55 results about "2-Methoxyestradiol" patented technology

The present invention provides improved sustained release formulations of estradiol metabolites, including 2-hydroxyestradiol, 2-methoxyestradiol, 4-hydroxyestradiol and 4-methoxyestradiol, useful for therapeutic treatments. The invention also provides methods of producing sustained release forms of estradiol metabolites. The compositions of the present invention include microparticles, nanoparticles, patches, crystals, gels, rods, stints, pallets, discs, lozenges, wafers, capsules, films, microcapsules nanocapsules, hydrogels, liposomes, implants and vaginal rings. Compositions also include formulations for transdermal and intravenous delivery of estradiol metabolites. The present invention provides numerous improvements over previous forms of estradiol metabolites, such advantages including the sustained release of normally short half-life compounds to maintain therapeutic blood levels.

Methods are provided for the treatment of pulmonary hypertension and other conditions associated therewith. In particular, the methods include treatment of pulmonary hypertension with an estradiol metabolite or alkoxy analogue of an estradiol metabolite. The estradiol metabolite or alkoxy analogue thereof may be associated with biodegradable microparticles or nanoparticles alone or in combination with other therapeutic agents. Preferred estradiol metabolites include 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol, and 4-hydroxyestradiol and preferred alkoxy analogues of estradiol metabolites include 2-ethoxyestradiol, and / or to synthetic derivatives and analogues thereof or prodrugs thereof. The compositions may also be in the form of a controlled release formulation.

Methods are provided for preventing or treating risk factors for cardiovascular disease in an individual, comprising administering a therapeutically effective amount of a composition comprising an estradiol metabolite to said individual. Such risk factors include obesity, the metabolic syndrome, diabetes mellitus, vascular disorders, and renal disorders. Preferred estradiol metabolites include 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol, and 4-hydroxyestradiol or prodrugs thereof. The compositions may also be in the form of a controlled release formulation. Methods are also provided for use of estradiol metabolites to treat or prevent insulin resistance, vascular endothelial dysfunction, hyperlipidemia, hypertension, diabetic nephropathy, proteinuria and reducing leptin levels. In addition, the methods provide a method of stabilizing glucose levels. These treatments may be used in either gender because of their lack of a feminizing estrogenic effect.

The present invention relates generally to methods and compositions of treating disease characterized by abnormal cell proliferation and / or abnormal or undesirable angiogenesis by administering antiangiogenic agents in combination with chemotherapeutic agents. More specifically, the present invention relates to a methods and compositions of treating diseases characterized by abnormal cell proliferation and / or abnormal or undesirable angiogenesis by administering 2-methoxyestradiol, in combination with chemotherapeutic agents.

The invention is of both a composition and method for inhibiting the proliferation of cancerous cells. The composition is, and the method is based on the use of a composition consisting (among active ingredients) substantially of 2-methoxyestradiol and / or one of a number of anaologues thereof. The present inventors have demonstrated beyond serious doubt that these compounds have a pronounced effect in inhibiting the proliferation of cancerous cells and, therefore, provide a desperately needed stepping stone for advancing toward meaningful treatment of cancer.

2-methoxyestradiol having greater than 98% purity is obtained by synthetic or purification methods. This highly pure 2-methoxy estradiol, lacking estrogenic components, is particularly suitable for clinical use in humans. The purification methods of the invention involve the use of liquid-solid chromatography (LSC) to separate 2-ME2 from other compounds. The chromatographic media is preferably silica. The solvent system comprises a non-polar solvent, such as chloroform, and a polar solvent, such as methanol.

2-methoxyestradiol having greater than 98% purity is obtained by synthetic or purification methods. This highly pure 2-methoxy estradiol, lacking estrogenic components, is particularly suitable for clinical use in humans. The purification methods of the invention involve the use of liquid-solid chromatography (LSC) to separate 2-ME2 from other compounds. The chromatographic media is preferably silica. The solvent system comprises a non-polar solvent, such as chloroform, and a polar solvent, such as methanol.

Compositions and methods for treating mammalian disease characterized by undesirable angiogenesis by administering derivatives of 2-methoxyestradiol of the general formula: wherein the variables are defined in the specification.

