Sustained release cancer treatment formulations

Abstract

Disclosed herein is a composition for treating cancer comprising an aqueous carrier, a hydrogel composed of tyramine-substituted hyaluronic acid, the hydrogel being formed by di-tyramine crosslinking, and the degree of tyramine substitution of the hydroxyl groups of the hyaluronic acid being from about 0.5% to about 3%; and a lipid phase, the lipid phase comprising an antitumor agent, dispersed in the aqueous carrier, and comprising a plurality of lipid microparticles.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 309,206, entitled Sustained Release Cancer Therapeutics Formulations, filed February 11, 2022, which is incorporated by reference in its entirety into this specification for all purposes. [Background technology]

[0002]

[0002] Multifocal tumors have few surgical treatment options in liver, pancreas, kidney and lung cancer. There is a need in the art for compositions and methods that provide sustained local delivery of antitumor agents to maximize efficacy and minimize systemic effects. Summary of the Invention

[0003]

[0003] The present specification discloses a composition for treating cancer comprising an aqueous carrier which is a hydrogel composed of tyramine-substituted hyaluronic acid, the hydrogel being formed by di-tyramine crosslinking, and the degree of tyramine substitution of the hydroxyl groups of the hyaluronic acid being from about 0.5% to about 3%; and a lipid phase containing an antitumor agent, the lipid phase being dispersed in the aqueous carrier and containing a plurality of lipid microparticles.

[0004] In certain embodiments, the salt form of the anti-tumor agent that is not bound by the plurality of lipid microparticles is dissolved in the aqueous carrier. According to further embodiments, the biological anti-tumor agent that is not bound by the plurality of lipid microparticles is dissolved in the aqueous carrier. In an exemplary implementation of these embodiments, the biological anti-tumor agent is bevacizumab.

[0005] In certain embodiments, the volume ratio between the aqueous carrier and the lipid microparticles is about 70-80 parts aqueous carrier to about 30-20 parts lipid microparticles.

[0006] In certain embodiments, the lipid microparticles comprise one or more fatty acids having an even number of carbons, hi certain embodiments, the one or more fatty acids comprise less than 50% of the total lipid composition of the lipid microparticles.

[0006]

[0007] In a further embodiment, the lipid microparticles comprise one or more fatty acids with an odd number of carbons. In an exemplary embodiment, the one or more fatty acids are selected from stearic acid, oleic acid, myristic acid, caprylic acid, capric acid, lauric acid, palmitic acid, arachidic acid, lignoceric acid, cerotic acid, and mixtures thereof, and the melting point of the lipid microparticles is greater than 37°C. In a further embodiment, the one or more fatty acids comprise a mixture of stearic acid and oleic acid, and the ratio of stearic acid to oleic acid is about 90:10. In yet a further embodiment, the lipid microparticles comprise about 12% myristic acid, about 32% palmitic acid, about 10% stearic acid, and about 10% oleic acid. In yet a further embodiment, the lipid microparticles comprise a mixture of lauric acid and caprylic acid, caproic acid, and / or oleic acid.

[0007]

[0008] According to certain embodiments, the lipid microparticles comprise paraffin, triglyceride, and / or wax. In further embodiments, the lipid microparticles comprise a mixture of carnauba wax and caprylic acid, caproic acid, and / or oleic acid.

[0008]

[0009] According to certain embodiments, the plurality of lipid microparticles comprises a first plurality of lipid microparticles and a second plurality of lipid microparticles, the first plurality of lipid microparticles being solid at about 37°C and the second plurality of lipid microparticles being liquid at 37°C.

[0009]

[0010] In certain embodiments, the lipid microparticle is not a liposome.

[0011] According to certain embodiments, the anti-tumor agent is selected from an anthracycline, an mTOR inhibitor, a VEGF-TKI agent, and an immunostimulant. In an exemplary embodiment, the anti-tumor agent is doxorubicin.

[0010]

[0012] In certain embodiments, the plurality of lipid microparticles ranges from about 5 μm to about 20 μm. In further embodiments, the plurality of lipid microparticles is about 5 μm or less.

[0013] Further disclosed herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising a hydrogel binding matrix; and a plurality of lipid microparticles dispersed in the hydrogel, the lipid microparticles comprising one or more antitumor agents. In certain embodiments, the composition is administered directly to the tumor site, via a guide needle, laparoscopically, or postoperatively after tumor removal. In further embodiments, the composition is administered by injection into a solid tumor via a guide needle, and tumor targeting is confirmed by ultrasound imaging. In yet further embodiments, the antitumor agent elutes from the composition over a period of between about 4 days and about 7 days.

[0011]

[0014] While multiple embodiments are disclosed, still other embodiments of the present disclosure will become apparent to those skilled in the art from the following detailed description, which shows and describes exemplary embodiments of the disclosed apparatus, systems and methods. As will be understood, the disclosed apparatus, systems and methods can be modified in various obvious aspects, all without departing from the spirit and scope of the present disclosure. Accordingly, the drawings and detailed description are to be regarded as illustrative in nature and not restrictive. [Brief description of the drawings]

[0012] [Figure 1]

[0015] FIG. 1 shows the dissolution profile of Formulation A according to certain embodiments. [Diagram 2]

[0016] FIG. 1 shows the dissolution profile of Formulation B according to certain embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013]

[0017] It is to be understood that the compounds, compositions, articles, systems, tools, and / or methods of the present invention are not limited to specific synthetic methods or specific reagents, unless otherwise specified, before being disclosed and described, and therefore may of course vary. It is also to be understood that the terminology used herein is intended to describe specific embodiments only, and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are described herein.

[0014]

[0018] As used herein, ranges can be expressed as from "about" (one particular value) and / or to "about" (another particular value). When such ranges are expressed, further aspects include from (one particular value) and / or to (the other particular value). Similarly, when values ​​are expressed as approximations, using the antecedent "about," it will be understood that the particular value forms a further aspect. It will further be understood that the endpoints of each range are significant both in relation to the other endpoint and independently of the other endpoint. It will also be understood that, although there are a number of values ​​disclosed herein, each value is also disclosed herein as "about" (that particular value) along with the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It will also be understood that each unit between two particular units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0015]

[0019] As used herein, the names of compounds, including organic compounds, may be given using common names, IUPAC, IUBMB, or CAS recommendations for nomenclature. When one or more stereochemical features are present, the Cahn-Ingold-Prelog rules for stereochemistry may be used to indicate stereochemical priority, E / Z designation, and the like. Those skilled in the art can easily ascertain the structure of a compound, given a name, by systematically reducing the compound structure using the naming rules, or by commercially available software, such as CHEMDRAW™ (Perkin Elmer Corporation, USA).

[0016]

[0020] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "functional group," an "alkyl," or a "residue" includes a mixture of two or more such functional groups, alkyls, or residues, etc.

[0017]

[0021] Unless otherwise indicated, reference herein to parts by weight of a particular element or component in a composition indicates the weight relationship between the element or component and any other elements or components in the composition or article for which the parts by weight are expressed, unless expressly stated otherwise. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, X and Y are present in a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are included in the compound.

[0018]

[0022] Unless specifically stated to the contrary, weight percent (wt%) of a component is based on the total weight of the formulation or composition in which the component is included.

[0023] As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and are meant to include cases where said event or circumstance occurs and cases where said description does not occur.

[0019]

[0024] As used herein, the term "subject" may be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. Thus, the subject of the methods disclosed herein may be a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig, or a rodent. The word does not indicate a particular age or sex. Thus, adult and newborn subjects, both male and female, as well as fetuses, are intended to be subjects. In one aspect, the subject is a mammal. A patient refers to a subject suffering from a disease or disorder. The word "patient" includes human and veterinary subjects.

[0020]

[0025] As used herein, the term "treatment" refers to the medical management of a patient with the intention of curing, improving, stabilizing, or preventing a disease, pathological condition, or disorder. This term includes active treatment, i.e., treatment specifically directed to ameliorate a disease, pathological condition, or disorder, and also includes causative treatment, i.e., treatment directed to remove the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, i.e., treatment designed to relieve symptoms rather than cure the disease, pathological condition, or disorder; preventive treatment, i.e., treatment directed to minimize or partially or completely inhibit the progression of the associated disease, pathological condition, or disorder; and adjunctive treatment, i.e., treatment used to supplement another specific treatment directed to ameliorate the associated disease, pathological condition, or disorder. In various embodiments, the term encompasses any treatment of a subject, including a mammal (e.g., a human), including (i) preventing the development of a disease in a subject who may be susceptible to the disease but has not yet been diagnosed as having the disease; (ii) inhibiting the disease, i.e., arresting its progression; or (iii) alleviating the disease, i.e., causing regression of the disease. In one embodiment, the subject is a mammal, e.g., a primate, and in a further embodiment, the subject is a human. The term "subject" also includes domestic animals (e.g., cats, dogs, etc.), farm animals (e.g., cows, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mice, rabbits, rats, guinea pigs, fruit flies, etc.).

