Sustained release of biotherapeutic from biodegradable polymer implants

Abstract

Disclosed herein are implants, methods of forming implants, and formulations comprising implants. The implants comprise a biodegradable polymer, a biotherapeutic, and vitamin E. The biodegradable polymer is a polyesteramide (PEA) of defined structure. The implant may be highly loaded with biotherapeutic and may exhibit desirable release properties in vivo.

Description

[0001] SUSTAINED RELEASE OF BIOTHERAPEUTIC FROM BIODEGRADABLE POLYMER IMPLANTS FIELD OF THE INVENTION

[0002]

[0001] Aspects of the invention relate to implants comprising polyesteramide polymers and biotherapeutics and methods of forming such implants. Such implants may be injection moldable at sufficiently low temperatures to allow for a wide range of biotherapeutics while limiting biotherapeutic degradation. Further, the implants may provide desirable in vivo performance characteristics that render them suitable, according to specific embodiments, for use in administering biotherapeutics with desirable release profiles.

[0003] BACKGROUND

[0004]

[0002] Biotherapeutics are medicinal products that are peptides, polypeptides, proteins, nucleic acids or nucleic acid based, monoclonal antibodies, vaccines, or formulations thereof. Biotherapeutics are manufactured in, extracted from, or semisynthesized from biological sources.

[0005]

[0003] Biotherapeutics are administered to patients for myriad medical reasons, often by injection or infusion. Due to limited plasma lifetime, administration of biotherapeutics may be required at frequent intervals. Certain biotherapeutics may have their properties modified to allow administration at weekly intervals, but longer intervals between injections is still desired.

[0006]

[0004] Sustained release or pulsatile release of the biotherapeutic after a single injection or implantation would reduce the number of injections required to achieve the desired therapeutic effect. Sustained release systems may release the biotherapeutic over the course of a few days to several months. Typically, limited burst release is desired so as to maintain efficient therapeutic concentration of the biotherapeutic.

[0007]

[0005] A pulsatile drug delivery system may involve the simultaneous administration of an immediate release component and a modified release component. The immediate release component may act as a first dose or provide an immediately felt impact on the patient, while the modified release component may act as a second dose and / or provide a longer-term benefit to the patient.

[0008]

[0006] One type of biotherapeutic is a glucagon-like peptide-1 receptor agonist (GLP-1 RA). GLP-1 RA treatments have become extremely popular for treating Type 2 diabetes and obesity. Examples of GLP-1 RA treatments are exenatide, tirzepatide, liraglutide, semaglutide, and2025P00127WG

[0009] dulaglutide. GLP-1 RA treatments require frequent subcutaneous injections. Such frequent injections are uncomfortable for patients and inhibit patient compliance.

[0010]

[0007] For example, tirzepatide requires weekly subcutaneous injections. The approved label for tirzepatide requires initial dosing for four weeks using a once weekly 2.5mg dose, increasing in 2.5 mg increments after at least 4 weeks until the recommended weekly maintenance dose of 10 mg or 15 mg is reached. Accordingly, several months of treatment may be required to achieve the desired dose for a particular patient. This can be prolonged if a dose is missed. Improved patient outcomes could be achieved if the desired dose could be achieved quicker and / or if less frequent subcutaneous injections were required for efficacy.

[0011]

[0008] Another popular GLP-1 agonist, semaglutide, also requires weekly subcutaneous injections. A dose-escalation schedule is required to reduce the risk of gastrointestinal adverse reactions.

[0012]

[0009] EP3159368B1 describes biodegradable polyesteramide copolymers which aim to exhibit a sustained release of bioactive agents in a controllable way. The biodegradable polyesteramide copolymers show surface erosion degradation which is caused enzymatically and also show degradation via a hydrolytic bulk erosion mechanism.

[0013]

[0010] US2009 / 0169632 discloses a sustained release composition comprising a polymer and manufacturing method thereof. The sustained release composition comprises a polymer, a bioactive agent, and a release rate determined agent, wherein the release rate determined agent is dispersed in the sustained release composition to control the release rate of the bioactive agent. The method comprises providing an oil phase comprising a bioactive agent, a polymer, and a release rate determined agent; providing an aqueous phase comprising a surfactant; mixing the oil phase with the aqueous phase to form the sustained release composition having a controlled release effect.

[0014]

[0011] WO2024 / 134493 describes biocompatible polymeric drug delivery systems for long-acting or controlled release of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide- 1 (GLP-1) dual agonist, or pharmaceutically acceptable salts thereof comprising a polymeric material to form a polymer matrix; and GIP and GLP-1 dual agonist is homogeneously dispersed within the polymer matrix, wherein the polymer matrix comprises a biodegradable polymer and pharmaceutically acceptable excipients. The biocompatible polymeric drug delivery system can be administered into a patient to release for long-acting or controlled or sustained period.

[0012] Drug delivery systems that are able to achieve the therapeutic effect of a biotherapeutic with a reduced number of injections would be desirable.

[0015] SUMMARY

[0016]

[0013] One alternative to frequent injections is a degradable, biotherapeutic-loaded implant. After implantation, the implant degrades over the course of one to many months while releasing biotherapeutic at a desired rate. A second procedure to remove the implant is not required as the implant will eventually be resorbed by the body.

[0017]

[0014] One desired aspect of such a drug delivery system is that an initial “burst” of biotherapeutic upon implantation should usually be maintained in a safe range. For sustained release, it is desired to rather release the biotherapeutic slowly over time and over the course of a few weeks to several months. This is also apparent given the dose-escalation schedules prescribed for existing GLP-1 agonists.

[0018]

[0015] In contrast to the objectives pursued in certain prior art sustained-release systems, such as those described in US2009 / 0169632, the present invention is not directed to eliminating or shortening an initial lag phase in drug release. Rather, the present invention is specifically concerned with achieving prolonged, controlled release over an extended duration while minimizing or avoiding an initial burst release of the active agent. The prior art emphasizes release profiles designed to prevent a lag phase following administration, often prioritizing early availability of the bioactive agent. By contrast, the present invention recognizes that, for certain therapeutic applications, excessive early release may be undesirable and may compromise safety, tolerability, or dosing control. Accordingly, the present invention focuses on formulations and material selections that suppress burst release and sustain delivery over time, thereby addressing a fundamentally different technical problem than that addressed by the prior art.

[0019]

[0016] Achieving sustained release profiles while ensuring sufficiently high loading of biotherapeutic is challenging. The administered implant must be injectable in a minimally invasive procedure, typically requiring an implant of sufficiently small size and of appropriate geometry. Increased biotherapeutic payload may negatively affect implant formation generally as there is naturally less of the other components of the formulation needed to form the implant as the amount of biotherapeutic increases.

[0020]

[0017] Furthermore, procedures for forming implants, such as injection molding or hot melt extrusion procedures, require elevated temperatures in order to sufficiently soften or melt thebiodegradable polymer. Such elevated temperatures may degrade the biotherapeutic or biodegradable polymer. Use of lesser temperatures may result in improper implant formation, such as misshapen or inhomogeneous implants. For example, it is possible that too much biotherapeutic is present at the surface of the implant, resulting in too high dose of biotherapeutic during the first few days. Such higher doses may cause undesired side effects.

[0021]

[0018] Still further, the formed implant must be sterilized. Sterilization procedures may involve high energy doses that have the potential to degrade the biotherapeutic and / or the biodegradable polymer.

[0022]

[0019] Aspects of the invention are associated with the discovery that implants comprising a high loading of biotherapeutic and exhibiting surprising sustained release properties can be formed from certain biodegradable polymer formulations and techniques. Benefits of the disclosed inventions may include, alone or in combination, an improved manufacturing process in terms of throughput and / or quality, less biotherapeutic degradation, better sterilization stability, improved release duration, limited burst release, a quicker achievement of a desired dose, reduced injection frequency, an improved dosing regimen, higher drug loading, patient comfort, patient compliance, reduced side effects, reduced gastrointestinal effect or discomfort, manufacturing efficiency or repeatability, and improved product stability.

[0023]

[0020] These and other embodiments, aspects, and advantages relating to the present invention are apparent from the following Detailed Description.

[0024] BRIEF DESCRIPTION OF THE DRAWINGS

[0025]

[0021] A more complete understanding of exemplary embodiments of the invention and the advantages thereof may be acquired by referring to the following description in consideration of the accompanying figures, which serve to illustrate various features and certain principles involved.

[0026]

[0022] Fig. 1 is a photograph of an injection molding apparatus used in the Examples herein.

[0027]

[0023] Fig. 2 is a chart of cumulative release (%) vs. time for certain implants tested in the Examples herein, wherein such implants are formed by injection molding or extrusion.

[0028]

[0024] Fig. 3 is a detail view of the boxed portion of Fig. 2.2025P00127WG

[0029] DETAILED DESCRIPTION

[0030]

[0025] The disclosures herein relate to implants comprising biotherapeutics, certain biodegradable polymers, and vitamin E. The biodegradable polymers are polyesteramides (PEAs) that are random copolymers comprising certain “units” as hereinafter described.

[0031]

[0026] As used herein, “tirzepatide” means a GIP / GLP1 dual agonist peptide as described in US 9,474,780 and described by CAS Registry Number: 2023788-19-2. US9474780 describes and claims tirzepatide. More specifically, tirzepatide is described in Example 1 of US 9,474,780, with the following sequence: YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS wherein Xi is Aib; X2 is Aib; K at position 20 is chemically modified through conjugation to the epsilon-amino group of the K side-chain with (2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2- (yGlu)i-CO-(CH2) 18-CO2H; and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 1).

[0032]

[0027] As used herein, “semaglutide” means a “Semaglutide” means a GLP-1 receptor agonist peptide as described in US 20210330748A1 and described by CAS Registry Number: 910463-68-2. Semaglutide is N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoyl- aminojbuty ry lamino] ethoxy } ethoxy jacetylamino] ethoxy } ethoxy jacetyl] [ Aib8, Arg34] GLP- 1 -(7-37) and may be prepared as described in Example 4 of W02006 / 097537.

