[go: up one dir, main page]

WO2025137096A1 - Implants médicamenteux contenant du talazoparib et méthodes d'utilisation associées - Google Patents

Implants médicamenteux contenant du talazoparib et méthodes d'utilisation associées Download PDF

Info

Publication number
WO2025137096A1
WO2025137096A1 PCT/US2024/060761 US2024060761W WO2025137096A1 WO 2025137096 A1 WO2025137096 A1 WO 2025137096A1 US 2024060761 W US2024060761 W US 2024060761W WO 2025137096 A1 WO2025137096 A1 WO 2025137096A1
Authority
WO
WIPO (PCT)
Prior art keywords
implant
drug implant
talazoparib
drug
tumor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/060761
Other languages
English (en)
Inventor
Pamela Munster
Scott Thomas
Maithili Rairkar
Pujan DESAI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California Berkeley
University of California San Diego UCSD
Alessa Therapeutics Inc
Original Assignee
University of California Berkeley
University of California San Diego UCSD
Alessa Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of California Berkeley, University of California San Diego UCSD, Alessa Therapeutics Inc filed Critical University of California Berkeley
Publication of WO2025137096A1 publication Critical patent/WO2025137096A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1092—Details
    • A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device

Definitions

  • a drug implant comprising: (a) a biocompatible, non-biodegradable polymer matrix; and (b) Talazoparib dispersed in the biocompatible, non-biodegradable polymer matrix.
  • the Talazoparib is present in the drug implant at an amount from about 10% w/w to about 80% w/w.
  • the Talazoparib is present in the drug implant at an amount from about 10% w/w.
  • the Talazoparib is present in the drug implant at an amount from about 30% w/w.
  • the Talazoparib is present in the drug implant at an amount from about 50% w/w.
  • the Talazoparib is present in the drug implant at an amount from about 70% w/w. In some cases, a total dose of the Talazoparib in the drug implant is from about 1 mg to about 20 mg. In some cases, the drug implant releases at least about 1.0 pg/day of the Talazoparib after implantation in a subject. In some cases, the drug implant releases at least about 8.0 pg/day of the Talazoparib after the implantation in a subject. In some cases, the drug implant releases the Talazoparib by zero order release. In some cases, the zero order release comprises at least about 1.0 pg/day of the Talazoparib after implantation in a subject.
  • the zero order release comprises at least about 8.0 pg/day of the Talazoparib after implantation in a subject.
  • the drug implant releases at least about 100.0 pg/day of the Talazoparib on Day 1, Day 2, Day 3, Day 4, or Day 5 after the implantation.
  • the drug implant releases a dose of the Talazoparib that is lower than 100.0 pg/day after Day 1, Day 2, Day 3, Day 4, or Day 5 after the implantation.
  • at least 10%, at least 15%, at least 20%, at least 25%, or at least 50% of the Talazoparib remains in the biocompatible, non-biodegradable polymer matrix after 100 days of implantation.
  • the Talazoparib remains in the biocompatible, non-biodegradable polymer matrix after 180 days of implantation.
  • the Talazoparib is in solid form.
  • the Talazoparib is in a crystalline form, a semi-crystalline form, or an amorphous form.
  • the Talazoparib is in an aqueous form.
  • the drug implant has a Shore A hardness of at least 20 durometer when loaded with Talazoparib.
  • the biocompatible, non- biodegradable polymer matrix comprises silicone.
  • the silicone is an acetoxy-cured silicone or a platinum-cured silicone.
  • the biocompatible, non-biodegradable polymer matrix comprises thermoplastic polyurethane. In some cases, the biocompatible, non-biodegradable polymer matrix comprises poly(ethylene vinyl acetate). In some cases, at least 99% by weight of the biocompatible, non-biodegradable polymer matrix remains in a target tissue of a subject after implantation for at least 12 months, at least 24 months, at least 36 months, at least 48 months, at least 60 months, or longer.
  • the drug implant is visible by ultrasound or MRI when disposed in a target tissue of a subject. In some cases, the drug implant inhibits modulation of the Talazoparib within the drug implant. In some cases, the modulation comprises degradation. In some cases, the drug implant is elongate.
  • the drug implant is cylindrical. In some cases, the drug implant is tubular. In some cases, the drug implant is rod-shaped. In some cases, the drug implant is circular. In some cases, the drug implant comprises a disk. In some cases, the drug implant comprises one or more rods. In some cases, the one or more rods are connected. In some cases, a diameter of the drug implant is from about 0.1 mm to about 5.0 mm. In some cases, a length of the drug implant is from about 1 mm to about 30 mm. In some cases, a volume of the drug implant is from about 0.1 mm 3 to about 30 mm 3 . In some cases, at least 50% of an outer surface of the drug implant is configured to directly contact a target tissue.
  • the drug implant is configured to be implanted into a target tissue or a tissue near or adjacent to the target tissue.
  • the target tissue is prostate tissue, bladder tissue, ovarian tissue, fallopian tissue, liver tissue, bone tissue, breast tissue, pancreatic tissue, lung tissue, gastric tissue, kidney tissue, gall bladder tissue, colon tissue, or a combination thereof.
  • the target tissue is prostate tissue.
  • the drug implant is configured to be delivered to the target tissue or the tissue near or adjacent to the target tissue using a lumen of a needle or a catheter.
  • the drug implant lacks at least one of a sheath, a scaffold, a retention member for retaining the drug implant within a target tissue, or a combination thereof.
  • the drug implant further comprises a coating. In some cases, the coating partially covers the drug implant. In some cases, the coating substantially covers the drug implant. In some cases, the coating covers the drug implant. In some cases, the coating comprises at least one additional therapeutic. In some cases, the at least one additional therapeutic comprises a cytotoxic therapeutic. In some cases, the at least one additional therapeutic comprises a hormonal therapeutic. In some cases, the at least one additional therapeutic comprises a biologic therapeutic. In some cases, the drug implant further comprises biodegradable material. In some cases, the drug implant is not a nanoparticle. In some cases, the Talazoparib is not encapsulated in a nanoparticle.
  • a method of treating a tumor in a subject comprising implanting, into the tumor or into a tissue adjacent to the tumor of the subject, at least one drug implant of any one of the preceding.
  • the one or more drug implants continuously delivers the Talazoparib to the subject for at least 6 months, at least 12 months, at least 24 months, at least 60 months, or longer.
  • a total dose of the Talazoparib administered to the subject is less than a total dose of the Talazoparib when administered to a subject by oral administration.
  • the total dose of the Talazoparib administered to the subject is less than 200 mg over a period of 6 months.
  • the implanting results in a blood plasma concentration of the Talazoparib that is less than a blood plasma concentration of the Talazoparib obtained when the Talazoparib is administered to a subject by oral administration.
  • the implanting occurs via transperineal administration.
  • the transperineal administration comprises using a template guided needle.
  • the implanting locally delivers the Talazoparib to the tumor.
  • the tumor is a prostate tumor, bladder tumor, an ovarian tumor, a fallopian tumor, a liver tumor, a bone tumor, a breast tumor, a pancreatic tumor, a lung tumor, a gastric tumor, a kidney tumor, a gall bladder tumor, a colon tumor, an unspecified tumor, or a combination thereof.
  • the method further comprises, after the implanting, administering to the subject at least one additional therapy to treat the tumor.
  • the method further comprises, after the implanting, recommending that the subject receive at least one additional therapy to treat the tumor.
  • the at least one additional therapy comprises radiation, chemotherapy, biologic therapy, immunologic therapy, hormonal therapy, or a combination thereof.
  • the at least one additional therapy comprises radiation.
  • the at least one additional therapy is more efficacious for treating the tumor after the implanting, as compared to after oral administration of the Talazoparib.
  • an amount of the at least one additional therapy needed to effectively treat the tumor is lower after the implanting, as compared to an amount of the at least one additional therapy needed to effectively treat the tumor in the absence of the Talazoparib.
  • the method results in decreased toxicity to the subject as compared to when the subject receives the at least one additional therapy without the Talazoparib.
  • the toxicity comprises weight loss, myelosuppression, fatigue, gastrointestinal (GI) toxicity, or a combination thereof of the subject.
  • the tumor is associated with a genetic mutation of BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof.
  • a method of manufacturing a drug implant of any one of the preceding comprising: (a) mixing an amount of polymer with an amount of the Talazoparib to generate a mixture; and (b) molding or extruding the mixture of (a) to create the drug implant.
  • the polymer comprises uncured polymer.
  • (b) is molding the mixture of (a).
  • the method further comprises curing the drug implant for a period of time.
  • the amount of the Talazoparib is from 10% w/w to 80% w/w of the uncured polymer.
  • the polymer comprises silicone, thermoplastic polyurethane, poly(ethylene vinyl acetate), or a combination thereof.
  • the curing further comprises heating the mixture at a temperature from about 100 °C to about 175 °C for about 3 to about 8 minutes.
  • the mixture further comprises a solvent.
  • the solvent is selected from the group consisting of: pentane, dichloromethane, tetrahydrofuran, heptane, toluene, and hexane.
  • the mixture is molded by a transfer molding process or by extrusion through a tube.
  • the molding comprises extruding the mixture using a ram extruder or a twin screw extruder.
  • the molding comprises injection molding.
  • the method further comprises performing an analysis on the drug implant.
  • the analysis is selected from the group consisting of: differential scanning calorimetry (DSC), deployment of the drug implant in surrogate tissue, elution testing, rheology, high pressure liquid chromatography (HPLC), simulated in vivo stability assay, and dynamic mechanical analysis (DMA).
  • DSC differential scanning calorimetry
  • HPLC high pressure liquid chromatography
  • DMA dynamic mechanical analysis
  • Fig. 1A and Fig. IB illustrate examples of different drug implant configurations containing Talazoparib.
  • Fig. 1A illustrates an example of a drug implant containing Talazoparib dispersed throughout a polymer matrix.
  • Fig. IB illustrates an example of a drug implant containing Talazoparib dispersed throughout a polymer matrix, coated with a control release layer. The addition of the control release layer may alter how the drug (e.g., Talazoparib) is eluted from the drug implant.
  • the drug e.g., Talazoparib
  • Figs. 2A-2C illustrate PARP inhibitor (e.g., Talazoparib) drug implant elution.
  • Fig. 2A illustrates average daily elution of Talazoparib over 70 to 200 days from a drug implant with a silicone matrix comprising 10%, 30%, 50%, or 70% of Talazoparib.
  • Fig. 2B illustrates cumulative elution from a drug implant with a silicone matrix comprising 10%, 30%, 50%, or 70% Talazoparib.
  • Fig. 2C illustrates cumulative elution from a drug implant with a poly(ethylene vinyl acetate) (EVA) or thermoplastic polyurethane (TPU) matrix
  • EVA poly(ethylene vinyl acetate)
  • TPU thermoplastic polyurethane
  • FIG. 3 illustrates assessment of cancer cell line models for testing the therapeutic efficacy of a drug implant described herein.
  • Cancer cells were genetically engineered to harbor homologous recombination deficiency (HRD) of breast cancer gene 1 (BRCA1) or breast cancer gene 2 (BRCA2) mutations. Functional HRD deficiency of BRCA1 or BRCA2 mutation was indicated by the loss of Rad51 foci induction by carboplatin in tissue cultured cells as compared to their wild type parental cells.
  • HRD homologous recombination deficiency
  • Figs. 4A-4C illustrate establishment and assessment of a prostate cancer cell model (PC3, clone IE 10) comprising BRCA2 deficiency, which is also the most commonly identified homologous recombinant (HR) deficiency in men.
  • the cells were engineered with CRISPR/Cas9 to introduce the BRCA2 mutation.
  • Fig. 4A illustrates BRCA2 protein in wild type (WT) cells versus CRISPR/Cas9 engineered PC3 prostate cancer clones.
  • Fig. 4B illustrates increased sensitivity to carboplatin in PC3-BRCA2 (1E10) clone versus WT cells.
  • Fig. 4C illustrates increased survivability of mice bearing the PC3-BRCA2 ( 1E10) xenograft when a 70% talazoparib implant is placed within the tumor compared to a placebo implant.
  • FIG. 5 illustrates efficacy of talazoparib formulated implants in two prostate cancer BRCA2 mutated PDX models: (A) LTL-610 and (B) TM00298.
  • Immune deficient (NRG) female mice were implanted with the respective BRCA2 mutated PDX tumor and allowed to grow to -300 mm 3 .
  • a 3 mm long implant containing 0% (placebo), 10%, or 50% talazoparib was implanted into the center of the growing xenograft via a syringe needle. Tumor volume was evaluated by caliper measurement over time and presented as the mean and standard deviation.
  • Figs. 6A-6C illustrate computerized tomography (CT) scan and irradiation protocol.
  • Fig. 6A and Fig. 6B illustrate coronal and semi-transparent 3D view respectively through a live mouse with tumor in virtual in vivo CT slices.
  • Fig. 6C illustrates schematic of mouse tumor irradiation using image guided techniques on SARRP Xstrahl research platform.
  • Figs. 7A-7C illustrate placement of a drug implant described herein.
  • Fig. 7A illustrates location of implantation in rat prostate lobes.
  • Fig. 7B illustrates a five millimeter implant into a rat prostate.
  • Fig. 7C illustrates surgical implantation of a drug implant described herein into a dog prostate by laparotomy. Two 18 gauge needles were used to insert two 15mm x 1mm implant in both prostate lobes from a ventro-cranial approach with transrectal ultrasound confirmation of implant placement.
  • drug implants containing Talazoparib and methods for increasing the therapeutic efficacy of Talazoparib and reducing adverse side effects associated with systemic administration of Talazoparib.
  • drug implants comprising a biocompatible polymer matrix and Talazoparib dispersed in the biocompatible polymer matrix.
