Implants for release of lipophilic or amphiphilic pharmaceutical substances

Abstract

To provide implants containing lipophilic or amphiphilic pharmaceutical substances that can be implanted in a patient to release the pharmaceutical substances, and to provide methods for making and using such structures.SOLUTION: Implants containing a lipophilic pharmaceutical agent are described. Excipients are used that provide a proper and controllable / tunable release of a lipophilic drug from the matrix of the implant. The implant can be implanted in a patient to release the pharmaceutical agent. Methods of making and using such implants are also described.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 689,735, filed June 25, 2018, the entire contents of which are incorporated herein by reference.

[0002] Technical Field Implants containing a lipophilic or amphiphilic pharmaceutical agent that can be implanted in a patient to release the pharmaceutical agent, as well as methods of making and using such structures, are provided. [Background technology]

[0003] 2. Background of the Invention Many patients require long-term and regular administration of drugs or medicinal substances. Several problems can occur during long-term administration of drugs by oral ingestion or other routes requiring frequent administration. Compliance with long-term medication regimens can often be inconvenient or difficult. For example, patients with impaired cognitive function (due to Alzheimer's disease or other disorders) may not be able to reliably self-administer drugs, and caregivers must ensure that medications are taken appropriately. Furthermore, enteral drug delivery is sometimes poorly tolerated or prohibited in patients with certain indications. Frequent or periodic administration, such as occurs with daily oral and sublingual delivery, can result in blood levels of the drug peaking soon after the initial dose and then dropping sharply before the next dose. Intravenous drug delivery requires trained personnel for administration and is impractical for long-term outpatient treatment.

[0004] Implants used for drug delivery can overcome some of the problems associated with oral, sublingual or intravenous administration of drugs. These implantable devices provide long-term and continuous delivery of drugs, ensure patient-independent compliance, maintain stable blood levels of drugs, and reduce the possibility of accidental use, abuse or diversion to sale. Continuous release of compounds in vivo over long periods of time can be achieved through implantation of a device containing a compound encapsulated in a polymer matrix. Examples of implantable polymeric devices for continuous drug release are described, for example, in U.S. Pat. Nos. 4,883,666, 5,114,719 and 5,601,835. Patel et al., U.S. Patent No. 7,736,665, U.S. Patent Application Publication Nos. 2004 / 0033250, 2007 / 0275031, and 2008 / 0026031, and Kleppner et al., 2006 J.Pharm. Pharmacol. 58:295-302, describe implantable devices containing buprenorphine blended with ethylene vinyl acetate (EVA copolymer). Patel et al., U.S. Patent Application Publication No. 2005 / 0031668, describe implantable polymeric devices for sustained release of nalmefene. Patel et al., U.S. Patent Application Publication No. 2005 / 0031667, describe implantable polymeric devices for sustained release of dopamine agonists. Additional drug delivery devices include stents coated with a drug-containing composition. Various devices and coatings are described in U.S. Patent No. 6,506,437 to Harish, U.S. Patent No. 7,364,748 to Claude, and U.S. Patent No. 7,384,660 to Hossainy. U.S. Patent No. 3,625,214 describes a drug delivery device manufactured in a spiral or "jelly roll" fashion for long-term drug delivery.U.S. Patent No. 3,926,188 describes a three-layer laminate drug dispenser that includes a core layer of a poorly water-soluble crystalline drug dispersed in a polymer matrix, interposed between outer layers made of a drug release rate controlling polymer.U.S. Patent No. 5,683,719 describes a controlled release composition that includes an extruded core of active material and excipients, the core being coated with a water-insoluble coating.

[0005] However, certain drugs are not released well from the implants. In particular, lipophilic and amphiphilic drugs can interact strongly with the materials from which the implant is manufactured, resulting in poor or no elution from the implant. Disclosed herein is an implant that overcomes this problem. Summary of the Invention

[0006] Brief Summary of the Invention Disclosed herein is an implant comprising a matrix, a pharmaceutical agent, and at least one excipient, wherein the pharmaceutical agent comprises a lipophilic moiety. The implant can be a subcutaneous implant. In some embodiments, at least about 50% more of the pharmaceutical agent is released from the implant disclosed herein than from a comparable implant lacking the excipient in an aqueous environment over a defined period of time. The defined period of time can be about 6 hours, about 24 hours, about 72 hours, or about 7 days. The aqueous environment can be selected from an aqueous solution, a subcutaneous location in a test animal, or a subcutaneous location in a human. The aqueous environment or aqueous solution can include an aqueous solution comprising about 137 mM NaCl, about 2.7 mM KCl, about 10 mM Na2HPO4, and about 1.8 mM KH2PO4 at about pH 7.4 and about 37°C.

[0007] In some embodiments, the excipient can include a compound selected from the group consisting of sugar alcohols and biodegradable polymers. In some embodiments, the excipient can include a compound selected from the group consisting of mannitol, glycerol, erythritol, threitol, arabitol, ribitol, xylitol, fucitol, galactitol, iditol, inositol, sorbitol, volemitol, isomalt, lactitol, and maltitol. In some embodiments, the excipient includes mannitol. In some embodiments, the excipient includes poly(lactic-co-glycolic) acid (PLGA).

[0008] In some embodiments, lipophilic pharmaceutical agents include lipids such as fatty acids, monoglycerides, diglycerides, triglycerides, phospholipids, and steroids.

[0009] In some embodiments, the lipophilic pharmaceutical agent comprises a lipidated peptide.

[0010] In some embodiments, the lipophilic pharmaceutical agent comprises a fatty acid covalently attached to a peptide, such as liraglutide.

[0011] In some embodiments, the matrix of the implant comprises a non-biodegradable polymer, such as a polymer selected from the group consisting of ethylene vinyl acetate, polyolefin, polyethylene, polypropylene, polybutylene, polyolefin copolymer, ethylene-methacrylic acid, ethylene-acrylic acid, vinyl aromatic polymer, polystyrene, vinyl aromatic copolymer, styrene-isobutylene copolymer, butadiene-styrene copolymer, polyvinyl alcohol, polyacetal, chloropolymer, polyvinyl chloride (PVC), fluoropolymer, polytetrafluoroethylene (PTFE), polyester, polyethylene terephthalate (PET), polyester-ether, polyamide, nylon-6, nylon-6,6, polyether, polyamide ether, silicone, polyurethane, polyurethane copolymer, polycarbonate, polycarbonate-based polyurethane, and mixtures or copolymers of any of the foregoing. In some embodiments, the non-biodegradable polymer comprises ethylene vinyl acetate.

[0012] Also disclosed herein is an implant comprising a matrix, a pharmaceutical agent, and at least one excipient, wherein the pharmaceutical agent forms micelles in an aqueous solution, in some embodiments, the aqueous solution is phosphate buffered saline (PBS) at about pH 7 to about pH 8.

[0013] Also disclosed herein is an implant comprising a matrix, a pharmaceutical agent, and at least one excipient, wherein the pharmaceutical agent is amphiphilic.

[0014] Also disclosed herein is an implant comprising a matrix, a pharmaceutical agent and at least one excipient, wherein the pharmaceutical agent is co-lyophilized with the excipient to form a pharmaceutical agent-excipient mixture, and then the pharmaceutical agent-excipient mixture is incorporated into the matrix. The pharmaceutical agent can be selected from the group consisting of pharmaceutical agents that include a lipophilic moiety, pharmaceutical agents that form micelles in aqueous solution, and pharmaceutical agents that are amphiphilic. In some embodiments, the pharmaceutical agent is liraglutide. In some embodiments, the excipient is a sugar alcohol such as mannitol. In some embodiments, the excipient is poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the matrix is ​​ethylene vinyl acetate (EVA).

[0015] In any of the embodiments disclosed herein, the ratio of excipient:drug agent can range from about 5:1 to about 1:10 by weight, such as from about 1:1 to about 1:6 by weight.

[0016] In any of the embodiments disclosed herein, the mass ratio of matrix:(drug substance+excipients) can range from about 10:1 to about 1:4, such as from about 5:1 to about 1:3.

[0017] Also disclosed herein is a subdermal implant comprising about 40% to about 60% by weight ethylene vinyl acetate and about 60% to about 40% by weight of a mannitol:liraglutide mixture, where the mannitol:liraglutide mixture comprises about 10% to about 30% by weight mannitol and about 90% to about 70% by weight liraglutide.The subdermal implant can comprise about 50% by weight ethylene vinyl acetate and about 50% by weight of a mannitol:liraglutide mixture, where the mannitol:liraglutide mixture comprises about 20% by weight mannitol and about 80% by weight liraglutide.

[0018] In any of the embodiments disclosed herein, the implant can be from about 1 cm to about 5 cm in length and from about 1 mm to about 3 mm in diameter.