Biodegradable implants sized and suitable for implantation in an ocular region or site and methods for treating ocular conditions. The implants such as microsheres provide an extended release of an active agent at a therapeutically effective amount for a period of time between 10 days and one year or longer. The active is selected from estradiols such as 2-methoxyestradiol or alpha2-adrenergic agonists such as brimonidine and its derivates or prostagladin analogis.

The invention relates to an estrogen amino-acid ester compound with antitumor activity as well as a synthetic method thereof, effectively solving the preparation problems of the estrogen amino-acid ester compound with the antitumor activity. The synthetic method comprises the following steps of: dissolving amino acids or small molecule peptides to an aqueous solution of sodium hydroxide or a saturated solution of sodium bicarbonate, dripping carbobenzoxy chloride, making the solution react until the solution is not purple by developing with ninhydrin or carrying out film detection; washing with aether, removing aether, adjusting the pH value of the water phase with hydrochloric acid until milky white solid occurs and extracting with ethyl acetate; washing mixed solution with distilled water and saturated common salt solution, drying with anhydrous magnesium sulfate, carrying out suction filtration, concentrating and purifying; and then, mixing the mixed solution with sterides nucleus and dissolving the mixture to a reaction solvent, adding a condensing agent and a catalyst, supplementing an additional condensing agent, carrying out film detection, filtering, concentrating and purifying, dissolving in a dissolving solvent, adding palladium carbon for catalytic hydrogenation, detecting the film, filtering, concentrating and purifying. The estrogen amino-acid ester compound withantitumor activity, provided by the invention, has favorable water solubility and is superior to 2-methoxyestradiol in the tumor cell resistance action.

Compositions and methods for treating mammalian disease characterized by undesirable angiogenesis by administering derivatives of 2-methoxyestradiol of the general formula: wherein the variables are defined in the specification.

The invention relates to a 2-methoxyestradiol nanosuspension frozen powder and a preparation method thereof, which effectively solves the problems of poor solubility, short half-life period, low oral bioavailability, difficulty for common injection to achieve high drug loading and targeting effect existing in 2-methoxyestradiol. The 2-methoxyestradiol nanosuspension frozen powder prepared by the invention comprises the following components by weight ratio: 1 part of 2-methoxyestradiol, 1-50 parts of surface active agent and 3-30 parts of cryoprotector. The preparation of the 2-methoxyestradiol nanosuspension frozen powder can be realized by the following method: 1. preparing primary nanosuspension by using a precipitation method or a dispersion method; 2. preparing nanosuspension by using the method of reducing the particle diameter including a high pressure homogenizer method and an ultrasound comminution method; 3. preparing the frozen powder; and 4. re-dissolving the frozen powder by water for injection when in use. The frozen powder for intravenous injection prepared by the invention has fine stability and is favor of transporting and storing drugs.

The invention relates to hydrogel nanoparticles used as an injectable subcutaneous implant agent, which can effectively solves the problem of fulfilling an aim of realizing tumor treatment by locally injecting the hydrogel nanoparticles beside a subcutaneous tumor, changing the hydrogel nanoparticles into a gel and slowly releasing nanoparticles in vivo. The hydrogel nanoparticles are prepared from hydrogel solution and 2-methoxyl estradiol liposome nanoparticle powder or solid liposome nanoparticle powder by a method which comprises the following steps of: adding the 2-methoxyl estradiol liposome nanoparticle powder or the solid liposome nanoparticle powder into the hydrogel solution; and uniformly mixing to form the hydrogel nanoparticles which can be used as an injectable subcutaneous implant agent, wherein 100mg of the 2-methoxyl estradiol liposome nanoparticle powder is added into every 1ml of the hydrogel solution. The injectable hydrogel implant agent of the invention can be used for treating subcutaneous tumors such as breast cancer and the like, keep an effective medicament concentration in a local target site, can realize sustained release and controlled release, can avoid medicament resistance caused by long-term medication, simultaneously improve a curative effect and reduce dosage, reduce toxic and side effects on a whole body, and also can prevent lymphatic metastasis of the tumors such as the breast cancer and the like.