  • the drug implant comprises a biocompatible, non-biodegradable polymer matrix.
  • the Talazoparib is dispersed in the biocompatible, non-biodegradable polymer matrix.
  • the drug implant comprises a biocompatible polymer matrix.
  • the biocompatible polymer matrix comprises non-biodegradable polymer matrix.
  • the polymer matrix comprises a polymer described herein.
  • the polymer comprises a biodegradable polymer.
  • the polymer comprises a non-biodegradable polymer.
  • the polymer consists of the non- biodegradable polymer.
  • the polymer comprises a bio-degradable polymer, a non-biodegradable polymer, or a combination thereof.
  • the polymer comprises a non-biodegradable polymer described herein.
  • the drug implant comprises a non-biodegradable polymer comprising silicone.
  • the drug implant comprises a non-biodegradable polymer comprising polyurethane.
  • the drug implant comprises a non-biodegradable polymer comprising poly(ethylene vinyl acetate).
  • the drug implant comprises Talazoparib.
  • Fig. 1A illustrates a drug implant design, where the PARP inhibitor (e.g., Talazoparib) is dispersed within the drug implant.
  • Fig. IB illustrates another drug implant design, where the drug implant comprises a coating.
  • the coating can lead to controlled release of the PARP inhibitor, such as, Talazoparib.
  • the drug implant delivers the Talazoparib locally to a target tissue or a tissue near or adjacent to the target tissue.
  • the target tissue comprises prostate tissue, bladder tissue, ovarian tissue, fallopian tissue, liver tissue, bone tissue, breast tissue, pancreatic tissue, lung tissue, gastric tissue, kidney tissue, gall bladder tissue, colon tissue, or a combination thereof.
  • the local delivery of the Talazoparib increases or potentiates therapeutic efficacy of a therapy such as radiation, chemotherapy, biologic therapy, immunologic therapy, hormonal therapy, or a combination thereof.
  • the local delivery of the Talazoparib increases or potentiates therapeutic efficacy of radiation therapy.
  • the local delivery of the Talazoparib decreases toxicity to a subject receiving the drug implant.
  • the decrease of toxicity stems from the subject needing a decreased dose of the Talazoparib, or a decreased dose of an additional therapy, such as radiation therapy.
  • the compositions and methods provided herein reduce (e.g., reduce occurrence of, reduce severity of, etc.) or eliminate adverse side effects associated with systemic administration.
  • Adverse side effects associated with systemic administration of Talazoparib include, without limitation, thrombocytopenia, anemia, neutropenia, leukopenia, palpitations, nausea, fatigue, constipation, vomiting, abdominal pain/distension, mucositis/stomatitis, diarrhea, dyspepsia, dry mouth, decreased appetite, urinary tract infection, AST/ALT elevation, myalgia, back pain, arthralgia, headache, dizziness, dysgeusia, insomnia, anxiety, nasopharyngitis, dyspnea, cough, rash, and hypertension.
  • the local delivery of the Talazoparib increases therapeutic efficacy for treating a disease or disorder in a subject.
  • the disease or disorder is associated with a tumor.
  • the tumor is associated with a genetic mutation of BRCAI, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof.
  • the method comprises implanting, into the tumor or into a tissue adjacent to the tumor of the subject, at least one drug implant described herein.
  • the method comprises continuously delivering the Talazoparib in the subject by the drug implant for at least 6 months, at least 12 months, at least 24 months, at least 60 months, or longer.
  • the use of the drug implant described herein results in a decreased total dose of the Talazoparib needed in the subject for achieving the same therapeutic efficacy compared to an oral dose of the Talazoparib needed in the subject.
  • the total dose of the Talazoparib administered to the subject by the implanting is less than 200 mg over a period of 6 months.
  • the method comprises implanting the drug implant into the subject by transperineal administration.
  • the method comprises implanting the drug implant into a target tissue or a tissue near or adjacent to the target tissue.
  • the target tissue comprises prostate tissue, bladder tissue, ovarian tissue, fallopian tissue, liver tissue, bone tissue, breast tissue, pancreatic tissue, lung tissue, gastric tissue, kidney tissue, gall bladder tissue, colon tissue, or a combination thereof.
  • the method increases or potentiates therapeutic efficacy of an additional therapy, such as radiation therapy.
  • the method decreases toxicity to a subject receiving the drug implant.
  • the decrease of toxicity stems from the subject needing a decreased dose of the Talazoparib or a decreased dose of an additional therapy, such as radiation therapy.
  • Non-limiting examples of the toxicity can include weight loss, myelosuppression, fatigue, gastrointestinal (GI) toxicity or a combination thereof.
  • the method increases therapeutic efficacy for treating a disease or disorder in a subject.
  • the disease or disorder is associated with a tumor.
  • the tumor is associated with a genetic mutation of BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof.
  • BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation or a combination thereof.
  • drug implants that are capable of delivering a therapeutically effective amount of Talazoparib directly to a target tissue.
  • drug implants that, when implanted into a target tissue, result in a high concentration of Talazoparib within the target tissue, and a low concentration of Talazoparib in the systemic circulation (e.g., in the blood plasma).
  • the ability of the drug implants provided herein to deliver a therapeutically effective amount of Talazoparib directly to the target tissue, while achieving low concentrations of Talazoparib in the systemic circulation may reduce or eliminate side effects or toxicity of Talazoparib treatment that would otherwise occur from systemic administration.
  • the drug implants provided herein arc capable of being loaded with a large amount of Talazoparib such that the drug implant is capable of sustained release of Talazoparib to the target tissue for extended periods of time.
  • Talazoparib may be dispersed within a polymer matrix of the implant which may provide particular advantages (e.g., faster elution times, higher drug loading within the implant, etc.).
  • the drug implants provided herein may contain Talazoparib at high concentrations such that a therapeutically effective amount of Talazoparib can be administered directly to prostate tissue for long periods of time (e.g., 6 months or greater) while maintaining low systemic concentrations of Talazoparib.
  • the drug implants disclosed herein may comprise a polymer matrix and Talazoparib.
  • Talazoparib may be dispersed within the polymer matrix.
  • the polymer matrix comprises a non-biodegradable polymer.
  • the polymer matrix comprises a biodegradable polymer.
  • the drug implants may be implanted into a target tissue, and may release a quantity of Talazoparib over time.
  • the drug implants containing Talazoparib may be effective to treat a disease or a symptom thereof.
  • a drug implant e.g., containing Talazoparib
  • methods of treating a disease by delivering a drug implant (e.g., containing Talazoparib) of the disclosure to a target tissue of a subject in need thereof in order to deliver a therapeutically effective amount of Talazoparib for extended periods of time. Additionally, methods of manufacturing drug implants and kits including drug implants are provided.
  • the implant comprises a polymer matrix and Talazoparib dispersed therein.
  • the implant comprises a biocompatible polymer.
  • the implant comprises a non-biodegradable polymer.
  • the implant comprises a biodegradable polymer.
  • the polymer matrix comprises a combination of a biodegradable polymer and a non-biodegradable polymer.
  • the drug implants described herein are large (e.g., millimeter- sized) polymer implants that are surgically implanted into a subject.
  • the implants may be suitable for treating a disease.
  • the disease is cancer.
  • the drug implant is suitable for treating a tumor.
  • the tumor is a prostate tumor, bladder tumor, an ovarian tumor, a fallopian tumor, a liver tumor, a bone tumor, a breast tumor, a pancreatic tumor, a lung tumor, a gastric tumor, a kidney tumor, a gall bladder tumor, a colon tumor, an unspecified tumor, or a combination thereof.
  • the polymer matrix may comprise any polymer material.
  • the polymer material is biocompatible.
  • biocompatible refers to a property of a material that allows for prolonged contact with a tissue in a subject without causing toxicity or significant damage.
  • a “biocompatible” polymer material is in accordance with the guidelines set forth by the International Organization for Standardization (ISO) 10993-1:2018.
  • the polymer material may be “non-biodegradable” or “substantially non- biodegradable”.
  • a substantially non-biodegradable implant of the disclosure may have at least 99% by weight of the polymer material remaining two years after implanting the device into a target tissue.
  • At least 99% by weight of the biocompatible, non-biodegradable polymer matrix remains in a target tissue of a subject after implantation for at least 12 months, at least 24 months, at least 36 months, at least 48 months, at least 60 months, or longer.
  • a “non-biodegradable” implant or polymer may be in accordance with the guidelines set forth by the Standard Guide for Assessment of Absorbable Polymeric Implants (ASTM F2902-16) by ASTM International.
  • the drug implant comprises biodegradable polymer.
  • the drug implant is at least partially biodegradable.
  • the polymer matrix may comprise polysiloxane (silicone).
  • the silicone may be any biocompatible silicone.
  • the silicone may be any biocompatible, non- biodegradable silicone.
  • the silicone may be a medical grade silicone.
  • the silicone may be hydrophobic.
  • the silicone may be a United States Pharmacopeia (USP) Class V or USP Class VI certified silicone.
  • the silicone may be an acetoxy-cure silicone.
  • the silicone may be a Silbione® silicone adhesive as manufactured by Elkem (e.g., Silbione® Biomedical ADH1 M200; accessible at silicones. elkem.eom/EN/our_offer/Product/90061907/_/SILB IONE-BIO- ADH1-M200 as of
  • the silicone may be a platinum-cure silicone.
  • the silicone may be any liquid silicone rubber (LSR).
  • the silicone may be a Silbione® Liquid Silicone Rubber (LSR) as manufactured by Elkem.
  • the Silbione® LSR may be one or more of Silbione® LSR 4301, Silbione® LSR 4305, Silbione® LSR 4310, Silbione® LSR 4325, Silbione® LSR 4330, Silbione® LSR 4340, Silbione® LSR 4350, Silbione® LSR 60, Silbione® LSR 4360, Silbione® LSR 4370, Silbione® LSR 4745, Silbione® LSR 4755, Silbione® LSR 4765, Silbione® LSR 4125, Silbione® LSR 4130, Silbione® LSR 4140, Silbione® LSR M301, Silbione® LSR M305, Silbione® LSR M310, Silbione® LSR M325, Silbione® LSR M330, Silbione® LSR M340, Silbione® LSR M350, Silbione® LSR M
  • the silicone may be Silbione® LSR D370. In some cases, the silicone may be a silicone manufactured by NuSilTM. In various aspects, the silicone may be DDU 4870 as manufactured by NuSilTM. In some cases, the silicone may be one or more of the following silicones as manufactured by NuSilTM: MED-4801, MED-4805, MED-4810, MED-5820, MED-5830, MED-5840, MED-5850, MED-5860, MED-5870, MED-4880, MED5O-5338, MED-5440, MED-4842, and MED1-4855.
  • the polymer material may be a thermoplastic polyurethane.
  • the thermoplastic polyurethane is biocompatible and non-biodegradable.
  • the polyurethane may be one or more of the following polyurethanes manufactured by Lubrizol: PY-PT72AE, PY-PT87AE, PY-PT87AS, PY-PT83AL, and PY-PT43DE20.
  • the Shore A hardness scale measures the hardness of rubbers. A higher number on the scale refers to a firmer material, whereas a lower number on the scale refers to a softer material.
  • the polymer material in the drug implant has a Shore A hardness of at least 30-durometer.
  • the polymer material may have a Shore A hardness of at least 30-durometer, at least 40-durometer, at least 50-durometer, at least 60-durometer, or at least 70-durometer.
  • the uncured polymer material may have a Shore A hardness of 30-durometer, and the cured polymer material may have a Shore A hardness of 70-durometer.
  • the implant may further comprise a therapeutically active agent (e.g., Talazoparib).
  • a therapeutically active agent e.g., Talazoparib
  • Talazoparib is dispersed or distributed within the polymer matrix.
  • the Talazoparib is dispersed or distributed throughout the polymer matrix.
  • Talazoparib is uniformly or homogeneously dispersed or distributed within the polymer matrix.
  • Talazoparib is heterogeneously dispersed or distributed within the polymer matrix.
  • Talazoparib is dispersed or distributed within the polymer matrix in a gradient.
  • Talazoparib is dispersed or distributed within the polymer matrix at the time of manufacture of the implant (e.g., Talazoparib is mixed with the polymer material prior to curing of the polymer material, as disclosed herein).
  • dispersing Talazoparib within the polymer matrix may be advantageous over other drug implants (e.g., those in which the drug is encapsulated in a capsule, or in the lumen of a tube).
  • dispersing Talazoparib within the polymer matrix may allow for higher loading of Talazoparib in the implant, faster elution rates, and the like.
  • the Talazoparib is not encapsulated in a microparticle, a nanoparticle, or other similar particle.
  • the implant may comprise Talazoparib in an amount from about 0.5% w/w to about 80% w/w.
  • the implant may comprise Talazoparib in an amount of about 0.5% w/w, about 1% w/w, about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, or about 80% w/w.
  • the implant may comprise Talazoparib in an amount of at least about 0.5% w/w, at least about 1% w/w, at least about 5% w/w, at least about 10% w/w, at least about 15% w/w, at least about 20% w/w, at least about 25% w/w, at least about 30% w/w, at least about 35% w/w, at least about 40% w/w, at least about 45% w/w, at least about 50% w/w, at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, or at least about 80% w/w.
  • Talazoparib is present in the implant in an amount of about 0.5% w/w, about 1% w/w, about 5% w/w, 10% w/w, about 30% w/w, about 45% w/w, or about 60% w/w.
  • the disclosure provides drug implants loaded with high concentrations of Talazoparib (e.g., about 60% w/w or greater).
  • the implant may contain Talazoparib in an amount of at least about 30% w/w.
  • the implant may contain Talazoparib in an amount of at least about 45% w/w.
  • the implant may comprise Talazoparib in an amount from about 5% volume/volume (v/v) to about 60% v/v.