[0019] In any of the embodiments disclosed herein, the implant can be a subdermal implant.

[0020] In any of the embodiments disclosed herein, the implant can be prepared by hot melt extrusion.

[0021] In any of the embodiments disclosed herein, the implant may be dip coated, for example, dip coated with ethylene vinyl acetate, which may be performed by immersing the implant in a 1% solution of EVA prepared in dichloromethane (DCM). [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows the average liraglutide in vitro release from 1.5 mm diameter by 26 mm length extrudates with an EVA dip coated shell on a 50% EVA core formulation, expressed as % payload released. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Detailed Description of the Invention Disclosed herein is an implant for long-lasting drug delivery of lipophilic or amphiphilic pharmaceutical agents. In one embodiment, the implant has reduced burst release upon implantation. The implant comprises a matrix, a pharmaceutical agent or agents, and at least one excipient, where the pharmaceutical agent comprises a lipophilic moiety, or when multiple pharmaceutical agents are present, at least one of the pharmaceutical agents comprises a lipophilic moiety, or at least one of the pharmaceutical agents is amphiphilic. A pharmaceutical agent that comprises a lipophilic moiety can comprise one lipophilic moiety, more than one lipophilic moiety, or the entire pharmaceutical agent can be considered as a lipophilic moiety (such as cholestane). The release rate of the one or more pharmaceutical agents, the total extent of release of the one or more pharmaceutical agents, or both the release rate and total extent of release of the one or more pharmaceutical agents from the implant is increased by the formulation of the implant with one or more pharmaceutical agents together with at least one excipient as compared to the release rate of the one or more pharmaceutical agents, the total extent of release of the one or more pharmaceutical agents, or both the release rate and total extent of release of the one or more pharmaceutical agents from an implant formulated with one or more pharmaceutical agents without at least one excipient.

[0024] Definitions and general explanations "Drug" and "pharmaceutical substance" are equivalent terms, used interchangeably, and include any substance intended for therapeutic, diagnostic or nutritional use in a patient, individual or subject in need thereof. "Drug" and "pharmaceutical substance" include, but are not limited to, diagnostic agents, therapeutic agents, hormones, nutrients, vitamins and minerals.

[0025] "Porogen" refers to a first material that is embedded in or mixed with a second material and that can be removed (e.g., by dissolution, diffusion, or decomposition) from the second material. Removal of the porogen results in the creation of pores in the second material.

[0026] "Biocompatible," when used to describe a material or system, indicates that the material or system causes no adverse reactions, or only minimally acceptable adverse effects, when in contact with a living organism, such as a human.

[0027] A "patient", "individual" or "subject" refers to a mammal, preferably a human, an agricultural animal such as a cow, pig, goat, sheep, or a domestic animal such as a dog or cat. In a preferred embodiment, the patient, individual or subject is a human.

[0028] "Treatment" of a disease or disorder with the implants and methods disclosed herein is defined as administering one or more implants disclosed herein to a patient in need thereof, with or without additional agents, to reduce or eliminate the disease or disorder, or one or more symptoms of the disease or disorder, or to slow the progression of the disease or disorder, or one or more symptoms of the disease or disorder, or to reduce or eliminate the severity of the disease or disorder, or one or more symptoms of the disease or disorder. "Suppression" of a disease or disorder with the implants and methods disclosed herein is defined as administering one or more implants disclosed herein to a patient in need thereof, with or without additional agents, to inhibit the clinical signs of the disease or disorder, or to inhibit the development of adverse symptoms of the disease or disorder. The difference between treatment and suppression is that treatment occurs after adverse symptoms of the disease or disorder appear in the patient, whereas suppression occurs before adverse symptoms of the disease or disorder appear in the patient. Suppression can be partial, substantially total, or total. Because some diseases or disorders are inherited, genetic screening can be used to identify patients at risk for the disease or disorder. The implants and methods as disclosed herein can then be used in asymptomatic patients at risk for developing clinical symptoms of the disease or disorder to inhibit the appearance of any adverse symptoms.

[0029] A "therapeutic use" of the implants disclosed herein is defined as using one or more implants disclosed herein to treat a disease or disorder, as defined above. A "therapeutically effective amount" of a drug, pharmaceutical substance, or therapeutic agent is an amount of the drug, pharmaceutical substance, or agent that, when administered to a patient, is sufficient to alleviate or eliminate a disease or disorder, or one or more symptoms of the disease or disorder, or slow the progression of a disease or disorder, or one or more symptoms of the disease or disorder, or reduce the severity of a disease or disorder, or one or more symptoms of the disease or disorder. A therapeutically effective amount can be administered to a patient as a single dose, or can be divided and administered as multiple doses. In the context of an implantable device, a therapeutically effective amount describes the amount released from the implant that is sufficient to alleviate or eliminate a disease or disorder, or one or more symptoms of the disease or disorder, or slow the progression of a disease or disorder, or one or more symptoms of the disease or disorder, or reduce the severity of a disease or disorder, or one or more symptoms of the disease or disorder. One or more implants can be used to deliver a therapeutically effective amount.

[0030] The "prophylactic use" of the implants disclosed herein is defined as using one or more implants disclosed herein to inhibit a disease or disorder, as defined above. A "prophylactically effective amount" of a drug, pharmaceutical substance, or therapeutic agent is an amount of the drug, pharmaceutical substance, or agent that, when administered to a patient, is sufficient to inhibit the onset of clinical symptoms of a disease or disorder, or inhibit the manifestation of adverse symptoms of a disease or disorder. A prophylactically effective amount can be administered to a patient as a single dose, or can be divided and administered as multiple doses. In the context of an implantable device, a prophylactically effective amount describes an amount released from the implant that is sufficient to reduce or eliminate a disease or disorder, or one or more symptoms of a disease or disorder, or to slow the progression of a disease or disorder, or to reduce the severity of a disease or disorder, or one or more symptoms of a disease or disorder. One or more implants can be used to deliver a prophylactically effective amount.

[0031] "Blood concentration" as used herein refers to the concentration of a drug, pharmaceutical agent, therapeutic agent, hormone, metabolite or other substance in the blood of a subject. Blood concentrations can be measured in whole blood, serum or plasma according to standard clinical laboratory practices for the substance being analyzed.

[0032] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated or the context clearly dictates otherwise.

[0033] In this specification, when the term "about" or "approximately" is used to express a numerical value, it is understood that both the specified value and a value reasonably close to the specified value are included. For example, the description "about 50°C" or "approximately 50°C" includes both the disclosure of 50°C itself and values ​​close to 50°C. Thus, the phrase "about X" or "approximately X" includes the value X itself. When a range is indicated, such as "approximately 50°C to 60°C" or "approximately 50°C to 60°C", it is understood that both values ​​specified at the ends are included, and for each or both ends, values ​​close to each or both ends are included. That is, "approximately 50°C to 60°C" ("approximately 50°C to 60°C") is equivalent to describing both "50°C to 60°C" and "approximately 50°C to approximately 60°C" (or "approximately 50°C to 60°C").

[0034] With respect to the numerical ranges disclosed in this description, a disclosed upper limit for an ingredient or parameter can be combined with a disclosed lower limit for that ingredient or parameter to provide a range (provided that the upper limit is greater than the lower limit with which it is combined). Each of these combinations of the disclosed upper and lower limits is expressly contemplated herein. For example, if a range of the amount of a particular ingredient or parameter is specified as 10%-30%, 10%-12%, and 15%-20%, then ranges of 10%-20% and 15%-30% are also contemplated, while a lower limit of 15% cannot be combined with an upper limit of 12%, and therefore is not contemplated.

[0035] Unless otherwise specified, the percentage of a component in a composition is expressed as weight percent or weight / weight percent. It is understood that a reference to a relative weight percent in a composition is based on the assumption that the total weight percent of all components in the composition totals 100. It is further understood that the relative weight percent of one or more components can be adjusted upward or downward so that the weight percents of the components in the composition together total 100, provided that the weight percent of a particular component does not exceed the range limit specified for that component.

[0036] The partition coefficient P of a compound is defined as the ratio of the concentration of the compound in an organic solvent to the concentration of the compound in water in a two-phase mixture of the organic solvent and water (where the organic solvent and water are immiscible). The base 10 logarithm of the partition coefficient, logP, is often used. Partition coefficients are often measured in octanol / water systems, and the partition coefficient in such systems is defined as:

[0037] Poct = [concentration in octanol] ÷ [concentration in water]

[0038] For compounds that can be ionized, the distribution coefficient D of a compound is defined as the ratio of the concentration of all species (ionized and non-ionized) of the compound in an organic solvent to the concentration of all species (ionized and non-ionized) of the compound in water in a two-phase mixture of organic solvent and water (where the organic solvent and water are immiscible). Log D can also be used. D depends on the pH at which D is measured, preferably D is measured at a physiological pH of 7.4. The distribution coefficient can be measured using octanol as the organic solvent. When D is measured at physiological pH, a solution of phosphate buffered saline (PBS) at pH 7.4 can be used as the aqueous solvent.

