Sustained-release cancer treatment

Abstract

This specification discloses compositions for treating tumors in subjects requiring such treatment, comprising an emulsion comprising an aqueous carrier; a liquid lipid phase dispersed as droplets in the aqueous carrier; and a first chemotherapeutic agent in the lipid phase. In certain embodiments, the first chemotherapeutic agent comprises a plurality of first chemotherapeutic agent crystals. In certain alternative embodiments, the first chemotherapeutic agent is dissolved in the lipid phase. In certain embodiments, the composition further comprises a plurality of second chemotherapeutic agent crystals in the aqueous carrier rather than in the lipid phase, the second plurality of chemotherapeutic agent crystals dissolve and elute from the emulsion at a faster rate than the first plurality of chemotherapeutic agent crystals. In certain embodiments, the composition further comprises one or more additional chemotherapeutic agents different from the first chemotherapeutic agent.

Description

[Technical Field]

[0001] Cross-reference of related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 454,507, entitled SUSTAINED RELEASE CANCER THERAPEUTICS FORMULATIONS, filed on 24 March 2023 under Section 119(e) of the U.S. Patent Act, which is incorporated herein by reference in its entirety. [Background technology]

[0002]

[0002] Multifocal tumors, such as liver cancer, pancreatic cancer, kidney cancer, and lung cancer, offer few surgical treatment options. In the art, there is a need for compositions and methods that provide sustained local delivery of antitumor agents to maximize efficacy and minimize systemic effects. Similarly, there is a need for targeted therapy to a single tumor before tumor resection. [Overview of the project]

[0003]

[0003] This specification discloses compositions for treating tumors in subjects requiring such treatment, comprising an emulsion comprising an aqueous carrier; a liquid lipid phase dispersed as droplets in the aqueous carrier; and a first chemotherapeutic agent in the lipid phase. In certain embodiments, the first chemotherapeutic agent comprises a plurality of first chemotherapeutic agent crystals. In certain alternative embodiments, the first chemotherapeutic agent is dissolved in the lipid phase. In certain embodiments, the composition further comprises a plurality of second chemotherapeutic agent crystals in the aqueous carrier rather than in the lipid phase, the second plurality of chemotherapeutic agent crystals dissolve and elute from the emulsion at a faster rate than the first plurality of chemotherapeutic agent crystals. In certain embodiments, the composition further comprises one or more additional chemotherapeutic agents different from the first chemotherapeutic agent.

[0004]

[0004] According to a particular embodiment, the lipid phase is about 10% to about 40% (w / v) of the composition. In a particular embodiment, the lipid phase comprises one or more triglycerides. In a particular embodiment, the lipid phase comprises about 15% to 80% (v / v) of soybean oil and about 15% to about 20% (v / v) of one or more medium-chain triglycerides. In a particular embodiment, the lipid phase comprises triptylate and / or stearate. In a particular further embodiment, the lipid phase also comprises one or more oils and / or waxes.

[0005]

[0005] In certain embodiments, the lipid phase further comprises oils and / or waxes that are solid at 25°C in an amount (w / w) of about 5% to about 30% of the lipid phase, the oils and / or waxes coating the chemotherapeutic agent crystals.

[0006]

[0006] In certain embodiments, the aqueous carrier further comprises an emulsifier and a polyol. In certain embodiments, the emulsifier is a hyaluronic acid, such as tyramine-substituted hyaluronic acid. In certain embodiments, the polyol is glycerol and is present in an amount of about 0.25 to about 2.5% (w / v) of the composition.

[0007]

[0007] According to certain embodiments, the lipid phase further comprises phospholipids. In certain embodiments, the phospholipids are present in an amount of about 0.1% to about 2.0% of the lipid phase. According to certain further embodiments, the lipid phase further comprises antioxidants. In exemplary embodiments, the antioxidants are present in an amount of about 0.01% to about 1% (w / v) of the composition.

[0008]

[0008] According to a particular embodiment, the emulsion further comprises lecithin. In a particular embodiment, the lecithin is present in an amount of 0.1 to 5% (w / v) of the emulsion.

[0009]

[0009] In a particular embodiment, the emulsion further contains dextrose, which is present in an amount of about 1-2% (w / v) of the emulsion.

[0010] In certain embodiments, the chemotherapeutic agent is present in amounts ranging from approximately 0.1 mg / g soybean oil to approximately 300 mg / g soybean oil. In certain embodiments, the chemotherapeutic agent is selected from anthracyclines, mTOR inhibitors, VEGF-TKI agents, and immunostimulants. In further embodiments, the chemotherapeutic agent is docetaxel or doxorubicin.

[0010]

[0011] Furthermore, this specification discloses a composition for treating tumors in a subject requiring such treatment, the composition comprising an emulsion comprising an aqueous carrier; a liquid lipid phase dispersed as droplets in the aqueous carrier; and a first chemotherapeutic agent in the lipid phase, wherein the first chemotherapeutic agent comprises a plurality of first chemotherapeutic agent crystals, and the liquid lipid phase further comprises one or more oils and / or waxes having a melting point greater than 25°C, wherein the one or more oils and / or waxes coat the plurality of first chemotherapeutic agent crystals. In certain embodiments, the one or more oils and / or waxes are coconut oil and / or carnauba wax. In certain embodiments, the coconut oil and / or carnauba wax is present in an amount of about 3% to about 30% (w / w) of the lipid phase.

[0011]

[0012] Furthermore, this specification discloses a composition for treating tumors in a subject requiring such treatment, comprising an emulsion comprising a lipid carrier phase; an aqueous phase dispersed as droplets in the lipid carrier phase; and a first chemotherapeutic agent in the aqueous phase. In certain embodiments, the first chemotherapeutic agent comprises a plurality of first chemotherapeutic agent crystals. In certain embodiments, the first chemotherapeutic agent is dissolved in the aqueous phase. According to certain embodiments, the composition also comprises a plurality of second chemotherapeutic agent crystals present in the lipid carrier rather than in the aqueous phase, the second plurality of chemotherapeutic agent crystals dissolving and eluting from the emulsion at a faster rate than the first plurality of chemotherapeutic agent crystals. In exemplary embodiments, the chemotherapeutic agent is hydrophilic and dissolved in the aqueous phase. In certain embodiments, the composition further comprises one or more additional chemotherapeutic agents different from the first chemotherapeutic agent.

[0012]

[0013] According to certain embodiments, the emulsions disclosed herein are stable for a period of about one month to about two years. In further embodiments, the emulsions are stable for a period of about six months to about twelve months. In certain embodiments, the emulsions are reversible.

[0013]

[0014] Furthermore, this specification discloses a method for treating a tumor in a subject requiring such treatment, comprising the step of administering to the subject an effective amount of a composition comprising an emulsion containing an aqueous carrier; a lipid phase dispersed as droplets in the aqueous carrier; and a first chemotherapeutic agent in the lipid phase. In certain embodiments, the chemotherapeutic agent comprises a plurality of chemotherapeutic agent crystals, and the composition further comprises a second plurality of chemotherapeutic agent crystals in the aqueous carrier rather than in the lipid phase, the second plurality of chemotherapeutic agent crystals dissolve and elute from the emulsion at a faster rate than the first plurality of chemotherapeutic agent crystals. In certain embodiments, the composition is administered directly to the tumor site by guide needle, laparoscopy, or postoperatively after tumor removal. In certain embodiments, the chemotherapeutic agent elutes from the composition over a period of about 4 to about 7 days.

[0014]

[0015] According to certain embodiments, the composition further comprises an immunostimulant. In certain embodiments, the lipid phase comprises one or more fatty acids in an amount sufficient to induce a local inflammatory response in the subject at the injection site (e.g., proximal to the tumor). In these embodiments, the local inflammation enhances the antitumor immune response of the subject, thus increasing the efficacy of the treatment.

[0015]

[0016] Furthermore, this specification discloses a method for treating lymphatic system cancer in a subject requiring such treatment by administering the compositions disclosed herein to the subject.

[0017] While multiple embodiments are disclosed, further other embodiments of the disclosure will become apparent to those skilled in the art from the following detailed description illustrating and describing exemplary embodiments of the disclosed devices, systems, and methods. As will be understood, all disclosed devices, systems, and methods can be modified in various express manner without departing from the spirit and scope of the disclosure. Accordingly, the drawings and detailed description are to be considered illustrative and not restrictive. [Brief explanation of the drawing]

[0016] [Figure 1]

[0018] This figure shows the time-course docetaxel plasma concentration (ng / mL) after intramuscular injection with INSB400 compared to standard docetaxel treatment in a specific embodiment. [Figure 2]

[0019] This figure shows the time-course doxorubicin plasma concentration (ng / mL) after intramuscular injection with INSB400 compared to standard docetaxel treatment in a specific embodiment. [Figure 3] Figure 3A:

[0020] This figure shows a microscopic image of sample 1 at 10x magnification according to a specific embodiment. Figure 3B:

[0021] This figure shows a microscopic image of sample 1 at 20x magnification according to a specific embodiment. [Figure 4] Figure 4A:

[0022] A diagram showing a microscopic image of sample 2 at a magnification of 10 times according to a specific embodiment. Figure 4B:

[0023] A diagram showing a microscopic image of sample 2 at a magnification of 20 times according to a specific embodiment. [Figure 5] Figure 5A:

[0024] A diagram showing a microscopic image of sample 3 at a magnification of 10 times according to a specific embodiment. Figure 5B:

[0025] A diagram showing a microscopic image of sample 3 at a magnification of 20 times according to a specific embodiment. [Figure 6] Figure 6A:

[0026] A diagram showing a microscopic image of sample 4 at a magnification of 10 times according to a specific embodiment. Figure 6B:

[0027] A diagram showing a microscopic image of sample 4 at a magnification of 20 times according to a specific embodiment. [Figure 7] Figure 7A:

[0028] A diagram showing a microscopic image of sample 5 at a magnification of 10 times according to a specific embodiment. Figure 7B:

[0029] A diagram showing a microscopic image of sample 5 at a magnification of 20 times according to a specific embodiment. [Figure 8] Figure 8A:

[0030] A diagram showing a microscopic image of sample 6 at a magnification of 10 times according to a specific embodiment. Figure 8B:

[0031] A diagram showing a microscopic image of sample 6 at a magnification of 20 times according to a specific embodiment. [Figure 9] [[ID=3,3]]Figure 9A:

[0032] A diagram showing a microscopic image of sample 7 at a magnification of 10 times according to a specific embodiment. Figure 9B:

[0033] A diagram showing a microscopic image of sample 7 at a magnification of 20 times according to a specific embodiment. [Figure 10] Figure 10A:

[0034] A diagram showing a microscopic image of sample 8 at a magnification of `10 times according to a specific embodiment. Figure` 10B:

[0035] A diagram showing a microscopic image of sample 8 at a magnification of 20 times according to a specific embodiment. [Figure 11] Figure 11A:

[0036] A diagram showing a microscopic image of sample 9 at a magnification of 10 times according to a specific embodiment. Figure 11B:

[0037] This figure shows a microscopic image of sample 9 at 20x magnification according to a specific embodiment. [Figure 12] Figure 12A:

[0038] This figure shows a microscopic image of sample 10 at 10x magnification according to a specific embodiment. Figure 12B:

[0039] This figure shows a microscopic image of sample 10 at 20x magnification according to a particular embodiment. [Figure 13] Figure 13A:

[0040] This figure shows a microscopic image of sample 11 at 10x magnification according to a specific embodiment. Figure 13B:

[0041] This figure shows a microscopic image of sample 11 at 20x magnification according to a specific embodiment. [Figure 14] Figure 14A:

[0042] This figure shows a microscopic image of sample 12 at 10x magnification according to a specific embodiment. Figure 14B:

[0043] This figure shows a microscopic image of sample 12 at 20x magnification according to a particular embodiment. [Figure 15] Figure 15A:

[0044] This figure shows a microscopic image of sample 13 at 10x magnification according to a specific embodiment. Figure 15B:

