Long-acting anticancer compositions

Abstract

The present invention relates generally to stable anti-cancer formulations.

Description

Invention Field

[0001] This invention relates to long-acting anticancer compositions. Background of the Invention

[0002] Cancer is a complex group of more than one hundred diseases characterized by their ability to invade adjacent tissues and spread throughout the body. Cancer is the second leading cause of death in the United States, where more than 9 million people live with cancer. Solid tumors account for more than 70% of new cancer diagnoses each year, or more than 1.75 million cases in the Western world.

[0003] Solid tumors are typically treated as both local and systemic diseases, with the tumor being surgically removed and / or ablated by irradiation or local heating or cryoablation. This may be followed by systemic chemotherapy. Standard chemotherapy is a systemic treatment administered via intravenous injection or oral administration, intended to kill tumor cells that may have spread locally or to new sites throughout the body.

[0004] In cancer patients, gastrointestinal and airway obstruction leads to severe difficulty eating and breathing. In many cases, stent placement can alleviate these symptoms. Maintaining stent patency is a factor affecting quality of life, but it is not without a high rate of complexity and risk. Patients are often largely pre-treated at the time of obstruction, but poor nutritional status makes it difficult to tolerate standard doses of systemic chemotherapy. Local delivery of high concentrations of anticancer drugs can prevent regrowth, but can lead to stent occlusion.

[0005] Although solid tumors are treated as localized diseases (surgery, irradiation, ablation), there is no such thing as local chemotherapy: local chemotherapy delivers a high dose of anticancer agent at the tumor site for a prolonged period of time with low systemic distribution. Local doses reaching concentrations up to 100 times higher than the maximum concentration achievable through systemic chemotherapy (without risk to the patient) can be used as an alternative to or supplement to surgery, irradiation, and systemic chemotherapy. Since most solid tumors are accessible via current biopsy techniques, local delivery systems that release effective doses of one or more anticancer agents can be used for several weeks to reduce tumor size preoperatively or to supplement postoperative eradication of remaining tumor cells in the tumor bed, as well as to treat inoperable solid tumors.

[0006] Clinical formulations for the treatment of head and neck cancer have been developed. IntraDose® injectable gel is an aqueous collagen solution containing cisplatin and epinephrine for recurrent squamous cell carcinoma of the head and neck, and OncoGel PLA-PEG is an aqueous solution loaded with paclitaxel for esophageal cancer. These systems, developed by MacroMed (Re-Gel) and Access Pharmaceuticals, failed in clinical trials due to toxicity and lack of efficacy due to drug clearance from the aqueous carrier shortly after injection into tissues. OncoGel™ (paclitaxel from Re-Gel, an injectable solution of a PEG-PLA copolymer gelled at body temperature in water at <20°C) has been in clinical development for several years. When the formulation gels, the drug leaches out with water, and only a small amount of residue is used for controlled release. In clinical studies, OncoGel did not show any effect on the primary endpoint of overall tumor response in a Phase IIb study that explored the use of OncoGel as a neoadjuvant therapy prior to surgery in patients with esophageal cancer, in addition to standard chemotherapy and radiotherapy. Follow-up studies of secondary outcome measures of patient survival have been discontinued because the expected impact may not exist.

[0007] Little has been done in developing safe and effective intratumoral extended lesion delivery of anticancer agents for the treatment of solid tumors. Key to a successful delivery system is a polymer carrier with predictable and reproducible molecular weight; predictable and controlled polydispersity, viscosity, and injectability (if designed as an injectable formulation and made from naturally metabolized and eliminated components); predictable and reproducible controlled release of the incorporated drug over a desired timeframe from one to eight weeks with minimal burst release to avoid toxic blood levels; no or tolerable toxicity at the injection site and in vivo; complete degradation to naturally occurring metabolic products and elimination from the body shortly after drug depletion; simple drug incorporation with little or no use of heat, shear forces, toxic solvents, aqueous media that may prematurely degrade the polymer carrier or affect the active agent; a process that does not require special equipment; and storage stability of the polymer and polymer-drug formulation for several months at refrigeration or room temperature.

[0008] Due to their surface-eroding properties, polyanhydrides have been investigated as carriers for controlled delivery of several drugs. Polyanhydrides are inherently highly reactive to water, leading to rapid hydrolytic degradation. Due to the high hydrolysis rate, polyanhydrides undergo surface erosion rather than bulk degradation. Gliadel wafer, an approved polyanhydride copolymer of carboxyphenoxypropane and sebacic acid, is a bioabsorbable pharmaceutical implant for delivering the anticancer agent carmustine to brain tumor sites. Polyanhydride-based particles have been extensively studied in many formulations for effective drug delivery. However, only one type of polyanhydride product is currently available on the market, compared to dozens of polyester products. Although polyanhydrides are easy to synthesize and scale up at low cost, they exhibit short shelf lives under common storage conditions. Polyanhydrides are prone to hydrolytic degradation and depolymerization via anhydride exchange during storage, and may therefore be generated along with decomposition products. Therefore, polyanhydrides need to be kept under frozen storage conditions, which limits their use in drug delivery products. Therefore, the availability of polyanhydride products in the medical field (e.g., drug carriers) is not very attractive. One such example of a stable polyanhydride is the poly(ester-anhydride) based on ricinoleic acid and sebacic acid reported in [1-3].

[0009] References

[0010] [1] US 10,774,176

[0011] [2] US 2020 / 0101163

[0012] [3] Domb et al., 2017, J of Controlled Release, 257, 156-162. Invention Overview

[0013] This invention describes a unique anticancer composition based on a biodegradable and biocompatible polymer. The polymeric anticancer agent can be injected or inserted into tissue via a needle or cannula. It then gels upon contact with bodily fluids to form a reservoir implant that releases the drug at the tumor site in a controlled manner over a period of several weeks. The delivery system provides a high local concentration of the anticancer drug, which destroys malignant cells that may survive surgery, thus preventing the regrowth and metastasis of solid tumors. The reservoir polymer implant provides extended release of the loaded drug over a period of several weeks with minimal systemic drug distribution, thus offering a safer and more effective alternative to standard systemic chemotherapy.

[0014] The polymer formulation of the present invention is based on a polyanhydride that exhibits improved properties compared to those previously disclosed in the art. The polyanhydride has the form -(SA-RA)n-, where SA is sebacic acid and RA is ricinoleic acid, and where n is an integer between 10 and 100. Prepared by melt condensation of SA and RA in a molar equivalent or less of acetic anhydride per carboxylic acid group and in the absence of a solvent, the polyanhydride is a narrowly polydisperse polymer. This polyanhydride is referred to herein as... The polymer of the present invention or The carrier of the present invention .

[0015] The absence of solvents and the sequential addition of multiple precursors allows for the production of a final product that is well-characterized and reproducible, meets the highest regulatory standards, and exhibits narrow polydispersity. When referring to the polymers of this invention, the term "..." Narrow polydispersity "" or any of its linguistic variations defines a set of materials having substantially the same composition (type and manner of repeating groups) and molecular weight. The narrow polydispersity of the polymers of the present invention, defined by the ratio Mw / Mn (where Mw is the weight-average molecular weight and Mn is the number-average molecular weight), is less than 2.5 or less than 2. In other words, the narrowly dispersed or narrowly polydisperse polymers of the present invention have a polydispersity value no greater than 2.5 or 2 (or a value between 2.5 and 1 or between 2 and 1).

[0016] The polymers of the present invention also exhibit high reproducibility, that is, reproducibility of polymer molecular weights with a deviation from the average molecular weight of the polymer of no more than 30%.

[0017] the term" In the absence of solvent "This refers to the nature of the process of the present invention when there is no solvent or a trace amount of solvent (which may originate from impurities present in the precursor materials). Such impurities will not exceed 0.001%, 0.005%, 0.01%, 0.05%, or 0.1% (w / w) of the total weight of the reaction materials used."

[0018] The polymer of the present invention is prepared by a process comprising the following steps:

[0019] Sebacic acid (SA) and ricinoleic acid (RA) are reacted under conditions that allow for the esterification of SA (to obtain a monoester or diester of SA or a mixture thereof); and

[0020] Esterified SA (monoester or diester or a mixture thereof) is converted into narrowly polydisperse polyanhydrides.

[0021] The process of this invention allows for direct condensation in the bulk (in the melt) without pre-reaction to form a polymer or oligomer of any of the material precursors used. In an exemplary process, sebacic acid (SA) (a dicarboxylic acid) reacts with ricinoleic acid (RA) (a hydroxy-alkyl acid) at a ratio of 30:70 w / w to form a mixture of SA-RA dimers and RA-SA-RA trimers, having minimal or no RA or RA-RA ester molecules in the reaction product. Subsequently, the SA-RA and RA-SA-RA mixture (containing no precursor molecules and RA-RA molecules) is treated with no more than one molar equivalent of acetic anhydride per free carboxylic acid group (typically two free carboxylic acid groups, and therefore no more than two molar equivalents) to acetylate the free esters, and the acetylated segments are then polymerized into a narrowly dispersed polyanhydride having a repeating …RA-SA-RA-SA… sequence. This process… Figure 1 Described in the text.