[0021]

[0026] As used herein, the term "cancer" refers to cells that have autonomous growth potential. Examples of such cells include cells that have an abnormal state or condition characterized by rapidly proliferating cell proliferation. The term is meant to include cancerous growths, e.g., tumors; oncogenic processes, metastatic tissues, and malignantly transformed cells, tissues, or organs, regardless of histopathological type or stage of invasiveness. Also included are malignant tumors of various organ systems, e.g., respiratory, cardiovascular, renal, reproductive, hematological, nervous, hepatic, gastrointestinal, and endocrine systems; and malignant tumors, e.g., adenocarcinomas, including most colon cancers, renal cell carcinomas, prostate cancer, and / or testicular tumors, non-small cell carcinomas of the lung, cancers of the small intestine, and cancers of the esophagus. "Naturally occurring" cancer includes any cancer that is not experimentally induced by transplanting cancer cells into a subject, including, for example, spontaneous cancer, cancer caused by exposure of a patient to a carcinogen, cancer caused by the insertion of a transgenic cancer gene or knockout of a tumor suppressor gene, and cancer caused by infection, such as viral infection. The term "carcinoma" is recognized in the art and refers to a malignant tumor of epithelial or endocrine tissue. In some embodiments, the method can be used to treat a subject with epithelial cancer, such as a solid tumor of epithelial origin, such as lung cancer, breast cancer, ovarian cancer, prostate cancer, renal cancer, pancreatic cancer, or colon cancer.

[0022]

[0027] As used herein, the term "diagnosed" means that one has been physically examined by a person skilled in the art, e.g., a physician, and found to have a condition that can be diagnosed or treated by a compound, composition, or method disclosed herein. For example, "diagnosed with cancer" means that one has been physically examined by a person skilled in the art, e.g., a physician, and found to have a condition that can be diagnosed or treated by a compound or composition that can reduce tumor size or slow tumor growth. A subject having cancer, tumor, or at least one cancer or tumor cell can be identified using methods known in the art. For example, the anatomical location, overall size, and / or cellular composition of the cancer cells or tumor can be determined using contrast-enhanced MRI or CT. Additional methods for identifying cancer cells include, but are not limited to, ultrasound, bone scans, surgical biopsies, and biological markers (e.g., serum protein levels and gene expression profiles). An imaging solution containing the cell sensitizing composition of the present invention can be used in combination with, for example, MRI or CT to identify cancer cells.

[0023]

[0028] As used herein, the term "prevent" or "preventing" refers to preventing, preventing, removing, forestalling, stopping, or impeding something from happening, especially by prior action. Where reduce, inhibit, or prevent are used herein, it is understood that the use of the other two words is also expressly disclosed, unless expressly indicated otherwise.

[0024]

[0029] As used herein, the phrase "identified as being in need of treatment for a disorder" refers to selecting a subject based on the need for treatment for a disorder. For example, a subject can be identified as being in need of treatment for a disorder based on a prior diagnosis by a person skilled in the art, and then receive treatment for the disorder. It is contemplated that in one aspect, this identification can be performed by a person different from the person who performs the diagnosis. It is also contemplated that in a further aspect, this identification can be performed by the person who subsequently administers.

[0025]

[0030] The terms "anti-tumor agent" and "chemotherapeutic agent" are used interchangeably herein and refer to agents for the treatment of cancer. Typically, anti-tumor agents are cytotoxic anti-neoplastic drugs administered as part of a standardized regimen. Without wishing to be bound by theory, anti-tumor agents act by killing rapidly dividing cells, which is one of the main characteristics of most cancer cells. Preferably, anti-tumor agents are not indiscriminately cytotoxic but rather target proteins that are aberrantly expressed in cancer cells and are essential for the proliferation of cancer cells. Non-limiting examples of anti-tumor agents include: angiogenesis inhibitors, such as angiostatin K1-3, DL-α-difluoromethyl-ornithine, endostatin, fumagillin, genistein, minocycline, staurosporine, and (±)-thalidomide; DNA intercalating / crosslinking agents, such as bleomycin, carboplatin, carmustine, chlorambucil, cyclophosphamide, cis-diammineplatinum(II) dichloride (cisplatin), melphalan, mitoxantrone, and oxaliplatin; DNA synthesis inhibitors, such as (±)-amethopterin (methotrexate), 3-amino-1,2,4-benzotriazine 1,4-dioxin, and 1,2,4-dioxin; cytosine β-D-arabinofuranoside, 5-fluoro-5'-deoxyuridine, 5-fluorouracil, ganciclovir, hydroxyurea, and mitomycin C; DNA-RNA transcription regulators, such as actinomycin D, daunorubicin, doxorubicin, homoharringtonine, and idarubicin; enzyme inhibitors, such as S(+)-camptothecin, curcumin, (-)-deguelin, 5,6-dichlorobenzimidazole 1-β-D-ribofuranoside, etoposide, formestane, fostriecin, hispidin, 2-imino-1-imidazolidineacetic acid (cyclocreatine), mevinolin, trichostatin A, tyrophostin AG 34, and Tyrophostin AG 879; gene regulators, such as 5-aza-2'-deoxycytidine, 5-azacytidine, cholecalciferol (vitamin D3), 4-hydroxytamoxifen, melatonin, mifepristone, raloxifene, all trans-retinal (vitamin A aldehyde), retinoic acid, all trans (vitamin A acid), 9-cis-retinoic acid,13-cis-retinoic acid, retinol (vitamin A), tamoxifen, and troglitazone; microtubule inhibitors such as colchicine, dolastatin 15, nocodazole, paclitaxel, podophyllotoxin, rhizoxin, vinblastine, vincristine, vindesine, and vinorelbine (navelbine); and unclassified antineoplastic agents such as 17-(allylamino)-17-demethoxygeldanamycin, 4-amino-1,8-naphthalimide, apigenin, brefeldin A, cimetidine, dichloromethylene-diphosphonic acid, leuprolide (leuprorelin), luteinizing hormone-releasing hormone, pifithrin-alpha, rapamycin, sex hormone-binding globulin, thapsigargin, and urinary trypsin inhibitor fragment (bikunin). The antineoplastic agent may be a neoantigen. Neoantigens are tumor-associated peptides that function as active pharmaceutical ingredients in vaccine compositions that stimulate antitumor responses, as described in US2011-0293637, which is incorporated herein by reference in its entirety. Antitumor agents include monoclonal antibodies, such as rituximab, alemtuzumab, ipilimumab, bevacizumab, cetuximab, panitumumab, and trastuzumab, vemurafenib imatinib mesylate, erlotinib, gefitinib, vismodegib, 90Y-ibritumomab tiuxetan, 131I-tositumomab, ado-trastuzumab emtansine, lapatinib, pertuzumab, ado-trastuzumab emtansine, regorafenib, sunitinib, denosumab, sorafenib, pazopanib, akimoto et al. The antitumor agent may be a cytokine, such as an interferon (INF), an interleukin (IL), or a hematopoietic growth factor. The antitumor agent may be an INF-α, IL-2, aldesleukin, IL-2, erythropoietin ...The antitumor agent may be a targeted therapy, such as toremifene, fulvestrant, anastrozole, exemestane, letrozole, ziv-aflibercept, alitretinoin, temsirolimus, tretinoin, denileukin diftitox, vorinostat, romidepsin, bexarotene, pralatrexate, lenaliomide, belinostat, pomalidomide, cabazitaxel, enzalutamide, abiraterone acetate, radium 223 chloride, or everolimus. The antitumor agent may be a checkpoint inhibitor, such as an inhibitor of the PD-1 (programmed death-1) pathway, such as an anti-PD1 antibody (nivolumab). The inhibitor may be an anti-cytotoxic T-lymphocyte-associated antigen (CTLA-4) antibody. The inhibitor may target another member of the CD28 CTLA4 Ig superfamily, such as BTLA, LAG3, ICOS, PDL1, or KIR. The checkpoint inhibitor may target a member of the TNFR superfamily, such as CD40, OX40, CD137, GITR, CD27, or TIM-3. In addition, the antitumor agent may be an epigenetic targeting drug, such as an HDAC inhibitor, a kinase inhibitor, a DNA methyltransferase inhibitor, a histone demethylase inhibitor, or a histone methylation inhibitor. The epigenetic drug may be azacitidine, decitabine, vorinostat, romidepsin, or ruxolitinib.

[0026]

[0031] The major categories into which some antiproliferative agents fall include antimetabolites, alkylating agents, antibiotic-type agents, hormonal anticancer agents, immunological agents, interferon-type agents, and various antineoplastic agent categories. Some antiproliferative agents act through multiple or unknown mechanisms and therefore may be classified into more than one category.

[0027]

[0032] As used herein, the terms "administering" and "administration" refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, intradermal administration, buccal administration, and parenteral administration, including those for injection, e.g., intravenous administration, intraarterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent.

[0028]

[0033] The term "contacting," as used herein, refers to bringing together the disclosed compositions with a cell (e.g., a tumor cell), target receptor, or other biological entity in such a manner that the compound can affect the activity of the target, either directly; i.e., by interacting with the target itself, or indirectly; i.e., by interacting with another molecule, cofactor, factor, or protein on which the activity of the target is dependent.

