Method for introducing bisphosphonates

FIELD: medicine.

SUBSTANCE: method involves applying N-bisphosphonates like Zoledronic acid and its derivatives for prolonged inhibiting bone tissue resorption in states distinguished by increased bone tissue renewal like it occurs in osteoporosis cases by periodically administering the drug at a dose of 2 to 10 mg. Pauses between drug introductions have become longer when compared to periodicity considered to be required in earlier times, while being greater than 6 months.

EFFECT: enhanced effectiveness of treatment.

10 cl, 1 tbl

 

The present invention relates to bisphosphonates, in particular to the use of bisphosphonates as pharmaceuticals for the treatment of conditions characterized by abnormally increased renewal of bone tissue, such as osteoporosis.

Bisphosphonates are widely used for inhibiting the activity of osteoclasts, in the treatment of various benign and malignant diseases characterized by increased bone resorption. So, for example, recently, bisphosphonates have started to apply for long-term treatment of patients suffering from multiple myeloma (MM). Such pyrophosphate analogues not only reduce the incidence of cases related to violation of skeletal function, but also improve the clinical condition of the patients and increase the survival rate. Bisphosphonates help to prevent bone resorption in vivo; therapeutic efficacy of bisphosphonates has been demonstrated in the treatment of Paget's disease induced tumor hypercalcemia, and recent bone metastases and multiple myeloma (MM) (see review .Fleisch, Bisphosphonates clinical, in: Bisphosphonates in Bone Disease. From the Laboratory to the Patient, the ed-ture: The Parthenon Publishing Group, New York/London, p.68-163, 1997). Mechanisms of inhibition of bone resorption by bisphosphonates is still insufficiently investigated and, apparently, they are argyrous depending on the specific question of bisphosphonates. It was found that bisphosphonates form a strong bond with hydroxyapatite crystals of bone tissue, reduce the update and bone resorption, reduce the levels of hydroxyproline or alkaline phosphatase in the blood and, in addition, inhibit both the activation and activity of osteoclasts.

In addition, the use of bisphosphonates to treat osteoporosis. For example, in patent US 4812304 (in the name of the firm Procter & Gamble) proposed a method of treating or preventing osteoporosis in humans, namely, that the patient affected or having a risk of electric osteoporosis, enter the connection, activating cells in the bone, and polyphosphonate, inhibiting bone resorption, according to the schedule, providing one or more cycles, each cycle includes: (a) the period of activation of bone tissue with a duration of from about 1 to about 5 days, during which the patient is given an activating cells in the bone number of connections, which has the ability to activate cells in the bone; then (b) the period of inhibition of bone resorption with a duration of from approximately 10 to approximately 20 days during which the patient is daily administered ethane-1-hydroxy-1,1-diphosphonic acid or its pharmaceutically acceptable with the eh or ether in an amount of from approximately 0.25 to approximately 3.3 mg P/kg/day; then (b) a rest period of from about 70 to about 180 days, during which the patient does not receive any compound that activates cells in the bone or polyphosphonate that inhibits bone resorption.

For example, in patent US 4761406 (in the name of the firm Procter & Gamble) proposed a method of treating or preventing osteoporosis in humans or lower animals affected or having a risk of electric osteoporosis, namely, that the specified person or lower animal is administered an effective amount polyphosphonate with the ability to inhibit bone resorption, according to the schedule, providing: (a) a period of from about 1 to about 90 days during which daily administered in a limited number polyphosphonate, which has the ability to inhibit bone resorption; followed by (b) a rest period of from approximately 50 to approximately 120 days; and (C) repeating steps (a) and (b) two or more times until, until it reaches the absolute increase in the mass of bone tissue in the human or animal.

With the invention it has been unexpectedly found that bisphosphonates, especially with the strong action of nitrogen-containing bisphosphonates, m is should be used for prolonged inhibition of bone resorption in the States with abnormally increased renewal of bone tissue by injecting, moreover, the periods of time between the introduction bisphosphonates are longer than the periods of time that were previously considered to be necessary to achieve satisfactory outcomes. In particular, unlike what you might expect, it was found that satisfactory treatment results can be obtained even if the intervals between dose significantly exceed the natural cycle of remodeling of bone tissue.

In accordance with the present invention, a method for treating conditions characterized by abnormally increased renewal of bone tissue in a patient in need of such treatment, involves periodic introduction to the patient an effective amount of bisphosphonates, and the period between the introduction of bisphosphonates is at least about 6 months.

In addition, the invention relates to the use of bisphosphonates for the preparation of medicines intended to treat conditions characterized by abnormally increased renewal of bone tissue, which provides for the periodic introduction of bisphosphonates and in which the period between the introduction of bisphosphonates is at least about 6 months.

Treatment conditions Hara is terisolasi abnormally increased renewal of bone tissue, which can be treated according to the present invention, include: treatment of postmenopausal osteoporosis, for example, in order to reduce the risk of osteoporotic fractures; prevention of postmenopausal osteoporosis, for example, prevention of postmenopausal bone loss; treatment or prevention of osteoporosis in men; treatment or prevention of corticosteroid-induced osteoporosis and other forms of bone loss resulting in side effects or a direct result of medical treatment, for example, substitution therapy with use of Deputy thyroid hormone, diphenylhydantoin; treatment or prevention of bone loss associated with being in a stationary state (immobilization) or with space flight; treatment or prevention of bone loss associated with rheumatoid arthritis, imperfect osteogenesis, hyperthyroidism, mental anorexia, organ transplantation, loose fit of the prosthesis joint and the treatment of other medical conditions. For example, the treatment of such other medical conditions might include the treatment or prevention of periarticular bone erosions in rheumatoid arthritis; treatment of osteoarthritis, for example, the prevention/treatment of subchondral the high osteosclerosis, subchondral cysts of bone tissue, formation of osteophytes and caused by osteoarthritis pain, for example, by reducing intraosseous pressure; treatment or prevention of hypercalcemia caused by increased bone resorption, which is a consequence of hyperthyroiditis, hyperthyroidism, sarcoidosis, or hypervitaminosis, caused by excessive amounts of vitamin D.

