implant for the release of lipophilic or amphiphilic pharmaceutical substances

Abstract

Implants containing lipophilic pharmaceutical agents are described. Excipients are used that provide adequate and controllable / tunable release of the lipophilic drug from the matrix of the implant. The implants can be implanted in a patient for release of the pharmaceutical agent. Methods for making and using such implants are also described.

Description

Technical Field

[0001] Cross - References to Related Applications This application claims priority to U.S. Provisional Patent Application No. 62 / 689,735, filed on Jun. 25, 2018. The entire contents of that application are incorporated herein by reference.

[0002] Technical Field Implants containing lipophilic or amphiphilic pharmaceutical substances, which can be implanted into a patient to release the pharmaceutical substance, as well as methods of manufacturing and using such constructs are provided.

Background Art

[0003] Background of the Invention Many patients require long - term and regular administration of drugs or pharmaceutical substances. During long - term drug administration via oral ingestion or other routes that require frequent dosing, several problems can occur. Adherence to long - term dosing 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 need to confirm that the drug is being taken appropriately. Additionally, enteral drug delivery is sometimes poorly tolerated or prohibited in patients with certain indications. Frequent or periodic dosing, such as that occurring with daily oral and sublingual delivery, can cause the drug's blood concentration to peak soon after the initial dose and then drop rapidly before the next dose. Intravenous drug delivery requires trained personnel for administration and is not practical for long - term outpatient treatment.

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

[0005] However, certain drugs are not released effectively from implants. In particular, lipophilic and amphiphilic drugs can strongly interact with the materials from which the implant is manufactured, resulting in insufficient or no leaching from the implant. Implants that overcome this problem are disclosed herein. [Overview of the Initiative]

[0006] Brief summary of the invention Disclosed herein are implants comprising a matrix, a pharmaceutical substance, and at least one excipient, wherein the pharmaceutical substance includes a lipophilic portion. The implant may be a subcutaneous implant. In some embodiments, at least about 50% more of the pharmaceutical substance is released from the implant disclosed herein than from an equivalent implant lacking an excipient, over a specified period in an aqueous environment. The specified period may be about 6 hours, about 24 hours, about 72 hours, or about 7 days. The aqueous environment may be an aqueous solution, a subcutaneous location in a test animal, or a subcutaneous location in a human. The aqueous environment or aqueous solution may include an aqueous solution at about pH 7.4 and about 37°C, containing about 137 mM NaCl, about 2.7 mM KCl, about 10 mM Na2HPO4, and about 1.8 mM KH2PO4.

[0007] In some embodiments, the excipient may include compounds selected from the group consisting of sugar alcohols and biodegradable polymers. In some embodiments, the excipient may include compounds selected from the group consisting of mannitol, glycerol, erythritol, slayitol, arabitol, ribitol, xylitol, fusitol, galactitol, iditol, inositol, sorbitol, boremitol, isomalt, lactitol, and maltitol. In some embodiments, the excipient includes mannitol. In some embodiments, the excipient includes poly(lactic acid-coglycol) acid (PLGA).

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

[0009] In some embodiments, the lipophilic pharmaceutical substance includes a lipid-modified peptide.

[0010] In some embodiments, the lipophilic pharmaceutical substance includes a fatty acid covalently bonded to a peptide such as liraglutide.

[0011] In some embodiments, the implant matrix includes non-biodegradable polymers such as ethylene vinyl acetate, polyolefins, polyethylene, polypropylene, polybutylene, polyolefin copolymers, ethylene-methacrylic acid, ethylene-acrylic acid, vinyl aromatic polymers, polystyrene, vinyl aromatic copolymers, styrene-isobutylene copolymers, butadiene-styrene copolymers, 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 polymers selected from the group consisting of any mixture or copolymer of the above. In some embodiments, the non-biodegradable polymer includes ethylene vinyl acetate.

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

[0013] Also disclosed herein are implants comprising a matrix, a pharmaceutical substance, and at least one excipient, wherein the pharmaceutical substance is amphiphilic.

[0014] Disclosed herein are implants comprising a matrix, a pharmaceutical substance, and at least one excipient, wherein the pharmaceutical substance is co-freezycrated with the excipient to form a pharmaceutical substance-excipient mixture, and then the pharmaceutical substance-excipient mixture is incorporated into the matrix. The pharmaceutical substance can be selected from the group consisting of pharmaceutical substances containing a lipophilic portion, pharmaceutical substances that form micelles in aqueous solution, and pharmaceutical substances that are amphiphilic. In some embodiments, the pharmaceutical substance is liraglutide. In some embodiments, the excipient is a sugar alcohol such as mannitol. In some embodiments, the excipient is poly(lactic acid-coglycolic acid) (PLGA). In some embodiments, the matrix is ​​ethylene vinyl acetate (EVA).

[0015] In any of the embodiments disclosed herein, the ratio of excipient to pharmaceutical substance can be in the range of about 5:1 to about 1:10 by mass, for example, about 1:1 to about 1:6 by mass.

[0016] In any of the embodiments disclosed herein, the mass ratio of matrix:(pharmaceutical substance + excipient) can be in the range of about 10:1 to about 1:4, for example, about 5:1 to about 1:3.

[0017] Also disclosed herein are subcutaneous implants comprising about 40% to about 60% by mass of ethylene vinyl acetate and about 60% to about 40% by mass of a mannitol:liraglutide mixture, wherein the mannitol:liraglutide mixture comprises about 10% to about 30% by mass of mannitol and about 90% to about 70% by mass of liraglutide. The subcutaneous implant may also comprise about 50% by mass of ethylene vinyl acetate and about 50% by mass of a mannitol:liraglutide mixture, wherein the mannitol:liraglutide mixture comprises about 20% by mass of mannitol and about 80% by mass of liraglutide.

[0018] In any of the embodiments disclosed herein, the implant may have a length of about 1 cm to about 5 cm and a diameter of about 1 mm to about 3 mm.