[0039] Some embodiments described herein are described as "comprising" or "comprises" with respect to their various elements. In alternative embodiments, these elements can be described using the transitional phrases "consisting essentially of" or "consists essentially of" when applied to those elements. In further alternative embodiments, these elements can be described using the transitional phrases "consisting of" or "consists of" when applied to those elements. Thus, for example, if a composition or method is disclosed herein as comprising A and B, alternative embodiments of that composition or method "consisting essentially of A and B" and alternative embodiments of that composition or method "consisting of A and B" are also considered to be disclosed herein. Similarly, embodiments described as "consisting essentially of" or "consisting of" with respect to their various elements can also be described as "comprising" when applied to those elements. Finally, embodiments described as "consisting essentially of" with respect to their various elements can also be described as "consisting of" when applied to those elements, and vice versa.

[0040] When an implant, device, composition or system is described as "consisting essentially of" recited elements, the implant, device, composition or system can include the elements explicitly recited and can include other elements that do not substantially affect the condition to be treated (composition for the treatment condition) or the properties of the recited implant, device or system; however, the implant, device, composition or system does not include other elements other than the elements explicitly recited (for a composition for treating a system) that substantially affect the condition to be treated or does not include other elements that substantially affect the properties of the implant, device or system, or if the implant, device, composition or system includes additional elements other than the recited elements that may substantially affect the condition to be treated or the properties of the system, the implant, device, composition or system does not include those additional elements in concentrations or amounts sufficient to substantially affect the condition to be treated by the composition or the properties of the implant, device or system. When a method is described as "consisting essentially of" recited steps, the method can include the recited steps and can include other steps that do not substantially affect the condition to be treated by the method or the properties of the implant, device or system produced or used by the method. However, the method does not include other steps, other than those explicitly recited, that materially affect the conditions treated by the method or the implant, device or system produced or used.

[0041] The present disclosure provides several embodiments. It is contemplated that any feature from any embodiment may be combined, where possible, with any feature from any other embodiment. As such, multiple configurations of the disclosed features are within the scope of the present disclosure.

[0042] Implant construction and manufacturing Physical parameters of the implant as disclosed herein In some embodiments, the implants disclosed herein are rod-shaped or approximately rod-shaped and are about 0.5 cm to 10 cm in length, e.g., about 1 cm to about 6 cm in length, or about 1 cm to about 5 cm in length, or about 1 cm to about 4 cm in length, or about 1 cm to about 3 cm in length, or about 1.5 cm to about 3.5 cm in length, or about 2 cm to about 4 cm in length, or about 2 cm to about 3 cm in length, or about 2 cm to about 5 cm in length, or about 2 cm to about 6 cm in length, or about 3 cm to about 5 cm in length, or about 3 cm to about 6 cm in length, or about 4 cm to about 5 cm in length, or about 4 cm to about 6 cm in length, or about 2.6 cm in length. In some embodiments, the implants are rod-shaped or approximately rod-shaped and are about 3 cm to about 5 cm in length, or about 3.5 cm to about 4.5 cm, or about 4 cm in length. In some embodiments, the implant is rod-shaped or approximately rod-shaped and is about 5 cm to about 7 cm in length, or about 5.5 cm to about 6.5 cm, or about 6 cm in length.

[0043] In some embodiments, the implant is rod-shaped or approximately rod-shaped and has a diameter of about 1 to about 3 mm. In some embodiments, the implant is rod-shaped or approximately rod-shaped and includes dimensions of about 0.5 to about 7 mm in diameter, or about 2 to about 5 mm in diameter, or about 2 to about 3 mm in diameter, or about 2.4 mm in diameter, or about 3 mm in diameter.

[0044] Any of the lengths listed can be combined with any of the diameters listed. In some embodiments, the implant is rod-shaped or approximately rod-shaped and includes dimensions of about 2.4 mm overall diameter and about 2.6 cm overall length.

[0045] Chemical composition of the implant: Implant matrix The implants described herein can be formulated from any biocompatible material that can be implanted into a subject, patient, or individual. The portion of the implant that acts as a carrier for the medicinal substances, excipients, and other substances contained in the implant is called the matrix or matrix material.

[0046] One such matrix is ​​the polymer ethylene vinyl acetate (EVA). EVA is a copolymer of the monomers ethylene and vinyl acetate. The composition of EVA is usually specified as the weight percent of vinyl acetate present, with the remaining percentage consisting of ethylene. Various ratios of monomers can be used, such as about 10% to about 50% by weight vinyl acetate and the remainder being ethylene, about 20% to about 45% by weight vinyl acetate, about 25% to about 40% by weight vinyl acetate, about 30% to about 36% by weight vinyl acetate, or about 33% by weight vinyl acetate.

[0047] In some embodiments as disclosed herein, the implant further comprises a radiopaque material. The radiopaque material is preferably opaque to X-ray radiation. The radiopaque material helps to pinpoint the location of the implant in a non-invasive manner, for example, by X-ray or CT scan. Barium salts, such as barium sulfate, are preferred radiopaque materials. Other radiopaque materials that can be used include, but are not limited to, zirconium oxide, bismuth oxide, bismuth salts, and tungsten compounds, such as calcium tungstate.

[0048] In some embodiments as disclosed herein, the implant further comprises a material detectable or identifiable by magnetic resonance imaging for use in locating the implant during an MRI scan. Iron oxide, such as paramagnetic iron oxide (Fe3O4), can be used as a material to visualize the implant on an MRI scan.

[0049] In some embodiments as disclosed herein, the implant further comprises both a radiopaque material and a material detectable by magnetic resonance imaging.

[0050] One or more detectable substances can be incorporated into the matrix of the implant, provided that such incorporation does not substantially affect the pharmacokinetics of drug release. Alternatively, the detectable substances can be limited to specific locations of the implant that do not interfere with the pharmacokinetics of drug release, such as within the core of the implant or at one or both end regions of the implant.

[0051] Pharmaceutical substances and drugs for use in implants A variety of medicinal substances and drugs can be used in the implants as disclosed herein.

[0052] Lipidated peptides: Lipidated peptides (also called lipopeptides) are peptides with lipid groups attached. Lipidation of peptides can modulate the pharmacokinetic and pharmacodynamic properties of peptides, such as by increasing their half-life in circulation or by increasing the membrane permeability of the peptides. Lipidated peptides have increased lipophilicity compared to non-lipidated peptides. The implants disclosed herein can be used as drug delivery devices for lipidated peptides.

[0053] The associated lipid may include a fatty acid, a monoglyceride, a diglyceride, a triglyceride, a phospholipid, a steroid, or a combination of two or more of the foregoing lipids.

[0054] Liraglutide: The lipidated peptide liraglutide is an analog of glucagon-like peptide-1 (GLP-1) with antihyperglycemic activity. Liraglutide differs from native human GLP-1(7-37) in that it has an arginine residue instead of a lysine residue at position 34 and a C-16 fatty acid (palmitic acid) is attached to the side chain of lysine-26 via a glutamic acid spacer (the amino acid residue position numbers are those of GLP-1(1-37), i.e., 37-amino acid long GLP-1; in liraglutide, biologically active GLP-1 is truncated at the N-terminus to represent GLP-1(7-37) with additional modifications as described). Liraglutide is typically administered subcutaneously. The half-life of liraglutide is 11-15 hours, which is thought to be due to reversible binding to albumin, preventing immediate degradation of the peptide.

[0055] Other lipidated peptides include echinocandins, capsofungin, surfactin, mycosubtilin, daptomycin and pepducins.

[0056] Peptides derivatized with hydrophobic or lipophilic moieties: In addition to the lipids mentioned above (fatty acids, monoglycerides, diglycerides, triglycerides, phospholipids, steroids or combinations thereof), other lipophilic moieties can be attached to the peptides and used in the implants of the present invention, including eicosanoids, prostaglandins, thromboxanes, leukotrienes, resolvins, eoxins, lipoxins, sphingolipids, arachidonic acid, secosteroids, retinoids, fat-soluble vitamins, vitamin D3, vitamin A, vitamin E, and vitamin K.

[0057] Proteolipids: Proteins having one or more lipid moieties attached thereto, such as myristoylated proteins (proteins having one or more myristic acid moieties attached thereto) or palmitoylated proteins (proteins having one or more palmitic acid moieties attached thereto), can be used in implants as disclosed herein.

