[go: up one dir, main page]

WO2025037276A1 - Compositions contenant des inhibiteurs de mtor et des lipides - Google Patents

Compositions contenant des inhibiteurs de mtor et des lipides Download PDF

Info

Publication number
WO2025037276A1
WO2025037276A1 PCT/IB2024/057966 IB2024057966W WO2025037276A1 WO 2025037276 A1 WO2025037276 A1 WO 2025037276A1 IB 2024057966 W IB2024057966 W IB 2024057966W WO 2025037276 A1 WO2025037276 A1 WO 2025037276A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
temsirolimus
weight ratio
guggulsterol
guggulsteryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2024/057966
Other languages
English (en)
Inventor
Shoukath M. Ali
Paul Chen
Ateeq Ahmad
Saifuddin Sheikh
Moghis U. Ahmad
Imran Ahmad
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jina Pharmaceuticals Inc
Original Assignee
Jina Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jina Pharmaceuticals Inc filed Critical Jina Pharmaceuticals Inc
Publication of WO2025037276A1 publication Critical patent/WO2025037276A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the invention relates to compositions comprising mTOR inhibitors and lipids.
  • the invention further relates to compositions comprising mTOR inhibitors, guggulsterol and/or guggulsterol derivatives.
  • the invention relates to composition comprising mTOR inhibitors, lipids including phosphatidylcholine, phosphatidylglycerol.
  • the invention relates to compositions comprising mTOR inhibitors, phosphatidylcholine, and guggulsterol or guggulsterol derivatives.
  • the invention further relates administering composition to a human subject in the treatment or prevention of diseases.
  • compositions according to the present invention are suitable for practice on an industrial manufacturing scale, and may be practiced, e.g., as a continuous method.
  • rapamycin The mammalian target of rapamycin (mTOR) is a member of the phosphatidylinositol 3 -kinase-related kinase (PIKK) family, which is one of the key players of cellular metabolism that is coupled with nutrient availability, energy, and homeostasis. It plays an important role in cell growth, differentiation, metastasis, and survival, and has become an important target of cancer treatment.
  • PIKK phosphatidylinositol 3 -kinase-related kinase
  • Rapamycin also known as sirolimus, a macrolide lactone, was initially described as an antifungal agent.
  • Sirolimus is initially approved for oral administration as immunosuppressant and indicated for the prophylaxis of organ rejection in patients aged >13 years receiving renal transplants. It is also used to coat coronary stents and to treat a rare lung disease called Lymphangioleiomyomatosis (LAM). Recently, sirolimus, protein-bound particles developed for intravenous use, has been approved for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa). Most recently, it is also approved for topical treatment in the form of 0.2% topical gel for facial angiofibroma associated with tuberous sclerosis.
  • PEComa locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor
  • everolimus is approved to treat postmenopausal advanced hormone receptor-positive, HER2-negative breast cancer in women, progressive neuroendocrine tumors of pancreatic origin (PNET), advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib, renal angiomyolipoma (AML), tuberous sclerosis complex (TSC), and subependymal giant cell astrocytoma (SEGA) associated with TSC as well as renal and liver transplantation.
  • PNET pancreatic origin
  • RRCC advanced renal cell carcinoma
  • AML renal angiomyolipoma
  • TSC tuberous sclerosis complex
  • SEGA subependymal giant cell astrocytoma
  • Temsirolimus is approved as a first-line treatment for advanced renal cell cancer.
  • Sirolimus an active metabolite of temsirolimus, is the principal metabolite in humans following intravenous treatment.
  • Tacrolimus is also a macrolide lactone structurally similar to sirolimus and is indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressants. It is also used as an ointment in the treatment of eczema, in particular atopic dermatitis. Because of the structural similarity between tacrolimus and sirolimus, and the ability of both to bind to FK506 binding protein 12 (FKBP12), it is hypothesized that tacrolimus can also inhibit the mTOR signaling, constituting a possible mechanism of 0 cell toxicity.
  • FKBP12 FK506 binding protein 12
  • Temsirolimus is marketed as Torisel® and is approved for the treatment of advanced renal cell carcinoma.
  • the recommended dose of TORISEL for advanced renal cell carcinoma is 25 mg administered as an intravenous infusion over a 30 - 60-minute period once a week.
  • Torisel® is supplied as a sterile non-aqueous clear solution (concentrate) for injection containing Temsirolimus 25 mg/mL, in dehydrated alcohol (39.5% w/v) and propylene glycol (50.3% w/v).
  • the product is provided with an additional vial as diluent containing polysorbate 80 (40.0% w/v), polyethylene glycol 400 (PEG400) (42.8% w/v), and dehydrated alcohol (19.9% w/v).
  • the concentrate and the diluent are intended for the preparation of a premix solution of temsirolimus at 10 mg/ml prior to dilution with 250 mL of 0.9% saline solution in an infusion bag.
  • the generic versions of Torisel® are also approved for marketing.
  • Temsirolimus is highly lipophilic and practically insoluble in water. Due to its insolubility, various solubilizers such as polysorbate 80, PEG400, propylene glycol, and dehydrated alcohol were successfully exploited to formulate for intravenous administration. However, hypersensitivity reactions and infusion related toxicities are associated with the use of Polysorbate 80, propylene glycol, and ethanol, and to reduce the risk of these side effects, patients are routinely premedicated with prior to the treatment of temsirolimus.
  • compositions containing mTOR inhibitors comprising mTOR inhibitors.
  • the composition comprises mTOR inhibitor, phosphatidylcholine and or phosphatidylglycerol.
  • the composition further comprises mTOR inhibitor and one or more of guggulsterol, guggulsterol derivatives.