[0022] Mixtures of dimers and trimers of SA and RA can be used to form heterogeneous polymers consisting of anhydride and ester bonds between SA and RA, and minimal ester bonds between two RA units. On the other hand, the formation of anhydride dimers of SA monomers along the polymer chain may limit the storage stability of the polymer. Therefore, in the process of the present invention, the molar ratio between SA and RA is generally equal or biased towards RA. In other words, the amount of RA is preferably equal to the amount of SA or twice the amount of SA (1:1 to 1:2 molar equivalents). In some embodiments, the weight ratios SA:RA are 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, and 1:2, respectively.

[0023] In some embodiments, the molar ratio between SA:RA is in the range of 1:1 and 1:2, respectively, to avoid the formation of ester bonds between RA units, such that the polymer contains only anhydride bonds and ester bonds between SA and RA.

[0024] In some implementations, the weight ratio of the SA structural unit to the RA structural unit is 30:70, 35:65, or 25:75, respectively.

[0025] Excess RA allows for both monoesterification and diesterization of SA (with a certain amount of monoesterified form) and avoids the formation of RA ester dimers. SA-RA and RA-SA-RA mixtures (referred to as "SA-RA and RA-SA-RA mixtures in this document") Dimer-trimer mixtureThe mixture of SA and RA in the indicated proportions is obtained by heating at a temperature above 80°C. In some embodiments, the temperature is between 80°C and 200°C, between 100°C and 190°C, between 100°C and 180°C, between 100°C and 170°C, between 100°C and 160°C, between 100°C and 150°C, between 100°C and 140°C, between 100°C and 130°C, or between 100°C and 120°C.

[0026] The condensation of the two components involves direct ester condensation to provide a mixture of dimer-trimer dicarboxylic acid oligomers. The dimer-trimer oligomers are polymerized into polyanhydrides by activating the carboxylic acid ends with acetic anhydride. The amount of acetic anhydride used is no greater than one molar equivalent of acetic anhydride for each free carboxylic acid group in the oligomer. The dimer SA-RA has two free carboxylic acid groups. Similarly, the trimer RA-SA-RA has two free carboxylic acid groups. Therefore, no more than 2 molar equivalents of acetic anhydride can be used. In some embodiments, the amount of acetic anhydride is 2 molar equivalents, 1.9 molar equivalents, 1.8 molar equivalents, 1.7 molar equivalents, 1.6 molar equivalents, 1.5 molar equivalents, 1.4 molar equivalents, or 1.3 molar equivalents.

[0027] In some embodiments, the acetylation step can be carried out at temperatures above 40°C. In some embodiments, the acetylation temperature is between 40°C and the boiling point of acetic anhydride. In some embodiments, the acetylation temperature is between 40°C and 90°C, between 40°C and 100°C, between 40°C and 110°C, or between 80°C and the boiling point of the acylated anhydride. The temperature used for the acylation-activation of the oligomer is a function of time; the longer the reaction time, the lower the temperature applied. The diacid oligomer can be reacted with acetic anhydride under pressure to accelerate the reaction, or the reaction can be carried out under microwave heating. These methods require adjustment of the reaction conditions so that the oligomer is acetylated without deterioration. Furthermore, other acetylation methods can be applied, including the reaction with acetyl chloride using an acid-scavenging agent.

[0028] The temperature can be increased after acetylation to condense the acetylated precursor to form the dimer / trimer mixture mentioned above.

[0029] The conversion to the narrowly polydisperse polymers of the present invention is achieved through polymerization. The polymerization of dimer-trimer mixtures into the polymers of the present invention can be achieved by heating the acetylated dimers and trimers at low pressure and high temperature. In some embodiments, polymerization can be carried out under vacuum and heating. The thermal conditions may involve heating the acetylated dimer-trimer mixture to temperatures between 100°C and 200°C, between 100°C and 190°C, between 100°C and 180°C, between 130°C and 170°C, between 130°C and 160°C, between 130°C and 150°C, or between 130°C and 140°C. In some embodiments, the temperature is between 120°C and 170°C or between 130°C and 160°C. Reaction time is an important parameter because the higher the reaction temperature, the shorter the reaction time. There exists a minimum time required to form oligomers and polymers; longer reaction times have no or minimal effect on the oligomer composition or polymer molecular weight. The reaction time depends on the batch size and reaction conditions, including the mixing method and the applied rate and vacuum profile.

[0030] In some implementations, polymerization can be carried out under vacuum under high-temperature conditions as specified.

[0031] In some implementations, the process includes:

[0032] SA and RA are reacted at temperatures between 80°C and 200°C to obtain a mixture of SA monoesters (SA-RA) and diesters (RA-SA-RA); and

[0033] The mixture is reacted with acetic anhydride under conditions that allow the monoesters and diesters to polymerize into polyanhydrides.

[0034] In some implementations, the process includes:

[0035] SA and RA are reacted at temperatures between 80°C and 200°C to obtain a mixture of SA monoesters (SA-RA) and diesters (RA-SA-RA); and

[0036] React the mixture with acetic anhydride to acetylate the mixture of monoesters and diesters; and

[0037] The acetylated mixture was heat-treated under conditions that allowed polymerization into polyanhydrides.

[0038] In some implementations, the process includes:

[0039] SA and RA were reacted in the presence of acetic anhydride at temperatures between 80°C and 200°C to obtain a mixture of monoesters and diesters of SA, as described herein; and

[0040] The acetylated mixture is heat-treated in a vacuum at temperatures between 100°C and 200°C, allowing polymerization to provide polyanhydrides.

[0041] Therefore, the polymers of the present invention are polyanhydrides, wherein mixtures or dimer dicarboxylic acids and trimer dicarboxylic acids are linked to the chain via anhydride bonds. The process of the present invention does not include a process for producing polydisperse polyanhydrides. The process of the present invention does not involve the steps of forming or utilizing polymers or oligomers derived from (consisting of SA) or derived from (consisting of RA). One such process is one utilizing SA and RA and disclosed in publications [1-3]. The polymers of the present invention are the subject of co-pending U.S. Patent Application No. 63 / 062,563 and any co-pending applications claiming priority thereto, each of which is incorporated herein by reference.

[0042] Therefore, the carrier is prepared in all its embodiments by methods or processes as described herein, wherein the methods or processes or preparation do not include the use of polysaccharide.

[0043] The present invention also provides a carrier as defined herein for use in the manufacture of an anticancer formulation comprising an anticancer agent. Use of the carrier or anticancer agent in the preparation of the formulation is also provided.

[0044] The highly reproducible batch-to-batch polymer molecular weight provides improved reproducible viscosity, allowing for predictable injectability; highly reproducible composition and drug release profiles; and predictable, manageable polymer degradation rates with narrow standard deviations; and high purity (minimal or no reactant impurities of acetic anhydride and acid anhydride molecules). The polymers of this invention are superior to those discussed in the art. Therefore, the availability of the polyanhydrides of this invention in the medical field, for example as drug carriers, opens the door to a new generation of drug carriers.

[0045] Therefore, in a first aspect, an anticancer formulation comprising the polymer of the present invention (as defined or as prepared) and at least one anticancer agent is provided.

[0046] The anticancer agent comprises at least one anticancer agent and a carrier in the form of a polyanhydride including sebacic acid (SA) and ricinoleic acid (RA), said carrier having an Mw / Mn value between 1 and 2.5. In some embodiments, the carrier is a polyanhydride of the formula -(SA-RA)n-, where n is an integer between 10 and 100. In some embodiments, the polyanhydride is prepared by: a. melt condensation of SA and RA to form a dicarboxylic acid oligomer; b. activation of the oligomer using acetic anhydride; c. melt polycondensation to form the polyanhydride. Oligomer activation can be carried out in the absence of a solvent in the presence of one molar equivalent or less of acetic anhydride per carboxylic acid group.

[0047] As used in this article, the term " preparation "" refers to a pharmaceutical-grade formulation or composition comprising at least one anticancer agent and a carrier comprising or composed of the polymer of the present invention. In some embodiments where the nature of the formulation of the present invention is to be altered, the carrier used may include other acceptable carriers besides the polymer of the present invention, such as, for example, mediators, excipients, excipients, or diluents. The selection of an additional carrier besides the polymer of the present invention will be determined in part by the specific anticancer agent, and by the specific method of administration of the composition and the specific form of the formulation.

[0048] The anticancer agent comprises an anticancer agent and a carrier in the form of a polyanhydride of the formula -(SA-RA)n-, wherein SA is sebacic acid and RA is ricinoleic acid, and wherein n is an integer between 10 and 100, and the carrier has a Mw / Mn value of less than 2.5 or less than 2 (where Mw is the weight-average molecular weight and Mn is the number-average molecular weight) or a value between 1 and 2.5 or between 1 and 2.

[0049] In some embodiments, the polyanhydride is prepared in the absence of a solvent by melt condensation of SA and RA with one molar equivalent or less of acetic anhydride per carboxylic acid group. In other words, the polyanhydride is not prepared by a process involving polymerization using a solvent or either RA or SA alone.