[0033]

[0028] As used herein, “vitamin E” means a group of compounds known collectively as vitamin E in the art, including both fat-soluble and water-soluble forms and derivatives thereof. Fat-soluble vitamin E compounds include tocopherols and tocotrienols, such as alpha-tocopherol, beta-tocopherol, gamma-tocopherol, delta-tocopherol, alpha-tocotrienol, beta-tocotrienol, gamma-tocotrienol, and delta-tocotrienol, as well as esters thereof, including acetate, succinate, and phosphate esters. Water-soluble vitamin E derivatives include vitamin E conjugates modified to increase hydrophilicity, such as tocopheryl polyethylene glycol succinate (vitamin E-TPGS), tocopheryl phosphate salts, and other polymer- or surfactant-modified tocopherol derivatives. Unless otherwise indicated, the term “vitamin E” encompasses any of the foregoing compounds and derivatives, whether naturally occurring or synthetic. In a preferred embodiment, the Vitamin E comprises alpha-tocopherol. In a preferred embodiment, the Vitamin E consists of alpha-tocopherol. In an embodiment, the vitamin E comprises a fatsoluble form of vitamin E. In an embodiment, the vitamin E consists of one or more fat-soluble forms of vitamin E. In an embodiment, the vitamin E comprises a water-soluble form of2025P00127WG

[0034] vitamin E. In an embodiment, the vitamin E consists of one or more water-soluble forms of vitamin E.

[0035]

[0029] In an embodiment, the biotherapeutic comprises a peptide, polypeptide, protein, nucleic acid, monoclonal antibody, or a mixture thereof. In an embodiment, the biotherapeutic comprises a peptide. In an embodiment, the biotherapeutic is a GLP-1 receptor agonist. In an embodiment, the peptide is a glucose-dependent insulinotropic polypeptide (GIP) agonist. In an embodiment, the biotherapeutic comprises exenatide, tirzepatide, liraglutide, semaglutide, or dulaglutide. In an embodiment, the biotherapeutic is tirzepatide. In an embodiment, the biotherapeutic is semaglutide.

[0036]

[0030] In an embodiment, the biotherapeutic comprises a peptide or polypeptide. In an embodiment, the biotherapeutic comprises from 15 to 100 amino acid residues. In an embodiment, the biotherapeutic comprises at least 15, 20, 25, or 30 amino acid residues. In an embodiment, the biotherapeutic comprises at most 100, 90, 80, 70, 60, 50 or 40 amino acid residues.

[0037]

[0031] In addition to amino acid residues, the biotherapeutic may comprise certain modifications to enhance cell uptake, binding to albumin, or stability. In an embodiment, the biotherapeutic comprises a peptide coupled to a fatty acid moiety, such as eicosanedioic acid.

[0038]

[0032] In an embodiment, the biotherapeutic has a molecular weight of from 3000 to 80,000 g / mol. In an embodiment, the biotherapeutic has a molecular weight of from 3000 to 6000 g / mol, preferably 3500 to 5500 g / mol. In an embodiment, the biotherapeutic has a molecular weight of from 4500 to 5200 g / mol.

[0039]

[0033] In an embodiment, the biotherapeutic is water-soluble.

[0040]

[0034] In an embodiment, the implant comprises from 20 wt% to 70 wt% biotherapeutic, based on the total weight of the implant, preferably 25 to 60 wt%. In an embodiment, the biotherapeutic is present in an amount of from 21 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt% 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, or 40 wt%, based on the total weight of the implant. In an embodiment, the biotherapeutic is present in an amount of from 69 wt%, 65 wt%, 60 wt%, 59 w%, 58 wt%, 57 wt%, 56 wt%, 55 wt%, 54, wt%, 53, wt%, 52 wt%, 51 wt%, or 50 wt%, based on the total weight of the implant.

[0041]

[0035] In an embodiment, the biodegradable polymer is present in an amount of from 29 wt% to 79 wt%, based on the total weight of the implant, preferably 35 to 75 wt%. In an embodiment, thebiodegradable polymer is present in an amount of from 78 wt%, 77 wt%, 76 wt%, 75 wt%, 74 wt%, 73 wt%, 72 wt%, 71 wt%, or 70 wt%, based on the total weight of the implant. In an embodiment, the biodegradable polymer is present in an amount from 30 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, or 45 wt%, based on the total weight of the implant.

[0042]

[0036] In an embodiment, the vitamin E is present in an amount of from 1 wt% to 10 wt%, based on the total weight of the biodegradable polymer in the implant, preferably 2 to 8 wt%. In an embodiment, the vitamin E is present in an amount of from 2 wt%, 3 wt%, 4 wt%, or 5 wt%, based on the total weight of the biodegradable polymer in the implant. In an embodiment, the vitamin E is present in an amount of from 9 wt%, 8 wt%, 7 wt%, or 6 wt%, based on the total weight of the biodegradable polymer in the implant.

[0043]

[0037] In an embodiment, the implant further comprises an additive. In an embodiment, the implant further comprises a surfactant, plasticizer, antioxidant, chelating agent, buffer, or osmotic agent. In an embodiment, the implant consists of the biodegradable polymer, the biotherapeutic, and the vitamin E.

[0044]

[0038] In an embodiment, the implant is prepared by one of the following methods.

[0045]

[0039] First, a first composition may be formed by dispersing the desired amount of biotherapeutic, biodegradable polymer, and vitamin E in a first solvent for the biodegradable polymer. In an embodiment, the first solvent is selected from the group consisting of ethanol, methanol, butanol, tert-butanol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, and mixtures thereof. In an embodiment, the first solvent is ethanol. In an embodiment, the biotherapeutic is not soluble in the first solvent.

[0046]

[0040] Next, the first composition is be cast and dried, thereby forming a thin film. The film is then broken or cut into small pieces. The film may optionally be milled, such as via a cryo-mill. These pieces may be loaded into an injector of an injection molding apparatus or loaded into an extruder.

[0047]

[0041] In an injection molding process, implants may be formed by loading the pieces into an injector, raising the temperature, injecting the melt into the mold at an injection pressure, and holding the mold at a holding pressure. Typically, the injection pressure may vary from 50 to 400 bar and the holding temperature may vary from 150 to 400 bar.

[0042] In an extrusion process, implants may be formed by loading the pieces into the hopper of a compounder, such as an Xplore MC 15 HT. Then the first composition is extruded at an elevated temperature. Residence time is typically 5 to 15 minutes. The extrudate is cut and cooled to form an implant.

[0048]

[0043] In an alternative method, the first composition may be formed without the biotherapeutic. The pieces may be loaded into an extruder and the biotherapeutic dosed in via a second stream.

[0049]

[0044] In another alternative method, the first composition may be formed with the biotherapeutic.

[0050] The film formed from the first composition may then be milled to a powder, sieving, and mixing the first composition powder with a powder containing biotherapeutic.

[0051]

[0045] Whether formed by injection molding or extrusion, the obtained implants are typically sterilized. High energy sterilization is generally preferred, though this may degrade susceptible materials.

[0052]

[0046] Injection molding and extrusion are known manufacturing methods and require elevated temperatures. Since many biotherapeutics are temperature-sensitive, these manufacturing methods must be performed at suitably low temperatures to avoid instability of the biotherapeutic. If temperatures are raised too high, the biotherapeutic can undergo undesirable denaturation or dimerization. The effect of a given manufacturing method on the stability of the biotherapeutic can be measured by assessing the high molecular weight protein fraction (HMWP). HMWP is a measure for the aggregates of HMWP, which can potentially lead to larger fibrils forming over time and could affect the safety of the drug. A lower HMWP, such as 1 wt% or less of the biotherapeutic, indicates that the process is of minimal impact to the biotherapeutic.

[0053]

[0047] It was surprisingly found that implants with high biotherapeutic loading can be formed while achieving a HMWP of less than 1%. In an embodiment, an implant comprises from 20 wt% to 70 wt% biotherapeutic, from 29.5 to 79 wt% of biodegradable polymer, and from 0.5 to 8 wt% of vitamin E, each based on the total weight of the implant, and has a HMWP of biotherapeutic of less than 1. In an embodiment, the HMWP is less than 0.75%. In an embodiment, the HMWP is less than 0.5%. The HMWP is measured according to the procedure described in the Examples section herein.

[0054]

[0048] The formulation disclosed enable processing of implants at surprisingly low temperatures. In an embodiment, a method of forming the implant comprises forming an implant at atemperature of less than 105 °C, such as from 65 °C to 105 °C or preferably from 75 °C to 100 °C. In an embodiment, the method of forming an implant comprises shaping the implant at a temperature of at most 105 °C, 100 °C, 95 °C, 90 °C, or 85 °C. In an embodiment, the method of forming an implant comprises shaping the implant at a temperature of from 65 °C to 100 °C, from 70 °C to 100 °C, from 75 °C to 95 °C, or 75 °C to 90 °C. In an embodiment, the mold is filled to at least 95% full.

[0055]

[0049] The resulting implant should have sufficient mechanical properties to allow for injection or implantation into a patient without damage. Damage may occur as cracking, surface degradation, or bending deformation. The implants disclosed herein desirably exhibit sufficient mechanical properties to avoid this damage.

[0056]

[0050] The implant may take various forms. In an embodiment, the implant is in the shape of a rod.

[0057] In an embodiment, the implant is in the shape of a disc.

[0058]

[0051] In an embodiment, the implant is injectable. For example, the implant may have a diameter of less than 2 mm to allow injection through a 12 gauge needed. In an embodiment, the implant is implantable.

