Pharmaceutical parenteral composition containing biphosphonate

 

The composition may be used for the treatment of diseases involving bone resorption, such as osteoporosis, Paget's disease, hypercalcemia in malignant tumors and metabolic disorder of bone tissue. The composition includes a bisphosphonate as an active ingredient, a pharmaceutically acceptable chelating agent and a pharmaceutically acceptable excipient. Chelating agent selected from EDTA and DTPA. Also described is a method of obtaining a composition and device for local and systemic sustained release. The device contains the specified composition and consists of an implanted osmotic pumps or located outside of the portable infusion pumps, United with the supplier capacity and/or sewn under the skin of the cannula. The composition is particularly useful for improving local tolerance parenteral bisphosphonates can reduce or avoid tissue damage, swelling and/or pain. 3 C. and 20 C.p. f-crystals, 8 ill.

The present invention relates to a parenteral composition comprising a bisphosphonic acid or its pharmaceutically acceptable salt (a bisphosphonate) as an active ingredient, pharmaceutically p and ways of its application in the treatment and prevention of diseases, involving bone resorption, especially osteoporosis, Paget's disease, hypercalcemia in malignant tumors and metabolic disorder of bone tissue. The composition is particularly useful for improving the local tolerance of the active component in a parenteral, especially subcutaneous route.

Bisphosphonates, i.e., bisphosphonic acids or their soluble pharmaceutically acceptable salts are synthetic analogs of natural pyrophosphate. Due to their significant affinity for the solid-phase calcium phosphate bisphosphonates are strongly linked with bone inorganic substance. Pharmacologically active bisphosphonates are well known in the art and are potent inhibitors of bone resorption and, therefore, useful in the treatment and prevention of diseases involving abnormal bone resorption, especially osteoporosis, Paget's disease, hypercalcemia in malignant tumors, and metabolic disorders of bone tissue.

Bisphosphonates as pharmaceutical agents are described, for example, in EP-A-170228, EP-A-197478, EP-A-22751, EP-A-252504, EP-A-252505, EP-A-258618, EP-A-350002, EP-A-273190, WO-A-90/00798 etc.

Pharmaceutical form selling bisphosphonates represent a Lek is, what do infusions. With the introduction in therapeutic doses they have a good system portability. However, bisphosphonates as a class of compounds are irritating to the skin and mucous membrane, leading to side effects in the digestive tract, such as adverse events related to the esophagus or gastro-intestinal disorders. Consequently, when using the oral route of administration should be followed uncomfortable for the patient's recommendations for use. Intravenous route of administration is complicated by undesirable manifestations in case of unsuccessful application. If Vienna is inaccurate found or if the drug is accidentally injected outside the vein, there are local tissue reactions, including necrosis. Thus, there is a significant need for improved pharmaceutical dosage forms of bisphosphonates to reduce or avoid tissue damage after parenteral administration, especially the subcutaneous route.

Pathophysiological mechanism caused by bisphosphonates tissue injury is unknown. Since local reactions are the same for different bisphosphonates, at least those caused by nitrogen-containing bisphosphonates (aminobisphosphonates), the trail is on nonspecific immune system protection.

Attempts were made to improve the tolerance of tissues to bisphosphonates by creating suspensions of insoluble or poorly soluble salts of bisphosphonates, providing slow release, for example described in EP-A-913007740, DE-A-4244422 and DE-A-4244423. However, it is proved that this approach is only marginally improves local tolerance.

Therefore, the problem underlying the present invention is to obtain a composition, which can minimize or eliminate the above mentioned disadvantages.

According to the present invention the problem is solved by using the input parenteral composition comprising a bisphosphonate, a pharmaceutically acceptable chelating agent and a pharmaceutically acceptable filler.

Applicants have discovered that the introduction of bisphosphonates in the composition comprising pharmaceutically acceptable chelating agent, clearly reduces the duration, frequency and intensity of side effects. The presence of additional divalent cation chelator, especially EDTA (ethylenediaminetetraacetic acid) or DTPA (diethylenetriaminepentaacetic acid), significantly reduces unwanted local reaction at the sites of injection when compared with the corresponding formula I are taken to illustrate and define the meaning and range of different terms used to describe in the context of the invention.