[0029]

[0034] As used herein, the words "effective amount" and "effective amount" refer to an amount that is sufficient to achieve a desired result or to have an effect on an undesired condition. For example, the specific effective amount for any particular subject will depend on a variety of factors, including: the disorder to be diagnosed and the severity of the disorder; the particular composition used; the age, weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the particular compound used; the duration of the diagnosis; drugs used in combination or concomitantly with the particular compound used, and similar factors well known in the medical field. For example, it is well within the skill of the art to start the dose of the compound at a level lower than that required to achieve the desired diagnostic effect, and gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses depending on the purpose of administration. Thus, a single dose composition can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. The dosage can vary and can be administered in one or multiple doses per day for one or several days. Guidance can be found in print for appropriate dosages for a given class of pharmaceutical products. Additionally, effective dosages can be initially estimated from in vitro assays. For example, initial dosages for use in animals can be formulated to achieve a circulating or serum concentration of the active compound equal to or greater than the IC50 of the particular compound as measured in an in vitro assay. It is well within the ability of one of ordinary skill in the art to calculate dosages to achieve such circulating or serum concentrations, taking into account the bioavailability of a particular active agent. For guidance, see Fingl & Woodbury, "General Principles," in Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, latest edition, Pergamagon Press (incorporated herein by reference in its entirety and in the references cited therein).

[0030]

[0035] The term "pharmaceutical acceptable" describes a substance that is not biologically or otherwise undesirable, i.e., does not cause unacceptable levels of undesirable biological effects or interact in an adverse manner.

[0031]

[0036] As used herein, the term "pharmaceutical acceptable carrier" refers to sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions immediately prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (e.g., glycerol, propylene glycol, and polyethylene glycol, etc.), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions can also contain auxiliary agents, such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid. It may also be desirable to include isotonic agents, such as sugars, and sodium chloride. Injectable pharmaceutical forms can prolong absorption by including agents such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers, such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). The release rate of the drug can be controlled by the ratio of drug to polymer and the nature of the particular polymer used. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable solvents immediately before use. Suitable inert carriers can include sugars, for example, lactose.

[0032]

[0037] The compounds described herein may contain one or more double bonds, which may give rise to cis / trans (E / Z) isomers as well as other conformational isomers, and unless otherwise stated, the present invention includes all such possible isomers, as well as mixtures of such isomers.

[0033]

[0038] Unless otherwise indicated, formulas in which chemical bonds are shown only with solid lines and not with wedges or dashed lines contemplate each possible isomer, e.g., each enantiomer and diastereomer, as well as mixtures of isomers, e.g., racemic or scalemic mixtures. Compounds described herein may contain one or more asymmetric centers, which may give rise to diastereomers and optical isomers. Unless otherwise indicated, the present invention includes all such possible diastereomers, as well as racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers, and pharma- ceutically acceptable salts thereof. Mixtures of stereoisomers, and isolated specific stereoisomers are also included. During the synthetic procedures used to prepare such compounds, or by using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

[0034]

[0039] Many organic compounds exist in optically active forms that have the ability to rotate the plane of plane-polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its chiral centers. The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these compounds are called stereoisomers and are identical except that they are non-superimposable mirror images of one another. Certain stereoisomers are also called enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture. Many of the compounds described herein may have one or more chiral centers and therefore may exist in different enantiomeric forms. Optionally, a chiral carbon may be represented by an asterisk ( * ). When a bond to a chiral carbon is drawn as a straight line in a disclosed formula, it is understood that both the (R) and (S) configurations of the chiral carbon, and thus both enantiomers and mixtures thereof, are encompassed in the formula. As used in the art, when it is desired to specify an absolute configuration for a chiral carbon, one of the bonds to the chiral carbon (the bond to an atom above the plane) can be drawn as a wedge, and the other bond (the bond to an atom below the plane) can be drawn as a series of short parallel lines or a wedge made of short parallel lines. The Cahn-Inglod-Prelog system can be used to assign an (R) or (S) configuration to a chiral carbon.

[0035]

[0040] The compounds described herein can contain both natural and non-natural isotopic abundances of atoms.The disclosed compounds can be isotopically labeled or isotopically substituted compounds that are identical to those described, except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from the atomic masses or mass numbers typically found in nature.Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 13 N, 15 N, 18 O. 17 O. 35 S, 18 F and 36 The compounds further include prodrugs thereof, as well as pharma- ceutically acceptable salts of said compounds or said prodrugs, that contain the aforementioned isotopes and / or other isotopes of other atoms within the scope of the invention. Certain isotopically labeled compounds of the invention, for example, those that contain radioactive isotopes, e.g., 3 H and 14 C incorporation is useful for drug and / or substrate tissue distribution assays. Tritium isotopes, i.e., 3 H isotope, and carbon-14 isotope, i.e. 14 C isotopes can be used because they are easy to prepare and detectable. Additionally, heavier isotopes, such as deuterium, i.e. 2 Substitution with H can confer certain advantages resulting from increased metabolic stability, e.g., increased half-life in vivo or reduced dosage requirements, and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the following procedures, substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0036]

[0041] Chemical substances are known to form solids that exist in various ordered states, called polymorphic forms or modifications. The various modifications of a polymorphic substance may have significantly different physical properties. The compounds according to the present invention may exist in various polymorphic forms, and it is possible that certain modifications are metastable. Unless otherwise stated, the present invention includes all such possible polymorphic forms.

[0037]

[0042] Certain substances, compounds, compositions, and components disclosed herein are commercially available or can be readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions can be obtained from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wis.), Acros Organics (Morris Plains, NJ), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.), or prepared by methods known to those of skill in the art following procedures described in references, such as Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, volumes 1-5 and supplements (Elsevier Science Publishers, 1989); Organic Reactions, volumes 1-40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry (John Wiley and Sons, 4th ed.); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0038]

[0043] Unless expressly stated otherwise, the methods described herein are in no way intended to be interpreted as requiring that the steps be performed in a particular order. Thus, unless a method claim actually recites an order in which the steps should be followed, or unless otherwise specifically stated in the claim or description that the steps are limited to a particular order, no order is intended to be inferred in any respect. This also applies to any possible implicit grounds for interpretation, including: logical matters regarding the arrangement or operational flow of the steps; plain meaning derived from grammatical constructions or punctuation; as well as the number or type of embodiments described herein.

[0039]

[0044] Disclosed are the components used to prepare the compositions of the present invention, and the compositions themselves used in the methods disclosed herein. These and other substances are disclosed herein, and when disclosing combinations, subsets, interactions, groups, etc. of these substances, it is understood that specific references to each of the various individual and collective combinations and permutations of these compounds cannot be explicitly disclosed, but each is specifically contemplated and described herein. For example, when a particular compound is disclosed and discussed, and a number of modifications that can be made to a number of molecules that include the compound are discussed, all combinations and permutations of the compounds and possible modifications are specifically contemplated, unless specifically indicated to the contrary. Thus, when a class of molecules A, B, and C is disclosed, a class of molecules D, E, and F is disclosed, and an example of a combination of molecules AD is disclosed, each is intended to mean that, individually and collectively, the combinations AE, AF, BD, BE, BF, CD, CE, and CF are considered to be disclosed, even if not listed individually. Similarly, any subset or combination of these is also disclosed. Thus, for example, the subgroups AE, BF, and CE are considered to be disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, where there are various additional steps that can be performed, it is understood that each of these additional steps can be performed in any particular embodiment or combination of embodiments of the method of the invention.

[0040]

[0045] It is understood that the compositions disclosed herein have certain functions. The specification discloses certain structural requirements to perform the disclosed functions, and it is understood that there are various structures that can perform the same functions related to the disclosed structures, and that these structures will generally achieve the same results.

[0041]

[0046] As used herein, the word "substantially" refers to the complete or nearly complete extent or degree of an action, attribute, property, state, structure, item, or result. For example, an object that is "substantially" enclosed means that the object is completely enclosed or nearly completely enclosed. The exact allowance for deviation from absolute completeness may depend on the particular context in some cases. Generally speaking, however, the closer one approaches a complete state, the more likely it is that the same overall result will be obtained as if an absolute and utter complete state had been obtained. The use of "substantially" is equally applicable when used in a negative sense, referring to a complete or nearly complete lack of an action, attribute, property, state, structure, item, or result. For example, a composition that is "substantially free of particles" is either completely devoid of particles or nearly completely devoid of particles such that the effect is the same as a complete lack of particles. In other words, a composition that is "substantially free of ingredients or elements" may still actually contain such items, so long as there is no measurable effect of them.

[0042]

[0047] As used herein, "drug reservoir" refers to a phase in which the anti-tumor drug is dissolved that is separate from the carrier phase.

[0048] As used herein, the words "preferred" and "preferably" refer to embodiments of the invention that may offer certain advantages, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Moreover, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention.

