Composition containing mTOR inhibitor and lipid

Abstract

The present invention relates to compositions of mTOR inhibitors and the administration of mTOR inhibitor compositions. Embodiments provide compositions comprising an mTOR inhibitor and at least one lipid and / or archaesterol and / or archaesterol derivative, and administering the compositions to a subject.

Description

[0001] Invention Field This invention relates to compositions comprising an mTOR inhibitor and lipids. It also relates to compositions comprising an mTOR inhibitor, cucurbitacin, and / or cucurbitacin derivatives. In some embodiments, this invention relates to compositions comprising an mTOR inhibitor and lipids (including phosphatidylcholine and phosphatidylglycerol). In a preferred embodiment, this invention relates to compositions comprising an mTOR inhibitor, phosphatidylcholine, and cucurbitacin or cucurbitacin derivatives. This invention also relates to administering the compositions to human subjects for the treatment or prevention of disease. Furthermore, this invention relates to administering the compositions to human subjects to achieve pharmacokinetic characteristics comparable to commercially available solvent-based tesiromoxetine injections. The compositions of this invention are suitable for industrial-scale production and can be produced, for example, using a continuous process. Background of the Invention Mammalian target of rapamycin (mTOR) belongs to the phosphatidylinositol 3-kinase-associated kinase (PIKK) family and is a key participant in cellular metabolism, closely related to nutrient utilization, energy, and homeostasis. It plays a crucial role in cell growth, differentiation, metastasis, and survival, and has become an important target for cancer therapy. Currently, several therapeutic drugs that inhibit mTOR have been developed, commonly referred to as mTOR inhibitors, including rapamycin and its analogues. Rapamycin, also known as sirolimus, is a macrolide antibiotic, initially described as an antifungal agent. However, it also possesses immunosuppressive, cell growth inhibitory, anti-angiogenic, and anti-proliferative properties, and its clinical applications have expanded to organ transplantation and oncology.

[0003] Sirolimus was initially approved as an oral immunosuppressant to prevent organ rejection in kidney transplant recipients aged 13 years and older. It is also used for coronary stent coating and to treat a rare lung disease called lymphangioleiomyomatosis (LAM). More recently, sirolimus, a protein-bound particle developed for intravenous injection, has been approved for the treatment of adult patients with locally advanced, unresectable, or metastatic perivascular epithelioid cell tumors (PEComa). Sirolimus has also recently been approved for topical treatment in the form of a 0.2% topical gel for the treatment of facial angiofibroma associated with tuberous sclerosis.

[0004] To explore its therapeutic properties, the most commonly developed rapamycin analogues currently include everolimus, tesirobolimus, deforolimus, and zotaolimus. Defoolimus and zotaolimus remain investigational candidates, while everolimus is approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer, progressive pancreatic neuroendocrine tumors (PNET), advanced renal cell carcinoma (RCC) after failure of sunitinib or sorafenib, renal angiomyolipoma (AML), tuberous sclerosis (TSC), and TSC-associated subependymal giant cell astrocytoma (SEGA), as well as kidney and liver transplantation. Tesirobolimus is approved for first-line treatment of advanced renal cell carcinoma. Tesirobolimus is the active metabolite of tesirobolimus and the main metabolite in the body after intravenous injection.

[0005] Tacrolimus is also a macrolide antibiotic, structurally similar to sirolimus, used to prevent organ rejection in adult and pediatric patients who have received allogeneic liver, kidney, heart, or lung transplants, and in combination with other immunosuppressants. It is also used as an ointment to treat eczema, particularly atopic dermatitis. Because tacrolimus and sirolimus have similar structures and both bind to FK506-binding protein 12 (FKBP12), it is speculated that tacrolimus may also inhibit mTOR signaling, which could be a mechanism by which it exerts toxicity on β-cells.

[0006] Torisel ® It is marketed under the brand name and approved for the treatment of advanced renal cell carcinoma. The recommended dose of TORISEL for the treatment of advanced renal cell carcinoma is 25 mg once a week, administered intravenously over 30-60 minutes.

[0007] Torisel ® This is a sterile, non-aqueous, clear injectable solution (concentrate) containing 25 mg / mL tesiromoxetine, dissolved in anhydrous ethanol (39.5% w / v) and propylene glycol (50.3% w / v). A separate vial of diluent is included, containing polysorbate 80 (40.0% w / v), polyethylene glycol 400 (PEG400) (42.8% w / v), and anhydrous ethanol (19.9% ​​w / v). The concentrate and diluent are used to prepare a 10 mg / mL tesiromoxetine premixed solution (before dilution with 250 mL of 0.9% saline), which is then placed into an infusion bag. Torisel ® Generic versions of the drug have also been approved for market launch.

[0008] Tesirolimus is highly lipophilic and practically insoluble in water. Due to its poor solubility, various solubilizers (such as polysorbate 80, PEG400, propylene glycol, and anhydrous ethanol) have been successfully formulated for intravenous administration. However, the use of polysorbate 80, propylene glycol, and ethanol may cause allergic reactions and infusion-related toxicities. To reduce the risk of these side effects, patients are usually pre-treated with tesirolimus before receiving treatment.

[0009] To avoid the toxic effects of mTOR inhibitors and excipients in currently marketed intravenous products, it is necessary to develop new compositions of mTOR inhibitors for parenteral administration, such as tesimolimus. Summary of the Invention

[0010] This invention provides compositions containing an mTOR inhibitor. In some embodiments, the composition comprises an mTOR inhibitor, phosphatidylcholine, and / or phosphatidylglycerol. In some embodiments, the composition further comprises an mTOR inhibitor and one or more of gulosterol and gulosterol derivatives. In some preferred embodiments, the composition further comprises other excipients. Some embodiments include a composition containing an mTOR inhibitor and administering the composition to a subject. In some embodiments, the subject is a mammal. In a preferred embodiment, the subject is a human.