[0045] This figure shows a microscopic image of sample 13 at 20x magnification according to a particular embodiment. [Figure 16] Figure 16A:

[0046] This figure shows a microscopic image of sample 14 at 10x magnification according to a specific embodiment. Figure 16B:

[0047] This figure shows a microscopic image of sample 14 at 20x magnification according to a particular embodiment. [Figure 17] Figure 17A:

[0048] This figure shows a microscopic image of sample 15 at 10x magnification according to a specific embodiment. Figure 17B:

[0049] This figure shows a microscopic image of sample 15 at 20x magnification according to a specific embodiment. [Figure 18] Figure 18A:

[0050] This figure shows a microscopic image of sample 16 at 10x magnification according to a specific embodiment. Figure 18B:

[0051] This figure shows a microscopic image of sample 16 at 20x magnification according to a particular embodiment. [Figure 19] Figure 19A:

[0052] This figure shows a microscopic image of sample 17 at 10x magnification according to a specific embodiment. Figure 19B:

[0053] This figure shows a microscopic image of sample 17 at 20x magnification according to a specific embodiment. [Figure 20] Figure 20A:

[0054] This figure shows a microscopic image of sample 18 at 10x magnification according to a specific embodiment. Figure 20B:

[0055] This figure shows a microscopic image of sample 18 at 20x magnification according to a particular embodiment. [Figure 21] Figure 21A:

[0056] This figure shows a microscopic image of sample 19 at 10x magnification according to a specific embodiment. Figure 21B:

[0057] This figure shows a microscopic image of sample 19 at 20x magnification according to a specific embodiment. [Figure 22] Figure 22A:

[0058] This figure shows a microscopic image of sample 20 at 10x magnification according to a specific embodiment. Figure 22B:

[0059] This figure shows a microscopic image of sample 20 at 20x magnification according to a particular embodiment. [Figure 23] Figure 23A:

[0060] This figure shows a microscopic image of sample 21 at 10x magnification according to a specific embodiment. Figure 23B:

[0061] This figure shows a microscopic image of sample 21 at 20x magnification according to a specific embodiment. [Figure 24] Figure 24A:

[0062] This figure shows a microscopic image of sample 22 at 10x magnification according to a specific embodiment. Figure 24B:

[0063] This figure shows a microscopic image of sample 22 at 20x magnification according to a specific embodiment. [Figure 25] Figure 25A:

[0064] This figure shows a microscopic image of sample 23 at 10x magnification according to a specific embodiment. Figure 25B:

[0065] This figure shows a microscopic image of sample 23 at 20x magnification according to a specific embodiment. [Figure 26]

[0066] This figure shows a microscopic image of sample 24 at 40x magnification according to a specific embodiment. [Figure 27]

[0067] This figure shows a microscopic image of sample 25 at 40x magnification according to a specific embodiment. [Modes for carrying out the invention]

[0017]

[0068] Before disclosing and describing the compounds, compositions, articles, systems, tools, and / or methods of the present invention, it should be understood that they are not limited to specific synthesis methods or specific reagents unless otherwise specified, and are therefore subject to change. It should also be understood that the terms used herein are intended to describe only specific aspects and are not intended to limit them. Any methods and substances similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but exemplary methods and substances are described herein.

[0018]

[0069] In this specification, a range can be expressed as "about" (one specific value) and / or "about" (another specific value). When expressing such a range, further embodiments include "from" (one specific value) and / or (another specific value). Similarly, when a value is expressed as an approximation using the antecedent "about", it will be understood that a specific value forms further embodiments. Furthermore, it will be understood that each endpoint of a range is important both in relation to other endpoints and independently of other endpoints. It will also be understood that although there are many values ​​disclosed in this specification, each value is also disclosed in this specification as "about" (its specific value) along with the value itself. For example, if the value "10" is disclosed, "about 10" is also disclosed. It will also be understood that each unit between two specific units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0019]

[0070] As used herein, names of compounds, including organic compounds, may be given using common names, IUPAC, IUBMB, or CAS nomenclature recommendations. Where one or more stereochemical features are present, the Cahn-Ingold-Prelog rules for stereochemistry may be used to indicate stereochemical priority and E / Z notation, etc. Those skilled in the art can readily determine the structure of a compound, given its name, by systematically reducing the compound structure using nomenclature rules, or by using commercially available software, such as CHEMDRAW® (Perkin Elmer Corporation, USA).

[0020]

[0071] As used herein, the singular forms "a," "an," and "the" include multiple references unless the context clearly indicates otherwise. Therefore, for example, references to "functional group," "alkyl," or "residue" include mixtures of two or more such functional groups, alkyls, or residues.

[0021]

[0072] Unless otherwise specified, references to parts by weight of a particular element or component in a composition herein indicate the weight relationship between the element or component and any other element or component in the composition or article in which the parts by weight are expressed, unless otherwise explicitly stated. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight of component Y, components X and Y exist in a weight ratio of 2:5, and in such a ratio whether or not additional components are present in the compound.

[0022]

[0073] Unless otherwise stated, the weight percentage (wt%) of an ingredient is based on the total weight of the formulation or composition in which the ingredient is contained.

[0074] As used herein, the terms “optional” or “optionally” mean that the events or circumstances described thereafter may or may not occur, and that this description includes both cases in which such events or circumstances occur and cases in which they do not occur.

[0023]

[0075] As used herein, the term “subject” may be a vertebrate, such as a mammal, fish, bird, reptile, or amphibian. Therefore, the subjects of the methods disclosed herein may be humans, non-human primates, horses, pigs, rabbits, dogs, sheep, goats, cattle, cattle, guinea pigs, or rodents. The word does not indicate a specific age or sex. Therefore, it is intended to refer to adult and neonatal subjects, as well as fetuses, regardless of sex. In one embodiment, the subject is a mammal. “Patient” refers to a subject suffering from a disease or disorder. The word “patient” includes human and veterinary subjects.

[0024]

[0076] 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 toward improvement of a disease, pathological condition, or disorder, and causal treatment, i.e., treatment directed toward the elimination of the cause of the associated disease, pathological condition, or disorder. Furthermore, this term includes expectant treatment, i.e., treatment designed to alleviate symptoms rather than cure a disease, pathological condition, or disorder; preventive treatment, i.e., treatment directed toward minimizing, or partially or completely inhibiting, the progression of the associated disease, pathological condition, or disorder; and adjunct treatment, i.e., treatment used to complement another specific treatment directed toward improvement of the associated disease, pathological condition, or disorder. In various aspects, this term encompasses all treatments of subjects, including mammals (e.g., humans), including (i) preventing the onset of disease in subjects who are susceptible to the disease but have not yet been diagnosed with the disease; (ii) inhibiting the disease, i.e., stabilizing its progression; or (iii) alleviating the disease, i.e., causing disease regression. In one aspect, the subject is a mammal, e.g., a primate, and in further aspects, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mice, rabbits, rats, guinea pigs, fruit flies, etc.).

[0025]

[0077] As used herein, the term “cancer” refers to cells that have autonomous proliferative capacity. Examples of such cells include cells that have an abnormal condition or situation characterized by rapidly growing cell proliferation. The term means cancerous proliferation, e.g., tumors; carcinogenic processes, metastatic tissues, and malignantly transformed cells, tissues, or organs, regardless of histopathological type or stage of invasiveness. It also includes malignant tumors of various organ systems, e.g., respiratory, cardiovascular, renal, reproductive, hematological, nervous, hepatic, gastrointestinal, and endocrine systems; as well as adenocarcinomas, e.g., most colon cancers, renal cell carcinomas, prostate cancers and / or testicular tumors, non-small cell lung cancers, small intestine cancers, and esophageal cancers. "Naturally occurring" cancers include any cancer that is not experimentally induced by transplanting cancer cells into a target, and include, for example, naturally occurring cancers, cancers caused by a patient's exposure to carcinogens, cancers resulting from transgenic oncogene insertions or tumor suppressor gene knockouts, and cancers caused by infection, such as viral infections. 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 subjects having epithelial cancers, such as solid tumors of epithelial origin, such as lung cancer, breast cancer, ovarian cancer, prostate cancer, kidney cancer, pancreatic cancer, or colon cancer.

[0026]

[0078] As used herein, the term “diagnosed” means that a person skilled in the art, for example, has undergone a physical examination by a physician and has been found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein. For example, “diagnosed with cancer” means that a person skilled in the art, for example, has undergone a physical examination by a physician and has been found to have a condition that can be diagnosed or treated by the compounds or compositions that can reduce the size of a tumor or slow the rate of tumor growth. Cancer, tumors, or subjects having at least one type of 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 cancer cells or tumors can be determined using contrast-enhanced MRI or CT. Further 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). Imaging solutions containing the cell-sensitizing compositions of this disclosure can be used, for example, in combination with MRI or CT to identify cancer cells.

[0027]

[0079] As used herein, the terms “prevent” or “preventing” mean preventing, stopping, removing, deterring, stopping, or hindering something from happening, especially through prior measures. Where “reduce,” “hinder,” or “prevent” are used herein, it is understood that the use of the other two words is also explicitly disclosed unless explicitly indicated otherwise.

[0028]

[0080] As used herein, phrases such as "identified as requiring treatment for a disorder" refer to the selection of a subject based on the need for treatment for a disorder. For example, a subject may be identified as requiring treatment for a disorder based on a prior diagnosis by a person skilled in the art, and subsequently receive treatment for the disorder. In one embodiment, this identification may be performed by a person different from the one performing the diagnosis. In a further embodiment, this identification may be performed by the person administering the treatment.

[0029]