[0050] The present invention also provides the use of a carrier in the form of a polyanhydride of the formula -(SA-RA)n- for the preparation of an anticancer formulation comprising at least one anticancer agent, wherein SA is sebacic acid and RA is ricinoleic acid, and wherein n is an integer between 10 and 100, the carrier having a Mw / Mn value of less than 2.5 or less than 2 (where Mw is weight-average molecular weight and Mn is number-average molecular weight) or a value between 1 and 2.5 or between 1 and 2.

[0051] In addition, an anticancer agent is provided for the preparation of an anticancer formulation comprising an anticancer agent and a carrier in the form of a polyanhydride of the formula -(SA-RA)n-, wherein SA is sebacic acid and RA is ricinoleic acid, and wherein n is an integer between 10 and 100, said carrier having a Mw / Mn value of less than 2.5 or less than 2 (where Mw is weight-average molecular weight and Mn is number-average molecular weight) or a value between 1 and 2.5 or between 1 and 2.

[0052] The formulations of the present invention can be formed as implantable or injectable formulations. Implantable formulations can be in the form of a gel or a flowable formulation that semi-solidifies upon contact with tissue by absorbing water to form an organic gel. Injectable polymer formulations form a highly viscous implant that remains in the injection site and gradually degrades and is removed therefrom. In some embodiments, the injectable formulation is contained in a syringe and delivered, for example, using a 23G syringe.

[0053] Formulations of the present invention, comprising an anticancer agent and the polymer of the present invention, can be formed in a variety of ways. In some cases, the formulation is formed by mixing the polymer of the present invention as defined with at least one anticancer agent. In such cases, a measurable dose-sized amount of the anticancer agent is mixed with an appropriate amount of the polymer to obtain a homogeneous formulation. In other cases, the formulation is formed by mixing the anticancer agent with a polymer precursor during the preparation of the polymer.

[0054] Regardless of the preparation method of the formulation of the present invention, the mixture of polymer and anticancer agent, in the form of a paste, can be loaded into a syringe, sealed in a bag, and sterilized by gamma irradiation. When used for intratumoral delivery, such as by injection, the polymer formulation increases its viscosity in the tissue due to its interaction with the tissue's aqueous environment. The anticancer agent is released into the surrounding tissue in a desired controlled manner, while the polymer implant slowly degrades and is eliminated from the body shortly after the drug has been depleted.

[0055] In some embodiments, the formulation of the present invention can be implanted into the body of a subject, for example, by introducing it into the tumor site after surgical removal of the tumor, or by injecting it directly into the tumor site via a needle or via minimally invasive laparoscopic surgery.

[0056] Generally, the formulations of the present invention can be formulated as controlled-release formulations when injected into the cancer site, particularly within the tumor, and sustained for several weeks, while safely degrading and being eliminated from the body. The term "..." Controlled delivery "In its broadest sense, the term is used herein to refer to a formulation by which an anticancer agent is modulated from the formulation and permeated through tissues, its accessibility and bioavailability in tissues and blood circulation, and / or targeted to a specific tissue of action to achieve a specific effect over time. Controlled delivery encompasses immediate delivery, prolonged delivery, and sustained delivery of the anticancer agent, drug protection against degradation, preferential metabolism, clearance, or delivery to a specific tissue. Controlled release of the anticancer agent contained in the formulations of the present invention can be achieved by several means as known in the art."

[0057] Typically, the formulations of the present invention are configured as extended delivery formulations or continuous delivery formulations.

[0058] the term" Extended delivery"This implies a delayed penetration and / or release of the anticancer agent from the formulation and into the tissue. In other words, in extended delivery, after the lag period, and in this case, at least approximately 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, or 180 minutes after administration, and also at least approximately 3, 4, 5, 6, 7, 8, 9, 10 hours or longer after administration, the agent can be detected or measured in the tissue or circulation. Extended delivery also applies to target organs and tissues, with the agent being detectable or measurable in the tissue or circulation at least approximately 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, or 140 minutes after administration." min, 150 min, 160 min, 170 min, 180 min, and additional lags of at least approximately 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h or longer after administration.

[0059] the term" Continuous delivery "This refers to the sustained release and / or penetration of the agent from the formulation into the tissues or circulation, or in other words, the release and / or penetration of the agent from the formulation into the tissues or circulation at least approximately 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, or 180 minutes after administration, and at least approximately 3, 4, 5, 6, 7, 8, 9, or 10 hours after administration, or longer, reaching a plateau or stable state, and the plateau or stable state persisting for at least approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 hours after administration." h, 19 h, 20 h or longer.

[0060] Anticancer agents can be any cytotoxic agent, protein- or nucleotide-based biological drug used to treat cancer. As is known in the art, cancer"Malignancy refers to any malignant condition, that is, a serious and progressively worsening disease that may pose a fatal threat to the suffering subject. Malignancy, such as malignant growths and malignant tumors, is used synonymously with cancer and is also a prefix for other oncology terms such as malignant ascites and malignant transformation."

[0061] When used to combat or manage malignant proliferative diseases or disorders (such as cancer), the anticancer agents presented in this article can be used to treat a broad spectrum of cancers (proliferative disorders), such as blastoma, carcinoma, lymphoma, leukemia, sarcoma, mesothelioma, glioma, germ cell tumor, choriocarcinoma, melanoma, glioblastoma, colorectal malignancies, head and neck malignancies, GI malignancies, and lymphomas, as well as any other proliferative diseases or disorders, which are collectively referred to as cancer. Other examples of cancers that can be treated using compounds according to some embodiments of the present invention include, but are not limited to, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer or uterine cancer, salivary gland cancer, kidney cancer or kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatic carcinoma, anal cancer, penile cancer, and head and neck cancer.

[0062] In some embodiments, the formulations of the present invention are used to manage solid cancers. Solid cancers occur in many forms, such as brain cancer, breast cancer, prostate cancer, head and neck sarcoma, and skin cancer. One form of skin cancer is melanoma. Melanoma is the most aggressive form of skin cancer and is well known to be resistant to current cancer treatment modalities.

[0063] The anticancer agents used according to the present invention can be general anticancer agents or anticancer agents specifically designed to treat or prevent specific types of cancer. Anticancer agents can be selected from cytotoxic agents, chemotherapeutic agents such as alkylating agents, intercalating drugs, topoisomerase inhibitors, antimetabolites and antimitotic drugs, as well as kinase inhibitors, monoclonal antibiotics, and others.

[0064] Non-limiting examples of anticancer agents include alkylating agents such as hexamethylmelamine, bendamustine, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, nitrogen mustard, melphalan, procarbazine, streptozotocin, temozolomide, thiotepa, and trabectedin; platinum complexes such as carboplatin, cisplatin, and oxaliplatin; antibiotics and cytotoxic agents such as bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, mitoxantrone, procainoxine, and pentorubicin; antimetabolites; folic acid antagonists such as methotrexate, pemetrexed, pralatrexate, and trimethotraxate; purine analogues such as azathioprine, cladribine, fludarabine, mercaptopurine, and thioguanine; and pyrimidines. Analogs, such as azacitidine, capecitabine, cytarabine, decitabine, fluorouridine, fluorouracil, gemcitabine, and trifluridine or ticipiraline; bioresponsive modifiers, such as adeleukin (Il-2), denileukin, and interferon-γ; histone deacetylase inhibitors, such as belistat, parbistat, romidesin, and vorinostat; antiandrogens, such as abiraterone, apalutamide, bicalutamide, cyproterone acetate, enzalutamide, flutamide, and nilumet; antiestrogens, such as anastrozole, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen, and toremifene; gonadotropin-releasing hormone analogs, such as degarelix, goserelin, histaminerelin, leuprorelin, and triptorelin; peptide hormones, such as lanreotide, Octreotide and parretide; monoclonal antibodies, such as alemtuzumab, atezolizumab, avelumumab, bevacizumab, bonatumab, brentuximab, cimiprimab, cetuximab, daratumumab, denutucimab, durvalumab, erlotuximab, gemutuzumab, ocintuzumab, ipilimumab, moglizumab, mosetumumab, nexitruzumab, nivolumab, oflamumab, olatumumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tosimomab, and trastuzumab; protein kinase inhibitors, such as abecil, acalabrutinib, afatinib, alectinib, axitinib, bimetinib, bortezomib, bosutinib, brigatinib. Cabozantinib, Carfilzomib, Ceritinib, Cobitinib, Cupannixib, Crizotinib, Dabrafenib, Dacomitinib, Dasatinib, Duveliximab, Ensidipine, Cannafenib, Erlotinib, Gefitinib, Giglitinib, Grazia, Ibrutinib, Adalaris, Imatinib, Avonib, Ixazomib, Lapatinib, Larotrectinib, Lenvatinib, Lorafenib Midotutolin, neratinib, nilotinib, niraparib, olaparib, osimertinib, palbociclib, pazopanib, pericidatinib, panatinib, regorafenib, ribobacillusinib, rucaparib, sumetinib, sonidira, sorafenib, sunitinib, taprazole, trametinib, vandetanib, vemurafenib, vemodirafenib, and zanubrutinib;Taxanes, such as cabazitaxel, docetaxel, and paclitaxel; topoisomerase inhibitors, such as etoposide, irinotecan, teniposide, and topotecan; vinca alkaloids, such as vincristine, vinorelbine, and vinorelbine; and other oncology drugs, such as asparaginase (pegaspargase), bexarotin, eribulin, everolimus, hydroxyurea, ixaprone, lenalidomide, mitotane, homoharringtonine, pomalidomide, tagraxofusp, teroseltamine, tansimolimus, thalidomide, and venetoclax. Each of the agents mentioned above constitutes a separate embodiment of the invention.