[0011] In some embodiments, the present invention provides a composition comprising an mTOR inhibitor and phosphatidylcholine for parenteral administration to human subjects. In some embodiments, the composition for parenteral administration is in suspension form.

[0012] In some embodiments, the compositions of the present invention comprise an mTOR inhibitor and phosphatidylglycerol for parenteral administration to human subjects. In some embodiments, the compositions for parenteral administration are in suspension form.

[0013] In some embodiments, this document provides compositions comprising an mTOR inhibitor and gucousterol for parenteral administration to human subjects. In some embodiments, the compositions for parenteral administration are in suspension form.

[0014] In some embodiments, the present invention provides a composition comprising an mTOR inhibitor and a gucousterol derivative for parenteral administration to human subjects. In some embodiments, the parenteral administration is in suspension form.

[0015] In some embodiments, the present invention provides a composition comprising an mTOR inhibitor, phosphatidylcholine, and gucousterol for parenteral administration to human subjects. In some embodiments, the parenteral administration is in suspension form.

[0016] In some embodiments, the present invention provides a composition comprising an mTOR inhibitor, phosphatidylcholine, and a gucousterol derivative for parenteral administration to human subjects. In some embodiments, the parenteral administration is in suspension form.

[0017] In some embodiments, the present invention provides a composition comprising an mTOR inhibitor, phosphatidylglycerol, and gucousterol for parenteral administration to human subjects. In some embodiments, the parenteral administration is in suspension form.

[0018] In some embodiments, the present invention provides a composition comprising an mTOR inhibitor, phosphatidylglycerol, and a gucousterol derivative for parenteral administration to human subjects. In some embodiments, the parenteral administration is in suspension form.

[0019] In some embodiments, the present invention provides a composition comprising an mTOR inhibitor, phosphatidylcholine, and phosphatidylglycerol for parenteral administration to human subjects. In some embodiments, the composition for parenteral administration is in suspension form.

[0020] In some embodiments, the present invention provides a composition comprising an mTOR inhibitor, phosphatidylcholine, phosphatidylglycerol, and gucousterol for parenteral administration to human subjects. In some embodiments, the composition for parenteral administration is in suspension form.

[0021] In some embodiments, the present invention provides a composition comprising an mTOR inhibitor, phosphatidylcholine, phosphatidylglycerol, and a gucousterol derivative for parenteral administration to human subjects. In some embodiments, the composition for parenteral administration is in suspension form.

[0022] In some embodiments, the present invention provides a composition comprising an mTOR inhibitor and one or more lipids for rectal administration to human subjects. In some embodiments, the composition for rectal administration is in suspension form.

[0023] In some embodiments, the mTOR inhibitor composition of the present invention is administered in combination with other drugs. Drugs that can be administered in combination with the mTOR inhibitor composition include, but are not limited to, anticancer drugs, such as doxorubicin, epirubicin, methotrexate, mitoxantrone, capecitabine, carboplatin, cisplatin, etoposide, 5-fluorouracil, cyclophosphamide, daunorubicin, bleomycin, gemcitabine, irinotecan, SN-38, mitoxantrone, cytarabine, capecitabine, mitomycin, sunitinib, sorafenib, tevozanib, etc. Ibrutinib, imatinib, erlotinib, acalatinib, cabozantinib, bevacizumab, paclitaxel, docetaxel, cabazitaxel, vincristine, abiraterone, bicalutamide, flutamide, etc.; antihypertensive drugs, such as dihydropyridines, antidepressants, antihistamines, etc.; corticosteroids, such as prednisone, methylprednisolone, dexamethasone, budesonide, hydrocortisone, etc.; antihistamines, such as diphenhydramine, chlorpheniramine, dextrochlorpheniramine, cetirizine, levocetirizine, loratadine, desloratadine, etc.; drugs for treating acid reflux, such as cimetidine, ranitidine, famotidine, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, etc.

[0024] The amount of mTOR inhibitor contained in the mTOR inhibitor composition of the present invention is not limited to any amount or percentage (by weight) of the final composition or weight. In some embodiments, the proportion of mTOR inhibitor is from about 0.1% to about 90% of the total weight, preferably from about 0.5% to about 75%, more preferably from about 1% to about 50%.

[0025] The amount of lipids contained in the mTOR inhibitor compositions of the present invention is not limited to any specific amount or percentage (by weight) of the final composition or weight. In some embodiments, the proportion of total lipids is from about 4% to about 100% of the total lipid weight, preferably from about 5% to about 60%, more preferably from about 8% to about 50%.

[0026] definition To facilitate understanding of this invention, some terms and phrases are defined below: As used herein, the terms “composition,” “formulation,” or “dosage form” refer to a combination of an active agent (e.g., an active pharmaceutical compound) with a carrier (inert or active) and excipients, making the composition particularly suitable for in vitro, in vivo, or ex vivo diagnostic or therapeutic use.

[0027] In this document, the term "active agent," when used to refer to a pharmaceutical preparation, composition, or compound, means an agent that, upon administration or application, produces a beneficial, desired, or anticipated result. Administration can be a single or multiple doses, application, or dosage, and is not limited to a specific dosage form or route of administration. The term is not limited to any level of activity. For example, the level of activity of one active agent dosage form need not be the same as that of another active agent dosage form, as long as the active agent in the dosage form has sufficient activity to achieve an effective amount of the active agent by applying the pharmaceutical dosage form.

