Amorphous alendronate monosodium, methods of production, based pharmaceutical composition and method of inhibition of bone resobrtion |
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IPC classes for russian patent Amorphous alendronate monosodium, methods of production, based pharmaceutical composition and method of inhibition of bone resobrtion (RU 2334751):
 Acidic phosphorous containing complex forming reagent and method of obtaining it (versions) / 2331651
The invention pertains to an acidic phosphorous containing reagent, is used in the oil industry, heat energy, textile industry, production of mineral fertilizers and household chemistry, and to methods of obtaining the reagent. The reagent (conventional name "АФК-1") contains the following in given mass %: acetoxyethylidenediphosphonic acid 50.0-95.0 mass %, acetic acid - 29.5-0.5 mass %, the rest is acetic anhydride to 100. The quantitative composition of the indicated reagent is determined by the method of obtaining it and the ratios of the initial reagents. The method of obtaining the reagent involves adding acetic anhydride to a suspension of acetic and phosphorous acid at temperature of 60-90°C for a period of 1.5 hours. The reaction mixture is kept at 100-110°C for 1 hour and acidic impurities are distilled off to a controlled volume of distillate. Similar methods are developed based on phosphorous containing wastes from production of acid chlorides of higher fatty acids. The wastes are treated with water or a water solution of acetic acid with subsequent separation of the organic layer of fatty acids, after which the residue, containing phosphorous acid, is treated with phosphorous tri-chloride and acetic anhydride at 115-130°C, and acidic impurities are distilled off to the controlled distillate volume.
 Acidic phosphorous containing complex-forming reagent and method of obtaining it / 2331650
Invention pertains to the chemistry of phosphorous organic compounds, and specifically to an acidic phosphorous containing complex-forming reagent, which can be used in the oil industry, heat energy, textile industry, production of mineral fertilizers and household chemistry, and to the method of obtaining it. The acidic phosphorous containing complex-forming reagent (conventional name "АФК-2") contains the following in mass %: acetoxyethylidenediphosphonic acid - 50-95 mass %, acetic acid - 50-5 mass %. The method of obtaining the composition involves adding phosphorous tri-chloride, acetic acid and water simultaneously to glacial acetic acid in molar ratios equal to 1:(4.5-5.5):(1.93-1.95), at temperature of 35-45°C with subsequent keeping of the reaction mixture at 110-120°C for a period of 2 hours and controlled distillation of acidic impurities to the required distillate volume.
Method of obtaining inhibitor of precipitation of mineral salts / 2329270
Invention pertains to the method of obtaining an inhibitor of precipitation of mineral salts, The inhibitor is obtained by reaction of hexamethylenediamine and ammonium chloride with formaldehyde and phosphorous acid in a medium of diluted hydrochloric acid at high temperature with subsequent neutralisation of the obtained solution using sodium hydroxide to pH of 6.5±1.0. The process is carried out with molar ratio of hexamethylenediamine to ammonium chloride of 1:3-6.
 Plasma carboxypeptidase b inhibitors / 2323223
Invention describes compound of the formula (I):
 Method for preparing monohydroperfluoroalkanes, bis-(perfluoroalkyl)phosphinates and perfluoroalkylphosphonates / 2319705
Invention describes a method for synthesis of monohydroperfluoroalkanes, bis-(perfluoroalkyl)phosphinates and perfluoroalkylphosphonates. Method involves treatment of at least one perfluoroalkylphosphorane with at least one base wherein base(s) are chosen from group consisting of alkali-earth metal hydroxides, metalloorganic compound in useful solvent or at least one organic base and an acid in useful reaction medium. Also, invention describes novel perfluoroalkylphosphonates and bis-(perfluoroalkyl)phosphinates, using novel perfluoroalkylphosphonates and bis-(perfluoroalyl)phosphinates as ionic liquids, catalysts of phase transfer or surfactants.