In the context of the present description, the term "treatment" or "treat" refer to both prophylactic or preventive treatment, and healing or modifying disease treatment, including treatment of patients with risk of disease or in respect of which there is the assumption that they are affected by the disease, and patients who suffer from the disease or diagnosed with a disease or medical condition. According to the most preferred options for implementation of the invention can be used for preventive treatment of osteoporosis and similar diseases. For example, bisphosphonates can regularly introduce individuals who have a risk of developing osteoporosis, with intervals between injections that make up at least 6 months, such as bisphosphonates can be entered in the usual way the women in the postmenopausal period with intervals between the injections the dose accounting for roughly 6 months, or less frequently, for example once a year.

According to the present invention, the interval between doses of bisphosphonates is at least about 6 months, for example, the introduction is carried out once every 180 days, or less frequently, usually once a year, or any intermediate interval, such as every 7, 8, 9, 10 or 11 months. You can use the intervals between injections in excess of one year, for example, to carry out the introduction once approximately every 18 months or approximately once every 2 years, or even less, for example, with a frequency of approximately once every 3 years or less.

Used according to the present invention bisphosphonates are usually compounds that inhibit bone resorption. These compounds and their pharmaceutically acceptable salts or any of its hydrates are characterized by the presence of two phosphonate groups attached to the same carbon atom, resulting in the structure R-s-R", for example, in the compound of the formula I:

where X denotes hydrogen, hydroxyl, amino, alkanoyl or amino group, mono - or disubstituted With1-C4by alkyl;

R denotes hydrogen or C1-C4alkyl and

Rx represents optionally substituted, hydrocarbon is inuu group.

For example, bisphosphonates, which can be used according to the invention, may include the following compounds or their pharmaceutically acceptable salts or any of its hydrates: 3-amino-1-hydroxypropane-1,1-diphosphonic acid (pamidronovu acid), for example, pamidronate (APD); 3-(N,N-dimethylamino)-1-hydroxypropane-1,1-diphosphonic acid, e.g. dimethyl-APD; 4-amino-1-hydroxybutane-1,1-diphosphonic acid (alendronate acid), for example, alendronate; 1-hydroxyethylaminophenol acid for example, etidronate; 1-hydroxy-3-(methylpentylamino)propylaminosulfonyl acid (ibandronate acid), for example, ibandronate; 6-amino-1-hydroxyhexane-1,1-diphosphonic acid, for example, aminohexyl-BP; 3-(N-methyl-N-n-pentylamine)-1-hydroxypropane-1,1-diphosphonic acid, for example, methylpentyl-APD (=VM 21.0955); 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid, for example, zoledronic acid; 1-hydroxy-2-(3-pyridyl)ethane-1,1-diphosphonic acid (risedronate acid), e.g. risedronate, including N-methylpyridinium salt, for example, iodide N-methylpyridine, such as NE-10244 or IU-10446; 1-(4-chlorophenylthio)methane-1,1-diphosphonic acid (tiludronic acid), for example, tiludronate; 3-[N-(2-phenylthiomethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonic acid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1,1-diphosphonic acid, e.g., EB 1053 (firms is Leo); 1-(N-phenylenecarbonyl)methane-1,1-diphosphonic acid, e.g. FR 78844 (firm Fujisawa); tetraethyl ester of 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid, e.g. U-81581 (firm decision Upjohn); 1-hydroxy-2-(imidazol[1,2-a]pyridine-3-yl)ethane-1,1-diphosphonic acid, for example, YM 529; and 1,1-dichloromethane-1,1-diphosphonic acid (clodronate acid), for example, clodronate; YM175.

Preferred bisphosphonates, which can be used according to the present invention are N-bisphosphonates, i.e. compounds that, in addition to which is the hallmark of bisphosphonates double slice (for example, "P-P-P") include carrying the nitrogen atom of the side chain, for example, the compound of formula I'

where X denotes hydrogen, hydroxyl, amino, alkanoyl or amino group, mono - or disubstituted With1-C4by alkyl;

R denotes hydrogen or C1-C4alkyl and

Rx' represents a side chain that contains optionally substituted by an amino group, or a nitrogen-containing heterocycle (including aromatic nitrogen-containing heterocycles),

and its pharmaceutically acceptable salt or any hydrate.