[0028] The terms “pharmaceutical” and “compound” are used interchangeably herein to refer to any mixture of atoms, molecules, or more complex compositions having specific properties. For example, “active agent” or “active compound” refers to any mixture of atoms, molecules, formulations, etc., that, upon administration or application, produces a beneficial, desired, or anticipated result.

[0029] As used herein, the terms “pharmaceutical acceptable” or “pharmacologically acceptable” mean a composition that, when administered to a subject, will substantially not produce adverse reactions (such as toxicity, anaphylaxis, or immune response).

[0030] As used herein, the terms “administration” or “application” refer to the act of supplying a drug, active agent, or therapeutic agent (such as the compositions of the present invention) to a physiological system (e.g., a subject or cells, tissues, and organs in vivo, in vitro, or ex vivo). Exemplary routes of administration to the human body may include oral (oral), transdermal (transdermal), ocular (ophthalmic), nasal (nasal), etc. Administration may be performed once or multiple times, by application, or by dosage, and is not limited to a specific route of administration.

[0031] As used herein, the term "combination administration" refers to the administration of at least two agents (e.g., two separate compositions containing different active ingredients) or therapies to a subject. In some embodiments, the combination administration of two or more agents or therapies is simultaneous. In other embodiments, the first agent / therapy is administered before the second agent / therapy. Those skilled in the art will understand that the dosage forms and / or routes of administration of the various agents or therapies used may differ. Those skilled in the art can readily determine the appropriate dosage for combination administration.

[0032] As used in this article, the term "parenteral" refers to a non-oral route of administration. Common parenteral routes of administration include intravenous (IV), intramuscular (IM), and subcutaneous (SC).

[0033] As used in this article, the term "disease" refers to any state, sign, and / or symptom associated with any impairment of the normal state of an animal or any of its organs or tissues that interrupts or alters normal function and may be a response to environmental factors.

[0034] The term "treatment" as used herein, or its grammatical equivalents, encompasses the improvement and / or reversal of symptoms of a disease (e.g., cancer) or a reduction in the risk of developing the disease. When used in the screening methods of this invention, compounds capable of improving any disease-related parameter can thus be identified as therapeutic compounds. The term "treatment" refers to therapeutic therapy. For example, the population that may benefit from treatment with the compositions of this invention includes individuals who already have a disease and / or condition (e.g., cancer or symptoms or pathology consistent with cancer).

[0035] As used in this article, the term "pharmacokinetics" refers to the process by which an active agent or drug enters, passes through, and is eliminated from the body after administration. This process includes absorption, such as how the active agent or drug moves from the site of administration to the site of action; distribution, such as the journey of the active agent or drug through the blood to various tissues of the body; metabolism, such as the breakdown of the drug in the body; and excretion, such as the removal of the drug from the body.

[0036] In the context of describing the invention (especially in the following claims), the terms “a,” “an,” and “the,” and similar designations should be interpreted to cover both the singular and the plural, unless otherwise stated herein or the context clearly contradicts it. The terms “comprising,” “including,” “having,” and “containing” should be interpreted as open-ended terms (i.e., meaning “including but not limited to”), unless otherwise indicated. The use of any and all examples or exemplary language (e.g., “such as”) provided herein is intended only to better illustrate the invention and does not limit the scope of the invention, unless otherwise stated. No language in the specification should be construed as indicating that any unclaimed element is essential for the practice of the invention. Attached Figure Description

[0037] Figure 1 This is a graph showing the change in tesimolimus blood concentration over time in Example 13.

[0038] Figure 2 This is a graph showing the blood concentration of sirolimus in Example 13 over time. Detailed Implementation

[0039] This invention relates to a composition comprising an mTOR inhibitor formulation. In some embodiments, the invention includes administering the mTOR composition to a human subject, for example, for treating a disease. In some embodiments, the composition comprising an mTOR inhibitor comprises a lipid, such as phosphatidylcholine or phosphatidylglycerol. In some embodiments, the composition comprising an mTOR inhibitor comprises gucousterol or a gucousterol derivative. In other embodiments, the composition comprises phosphatidylcholine or phosphatidylglycerol and / or gucousterol, a gucousterol derivative.

[0040] Embodiments of the present invention have been described in the summary and detailed description. Although the present invention has been described in conjunction with specific embodiments, the claimed invention should not be unduly limited to these specific embodiments.

[0041] Examples of mTOR inhibitors suitable for use in the compositions of the present invention include tesimolimus, sirolimus, everolimus, deforolimus, and zotalimus. In some embodiments, the compositions of the present invention further comprise tacrolimus.

[0042] Examples of phosphatidylcholine suitable for use in the compositions of the present invention include soybean phosphatidylcholine (SPC), hydrogenated soybean phosphatidylcholine (HSPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearyl phosphatidylcholine (DSPC). Examples of phosphatidylglycerols include dimyristoyl phosphatidylglycerol (DMPG), distearyl phosphatidylglycerol (DSPG), and dipalmitoyl phosphatidylglycerol (DMPG).

[0043] Examples of gugusterol derivatives suitable for use in the compositions of the present invention include gugusterol laurate, gugusterol myristate, gugusterol palmitate, gugusterol stearate, gugusterol oleate, gugusterol linoleate, and gugusterol linoleate.

[0044] In some embodiments, the compositions of the present invention comprise antioxidants and / or stabilizers. Examples of antioxidants suitable for use in the compositions of the present invention include: α-tocopherol (vitamin E), α-tocopherol polyethylene glycol succinate (TPGS), ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite (SMB), propyl gallate, cysteine, and citric acid.

[0045] In some embodiments, the compositions of the present invention contain a buffer. Examples of bases or buffers include, but are not limited to, sodium citrate, sodium succinate, sodium phosphate, sodium acetate, sodium hydroxide, and saline solution.