  • the composition comprises mTOR inhibitor, phosphatidylcholine and or phosphatidylglycerol, and one or more of guggulsterol, guggulsterol derivatives.
  • the composition further comprises other excipients.
  • Certain embodiments comprise a composition comprising mTOR inhibitors and administering the composition to a subject.
  • the subject is a mammal.
  • the subject is human.
  • this invention provides compositions comprising mTOR inhibitor and phosphatidylcholine for parenteral delivery to a human subject.
  • the composition for parenteral delivery is in the form of suspension.
  • compositions of the present invention comprise mTOR inhibitor and phosphatidylglycerol for parenteral delivery to a human subject.
  • the composition for parenteral delivery is in the form of suspension.
  • compositions comprising mTOR inhibitor and guggulsterol for parenteral delivery to a human subject.
  • the composition for parenteral delivery is in the form of suspension.
  • compositions comprising mTOR inhibitor and a guggulsterol derivative for parenteral delivery to a human subject.
  • parenteral delivery is in the form of suspension.
  • compositions comprising mTOR inhibitor, phosphatidylcholine, and guggulsterol for parenteral delivery to a human subject.
  • the parenteral delivery is in the form of suspension.
  • compositions comprising mTOR inhibitor, phosphatidylcholine, and guggulsterol derivative for parenteral delivery to a human subject.
  • the parenteral delivery is in the form of suspension.
  • compositions comprising mTOR inhibitor, phosphatidylglycerol, and guggulsterol for parenteral delivery to a human subject.
  • the parenteral delivery is in the form of suspension.
  • compositions comprising mTOR inhibitor, phosphatidylglycerol, and guggulsterol derivative for parenteral delivery to a human subject.
  • the parenteral delivery is in the form of suspension.
  • this invention provides compositions comprising mTOR inhibitor, phosphatidylcholine, and phosphatidylglycerol for parenteral delivery to a human subject.
  • the composition for parenteral delivery is in the form of suspension.
  • this invention provides compositions comprising mTOR inhibitor, phosphatidylcholine, phosphatidylglycerol, and guggulsterol for parenteral delivery to a human subject.
  • the composition for parenteral delivery is in the form of suspension.
  • this invention provides compositions comprising mTOR inhibitor, phosphatidylcholine, phosphatidylglycerol, and guggulsterol derivative for parenteral delivery to a human subject.
  • the composition for parenteral delivery is in the form of suspension.
  • this invention provides compositions comprising mTOR inhibitor, and lipid(s) for rectal delivery to a human subject.
  • the composition for rectal delivery is in the form of suspension.
  • a mTOR inhibitors composition of present invention is coadministered with other drugs.
  • Drugs that can be co-administered along with mTOR inhibitors composition include but are not limited to anticancer drugs such as doxorubicin, epirubicin, methotrexate, mitoxantrone, capecitabine, carboplatin, cisplatin, etoposide, 5-flurouracil, cyclophosphamide, daunomycin, bleomycin, gemcitabine, irinotecan, SN-38, mitoxantrone, cytrabine, capecitabine, mitomycin, sunitinib, sorafenib, tivozanib, ibrutinib, imatinib, erlotinib, acalabrutinib, carbozantinib, bevacizumab, paclitaxel, docetaxel, cabazitaxel,
  • the amount of mTOR inhibitor included in a mTOR inhibitors composition according to 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 about 0.1% to about 90% of the total weight, preferably about 0.5% to about 75% of the total weight, more preferably about 1% to about 50% of the total weight.
  • the amount of lipid(s) included in a mTOR inhibitor composition according to present invention is not limited to any particular amount or percentage (by weight) of the final composition or weight. In some embodiments, the proportion of total lipid is about 4% to about 100% by weight of total lipid, preferably about 5% to about 60% by weight of total lipid or more preferably about 8% to about 50% by weight of total lipid.
  • composition “preparation” or “formulation” refers to the combination of an active agent (e.g, an active pharmaceutical compound) with a carrier, inert or active, excipients, making the composition especially suitable for diagnostic or therapeutic use in vitro, in vivo, or ex vivo.
  • active agent e.g, an active pharmaceutical compound
  • carrier inert or active, excipients
  • the term “active” as used in reference to an agent, composition, or compound refers to an agent that, upon administration or application, causes a beneficial, desired, or expected result.
  • the administration may be in one or more administrations, applications, dosages and is not intended to be limited to a particular formulation or administration route.
  • the term is not limited to any level of activity.
  • a formulation of an active agent need not have the same level of activity as a different formulation of an active agent, so long as the active agent in the formulation is sufficiently active that an effective amount of the active agent can be administered by administration of the formulation of the agent.
  • agent and “compound” are used herein interchangeably to refer to any atom, molecule mixture or more complex composition having an attributed feature.
  • an ‘active agent” or “active compound” refers to any atom, molecule, preparation mixture, etc. that, upon administration or application, causes beneficial, desired, or expected result.
  • compositions that do not substantially produce adverse reactions, e.g, toxic, allergic, or immunological reactions, when administered to a subject.
  • administration refers to the act of giving a drug, or active agent, or therapeutic treatment (e.g., composition of the present invention) to a physiological system (e.g., a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs).
  • a physiological system e.g., a subject or in vivo, in vitro, or ex vivo cells, tissues, and organs.