The term “bisphosphonate” means a compound characterized by the presence of two links WITH RHO2-3. If these two relations are at one and the same carbon atom, the compounds are called genialnymi with bisphosphonates. It should be noted that the term “bisphosphonate”, as it is used in the context related to therapeutic agents of the present invention, also includes diphosphonates, biphosphonate acids and diphosphonic acids and salts and derivatives of these compounds. The use of a specific item at the mention of bisphosphonates or bisphosphonates does not limit the present invention unless specifically indicated.

The term “chelating agent” or “chelator” means organic or inorganic compound, which by means of two or more of its functional groups forms a stable cyclic complexes with metal cations. It should be noted that bisphosphonates also have chelating activity. Therefore, the term “chelating agent” is understood as a chelator, which captures metal ions competitive against the bisphosphonates used as the active Comte, means that salts or chelating agents are acceptable from the standpoint of toxicity.

The term “pharmaceutically acceptable salt” refers to salts of ammonium, salts of alkali metals such as potassium salts or sodium (including mono-, di - and trinitramine) salts (which are preferred), salts of alkaline earth metals such as calcium and magnesium salts, salts with organic bases, such as salts dicyclohexylamine, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so on,

The term “alkyl”, alone or in combination, signifies an alkyl group with a linear chain, branched chain or cyclic, containing up to 30, preferably up to 10 and more preferably a maximum of 7 carbon atoms, for example methyl, ethyl, n-propyl, 2-methylpropyl (isobutyl), 1-methylethyl (isopropyl), H-butyl, 1,1-dimethylethyl (tert - butyl) and pencil. The term “alkyl” also includes the above groups, optionally substituted phenyl, pyridium, TuranAlem, pyrrolidinium, imidazolium, amino, mono - or dialkylamino, hydroxy, SH, alkoxy.

The term “diluent” means an ingredient in medicinal drug that is devoid of pharmacological activity, but the two who ia injection of the drug, for example water.

The term “solvent” refers to a liquid that holds another substance in solution, i.e., it dissolves, for example water.

The term “preservative” refers to a substance added to a pharmaceutical drug to prevent the growth of bacteria.

The term “device” means a device for a specific purpose. According to the present invention the aim is to make it possible, to ensure or facilitate parenteral administration of the drug.

The term “local anesthetic” refers to a compound that reversibly inhibits the function of a neuron in place, causing loss of ability to perceive pain and/or other sensations, such as hydrochloride lidocaine.

In more detail, the present invention relates to a parenteral composition comprising a bisphosphonate and a pharmaceutically acceptable chelating agent. Parenteral compositions can take the form of a liquid such as an aqueous solution, or a sterile powder, and/or lyophilisate. Liquid, for example water, can be added to a sterile powder and/or freeze-dried, to form a solution for injection.

In a preferred variant embodiment of the present invention described above, the composition is in for example, in US patent No. 4509012, US patent No. 4666895, US patent No. 4719203, EP-A-252504, EP-A-252505, US patent No. 4777163, US patent No. 5002937, US patent No. 4971958, US patent No. 4958839.

Methods of obtaining bisphosphonic acids can be found, for example, in US patent No. 3962432, US patent No. 40-54592, US patent No. 4267108, US patent No. 4327039, US patent No. 4404761, US patent No. 4621077, US patent No. 4624947, US patent No. 47466654, US patent No. 4922077, US patent No. 4970335, US patent No. 5019651, US patent No. 4761406, US patent No. 4876248; J. Org. Chem. 32, 4111 (1967) and EP-A-252504. Pharmaceutically acceptable salts bisphosphonic acids can also be used in this invention. Examples of salts bisphosphonic acids with bases include ammonium salts, alkali metal salts, such as potassium and sodium (including mono-, di - and trinitramine) salts (which are preferred), salts of alkaline earth metals such as calcium and magnesium salts, salts with organic bases, such as salts dicyclohexylamine, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, etc. are Preferred non-toxic, physiologically acceptable salts. Salts can be obtained by well-known specialists of ways, such as described in published European patent application No. 252504 or in US patent No. 49 the present invention compounds of General formula