[0081] The terms “antitemory agent” and “chemotherapeutic agent (CA)” are used interchangeably herein and refer to drugs for the treatment of cancer. Typically, an antitumor agent is a cytotoxic antineoplastic drug administered as part of a standardized regimen. While not bound by theory, antitumor agents work by killing rapidly dividing cells, which is one of the primary characteristics of most cancer cells. Preferably, rather than exhibiting indiscriminate cytotoxicity, antitumor agents target proteins essential for cancer cell proliferation that are abnormally expressed in cancer cells. Non-exclusive examples of antitumor agents include: angiogenesis inhibitors, e.g., angiostatin K1-3, DL-α-difluoromethyl-ornithine, endostatin, fumagiline, genistein, minocycline, staurosporine, and (±)-thalidomide; DNA insertion / crosslinking agents, e.g., bleomycin, carboplatin, carmustine, chlorambucil, cyclophosphamide, cis-diammineplatin(II) dichloride (cisplatin), melphalan, mitoxantrone, and oxaliplatin; DNA synthesis inhibitors, e.g., (±)-ametopterin (methotrexate), 3-amino-1,2,4-benzotriazine 1,4-diox 5,6-dichlorobenzimidazole, aminopterin, cytosine β-D-arabinofuranoside, 5-fluoro-5'-deoxyuridine, 5-fluorouracil, ganciclovir, hydroxyurea, and mitomycin C; DNA-RNA transcription regulators, e.g., actinomycin D, daunorubicin, doxorubicin, homohalintonin, and idarubicin; enzyme inhibitors, e.g., S(+)-camptothecin, curcumin, (-)-deguerin, 5,6-dichlorobenzimidazole, 1-β-D-ribofuranoside, etoposide, formestan, fostoriesin, hispidin, 2-imino-1-imidazolidinedacetate (cyclocreatine), mebinolin, trichostatin A, thyrophostine AG 34, and thyrophostine AG 879; gene regulators, e.g., 5-aza-2'-deoxycytidine, 5-azacitidine, cholecalciferol (vitamin D3), 4-hydroxytamoxifen, melatonin, mifepristone, raloxifen, 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, e.g., colchicine, drastatin 15, nocodazole, paclitaxel, podophyllotoxin, rhizoxin, vinblastine, vincristine, vindesine, and vinorelbine (navelbine); and unclassified antitumor agents, e.g., 17-(allylamino)-17-demethoxygeldanamycin, 4-amino-1,8-naphthalimide, apigenin, brefelzin A, cimetidine, dichloromethylene-diphosphonic acid, leuprolide (leuprorelin), luteinizing hormone-releasing hormone, pifislin-α, rapamycin, sex hormone-binding globulin, thapsigardin, and urinary trypsin inhibitor fragments (bikunin). Antitumor agents may be novel antigens. The novel antigen is a tumor-related peptide that functions as a pharmacoactive ingredient in a vaccine composition that stimulates an antitumor response, and is 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, bismodegib, 90Y-ibritumomab tiuxetan, 131I-tositumomab, ad-trastuzumab emtansine, lapatinib, pertuzumab, ad-trastuzumab emtansine, regorafenib, sunitinib, denosumab, sorafenib, pazopanib, and aki. The antitumor agents may be citinib, dasatinib, nilotinib, bosutinib, ofatumumab, obinutuzumab, ibrutinib, idelalisib, crizotinib, erlotinib (Tarceva®), afatinib dimaleate, ceritinib, tocitumomab and 131I-tocitumomab, ibritumomab tiuxetan, brentuximab vedotin, bortezomib, siltuximab, trametinib, dabrafenib, pembrolizumab, carfilzomib, ramucirumab, cabozantinib, and vandetanib. The antitumor agents may be cytokines, such as interferon (INF), interleukin (IL), or hematopoietic growth factors. The antitumor agents may be INF-α, IL-2, aldesleukin, IL-2, erythropoietin,The antitumor agent may be granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor. The antitumor agent may be targeted therapy, such as toremifene, fulvestrant, anastrozole, exemestane, letrozole, ziv-aflibercept, alitretinoin, temsirolimus, tretinoin, denileukin difutitox, vorinostat, romidepsin, bexarotene, pralatrexate, lenaliomide, belinostat, pomalidomide, cabazitaxel, enzalutamide, abiraterone acetate, radium-223 chloride, or everolimus. The antitumor agent may be an inhibitor of the PD-1 (programmed death-1) pathway, such as a checkpoint inhibitor like an anti-PD1 antibody (nivolumab). The inhibitor may be an anticytotoxic T lymphocyte-associated antigen (CTLA-4) antibody. Inhibitors may target other members of the CD28 CTLA4 Ig superfamily, such as BTLA, LAG3, ICOS, PDL1, or KIR. Checkpoint inhibitors may target members of the TNFR superfamily, such as CD40, OX40, CD137, GITR, CD27, or TIM-3. Furthermore, antitumor agents may be epigenetic targeted agents, such as HDAC inhibitors, kinase inhibitors, DNA methyltransferase inhibitors, histone demethylase inhibitors, or histone methylation inhibitors. Epigenetic drugs may include azacitidine, decitabine, vorinostat, romidepsin, or luxolitinib.

[0030]

[0082] Some antiproliferative agents are classified into several main categories, including antimetabolites, alkylating agents, antibiotic-type drugs, hormonal anticancer agents, immunological agents, interferon-type drugs, and various antineoplastic agents. Some antiproliferative agents act through multiple or unknown mechanisms and may therefore be classified into two or more categories.

[0031]

[0083] As used herein, the terms “administering” and “administer” refer to any method of providing a pharmaceutical preparation. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, inhalation administration, nasal administration, topical administration, vaginal administration, ophthalmic administration, intraotoral administration, intracerebral administration, rectal administration, sublingual administration, intradermal administration, buccal administration, and parenteral administration including infusions such as intravenous ("IV") administration, intra-arterial administration, intramuscular ("IM") administration, and subcutaneous administration. Administration may be continuous or intermittent.

[0032]

[0084] The term "contacting," as used herein, means bringing together the disclosed composition with cells (e.g., tumor cells), target receptors, or other biological entities in such a manner that the compound can influence the activity of the target, either directly—that is, by interacting with the target itself—or indirectly—that is, by interacting with another molecule, cofactor, factor, or protein on which the activity of the target depends.

[0033]

[0085] As used herein, the words “effective dose” and “effective amount” refer to the amount sufficient to achieve a desired outcome or to have an effect against an undesirable condition. For example, a specific effective dose for any particular subject depends on a variety of factors, including: the disorder to be diagnosed and its severity; the specific composition used; the patient’s age, weight, overall health, sex, and diet; the time of administration; the route of administration; the elimination rate of the specific compound used; the diagnostic period; drugs used in combination with or concurrently with the specific compound used, as well as similar factors well known in the medical field. For example, it is well within the scope of the art to start the dose of a compound at a level lower than the level required to achieve the desired diagnostic effect and gradually increase the dose 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 may contain such an amount or a fraction thereof to constitute a daily dose. Dosages can be adjusted by the individual physician if there are contraindications. Dosages vary and can be administered once or multiple times a day for a day or several days. Guidance on appropriate dosages for a given class of pharmaceutical products can be found in printed materials. Furthermore, effective doses can be initially estimated from in vitro assays. For example, initial doses for use in animals may be formulated to achieve circulating blood or serum concentrations of the active compound with an IC50 of or greater than that of a particular compound measured in an in vitro assay. Calculating the dose to achieve such circulating blood or serum concentrations, taking into account the bioavailability of a particular active agent, is well within the capabilities of those skilled in the art. For guidance, see Fingl & Woodbury, "General Principles," in Goodman and Gilman's *The Pharmaceutical Basis of Therapeutics*, Chapter 1, pp. 1-46, latest edition, Pergamagon Press (the entire text and its cited references are incorporated herein by reference).

[0034]

[0086] The term "pharmaceutically acceptable" refers to a substance that is not undesirable from a biological or otherwise criminal standpoint; that is, it does not cause undesirable levels of undesirable biological effects or harmful interactions.

[0035]

[0087] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injection solutions or dispersions immediately before 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), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injection organic esters, such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of coating substances such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain auxiliary agents, such as preservatives, humectants, emulsifiers, and dispersants. Microbial activity can be reliably prevented by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid. The inclusion of isotonic agents, such as sugars and sodium chloride, may also be desirable. Injectable pharmaceutical formulations can have their absorption extended by containing drugs, such as aluminum monostearate and gelatin, which slow down absorption. Injectable depot formulations are made by forming a microcapsule matrix of drugs in biodegradable polymers, such as polylactide-polyglycolide, poly(orthoester), and poly(anhydride). The rate of drug release can be controlled by the drug-to-polymer ratio and the properties of the specific polymer used. Depot injection formulations are also prepared by encapsulating drugs in liposomes or microemulsions that conform to body tissues. Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection solvent immediately before use. Suitable inert carriers include sugars, such as lactose.

[0036]

[0088] The compounds described herein may, by the presence of one or more double bonds, result in cis / trans (E / Z) isomers and other conformational isomers. Unless otherwise stated, this disclosure includes all such possible isomers and mixtures of such isomers.

[0037]

[0089] Unless otherwise stated, chemical bonds are shown only with solid lines, and formulas not shown with wedges or dashed lines are intended to represent each possible isomer, e.g., each enantiomer and diastereomer, as well as mixtures of isomers, e.g., racemic or scalemic mixtures. The compounds described herein may, by including one or more chiral centers, result in diastereomers and optical isomers. Unless otherwise stated, this disclosure includes all such possible diastereomers, as well as their racemic mixtures, their substantially pure divided enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. Mixtures of stereoisomers and specific isolated stereoisomers are also included. In the course of 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.

[0038]

[0090] 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 center. The prefixes d and l or (+) and (-) are used to indicate the sign of the rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. With respect to a given chemical structure, these compounds are called stereoisomers and are identical except that they are mirror images that cannot be superimposed on each other. Certain stereoisomers are also called enantiomers, and mixtures of such isomers are often called enantiomer 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 enantiomer forms. If desired, the chiral carbon is represented by an asterisk ( * ) can be shown as follows. When the bonds to the chiral carbon are depicted as straight lines in the disclosed formula, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore enantiomers and mixtures thereof, are included in the formula. If we want to specify the absolute configuration for a chiral carbon, as used in the art, one of the bonds to the chiral carbon (bonds to atoms above the plane) can be depicted as a wedge, and the other bond (bonds to atoms below the plane) can be depicted as a series of short parallel lines or a wedge consisting of short parallel lines. The Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0039]

[0091] The compounds described in this specification can contain atoms in both natural and unnatural isotope abundances. 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 having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as, respectively 2 H, 3 H, 13 C, 14 C, 13 N, 15 N, 18 O, 17 O, 35 S, 18 F and 36 Cl. The compounds further include their prodrugs, which contain the aforementioned isotopes and / or other isotopes of other atoms within the scope of the present disclosure, as well as pharmaceutically acceptable salts of the above compounds or the above prodrugs. Certain isotopically labeled compounds of the present disclosure, for example, those incorporating radioactive isotopes, such as 3 H and 14 C, are useful in tissue distribution assays of drugs and / or substrates. Tritium isotopes, i.e., 3 H isotopes, and carbon-14 isotopes, i.e., 14 C isotopes, can be used because they are easy to prepare and detectable. Furthermore, substitution with heavier isotopes, such as deuterium, i.e., 2 H, can provide certain advantages resulting from improved metabolic stability, such as an extended half-life in vivo or a reduced dosage requirement, and may therefore be preferred in certain situations. The isotopically labeled compounds and their prodrugs of the present disclosure can generally be prepared by using readily available isotopically labeled reagents in place of non-isotopically labeled reagents and performing the following procedures.

[0040]

[0092] Chemical substances are known to form solids that exist in various ordered states called polymorphs or transformations. The various transformations of polymorphic substances can have significantly different physical properties. The compounds according to this disclosure can exist in various polymorphic forms, and certain transformations can be metastable. Unless otherwise stated, this disclosure includes all such possible polymorphic forms.

[0041]

[0093] Certain substances, compounds, compositions, and components disclosed herein are commercially available or can be readily synthesized using methods generally known to those skilled in the art. For example, the starting materials and reagents used to prepare the disclosed compounds and compositions are available from commercial suppliers, e.g., 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 skilled in the art, following the procedures described in references, e.g., Fieser and Fieser's Reagents for Organic Synthesis, Vols. 1–17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Vols. 1–5 and Supplement (Elsevier Science Publishers, 1989); Organic Reactions, Vols. 1–40 (John Wiley and Sons, 1991); March's Advanced Organic Chemistry (John Wiley and Sons, 4th edition); and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0042]

[0094] Unless otherwise explicitly stated, the methods described herein are never intended to be construed as requiring the steps to be performed in a specific order. Therefore, if a claim of a method does not actually enumerate the order in which the steps should be followed, or if there is no other specific statement in the claim or description that the steps are limited to a particular order, no order is ever intended to be inferred. This also applies to any possible implicit basis for interpretation, including: logical matters relating to the arrangement or flow of operations of the steps; plain meaning derived from grammatical construction or punctuation; and the number or type of embodiments described herein.

[0043]

[0095] The components used to prepare the compositions of this disclosure, and the compositions themselves used in the manner disclosed herein, are disclosed. These and other substances are disclosed herein, and when combinations, subsets, interactions, groups, etc., of these substances are disclosed, specific references to each of the various individual and collective combinations and permutations of these compounds cannot be explicitly disclosed, but each is understood to be specifically contemplated and described herein. For example, when a particular compound is disclosed and discussed, and numerous modifications that can be made to a number of molecules containing that compound are discussed, all combinations and permutations of the compound, as well as possible modifications, are specifically contemplated unless otherwise indicated. Thus, when classes of molecules A, B, and C are disclosed, classes of molecules D, E, and F are disclosed, and examples of combinations of molecules A and D are disclosed, each is intended to be considered, individually and collectively, as disclosed, even if not individually enumerated. Similarly, any subsets or combinations of these are also disclosed. Thus, for example, the subgroups of AE, BF, and CE are considered disclosed. This concept applies to all embodiments of this application, including but not limited to steps in the methods for producing and using the compositions of the present disclosure. Therefore, where various additional steps are possible, each of these additional steps is understandable as being implementable in any particular embodiment or combination of embodiments of the methods of the present disclosure.