  • exemplary routes of administration to the human body can be through mouth (oral), skin (transdermal), eyes (ophthalmic), nose (nasal), and the like.
  • Administration may be in one or more administrations, applications, or dosages, and is not intended to be limited to a particular administration route.
  • co-administration refers to the administration of at least two agents(s) (e.g., two separate compositions, containing different active agents) or therapies to a subject. In some embodiments, the co-administration of two or more agents or therapies are concurrent. In other embodiments, a first agent/therapy is administered prior to a second agent/therapy.
  • agents or therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art.
  • parenteral refers to non-oral means of administration.
  • the common parenteral route of administration includes intravenous (IV), intramuscular (IM), and subcutaneous (SC).
  • disease refers to a state, signs, and/or symptoms that are associated with any impairment of the normal state of a living animal or any of its organs or tissues that interrupts or modifies the performance of normal functions and may be a response to environmental factors.
  • treatment encompasses the improvement and/or reversal of the symptoms of disease (e.g., cancer), or reduction of risk of occurrence of disease.
  • a compound which causes an improvement in any parameter associated with disease when used in the screening methods of the instant invention may thereby be identified as a therapeutic compound.
  • treatment refers to therapeutic treatment.
  • those who may benefit from treatment with compositions of the present invention include those already with a disease and/or disorder (e.g., cancer, or symptoms or pathologies consistent with cancer).
  • pharmacokinetic refers to the passage of active agents or drugs after administration into body, through it, and out of body.
  • the passage include absorption, for example, how the active agent or drug moves from the site of administration to the site of action; distribution, for example, the journey of the active agent or drug through the bloodstream to various tissues of the body; metabolism, for example, the process that breaks down the drug inside body; and excretion, for example, the removal of the drug from the body.
  • FIG. 1 is a graph showing the blood concentrations of temsirolimus over time in Example 13.
  • FIG. 2 is a graph showing the blood concentrations of sirolimus over time in Example 13.
  • the invention relates to a composition comprising mTOR inhibitors formulation.
  • the invention comprises administrating a mTOR composition to a human subject, e.g., to treat a disease.
  • the composition comprising mTOR inhibitors comprises lipids, for example, phosphatidylcholine or phosphatidylglycerol.
  • the composition comprising mTOR inhibitors comprises guggulsterol or a guggulsterol derivative.
  • the composition comprises phosphatidylcholine or phosphatidylglycerol and/or guggulsterol, a guggulsterol derivative.
  • mTOR inhibitors suitable for use in the composition of the present invention include Temsirolimus, Sirolimus, Everolimus, Deforolimus, and Zotarolimus.
  • the composition of the present invention also includes Tacrolimus.
  • phosphatidylcholine suitable for use in the composition of the present invention examples include soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC).
  • SPC soy phosphatidylcholine
  • HSPC hydrogenated soy phosphatidylcholine
  • DMPC dimyristoylphosphatidylcholine
  • DPPC dipalmitoylphosphatidylcholine
  • DSPC distearoylphosphatidylcholine
  • DMPG dimyristoylphosphatidylglycerol
  • DSPG distearoylphosphatidylglycerol
  • DMPG dipalmitoylphosphatidylglycerol
  • guggulsterol derivatives suitable for use in the composition of the present invention include guggulsteryl laurate, guggulsteryl myristate, guggulsteryl palmitate, guggulsteryl stearate, guggulsteryl oleate, guggulsteryl linoleate, guggulsteryl linoleneate.
  • the composition of the present invention comprises antioxidants and or stabilizers.
  • antioxidants suitable for use in the composition of present invention include, alpha-tocopherol (Vitamin E), alpha-tocopherol polyethylene glycol succinate (TPGS), ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite (SMB), propyl gallate, cysteine, citric acid.
  • the composition of the present invention contains buffers.
  • base or buffer include but are not limited to sodium citrate, sodium succinate, sodium phosphate, sodium acetate, sodium hydroxide, saline, and the like.
  • compositions comprising mTOR inhibitors and delivering such compositions to a subject, e.g., a human subject.
  • a subject e.g., a human subject.
  • Any suitable amount of mTOR inhibitors sufficient to produce a desired effect, e.g., a therapeutic effect, can be used.
  • suitable amounts of mTOR inhibitors are those amounts that can be suitably incorporated into a suspension, solution, nanoparticles, of the present invention.
  • a composition according to the present invention comprises homogenous suspension, liposomes, micelles, vesicles, nanoparticles that have a mean diameter of about 5 microns or less, while in some embodiments, homogenous suspension, liposomes, micelles, vesicles, nanoparticles that have a diameter of about 1 micron or less. In some embodiments, the homogenous suspension, liposomes, micelles, vesicles, nanoparticles that have a diameter of about 500 nm or less, while in some embodiments, the homogenous suspension, liposomes, micelles, vesicles, nanoparticles that have a diameter of about 200 nm or less. In some preferred embodiments, homogenous suspension, liposomes, micelles, vesicles, nanoparticles that have a diameter of about 100 nm or less.
  • a composition according to the present invention is in a lyophilized form.
  • the composition further comprises a cryoprotectant.
  • the cryoprotectant comprises one or more sugars, while in particularly preferred embodiments; the one or more sugars comprise sucrose, lactose, glucose, dextrose, trehalose, maltose, mannitol, and/or sorbitol.
