a local, transdermal, or subcutaneous anesthetic agent may be administered at the implantation site. A small incision can be made in the skin and the trocar inserted subcutaneously and then loaded with an implant. A probe (stylus) may be inserted to secure the implant in place, and then the trocar carefully removed, leaving the implant in the subcutaneous space. Each site may be sutured closed and later inspected. Complications such as skin irritation, inflammation, infection or other specific site adverse reactions may be monitored and treated as needed, for example, with antibiotics.

In various embodiments, the implant may reside in vivo for up to about 3 months; for example, it may reside in the body for about 1 month to about two months, about two months to about 3 months, or about 1 month to about 3 months. In various embodiments, the implant may reside in vivo for up to about 6 months; for example, it may reside in the body for about 1 month to about 6 months, about 3 months to about 6 months, or about 5 months to about 6 months. In various embodiments, the implant may reside in vivo for up to about 1 year; for example, it may reside in the body for about 6 months to about 1 year or about 9 months to about 1 year. The time for sustained release of the drug into the body may be from about 3 months to about 1 year or longer, such as from at least about 3 months to about 6 months, from at least about 6 months to about 9 months, from at least about 9 to about 1 year, from at least about 12 months to about 18 months, from at least about 15 months to about 24 months, from at least about 18 months to about 24 months, from at least about 21 months to about 24 months, or up to about 24 months. In some embodiments, the implant may reside in vivo for up to 1 year. At the end of the treatment period, forceps may be used to remove the implant from the body through an incision (e.g., a 3-mm incision).

For example, the second implant may be used to deliver a drug substance to counteract any adverse effects caused by the drug released from the first implant.

Multiple implants may be inserted into a single individual to regulate the delivery of a single drug or to deliver multiple drugs.

Instructions for use

One or more of the implants disclosed herein may be used to treat itch. One or more of the implants disclosed herein may be used to treat chronic pruritus, i.e., pruritus that lasts for more than six weeks. One or more of the implants disclosed herein may be used to treat uremic itch. One or more of the implants disclosed herein may be used to treat itch caused by such reasons as: itching associated with chronic liver disease, paresthesia back pain (notalgia paresthetica), eczema, dermatitis, atopic dermatitis, psoriasis, burns or scarring.

In other embodiments, the disclosure includes an implant comprising a kappa opioid receptor agonist for use in treating pruritis. In other embodiments, the disclosure includes an implant comprising a kappa opioid receptor agonist for use in treating uremic itch. In other embodiments, the present disclosure includes an implant comprising a kappa opioid receptor agonist for treating pruritus caused by such causes as itch associated with chronic liver disease, paresthesia back pain, eczema, dermatitis, atopic dermatitis, psoriasis, burns, or scarring.

In other embodiments, the present disclosure includes the use of kappa opioid receptor agonists and polymers as disclosed herein for the preparation of implants for the treatment of itch. In other embodiments, the present disclosure includes the use of kappa opioid receptor agonists and polymers as disclosed herein for the preparation of implants for the treatment of uremic itch. In other embodiments, the disclosure includes the use of kappa opioid receptor agonists and polymers as disclosed herein for the preparation of implants for the treatment of itch caused by such causes as itch associated with chronic liver disease, paresthesia back pain, eczema, dermatitis, atopic dermatitis, psoriasis, burns or scarring.

Example 1

Plasma levels in rats from compound a implants

10 co-extruded implants were prepared containing a core comprising 50% compound a (as salt) and 50% ethylene-vinyl acetate, and a shell comprising 3% compound a and 97% ethylene-vinyl acetate. The implant was 26mm long, 1.5mm in diameter, 48mg in weight, and contained 17.5mg of Compound A. After extrusion, the implants were washed, dried, packaged and sterilized by electron beam irradiation at 25 KGy.

Implants were implanted into rats (one implant per rat) and plasma levels were measured. The results are shown in FIG. 1. After the drug on the implant surface reached the initial peak, the rat plasma level was maintained in the range of about 1.4ng/ml to about 4ng/ml for about 2000 hours (about 83 days).

