Highly loaded implantable devices with high tensile strength for drug delivery

Abstract

Implantable devices for treatment of chronic diseases and conditions, and methods of treatment and kits thereof, are provided. The implantable devices include a biocompatible, nonerodible polymeric matrix that contains a pharmaceutical substance at a loading of at least about 90% (w / w), and which releases the pharmaceutical substance continuously with generally linear release kinetics for extended periods of time. The devices may be administered subcutaneously to an individuals in need of continuous treatment with the pharmaceutical substance contained therein.

Description

[0001] HIGHLY LOADED IMPLANTABLE DEVICES WITH HIGH TENSILE STRENGTH

[0002] FOR DRUG DELIVERY

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 552,916. filed on February 13, 2024, which is incorporated by reference herein in its entirety.

[0005] FIELD OF THE INVENTION

[0006]

[0002] The invention relates to implantable devices for sustained release of pharmaceutical substances over extended periods of time, in particular implantable devices that contain high loading of pharmaceutical substances in a nonerodible polymeric matrix for treatment of chronic diseases or conditions.

[0007] BACKGROUND

[0008]

[0003] Many patients require long-term, regular dosing with drugs or pharmaceutical substances for chronic illnesses. Effective treatment often necessitates the ingestion of multiple tablets per day. Compliance with such a dosing scheme is often difficult. Furthermore, enteral drug delivery is sometimes poorly tolerated or prohibited in patients with particular indications. In addition, oral tablets may be subject to abuse or other illicit use. Oral and sublingual delivery can result in plasma concentrations of drug peaking quickly and dropping steeply. Continuous parenteral delivery of drug substances is expensive, cumbersome and dependent on the availability of refrigeration, medical equipment such as catheters and pumps, and trained personnel. These methods can result in poor patient compliance with dosing regimes. Thus, there is a need for devices which regularly dose patients with drug substances to treat chronic illnesses.

[0009]

[0004] Implantable devices may be used for drug delivery. These devices can produce longterm delivery of drugs, ensuring compliance independent of the patient, maintaining stable plasma levels of medication and reducing the likelihood of abuse or diversion. Continuous release of a compound in vivo over an extended duration may be achieved via implantation of a device containing the compound encapsulated, z.<?., dispersed, in a nonerodible polymeric matrix. Examples of implantable, nonerodible polymeric devices for continuous drug release are described in. e.g, U.S. Pat. Nos. 4,883,666. 5,114,719. 5,601,835, 7,736,665, 8,852,623,9,278,163, and 10,111,830. Implantation ofthe device and extended release of a pharmaceutical substance improves compliance with a treatment regimen, and avoids less convenient drug delivery mechanisms such as repeated injections, ingestion of pills or tablets, or manipulations associated with a mechanical infusion pump. In addition, an implantable, sustained-release device permits achievement of more constant blood levels than injectable or oral administration, thus permitting lower dosing levels than conventional administration methods, thereby minimizing side effects and improving therapeutic effectiveness.

[0010]

[0005] Implantable devices that have been previously described become fragile at drug substance loading greater than 70%, which limits the amount of drug substance that can be incorporated into the device and the length of time during which the device will continue to deliver therapeutical levels of the substance to a patient. Such highly loaded devices have very low tensile strength and are easily broken during implantation, explantation, and in situ for the duration of treatment. Implantable devices which maintain tensile strength at high levels of incorporation of therapeutic substances, and which may remain implanted in a patient indefinitely, are needed.

[0011] BRIEF SUMMARY OF THE INVENTION

[0012]

[0006] Implantable devices for delivery of therapeutic substances, kits, and methods of use thereof, are provided herein.

[0013]

[0007] In one aspect, implantable devices are provided for delivery of a pharmaceutical substance to an individual. The implantable devices include a polymeric matrix that is composed of a mixture of two or more ethylene vinyl acetate (EVA) copolymers blended with one or more pharmaceutical substance(s) (<?.g., one pharmaceutical substance or a multiplicity or two or more pharmaceutical substances) at a total pharmaceutical substance loading of at least about 90% (w / w). When implanted in a patient, the one or more pharmaceutical substance is continuously released through pores in the polymeric matrix that open to the surface of the device at a rate that results in a therapeutically effective steady state plasma level in the patient, ty pically for a period of time from several months to many years. In some embodiments, the one or more pharmaceutical substance is continuously released, when implanted in an individual, for a period of time from about 3 months to about 5 years.

[0014]

[0008] In some embodiments, the implantable device has dimensions that include a length of about 1 mm to about 150 mm and a diameter of about 0. 1 mm to about 6 mm.