[0065] In some implementations, the anticancer agent is paclitaxel, cisplatin, or tamoxifen.

[0066] The present invention also provides a method of treatment or prevention using the preparations of the present invention.

[0067] In one aspect, a method is provided for treating or delaying or preventing the progression of a proliferative disorder (e.g., cancer), the method comprising administering an effective amount of an anticancer agent to a subject in need of the invention in the form described herein.

[0068] As the term "as used in this article" treat "Refers to the administration of a therapeutic dose of the formulation of the present invention, which effectively improves undesirable symptoms associated with the disease, prevents the manifestation of such symptoms before they occur, slows the progression of the disease (also referred to herein as "delayed progression"), slows the deterioration of symptoms, enhances the occurrence of remission periods, slows irreversible damage caused in the progressive chronic phase of the disease, delays the occurrence of said progressive phase, reduces the severity of the disease or cures the disease, improves survival or faster recovery, or prevents the occurrence of the disease or a combination of two or more of the above.

[0069] As the term "as used in this article" Effective amount "The effective amount is determined by considerations such as those known in the art. This amount must effectively achieve the desired therapeutic effect as described above, which depends particularly on the type and severity of the disease to be treated and the treatment regimen. The effective amount is typically determined in a properly designed clinical trial (dose range study), and those skilled in the art will know how to properly conduct such a trial to determine the effective amount. As is generally known, the effective amount depends on a variety of factors, including the affinity of the ligand for the receptor, the distribution profile of the effective amount in the body, various pharmacological parameters such as the in vivo half-life, undesirable side effects (if any), factors such as age and sex, etc."

[0070] The anticancer agent may be present in the formulations of the present invention in a certain amount or dose, which will depend on a variety of considerations known to those skilled in the art. Not wishing to be bound by any specific dosage, the anticancer agent may typically be present in amounts between 0.1% w / w and 75% w / w, depending on the potency of the drug, the volume of the formulation prepared for, for example, injection, and the desired release profile. The hydrophobic properties of the polymers of the present invention can partially protect the incorporated drug from degradation during storage and in the patient due to photointeraction, oxidation, or hydrolysis. The paste polymer can be injected into tumors or tissues, or diffused onto disease surfaces such as the lungs, colon, and other tissues with diffused cancer cells and tissues. Following, for example, intratumoral injection, the distribution of the active agent in the surrounding cancerous tissue depends on the tissue properties; typically, diffusion can reach 15 mm or more from the injection site. The diffusion of the active agent can be improved by adding agents that enhance tissue penetration, such as azone, isopropyl myristate, decyl oleate, oleyl alcohol, and triacetin. The polymer containing the drug can be dispersed in water for injection to form a dispersion that can be injected or diffused into and onto tissues. The release of the active agent can have a zero-order or first-order profile, lasting from a few days to approximately 8 weeks.

[0071] The formulations of the present invention can be delivered in a variety of ways. In some embodiments, an effective amount of the anticancer agent is administered via one or more of the following routes: intramucosa, nasal, enteral, parenteral, intramuscular, subcutaneous, intramedullary, intrathecal, direct intracardiac, intravenous, intraperitoneal, intranasal, or intraocular injection.

[0072] In some implementations, the formulation is administered by injection.

[0073] In some implementations, the formulation is administered by injection into the tumor (intertumoral).

[0074] In some implementations, the formulation is administered by implanting it into a tissue or organ.

[0075] Therefore, the present invention provides a method of administering a formulation according to the invention, wherein the method comprises administering the formulation to a subject by:

[0076] (i) Injected into the tumor site;

[0077] a. Before the tumor is removed;

[0078] b. After tumor removal or for a period of time after tumor removal;

[0079] c. After tumor recurrence at the treated site;

[0080] (ii) Implanting a device containing or composed of the formulation of the present invention near or adjacent to a tumor site;

[0081] a. Before the tumor is removed;

[0082] b. After tumor removal or for a period of time after tumor removal;

[0083] c. After tumor recurrence at the treated site;

[0084] (iii) After tumor removal, the preparation is layered and stacked onto the tumor or tissue at the tumor site;

[0085] (iv) Delivery of the formulation of the present invention via laparoscopy;

[0086] (v) Any of the combined chemotherapy or radiation therapy mentioned above;

[0087] (vi) Coating or loading the formulation onto or into a device or implant to be contacted with or near a tumor site or at a tumor site;

[0088] (vii) Injected into the body for systemic administration of anticancer agents, for prolonged systemic release of anticancer drugs.

[0089] As used in this article, the term " nearby "and" Neighbor "This refers to the distance from the tumor or diseased tissue to be treated. This distance ranges from 1 cm to 10 cm from the site of the tumor or tissue. Therefore, these terms refer to a distance between 0 cm and 10 cm, where 0 cm indicates the center of the tumor or diseased tissue. In some embodiments, application is applied directly to the tumor or directly into the tumor. In other embodiments, application is applied around the tumor at a distance of up to 10 cm."

[0090] A kit is also provided, comprising a carrier and an anticancer agent as defined or prepared as described. In some embodiments, the carrier and agent are contained separately, i.e., each contained in a different container. In some embodiments, they are contained together. In some embodiments, the kit is a syringe or includes a syringe. The kit will also include instructions for use.

[0091] According to the method of use and application of the present invention, a carrier in the form of a polyanhydride of the formula -(SA-RA)n- is used, wherein SA is sebacic acid and RA is ricinoleic acid, and wherein n is an integer between 10 and 100, the carrier having a Mw / Mn value of less than 2.5 or less than 2 (where Mw is weight-average molecular weight and Mn is number-average molecular weight) or a value between 1 and 2.5 or between 1 and 2.

[0092] In some implementations, the carrier is prepared using any of the processes disclosed herein.

[0093] In some embodiments, the formulations used according to the invention comprise an anticancer agent as defined and a carrier as defined, wherein the carrier is prepared by a melt polycondensation process comprising RA and SA in the presence of acetic anhydride in an amount not exceeding one molar equivalent of acetic anhydride per free carboxylic acid group and in the absence of a solvent. Brief description of the attached diagram

[0094] The invention can be more clearly understood after reading the following detailed description of non-limiting exemplary embodiments of the invention, with reference to the accompanying drawings, in which:

[0095] Figure 1 This is the synthesis scheme of the polyanhydride carrier of the present invention.

[0096] Figure 2 This is a graphical representation of the cumulative in vitro release of cisplatin from a cisplatin-loaded PSA:RA 3:7 formulation at 37°C. Over a 25-day period, ~75% and ~10% of the incorporated drug were released from 0.5% (w / w) and 20% (w / w) and 5% (w / w) and 10% (w / w) formulations, respectively.

[0097] Figures 3A-3D It shows Figure 3A The drug is released in total from a 50 mg sample in 50 mL buffer. Figure 3B The drug is released in total from a 100 mg sample in 50 mL buffer. Figure 3C The drug was released in total from a 200 mg sample in 50 mL buffer. Figure 3D Comparison of daily drug release in mg.

[0098] Figure 4 The study showed changes in the subjects' weight.

[0099] Figure 5 The results showed the effects of IV chemotherapy versus cisplatin-polymer on kidney performance and body weight. Figure 4 A comparison of ).

[0100] Figure 6The comparison of blood cell counts between IV chemotherapy and TumoCure is shown. Invention Details

[0101] Example 1: Controlled synthesis of oligomers of different types of dicarboxylic acids and hydroxy acids forming the carrier according to the present invention

[0102] Objective: To develop alternative methods for synthesizing oligomers of different types of dicarboxylic acids and hydroxy acids.

[0103] Materials: SUA and DDDA are used as is. Ricinoleic acid (RA) is prepared by hydrolysis of castor oil, as described in the synthesis section.

[0104] Spectral analysis

[0105] The results were obtained using a Varian 300 MHz NMR spectrometer with CDCl3 as the solvent and tetramethylsilane as the shift reference. 1 H and 13 C10 NMR spectroscopy. Fourier transform infrared (FTIR) spectroscopy was performed using the Smart iTR ATR sampling accessory on a Nicolet iS10 spectrometer with a diamond crystal (ThermoScientific, Massachusetts).