  • the implant may comprise Talazoparib in an amount of about 5% v/v, about 10% v/v, about 15% v/v, about 20% v/v, about 25% v/v, about 30% v/v, about 35% v/v, about 40% v/v, about 45% v/v, about 50% v/v, about 55% v/v, or about 60% v/v.
  • the implant may comprise a therapeutically active agent (e.g., Talazoparib) in an amount of at least about 5% v/v, at least about 10% v/v, at least about 15% v/v, at least about 20% v/v, at least about 25% v/v, at least about 30% v/v, at least about 35% v/v, at least about 40% v/v, at least about 45% v/v, at least about 50% v/v, at least about 55% v/v, or at least about 60% v/v.
  • Talazoparib is present in the implant in an amount of at least about 30% v/v.
  • an implant of the disclosure may include Talazoparib in a total amount of at least about 1 mg, for example, from about 1 mg to about 20 mg. In some cases, the total amount of Talazoparib in the implant may be from about 8 mg to about 20 mg.
  • the implant may include Talazoparib in a total amount of about 1 mg, about 1.2 mg, about 1.3 mg, about 1.4 mg, about 1.5 mg, about 1.6 mg, about 1.7 mg, about 1.8 mg, about 1.9 mg, about 2.0 mg, about 2.1 mg, about 2.2 mg, about 2.3 mg, about 2.4 mg, about 2.5 mg, about 2.6 mg, about 2.7 mg, about 2.8 mg, about 2.9 mg, about 3.0 mg, about 3.1 mg, about 3.2 mg, about 3.3 mg, about 3.4 mg, about 3.5 mg, about 3.6 mg, about 3.7 mg, about 3.8 mg, about 3.9 mg, about 4.0 mg, about 4.1 mg, about 4.2 mg, about 4.3 mg, about 4.4 mg, about 4.5 mg, about 4.6 mg, about 4.7 mg, about 4.8 mg, about 4.9 mg, about 5.0 mg, about 5.1 mg, about 5.2 mg, about 5.3 mg, about 5.4 mg, about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about
  • the polymer material may be cured with the Talazoparib present therein.
  • curing refers to a chemical process that results in the hardening of a polymer material by cross-linking polymer chains. Any method may be used to cure a polymer of the disclosure, including the use of electron beams, heating, and/or the addition of additives.
  • Talazoparib may be mixed with an uncured polymer material prior to curing.
  • the polymer matrix may be at least 95% cured, at least 96% cured, at least 97% cured, at least 98% cured, at least 99% cured, at least 99.9% cured, or 100% cured.
  • the polymer material has a molding or curing temperature that is lower than the melting temperature of Talazoparib, e.g., to prevent melting and/or degradation of the drug.
  • the polymer material may have a molding or curing temperature that is lower than 195 °C, lower than 190 °C, lower than 185 °C, lower than 180 °C, lower than 175 °C, lower than 170 °C, lower than 165 °C, lower than 160 °C, lower than 155 °C, or lower than 150 °C.
  • the polymer is a thermo-melt or thermoplastic that becomes moldable at elevated temperature and hardens upon cooling (e.g., polyurethane).
  • Talazoparib may have a melting temperature of about 245 °C to about 255 °C, and the polymer may have a molding or curing temperature of less than about 175 °C (e.g., about 150 °C).
  • Talazoparib may have a melting temperature of about 250 °C.
  • the polymer may have a molding or curing temperature of about 150 °C to about 160 °C.
  • the polymer is a thermoset that is irreversibly hardened by curing (e.g., silicone) which may be promoted by addition of a catalyst and/or heat.
  • the polymer material may be cured at room temperature (e.g., about 25 °C).
  • the polymer requires exposure to air to cure.
  • Talazoparib may be present in the implant in solid form.
  • solid Talazoparib may be dissolved upon contact with biological fluids (e.g., after implantation into a tissue), and may diffuse out of the implant and into the target tissue.
  • Talazoparib is present in the implant in a dissolved form, in crystalline form, in a semicrystalline form, or in an amorphous form.
  • the particle size of Talazoparib within the implant may be important for drug content uniformity within the implant. Without wishing to be bound by theory, a small particle size may ensure a uniform distribution within the formulation and between implants upon molding of the formulation.
  • the Talazoparib present in the implant may have a median particle size (e.g., D50 particle size) of less than about 10 pm. In some cases, the Talazoparib present in the implant may have a D90 particle size of less than about 15 pm.
  • an implant of the disclosure has mechanical properties such that the implant can be successfully deployed into a target tissue.
  • an implant of the disclosure may be sufficiently stiff such that it can be deployed into a target tissue successfully, but not too stiff that it breaks during deployment.
  • the mechanical properties of devices described herein may vary depending on the polymer material used, and may be determined empirically.
  • the implant containing the Talazoparib may have a Shore A hardness of at least 30 durometer.
  • the implant may have a three-dimensional shape.
  • the three-dimensional shape may be any suitable shape.
  • the implant may be cylindrical or substantially cylindrical.
  • the implant may be tubular or substantially tubular.
  • the implant may be elongate (e.g., may have a length greater than a width).
  • the implant may be not hollow.
  • the implant may be a rod, rod-shaped, or rod-like.
  • the implant may be circular.
  • the implant may comprise one or more rods.
  • the one or more rods arc connected.
  • the implant may be a disk.
  • the implant may have a diameter.
  • a diameter of the implant may be from about 0.1 mm to about 5.0 mm.
  • a diameter of the implant may be from about 0.7 mm to about 5.0 mm.
  • a diameter of the implant may be from about 0.9 mm to about 1.1 mm.
  • a diameter of the implant may be at least about 0.1 mm, for example, at least about 0.1 mm, at least about 0.2 mm, at least about 0.3 mm, at least about 0.4 mm, at least about 0.5 mm, at least about 0.6 mm, at least about 0.7 mm, at least about 0.8 mm, at least about 0.9 mm, at least about 1.0 mm, at least about 1.1 mm, at least about 1.2 mm, at least about 1.3 mm, at least about 1.4 mm, or at least about 1.5 mm.
  • a diameter of the implant may be less than about 1 mm, for example, less than about 1 mm, less than about 0.9 mm, less than about 0.8 mm, less than about 0.7 mm, less than about 0.6 mm, less than about 0.5 mm, less than about 0.4 mm, less than about 0.3 mm, less than about 0.2 mm, or less than about 0.1 mm.
  • a diameter of the implant may be at least about 0. 1 mm.
  • a diameter of the implant may be at least about 0.8 mm.
  • a diameter of the implant may be about 1 mm.
  • a diameter of the implant may be about 2 mm.
  • a diameter of the implant may be about 3 mm.
  • a diameter of the implant may be about 4 mm.
  • a diameter of the implant may be about 5 mm.
  • the implant may have a length. In some cases, a length of the implant may be from about 1 mm to about 30 mm. In some cases, a length of the implant may be from about 5 mm to about 25 mm. In some cases, a length of the implant may be from about 10 mm to about 20 mm. In some cases, a length of the implant may be from about 12 mm to about 18 mm.
  • a length of the implant may be at least about 1 mm, at least about 2 mm, at least about 3 mm, at least about 4 mm, at least about 5 mm, at least about 6 mm, at least about 7 mm, at least about 8 mm, at least about 9 mm, at least about 10 mm, at least about 11 mm, at least about 12 mm, at least about 13 mm, at least about 14 mm, at least about 15 mm, at least about 16 mm, at least about 17 mm, at least about 18 mm, at least about 19 mm, at least about 20 mm, at least about 21 mm, at least about 22 mm, at least about 23 mm, at least about 24 mm, at least about 25 mm, at least about 26 mm, at least about 27 mm, at least about 28 mm, at least about 29 mm, or at least about 30 mm.
  • a length of the implant is at least about 1 mm. In some cases, a length of the implant is at least about 3 mm. In some cases, a length of the implant is about 15 mm. In some cases, a length of the implant may be less than about 30 mm, for example, less than about 30 mm, less than about 29 mm, less than about 28 mm, less than about 27 mm, less than about 26 mm, less than about 25 mm, less than about 24 mm, less than about 23 mm, less than about 22 mm, less than about 21 mm, less than about 20 mm, less than about 19 mm, less than about 18 mm, less than about 17 mm, less than about 16 mm, less than about 15 mm, less than about 14 mm, less than about 13 mm, less than about 12 mm, less than about 11 mm, less than about 10 mm, less than about 9 mm, less than about 8 mm, less than about 7 mm, less than about 6 mm, less than about 5 mm
  • the implant may have a volume.
  • the volume of the implant may be from about 0.1 mm 3 to about 30 mm 3 .
  • the volume of the implant may be about 0.1 mm 3 , about 0.5 mm 3 , about 1 mm 3 , about 5 mm 3 , about 10 mm 3 , about 15 mm 3 , about 20 mm 3 , about 25 mm 3 , or about 30 mm 3 .
  • the volume of the implant may be about 10 mm 3 .
  • the implant may lack a coating, covering, or a sheath.
  • the implant lacks at least one of a sheath, a scaffold, a retention member for retaining the drug implant within a target tissue, or a combination thereof.
  • a portion of the outer surface of the implant may not be coated or covered such that the outer surface of the uncoated or uncovered portion of the implant is directly exposed to or directly contacts the biological environment (e.g., a target tissue, a biological fluid) after implantation.
  • the entire outer surface or substantially the entire outer surface of the implant is uncovered or uncoated such that the entire outer surface or substantially the entire outer surface of the implant is directly exposed to or directly contacts a biological environment after implantation.
  • less than the entire outer surface of the implant is directly exposed to or directly contacts a biological environment after implantation.
  • the implant may lack a sheath, a scaffold, a retention member, a retention frame, or any other additional means for retaining the implant within the target tissue.
  • the implant may consist essentially of the polymer matrix and the therapeutically active agent (e.g., Talazoparib) dispersed therein.
  • the implant may comprise a coating.
  • the coating may cover the implant.
  • the coating may partially cover the implant.
  • the coating may substantially cover the implant.
  • the implant may comprise a core made of a first polymer material, and a coating of a second polymer material.
  • an implant of the disclosure may include a non-silicone core, surrounded by a silicone coating.
  • an implant of the disclosure does not comprise a metal.
  • the coating modulates the release of the Talazoparib.
  • the coating allows the drug implant to release the Talazoparib by zero order release.
  • the zero order release comprises at least about 1.0 pg/day of the Talazoparib after implantation in a subject. In some embodiments, the zero order release comprises at least about 8.0 pg/day of the Talazoparib after implantation in a subject. In some embodiments, the drug implant releases at least about 100.0 pg/day of the Talazoparib on Day 1, Day 2, Day 3, Day 4, or Day 5 after the implantation. In some embodiments, the drug implant releases a dose of the Talazoparib that is lower than 100.0 ug/day after Day 1, Day 2, Day 3, Day 4, or Day 5 after the implantation.
  • the coating comprises at least one additional therapeutic.
  • the at least one additional therapeutic can be dispersed in the coating to be eluted after insertion of the drug implant into the subject.
  • the at least one additional therapeutic comprises a cytotoxic therapeutic.
  • the at least one additional therapeutic comprises a hormonal therapeutic.
  • the at least one additional therapeutic comprises a biologic therapeutic.
  • the implant may prevent modulation of the Talazoparib contained therein when the implant is implanted into a subject.
  • Modulation can include, but is not limited to, degradation, chemical modification, and the like.
  • the biological environment of a tissue may include degradants that are capable of degrading the drug (e.g., esterases, amidases).
  • the implant may protect the therapeutically active agent from degradation by preventing the degradant from penetrating the implant.
  • in vitro stability testing may be performed to determine the protective effect of the implant on the therapeutically active agent contained therein. In such cases, the therapeutically active agent may be capable of diffusing out of the implant while maintaining in vivo stability within the implant.
  • the ability of a degradant to degrade a therapeutically active agent within the implant may be determined by a simulated in vivo stability assay.
  • an implant of the disclosure comprising a therapeutically active agent may be incubated in a solution comprising a degradant (known to degrade the therapeutically active agent). After a period of incubation, the therapeutically active agent may be extracted from the implant and degradation peaks may be measured (e.g., by high- performance liquid chromatography (HPLC)).
  • HPLC high- performance liquid chromatography
  • an implant of the disclosure may be configured to be delivered directly to a target tissue of a subject.
  • the target tissue may be prostate tissue.
  • an implant of the disclosure may be configured to be delivered to a tissue adjacent to or nearby a target tissue.
  • the therapeutically active agent may diffuse out of the implant in a controlled manner and act directly on the target tissue.
  • an implant of the disclosure may be configured to remain within the target tissue for a period of time. In some cases, an implant of the disclosure may be configured to remain within the target tissue indefinitely (e.g., is never removed). In some cases, two or more implants of the disclosure may be implanted into the target tissue. For example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more than 20 implants may be implanted in the target tissue. In some cases, the two or more implants may be implanted in different sites of the target tissue (e.g., to deliver drug to different sites of the target tissue). In some cases, the two or more implants may be implanted in close proximity to one another within the target tissue.
  • one or more initial implants may be implanted, and additional implants may be later implanted after the drug has been exhausted from the initial implants.
  • additional implants may be implanted after a drug has stopped, or substantially stopped, eluting from one or more initial implants.
  • an implant of the disclosure may be visible by ultrasound when disposed within the target tissue of the subject.
  • an implant of the disclosure may be visible by MRI when disposed within the target tissue of the subject. In such cases, the position of the implant may be monitored non-invasively.