[0009] In some embodiments, the pharmaceutical substance may be, but is not limited to, an anti-cancer agent, a pain medication, or an addiction treatment drug. The pharmaceutical substance may be a small molecule or a large molecule, and may be thermolabile or thermostable. In certain embodiments, the pharmaceutical substance is a small molecule, such as. but not limited to, anastrozole, tamoxifen, afatinib, or naltrexone. In certain embodiments, the pharmaceutical substance is a large molecule, such as, but not limited to. semaglutide, etanercept, or canakinumab.

[0015]

[0010] In some embodiments, the loading of the pharmaceutical substance in the implantable device is at least about 90% (w / w), at least about 91% (w / w). at least about 92% (w / w). at least about 93% (w / w), at least about 94%. at least about 95%. or about 90% (w / w) to about 95% (w / w).

[0016]

[0011] In some embodiments, the mixture of two or more EVA copolymers includes EVA copolymers that each contain about 10% (w / w) to about 50% (w / w) vinyl acetate, for example, in ratios in accordance with Table 1.

[0017]

[0012] In some embodiments, the implantable device further includes a bioerodible polymer, which controls the release rate of the pharmaceutical substance. The bioerodible polymer may include, but is not limited to. a poly orthoester, a polyanhydride, a polyesteramide, a polyamide, or a mixture thereof. For example, the bioerodible polymer may increase or decrease the release rate of the pharmaceutical substance by about 1-fold to about 10-fold. In some embodiments, the pharmaceutical substance may be blended with the bioerodible polymer prior to incorporation into the polymeric matrix. In some embodiments, the implantable device includes about 5% to about 10% EVA copolymer mixture (mixture of two or more EVA copolymers), about 10% to about 80% bioerodible polymer, and the remainder pharmaceutical substance. In one embodiment, the pharmaceutical substance is insoluble in water and the bioerodible polymer increases the release rate of the pharmaceutical substance from the device when the device is implanted in a patient, in comparison to an identical device that does not include the bioerodible polymer. In another embodiment, the pharmaceutical substance is soluble in water and the bioerodible polymer decreases the release rate of the pharmaceutical substance from the device when the device is implanted in a patient, in comparison to an identical device that does not include the bioerodible polymer. For example, the water soluble pharmaceutical substance may be coated with the bioerodible polymer to decrease the release rate of the pharmaceutical substance from the device when the device is implanted in a patient.

[0013] In some embodiments, the implantable device includes at least one, e.g., one or more outer layer(s) that surrounds a core that is composed of the polymeric matrix (the mixture of two or more EVA copolymers blended with the pharmaceutical substance). The outer layer may include a pharmaceutical substance that is the same or different than the pharmaceutical substance in the core. The outer layer may include an EVA copolymer with different vinyl acetate content than the core and / or may include different loading of pharmaceutical substance(s) than the core.

[0018]

[0014] In some embodiments, the pharmaceutical substance is encapsulated prior to incorporation in the polymeric matrix of the implantable device, which may control the release rate of the pharmaceutical substance and / or increase the bulk density and / or volume of solids incorporated into the device. For example, the pharmaceutical substance may be encapsulated in a polysaccharide, such as but not limited to, cyclodextrin, cellulose, starch, chitosan, and / or agar, and / or in a bioerodible polymer, such as but not limited to, a poly orthoester, a polyanhydride, a polyester-amide, and / or a polyamide.

[0019]

[0015] In another aspect, methods are provided for treatment of a chronic condition. The methods include subcutaneously implanting at least one implantable device as described herein in an individual in need thereof. The pharmaceutical substance is continuously- released through the pores that open to the surface of the device over a sustained period of time at a rate that results in a steady state plasma level of the pharmaceutical substance for an extended period of time. In some embodiments, the device is not explanted from the individual when treatment is completed or when the plasma level of the pharmaceutical substance declines. In other embodiments, the device is explanted from the individual when treatment is completed or when the plasma level of the pharmaceutical substance declines. In some embodiments, the pharmaceutical substance is continuously released from the implantable device for a period of time from about 3 months to about 5 years. In some embodiments, the chronic condition is cancer, pain, or addiction. In some embodiments, the individual is human or a non-human animal, such as anon-human mammal.

[0020]

[0016] In another aspect, methods are provided for producing an implantable device as described herein. In various embodiments, the device is produced by molding, extrusion (e.g., hot-melt extrusion), or 3D printing.

[0021]

[0017] In another aspect, kits are provided that include an implantable device as described herein, and instructions for use in a method for treatment of a chronic condition, such as but not limited to, cancer, pain, or addiction.

[0018] In another aspect, implantable devices are provided as described herein, for use in the treatment of a chronic condition, such as but not limited to, cancer, pain, or addiction.