[0019] In any of the embodiments disclosed herein, the implant may be a subcutaneous 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, with ethylene vinyl acetate. The dip coating may be carried out by immersing the implant in a 1% solution of EVA prepared in dichloromethane (DCM). [Brief explanation of the drawing]

[0022] [Figure 1] Figure 1 shows the average in vitro release of liraglutide from a 1.5 mm diameter × 26 mm length extruder with an EVA dip-coated shell on a 50% EVA core formulation, expressed as the released payload %. [Modes for carrying out the invention]

[0023] Detailed description of the invention Disclosed herein is an implant for the long-term sustained drug delivery of lipophilic or amphiphilic pharmaceutical substances. In one embodiment, the implant has reduced burst release upon implantation. The implant comprises a matrix, one pharmaceutical substance or a plurality of pharmaceutical substances, and at least one excipient, wherein the pharmaceutical substance comprises a lipophilic moiety, or when a plurality of pharmaceutical substances are present, at least one of the pharmaceutical substances comprises a lipophilic moiety, or at least one of the pharmaceutical substances is amphiphilic. A pharmaceutical substance comprising a lipophilic moiety can comprise one lipophilic moiety, more than one lipophilic moiety, or the entire pharmaceutical substance can be considered a lipophilic moiety (such as cholestane). The release rate of one or more pharmaceutical substances from the implant, the total release range of one or more pharmaceutical substances, or both the release rate and the total release range of one or more pharmaceutical substances is increased as compared to the release rate of one or more pharmaceutical substances, the total release range of one or more pharmaceutical substances, or both the release rate and the total release range of one or more pharmaceutical substances from an implant formulated using one or more pharmaceutical substances without using at least one excipient, by the formulation of the implant using one or more pharmaceutical substances and at least one excipient together.

[0024] Definitions and General Description "Drug" and "pharmaceutical substance" are equivalent terms and are used interchangeably to include any substance intended for use in a patient, individual or subject who needs it for therapeutic, diagnostic or nutritional use. "Drugs" and "pharmaceutical substances" 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 or mixed in a second material and can be removed from the second material (e.g., by dissolution, diffusion or degradation). Removal of the porogen results in the creation of pores in the second material.

[0026] "Biocompatibility" indicates that when used to describe a material or system, the material or system does not cause a harmful reaction or causes only minimal acceptable adverse effects when in contact with an organism such as a human.

[0027] "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 by the implants and methods disclosed herein is defined as administering one or more of the 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. "Suppression" of a disease or disorder by the implants and methods disclosed herein is defined as administering one or more of the 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 manifestation of the adverse symptoms of the disease or disorder. The difference between treatment and suppression is that treatment is performed after the adverse symptoms of the disease or disorder have appeared in the patient, whereas suppression is performed before the adverse symptoms of the disease or disorder have appeared in the patient. Suppression can be partial, substantially total or total. Since some diseases or disorders are genetic, genetic screening can be used to identify patients at risk of the disease or disorder. Next, the implants and methods as disclosed herein can be used in asymptomatic patients at risk of developing the clinical symptoms of the disease or disorder to suppress the appearance of any adverse symptoms.

[0029] The “therapeutic use” of the implants disclosed herein is defined as the use of one or more implants disclosed herein to treat a disease or disorder, as defined above. The “therapeutic effective dose” of a drug, medicinal substance or therapeutic agent is the amount of drug, medicinal 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 a disease or disorder, or to slow the progression of a disease or disorder, or one or more symptoms 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. The therapeutic effective dose may be administered to a patient as a single dose or as multiple divided doses. In the context of implantable devices, the therapeutic effective dose is the amount released from the implant that is sufficient to alleviate 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 one or more symptoms 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 an effective therapeutic dose.

[0030] The “prophylactic use” of the implants disclosed herein is defined as the use of one or more implants disclosed herein to suppress a disease or disorder, as defined above. The “prophylactic effective dose” of a drug, medicinal substance or therapeutic agent is the amount of the drug, medicinal substance or agent that, when administered to a patient, is sufficient to suppress the onset of the clinical symptoms of a disease or disorder, or to suppress the occurrence of adverse symptoms of a disease or disorder. The prophylactic effective dose may be administered to a patient as a single dose or as multiple divided doses. In the description of an implantable device, the prophylactic effective dose is the 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 one or more symptoms 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. The prophylactic effective dose may be delivered using one or more implants.

[0031] As used herein, "blood concentration" refers to the concentration of a drug, pharmaceutical substance, therapeutic agent, hormone, metabolite, or other substance in the blood of the substance being analyzed. Blood concentration can be measured in whole blood, serum, or plasma in accordance with 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 indicates otherwise.

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

[0034] With respect to the numerical ranges disclosed herein, the disclosed upper limit of a component or parameter can be combined with the disclosed lower limit of that component or parameter to provide a range (provided the upper limit is greater than the lower limit with which it is combined). Each of these combinations of disclosed upper and lower limits is expressly assumed herein. For example, if the ranges of amounts of a particular component or parameter are specified as 10% to 30%, 10% to 12%, and 15% to 20%, then the ranges of 10% to 20% and 15% to 30% are also assumed, while the combination of a lower limit of 15% and an upper limit of 12% is not assumed because it is impossible.

[0035] Unless otherwise specified, the percentages of components in a composition are expressed as mass percentages or mass / mass percentages. References to relative mass percentages in a composition are understood to assume that the total mass percentages of all components in the composition add up to 100. Furthermore, the relative mass percentage of one or more components may be adjusted upward or downward so that the total mass percentages of the components in the composition add up to 100, provided that the mass percentage of a particular component does not exceed the specified limit for that component.

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

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

[0038] For ionizable compounds, the distribution coefficient D of the compound is defined as the ratio of the concentrations of all species (ionized and non-ionized) of the compound in the organic solvent to the concentrations of all species (ionized and non-ionized) of the compound in the water in a two-phase mixture of organic solvent and water (when the organic solvent and water are immiscible). Log D can also be used. D varies depending 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 measuring D 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 may be described using the transitional phrase "consisting essentially of" or "consists essentially of" when applied to those elements. In further alternative embodiments, these elements may be described using the transitional phrase "consisting of" or "consists of" when applied to those elements. For example, if a composition or method is disclosed herein as comprising A and B, then 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 disclosed herein. Similarly, embodiments described as "consisting essentially of" or "consisting of" their various elements may also be described as "comprising" when applied to those elements. Finally, embodiments described as "essentially consisting of" those various elements may also be described as "consisting of" when applied to those elements, and embodiments described as "consisting of" those various elements may also be described as "essentially consisting of" when applied to those elements.

[0040] When an implant, device, composition, or system is described as "essentially consisting of" the enumerated elements, the implant, device, composition, or system may include the explicitly enumerated elements and other elements that do not substantially affect the conditions of treatment (composition for the treatment conditions) or the properties of the described implant, device, or system. However, the implant, device, composition, or system may not include any other elements that substantially affect the conditions of treatment, or any 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 enumerated elements that could substantially affect the conditions of treatment or the properties of the system, the implant, device, composition, or system may not include these additional elements in concentrations or amounts sufficient to substantially affect the conditions of treatment by the composition or the properties of the implant, device, or system. When a method is described as "essentially consisting of" the enumerated steps, the method may include the steps that do not substantially affect the conditions of treatment by the method or the properties of the implant, device, or system produced or used by the method. However, this method does not include any other steps, other than those explicitly listed, that substantially affect the conditions treated by the method or the implants, devices, or systems manufactured or used.