[0059]

[0052] In an embodiment, the implant has a width of from 1 mm to 6 mm. In an embodiment the implant has a width of from 1 mm, 1.5 mm, 2 mm, 2.5 mm, or 3 mm. In an embodiment, the implant has a width of at most 6 mm, 5.5 mm, 5 mm, 4.5 mm, 4 mm, 3.5 mm, or 3 mm.

[0060]

[0053] In an embodiment, implant has a length of from 10 mm to 250 mm. In an embodiment, the implant has a length of from 10 mm, 15 mm, 20 mm, or 25 mm. In an embodiment, the implant has a width of at most 250 mm, 200 mm, 150 mm, 100 mm, 75 mm, 50 mm, or 30 mm. In an embodiment, the implant has a length of from 20 mm to 40 mm.

[0061]

[0054] In an embodiment, the implant further comprises a coating. In an embodiment, the coating comprises a biodegradable polymer that is devoid of biotherapeutic or that contains biotherapeutic at a different loading than the body of the implant. In an embodiment, the coating comprises the polyester amide as disclosed herein. In another embodiment, the coating is formed from another degradable polymer, such as degradable polyester. In an embodiment, the coating comprises PLA, PLLA, PLGA, or a combination thereof.

[0062]

[0055] In an embodiment, the coating fully covers the implant surface. In another embodiment, the coating comprises the circumference of a cylindrical implant. In an embodiment, one end of the implant is uncoated. In an embodiment, both ends of the implant are uncoated.

[0056] In an embodiment, less than 20% of the biotherapeutic is released from the implant after seven days in phosphate buffer at pH 7.4 containing 137 mM NaCl, 2.7 mM KC1, 10 mM Na2HPC>4 and 1.8 mM KH2PO4 at 37 °C. In an embodiment, less than 15% of the biotherapeutic is released from the implant after seven days in phosphate buffer at pH 7.4 containing 137 mM NaCl, 2.7 mM KC1, 10 mM Na2HPO4 and 1.8 mM KH2PO4 at 37 °C.

[0063]

[0057] The biodegradable polymer is a polyester amide (PEA) as described herein. The PEA has a structure that includes, or that may consist of, n units, each unit having residues, for example 2, 3, or 4 different types of residues, as defined below, which are present in each unit at respective molar equivalents that are designated by m, p, q, and x, in which m+p+q+x=l. The n units may be characterized as “repeating” units to the extent that the defined values or ranges of m, p, q, and x are consistent from one unit to the next, although it is not required for each unit to be identical in structure, as long as the defined values or ranges are met. As is apparent from the structures of residues given below, they are linked by amide bonds [(-C=O)NH-)], whereas certain of these residues include ester bonds [(-C=O)O-)] that help confer water permeability. Given the teachings herein, those skilled in the art will be able to appreciate the structural modifications and corresponding adjustments in synthesis procedures that influence certain properties described herein.

[0064]

[0058] For ease of understanding, dashed lines are used in structures of the individual residues, and in other structures, to emphasize that they represent points of attachment (bonding) and not methyl groups. To the extent that structures may include chiral carbon atoms, the lack of an express illustration of stereochemistry is meant to convey that all stereoisomers are intended. However, those skilled in organic chemistry, given the teachings herein including the specific synthesis procedures, will be able to ascertain particular stereochemical configurations that are representative of PEA polymers in preferred embodiments.

[0065]

[0059] More specifically, the n units in the in the structure of the PEA may have:

[0066] m molar equivalents of a first residue having the formula

[0067] O O H O O H

[0068] - C - R1- C - N - C - C - O - R5- O - C - C - N - I I I I

[0069]

[0070] H R3R3H p molar equivalents of a second residue having the formulaO O H O O H - C - R1- C - N - C - C - O - R6- O - C - C - N -

[0071]

[0072] H R4R4H q molar equivalents of a third residue having the formula

[0073] O O H H

[0074] - C - R1- C - N - C - R8- N - H C - O - R7

[0075]

[0076] 0, and

[0077] x molar equivalents of a fourth residue having the formula

[0078] O O H H

[0079] - C - R1- C - N - C - R8- N - H C - O - H

[0080]

[0081] O

[0082]

[0060] The values m, p, q, and x represent molar equivalents of the corresponding first, second, third, and fourth residues in the units of the random copolymer, which molar equivalents are scaled such that m+p+q+x=l, thereby indicating relative molar equivalents among the residues.

[0083]

[0061] According to a first embodiment, m is from 0 to 0.8, p is from 0 to 0.95, m+p is from is from 0.5 to 1, q is from 0.02 to 0.25, and x is from 0.05 to 0.25; n is from 5 to 300; R1is (C2- C2o)alkylene; R3and R4are selected from the group consisting of hydrogen, (Ci-C6)alkyl, (C2- C6)alkenyl, (C2-C6)alkynyl, (C6-Cio)aiyl, -CH2SH, -(CH2)2S(CH3), -CH2OH, -CH(OH)CH3, -(CH2)4NH3+, -(CH2)3NHC(=NH2+)NH2, -CH2COOH, -CH2-CO-NH2, -CH2CH2-CO-NH2, -CH2CH2COOH, CH3-CH2-CH(CH3)-, (CH3)2CH-CH2-, H2N-(CH2)4-, Ph-CH2-, CH=C-CH2- , (CH3)2CH-, Ph-NH-, NH-(CH2)3-C-, or NH-CH=N-CH=C-CH2-, wherein R3and R4are the 1 _ 1 1 - 1

[0084] same or different; R5is (C2-C2o)alkylene, optionally having one or more alkylene carbon atoms(-C-) replaced by an oxygen atom (-O-), and / or optionally having 5 or 6 consecutive alkylene carbon atoms together form a respective 5- or 6-membered carbocyclic ring;

[0085] R6is

[0086]

[0087] R7is (C6-Cio)aryl(Ci-C6)alkylene; and R8is (C3-Cs)alkylene. In such PEA polymers, higher values of p, i.e. , increased proportions of the second residue, can lead to a higher glass transition temperature, and more particularly a higher glass transition temperature of the polymer in its hydrated state (wet Tg).

[0088]

[0062] As used herein, the term “alkyl” means a monovalent straight or branched chain hydrocarbon group including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like, with more specific alkyl groups being limited according to ranges of carbon atom numbers, as indicated in parentheses, preceding “alkyl.”

[0089]

[0063] As used herein, the term “alkylene” means a divalent straight or branched chain hydrocarbon group such as -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CIfc)?-, and the like, with more specific alkyl groups being limited according to ranges of carbon atom numbers, as indicated in parentheses, preceding “alkylene.”

[0090]

[0064] As used herein, the term “alkenyl” means a monovalent straight or branched chain hydrocarbon group having at least one carbon-carbon double bond in the main chain or in a side chain, with more specific alkenyl groups being limited according to ranges of carbon atom numbers, as indicated in parentheses, preceding “alkenyl.”

[0091]

[0065] As used herein, the term “alkenylene” means a divalent straight or branched chain hydrocarbon group having at least one carbon-carbon double bond in the main chain or in a side chain, with more specific alkenylene groups being limited according to ranges of carbon atom numbers, as indicated in parentheses, preceding “alkenylene.”

[0066] As used herein, “alkynyl” means a monovalent straight or branched chain hydrocarbon group having at least one carbon-carbon triple bond in the main chain or in a side chain, with more specific alkynyl groups being limited according to ranges of carbon atom numbers, as indicated in parentheses, preceding “alkynyl.”

[0092]

[0067] As used herein, “aryl” means an unsubstituted or optionally substituted phenyl radical or an unsubstituted or optionally substituted ortho-fused bicyclic carbocyclic radical having nine or ten ring atoms, in which at least one ring is aromatic. Examples of aryl include, but are not limited to, phenyl, naphthyl, and nitrophenyl.

[0093]

[0068] As used herein, “biodegradable" means a material which is capable of being completely or substantially degraded or eroded when exposed to an in vivo environment. A polymer is capable of being degraded or eroded when it can be gradually broken down, resorbed, absorbed, and / or eliminated by, for example, hydrolysis, enzymolysis, oxidation, metabolic processes, bulk or surface erosion, and the like. As noted above, in preferred embodiments, PEA polymers may be characterized as being biodegradable. This leads to advantages in the use of such polymers in delivery of biotherapeutics.

[0094]

[0069] According to the PEA structure as defined above and including n units, each having residues, for example 2, 3, or 4 different types of residues, in the case of a “random copolymer,” the residues, present in each unit at respective molar equivalents that are designated by m, p, q, and x, are distributed randomly throughout the units and throughout the copolymer.

[0095]

[0070] Given the structures of the monomers above, it can be appreciated that, in any of the embodiments as defined herein, the PEA may have the following structure:

[0096] O O H O O H II , . — C— R1-C— N— C— C-O— R5-O-C— C— N c— R1-c— N— c— C-O— R6-O-C— c— N I I I I H R3R3H R4R4H

[0097] O O H H O O H H II , II c— R1-c— N— c1«

[0098] — R8-N1II , II - C— R1-C— N— C1«

[0099] — R8-N1I I H C-O— R7H C-O— H

[0100]

[0101] wherein n, m, p, q, and x, as well as the substituents R1, R3, R4, R5, R6, R7, and R8are as defined above.