[0046] This invention provides compositions comprising an mTOR inhibitor and delivers such compositions to subjects, such as human subjects. Any suitable dose of the mTOR inhibitor sufficient to produce the desired effect (e.g., therapeutic effect) can be used. In a preferred embodiment, a suitable dose of the mTOR inhibitor refers to a dose that can be appropriately incorporated into the suspension, solution, or nanoparticles of this invention.

[0047] In some embodiments, the compositions of the present invention comprise homogenized suspensions, liposomes, micelles, vesicles, and nanoparticles with an average diameter of about 5 micrometers or less; while in some embodiments, they comprise homogenized suspensions, liposomes, micelles, vesicles, and nanoparticles with a diameter of about 1 micrometer or less. In some embodiments, the homogenized suspensions, liposomes, micelles, vesicles, and nanoparticles have a diameter of about 500 nanometers or less; while in some embodiments, the homogenized suspensions, liposomes, micelles, vesicles, and nanoparticles have a diameter of about 200 nanometers or less. In some preferred embodiments, the homogenized suspensions, liposomes, micelles, vesicles, and nanoparticles have a diameter of about 100 nanometers or less.

[0048] This invention is not limited to any form of composition; for example, in some embodiments, the compositions of this invention are in lyophilized form. In some embodiments, the compositions further comprise cryoprotectants. In some preferred embodiments, the cryoprotectant comprises one or more sugars; while in particularly preferred embodiments, the one or more sugars include sucrose, lactose, glucose, dextrose, trehalose, maltose, mannitol, and / or sorbitol. In some embodiments of this invention, the cryoprotectant comprises glycine and polyvinylpyrrolidone (PVP). The percentage of sugar in the composition can range from about 10% to about 90%.

[0049] In some embodiments, the lyophilized form is reconstituted with a suitable carrier to achieve the desired mTOR inhibitor concentration. The reconstitution carrier includes, but is not limited to, water for injection, sodium chloride solution, glucose solution, or any pharmaceutically acceptable buffer. The desired mTOR inhibitor concentration after reconstitution is from 0.5 mg / mL to about 20 mg / mL, preferably from about 1 mg / mL to about 10 mg / mL, or more preferably from about 1 mg / mL to about 5 mg / mL.

[0050] In some embodiments, the reconstituted product composition is further diluted to the mTOR inhibitor concentration required for administration. The required mTOR inhibitor concentration is a fixed concentration or an administration concentration based on the subject's weight. Dilution carriers include, but are not limited to, 0.9% saline and 5% glucose solutions or any pharmaceutically acceptable administration carrier.

[0051] In some embodiments, the pH range of the compositions of the present invention is from about 2 to about 11, preferably from about 3 to about 8, and more preferably from about 3.5 to pH 8.0.

[0052] In some embodiments, the compositions of the present invention contain about 4% to about 100% by weight of total lipids, preferably about 5% to about 60% by weight of total lipids, or more preferably about 8% to about 50% by weight of total lipids.

[0053] In some embodiments, the compositions of the present invention comprise an mTOR inhibitor and total lipids in a weight ratio between 1:1 and 1:80; for example, weight ratios between 1:1 and 1:10, 1:1 and 1:20, 1:1 and 1:30, 1:1 and 1:40, 1:1 and 1:50, 1:1 and 1:60, 1:1 and 1:70, and 1:1 and 1:80. In preferred embodiments, the compositions of the present invention comprise an mTOR inhibitor and total lipids in a weight ratio between 1:5 and 1:50. The term “between” as used herein includes boundary values ​​of this range. For example, a weight ratio between 1:5 and 1:50 includes weight ratios of 1:5 and 1:50.

[0054] In some embodiments, the compositions of the present invention comprise an mTOR inhibitor and phosphatidylcholine in a weight ratio between 1:1 and 1:80; for example, weight ratios between 1:1 and 1:10, 1:1 and 1:20, 1:1 and 1:30, 1:1 and 1:40, 1:1 and 1:50, 1:1 and 1:60, 1:1 and 1:70, or 1:1 and 1:80. In a preferred embodiment, the compositions of the present invention comprise an mTOR inhibitor and total lipids in a weight ratio between 1:5 and 1:50. The term “between” as used herein includes boundary values ​​of this range. For example, a weight ratio between 1:5 and 1:50 includes weight ratios of 1:5 and 1:50. Examples of phosphatidylcholine include soybean phosphatidylcholine (SPC), hydrogenated soybean phosphatidylcholine (HSPC), dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), and distearate phosphatidylcholine (DSPC).

[0055] In some embodiments, the compositions of the present invention comprise an mTOR inhibitor and phosphatidylglycerol in a weight ratio between 1:1 and 1:80; for example, weight ratios between 1:1 and 1:10, 1:1 and 1:20, 1:1 and 1:30, 1:1 and 1:40, 1:1 and 1:50, 1:1 and 1:60, 1:1 and 1:70, and 1:1 and 1:80. In preferred embodiments, the compositions of the present invention comprise an mTOR inhibitor and total lipids in a weight ratio between 1:5 and 1:50. The term “between” as used herein includes boundary values ​​of this range. For example, a weight ratio between 1:5 and 1:50 includes weight ratios of 1:5 and 1:50. Examples of phosphatidylglycerols include dimyristoyl phosphatidylglycerol (DMPG), distearate phosphatidylglycerol (DSPG), and dipalmitoyl phosphatidylglycerol (DMPG).