[0041] This disclosure provides several embodiments. Any feature from any embodiment can, if possible, be combined with any feature from any other embodiment. Thus, composite configurations of the disclosed features are within the scope of this disclosure.

[0042] Implant structure and manufacturing The physical parameters of the implant as disclosed herein In some embodiments, the implants disclosed herein are rod-shaped or nearly rod-shaped and have a length of about 0.5 cm to 10 cm, for example, about 1 cm to about 6 cm, or about 1 cm to about 5 cm, or about 1 cm to about 4 cm, or about 1 cm to about 3 cm, or about 1.5 cm to 3.5 cm, or about 2 cm to 4 cm, or about 2 cm to about 3 cm, or about 2 cm to about 5 cm, or about 2 cm to about 6 cm, or about 3 cm to about 5 cm, or about 3 cm to about 6 cm, or about 4 cm to about 5 cm, or about 4 cm to about 6 cm, or about 2.6 cm. In some embodiments, the implants are rod-shaped or nearly rod-shaped and have a length of about 3 cm to about 5 cm, or about 3.5 cm to about 4.5 cm, or about 4 cm. In some embodiments, the implant is rod-shaped or nearly rod-shaped, with a length of approximately 5 cm to 7 cm, or approximately 5.5 cm to 6.5 cm, or approximately 6 cm.

[0043] In some embodiments, the implant is rod-shaped or nearly rod-shaped and has a diameter of approximately 1 to 3 mm. In some embodiments, the implant is rod-shaped or nearly rod-shaped and includes dimensions of approximately 0.5 to 7 mm in diameter, or approximately 2 to 5 mm in diameter, or approximately 2 to 3 mm in diameter, or approximately 2.4 mm in diameter, or approximately 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 nearly rod-shaped and includes dimensions of approximately 2.4 mm in total diameter and approximately 2.6 cm in total length.

[0045] Chemical composition of implants: implant matrix The implants described herein may be formulated from any biocompatible material that can be implanted into a subject, patient, or individual. The portion of the implant that functions as a carrier for the pharmaceutical substances, excipients, and other substances contained within 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 mass percentage of vinyl acetate present, with the remaining percentage consisting of ethylene. Various ratios of monomers can be used, for example, about 10% to about 50% by mass of vinyl acetate with the remainder being ethylene, about 20% to about 45% by mass of vinyl acetate, about 25% to about 40% by mass of vinyl acetate, about 30% to about 36% by mass of vinyl acetate, or about 33% by mass of vinyl acetate.

[0047] In some embodiments disclosed herein, the implant further comprises a radiopaque material. The radiopaque material is preferably opaque to X-ray radiation. The radiopaque material helps to accurately locate 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 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 oxides, such as paramagnetic iron oxide (Fe3O4), can be used as materials for visualizing the implant in an MRI scan.

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

[0050] One or more detectable substances may be mixed into the implant matrix if the mixture does not substantially affect the pharmacokinetics of drug release. Alternatively, the detectable substances may be limited to specific locations on the implant that do not interfere with the pharmacokinetics of drug release, such as within the implant core or in the terminal regions of one or both of the implant.

[0051] Pharmaceutical substances and drugs for use in implants Various pharmaceutical substances and drugs can be used in implants as disclosed herein.

[0052] Lipidized peptides: Lipidized peptides (also called lipopeptides) are peptides to which lipid groups are attached. Lipidization of peptides can modify their pharmacokinetic and pharmacodynamic properties, such as by increasing their half-life in circulation or by increasing their membrane permeability. Lipidized peptides exhibit increased lipophilicity compared to unlipidized peptides. The implants disclosed herein can be used as drug delivery devices for lipidized peptides.

[0053] The bound lipids may include fatty acids, monoglycerides, diglycerides, triglycerides, phospholipids, steroids, or combinations of two or more of the aforementioned lipids.

[0054] Liraglutide: Liraglutide, a lipid-containing peptide, is an analog of glucagon-like peptide-1 (GLP-1) with antihyperglycemic activity. Liraglutide differs from natural 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 bound to the side chain of lysine-26 via a glutamate spacer (the amino acid residue position numbers are those of GLP-1(1-37), i.e., it is 37-amino acid length GLP-1, and in liraglutide, the biologically active GLP-1 is truncated at the N-terminus, representing GLP-1(7-37) with the additional modifications 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 lipid-containing peptides include echinocandin, capsofungin, surfactin, mycosbutyrin, daptomycin, and pepducin.

[0056] Peptides derivatized at their 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 peptides and used in the implants of the present invention. Examples of these lipophilic moieties include 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] Proteolipide: Proteins to which one or more lipid moieties are attached, such as myristoylated proteins (proteins to which one or more myristic acid moieties are attached) or palmitoylated proteins (proteins to which one or more palmitic acid moieties are attached), can be used in implants as disclosed herein.

[0058] Micelle-forming pharmaceutical substances and amphiphilic pharmaceutical substances: Pharmaceutical substances that form micelles in aqueous solutions can also be used in implants. Micelle-forming substances are typically amphiphilic molecules with both lipophilic and hydrophilic parts. In aqueous solutions, the molecules self-organize into clusters in a nearly 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, where they can interact with the aqueous solution.

[0059] Micelles can be freeze-dried and reconstituted in aqueous solution. However, when freeze-dried micelle powder is combined with a matrix and extruded under hot-melt extrusion conditions, the micelle structure is destroyed by the high-temperature extrusion. Since the matrix material is typically hydrophobic, the destruction of the micelle structure causes the lipophilic portion of the molecules to strongly interact with the matrix, resulting in poor elution of amphiphilic or micelle-forming pharmaceutical substances from the matrix. It is believed that using the excipients described herein together with amphiphilic or micelle-forming pharmaceutical substances stabilizes and protects the micelle structure of the pharmaceutical substance during hot-melt extrusion, thereby enhancing the ability to elute the pharmaceutical substance from the matrix of the implant.