  • the cryoprotectant comprises glycine and polyvinylpyrrolidone (PVP). The percentage of sugar in the composition may range from about 10% to about 90%.
  • the lyophilized form is reconstituted with a suitable vehicle to achieve desired mTOR inhibitor concentration.
  • vehicle for reconstitution includes but not limited to water for injection, sodium chloride solution, dextrose solution, or any pharmaceutically acceptable buffer.
  • the desired mTOR inhibitor concentration upon reconstitution is in between 0.5 mg/mL to about 20 mg/ mL. preferably about 1 mg/ mL to about 10 mg/mL or preferable to about 1 mg/mL to about 5 mg/mL.
  • the reconstituted product composition is further diluted to desired mTOR inhibitor concentration for administration.
  • the desired mTOR inhibitor concentration is either fixed concentration or concentration for administration based on the body weight of the subject.
  • the vehicle for dilution includes but not limited to 0.9% saline and 5% dextrose solution or any pharmaceutically acceptable vehicle for administration.
  • the pH of the composition of the invention ranges from about 2 to about 11 , preferably having pH of about 3 to about 8, and more preferably having pH of about 3.5 to pH 8.0.
  • the composition of the present invention contains about 4% to about 100% by weight of total lipid, preferably about 5% to about 60% by weight of total lipid or more preferably about 8% to about 50% by weight of total lipid.
  • the composition of the present invention contains mTOR inhibitor and total lipid(s) in weight-to- weight ratio between 1 :1 and 1:80; for example, in between 1:1 and 1: 10 weight ratio or in between 1: 1 and 1 :20 weight ratio or in between 1 :1 and 1 :30 weight ratio, or in between 1: 1 and 1 :40 weight ratio or in between 1 : 1 and 1:50 weight ratio, or in between 1 : 1 and 1 :60 weight ratio, or in between 1 : 1 and 1 :70 weight ratio or in between 1 : 1 and 1 :80 weight ratio.
  • the composition of present invention contains mTOR inhibitors and total lipid(s) in weight-to- weight ratio between 1 :5 and 1 :50.
  • the term “in between” is inclusive of the limits of the range.
  • a weight-to-weight ratio in between 1 :5 and 1:50 weight ratio includes weight ratio of 1 :5 and 1:50.
  • the composition of the present invention contains mTOR inhibitor and phosphatidylcholine in weight-to-weight ratio between 1 : 1 and 1 :80; for example, in between 1 : 1 and 1: 10 weight ratio or in between 1 : 1 and 1 :20 weight ratio or in between 1 : 1 and 1 :30 weight ratio, or in between 1: 1 and 1 :40 weight ratio or in between 1 : 1 and 1:50 weight ratio, or in between 1 : 1 and 1 :60 weight ratio, or in between 1 : 1 and 1 :70 weight ratio or in between 1 : 1 and 1 :80 weight ratio.
  • mTOR inhibitor and phosphatidylcholine in weight-to-weight ratio between 1 : 1 and 1 :80; for example, in between 1 : 1 and 1: 10 weight ratio or in between 1 : 1 and 1 :20 weight ratio or in between 1 : 1 and 1 :30 weight ratio, or in between 1: 1 and 1 :40 weight ratio or in between 1 : 1 and 1:50
  • the composition of present invention contains mTOR inhibitors and total lipid(s) in weight-to-weight ratio between 1 :5 and 1 :50.
  • the term “in between” is inclusive of the limits of the range.
  • a weight-to-weight ratio in between 1 :5 and 1:50 weight ratio includes weight ratio of 1 :5 and 1:50.
  • phosphatidylcholine include soy phosphatidylcholine (SPC), hydrogenated soy phosphatidylcholine (HSPC), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC).
  • the composition of the present invention contains mTOR inhibitor and phosphatidylglycerol in weight-to-weight ratio between 1: 1 and 1:80; for example, in between 1: 1 and 1 :10 weight ratio or in between 1: 1 and 1:20 weight ratio or in between 1 : 1 and 1 :30 weight ratio, or in between 1 : 1 and 1 :40 weight ratio or in between 1 : 1 and 1 :50 weight ratio, or in between 1: 1 and 1 :60 weight ratio, or in between 1: 1 and 1:70 weight ratio or in between 1 :1 and 1:80 weight ratio.
  • mTOR inhibitor and phosphatidylglycerol in weight-to-weight ratio between 1: 1 and 1:80; for example, in between 1: 1 and 1 :10 weight ratio or in between 1: 1 and 1:20 weight ratio or in between 1 : 1 and 1 :30 weight ratio, or in between 1 : 1 and 1 :40 weight ratio or in between 1 : 1 and 1 :50 weight ratio, or
  • the composition of present invention contains mTOR inhibitors and total lipid(s) in weight-to- weight ratio between 1:5 and 1:50.
  • the term “in between” is inclusive of the limits of the range.
  • a weight-to-weight ratio in between 1 : 5 and 1 : 50 weight ratio includes weight ratio of 1 :5 and 1 :50.
  • phosphatidylglycerol include dimyristoylphosphatidylglycerol (DMPG), distearoylphosphatidylglycerol (DSPG), dipalmitoylphosphatidylglycerol (DMPG).
  • the composition of the present invention contains mTOR inhibitor and guggulsterol or guggulsterol derivative in weight-to-weight ratio between 1:0.1 and 1: 10; for example, in between 1 :0.1 and 1:0.2 weight ratio or in between 1:0.1 and 1:0.3 weight ratio or in between 1:0.1 and 1:0.4 weight ratio, or in between 1:0.1 and 1:0.5 weight ratio or in between 1: 0.1 and 1:0.6 weight ratio, or in between 1:0.1 and 1:0.7 weight ratio, or in between 1 :0.1 and 1 :0.8 weight ratio or in between 1 :0.1 and 1:0.9 weight ratio, or in between 0.1 and 0.10 weight ratio.
  • the term “in between” is inclusive of the limits of the range.
  • a weight-to-weight ratio in between 1:0.1 and 1 :10 weight ratio includes weight ratio of 1:0.1 and 1: 10.
  • guggulsterol derivatives include guggulsteryl laurate, guggulsteryl myristate, guggulsteryl palmitate, guggulsteryl stearate, guggulsteryl oleate, guggulsteryl linoleate, guggulsteryl linoleneate.
  • the composition of the present invention contains mTOR inhibitor and mixture of phosphatidylcholine and guggulsterol or guggulsterol derivative.