  • the implant may be sterilized prior to implantation into a subject. In some cases, the implant is sterilized via gamma sterilization.
  • an implant of the disclosure may be capable of delivering a sustained release of Talazoparib for a period of time.
  • an implant of the disclosure may be capable of sustained release of the Talazoparib.
  • sustained release refers to the capability of the implant to release an amount of drug for an extended period of time after implantation into a target tissue.
  • an implant of the disclosure may be capable of delivering an amount of drug to a target tissue for at least 6 months, at least 9 months, at least 12 months, at least 18 months, or at least 24 months.
  • an implant of the disclosure may be capable of delivering at least 0.5 pg/day of Talazoparib for at least 6 months after implantation into a target tissue (e.g., prostate tissue or tissue adjacent or near the prostate). In some cases, an implant of the disclosure may be capable of delivering at least 0.1 pg/day of Talazoparib (e.g., to a target tissue) for up to 24 months after implantation into a target tissue (e.g., prostate tissue or tissue adjacent or near the prostate).
  • a target tissue e.g., prostate tissue or tissue adjacent or near the prostate.
  • a drug implant of the disclosure may exhibit one or more, or all of the following characteristics: cumulative release of the Talazoparib in an in vitro model of no more than 5,000 micrograms by day 1, cumulative release of the Talazoparib in an in vitro model of no more than 12,000 micrograms by day 60, and cumulative release of the Talazoparib in an in vitro model of no more than 16,000 micrograms by day 120.
  • a drug implant of the disclosure may exhibit one or more, or all of the following characteristics: cumulative release of the Talazoparib in an in vitro model of at least 5 micrograms by day 1, cumulative release of the Talazoparib in an in vitro model of at least 60 micrograms by day 60, and cumulative release of the Talazoparib in an in vitro model of at least 100 micrograms by day 120.
  • the in vitro model may include incubation of the drug implant in 1% sodium dodecyl sulfate (SDS) in water at 37 °C for the specified time period with continuous agitation.
  • SDS sodium dodecyl sulfate
  • a nonlimiting example of a method for manufacturing a drug implant of the disclosure may be as provided in Examples 1-4.
  • the methods may involve mixing an amount of polymer material with an amount of Talazoparib to form a mixture.
  • the polymer is a thermoset and the Talazoparib is mixed into the uncured polymer material.
  • the polymer is a thermoplastic and the Talazoparib is mixed into a solution or melt of the polymer material.
  • the methods may further involve molding the mixture to create a molded structure.
  • the molded structure may be formed by molding the mixture in a mold (e.g., transfer molding process), by extruding the mixture (e.g., through a tube), or by any other process.
  • the methods may further involve allowing the molded mixture to cure for a period of time with or without elevated temperature.
  • the polymer material may be any biocompatible silicone provided herein.
  • the silicone may be Silbione® ADH1 M200.
  • the silicone may be a platinum-cure silicone, e.g., Silbione® D370.
  • the mixture may be molded as described at elevated temperature and cooled to solidify the polymer.
  • the thermoplastic may be any biocompatible polyurethane provided herein.
  • the molding includes extruding the mixture using a ram extruder or a twin screw extruder. In some cases, the molding includes injection molding.
  • the mixture may further comprise a solvent.
  • solvents that may be used include pentane, heptane, toluene, dichloromethane, tetrahydrofuran, and hexane.
  • a solvent may be used to, e.g., reduce the viscosity of the liquid polymer.
  • the mixture may be molded by a transfer molding process or by extrusion (e.g., through a tube).
  • the therapeutically active agent e.g., Talazoparib
  • a total amount of active agent in the implant may be from about 0.5% w/w to about 80% w/w, for example, about 0.5% w/w, about 1% w/w, about 5% w/w, about 10% w/w, about 15% w/w, about 20% w/w, about 25% w/w, about 30% w/w, about 35% w/w, about 40% w/w, about 45% w/w, about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, or about 80% w/w.
  • the total amount of active agent (e.g., Talazoparib) in the implant may be at least about 0.5% w/w, at least about 1% w/w, at least about 5% w/w, at least about 10% w/w, at least about 15% w/w, at least about 20% w/w, at least about 25% w/w, at least about 30% w/w, at least about 35% w/w, at least about 40% w/w, at least about 45% w/w, at least about 50% w/w, at least about 55% w/w, at least about 60% w/w, at least about 65% w/w, at least about 70% w/w, at least about 75% w/w, or at least about 80% w/w.
  • Talazoparib may be provided in the mixture in an amount such that a total amount of Talazoparib in the implant may be from about 1 mg to about 10 mg.
  • the thermomolding comprises heating and molding of the mixture (e.g., transfer molding, extrusion, or another process) at about 100 °C to about 175 °C, for example, about 150 °C, about 155 °C, about 160 °C, about 165 °C, about 170 °C, or about 175 °C.
  • the molding temperature generally depends on the polymer material selected. Generally, the molding temperature of the polymer material is selected such that it is lower than the melting temperature of the therapeutically active agent. For a thermoplastic, the mixture is heated for sufficient time to achieve a moldable state prior to molding.
  • the mixture is heated from about 3 minutes to about 8 minutes, for example, for about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, or about 8 minutes.
  • the melting temperature of Talazoparib e.g., about 245 °C to about 255 °C
  • the mixture may further comprise a solvent.
  • solvents include pentane, heptane, toluene, dichloromethane, tetrahydrofuran, and hexane.
  • a solvent may be used to, e.g., reduce the viscosity of the liquid polymer.
  • the mixture may be molded by a transfer molding process or by extrusion (e.g., through a tube).
  • the methods may further comprise performing one or more analyses on the implant.
  • the one or more analyses may be differential scanning calorimetry (DSC) (e.g., to determine the rate of curing of the implants and/or to evaluate properties of the drug).
  • the one or more analyses may be deployment of the implant into surrogate tissue.
  • the one or more analyses may be elution testing (e.g., to assess the rate of elution of drug from the implant).
  • the one or more analyses may be in vivo stability testing (e.g., to assess the ability of degradants to penetrate the implant).
  • the one or more analyses may be viscometry.
  • the one or more analyses may be the use of a rheometer (e.g., to assess the viscosity and curing profile for the formulation).
  • the one or more analyses may be high pressure liquid chromatography (e.g., to confirm content uniformity and assess impurities in the drug formulation and the molded implant).
  • the one or more analyses may be dynamic mechanical analysis (DMA) (e.g., to assess the mechanical properties of the implant to ensure it can be deployed correctly).
  • the one or more analyses may be high pressure liquid chromatography (HPLC).
  • treating includes ameliorating, abrogating, reducing, relieving, or curing the disease or disorder.
  • Treating a disease or disorder also includes ameliorating, abrogating, reducing, relieving, or curing one or more symptoms associated with a disease or disorder.
  • treating includes diminishing or reducing the size of the tumor or tumor volume.
  • the subject may have been diagnosed with, may be suspected of having, or may be at risk of having the disease (or one or more symptoms thereof).
  • the methods comprise implanting an implant of the disclosure into a target tissue of a subject.
  • An implant of the disclosure may be implanted into a target tissue by any method.
  • the implant may be implanted into a target tissue by a surgical method or a non-surgical method.
  • the implant may be implanted using standard surgical tools, for example, tools commonly used for biopsies or brachytherapy.
  • the implant may be implanted into a target tissue by use of, e.g., a needle, forceps, a catheter (e.g., with a lumen).
  • the implant may be implanted into a target tissue by deployment from the lumen of a needle or a catheter.
  • the implant may be implanted into a target tissue using a cannula of a prostate biopsy needle.
  • the implant may be implanted into a target tissue using a Mick® needle.
  • deployment of the implant may be guided by ultrasound.
  • deployment of the implant may be guided by MRI.
  • the implant may be implanted by transperineal implantation (e.g., by use of a template guided needle).
  • the implant may be sterile and disposed within a packaging.
  • a method of deploying an implant of the disclosure into a target tissue may involve disposing a distal end of an elongate tube into the target tissue (e.g., the prostate or tissue adjacent the prostate).
  • the elongate tube may be a needle having a lumen.
  • the elongate tube may have a sharp end such that the distal end of the elongate tube can penetrate the target tissue.
  • the distal end of the elongate tube may be disposed through a first portion of a grid (e.g., a guide template) such that a first position of the elongate tube in the subject is determined.
  • the grid may allow for proper placement of the implant into the target tissue.
  • a trocar is disposed within the lumen of the elongate tube.
  • the methods may involve inserting the elongate tube (with or without a trocar disposed within a lumen of the elongate tube) into the target tissue.
  • the methods may further involve, when using a trocar, removing the trocar from the lumen of the elongate tube, while maintaining the distal end of the elongate tube within the target tissue.
  • the methods may further involve placing an implant of the disclosure within the lumen of the elongate tube.
  • the implant may be pushed through the lumen of the elongate tube by a blunt-ended rod (e.g., a stylet) that is sized to fit within the lumen of the elongate tube.
  • a blunt-ended rod e.g., a stylet
  • the stylet may be used to push the implant from a proximal end of the elongate tube to the distal end of the elongate tube.
  • the methods may further involve, while maintaining the stylet in position, removing the elongate tube from the target tissue. As the elongate tube is removed from the target tissue, the stylet may push the implant out of the elongate tube and into the target tissue.
  • the methods may further involve removing both the stylet and the elongate tube together from the target tissue.
  • the methods may involve implanting more than one implant into a target tissue of the subject.
  • the methods may involve implanting a first implant into a first portion of the target tissue, and a second implant into a second portion of the target tissue.
  • the first portion of the target tissue and the second portion of the target tissue may be different.
  • the first implant may comprise a first therapeutically active agent (e.g., Talazoparib) and the second implant may comprise a second therapeutically active agent.
  • the first therapeutically active agent e.g., Talazoparib
  • the second therapeutically active agent may be the same.
  • the first therapeutically active agent e.g., Talazoparib
  • the second therapeutically active agent may be different.
  • a grid e.g., a guide template
  • the first implant and/or the second implant may be positioned with the use of ultrasound guidance.
  • the first implant and/or the second implant may be positioned with the use of MRI guidance.
  • the methods may further comprise implanting additional implants into the target tissue.
  • the methods may further comprise implanting a third implant into a third portion of the target tissue, implanting a fourth implant into a fourth portion of the target tissue, implanting a fifth implant into a fifth portion of the target tissue, implanting a sixth implant into a sixth portion of the target tissue, implanting a seventh implant into a seventh portion of the target tissue, implanting an eighth implant into an eighth portion of the target tissue, and so forth.
  • the third, fourth, fifth, sixth, seventh, eighth, or more, therapeutically active agents may each be the same, different, or combinations thereof.
  • at least three implants are implanted into a target tissue.
  • At least three implants may be implanted into the prostate or tissue adjacent or near the prostate by transperineal administration.
  • the implant(s) are implanted into a target tissue via a minimally invasive approach.
  • one or more implants may be implanted into a target tissue (e.g., prostate or tissue adjacent or near a prostate) prior to a surgical procedure to treat e.g., prostate cancer.
  • a target tissue e.g., prostate or tissue adjacent or near a prostate
  • a surgical procedure to treat e.g., prostate cancer e.g., one or more implants may be implanted into a prostate or tissue adjacent or near a prostate prior to performing a prostatectomy (e.g., a week before, two weeks before, three weeks before, etc.). In such cases, the prostatectomy may remove the prostate or a portion thereof.
  • the prostatectomy may remove one or more of the implants from the subject.
  • one or more implants may be implanted into a target tissue (e.g., prostate or tissue adjacent or near a prostate), and may remain in the target tissue indefinitely.
  • the one or more implants may provide a therapeutically effective amount of Talazoparib to the target tissue for a period of time such that the subject is in remission, is in non-progression, or is cured of the cancer.
  • the disease or disorder is a tumor in the subject
  • the method comprises comprising implanting, into the tumor or into a tissue adjacent to the tumor of the subject, at least one drug implant described herein.
  • the at least one drug implant continuously delivers the Talazoparib to the subject for at least 6 months, at least 12 months, at least 24 months, at least 60 months, or longer.
  • a total dose of the Talazoparib administered to the subject by the implanting is less than a total dose of the Talazoparib when administered to a subject by oral administration.
  • a total dose of the Talazoparib administered to the subject by the implanting is less than 200 mg over a period of 6 months.
  • the implanting results in a blood plasma concentration of the Talazoparib that is less than a blood plasma concentration of the Talazoparib obtained when the Talazoparib is administered to a subject by oral administration.
  • the implanting occurs via transperineal administration (e.g., by using a template guided needle).
  • the implanting locally delivers the Talazoparib to the tumor.