where a and X independently from each other selected from the group consisting of hydrogen, hydroxy, halogen, amino, SH, phenyl, alkyl, mono - or dialkylamino, mono - or diaminoalkyl, alkoxy, thioalkyl, thiophenyl, and aryl or heteroaryl residue selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazolyl and benzyl, where the aryl or heteroaryl residue optionally substituted by alkyl.

In the above chemical formula And may include X, and X can include, so two residue can form part of the same cyclic structure.

It is also assumed that the above chemical formula covers carbocyclic, aromatic and heteroaromatic structures for the substituents a and/or X, for example naphthyl, hinely, ethanolic, substituted and chlorophenylthio.

Preferred structures are those in which a is chosen from the group consisting of hydrogen, hydroxy and halogen, and X is chosen from the group consisting of alkyl, halogen, thiophenyl, thioalkyl, dialkylamino of alkyl.

More preferred structures are those in which a is chosen from the group consisting of hydrogen, hydroxy and chlorine atom, and X is chosen from g the tours are belong to the above compounds, provided that does not include alendronate.

Most preferred are compounds in which a represents hydroxy and X is (N-methyl-N-pentyl)aminoethyl, i.e. ibandronate. Examples of bisphosphonates, i.e. bisphosphonic acids and their pharmaceutically acceptable salts that can be used as active ingredients of this invention include:

a) 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (alendronate),

b) N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,

b) 4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid,

g) 3-amino-1-hydroxypropylamino-1,1-bisphosphonic acid) (pamidronate),

d) 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-bisphosphonic acid (ibandronate acid),

e) monohydrate, monosodium salt [3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-bisphosphonate acid (ibandronate),

g) 1-hydroxy-3-(N-methyl-N-pentylamine)propylidene-1,1-bisphosphonic acid,

C) 1-hydroxy-2-[3-pyridinyl]ethylidene-1,1-bisphosphonic acid (risedronate),

I) 4-(hydroxymethylene-1,1-diphosphonic acid)piperidine,

K) cycloheptylamine-1,1-bisphosphonic acid (comadronas),

l) 1,1-dihlormetilen-1,1-diphosphonic acid and disodium salt (clodronate),

m) 1-hydroxy-3-(1-pyrrole the GTC),

a) 6-amino-1-hydroxybenzylidene-1,1-bisphosphonic acid (meridional),

p) 3-(dimethylamino)-1-hydroxypropylamino-1,1-bisphosphonic acid (olpadronate),

R) [2-(2-pyridinyl)ethylidene]-1,1-bisphosphonic acid (Piedmont),

(C) (4-chlorophenyl)Tibetan-1,1-diphosphonic acid (tiludronate),

t) 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (alendronate),

y) [(cyclohexylamino)methylene]bisphosphonic acid (cadrona) and/or

f) [1-hydroxy-2-imidazo-(1,2-a)pyridine-3-iletiler]bisphosphonic acid and their pharmaceutically acceptable salts.

In a preferred variant embodiment of the invention, the bisphosphonate can be selected from the group consisting of compounds of paragraphs b-f and their pharmaceutically acceptable salts.

Preferred bisphosphonates are selected from the group consisting of cimatrone, clodronate, tiludronate, etidronate, ibandronate, risedronate, peregrinate, pamidronate, zolendronate and their pharmaceutically acceptable salts.