So, for example, N-bisphosphonates, which can be used according to the invention, may include the following compounds or their pharmaceutically acceptable salts or any of their Hydra is s: 3-amino-1-hydroxypropane-1,1-diphosphonic acid (pamidronovu acid), for example, pamidronate (APD); 3-(1N,N-dimethylamino)-1-hydroxypropane-1,1-diphosphonic acid, e.g. dimethyl-APD; 4-amino-1-hydroxybutane-1,1-diphosphonic acid (alendronate acid), for example, alendronate; 1-hydroxy-3-(methylpentylamino)propylaminosulfonyl acid (ibandronate acid), for example, ibandronate; 6-amino-1-hydroxyhexane-1,1-diphosphonic acid, for example, aminohexyl-BP; 3-(N-methyl-N-n-pentylamine)-1-hydroxypropane-1,1-diphosphonic acid, for example, methylpentyl-APD (=VM 21.0955); 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid, e.g., zoledronic acid; 1-hydroxy-2-(3-pyridyl)ethane-1,1-diphosphonic acid (risedronate acid), e.g. risedronate, including N-methylpyridinium salt, for example, iodide N-methylpyridine, such as NE-10244 or NE-10446; 3-[N-(2-phenylthiomethyl)-N-methylamino]-1-hydroxypropane-1,1-diphosphonic acid; 1-hydroxy-3-(pyrrolidin-1-yl)propane-1,1-diphosphonic acid, e.g., EB 1053 (firm Leo); 1-(N-phenylenecarbonyl)methane-1,1-diphosphonic acid, e.g. FR 78844 (firm Fujisawa); tetraethyl ester of 5-benzoyl-3,4-dihydro-2H-pyrazole-3,3-diphosphonic acid, for example, U-81581 (firm decision Upjohn); 1-hydroxy-2-(imidazol[1,2-a]pyridine-3-yl)ethane-1,1-diphosphonic acid, for example, YM 529.

In one of the embodiments most preferred N-bisphosphonate, which can be used according to the invention, CR is dstanley a compound of formula II

where Het represents an imidazole, oxazole, isoxazol, oxadiazole, thiazole, thiadiazole, pyridine, 1,2,3-triazole, 1,2,4-triazole, or a benzimidazole moiety, optionally substituted by alkyl, alkoxygroup, halogen, hydroxyl, carboxyla, amino, optionally substituted alkyl or alkanolamine radical or benzyl radical, optionally substituted by alkyl, nitro, amino or aminoalkyl;

And denotes a saturated or unsaturated hydrocarbon fragment with a straight or branched chain, bearing 1-8 carbon atoms;

X' denotes a hydrogen atom, optionally substituted by alkanoyl, or amino group, optionally substituted by alkyl or alkanoyl, and

R denotes a hydrogen atom or alkyl, and its pharmacologically acceptable salts.

In another embodiment, the most preferred bisphosphonate, which can be used according to the invention, is a compound of formula III

where Het' denotes a substituted or unsubstituted heteroaromatic 5-membered ring selected from the group comprising imidazolyl, imidazolyl, isoxazolyl, oxazolyl, oxazolyl, thiazolyl, thiazolyl, triazolyl, oxadiazolyl and thiadiazolyl, where the ring may be partially gidrirovanie and as for the estately choose at least one representative from the group, include1-C4alkyl, C1-C4alkoxy, phenyl, cyclohexyl, cyclohexylmethyl, halogen and amino group, and where two adjacent alkyl substituent Het' together may form a second ring;

Y denotes hydrogen or C1-C4alkyl;

X denotes hydrogen, hydroxyl, amino group or the amino group, substituted C1-4the alkyl, and

R denotes hydrogen or C1-C4alkyl;

and its pharmacologically acceptable salts, and isomers.

In another embodiment, the most preferred bisphosphonate, which can be used according to the invention, is a compound of formula IV

where Het"′ denotes imidazolyl, 2H-1,2,3-, 1H-1,2,4 - or 4H-1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl or thiadiazolyl, which is unsubstituted or in which one or two carbon atoms replaced by (ness.)the alkyl, (ness.)alkoxygroup, phenyl, which may in turn be mono - or disubstituted by (ness.)the alkyl, (ness.)alkoxygroup and/or by halogen, hydroxy, di(ness.)alkylamino, (ness.)alkylthiophene and/or halogen, and N is substituted on the nitrogen atom, which may have substituents, (ness.)the alkyl or phenyl(ness.)the alkyl, phenyl fragment which in turn can be mo is about - or disubstituted by (ness.)the alkyl, (ness.)alkoxygroup and/or halogen, and

R2 denotes hydrogen, hydroxy, amino, (ness.)alkylthio or halogen, lower radicals, carrying up to 7 carbon atoms, inclusive, or its pharmacologically acceptable salt.

Examples of preferred N-bisphosphonates, which can be used according to the invention, are:

2-(1-Mei-2-yl)-1-hydroxyethane-1,1-diphosphonic acid,

2-(1-benzylimidazole-2-yl)-1-hydroxyethane-1,1-diphosphonic acid,

2-(1-Mei-4-yl)-1-hydroxyethane-1,1-diphosphonic acid,

1-amino-2-(1-Mei-4-yl)ethane-1,1-diphosphonic acid,

1-amino-2-(1-benzylimidazole-4-yl)ethane-1,1-diphosphonic acid,

2-(1-Mei-2-yl)ethane-1,1-diphosphonic acid,

2-(1-benzylimidazole-2-yl)ethane-1,1-diphosphonic acid,

2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid,

2-(imidazol-1-yl)ethane-1,1-diphosphonic acid,

2-(4H-1,2,4-triazole-4-yl)-1-hydroxyethane-1,1-diphosphonic acid,

2-(thiazol-2-yl)ethane-1,1-diphosphonic acid,

2-(imidazol-2-yl)ethane-1,1-diphosphonic acid,

2-(2-Mei-4(5)-yl)ethane-1,1-diphosphonic acid,

2-(2-phenylimidazol-4(5)-yl)ethane-1,1-diphosphonic acid,

2-(4,5-dimethylimidazole-1-yl)-1-hydroxyethane-1,1-diphosphonic acid and

2-(2-Mei-4(5)-yl)-1-hydroxyethane-1,1-diphosphonic acid and their pharmacologically acceptable is salt.

The most preferred N-bisphosphonates, which can be used according to the invention is 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid (zoledronicaa acid) or its pharmacologically acceptable salt.