[0102]

[0071] In more specific embodiments, the PEA is defined as according to the first embodiment, wherein m may be from 0, 0.10, 0.15, 0.20, or 0.25 to 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, or 0.35. In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein p may be from 0.10, 0.20, 0.30, 0.35, or 0.40 to 0.95, 0.90, 0.85, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, or 0.45. In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein p may be greater than or equal to m. In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein m and p may be both greater than zero. In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein m:p may be from 2:1, 1 : 1, or 2:3 to 1:5, 1:4, 1 :3, or 1:2. In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein q is from 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20 to 0.25, 0.23, 0.21, 0.20, 0.19, 0.18, 0.17, 0.16, 0.15, 0.11, 0.10, 0.09, 0.08, or 0.07. In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein x is from 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20 to 0.30, 0.25, 0.20, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, or 0.10. In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein the ratio q:x is from 80:20, 75:25, 65:35, 60:40, 55:45, 50:50, 45:55, 40:60, or 35:65 to 20:80, 25:75, 30:70, or 35:65. In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein the ratio q:x is from 20:80 to 80:20. In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein m is about 0.3, p is about 0.45, q is about 0.19, and x is about 0.06 (X25). In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein m is about 0.3, p is about 0.45, q is about 0.13, and x is about 0.13 (X50). In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein mis about 0.3, p is about 0.45, qis about 0.10, and x is about 0.15 (X60). In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein m is about 0.3, p is about 0.45, q is about 0.09, and x is about 0.16 (X65). In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein m is about 0.3, p is about 0.45, q is about 0.08, and x is about 0.18 (X70). In other more specific embodiments, the PEA is defined as according to the first embodiment, wherein m is about 0.3, p is about 0.45, q is about 0.06, and x is about 0.19 (X75). In other more specific embodiments, the PEA is definedas according to the first embodiment, wherein n is from 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 to 300, 290, 280, 270, 260, 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, or 150. In other more specific embodiments, the PEA is defined as according to the first embodiment and has a number average molecular weight (Mn) of at least 15,000 g / mol, at least 20,000 g / mol, at least 25,000 g / mol, at least 30,000 g / mol, or at least 35,000 g / mol. In other more specific embodiments, the PEA is defined as according to the first embodiment and has an Mn of at most 250,000 g / mol, at most 225,000 g / mol, at most 200,000 g / mol, at most 175,000 g / mol, at most 150,000 g / mol, at most 125,000 g / mol, at most 100,000 g / mol, or at most 75,000 g / mol. Mn is measured via gel permeation chromatography (GPC) in tetrahydrofuran (THF) with polystyrene as standard.

[0103]

[0072] In yet further specific embodiments, the PEA is defined as according to the first embodiment, and may have any one or more of: ranges of m as defined above; ranges of p as defined above; p being greater than m; m and p being both greater than zero; ranges of m:p as defined above; ranges of q as defined above; ranges of x as defined above; ranges of q:x as defined above; values of m, p, q, and x as defined above; ranges of n as defined above; lower limits of Mn as defined above; and / or upper limits of Mn as defined above.

[0104]

[0073] In yet further specific embodiments, the PEA is defined as according to the first embodiment, and may be more particularly characterized by any one or more of: R3is selected from the group consisting of hydrogen, (Ci-C6)alkyl, CH3-CH2-CH(CH3)-, (CFE CH-CEE-, PI1-CH2-, and (CHshCH-; R4is selected from the group consisting of hydrogen, (Ci-C6)alkyl, CH3-CH2- CH(CH3)-, (CH3)2CH-CH2-, Ph-CH2-, and (CH3)2CH-; R3and R4are the same; R5is (C2- C2o)alkylene; R7is (Ce)aryl-CH2- (z.e. benzyl or phenylmethyl); and / or R8is -(CH2)4-.

[0105]

[0074] In yet further specific embodiments, the PEA is defined as according to the first embodiment, and may be more particularly characterized by any one or more of: p is from 0 to 0.8 and m+p is from 0.5 to 0.9; q is from 0.05 to 0.15; x is from 0.10 to 0.25; q:x is from 50:50 to 20:80, or more particularly from 45:55 to 25:75, or more particularly from 40:60 to 30:70; and / or m is 0.

[0106]

[0075] In yet further specific embodiments, the PEA is defined as according to the first embodiment, and may be more particularly characterized by any one or more of: m is from 0.1 to 0.5, p is from 0.1 to 0.75, m+p is from 0.5 to 0.8, q is from 0.05 to 0.15, and x is from 0.10 to 0.25; R1is (C2-Cio)alkylene; R3and R4are (Ci-C6)alkyl; R5is (C2-Cio)alkylene;R6is

[0107]

[0108] '» ; R7is Ph-(Ci-C6)alkylene; and R8is (C3-C6)alkylene. For example, the PEA may be characterized by one or more of these definitions of m, p, m+p, q, x, R1, R3, R4, R5, R6, R7, and R8, such as in the case of the PEA being characterized by all of these definitions.

[0109]

[0076] Polyesteramide random copolymers may be synthesized by adapting a procedure known in the art from Katsarava et al. (WON J POLYM SCI A: POLYM CHEM 1999:37 : 391-407). Briefly, the polymers are prepared via solution polycondensation of di-p-toluenesulfonic or hydrochloric acid salts of bis-(a-amino acid) a,co-diol diesters, lysine benzyl ester, lysine, and / or di-N- hydroxysuccinimide ester of sebacic acid in anhydrous DMSO. Typically, the salts are converted to free amines by addition of triethylamine and these amines are further reacted with the di-acid derivative. The usage of pre-activated acid in the reaction allows polymerization at relatively low temperature, such as 65 °C, affording side-product free polycondensates and predictable degradation products. Subsequently, the obtained reaction mixture is purified via a water precipitation followed by an organic precipitation and filtration. Drying under reduced pressure yields the polyesteramide random copolymer.

[0110]

[0077] For example, such polymers may be prepared by reacting lysine, lysine benzyl ester, and hexahydrofuro[3,2-b]furan-3,6-diyl bis(2-amino-4-methylpentanoate) with di-N- hydroxysuccinimide ester activated sebacic acid in DMSO for 24 hours. The polymer is then isolated from the reaction mixture in two precipitation steps and characterized by means of proton NMR and THF-based GPC relative to polystyrene standards.

[0111] EXAMPLES

[0112]

[0078] The following examples are set forth as representative of the present invention. These examples are not to be construed as limiting the scope of the invention as other equivalent embodiments will be apparent in view of the present disclosure and appended claims.

[0113] Preparation of Copolymers

[0079] PEA-X50 is a random copolymer within the scope of PEA polymers as described herein and has the structure:

[0114] O O H O O H IIdII I II ,. H I C— R1-C— N— C— C-O— R6-O— C— C— N I I I I H R4R4H

[0115] O O H H O o H II

[0116] C— R1-C— N— C— R8-N C— I R1-C— N— C— R8- I H C-O— R7H c-o— H II

[0117] o

[0118]

[0119] This PEA polymer therefore has residues with the structures as described generally herein, in which m is 0.30, p is 0.45, q is about 0.0125, and x is about 0.125; R1is octylene [(Cs)alkylene]; R3and R4are isobutyl; R5is hexylene [(Ce)alkylene] ;

[0120] R

[0121]

[0122] 6is \ ;

[0123] R7is benzyl [Ph-(Ci)alkylene, or phenylmethyl]; and R8is butylene [(C4)alkylene] . This PEA copolymer was prepared according to the following description.

[0124]

[0080] Triethylamine (32 ml, 0.229 mole) and DMSO (55 ml, 0.78 mole) were added to a mixture of di-N- hydroxysuccinimide ester of sebacic acid (Di-NHS-sebacic acid) (40.3397 g, 0.102 mole), L-leucine- (DAS)-2TosOH (33.2614 g, 0.047 mole), L-leucine(6)-2TosOH (21.3007 g, 0.031 mole), L- lysine-2HCl (2.8236 g, 0.013 mole) and L4ysine(Bz)-2TosOH (7.4847 g, 0.013 mole) in a nitrogen flushed 500 ml round bottomed flask equipped with an overhead stirrer at room temperature. The subsequent mixture was heated to 60°C to allow the reaction to proceed, with monitoring by GPC analysis in THF. After 36 hours, a stable molecular weight was obtained. The reaction mixture was diluted with 250 ml DMSO and was allowed to cool to room temperature. At room temperature, acetic anhydride (1.89 ml, 0.0199 mole) was added to acylate the aminofunctional end groups of the polymer. Next, the mixture was stirred at room temperature for 24 hours.

[0125]

[0081] The obtained crude polymer mixture was precipitated in water at a 10:1 ratio (water: reaction mixture). The polymer was collected and dissolved in ethanol (500 ml, 8.57 mole) and then precipitated a second time. The polymer was again dissolved in ethanol (500 ml, 8.57 mole) and precipitated in ethylacetate (5000 ml, 50.91 mole) by dropwise addition to a stirring solution. The precipitated polymer was washed with ethylacetate (100 ml, 1.00 mole), the supernatant was removed, and the precipitate was washed again with ethylacetate (100 ml, 1.00 mole). After the removal of the supernatant, the precipitate was dried and dissolved in ethanol (500 ml, 8.57 mole), and filtered over a 0.2 pm PTFE membrane filter. The filtered polymer solution was dried under reduced pressure at 65°C. From this synthesis procedure, a typical yield is 75%, and the number average molecular weight (Mn) is normally in the range of 40- 70 kDa, measured via gel permeation chromatography (GPC) using tetrahydrofuran (THF) as the mobile phase on dried samples, and determined relative to polystyrene standards.

[0126] Implant Formulation Methods - Injection Moldins

[0127]

[0082] The injection-molding implants were performed with a Haake MiniJet Piston Injection Molding (IM) apparatus in a mold (dimensions: 12 mm x 2.0 mm) equipped with a stopper to select the desired number of implants. See Fig. 1, wherein S denotes the stopper. The depicted mold is capable of forming two implants, one on each side below the stopper.

[0128]

[0083] Semaglutide powder (HMWP measured at 500pg / ml SEMA in PBS was 0.39%) was suspended in a solution of PEA III X50 and ethanol, and vitamin E (DL-alpha-Tocopherol, Thermo Scientific Chemicals, Batch 10188932, Cat# A17039.0B; appearance: clear yellowish brown viscous liquid), if present. The suspension was used to cast a thin film. The film was further dried in ovens under vacuum at 40°C. The film was particularized. In a heating barrel, the particles were heated to 120°C then pushed by a plunger into the pre-warmed mold.