Example 2

Prolonged efficacy of compound a in a mouse pruritus model by chronic delivery with a mouse prototype EVA implant

Compound a implants were formulated in an Ethylene Vinyl Acetate (EVA) matrix for testing in male C57BL/6 mice. Because of the small size of mice, this mouse model study used a test implant prototype (25 mm x 1.5 mm) containing a limited amount of drug (10 mg). The mouse implant contained a core comprising 50% compound a (as a salt) and 50% ethylene-vinyl acetate, and a shell comprising 3% compound a and 97% ethylene-vinyl acetate. After extrusion, the implant prototype was washed, dried, packaged and sterilized by electron beam irradiation of 25 KGy.

Following implantation of one compound a implant in each mouse, mice treated with the drug-containing implant (n=5) and untreated control mice (n=7) with placebo implants or sham surgery were challenged with 5 '-guanylna Qu Yinduo (5' gnti) on days 1, 14 and 28 post implantation. A scratching event is monitored. As shown in fig. 2, the results demonstrate that a compound a prototype implant at 1 implant dose per mouse provided sustained pruritus inhibition for up to 14 days post-implantation, with the scratching behavior of the animals returning to control levels at day 28.

Example 3

Pharmacokinetic assessment of Compound A mouse plasma concentration from subcutaneous acute injection and from EVA mouse prototype implant

After subcutaneous acute injection of saline solution of compound a (0.3 mg/kg drug administered with an injection volume of 10 mL/kg) or after implantation of one compound a implant in each mouse, male C57BL/6 mice were sampled for pharmacokinetic analysis. The implants used were as described in example 2.

As shown in fig. 3, the results demonstrate that compound a murine prototype implant provided a plasma concentration of compound a at 14 days post-implantation that was far higher than the level of therapeutic antipruritic activity estimated with acute 0.3mg/kg subcutaneous injection.

Example 4

Mimicking plasma levels

The simulated plasma levels of the kappa opioid receptor agonist CR-845 were calculated for implants containing compound A and for intravenous bolus doses. CR-845 is commonly known as Difelikefalin acetate (Difekefalin) under the trade nameAnd (5) selling.

Figure 4 shows simulated human plasma levels within 1 week after implantation of an implant containing compound a (0.5 mg/day (filled circles) or 0.1 mg/day (open circles)) and as a 0.08mg IV bolus (dashed lines) for CR-845, compared to the plasma levels (dashed lines) of the illegal line acetate injection (320 pg/mL) required for 75% kappa opioid receptor occupancy. By hetero-scaling to human (factor 13.7), the mouse subcutaneous data was used in the simulation to define the pharmacokinetic parameters for distribution and elimination.

Example 5

Implants containing compound a reduced scratching events in mice over 84 days

Male C57BL/6 mice (8-14 weeks old, N=7-8) were each implanted with one implant containing Compound A (26x2.6mm, 50% load, 60mg Compound A/implant). The control was untreated mice or mice implanted with placebo (EVA only) implants (n=5-7). On days 28, 56 and 84 post-implantation, mice were transferred to the behavioral chambers at least 2 hours prior to challenge with the pruritic 5' -GNTI during the light cycle to minimize the effects of stress on combing and movement. 5' GNTI (0.1 mg/kg) was subcutaneously injected in the head/neck near the tail and immediately after the primordial challenge, the mice were placed in a viewing room (25 x 25 cm) fitted with plexiglas walls and light-colored melamine floors and video recorded from above for up to 90 minutes, and then removed and returned to the living cages of their living population. The video recordings were then analyzed for the amount of scratching behavior, which in the first 30 minutes observation was classified as front paw scratching behind the ear or back paw scratching on the side/back of the animal.

Figure 5 shows reduced scratching events in mice with implants containing compound a compared to control mice. (d28c=control mice on day 28, d28a=mice implanted with compound a on day 28, d56c=control mice on day 56, d56a=mice implanted with compound a on day 56, d84c=control mice on day 84, d84a=mice implanted with compound a on day 84).

Although the foregoing disclosure of compositions, articles, implants, methods, kits, and other disclosures have been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those of skill in the art that certain changes and modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, the description is not to be construed as limiting the scope of the invention.

All publications, patents, and patent applications cited herein are incorporated by reference in their entirety.

Claims

1. A method of treating itch in an individual comprising:

administering to the individual an implant comprising a sustained release composition, wherein the sustained release composition comprises a kappa-opioid receptor agonist and a biocompatible polymer matrix,

wherein the extended release composition is configured to release a therapeutically effective amount of the kappa-opioid agonist upon administration.