Pharmacologically acceptable salts are preferred are salts with bases, usually salts of metals from groups Ia, IB, IIa, IIB of the Periodic table of elements, including alkali metal salts, for example, potassium and especially sodium salts, or salts of alkaline earth metals, preferably calcium or magnesium salts, and also ammonium salts with ammonia or organic amines.

The preferred pharmaceutically acceptable salts are salts in which one, two, three, or four, especially one or two acidic hydrogen atom bisphosphonates acid replaced by a pharmaceutically acceptable cation, in particular a cation of sodium, potassium or ammonium, primarily sodium.

Especially preferred group of pharmaceutically acceptable salts is characterized by the presence of one acidic hydrogen atom and one pharmaceutically acceptable cation, especially sodium, in each of the groups of the phosphonic acid.

The above specific derivatives bisphosphonates acids are well known from literary sources. Described also is receiving (see, for example, EP-A-513760, p.13-48). For example, 3-amino-1-hydroxypropane-1,1-diphosphonic acid is obtained according to the method described in patent US 3962432, and its disodium salt according to the method described in patents US 4639338 and 4711880, and 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid is obtained according to the method described in patent US 4939130.

Bisphosphonates (below in the present description called agents according to the invention) can be applied in the form of an isomer or mixture of isomers, if it is valid, usually in the form of optical isomers, such as enantiomers or diastereoisomers, or geometric isomers, as a rule, CIS-TRANS-isomers. Optical isomers is obtained in the form of pure antipodes and/or in the form of racemates.

The agents according to the invention can be applied also in the form of their hydrates or form, to include other solvents used for crystallization.

The agents according to the invention is preferably used in the form of pharmaceutical compositions that contain a therapeutically effective amount of the active substance optionally in combination or in a mixture with inorganic or organic, solid or liquid pharmaceutically acceptable carriers suitable for injection.

The agents according to the invention can be entered individually or in combination with other drugs possessing intercourse is the want to make in relation to bone tissue, either in the form of fixed combinations or separately (i.e. as separate components, and in various points in time), including hormones such as steroid hormone, such as estrogen; partial agonist of estrogen or combination estrogen-gestagen; calcitonin or an analogue or derivative, for example, parathyroid hormone, calcitonin salmon, eel or human rights or its analogs, for example, PTH (1-84), PTH (1-34), PTH (1-36), PTH (1-38), PTH (1-31)NH2or PTS 893; SERM (selective modulator of estrogen receptor), such as raloxifene, lasofoxifene, TSE-424, FC1271, tibolone (Livial®); vitamin D or its analogues. Such additional possessing activity against bone medicines you can enter more often than a bisphosphonate.

The pharmaceutical composition may constitute, for example, compositions for enteral administration, such as oral, rectal administration, introduction by inhalation of an aerosol or nasal introduction, compositions for parenteral administration, such as intravenous or subcutaneous administration, or the composition for transdermal administration (for example, passive or informationstore introduction).

Preferably the pharmaceutical composition adapted for oral or parenteral (especially intravenous, subcutaneous, intramuscular or transder the material) introduction. The most important are intravenous and oral administration, especially intravenous. Preferably the active substance, i.e. a bisphosphonate, is in a form suitable for parenteral, most preferably intravenous injection.

Native hospital physician may choose a specific route of administration and dose, taking into account individual peculiarities of the patient, first of all, the age, body weight, lifestyle, level of activity, hormonal status (e.g., postmenopausal) and mineral density of bone tissue, respectively.

The dose of the agents according to the invention may depend on various factors such as the efficiency and duration of action of the active substance, for example, including the relative effectiveness of bisphosphonates, route of administration, species of warm-blooded animals and/or gender, age, body weight and individual condition of the warm-blooded animal.

Typically, the dose that is administered warm-blooded animal weighing approximately 75 kg is a single dose of the active substance, i.e. bisphosphonates, component of 0.005-20 mg/kg, especially from 0.01 to 10 mg/kg

"mg/kg" is used to indicate the quantity of the drug in mg / kg of body weight to be processed of a mammal, including humans.

The above dose is usually BBO is it periodically with the interval between injections, comprising at least 6 months. The interval between doses of bisphosphonates can be longer, for example, conveniently be introduction once a year, once in 18 months or once every two years, or even use a longer interval, or any intermediate interval.

Compositions in the form of a single standard dosage forms preferably contain from about 1 to about 90%, and compositions that do not represent a single standard dosage form, preferably contain from approximately 0.1 to approximately 20% active ingredient. Single standard dosage forms, such as ampoules containing solution for infusion or solid substance for preparation of a dose of solution for infusion, capsules, tablets or coated tablets contain, for example, from about 0.5 to about 500 mg of active substance. It should be borne in mind that effective applicable standard dose should depend among other things on the effectiveness of bisphosphonates, the interval between dose and route of administration. Thus, the size of a standard dose, as a rule, the smaller, the greater the effectiveness of bisphosphonates, and the more, the longer the interval between injections. For example, for more efficient N-bisphosphonates, such as zoledronicaa acid, for couples who naturalnego, for example, intravenous injection, you can use the standard dose of from about 1 to about 10 mg. for Example, for more efficient N-bisphosphonates can be entered parenteral every 6 months standard dose of from about 1 to about 5 mg; whereas parenteral doses once a year you can apply a dose of from about 2 to about 10 mg.