[0022] BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 shows an embodiment of an implantable device as described herein, which includes an inner core that is surrounded by an outer layer.

[0024] DETAILED DESCRIPTION

[0025]

[0019] Polymeric implantable devices for sustained release of pharmaceutical substances are provided. The devices described herein contain one or more pharmaceutical substances in anonerodible polymeric matrix that is composed of a mixture of two or more EVA copolymers, with loading of the pharmaceutical substance in the device of at least about 90% (w / w). Methods of using the disclosed devices for treatment of chronic diseases or conditions are also provided.

[0026] Definitions

[0027]

[0020] Numeric ranges provided herein are inclusive of the numbers defining the range.

[0028]

[0021] ‘ ’A,” “an” and “the” include plural references unless the context clearly dictates otherwise.

[0029]

[0022] The term “about” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±5%, ±1%, or ±0. 1% from the specified value, as such variations are appropriate to perform the disclosed methods or in connection with a disclosed composition.

[0030]

[0023] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, / .<?., elements that are conjunctively present in some cases and disjunctively present in other cases. Additional elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified, unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and / or B,” when used in conjunction with open ended language such as “comprising” can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0024] An “approximately constant release rate'’ indicates that an approximately constant level of a pharmaceutical substance is released from an implantable device as described herein over a period of time, such as over a day, over a week, over a month, over three months, over six months, or over nine months, or over an extended period of time as described herein, such as about 3 months to about 5 years, or any of at least about 3 months. 6 months. 9 months, 12 months. 15 months. 18 months. 21 months, 24 months, 27 months, 30 months, 33 months, 36 months, 39 months, 42 months, 45 months, 48 months, 51 months, 54 months, 57 months, 60 months, or longer.

[0031]

[0025] A “bioerodible polymer’" erodes via biological processes that solubilize the polymer when in contact with a biological system.

[0032]

[0026] A “drug” or “pharmaceutical substance,” used interchangeably herein, is any biologically active agent or other substance that has therapeutic value to or a therapeutic effect on a living organism.

[0033]

[0027] “Essentially constant” means that for about 95% of an extended period of time, the concentration of pharmaceutical substance in blood plasma of the individual is within about three, about two, or preferably about one standard deviation of the mean blood plasma level.

[0034]

[0028] “Extended period of time” means from about 3 months to about 1 year, or longer, e.g., about 3 months to about 5 years, or any of at least about 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, 36 months, 39 months, 42 months, 45 months, 48 months, 51 months, 54 months, 57 months, 60 months, or longer.

[0035]

[0029] An “individual” or “patient” refers to humans and non-human animals, such as nonhuman mammals, typically a human or a non-human mammal who is in need of treatment. Non-human mammals include, but are not limited to, pet animals, such as dogs or cats, farm animals, sport animals, such as horses, primates, and rodents, such as mice or rats.

[0036]

[0030] As used herein, “nonerodible matrix” refers to a polymeric carrier that is sufficiently resistant to chemical and / or physical destruction by the environment of use such that the matrix remains essentially intact throughout the release period. The polymer is generally hydrophobic so that it retains its integrity for a suitable period of time when placed in an aqueous environment, such as the body of a mammal, and stable enough to be stored for an extended period before use.

[0037]

[0031] “Pharmaceutical” implies that a composition, reagent, method, and the like, are capable of a pharmaceutical effect, and also that the composition is capable of being administered to a subject. ‘‘Pharmaceutical effect,” without limitation, can imply that the composition, reagent, or method is capable of stimulating a desired biochemical, genetic, cellular, physiological, or clinical effect, in at least one individual, such as a mammalian subject, for example, a human or non-human mammal, in at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of a population of subjects, and the like.

[0038]

[0032] A “polymer” or “polymeric material” means a macromolecule with repeating monomer units or co-monomer units. A polymer may be bioerodible or non-bioerodible. The polymer may be a homopolymer, copolymer, terpolymer, or may contain more than three monomers. The polymer is preferably biocompatible.

[0039]

[0033] “Steady state plasma level” refers to an approximately constant level of drug over a period of time in the plasma of an individual.

[0040]

[0034] “Sustained release” refers to the release of a pharmaceutical substance such that the blood concentration remains within the therapeutic range but below toxic levels for an extended duration.

[0041]

[0035] “Treating” or “treatment” of any disease or condition refers, in one embodiment, to ameliorating the disease or condition (z.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may or may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or condition, either physically (e g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both.