  • the tumor is a prostate tumor, bladder tumor, an ovarian tumor, a fallopian tumor, a liver tumor, a bone tumor, a breast tumor, a pancreatic tumor, a lung tumor, a gastric tumor, a kidney tumor, a gall bladder tumor, a colon tumor, an unspecified tumor, or a combination thereof.
  • the method further comprises, after the implanting, administering to the subject at least one additional therapy to treat the tumor.
  • the method further comprises, after the implanting, recommending that the subject receive at least one additional therapy to treat the tumor.
  • the at least one additional therapy comprises radiation, chemotherapy, biologic therapy, immunologic therapy, hormonal therapy, or a combination thereof.
  • the at least one additional therapy comprises radiation. In some embodiments, the at least one additional therapy is more efficacious for treating the tumor after the implanting than after oral administration of the Talazoparib. In some embodiments, an amount of the at least one additional therapy needed to effectively treat the tumor is lower after the implanting, as compared to an amount of the at least one additional therapy needed to effectively treat the tumor in the absence of the Talazoparib. In some embodiments, the method results in decreased toxicity to the subject as compared to when the subject receives the at least one additional therapy without the Talazoparib. In some embodiments, the toxicity comprises weight loss, myelosuppression, fatigue, gastrointestinal (GI) toxicity, or a combination thereof of the subject.
  • GI gastrointestinal
  • the tumor is associated with a genetic mutation of BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof.
  • BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation or a combination thereof.
  • the term “subject”, as used herein, generally refers to a vertebrate, such as a mammal, e.g., a human. Mammals include, but are not limited to, murines, simians, humans, research animals, farm animals, sport animals, and pets.
  • the methods described herein may be used on tissues derived from a subject and the progeny of such tissues.
  • the tissues may be obtained from a subject in vivo. In some cases, the tissues may be cultured in vitro.
  • the methods provided herein may be used to treat a subject in need thereof.
  • the subject may suffer from a disease.
  • the subject may be a human.
  • the human may be a patient at a hospital or a clinic.
  • the subject may be a non-human animal, for example, a non-human primate, a livestock animal, a domestic pet, or a laboratory animal.
  • a non-human animal can be an ape (e.g., a chimpanzee, a baboon, a gorilla, or an orangutan), an old world monkey (e.g., a rhesus monkey), a new world monkey, a dog, a cat, a bison, a camel, a cow, a deer, a pig, a donkey, a horse, a mule, a lama, a sheep, a goat, a buffalo, a reindeer, a yak, a mouse, a rat, a rabbit, or any other non-human animal.
  • an ape e.g., a chimpanzee, a baboon, a gorilla, or an orangutan
  • an old world monkey e.g., a rhesus monkey
  • a new world monkey e.g., a dog, a cat, a bison, a came
  • the subject may be of any age. In some cases, the subject may be about 50 years or older. In some cases, the subject may be about 55 years or older. In some cases, the subject may be about 60 years or older. In some cases, the subject may be about 65 years or older. In some cases, the subject may be about 70 years or older. In some cases, the subject may be about 75 years or older. In some cases, the subject may be about 80 years or older. In some cases, the subject may be about 85 years or older. In some cases, the subject may be about 90 years or older. In some cases, the subject may be about 95 years or older. In some cases, the subject may be about 100 years or older.
  • the subject may be about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or greater than 100 years old.
  • the subject may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or greater than 20 years old.
  • the implants provided herein may be used for the prevention of cancer (e.g., in a subject from 20 years old to 50 years old). In some cases, the implants provided herein may be used for the treatment of cancer (e.g., in a subject from 20 years old to 85 years old).
  • the methods provided herein may treat a disease in a subject. In some cases, the methods provided herein may alleviate or reduce a symptom of a disease. In some cases, the methods provided herein may result in a reduction in the severity of one or more symptoms associated with a disease. In some cases, the methods provided herein may slow, halt, or reverse the progression of one or more symptoms associated with a disease. In some cases, the methods provided herein may prevent the development of one or more symptoms associated with a disease. In some cases, the methods provided herein may slow, halt, or reverse the progression of a disease, as measured by the number and severity of symptoms experienced. In some cases, the methods provided herein may prevent the occurrence of cancer.
  • the disease may be a proliferative disease or disorder.
  • the proliferative disease or disorder may be cancer.
  • the subject may have a tumor.
  • the tumor is associated with a genetic mutation of BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, RAD51, FANCA, any homologous recombination deficiency (HRD) mutation, or a combination thereof.
  • the tumor is a prostate tumor, bladder tumor, an ovarian tumor, a fallopian tumor, a liver tumor, a bone tumor, a breast tumor, a pancreatic tumor, a lung tumor, a gastric tumor, a kidney tumor, a gall bladder tumor, a colon tumor, an unspecified tumor, or a combination thereof.
  • the methods may reduce the size of a tumor. In some cases, the methods may reduce the size of a tumor by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or by about 100%.
  • the proliferative disease or disorder may be a proliferative disease or disorder of the prostate.
  • the proliferative disease or disorder of the prostate may be prostate cancer.
  • Prostate cancer can be adenocarcinoma, sarcoma, neuroendocrine tumors, small cell carcinoma, transitional cell carcinoma, or squamous cell carcinoma.
  • the methods may be employed to deliver a therapeutically effective amount of Talazoparib to a target tissue. In some cases, the methods may involve delivering a drug implant to a target tissue (or a tissue adjacent to the target tissue) of the subject. Any tissue may be suitable for delivery of a drug implant of the disclosure.
  • the target tissue may be the prostate, tissue adjacent to the prostate, or both.
  • target tissue includes breast, pancreas, bladder, brain, skin, kidney, lung, liver, tongue, esophagus, stomach, intestine, gallbladder, heart, pituitary gland, pineal gland, thyroid gland, parathyroid gland, adrenal gland, eye, bone, fallopian tubes, uterus, ovary, sinuses, inner ear (eustachian tube), testes, and neck.
  • the methods provide for implanting a drug implant of the disclosure into the target tissue (or an adjacent tissue) of a subject, wherein the implant delivers a therapeutically effective amount of Talazoparib to the target tissue.
  • a “therapeutically effective amount” when used in reference to a drug or therapeutically active agent refers to an amount of drug or therapeutically active agent that is capable of eliciting a therapeutic response in a subject.
  • the implant may deliver a therapeutically effective amount of drug to a tissue of the subject from 6 months to 60 months or longer.
  • the implant may deliver a therapeutically effective amount of drug to a tissue of the subject for 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 36 months, 48 months, 60 months, or longer.
  • the implant may deliver a therapeutically effective amount of drug to a tissue of the subject for at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, at least 24 months, at least 36 months, at least 48 months, at least 60 months, or longer.
  • a therapeutically effective amount of drug may be at least about 0.1 pg/day. In some cases, a therapeutically effective amount of drug may be at least about 0.1 pg/day, about 0.2 pg/day, about 0.3 pg/day, about 0.4 pg/day, about 0.5 pg/day, about 0.6 pg/day, about 0.7 pg/day, about 0.8 pg/day, about 0.9 pg/day, about 1 pg/day, about 2 pg/day, about 3 pg/day, about 4 pg/day, about 5 pg/day, about 6 pg/day, about 7 pg/day, about 8 pg/day, about 9 pg/day, about 10 pg/day, about 15 pg/day, about 20 pg/day, about 25 pg/day, about 30 pg/day, about 35 pg/day, about 40 pg/
  • the implant may result in cumulative release of Talazoparib from the implant into the target tissue.
  • the cumulative release of Talazoparib from the implant in vitro may be at least 20 pg on day 1. In some cases, the cumulative release of Talazoparib from the implant in vitro may be at least 140 pg on day 1. In some cases, the cumulative release of Talazoparib from the implant in vitro may be at least 80 pg on day 60. In some cases, the cumulative release of Talazoparib from the implant in vitro may be at least 1,000 pg on day 60. In some cases, the cumulative release of Talazoparib from the implant in vitro may be at least 100 pg on day 120.
  • the cumulative release of Talazoparib from the implant in vitro may be at least 1,500 pg on day 120. In some cases, at least 10%, at least 15%, at least 20%, at least 25%, or at least 50% of the total amount of Talazoparib present within the implant at the time of implantation remains in the polymer matrix at 100 days post-implantation. In some cases, at least 10%, at least 15%, at least 20%, at least 25%, or at least 50% of the total amount of Talazoparib present within the implant at the time of implantation remains in the polymer matrix at 180 days post-implantation.
  • the implant may result in cumulative release of the Talazoparib in an in vitro model of one or more of: no more than 2,000 micrograms by day 1, no more than 12,000 micrograms by day 60, and no more than 16,000 micrograms by day 120.
  • the implant may result in cumulative release of the Talazoparib in an in vitro model of one or more of: at least 10 micrograms by day 1, at least 80 micrograms by day 60, and at least 100 micrograms by day 120.
  • the in vitro model may include incubating the drug implant in 1% sodium dodecyl sulfate (SDS) in water at 37 °C for the specified time period with continuous agitation.
  • SDS sodium dodecyl sulfate
  • the implant may be configured to remain within the target tissue for a period of time.
  • the implant may be configured to remain within the target tissue for long periods of time (e.g., months to years) or indefinitely (e.g., may never be removed).
  • the implant after the implant has delivered all of the therapeutically active agent contained therein to the subject, the implant (devoid of the therapeutically active agent) may remain within the target tissue.
  • the implant may be composed of a non-biodegradable and/or non-resorbable polymer material such that the polymer material remains substantially intact within the target tissue for long periods of time or indefinitely.
  • the implants of the disclosure are capable of delivering a therapeutically effective amount of Talazoparib to the prostate tissue, or tissue adjacent or near the prostate, for extended periods of time (e.g., at least 6 months). Additionally, the implants of the disclosure are capable of delivering a high concentration of Talazoparib locally to the prostate, while maintaining low systemic concentrations of Talazoparib. In some cases, the implants of the disclosure may reduce or prevent toxicity due to high systemic concentrations of Talazoparib. In some cases, the implants of the disclosure may reduce or prevent toxicity to a subject as compared to when the subject receives the at least one additional therapy without the Talazoparib. In some embodiments, the toxicity includes weight loss, myelosuppression, fatigue, gastrointestinal (GI) toxicity, or a combination thereof.
  • GI gastrointestinal
  • a total dose of Talazoparib administered to the subject by an implant of the disclosure is less than a total dose of Talazoparib when administered to a subject by systemic (e.g., oral) administration.
  • Standard oral dosing regimens of Talazoparib include 1 mg/day Talazoparib monotherapy for breast cancer, and 0.5 mg/day Talazoparib monotherapy for prostate cancer.
  • the implants of the disclosure provide for administration of lower total doses of Talazoparib relative to oral dosing regimens.
  • the total amount of Talazoparib administered to a subject is less than 100 mg over a 6-month period.
  • implanting a drug implant of the disclosure into the prostate or tissue adjacent or near the prostate results in a blood plasma concentration of Talazoparib that is substantially less than a blood plasma concentration of Talazoparib obtained when Talazoparib is administered to a subject by systemic (e.g., oral) administration.
  • systemic e.g., oral
  • the mean ( ⁇ %CV) area under the curve (AUC) at steady state is reported to be about 208 (( ⁇ 37%) ngxhr/mL.
  • the maximum observed plasma concentration (Cmax) is reported to be about 16.4 ( ⁇ 32%) ng/mL.
  • implanting an implant of the disclosure into the prostate or tissue adjacent or near the prostate results in a peak blood plasma concentration of Talazoparib that is less than 16.4 ng/mL. In some cases, implanting an implant of the disclosure into the prostate or tissue adjacent or near the prostate results in a peak blood plasma concentration of Talazoparib that is more than 16.4 ng/mL.
  • kits may comprise one or more implants as described herein.
  • a kit may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more than 20 implants.
  • the one or more implants may comprise a therapeutically active agent contained therein.
  • each of the one or more implants may comprise Talazoparib.
  • each of the one or more implants may comprise one or more different therapeutically active agents.
  • kits may comprise one or more surgical tools, such as a needle or forceps.
  • a kit may be packaged in a sterilized package.
  • the sterilized package comprises a foil.
  • a kit may further comprise instructions for implanting the implant into a tissue of a subject.
  • ranges and amounts can be expressed as “about” a particular value or range. About also includes the exact amount. Hence “about 5 pL” means “about 5 pL” and also “5 pL.” Generally, the term “about” includes an amount that would be expected to be within experimental error, e.g., within 15%, 10%, or 5%.
  • Example 1 Methods for making implants - platinum-cure silicone
  • Manufacture of the implant includes two main steps: formulation of the active pharmaceutical ingredient (API) (e.g., Talazoparib) with an elastomer (e.g., medical-grade, platinum-cure silicone) to ensure uniform mixing of the API within the polymer matrix, and molding of the implants to ensure the product can be deployed to the organ as intended.
  • API active pharmaceutical ingredient