[0129]

[0084] The particles were injected in a specifically designed mold with 10 side channels of dimensions 12 mm x 2.0 mm, with a stopper present such that only the first two channels are used. The temperature of injection molding was kept constant, and the injection pressure was of 50 bar, while the holding pressure was between 150 and 400 bar. The total time of exposure at high temperatures was 12 minutes.

[0130] Implant Formulation Methods - Hot Melt Extrusion

[0085] A solution of PEA III X50, vitamin E (if present), and ethanol was formed. The solution was used to cast a thin film. The film was further dried in ovens under vacuum at 40°C. The film was then particularized. The particles are then mixed with a powder of semaglutide.

[0131]

[0086] The hot-melt extrusion implants were performed with a 5-mm twin-screw extruder (Three-Tec ZE5) apparatus. The mixture of semaglutide and PEA was loaded via a closed feeder system (batch size 15 cc; extrudate mass of 10 g) to the throat of the extruder. Extrusion was performed at a pre-defined temperature (below 100°C) through a 2-mm die.

[0132] Biotherapeutic loading analysis by UPLC-PDA

[0133]

[0087] The loading of semaglutide was analyzed via UPLC on an Acquity UPLC with an H-class Quaternary Solvent Manager apparatus, equipped with a photodiode array UV-VIS detector operating at 280 nm. The chromatographic column was ACQUITY Premier BEH Cl 8 column (50 mm x 2.1 mm, 1.7 pm particle size). Binary gradient was used, with mobile phase A = 0.1% TriFluoroAcetic Acid (TFA) in MilliQ® water and mobile phase B = Acetonitrile + 0.1% TFA. The gradient used is specified in Table 1:

[0134] Table 1: UPLC Gradient for Measuring Semaglutide Loading

[0135] Time (minutes) Flow rate (mL / min) A (%) B (%)

[0136] 0 0.4 95 5

[0137] 1 0.4 95 5

[0138] 3.5 0.4 35 65

[0139] 4.5 0.4 35 65

[0140] 4.6 0.4 95 5

[0141]

[0142] 6 0.4 95 5

[0143]

[0088] The total run time was 6 minutes, the flow rate was maintained at 0.4 mL / min, the column’s temperature was set at 35°C and the injection volume was set at 3 pL. The sample was prepared by dissolving an implant in DMSO, with a target concentration of 0.5 mg semaglutide / mL DMSO.

[0144] Semaglutide burst release analysis by UPLC-PDA

[0145]

[0089] The burst release was analyzed via UPLC on an Acquity UPLC with an H-class Quaternary Solvent Manager apparatus, equipped with a photodiode array UV-VIS detector operating at 280 nm. The chromatographic column was ACQUITY Premier BEH Cl 8 column (50 mm x 2.1 mm, 1.7 pm particle size). Binary gradient was used, with mobile phase A = 0.1%TriFluoroAcetic Acid (TFA) in MilliQ® water and mobile phase B = Acetonitrile + 0.1% TFA. The gradient used is specified in Table 2:

[0146] Table 2: UPLC Gradient for Measuring Semaglutide Burst Release

[0147] Time (minutes) Flow rate (mL / min) A (%) B (%)

[0148] 0 0.4 75 25

[0149] 1 0.4 75 25

[0150] 2.5 0.4 35 65

[0151] 3.5 0.4 35 65

[0152] 3.6 0.4 75 25

[0153]

[0154] 5 0.4 75 25

[0155]

[0090] The total run time was of 5 minutes, the flow rate was maintained at 0.4 mL / min, the column’s temperature was set at 35°C and the injection volume was set at 10 pL. The sample was prepared by placing an extruded or injection molded implant of approximately 75 mg in 16 mL of phosphate buffer solution + 0.05 wt.% NaN3 to study the burst release. Buffer solution is replaced after each measurement.

[0156]

[0091] of implant in 16 mL of phosphate buffer solution (PBS) + 0.05 wt.% NaNs. The buffer solution was refreshed for every time point repetition.

[0157] Semaglutide HMWP analysis by SEC-PDA

[0158]

[0092] The semaglutide HMWP was analyzed by Size Exclusion Chromatography (SEC) on an Acquity Arc (Waters) apparatus with a Waters 2998 photodiode array operating at 280 nm. The chromatography column was a Waters Insulin Diol (OH) column (300 mm x 7.8 mm, 10 pm particle size, 125A). The mobile phase was isocratic, and contained 500 mM NaCl, 10 mM NaH2PO4, 5 mM H3PO4 and 50 vol.% 2-propanol. The total run time was 30 minutes (RT = 16.8 mins), the flow rate was maintained at 0.5 mL / min, the temperature was set at 50°C and the injection volume was set at 50 pL.

[0159]

[0093] The sample was prepared by first cooling the implant to room temperature after molding and then dissolving 15 mg of implant in 1 mL DMSO. The dissolved implant solution is then added to 9 mL of PBS and 0.05 wt.% NaNs causing the PEA to precipitate. The PEA is then filtered out. The HMWP is calculated as follows:

[0160] HMWP Peak Area

[0161] HMWP (%) = - HMWP Peak Area + Main Peak Area

[0094] In order to ensure that the semaglutide was isolated properly during sample preparation, the isolation efficiency is calculated as the concentration of the main peak area divided by the theoretical semaglutide loading in the implant. An isolation efficiency of 100 + / - 5% indicates that the semaglutide is well isolated and confirms accuracy of the calculated HMWP.

[0162] Semaglutide Total Drug Assay

[0163]

[0095] The implant’s total drug assay was analyzed via LC-MS on an Agilent G6540A Q-TOF LC / MS apparatus, operating at 220 nm and 278 nm. The chromatographic column type was a BEH C18 column (50 mm x 3.0 mm, 1.7 pm particle size). Binary gradient was used, with mobile phase A = 0.1% formic acid + water and mobile phase B = THF + 0.1% formic acid. The gradient used is specified in Table 3:

[0164] Table 3: UPLC Gradient for Total Drug Assay

[0165] Time (minutes) Flow rate (mL / min) A (%) B (%)

[0166] 0 0.4 50 50

[0167] 10 0.4 50 50

[0168] 15 0.4 2 98

[0169] 17 0.4 2 98

[0170]

[0171] 17.10 0.4 75 25

[0172]

[0096] The total run time was 20 minutes, and the flow rate was maintained at 0.4 mL / min.

[0173]

[0097] The sample was prepared by dissolving an implant in DMSO, with a target concentration of 0.5 mg semaglutide / mL DMSO

[0174] Effect of Implant Manufacturing Method on semaglutide

[0175]

[0098] Sample formulations were prepared. The sample formulation were either injection molded or extruded according to the procedures described. Formulations 1-9 are injection molded. Formulation 10 is hot melt extruded. Measurements are taken using the described procedures. Results are shown in Table 4a and 4b below.Table 4a: Evaluation of processing conditions on HMWP Formulation Temperature (°C) HMWP via Isolation Efficiency DMSO (%) via DMSO (%) 100% PEA 120 n.a. n.a.

[0176] 25% biotherapeutic 120 3.21 n.a. in PEA

[0177] 25% semaglutide in 100 0.78 n.a.

[0178] PEA

[0179] 25% semaglutide in 90 0.55 106.04 PEA

[0180] 25% semaglutide in 80 0.47 96.53 PEA (71.25%) +

[0181] vitamin E (3.75%)

[0182] 25% semaglutide in 80 n.a. n.a.

[0183] PEA (71.25%) +

[0184] vitamin E (3.75%)

[0185] 50% semaglutide in 90 0.50 99.81 PEA

[0186] 40% semaglutide in 90 0.59 103.98 PEA

[0187] 40% semaglutide in 80 0.42 99.4 PEA (57%) +

[0188] vitamin E (3%)

[0189] Extruded (25% 90 4.59 97.85 semaglutide in PEA

[0190] (71.25%) + vitamin

[0191] E (3.75%))

[0192]

[0193] Table 4b: Evaluation of processing conditions on loading and recovery Formulation Loading Loading UPLC Total Drug Assay UPLC (%) Recovery (%) Recovery (%)

[0194] 4 25% semaglutide in 24.92 98.85 101 PEA

[0195] 5 25% semaglutide in 23.62 94.75 105 PEA (71.25%) +

[0196] vitamin E (3.75%)

[0197] 6 25% semaglutide in 24.69 96.07 96 PEA (71.25%) +

[0198] vitamin E (3.75%)

[0199] 7 50% semaglutide in 49.73 99.28 - PEA

[0200] 8 40% semaglutide in 38.59 95.10 - PEA

[0201] 9 40% semaglutide in 37.51 93.17 - PEA (57%) + vitamin

[0202] E (3%)

[0203] 10 Extruded (25% of 26.32 n.a.

[0204] semaglutide in PEA

[0205] (71.25%) + vitamin E

[0206]

[0207] (3.75%))

[0208]

[0099] The implants produced by injection molding (IM) showed an advantageous compatibility with the semaglutide, as indicated by HMWP values lower than 1% for IM temperatures above 90°C with a loading recovery greater than 90%. Each implant could withstand 75N before breaking in a 3 -point bending test, indicaing that the mechanical behavior of the implants was satisfactory. Moreover, the addition of vitamin E allowed a reduction of the extrusion temperature and such implants exhibited a lower HMWP.

[0209] Burst Release

[0210]

[0100] A comparison of the burst release of implants produced by different methods is shown in Figure 2 and Figure 3. Figure 3 is a detailed view of the boxed portion of Figure 2.

[0211]

[0101] The burst release of implants was better controlled due to the addition of vitamin E to the IM implants containing 25 wt% of semaglutide.