[0043]

[0049] Disclosed herein are compositions and methods for the treatment of cancer. In certain embodiments, the disclosed compositions include a hydrogel matrix, a plurality of nanoparticles dispersed in the hydrogel, and one or more anti-tumor agents dispersed in the nanoparticles. The disclosed compositions and methods allow the targeted agent to be placed in a desired tissue site at a high concentration and eluted from the mass at a desired rate. In certain embodiments, the anti-tumor agent can be placed in a tumor or tumor site at a relatively high concentration and eluted at a desired rate to shrink or eliminate solid tumors. Multifocal tumors, such as those found in liver, kidney, and lung cancer, leave few options. Shrinking or eliminating the tumor can extend the life of the patient. The targeted agent can be designed to elute the anti-proliferative agent over a period of days to ensure a high enough concentration of the therapeutic agent locally to make the therapeutic agent more effective while simultaneously reducing the systemic concentration of the therapeutic agent to alleviate symptoms caused by the therapeutic agent. Many anti-proliferative agents work by interfering with DNA replication and cell division. Maintaining a high concentration of these anti-proliferative agents locally will make them more effective. In some cases, the formulations can also be embolized to directly kill tumor cells and then the area can be treated with a therapeutic agent to ensure that all cancer cells are treated. These are examples of cancer treatments where surgery or removal is not an option otherwise. In further embodiments, the liposome or hydrogel-based drug reservoir particles have endotoxins / pyrogenic substances that elicit a large local immune response without the need for an active biological agent (i.e., bacteria) and can cause tissue damage or, if systemic, can establish a potentially fatal infection. The large local immune response would allow the patient's immune system to activate and recognize the nearby cancer in an artificially induced infection-like response and attack the tumor cells. IL-2 or similar immune system activators can also be used to elicit a similar response. Other immunostimulants can be provided in addition to the cancer therapeutic agent in the same formulation or in addition to the therapeutic agent in a second procedure.

[0044]

[0050] According to certain embodiments, the disclosed compositions comprise a carrier phase and a drug reservoir phase containing an API (e.g., an antitumor agent), which is released into a biological system for a targeted therapeutic period. In this context, the main function of the carrier phase is to disperse the drug reservoir particles (drug-loaded components) to create a stable homogenous mass, allowing a dose to be drawn up from a container using a delivery tool, e.g., a syringe, and delivered to a target tissue, i.e., parenteral injection, intravascular injection, wound injection, wound packing, or massing or coating of a tissue surface. In certain embodiments, the drug reservoir is a separate physical phase, a collection of particles, contained in, but not indistinguishable from, the carrier phase. The reservoir phase contains the active pharmaceutical agent dissolved in the reservoir material, and may be unsaturated, saturated, supersaturated, or saturated with pure pharmaceutical phase material (crystals for small molecules). In some forms, the carrier may also contain the antineoplastic agent in a different form than the reservoir, for example, antineoplastic agent salt in an aqueous carrier and antineoplastic agent in base form in a lipid reservoir. The system may not be set up solely in an aqueous / hydrophobic phase, but in an opposite or different physical phase (polymer).

[0045]

[0051] In certain embodiments, the carrier phase is a hydrogel. The word "hydrogel" as used herein refers to a three-dimensional hydrophilic or amphiphilic polymer network that can incorporate large amounts of water. The network is composed of homopolymers or copolymers (sometimes referred to herein as polymer backbones) and is insoluble due to the presence of covalent chemical or physical (ionic, hydrophobic interactions, entanglement) crosslinks. The crosslinks provide the network structure and physical integrity. Hydrogels exhibit thermodynamic compatibility with water, which allows them to swell in aqueous media.

[0046]

[0052] In certain embodiments, the hydrogel is composed of tyramine-substituted hyaluronic acid (THA) crosslinked by di-tyramine linkages. The preparation of THA is described in U.S. Patent No. 6,982,298, which is incorporated herein by reference in its entirety. The degree of tyramine substitution significantly affects the properties of the resulting hydrogel. Throughout this disclosure, the degree of tyramine substitution refers to the percentage of total HA carboxyl groups substituted by tyramine. For example, in 2% substituted THA, 2% of total HA carboxyl groups are substituted by tyramine. The percent tyramine substitution in each THA preparation is calculated by measuring: 1) the concentration of tyramine present in the preparation, which is spectrophotometrically determined based on the inherent UV absorption properties of tyramine at 275 nm; and 2) the concentration of total carboxyl groups in the HA preparation, which is spectrophotometrically determined by standard hexuronic acid assay.

[0047]

[0053] As described further below, hydrogels can be tailored to have specific osmotic pressures, physical properties, anti-tumor drug elution rates or tissue responses by adjusting the concentration of tyramine-substituted polymer backbone, the degree of substitution of tyramine on the polymer backbone, the molecular weight of the polymer backbone, the hydrophobicity of the polymer backbone, the type of polymer backbone, and the concentration of targeting molecules, salts, buffers or drug depot (reservoir) particles contained within the hydrogel.

[0048]

[0054] The hydrogel binding matrix is ​​composed of a biopolymer backbone that contains carboxyl chemical functional groups. Examples of biopolymer backbones include hyaluronic acid and proteins. In certain embodiments, the carboxyl groups are reacted with tyrosine at a concentration of about 0.25% to about 7%. According to certain further embodiments, the tyrosine concentration is lower or higher. Examples provided in the present disclosure range from about 1 to about 5.5% tyrosine substitution. The tyrosine-substituted hyaluronic acid is then placed in a solution with a liposome mixture as the solvent phase. In the examples used in the present disclosure, the solution contains about 0.1% to about 4% at a preferred concentration. The liposomes may be replaced by dense hydrogel particles, or a mixture of particles of various consistencies, or may include liposomes and dense particles to control the delivery rate of the target molecule. The dense particles may be 5.5% tyramine substituted and up to 10%, and in some cases more than 10%, of the biopolymer backbone.

[0049]

[0055] The density of the gel can be used to control the elution rate of the antitumor agent from the gel into the target tissue. A 1% hydrogel elutes the antitumor agent for more than 72 hours, but a 10% gel extends the elution time to more than 100 hours. Depending on the size of the antitumor agent or biological material and its affinity for the hydrogel components, the elution rate can be adjusted to a desired elution rate that allows the hydrogel to function as a drug reservoir for several days.

[0050]

[0056] Hydrogel physical properties can also be adjusted by changing the type of polymer backbone. For example, collagen can be used as a polymer backbone, but it is much less hydrophilic than saccharide-based polymer backbones. Collagen gels do not swell in the same way as polysaccharide gels and have a much lower molecular weight and concentration. It can be envisioned that the polymer backbone can be changed to utilize the physical and chemical properties of a single polymer, or that several types can be combined into a copolymer or block copolymer to change the physical and chemical properties of the gel and the body's interaction with the gel. Some polymers have a higher degree of affinity for the antitumor agent, which affects the antitumor agent elution rate if a polymer or part of a polymer with a higher binding affinity for the antitumor agent is selected. It can also be envisioned that by using a polymer / antitumor agent combination in which the binding affinity of the antitumor agent to the backbone polymer is pH or temperature dependent, the gel formulation can be adjusted to maximize binding at T=0 and then release more antitumor agent as the pH and temperature approach physiological conditions after exposure to the target tissue. In a further embodiment, the diffusion rate of the anti-tumor agent is affected by changes in the melting point of the lipid microparticles (as further described below) since enhanced diffusion can be achieved by the diffusion flow at the liquid-liquid interface (achieved upon melting of the lipid microparticles) being higher than that at the solid-liquid interface.

[0051]

[0057] The osmotic pressure of the hydrogel can also be adjusted by the degree of tyramine substitution and concentration. Concentrated high-substitution hydrogels will by themselves expel water or syneresis, but in the example of hyaluronic acid, the gel can be made osmotically neutral or slightly swollen by increasing the concentration of the polymer backbone or by adding salts, buffers and / or antitumor substances to the formulation. For example, a 5.5% substituted gel can be made to swell when the backbone polymer concentration is set at 1.5%. It is envisioned that the gel can be made to swell further as the osmotic pressure is increased by adding buffers, salts and API components. In certain aspects, the hydrogel is composed of tyramine-substituted hyaluronic acid. According to certain embodiments, the hydrogel is formed by di-tyramine crosslinking.

[0052]

[0058] The concentration and degree of substitution of the backbone polymer can also be adjusted to suit the intended route of administration. Gels with substitution levels of 0.1 to 1% can be delivered through a needle; 1-2% can be delivered through a large bore needle, i.e., 14-16 gauge, and above 2% require application through an applicator to the tumor surface. Higher viscosity gels can be used to increase retention at the tumor site.

[0053]

[0059] The density of the hydrogel can be used to control the elution rate of the antitumor agent from the gel into the target tissue. A 1% hydrogel elutes the antitumor agent for more than 72 hours, but a 10% gel extends the elution time to more than 100 hours. Depending on the size of the API or biomaterial and its affinity for the hydrogel components, the elution rate can be adjusted to a desired elution rate that allows the hydrogel to function as a drug reservoir for several days.