In a more preferred variant of embodiment of the present invention, the bisphosphonate is a 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-bisphosphonic acid (ibandronate acid) or its pharmaceutically acceptable salt, or even more preferred is asepticheski acceptable chelating agent, or chelator, or its pharmaceutically acceptable salt according to the present invention is a compound that forms through two or more functional groups sustainable cyclic complexes with metal cations, for example preferably polixena acid or its pharmaceutically acceptable salt, similar to EDTA and DTPA. Chelating agents are complex compounds that unlike simple ligands, such as ferrocyanide [Fe(CN)64-] forming a complex salt with one relationship at the expense of the free electron pair able to form more than one connection. For example, Ethylenediamine is bidentata (two communications), trapidil is tridentata (three bonds), and ethylenediaminetetraacetic acid (EDTA) is hexadentate (six ties), which makes it particularly effective as pharmaceutical chelating agent. One of the consequences of chelation is the formation of a cyclic structure, which has a high thermodynamic and thermal stability similar to that of the aromatic cycles. Moreover, the chelate complex is usually more stable than the ligand, as would be the destruction of the two links the chelate effect.

Preferably the chelating agent is a divalent cation chelator, and more preferably, the chelator selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylene glycol-bis--aminoacylase ether)tetraoxane acid (EGTA), N-(hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), triethanolamine, 8-hydroxyquinoline solution, citric acid, tartaric acid, phosphoric acid, gluconic acid, some saccharine acid, thiodipropionic acid, aacondicionado acid, lecithin, di(hydroxyethyl)glycine, phenylalanine, tryptophan, glycerol, sorbitol and their pharmaceutically acceptable salts.

More preferably, the chelating agent is selected from the group consisting of EDTA, DTPA, citric acid, tartaric acid, phosphoric acid, gluconic acid or their pharmaceutically acceptable salts, and even more preferably, the pharmaceutically acceptable agent is EDTA or DTPA, or their pharmaceutically acceptable salt.

In a preferred variant embodiment of the present invention the molar ratio between bisphosphonates and a pharmaceutically acceptable chelating agent siteline about 1:10.

For example, a mixture containing 1 mg of ibandronate/ml of physiological solution, brought to pH 7.4. To a solution of ibandronate add EDTA in a concentration range of 0.1-10 mg/ml, This corresponds to a molar ratio of ibandronate EDTA and about 1:0.1 to 1:10, it is Shown that enhance the action of EDTA is dose-dependent. At the lowest ratio of 1:0.1 to another, there is some beneficial effect, while the highest ratio of 1:10 is still unable to completely avoid undesirable local reactions. Thus, it can be expected that a much higher and lower molar ratios are also applicable to improve local tolerance input parenteral bisphosphonate mixtures. In addition, the effect of EDTA on a local reaction caused by alendronate, and the effectiveness of EDTA as a chelating agent could also be demonstrated.

Composition, as described above, may contain one or more additional pharmaceutically acceptable chelating agent, as indicated above.

Fillers can be selected from diluents, solvents and/or preservatives, such as water, alcohols, polyols, glycerine and vegetable oils. The compositions of the present image is a variant of the embodiment of the present invention composition, as described above, may include a bisphosphonate or farmatsevticheskii acceptable salt, pharmaceutically acceptable chelating agent, tonicity agent (control toychest agent, as described below), regulating the pH of the agent (i.e., a base, a buffer, as described below) and the solvent. In addition, these compositions optionally can contain a local anesthetic.

In a more preferred embodiment of the present invention the pH value of the solution of the above compositions is in the range of 2-10, preferably 4-9, more preferably 6-8, and most preferably 7-8, for example, about 7.4.

In an even more preferred variant of the embodiment according to the present invention is the above composition is a parenteral composition, including:

a) 0.1 to 10 mg of the monohydrate, monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-bisphosphonate acid;

b) 0.5 to 50 mg of the dihydrate disodium salt of EDTA.

For example, the above composition may include:

a) 0.1 to 10 mg of the monohydrate, monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-bostonboy acid;

b)DT-50 mg dihydrate disodium salt EDTA;

C) about 9.0 mg of sodium chloride;

d) sodium hydroxide in sufficient quantity to a pH of approximately 7.4;Preferably, the composition for parenteral administration may contain about 1,125 mg of sodium salt of ibandronate, about 10 mg of the dihydrate disodium salt EDTA, about 5,78 mg hydrochloride lidocaine, about 9.0 mg of sodium chloride, sodium hydroxide in sufficient quantity to pH 7.4 and water for injection sufficient to 1.0 ml.