Standard dose you can enter as a single or divided dose, i.e. the dose at which the standard dose is divided into two or more equal or unequal parts, and these parts are administered to a patient simultaneously, during overlapping time periods or at different points in time. If the standard dose is administered in divided doses at different points in time, the interval between the introduction of split doses may range from a few hours, for example 1 hour to about 1 month (approximately 30 days). According to the invention the time interval between the introduction of the last part divided doses and the introduction of the first part of the following divided doses is at least 6 months or more, for example about 1 year.

For example, the standard dose of 10 mg can be entered in two equal portions 5 mg with an interval between doses of parts, components from priblizitelen is 1 week to about 1 month, for example, approximately 2 weeks. Alternatively, a standard dose of 5 mg you can enter, for example, in the form of two unequal parts 4 and 1 mg (or 3 and 2 mg) with an interval between doses of parts from 1-3 days 1-3 weeks, for example, at intervals, constituting approximately 1 week.

Pharmaceutical compositions for enteral and parenteral administration are, for example, in the form of such a standard dosage forms, such as pills, tablets or capsules, and capsules. Get them a well-known method, for example, using conventional mixing, granulation, packing, dissolution or lyophilization. For example, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating the resulting mixture and, if it is desirable or necessary, processing the mixture or granules, after adding suitable auxiliaries to obtain tablets or dragee cores.

Suitable carriers are primarily fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, preparations based on cellulose, and also binders, such as starch pastes, obtained, for example, from corn, wheat, rice or potato starch, as is Athyn, tragakant, methylcellulose and/or polyvinylpyrrolidone, and, if it is appropriate, leavening agents, such as the above mentioned starches, and also carboxymethylate starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate. Excipients are primarily agents for regulating yield and oil, for example, silicic acid, talc, stearic acid or its salts, such as magnesium stearate or calcium, and/or polyethylene glycol. At the core tablets put suitable coatings that may be resistant to gastric juices, which are used inter alia concentrated sugar solutions which optionally contain gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents or mixtures of solvents, or to produce coatings resistant to gastric juices, solutions of suitable preparations based on cellulose, such as cellulose acetate phthalate or phthalate of hydroxypropylmethylcellulose. In coating for pills or tablets, you can add dyes or pigments, for example, for the purpose of identification or to indicate different doses of active ingredient.

Other oral input by a pharmacist is ical compositions are gelatin capsules, filled with dry product, and also soft sealed capsules consisting of gelatin and a plasticizer, such as glycerol or sorbitol. Capsules filled with dry product may contain the active substance in the form of granules, for example, in a mixture with fillers, such as lactose, binders, such as starches, and/or substances that improve the slip, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols, and you can also add stabilizers.

Parenteral compositions are primarily injectable fluids that are injected in different ways, for example, intramuscularly, intraperitoneally, intranasally, intradermally, subcutaneously or preferably intravenously. Such fluid is preferably represent an isotonic aqueous solutions or suspensions which can be prepared before use, for example from lyophilised preparations that contain the active ingredient individually or in combination with pharmaceutically acceptable carrier, or from concentrated solutions. The pharmaceutical compositions can be sterile and/or contain the substance of excipients, for example preservatives, stabilisers, wetting agents and/or emulsifiers, soljubilizatory, salts for regulating osmotic pressure and/or buffers.

Compositions suitable for transdermal administration, contain an effective amount of active ingredient in combination with a carrier. Preferred carriers include an easy to absorb pharmacologically acceptable solvents that are used to facilitate the passage through the skin of the host. Typically, devices for transdermal injection are in the form of a bandage comprising a supporting element, a reservoir containing the compound optionally in combination with carriers, optionally controlling the speed barrier for the active substance has received on the skin of the host with a controlled and predetermined rate over a prolonged period of time, and means for fastening the device on the skin.

The following examples serve to illustrate the above-described inventions.

In the examples below, the term "active substance" refers to any of the above derivatives bisphosphonates acid, which can be used according to the present invention.

EXAMPLES

Example 1: Capsules containing the active substance, such as a pentahydrate of dinitrophenolate, in the form of coated PE the Letov:

The core pellets:

active substance (grinded)197,3 mg
microcrystalline cellulose
(Avicel® PH 105)52,7 mg

250.0 mg

+ Internal coating:

cellulose HP-M 60310.0 mg
the polyethylene glycol2.0 mg
talc8.0 mg

270,0 mg

+ Outer coating resistant to gastric juices:

Eudragit® L 30 D (solid)90,0 mg
triethylcitrate21,0 mg
Antifoam® AF2.0 mg
water
talc7,0 mg

390,0 mg

A mixture of dinitrophenolate with Avicel® PH 105 moistened with water and kneaded, ekstragiruyut and the molded product in the form of spheres. Then the dried pellets consistently applied in the fluidized bed inner coating consisting of cellulose HP-M 603, polyethylene glycol (PEG) 8000 and talc, and water resistant to gastric juices coating comprising Eudragit® L 30 D, triethylcitrate and Antifoam® AF. Pellets coated with pokr is a tie optivault talc and fill their capsules (size capsules 0) using a commercially available machine for filling capsules, for example supplied by the company Höfliger and Karg.

Example 2: Monolithic adhesive transdermal system containing as active substance, for example, 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid:

Composition:

polyisobutylene (PIB) 3005.0 g
(Oppanol B1, BASF)
PIB 350003.0 g
(Oppanol 10, BASF)
PIB 12000009.0 g
(Oppanol 100, BASF)
hydrogenated hydrocarbon resin43,0 g
(Escorez 5320, Exxon company)
1-dodecylsulfate-2-he20,0 g
(Azone, firm Nelson Res., Irvine/California)
the active ingredient20,0 g
Only100.0 g

Receive:

The above ingredients together dissolved in 150 g of an oil fraction having a specific boiling point 100-125°by rotating on a platform with a roller mechanism. The solution was applied on a polyester film (firm Hostaphan, Kalle) using a distribution device using a squeegee size 300 mm, receiving pok the eve ENT with a density of approximately 75 g/m 2. After drying (15 minutes at 60° (C)treated with silicone polyester film (thickness 75 mm, the firm Laufenberg) is used as an adhesive film. End (ready to use) system squeeze punch of the desired shape and size from 5 to 30 cm2using a punching device. The finished system sealed separately in sachets of aluminized paper.