[0212]

[0102] Moreover, without vitamin E, the mold was not filled completely due to insufficient flow with an injection molding at 90°C. With vitamin E, the mold was filled at least above 95% or completely with an injection molding at 80°C.

[0103] Those skilled in the art having knowledge of the present disclosure will recognize that various changes can be made to these polymers and their applications, to attain these and other advantages, without departing from the scope of the present disclosure. As such, it should be understood that the features of the disclosure are susceptible to modifications and / or substitutions without departing from the scope of the invention. The specific embodiments illustrated and described herein are for illustrative purposes only, and not limiting of the invention as set forth in the appended claims.

[0213] EXEMPLARY DESCRIPTION OF CERTAIN EMBODIMENTS

[0214] 1. An implant comprising a biotherapeutic, a biodegradable polymer, and vitamin E, wherein the biodegradable polymer comprises a random copolymer having a structure including n units of:

[0215] m molar equivalents of a first residue having the formula

[0216] O O H O O H

[0217] - C - R1- C - N - C - C - O - R5- O - C - C - N -

[0218]

[0219] H I RI3R I3HI p molar equivalents of a second residue having the formula

[0220] O O H O O H

[0221] - C - R1- C - N - C - C - O - R6- O - C - C - N -

[0222]

[0223] H R4R4H q molar equivalents of a third residue having the formula

[0224] O O H H

[0225] - C - R1- C - N - C - R8- N - H C - O - R7

[0226]

[0227] 0, and

[0228] x molar equivalents of a fourth residue having the formulaO O H H

[0229] - C - R1- C - N - C - R8- N - H C - O - H

[0230]

[0231] O

[0232] wherein m+p+q+x = 1 ;

[0233] m is from 0 to 0.5, p is from 0.1 to 0.95, m+p is from 0.5 to 0.95, q is from 0.02 to 0.25, and x is from 0.05 to 0.25;

[0234] n is from 5 to 300;

[0235] the ratio q:x is from 60:40 to 20:80;

[0236] R1is (C2-C2o)alkylene;

[0237] R3and R4are selected from the group consisting of hydrogen, (Ci-C6)alkyl, (C2-Ce)alkenyl, (C2-C6)alkynyl, (C6-Cio)aryl, -CH2SH, -(CH2)2S(CH3), -CH2OH, -CH(OH)CH3, -(CH2)4NH3+, -(CH2)3NHC(=NH2+)NH2, -CH2COOH, -CH2-CO-NH2, -CH2CH2-CO-NH2, -CH2CH2COOH, CH3-CH2-CH(CH3)-, (CH3)2CH-CH2-, H2N-(CH2)4-, Ph-CH2-, CH=C-CH2-, (CH3)2CH-, Ph-NH-, NH-(CH2)3-C-, or NH-CH=N-CH=C-CH2-, wherein R3

[0238]

[0239] I _ I I - 1 and R4are the same or different;

[0240] R5is (C2-C2o)alkylene, optionally having one or more alkylene carbon atoms (-C-) replaced by an oxygen atom (-O-), and / or optionally having 5 or 6 consecutive alkylene carbon atoms together form a respective 5- or 6-membered carbocyclic ring;

[0241] R6is

[0242]

[0243] R7is (C6-Cio)aryl(Ci-C6)alkylene; and

[0244] R8is (C3-Cs)alkylene.The implant of the previous exemplary embodiment, wherein the biodegradable polymer has the following formula:

[0245] O O H O O H O O H O O H II , II II — C— R1-C— N C1-C11-O-R 55- O' -C-C— N C— R1

[0246] 1.. -C— N C— C- o— R A6-O-C11— c1- N — I I I H R3R3H H R4R4HJP

[0247] O o H H O O H H — C— R1-C— N— C— R8-N- C— Rq-C— N C— R8-N — H C-O-R7H C-O— H o qLoJx

[0248]

[0249] n wherein the units m, p, q, and x are randomly distributed throughout the biodegradable polymer.

[0250] The implant of any one of the previous exemplary embodiments, wherein, in the structure of the biodegradable polymer, p is from 0.3 to 0.8 and m+p is from is from 0.6 to 0.9.

[0251] The implant of any one of the previous exemplary embodiments, wherein, in the structure of the biodegradable polymer, q is from 0.05 to 0.15.

[0252] The implant of any one of the previous exemplary embodiments, wherein, in the structure of the biodegradable polymer, x is from 0.08 to 0.25.

[0253] The implant of any one of the previous exemplary embodiments, wherein, in the structure of the biodegradable polymer, x is from 0.10 to 0.20.

[0254] The implant of any one of the previous exemplary embodiments, wherein, in the structure of the biodegradable polymer, q:x is from 40:60 to 30:70.

[0255] The implant of any one of the previous exemplary embodiments, wherein, in the structure of the biodegradable polymer, q:x is from 55:45 to 35:65.

[0256] The implant of any one of the previous exemplary embodiments, wherein, in the structure of the biodegradable polymer, m is 0.The implant of any one of the previous exemplary embodiments, wherein m is from 0, 0.10, 0.15, 0.20, or 0.25 to 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, 0.45, 0.40, or 0.35.

[0257] The implant of any one of the previous exemplary embodiments, wherein p is from 0.10, 0.20, 0.30, 0.35, or 0.40 to 0.95, 0.90, 0.85, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50, or 0.45.

[0258] The implant of any one of the previous exemplary embodiments, wherein m:p is from 2:1, 1:1, or 2:3 to 1:5, 1:4, 1:3, or 1:2.

[0259] The implant of any one of the previous exemplary embodiments, q is from 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20 to 0.25, 0.23, 0.21, 0.20, 0.19, 0.18, 0.17, 0.16, 0.15, 0.11, 0.10, 0.09, 0.08, or 0.07.

[0260] The implant of any one of the previous exemplary embodiments, wherein x is from 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.20 to 0.30, 0.25, 0.20, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, or 0.10.

[0261] The implant of any one of the previous exemplary embodiments, wherein the ratio q:x is from 80:20 to 20:80.

[0262] The implant of any one of the previous exemplary embodiments, wherein the ratio q:x is from 80:20, 75:25, 65:35, 60:40, 55:45, 50:50, 45:55, 40:60, or 35:65 to 20:80, 25:75, 30:70, or 35:65.

[0263] The implant of any one of the previous exemplary embodiments, wherein m is about 0.3, p is about 0.45, q is about 0.10, and x is about 0.15.

[0264] The implant of any one of the previous exemplary embodiments, wherein m is about 0.3, p is about 0.45, q is about 0.09, and x is about 0.16.

[0265] The implant of any one of the previous exemplary embodiments, wherein m is about 0.3, p is about 0.45, q is about 0.08, and x is about 0.18.

[0266] The implant of any one of the previous exemplary embodiments, wherein m is about 0.3, p is about 0.45, q is about 0.06, and x is about 0.19.The implant of any one of the previous exemplary embodiments, wherein m is from 0.1 to 0.5, p is from 0.1 to 0.75, m+p is from 0.5 to 0.8, q is from 0.05 to 0.15, and x is from x is from 0.10 to 0.25.

[0267] The implant of any one of the previous exemplary embodiments, wherein n is from 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, or 75 to 300, 290, 280, 270, 260, 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, or 150.

[0268] The implant of any one of the previous exemplary embodiments, wherein the biodegradable polymer has a number average molecular weight (Mn) of at least 15,000 g / mol, at least 20,000 g / mol, at least 25,000 g / mol, at least 30,000 g / mol, or at least 35,000 g / mol.

[0269] The implant of any one of the previous exemplary embodiments, wherein the biodegradable polymer has a Mn of at most 250,000 g / mol, at most 225,000 g / mol, at most 200,000 g / mol, at most 175,000 g / mol, at most 150,000 g / mol, at most 125,000 g / mol, at most 100,000 g / mol, or at most 75,000 g / mol.

[0270] The implant of any one of the previous exemplary embodiments, wherein m is from 0.1 to 0.5, p is from 0.1 to 0.75, m+p is from 0.5 to 0.8, q is from 0.05 to 0.15, and x is from 0.10 to 0.25;

[0271] R1is (C2-Cio)alkylene;

[0272] R3and R4are (Ci-C6)alkyl;

[0273] R5is (C2-Cio)alkylene;

[0274] R6is

[0275]

[0276] R7is Ph-(Ci-Ce)alkylene; and

[0277] R8is (C3-Ce)alkylene.The implant of any one of the previous exemplary embodiments, wherein the structure of the biodegradable polymer is further characterized by one or more of the following: m is from 0.1 to 0.5, p is from 0.1 to 0.75, m+p is from is from 0.5 to 0.8, q is from 0.05 to 0.15, and x is from 0.10 to 0.25;

[0278] R1is (C2-Cio)alkylene;

[0279] R3and R4are (Ci-C6)alkyl or (CHs CH-CTh-;

[0280] R5is (C2-Cio)alkylene;

[0281] R6is

[0282]

[0283] R7is Ph-(Ci-Ce)alkylene; and

[0284] R8is (C3-C6)alkylene.

[0285] The implant of any one of the previous exemplary embodiments, wherein the structure of the biodegradable polymer is further characterized by: m is 0.2-0.4, p is 0.3-0.6, q is 0.05-0.15, and x is 0.10-0.25;

[0286] The implant of any one of the previous exemplary embodiments, wherein the structure of the biodegradable polymer is further characterized by one or more of the following: m is 0.3, p is 0.45, q is 0.05-0.15, and x is 0.10-0.25;

[0287] R1is octylene;

[0288] R3and R4are isobutyl;

[0289] R5is hexylene;

[0290] R6is

[0291]

[0292] R7is benzyl; and

[0293] R8is butylene.

[0294] The implant of any one of the previous exemplary embodiments, wherein the biodegradable polymer is amorphous.

[0295] The implant of any one of the previous exemplary embodiments, wherein the implant further comprises a second biodegradable polymer.