[0056] In some embodiments, the compositions of the present invention comprise an mTOR inhibitor and cucurbitacin or a cucurbitacin derivative in a weight ratio between 1:0.1 and 1:10; for example, weight ratios between 1:0.1 and 1:0.2, between 1:0.1 and 1:0.3, between 1:0.1 and 1:0.4, between 1:0.1 and 1:0.5, between 1:0.1 and 1:0.6, between 1:0.1 and 1:0.7, between 1:0.1 and 1:0.8, between 1:0.1 and 1:0.9, and between 0.1 and 0.10. The term “between” as used herein includes the boundary values ​​of this range. For example, a weight ratio between 1:0.1 and 1:10 includes weight ratios of 1:0.1 and 1:10. Examples of gugusterol derivatives include gugusterol laurate, gugusterol myristate, gugusterol palmitate, gugusterol stearate, gugusterol oleate, gugusterol linoleate, and gugusterol linoleate.

[0057] In some embodiments, the compositions of the present invention comprise an mTOR inhibitor and a mixture of phosphatidylcholine and cucurosterol or a cucurosterol derivative. The weight ratio of the mTOR inhibitor to the mixture of phosphatidylcholine and cucurosterol or a cucurosterol derivative is between 1:1 and 1:80; for example, a weight ratio between 1:1 and 1:10, between 1:1 and 1:20, between 1:1 and 1:30, between 1:1 and 1:40, between 1:1 and 1:50, between 1:1 and 1:60, between 1:1 and 1:70, or between 1:1 and 1:80. In a preferred embodiment, the compositions of the present invention comprise an mTOR inhibitor and a mixture of phosphatidylcholine and cucurosterol or a cucurosterol derivative in a weight ratio between 1:5 and 1:50. The term “between” as used herein includes the boundary values ​​of this range. For example, weight ratios between 1:5 and 1:50 include weight ratios of 1:5 and 1:50.

[0058] In some embodiments, the compositions of the present invention comprise an mTOR inhibitor and a mixture of phosphatidylglycerol and gulosterol or a gulosterol derivative. The weight ratio of the mTOR inhibitor to the mixture of phosphatidylglycerol and gulosterol or a gulosterol derivative is between 1:1 and 1:80; for example, between 1:1 and 1:10, or between 1:1 and 1:20, or between 1:1 and 1:30, or between 1:1 and 1:40, or between 1:1 and 1:50, or between 1:1 and 1:60, or between 1:1 and 1:70, or between 1:1 and 1:80. In a preferred embodiment, the compositions of the present invention comprise an mTOR inhibitor and a mixture of phosphatidylglycerol and gulosterol or a gulosterol derivative in a weight ratio between 1:5 and 1:50. The term “between” as used herein includes the boundary values ​​of this range. For example, weight ratios between 1:5 and 1:50 include weight ratios of 1:5 and 1:50.

[0059] In some embodiments, the compositions of the present invention comprise an mTOR inhibitor and a mixture of phosphatidylcholine, phosphatidylglycerol, and gucousterol or a gucousterol derivative. The weight ratio of the mTOR inhibitor to the mixture of phosphatidylcholine, phosphatidylglycerol, and gucousterol or a gucousterol derivative is between 1:1 and 1:80; for example, a weight ratio between 1:1 and 1:10, or between 1:1 and 1:20, or between 1:1 and 1:30, or between 1:1 and 1:40, or between 1:1 and 1:50, or between 1:1 and 1:60, or between 1:1 and 1:70, or between 1:1 and 1:80. In a preferred embodiment, the compositions of the present invention comprise an mTOR inhibitor and a mixture of phosphatidylcholine, phosphatidylglycerol, and gucousterol or a gucousterol derivative in a weight ratio between 1:5 and 1:50. The term “between” as used in this article includes the boundary values ​​of the range. For example, a weight ratio between 1:5 and 1:50 includes both weight ratios of 1:5 and 1:50.

[0060] In some embodiments, the compositions of the present invention comprise antioxidants. Examples of antioxidants include, but are not limited to, α-tocopherol (vitamin E), α-tocopherol polyethylene glycol succinate (TPGS), ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite (SMB), propyl gallate, cysteine, citric acid, etc.

[0061] In some embodiments, the compositions of the present invention contain an mTOR inhibitor in an amount of about 0.1% to about 90% by weight, preferably about 0.5% to about 75% by weight, and more preferably about 1% to about 50% by weight.

[0062] In some embodiments, the present invention provides a composition comprising an mTOR inhibitor and a lipid, and administers the mTOR inhibitor and lipid to a human subject. In some embodiments, the composition is administered via a parenteral route. In some embodiments, the composition is administered via a rectal route.

[0063] In some embodiments, the composition comprising an mTOR inhibitor and lipids is administered in the form of a suspension, solution, nanoparticles, vesicles, or emulsion.

[0064] In some embodiments, the compositions of the present invention, when administered parenterally, provide similar pharmacokinetic characteristics to a reference product administered at an equivalent dose of tesiromolimus. These pharmacokinetic characteristics include blood concentrations of tesiromolimus and its metabolite sirolimus at different time points following administration of the compositions of the present invention and the reference product. Examples of reference products include commercially available solvent-based tesiromolimus injections containing anhydrous ethanol, propylene glycol, polysorbate 80, and polyethylene glycol 400 (PEG400).

[0065] In a more preferred embodiment, the lyophilized powder composition of the present invention is reconstituted with water for injection and diluted to the desired concentration with 0.9% sodium chloride solution. Similarly, a commercially available reference product—tesiromoximide injection containing anhydrous ethanol (39.5% w / v) and propylene glycol (50.3%)—is diluted with the diluent provided with the reference product, which contains polysorbate 80 (40.0% w / v), polyethylene glycol 400 (42.8% w / v), and 19.9% ​​w / v, and then further diluted to the desired concentration with 0.9% sodium chloride solution. In the preferred embodiment, equal doses of tesiromoximide from the diluted composition of the present invention and the diluted reference product have similar pharmacokinetic characteristics after intravenous administration. The pharmacokinetic profiles include the concentrations of tesiromoximide and its metabolite sirolimus in the blood at different time intervals after intravenous injection of the diluted composition of the present invention and the reference product.