Example 3: a Vial containing 1.0 mg dry lyophilized 1-hydroxy-2-(imidazol-1-yl)ethane-1,1-diphosphonic acid (mixture of its sodium salt). After diluting 1 ml of water get solution (concentration 1 mg/ml) for I.V infusion.

Composition:

the active ingredient
(free diphosphonic acid)1.0 mg
mannitol46,0 mg
trinatriytsitrat·2H2Oapproximately 3.0 mg
water1 ml
water for injection1 ml

The active substance together with triatriatum·2H2O triturated in 1 ml of water to achieve a pH of 6.0. Then add mannitol solution lyophilizer and lyophilized fill the bubble.

Example 4: Capsules containing the active substance, for example, pentahydrate, distribuito the ATA, dissolve in water. After dilution gain solution (concentration 3 mg/ml) for I.V infusion.

Composition:
The active ingredient

(5.0 mg of anhydroustab

the active substance)19,73 mg
mannitol250 mg
water for injection5 ml

Example 5: Treatment of patients

"Multinational randomized, double-conducted in parallel groups of patients "blindly" using placebo as a control study of the dose range, the safety and efficacy of zoledronate as intravenous bolus injections in the treatment of postmenopausal osteoporosis"

This experience was a 12-month study aimed at determining the dose and mode of doses by zoledronate acid at its centuries the introduction patients suffering from postmenopausal osteoporosis. Three hundred fifty one patient was randomly divided into six groups, which were subjected to various processing modes. Excluded patients who shortly before the start of the experiment took drugs having activity is in relation to bone tissue, for example, bisphosphonates, estrogen, calcitonin, relfexes or who had a history of metabolic diseases of bone tissue. All patients were examined before the start of the experiment (baseline) and during visits every 3 months. Zoledronic acid or placebo at each visit was administered by I.V bolus injection into a peripheral vein for 5 minutes

The effectiveness was evaluated by comparing the results of measurements of the percentage change in mineral bone density (BMD) relative to the base level held by the method of absorptiometry dual-energy x-rays (DEXA), with placebo after 6, 9 and 12 months.

As a special security measures in several patients from all treatment groups after 12 months took biopsy samples from the iliac bone, and also before the beginning of experiment and after 12 months were chest x-ray and lumbar spine to detect the occurrence of cracks in the spine. In addition, the Central laboratory has been evaluated and measured every 3 months the degree and duration of suppression of biochemical markers of regeneration of bone tissue - parathyroid hormone (PTH), specific for bone alkaline phosphatase (SAP), serum C-telopeptide (CTX), serum osteocalcin, the ratio of the levels of N-bodies of the peptide(MTX)/creatinine in urine, the ratio of deoxypyridinoline (d-pyd)/creatinine in urine, the ratio of the levels of pyridinoline (pyd)/creatinine in the urine.

Group processing

Placebo

0.25 mg by zoledronate acid every 3 months

0.5 mg with zoledronate acid every 3 months

1.0 mg of zoledronate acid every 3 months

2.0 mg-zoledronate acid every 6 months

4.0 mg by zoledronate acid every 12 months

The results of the 12-month study indicate that all processing groups, the percentage change in BMD relative to baseline was significantly (p<0,001) higher than the corresponding change identified in the group that was treated with placebo, and the nature of these changes are similar to each other (table 1).

Table 1
The generalization step-by-step comparisons of the impact of effective doses of zoledronate and placebo in percent change in mineral bone density of the lumbar spine relative to the base level; zadneprianniy Department (L1-L4), after 12 months, confirming the analysis of the ITT population
Step numberThe most significant differenceThe differenceThe standard deviation of the differenceThe bottom of 97.5% confidence limitA value of p
1zoledronate 4×0.25 mg placebo5,10,553,7<0,001
2zoledronate 4×0.5 mg placeboa 4.90,563,5<0,001
3zoledronate 1×4.0 mg placebo4,60,533,3<0,001
4zoledronate 4×1.0 mg placebo4,50,553,2<0,001
5zoledronate 2×2.0 mg placebo4,20,573,1<0,001
Note: Used multiple step-by-step comparison of effective doses of zoledronate and placebo in unidirectional multiple level alpha of 2.5%, adjusted for multiple comparisons according to the method described by Marcus, Peritz and Gabriel (1976).

Mineral bone density was increased compared with placebo in the spine, hip, distal radial bone in "whole body". The presence of suppression of biochemical markers of bone formation and bone resorption confirms and complements the results of the analysis BDM, indicating suppression of regeneration of bone tissue on premenopausal level for 6 - and 12-month intervals of doses.

The results of BMD measurements indicate that the introduction of zoledronate acid with large time intervals, i.e. every 6 or 12 months, may lead to statistically significant and important from a medical point of view safe increase in bone mass. It can be assumed that these data also suggest that the likely new bone tissue is stored for more than one year without the introduction of additional doses of the medicinal product or that it is possible to further bone formation. It can be assumed that the re-processing in the form of additional cycles every 6, 12 months or less will lead to a further increase in BMD. It should be expected that the increase in bone mass will be accompanied by a reduction in the risk of fracture due to osteoporosis.