  • the weight-to-weight ratio of mTOR inhibitors and the mixture of phosphatidylcholine and guggulsterol or guggulsterol derivative is in between 1:1 and 1 :80; for example, in between 1:1 and 1: 10 weight ratio or in between 1: 1 and 1:20 weight ratio or in between 1: 1 and 1:30 weight ratio, or in between 1 : 1 and 1 :40 weight ratio or in between 1 : 1 and 1:50 weight ratio, or in between 1 : 1 and 1 :60 weight ratio, or in between 1 : 1 and 1 :70 weight ratio or in between 1:1 and 1 :80 weight ratio.
  • the composition of present invention contains mTOR inhibitors and mixture of phosphatidylcholine and guggulsterol or guggulsterol derivative in weight-to- weight ratio between 1 :5 and 1:50.
  • the term “in between” is inclusive of the limits of the range.
  • a weight-to- weight ratio in between 1 : 5 and 1 :50 weight ratio includes weight ratio of 1 : 5 and 1:50.
  • the composition of the present invention contains mTOR inhibitor and mixture of phosphatidylglycerol and guggulsterol or guggulsterol derivative.
  • the weight-to-weight ratio of mTOR inhibitors and the mixture of phosphatidylglycerol and guggulsterol or guggulsterol derivative is in between 1: 1 1 :80; for example, in between 1 : 1 and 1:10 weight ratio or in between 1: 1 and 1:20 weight ratio or in between 1:1 and 1 :30 weight ratio, or in between 1 :1 and 1:40 weight ratio or in between 1 : 1 and 1 :50 weight ratio, or in between 1 : 1 and 1 :60 weight ratio, or in between 1 : 1 and 1 :70 weight ratio or in between 1 : 1 and 1 :80 weight ratio.
  • the composition of present invention contains mTOR inhibitors and mixture of phosphatidylglycerol and guggulsterol or guggulsterol derivative in weight-to-weight ratio between 1:5 and 1:50.
  • the term “in between” is inclusive of the limits of the range.
  • a weight-to-weight ratio in between 1 : 5 and 1 : 50 weight ratio includes weight ratio of 1 : 5 and 1:50.
  • the composition of the present invention contains mTOR inhibitor and mixture of phosphatidylcholine, phosphatidylglycerol and guggulsterol or guggulsterol derivative.
  • the weight-to-weight ratio of mTOR inhibitors and the mixture of phosphatidylcholine, phosphatidylglycerol, and guggulsterol or guggulsterol derivative is in between 1 : 1 and 1:80; for example, in between 1 : 1 and 1: 10 weight ratio or in between 1 : 1 and 1:20 weight ratio or in between 1:1 and 1:30 weight ratio, or in between 1: 1 and 1 :40 weight ratio or in between 1: 1 and 1:50 weight ratio, or in between 1: 1 and 1 :60 weight ratio, or in between 1 :1 and 1:70 weight ratio or in between 1: 1 and 1 :80 weight ratio.
  • the composition of present invention contains mTOR inhibitors and mixture of phosphatidylcholine, phosphatidylglycerol and guggulsterol or guggulsterol derivative in weight-to-weight ratio between 1 :5 and 1:50.
  • the term “in between” is inclusive of the limits of the range.
  • a weight-to-weight ratio in between 1 : 5 and 1 : 50 weight ratio includes weight ratio of 1 :5 and 1:50.
  • compositions of the present invention include antioxidants.
  • antioxidants include but are not limited to alpha-tocopherol (Vitamin E), alpha- tocopherol polyethylene glycol succinate (TPGS), ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite (SMB), propyl gallate, cysteine, citric acid, etc.
  • compositions of the present invention contain mTOR inhibitor about 0.1% to about 90% of the total weight, preferably about 0.5% to about 75% of the total weight, more preferably about 1% to about 50% of the total weight.
  • this invention provides compositions comprising mTOR inhibitors and lipid(s) and administering said mTOR inhibitors and lipid(s) to a human subject.
  • the administering of said composition is through a parenteral route of administration.
  • the administering of said composition is through a rectal route of administration.
  • the administration of said composition comprising mTOR inhibitors and lipid(s) is in the form of suspension, solution, nanoparticles, vesicles, emulsion.
  • the composition of present invention after parenteral administration provides a similar pharmacokinetic profile compared to the reference product when equal dose of temsirolimus is administered.
  • the said pharmacokinetic profile includes concentrations of temsirolimus and its metabolite, sirolimus in blood at different time points after said administration of the composition of present invention and the reference product.
  • Example of reference product include commercially available solvent based temsirolimus injection product comprising dehydrated alcohol, propylene glycol, polysorbate 80, polyethylene glycol 400 (PEG400).
  • the composition of the present invention in lyophilized powder form is reconstituted with water for injection and diluted with 0.9% sodium chloride solution to a desired concentration.
  • the commercially available reference product, temsirolimus injection comprising dehydrated alcohol (39.5% w/v) and propylene glycol (50.3%) is diluted with the diluent provided with the said reference product comprising polysorbate 80 (40.0% w/v), PEG400 (42.8% w/v), and 19.9% w/v) and further diluted with 0.9% sodium chloride solution to a desired concentration.
  • equal doses of temsirolimus from said diluted composition of present invention and the said diluted reference product provides similar pharmacokinetic profile after intravenous administration.
  • the said pharmacokinetic profile includes concentrations of temsirolimus and its metabolite, sirolimus in blood at different time point intervals after said intravenous administration of the diluted composition of present invention and the reference product.
  • the composition of present invention after spiking in whole human blood provides a similar temsirolimus concentration compared to the reference product when equal dose of temsirolimus is spiked and incubated at 37 °C.
  • Example of reference product include commercially available solvent based temsirolimus injection product comprising dehydrated alcohol, propylene glycol, polysorbate 80, polyethylene glycol 400 (PEG400).