 Method for preparing copper (ii), zinc (ii), nickel (ii) and cobalt (ii) nitrilotri-(methylenephosphonates)(2-) / 2314313
Invention relates to a method for preparing copper (II), zinc (II), nickel (II) and cobalt (II) nitrilotri-(methylenephosphonates)(2-) that involves crystallization from aqueous solutions prepared by interaction of metal (II) compound with nitrilotri-(methylenephosphonic) acid or its salt with sodium potassium or ammonium in aqueous medium at temperature from -5°C to 105°C under atmosphere pressure. As a reactive of the metal (II) compound source the waste from manufacturing printing plates and galvanic covers can be used. The end products can be used in preparing the complex electrolytes and solutions for applying metallic covers by electrochemical and chemical methods in aims for inhibition against the equipment corrosion, and for preparing other compounds of metals with nitrilotri-(methylenephosphonic) acid.
 Phosphonic acid compounds as serine proteinase inhibitors / 2311421
Invention relates to phosphonic acid compounds used as inhibitors of serine proteinase of the general formula (I):
 Method for preparing n-phosphonomethylglycine / 2311420
Invention relates to a novel method for synthesis of N-phosphonomethylglycine. Method involves interaction of hexahydrotriazine compound with triacyl phosphite in organic solvent, saponification of formed phosphonic compound after preliminary extraction into aqueous phase, separation of organic phase and precipitation of N-phosphonomethylglycine by pH value control in the range from 0.5 to 2.0. Invention prevents decomposition of an organic solvent in saponification.
Method of production of the water solution of disodium or dipotassium salt of zinc oxyethylidene phosphonate with concentration of fifteen - twenty three percent / 2305102
The invention is pertaining to the method of production of the water solutions of disodium or dipotassium salt of zinc oxyethyledene phosohonate with concentration of 15-23 % used as the mineral salts sediments inhibitors and as the microfertilizers and having the properties to inhibit corrosion. The method provides for interaction of the water solution of the sodium zincate or the potassium zincate with the 20-60 % water solution of the oxyethyledenephosphonic acid at the temperature of 60-80°С. As a rule, the sodium zincate or the potassium zincate are produced by interaction of 5-20 % water solution of the sodium hydroxide or the potassium hydroxide with zinc oxide at the temperature of 50-75°С at the molar relation of 2:1.
 Heterogeneous composition for treatment of process and waste waters polluted with suspended particles dispersed by lubrication oils and/or petroleum products and a method for preparation thereof / 2301200
Composition contains 10-25% sodium alkylaminophosphonates having general formula:
 New tetracyclic compounds containing heteroatom, used as selective modulators of oestrogen receptors / 2331645
Invention pertains to new tetracyclic compounds containing a heteroatom. The compounds can be used in treating and/or prevention of disorders, associated with oestrogen depletion, such as hot flash, vaginal dryness, osteopenia and osteoporosis; sensitive cancerous diseases hormone and hyperplasia of the lacteal gland, endometrium, cervix uteri and prostate; endometriosis, uterus fibrosis and osteoarthritis, and as contraceptive agents, used either separately or combined with progestogen or a progestogen antagonist.
 Pharmaceutical compositions and methods, that include combinations of 2-alkyldien-19-nor-vitamin d derivatives and estrogens agonist/antagonist / 2331425
Invention relates to pharmaceutical composition for senile osteoporosis, post-menopausal osteoporosis, bone fractures, bone transplant, and osteopenia or male osteoporosis treatment, that include effective therapeutic quantity, in amount 0.01 mcg/kg/day to 10 mcg/kg/day of compound 2-methylene-19-nor-20(S)-1α,25-dihydroxyvitamin D3, and effective therapeutic quantity, in amount 0.01 mcg/kg/day to 200 mcg/kg/day of selective estrogen receptor modulator, which bounds to estrogen receptor; the selective estrogen receptor modulator mentioned being chosen from the group comprising estrogen agonist, estrogen antagonist, or its pharmaceutically acceptable salt.