[0106] Preparation of ricinoleic acid from castor oil: In a 1000 mL round-bottom flask, 48 g of KOH was dissolved in 400 mL of ethanol by heating (65 °C). Then, 200 g of castor oil was added and the mixture was appropriately mixed. The mixture was then refluxed at 140 °C with continuous stirring for 2 hours. After reflux, the solvent was evaporated using an evaporator. Then, 200 mL of double-distilled water, 150 mL of diisopropyl ether, and 150 mL of H₃PO₄ were added, and the total mixture was transferred to a separatory funnel. It was then washed repeatedly with double-distilled water (3-5 times, 200 mL each time) until the pH of the aqueous phase was ~4. The organic phase was then collected by passing sodium phosphate and evaporated to dryness to obtain 185 g of pure ricinoleic acid (yield 92.5%). 1 H NMR confirmed.

[0107] Synthesis of SUA-RA and DDDA-RA oligomers: SUA-RA and DDDA-RA oligomers were synthesized by esterification of octanoic acid and dodecanoic acid with ricinoleic acid at 170 °C. In a round-bottom flask, 15 g of SUA, 15 g of RA, and a catalytic amount (1%) of phosphoric acid were added, and the mixture was heated to 170 °C for 5 hours under nitrogen. Then, another 15 g of RA was added to the round-bottom flask, and heating continued for another 4 hours under rapid nitrogen flow. Finally, another 5 g of RA was added, and the mixture was heated again overnight under vacuum to produce SUA-RA oligomers with a 30:70 ratio of SUA and RA. 1 H NMR characterization. DDDA-RA oligomers with a DDDA:RA ratio of 30:70 were synthesized following the same procedure, and also by H NMR characterization. 1 H NMR characterization.

[0108] Discussion of Results: Two different oligomers were synthesized using two different dicarboxylic acids and hydroxy acids. RA was esterified with SUA or DDDA under melt and vacuum conditions, with H3PO4 used as a catalyst. Under these reaction conditions, 100% of RA was consumed in the esterification reaction with SUA or DDDA, which was due to... 1 ¹H NMR confirmed this, as the signal of the alcohol proton at 3.6 ppm was lost after the final step of esterification. Furthermore, the self-condensation of RA in this scheme was avoided (via the stepwise addition of RA to SUA or DDDA); evidence comes from… 1 H NMR showed no signal at 4.1 ppm. Therefore, the process yields well-defined SUA-RA oligomers or DDDA-RA oligomers without any residual or self-condensed RA.

[0109] Example 2: Exploring the Synthesis of Poly(Ester-Anhydride) Using Alternative Methods

[0110] The goal is to develop an alternative method for synthesizing biodegradable poly(ester-anhydride) copolymers. Here, the focus is on two characteristics:

[0111] 1) Use sebacic acid (SA) and ricinoleic acid (RA) or 12-hydroxystearic acid (HSA) to prepare SA-RA oligomers or SA-HSA oligomers by direct condensation.

[0112] 2) Use a small amount (1:1 equivalent or less) of acetic anhydride to activate the oligomers for polymerization.

[0113] 3) The molecular weight of poly(ester-anhydride) depends on the amount of acetic anhydride used in the prepolymerization step.

[0114] Materials: Sebacic acid (SA, 99% pure; Aldrich, USA), 12-hydroxystearic acid (HSA), and acetic anhydride (Merck, Germany) were used as is. Ricinoleic acid (RA) was prepared by hydrolysis of castor oil, as described in the synthesis section.

[0115] Spectroscopic analysis: The results were obtained using a Varian 300 MHz NMR spectrometer with CDCl3 as the solvent and tetramethylsilane as the shift reference. 1 H and 13 C10 NMR spectroscopy. Fourier transform infrared (FTIR) spectroscopy was performed using the Smart iTR ATR sampling accessory on a Nicolet iS10 spectrometer with a diamond crystal (Thermo Scientific, Massachusetts).

[0116] Molecular weight determination: Molecular weight was determined using a gel permeation chromatography (GPC) system, Waters 1515. An isocratic HPLC pump with a Waters 2410 refractive index detector, a Waters 717 plus autosampler, and a Rheodyne (Cotati, CA) injection valve with a 20 μL loop was used. The sample was eluted with CHCl3 (HPLC grade) through a linear Styragel HR5 column (Waters) at a flow rate of 1 mL / min. Molecular weight was determined relative to polystyrene standards.

[0117] Synthesis and Characterization: SA-RA Oligomers: SA-RA oligomers were synthesized by heating castor oil acid and sebacic acid at 175 °C. In a round-bottom flask, 30 g of SA, 30 g of RA, and a catalytic amount (0.1%) of phosphoric acid were placed and heated to 170 °C for 5 hours under nitrogen. Then, another 30 g of RA was added to the round-bottom flask, and heating continued for another 4 hours under rapid nitrogen permeation. Finally, another 10 g of RA was added, and the mixture was heated again overnight under vacuum to produce SA-RA oligomers with a 30:70 SA:RA ratio. 1 Characterized by 1H NMR and FTIR. SA-RA oligomers with different ratios were also prepared using the same process, and characterized by... 1 H NMR characterization. Detailed descriptions are given in Table 1 below.

[0118] Table 1: SA-RA oligomers

[0119]

[0120] SA-HSA oligomers

[0121] SA-HSA oligomers were also synthesized by heating 12-hydroxystearic acid and sebacic acid at 175 °C. In a round-bottom flask, 15 g of SA, 15 g of HSA, and a catalytic amount (0.1%) of phosphoric acid were placed and heated to 170 °C for 5 hours under nitrogen. Then, another 15 g of HSA was added to the round-bottom flask, and heating continued for another 4 hours under rapid nitrogen permeation. Finally, another 5 g of HSA was added, and the mixture was heated again overnight under vacuum to produce SA-HSA oligomers with a 30:70 SA:HSA ratio. 1 Characterized by 1H NMR and FTIR. SA-HSA oligomers in a 20:80 ratio were also prepared using the same process. Detailed descriptions are given in Table 2 below.

[0122] Table 2: SA-RA oligomers

[0123]

[0124] poly(SA-RA)

[0125] In a typical synthesis, 10 g of SA-RA oligomers in ratios of 20:80, 25:75, 30:70, and 35:65 were individually melted at 140 °C under a nitrogen atmosphere. A 1:5 equivalent of acetic anhydride was then added to the molten SA-RA oligomers, and the mixture was refluxed at 140 °C for 60 min. Excess acetic anhydride or acetic acid was evaporated. The residue was then subjected to melt condensation at 160 °C and 10 mbar for 4 h. SA-RA oligomers in a 30:70 ratio were also polymerized under the same procedure, using different amounts (1 equivalent, 0.7 equivalent, 0.5 equivalent, 0.35 equivalent, 0.25 equivalent, 0.15 equivalent) of acetic anhydride (refluxed at 140 °C overnight) to use less acetic anhydride and control the molecular weight.

[0126] poly(SA-HSA)

[0127] Following the same procedure as for poly(SA-RA), 10 g of SA-HSA oligomers in 20:80 and 30:70 ratios were individually melted at 140 °C under a nitrogen atmosphere. Acetic anhydride was then added in a 1:5 equivalent ratio to both molten SA-HSA oligomers, and the mixture was refluxed at 140 °C for 60 min. Excess acetic anhydride or acetic acid was evaporated. The residue was then subjected to melt condensation at 160 °C under vacuum (~10 mbar) for 4 h.

[0128] Discussion of the results:

[0129] Two poly(ester-anhydride) copolymers were synthesized via a solvent-free melt polycondensation process, in which sebacic acid was used directly instead of poly(SA) as the starting material to synthesize SA-RA oligomers or SA-HSA oligomers. RA or HSA was esterified with SA under melt and vacuum conditions, with up to 1% H3PO4 used as a catalyst in some cases. Under these reaction conditions, 100% of RA or HSA was consumed in the esterification reaction with SA, which was caused by… 1 1H NMR confirmed this, as the signal of the alcohol proton at 3.6 ppm was lost after the final step of esterification. Furthermore, the self-condensation of RA or HSA in this scheme was avoided (via the stepwise addition of RA or HSA to SA); evidence comes from... 1 ¹H NMR showed no signal at 4.1 ppm. Therefore, the process yielded well-defined SA-RA or SA-HSA oligomers without any residual or self-condensed RA or HSA. Protons of the esterified polymer chemical shift were observed at ~4.8 ppm. The two protons adjacent to the ester and anhydride bonds appeared at 2.43 ppm and 2.33 ppm, respectively.

[0130] The molecular weight of the synthesized polymer was measured by GPC. A detailed description of the molecular weight and its variations is given in Table 3 below, and the molecular weight is controlled depending on the acetic anhydride used.

[0131] Table 3: Molecular weight and differences of the polymers of the present invention

[0132]

[0133] Example 3: Synthesis of poly(SA-RA) with reduced reaction time

[0134] Objective: The objective of this project is to utilize biodegradable poly(sebacic acid-ricinoleic acid) copolymers. 1 ¹H NMR was used to monitor the synthesis process in order to reduce reaction time.