[0042]

[0036] “Therapeutically effective amount” or “therapeutically effective level,” used interchangeably herein, means the amount of a compound that when administered to an individual for treating a disease or condition, is sufficient to effect such treatment for the disease or condition or to reduce severity of or eliminate at least one symptom of the disease or condition, i.e., to render a desired therapeutic outcome. The therapeutically effective amount can vary depending on the compound, the disease or condition to be treated and its severity, and the age, weight, etc., of the individual to be treated.

[0043] Polymeric matrix

[0044]

[0037] An implantable device as described herein contains one or more pharmaceutical substance in a nonerodible polymeric matrix that contains two or more ethylene vinyl acetate (EVA) copolymers, z.e., two or more different EVA copolymers. EVA is a copolymer of ethylene and vinyl acetate. The weight percent of vinyl acetate typically varies from 10% to 50%. with the remainder ethylene. Two or more EVA copolymers with different vinyl acetate percentages are combined to provide a polymeric matrix of an implantable device as described herein.

[0045]

[0038] The polymeric matrix contains openings or pores that allow the pharmaceutical substance(s) to release from the device when implanted into an individual, such that a therapeutically effective steady state plasma level is achieved in the individual for treatment of a disease or condition for which administration of the pharmaceutical substance(s) provides a therapeutic benefit. The pharmaceutical substance is released in a controlled manner over an extended period of time through multiple pores that open to the outer surface of the polymeric matrix. The pharmaceutical substance is loaded within the polymeric matrix at a loading of about 90% (w / w) to about 95% (w / w), or at least about 90% (w / w). 91% (w / w), 92% (w / w), 93% (w / w), 94% (w / w), or 95% (w / w), and the two or more polymers are selected such that the implantable device maintains high drug loading (at least about 90% (w / w)) and high tensile strength.

[0046]

[0039] EVA copolymers with different vinyl acetate content are mixed to increase the tensile strength of the implant, which permits drug loading at the levels described herein. For example, each of the two or more EVA copolymers may contain about 5% (w / w) to about 50% (w / w), about 10% (w / w) to about 50% (w / w), about 5% (w / w) to about 35% (w / w), about 10% (w / w) to about 30% (w / w), or about 15% (w / w) to about 35% (w / w) vinyl acetate. Exemplary, but nonlimiting ratios of EVA copolymers for use in an implantable device as described herein are provided in Table 1.

[0047] Table 1

[0048]

[0040] For example, the implantable device may contain about 10% to about 30% of 7% (w / w) to about 18% (w / w), about 5% (w / w) to about 20% (w / w), about 10% (w / w) to about 20% (w / w). about 10% (w / w) to about 15% (w / w), or about 15% (w / w) to about 20% (w / w) EVA, and about 70% to about 90% of 28% (w / w) to about 33% (w / w) EVA, about 25% (w / w) to about 35% (w / w), about 25% (w / w) to about 30% (w / w), or about 30% (w / w) to about 35% (w / w) EVA.

[0049]

[0041] In some embodiments, the pharmaceutical substance is blended with a bioerodible polymer prior to incorporation in the polymeric matrix, which may increase or decrease the release rate of the pharmaceutical substance from the implantable device when implanted in an individual. For example, the release rate of the pharmaceutical substance may be increased or decreased about 1-fold to about 10-fold, or increased or decreased any of at least about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, in comparison to an identical implantable device that does not include the bioerodible polymer. The bioerodible polymer may be, but is not limited to, a poly orthoester, a polyanhydride, a polyester-amide, a polyamide, or mixtures thereof. The device may include about 5% (w / w) to about 10% (w / w) EVA copolymer mixture, about 10% (w / w) to about 80% (w / w), or any of about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, or 80% (w / w), or any of about 10% (w / w) to about 25% (w / w), about 25% (w / w) to about 80% (w / w), about 30% (w / w) to about 60% (w / w), about 10% (w / w) to about 30% (w / w), about 20% (w / w) to about 40% (w / w), about 30% (w / w) to about 50% (w / w), about 40% (w / w) to about 60% (w / w), about 50% (w / w) to about 70% (w / w), or about 60% (w / w) to about 80% (w / w) bioerodible polymer, and the remainder pharmaceutical substance. In some embodiments, the pharmaceutical substance is insoluble in water and the bioerodible polymer increases the release rate of the substance when the device is implanted in an individual, such as increases the release rate of the pharmaceutical substance by about 1-fold to about 10-fold, or any of at least about 1-fold, 2-fold, 3-fold, 4- fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, in comparison to an identical implantable device that does not include the bioerodible polymer. In some embodiments, the pharmaceutical substance is soluble in water and the bioerodible polymer decreases the release rate of the pharmaceutical substance by about 1-fold to about 10-fold, or any of at least about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, in comparison to an identical implantable device that does not include the bioerodible polymer. For example, the water soluble pharmaceutical substance may be coated with the bioerodible polymer, which decreases the release rate.