 Applications of bisphosphonic acids for osteoporosis treatment and prevention / 2329809
Application of ibandronic acid or its acceptable salts for production of medical products for treatment of diseases characterised by pathologically bone hyperresorption, especially for osteoporosis prevention and treatment is offered. At that medical product contains 50-250 mg of specified acid or its salt, and it introduced orally within one day per month. Invention provides both decreased bones fragility, and eliminates by-effects of ibandronic acid.
 Pharmaceutical formulations and methods including combinations of 2-alkyliden derivatives of 9-nor-vitamin d and bisphosphonate / 2326695
Invention refers to pharmaceutical formulation and therapeutic method including introduction to related patient of composition 2-alkyliden derivative of 19-nor-vitamin D and bisphosphonate. In particular, this invention refers to pharmaceutical formulation and therapeutic methods including introduction to related patient of 2-methylene-19-nor-20(S)-1α,25- dihydroxyvitamin D3 and bisphosphonate selected from tyludronate, alendronate, zoledronate, ibanedronate, risedronate, ethydronate, clodronate or pamydronate. Stated invention allows increasing of therapeutic efficiency of such diseases as senile osteoporosis, postclimacteric osteoporosis, bone fracture, bone graft, osteopeny and male osteoporosis.
 Pharmaceutical formulation of atorvastatin / 2325903
Invention refers to medicine and pharmaceutics. Dry granulated pharmaceutical formulation containing atorvastatin or its pharmaceutically acceptable salt, in combination with at least one other active medicinal agent, method of specified formulations production, sets including such formulations, and treatment of hypercholesterolemia and/or hyperlipidemia, osteoporosis, benign prostate hyperplasia (BPG) and Alzheimer's disease by using pharmaceutical formulation in amount providing therapeutic effectiveness. Offered pharmaceutical formulation of atorvastatin is characterised with good solubility, bioavailability, dosage homogeneity, and method of atorvastatin production with low content of impurities and adequate stability.
 Pharmaceutical formulation applied for prevention and treatment of bone tissue resorption of any etiology, transdermal delivery and treatment technique / 2325165
Given invention refers to pharmaceutical field, specifically to pharmaceutical formulation of gel dosage form applied for prevention and treatment of osteoporosis including as an active component bisphosphonate incorporated in phospholipid vesicles generated from lipid and hydrophilic phases, including components in the following proportions, mass %: bisphosphonate 0.01-2.0; egg lecithin 1.0-6.0; pine essence 0.05-0.2; camphor oil 0.01-1.0; olive oil 0.01-5.0; vitamin E 0.01-0.15; vitamin D 0.01-0.2; vitamin F 0.2-0.4; carbopole 0.4-0.6; NaOH 0.42; glycerol 2.0-4.0; nipagine 0.3; nypazole 0.1; water and others. In addition invention refers to treatment of bone tissue resorption of any etiology and osteoporosis for patients suffering from gastrointestinal disturbance with this composition.
 5-cnac as agent for oral delivery of parathyroid hormone fragments / 2322256
Invention relates to a pharmaceutical composition used in treatment and prophylaxis of osteoporosis and for effective administration of parathyroid hormone fragments (PTH) (1-28) - (1-14). Also, invention relates to a method for oral administration of indicated composition and to a method for stimulation of osseous tissue formation in osteoporosis, to a method for treatment or prophylaxis of osteoporosis, and to using 5-CNAC for preparing pharmaceutical composition containing fragments PTH (1-28) - (1-14) used for treatment or prophylaxis of osteoporosis. The claimed invention provides achievement of higher blood concentrations of PTH fragments (1-28) - (1-14) and to retain these concentrations for a longer time. Using 5-CNAC as a component of the composition allows carrying out oral administration of PTH fragments.