[0135] Materials: Sebacic acid (SA, 99% pure; Aldrich, USA) was used as is. Ricinoleic acid (RA) was prepared by hydrolysis of castor oil, as described in the synthesis section.

[0136] Spectroscopic analysis: Obtained using CDCl3 as solvent on a Varian 300 MHz NMR spectrometer. 1 1H NMR spectroscopy. Fourier transform infrared (FTIR) spectroscopy was performed using the Smart iTR ATR sampling accessory on a Nicolet iS10 spectrometer with a diamond crystal (Thermo Scientific, Massachusetts).

[0137] Molecular weight determination: Molecular weight was determined using a gel permeation chromatography (GPC) system, Waters 1515. An isocratic HPLC pump with a Waters 2410 refractive index detector, a Waters 717 plus autosampler, and a Rheodyne (Cotati, CA) injection valve with a 20 μL loop was used. The sample was eluted with CHCl3 (HPLC grade) through a linear Styragel HR5 column (Waters) at a flow rate of 1 mL / min. Molecular weight was determined relative to polystyrene standards.

[0138] Synthesis of SA-RA oligomers: SA-RA oligomers were synthesized by heating ricinoleic acid and sebacic acid at 170 °C. In a round-bottom flask, 15 g of SA, 15 g of RA, and a catalytic amount (0.1%) of phosphoric acid were placed and heated to 170 °C for 2 hours under nitrogen. Then, another 15 g of RA was added to the round-bottom flask, and heating was continued under vacuum for 15 minutes, followed by rapid nitrogen permeation for another 2 hours. Finally, 5 g of RA was added, and heating was continued under vacuum for another 8 hours to produce SA-RA oligomers with a 30:70 w / w ratio of SA to RA. 1 H NMR characterization.

[0139] Poly(SA-RA): In a typical synthesis, 10 g of SA-RA oligomers with a 30:70 ratio are melted at 140 °C under a nitrogen atmosphere. Then, acetic anhydride, in an amount equal to 1 equivalent of the acid in the oligomers, is added to the molten SA-RA oligomers, and the mixture is refluxed at 140 °C for 2 hours. Excess acetic anhydride or acetic acid is evaporated. The residue is then subjected to melt condensation at 160 °C under vacuum (~10 mbar) for 4 hours.

[0140] Discussion of the results:

[0141] RA was esterified with SA under molten and vacuum conditions without any other additives. No acid (H3PO4) was needed as a catalyst because complete conversion of the ester dimer and trimer was achieved without the addition of any acid. Under these reaction conditions, 100% of the RA was consumed in the esterification reaction with SA within 12 hours. Therefore, this is achieved by… 1 ¹H NMR confirmed this, as the signal of the alcohol proton at 3.6 ppm was lost after the final step of esterification. Furthermore, the self-condensation of RA in this scheme was avoided (via the stepwise addition of RA to SA); evidence comes from… 1¹H NMR was performed, but no signal was detected at 4.1 ppm. The oligomers were then polymerized by refluxing with 1 equivalent of acetic anhydride at 140 °C for 2 hours, followed by heating under vacuum at 160 °C for 4 hours. The molecular weight of the polymer was measured by GPC and compared with a polymer synthesized from the same SA-RA oligomers with a 30:70 ratio by refluxing with 1 equivalent of acetic anhydride overnight at 140 °C, followed by heating under vacuum at 160 °C for 4 hours. It is noted that both processes yielded nearly identical molecular weights (~11500 Daltons).

[0142] Example 4: Cisplatin-loaded poly(SA-RA) injectable formulation

[0143] Materials and Methods: Materials: a) Cisplatin (99.99%), lot number # A0402164, CAS #15663-27-1, obtained from ACROS ORGANICS; b) PSA:RA 3:7 ( Mw 11675, PDI 2.63) synthesized in the laboratory; c) o-phenylenediamine (OPDA); d) sodium chloride; and dimethylformamide (DMF) obtained from Sigma Aldrich.

[0144] program:

[0145] A 1 mg / mL cisplatin stock solution was prepared in phosphate buffer (pH 7.2) containing 1% NaCl. Different cisplatin dilutions were prepared from the stock solution, ranging from 0.5 µg / mL to 5 µg / mL. Then, 1 mL of 1.2 mg / mL OPDA solution in DMF was added, and the mixture was heated at 90 °C for 20 min to obtain a light green solution. The prepared colored solution was cooled to room temperature and measured at 705 nm using a UV-Vis spectrophotometer.

[0146] result:

[0147] The presence of cisplatin in PSA:RA does not affect its injectability. Furthermore, the formulation immediately hardens into a gel upon the addition of a buffer medium. Release profiles from the four formulations are shown in [link to data]. Figure 2 The information is provided in the text. Figure 2 The in vitro cumulative release of cisplatin from cisplatin-loaded PSA:RA 3:7 was demonstrated at 37 °C. During a 25-day period, ~75% and ~10% of the incorporated drug were released from 0.5% (w / w) and 20% (w / w) and 5% (w / w) and 10% (w / w) formulations, respectively.

[0148] The presence of a large amount of cisplatin in PSA:RA does not affect the gelling properties of PSA:RA. No burst release was observed in the formulation after adding 50 mL of release medium at 37°C with shaking at 175 rpm.

[0149] Example 5: In vivo testing of the radiotherapy efficacy of cisplatin formulations for the treatment of head and neck cancer

[0150] In this study, three experimental groups were used, with six nude mice in each group. All mice were injected with 600,000 tumor cells. Twenty days after cell injection, mice received either an intraperitoneal injection (IP) of cisplatin solution or a subcutaneous injection of a polymer and polymer-cisplatin formulation (10 μL of 0.5% cisplatin) used only as a reference. Cisplatin solution was administered via IP for four consecutive weeks, for a total of four administrations. Animals were irradiated with 8 Gy on days 21 and 24. The experiment was terminated on day 50. Animals treated with the drug-free polymer and cisplatin solution showed no effect on tumors and experienced a significant increase in tumor size. However, the groups treated with polymer-cisplatin and irradiation showed complete tumor reduction.

[0151] Over time, polymer-cisplatin has proven effective in reducing tumor growth rate. Tumor growth rate decreases with varying cisplatin-polymer dosage.

[0152] Paclitaxel Delivery: Paclitaxel powder (100 mg) was mixed with poly(SA-RA) 20:80 (900 mg) to form a homogeneous white paste, which was loaded into a 1 ml syringe. The formulation was added to 50 ml conical plastic tubes, 100 mg per tube, along with phosphate buffer (pH 7.4) containing 0.1% w / w SDS (50 ml). The vials were incubated at 37°C with shaking, and the solution was replaced periodically after 1, 3, 7, 14, 21, and 28 days. Paclitaxel release into the medium was determined by HPLC. Sustained release of approximately 50% of the loaded drug was observed within 28 days. The remaining paclitaxel in the polymer residue comprised the majority of the expected amount.

[0153] Tamoxifen Delivery: Solid poly(SA-RA) 70:30 w / w implants loaded with 10% and 20% drug were prepared via a melt process, wherein the drug was mixed in the molten polymer, and after mixing to form a homogeneous melt, the formulation was cast into a thin road using a mold. All experiments using tamoxifen citrate were conducted in the dark because the drug is highly photosensitizing. The drug was loaded into the polymer at concentrations of 10% w / w and 20% w / w. Cylindrical implants were prepared by incorporating a homogeneous mixture of tamoxifen citrate and poly(SA-RA) 70:30 w / w into a cylindrical mold with a diameter of 1.5 mm. The drug content in the implants was determined by HPLC. Tamoxifen was continuously released for more than 4 weeks. Instead of the solid poly(SA-RA) 70:30 carrier, a paste-like injectable polymer formulation was prepared and characterized using a poly(SA-RA) 30:70 w / w paste polymer.

[0154] Other anticancer agents, including methotrexate, doxorubicin, temozolomide, acridine yellow, and nintedanib, were incorporated into a paste polymer, either alone or in combination with other drugs, by simply mixing the drug powder with the polymer at room temperature and loading it into a syringe. The in vitro release of the paste formulation was tested, with sustained drug release over 30 days.

[0155] Example 6: Toxicity of polymeric cisplatin:

[0156] In this study, a poly(SA:RA) 30:70 polymer with molecular weights of Mw=9400 and Mn=8200 (determined by GPC using polystyrene standards) prepared as described above was used. This polymer is an injectable viscous gel. Viscosity was unaffected at a 20% drug loading. Formulations loaded with the polymer and cisplatin underwent sterilization by γ-irradiation at doses suitable for medical application devices and combination devices ranging from 35 kGy to 45 kGy. No changes were observed in polymer molecular weight, drug content, or drug release. This indicates that the polymer and cisplatin formulations are stable to γ-irradiation sterilization.

[0157] Formulations: Two formulations containing 10% (w / w) and 20% (w / w) of the drug were prepared. Once prepared, they were transferred to pre-filled glass syringes and then transported for sterilization under gamma irradiation.