[0050]

[0042] In some embodiments, the pharmaceutical substance is encapsulated prior to incorporation in the polymeric matrix, e.g., prior to blending with the EVA copolymers. Encapsulation may serve to control the release rate (increase or decrease the release rate) of the pharmaceutical substance from the implantable device, and / or may service to increase the bulk density’ and / or volume of solids that may be incorporated into the polymeric matrix. In some embodiments, the pharmaceutical substance is encapsulated in a polysaccharide prior to incorporation into the polymeric matrix, such as, but not limited to, cyclodextrin, cellulose, starch, chitosan, agar, or mixtures thereof. In some embodiments, the pharmaceutical substance is encapsulated in a bioerodible polymer prior to incorporation into the polymeric matrix, such as, but not limited to, a polyorthoester, a polyanhydride, a polyester-amide, a polyamide, or mixtures thereof.

[0051]

[0043] In some embodiments, the pharmaceutical substance is soluble in and is dissolved in the EVA copolymers, e.g., as a homogenous or substantially homogenous mixture. In other embodiments, the pharmaceutical substance is not soluble in the EVA copolymers and is mixed with the EVA copolymers, e.g., as a heterogenous mixture.

[0052]

[0044] In some embodiments, an implantable device as described herein contains a radiopaque substance, such as. but not limited to, banum sulfate, to easily locate the implant, e.g., via x-ray, ultrasound, or magnetic resonance imaging (MRI).

[0053] Pharmaceutical substances

[0054]

[0045] An implantable device as described herein may include one or more pharmaceutical substance(s) for treatment of any disease or condition for which administration of the substance(s) may be therapeutically beneficial. For example, the pharmaceutical substance may be therapeutically beneficial for treating a chronic condition, such as, but not limited to, cancer, pain, or addiction (e.g., addiction to opioids or other addictive substances). In certain embodiments, the pharmaceutical substance is a chemotherapeutic substance for treatment of cancer, an analgesic substance for treatment of pain, or a substance for treatment of addiction, such as a substance that assists with reduction of self-administration of addictive substances such as nonprescribed drugs. The pharmaceutical substance may be a small molecule or a large molecule, and may be thermolabile or thermostable.

[0055]

[0046] In some embodiments, the pharmaceutical substance is a small molecule, such as, but not limited to, anastrozole, tamoxifen, afatinib, or naltrexone.

[0056]

[0047] In some embodiments, the pharmaceutical substance is a large molecule, such as, but not limited to, semaglutide, etanercept, or canakinumab.

[0057] Implantable devices

[0048] Implantable devices are provided herein, for use in sustained release of pharmaceutical substances when implanted in an individual in need thereof. An implantable device includes a nonerodible polymeric matrix as described herein, which contains one or more pharmaceutical substance and two or more EVA copolymers. Optionally, the implantable device includes one or more bioerodible polymer as described herein. Optionally, the implantable device contains one or more outer layer that surrounds the polymeric matrix in the core of the device.

[0058]

[0049] An implantable device as described herein may be in any suitable dimensions for implantation, e.g., subcutaneous implantation, in an individual. For example, the device may have a length of about 1 mm to about 150 mm, about 1 mm to about 5 mm, about 1 mm to about 10 mm, about 1 mm to about 50 mm, about 5 mm to about 25 mm, about 10 mm to about 150 mm, about 10 mm to about 50 mm, about 20 mm to about 60 mm, about 30 mm to about 80 mm, about 50 mm to about 90 mm, about 60 mm to about 110 mm, about 70 mm to about 120 mm, about 80 mm to about 130 mm. about 90 mm to about 140 mm, about 100 mm to about 150 mm, about 10 mm to about 90 mm, about 50 mm to about 150 mm, or about 25 mm to about 75 mm, and a diameter of about 0. 1 mm to about 6 mm, about 0. 1 mm to about 0.5 mm, about 0.5 mm to about 3 mm, 0.5 mm to about 6 mm, about 1 mm to about 3 mm, about 2 mm to about 4 mm, about 3 mm to about 5 mm, about 4 mm to about 6 mm, about 0.5 mm to about 2.5 mm, about 3 mm to about 6 mm, or about 1 mm to about 5 mm.