[0060] Lipidized peptides (lipopeptides) often form micelles in aqueous solutions, and the above mechanism is thought to enhance the elution of lipidized peptides from implants containing a matrix, one or more lipidized peptides as pharmaceutical substances, and one or more excipients, compared to the elution of lipidized peptides from implants containing a matrix and lipidized peptides but without excipients.

[0061] Pharmaceutical substances and drugs for use in implants can form micelles in one or more different aqueous solutions, such as distilled water, buffer water with a pH of approximately 7 to 8, phosphate-buffered saline (PBS) with a pH of approximately 7 to 8, or PBS with a pH of approximately 7.4.

[0062] Hydrophobic drugs and hydrophobic pharmaceutical substances: Relatively hydrophobic pharmaceutical substances can also be used in implants. 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 the octanol-aqueous system, which is at least about 100 times, at least about 1,000 times, or at least about 10,000 times higher in the octanol phase than in the aqueous phase, respectively). 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 elution of pharmaceutical substances from the implant matrix. In the absence of excipients, elution does not occur, occurs at a slower rate, or, as a result, the total amount of pharmaceutical substance delivered over the life of the implant is reduced. Examples of excipients that can be used are sugar alcohols and biodegradable polymers. Mixtures of any two or more excipients described herein can also be used.

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

[0065] Examples of biodegradable polymers that can be used as excipients in implants include poly(lactic acid-coglycolic acid) (PLGA). Other biodegradable polymers that can be used in implants disclosed herein include biodegradable or bioerosive forms of polyamides, aliphatic polycarbonates, polyalkylcyanoacrylates, polyalkylene oxalates, polyanhydrides, polycarboxylic acids, polyesters, poly(hydroxybutyrate), polyimides, poly(iminocarbonates), polycaprolactone (PCL), poly-D,L-lactic acid (DL-PLA), polydioxanone, poly(glycolic acid), poly-L-lactic acid (L-PLA), poly-L-lactic acid-coglycolic acid (PLGA), polyorthoesters, polyphosphazenes and polyphosphoesters, poly(trimethylene carbonate), cellulose esters, and their derivatives and mixtures.

[0066] The excipient-to-drug ratio can range by mass from about 5:1 to about 1:10, for example, 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-to-drug ratio is about 1:4.

[0067] Excipients can increase the amount of medicinal substance released from an implant over a specified period in an aqueous environment. For example, over a specified period, an implant containing an excipient will release at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, at least approximately 80%, at least approximately 90%, or at least approximately 100% more medicinal substance than an equivalent implant without an excipient. Alternatively, over a specified period, an implant containing an excipient will release up to approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, at least approximately 80%, at least approximately 90%, or at least approximately 100% more medicinal substance than an equivalent implant without an excipient. The specified period can be approximately 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 10 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 20 days, 3 weeks, 4 weeks, 6 weeks, 2 months, 3 months, 4 months, 5 months, or 6 months. For in vitro testing purposes, it is preferable to measure comparative release from implants with and without excipients over a specified period of approximately 6 hours to 7 days, for example, 6 hours, 24 hours, 72 hours, or 7 days.

[0068] The aqueous environment in which comparative release is studied can be selected from water, aqueous solution, subcutaneous location in test animals, or subcutaneous location in humans. Test animals can be dogs such as beagles, pigs, chimpanzees, or apes such as monkeys. The aqueous environment can be pure water such as distilled water. The water used in the aqueous environment can be distilled water. For in vitro tests of comparative release, an aqueous solution of phosphate-buffered saline (PBS) is preferred. The pH of PBS can be between approximately pH 7 and approximately pH 8, such as approximately pH 7.4, to approximate physiological pH. The temperature of PBS is preferably between approximately 35°C and approximately 40°C, such as approximately 37°C, to approximate human body temperature. Samples to be tested in PBS can be suspended in PBS in a wire basket or other suitable support. PBS can be stirred at approximately 20 RPM to approximately 100 RPM, such as approximately 50 RPM, using a paddle or magnetic stirrer. In one embodiment, PBS contains about 137 mM NaCl, about 2.7 mM KCl, about 10 mM Na2HPO4, and about 1.8 mM KH2PO4, and preferably PBS has a pH of about 7.4 and a temperature of about 37°C.

[0069] Diseases treatable with implants as disclosed herein The implants disclosed herein, once implanted in a subject or patient, can be used to treat diseases through the sustained and long-term release of pharmaceutical substances from the implant.

[0070] Liraglutide and related compounds are described in U.S. Patent Nos. 6,268,343 and 8,846,618, and their use is described for methods of lowering blood glucose levels, treating type 1 diabetes, treating type 2 diabetes, treating impaired glucose tolerance, blood glucose control, treating obesity, weight loss, inhibiting gastric acid secretion, treating gastric ulcers, treating myocardial infarction, inhibiting β-cell apoptosis, stimulating β-cell proliferation, treating dyslipidemia, treating stroke, treating left ventricular hypertrophy, treating arrhythmias, treating bacteremia, treating sepsis, treating irritant bowel disease, or treating functional dyspepsia.

[0071] Liraglutide (marketed under the brand names VICTOZA® and SAXENDA®, trademarks of Novo Nordisk) is approved in the United States for the treatment of type 2 diabetes, particularly for controlling blood glucose levels in individuals with type 2 diabetes, for the treatment of obesity and to help obese or overweight individuals lose weight, and to reduce the risk of heart attack or stroke in individuals 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 for reducing blood glucose levels, treating type 1 diabetes, treating type 2 diabetes, treating impaired glucose tolerance, blood glucose control, treating obesity, weight loss, inhibiting gastric acid secretion, treating gastric ulcers, treating myocardial infarction, inhibiting β-cell apoptosis, stimulating β-cell proliferation, treating dyslipidemia, treating stroke, treating left ventricular hypertrophy, treating arrhythmias, treating bacteremia, treating sepsis, treating irritant bowel disease, treating functional dyspepsia, reducing the risk of heart attack or stroke, reducing the risk of heart attack or stroke in subjects with diabetes, reducing the risk of heart attack or stroke in subjects with type 1 diabetes, or reducing the risk of heart attack or stroke in subjects with type 2 diabetes.

[0073] Exemplary polymers for use in implants A preferred polymer for use in implants is ethylene vinyl acetate (EVA; poly(ethylene-co-vinyl acetate)). However, other biocompatible polymers may be used in the implants disclosed herein. As used herein, “polymer” or “polymer material” means a polymer containing repeating monomer units or comonomer units. A polymer may be a homopolymer, copolymer, terpolymer, or may contain more than three monomers.