[0044]

[0096] It is understood that the compositions disclosed herein have a particular function. This specification discloses certain structural requirements for performing the disclosed function, and it is understood that there are various structures that can perform the same function related to the disclosed structure, and that these structures typically achieve the same result.

[0045]

[0097] As used herein, the word “substantially” refers to the complete or near-complete range or degree of an action, quality, characteristic, state, structure, item, or result. For example, an object “substantially” enclosed means that the object is either completely enclosed or nearly completely enclosed. The exact degree of tolerance for deviation from absolute completeness may, in some cases, depend on the specific context. However, generally speaking, approaching a complete state results in the same overall outcome as if an absolute and complete state had been achieved. The use of “substantially” is equally applicable when used in a negative sense to refer to the complete or near-complete absence of an action, quality, characteristic, state, structure, item, or result. For example, a “substantially particle-free” composition either completely lacks particles or nearly completely lacks particles, so that its effect is the same as if it were completely particle-free. In other words, a “substantially component or element-free” composition may still actually contain such item, as long as its measurable effect is not present.

[0046]

[0098] As used herein, "drug reservoir" refers to the phase in which an antitumor agent is dissolved separately from the carrier phase.

[0099] As used herein, the words “preferred” and “preferred” refer to embodiments of the Disclosure that may provide certain advantages under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. Furthermore, the enumeration of one or more preferred embodiments does not imply that other embodiments are unhelpful, nor is it intended to exclude other embodiments from the scope of the Disclosure.

[0047]

[0100] Chemotherapy drug molecules and biological compounds elute from custom-formulated, multiphase, stable emulsions to induce tumor cell death and apoptosis in animals with malignant tumors. Depending on the chemotherapeutic components contained in the drug reservoir, other useful therapeutic and clinical applications besides tumor death, such as elimination of fibroids, may be provided. Generally, stable emulsions containing solid crystals or dissolved chemotherapeutic agents and / or solid-phase drug reservoirs are contained within a continuous carrier phase that forms a liquid emulsion, which allows for delivery via catheters or via syringes and subcutaneous needles through applicators. Alternative forms may have liquid, solid, or semi-solid drug reservoirs, or mixtures of multiple drug reservoirs formed in the emulsion.

[0048]

[0101] An emulsion can be considered stable if the remaining unmiscible phase does not separate for a commercially useful period. The commercially useful period is the period that allows sufficient time to carry out all relevant testing, transport, storage, and use. In some embodiments, the commercially useful period may range from about one week to about five years. In further embodiments, the commercially useful period may range from about one month to about two years. In preferred embodiments, the commercially useful period may range from about six months to about twelve months.

[0049]

[0102] Emulsions can also be reversible. A reversible emulsion is one in which, when an immiscible phase separates, it can return to a stable, unseparated state with a gentler mixing than was required to initially mix the immiscible phase.

[0050]

[0103] The drugs disclosed herein are stable emulsions, either with or without solid crystals dispersed throughout, that offer excellent sustained-release performance for low molecules such as doxorubicin and docetaxel. The products offer extended dissolution, which has the advantage of leaving little to no chemotherapeutic agent (CA) or drug excipients in the body after 14 days. Another advantage of the drugs is that they utilize body tissues to absorb and remove the drugs in order to deliver high local concentrations of CA while minimizing high systemic levels. Furthermore, animal studies have shown that the drugs are removed through the lymphatic system, similar to the pathway of metastatic cancer cells. This allows the formulation to potentially treat metastatic malignant cancer cells. INSB400 is primarily designed to act as a first-line chemotherapeutic agent for solid tumors.

[0051]

[0104] In certain embodiments, additional components, such as fatty acids, histamine, or Corey's toxin (pyrogenic activators), are added to the formulation to initiate a local immune response, which would allow the patient's immune system to target tumor-specific antigens and eliminate all tumor cells from the body. In further embodiments, systemically acting immune activators or activators that enhance the immune response are included in the formulation at concentrations that allow an effective dose to be delivered into the body.

[0052]

[0105] Formulations can be developed that deliver high local and low systemic concentrations of CA to reduce CA-related adverse events while maintaining high local tumor exposure concentrations. Furthermore, if desired, formulations can be developed so that the drug delivers high local concentrations of CA while maintaining systemic exposure similar to standard treatment for potentially treating metastatic cells located outside the primary tumor.

[0053]

[0106] Traditional systemic routes of administration for CA involve varying levels of first-pass metabolism by the liver, depending on the CA used. For this reason, having drugs remaining in the peritumoral area while providing high tumor-site exposure to CA can yield beneficial results for the treated patient.

[0054]

[0107] The inherent properties of the compositions disclosed herein enable the storage and retention of CA (e.g., docetaxel) and the limitation of its elution rate. Solid particles in emulsions typically allow the lipid and aqueous phases to coalesce, destabilizing the emulsion. In the formulations disclosed herein, the solid particles do not destabilize the emulsion, and the emulsion is a homogeneous liquid that retains the solid particles dispersed throughout the two liquid phases.

[0055]

[0108] Typically, emulsions cannot deliver a therapeutically effective dose of CA for several days because they cannot carry a sufficient load of CA. This is because emulsions are limited by the solubility of CA in the emulsion components. Stable emulsions typically do not contain solid particles that can initiate the maturation of the lipid and aqueous phases. Previous iterations of INSB200 formulations containing non-chemotherapy APIs were capable of holding up to 28% by weight of solid API particles in the emulsion relative to the lipid components, or 12% by weight relative to the total drug without phase separation. In some formulations, the described emulsions can carry up to 15% of API relative to the total drug weight. Many lipid components, such as triglycerides, have low CA solubility in the body and at ambient temperatures, preventing the dissolution of pharmaceutically effective amounts of CA. INSB400, due to its unique mixture of components and manufacturing process, produces stable emulsions with solid CA crystals. In certain embodiments, the crystals are present in both the lipid and aqueous phases.

[0056]

[0109] In certain alternative embodiments, the CA is at a concentration where no solid crystals are present, and a sustained-release profile is also achieved. In formulations where the CA is hydrophilic, such as doxorubicin, the continuous phase can be inverted so that water droplets carry doxorubicin in the continuous oil phase, or alternatively, so that a hydrophobic CA, such as docetaxel, can be carried by oil droplets in the continuous aqueous phase. Other drug reservoirs, such as solid fatty acids or triglyceride particles, may be used to enhance the oncotoxic response to the drug. In other examples, fatty acids and certain triglycerides can be added to emulsion formulations as part of a liquid emulsion rather than as solid particles. In various embodiments, the concentration of CA may range from about 0.1% (w / w) to about 20% (w / w) in the overall formulation. In further embodiments, the concentration of CA may range from about 1% (w / w) to about 10% (w / w) in the overall formulation. In further embodiments, the concentration of CA may also be about 2% (w / w) to about 5% (w / w) in the whole formulation. In a particular embodiment, the concentration of CA may be about 3.009% (w / w) in the whole formulation, which is about 29.34 mg / mL.

[0057]

[0110] In the provided example, lipophilic CA molecules such as docetaxel have very low solubility in water, which creates a first barrier to CA diffusion into the surrounding tissue. While not bound by theory, the low solubility of the API in the aqueous phase is thought to prevent the rapid dissolution of docetaxel crystals present in the formulation. For docetaxel to dissolve in the aqueous phase, the docetaxel already present in the saturated aqueous phase must diffuse out of the emulsion and into the surrounding tissue. The solubility of docetaxel in the aqueous phase limits the rate at which docetaxel can diffuse out of the emulsion. Oil droplets in the emulsion also have low solubility for docetaxel, which limits the amount of docetaxel that can diffuse from the lipid droplets into the aqueous continuous phase, creating a second barrier to diffusion. Once the CA in the aqueous phase is depleted, the CA in the lipid phase must move across the liquid / liquid interface, moving from one low-solubility liquid phase to another low-solubility liquid. A third barrier to diffusion is the migration of the solid API crystals to the liquid solute phase. The lipid liquid phase and aqueous liquid phase have low CA solubility, and consequently, they both limit the mass migration of the crystalline solid phase to the liquid solute phase. Due to these inherent dissolution characteristics of INSB400, the formulation persists for 3 to 7 days, and autopsy results indicate that the drug was excreted or largely excreted within 14 days. The following is an exemplary embodiment of a three-phase formulation comprising a lipid phase, an aqueous phase, and a solid crystalline phase according to a particular embodiment.

[0058]

[0111] In certain embodiments, the stability of a formulation increases as the relative amount of CA crystals dispersed in the lipid phase of the formulation increases. This increase in stability is unexpected, as stability decreases when more suspended material is added to a suspension or emulsion, as aggregation and precipitation of the suspended material can occur.

[0059]

[0112] In another iteration of the formulation, both a hydrophilic agent, e.g., doxorubicin, and a hydrophobic agent, e.g., docetaxel, are included in the same emulsion formulation and act on the tumor through two different mechanisms. In these embodiments, the two CAs also elute from the emulsion at different rates due to their chemical properties, thus allowing for continuous and controllable exposure to CA concentrations before being leached and eliminated from the tumor site. Treating the tumor simultaneously with multiple agents has the potential to prevent tumor resistance to CAs and provide a more effective treatment. It is understood that other CAs, such as cisplatin, can be added to the emulsion so that three or more CAs may be present in the formulation at the same time.

[0060]

[0113] In a particular embodiment, the disclosed stable emulsion comprises an aqueous carrier; a lipid phase dispersed as droplets within the aqueous carrier; and a first plurality of chemotherapeutic agent crystals within the lipid phase. In a particular embodiment, a second plurality of chemotherapeutic agent crystals are present in the aqueous carrier rather than in the lipid phase, and these second plurality of chemotherapeutic agent crystals dissolve and elute from the stable emulsion at a faster rate than the first plurality of chemotherapeutic agent crystals. lipid phase

[0114] In certain embodiments, the lipid phase is dispersed in an aqueous phase, and the dispersed droplets contain CA. In certain embodiments, CA exists in the lipid phase in the form of CA crystals. In further embodiments, CA is dissolved in the lipid phase. In certain embodiments, the lipid phase may contain one or more triglycerides and is liquid at room temperature.

[0061]

[0115] In certain embodiments, a vegetable oil or wax with a higher melting point (e.g., coconut oil and / or carnauba wax) is included in the lipid phase. In certain embodiments of these embodiments, the CA crystals in the lipid phase are coated with the oil and / or wax with a higher melting point. In certain embodiments of these embodiments, such coating of the CA crystals further increases the time frame for which CA elutes from the chemical. In exemplary embodiments, the oil and / or wax with a higher melting point is present in an amount of about 3 to about 30% of the weight of the lipid phase. aqueous phase

[0116] According to certain embodiments, the aqueous phase may be dispersed as droplets in a lipid liquid continuous phase. CA may be present in the aqueous phase as a solute, or in the solid crystalline phase. Multiple CAs may be present in the droplets of the aqueous phase. Additional lipophilic CAs may be present in the lipid continuous phase together with hydrophilic CAs in the water droplets. In certain embodiments, the aqueous phase may contain further excipients, salts, and / or antioxidants, as further described below. Triglycerides

[0117] Triglycerides are esters of glycerol and three fatty acids, which may be all the same fatty acid or a mixture of different fatty acids. Fatty acids can be saturated (no carbon double bonds in the fatty acid chain), unsaturated (one or more carbon double bonds in the fatty acid chain), or a mixture of both saturated and unsaturated fatty acid chains. Triglycerides are the main components of animal fats and vegetable oils.

[0062]

[0118] Triglycerides have long been used as carriers for pharmaceutical ingredients. Castor oil, soybean oil, and peanut oil are all used as carriers for hydrophobic causates (CAs). These formulations are used when a pharmaceutically effective dose can be dissolved in the carrier volume, and when that volume is small enough not to cause significant discomfort in the recipient.