In addition, the invention discloses a method of obtaining a composition as described above, comprising mixing at least one of bisphosphonates at least one pharmaceutically acceptable chelating agent and a pharmaceutically acceptable filler.

The invention also includes a method of obtaining a composition as described above, by mixing at least one of bisphosphonates at least one pharmaceutically acceptable chelating agent and a local anesthetic.

The compositions of the present invention is applicable to the treatment and prevention of diseases, including bone resorption, especially osteoporosis, Paget's disease, hypercalcemia when zacateca and disease prevention, including bone resorption, especially osteoporosis, Paget's disease, hypercalcemia in malignant tumors and metabolic bone tissue, comprising the step of introducing the patient a composition as described above.

In addition, the invention includes a device for local and systemic injections with a slow release, including composition, as described above.

In more detail, the composition, as described above, may contain additional excipients selected from the solvents and co-solvents (water for injection, ethanol, glycerine, propylene glycol or polyethylene glycol, various oils), solubilizers, moisturizing, suspendida or thickening agents (carboxymethylcellulose, Cremophore EL, desoxycholate sodium, gelatin, lecithin, Polysorbate 20 and 80, poloxamer), antioxidants and reducing agents (ascorbic acid, sodium bisulfite, sodium metabisulfite), antimicrobial preservatives (benzyl alcohol, propyl paraben and methyl paraben), buffers and regulating the pH of agents (acetate, citrate, lactate, hydrochloric acid, sodium hydroxide), protection of the body and regulators toychest (sodium chloride, glucose, mannitol) or metastases the invention the composition is a parenteral, comprising a bisphosphonate and a pharmaceutically acceptable chelating agent(s), as described above.

Parenteral administration of the compositions, as described above, typically includes subcutaneous, intramuscular, intravenous, transdermal, intradermal, intranasal, intraarterial and intraperitoneal injection or infusion. Preferably parenteral includes subcutaneous, intramuscular and intravenous injection or infusion, and more preferably subcutaneous injection or infusion.

In addition, the invention relates to the use of the above compositions for the preparation of drugs used in the treatment and prevention of diseases involving bone resorption, especially osteoporosis, Paget's disease, hypercalcemia in malignant tumors and metabolic bone tissue. The invention relates also to the use of the above composition to obtain drugs used to prevent tissue damage after parenteral administration of bisphosphonates, preferably by introducing an aqueous solution.

In addition, the invention relates also to a device for local and systemic sustained release, including the ical pumps or located outside of the portable infusion pumps, United with the supplier capacity and/or sewn under the skin of the cannula.

In addition, the invention relates also to a device making it possible, provide or facilitate parenteral administration of a composition as described above. For example, you can use the device to achieve local and systemic sustained release, including portable infusion pumps, United with the supplier capacity and/or sewn under the skin of the cannula (e.g., portable injection device; US patent No. 886999) to reduce local pain caused by injection, such as needleless injectors (e.g., MicroPor, MedijectorTM).

In addition, the invention relates to injectable compounds, which release composition as described above, the slow way and can reduce local pain caused by the injection. For example, a mixture of slow release may include forming a depot form compounds such as various pharmaceutically acceptable oil, thickener (carboxymethyl cellulose, poloxamer, gelatin), biodegradable microparticles, forming polymers (polymers based on lactide/glycolide, polyanhydride, chitosan), or pharmaceutically acceptable polyelectrolyte>Example 1: local tolerance, experience I.