The invention relates to a 2-methoxy-estradiol analogue and a preparation method and application thereof, aiming to solve the problem of preparation of the 2-methoxy-estradiol analogue and realize the application of the 2-methoxy-estradiol analogue to preparation of anti-tumor medicaments. The method comprises the following steps: dissolving 2-methoxy-3-benzyloxy-estradiol-1,3,5-(10)-triene-17beta-alcohol or 17beta-amine serving as a raw material into an organic solvent; in the presence of Lewis alkali, carrying out an acylation reaction on the raw materials and a compound (1) to obtain a 2-methoxy-3-benzyloxy-estradiol-1,3,5-(10)-triene-17beta-ester or 17beta-amide compound (2); carrying out a catalytic hydrogenation to obtain a compound (3); carrying out an acylation reaction or a hydrocarbylation reaction to obtain a compound, namely, the 2-methoxy-estradiol analogue (4), wherein a reaction formula is shown in the specifications. The preparation method of the 2-methoxy-estradiol analogue has the advantages of easiness, mild conditions and high yield, and can be effectively applied to development of anti-tumor medicaments.

The invention relates to a 2-methoxy estradiol injectable hydrogel implant which can effectively solve the problems of maintaining the effective concentration of the target part of 2-methoxy estradiol and enhancing the treatment effect. The invention has the technical scheme that a temperature sensitive type PLGA-PEG-PLGA segmented copolymer having temperature sensitive hydrogel properties is adopted to be mixed with water to prepare dissolution swelling solution; the solution is mixed with the 2-methoxy estradiol to prepare an injection; the temperature sensitive type PLGA-PEG-PLGA segmented copolymer is uniformly mixed with the water to be kept stewing at 0 to 25 DEG C; the temperature sensitive type PLGA-PEG-PLGA segmented copolymer is fully dissolved and swelled into the solution; and the 2-methoxy estradiol is added to be uniformly mixed with solution at 0 to 25 DEG C on the use day or one day before use. The invention has scientific formula, easy production, low cost and good injection effect, can effectively maintain the effective concentration of the target part of the 2-methoxy estradiol and enhance the treatment effect is enhanced and is the innovation on the path of cancer treatment drug forms and drug administration.

The invention relates to a 2-methoxyestradiol nano-emulsion for intravenous injection. The nano-emulsion contains 0.05-0.5 w / v% of 2-methoxyestradiol, 5-50 w / v% of oil for injection, 0.05-0.5 w / v% of emulsifier, 2-6 w / v% of isoosmotic adjusting agent, pH regulators and water for injection in balance, wherein 2-methoxyestradiol and emulsifier are dissolved with organic solvents and then evaporated under reduced pressure to remove organic solvents completely, so as to obtain a crystalline or solid dispersion of emulsifier; the oil for injection is filtered and then added in the dispersion or water phase is filtered and then added in the dispersion, followed by stirring, to obtain a primary emulsion; the primary emulsion is subjected to a high-pressure homogenizer, the pH regulator is added to regulate the pH value and the water for water is added; and the resulting mixture is further filtered, sealed, sterilized and cooled down to room temperature. The nano-emulsion is suitable for intravenous injection and has properties of sustained release and target drug delivery in vivo. The nano-emulsion has no problems of oral preparations and has high safety and reliability. The invention is an innovation in the medicine field and has significant social and economic benefits.

The invention relates to 2-methoxyl estradiol lipidosome freeze-dried powder injection and a preparation method thereof. The invention can effectively solve the problems of poor water solubility of 2-methoxyl estradiol, short half-life and low oral administration bioavailability, and adopts the technical proposal that the 2-methoxyl estradiol lipidosome freeze-dried powder injection comprises the following raw materials in weight portion: 1 portion of the 2-methoxyl estradiol, 3 to 100 portions of phospholipid, 1 to 30 portions of cholesterol, surfactant and freeze-dried preservative, wherein according to the weight ratio of the phospholipid, 0.1 to 10 portions of the freeze-dried preservative is added into 1 portion of the phospholipid, and the adding quantity of the surfactant is 0.2 to 3 percent of the total amount of the freeze-dried powder injection. The freeze-dried powder injection using the components as raw materials can be realized by three preparation methods, namely, a film dispersion method, a reverse phase evaporation method and an injection method, has high medicament content, is suitable for intravenous administration, has the advantages of slow release capability, in vivo targeting property and the like, can overcome the defects of oral preparations, is safe and reliable, and has large economic benefit and social benefit.