  • elastomer e.g., medical-grade, platinum-cure silicone
  • the implant formulation includes medical grade silicone as an excipient mixed with the API.
  • a solvent is used for reducing the viscosity of the silicone, if needed, to incorporate the desired API loading.
  • the Talazoparib formulation is made using a centrifugal mixer.
  • the required amount of silicone Part A and Part B is added to the mixing cup with an equal weight of a solvent (that dissolves silicone; e.g., pentane) added.
  • the silicone and solvent are speed-mixed until the viscosity of the silicone is reduced such that it flows.
  • the API powder is then incorporated into the mixing cup and speed-mixed until a visibly smooth mixture is obtained with no dry API spots.
  • the solvent is then removed (with or without vacuum) leaving a paste of silicone and API.
  • Table 1 below shows an example for the formulation of Talazoparib made to 10% load by weight.
  • This method may be used to formulate active pharmaceutical ingredient (e.g., Talazoparib) with an elastomer (e.g., platinum-cure silicone) from as low as 10% load by weight, to above 70% load by weight.
  • active pharmaceutical ingredient e.g., Talazoparib
  • elastomer e.g., platinum-cure silicone
  • Implant rods are made using a (e.g., aluminum) mold (e.g., via a transfer molding process) or by extruding the talazoparib formulation (e.g., through a tube).
  • the molded rods arc cured for a predetermined time (e.g., about 3 to 8 minutes) at a certain temperature (e.g., about 125°C to 175°C) based on the silicone supplier’s recommendations for curing.
  • Post-curing the mold is cooled, and the rods are de-molded for characterization.
  • the implant formulation includes a medical-grade silicone with an acetoxycure silicone with an alternative curing chemistry to platinum-cure to be used as an excipient mixed with the API.
  • the implant formulation includes medical grade silicone as an excipient mixed with the API.
  • a solvent is used for reducing the viscosity of the silicone, if needed, to incorporate the desired API loading.
  • the Talazoparib formulation is made using a centrifugal mixer.
  • the required amount of silicone is added to the mixing cup with an equal weight of a solvent (that dissolves silicone; e.g., pentane) added.
  • the silicone and solvent are speed-mixed until the viscosity of the silicone is reduced such that it flows.
  • the API powder is then incorporated into the mixing cup and speed- mixed until a visibly smooth mixture is obtained with no dry API spots.
  • the solvent is then removed (with or without vacuum) leaving a paste of silicone and API.
  • a portion of the solvent (as high as 50% w/w) may be left in the mixture to slow the curing process and extend pot life as well as reduce viscosity to aid in molding or extrusion.
  • Table 3 shows an example for the formulation of Talazoparib made to 10% load by weight.
  • This method may be used to formulate active pharmaceutical ingredient (e.g., Talazoparib) with an elastomer (e.g., acetoxy-cured silicone) from as low as 10% load by weight, to above 70% load by weight.
  • active pharmaceutical ingredient e.g., Talazoparib
  • elastomer e.g., acetoxy-cured silicone
  • Implant rods are made by extruding the Talazoparib formulation (e.g., through a tube). The molded rods are cured for a predetermined time (about 1-3 days) at an ambient temperature to ensure the silicone has cured. Post-curing, the rods are pulled out of the tubing and cut to length, and are characterized.
  • Example 3 Methods for making implants - thermoplastic polyurethane solvent process
  • the implant formulation includes thermoplastic polyurethane as an excipient mixed with the API.
  • a solvent is used for dissolution of the polyurethane to allow compounding with the API to create a uniform dispersion at the desired loading. After compounding, the solvent is removed and the resulting polyurethane- API pellet is molded into implant rods by transfer molding or extrusion. [0106] The polyurethane pellets are added to a mixing cup with solvent (e.g., dichloromethane) and incubated at 37 °C with agitation for several hours until dissolution of the polyurethane is achieved. The ratio of polyurethane to solvent is selected to achieve full dissolution of the polyurethane and a solution of sufficiently low viscosity for mixing (e.g., about 20% solids content by weight).
  • solvent e.g., dichloromethane
  • API powder is then added to the solution and speed-mixed until a visibly smooth mixture is obtained with no dry API spots.
  • Table 4 below shows an example for a formulation made with 30% API w/w.
  • the solvent is then removed under vacuum leaving a large pellet consisting of polyurethane, API, and residual solvent that may be used for thermomolding.
  • Table 5 below shows an example set of solvent removal conditions.
  • Other solvents e.g., tetrahydrofuran, dimethylformamide, dimethylacetamide, etc.
  • solvents e.g., tetrahydrofuran, dimethylformamide, dimethylacetamide, etc.
  • dissolve polyurethane may also be used for formulation.
  • Implant rods are made using a (e.g., aluminum) mold (e.g., via a transfer molding process) or by extruding the Talazoparib formulation (e.g., through a tube). The formulation is melted for several minutes (about 3 to 8 minutes) at a certain temperature (about 150° C to 200° C) before injection or extrusion. Post-curing, the mold is cooled, and the rods are de-molded for characterization .
  • a e.g., aluminum
  • the Talazoparib formulation e.g., through a tube.
  • the formulation is melted for several minutes (about 3 to 8 minutes) at a certain temperature (about 150° C to 200° C) before injection or extrusion. Post-curing, the mold is cooled, and the rods are de-molded for characterization .
  • Example 4 Methods for making implants - thermoplastic polyurethane and polyethylene vinyl acetate extrusion process
  • the implant formulation includes thermoplastic polyurethane or polyethylene vinyl acetate as an excipient mixed with the API.
  • Milled excipient powder thermoplastic polyurethane or polyethylene vinyl acetate
  • API Tetrachloroethylene
  • Table 6 shows typical measurements for a 2-gram powder mix at 50% API load by weight. Ratios are adjusted for different targeted loads.
  • Implant rods are made with an extrusion process using either ram or twin-screw extruder.
  • An aliquot of the powder mix (0.5-10 g) is placed in the extruder cavity and heated to approximately 150 °C for 1-3 minutes.
  • a plunger or rotating screws are activated to force the melted powder mix through the extrusion nozzle or die.
  • the nozzle or die diameter and the conveyor speed can be adjusted to obtain an implant of a certain diameter. After it has cooled for a few seconds, it can be cut to desired lengths for implant rods.
  • An alternative method uses vacuum molding (e.g., MeltPrep Vacuum Compression Molding) to melt and mold the Talazoparib polymer powder mix for smaller batch sizes.
  • a small amount of powder mix ( ⁇ 15 mg) is packed in a piece of polytetrafluoroethylene (PTFE) tubing of desired diameter.
  • the tube is placed in a heated vacuum chamber.
  • the chamber is heated to 150-200 °C for 5-15 minutes and a metal piston compresses the mix as the polymer melts under negative pressure.
  • the chamber is cooled and the resulting rod is removed from the tubing using a metal piston.
  • An alternative method uses a twin-screw extruder (e.g., ThermoFisher HAAKE MiniCTW) to melt and extrude the Talazoparib polymer powder mix for larger batch sizes.
  • the mix is introduced into the barrel of the extrude which is heated to 150-200 °C and the melted mix is pushed through a die to produce an extruded strand of desired diameter.
  • a conveyor belt carries the extruded strand which is allowed to cool and then cut to desired lengths for implant rods.
  • This process can be completed with powder mixes containing a milled excipient and API powder, or even pellets from solvent mixes as described herein.
  • Example 5 Characterization of Talazoparib containing formulation and implants
  • Various analytical techniques are used for characterization of the formulation and molded implants. Differential Scanning Calorimetry (DSC) is used to e.g., determine the rate of curing of the implants and to evaluate properties of the drug. Elution testing is used to assess the rate of elution of drug from the implant. High Pressure Liquid Chromatography (HPLC) is used to e.g., confirm content uniformity and assess impurities in the drug formulation and molded rods.
  • DSC Differential Scanning Calorimetry
  • HPLC High Pressure Liquid Chromatography
  • Example 6 Selection of optimal implant formulation for localized drug delivery to potentiate radiation therapy
  • the most effective PARP inhibitor (PARPi) seed implant for local delivery and define the maximal load is selected for stability and long-term release within a polymer scaffold and the optimal excipient to provide an early release burst.
  • PARPi elution rate increases with the amount loaded, compound structure, and ratio of drug to polymer. Decreasing the percentage of polymer (w/w) increases implant fragility but increases burst and release plateau.
  • the in vitro model may include incubating the drug implant in 1% sodium dodecyl sulfate (SDS) in water at 37 °C for the specified time period with continuous agitation. Fig.
  • FIG. 2A illustrates average daily elution of Talazoparib over 50 days from a drug implant comprising 10%, 30%, 50%, or 70% of Talazoparib in a silicone matrix.
  • Fig. 2B illustrates cumulative elution from a drug implant comprising 10%, 30%, 50%, or 70% of Talazoparib in a silicone matrix.
  • Increasing Talazoparib to its maximum percentage (w/w) in a silicone scaffold resulted in increased daily and cumulative drug release in ongoing elution studies for 180 days, which are projected to elute PARPi for >1 year.
  • Methods for Talazoparib quantification arc developed using an Agilent 1100 HPLC coupled to a Phenomenex Kinetex Cis column (100 x 4.6 mm, 5 um particle size).
  • the release of PARPi is modulated by varying the ratio of polymer and API blending and increased by co-formulating with excipients such as lactose. This increases both the amplitude of the initial burst, as well as the daily release rate, while maintaining a minimal 1- year delivery duration.
  • excipients such as lactose.
  • In vitro:in vivo correlations are determined from the studies in Example 7. The optimal implant formulation is used for subsequent in vivo murine, rat, or canine studies.
  • Experimental data and polymer (EVA and silicone) properties suggest that Talazoparib can be a suitable candidate.
  • the optimal implant formulation delivers the highest (e.g., supra-therapeutic) PARPi level with rapid prostate tissue distribution, which transitions to therapeutic levels maintained for at least 12 months.
  • the therapeutic goal is to have daily elution of at least lOx over the IC50 of prostate tumors for the respective PARPi during the course of at least one year.
  • the long- and short-term release of polymer-based formulations is qualitatively and quantitatively compared to preliminary studies with the goal to minimally release from >100 my/d during burst and then 10-30 pg per day of Talazoparib for >365 days to achieve these supratherapeutic levels (e.g., 11,200 pg of drug per 80% implant). If necessary, dip-coating implants with a higher durometer silicone is used to retard drug release to prolong exposure. PARPi and excipient compatibility and release profile are determined for Talazoparib to identify implant designs that meet the dose and duration goals.
  • Optimal sterilization and radiation therapy inertness is determined for sterilizing the drug implant and co-formulated drug for in vivo testing (e.g., Example 7).
  • Common forms of device and drug sterilization include gamma and electron beam irradiation, ethylene oxide incubation, and autoclaving.
  • the preferred method is radiation sterilization as it has been shown that three of the four polymers are impervious to radiation therapy ( ⁇ 25 kGy) which far exceed therapeutic radiation therapy doses used in patients and proposed in Example 7.
  • the proposed PARPi is inert to radiation therapy but is further tested for long term stability after radiation.
  • Drug implant and PARPi stability is tested.
  • Lead drug implant with EVA, TPU, or silicone is mechanically tested to assess compression, tension, and relaxation. Additional testing to assess silicone cure is conducted, which includes differential scanning calorimetry (DSC) and rheology. Curing of silicone can be poisoned by contaminates (e.g., latex from gloves), as well as drugs that are being incorporated. Although firm and undetectable by touch, DSC and rheology can detect partially cured silicone.
  • DSC differential scanning calorimetry
  • PARPi durability and stability is a significant concern and can be tested during elution studies of implants, monthly. At the conclusion of elution studies, all remaining PARPi and degradative products are recovered using an established solvent extraction method using tetrahydrofuran. Samples are evaluated by HPLC for retention time impurities, percent impurity is correlated with time for degradation pre- and post-radiation.
  • PARPi implant is placed within the prostate 6-8 weeks prior to radiation therapy to allow sufficient time for the PARPi to sensitize the tumor cells to radiation and then continue PARPi elution for at least 12 months and possibly 2 years. This is similar to current approved adjuvant hormonal therapy in radiation therapy in high-risk men which is given for 6 months to 2 years. 8-16 implants (1.5 cm in length by 0.95 mm in diameter) are accommodated for surgical insertion with an 18-gauge biopsy needle in a 30-minute procedure.
  • Each of the proposed models validates its own responsiveness to PARPi and radiation.
  • the greatest radiation and PARPi sensitivity in BRCA1 or BRCA2 mutations, less effective to Ataxia-Telangiesctasia Mutated (ATM) mutations and lesser still for Checkpoint kinase 2 (CHEK2), and ineffective for intact HR tumors are examined.
  • the radiation dose for safety and effect size in each setting before comparing the effects of combined PARPi and XRT is established (Table 7).
  • the effect of PARPi on radiation therapy efficacy in HR-intact PC3 and DU145 prostate cancer cells is assessed. Significantly less response to the PARPi delivered via the PARPi eluting implant in the parental HR intact prostate cells and potentiation of XRT compared to HRD variants is expected.
  • the combined efficacy is determined in two established HR competent prostate cancer xenograft models (A), followed by assessing the impact of BRCA1/2 and ATM (or) mutations on the ability of PARPi to potentiate radiation therapy. This is done with CRISPR engineered HR-mutated PC3 and DU 145 prostate cancer cell line models (B).