[0063]

[0119] Triglycerides are used as nutritional supplements intravenously or orally and are one of the main energy storage molecules in mammals. Stable emulsions are used in the pharmaceutical industry, but most formulations do not contain solid CA crystals.

[0064] [Table 1-1]

[0065] [Table 1-2]

[0066] [Table 2-1]

[0067] [Table 2-2]

[0068] [Table 2-3]

[0069] [Table 2-4]

[0070] [Table 2-5]

[0071] [Table 2-6]

[0072] [Table 2-7]

[0073] [Table 3-1]

[0074] [Table 3-2]

[0075] [Table 4]

[0076] [Table 5]

[0077] [Table 6]

[0078] Conjugated fatty acids can also be used alone or in mixtures with other fatty acids to produce triglycerides.

[0079] [Table 7]

[0080] [Table 8-1]

[0081] [Table 8-2]

[0082]

[0120] As those skilled in the art will understand, fatty acids can evoke an inflammatory response in a subject. In certain situations, such as the injection of a formulation containing inflammation-inducing fatty acid oils, the inflammatory response may be desirable in that it can stimulate the subject's immune system to act at the site of the drug's action. This local immune response is preferable to a systemic immune response because it reduces the risk of immune cells targeting healthy cells. When a formulation containing inflammation-inducing fatty acid oils is injected into a tumor of the subject, the inflammatory response can provide a synergistic effect in fighting the tumor, both through the API in the formulation and through an increased immune response of the subject against the tumor.

[0083]

[0121] In various embodiments, the concentration of oil, which is triglycerides, free fatty acids, or both, may be about 15% (w / w) to about 80% (w / w) of the whole formulation. In further embodiments, the oil concentration may be about 20% (w / w) to about 50% (w / w) of the whole formulation. In yet another embodiment, the oil concentration may be about 30% (w / w) to about 40% (w / w) of the whole formulation. In one particular embodiment, the oil concentration may be about 37.62% (w / w) of the whole formulation, which is about 366.80 mg / mL. Excipients

[0122] According to certain embodiments, low concentrations of other excipients may be added to supplement or improve stability or to act as antioxidants. Naturally derived triglycerides contain unsaturated moieties, polymerize, and can be oxidized in the presence of oxygen. α-Tocopherol may be added to the triglycerides before sterile filtration to act as an antioxidant without affecting the stability or elution properties of the emulsion. Other hydrophobic antioxidants, such as lycopene, retinol, carotenoids, and other tocopherols, may be used.

[0084]

[0123] Similarly, hydrophilic antioxidants, such as ascorbic acid, may be added to protect hydrophilic CA. In certain embodiments of the formulation, sodium hydroxide is used to maintain a desired pH of about 8 to control the elution of API from the lipid excipient. In further embodiments, other salts or weak acids are used to adjust and maintain the formulation at a desired pH. It is in the knowledge of those skilled in the art to adjust buffers to ensure a stable pH over time, if present.

[0085]

[0124] In certain embodiments, glycerol is used as an aqueous modifier to provide a stable emulsion. In further embodiments, but not limited to these, other polyols, including sorbitol and manitol, are used to further modify the formulation to obtain similar results. In various embodiments, the concentration of glycerol may range from about 0.05% (w / w) to about 15% (w / w) in the overall formulation. In further embodiments, the concentration of glycerol may range from about 0.1% (w / w) to about 10% (w / w) in the overall formulation. In even further embodiments, the concentration of glycerol may also range from about 1% (w / w) to about 5% (w / w) in the overall formulation. In a particular embodiment, the concentration of glycerol may be about 1.743% (w / w) in the overall formulation, which is about 17.000 mg / mL.

[0086]

[0125] According to certain embodiments, hyaluronic acid, hyaluron, and sodium hyaluronate (collectively referred to herein as "HA") are considered the same compound herein and consist of long-chain polymers containing linear glycosaminoglycans (GAGs). HA can have various molecular weights (MW), and the variation in MW used affects the viscosity of the formulation and the stability of the emulsion. In the formulations disclosed herein, hyaluronic acid is used as an emulsifier and aqueous phase thickener. Higher concentrations result in a higher ratio of lipid to aqueous phase that can be achieved, thus increasing the total amount of CA available for dissolution. In various embodiments, the concentration of HA may range from about 0.001% (w / w) to about 5% (w / w) in the overall formulation. In further embodiments, the concentration of HA may range from about 0.005% (w / w) to about 2.5% (w / w) in the overall formulation. In further embodiments, the concentration of HA may also be about 0.01% (w / w) to about 1% (w / w) in the whole formulation. In a particular embodiment, the concentration of HA may be about 0.082% (w / w) in the whole formulation, which is about 0.8000 mg / mL.

[0087]

[0126] In further embodiments, amphiphilic polysaccharides having both polar hydroxyl and nonpolar methyl ether moieties, acting as thickeners, are used to achieve effects similar to those of HA. In certain embodiments, polyethylene glycol functions as an emulsifier / thickener. In further embodiments, the aforementioned combinations are used to thicken and stabilize emulsions.

[0088]

[0127] Lecithin, a mixture of phospholipids obtained from soybeans or eggs, can be used to produce the same results. In certain embodiments, lecithin obtained from other sources, such as sunflower seeds or canola seeds, can be used to produce similar results. In this case, phospholipids are called a class of lipids comprising one hydrophilic phosphate group and two hydrophobic fatty acid groups linked by one alcohol residue. It is known to those skilled in the art that the hydrophilic phosphate "head" group may contain different amino acid chemical moieties. Furthermore, it is known to those skilled in the art that the hydrophobic "tail" group may contain saturated, monounsaturated, and polyunsaturated fatty acids and may have varying chain lengths of 14 to 18 carbon atoms.

[0089]

[0128] In certain embodiments, phospholipids may be combined with other emulsifiers, such as sorbitan esters, polysorbates, propylene oxides, ethoxylates, copolymers, and macromolecules, to produce similar results, although this is not limited to these.

[0090]

[0129] In various embodiments, the concentration of lecithin containing the same compound may range from about 0.1% (w / w) to about 20% (w / w) in the entire formulation. In further embodiments, the concentration of lecithin may range from about 1% (w / w) to about 10% (w / w) in the entire formulation. In yet another embodiment, the concentration of lecithin may range from about 2% (w / w) to about 5% (w / w) in the entire formulation. In a particular embodiment, the concentration of lecithin may be about 3.009% (w / w) in the entire formulation, which is about 29.34 mg / mL.

[0091]

[0130] According to a particular embodiment, the emulsion components and the range of amounts of such components are shown in Table 9.

[0092] [Table 9]

[0093] Method for formulating a stable, multiphase emulsion

[0131] There are two main methods for producing stable emulsions. The first method utilizes a common solvent, such as acetone (acetone is preferred), other ketone solvents, or a mixture thereof, that can dissolve triglyceride oil, lipophilic excipients, and CA. The second method uses heated triglyceride oil to dissolve an effective amount of CA. Solvent method

[0132] Regarding the solvent preparation method, CA and lipophilic excipients are added to a solvent, such as acetone. Once the CA is completely dissolved and a clear solution is obtained, the solution can be sterile filtered through a filter medium with a pore size of 0.2 microns or less. The resulting solution is then subjected to a crystallization unit operation, where the solvent is removed from the solution and crystallization of the CA component occurs in the liquid triglyceride phase. The solvent can be completely removed by various methods; for example, the solvent can be removed by the steps of drawing a vacuum over the solvent phase and removing the solvent from the liquid lipid phase by draining or condensing it. Heating may be used to increase the vapor pressure of the solvent and facilitate its removal from the solution. Any residual solvent can be volatilized from the liquid lipid phase using air, nitrogen, or other inert gases. Once the solvent has been removed from the liquid triglyceride phase, the resulting slurry will contain CA crystals. The aqueous phase, containing all remaining emulsifiers and excipients, is then sterile filtered through a 0.2 μm filter medium and added to the liquid triglyceride phase. The two phases are thoroughly mixed to produce a homogeneous two-phase liquid, which is then exposed to a stator-rotor emulsifier or fed into an in-line emulsifier to produce a stable, homogeneous emulsion containing CA. The resulting emulsion is transferred to a stock tank / bag, which can then be packaged in vials, syringes, or other delivery devices. One advantage of using the solvent method described above is its ability to dissolve temperature-sensitive CA in solution without the need for heating. This also allows for the formation of high-concentration CA formulations that cannot be produced using heating processes. heating method

[0133] The thermal manufacturing method utilizes an unexpected and non-trivial way of dissolving CA in the lipid phase, which allows for sterile filtration of the solution before emulsion formation. While many solvents can contain more solute in solution as the solvent is heated, in most cases a significant amount of solute remains present in the solution at lower temperatures, such as room temperature (22°C). In the case of triglyceride oil, CA is almost completely insoluble in the oil at room temperature, but this can increase when the solution is heated. This allows for sterile filtration of CA in the solution when heated. Another inherent aspect of this formulation is that when heated, it comes into contact with the aqueous component and, as it cools as an emulsion forms, the resulting crystals are smaller, with the majority of CA molecules remaining in the oil droplets. Without this thermal emulsification, very large amounts of CA would deposit in the formulation as large crystals, failing to achieve the desired elution profile to tumors over several days.

[0094]

[0134] In certain embodiments, the composition further comprises a radiopaque contrast agent.

[0135] Furthermore, this specification discloses a method for treating cancer in a subject requiring such treatment, comprising the step of administering to the subject an effective amount of a composition comprising a stable multiphase emulsion disclosed herein.

[0095]

[0136] In certain embodiments, the immiscible carrier phase is a hydrogel composed of, for example, a substituted hyaluronic acid having a tyramine moiety, thereby increasing stability while reducing the migration of anticancer agents from the tumor site.

[0096]

[0137] In certain embodiments, the antitumor agent is selected from one or more of the following: angiogenesis inhibitors, e.g., angiostatin K1-3, DL-α-difluoromethyl-ornithine, endostatin, fumagiline, genistein, minocycline, staurosporine, and (±)-thalidomide; DNA insertion / crosslinking agents, e.g., bleomycin, carboplatin, carmustine, chlorambucil, cyclophosphamide, cis-diammineplatin(II) dichloride (cisplatin), melphalan, mitoxantrone, and oxaliplatin; DNA synthesis inhibitors, e.g., (±)-ametopterin (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, e.g., actinomycin D, daunorubicin, doxorubicin, homohalintin, and idarubicin; enzyme inhibitors, e.g., S(+)-camptothecin, curcumin, (-)-deguerin, 5,6-dichlorobenzimidazole 1-β-D-ribofuranoside, etoposide, formestan, fostoriesin, hispidin, 2-imino-1-imidazolidinedacetate (cyclocreatine), mebinolin, trichostatin A, thyrophostine AG 34, and thyrophostine AG 879; gene regulators, e.g., 5-aza-2'-deoxycytidine, 5-azacitidine, cholecalciferol (vitamin D3), 4-hydroxytamoxifen, melatonin, mifepristone, raloxifen, 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, e.g., colchicine, drastatin 15, nocodazole, paclitaxel, podophyllotoxin, rhizoxin, vinblastine, vincristine, vindesine, and vinorelbine (navelbine); and unclassified antitumor agents, e.g., 17-(allylamino)-17-demethoxygeldanamycin, 4-amino-1,8-naphthalimide, apigenin,Brefelzin A, cimetidine, dichloromethylene-diphosphonic acid, leuprolide (leuprorelin), luteinizing hormone-releasing hormone, pifislin-α, rapamycin, sex hormone-binding globulin, thapsigardin, and urinary trypsin inhibitor fragment (bikunin). Antitumor agents may be novel antigens. Novel antigens are tumor-related peptides that function as pharmacokinetic active ingredients in vaccine compositions that stimulate an antitumor response, and are 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, bismodegib, 90Y-ibritumomab tiuxetan, 131I-tocitumomab, ad-trastuzumab emtansine, lapatinib, pertuzumab, ad-trastuzumab emtansine, regorafenib, sunitinib, denosumab, sorafenib, pazopanib, and aki. The antitumor agents may be citinib, dasatinib, nilotinib, bosutinib, ofatumumab, obinutuzumab, ibrutinib, idelalisib, crizotinib, erlotinib (Tarceva®), afatinib dimaleate, ceritinib, tocitumomab and 131I-tocitumomab, ibritumomab tiuxetan, brentuximab vedotin, bortezomib, siltuximab, trametinib, dabrafenib, pembrolizumab, carfilzomib, ramucirumab, cabozantinib, and vandetanib. The antitumor agents may be cytokines, such as interferon (INF), interleukin (IL), or hematopoietic growth factors. The antitumor agents may be INF-α, IL-2, aldezleukin, IL-2, erythropoietin, granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte colony-stimulating factor. The antitumor agents are targeted therapies, such as toremifene, fulvestrant, anastrozole, exemestane, letrozole, ziv-aflibercept, alitretinoin, temsirolimus, tretinoin, denileukin difutitox, vorinostat, romidepsin, bexarotene, pralatrexate, lenariomide, bellinostat, pomalidomide, cabazitaxel.The antitumor agent may be enzalutamide, abiraterone acetate, radium-223 chloride, or everolimus. The antitumor agent may be a PD-1 pathway inhibitor, such as a checkpoint inhibitor such as an anti-PD1 antibody (nivolumab). The inhibitor may be an anticytotoxic 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. Furthermore, the antitumor agent may be an epigenetic targeting agent, such as an HDAC inhibitor, kinase inhibitor, DNA methyltransferase inhibitor, histone demethylase inhibitor, or histone methylation inhibitor. Epigenetic drugs may include azacitidine, decitabine, vorinostat, romidepsin, or luxolitinib.