 Method for treating and preventing the loss of bony tissue / 2319483
The present innovation deals with treating and preventing the loss of bony tissue and/or increased development of bony tissue. For this purpose it is necessary to apply 15-lipoxygenase inhibitors. These molecules could be introduced either individually or in combination with agents that inhibit the resorption of bony tissue or additional agents that regulate calcium resorption out of bony tissue or increase the accumulation of bony tissue. The innovation enables to widen the assortment of medicinal preparations for treating diseases associated with the loss of bony tissue, such as osteoporosis, osteoarthritis, Paget's disease and those of periodontium and, also, the fractures.
Composition with high dose of ibandronat / 2315603
Invention describes a pharmaceutical composition for oral using as a tablet designated for treatment of bone diseases and some disturbances of calcium metabolism. A table core comprises bisphosphonates or their physiologically safe salts as an active substance. Preferably, the active substance is ibandronic acid. Preferably, a table core comprises 100 mg or 150 mg of bisphosphonates or equivalent amount of their physiologically safe salts. Also, invention describes a method for preparing the composition by addition of a raising agent at granulation step simultaneously with bisphophonate and part of raising agent. Invention provides enhanced stability of tablets in their storage by such parameters as temperature and humidity.
 Casr antagonist / 2315036
Invention relates to a novel compound represented by the following formula (1)
Pharmaceutical formulation applied for prevention and treatment of bone tissue resorption of any etiology, transdermal delivery and treatment technique / 2325165
Given invention refers to pharmaceutical field, specifically to pharmaceutical formulation of gel dosage form applied for prevention and treatment of osteoporosis including as an active component bisphosphonate incorporated in phospholipid vesicles generated from lipid and hydrophilic phases, including components in the following proportions, mass %: bisphosphonate 0.01-2.0; egg lecithin 1.0-6.0; pine essence 0.05-0.2; camphor oil 0.01-1.0; olive oil 0.01-5.0; vitamin E 0.01-0.15; vitamin D 0.01-0.2; vitamin F 0.2-0.4; carbopole 0.4-0.6; NaOH 0.42; glycerol 2.0-4.0; nipagine 0.3; nypazole 0.1; water and others. In addition invention refers to treatment of bone tissue resorption of any etiology and osteoporosis for patients suffering from gastrointestinal disturbance with this composition.
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FIELD: chemistry. SUBSTANCE: invention refers to method of production of amorphous alendronate monosodium and to solid pharmaceutical composition having property to invoke bone bulk expansion and containing therapeutically effective amount of amorphous alendronate monosodium, produced by stated method. Method of production of amorphous alendronate monosodium includes solvent removal from alendronate monosodium solution using spray drying. EFFECT: development of production method of amorphous alendronate monosodium. 4 cl, 1 dwg, 3 ex
This invention relates to acceptable in pharmacology salts 4-amino-1-hydroxybutylidene-biphosphonates acid (salts-alendronate) in amorphous form and the way they are received. Alendronate sodium is an inhibitor of bone resorption, suitable for the treatment of diseases such as deforming osteodystrophy and osteoporosis. The methods used above to get alendronate sodium, result in a crystalline product. In EP 402152 describes how to obtain the three-hydrate of alendronate of monolatry, which is crystalline. In EP 462663 describes an improved method of producing alendronato in crystalline form, and this method is not used very acidic hydrolytic environment. Pharmaceutical composition containing anhydrous crystalline form of alendronate sodium, is described in WO 96/39149. To simplify the process of making the pharmaceutical compositions preferably salt-alendronate, for example, alendronate sodium, has a high solubility. High solubility is also desirable from the point of view of the pharmacological properties of this connection. This invention is based on the discovery of the fact that acceptable in pharmacology salt-alendronate in amorphous form hygroscopic and show significantly better characteristics solubility. the tion, for example, a crystalline trihydrate of alendronate sodium. In particular, alendronate in amorphous form as proposed in the present invention, dissolved in water much faster than crystalline substance. Thus, this invention provides acceptable in pharmacology Sol-alendronate in amorphous form. In particular, this invention relates to a monatomic acceptable in pharmacology salt of alendronate in