  • FIG. 3 illustrates assessment of mouse models for testing the therapeutic efficacy of a drug implant described herein.
  • Mice were genetically engineered to harbor homologous recombination deficiency (HRD) of BRCA1 or BRCA2 mutations.
  • HRD homologous recombination deficiency
  • Functional HRD deficiency of BRCA1 or BRCA2 mutations was indicated by the loss of Rad51 foci induction by carboplatin in the transgenic mice as compared to wild type mice.
  • Fig. 4A illustrates BRCA2 protein in wild type (WT) cells versus CRISPR/Cas9 engineered PC3 prostate cancer clones.
  • Fig. 4B illustrates increased sensitivity to carboplatin in IE 10 clone versus WT cells.
  • FIG. 4C illustrates increased survivability of mice bearing the PC3-BRCA2 (1E10) tumor xenografts when receiving 70% talazoparib implants intratumorally compared to placebo implants.
  • the functional loss of BRCA2 caused increased sensitivity to carboplatin (Fig. 3).
  • Fig. 3 illustrates assessment of mouse models for testing the therapeutic efficacy of a drug implant described herein.
  • PC3 prostate cancer cells were genetically engineered to harbor homologous recombination deficiency (HRD) of breast cancer gene 1 (BRCA1) or breast cancer gene 2 (BRCA2) mutations.
  • HRD homologous recombination deficiency
  • a safe XRT dose and its effect size is determined. Prior data suggests that these mice can tolerate 6 Gray unity (Gy) given once in 5 fractions. Three male NRG mice each are implanted with the respective cells (PC3 and DU145, see Fig. 4 and Fig. 5).
  • Fig. 5 illustrates prostate cancer PDX-BRCA2 tumors (e.g., LTL-610 and TM00298) implanted with placebo, 10%, or 50% Talazoparib implant. When tumors reach a size of 150-200 mm 3 , each mouse has one (3 x 1 mm) sham implant implanted into the center of their tumor.
  • mice are treated with 1 , 3 or 5 fractions of 6 Gy radiation therapy to assess tolerability and the effect size. If mice exhibit >20% weight loss or distress, this is considered toxic, and the XRT dose is lowered. To be able to assess combination effects, an XRT dose resulting in a ⁇ 20% effect on tumor growth is selected. Three mice can then be implanted with a (3 mm x 1 mm) PARPi-containing implant to test the feasibility and preliminary release properties in an assessment period of 30 days. All mice undergo necropsy to evaluate pathology. The prostate and surrounding tissue are collected for formalin-fixed, paraffin-embedded (FFPE) and tissue histology analyzed for pathology.
  • FFPE formalin-fixed, paraffin-embedded
  • mice When tumors reach -150-200 mm 3 , mice are randomized into four cohorts of six (four animals with outlier tumor volumes can be removed): Cohort 1 - Sham implant, Cohort 2 - PARPi implant, Cohort 3 - Sham implant, XRT only, and Cohort 4 - PARPi implant and radiation. Implants are placed in the middle of palpable tumors along the longest diameter. Treatment assignment is blinded to limit potential for bias during data acquisition or analysis. Image guided radiation treatment is initiated 3-7 days depending on PARPi penetrance as determine above and to assess the efficacy of the PARPi alone. XRT is given in 5 (or as determined in the safety study) daily doses of 6 Gy. The primary endpoint is comparison of tumor growth during therapy and tumor burden at experimental termination.
  • Fig. 6 illustrate coronal and semi-transparent 3D view respectively through a live mouse with tumor in virtual in vivo CT slices.
  • 6C illustrates schematic of mouse tumor irradiation using image guided techniques on SARRP Xstrahl research platform.
  • the absolute dosimetry is independently verified.
  • Image-guided techniques improve the translational potential of these studies.
  • a preliminary 3-7-day time point for pretreatment prior to radiation has been deemed optimal to reflect tumor growth and the ability to measure difference based on initial data. Timing of radiation is changed if experimental data suggest that shorter or longer PARPi pre-treatments or multiple radiation therapy time points are needed.
  • mice are euthanized, major organs, blood, and tumor collected, processed and drug concentrations are quantified.
  • Half of the tumors are processed for drug penetration and the other half for biomarker modulation (e.g., reduced RAD51 foci induction; Fig. 3); Ki67 down regulation; caspase cleavage and TUNEL staining).
  • biomarker modulation e.g., reduced RAD51 foci induction; Fig. 3
  • Ki67 down regulation e.g., reduced RAD51 foci induction; Fig. 3
  • caspase cleavage and TUNEL staining e.g., reduced RAD51 foci induction; Fig. 3
  • Ki67 down regulation caspase cleavage and TUNEL staining
  • PK quantification drug is extracted from tissues by protein precipitation and quantified using validated LC-MS/MS method. Additionally, tumor is flash frozen and embedded in gelatin for sectioning and MALDI-mass spectrometry imaging (MSI).
  • the effect size of 2.7 is adequate when comparing combination treatments with PARPi to PARPi alone, and more than adequate to show statistically significant pairwise differences between PARPi alone (mean of 1.3) and control (mean of 10 with common SD: 0.45) resulting in an effect size of 16.
  • Tumor volume is log-transformed.
  • An independent two-sample independent t-test is used for pair-wise comparisons between interventions of log transformed tumor- volume.
  • BRCA2 in the PC3 prostate cancer cell line model has been dysregulated and shown these cells were more sensitive to carboplatin and PARPi. Initial experiments further showed that these cell lines grew as xenografts rendering the PC3 studies feasible. Loss of BRCA function through CRISPR-Cas9 engineering can be established for BRCA1 and ATM in PC3 and DU 145. An alternate CRISPR approach (dCAS9-CRISPR interference or CRISPRi) can be used. Tumor penetrance and insertion modalities have been established in preliminary studies and implants are radiation therapy inert. Implanting the drug eluting seed can give a broader understanding of drug distribution from an implant across a tumor.
  • the most potent formulation can be used to validate the mechanism of action, including mutation setting and distribution properties. Other formulations can be tested if drug distribution is poor, or release is too slow.
  • This example can provide insights into drug distribution and XRT efficacy in a tumor.
  • Another major goal of this example is to define whether PARPi can potentiate XRT and in which setting (e.g., HR proficient, BRCA1/2- and ATM- mutated, CHEK2 if feasible).
  • rats and canine prostates are implanted with a single drug-eluting (silicone, TPU or EVA) implant in each lobe (2 implants per animal). Drug implants have been shown to be safely placed (Fig. 7). Fig.
  • FIG. 7A illustrates location of implantation in rat prostate lobes.
  • Fig. 7B illustrates a five millimeter implant into a rat prostate.
  • Fig. 7C illustrates surgical implantation of a drug implant described herein into a dog prostate by laparotomy. Two 18 gauge needles were used to insert two 15 mm x 1 mm implant in both prostate lobes from a ventro-cranial approach with transrectal ultrasound confirmation of implant placement.
  • Rat and canine prostate models are used to determine safety, toxicity and PK/PD of the lead PARPi implants.
  • the optimized lead implant are expected to have a high initial burst, and then to deliver therapeutic PARPi levels for > 12m.
  • Rat studies can assess safety and drug biodistribution of PARPi-eluting implant formulations at short- and long-term intervals.
  • the primary goal is to identify a lead formulation for use in IND- enabling canine GLP safety /toxicity and PK studies for clinical translation.
  • feasibility studies are performed in rats with the four lead formulations identified in Example 6.
  • the rat model is conducted to reduce the number of experiments to be performed in a larger canine model to avoid unnecessary and costly usage of canines.
  • N 6 for each time point).
  • Implants are placed in each of the ventral prostrate lobes of sexually mature naive Sprague-Dawley rats (>6 months in age) via an open abdominal approach using an 18G needle to ascertain easy placement and assurance that implants stay in situ.
  • the ventral prostate lobes measure -0.5-1 g, with -7 mm diameter and are easily accessed via an open laparotomy to fit an implant segment 3 mm in length (Fig. 7).
  • N 60 rats are needed for this study.
  • Plasma is collected throughout the study (0, 1, 2, 3, 7, 14, 28, 42 and 56 days) and tissue samples from prostate and off-target organs are collected at necropsy and analyzed for PARPi levels. Additionally, histopathology are assessed from formalin fixed paraffin-embedded tissue sections to evaluate implant related tissue reactions and toxicities. An LC-MS/MS method is developed and qualified prior to use for sample analysis. Drug levels in plasma at different timepoints over 14 days and in the prostate (collected at necropsy) for the PARPi formulation implants is compared to that from orally administered PARPi.
  • Implants are also recovered at necropsy for extraction and analysis of remaining drug amount via an existing HPLC method and back-estimation of the in vivo drug elution profile.
  • At least one prostate section in each group is flash frozen and embedded in gelatin for sectioning and MALDI-mass spectrometry imaging (MSI; contracted through ImaBiotech).
  • MSI MALDI-mass spectrometry imaging
  • Tissue sections are imaged for drug distribution at 80 pM spatial resolution using a Bruker 7T FTICR-HR-MALDI MSI system. Image acquisition and quantification is carried out using Multimaging QMSI software.
  • MSI is overlaid with H&E-stained sections for anatomical referencing and correlated molecular biomarker IHC analysis. Together these results form a topographic representation of prostate drug distribution and action.
  • the data collected is used to demonstrate feasibility of using the rat model for longer term studies by establishing that the PARPi seed implants: (i) are well tolerated by prostate tissue and are not toxic to surrounding tissue; (ii) show PARPi levels in vivo that compare favorably with those achieved by oral administration; and (iii) show an in vivo PARPi elution profile that anticipates favorable translation to canines.
  • Two PARPi implant formulations that best meet these criteria are chosen for further long term rat study. Descriptive statistics are provided at each scheduled sampling time point for drug concentration and tissue response: number of rats, mean, SD, CV, geometric mean (where applicable), median, minimum, and maximum.
  • the concentrationtime profiles is estimated for all evaluable rats can on the actual sampling times in all computations involving sampling times.
  • the PK Analyses are performed using 6 cohorts including Cmax (maximum concentration), T ma x (Time at which Cma occurred), ti/2 (elimination half-life), AUCo-t (Area under the concentration-time curve) and AUCo-inf.
  • Cmax maximum concentration
  • T ma x Time at which Cma occurred
  • ti/2 elimination half-life
  • AUCo-t Re under the concentration-time curve
  • AUCo-inf AUCo-inf
  • the descriptive statistics are provided at each scheduled timepoint for drug concentration and tissue response: number of rats, mean, SD, CV, geometric mean (where applicable), median, minimum, and maximum.
  • the plasma concentration-time profiles are estimated for all evaluable rats based on the actual sampling times.
  • Statistical Analyses include: (i) tissue and plasma samples for determining PARPi levels; (ii) toxicity in other major organs; (iii) PARPi effects on proliferation in prostate tissue; (iv) drug distribution by MSI; and (v) measurement of residual drug in the implants.
  • the implants are removed, and residual drug concentration are measured to determine which implant formulation is most likely to provide a projected 2-year in vivo release profile.
  • Optimized PARPi-eluting implant developed in Example 6 and down selected to the final lead implant and study its safety, local and systemic toxicity, and PARPi tissue distribution profile in a canine prostate model in preparation for IND enable GLP studies are examined.
  • This model has been chosen based on the robustness to predict prcclinical release rate across different studies and its translatability to clinical findings. They are implanted into the two lobes of the prostate of 3 male purpose-bred canine mongrel each for an 8- and 24-week study.
  • Canines are monitored continuously to assess the procedural implant safety, adverse effects while carrying the implant, impact on spermatogenesis, and drug biodistribution in the prostate and other major organs in an implant.
  • This canine experiment including implantation, housing, and care as well as subsequent tissue collection are carried out.
  • the study is conducted under an IACUC approved protocol.
  • To minimize the use of suboptimal implants a full analysis of implants for short- and long-term placements is conducted in rats with full PK characterization and correlation of the biodistribution in the prostate with drugs levels remaining in the explanted implants.
  • the extensive in vitro elution profiles and the long-term rat studies allows a two time point abbreviated study.
  • the 8-week time point mimics the time point when men are expected to receive radiation therapy after the neoadjuvant hormonal therapy, and the 24-week time coincides with the end of the hormonal therapy (hormonal may be given for 2 years but is not easily tolerable).
  • Implant dimensions are limited to 18-gauge needle/catheter delivery. Implants fit within a brachytherapy needle and are placeable using a transperineal approach. Dogs can undergo laparotomy under general anesthesia. A brachytherapy needle is inserted from the cranial toward the caudal end of the prostate and a single implant (1.5 cm 1 mm) is implanted into the glandular region of each prostatic lobe.
  • the drug implant delivery steady state is reached at 8 weeks which is verified in the rat studies.
  • blood for plasma PK is collected at 2, 24, and 48 hours for PARPi levels and compared to prostate and off-target tissue levels at necropsy by LC-MS and analyzed as described in this example.
  • LC-MS LC-MS
  • a more in-depth analysis of prostate to evaluate drug distribution across the prostate is done by mass spectrometry imaging.
  • the prostate is sectioned into slices and drug distribution correlated with findings from histopathology to map histological changes to PARPi tissue levels.
  • MSI of canine and rat study prostates help define the spacing and number of implants required to achieve therapeutic levels across the tumor and remaining prostate. This implant is inserted via an 18-gauge biopsy needle and visualized by ultrasound and MRI, the same gauge used for routine prostate screening and brachytherapy seed delivery, supporting the feasibility of multiple implants and its adoption in the clinic.