[0296] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic comprises a peptide, polypeptide, protein, nucleic acid, monoclonal antibody, or a mixture thereof.

[0297] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic is water-soluble.

[0298] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic comprises a peptide.

[0299] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic comprises from 15 to 100 amino acid residues.

[0300] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic comprises at least 15, 20, 25, or 30 amino acid residues.

[0301] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic comprises at most 100, 90, 80, 70, 60, 50 or 40 amino acid residues.The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic comprises a peptide coupled to a fatty acid moiety.

[0302] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic has a molecular weight of from 3000 to 80,000 g / mol.

[0303] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic has a molecular weight of from 3000 to 6000 g / mol, preferably 3500 to 5500 g / mol.

[0304] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic has a molecular weight of from 4500 to 5200 g / mol.

[0305] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic is a GLP-1 receptor agonist.

[0306] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic comprises exenatide, tirzepatide, liraglutide, semaglutide, or dulaglutide.

[0307] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic is tirzepatide.

[0308] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic is semaglutide.

[0309] The implant of any one of the previous exemplary embodiments, wherein the implant comprises from 20 wt% to 70 wt% biotherapeutic, based on the total weight of the implant.

[0310] The implant of any one of the previous exemplary embodiments, wherein the implant comprises from 25 to 60 wt% biotherapeutic, based on the total weight of the implant.

[0311] The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic is present in an amount of from 21 wt%, 21 wt%, 22 wt%, 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt% 29 wt%, 30 wt%, 31 wt%, 32 wt%, 33 wt%, 34 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, or 40 wt%, based on the total weight of the implant.The implant of any one of the previous exemplary embodiments, wherein the biotherapeutic is present in an amount of from 69 wt%, 65 wt%, 60 wt%, 59 w%, 58 wt%, 57 wt%, 56 wt%, 55 wt%, 54, wt%, 53, wt%, 52 wt%, 51 wt%, or 50 wt%, based on the total weight of the implant.

[0312] The implant of any one of the previous exemplary embodiments, wherein the biodegradable polymer is present in an amount of from 29 wt% to 79 wt%, based on the total weight of the implant.

[0313] The implant of any one of the previous exemplary embodiments, wherein the biodegradable polymer is present in an amount of from 35 to 75 wt%, based on the total weight of the implant.

[0314] The implant of any one of the previous exemplary embodiments, wherein the biodegradable polymer is present in an amount of from 78 wt%, 77 wt%, 76 wt%, 75 wt%, 74 wt%, 73 wt%, 72 wt%, 71 wt%, or 70 wt%, based on the total weight of the implant.

[0315] The implant of any one of the previous exemplary embodiments, wherein the biodegradable polymer is present in an amount from 30 wt%, 35 wt%, 36 wt%, 37 wt%, 38 wt%, 39 wt%, 40 wt%, 41 wt%, 42 wt%, 43 wt%, 44 wt%, or 45 wt%, based on the total weight of the implant.

[0316] The implant of any one of the previous exemplary embodiments, wherein the vitamin E is present in an amount of from 1 wt% to 10 wt%, based on the total weight of the biodegradable polymer in the implant.

[0317] The implant of any one of the previous exemplary embodiments, wherein the vitamin E is present in an amount of from 2 to 8 wt% based on the total weight of the biodegradable polymer in the implant.

[0318] The implant of any one of the previous exemplary embodiments, wherein the vitamin E is present in an amount of from 2 wt%, 3 wt%, 4 wt%, or 5 wt%, based on the total weight of the biodegradable polymer in the implant.The implant of any one of the previous exemplary embodiments, wherein the vitamin E is present in an amount of from 9 wt%, 8 wt%, 7 wt%, or 6 wt%, based on the total weight of the biodegradable polymer in the implant.

[0319] The implant of any one of the previous exemplary embodiments, wherein the vitamin E comprises alpha-tocopherol, beta-tocopherol, gamma-tocopherol, or delta-tocopherol.

[0320] The implant of any one of the previous exemplary embodiments, wherein the vitamin E comprises alpha-tocopherol.

[0321] The implant of any one of the previous exemplary embodiments, wherein the vitamin E consists of alpha-tocopherol.

[0322] The implant of any one of the previous exemplary embodiments, wherein the vitamin E comprises a fat-soluble form of vitamin E.

[0323] The implant of any one of the previous exemplary embodiments, wherein the vitamin E consists of one or more fat-soluble forms of vitamin E.

[0324] The implant of any one of the previous exemplary embodiments, wherein the vitamin E comprises a water-soluble form of vitamin E.

[0325] The implant of any one of the previous exemplary embodiments, wherein the vitamin E consists of one or more water-soluble forms of vitamin E.

[0326] The implant of any one of the previous exemplary embodiments, wherein the implant further comprises an additive.

[0327] The implant of any one of the previous exemplary embodiments, wherein the implant further comprises a surfactant, plasticizer, antioxidant, chelating agent, buffer, or osmotic agent.

[0328] The implant of any one of the previous exemplary embodiments, wherein the implant consists of the biodegradable polymer, vitamin E, and the biotherapeutic.The implant of any one of the previous exemplary embodiments, wherein the implant comprises from 20 wt% to 70 wt% biotherapeutic, from 29.5 to 79 wt% of biodegradable polymer, and from 0.5 to 8 wt% of vitamin E.

[0329] The implant of any one of the previous exemplary embodiments, wherein the implant further comprises a coating.

[0330] The implant of any one of the previous exemplary embodiments, wherein the implant further comprises a coating and the coating comprises a biodegradable polymer that is devoid of biotherapeutic or that contains biotherapeutic at a different loading than the body of the implant.

[0331] The implant of any one of the previous exemplary embodiments, wherein the implant further comprises a coating and wherein the coating comprises the polyester amide as disclosed herein.

[0332] The implant of any one of the previous exemplary embodiments, wherein the implant further comprises a coating and wherein the coating is formed from another degradable polymer, such as degradable polyester.

[0333] The implant of any one of the previous exemplary embodiments, wherein the implant further comprises a coating and wherein the coating comprises PLA, PLLA, PLGA, or a combination thereof.

[0334] The implant of any one of the previous exemplary embodiments, wherein the implant further comprises a coating and wherein the coating fully covers the implant surface.

[0335] The implant of any one of the previous exemplary embodiments, wherein the implant further comprises a coating and wherein the coating comprises the circumference of a cylindrical implant.

[0336] The implant of any one of the previous exemplary embodiments, wherein the implant further comprises a coating and wherein one end of the implant is uncoated.The implant of any one of the previous exemplary embodiments, wherein the implant further comprises a coating and wherein the ends of the implant are uncoated.

[0337] The implant of any one of the previous exemplary embodiments, wherein the implant has a HMWP of biotherapeutic of less than 1%, as measured according to the procedure described herein.

[0338] The implant of any one of the previous exemplary embodiments, wherein the implant has a HMWP of biotherapeutic of less than 0.75%, as measured according to the procedure described herein.

[0339] The implant of any one of the previous exemplary embodiments, wherein the implant has a HMWP of biotherapeutic of less than 0.5%, as measured according to the procedure described herein.

[0340] The implant of any one of the previous exemplary embodiments, wherein less than 25% of the biotherapeutic is released from the implant after twenty -four hours in phosphate buffer at pH 7.4 containing 137 mM NaCl, 2.7 mM KC1, 10 mM Na2HPO4 and 1.8 mM KH2PO4at 37 °C.

[0341] The implant of any one of the previous exemplary embodiments, wherein less than 20% of the biotherapeutic is released from the implant after twenty -four hours in phosphate buffer at pH 7.4 containing 137 mM NaCl, 2.7 mM KC1, 10 mM Na2HPO4 and 1.8 mM KH2PO4at 37 °C.

[0342] The implant of any one of the previous exemplary embodiments, wherein less than 15% of the biotherapeutic is released from the implant after twenty -four hours in phosphate buffer at pH 7.4 containing 137 mM NaCl, 2.7 mM KC1, 10 mM Na2HPO4 and 1.8 mM KH2PO4at 37 °C.

[0343] The implant of any one of the previous exemplary embodiments, wherein less than 10% of the biotherapeutic is released from the implant after twenty -four hours in phosphate buffer at pH 7.4 containing 137 mM NaCl, 2.7 mM KC1, 10 mM Na2HPO4 and 1.8 mM KH2PO4at 37 °C.The implant of any one of the previous exemplary embodiments, wherein less than 25% of the biotherapeutic is released from the implant after 7 days in phosphate buffer at pH 7.4 containing 137 mM NaCl, 2.7 mM KC1, 10 mM Na2HPO4 and 1.8 mM KH2PO4at 37 °C.

[0344] The implant of any one of the previous exemplary embodiments, wherein less than 20% of the biotherapeutic is released from the implant after seven days in phosphate buffer at pH 7.4 containing 137 mM NaCl, 2.7 mM KC1, 10 mM Na2HPO4and 1.8 mM KH2PO4at 37 °C.

[0345] The implant of any one of the previous exemplary embodiments, wherein less than 15% of the biotherapeutic is released from the implant after seven days in phosphate buffer at pH 7.4 containing 137 mM NaCl, 2.7 mM KC1, 10 mM Na2HPO4 and 1.8 mM KH2PO4at 37 °C.

[0346] The implant of any one of the previous exemplary embodiments, wherein the implant is injectable.

[0347] The implant of any one of the previous exemplary embodiments, wherein implant is in the shape of a rod.

[0348] The implant of any one of the previous exemplary embodiments, wherein the implant is in the shape of a disc.

[0349] The implant of any one of the previous exemplary embodiments, wherein the implant is injectable through a 12 gauge needed.

[0350] The implant of any one of the previous exemplary embodiments, wherein the implant has a maximum width of 2 mm.