1. A method of treatment of conditions characterized by abnormally increased renewal of bone tissue in patients in need of such treatment, which consists in the fact that the patient is periodically administered zoledronic acid, or its pharmaceutically acceptable salt or any hydrate in an amount of from 2 to 10 mg, with between doses is longer than 6 months.

2. The method according to claim 1, where the interval between injections is at least 1 year.

3. The method according to claim 1 for the preventive treatment of osteoporosis, where the period between the in the introduction is two years or more.

4. The method according to claim 1 for the preventive treatment of osteoporosis, where the period between the introduction is 18 months or more.

5. The method according to claim 1, where zoledronic acid, or its pharmaceutically acceptable salt or any hydrate is administered parenterally.

6. The method according to claim 1, where zoledronic acid, or its pharmaceutically acceptable salt or any hydrate administered intravenously, subcutaneously, intramuscularly, or transdermal.

7. Application zoledronate acid, or its pharmaceutically acceptable salt or any hydrate for preparing a medicinal product intended for the treatment of conditions characterized by abnormally increased renewal of bone tissue, wherein the drug comprises from 2 to 10 mg of zoledronate acid, or its pharmaceutically acceptable salt or any hydrate, and this number is effective when the injection mode, when the period between the introduction is more than 6 months.

8. The use according to claim 7, where the interval between injections is at least one year.

9. The use according to claim 7 for the preventive treatment of osteoporosis, where the period between the introduction is a year or more.

10. The use according to claim 7 for the preventive treatment of osteoporosis, where the period between the introduction is two years or more.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: pharmaceutics.

SUBSTANCE: a solid pharmaceutical composition contains therapeutically efficient quantity of peptide as a pharmacological active substance, crospovidone or povidone, and an agent that favors peptide's introduction. A peptide is being calcitonin, salmon's calcitonin preferably. The above-mentioned agent is being 5-CNAC (N-(5-chlorsalicyloyl)-8-aminocaprylic acid), preferably, disodium salt 5-CNAC. The composition suggested provides high biological availability of peptides, such, for example, as calcitonin.

EFFECT: higher efficiency of application.

9 cl, 5 ex, 4 tbl

FIELD: biotechnology.

SUBSTANCE: invention relates to inhibitor of matrix metalloproteinases representing extract from fungus Canoderma atrum obtained by using of water and/or lower alcohols as extractant. Also disclosed are pharmaceutical agent for inhibition of tumor metastasis containing of 0.03-10 wt.% of abovementioned extract and foodstuff containing claimed extract.

EFFECT: improved inhibitor of matrix proteinases.

3 cl, 18 ex, 4 tbl

FIELD: medicine, medicinal biochemistry, pharmaceutical technology.

SUBSTANCE: invention proposes the composite that comprises complex of vitamins D3, B6, C, K and calcium salts, citric acid, lactose and sorbitol as the special supplement, and lubricating agent and correcting agent for taste and/or odor. The method for preparing the composite involves mixing the above said components and if necessary the following tableting process of the prepared mixture. The new composite shows stability of quality indices in the store process being among them index "the content of vitamin D3" that provides the fitness time above 2 years and absence of by-side adverse toxic effect that is typical for destruction products of active components.

EFFECT: improved preparing method, improved and valuable properties of composite.

7 cl, 1 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

FIELD: medicine, orthopedics.

SUBSTANCE: the present innovation deals with treating osseous diseases caused by calcium exchange disorders. For this purpose certain calcium preparations should be reduced up to amorphous state to be perorally applied per 0.5-1.0 g, 2-4 times daily, at courses of not less than 10 d. The innovation provides efficient treatment due to high biodigestibility of amorphous calcium and its active accumulation in bony tissue.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex

FIELD: medicine; medical engineering.

SUBSTANCE: biotransplant has genetically unmodified mesenchyma stem cell culture as active component obtained from fetal donor autologous material. The tissue is subjected to disaggregation and the produced cell suspension is resuspended and cultivated on growth medium containing transferrin, insulin, fibroblast growth factor and heparin to accumulate mature stroma in cell culture. Method involves intravenously dropping mesenchyma stem cell culture in the amount of 50 to 500 mln in 50-100 ml of physiologic saline.

EFFECT: accelerated recovery of bone tissue; positive biochemical factors dynamics; improved patient locomotor activity.

6 cl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted 2-aryl-3-(heteroaryl)imidazo[1,2-a]-pyrimidines of the formula (I):

or to their pharmaceutically acceptable salts wherein: (a) R1 is taken among the group consisting of -NH2, C1-5-alkylamino-, di-C1-5-alkylamino-, phenylmethylamino-group; (b) Y is taken among the group consisting of hydrogen atom (H), halogen atom, piperidine, OR4, SR4, -SO2CH3, NHR4 and NR4R5 wherein R4 and R5 are taken independently among hydrogen atom (H), α-alkylphenyl-C1-5-alkyl, linear or branched alkyl substituted optionally with C3-5-carbocycle, phenyl or substituted phenyl wherein indicated phenyl can be substituted with one or some substituted taken among C1-5-alkoxy-group; (c) R2 represents from one to five members taken independently among the group including hydrogen atom (H), halogen atom, trifluoromethyl; (d) R3 represents hydrogen atom (H), or radicals R3 taken in common form aromatic ring; (e) X represents nitrogen atom (N) or -CH. Also, invention relates to methods for preparing indicated compounds and to a method for treatment based on these compounds. Invention provides preparing novel compounds that can be used in relief states by reducing the level of inflammatory cytokines, for example, the indicated state represents proliferative (rheumatic) arthritis.