Groups of 3 rats were treated with the studied mixtures containing 1 mg ibandronate/ml saline solution, buffered at pH 7.4. One group of rats received the test solution without additional additives, another group received the test solution with 1 mg/ml EDTA as an additive. The day before treatment to rats shaved back. Three volume, 5 ml each, were injected subcutaneously in three different plot right side of the shaved back. The left side of the back was treated with the appropriate mixture without ibandronate (placebo). Local reactions were assessed by a points system for swelling: 0-no reaction, 0.5 to barely noticeable swelling, 1 - slight swelling, 2-moderate swelling, 3 - pronounced swelling, 4 - severe swelling. Animals were monitored for 9 days, after which he opened. At autopsy, measured the diameter of subcutaneous lesions, mainly consisting of redness or swelling. The results are presented in Fig.1 and 2.

Example 2: local tolerance, experience II.

The same schema as described in example 1 was used to study the dependence of the action of EDTA concentration. Added EDTA at concentrations of 0.1, 1.0 and 10 mg/ml the Results are presented in Fig.3 and 4.

Example 3: local tolerantnosti response to subcutaneously introduced ibandronate. Added DTPA at a concentration of 10 mg/ml the Results are shown in Fig.5 and 6.

Example 4: local tolerance, experience IV.

The same schema as described in example 1 was used to study the effectiveness of EDTA in the local response to subcutaneously introduced alendronate. The investigated mixtures contained 3 mg alendronate/ml saline solution, buffered at pH 7.4. Added EDTA at a concentration of 10 mg/ml the Results are presented in Fig.7 and 8.

As a result, there is a clear evidence that the presence of such a chelating agent like EDTA or DTPA, dosage forms for injection bisphosphonates such as alendronate or ibandronate reduces both the intensity and duration of local swelling at the injection site, and the severity of the skin lesions found at autopsy in 9 days.

Example 5: parenteral composition I, mg:

Sodium salt of ibandronate 1,125

The dihydrate disodium salt EDTA 10,0

Sodium chloride 9,0

Sodium hydroxide in sufficient quantity To pH 7.4

Water for injection sufficient To 1.0 ml

Example 6: parenteral composition II, mg:

Sodium salt of ibandronate 1,125

DTPA 10,0

Sodium chloride 9,0

Sodium hydroxide in sufficient quantity To pH 7.4

Water for injection to access the salt EDTA 10,0

Sodium chloride 9,0

Sodium hydroxide in sufficient quantity To pH 7.4

Water for injection sufficient To 1.0 ml

Example 8: parenteral composition IV, mg:

Sodium salt of ibandronate 1,125

The dihydrate disodium salt EDTA 10,0

Hydrochloride lidocaine 5,78

Sodium chloride 9,0

Sodium hydroxide in sufficient quantity To pH 7.4

Water for injection sufficient To 1.0 ml

Captions to drawings

Fig.1 - the average degree of swelling after subcutaneous injection of a solution of ibandronate, pH 7.4, with 0.1% EDTA and without (n=9).

Fig.2 - the average diameter of subcutaneous changes through 9 days after subcutaneous injection of a solution of ibandronate, pH 7.4, with 0.1% EDTA and without (n=9).

Fig.3 - average degree of swelling after subcutaneous injection of a solution of ibandronate, pH 7.4, EDTA and without (n=9). Data with 0.1% EDTA combined with the results of the first experiment (n=18).

Fig.4 - the average diameter of subcutaneous changes through 9 days after subcutaneous injection of a solution of ibandronate, pH 7.4, EDTA and without (n=9). Data with 0.1% EDTA combined with the results of the first experiment (n=18).

Fig.5 - average degree of swelling after subcutaneous injection of a solution of ibandronate, pH 7.4, with 1% DTPA and without (n=12).

Fig.6 - the average diameter of subcutaneous changes through 9 days after subcutaneous injection of a solution ibandronate 7,4, with 1% EDTA and without (n=9).

Fig.8 - the average diameter of subcutaneous changes through 9 days after subcutaneous injection of a solution of alendronate, pH 7.4, EDTA and without (n=9).