[0054]

[0060] In certain embodiments, the degree of tyramine substitution of the hydroxyl groups of hyaluronic acid ranges from about 0.25% to about 8%. In further embodiments, the degree of tyramine substitution of the hydroxyl groups of hyaluronic acid ranges from about 0.5% to about 3%.

[0055]

[0061] In yet a further embodiment, the tyramine substituted hyaluronic acid is present in the aqueous phase at about 0.1% to about 4%.

[0062] In certain embodiments, the tyramine-substituted hyaluronic acid is present in the aqueous phase at about 0.1% to about 1%. In further embodiments, the tyramine-substituted hyaluronic acid is present in the aqueous phase at about 0.25%. lipid microparticles

[0063] According to certain embodiments, the lipid microparticles of the disclosed composition are composed of one or more fatty acids.In certain embodiments, the one or more fatty acids have an even number of carbons.In certain embodiments, the fatty acid is selected from stearic acid, oleic acid, myristic acid, caprylic acid, capric acid, lauric acid, palmitic acid, arachidic acid, lignoceric acid, cerotic acid, and mixtures thereof.

[0056]

[0064] In certain exemplary embodiments, when the fatty acid microparticles are composed of a mixture of fatty acids, the fatty acids are present in a particular ratio, for example, in certain embodiments, the mixture of fatty acids comprises a 90:10 ratio of stearic acid to oleic acid.

[0057]

[0065] Fatty acids of various carbon lengths are widespread throughout the living world and are utilized by animals as part of cell membranes, as energy stores, and for thermoregulation. Fatty acids consist of carboxylic acids attached to an aliphatic carbon chain. In general, fatty acids are insoluble in water, but as the carbon chain length decreases, the acidity increases. Fatty acids may be saturated or contain no carbon-carbon double bonds. Alternatively, fatty acids may be unsaturated, containing one or more carbon-carbon double bonds in the aliphatic carbon chain. Mammalian organisms can process and make fatty acids with even carbon chains. Odd-numbered fatty acids are produced by some bacteria and are found in the milk of ruminants, but most are even-numbered due to metabolic processes that add two carbons at a time to the chain. Table 1 lists fatty acids typically found in plants and animals. The lipid number includes the number of carbons in the aliphatic chain followed by the number of double bonds. In some listings, the position of the double bonds is included in the lipid number. In most cases, the fatty acids are usually part of a triglyceride molecule, which can contain up to three fatty acids of the same or different carbon lengths.

[0058]

[0066] In certain embodiments, even carbon fatty acids are selected. A mixture of fatty acids can be made to tailor the melting point of the microparticles. In certain embodiments, a mixture of 90% stearic acid with 10% oleic acid is used. This creates a microparticle that melts at 35°C (95°F). A similar melting point is achieved by mixing 12% myristic acid, 32% palmitic acid, 10% stearic acid, and 10% oleic acid. According to a further embodiment, fatty acid microparticles are formed from a mixture of lauric acid, caprylic acid, and caproic acid. An important factor when selecting a microparticle formulation is the melting point and the antineoplastic agent solubility in the main fatty acid. The melting point is important in that the particles close to physiological body temperature become liquid or soft semi-solid, increasing the rate of diffusion (across the liquid-liquid interface). This may or may not be desirable depending on the particular application. In certain embodiments, a combination of low and high melting microparticles (e.g., below 37°C and above 37°C) are combined. Antitumor agent solubility varies with fatty acid chain length and microparticle formulation, and it may be desirable to adjust the antitumor agent concentration and affinity for the major microparticle fatty acid components. In some formulations, increasing the molecular weight and chain length of the fatty acid counterintuitively alters the solubility of partially polar antitumor agents. In certain embodiments, the concentration of the antitumor agent in the fatty acid microparticle is about 1-25% by weight.

[0059]

[0067] According to certain alternative embodiments, odd-numbered fatty acids are used as alternative fatty acids in the formulation.Monounsaturated fatty acids, such as oleic acid, can be used alone or in combination with other fatty acids as well.In certain embodiments, polyunsaturated fatty acids can be used, but are not preferred because they are easily oxidized and may polymerize depending on the formulation.Monounsaturated fatty acids in cis configuration (mostly plant-derived) are preferred.

[0060]

[0068] According to certain alternative embodiments, the lipid microparticles comprise one or more triglycerides or mixtures of triglycerides, and the lipid microparticles comprise one or more triglycerides or mixtures of triglycerides. In further alternative embodiments, the lipid microparticles comprise paraffin and / or wax.

[0061] [Table 1-1]

[0062] [Table 1-2]

[0063] [Table 2]

[0064]

[0069] In certain embodiments, polyunsaturated fatty acids are used to create microparticles, either alone or in mixtures with other fatty acids. Polyunsaturated fats typically have a lower melting point than saturated fatty acid analogs of comparable carbon numbers. Examples of two essential fatty acids are linoleic acid (C18:2) and alpha-linoleic acid (C18:3). The human body cannot make these fatty acids, but it needs them and must obtain them from the diet. The human body can metabolize them, so they can be used to create microparticle drug reservoirs, but they have multiple double bonds that are easily oxidized and may react with some APIs.

[0065] [Table 3]

[0066] [Table 4]

[0067]

[0070] Conjugated fatty acids can also be used alone or in mixtures with other fatty acids to create particulate drug reservoirs with desirable API solubility / affinity and physical properties.

[0068] [Table 5]

[0069]

[0071] Drug reservoir microparticles can also be made from animal ester waxes, such as beeswax, vegetable waxes, lanolin and derivatives. Animal ester waxes typically include triacontanyl palitate, and a mixture of palmitic acid esters, palmitoleic acid esters, oleic acid esters, triglycerides and fatty alcohols. Additives, such as cholesterol, triglycerides and fatty alcohols, can be added to change the physical properties of the microparticles, the solubility and affinity of antitumor agents to the microparticles, and act as carrier molecules that help the antitumor agents diffuse out of the microparticles.

[0070]

[0072] Mineral waxes, mineral oils and lanolin derivatives can be added to modify the physical and chemical properties of the fatty acid microparticles.

[0073] Plant-derived waxes can also be used to create the primary phase of the microparticles. Plant waxes have the advantage over animal waxes that the environmental conditions are easier to control and there is less batch-to-batch variation because they are from the same organism (palm or plant). Suitable animal and plant waxes are listed in Table 8. In certain embodiments, the fatty acid microparticles are comprised of carnauba wax. In further embodiments, the fatty acid microparticles are comprised of a combination of carnauba wax and fatty acids. In an exemplary embodiment, the mixture is carnauba wax and oleic acid, caproic acid, caprylic acid, and / or mixtures of the foregoing.

[0071] [Table 6]

[0072] [Table 7]

[0073] [Table 8]

[0074] Triglycerides are an alternative to pure fatty acids. They have similar physical properties and similar solubility of antitumor agents as their pure counterparts. Triglycerides are found throughout the body and are better tolerated because of the metabolic pathways that absorb and metabolize lipids. Table 9 lists triglycerides that can replace fatty acids as lipid drug reservoir particles. In general, even-numbered fatty acid components are chosen because even-numbered fatty acids are more abundant in tissues. There are some odd-numbered fatty acid triglycerides that are utilized in the body, such as triheptanoin found in milk, which are also suitable. Unsaturated fatty acid-based triglycerides, such as triolein, can be used to soften lipid particles or to create emulsion droplets if a multiphase formulation is desired. Unsaturated triglycerides, such as tripalmitolein, the main component of mammalian fat, are found throughout the body. Utilizing triglycerides already found in the body improves tolerance and / or reduces the likelihood of adverse reactions. In certain embodiments, the concentration of the anti-tumor agent in the triglyceride microparticles is about 1 to about 16% by weight.

[0075] [Table 9-1]

[0076] [Table 9-2]

[0077] In certain embodiments, the hydrogel composition comprises a plurality of lipid microparticles having different characteristics with respect to lipid composition, size, and / or antineoplastic agent concentration. In these embodiments, a mixture of lipid microparticles is used to improve the elution rate of the drug and to adjust the elution to provide a steady first-order release from the particles. By adjusting the ratio of particle volume to carrier phase volume, the release time of the antineoplastic agent is extended.

[0078]

[0076] In an exemplary embodiment, fatty acids comprise up to 50% (wt%) of the total lipid content of the lipid microparticles. In an exemplary embodiment, the lipid microparticle is not a liposome.

[0079]

[0078] In certain embodiments, the lipid microparticles are formulated to be solid when implanted in a subject (e.g., at a temperature of about 37°C). In further embodiments, the lipid microparticles are formulated to be liquid when implanted in a subject, the effect being to increase the elution rate from such liquid microparticles compared to solid microparticles having a similar concentration of antineoplastic agent. In yet further embodiments, the composition includes both of the aforementioned microparticles, such that upon implantation in a subject, some of the microparticles remain solid while some become liquid. The relative balance of the two types of microparticles can be adjusted to achieve the desired elution characteristics.