2. The method of claim 1, wherein the kappa-opioid receptor agonist comprises a peptide.

3. The method of claim 2, wherein the kappa-opioid receptor agonist comprises a compound of formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein R is:

wherein n is an integer from 1 to 4;

X is-NR ₂ R ₃ or-NR ₂ R ₃ R ₄ ；

R ₁ 、R ₂ 、R ₃ And R is ₄ Each independently is hydrogen, C ₁ -C ₅ Alkyl, C ₁ -C ₅ Substituted alkyl, C ₂ -C ₅ Alkenyl, C ₂ -C ₅ Substituted alkenyl, C ₂ -C ₅ Alkynyl, C ₂ -C ₅ Substituted alkynyl, C ₃ -C ₆ Cycloalkyl, C ₆ -C ₁₀ Aryl, C ₆ -C ₁₀ Substituted aryl or-C ₁ -C ₅ alkyl-C ₆ -C ₁₀ An aryl group;

R ₇ is hydrogen, C ₁ -C ₅ Alkyl, C ₁ -C ₅ Substituted alkyl, C ₂ -C ₅ Alkenyl, C ₂ -C ₅ Substituted alkenyl, C ₂ -C ₅ Alkynyl, C ₂ -C ₅ Substituted alkynyl, C ₃ -C ₆ Cycloalkyl, C ₆ -C ₁₀ Aryl, C ₆ -C ₁₀ Substituted aryl, -C ₁ -C ₅ alkyl-C ₆ -C ₁₀ Aryl or-NR ₈ R ₉ ；

R ₅ 、R ₆ 、R ₈ And R is ₉ Independently hydrogen, C ₁ -C ₅ Alkyl, C ₁ -C ₅ Substituted alkyl, C ₁ -C ₅ Alkenyl, C ₁ -C ₅ Substituted alkenyl, C ₁ -C ₅ Alkynyl, C ₁ -C ₅ Substituted alkynyl, C ₃ -C ₆ Cycloalkyl, C ₆ -C ₁₀ Aryl, C ₆ -C ₁₀ Substituted aryl or-C ₁ -C ₅ alkyl-C ₆ -C ₁₀ An aryl group; or alternatively

Alternatively, R ₅ And R is ₉ Together with the nitrogen atom to which they are attached, form a heterocyclic ring; or alternatively

Alternatively, R ₆ And R is ₉ Together with the nitrogen atom to which they are attached form a heterocyclic ring.

4. The method of claim 3, wherein R is:

5. the method of claim 3, wherein R is:

or->

6. The method of claim 3, wherein R is:

7. the method of claim 3, wherein R is:

or->

8. The method of claim 3, wherein R is:

or alternatively

9. The method of claim 3, wherein R is:

or alternatively

10. The method of claim 3, wherein R is:

11. The method of any one of claims 1-10, wherein the biocompatible polymer matrix comprises an ethylene-vinyl acetate (EVA) copolymer, a crosslinked poly (vinyl alcohol), a poly (hydroxyethyl methacrylate), an acyl substituted cellulose acetate, a hydrolyzed olefin-vinyl acetate copolymer, polyvinyl chloride, polyvinyl acetate, a polyvinyl alkyl ether, polyvinyl fluoride, polycarbonate, polyurethane, polyamide, polysulfone, a styrene-acrylonitrile copolymer, a crosslinked poly (ethylene oxide), a poly (alkylene), a poly (vinylimidazole), a poly (ester), a poly (ethylene terephthalate), a polyphosphazene, a chlorosulfonated polyolefin, a Polylactide (PLA), a Polyglycolide (PGA), a polylactic glycolic acid copolymer (PLGA), or a combination thereof.

12. The method of any one of claims 1-10, wherein the biocompatible polymer matrix comprises an ethylene-vinyl acetate (EVA) copolymer.

13. The method of claim 12 wherein the EVA copolymer comprises from about 20% to about 40% vinyl acetate by total weight of the copolymer.

14. The method of claim 12 wherein the EVA copolymer comprises about 33% vinyl acetate by total weight of the copolymer.

15. The method of any one of claims 1-14, wherein the kappa-opioid agonist comprises from about 10% to about 85% by total weight of the extended release composition.