Landscapes

  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des implants médicamenteux comprenant du Talazoparib pour le traitement d'une maladie chez un patient. Dans certains cas, l'implant médicamenteux peut comprendre une matrice polymère et du Talazoparib contenu par celle-ci. De plus, l'invention concerne des procédés de fabrication des implants médicamenteux et des méthodes de traitement de maladies avec les implants. Dans certains cas, les implant médicamenteux peuvent être utilisés pour le traitement d'une maladie proliférative.
PCT/US2024/060761 2023-12-19 2024-12-18 Implants médicamenteux contenant du talazoparib et méthodes d'utilisation associées Pending WO2025137096A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363612036P 2023-12-19 2023-12-19
US63/612,036 2023-12-19

Publications (1)

Publication Number Publication Date
WO2025137096A1 true WO2025137096A1 (fr) 2025-06-26

Family

ID=96137942

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/060761 Pending WO2025137096A1 (fr) 2023-12-19 2024-12-18 Implants médicamenteux contenant du talazoparib et méthodes d'utilisation associées

Country Status (1)

Country Link
WO (1) WO2025137096A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190300525A1 (en) * 2018-03-29 2019-10-03 Oncoarendi Therapeutics S.A. Dipeptide piperidine derivatives
US20230139842A1 (en) * 2017-11-09 2023-05-04 The Board Of Regents Of The University Of Oklahoma Nanocrystal microparticles of poorly soluble drugs and methods of production and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230139842A1 (en) * 2017-11-09 2023-05-04 The Board Of Regents Of The University Of Oklahoma Nanocrystal microparticles of poorly soluble drugs and methods of production and use thereof
US20190300525A1 (en) * 2018-03-29 2019-10-03 Oncoarendi Therapeutics S.A. Dipeptide piperidine derivatives

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Implantable Drug-Eluting Devices: A Novel Approach to Patient Care", LUBRIZOL LIFESCIENCES, 1 March 2016 (2016-03-01), pages 1 - 12, XP093331726, Retrieved from the Internet <URL:https://www.pharmaexcipients.com/wp-content/uploads/attachments/Implantable+Drug-Eluting+Devices.pdf?t=1485119925> *
BELZ JODI, KUMAR RAJIV, BALDWIN PAIGE, OJO NOELLE, LEAL ANA, ROYCE DARLENE, ZHANG, VAN DE VEN ANNE L., LIBY KAREN, SRIDHAR SRINIVA: "Sustained Release Talazoparib Implants for Localized Treatment ofBRCA1-deficient Breast Cancer", THERANOSTICS, vol. 7, no. 17, 26 September 2017 (2017-09-26), AU , pages 4340 - 4349, XP009554622, ISSN: 1838-7640, DOI: 10.7150/thno.18563 *
SOBCZAK MARCIN, KEDRA KAROLINA: "Biomedical Polyurethanes for Anti-Cancer Drug Delivery Systems: A Brief, Comprehensive Review", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 23, no. 15, 1 January 2022 (2022-01-01), Basel, CH , pages 1 - 18, XP093331721, ISSN: 1422-0067, DOI: 10.3390/ijms23158181 *
ZHANG DI, SINGH BIJAY, MOERLAND JESSICA, MITCHELL OWEN, LOCKWOOD LIZBETH, CARAPELLUCCI SARAH, SRIDHAR SRINIVAS, LIBY KAREN T.: "Sustained, local delivery of the PARP inhibitor talazoparib prevents the development of mammary gland hyperplasia in Brca1-deficient mice", SCIENTIFIC REPORTS, vol. 11, no. 1, 1 January 2021 (2021-01-01), US , pages 1 - 10, XP093331728, ISSN: 2045-2322, DOI: 10.1038/s41598-020-79663-7 *

Similar Documents

Publication Publication Date Title
Patel et al. Effect of injection site on in situ implant formation and drug release in vivo
RU2510263C2 (ru) Способы и композиции, содержащие клонидин, предназначенные для лечения послеоперационной боли
JP4584331B2 (ja) オクトレオチドの放出制御製剤
CN113633609B (zh) 抗寄生虫药物原位固化缓释注射剂及其制备方法
US20230255883A1 (en) Drug implants containing enzalutamide and methods of use thereof
WO2025137096A1 (fr) Implants médicamenteux contenant du talazoparib et méthodes d&#39;utilisation associées
CN101001640A (zh) 缓释组合物
US11338119B2 (en) Implantable drug delivery devices for localized drug delivery
US11344526B2 (en) Implantable drug delivery devices for localized drug delivery
US11173291B2 (en) Implantable drug delivery devices for localized drug delivery
JP7665645B2 (ja) 局所的な薬物送達のための移植可能な薬物送達デバイス
US20240033249A1 (en) Drug Implants Containing Darolutamide and Methods of Use Thereof
US20240016731A1 (en) Drug Implants Containing Apalutamide and Methods of Use Thereof
WO2025230428A1 (fr) Forme pharmaceutique de bolus à libération prolongée
WO2021207806A1 (fr) Implant sous-cutané réabsorbable de longue durée à libération contrôlée de substance pharmacologiquement active pré-concentrée en polymère pour le traitement de l&#39;endométriose

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24908824

Country of ref document: EP

Kind code of ref document: A1