[0158] In vitro release: The in vitro release test was performed in triplicate, with 50 mg, 100 mg, and 200 mg formulations (10% (w / w) and 20% (w / w)) transferred to 50 mL glass vials. 50 mL of PBS buffer (100 mM, pH 7 / 4, and 1% NaCl) was added to each vial, and the vials were changed daily. The drug concentration in the discarded solutions was determined spectrophotometrically to assess the amount of drug released (mg).

[0159] As from Figures 3A-3C As can be seen, the higher the surface area (the smaller the amount introduced), the faster the drug is released, meaning the polymer is more easily hydrolyzed, i.e., degrades faster. Furthermore, the maximum release is independent of the amount tested, and it occurs between the second and third days after injection, as in... Figure 3D It can be seen in the image.

[0160] Pharmacokinetic studies in rats: Due to dose limitations, we focused on the 10% formulation, where we injected and compared the sterilized 10% formulation with the IV drug alone and PSARA to assess MTD, PK, and overall organ and body effects.

[0161] The polymer-cisplatin was administered subcutaneously to mice at doses of 10 µL, 20 µL, and 40 µL per mouse (i.e., 4 mg cisplatin / kg, 8 mg cisplatin / kg, and 16 mg cisplatin / kg, respectively). As a control, mice were administered 50 µL of the drug-free polymer at a dose of 5 mg / kg and 200 µL via intravenous injection. Morbidity and mortality were observed daily, and general clinical signs (cage-side observation) were also observed daily: changes in skin, fur, eyes, nose, mouth, head, respiration, urine, feces, movement, and overall health.

[0162] According to Clinical Signs, SOP-06-019, animals at one of the humane endpoints were euthanized and underwent termination procedures. Blood collection for cisplatin content was conducted at 0 (baseline), 1 h, 4 h, 8 h, 24 h, 48 h, 96 h, and 168 h, weekly thereafter until week 4. Blood collection for CBC and biochemistry was conducted at 0 (baseline), 24 h, 72 h, and 168 h, weekly thereafter until sacrifice. For mice that received IV injections, plasma was collected at 0 (baseline), 5 m, 15 m, 30 m, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, and 96 h. Whole blood and blood biochemistry were collected at 0 (baseline), 24 h, and 96 h. Whole blood was collected from each animal and processed according to standard procedures. Urine collection volumes were recorded at 0 h–6 h, 12 h–24 h, 48 h–72 h, 72 h–96 h, and 96 h–120 h, and thereafter weekly.

[0163] result:

[0164] Body parameters throughout the study Figure 4 The information is provided in [the document / reference]. Blood analysis is... Figure 5 The information is provided in the text.

[0165] Group 1 (SC polymer control): No toxic effects as seen in weight gain, normal behavior, and pathology.

[0166] Group 2 (IV cisplatin solution): Severe adverse effects in rats immediately following injection, manifesting behaviorally as kyphosis, piloerection / ruffled fur, signs of dehydration, and abnormal vocalization. This translated into lower body weight, blood cell count, and deteriorated renal performance through increased creatinine and urea excretion.

[0167] Groups 3-5 (SC polymeric cisplatin 4 mg / kg, 8 mg / kg, 16 mg / kg): A significant correlation was found between weight loss and release rate (dose) in the first 3 days. Although in Group 5, a dose of 4x the amount administered to Group 2 (IV) indicated similar behavior to Group 2, Group 5 appeared to be better than Group 2 (IV) because the drug was released slowly, giving the body time to heal itself. This was clearly seen in renal function, which deviated slightly from normal values ​​compared to Group 2.

[0168] The blood cell counts in groups 3-5 support the hypothesis that slow release and organ recovery are better achieved using the TumoCure system, as the decreases in HGB, RBG, and HCT are negligible compared to group 2 (IV), which showed a sharp decline in markers.

[0169] Example 7: Toxicity and Elimination of Polymers

[0170] Toxicity and elimination of poly(SA:RA) 30:70 when administered intramuscularly and subcutaneously in rats were evaluated. Rats were injected with doses ranging from 100 μL to 300 μL, and degradation and local toxicity were determined over 3 months. No general toxicity was observed, animal behavior was normal, and weight gain was similar to that of the control group. The polymer was gradually eliminated from the injection site over an 8-week period, with complete healing.

[0171] Example 8: Release of LHRH and somatostatin peptides from polymers for cancer treatment

[0172] Prolonged release of LHRH agonists was used to treat prostate cancer. In this study, LHRH, 10 mg of a mixture of LHRH, 2 mg and 8 mg of glucose powder were manually mixed into a paste polymer (SA:RA) 30:70 (190 mg), and the formulation was placed in a cap for in vitro release studies. The cap containing the LHRH formulation was placed in 10 ml of phosphate buffer (pH 7.4) at 37°C. The buffer was changed periodically for two weeks, and the LHRH content in the release medium was determined by HPLC. Prolonged release of LHRH was observed over the two-week period, with a total drug content of 60% being released.

[0173] Similarly, somatostatin was incorporated into the polymer and showed sustained release for up to 2 weeks.

[0174] Similarly, a mixture of VEGF inhibitors in amino acids, salts, and sugars was used, protecting proteins from aggregation and degradation when in aqueous media or in dry form. The powder was incorporated into the polymer paste by manual mixing at room temperature to form a homogeneous paste. In vitro release showed sustained release over one week.

[0175] Example 9: Release of siRNA from the polymer

[0176] Small interfering RNA (siRNA) technology has shown great promise as a novel class of therapeutic interventions for cancer treatment. siRNAs have been widely used to block multiple genes and are currently being evaluated as therapeutic agents for various cancers. Despite the excitement surrounding this remarkable biological process of sequence-specific gene regulation, major limitations to its use include rapid degradation by serum nucleases, poor cellular uptake, rapid renal clearance after systemic delivery, off-target effects, and induction of immune responses.

[0177] Local delivery at the tumor site should provide a solution to these drawbacks, as the agent is delivered locally, rather than via the bloodstream, and it is released within days or weeks at the tumor or tissue site. Naked siRNA, or a mixture / complex with cationic lipids and buffers, was incorporated into a polymeric paste, and release studies were conducted as described above. Continuous release was observed for one week, followed by minimal release over the next six weeks.

Claims

1. An anticancer agent comprising at least one anticancer agent and a carrier in the form of a polyanhydride of the formula -(SA-RA)n-, wherein SA is sebacic acid and RA is ricinoleic acid, and wherein n is an integer between 10 and 100, said carrier having an Mw / Mn value between 1 and 2.5, wherein Mw is a weight-average molecular weight and Mn is a number-average molecular weight, each determined by gel permeation chromatography (GPC) using a linear Styragel HR5 column.

2. An anticancer agent comprising at least one anticancer agent and a carrier in the form of a polyanhydride including sebacic acid (SA) and ricinoleic acid (RA), said carrier having an Mw / Mn value between 1 and 2.5, said polyanhydride being prepared by a process comprising: a. melt condensation of SA and RA to form a dicarboxylic acid oligomer; b. activation of the obtained oligomer with acetic anhydride in the absence of a solvent in the presence of one molar equivalent or less of acetic anhydride for each carboxylic acid group; c. melt polycondensation to form the polyanhydride, wherein said preparation does not include the use of polysaccharide.

3. The formulation according to claim 1 or 2, in the form of an implantable formulation or device or an injectable formulation.

4. The formulation of claim 3, wherein the implantable formulation is in the form of a gel or a flowable formulation, wherein the gel or flowable formulation is semi-solid when in contact with body fluids.

5. The formulation according to claim 3, wherein the injectable formulation is an injectable viscous formulation.

6. The formulation according to claim 3, wherein the formulation is injectable via a 23G needle.

7. The formulation according to claim 1 or 2, in the form of a paste.

8. The formulation according to claim 1 or 2, suitable for intratumoral delivery of the anticancer agent.

9. The formulation according to claim 1 or 2, suitable for implantation at the tumor site after surgical resection of the tumor or suitable for injection into the tumor site via a needle.

10. The formulation according to claim 1 or 2 is a controlled delivery formulation.

11. The formulation according to claim 8 is an extended delivery formulation or a continuous delivery formulation.

12. The formulation according to any one of claims 1, 2, 4-6 and 11, wherein the anticancer agent is a cytotoxic agent for cancer treatment, or a protein- or nucleotide-based biological drug.

13. The formulation according to any one of claims 1, 2, 4-6 and 11, for use in the administration of at least one cancer selected from the group consisting of: blastoma, carcinoma, leukemia, sarcoma, mesothelioma, germ cell tumor, melanoma, glioblastoma, colorectal malignancy, head and neck malignancy, gastrointestinal malignancy and lymphoma.

14. The formulation according to any one of claims 1, 2, 4-6 and 11, for use in the administration of at least one cancer selected from glioma and choriocarcinoma.

15. The formulation according to any one of claims 1, 2, 4-6 and 11, for the administration of solid cancer.

16. The formulation according to claim 15, wherein the solid cancer is brain cancer, breast cancer, prostate cancer, head and neck sarcoma, lung cancer, and skin cancer.