[0066] In some embodiments, the concentration of the composition of the present invention, after addition to whole blood, is similar to that of a reference product when an equal dose of tesiromolimus is added and incubated at 37°C. Examples of reference products include commercially available solvent-based tesiromolimus injection products containing anhydrous ethanol, propylene glycol, polysorbate 80, and polyethylene glycol 400 (PEG400).

[0067] In a more preferred embodiment, the lyophilized powder composition of the present invention is reconstituted with water for injection and diluted to the desired concentration with 0.9% sodium chloride solution. Similarly, a commercially available reference product, i.e., a tesiromoximide injection containing anhydrous ethanol (39.5% w / v) and propylene glycol (50.3%), is diluted with a diluent provided with the reference product, which contains polysorbate 80 (40.0% w / v), polyethylene glycol 400 (42.8% w / v), and 19.9% ​​w / v), and then further diluted to the desired concentration with 0.9% sodium chloride solution. In the preferred embodiment, equivalent doses of tesiromoximide from the diluted composition of the present invention and the diluted reference product, after addition to whole blood and incubation at 37°C, provide comparable tesiromoximide concentrations.

[0068] In some embodiments, the concentration of the composition of the present invention after addition to human plasma is similar to that of a reference product when an equal dose of tesiromolimus is added and cultured at 37°C. Examples of reference products include commercially available solvent-based tesiromolimus injection products containing anhydrous ethanol, propylene glycol, polysorbate 80, and polyethylene glycol 400 (PEG400).

[0069] In a more preferred embodiment, the lyophilized powder composition of the present invention is reconstituted with water for injection and diluted to the desired concentration with 0.9% sodium chloride solution. Similarly, a commercially available reference product, i.e., a tesiromosinus injection product containing anhydrous ethanol (39.5% w / v) and propylene glycol (50.3%), is diluted with a diluent provided with the reference product, which contains polysorbate 80 (40.0% w / v), polyethylene glycol 400 (42.8% w / v), and 19.9% ​​w / v), and then further diluted to the desired concentration with 0.9% sodium chloride solution. In the preferred embodiment, equivalent doses of tesiromosinus from the diluted composition of the present invention and the diluted reference product provide comparable tesiromosinus concentrations after addition to human plasma and incubation at 37°C.

[0070] The compositions of the present invention can be administered in any dosage form and via any system capable of delivering an active mTOR inhibitor in vivo. In some embodiments, the compositions of the present invention are delivered in dosage forms selected from parenteral and rectal administration. In some embodiments, the compositions are formulated into desired dosage forms to achieve immediate, sustained, or delayed release characteristics in vivo after administration.

[0071] Experimental Example Example 1 Soybean phosphatidylcholine (1.2 g) was dissolved in a sodium disuccinate aqueous solution (2.16 mg / L, pH 6.0; 25 mL) and manually homogenized under high pressure four times. Tesirolimus (30 mg) was added, and homogenization under high pressure continued until the desired particle size was achieved. Sucrose (2.25 g) was dissolved in a sodium disuccinate solution (5 mL), added to the tesirolimus solution, stirred, and filtered through a 0.2 μm filter. Particle size was determined using a Nicomp 380 particle size analyzer. The average volume-weighted particle size was less than 200 nm. Particle size distribution: average particle size: 46.2 nm, D90: 95.9 nm, D99: 196.8 nm.

[0072] Example 2 Soybean phosphatidylcholine (1.16 g) and gucousterol laurate (40.2 mg) were dissolved in 0.2% sodium citrate aqueous solution (25 mL) and manually homogenized under high pressure four times. Tesirolimus (60 mg) was added, and homogenization under high pressure continued until the desired particle size was achieved. Sucrose (2.25 g) was dissolved in 0.2% sodium citrate solution (5 mL), added to the tesirolimus-SPC-gucousterol laurate suspension, stirred, filtered through a 0.2 μm filter membrane, and lyophilized. Particle size was determined using a Nicomp 380 particle size analyzer. The average volume-weighted particle size was less than 200 nm. Particle size distribution: average particle size: 34.6 nm, D90: 67.5 nm, D99: 131.4 nm.

[0073] Example 3 Soybean phosphatidylcholine (2.0 g) was dissolved in 0.2% sodium citrate solution (25 mL) and water (40 mL), and homogenized manually under high pressure four times. Tesirolimus (100 mg) was added, and homogenization under high pressure continued until the desired particle size was achieved. Sucrose (3.75 g) was dissolved in 10 mL and added to the SPC-tesirolimus suspension. The mixture was stirred, filtered through a 0.2 μm filter, and then lyophilized. Particle size was determined using a Nicomp 380 particle size analyzer. The average volume-weighted particle size was less than 200 nm. Particle size distribution: Average: 18.5 nm, D90: 42.5 nm, D99: 89.9 nm.

[0074] Example 4 Soybean phosphatidylcholine (4.0 g) was dissolved in 0.2% sodium citrate solution (80 mL) and homogenized manually under high pressure four times. Tesirolimus (200 mg) was added, and homogenization under high pressure continued until the desired particle size was achieved. Sucrose (7.5 g) was dissolved in 0.2% sodium citrate solution (7.5%, 20 mL), added to the SPC-tesirolimus suspension, stirred, filtered through a 0.2 μm filter membrane, and then lyophilized. Particle size was determined using a Nicomp 380 particle size analyzer. The average volume-weighted particle size was less than 200 nm. Particle size distribution: average particle size: 32.7 nm, D90: 90.8 nm, D99: 176.9 nm.