  • the composition of the present invention in lyophilized powder form is reconstituted with water for injection and diluted with 0.9% sodium chloride solution to a desired concentration.
  • the commercially available reference product, temsirolimus injection comprising dehydrated alcohol (39.5% w/v) and propylene glycol (50.3%) is diluted with the diluent provided with the said reference product comprising polysorbate 80 (40.0% w/v), PEG400 (42.8% w/v), and 19.9% w/v) and further diluted with 0.9% sodium chloride solution to a desired concentration.
  • equal doses of temsirolimus from said diluted composition of present invention and the said diluted reference product provides comparable temsirolimus concentration after spiking in whole human blood and incubating at 37 °C.
  • the composition of present invention after spiking into human plasma provides a similar temsirolimus concentration compared to the reference product when equal dose of temsirolimus is spiked and incubated at 37 °C.
  • Example of reference product include commercially available solvent based temsirolimus injection product comprising dehydrated alcohol, propylene glycol, polysorbate 80, polyethylene glycol 400 (PEG400).
  • the composition of the present invention in lyophilized powder form is reconstituted with water for injection and diluted with 0.9% sodium chloride solution to a desired concentration.
  • the commercially available reference product, temsirolimus injection comprising dehydrated alcohol (39.5% w/v) and propylene glycol (50.3%) is diluted with the diluent provided with the said reference product comprising polysorbate 80 (40.0% w/v), PEG400 (42.8% w/v), and 19.9% w/v) and further diluted with 0.9% sodium chloride solution to a desired concentration.
  • equal doses of temsirolimus from said diluted composition of present invention and the said diluted reference product provides comparable temsirolimus concentration after spiking in human plasma and incubating at 37 °C.
  • composition of the present invention may be administered in any dosage form and via any system that delivers the active compound mTOR inhibitors in vivo.
  • a composition of the present invention is delivered in a dosage form selected from parenteral and rectal form.
  • the composition is formulated into a desired dosage form to achieve immediate release profile, extended-release profile, or delayed release profile in vivo upon administration.
  • Soy phosphatidylcholine (1.2 g) was taken in disodium succinate solution in water (2.16 mg/L, pH 6.0; 25 mL) and subjected to high pressure hand homogenization four times. Temsirolimus (30 mg) was added the high-pressure homogenization was continued until desired particle size is achieved.
  • Sucrose (2.25 g) was dissolved in disodium succinate solution (5 mL) and added to temsirolimus, stirred, and filtered through 0.2 p filter. The particle size was determined using Nicomp particle sizer 380. The mean volume weighting diameter amounted to less than 200 nm.
  • Particle size distribution Mean: 46.2 nm, D90: 95.9 nm, D99: 196.8 nm.
  • Soy phosphatidylcholine (1.16 g) and guggulsteryl laurate (40.2 mg) were taken in 0.2% sodium citrate solution (25 mL) in water and subjected to high pressure hand homogenization four times. Temsirolimus (60 mg) was added the high-pressure homogenization was continued until desired particle size is achieved.
  • Sucrose (2.25 g) was dissolved in 0.2% sodium citrate solution (5 mL) and added to Temsirolimus-SPC-guggul laurate suspension, stirred, and filtered through 0.2 p filter and lyophilized. The particle size was determined using Nicomp particle sizer 380. The mean volume weighting diameter amounted to less than 200 nm. Particle size distribution: Mean: 34.6 nm, D90: 67.5 nm, D99: 131.4 nm.
  • Soy phosphatidylcholine (2.0 g) was taken in 0.2% sodium citrate solution (25 mL) in water (40 mL) and subjected to high pressure hand homogenization four times. Temsirolimus (100 mg) was added the high-pressure homogenization continued until desired particle size is achieved.
  • Sucrose (3.75 g) was dissolved in (10 mL) and added to SPC-Temsirolimus suspension, stirred, and filtered through 0.2 p filter and lyophilized. The particle size was determined using Nicomp particle sizer 380. The mean volume weighting diameter amounted to less than 200 nm.
  • Particle size distribution Mean: 18.5 nm, D90: 42.5 nm, D99: 89.9 nm.
  • Soy phosphatidylcholine (4.0 g) was taken in 0.2% sodium citrate solution (80 mL) and subjected to high pressure hand homogenization four times. Temsirolimus (200 mg) was added the high-pressure homogenization was continued until desired particle size is achieved.
  • Sucrose (7.5 g) was dissolved in 0.2% sodium citrate solution (7.5%, 20 mL) was added to SPC-Temsirolimus suspension, stirred, and filtered through 0.2 p filter and lyophilized. The particle size was determined using Nicomp particle sizer 380. The mean volume weighting diameter amounted to less than 200 nm. Particle size distribution: Mean: 32.7 nm, D90: 90.8 nm, D99: 176.9 nm.
  • Soy phosphatidylcholine (1.0 g) was taken in 0.2% sodium citrate solution (20 mL) and subjected to high pressure hand homogenization four times. Sirolimus (25 mg) was added the high-pressure homogenization was continued until desired particle size is achieved.
  • Sucrose (1.875 g) was dissolved in 0.2% sodium citrate solution (7.5%, 5 mL) was added to SPC-Temsirolimus suspension, stirred, and filtered through 0.2 p filter and lyophilized. The particle size was determined using Nicomp particle sizer 380. The mean volume weighting diameter amounted to less than 200 nm. Particle size distribution: Mean: 38.5 nm, D90: 76.3 nm, D99: 156.8 nm.
  • Soy phosphatidylcholine (4.0 g) was taken in 0.2% sodium citrate solution (80 mL) and subjected to high pressure hand homogenization four times. Temsirolimus (100 mg) was added the high-pressure homogenization continued until desired particle size is achieved.
  • Sucrose (7.5 g) was dissolved in 0.2% sodium citrate solution (7.5%, 20 mL) was added to SPC- Temsirolimus suspension, stirred, and filtered through 0.2 p filter and lyophilized. The particle size was determined using Nicomp particle sizer 380. The mean volume weighting diameter amounted to less than 200 nm. Particle size distribution: Mean: 29.0 nm, D90: 64.0 nm, D99: 128.1 nm.