17. The formulation according to claim 12, wherein the cancer is selected from squamous cell carcinoma, lung cancer, peritoneal cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colorectal cancer, uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, and head and neck cancer.

18. The formulation according to claim 12, wherein the cancer is selected from small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, rectal cancer, endometrial cancer, gastric cancer, and hepatocellular carcinoma.

19. The formulation according to any one of claims 1, 2, 4-6, 11, 16, 17 and 18, wherein the anticancer agent is selected from cytotoxic agents, chemotherapeutic agents, intercalating drugs, topoisomerase inhibitors, antimetabolites, antimitotic drugs, kinase inhibitors and monoclonal antibiotics.

20. The formulation according to claim 1 or 2, wherein the anticancer agent is an alkylating agent selected from the following: hexamethylmelamine, bendamustine, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, nitrogen mustard, melphalan, procarbazine, streptozotocin, temozolomide, thiotepa, and trabectedin.

21. The formulation according to claim 1 or 2, wherein the anticancer agent is a platinum complex selected from carboplatin, cisplatin and oxaliplatin.

22. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the following cytotoxic agents: bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, mitomycin, mitoxantrone, procainoxicin, and pentorubicin.

23. The formulation according to claim 1 or 2, wherein the anticancer agent is an antimetabolite.

24. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the following folic acid antagonists: methotrexate, pemetrexed, pralatrexate, and trimethoprim.

25. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the group consisting of azathioprine, cladribine, fludarabine, mercaptopurine, and thioguanine.

26. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the following pyrimidine analogs: azacitidine, capecitabine, cytarabine, decitabine, fluorouracil, fluorouracil, gemcitabine, trifluridine, and ticipiridin.

27. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the group consisting of: aldehyde interleukin (Il-2), dine interleukin, and interferon γ.

28. The formulation according to claim 1 or 2, wherein the anticancer agent is a histone deacetylase inhibitor selected from the group consisting of belistat, parbistat, romidesin, and vorinostat.

29. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the group consisting of: abiraterone, apalutamide, bicalutamide, cyproterone acetate, enzalutamide, flutamide, and nilutet.

30. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the group consisting of anastrozole, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen, and toremifene.

31. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the following gonadotropin-releasing hormone analogs: degarelix, goserelin, histaminerelin, leuprorelin, and triptorelin.

32. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the peptide hormones: lanreotide, octreotide, and parreotide.

33. The formulation according to claim 1 or 2, wherein the anticancer agent is a monoclonal antibody selected from the following: alemtuzumab, atezolizumab, avelumumab, bevacizumab, bonatumab, brentuximab, cimiprimab, cetuximab, daratumumab, denutucimab, durvalumab, erlotuximab, gemutuzumab, osintuximab, ipilimumab, moglizumab, mosetumumab, nexituximab, nivolumab, ofamumumab, olatumumab, panitumumab, pembrolizumab, pertuzumab, ramucirumab, rituximab, tosimomumab, and trastuzumab.

34. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the group consisting of protein kinase inhibitors: abexicillin, acalatinib, afatinib, alectinib, axitinib, bimetinib, bortezomib, bosutinib, brigatinib, cabozantinib, carfilzomib, ceritinib, cobitinib, cupanixinib, crizotinib, dabrafenib, dacomitinib, dasatinib, duveliximab, ensidipine, cannefenib, erlotinib, gefitinib, giglitinib, glaggib, etc. Rutinib, Adelaide, Imatinib, Avonib, Ixazomib, Lapatinib, Larotrectinib, Lenvatinib, Lorlatinib, Midotutolin, Lenatinib, Nilotinib, Niraparib, Olaparib, Osimertinib, Palbociclib, Pazopanib, Percidatinib, Panatinib, Regorafenib, Ribocicib, Lucaparib, Ruxolitinib, Smectinib, Sonicate, Sorafenib, Sunitinib, Talaparib, Trametinib, Vandetanib, Vemurafenib, Vemodagib, and Zanubrutinib.

35. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the group consisting of cabazitaxel, docetaxel and paclitaxel.

36. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the group consisting of topoisomerase inhibitors: etoposide, irinotecan, teniposide, and topotecan.

37. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the following vinca alkaloids: vincristine, vinblastine and vinorelbine.

38. The formulation according to claim 1 or 2, wherein the anticancer agent is selected from the following oncology drugs: asparaginase, bexarotin, eribulin, everolimus, hydroxyurea, ixaprone, lenalidomide, mitotane, homoharringtonine, pomalidomide, tagraxofusp, teroseltamine, tansimolimus, thalidomide, and venetoclax.

39. The formulation according to claim 1 or 2, wherein the anticancer agent is the tumor drug pegaspargase.

40. Use of a carrier in the form of a polyanhydride in the preparation of an agent for treating or delaying or preventing the progression of cancer, the agent comprising an effective amount of an anticancer agent and the polyanhydride, wherein the polyanhydride has the formula -(SA-RA)n-, wherein SA is sebacic acid and RA is ricinoleic acid, and wherein n is an integer between 10 and 100, and the carrier has an Mw / Mn value between 1 and 2.

5.

41. The use according to claim 40, wherein the polyanhydride is prepared by melt condensation of SA and RA.

42. The use according to claim 41, wherein the melt condensation is carried out in the absence of a solvent in the presence of one molar equivalent or less of acetic anhydride for each carboxylic acid group, and wherein the preparation does not include the use of polysaccharide.

43. Use of the formulation according to claim 3 in the preparation of a medicament for treating or delaying or preventing the progression of cancer.

44. The use according to claim 43, wherein the carrier is in the form of a polyanhydride of the formula -(SA-RA)n-, wherein SA is sebacic acid and RA is ricinoleic acid, and wherein n is an integer between 10 and 100, and the carrier has an Mw / Mn value between 1 and 2.

5.

45. The use according to claim 43 or 44, wherein when the drug is used, the formulation is administered by injection.

46. ​​The use according to claim 45, wherein the formulation is injected into a tumor or tissue or diffused onto the surface of a diseased tissue.

47. The use according to claim 43 or 44, wherein when the drug is used, the formulation is administered by a mode of administration selected from the following: via mucosal, nasal, enteral, parenteral, intramuscular, subcutaneous, intramedullary, intrathecal, intravenous, intravenous, intraperitoneal, intranasal, or intraocular injection.

48. The use according to claim 47, wherein the formulation is administered by injection.

49. The use according to claim 48, wherein the formulation is administered by injection into a tumor.

50. The use according to claim 47, wherein the formulation is administered by implanting the formulation into a tissue or organ.

51. The use according to claim 43 or 44, wherein when the drug is used, the formulation is administered to the subject by: A. Injected into the tumor site; a. Before the tumor is removed; or b. After tumor removal or for a period of time after tumor removal; or c. After recurrence of the tumor at the treated site; or B. Implantation of a device containing or composed of the preparation near or adjacent to the tumor site; a. Before the tumor is removed; or b. After tumor removal or for a period of time after tumor removal; or c. After recurrence of the tumor at the treated site; or C. After tumor resection, the preparation is layered and stacked onto the tumor or tissue at the tumor site; or D. Delivery of the formulation via laparoscopy; or E. Combined chemotherapy or radiation; or F. Coating or loading the formulation onto or into a device or implant to be contacted with, near, or at the tumor site; or G. Injected into the body to achieve systemic administration of the anticancer agent.

52. The use of a carrier in the form of a polyanhydride of the formula -(SA-RA)n- for the preparation of an anticancer preparation comprising at least one anticancer agent, wherein SA is sebacic acid and RA is ricinoleic acid, and wherein n is an integer between 10 and 100, and the carrier has an Mw / Mn value between 1 and 2.

5.

53. Use of an anticancer agent in the preparation of an anticancer formulation comprising the anticancer agent and a carrier in the form of a polyanhydride of the formula -(SA-RA)n-, wherein SA is sebacic acid and RA is ricinoleic acid, and wherein n is an integer between 10 and 100, and the carrier has an Mw / Mn value between 1 and 2.

5.

54. A carrier in the form of a polyanhydride of the formula -(SA-RA)n- for use in the preparation of an anticancer formulation comprising at least one anticancer agent, wherein SA is sebacic acid and RA is ricinoleic acid, and wherein n is an integer between 10 and 100, said carrier having an Mw / Mn value between 1 and 2.

5.

55. The carrier according to claim 54, prepared by melt condensation of SA and RA in the absence of a solvent, wherein the preparation does not include the use of polysaccharide.

56. The carrier according to claim 54 or 55, prepared in the presence of the at least one anticancer agent.

57. A kit comprising an anticancer drug and a carrier in the form of a polyanhydride of the formula -(SA-RA)n-, wherein SA is sebacic acid and RA is ricinoleic acid, and wherein n is an integer between 10 and 100, said carrier having an Mw / Mn value between 1 and 2.5; and instructions for use.

58. The kit according to claim 57, wherein the drug and the carrier are contained separately.

59. The kit according to claim 57, wherein the drug and the carrier are formulated.

60. The kit according to any one of claims 57 to 59, in the form of a syringe.

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