[0059]

[0050] In certain embodiments, the implantable device includes one or more outer layer that surrounds the polymeric matrix as described herein as the core of the device. For example, the implantable device may include a core polymeric matrix containing a core pharmaceutical substance, surrounded by a first layer that contains a first layer polymeric material and optional first layer pharmaceutical substance(s), and optionally further surrounded by one or more additional layer each containing an additional polymeric material and optional additional pharmaceutical substance(s). The core, first layer, and optional additional pharmaceutical substances may be the same or different. The core, first layer, and optional additional polymeric materials may be the same or different. In some embodiments, the outer layer(s) contain one or more EVA copolymer, e.g., in different ratios or with different vinyl acetate content than the core. In other embodiments, the outer layer(s) contain the same polymeric composition as the core. In some embodiments, the outer layer(s) contain different loading of the same pharmaceutical substance as the pharmaceutical substance that is in the core, i.e., the loading of the pharmaceutical substance in the core is different than the loading of the pharmaceutical substance in the first layer and the loading in optional additional layers may be the same or different than the loading in the first layer. In some embodiments, the loading of the pharmaceutical substance in one or more outer layer(s) is 90% (w / w) or greater.

[0060]

[0051] In an implantable device with a single polymeric core, and no outer layers, drug delivery can have a controlled release during the life of implant. In a device with one or more outer layer, the varying concentration of drug in different layers can be used to modulate the rate of drug delivery over time. In one embodiment, the device displays a generally linear release of drug over time. In another embodiment, drug release from the device is approximately constant or essentially constant over the lifetime of the device, or for a specified period within the lifetime of the device. The drug may be released from the device, layer by layer, from outer-most to inner-most layers to the core. However, each layer will have a diameter and surface area smaller than the layer outside it. Thus, the core and layers closer to the interior will need to have a higher concentration of drug than more outer layers, in order to maintain an approximately constant or essentially constant rate of drug release. In another embodiment, the concentrations of drug layer-by-layer can be designed to create different rates of drug release. For example, if each layer contains the same or a lower drug concentration than the adjoining further outer layer, this will result in a tapered, ever-decreasing rate of drug delivery'. Modulating concentrations of drug layer- by-layer can also produce a slow rise in drug delivery over the lifetime of the implant or over a specified period during the lifetime of the implant. Alternating layers of relatively high and low concentrations of drug can produce a pulsed rate of drug delivery that rises and falls over time.

[0061]

[0052] The device may be designed to provide a steady-state concentration of drug in the blood plasma of the individual in whom the device is implanted. The device may be designed such that the resulting concentration of drug in the blood plasma remains essentially constant over an extended period of time. The device may be designed such that the resulting concentration of drug in the blood plasma remains approximately constant over an extended period of time. Steady state plasma levels remain in the therapeutic window for a particular pharmaceutical substance over an extended period of time, such as about 3 months to about 5 years, or any of at least about 3 months, 6 months, 9 months, 12 months. 15 months. 18 months. 21 months, 24 months, 27 months, 30 months, 33 months, 36 months, 39 months, 42 months, 45 months, 48 months, 51 months, 54 months, 57 months, 60 months, or longer.

[0062]

[0053] The implantable devices described herein may be produced, for example, in a process that includes molding, extrusion (e.g., hot melt extrusion), or 3D printing.

[0063] Methods of treatment

[0064]

[0054] Methods of treatment are provided, which include administration of one or more implantable device as described herein in an individual in need thereof, z.e., an individual in need of continuous treatment with a pharmaceutical substance. The implantable device(s) include one or more pharmaceutical substance(s). The pharmaceutical substance(s) are released continuously through pores that open to the surface of the polymeric matrix, at a rate that results in a steady state plasma level of the pharmaceutical substance(s) over an extended period of time. The steady state plasma level may be maintained, for example, for about 3 months to about 5 years, or for any of at least about 3 months, 6 months. 9 months. 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, 36 months, 39 months, 42 months, 45 months, 48 months, 51 months, 54 months, 57 months, 60 months, or longer. In some embodiments, the implantable device is not explanted from the individual when treatment is completed. In some embodiments, the implantable device is not explanted from the individual when the plasma level declines. The individual may be a human or a non-human animal, e.g., a non-human mammal.

[0065]

[0055] In some embodiments, a multiplicity (z.e., two or more) implantable devices as described herein are implanted in the individual. Each of the implanted devices may contain the same pharmaceutical substance(s) or different pharmaceutical substance(s) than other device(s) that are implanted in the individual. In some embodiments, multiple implantable devices or implantable devices of different sizes or dimensions may be implanted concurrently to achieve a target plasma level for a pharmaceutical substance or target plasma levels for multiple (two or more) pharmaceutical substances. In various embodiments, multiple (two or more) pharmaceutical substances can be delivered from a single implantable device or from separate implantable devices that are implanted together in the same location or at different locations in the individual.