Claims

1. Parenteral composition comprising (1) a bisphosphonate selected from the group consisting of (a) N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonate acid; b) 4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonate acid; 3-amino-1-hydroxypropylamino-1,1-bisphosphonate acid (pamidronate); g) 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-bisphosphonate acid (ibandronic acid administered intravenously)e) monohydrate, monosodium salt [3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-bisphosphonate acid (ibandronate); e) 1-hydroxy-3-(N-methyl-N-pentylamine)propylidene-1,1-bisphosphonate acid; g) 1-hydroxy-2-[3-pyridinyl]ethylidene-1,1-bisphosphonate acid (risedronate); C) 4-(hydroxymethylene-1,1-bisphosphonic acid)piperidine, and cycloheptylmethyl-1,1-bisphosphonate acid (comadrona); K) 1,1-dihlormetilen-1,1-diphosphonic acid disodium salt (clodronate); l) 1-hydroxy-3-(1-pyrrolidinyl)propylidene-1,1-bisphosphonate acid (EB-1053); m) 1-hydroxyethane-1,1-diphosphonic acid (etidronate acid); n) 6-amino-1-hydroxyhexanoate); p) [2-(2-pyridinyl)ethylidene]-1,1-bisphosphonate acid (peregrinate); p) (4-chlorophenyl)Tibetan-1,1-diphosphonic acid (tiludronate) and/or (C) 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonate acid (zoledronate); t) [(cyclohexylamino)methylene]bisphosphonates acid (ekadanta) and/or y) [1-hydroxy-2-imidazo-(1,2-a)pyridine-3-iletiler]bisphosphonates acids and their pharmaceutically acceptable salts; (2) a pharmaceutically acceptable chelating agent selected from EDTA and DTPA and their pharmaceutically acceptable salts, and (3) pharmaceutically acceptable excipient.

2. The composition according to p. 1, where a bisphosphonate selected from the group consisting of cimatrone, clodronate, tiludronate, etidronate, ibandronate, risedronate, peregrinate, pamidronate, zolendronate and their pharmaceutically acceptable salts.

3. Composition under item 1 or 2, where the bisphosphonates is 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-bisphosphonic acid (ibandronic acid) or its pharmaceutically acceptable salt.

4. Composition according to any one of paragraphs.1-3, where the bisphosphonates is monohydrate, monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-bisphosphonate acid.

5. Composition according to any one of paragraphs.1-4, where the molar ratio of bisphosphonates and pharmaceuti PP.1-5, where the molar ratio of bisphosphonates and pharmaceutically acceptable chelating agent is from about 1:0.1 to about 1:50.

7. Composition according to any one of paragraphs.1-6, where the molar ratio of bisphosphonates and pharmaceutically acceptable chelating agent is about 1:10.

8. Composition according to any one of paragraphs.1-7, where the composition includes one or more additional pharmaceutically acceptable chelating agents.

9. The composition according to p. 8, wherein the excipients selected from diluents, solvents, and/or preservatives.

10. Composition according to any one of paragraphs.1-9, comprising a bisphosphonate or pharmaceutically acceptable salt, pharmaceutically acceptable chelating agent, tonicity agent, regulating the pH of the agent and the solvent.

11. Composition according to any one of paragraphs.1-10, additionally containing a local anesthetic.

12. Composition according to any one of paragraphs.1-11, where the pH value is in the range of 2-10.

13. Composition according to any one of paragraphs.1-12, where the pH value is in the range of 4-9.

14. Composition according to any one of paragraphs.1-13, where the pH value is in the range of 6-8.

15. Composition according to any one of paragraphs.1-14, where the pH value is in the range of 7-8.

16. Composition according to any one of paragraphs.1-15, where the pH is around 7.4.

17. The composition according to lubitel-N-pentyl)amino-1-hydroxypropane-1,1-bisphosphonate acid and b) 0.5 to 50 mg of the dihydrate disodium salt of EDTA.

18. Composition according to any one of paragraphs.1-17, comprising a) 0.1 to 10 mg of the monohydrate, monosodium salt of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-bisphosphonate acid; b) 0.5 to 50 mg of the dihydrate disodium salt EDTA; about 9.0 mg of sodium chloride; sodium hydroxide in sufficient quantity to a pH of about 7.4 and d) water for injection sufficient to 0.5 or 1.0 ml.