[0080]

[0079] The size of the lipid microparticles, in certain embodiments, ranges from about 1 μm to about 20 μm in size. In further embodiments, the size of the lipid microparticles ranges from about 5 μm to about 15 μm in size. In certain exemplary embodiments, the lipid microparticles are about 5 μm. In further exemplary embodiments, the lipid microparticles are less than about 5 μm.

[0081]

[0080] In certain embodiments, the dissolution characteristics of the disclosed compositions are influenced by the volume ratio of the aqueous phase to the lipid phase in the composition. According to certain embodiments, the ratio of the aqueous phase to the lipid phase is about 50% to 80% by volume of water to about 20% to 50% by volume of lipid phase. According to further embodiments, the ratio of the aqueous phase to the lipid phase is about 60% to 80% by volume of water to about 20% to 40% by volume of lipid phase. According to yet further embodiments, the ratio of the aqueous phase to the lipid phase is about 70% by volume of water to about 30% by volume of lipid phase.

[0082]

[0081] According to certain further embodiments, the composition comprises two or more lipid phases in the aqueous carrier phase. In certain implementations of these embodiments, distributed in the aqueous phase are a lipid microparticle phase and a secondary lipid phase, which may take the form of an emulsion or multiple lipid microparticles in the aqueous phase, as described above, from which the antineoplastic agent elutes at a faster rate than the primary lipid microparticle phase. The effect of the aqueous phase is to support the microparticles and the secondary lipid phase and to keep these components uniform throughout the formulation. It provides volume so that precise doses can be delivered to the tumor site and may include a salt form of the antineoplastic agent. The salt form of the antineoplastic agent delivers an initial burst of drug equivalent to a saline form of the antineoplastic agent at a similar dose. The primary lipid phase, or drug reservoir microparticle, contains the maximum amount of the antineoplastic agent in the base form and slowly elutes the drug component into the aqueous phase after an initial burst has eluted from the drug into the surrounding tissue. Mass transfer is limited by the solubility of the base form in the aqueous carrier phase and the hydrophilic lipophilic balance (HLB) ratio of the microparticles. The base form has a high affinity to the lipid phase, and because of the affinity of the drug to the lipid phase, some of the antitumor agent always exists in the lipid phase after dissolution is completed. The secondary lipid phase, or emulsion phase (which may be a second type of solid particles in some formulations) delivers the antitumor agent at a faster rate than the solid phase particulates, and together they increase the dissolution rate in the intermediate phase. When the target period is reached, the dissolution rate decreases to zero and is below the pharmacologic effective dose. In certain embodiments, the composition comprises an emulsion phase as described above, but does not comprise a plurality of solid particulates.

[0083]

[0082] A suitable lipid for the second lipid emulsion phase is any lipid or mixture of lipids that is liquid at 37°C. Examples include, but are not limited to, stearic acid, oleic acid, caprylic acid, capric acid, lauric acid, palmitic acid, arachidic acid, lignoceric acid, cerotic acid. In certain embodiments, a mixture of stearic acid and oleic acid is the lipid in the lipid emulsion phase. In further embodiments, triglycerides (e.g., trioleic acid esters or tripaltimin and trioleic acid esters) form the second lipid emulsion phase. According to certain embodiments, an emulsifier is used to stabilize the emulsion. An emulsifier, such as TWEEN® or other emulsifiers known in the art, is suitable.

[0084]

[0083] In certain embodiments, the antitumor drug elution characteristics of the disclosed compositions are influenced by the volume ratio of two or more lipid phases. According to certain embodiments, the ratio of solid particulate lipid to emulsion lipid phase is about 50% to 75% solids to about 25% to 50% emulsion phase by volume. According to certain embodiments, the ratio of solid particulate lipid to emulsion lipid phase is about 66% solids to about 34% emulsion phase by volume. Methods for formulating lipid microparticle hydrogel compositions According to certain embodiments, lipid microparticles are made by stirring a solution of the fatty acid phase containing the antitumor agent in a much larger volume of aqueous phase. The preferred ratio of aqueous phase to lipid phase is 95%-99.5% aqueous phase to 0.5%-5% lipid phase. The aqueous phase is preferably saturated with the API present in the lipid phase. In certain embodiments, the salt at a concentration of more than 25 mmol is present in the aqueous phase, preferably between 25 and 150 mmol, more preferably between 45 and 65 mmol. The tyramine-substituted hyaluronic acid is present in the aqueous phase at a concentration of 0.1% to 4%, preferably between 0.1 and 1%, especially 0.5%. The two-phase mixture is stirred and cooled until microparticles are made. The particles are concentrated using a centrifuge, filter or settler, and the aqueous phase is decanted, leaving the microparticles behind. The released particles are suspended in this solution with the addition of an additional aqueous phase containing tyramine-substituted hyaluronic acid and horseradish peroxidase in a volume ratio of 30% lipid to 70% aqueous phase. A hydrogel is formed by the addition of hydrogen peroxide. The hydrogel keeps the particles separated and allows for easy delivery via a syringe.

[0085] According to certain embodiments, formulations having two or more lipid phases (e.g., lipid microparticles and emulsions) can be prepared similarly to the preceding paragraph, except that prior to addition of the microparticles to the aqueous phase, the antineoplastic agent is dissolved in a liquid lipid phase (in certain embodiments, a mixture of stearic and oleic acids) and vigorously mixed with the aqueous phase until an emulsion is formed. After emulsion formation, lipid microparticles are added as described above.

[0086]

[0086] Without wishing to be bound by theory, it is believed that the zeta potential is increased by the addition of salt (e.g., NaCl) to the aqueous phase, increasing the surface charge and causing the particles to repel one another, allowing for the formation of smaller particles, and preventing the particles from coalescing to form larger particles prior to solidification. In certain embodiments, the hydrogel comprises between 10 mM and about 70 mM salt. In further embodiments, the salt concentration is between about 25 mM salt and about 50 mM salt. In further embodiments, the hydrogel comprises at least about 50 mM salt. In certain embodiments, the salt is NaCl. Other salts are possible, as will be appreciated by those skilled in the art.

[0087]

[0087] In certain embodiments of the disclosed compositions, the anti-tumor agent comprises ropivacaine. In exemplary embodiments, the ropivacaine is present in the lipid microparticles in an amount of about 1 to about 25%. In further embodiments, the lipid microparticles are composed of triglycerides.

[0088] According to certain alternative embodiments, the anti-tumor agent not bound by the lipid microparticles is dispersed throughout the hydrogel. According to these embodiments, the API dispersed throughout the hydrogel provides an immediate burst dose, while the API bound in the lipid microparticles provides a long-term sustained release.

[0089] In certain embodiments, the composition further comprises a radiopaque contrast agent.

[0090] Further disclosed herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising an immiscible carrier phase and a plurality of lipid microparticles dispersed in the immiscible carrier phase, the lipid microparticles comprising an antitumor agent. In certain embodiments, the immiscible carrier phase is a hydrogel, a viscous liquid, a stable emulsion, or a cream.

[0090]

[0091] In an exemplary embodiment, the immiscible carrier phase is a hydrogel (eg, the hydrogel is composed of tyramine-substituted hyaluronic acid).