16. The method of any one of claims 1-14, wherein the kappa-opioid agonist comprises from about 30% to about 70% by total weight of the extended release composition.

17. The method of any one of claims 1-16, wherein the implant is a rod-like device having a diameter of about 0.5mm to about 10mm and a length of about 0.5cm to about 10 cm.

18. The method of any one of claims 1-16, wherein the implant is a rod-like device having a diameter of about 2mm to about 3mm and a length of about 2cm to about 4 cm.

19. The method of any one of claims 1-18, wherein the implant releases about 0.1mg to about 10mg of the kappa-opioid receptor agonist per day, about 0.1mg to about 0.5mg of the kappa-opioid receptor agonist per day, about 0.5mg to about 1.0mg of the kappa-opioid receptor agonist per day, about 1.0mg to about 3.0mg of the kappa-opioid receptor agonist per day, or about 3.0mg to about 5.0mg of the kappa-opioid receptor agonist per day.

20. The method of any one of claims 1-19, wherein the implant is administered subcutaneously.

21. The method of any one of claims 1-20, wherein the implant comprises a core comprising the sustained release composition and a first layer comprising a first layer of biocompatible polymer matrix surrounding the core.

22. The method of claim 21, wherein the first layer of biocompatible polymer matrix comprises ethylene-vinyl acetate (EVA) copolymer, crosslinked poly (vinyl alcohol), poly (hydroxyethyl methacrylate), acyl substituted cellulose acetate, hydrolyzed olefin-vinyl acetate copolymer, polyvinyl chloride, polyvinyl acetate, polyvinyl alkyl ether, polyvinyl fluoride, polycarbonate, polyurethane, polyamide, polysulfone, styrene-acrylonitrile copolymer, crosslinked poly (ethylene oxide), poly (alkylene), poly (vinylimidazole), poly (ester), poly (ethylene terephthalate), polyphosphazene, chlorosulfonated polyolefin, polylactide (PLA), polyglycolide (PGA), polylactic glycolic acid copolymer (PLGA), or a combination thereof.

23. The method of claim 21, wherein the first layer of biocompatible polymer matrix comprises an Ethylene Vinyl Acetate (EVA) copolymer.

24. The method of claim 23, wherein the EVA copolymer of the first layer of biocompatible polymer matrix comprises from about 20% to about 40% vinyl acetate by total weight of the copolymer.

25. The method of claim 23, wherein the EVA copolymer of the first layer of biocompatible polymer matrix comprises about 33% vinyl acetate by total weight of the copolymer.

26. The method of any one of claims 21-25, wherein the implant further comprises one or more additional layers comprising a biocompatible polymer matrix.

27. The method of any one of claims 21-26, wherein any one of the core, the first layer, and the one or more additional layers (if present) further comprises one or more other drug substances.

28. The method of any one of claims 1-27, wherein the implant remains in the subject for at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, at least about 21 months, or at least about 24 months.

29. The method of claim 28, wherein the concentration of drug substance in the plasma is approximately constant or substantially constant for at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 15 months, at least about 18 months, at least about 21 months, or at least about 24 months.

30. An implant comprising a sustained release composition, wherein the sustained release composition comprises a kappa-opioid receptor agonist and a biocompatible polymer matrix,

wherein the implant comprises a core comprising the sustained release composition, and a first layer comprising a first layer of biocompatible polymer matrix surrounding the core; and

wherein the extended release composition is configured to release a therapeutically effective amount of the kappa opioid receptor agonist upon administration.

31. The implant of claim 30, wherein the implant further comprises one or more additional layers comprising a biocompatible polymer matrix.

32. The implant of claim 30 or claim 31, wherein any one of the core, first layer, and one or more additional layers (if present) further comprises one or more other drug substances.

33. The method of any one of claims 1-29, wherein the itch is chronic itch.

34. The method of any one of claims 1-29, wherein the itch is uremic itch.

35. The method of any one of claims 1-29, wherein the itch is caused by dermatitis.

36. The method of any one of claims 1-29, wherein the itch is caused by atopic dermatitis.

37. The method of any one of claims 1-29, wherein the itch is caused by chronic liver disease.

38. The method of any one of claims 1-29, wherein the itch is caused by paresthesia back pain.