[0075] Example 5 Soybean phosphatidylcholine (1.0 g) was dissolved in 0.2% sodium citrate solution (20 mL) and homogenized manually under high pressure four times. Sirolimus (25 mg) was added, and homogenization under high pressure continued until the desired particle size was achieved. Sucrose (1.875 g) was dissolved in 0.2% sodium citrate solution (7.5%, 5 mL), added to the SPC-tesilolimus suspension, stirred, filtered through a 0.2 μm filter membrane, and then lyophilized. Particle size was determined using a Nicomp 380 particle size analyzer. The average volume-weighted particle size was less than 200 nm. Particle size distribution: average particle size: 38.5 nm, D90: 76.3 nm, D99: 156.8 nm.

[0076] Example 6 Soybean phosphatidylcholine (4.0 g) was dissolved in 0.2% sodium citrate solution (80 mL) and homogenized manually under high pressure four times. Tesirolimus (100 mg) was added, and homogenization under high pressure continued until the desired particle size was achieved. Sucrose (7.5 g) was dissolved in 0.2% sodium citrate solution (7.5%, 20 mL), added to the SPC-tesirolimus suspension, stirred, filtered through a 0.2 μm filter membrane, and then lyophilized. Particle size was determined using a Nicomp 380 particle size analyzer. The average volume-weighted particle size was less than 200 nm. Particle size distribution: Average: 29.0 nm, D90: 64.0 nm, D99: 128.1 nm.

[0077] Example 7 Soybean phosphatidylcholine (5.0 g), tesimolimus (250 mg), sodium citrate (200 mg), and sucrose (24.05 g) were mixed with water for injection and stirred using a top-mounted stirrer. The resulting suspension was homogenized using a high-pressure homogenizer until the desired particle size was achieved. The suspension volume was adjusted to the desired level, filtered through a 0.2 μm filter membrane, and then lyophilized. The particle size was determined using a Nicomp 380 particle size analyzer. The average volumetric particle size was less than 200 nm.

[0078] Example 8 Acute intravenous toxicity study of tesiromosine lipid suspension for injection in Wistar rats Tesilimoloximide lipid suspension (prepared according to Example 6) was reconstituted with 0.9% saline and diluted, then administered intravenously to Wistar rats (n=10 per dose, 5 males and 5 females) at dose levels of 0, 5, 10, and 25 mg / kg tesilimoloximide / body weight. Control rats (0 mg dose level) were similarly administered an equal volume of saline intravenously per kg body weight. Clinical signs, body weight, mortality, necropsy (gross pathology), and histopathology were monitored in the animals. Results showed that tesilimoloximide lipid suspension did not cause serious adverse reactions at any of the tested dose levels. The maximum tolerated dose (MTD) was found to be 25 mg / kg (high dose) when administered intravenously to Wistar rats. Dose levels: 0, 5, 10, 25 mg / kg.

[0079] Example 9 Acute intravenous toxicity study of tesiromosine lipid suspension for injection in Swiss albino mice. Tesilimoloxetine lipid suspension (prepared according to Example 6) was reconstituted and diluted with 0.9% saline and administered intravenously to Swiss albino mice (n=10 per dose, 5 males and 5 females) at dose levels of 0, 10, 20, and 50 mg / kg tesilimoloxetine / body weight. Control mice (0 mg dose level) were similarly administered intravenously with an equal volume of saline per kg body weight. Clinical signs, body weight, mortality, necropsy (gross pathology), and histopathology were monitored. Results showed that tesilimoloxetine lipid suspension did not cause serious adverse reactions at any of the tested dose levels. The maximum tolerated dose (MTD) was found to be 50 mg / kg (high dose) when administered intravenously to Swiss albino mice. Dose levels: 0, 10, 20, and 50 mg / kg.

[0080] Example 10 Stability of infusion formulation (0.1 mg / mL) at room temperature The tesimolimus lipid suspension (prepared according to Example 6) was reconstituted and diluted with 0.9% NaCl to the recommended infusion concentration, i.e., 0.1 mg tesimolimus / mL. The infusion formulation was incubated at room temperature for up to 4 hours. The concentration of tesimolimus was monitored at 0.5 hours and 4 hours using a validated LC-MS / MS method. At room temperature, the concentration of tesimolimus remained almost unchanged over 4 hours.

[0081] Table 1

[0082] Example 11 At 37°C, the distribution of tirolimus lipid suspension for injection (test product) or tirolimus injection (reference product) in human whole blood was comparable in red blood cells (RBCs) and plasma.

[0083] Texilolimus lipid suspension for injection (test product, T): The lyophilized product (prepared according to Example 6) was reconstituted with water for injection to achieve a tesiromolimus concentration of 1 mg / mL, and further diluted with 0.9% sodium chloride to achieve a tesiromolimus concentration of 50 µg / mL.

[0084] Tesirolimus injection (reference product, R): A vial containing anhydrous ethanol (39.5% w / v) and propylene glycol (50.3%) was diluted with the diluent provided with the reference product, which contains polysorbate 80 (40.0% w / v), PEG400 (42.8% w / v) and 19.9% ​​w / v), and then further diluted with 0.9% sodium chloride solution to achieve a tesirolimus concentration of 50 µg / mL.