EFFECT: valuable medicinal properties of compounds and compositions.

40 cl, 1 tbl, 4 ex

FIELD: medicine, phytotherapy, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to using Belamcanda chinensis extract for preparing organ-selective medicinal preparation without uterotropic effect or with minimal such effect that is used as estrogen-like preparation. This preparation is used in selective treatment and/or prophylaxis of cardiovascular diseases, in particular, atherosclerosis and osteoporosis, climacteric disturbances, especially for prophylaxis or softening congestions of blood. Extract is used in manufacturing a medicinal preparation in ready formulation for selective treatment and/or prophylaxis of cardiovascular diseases, in particular atherosclerosis, and for selective treatment and/or prophylaxis of osteoporosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood. Extract promotes to effective prophylaxis and/or treatment of cardiovascular diseases, in particular, atherosclerosis, climacteric disturbances, especially for prophylaxis and softening congestions of blood.

EFFECT: valuable medicinal properties of extract.

4 cl, 4 ex

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: the present innovation deals with rectal suppositories that contain biphosphonic acids and their pharmacologically acceptable salts applied for preventing and treating diseases caused by affected calcium and magnesium balance in the body. The suggested new suppositories contain 0.1-10 weight% xydiphone and 0.5-10 weight emulsifiers, the rest - the foundation for one suppository of 1.125-2.5 g weight. Rectal xydiphone-containing suppositories could additionally contain medicinal and/or biologically active supplements, for example 0.1-1.0 weight% trisodium salt of phosphonoformic acid as medicinal additive, and, also, biologically active additive chosen out of the group of vitamin B6, B12 or carbon dioxide solution of common camomile, olive oil. The innovation provides the chance to avoid some complications occurred at applying this preparation in known forms and, also, in some cases leads to its increased efficiency.

EFFECT: higher efficiency of application.

4 cl, 4 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: the present innovation deals with applying biphosphonate for treating osteonecrosis and/or osteonecrosis dissecans. This medicinal preparation could be additionally applied for preventing the development of osteonecrosis and/or osteonecrosis dissecans and any complications associated with both diseases. Biphosphonate acts for the decrease or prevention of severe degree of deformation and/or destruction of a bone or a cartilage and provides the chance to form new bony tissue in a patient.

EFFECT: higher efficiency of therapy.

38 cl, 7 dwg, 1 tbl

FIELD: medicine, pharmacy, pharmaceutical technology.

SUBSTANCE: invention relates to pharmaceutical compositions as tablets, namely, to a tablet preparing by direct pressing and comprising 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or its pharmaceutically acceptable salts as an active component taken in the amount from 5 to 140 mg as measured for a pure acid, an excipient, a dry binding agent, a disintegrating agent and a lubricating substance, and to a method for its preparing. As an excipient the claimed composition comprises the combination of at least two recipients but with exception of lactose, and it comprises 20-80 weight% of excipient chosen from group comprising microcrystalline or powder-like cellulose and calcium hydrophosphate, and 0.001-50 weight% of one or more recipients chosen from group comprising mannitol and phosphates or hydrophosphates of alkaline or alkaline-earth metals. As a disintegrating agent the composition comprises maize starch taken in the amount 7-15%. The content of lubricating agent is 1%.

EFFECT: improved preparing method of tablet.

3 cl, 19 tbl, 7 ex

FIELD: experimental medicine.

SUBSTANCE: on should introduce solution into fracture area at the following ratio of ingredients, g/l: 1-hydroxyethylidenediphosphonic acid 1.80 - 2.06, water-free calcium chloride 1.44 - 2.22, gadolinium (III) nitrate hexahydrate 0.30 - 0.40, dysprosium (III) chloride hexahydrate 0.038 - 0.076, moreover, solution's pH corresponds to 7.3 - 7.8. The present innovation enables to shorten the process of bony tissue regeneration in the site of its lesion or defect and, also, shorten the period for restoring normal physiological function of traumatized bone.

EFFECT: higher efficiency of regeneration.

22 ex, 1 tbl

The invention relates to new derivatives of anhydride methylenephosphonic acid of the formula I, where Y1, Y2, Y3and Y4group OR1, NR2R3, OCOR1, OCNR2R3, O(CO)OR1, O(SO2R1or OP(O)R2(OR3), where R1, R2and R3- H, C1-22alkyl, aryl, possibly substituted, or SiR3where R3- C1-C4alkyl, provided that at least one of the groups Y1, Y2, Y3and Y4other than the group OR1or NR2R3, Q1and Q2Is H, F, Cl, Br, I, methods of obtaining these new compounds as well as pharmaceutical preparations containing these new compounds

The invention relates to medicine, namely to pharmaceutical drugs ibandronate or its physiologically acceptable salts for oral administration, and is a drug for the treatment of hypercalcemia, osteoporosis, tumor osteolysis, Paget's disease
The invention relates to medicine

FIELD: experimental medicine.

SUBSTANCE: on should introduce solution into fracture area at the following ratio of ingredients, g/l: 1-hydroxyethylidenediphosphonic acid 1.80 - 2.06, water-free calcium chloride 1.44 - 2.22, gadolinium (III) nitrate hexahydrate 0.30 - 0.40, dysprosium (III) chloride hexahydrate 0.038 - 0.076, moreover, solution's pH corresponds to 7.3 - 7.8. The present innovation enables to shorten the process of bony tissue regeneration in the site of its lesion or defect and, also, shorten the period for restoring normal physiological function of traumatized bone.

EFFECT: higher efficiency of regeneration.

22 ex, 1 tbl

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