The invention relates to a preparation method of 2-methoxyestradiol nano-emulsion for intravenous injection, which radically eliminates residues of physiologically sensitive organic solvents in nano-emulsion final products and utilizes a high-pressure homogenizer to ensure the production of high-content 2-methoxyestradiol preparations. The technical proposal is that: firstly, a 2-methoxyestradiol micro-dispersion is prepared; emulsifiers, oil for injection and isoosmotic adjusting agent are added in the micro-dispersion and then stirred to form a primary emulsion; the primary emulsion is treated with the high-pressure homogenizer to form a nano-emulsion; and the nano-emulsion is further treated with pH regulators, filtered, sealed, sterilized and cooled down to room temperature. The invention can completely eliminate organic solvent residues in final products. The preparation method has good operation continuity, is suitable for industrialized production, ensures high drug content in final products, prevents blockage of the high-pressure homogenizer, and is easy to operate.

The invention relates to a sustained-release microsphere injection containing an antitumor drug (2-methoxyestradiol), and the sustained-release microsphere injection can be used for effectively solving the problems that a conventional drug delivery system for 2-methoxyestradiol is not ideal in tumor treatment effect and has side effects. The technical scheme adopted for solving the problems is as follows: the sustained-release microsphere injection consists of the following parts by weight percent: 5-50% of sustained-release microspheres and 50-95% of solvent system, or independent sustained-release microsphere. The sustained-release microsphere injection can be used for realizing the purpose that the effect of drug can be sustained for a long time by one-time drug delivery, and overcoming the defects and shortcomings of a conventional 2-methoxyestradiol delivery system; and according to the sustained-release microsphere injection, the effective blood concentration can be maintained in the body for a long time, the dosage amount is only 1 / 30 that of the conventional drug delivery, the tumor inhibiting efficiency is 62% and is higher than that of the intravenous injection drug delivery by about 45%. The sustained-release microsphere injection can be used for reducing the dosage of the drug (toxic and side effects) and has the obvious advantages of improving the drug therapeutic effect.

Compositions and methods for treating mammalian disease characterized by undesirable angiogenesis by administering derivatives of 2-methoxyestradiol of the general formula:wherein the variables are defined in the specification.

Methods are provided for the treatment of pulmonary hypertension and other conditions associated therewith. In particular, the methods include treatment of pulmonary hypertension with estradiol metabolite or estradiol metabolite associated with biodegradable microparticles or nanoparticles alone or in combination with another therapeutic agent. Preferred estradiol metabolites include 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol, and 4-hydroxyestradiol, and / or to synthetic derivatives and analogues thereof or prodrugs thereof. The compositions may also be in the form of a controlled release formulation.

The invention relates to a preparation method and an application of a 2-methoxyestradiol albumin nano freeze-dried agent, and effectively solves the problems in preparation of the 2-methoxyestradiol albumin nano freeze-dried agent and application of the freeze-dried agent to preparation of medicines for treating tumors. The method comprises the following steps: dissolving 2-methoxyestradiol albumin in an organic solvent-absolute ethanol to prepare a solution A; dissolving bovine serum albumin in ultra-pure water to prepare a solution B, adding a surfactant, and adjusting the pH value to be 8-10 by an NaOH solution; adding the solution A into the solution B to prepare a mixed solution C; adding glutaraldehyde into the mixed solution C, stirring evenly, standing and solidifying; performing rotary evaporation to remove the organic solvent to prepare a nano solution D; adding a freeze-drying protective agent into the nano solution D, and performing freeze-drying to prepare the 2-methoxyestradiol albumin nano freeze-dried agent. The 2-methoxyestradiol albumin nano freeze-dried agent is simple in method, easy to produce and prepare, good in stability, long in medicine effect, high in targeting property, rapid in acting, small in negative effect, low in administration frequency, high in bioavailability and simple to prepare; the medicines can be protected from being affected by an environment.

The present invention relates generally to methods and compositions for treating diseases characterized by abnormal cell proliferation and / or abnormal or undesirable angiogenesis by administering antiangiogenic agents in combination with anti-cancer agents. More specifically, the present invention relates to methods and compositions for treating diseases characterized by abnormal cell proliferation and / or abnormal or undesirable angiogenesis by administering 2-methoxyestradiol analogs, in combination with anti-cancer agents.