amorphous form. More precisely, this invention provides alendronate of monolatry in amorphous form. The term "amorphous" means a physical condition that is not crystalline and can be confirmed using x-ray diffraction and other means, including, but without limitation, observation through a polarizing microscope and differential scanning calorimetry. More specifically, the amorphous Sol-alendronate in accordance with this invention preferably should be free from salts-alendronato in crystalline form. The present invention offers acceptable in pharmacology Sol-alendronate in amorphous form, preferably containing less than 3%, and more preferably less than 1% water. In particular, this invention relates to a monatomic acceptable in pharmacology salt of alendronate in amorphous form, predpochtite the flax, containing less than 3%, and more preferably less than 1% water. More specifically, the present invention offers the alendronate of monolatry in amorphous form, preferably containing less than 3%, and more preferably less than 1% water. The present invention also offers an amorphous alendronate of moonacre with the diffraction pattern of x-rays, shown in the accompanying drawing. The invention also includes a pharmaceutical composition comprising a therapeutically effective amount acceptable in pharmacology salt of alendronate in amorphous form (in the particular case of the alendronate of monolatry in amorphous form) together with acceptable for pharmaceutical carrier, diluent or inert filler. The present invention also proposes a method of inhibition of bone resorption in a patient, and this method includes the introduction of a patient suffering from bone resorption or susceptible thereto, a therapeutically effective amount acceptable in pharmacology salt of alendronate in amorphous form, in particular, of alendronate monolatry in amorphous form or pharmaceutical composition containing substances mentioned here. The term "inhibition of bone resorption" refers here to the treatment and prevention of bone rarefaction, in particular, to delay the removal of living bone, for example, using a direct or naramig the changes polykaryocytes formation or activity. Thus, acceptable in pharmacology Sol-alendronate in amorphous form as proposed in the present invention, may, for example, to prevent the bone loss via direct or indirect changes polykaryocytes formation or activity and may increase bone mass in groups treated patients. Such methods of treatment in accordance with this invention is suitable for treatment of fractures, damage or changes in the bones, which may arise from pathological conditions in osteoporosis, osteoarthritis, deforming osteodystrophies, osteomalacia, bone loss occurring from multiple myeloma and other forms of cancer, bone loss occurring side effect-terminated other conservative treatment (such as steroids), the bone loss associated with rheumatoid phenomena and the process of aging, etc. Methods proposed in this invention may in particular be useful for the treatment of women during menopause. The terms "treatment" or "braking", as used here regarding the methods proposed in this invention, the means providing the patient with some acceptable pharmacology salt of alendronate in amorphous form, sufficient to preventive effect on the above painful condition associated with p is sorbcia bones of the patient, and/or providing the patient with some acceptable pharmacology salt of alendronate in amorphous form, sufficient to alleviate or eliminate the painful conditions associated with bone resorption in a patient. On the other hand, the present invention proposes a method of obtaining acceptable in pharmacology salt of alendronate in amorphous form (in particular, the alendronate of monolatry in amorphous form, and this method comprises removing solvent from a solution of salt of alendronate order to obtain an amorphous product, proposed in this invention. In the method according to this invention the solvent is removed from a solution of salt of alendronate to form amorphous alendronate proposed in this invention. The preferred solvent is water, as acceptable in pharmacology salt-alendronate in amorphous form is poorly soluble in other well-known solvents. In principle, however, it is possible to use any solvent. The solution of salt of alendronate should not contain crystalline Sol-alendronate. The solution, however, may contain little (non-crystalline) weighted salt of alendronate, forming an opaque solution, though it is not recommended. The solution of salt of alendronate can be prepared in any suitable way. For example, it is possible to prepare peterstone of alendronate sodium, taken in the form of three-hydrate or anhydrous product, in any solvent. The mixture can be heated to promote dissolution: in the event of an aqueous