[0351] The implant of any one of the previous exemplary embodiments, wherein the implant has a width of from 1 mm to 6 mm.

[0352] The implant of any one of the previous exemplary embodiments, wherein the implant has a width of from 1 mm, 1.5 mm, 2 mm, 2.5 mm, or 3 mm.The implant of any one of the previous exemplary embodiments, wherein the implant has a width of at most 6 mm, 5.5 mm, 5 mm, 4.5 mm, 4 mm, 3.5 mm, or 3 mm.

[0353] The implant of any one of the previous exemplary embodiments, wherein implant has a length of from 10 mm to 250 mm.

[0354] The implant of any one of the previous exemplary embodiments, wherein the implant has a length of from 10 mm, 15 mm, 20 mm, or 25 mm.

[0355] The implant of any one of the previous exemplary embodiments, wherein the implant has a width of at most 250 mm, 200 mm, 150 mm, 100 mm, 75 mm, 50 mm, or 30 mm.

[0356] The implant of any one of the previous exemplary embodiments, wherein the implant has a length of from 20 mm to 40 mm.

[0357] A method of forming an implant comprising the steps of shaping a formulation comprising a biotherapeutic, a biodegradable polymer, and vitamin E.

[0358] . The method of the previous exemplary embodiment, wherein the biotherapeutic, the biodegradable polymer, and / or the vitamin E is as described in any of the previous exemplary embodiments.

[0359] . The method of any one of the previous exemplary embodiments, wherein the shaping comprises injection molding the formulation in a mold.

[0360] . The method of any one of the previous exemplary embodiments, wherein the shaping comprises extruding the formulation through a die.

[0361] . The method of any one of the previous exemplary embodiments, wherein the shaping is carried out at a temperature of less than 105 °C.. The method of any one of the previous exemplary embodiments, wherein the shaping is carried out at a temperature of from 65 °C to 105 °C.

[0362] . The method of any one of the previous exemplary embodiments, wherein the shaping is carried out at a temperature of 75 °C to 100 °C.

[0363] . The method of any one of the previous exemplary embodiments, wherein the shaping is carried out at a temperature of 75 °C to 95 °C.

[0364] . The method of any one of the previous exemplary embodiments, wherein the shaping is carried out at a temperature of at most 105 °C, 100 °C, 95 °C, 90 °C, or 85 °C.

[0365] . The method of any one of the previous exemplary embodiments, wherein the shaping is carried out at a temperature of from 65 °C to 100 °C, from 70 °C to 100 °C, from 75 °C to 95 °C, or 75 °C to 90 °C.

[0366] . The method of any one of the previous exemplary embodiments, wherein the shaping comprises injecting the formulation into a mold at an injection pressure of from 50 to 400 bar holding the formulation in the mold at a temperature of from 150 to 400 bar.

[0367] . The method of any one of the previous exemplary embodiments, wherein the shaping comprises filling a mold to at least 95% full.

[0368] . An implant formed by the method of any one of the previous exemplary embodiments.

[0369] . An implant formed by the method of any one of the previous exemplary embodiments, wherein the implant has one or more of the characteristics of any one of the previous exemplary embodiments.

[0370] . A method for administering a biotherapeutic to a patient comprising the step of inj ecting the implant according to any one of the previous exemplary embodiments.. A method for administering a biotherapeutic to a patient comprising the step of injecting the implant according to any one of the previous exemplary embodiments, wherein less than 20% of the biotherapeutic is released from the implant after twenty-four hours.

[0371] . A method for administering a biotherapeutic to a patient comprising the step of inj ecting the implant according to any one of the previous exemplary embodiments, wherein less than 25% of the biotherapeutic is released from the implant after 7 days.

Claims

CLAIMS:

1. An implant comprising a biotherapeutic, a biodegradable polymer, and vitamin E, wherein the biodegradable polymer comprises a random copolymer having a structure including n units of:m molar equivalents of a first residue having the formulaO O H O O H- C - R1- C - N - C - C - O - R5- O - C - C - N -H I RI3R I3HI p molar equivalents of a second residue having the formulaO O H O O H- C - R1- C - N - C - C - O - R6- O - C - C - N -H R4R4H q molar equivalents of a third residue having the formulaO O H H- C - R1- C - N - C - R8- N - H C - O - R70, andx molar equivalents of a fourth residue having the formulaO O H H- C - R1- C - N - C - R8- N - H C - O - HOwherein m+p+q+x = 1 ;m is from 0 to 0.5, p is from 0.1 to 0.95, m+p is from 0.5 to 0.95, q is from 0.02 to 0.25, and x is from 0.05 to 0.25;n is from 5 to 300;the ratio q:x is from 60:40 to 20:80;R1is (C2-C2o)alkylene;R3and R4are selected from the group consisting of hydrogen, (Ci-C6)alkyl, (C2-Ce)alkenyl, (C2-C6)alkynyl, (C6-Cio)aryl, -CH2SH, -(CH2)2S(CH3), -CH2OH, -CH(OH)CH3, -(CH2)4NH3+, -(CH2)3NHC(=NH2+)NH2, -CH2COOH, -CH2-CO-NH2, -CH2CH2-CO-NH2, -CH2CH2COOH, CH3-CH2-CH(CH3)-, (CH3)2CH-CH2-, H2N-(CH2)4-, Ph-CH2-, CH=C-CH2-, (CH3)2CH-, Ph-NH-, NH-(CH2)3-C-, or NH-CH=N-CH=C-CH2-, wherein R3I _ I I - 1 and R4are the same or different;R5is (C2-C2o)alkylene, optionally having one or more alkylene carbon atoms (-C-) replaced by an oxygen atom (-O-), and / or optionally having 5 or 6 consecutive alkylene carbon atoms together form a respective 5- or 6-membered carbocyclic ring;R6isR7is (C6-Cio)aryl(Ci-C6)alkylene; andR8is (C3-Cs)alkylene.

2. The implant of any one of the previous claims, wherein, in the structure of the biodegradable polymer, p is from 0.3 to 0.8 and m+p is from is from 0.6 to 0.9.

3. The implant of any one of the previous claims, wherein, in the structure of the biodegradable polymer, q:x is from 40:60 to 35:65.

4. The implant of any one of the previous claims, wherein the biotherapeutic comprises a peptide, polypeptide, protein, nucleic acid, monoclonal antibody, or a mixture thereof.

5. The implant of any one of the previous claims, wherein the biotherapeutic is water-soluble.

6. The implant of any one of the previous claims, wherein the biotherapeutic comprises a peptide comprising from 15 to 100 amino acid residues.

7. The implant of any one of the previous claims, wherein the biotherapeutic comprises a GLP-1 receptor agonist.

8. The implant of any one of the previous claims, wherein the implant comprises from 25 to 60 wt% biotherapeutic, based on the total weight of the implant.

9. The implant of any one of the previous claims, wherein the biodegradable polymer is present in an amount of from 29 wt% to 79 wt%, based on the total weight of the implant.

10. The implant of any one of the previous claims, wherein the vitamin E is present in an amount of from 1 wt% to 10 wt%, based on the total weight of the biodegradable polymer in the implant.

11. The implant of any one of the previous claims, wherein the implant further comprises a coating.

12. The implant of any one of the previous claims, wherein the implant has a HMWP of biotherapeutic of less than 1%, as measured according to the procedure in the Examples.

13. The implant of any one of the previous claims, wherein less than 15% of the biotherapeutic is released from the implant after twenty -four hours in phosphate buffer at pH 7.4 containing 137 mM NaCl, 2.7 mM KC1, 10 mM Na2HPO4 and 1.8 mM KH2PO4at 37 °C.

14. A method of forming an implant comprising the steps of shaping a formulation comprising from 20 wt% to 70 wt% biotherapeutic, from 29.5 to 79 wt% of biodegradable polymer, and from 0.5 to 8 wt% of vitamin E, based on the total weight of the formulation, wherein the biodegradable polymer comprises a random copolymer having a structure including n units of:m molar equivalents of a first residue having the formulap molar equivalents of a second residue having the formulaq molar equivalents of a third residue having the formulaO O H H- C - R1- C - N - C - R8- N - H C - O - R70, andx molar equivalents of a fourth residue having the formulaO O H H- C - R1- C - N - C - R8- N - H C - O - HOwherein m+p+q+x = 1 ;m is from 0 to 0.5, p is from 0.1 to 0.95, m+p is from 0.5 to 0.95, q is from 0.02 to 0.25, and x is from 0.05 to 0.25;n is from 5 to 300;the ratio q:x is from 60:40 to 20:80;R1is (C2-C2o)alkylene;R3and R4are selected from the group consisting of hydrogen, (Ci-C6)alkyl, (C2-Ce)alkenyl, (C2-C6)alkynyl, (C6-Cio)aryl, -CH2SH, -(CH2)2S(CH3), -CH2OH, -CH(OH)CH3,-(CH2)4NH3+, -(CH2)3NHC(=NH2+)NH2, -CH2COOH, -CH2-CO-NH2, -CH2CH2-CO-NH2, -CH2CH2COOH, CH3-CH2-CH(CH3)-, (CH3)2CH-CH2-, H2N-(CH2)4-, Ph-CH2-, CH=C-CH2-, (CH3)2CH-, Ph-NH-, NH-(CH2)3-C-, or NH-CH=N-CH=C-CH2-, wherein R3and R4are the same or different;R5is (C2-C2o)alkylene, optionally having one or more alkylene carbon atoms (-C-) replaced by an oxygen atom (-O-), and / or optionally having 5 or 6 consecutive alkylene carbon atoms together form a respective 5- or 6-membered carbocyclic ring;R6isR7is (C6-Cio)aryl(Ci-C6)alkylene; andR8is (C3-Cs)alkylene.

15. The method of claim 14, wherein the shaping is carried out at a temperature of 75 °C to 95

Images