[0097]

[0138] This specification also provides kits of pharmaceutical formulations comprising the disclosed compounds or compositions. The kits may be configured to represent a single formulation or a combination of formulations. The compositions may be subdivided to contain appropriate amounts of the compounds. Unit doses may be in the form of packaged compositions, such as powders, vials, ampoules, filled syringes, or sachets containing liquids.

[0098]

[0139] The compounds or compositions described herein may be in single doses or for continuous or periodic discontinuous administration. In the case of continuous administration, the kit may contain the compound in each dose unit. In the case of periodic discontinuation, the kit may contain a placebo during the period when the compound is not delivered. If it is desirable to change the concentration of the composition, the components of the composition, or the relative ratio of the compound or other drugs in the composition over time, the kit may contain a series of dose units.

[0099]

[0140] The kit may include packaging or containers containing a compound formulated for a desired route of delivery. The kit may also include instructions for administration, accompanying documents related to the compound, instructions for monitoring the circulating levels of the compound, or a combination thereof. Further items for carrying out the use of the compound may be included, but are not limited to reagents, well plates, containers, and markers or labels. Such a kit is packaged in a manner suitable for the treatment of the desired indication. To those skilled in the art, other suitable components to be included in such a kit will be readily apparent, given the desired indication and route of delivery. The kit may also include, or be packaged with, instruments to assist in injecting / administering or placing the compound into the subject's body. Such instruments include, but are not limited to, syringes, pipettes, forceps, measuring spoons, eyedroppers, or any such medically approved means of delivery. Other instruments may include tools that enable the reading or monitoring of in vitro reactions.

[0100]

[0141] The compounds or compositions in these kits may also be supplied in dry, lyophilized, or liquid form. When reagents or components are supplied in dry form, reconstitution is generally carried out by adding a solvent. The solvent may be supplied in a separate packaging method, which can be selected by those skilled in the art.

[0101]

[0142] Many packages or kits for dispensing pharmaceuticals are known to those skilled in the art. In one embodiment, the package is a labeled blister package, a dial dispenser package, or a bottle.

[0102]

[0143] According to a particular embodiment, the anthracycline (doxorubicin) formulation is delivered to the tumor or surrounding space via a guide needle, laparoscopy, or postoperatively after tumor removal. 100-120 mg of doxorubicin hydrochloride is supplied as droplets of aqueous phase dispersed in a continuous lipid phase contained in a lipid carrier. mTOR

[0144] In certain embodiments, the disclosed stable emulsion is effective in the treatment of tumors, such as renal tumors. In these embodiments, the disclosed stable emulsion contains up to 20 mg of an mTOR inhibitor, such as rapamycin (sirolimus). The lipid phase may contain rapamycin at concentrations of 2 to 20 mg or more, depending on the formulation and dissolution rate of the lipid components. The lipid phase may be present at a volume / volt concentration between 5% and 50%. Those skilled in the art can develop similar formulations for other mTOR inhibitors, such as everolimus, temsirolimus, and similar drugs. VEGF-TKI

[0145] Vascular endothelial growth factor (VEGF) and tyrosine kinase inhibitors (TKIs), such as sorafenib, are supplied in a lipid phase and supported in a hydrogel aqueous formulation. A sustained dose of sorafenib can be delivered to the tumor or peritumoral site for several days or longer by ultrasound-guided needle delivery, fluoroscopy, laparoscopy, or intraoperative injection. In some formulations, 600–800 mg of sorafenib is contained in the lipid phase within the aqueous carrier phase and is injected into a solid tumor, into the space surrounding the tumor, or into the surgical site after tumor resection. Those skilled in the art can develop similar formulations for VEGF-TKI agents, such as lenvatinib, axitinib, and similar drugs. targeted therapy

[0146] Many biologics, such as bevacizumab and interferon, exhibit good water solubility, and their formulations can be modified to include a drug reservoir in which the hydrogel component is supported in a water / saline carrier or in a liquid lipid formulation. Aqueous nanoparticles may be present at volume / volume concentrations between 5% and 50%. Those skilled in the art can develop similar formulations specifically for targeted therapeutic agents. Direct injection into the tumor

[0147] In certain embodiments, the therapeutic formulation can be delivered directly into a solid tumor via a guide needle. intravascular delivery

[0148] In certain embodiments, the disclosed emulsion can be delivered directly to the vascular system and circulated in the bloodstream for several days until the particles and carrier are absorbed and the therapeutic agent is delivered throughout the body. In this embodiment, the therapeutic agent is delivered at a sustained-release concentration to ensure stable delivery of the therapeutic agent for 1 to 5 days or more, depending on the therapeutic agent.

[0103]

[0149] Various aspects and embodiments of this disclosure are defined by the following numbered sections. 1. A composition for treating tumors in a subject requiring it, an aqueous carrier; a liquid lipid phase dispersed as droplets in the aqueous carrier; and a first chemotherapeutic agent in the lipid phase. emulsion containing A composition containing the following: 2. The composition according to item 1, wherein the first chemotherapeutic agent comprises a plurality of first chemotherapeutic agent crystals. 3. The composition according to item 1, wherein the first chemotherapeutic agent is dissolved in the lipid phase. 4. The composition according to claim 2, further comprising a second plurality of chemotherapeutic agent crystals in an aqueous carrier rather than in a lipid phase, wherein the second plurality of chemotherapeutic agent crystals dissolve and elute from the emulsion at a faster rate than the first plurality of chemotherapeutic agent crystals. 5. The composition according to any one of claims 1 to 4, further comprising one or more additional chemotherapeutic agents different from the first chemotherapeutic agent. 6. A composition according to any one of items 1 to 5, wherein the lipid phase comprises triglycerides. 7. The composition according to any one of items 1 to 6, wherein the aqueous carrier further comprises an emulsifier and a polyol. 8. The composition according to item 7, wherein the emulsifier is hyaluronic acid. 9. The composition according to item 7, wherein the polyol is glycerol and is present in an amount of about 0.25 to about 2.5% (w / v) of the composition. 10. The composition according to item 8, wherein the hyaluronic acid is tyramine-substituted hyaluronic acid. 11. The composition according to any one of items 1 to 10, wherein the lipid phase further comprises phospholipids present in an amount of about 0.1% to about 2.0% of the lipid phase. 12. The composition according to any one of items 1 to 11, further comprising an antioxidant present in the lipid phase in an amount of about 0.01% to about 1% (w / v) of the composition. 13. A composition according to any one of items 1 to 12, wherein the lipid phase is approximately 10% to approximately 40% (w / v). 14. The composition according to any one of claims 1 to 13, wherein the emulsion further contains lecithin, the lecithin present in an amount of 0.1 to 5% (w / v) of the emulsion. 15. The composition according to item 1, wherein the emulsion further comprises dextrose, the dextrose present in an amount of about 1-2% (w / v) of the emulsion. 16. The composition according to item 1, wherein the emulsion further comprises Tween 80, said Tween 80, present in an amount of about 0-5% (w / v) of the emulsion. 17. The composition according to item 1, wherein the emulsion further contains sorbitol, which is present in an amount of about 0.1-2% (w / v) of the emulsion. 18. The composition according to item 1, wherein the emulsion further comprises PEG, the PEG present in an amount of about 0.1 to 0.5% (w / v) of the emulsion. 19. The composition according to item 1, wherein the lipid phase comprises about 15% to 80% (v / v) of soybean oil and about 15% to about 20% (v / v) of one or more medium-chain triglycerides. 20. The composition according to item 19, wherein the chemotherapeutic agent is present in an amount ranging from about 0.1 mg / g of soybean oil to about 300 mg / g of soybean oil. 21. The composition according to item 1, wherein the chemotherapeutic agent is selected from anthracyclines, mTOR inhibitors, VEGF-TKI agents, and immunostimulants. 22. The composition according to any one of items 1 to 21, wherein the lipid phase comprises triptylate and / or stearate. 23. The composition according to item 2, wherein the lipid phase further comprises, in an amount (w / w) of about 5% to about 30% of the lipid phase, an oil and / or wax that is solid at 25°C, and the oil and / or wax coats a chemotherapeutic agent crystal. 24. The composition according to any one of items 1 to 23, wherein the chemotherapeutic agent is docetaxel. 25. The composition according to any one of items 1 to 23, wherein the antitumor agent is doxorubicin. 26. A composition for treating tumors in a subject requiring it, A lipid carrier phase; an aqueous phase dispersed as droplets in the lipid carrier phase; and a first chemotherapeutic agent in the aqueous phase. emulsion containing A composition containing the following: 27. The composition according to item 26, wherein the first chemotherapeutic agent comprises a plurality of first chemotherapeutic agent crystals. 28. The composition according to item 26, wherein the first chemotherapeutic agent is dissolved in an aqueous phase. 29. The composition according to item 27, further comprising a second plurality of chemotherapeutic agent crystals present in a lipid carrier rather than in an aqueous phase, wherein the second plurality of chemotherapeutic agent crystals dissolve and elute from the emulsion at a faster rate than the first plurality of chemotherapeutic agent crystals. 30. The composition according to item 29, wherein the chemotherapeutic agent is hydrophilic and dissolved in the aqueous phase. 31. The composition according to item 26, further comprising one or more additional chemotherapeutic agents different from the first chemotherapeutic agent. 32. A composition for treating a tumor in a subject requiring the treatment thereof, comprising an emulsion comprising an aqueous carrier; a liquid lipid phase dispersed as droplets in the aqueous carrier; and a first chemotherapeutic agent in the lipid phase, wherein the first chemotherapeutic agent comprises a plurality of first chemotherapeutic agent crystals, and the liquid lipid phase further comprises one or more oils and / or waxes having a melting point greater than 25°C, wherein the one or more oils and / or waxes coat the plurality of first chemotherapeutic agent crystals. 33. The composition according to item 32, wherein one or more oils and / or waxes are coconut oil and / or carnauba wax. 34. The composition according to item 33, wherein coconut oil and / or carnauba wax are present in an amount of about 3% to about 30% (w / w) of the lipid phase. 35. The composition according to any one of items 1 to 34, wherein the emulsion is stable for a period of about one month to about two years. 36. The composition according to item 35, wherein the emulsion is stable for a period of about 6 to about 12 months. 37. The composition according to any one of items 1 to 36, wherein the emulsion is reversible. 38. A method for treating a tumor in a subject requiring the treatment thereof, comprising: an aqueous carrier; a lipid phase dispersed as droplets in the aqueous carrier; and a first chemotherapeutic agent in the lipid phase. A method comprising the step of administering an effective amount of a composition containing the composition to a subject. 39. The method according to claim 38, wherein the chemotherapeutic agent comprises a plurality of chemotherapeutic agent crystals, and the composition further comprises a second plurality of chemotherapeutic agent crystals in an aqueous carrier rather than in a lipid phase, wherein the second plurality of chemotherapeutic agent crystals dissolve and elute from the emulsion at a faster rate than the first plurality of chemotherapeutic agent crystals. 40. The method according to item 38 or 39, wherein the composition is administered directly to the tumor site by guide needle, laparoscopy, or postoperatively after tumor removal. 41. The method according to any one of items 38 to 40, wherein the chemotherapeutic agent is eluted from the composition over a period of time between approximately 4 and 7 days. 42. The method according to any one of items 38 to 41, wherein the composition further comprises an immunostimulant. 43. The method according to any one of items 38 to 42, wherein the lipid phase comprises one or more fatty acids in an amount sufficient to induce a local inflammatory response in the subject at the injection site. 44. A method for treating lymphatic cancer in a subject requiring the treatment thereof, comprising the step of administering to the subject a composition described in any of items 1 to 37. [Examples]