solution, we have found that it is advantageous to heat up to 50-60°C. Otherwise Sol-alendronate may be formed directly in the solvent. One example of this is adding in a suspension alendronova acid in water solution of sodium hydroxide for the formation of alendronate sodium in aqueous solution. More precisely, one volume alendronova acid is weighed into 30 volumes of water and then the pH is brought to 4.3 and 4.4 using caustic soda. The salt solution is alendronate used in the method proposed in this invention will preferably have a volume ratio of salt of alendronate to solvent of 1:10-1:30 or more depending on the rate of solubility in this solvent. For aqueous solutions, preferably a ratio of 1:10. In General, decreasing the amount of solvent decreases the need in its removal for the formation of an amorphous product, for this reason it is preferable to use a smaller amount of solvent. Removal of the solvent can be performed in any suitable way, corresponding to the applied solvent, from simple to more intensive evaporation processes. In most normal cases, use of water rest the ditch we prefer to spray-drying. When spray drying of aqueous solutions, the inlet temperature is preferably from 120°, 250°, the output is preferably from 70°to 120°and a feed rate of from 5 to 25 ml/min But you can use other values of temperature and velocity. The product can be characterized using powder x-ray crystallography. Amorphous alendronate sodium characterized by the absence of a well defined pattern. A typical diffraction pattern is shown in the accompanying figure. When observed through a microscope amorphous product according to this invention has the form of spherical grains, whereas in contrast, crystalline substance has the form of a rhombic structure. The moisture content in amorphous alendronate sodium as proposed in the present invention is not more than 3 mass%, more preferably less than 1%. With the high moisture content of the amorphous product is stable. The method proposed in this invention is illustrated by the following examples. Obtaining amorphous alendronate sodium Example 1 25 g of the three-hydrate alendronate sodium were heated in 250 ml of water at 60°to get a clear solution. This solution was subjected to spray drying in a laboratory setup for spray drying SD05 at a temperature input 200°S, t is mperature output 100° With the speed of the compressed air 0.3 m3/h at a feed rate of 15 ml/min, to obtain 20 g of the product. The amorphous product was characterized using powder x-ray diffraction. Moisture content: less than 1%. Example 2 25 g of crystalline anhydrous alendronate sodium were heated in 500 ml of water to 50°to get an almost clear solution. This solution was subjected to spray drying in a laboratory setup for spray drying SD05 at a temperature input 160°C, the outlet temperature is 80°C, the speed of the compressed air 0.3 m3/h at a feed rate of 8 ml/min, to obtain 18 g of the product. The amorphous product was characterized using powder x-ray diffraction. Example 3 To a suspension of 25 g alendronova acid in 750 g of water was added 20%sodium hydroxide solution and adjusted the pH to 4.3 and 4.4, in order to obtain a clear solution. This solution was subjected to spray drying in a laboratory setup for spray drying SD05 at a temperature input 180°C, the outlet temperature is 90°C, the speed of the compressed air 0.3 m3/h at a feed rate of 10 ml/min, to obtain 20 g of the product. The amorphous product was characterized using powder x-ray diffraction. In accordance with another aspect of the present invention amorphous alendronate sodium can enter in the composition of the pharmaceutical compositions for example, tablets (coated or uncoated) or capsules for oral administration. Appropriate carriers are, for example, sugar, starch and its derivatives, cellulose and its derivatives, resins and polyalcohol. The composition may also contain additional ingredients, such as lubricants, excipients for pressing, flavors, sweeteners and preservatives. 1. The way to get alendronate of monolatry in amorphous form, comprising removing solvent from a solution of alendronate of moonacre using spray drying. 2. The method according to claim 1, wherein the solvent contains water. 3. The method according to claim 2, in which the said solution of alendronate monolatry is produced by adding to the suspension alendronova acid in water aqueous solution of sodium hydroxide to obtain a pH of 4.3 and 4.4. 4. Pharmaceutical composition in solid form, having the property of increasing bone mass, containing a therapeutically effective amount of alendronate of monolatry in amorphous form obtained by the method according to any one of claims 1 to 3, and acceptable pharmaceutical carrier, diluent or excipient.
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