[0058] Micelle-forming and amphiphilic drug substances: Pharmaceutical substances that form micelles in aqueous solutions can also be used in implants. Micelle-forming substances are typically amphiphilic molecules with lipophilic and hydrophilic parts. In aqueous solutions, the molecules self-assemble into clusters in an approximately spherical arrangement, with the lipophilic parts facing into the bulk of the spherical micelles (away from the aqueous solution) and the hydrophilic parts on the surface of the spherical micelles, which can interact with the aqueous solution.

[0059] Micelles can be lyophilized (freeze-dried) and reconstituted in an aqueous solution. However, when lyophilized micelle powders are combined with a matrix and extruded under hot melt extrusion conditions, the high temperature of extrusion destroys the micelle structure. Because the matrix material is typically hydrophobic, destruction of the micelle structure causes the lipophilic portion of the molecule to strongly interact with the matrix, resulting in poor dissolution of the amphiphilic or micelle-forming drug substance from the matrix. The use of excipients described herein with amphiphilic or micelle-forming drug substances is believed to stabilize and protect the micellar structure of the drug substance during hot melt extrusion, thereby enhancing the ability of the drug substance to dissolve from the matrix of the implant.

[0060] Lipidated peptides (lipopeptides) often form micelles in aqueous solutions, and the above mechanism is believed to provide enhanced elution of lipidated peptides from implants comprising a matrix, one or more lipidated peptides as pharmaceutical agents, and one or more excipients, compared to elution of the lipidated peptide from an implant comprising the matrix and lipidated peptide, but no excipients.

[0061] Pharmaceutical substances and drugs for use in the implant may form micelles in a variety of aqueous solutions, such as one or more of distilled water, buffered water at a pH of about 7 to about 8, phosphate buffered saline (PBS) at a pH of about 7 to about 8, or PBS at a pH of about 7.4.

[0062] Hydrophobic drugs and medicinal substances: Relatively hydrophobic pharmaceutical substances can also be used in the implant. Such substances typically have relatively high log P(oct) or log D(oct) values, for example, at least about 2, at least about 3, or at least about 4 (representing the concentration in an octanol-water system, which is at least about 100 times, at least about 1,000 times, or at least about 10,000 times higher, respectively, in the octanol phase than in the water phase). Examples of such substances include iloprost (log Poct of about 4.8) and levothyroxine (log Poct of about 4) (values ​​reported by PubChem, URL pubchem.ncbi.nlm.nih.gov).

[0063] Excipients for use in implants Excipients are used in implants to provide for the elution of pharmaceutical substances from the implant matrix that would not occur in the absence of the excipient, would occur at a slower rate in the absence of the excipient, or would result in less total delivery of pharmaceutical substances over the life of the implant.Examples of excipients that can be used are sugar alcohols and biodegradable polymers.Mixtures of any two or more of the excipients described herein can also be used.

[0064] Sugar alcohols that can be used as excipients in implants include mannitol, glycerol, erythritol, threitol, arabitol, ribitol, xylitol, fucitol, galactitol, iditol, inositol, sorbitol, volemitol, isomalt, lactitol and maltitol. A subset of sugar alcohols that can be used includes the six-carbon compounds mannitol, fucitol, galactitol, iditol, inositol and sorbitol. In one embodiment, mannitol is used as an excipient.

[0065] Biodegradable polymers that can be used as excipients in implants include poly(lactic-co-glycolic acid) (PLGA). Other biodegradable polymers that can be used in the implants disclosed herein include biodegradable or bioerodible forms of polyamides, aliphatic polycarbonates, polyalkylcyanoacrylates, polyalkylene oxalates, polyanhydrides, polycarboxylic acids, polyesters, poly(hydroxybutyrates), polyimides, poly(iminocarbonates), polycaprolactones (PCL), poly-D,L-lactic acid (DL-PLA), polydioxanones, poly(glycolic acid), poly-L-lactic acid (L-PLA), poly-L-lactic-co-glycolic acid (PLGA), polyorthoesters, polyphosphazenes and polyphosphoesters, poly(trimethylene carbonate), cellulose esters, and derivatives and mixtures thereof.

[0066] The excipient:drug ratio can range from about 5:1 to about 1:10 by mass, e.g., from about 1:1 to about 1:6 (e.g., about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, or about 1:6), or from about 1:3 to about 1:6. In one embodiment, the excipient:drug ratio is about 1:4.

[0067] The excipient can increase the amount of pharmaceutical substance released from the implant in an aqueous environment over a specified period of time. For example, at least about 20% more, at least about 30% more, at least about 40% more, at least about 50% more, at least about 60% more, at least about 70% more, at least about 80% more, at least about 90% more, or at least about 100% more pharmaceutical substance is released from the implant containing the excipient than from a comparable implant lacking the excipient over a specified period of time. Alternatively, up to about 20% more, up to about 30% more, up to about 40% more, up to about 50% more, up to about 60% more, up to about 70% more, up to about 80% more, up to about 90% more, or up to about 100% more pharmaceutical substance is released from the implant containing the excipient than from a comparable implant lacking the excipient over a specified period of time. The defined period can be about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 10 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days, about 14 days, about 20 days, about 3 weeks, about 4 weeks, about 6 weeks, about 2 months, about 3 months, about 4 months, about 5 months, or about 6 months. For the purposes of in vitro testing, measurements of comparative release from implants containing excipients and implants without excipients over a defined period of about 6 hours to about 7 days, e.g., 6 hours, 24 hours, 72 hours, or 7 days, are preferred.

[0068] The aqueous environment in which the comparative release is studied can be selected from water, an aqueous solution, a subcutaneous location in a test animal, or a subcutaneous location in a human. The test animal can be a dog, such as a beagle, a pig, a chimpanzee, or an ape, such as a monkey. The aqueous environment can be pure water, such as distilled water. The water used for the aqueous environment can be distilled water. For in vitro testing of comparative release, an aqueous solution of phosphate buffered saline (PBS) is preferred. The pH of the PBS can be between about pH 7 and about pH 8, such as about pH 7.4, to approximate physiological pH. The temperature of the PBS is preferably between about 35° C. and about 40° C., such as about 37° C., to approximate human body temperature. Samples for testing in PBS can be suspended in the PBS in a wire basket or other suitable support. The PBS can be stirred at about 20 RPM to about 100 RPM, such as about 50 RPM, using a paddle or magnetic stirrer. In one embodiment, the PBS contains about 137 mM NaCl, about 2.7 mM KCl, about 10 mM Na2HPO4, and about 1.8 mM KH2PO4, preferably the PBS is at about pH 7.4 and about 37°C.

[0069] Diseases treatable with the implants as disclosed herein The implants disclosed herein, when implanted into a subject or patient, can be used to treat disease by sustained and prolonged release of pharmaceutical agents from the implant.

[0070] Liraglutide and related compounds are described in U.S. Pat. Nos. 6,268,343 and 8,846,618, which describe the use of the compounds for methods of lowering blood glucose levels, treating type I diabetes, treating type II diabetes, treating impaired glucose tolerance, glycemic control, treating obesity, reducing weight, inhibiting gastric acid secretion, treating gastric ulcers, treating myocardial infarction, inhibiting beta cell apoptosis, stimulating beta cell proliferation, treating dyslipidemia, treating stroke, treating left ventricular hypertrophy, treating arrhythmias, treating bacteremia, treating sepsis, treating irritable bowel disease, or treating functional dyspepsia.

[0071] Liraglutide (sold under the brand names VICTOZA® and SAXENDA®, trademarks of Novo Nordisk) is approved for use in the United States for the treatment of type 2 diabetes, particularly for blood sugar control in subjects with type 2 diabetes, for the treatment of obesity and to help obese or overweight subjects lose weight, and to reduce the risk of heart attack or stroke in subjects with type 2 diabetes.

[0072] In one embodiment, an implant as disclosed herein comprising liraglutide and at least one excipient is used in a method of lowering blood glucose levels, treating type I diabetes, treating type II diabetes, treating impaired glucose tolerance, glycemic control, treating obesity, reducing weight, inhibiting gastric acid secretion, treating gastric ulcers, treating myocardial infarction, inhibiting beta cell apoptosis, stimulating beta cell proliferation, treating dyslipidemia, treating stroke, treating left ventricular hypertrophy, treating arrhythmias, treating bacteremia, treating sepsis, treating irritable bowel disease, treating functional dyspepsia, reducing the risk of heart attack or stroke, reducing the risk of heart attack or stroke in a subject with diabetes, reducing the risk of heart attack or stroke in a subject with type 1 diabetes, or reducing the risk of heart attack or stroke in a subject with type 2 diabetes.