[0074] Additional polymers that can be used in implants disclosed herein include polyolefins including polyethylene, polypropylene, and polybutylene, ethylene-vinyl acetate, as well as polyolefin copolymers such 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, 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 above.

[0075] The implant may contain a single type of polymer or a mixture of two or more polymers. A mixture of two polymers can regulate the drug release rate. It is desirable that an effective therapeutic amount of drug be released from the implant as disclosed herein over a reasonably long period of time. Yang et al., U.S. Patent No. 6,258,121, discloses a method for 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 burst release of the drug at the time of implantation.

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

[0077] Pologenshell In some embodiments, the implant may include a pologen-containing shell, which can further help in regulating the release of the drug from the implant. An implant including a pologen-containing shell is disclosed in International Patent Application No. WO2018 / 067882, and the pologen shell described therein can be applied to the implant 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 pologen-containing shell include polyethylene, polypropylene, and polyolefins including polybutylene, ethylene-vinyl acetate, as well as polyolefin copolymers such 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, 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 above. In one embodiment, the pologen-containing shell contains the same polymer that constitutes the interior of the implant containing the pharmaceutical substance and excipients. In one embodiment, the pologen-containing shell contains a polymer different from the polymer that constitutes the interior of the implant containing the pharmaceutical substance and excipients.

[0078] Examples of pologens that can be used in the shell include alkylcelluloses and hydroxyalkylcelluloses such as ethylcellulose, methylcellulose, and hydroxymethylcellulose; 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). Pologen particles are preferably used in a narrow size distribution to allow control of pore size. The average diameter of the pologens used can be about 1 micrometer to about 300 micrometers. In some embodiments, the average diameter of the pologens is greater than the thickness of the shell. In some embodiments, the average diameter of the pologens is approximately equal to the thickness of the shell. In some embodiments, the average diameter of the pologens is less than the thickness of the shell. In some embodiments, the average diameter of the pologens is less than about 75% of the thickness of the shell. In some embodiments, the average diameter of the pologens is less than about 50% of the thickness of the shell. In some embodiments, the average diameter of the pologens is less than about 25% of the thickness of the shell.

[0079] A single material can be used as the pologen for the shell, or two or more different pologen materials can be used.

[0080] Pologen can be removed from the implant shell before implantation. In other embodiments, the implant can be implanted without removing the pologen, which can then be dissolved after implantation.

[0081] Implant coating Implants as disclosed herein may be partially or entirely coated with a coating for controlling drug release, as applicable. Implants may be coated by dip coating, spray coating, pan coating, or in a fluidized bed system. When implants are manufactured by extrusion, the coating may be applied by co-extrusion.

[0082] Rod-shaped implants can be coated across their entire surface, and then small portions of each end of the rod can be cut off. This results in partially coated rods, where the drug-containing matrix is ​​exposed on the flat surfaces at both ends of the rod, while the curved, cylindrical sides are coated. If the coating is applied to the curved, cylindrical sides by co-extrusion, then when the extruded rod is cut into pieces to form individual implants, the drug-containing matrix is ​​exposed at both ends of the rod.

[0083] The coating can be impermeable to drugs, in which case the coating should only partially cover the implant so that the drug is released from the uncoated portion of the implant. Alternatively, the coating should dissolve or decompose after a certain period, allowing the drug to be released from the newly exposed drug-containing matrix. Or, the coating can be more or less permeable to drugs, allowing for regulation 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 (e.g., a 1% solution). The implant can be dipped once or multiple times (e.g., two, three, four, or more times if a thicker coating is desired).

[0085] Manufacturing of implants as disclosed herein In some embodiments, implants as disclosed herein can be manufactured by blending polymer microparticles with medicinal substance particles of a desired size and co-extruding the blend. The blend 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 homogenized as needed. The mixture is then co-extruded, for example, through a microtruder screw extruder, model number RCP-025, Randcastle Extrusion Systems, Cedar Grove, NJ, or other extruder known in the industry. The extrusion diameter, temperature, pressure, and other parameters can be appropriately controlled for each polymer and medicinal substance.

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

[0087] After washing the extruded material, it can be dried to remove the washing solvent. Drying is typically carried out at approximately 30°C to 60°C for about 6 to 24 hours, for example, at approximately 40°C for about 12 hours.

[0088] After drying, packaging and sterilization can be performed. The implants may be vacuum-packed in a moisture-proof foil pouch, heat-sealed and / or vacuum-sealed, and then sterilized using gamma irradiation such as approximately 20–30 kilogray, or approximately 25 kilogray, or approximately 2.5–3.5 megarads, or approximately 2.9–3.1 megarads, or approximately 3 megarads.

[0089] Liraglutide implants Liraglutide-containing implants suitable for use in subjects, individuals, or patients are also described herein. Liraglutide implants include the following:

[0090] A matrix comprising ethylene vinyl acetate (EVA), wherein the EVA contains about 10% to about 50% by mass of vinyl acetate, with the remainder being ethylene, and the matrix 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] Pharmaceutical substances containing liraglutide or pharmaceutically acceptable salts thereof, and

[0092] Excipients containing sugar alcohols or biodegradable polymers.

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

[0094] The excipient:liraglutide ratio can be in the range of about 5:1 to about 1:10, about 1:1 to about 1:6, or 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 acid-coglycolic acid) (PLGA), more preferably mannitol. The mass ratio of the matrix to (pharmaceutical substance + excipient) is in the range of 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 nearly rod-shaped. In some embodiments, the liraglutide implant is about 0.5 cm to 10 cm in length, for example, about 1 cm to 6 cm, or about 1 cm to 5 cm, or about 1 cm to 4 cm, or about 1 cm to 3 cm, or about 1.5 cm to 3.5 cm, or about 2 cm to 4 cm, or about 2 cm to 3 cm. In some embodiments, the liraglutide implant has a diameter of about 1 to 3 mm. In some embodiments, the implant has a diameter of about 0.5 to 7 mm, or about 2 to 5 mm, or about 2 to 3 mm, or about 2.4 mm, or about 3 mm. In some embodiments, the liraglutide implant has an overall diameter of about 2.4 mm and an overall length of about 2.6 cm.

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

[0098] Implants as disclosed herein may be designed to provide a steady-state concentration of a drug in the blood (e.g., in plasma or serum). Implants as disclosed herein may be designed so that the resulting drug concentration in the blood remains essentially constant over a long period of time. Implants as disclosed herein may be designed so that the resulting drug concentration in the blood remains substantially constant over a long period of time.

[0099] The release of drugs from implants 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 the coating of any component, and other parameters.