  • Soy phosphatidylcholine (5.0 g), Temsirolimus (250 mg), Monosodium citrate (200 mg), and Sucrose (24.05 g) were mixed in water for injection under stirring using overhead stirrer.
  • the resulting suspension was homogenized using high-pressure homogenization until desired particle size is achieved.
  • the volume of the suspension was adjusted to desired volume and filtered through 0.2 p filter and lyophilized.
  • the particle size was determined using Nicomp particle sizer 380. The mean volume weighing diameter amounted to less than 200 nm.
  • the temsirolimus lipid suspension (prepared according to Example 6) was reconstituted with 0.9% saline and diluted at dose levels of 0, 5, 10, and 25 mg/kg temsirolimus/body weight was administered intravenously to Wistar rats (10 animals/dose, 5 males and 5 females).
  • the rats in the control group (0 mg dose level) were similarly treated with n-saline intravenously at the equivalent volume as per kg body weight.
  • the animals were monitored for clinical signs, body weight, mortality, necropsy (gross pathology) and histopathology. The results suggested that temsirolimus lipid suspension has no serious adverse effects at all dose levels tested.
  • MTD Tolerated Dose
  • the temsirolimus lipid suspension (prepared according to Example 6) was reconstituted with 0.9% saline and diluted at dose levels of 0, 10, 20, and 50 mg/kg temsirolimus/body weight was administered intravenously to Swiss Albino mice (10 animals/dose, 5 males and 5 females).
  • the mice in the control group (0 mg dose level) were similarly treated with n-saline intravenously at the equivalent volume as per kg body weight.
  • the animals were monitored for clinical signs, body weight, mortality, necropsy (gross pathology) and histopathology. The results suggested that temsirolimus lipid suspension has no serious adverse effects at all dose levels tested.
  • MTD Tolerated Dose
  • the temsirolimus lipid suspension (prepared according to Example 6) was reconstituted and diluted with 0.9% NaCl to recommended concentration for infusion at 0.1 mg temsirolimus/mL.
  • the infusion preparations were incubated at room temperature for up to 4 hrs.
  • the concentrations of temsirolimus were monitored with a validated LC-MS/MS method at 0.5 and 4 hrs., respectively. There is little change in concentration of temsirolimus over a period of 4 hrs at room temperature.
  • Temsirolimus Comparable Partitioning of Temsirolimus in red blood cells (RBC) and plasma following incubation of Temsirolimus Lipid Suspension for Injection (Test Product) or Temsirolimus Injection (Reference Product) in human whole blood at 37 °C.
  • Temsirolimus Lipid Suspension for Injection (Test Product, T): The lyophilized product (prepared according to Example 6) was reconstituted with water for injection to achieve 1 mg/mL temsirolimus concentration and further diluted with 0.9% sodium chloride to achieve 50 pg /mL temsirolimus concentration.
  • Temsirolimus Injection (Reference Product, R): The reference product vial comprising dehydrated alcohol (39.5% w/v) and propylene glycol (50.3%) was diluted with the diluent provided with the said reference product comprising polysorbate 80 (40.0% w/v), PEG400 (42.8% w/v), and 19.9% w/v) and further diluted with 0.9% sodium chloride solution to achieve 50 pg /mL temsirolimus concentration.
  • Temsirolimus Lipid Suspension for Injection (Test Product, T): The lyophilized product (prepared according to Example 6) was reconstituted with water for injection to achieve 1 mg/mL temsirolimus concentration and further diluted with 0.9% sodium chloride to achieve 50 pg /mL temsirolimus concentration.
  • Temsirolimus Injection (Reference Product, R): The reference product vial comprising dehydrated alcohol (39.5% w/v) and propylene glycol (50.3%) was diluted with the diluent provided with the said reference product comprising polysorbate 80 (40.0% w/v), PEG400 (42.8% w/v), and 19.9% w/v) and further diluted with 0.9% sodium chloride solution to achieve 50 pg/mL temsirolimus concentration.
  • Test or Reference formulations were spiked into human plasma to achieve approx. 1 pg/mL final concentration.
  • the plasma samples were incubated for up to 4 hrs. at 37 °C and level of free (protein unbound) temsirolimus in plasma was measured at 0.5 and 4 hrs. time points with a validated LC-MS/MS method. The results showed that the plasma level of free temsirolimus from Test and Reference formulations are comparable.
  • Table 3 Table 3
  • Temsirolimus Lipid Suspension for Injection (Test Product, T): The lyophilized product (prepared according to Example 6) was reconstituted with water for injection to achieve 1 mg/mL temsirolimus concentration and used without further dilution.
  • Temsirolimus Injection (Reference Product, R): The reference product vial comprising dehydrated alcohol (39.5% w/v) and propylene glycol (50.3%) was diluted with the diluent provided with the said reference product comprising polysorbate 80 (40.0% w/v), PEG400 (42.8% w/v), and 19.9% w/v) and further diluted with 0.9% sodium chloride solution to achieve 1 mg/mL temsirolimus concentration.
  • Test Product (T) or Reference Product (R) was administered intravenously in ICR (CD-I) mice.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Biophysics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions d'inhibiteurs de mTOR et l'administration de compositions d'inhibiteurs de mTOR. Des modes de réalisation concernent des compositions comprenant des inhibiteurs de mTOR avec au moins un lipide et/ou du guggulstérol, et/ou des dérivés de guggulstérol, et l'administration des compositions chez un sujet.
PCT/IB2024/057966 2023-08-16 2024-08-16 Compositions contenant des inhibiteurs de mtor et des lipides Pending WO2025037276A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363520000P 2023-08-16 2023-08-16
US63/520,000 2023-08-16