[0073] Exemplary Polymers for Use in Implants A preferred polymer for use in the implants is ethylene vinyl acetate (EVA; poly(ethylene-co-vinyl acetate)). However, other biocompatible polymers can be used in the implants disclosed herein. As used herein, "polymer" or "polymeric material" means a macromolecule that contains repeating monomeric or comonomer units. A polymer can be a homopolymer, copolymer, terpolymer, or can contain more than three monomers.

[0074] Additional polymers that can be used in the implants disclosed herein include polyolefins including polyethylene, polypropylene, and polybutylene; polyolefin copolymers such as ethylene-vinyl acetate, as well as ethylene-methacrylic acid and ethylene-acrylic acid; vinyl aromatic polymers such as polystyrene; vinyl aromatic copolymers such as styrene-isobutylene copolymer and butadiene-styrene copolymer; polyvinyl alcohol, polyacetals, chloropolymers including polyvinyl chloride (PVC); fluoropolymers including polytetrafluoroethylene (PTFE); polyesters including polyethylene terephthalate (PET), polyester-ethers, polyamides such as nylon 6 and nylon 6,6, polyethers, polyamide ethers, silicones, polyurethanes and polyurethane copolymers, polycarbonates, polycarbonate-based polyurethanes, and mixtures or copolymers of any of the foregoing.

[0075] The implant can include a single type of polymer or a mixture of two or more polymers. The mixture of two polymers can adjust the release rate of the drug. It is desirable that an effective therapeutic amount of the drug is released from the implant as disclosed herein for a reasonably long period of time. Yang et al., U.S. Pat. No. 6,258,121, disclosed a method of modifying the release rate by blending two polymers with different release rates and incorporating them into a single layer. This technique can also help reduce the burst release of the drug upon implantation.

[0076] The mass / mass ratio of matrix material to the combination of pharmaceutical agent and excipients in the implant can range from about 10:1 matrix / (pharmaceutical agent+excipients) to about 1:4 matrix / (pharmaceutical agent+excipients), i.e., from about 91% matrix and about 9% (pharmaceutical agent+excipients) to about 20% matrix and about 80% (pharmaceutical agent+excipients). In further embodiments, the ratio can range from about 5:1 matrix / (pharmaceutical agent+excipients) to about 1:3 matrix / (pharmaceutical agent+excipients), from about 3:1 matrix / (pharmaceutical agent+excipients) to about 1:3 matrix / (pharmaceutical agent+excipients), or from about 2:1 matrix / (pharmaceutical agent+excipients) to about 1:2 matrix / (pharmaceutical agent+excipients). In further embodiments, the ratio is about 1:1 matrix / (pharmaceutical agent+excipients).

[0077] Porogen Shell In some embodiments, the implant can include a porogen-containing shell, which can further help regulate the release of the drug from the implant. Implants that include a porogen-containing shell are disclosed in International Patent Application WO2018 / 067882, and the porogen shells described therein can be applied to the implants described herein. A preferred polymer for the shell of the implant as disclosed herein is ethylene vinyl acetate (EVA). Other materials that can be used in the porogen-containing shell include polyolefins including polyethylene, polypropylene, and polybutylene, polyolefin copolymers such as ethylene-methacrylic acid and ethylene-acrylic acid in addition to ethylene-vinyl acetate, vinyl aromatic polymers such as polystyrene, vinyl aromatic copolymers such as styrene-isobutylene copolymer and butadiene-styrene copolymer, polyvinyl alcohol, polyacetal, chloropolymers including polyvinyl chloride (PVC), fluoropolymers including polytetrafluoroethylene (PTFE), polyesters including polyethylene terephthalate (PET), polyester-ethers, polyamides such as nylon 6 and nylon 6,6, polyethers, polyamide ethers, silicones, polyurethanes and polyurethane copolymers, polycarbonates, polycarbonate-based polyurethanes, and mixtures or copolymers of any of the foregoing. In one embodiment, the porogen-containing shell comprises the same polymer as that which constitutes the interior of the implant containing the pharmaceutical agent and excipients. In one embodiment, the porogen-containing shell comprises a different polymer than that which constitutes the interior of the implant containing the pharmaceutical agent and excipients.

[0078] Examples of porogens that can be used in the shell include alkyl celluloses and hydroxyalkyl celluloses such as ethyl cellulose, methyl cellulose and hydroxymethyl cellulose, fatty acids such as stearic acid, palmitic acid, myristic acid and linoleic acid, biocompatible salts such as sodium chloride, calcium chloride or sodium phosphate, and soluble polymers such as low molecular weight polyvinylpyrrolidone (PVP). Porogen particles are preferably used with a narrow size distribution to allow control of the pore size. The average diameter of the porogens used can be from about 1 micrometer to about 300 micrometers. In some embodiments, the average diameter of the porogens is greater than the thickness of the shell. In some embodiments, the average diameter of the porogens is about equal to the thickness of the shell. In some embodiments, the average diameter of the porogens is less than the thickness of the shell. In some embodiments, the average diameter of the porogens is less than about 75% of the thickness of the shell. In some embodiments, the average diameter of the porogens is less than about 50% of the thickness of the shell. In some embodiments, the average diameter of the porogens is less than about 25% of the thickness of the shell.

[0079] The porogen used in the shell can be a single material, or two or more different porogen materials can be used.

[0080] The porogen can be removed from the implant shell prior to implantation, hi other embodiments, the implant can be implanted without removing the porogen, and then the porogen can be dissolved after implantation.

[0081] Implant Coating The implants as disclosed herein can optionally be partially or fully coated with a coating to control drug release. The implants can be coated by dip coating, spray coating, pan coating or in a fluidized bed system. When the implants are made by extrusion, the coating can be applied by coextrusion.

[0082] Rod-shaped implants can be coated over their entire surface and then a small portion of the end of each rod can be cut off, resulting in a partially coated rod with the drug-containing matrix exposed on the flat surfaces of both ends of the rod, while the curved tubular sides are coated. If the coating is applied to the curved tubular sides by coextrusion, when the extruded rod is cut into pieces to form individual implants, the drug-containing matrix is ​​exposed on both ends of the rod.

[0083] The coating can be impermeable to the drug, in which case it should only partially cover the implant so that the drug is released from the uncoated portions of the implant, or it should dissolve or degrade after a period of time to allow the drug to be released from the newly exposed drug-containing matrix, or the coating can be more or less permeable to the drug, allowing for modulation of drug release.

[0084] The implant can be dip-coated with ethylene vinyl acetate. Dip-coating with ethylene vinyl acetate can be performed by immersing the implant in a solution of ethylene vinyl acetate in dichloromethane (such as a 1% solution). The implant can be dipped once or multiple times (e.g., 2, 3 or 4 or more times if a thicker coating is desired).

[0085] Manufacturing the implant as disclosed herein In some embodiments, the implants as disclosed herein can be manufactured by blending microparticles of a polymer with particles of a pharmaceutical agent of a desired size and co-extruding the blend. The blended mixture is heated to a temperature suitable for extrusion, such as the softening point of the polymer. At this point, the softened mixture can be optionally homogenized, if necessary. The mixture is then co-extruded, for example, via a Microtruder screw extruder, model number RCP-025, Randcastle Extrusion Systems, Cedar Grove, NJ, or other extrusion equipment known in the industry. The diameter, temperature, pressure, and other parameters of the extrusion can be controlled appropriately for each polymer and pharmaceutical agent.

[0086] The extrudate can be extruded horizontally and collected for further processing. The extrudate can be cut to a desired length, for example, about 1 to about 3 cm. The extrudate can then be washed or immersed in one or more solvents that remove excess drug from the surface of the implant. Examples of solvents that can be used to wash the extrudate include water, saline solutions, aqueous buffers, and alcohols such as ethanol or isopropanol. Mixtures of water and alcohols, such as ethanol-water mixtures, can also be used. A preferred solvent is 100% ethanol or a water-ethanol mixture. For implants that use a porogen shell, if it is desired to remove the porogen before implantation, the implant can be washed with a solvent that removes the porogen from the shell.

[0087] After the extrudates are washed, they can be dried to remove the washing solvent, typically at about 30° C. to about 60° C. for about 6 to about 24 hours, for example, at about 40° C. for about 12 hours.

[0088] After drying, packaging and sterilization can take place. The implants can be vacuum packed in moisture-proof foil pouches, heat sealed and / or vacuum sealed, and then sterilized using gamma radiation, such as about 20 to 30 kilograys, or about 25 kilograys, or about 2.5 to about 3.5 megarads, or about 2.9 to about 3.1 megarads, or about 3 megarads.