[0085] The test product or reference product (50 µg / mL) was added to whole blood to achieve a tesimolimus concentration of approximately 1 µg / mL. This level is close to the peak concentration (Cmax) reached by patients after infusion of a 25 mg dose over 0.5–1 hour. After incubation at 37 °C, erythrocytes were isolated, and the concentrations of tesimolimus in erythrocytes and plasma were determined using a validated LC-MS / MS method. The results showed no statistically significant difference in the distribution of tesimolimus in erythrocytes between the test product and the reference product.

[0086] Table 2

[0087] Example 12 At 37°C, the levels of free (unbound plasma protein) texiromoximide in texiromoximide lipid suspension for injection (test product) or texiromoximide injection (reference product) were comparable.

[0088] Texilolimus lipid suspension for injection (test product, T): The lyophilized product (prepared according to Example 6) was reconstituted with water for injection to achieve a tesiromolimus concentration of 1 mg / mL, and further diluted with 0.9% sodium chloride to achieve a tesiromolimus concentration of 50 µg / mL.

[0089] Tesirolimus injection (reference product, R): The reference product vial containing anhydrous ethanol (39.5% w / v) and propylene glycol (50.3%) was diluted with the diluent provided with the reference product, which contains polysorbate 80 (40.0% w / v), PEG400 (42.8% w / v) and 19.9% ​​w / v), and then further diluted with 0.9% sodium chloride solution to achieve a tesirolimus concentration of 50 µg / mL.

[0090] The diluted test or reference formulation was added to human plasma to achieve a final concentration of approximately 1 µg / mL. Plasma samples were incubated at 37°C for up to 4 hours, and the level of free (unbound protein) tesimolimus in plasma was determined at 0.5 h and 4 h using a validated LC-MS / MS method. The results showed that the plasma levels of free tesimolimus in the test and reference formulations were comparable.

[0091] Table 3

[0092] Example 13 Pharmacokinetic comparison of tesiromoximide lipid suspension for injection (test product) and tesiromoximide injection (reference product) in ICR (CD-I) mice. Tesirolimus lipid suspension for injection (test product, T): The lyophilized product (prepared according to Example 6) was reconstituted with water for injection to achieve a tesirolimus concentration of 1 mg / mL, which can be used without further dilution.

[0093] Tesirolimus injection (reference product, R): A vial containing anhydrous ethanol (39.5% w / v) and propylene glycol (50.3%) was diluted with the diluent provided with the reference product, which contains polysorbate 80 (40.0% w / v), PEG400 (42.8% w / v) and 19.9% ​​w / v), and then further diluted with 0.9% sodium chloride solution to achieve a tesirolimus concentration of 1 mg / mL.

[0094] ICR (CD-I) mice were administered a single intravenous injection of an equal dose of the test product (T) or the reference product (R).

[0095] Results: In ICR (CD-I) mice, the pharmacokinetics of tesimolimus and its major metabolite sirolimus were evaluated after a single intravenous injection of either tesimolimus lipid suspension (test product) or solvent-based tesimolimus injection (reference product) at a dose level of 10 mg / kg body weight. One blood sample was collected from each mouse within 24 hours after equal-dose administration (3 mice per time point). Plasma concentrations of tesimolimus and sirolimus in each sample were analyzed using HPLC. Plasma concentrations of tesimolimus and sirolimus were calculated from the standard curve, as shown below. Figure 1 and Figure 2 As shown, the blood concentrations of tesiromoximide and sirolimus were comparable in the test and reference formulations.

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Claims

1. A composition, characterized in that, The composition comprises an mTOR inhibitor and at least one lipid and / or gucousterol or gucousterol derivative.

2. The composition according to claim 1, characterized in that, The mTOR inhibitors are selected from sirolimus, everolimus, tesilolimus, deforolimus, zotalimus, and tacrolimus.

3. The composition of claim 1, characterized in that, The at least one lipid is selected from the group consisting of soybean phosphatidylcholine (SPC), hydrogenated soybean phosphatidylcholine, dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylcholine (DPPC), distearate phosphatidylglycerol (DSPG), and dipalmitoyl phosphatidylglycerol (DMPG).

4. The composition according to claim 1, characterized in that, The gugusterol derivatives are selected from the group consisting of gugusterol laurate, gugusterol myristate, gugusterol palmitate, gugusterol stearate, gugusterol oleate, gugusterol linoleate and gugusterol linoleate.

5. The composition according to claim 1, characterized in that, The composition also contains a cryoprotectant.

6. The composition according to claim 5, characterized in that, The cryoprotectant is selected from lactose, glucose, dextrose, trehalose, maltose, mannitol, and sorbitol.

7. The composition according to claim 1, characterized in that, The composition is in powder form.

8. The composition according to claim 1, characterized in that, The composition is in suspension form.

9. The composition according to claims 1 and 8, characterized in that, The concentration of the mTOR inhibitor in the suspension is between 1 mg / mL and 5 mg / mL.

10. The composition according to claim 1, characterized in that, The mTOR inhibitor content is from about 0.5% to about 50% of the total weight.

11. The composition according to claim 1, characterized in that, The weight ratio of the mTOR inhibitor to lipids is between 1:5 and 1:

50.

12. The composition according to claim 1, characterized in that, The weight ratio of the mTOR inhibitor to cucurbitacin or cucurbitacin derivative is between 1:0.1 and 1:

10.

13. The composition according to claims 1, 7, and 8, characterized in that, The composition includes parenteral administration to the subject.

14. The composition according to claims 1 and 13, characterized in that, The parenteral administration provides mTOR inhibitor pharmacokinetics comparable to that of tesiromoxim injection containing anhydrous ethanol, propylene glycol, polysorbate 80, and polyethylene glycol 400 (PEG400) after administration.

15. The composition according to claims 13 and 14, characterized in that, The subjects were humans.

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