[0100] The drug release rate is also affected by cleaning the implant before insertion into the patient. Implants can be cleaned with solvents such as water, ethanol, and isopropanol, which can help reduce burst release during the initial implantation of the implant.

[0101] "Nearly constant blood concentration" refers to a nearly constant concentration of a drug in the blood of a subject or patient 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 the 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 nearly constant blood concentration of a drug is one in which the concentration changes by approximately ±30% or less 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 nearly constant concentration of a drug changes by approximately ±20% or less over a day, week, month, three months, six months, or nine months, compared to the average blood concentration over that period. In yet another embodiment, a nearly constant concentration of a drug changes by approximately ±10% or less over a day, week, month, three months, six months, or nine months, compared to the average blood concentration over that period. "Nearly constant release rate" indicates that a nearly constant amount of the pharmaceutical substance is released from the 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, a nearly constant release rate means that, compared to the mean release, the variation over the indicated period is no more than about ±50%, about ±40%, about ±30%, about ±20%, or about ±10%. A nearly constant release rate is preferred to achieve a nearly constant blood concentration. "Essentially constant" means that for about 95% of a long period, the blood drug concentration is within about 3, about 2, or preferably about 1 standard deviation of the mean blood concentration. Blood concentration measurements can be performed hourly, twice daily, daily, twice weekly, weekly, every two weeks, monthly, or at any other regular interval to determine the mean blood concentration. For example, if the average blood concentration of a drug sampled at one-week intervals is 2.0 ng / ml, and the standard deviation of the measured values ​​is ±0.1 ng / ml, then the blood concentration at which approximately 95% of the measured values ​​fall within approximately ±0.3 ng / ml, approximately 0.2 ng / ml, or preferably approximately ±0.1 ng / ml is considered to be essentially constant."Long term" means a period of approximately 3 months to approximately 1 year or longer. For example, a long term can be approximately 3 months or at least approximately 3 months, approximately 4 months or at least approximately 4 months, approximately 5 months or at least approximately 5 months, approximately 6 months or at least approximately 6 months, approximately 9 months or at least approximately 9 months, approximately 12 months or at least approximately 12 months, approximately 15 months or at least approximately 15 months, approximately 18 months or at least approximately 18 months, approximately 21 months or at least approximately 21 months, approximately 24 months or at least approximately 24 months, or more than 24 months.

[0102] Implant insertion and removal Another aspect of this 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 into the patient from the one or more implants. In a preferred method of this disclosure, the implants as disclosed herein are administered by subcutaneous implantation. In various embodiments, the implants are subcutaneously implanted in a site selected from the group consisting of the upper arm, scapular region, back, leg, and abdomen. Prior to implantation, the patient is lightly anesthetized with, for example, isoflurane or other anesthetics known in the art, and / or a topical, percutaneous, or subcutaneous anesthetic can be applied to the implantation site. A small incision is made in the skin, a trocar is inserted subcutaneously, and then one implant is attached. 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 is sutured closed and can be examined later. Complications such as skin irritation, inflammation, infection, or other site-specific side effects can be monitored and treated with antibiotics or other means as needed.

[0103] In various embodiments, implants as disclosed herein can remain in the body for up to about one year, about two years, or longer. Implants can remain in the body for up to about three months, up to about six months, up to about nine months, up to about twelve months, up to about fifteen months, up to about eighteen months, up to about twenty-one months, or up to about twenty-four months, or longer. Thus, the duration of sustained release of the drug into the body is about one month to about one year or longer, or about three months to about one year or longer, for example, at least about three months, at least about six months, at least about nine months, at least about twelve months, at least about fifteen months, at least about eighteen months, at least about twenty-one months, or at least twenty-four months or longer. In some embodiments, implants can remain in the body for more than one 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 pharmaceutical substance to counteract the 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 drug or to deliver multiple drugs.

[0106] Exemplary Embodiments The present invention is further described by the following embodiments. Features of each embodiment can be combined with any of the other embodiments where appropriate and practical.

[0107] Embodiment 1. An implant comprising a matrix, a pharmaceutical substance, and at least one excipient, wherein the pharmaceutical substance includes a lipophilic portion.

[0108] Embodiment 2. The implant described above is a subcutaneous implant, as in Embodiment 1.

[0109] Embodiment 3. The implant according to Embodiment 1, wherein, in an aquatic environment over a specified period, at least approximately 50% more pharmaceutical substances are released from the implant compared to those released from a comparable implant lacking excipients.

[0110] Embodiment 4. The implant according to Embodiment 3, wherein the specified period is approximately 6 hours, approximately 24 hours, approximately 72 hours, or approximately 7 days.

[0111] Embodiment 5. The aforementioned aqueous environment is selected from an aqueous solution, a subcutaneous location in a test animal, or a subcutaneous location in a human, as described in Embodiment 3 or Embodiment 4 of the implant.

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

[0113] Embodiment 7. The implant according to any one of Embodiments 1 to 4, wherein the excipient comprises a compound selected from the group consisting of sugar alcohols and biodegradable polymers.

[0114] Embodiment 8. The implant according to any one of Embodiments 1 to 7, wherein the excipient comprises a compound selected from the group consisting of sugar alcohols.

[0115] Embodiment 9. The implant according to any one of Embodiments 1 to 7, wherein the excipient comprises a compound selected from the group consisting of mannitol, glycerol, erythritol, slayitol, arabitol, ribitol, xylitol, fusitol, galactitol, iditol, inositol, sorbitol, boremitol, isomalt, lactitol, and maltitol.

[0116] Embodiment 10. The implant according to any one of Embodiments 1 to 7, wherein the excipient comprises mannitol.

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

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

[0119] Embodiment 13. The implant according to Embodiment 1, wherein the lipophilic pharmaceutical substance includes a lipid.

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

[0121] Embodiment 15. The implant according to Embodiment 1, wherein the lipophilic pharmaceutical substance includes a lipid-derived peptide.

[0122] Embodiment 16. The implant according to Embodiment 1, wherein the lipophilic pharmaceutical substance includes a fatty acid.

[0123] Embodiment 17. The implant according to Embodiment 1, wherein the lipophilic pharmaceutical substance contains a fatty acid covalently bonded to a peptide.

[0124] Embodiment 18. The implant according to Embodiment 17, wherein the lipophilic pharmaceutical substance containing a fatty acid covalently bonded to a peptide includes liraglutide.

[0125] Embodiment 19. The implant according to Embodiment 1, wherein the matrix comprises a non-biodegradable polymer.