[0089] Liraglutide Implant Also described herein are implants comprising liraglutide suitable for use in a subject, individual or patient.

[0090] a matrix comprising ethylene vinyl acetate (EVA), wherein the EVA comprises about 10% to about 50% vinyl acetate by weight, the remainder being ethylene, comprising about 20% to about 45% vinyl acetate, about 25% to about 40% vinyl acetate, about 30% to about 36% vinyl acetate, or about 33% vinyl acetate;

[0091] A pharmaceutical substance comprising liraglutide or a pharma- ceutical acceptable salt thereof, and

[0092] An excipient comprising a sugar alcohol or a biodegradable polymer.

[0093] The EVA in the liraglutide implant is preferably about 33% vinyl acetate.

[0094] The excipient:liraglutide ratio can range from about 5:1 to about 1:10, from about 1:1 to about 1:6, or from about 1:3 to about 1:6 by mass. In a preferred embodiment, the excipient:drug ratio is about 1:4.

[0095] The excipient is preferably mannitol or poly(lactic-co-glycolic acid) (PLGA), more preferably mannitol. The mass ratio of the matrix to (drug substance + excipient) ranges from about 10:1 to about 1:4, about 5:1 to about 1:3, about 3:1 to about 1:3, preferably about 2:1 to about 1:2, or more preferably about 1:1.

[0096] In some embodiments, the liraglutide implant is rod-shaped or approximately rod-shaped. In some embodiments, the liraglutide implant is about 0.5 cm to 10 cm long, for example, about 1 cm to about 6 cm long, or about 1 cm to about 5 cm long, or about 1 cm to about 4 cm long, or about 1 cm to about 3 cm long, or about 1.5 cm to 3.5 cm long, or about 2 cm to about 4 cm long, or about 2 cm to about 3 cm long. In some embodiments, the liraglutide implant is about 1 to about 3 mm in diameter. In some embodiments, the implant is about 0.5 to about 7 mm in diameter, or about 2 to about 5 mm in diameter, or about 2 to about 3 mm in diameter, or about 2.4 mm in diameter, or about 3 mm in diameter. In some embodiments, the liraglutide implant is about 2.4 mm in total diameter and about 2.6 cm in total length.

[0097] Pharmacological properties of the implant Pharmacokinetics The implant can provide a nearly constant blood concentration of a pharmaceutical substance or drug. The level of drug delivery should be within the therapeutic range of the drug and below the concentration that causes unacceptable toxicity. In one embodiment, the implant as disclosed herein can contain multiple drugs. In one embodiment, multiple implants can be inserted into a patient, where the implants contain the same drug and achieve a desired level of drug concentration in the blood. In one embodiment, multiple implants can be inserted into a patient, where the implants contain different drugs and achieve a desired level of drug concentration in the blood for each of the different drugs.

[0098] Implants as disclosed herein can be designed to provide a steady state concentration of drug in the blood (e.g., in plasma or serum). Implants as disclosed herein can be designed such that the resulting concentration of drug in the blood remains essentially constant over an extended period of time. Implants as disclosed herein can be designed such that the resulting concentration of drug in the blood remains approximately constant over an extended period of time.

[0099] The release of a drug from an implant as disclosed herein depends on the dissolution rate of the drug in the matrix, passive diffusion of the drug through the polymer matrix, diffusion of the drug through any optional coatings, and other parameters.

[0100] The rate of drug release can also be influenced by washing the implant prior to insertion into the patient. The implant can be washed with solvents such as water, ethanol, or isopropanol, which can help reduce the burst release upon initial implantation of the implant.

[0101] "Approximately constant blood concentration" refers to a drug in the blood of a subject or patient at a substantially constant concentration over a period of time. As defined above, "blood concentration" refers to the concentration of a drug, hormone, metabolite or other substance in the blood of a subject, and can be measured in whole blood, serum or plasma according to standard clinical laboratory practices for the substance being analyzed. In one embodiment, a substantially constant blood concentration of a drug varies by no more than about ±30% over a day, week, month, three months, six months or nine months, compared to the mean or average blood concentration over that period. In another embodiment, a substantially constant concentration of a drug varies by no more than about ±20% over a day, week, month, three months, six months or nine months, compared to the mean blood concentration over that period. In another embodiment, a substantially constant concentration of a drug varies by no more than about ±10% over a day, week, month, three months, six months or nine months, compared to the mean blood concentration over that period. "Approximately constant release rate" refers to an approximately constant amount of pharmaceutical agent released from an implant as disclosed herein over a period of time, such as one day, one week, one month, three months, six months, or nine months. In some embodiments, the approximately constant release rate varies by no more than about ±50%, about ±40%, about ±30%, about ±20%, or about ±10% over the indicated period compared to the average release. To achieve approximately constant blood levels, an approximately constant release rate is preferred. By "essentially constant" it is meant that the drug concentration in the blood is within about 3, about 2, or preferably about 1 standard deviation of the average blood level for about 95% of the time period. Blood level measurements can be made hourly, twice daily, daily, twice weekly, weekly, biweekly, monthly, or at any other regular interval to determine the average blood level. For example, if the mean blood concentration of a drug sampled at weekly intervals is 2.0 ng / ml and one standard deviation of the measurements is ±0.1 ng / ml, then a blood concentration in which about 95% of the measurements fall within about ±0.3 ng / ml, about 0.2 ng / ml, or preferably about ±0.1 ng / ml, would be considered to be essentially constant.By "long-term" is meant a period of from about 3 months to about 1 year or more; for example, a long-term period can be about or at least about 3 months, about or at least about 4 months, about or at least about 5 months, about or at least about 6 months, about or at least about 6 months, about or at least about 9 months, about or at least about 12 months, about or at least about 12 months, about or at least about 15 months, about or at least about 18 months, about or at least about 18 months, about or at least about 21 months, about or at least about 24 months, or more than 24 months.

[0102] Insertion and removal of implants Another aspect of the present disclosure is a method for delivering a pharmaceutical substance or drug to a patient in need thereof, comprising inserting one or more implants as disclosed herein into the patient, wherein the pharmaceutical substance or drug is released from the one or more implants into the patient. In a preferred method of the present disclosure, the implants as disclosed herein are administered by subcutaneous implantation. In various embodiments, the implants are subcutaneously implanted at a site selected from the group consisting of the upper arm, scapular region, back, leg, and abdomen. Prior to implantation, the patient may be lightly anesthetized, for example with isoflurane or other anesthetics known in the art, and / or a local, transdermal, or subcutaneous anesthetic may be applied to the implantation site. A small incision is made in the skin and a trocar is inserted subcutaneously before placing one implant. A stylet is inserted to hold the implant in place, and the trocar is carefully removed, leaving the implant in the subcutaneous space. Each site can be sutured closed and examined later. Complications such as skin irritation, inflammation, infection, or other site-specific side effects can be monitored and treated, for example, with antibiotics, as needed.

[0103] In various embodiments, the implant as disclosed herein can remain in the body for up to about 1 year, about 2 years or more. The implant can remain in the body for up to about 3 months, up to about 6 months, up to about 9 months, up to about 12 months, up to about 15 months, up to about 18 months, up to about 21 months or up to about 24 months or more. Thus, the period of sustained release of the drug in the body is from about 1 month to about 1 year or more, or from about 3 months to about 1 year or more, for example, 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 or more. In some embodiments, the implant can remain in the body for more than 1 year. At the end of the treatment period, the implant can be removed from the body using forceps through an incision, for example, a 3 mm incision.

[0104] The second implant may be used, for example, to deliver a medicinal substance to counteract side effects caused by the drug released from the first implant.

[0105] Multiple implants can be inserted into a single patient to regulate the delivery of a single agent or to deliver multiple drugs.

[0106] Exemplary embodiments The present invention is further described by the following embodiments, the features of each of which may be combined with any of the other embodiments where appropriate and practical.

[0107] Embodiment 1. An implant comprising a matrix, a pharmaceutical agent and at least one excipient, wherein the pharmaceutical agent comprises a lipophilic moiety.

[0108] Embodiment 2. The implant of embodiment 1, wherein the implant is a subdermal implant.

[0109] Embodiment 3. The implant of embodiment 1, wherein at least about 50% more of the pharmaceutical agent is released from the implant in an aqueous environment over a defined period of time as compared to that released from a comparable implant lacking the excipient.

[0110] Embodiment 4. The implant of embodiment 3, wherein the defined period of time is about 6 hours, about 24 hours, about 72 hours, or about 7 days.

[0111] Embodiment 5. The implant of embodiment 3 or embodiment 4, wherein said aqueous environment is selected from an aqueous solution, a subcutaneous location in a test animal, or a subcutaneous location in a human.