[0104]

[0150] The following examples are provided to fully disclose and illustrate to those skilled in the art how the compounds, compositions, articles, tools and / or methods claimed herein are prepared and evaluated, and are intended to be purely illustrative of the present disclosure and not intended to limit the scope of what the inventors consider to be the present disclosure. However, those skilled in the art will understand that many modifications can be made to the specific embodiments disclosed in light of the present disclosure, and still equivalent or similar results can be obtained without departing from the spirit and scope of the present disclosure.

[0105] Example 1 Preparation of stable emulsions

[0151] A stable emulsion containing CA docetaxel or doxorubicin was prepared according to the following protocol. 1. Docetaxel or doxorubicin was added to soybean oil (up to 13% by weight of the oil). 2.0.75 g of lecithin was added to the soybean oil mixture. 3. The CA / oil slurry was heated to 100°C while vigorously mixing the slurry until the CA crystals were completely dissolved in the solution. 4. Soybean oil containing CA was sterile filtered at a temperature of 100°C using a 0.2 μm vacuum filter. A 5.0.15% aqueous solution of sodium and 0.51% g of glycerol (w / v) was prepared at 4°C. 6. The aqueous solution was heated to 100°C, sterilized by filtration through a 0.2 μm filter medium, and then mixed with warmed soybean oil, lecithin, and CA-based solution. 7.2 The two phases were emulsified in a main mixing vessel using a rotor-stator emulsifier or by supplying the two-phase mixture to an in-line emulsifier until a stable emulsion was formed. 8. Emulsification was continued until the mixture cooled to room temperature for subsequent use or storage.

[0106] Example 2 Docetaxel plasma concentration in rats

[0152] Rats received standard treatment docetaxel delivered via IM or IV infusion of a stable emulsion of docetaxel prepared according to the protocol of Example 1. Figure 1 shows the plasma concentrations of docetaxel over time for the 9.6 mg / kg stable emulsion formulation. The docetaxel-positive control line (6.45 mg / kg) represents the response to standard treatment. The stable emulsion formulation provided a significant amount of docetaxel for longer than 170 hours, significantly exceeding the SOC docetaxel treatment group.

[0107] Example 3 Doxorubicin plasma concentration in rats

[0153] Rats received standard treatment doxorubicin delivered via IM or IV infusion of a stable emulsion of doxorubicin prepared according to the protocol of Example 1. Figure 2 shows the plasma concentrations of doxorubicin over time for the 6.48 mg / kg stable emulsion formulation. The docetaxel-positive control line represents the response to standard treatment. The stable emulsion formulation provides a significant amount of docetaxel for longer than 120 hours and reduces systemic exposure to CA. Variations of formulations

[0154] In Examples 4–10, the base formulation is used with various substitutions prepared for each example. The base formulations are given in Table 10 below. The components of the base formulation are mixed using a benchtop mixer with a standard 5.08 cm (2 inch) head at 6000 RPM. This base formulation, and the various substitutions in these examples, are merely illustrative embodiments and are not intended to be limiting.

[0108] [Table 10]

[0109] Example 4 Types of lecithin

[0155] As is understood, lecithin composition varies depending on its origin (plant, animal, egg), whether it is defatted, and the degree of processing. Lecithins with a high percentage of phosphatidylcholine are often used in injectable products and must meet the USP National Formulary requirements for injectables containing a phosphatidylcholine concentration of >70%. Lecithins with lower concentrations of phosphatidylcholine are typically used for oral and topical medicines, foods, and cosmetics. Lecithins with lower phosphatidylcholine yield more stable emulsions with less energy added during formation, while lecithins with higher phosphatidylcholine concentrations form even more stable emulsions but require higher energy to be added during formation. In this example, five samples, Samples 1-5, were developed and analyzed using lecithins of different compositions.

[0110]

[0156] Sample 1 uses the base formulation, but instead of lecithin, it uses Spectrum NF (50-60% phosphatidylcholine). Images of the obtained substance are shown in Figure 3A at 10x magnification and in Figure 3B at 20x magnification. The oil droplets are small, and the API crystals are elongated needle-shaped. The emulsion remained stable for 14 days. The sample forms a white, impermeable emulsion / suspension.

[0111]

[0157] Sample 2 uses the base formulation, but instead of lecithin, it uses Cargill Metarin lecithin (19-27% phosphatidylcholine). Images of the obtained substance are shown in Figure 4A at 10x magnification and in Figure 4B at 20x magnification. The oil droplets are small, and the API crystals are long, needle-shaped. The emulsion remained stable for 1 day. The sample forms a white, impermeable emulsion / suspension.

[0112]

[0158] Sample 3 uses the base formulation, but instead of lecithin, it uses Cargill Epikuron lecithin (19-27% phosphatidylcholine). Images of the obtained substance are shown at 10x magnification in Figure 5A and 20x magnification in Figure 5B. The oil droplets are small, and the API crystals are long, needle-shaped. The emulsion remained stable for 1 day, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking. The sample forms a white, impermeable emulsion / suspension.

[0113]

[0159] Sample 4 uses the base formulation, but instead of lecithin, it uses Lipoid S75 (>70% phosphatidylcholine). Images of the obtained substance are shown at 10x magnification in Figure 6A and 20x magnification in Figure 6B. The oil droplets are small, and the API crystals are elongated needle-shaped. The emulsion remained stable for 4 days, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking. The sample forms a white, impermeable emulsion / suspension.

[0114]

[0160] Sample 5 uses the base formulation, but instead of lecithin, it uses Lipoid S80 (73-79% phosphatidylcholine). Images of the obtained substance are shown at 10x magnification in Figure 7A and 20x magnification in Figure 7B. The oil droplets are small, and the API crystals are long, needle-shaped. The emulsion remained stable for 1 day, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking. The sample forms a white, impermeable emulsion / suspension.

[0115] Example 6 Lecithin concentration in soybean oil

[0161] Those skilled in the art will understand that lecithin concentration can affect a formulation by altering the interaction between the aqueous and lipid phases at their boundaries. Typically, a higher lecithin ratio to lipid phase concentration results in smaller, discontinuous phase droplets. However, higher lecithin concentrations may also prevent API crystal aggregation. Higher lecithin concentrations can also make the formulation highly viscous. In the case of cancer therapeutics, higher viscosity may be acceptable if the delivery needle can be a larger gauge needle for drug placement. In this example, five samples, samples 6–10, were developed and analyzed using different concentrations of lecithin.

[0116]

[0162] Sample 6 uses the base formulation, but the lecithin component is reduced to 0.5% and replaced with soybean oil. Images of the resulting substance are shown at 10x magnification in Figure 8A and 20x magnification in Figure 8B. The oil droplets are small, and the API crystals are long, needle-shaped. The emulsion remained stable for 3 days, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking. The sample forms a white, impermeable emulsion / suspension. Note that the large voids in Figures 8A and 8B are air pockets trapped in the sample.

[0117]

[0163] Sample 7 uses the base formulation, but the lecithin component is slightly reduced to 2.5% and replaced with soybean oil. Images of the resulting substance are shown at 10x magnification in Figure 9A and 20x magnification in Figure 9B. The oil droplets are small, and the API crystals are elongated needle-shaped. The emulsion remained stable for 4 days, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking. The sample forms a white, impermeable emulsion / suspension. Note that the large voids in Figures 9A and 9B are air pockets trapped in the sample.

[0118]

[0164] Sample 8 uses the base formulation, but the lecithin component is increased to 5%, and soybean oil is removed to balance the composition. Images of the resulting substance are shown at 10x magnification in Figure 10A and 20x magnification in Figure 10B. The oil droplets are small, and the API crystals are elongated needle-shaped. The emulsion remained stable for 9 days, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking. The sample forms a white, impermeable emulsion / suspension. Note that the large voids in Figures 10A and 10B are air pockets trapped in the sample.

[0119]

[0165] Sample 9 used the base formulation, but the lecithin component was increased to 10%, and soybean oil was removed to balance it. Images of the resulting substance are shown at 10x magnification in Figure 11A and 20x magnification in Figure 11B. The oil droplets were very small, and the API crystals were in a long, needle-like form. The crystals in the sample had aggregated into clumps. The emulsion remained stable for 23+ days. The sample forms a white, impermeable emulsion / suspension. Note that the large voids in Figures 11A and 11B are trapped air pockets in the sample.

[0120]

[0166] Sample 10 uses the base formulation, but the lecithin component is increased to 20%, and soybean oil is removed to balance it. Images of the resulting substance are shown at 10x magnification in Figure 12A and 20x magnification in Figure 12B. The oil droplets are very small, and the API crystals are in a long needle-like morphology. The crystals in the sample are separated from each other and show very slight aggregation. The emulsion remained stable for 15 days. The sample forms a very viscous white, impermeable emulsion / suspension, which would be difficult to inject.

[0121] Example 7 Thickening of the aqueous phase

[0167] In this embodiment, sodium hyaluronate was used as a thickener for the aqueous phase to delay or hinder the interaction between droplets in the lipid discontinuous phase and stabilize the emulsion. Hyaluronic acid from sodium hyaluronate can also act as an emulsifier because its molecule has both polar and nonpolar parts. In this embodiment, the sodium hyaluronate concentration is measured relative to the aqueous phase, rather than the total drug.

[0122]

[0168] Sample 11 uses the base formulation but does not contain sodium hyaluronate in the aqueous phase. Images of the obtained substance are shown at 10x magnification in Figure 13A and 20x magnification in Figure 13B. The oil droplets are large, and the API crystals are elongated needle-shaped. The emulsion of the sample broke down rapidly—within minutes—and separated into oil and aqueous phases.

[0123]

[0169] Sample 12 uses the base formulation but has a 0.1 percent concentration of sodium hyaluronate in the aqueous phase. Images of the obtained substance are shown at 10x magnification in Figure 14A and 20x magnification in Figure 14B. The oil droplets are smaller than those of Sample 11. The API crystals are elongated needle-shaped. The emulsion remained stable for 2 days, but can be resuspended or reemulsified into an acceptable emulsion by stirring, such as by shaking.

[0124]

[0170] Sample 13 uses the base formulation but has a 0.15 percent concentration of sodium hyaluronate in the aqueous phase. Images of the obtained material are shown at 10x magnification in Figure 15A and 20x magnification in Figure 15B. The oil droplets are small and relatively uniform. The API crystals are elongated needle-shaped. The emulsion showed increased stability compared to sample 11.