[0126] Embodiment 20. The implant according to 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 a polymer selected from the group consisting of any mixture or copolymer of the above.

[0127] Embodiment 21. The implant according to Embodiment 19, wherein the non-biodegradable polymer includes ethylene vinyl acetate.

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

[0129] Embodiment 23. The implant according to Embodiment 22, wherein the aqueous solution is phosphate-buffered saline (PBS) with a pH of approximately 7 to approximately 8.

[0130] Embodiment 24. An implant comprising a matrix, a pharmaceutical substance, and at least one excipient, wherein the pharmaceutical substance is amphiphilic. [Examples]

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

[0132] Example 1 Preparation of liraglutide-EVA test samples Liraglutide without excipients: Liraglutide (Auro Peptides) was used as the active pharmaceutical ingredient (API). For API processing, a mild, buffered, endotoxin-free base solution (ammonium bicarbonate, pH=7.4, filtered through a 0.2 μm PTFE membrane) was prepared. 0.53 g of API was dissolved in 100 mL of the 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) mixture: 100 mg of API was suspended in a 5 mL 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 freeze-dried to obtain a dry powder.

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

[0135] Extrusion method: API was blended with cold-ground EVA powder and extruded. Extrusion was performed using a Thermo Scientific Haake Minilab microcompounding machine Type 5572200 equipped with a co-rotating screw and force feeder. The extruder screw was a Therma Pharma MiniHME screw, and the barrel plate was a corrosion-resistant R&D part used for clamshell assembly. The barrel temperature was set to 80°C, and each powder blend was manually loaded into the force feeder auger. The screw torque was set to a fixed level of 50 N·cm, and the product was extruded from a 1.5 mm nozzle. The extruded rods were approximately 26 mm in length and 1.5 mm in diameter.

[0136] Pellet press: The pellets were pressed to simulate a smaller-scale hot-melt process than would be possible using the extrusion method. 100 mg portions of each dry powder (liraglutide, liraglutide-PLGA, and liraglutide-mannitol, without excipients) prepared as described above were manually blended with 100 mg of cryogenically ground EVA resin (lot ENG-EVA-B060816). The 200 mg powder blend was then pressed into five individual pellets, each weighing approximately 40 mg, using a hydraulic press and a pellet die heated 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 culture medium was 100 mL of pH 7.4 phosphate-buffered saline maintained at 37°C and 50 RPM. The rods and pellets were wrapped in wire sinkers. Samples were taken at 6 hours and 24 hours. 100 μL was withdrawn at each time point and replaced with fresh medium.

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

[0139] The formulated test specimens (API-EVA mixture) were compared to the API reference standard and a control sample consisting of a powder blend of API and cryogenically ground EVA. The sample portion was placed in a small vial, dissolved in 2 mL of DCM, and then allowed to stand overnight until dissolved. Next, 0.1 mL of the dissolved solution was sampled using a volumetric pipette and diluted to 10 mL in pH 8.0 phosphate buffer. The solution was thoroughly mixed, and approximately 1 mL was microcentrifuged and analyzed by HPLC.

[0140] Example 3 In vitro release of liraglutide API without excipients Liraglutide was blended with cryogenically ground EVA powder and extruded at a drug load of 50% (w / w) as described above. The average recovery rate of the API / EVA powder blend sampled for in vitro release before being fed into the extruder was 94% w / w. After extrusion into a rod 26 mm long and 1.5 mm in diameter, the in vitro recovery rate of API from the rod varied from 14% to 20%.

[0141] Example 4 Comparison of in vitro release of liraglutide API with and without excipients The pellets were prepared as described in Example 1 and contained liraglutide without excipients, liraglutide with mannitol excipients, and liraglutide with PLGA excipients. 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 containing mannitol excipient from an extruded rod. The extruded rods were prepared as described above using a liraglutide-mannitol mixture and EVA. The molten material recovered from the extruder barrel was tested for the payload (n=3), and a drug content measurement of 39.9 ± 2.8 mass% was obtained from a theoretical load of 42%. The tested extruded samples (n=3) yielded an average API content of 50.4 ± 1.5%.

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

[0144] Example 6 In vitro release of liraglutide containing mannitol excipient from extruded, dip-coated rods. Extruded rods containing a liraglutide-mannitol mixture were overcoated with EVA resin by immersion in a 1% solution of EVA prepared in dichloromethane (DCM). Each sample was immersed three times individually, with drying between immersions. The mean drug load (n=3) of the dip-coated specimens was 50.3 ± 1.4%. The dip-coated ends of each sample were trimmed before testing to mimic co-extrusion of a cut core / shell with an open end. Figure 1 shows the amount of drug released as a percentage of the load over time up to 72 hours.

[0145] While the above-described invention has been explained in some detail as an example and illustration to clarify its meaning, it will be apparent to those skilled in the art that certain changes and modifications can be implemented without departing from the spirit and scope of the invention. Therefore, this description should not be construed as limiting the scope of the invention.

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

Claims

1. It is an implant, Non-biodegradable matrix, and, A mixture of a pharmaceutical substance and at least one excipient incorporated into the matrix of the implant at a mass percentage of approximately 9 to 80 percent. Includes, An implant comprising a matrix containing a non-biodegradable polymer, a pharmaceutical substance being a lipophilic pharmaceutical substance containing a lipophilic portion, and at least one excipient being one or more sugar alcohols or one or more biodegradable polymers.

2. The implant according to claim 1, wherein the implant is a subcutaneous implant.

3. The implant according to claim 1, wherein, in an aquatic environment over a specified period, at least about 50% more pharmaceutical substances are released from the implant compared to those released from a comparable implant lacking excipients.

4. The implant according to claim 3, wherein the prescribed period is approximately 6 hours, approximately 24 hours, approximately 72 hours, or approximately 7 days.

5. The implant according to claim 3 or 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 aforementioned aqueous environment has a pH of approximately 7.4 and a temperature of approximately 37°C, and contains approximately 137 mM NaCl, approximately 2.7 mM KCl, and approximately 10 mM Na. ２ HPO ４ and approximately 1.8 mM KH ２ PO ４ The implant according to claim 3 or claim 4, comprising an aqueous solution containing the following.

7. The implant according to any one of claims 1 to 6, wherein the excipient is one or more sugar alcohols.

8. The implant according to any one of claims 1 to 6, wherein the one or more sugar alcohols include one or more selected from the group consisting of mannitol, glycerol, erythritol, slayitol, arabitol, ribitol, xylitol, fusitol, galactitol, iditol, inositol, sorbitol, boremitol, isomalt, lactitol, and maltitol.