[0112] Embodiment 6. The implant of embodiment 3 or embodiment 4, wherein the aqueous environment comprises an aqueous solution comprising about 137 mM NaCl, about 2.7 mM KCl, about 10 mM Na2HPO4, and about 1.8 mM KH2PO4 at about pH 7.4 and about 37°C.

[0113] Embodiment 7. The implant according to any one of the preceding embodiments, wherein the excipient comprises a compound selected from the group consisting of a sugar alcohol and a biodegradable polymer.

[0114] Embodiment 8. The implant according to any one of the preceding embodiments, wherein said excipient comprises a compound selected from the group consisting of sugar alcohols.

[0115] EMBODIMENT 9. The implant according to any one of the preceding embodiments, wherein the excipient comprises a compound selected from the group consisting of mannitol, glycerol, erythritol, threitol, arabitol, ribitol, xylitol, fucitol, galactitol, iditol, inositol, sorbitol, volemitol, isomalt, lactitol and maltitol.

[0116] EMBODIMENT 10. The implant of any one of embodiments 1 to 7, wherein the excipient comprises mannitol.

[0117] Embodiment 11. The implant of any one of embodiments 1 to 7, wherein said excipient comprises a compound selected from the group consisting of biodegradable polymers.

[0118] Embodiment 12. The implant of any one of embodiments 1 to 7, wherein the excipient comprises poly(lactic-co-glycolic) acid (PLGA).

[0119] Embodiment 13. The implant of embodiment 1, wherein the lipophilic pharmaceutical agent comprises a lipid.

[0120] Embodiment 14. The implant of embodiment 13, wherein the lipid is selected from the group consisting of fatty acids, monoglycerides, diglycerides, triglycerides, phospholipids and steroids.

[0121] EMBODIMENT 15. 2. The implant of embodiment 1, wherein the lipophilic pharmaceutical agent comprises a lipidated peptide.

[0122] EMBODIMENT 16. The implant of embodiment 1, wherein the lipophilic pharmaceutical agent comprises a fatty acid.

[0123] EMBODIMENT 17. The implant of embodiment 1, wherein the lipophilic pharmaceutical agent comprises a fatty acid covalently attached to a peptide.

[0124] EMBODIMENT 18. The implant of embodiment 17, wherein the lipophilic pharmaceutical agent comprising a fatty acid covalently attached to a peptide comprises liraglutide.

[0125] EMBODIMENT 19. 2. The implant of embodiment 1, wherein the matrix comprises a non-biodegradable polymer.

[0126] EMBODIMENT 20. 20. The implant of embodiment 19, wherein the non-biodegradable polymer comprises a polymer selected from the group consisting of ethylene vinyl acetate, polyolefin, polyethylene, polypropylene, polybutylene, polyolefin copolymer, ethylene-methacrylic acid, ethylene-acrylic acid, vinyl aromatic polymer, polystyrene, vinyl aromatic copolymer, styrene-isobutylene copolymer, butadiene-styrene copolymer, polyvinyl alcohol, polyacetal, chloropolymer, polyvinyl chloride (PVC), fluoropolymer, polytetrafluoroethylene (PTFE), polyester, polyethylene terephthalate (PET), polyester ether, polyamide, nylon-6, nylon-6,6, polyether, polyamide ether, silicone, polyurethane, polyurethane copolymer, polycarbonate, polycarbonate-based polyurethane, and mixtures or copolymers of any of the foregoing.

[0127] EMBODIMENT 21. The implant of embodiment 19, wherein the non-biodegradable polymer comprises ethylene vinyl acetate.

[0128] EMBODIMENT 22. An implant comprising a matrix, a pharmaceutical agent and at least one excipient, wherein the pharmaceutical agent forms micelles in aqueous solution.

[0129] EMBODIMENT 23. 23. The implant of embodiment 22, wherein the aqueous solution is phosphate buffered saline (PBS) at about pH 7 to about pH 8.

[0130] EMBODIMENT 24. An implant comprising a matrix, a pharmaceutical agent and at least one excipient, wherein the pharmaceutical agent is amphiphilic. EXAMPLES

[0131] The following examples are intended to illustrate the invention and are not intended to limit the invention to the exemplified embodiments.

[0132] Example 1 Preparation of Liraglutide-EVA test samples Liraglutide without excipients: Liraglutide (Auro Peptides) was used as the active pharmaceutical ingredient (API). A mild, buffered, endotoxin-free base solution (ammonium bicarbonate, pH=7.4, filtered through a 0.2 μm PTFE membrane) was prepared for processing of the API. The API (0.53 g) was dissolved in 100 mL of base solution and lyophilized in two equal aliquots. After lyophilization, removal of ammonium bicarbonate solids was incomplete. The sample was neutralized with excess acetic acid, dried, redissolved in NH4OH solution (pH=9.0), and lyophilized again to obtain the final product.

[0133] Liraglutide-poly(lactide-co-glycolide) (liraglutide-PLGA) blend: 100 mg of API was suspended in 5 mL of a solution of 100 mg of PLGA (50 / 50) in dichloromethane / acetone (1:1 by volume). The suspension was then added dropwise to pyrogen-free water while homogenizing with a handheld rotor-stator mixer. The resulting emulsion was stirred overnight to evaporate the remaining solvent and then lyophilized to obtain a dry powder.

[0134] Liraglutide-mannitol mixture: A stock solution of 0.4 M mannitol (Aldrich) was prepared. An aliquot containing an estimated 1.001 g of mannitol was then combined with 100 mL of basified liraglutide solution (NH4OH, pH=8.5) containing 5.007 g of active substance. The resulting clear solution was lyophilized to obtain a dry powder with a mass of 5.975 g and containing 83.3% w / w liraglutide.

[0135] Extrusion Method: The API was blended with cryo-milled EVA powder and extruded. Extrusion was performed using a Thermo Scientific Haake Minilab microcompounding machine Type 5572200 equipped with a co-rotating screw and a force feeder. The extruder screw was a Therma Pharma MiniHME screw and the barrel plates were corrosion-resistant R&D parts used in the assembly of clamshells. The barrel temperature was set at 80 °C and the respective powder blends were manually loaded into the force feeder auger. The screw torque was set at a fixed level of 50 N·cm and the products were extruded through a 1.5 mm nozzle. The extruded rods were approximately 26 mm long and 1.5 mm in diameter.

[0136] Pellet Press: The pellets were pressed to simulate the hot melt process on a smaller scale than possible using the extrusion process. A 100 mg portion of each dry powder (liraglutide without excipients, liraglutide-PLGA and liraglutide-mannitol) as prepared above was manually blended with 100 mg cryo-milled EVA resin (lot ENG-EVA-B060816). 200 mg of the powder blend was then pressed into five individual pellets, each weighing approximately 40 mg, using a hydraulic press and a pellet die warmed to 80° C. The pellets were then compared for their respective in vitro release characteristics.

[0137] Example 2 In vitro release and analysis The extruded rods and pellets were tested for in vitro release in a bottle set in a shaking water bath. The medium was 100 mL of pH 7.4 phosphate buffered saline kept at 37°C and 50 RPM. The rods and pellets were wrapped in a wire sinker. Samples were taken at 6 hours and 24 hours. At each time point, 100 μL was withdrawn and replaced with fresh medium.

[0138] Liraglutide content was analyzed by HPLC using a Supelco Discovery C18 column (150 × 4.6 mm, 5 μm) with a mobile phase consisting of 20 mM potassium phosphate buffer (pH 8.0) combined with acetonitrile in a ratio of 85:15 (v:v) at a flow rate of 1.0 mL / min. The column temperature was 40 °C, detection was measured at 214 nm, injection volume was 20 μL, and analysis time was 20 min. Standards were prepared in phosphate buffer at pH 8.0.

[0139] The compounded specimens (API-EVA mixtures) were compared to a reference standard of API and a control sample consisting of a powder blend of API and cryogenically milled EVA. Sample portions were placed in small vials and dissolved in 2 mL of DCM and then left overnight until dissolved. 0.1 mL of the dissolved solution was then sampled with a positive displacement pipette and diluted to 10 mL in pH 8.0 phosphate buffer. The solution was mixed thoroughly and a volume of approximately 1 mL was microcentrifuged and analyzed by HPLC.

[0140] Example 3 In vitro release of excipient-free liraglutide API Liraglutide was blended with cryo-milled EVA powder and extruded as described above at a drug loading of 50% (w / w). The average recovery of API / EVA powder blends sampled for in vitro release prior to being fed to the extruder was 94% w / w. After extrusion into rods 26 mm long and 1.5 mm in diameter, the in vitro recovery of API from the rods varied from 14% to 20%.