Publications (1)

Publication Number Publication Date
WO2025037276A1 true WO2025037276A1 (fr) 2025-02-20

Family

ID=94632345

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/057966 Pending WO2025037276A1 (fr) 2023-08-16 2024-08-16 Compositions contenant des inhibiteurs de mtor et des lipides

Country Status (1)

Country Link
WO (1) WO2025037276A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100068251A1 (en) * 2006-10-10 2010-03-18 Jina Pharmaceuticals, Inc. Aqueous Systems For The Preparation Of Lipid Based Pharmaceutical Compounds; Compositions, Methods, And Uses Thereof
US20110212167A1 (en) * 2008-09-27 2011-09-01 Jina Pharmaceuticals, Inc. Lipid based pharmaceutical preparations for oral and topical application; their compositions, methods, and uses thereof
US20170065520A1 (en) * 2015-09-09 2017-03-09 Manli International Ltd Stable liposomal formulations of rapamycin and rapamycin derivatives for treating cancer
US20210008008A1 (en) * 2017-09-12 2021-01-14 Jina Pharmaceuticals, Inc. Methods of preparing composition containing thymoquinone

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100068251A1 (en) * 2006-10-10 2010-03-18 Jina Pharmaceuticals, Inc. Aqueous Systems For The Preparation Of Lipid Based Pharmaceutical Compounds; Compositions, Methods, And Uses Thereof
US20110212167A1 (en) * 2008-09-27 2011-09-01 Jina Pharmaceuticals, Inc. Lipid based pharmaceutical preparations for oral and topical application; their compositions, methods, and uses thereof
US20170065520A1 (en) * 2015-09-09 2017-03-09 Manli International Ltd Stable liposomal formulations of rapamycin and rapamycin derivatives for treating cancer
US20210008008A1 (en) * 2017-09-12 2021-01-14 Jina Pharmaceuticals, Inc. Methods of preparing composition containing thymoquinone

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RODRIGUEZ-RODRIGUEZ, ANA ELENA ET AL.: "Inhibition of the mTOR pathway: A new mechanism of β cell toxicity induced by tacrolimus", AM. J. TRANSPLANT., vol. 19, 2019, pages 3240, XP072349946, DOI: 10.1111/ajt.15483 *

Similar Documents

Publication Publication Date Title
US11648199B2 (en) Inhalable rapamycin formulation for treating age-related conditions
US20230255944A1 (en) Inhalable rapamycin formulation for the treatment of pulmonary hypertension
DE602004004520T2 (de) Antineoplastische zusammensetzungen
CN106573067A (zh) 用于淋巴管平滑肌瘤病治疗的雷帕霉素
KR20160088300A (ko) 림프관평활근종증의 치료를 위한 라파마이신
WO2016130645A1 (fr) Rapamycine destinée au traitement de la lymphangioléiomyomatose
WO2025037276A1 (fr) Compositions contenant des inhibiteurs de mtor et des lipides
TWI887545B (zh) 包含雷帕黴素或其衍生物之脂質體及其在治療中之使用
HK40096520A (en) An inhalable rapamycin formulation for treating age-related conditions
WO2024013152A1 (fr) Formulation inhalable destinée à être utilisée dans le traitement d'infections pulmonaires bactériennes
CN116407503A (zh) 以五环三萜类化合物为膜材的空白脂质体组合及其制备方法和应用

Legal Events

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

Ref document number: 24853967

Country of ref document: EP

Kind code of ref document: A1