9. The implant according to any one of claims 1 to 6, wherein the one or more sugar alcohols include mannitol.

10. The implant according to any one of claims 1 to 6, wherein the excipient is one or more biodegradable polymers.

11. The implant according to any one of claims 1 to 6, wherein the one or more biodegradable polymers include poly(lactic acid-coglycol) acid (PLGA).

12. The implant according to claim 1, wherein the lipophilic pharmaceutical substance includes a lipid.

13. The implant according to claim 12, wherein the lipid is selected from the group consisting of fatty acids, monoglycerides, diglycerides, triglycerides, phospholipids, and steroids.

14. The implant according to claim 1, wherein the lipophilic pharmaceutical substance comprises a lipid-derived peptide.

15. The implant according to claim 1, wherein the lipophilic pharmaceutical substance includes a fatty acid.

16. The implant according to claim 1, wherein the lipophilic pharmaceutical substance comprises a fatty acid covalently bonded to a peptide.

17. The implant according to claim 16, wherein the lipophilic pharmaceutical substance containing a fatty acid covalently bonded to a peptide contains a glucagon-like peptide-1 analog.

18. The implant according to claim 17, wherein the lipophilic pharmaceutical substance containing a fatty acid covalently bonded to a peptide comprises liraglutide.

19. The implant according to claim 1, 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 a mixture or copolymer of any of the above.

20. The implant according to claim 1, wherein the non-biodegradable polymer includes ethylene vinyl acetate.

21. The implant according to claim 1, wherein the mass percentage of the matrix is ​​about 20% to about 91% of the implant.

22. It is an implant, Non-biodegradable matrix, and A mixture of a pharmaceutical substance and at least one excipient incorporated into the matrix of the implant at a concentration of approximately 9% to 80% by mass. Includes, An implant wherein the matrix comprises a non-biodegradable polymer, the pharmaceutical substance comprises a lipid-containing peptide, and the at least one excipient is selected from one or more sugar alcohols or one or more biodegradable polymers.

23. The implant according to claim 5, wherein the aqueous solution is phosphate-buffered saline (PBS) with a pH of approximately 7 to approximately 8.

24. It is an implant, Non-biodegradable matrix, and A mixture of a pharmaceutical substance and at least one excipient incorporated into the matrix of the implant at a concentration of approximately 9% to 80% by mass. Includes, An implant wherein the matrix comprises a non-biodegradable polymer, the pharmaceutical substance is amphiphilic, and the at least one excipient is selected from one or more sugar alcohols or one or more biodegradable polymers.

25. An implant comprising a non-biodegradable matrix, a pharmaceutical substance, and at least one excipient, wherein the matrix comprises a non-biodegradable polymer, the at least one excipient is selected from one or more sugar alcohols or one or more biodegradable polymers, the pharmaceutical substance and the at least one excipient are incorporated into the matrix as a pharmaceutical substance-excipient mixture in an amount of about 9% to about 80% by mass of the implant, and the pharmaceutical substance is selected from the group consisting of pharmaceutical substances containing lipophilic moieties, lipid-containing peptides, and amphiphilic pharmaceutical substances.

26. The implant according to claim 25, wherein the pharmaceutical substance containing the lipidized peptide is liraglutide.

27. The implant according to claim 25 or 26, wherein the excipient is a sugar alcohol.

28. The implant according to claim 27, wherein the sugar alcohol is mannitol.

29. The implant according to any one of claims 1 to 28, wherein the matrix is ​​ethylene vinyl acetate (EVA).

30. The implant according to any one of claims 1 to 29, wherein the ratio of the excipient to the pharmaceutical substance is in the range of about 5:1 to about 1:10 by mass.

31. The implant according to claim 30, wherein the ratio of the excipient to the pharmaceutical substance is in the range of about 1:1 to about 1:6 by mass.

32. The implant according to any one of claims 1 to 31, wherein the mass ratio of the matrix to (pharmaceutical substance + excipient) is in the range of approximately 10:1 to approximately 1:

4.

33. The implant according to claim 32, wherein the mass ratio of the matrix to (pharmaceutical substance + excipient) is in the range of approximately 5:1 to approximately 1:

3.

34. The implant according to any one of claims 1 to 26 and 29 to 33, wherein the at least one excipient comprises a sugar alcohol, and the sugar alcohol comprises mannitol.

35. The implant according to any one of claims 1 to 26 and 29 to 33, wherein the at least one excipient comprises a biodegradable polymer, and the biodegradable polymer comprises poly(lactic acid-coglycolic acid) (PLGA).

36. A non-biodegradable matrix containing approximately 40% to 60% by mass of ethylene vinyl acetate, and A mixture of one or more sugar alcohols in an amount of approximately 60% to 40% by mass, and a lipid-containing peptide containing a glucagon-like peptide-1 analog. A subcutaneous implant comprising a mixture comprising about 10% to about 30% by mass of one or more sugar alcohols and about 90% to about 70% by mass of a lipid-modified peptide containing a glucagon-like peptide-1 analog.

37. A non-biodegradable matrix containing approximately 50% by mass of ethylene vinyl acetate, and A mixture of one or more sugar alcohols and a lipid-containing peptide containing a glucagon-like peptide-1 analog, approximately 50% by mass. A subcutaneous implant comprising a mixture comprising about 20% by mass of one or more sugar alcohols and about 80% by mass of a lipidized peptide containing a glucagon-like peptide-1 analog.

38. The implant according to any one of claims 1 to 37, wherein the implant has a length of approximately 1 cm to approximately 5 cm and a diameter of approximately 1 mm to approximately 3 mm.

39. The implant according to any one of claims 1 to 38, wherein the implant is a subcutaneous implant.

40. A mixture of pharmaceutical substances and excipients is mixed with a non-degradable matrix. Extruding the mixture by hot-melt extrusion. A method for manufacturing an implant according to any one of claims 1 to 39, including the method described above.

41. The implant according to any one of claims 1 to 39, wherein the implant is dip-coated.

42. The implant according to claim 41, wherein the implant is dip-coated with ethylene vinyl acetate.

43. The implant according to claim 41, wherein the implant is dip-coated with ethylene vinyl acetate by immersing the implant in a 1% solution of ethylene vinyl acetate prepared in dichloromethane (DCM).

44. The implant according to claim 36 or 37, wherein the one or more sugar alcohols include mannitol.

45. The implant according to claim 36 or 37, wherein the lipidized peptide containing a glucagon-like peptide-1 analog comprises liraglutide.

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