[0092] In certain embodiments, the antitumor agent is selected from one or more of the following: angiogenesis inhibitors, such as angiostatin K1-3, DL-α-difluoromethyl-ornithine, endostatin, fumagillin, genistein, minocycline, staurosporine, and (±)-thalidomide; DNA intercalating / crosslinking agents, such as bleomycin, carboplatin, carmustine, chlorambucil, cyclophosphamide, cis-diammineplatinum(II) dichloride (cisplatin), melphalan, mitoxantrone, and oxaliplatin; DNA synthesis inhibitors, such as (±)-amethopterin (methotrexate), 3-amino-1,2,4-benzotriazine 1, 4-dioxide, aminopterin, cytosine β-D-arabinofuranoside, 5-fluoro-5'-deoxyuridine, 5-fluorouracil, ganciclovir, hydroxyurea, and mitomycin C; DNA-RNA transcription regulators, such as actinomycin D, daunorubicin, doxorubicin, homoharringtonine, and idarubicin; enzyme inhibitors, such as S(+)-camptothecin, curcumin, (-)-deguelin, 5,6-dichlorobenzimidazole 1-β-D-ribofuranoside, etoposide, formestane, fostriecin, hispidin, 2-imino-1-imidazolidineacetic acid (cyclocreatine), mevinolin, trichostatin A, tyrophostin AG 34, and Tyrophostin AG 879; gene regulators, such as 5-aza-2'-deoxycytidine, 5-azacytidine, cholecalciferol (vitamin D3), 4-hydroxytamoxifen, melatonin, mifepristone, raloxifene, all trans-retinal (vitamin A aldehyde), retinoic acid, all trans(vitamin A acid), 9-cis-retinoic acid, 13-cis-retinoic acid, retinol (vitamin A), tamoxifen, and troglitazone; microtubule inhibitors such as colchicine, dolastatin 15, nocodazole, paclitaxel, podophyllotoxin, rhizoxin, vinblastine, vincristine, vindesine, and vinorelbine (navelbine); and unclassified antitumor agents such as 17-(allylamino)-17-demethoxygeldanamycin, 4-amino-1,8-naphthalimide, apigenin,Brefeldin A, cimetidine, dichloromethylene-diphosphonic acid, leuprolide (leuprorelin), luteinizing hormone releasing hormone, pifithrin-α, rapamycin, sex hormone binding globulin, thapsigargin, and urinary trypsin inhibitor fragment (bikunin). The antitumor agent can be a neoantigen. Neoantigens are tumor-associated peptides that function as active pharmaceutical ingredients in vaccine compositions that stimulate antitumor responses, and are described in US2011-0293637, the entirety of which is incorporated herein by reference. Antitumor agents include monoclonal antibodies, such as rituximab, alemtuzumab, ipilimumab, bevacizumab, cetuximab, panitumumab, and trastuzumab, vemurafenib imatinib mesylate, erlotinib, gefitinib, vismodegib, 90Y-ibritumomab tiuxetan, 131I-tositumomab, ado-trastuzumab emtansine, lapatinib, pertuzumab, ado-trastuzumab emtansine, regorafenib, sunitinib, denosumab, sorafenib, pazopanib, akimoto, It can be citinib, dasatinib, nilotinib, bosutinib, ofatumumab, obinutuzumab, ibrutinib, idelalisib, crizotinib, erlotinib (Tarceva®), afatinib dimaleate, ceritinib, tositumomab and 131I-tositumomab, ibritumomab tiuxetan, brentuximab vedotin, bortezomib, siltuximab, trametinib, dabrafenib, pembrolizumab, carfilzomib, ramucirumab, cabozantinib, vandetanib. The antitumor agent can be a cytokine, such as an interferon (INF), an interleukin (IL), or a hematopoietic growth factor. The antitumor agent may be INF-α, IL-2, aldesleukin, IL-2, erythropoietin, granulocyte macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor. The antitumor agent may be a targeted therapy, such as toremifene, fulvestrant, anastrozole, exemestane, letrozole, ziv-aflibercept, alitretinoin, temsirolimus, tretinoin, denileukin diftitox, vorinostat, romidepsin, bexarotene, pralatrexate, lenaliamide, belinostat, pomalidomide, cabazitaxel,The antitumor agent may be enzalutamide, abiraterone acetate, radium 223 chloride, or everolimus. The antitumor agent may be an inhibitor of the PD-1 pathway, such as a checkpoint inhibitor, such as an anti-PD1 antibody (nivolumab). The inhibitor may be an anti-cytotoxic T-lymphocyte-associated antigen (CTLA-4) antibody. The inhibitor may target another member of the CD28 CTLA4 Ig superfamily, such as BTLA, LAG3, ICOS, PDL1, or KIR. The checkpoint inhibitor may target a member of the TNFR superfamily, such as CD40, OX40, CD137, GITR, CD27, or TIM-3. In addition, the antitumor agent may be an epigenetic targeting drug, such as an HDAC inhibitor, a kinase inhibitor, a DNA methyltransferase inhibitor, a histone demethylase inhibitor, or a histone methylation inhibitor. The epigenetic drug can be azacitidine, decitabine, vorinostat, romidepsin, or ruxolitinib.

[0091]

[0093] In certain embodiments of the disclosed methods, the composition is administered to a subject and delivered in the vicinity of a nerve or nerve bundle of the subject. In an exemplary embodiment, the nerve or nerve bundle innervates the surgical incision area of ​​the subject. The composition can be delivered by a syringe or hypodermic injector, or other delivery methods known in the art. In an exemplary embodiment of the disclosed methods, administration of the compositions described herein provides sustained elution of the antitumor agent in the vicinity of the tumor for more than 110 hours.

[0092]

[0094] This specification also provides a kit of pharmaceutical preparations containing the disclosed compounds or compositions.The kit can be configured to represent a single preparation or a combination of preparations.The composition can be subdivided to contain an appropriate amount of the compound.The unit dosage can be a packaged composition, for example, a packeted powder, a vial, an ampoule, a pre-filled syringe, or a sachet containing liquid.

[0093]

[0095] The compounds or compositions described herein may be single doses or may be for continuous or periodic discontinuous administration. For continuous administration, the kit may contain the compound in each dosage unit. For periodic discontinuation, the kit may contain a placebo for the period during which the compound is not delivered. If it is desired to change the concentration of the composition, the components of the composition, or the relative ratio of the compound or other agents in the composition over time, the kit may contain a series of dosage units.

[0094]

[0096] The kit may include a package or container with the compound formulated for a desired delivery route. The kit may also include administration instructions, a package insert associated with the compound, instructions for monitoring circulating levels of the compound, or a combination thereof. Further items for carrying out the use of the compound may be included, including but not limited to, reagents, well plates, containers, and markers or labels. Such kits are packaged in a manner suitable for treating the desired indication. Other suitable components to be included in such kits will be readily apparent to those skilled in the art, given the desired indication and delivery route. The kit may also include or be packaged with an instrument to assist in injecting / administering or placing the compound in the subject's body. Such instruments include but are not limited to syringes, pipettes, forceps, measuring spoons, eye droppers, or any such medically approved means of delivery. Other instruments may include tools that allow for reading or monitoring of reactions in vitro.

[0095]

[0097] The compounds or compositions of these kits can also be provided in dry, lyophilized, or liquid form. When reagents or components are provided in dry form, reconstitution is generally performed by adding a solvent. The solvent may be provided in another packaging means and can be selected by those skilled in the art.

[0096]

[0098] Many packages or kits for dispensing pharmaceutical agents are known to those of skill in the art. In one embodiment, the package is a labeled blister package, a dial dispenser package, or a bottle.

[0097]

[0099] According to certain embodiments, a formulation of anthracycline (doxorubicin) is delivered to the tumor or peritumoral space via an introducer, laparoscopically, or postoperatively injected after tumor removal. 100-120 mg of doxorubicin hydrochloride is provided in hydrogel particles contained in a lipid carrier. In another formulation, doxorubicin base is contained in lipid drug reservoir nanoparticles carried in an aqueous hydrogel solution. mTOR

[0100] A formulation effective for treating tumors, e.g., renal tumors, includes lipid-based microparticles containing up to 20 mg of an mTOR inhibitor, e.g., rapamycin (sirolimus), in a hydrogel carrier. The hydrogel carrier suspends the particles and prevents their aggregation prior to injection into the tumor or peritumoral site. The lipid component drug reservoir may contain rapamycin at a concentration of 2-20 mg or more, depending on the lipid component formulation and elution rate. The lipid nanoparticles may be present at a volume / volume concentration between 5% and 50%. The hydrogel polymer carrier concentration may be between 0.25 and 5.5%. One skilled in the art may develop similar formulations for mTOR inhibitors, e.g., everolimus, temsirolimus, and similar agents. VEGF-TKI

[0101] Vascular endothelial growth factor (VEGF) and tyrosine kinase inhibitors (TKIs), such as sorafenib, can be provided in lipid nanoparticle drug reservoirs and loaded into hydrogel aqueous formulations to deliver sustained doses of sorafenib to tumor or peritumoral sites for several days or longer by ultrasound-guided needle, fluoroscopic, laparoscopic, or visual injection during surgery. In one formulation, 600-800 mg of sorafenib is contained in lipid nanoparticles in a hydrogel carrier and injected into solid tumors, into the peritumoral space, or into a surgical site following tumor resection. Depending on the lipid nanoparticle formulation, higher loadings of sorafenib can be contained in the lipid particles. The lipid nanoparticles can be present at a volume / volume concentration between 5% and 50%. The hydrogel polymer carrier concentration can be between 0.25 and 5.5%. One skilled in the art can develop similar formulations for VEGF-TKI agents, such as lenvatinib, axitinib, and similar agents. targeted therapy

[0102] Many biologics, such as bevacizumab and interferon, are well soluble in water, and the formulation can be modified to make the hydrogel component a drug reservoir carried in a water / saline carrier or in a liquid lipid formulation. Aqueous nanoparticles can be present in a volume / volume concentration between 5% and 50%. Those skilled in the art can develop similar formulations specifically for targeted therapeutic agents. Direct injection into tumors

[0103] In certain embodiments, the therapeutic formulation can be delivered directly into a solid tumor via an introducer needle. The echogenic properties of the nanoparticles appear as a cloud with a shadow behind it, indicating proper placement of the therapeutic formulation. Inhalation or aerosolization into bronchial / lung tissue

[0104] In certain embodiments, the drug formulation can be micronized into solid particles less than 5 microns that can be sprayed into the terminal bronchi. The powder is deposited on the endothelial tissue surface and delivered to cancer cells adjacent to or directly in the bronchial / alveolar space. The particles can also be sprayed onto tumors during laparoscopic surgery or onto wound surfaces after surgical removal of tumors. intravascular delivery

[0105] Thin liquid formulations containing nanoparticles sub-5 microns can be delivered directly to the vasculature and circulate in the bloodstream for several days before the particles and carrier are absorbed and the therapeutic is delivered systemically. In this embodiment, the therapeutic is delivered in sustained release concentrations to ensure a steady delivery of the therapeutic for 1-5 days or longer depending on the therapeutic. Liposomes