[0066]

[0056] The implantable devices may be administered by subcutaneous implantation. In various embodiments, the devices are subcutaneously implanted at a site selected from the upper arm, the back, and the abdomen.

[0057] The methods described herein may be applied to treatment of a chronic disease or condition, such as, but not limited to, cancer, chronic pain, or addiction, such as opioid addiction, i.e., a method for treatment of cancer (i.e., treatment for amelioration or elimination of at least one symptom of cancer), chronic pain (i.e., treatment for alleviation of pain), or addiction (i.e., treatment and / or management of a substance use disorder, such as but not limited to opioid use disorder or alcohol use disorder).

[0067]

[0058] In the methods described herein, the implantable device(s) deliver the pharmaceutical substance(s) therein at a rate that results in a steady state plasma level of the pharmaceutical substance(s) in the individual over an extended period of time. For example, the steady state plasma level of the pharmaceutical substance may vary by no more than about ±30%, ±20%, or ±10% over a day, over a week, over about 3 months to about 5 years, or over any of at least about 3 months, 6 months, 9 months, 12 months, 15 months. 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, 36 months, 39 months. 42 months. 45 months. 48 months, 51 months, 54 months, 57 months, 60 months, or longer, as compared to the mean or average plasma level over that time period. In some embodiments, the approximately constant release rate is no more than about ±30%, ±20%, or ±10% over the time period indicated, such over a day, over a week, over about 3 months to about 5 years, or over any of at least about 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months, 24 months, 27 months, 30 months, 33 months, 36 months, 39 months, 42 months, 45 months, 48 months, 51 months, 54 months, 57 months, 60 months, or longer, as compared to the average or mean release rate. In some embodiments, the release rate may be essentially constant over the extended time period, i.e., for about 95% of the extended period of time. In some embodiments, the concentration of the pharmaceutical substance is within about three, about two, or preferably about one standard deviation of the mean blood plasma level.

[0068] Kits

[0069]

[0059] Kits are provided which include one or a multiplicity of implantable devices as described herein, and instructions for use in treatment of a disease or condition. Instructions may be provided in printed form or in the form of an electronic medium such as a CD or DVD, or in the form of a website address where such instructions may be obtained or a mobile application.

[0060] The kits include at least one implantable, nonerodible device of the type herein described, capable of delivering long-term therapeutic levels of one or more pharmaceutical substance(s), in suitable packaging, along with instructions providing information to the user and / or health care provider regarding subcutaneous implantation and use of the device(s) for treating a disease or condition, such as cancer, pain, or addiction. Kits may also include literature discussing performance of the implantable devices.

[0070]

[0061] Kits include a deliver}' system, i.e., one or a multiplicity of implantable devices, capable of providing sustained release of therapeutic levels of one or more pharmaceutical substance(s) for at least about 3 months, 6 months, 9 months, 12 months, 15 months, 18 months. 21 months. 24 months, 27 months, 30 months, 33 months, 36 months, 39 months, 42 months, 45 months, 48 months, 51 months, 54 months, 57 months, 60 months, or longer.

[0071]

[0062] Kits may include implantable devices that are preloaded into devices such as, for example, syringes or trocars, capable of administering the devices by subcutaneous implantation into patients.

[0072]

[0063] Although the foregoing invention has been described in some detail by way of illustration and examples for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced without departing from the spirit and scope of the invention, which is delineated in the appended claims. Therefore, the description should not be construed as limiting the scope of the invention.

[0073]

[0064] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entireties for all purposes and to the same extent as if each individual publication, patent, or patent application were specifically and individually indicated to be so incorporated by reference.

Claims

CLAIMSWe claim:

1. An implantable device for delivery of a pharmaceutical substance to a patient, comprising: a nonerodible polymeric matrix that comprises a mixture of two or more ethylene vinyl acetate (EVA) copolymers blended with a pharmaceutical substance at a loading of at least about 90% (w / w), wherein the pharmaceutical substance is continuously released through pores that open to the surface of the device at a rate that results in a therapeutically effective steady state plasma level when the device is implanted in the patient.

2. The implantable device according to claim 1, wherein the device comprises dimensions comprising a length of about 1 mm to about 150 mm and a diameter of about 0. 1 mm to about 6 mm.

3. The implantable device according to claim 1, wherein the pharmaceutical substance is an anti-cancer agent, a pain medication, or an addiction treatment drug.

4. The implantable device according to claim 1, wherein the pharmaceutical substance comprises a small molecule or a large molecule, and wherein the pharmaceutical substance is thermolabile or thermostable.

5. The implantable device according to claim 4, wherein the pharmaceutical substance comprises a small molecule selected from anastrozole, tamoxifen, afatinib, and naltrexone.