[0125]

[0171] Sample 14 uses the base formulation but contains a 1% concentration of sodium hyaluronate in the aqueous phase. Images of the obtained substance are shown at 10x magnification in Figure 16A and 20x magnification in Figure 16B. The oil droplets are small and relatively uniform. The API crystals are elongated needle-shaped. The emulsion remained stable for 8 days.

[0126]

[0172] As can be observed, at concentrations below 0.1 percent, the emulsion rapidly broke down and separated. At concentrations above 0.1 percent, the emulsion gradually became more stable.

[0127] Example 8 Adding glycerol

[0173] In this example, glycerol was added as an aqueous phase modifier for the aqueous phase, which tended to increase the viscosity of the aqueous phase. In this example, the glycerol concentration is measured for the entire formulation, rather than for any specific phase.

[0128]

[0174] Sample 15 uses the base formulation but has a glycerol concentration of 1.7% relative to the total formulation. Images of the obtained substance are shown in Figure 17A at 10x magnification and in Figure 17B at 20x magnification. The oil droplets are small and relatively uniform. The API crystals are elongated needle-shaped. The emulsion remained stable for 1 day.

[0129]

[0175] Sample 16 uses the base formulation but has a glycerol concentration of 3.0% relative to the total formulation. Images of the obtained substance are shown at 10x magnification in Figure 18A and 20x magnification in Figure 19B. The oil droplets are small and relatively uniform. The API crystals are elongated needle-shaped. The emulsion remained stable for 1 day.

[0130]

[0176] Sample 17 uses the base formulation but has a glycerol concentration of 5.0% relative to the total formulation. Images of the obtained substance are shown at 10x magnification in Figure 19A and 20x magnification in Figure 19B. The oil droplets are small and relatively uniform. The API crystals are elongated needle-shaped. The emulsion remained stable for 1 day.

[0131]

[0177] Sample 18 uses the base formulation but has a glycerol concentration of 10% relative to the total formulation. Images of the obtained material are shown at 10x magnification in Figure 20A and 20x magnification in Figure 20B. The oil droplets are smaller and more uniform than those of samples 18, 19, and 20. The API crystals are elongated needle-shaped. The emulsion remained stable for 1 day.

[0132]

[0178] Since sample 18 showed improvement in droplet size and robustness, there is a positive correlation between the concentration of glycerol or a similar solvent and droplet robustness. A negative correlation can be observed between glycerol / solvent concentration and droplet size.

[0133] Example 9 Lipid phase thickening

[0179] In this example, either coconut oil or carnauba wax was added to the lipid phase of the formulation to increase its viscosity. Coconut oil or carnauba wax was added to the formulation as a thickener, and the mass of added soybean oil was reduced to an equivalent amount to maintain the total volume of the lipid phase of the formulation. In this example, the thickener concentration is measured for the entire formulation, not for any specific phase.

[0134]

[0180] Sample 19 uses the base formulation, but 10% of the formulation consists of coconut oil and an equivalent amount of soybean oil. Images of the obtained substance are shown at 10x magnification in Figure 21A and 20x magnification in Figure 21B. The oil droplets are generally small, but an increase in size and the number of larger oil droplets can be observed. The API crystals are elongated needle-shaped. The product was a stable emulsion.

[0135]

[0181] Sample 20 uses a base formulation, but 1.0% of the formulation consists of a reduction of carnauba wax and an equivalent amount of soybean oil. Images of the obtained substance are shown at 10x magnification in Figure 22A and 20x magnification in Figure 22B. The API crystals are elongated needle-shaped, and the wax and lipids tend to coat the crystals. The product was a stable emulsion.

[0136]

[0182] Sample 21 uses the base formulation, but 2.5% of the formulation consists of a reduction of carnauba wax and an equivalent amount of soybean oil. Images of the obtained substance are shown at 10x magnification in Figure 23A and 20x magnification in Figure 23B. The API crystals are elongated needle-shaped. The wax and lipid coatings on the crystals are thicker than those seen in Sample 20. The product was a stable emulsion.

[0137]

[0183] Sample 22 uses a base formulation, but 5.0% of the formulation consists of a reduction of carnauba wax and an equivalent amount of soybean oil. Images of the obtained substance are shown at 10x magnification in Figure 24A and 20x magnification in Figure 24B. The API crystals are elongated needle-shaped. The wax and lipids coated the crystals and formed fine particles separated from the crystals. The product was a stable emulsion.

[0138]

[0184] Carnauba wax appeared to coat the crystal surface more effectively. At higher concentrations, e.g., 5%, carnauba wax also detached from the crystals, forming fine particles. As can be understood, this tendency of waxes and lipids to coat API crystals may result in an increased barrier to the diffusion of the API from the formulation to the target. This increased barrier to diffusion may result in a slower, more consistent release of the API to the target. This slower, more consistent release of the API allows for the administration of more formulation at once, due to a slower rate of introduction into the target.

[0139]

[0185] Example 10 Continuous lipid phase

[0186] In some embodiments, and in this embodiment, it may be preferable to disperse the aqueous phase in the continuous lipid phase rather than the lipid phase in the continuous aqueous phase, as in other embodiments. Having a continuous lipid phase may be beneficial when the API used is hydrophilic rather than hydrophobic. The formulation for sample 23 consisted of 60 vol% lipid phase and 40 vol% aqueous phase, with the components of each phase maintaining relative proportions unless otherwise stated. The sodium hyaluronate in the formulation was 0.15 wt% relative to the aqueous phase.

[0140]

[0187] Images of the obtained material are shown in Figure 25A at 10x magnification and in Figure 25B at 20x magnification. The API crystals have a long, needle-like morphology. The aqueous droplets were of various sizes.

[0141] Example 11 Increase in mixed energy

[0188] Sample 24 used the base formulation but employed a more aggressive mixing energy. This was achieved by using a 3 / 4 horsepower Silverson high-shear rotor-stator homogenizer at 6000 RPM. An image of the resulting material is shown in Figure 26 at 40x magnification. The oil droplets are smaller than those found in formulations prepared using standard mixing energies. The smaller oil droplets tend to coat the surface of the API crystals. The emulsion remained stable for longer than 7 months.

[0142]

[0189] Sample 25 used the base formulation, but was prepared using a 3 / 4 horsepower Silverson high-shear rotor-stator homogenizer at 12,000 RPM. An image of the obtained material is shown in Figure 27 at 40x magnification. API crystal aggregates formed as a result of higher mixing energy. These aggregates remained stable and did not separate. Increased mixing energy also increased the size distribution of API crystals and the amount of crystal aggregates.

[0143] Example 12 Increased CA load

[0190] In a comparison between a formulation without CA (placebo) and a formulation containing CA (active), it was observed that the placebo formulation broke down, while the active formulation did not. However, samples with higher CA concentrations in the form of ropivacaine were less stable than samples with lower concentrations. A sample with 29.34 mg / mL of ropivacaine was more stable than a sample with 38.51 mg / mL of ropivacaine, which was more stable than a sample with 47.69 mg / mL of ropivacaine, which was more stable than the placebo. The 29.34 mg / mL ropivacaine sample remained stable for at least 7 months.

[0144]

[0191] While this disclosure has been described with reference to preferred embodiments, those skilled in the art will recognize that modifications may be made in form and detail without departing from the spirit and scope of the disclosed devices, systems and methods.

Claims

1. A composition for treating tumors in subjects requiring it, an aqueous carrier; a liquid lipid phase dispersed as droplets in the aqueous carrier; and a first chemotherapeutic agent in the lipid phase. emulsion containing A composition containing the following:

2. The composition according to claim 1, wherein the first chemotherapeutic agent comprises a plurality of first chemotherapeutic agent crystals.

3. The composition according to claim 1, wherein the first chemotherapeutic agent is dissolved in the lipid phase.

4. The composition according to claim 2, further comprising a second plurality of chemotherapeutic agent crystals in an aqueous carrier rather than in a lipid phase, wherein the second plurality of chemotherapeutic agent crystals dissolve and elute from the emulsion at a faster rate than the first plurality of chemotherapeutic agent crystals.

5. The composition according to claim 1, further comprising one or more additional chemotherapeutic agents different from the first chemotherapeutic agent.

6. The composition according to claim 1, wherein the lipid phase comprises triglycerides.

7. The composition according to claim 1, wherein the aqueous carrier further comprises an emulsifier and a polyol, the emulsifier being tyramine-substituted hyaluronic acid and the polyol being glycerol, present in an amount of about 0.25 to about 2.5% (w / v) of the composition.

8. The composition according to claim 1, wherein the lipid phase further comprises phospholipids present in an amount of about 0.1% to about 2.0% of the lipid phase.

9. The composition according to claim 1, wherein the lipid phase is approximately 10% to approximately 40% (w / v).

10. The composition according to claim 1, wherein the stable emulsion further contains lecithin, the lecithin present in an amount of 0.1 to 5% (w / v) of the emulsion.

11. The composition according to claim 1, wherein the emulsion further contains dextrose, the dextrose present in an amount of about 1-2% (w / v) of the emulsion.

12. The composition according to claim 1, wherein the emulsion further contains sorbitol, the sorbitol present in an amount of about 0.1 to 2% (w / v) of the emulsion.

13. The composition according to claim 1, wherein the lipid phase comprises about 15% to 80% (v / v) of soybean oil and about 15% to about 20% (v / v) of one or more medium-chain triglycerides.

14. The composition according to claim 13, wherein the chemotherapeutic agent is present in an amount ranging from about 0.1 mg / g of soybean oil to about 300 mg / g of soybean oil.

15. The composition according to claim 1, wherein the chemotherapeutic agent is selected from anthracyclines, mTOR inhibitors, VEGF-TKI agents, and immunostimulants.

16. The composition according to claim 1, wherein the lipid phase comprises triptylate and / or stearate.

17. The composition according to claim 2, wherein the lipid phase further comprises an oil and / or wax that is solid at 25°C in an amount (w / w) of about 5% to about 30% of the lipid phase, and the oil and / or wax coats chemotherapeutic agent crystals.

18. The composition according to claim 1, wherein the emulsion is stable for at least six months.

19. The composition according to claim 1, wherein the chemotherapeutic agent is docetaxel and / or doxorubicin.

20. A composition for treating tumors in subjects requiring it, A lipid carrier phase; an aqueous phase dispersed as droplets in the lipid carrier phase; and a first chemotherapeutic agent in the aqueous phase. emulsion containing A composition containing the following:

21. The composition according to claim 20, wherein the first chemotherapeutic agent comprises a plurality of first chemotherapeutic agent crystals.

22. The composition according to claim 21, further comprising a second plurality of chemotherapeutic agent crystals present in a lipid carrier rather than in an aqueous phase, wherein the second plurality of chemotherapeutic agent crystals dissolve and elute from the emulsion at a faster rate than the first plurality of chemotherapeutic agent crystals.

23. The composition according to claim 22, wherein the chemotherapeutic agent is hydrophilic and dissolved in the aqueous phase.

24. The composition according to claim 20, further comprising one or more additional chemotherapeutic agents different from the first chemotherapeutic agent.

25. A method of treating tumors in subjects that require it, an aqueous carrier; a lipid phase dispersed as droplets in the aqueous carrier; and a first chemotherapeutic agent in the lipid phase. emulsion containing The step includes administering an effective amount of a composition containing to the subject, wherein the chemotherapeutic agent elutes from the composition over a period of about 4 to about 7 days. method.

26. The method according to claim 25, wherein the chemotherapeutic agent comprises a plurality of chemotherapeutic agent crystals, and the composition further comprises a second plurality of chemotherapeutic agent crystals in an aqueous carrier rather than in a lipid phase, wherein the second plurality of chemotherapeutic agent crystals dissolve and elute from the emulsion at a faster rate than the first plurality of chemotherapeutic agent crystals.

27. The method according to claim 25, wherein the composition further comprises an immunostimulant.

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