[0141] Example 4 Comparison of in vitro release of liraglutide API with and without excipients Pellets were prepared as described in Example 1 and contain liraglutide without excipient, liraglutide with mannitol excipient, and liraglutide with PLGA excipient. In vitro release was tested as described in Example 2. The results are shown in Table 1. [Table 1]

[0142] Example 5 In vitro release of liraglutide with mannitol excipient from extruded rods Extruded rods were prepared as described above using the liraglutide-mannitol mixture and EVA. The molten material recovered from the extruder barrel was tested for payload (n=3), yielding a measured drug content of 39.9±2.8% by weight from a theoretical loading of 42%. The extrudate samples tested (n=3) yielded an average API content of 50.4±1.5%.

[0143] In vitro measurements of liraglutide release from extruded rods showed a mean release of 38.7±2.6% after 24 hours. Therefore, dip coating of the rods was investigated to modulate the release rate.

[0144] Example 6 In Vitro Release of Liraglutide with Mannitol Excipient from Extruded Dip-Coated Rods Extruded rods containing the liraglutide-mannitol mixture were overcoated with EVA resin by immersion in a 1% solution of EVA prepared in dichloromethane (DCM). Samples were individually immersed three times and allowed to dry between immersions. The average drug loading of the dip-coated specimens (n=3) was 50.3±1.4%. The dip-coated ends of each sample were trimmed prior to testing to mimic a truncated core / shell coextrusion with open ends. Figure 1 shows the amount of drug released as % of loading over time up to 72 hours.

[0145] Although the foregoing invention has been described in some detail by way of illustration and example for clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications can be made without departing from the spirit and scope of the invention. Accordingly, the description should not be construed as limiting the scope of the invention.

[0146] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. 1. An implant comprising a matrix, a pharmaceutical agent, and at least one excipient, wherein the pharmaceutical agent is a lipophilic pharmaceutical agent that comprises a lipophilic moiety.

2. The implant of claim 1 , wherein the implant is a subdermal implant.

3. 10. The implant of claim 1, wherein at least about 50% more of the pharmaceutical agent is released from the implant in an aqueous environment over a defined period of time as compared to that released from a comparable implant lacking the excipient.

4. 4. The implant of claim 3, wherein the prescribed period is about 6 hours, about 24 hours, about 72 hours, or about 7 days.

5. 5. The implant of claim 3 or claim 4, wherein the aqueous environment is selected from an aqueous solution, a subcutaneous location in a test animal, or a subcutaneous location in a human.

6. The aqueous environment is about 137 mM NaCl, about 2.7 mM KCl, about 10 mM NaCl, about 2.5 mM NaCl, about 2.5 mM KCl, about 2.5 mM Na ... ２ H.P.O. ４ and about 1.8 mM KH ２ P.O. ４ 5. The implant of claim 3 or claim 4, comprising an aqueous solution comprising:

7. The implant of any one of claims 1 to 4, wherein the excipient comprises a compound selected from the group consisting of sugar alcohols and biodegradable polymers.

8. The implant of any one of claims 1 to 7, wherein the excipient comprises a compound selected from the group consisting of sugar alcohols.

9. 8. The implant of claim 1, wherein the excipient comprises a compound selected from the group consisting of mannitol, glycerol, erythritol, threitol, arabitol, ribitol, xylitol, fucitol, galactitol, iditol, inositol, sorbitol, volemitol, isomalt, lactitol and maltitol.

10. The implant of any one of claims 1 to 7, wherein the excipient comprises mannitol.

11. The implant of any one of claims 1 to 7, wherein the excipient comprises a compound selected from the group consisting of biodegradable polymers.

12. The implant of any one of claims 1 to 7, wherein the excipient comprises poly(lactic-co-glycolic) acid (PLGA).

13. The implant of claim 1 , wherein the lipophilic pharmaceutical agent comprises a lipid.

14. 14. The implant of claim 13, wherein the lipid is selected from the group consisting of fatty acids, monoglycerides, diglycerides, triglycerides, phospholipids and steroids.

15. The implant of claim 1 , wherein the lipophilic pharmaceutical agent comprises a lipidated peptide.

16. The implant of claim 1 , wherein the lipophilic pharmaceutical agent comprises a fatty acid.

17. The implant of claim 1 , wherein the lipophilic pharmaceutical agent comprises a fatty acid covalently attached to a peptide.

18. 20. The implant of claim 17, wherein the lipophilic pharmaceutical agent comprising a fatty acid covalently attached to a peptide comprises liraglutide.

19. The implant of claim 1 , wherein the matrix comprises a non-biodegradable polymer.

20. 20. The implant of claim 19, wherein the non-biodegradable polymer comprises a polymer selected from the group consisting of ethylene vinyl acetate, polyolefin, polyethylene, polypropylene, polybutylene, polyolefin copolymer, ethylene-methacrylic acid, ethylene-acrylic acid, vinyl aromatic polymer, polystyrene, vinyl aromatic copolymer, styrene-isobutylene copolymer, butadiene-styrene copolymer, polyvinyl alcohol, polyacetal, chloropolymer, polyvinyl chloride (PVC), fluoropolymer, polytetrafluoroethylene (PTFE), polyester, polyethylene terephthalate (PET), polyester-ether, polyamide, nylon-6, nylon-6,6, polyether, polyamide ether, silicone, polyurethane, polyurethane copolymer, polycarbonate, polycarbonate-based polyurethane, and mixtures or copolymers of any of the foregoing.

21. 20. The implant of claim 19, wherein the non-biodegradable polymer comprises ethylene vinyl acetate.

22. An implant comprising a matrix, a pharmaceutical agent and at least one excipient, wherein the pharmaceutical agent forms micelles in aqueous solution.

23. 23. The implant of claim 22, wherein the aqueous solution is phosphate buffered saline (PBS) at about pH 7 to about pH 8.

24. An implant comprising a matrix, a pharmaceutical agent and at least one excipient, wherein the pharmaceutical agent is amphiphilic.

25. An implant comprising a matrix, a pharmaceutical agent and at least one excipient, wherein the pharmaceutical agent is co-lyophilized with the excipient to form a pharmaceutical agent-excipient mixture, and the pharmaceutical agent-excipient mixture is then incorporated into the matrix.

26. The pharmaceutical agent is a pharmaceutical agent comprising a lipophilic moiety; A pharmaceutical substance that forms micelles in aqueous solution, and Medicinal substances that are amphiphilic, 26. The implant of claim 25, selected from the group consisting of:

27. 26. The implant of claim 25, wherein the pharmaceutical agent is liraglutide.

28. The implant of any one of claims 25 to 27, wherein the excipient is a sugar alcohol.

29. 29. The implant of claim 28, wherein the sugar alcohol is mannitol.

30. The implant of any one of claims 1 to 29, wherein the matrix is ​​ethylene vinyl acetate (EVA).

31. 31. The implant of any one of claims 1 to 30, wherein the excipient:drug ratio ranges from about 5:1 to about 1:10 by mass.

32. 32. The implant of claim 31, wherein the excipient:drug ratio ranges from about 1:1 to about 1:6 by mass.

33. 33. The implant of any one of claims 1 to 32, wherein the matrix to (drug substance plus excipients) mass ratio ranges from about 10:1 to about 1:

4.

34. 34. The implant of claim 33, wherein the matrix to (drug substance plus excipients) weight ratio ranges from about 5:1 to about 1:

3.

35. The implant of any one of claims 1 to 34, wherein the excipient comprises mannitol.

36. The implant of any one of claims 1 to 34, wherein the excipient comprises poly(lactic-co-glycolic acid) (PLGA).

37. about 40% to about 60% by weight of ethylene vinyl acetate; and About 60% to about 40% by weight mannitol:liraglutide mixture wherein the mannitol:liraglutide mixture comprises about 10% to about 30% mannitol and about 90% to about 70% liraglutide by weight.

38. About 50% by weight ethylene vinyl acetate, and Approximately 50% by weight mannitol:liraglutide mixture wherein the mannitol:liraglutide mixture comprises about 20% by weight mannitol and about 80% by weight liraglutide.

39. The implant of any one of claims 1 to 38, wherein the implant is about 1 cm to about 5 cm in length and about 1 mm to about 3 mm in diameter.

40. The implant of any one of claims 1 to 39, wherein the implant is a subcutaneous implant.

41. The implant of any one of claims 1 to 40, wherein the implant is prepared by hot melt extrusion.

42. The implant of any one of claims 1 to 41, wherein the implant is dip coated.

43. 43. The implant of claim 42, wherein the implant is dip coated with ethylene vinyl acetate.

44. 43. The implant of claim 42, wherein the implant is dip coated with ethylene vinyl acetate by immersing the implant in a 1% solution of EVA prepared in dichloromethane (DCM).

Images