6. The implantable device according to claim 4, wherein the pharmaceutical substance comprises a large molecule selected from semaglutide, etanercept, and canakinumab.

7. The implantable device according to claim 1 , wherein the loading of the pharmaceutical substance is about 90% to about 95% (w / w).

8. The implantable device according to claim 1. wherein the mixture of EVA copolymerscomprises two or more EVA copolymers each comprising about 10% (w / w) to about 50% (w / w) vinyl acetate.

9. The implantable device according to claim 1, wherein the mixture of EVA copolymers comprises EVA copolymers with vinyl acetate percentage and in ratios in accordance with Table 110. The implantable device according to claim 1, wherein the pharmaceutical substance is continuously released, when implanted in a patient, for a period of time from about 3 months to about 5 years.

11. The implantable device according to claim 1, wherein the device further comprises a bioerodible polymer which controls the release rate of the pharmaceutical substance.

12. The implantable device according to claim 11 , wherein the bioerodible polymer increases or decreases the release rate of the pharmaceutical substance by about 1-fold to about 10-fold.

13. The implantable device according to claim 11, wherein the pharmaceutical substance is blended with the bioerodible polymer prior to incorporation into the polymeric matrix.

14. The implantable device according to claim 13, wherein the device comprises the nonerodible polymeric matrix at about 5% to about 10%, the bioerodible polymer at about 10% to about 80%, and the remainder pharmaceutical substance.

15. The implantable device according to claim 11 , wherein the bioerodible polymer comprises a polyorthoester, a polyanhydride, a polyester-amide, a polyamide, or a mixture thereof.

16. The implantable device according to any of claim 1 1 , wherein the pharmaceutical substance is insoluble in w ater and the bioerodible polymer increases the release rate of the pharmaceutical substance from the device when the device is implanted in a patient.

17. The implantable device according to claim 11, wherein the pharmaceutical substance is soluble in water and the bioerodible polymer decreases the release rate of the pharmaceutical substance from the device when the device is implanted in a patient.

18. The implantable device according to claim 1, wherein the device comprises at least one outer layer that surrounds a core comprising the nonerodible polymeric matrix, wherein the outer layer comprises a pharmaceutical substance.

19. The implantable device according to claim 18, wherein the pharmaceutical substance in the core and the pharmaceutical substance in the outer layer are the same.

20. The implantable device according to claim 18, wherein the pharmaceutical substance in the core and the pharmaceutical substance in the outer layer are different.

21. The implantable device according to claim 18, wherein the outer layer comprises an EVA copolymer or a mixture of EVA copolymers with different vinyl acetate content than the EVA copolymers in the polymeric matrix in the core and / or comprises different loading of pharmaceutical substance(s) than the core.

22. The implantable device according to claim 1, wherein the pharmaceutical substance is encapsulated prior to incorporation in the polymeric matrix to control release rate of the pharmaceutical substance and / or to increase bulk density and / or volume of solids incorporated into the implantable device.

23. The implantable device according to claim 22, wherein the pharmaceutical substance is encapsulated in a polysaccharide and / or a bioerodible polymer.

24. The implantable device according to claim 23, wherein the polysaccharide comprises cyclodextrin, cellulose, starch, chitosan, and / or agar.

25. The implantable device according to claim 23, wherein the bioerodible polymer comprises a poly orthoester, a polyanhydride, a polyester-amide. a polyamide, or a mixture thereof.

26. The implantable device according to claim 1, further comprising a radiopaque substance.

27. A method for treatment of a chronic condition, comprising subcutaneously implanting at least one implantable device according to any of claims 1 to 26 in an individual in need thereof. wherein the pharmaceutical substance is continuously released through the pores that open to the surface of the device over a sustained period of time at a rate that results in a steady state plasma level of the pharmaceutical substance for an extended period of time.

28. The method according to claim 27, wherein the device is not explanted from the individual when treatment is completed or when the plasma level declines.

29. The method according to claim 27, wherein the extended period of time is about 3 months to about 5 years.

30. The method according to claim 27, wherein the chronic condition comprises cancer, pain, or addiction.

31. The method according to claim 27, wherein the patient is a human.

32. A method of producing an implantable device according to any of claims 1 to 26, wherein the device is produced by molding, extrusion, or 3D printing.

33. A kit comprising an implantable device according to any of claims 1 to 26. and instructions for use in a method for treatment of a chronic condition.

34. The kit according to claim 33, wherein the chronic condition comprises cancer, pain, or addiction.

35. An implantable device according to any of claims 1 to 26 for use in the treatment of a chronic condition.

36. The implantable device according to claim 35, wherein the chronic condition comprises cancer, pain, or addiction.

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