[0106] In some applications, liposomes may act as a delivery reservoir. Therapeutic agents may be contained in liposomes contained in the aqueous carrier hydrogel. Liposomes may be used when the therapeutic agent can be directly introduced into tumor cells. Liposomes may also hold water-soluble drugs that cannot be made into lipid-based carriers. Liposomes may be loaded with immune system stimulants, such as, but not limited to, interleukin-2, and other cytokines. A strong local immune response may be generated against the tumor tissue adjacent to the embedded hydrogel / liposome mass, acting as an effective treatment to the tumor / target tissue. Treatment of abnormal tissue growth

[0107] Antitumor drugs can be encapsulated in liposomes and then used to create hydrogel / liposomal masses that can be delivered to target tissues to kill unwanted benign / non-cancerous growths or can be used to target cancer tissues. Localized placement of antitumor drugs not only dramatically reduces systemic effects and relieves symptoms from exposure to the antitumor drug, but also maintains a medically effective dose of the antitumor drug near the target tissue / tumor. In certain embodiments, this approach is used to treat solid tumors, fibroids, vasculitis, and keratin hyperplasia, etc. Cells are constantly exposed to the elution of antitumor substances near the target tissue, ensuring that they are unable to repair themselves and survive treatment. Systemic effects of antitumor drugs are often a limiting factor in the treatment of refractory tumors. This difficulty is overcome using the compositions and methods disclosed herein to minimize systemic exposure while maximizing exposure to the target tissue. EXAMPLES

[0098]

[0108] The following examples are set forth to fully disclose and explain to one of ordinary skill in the art how the compounds, compositions, articles, tools and / or methods claimed herein are made and evaluated, are intended to be purely illustrative of the invention, and are not intended to limit the scope of what the inventors regard as the invention. However, those of ordinary skill in the art will, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain equivalent or similar results without departing from the spirit and scope of the invention.

[0099]

[0109] In the following examples, ropivacaine base is used as a substitute for antitumor drugs such as docetaxel, paclitaxel, temsirolimus, rapamycin, VEGF-TKIs such as sorafenib, cabozantinib, and other non-polar drugs with poor water solubility. Ropivacaine has a molecular weight of 274 and is considered to be a small molecule API, similar to most hydrophobic chemotherapeutic drugs such as docetaxel with Mw=807. Those skilled in the art can conclude that non-biological hydrophobic small molecule drugs will have similar dissolution behavior to ropivacaine, since there is no chemical or ionic interaction with excipients. Using ropivacaine as a substitute is a safer means to perform dissolution tests in rats. Example 1 - Formulation A

[0110] Carnauba wax / caprylic acid microparticles (90 / 10) and a carnauba wax / caprylic acid (10 / 90) secondary lipid phase. The lipid phase comprises: 130 mg ropivacaine base per gram of lipid phase. Total drug amount in lipid phase of 30%. Ratio of MP to secondary lipid phase of 66 / 34. Crosslinked hydrogel in aqueous phase. Formulation A comprises solid lipid-based microparticles comprising ropivacaine, an alternative hydrophobic API, that exhibits a sustained release profile (as shown in Figure 1) of at least 120 hours. Formulation A comprises solid lipid microparticles that are in a secondary lipid liquid phase and contained in a continuous aqueous phase.

[0100]

[0111] Rats were injected intramuscularly with 0.1-0.13 mL of the drug near the sciatic nerve and monitored for cardiovascular and CNS adverse events. Blood samples were collected up to 120 hours and analyzed for ropivacaine concentrations in plasma. As shown in Figure 1, the formulation exhibited a sustained release behavior for over 120 hours. Example 2 - Formulation B

[0112] Lauric / caprylic MP (90 / 10) and lauric / caprylic (10 / 90) secondary lipid phase. 130 mg ropivacaine in lipid phase. 30% lipid phase by volume. 66 / 34 volume ratio of microparticles to secondary lipid phase. Formulation B contains solid lipid-based microparticles containing ropivacaine, an alternative hydrophobic API, that exhibits a sustained release profile of at least 120 hours. Formulation B contains solid lipid microparticles in a secondary lipid liquid phase and contained in a continuous aqueous phase. Formulation B does not exhibit the same first-order release kinetics as Formulation A, and for applications where short exposure to the chemotherapeutic agent is desired, Formulation B may be preferred. For clinical applications where long-term continuous exposure is required, Formulation A is preferred.

[0101]

[0113] Rats were injected intramuscularly with 0.1-0.13 mL of the drug near the sciatic nerve and monitored for cardiovascular and CNS adverse events. Blood samples were taken up to 120 hours and analyzed for ropivacaine concentrations in plasma. The formulation showed a sustained release behavior beyond 120 hours.

[0102]

[0114] This formulation has a similar composition to Formulation A, but uses lauric acid as the primary lipid component as opposed to carnauba wax in Formulation A. Both formulations use caprylic acid as the lipid regulating agent.

[0103]

[0115] Although the present disclosure has been described with reference to preferred embodiments, workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the disclosed devices, systems and methods.

Claims

1. an aqueous carrier, the aqueous carrier being a hydrogel composed of tyramine-substituted hyaluronic acid, the hydrogel being formed by di-tyramine crosslinking, the degree of tyramine substitution of the hydroxyl groups of the hyaluronic acid being from about 0.5% to about 3%; a lipid phase comprising an antitumor agent, the lipid phase being dispersed in an aqueous carrier and comprising a plurality of lipid microparticles; 16. A composition for treating cancer comprising:

2. The composition of claim 1 , wherein the salt form of the anti-tumor agent not bound by the plurality of lipid microparticles is dissolved in an aqueous carrier.

3. The composition of claim 1 , wherein the biological anti-tumor agent not bound by the plurality of lipid microparticles is dissolved in an aqueous carrier.

4. The composition of claim 3, wherein the biological anti-tumor agent is bevacizumab.

5. 10. The composition of claim 1, wherein the volume ratio between the aqueous carrier and the lipid microparticles is about 70-80 parts aqueous carrier to about 30-20 parts lipid microparticles.

6. 10. The composition of claim 1, wherein the lipid microparticles comprise one or more fatty acids having an even number of carbons.

7. 7. The composition of claim 6, wherein the one or more fatty acids comprise less than 50% of the total lipid composition of the lipid microparticle.

8. The composition of claim 1 , wherein the lipid microparticles comprise one or more fatty acids having an odd number of carbons.

9. 9. The composition of claim 8, wherein the one or more fatty acids are selected from stearic acid, oleic acid, myristic acid, caprylic acid, capric acid, lauric acid, palmitic acid, arachidic acid, lignoceric acid, cerotic acid, and mixtures of the foregoing, and the melting point of the lipid microparticles is greater than 37°C.

10. 10. The composition of claim 9, wherein the one or more fatty acids comprise a mixture of steric and oleic acids, the ratio of steric to oleic acids being about 90:

10.

11. 11. The composition of claim 10, wherein the lipid microparticles comprise about 12% myristic acid, about 32% palmitic acid, about 10% stearic acid, and about 10% oleic acid.

12. 12. The composition of claim 11, wherein the lipid microparticles comprise a mixture of lauric acid and caprylic acid, caproic acid, and / or oleic acid.

13. The composition of claim 5 , wherein the lipid microparticles comprise paraffin, triglyceride, and / or wax.

14. 14. The composition of claim 13, wherein the lipid microparticles comprise a mixture of carnauba wax and caprylic acid, caproic acid, and / or oleic acid.

15. 2. The composition of claim 1, wherein the plurality of lipid microparticles comprises a first plurality of lipid microparticles and a second plurality of lipid microparticles, the first plurality of lipid microparticles being solid at about 37° C. and the second plurality of lipid microparticles being liquid at 37° C.

16. The composition of claim 1 , wherein the lipid microparticle is not a liposome.

17. The composition of claim 1, wherein the anti-tumor agent is selected from an anthracycline, an mTOR inhibitor, a VEGF-TKI agent, and an immune stimulant.

18. The composition of claim 1 , wherein the antitumor agent is doxorubicin.

19. 2. The composition of claim 1, wherein the plurality of lipid microparticles ranges from about 5 μm to about 20 μm.

20. 2. The composition of claim 1, wherein the plurality of lipid microparticles are about 5 μm or less.

21. 1. A method of treating cancer in a subject in need thereof, comprising: A method comprising: administering to a subject an effective amount of a composition comprising: a hydrogel binding matrix; and a plurality of lipid microparticles dispersed in the hydrogel, the lipid microparticles comprising one or more anti-tumor agents.

22. 21. The method of claim 20, wherein the composition is administered directly to the tumor site, via an introducer, laparoscopically, or post-operatively following tumor removal.

23. 22. The method of claim 21, wherein the composition is administered by injection into the solid tumor with a guide needle and targeting of the tumor is confirmed by ultrasound imaging.

24. 21. The method of claim 20, wherein the anti-tumor agent elutes from the composition over a period of between about 4 and about 7 days.

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