The invention relates to hydrogel nanoparticles used as an injectable subcutaneous implant agent, which can effectively solves the problem of fulfilling an aim of realizing tumor treatment by locally injecting the hydrogel nanoparticles beside a subcutaneous tumor, changing the hydrogel nanoparticles into a gel and slowly releasing nanoparticles in vivo. The hydrogel nanoparticles are prepared from hydrogel solution and 2-methoxyl estradiol liposome nanoparticle powder or solid liposome nanoparticle powder by a method which comprises the following steps of: adding the 2-methoxyl estradiol liposome nanoparticle powder or the solid liposome nanoparticle powder into the hydrogel solution; and uniformly mixing to form the hydrogel nanoparticles which can be used as an injectable subcutaneous implant agent, wherein 100mg of the 2-methoxyl estradiol liposome nanoparticle powder is added into every 1ml of the hydrogel solution. The injectable hydrogel implant agent of the invention can be used for treating subcutaneous tumors such as breast cancer and the like, keep an effective medicament concentration in a local target site, can realize sustained release and controlled release, can avoid medicament resistance caused by long-term medication, simultaneously improve a curative effect and reduce dosage, reduce toxic and side effects on a whole body, and also can prevent lymphatic metastasis of the tumors such as the breast cancer and the like.

The invention relates to 2-methoxyestradiol injection, an anti-tumor drug containing cyclodextrin or cyclodextrin derivatives, and solves the problem that 2-methoxyestradiol is hard to be dissolved in water. The technical scheme to be solved is as follows: the anti-tumor drug, that is, the 2-methoxyestradiol injection containing cyclodextrin or cyclodextrin derivatives, is prepared from 2-methoxyestradiol and cyclodextrin or cyclodextrin derivatives with the mole ratio being 1:(2-10); and the mass concentration of 2-methoxyestradiol in the final water solution of the 2-methoxyestradiol injection is 0.1mg / ml to 25mg / ml. The invention is prepared by mixing 2-methoxyestradiol and cyclodextrin or cyclodextrin derivatives having good water solubility and biocompatibility, thereby effectively solving the problem that 2-methoxyestradiol is hard to be dissolved in water, avoiding the allergic reaction, greatly reducing the hemolytic activity and ensuring good cell inhibitory activity and high stability. The invention is an innovation in the field of medicine.

Compounds and methods for modulating mesenchymal cell function, for instance smooth muscle and fibroblast proliferation or cytokine expression, and for treating conditions associated with mesenchymal cell function, for instance airway hyperresponsiveness associated with asthma. The compounds also supress inflammation. The compounds are a class of estratriene derivates, and includes various derivatives of 2-methoxyestradiol comprising a group A, including a substituted aromatic substituent in the 2-, 6- or 17- position.

Compounds and methods for modulating mesenchymal cell function, for instance smooth muscle and fibroblast proliferation or cytokine expression, and for treating conditions associated with mesenchymal cell function, for instance airway hyperresponsiveness associated with asthma. The compounds also suppress inflammation. The compounds are a class of estratriene derivates, and includes various derivatives of 2-methoxyestradiol comprising a group A, including a substituted aromatic substituent in the 2-, 6- or 17-position.

Methods are provided for the treatment of pulmonary hypertension and other conditions associated therewith. In particular, the methods include treatment of pulmonary hypertension with estradiol metabolite or estradiol metabolite associated with biodegradable microparticles or nanoparticles alone or in combination with another therapeutic agent. Preferred estradiol metabolites include 2-methoxyestradiol, 4-methoxyestradiol, 2-hydroxyestradiol, and 4-hydroxyestradiol, and / or to synthetic derivatives and analogues thereof or prodrugs thereof. The compositions may also be in the form of a controlled release formulation.

The invention relates to a self-emulsified 2-methoxyestradiol intravenous injection and a preparation method thereof, and belongs to the field of medicinal preparation. The self-emulsified 2-methoxyestradiol intravenous injection comprises, by weight, 0.1-10% of 2-methoxyestradiol, 4.9-30% of oil for injection, 10-80% of emulsifier and 0-85% of co-emulsifier. The prepared self-emulsified 2-methoxyestradiol intravenous injection is high in drug-loading rate and good in stability and has a certain targeting ability, the efficacy is increased, the toxic and side effects are reduced, and safety is good; and the preparation technology is simple, the cost is low, and good industrialization and commercialization prospects are achieved.