19. Composition according to any one of paragraphs.1-18, comprising approximately 1.125 mg of sodium salt of ibandronate, about 10 mg of the dihydrate disodium salt EDTA, about 9.0 mg of sodium chloride, sodium hydroxide in sufficient quantity to pH 7.4 and water for injection sufficient to 1.0 ml.

20. Composition according to any one of paragraphs.1-19, comprising approximately 1.125 mg of sodium salt of ibandronate, about 10 mg of the dihydrate disodium salt EDTA, about 5,78 mg hydrochloride lidocaine, about 9.0 mg of sodium chloride, sodium hydroxide in sufficient quantity to pH 7.4 and water for injection sufficient to 1.0 ml.

21. A method of obtaining a composition according to any one of paragraphs.1-20, comprising mixing at least one of bisphosphonates with at least one pharmaceutically acceptable chelating agent and a pharmaceutically acceptable excipient.

22. The method of obtaining the composition according to p. 21, vcliuciaiushim agent and a local anesthetic.

23. Device for local and systemic sustained release containing composition according to any one of paragraphs.1-20 and consisting of implanted osmotic pumps or located outside of the portable infusion pumps, United with the supplier capacity and/or sewn under the skin of the cannula.

 

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The invention relates to medicine, in particular to urology and endocrinology

The invention relates to new derivatives of amine of the formula (I), where R1is karbamoilnuyu group (which may have one or two Deputydescribed later), thiocarbamoyl group (which may have one or two Deputydescribed later), sulfonyloxy group (which has one Deputydescribed next) or carbonyl group (which has one Deputydescribed below); R2represents a hydrogen atom; R3represents C1-C10alkyl group; W1, W2and W3each represents a single bond or C1-C8alkylenes group; X represents an oxygen atom or a sulfur atom; Y represents an oxygen atom; Q represents a sulfur atom; Z represents = CH-group or a nitrogen atom; Ar represents a benzene or naphthalene ring; L represents 1 to 2 substituents in Ar ring and each Deputy represents a hydrogen atom, a C1-C6alkyl group; Deputyrepresents (i) C1-C10alkyl group, (ii)3-Сu/chr/947.gif" ALIGN="ABSMIDDLE">described later), and so on; Deputyrepresents (i) C1-C6alkyl group, (ii) C1-C6halogenating group, (iii) C1-C6CNS group, (iv) halogen atom, (v) hydroxyl group, (vi) cyano, (vii) a nitro-group, (viii) alkylenedioxy; or its pharmaceutically acceptable salts or esters

The invention relates to the pharmaceutical industry and relates to improved pharmaceutical preparations containing dehydroepiandrosterone (DHEA), enriched to polymorphic forms I or II, for therapeutic purposes
The invention relates to medicine, in particular to methods of stimulation of osteogenesis

The invention relates to new thiazole derivative of the formula (I) in which R1denotes a group of formula (a)-(d), where R2denotes a group of formula (II), R3denotes hydrogen, alkyl, cycloalkyl, and so on; R4denotes alkyl, phenyl, heteroaryl; R5and R6each independently of one another denote hydrogen, heteroaryl; R7and R8each independently of one another denotes hydrogen, or R7and R8together with the N atoms to which they are linked, form a 5-6-membered heterocycle; R9denotes hydrogen, alkyl, cycloalkyl; R10denotes phenyl, benzyl, and so on; And denotes a carbonyl or sulfonyl; In denotes hydrogen; and m each represents zero or a positive number from zero to 2, but not equal to zero when R1denotes-NH2; b denotes a number from zero to 4; C, d, f, g, k, l and m each independently of one another denotes zero or 1, so that each of the C, f and g cannot simultaneously denote zero and thus m does not denote zero when f or g represents 1; q represents zero or 1, and each k and l also denotes zero, when i denotes zero; e denotes a number from zero to 3; h represents a number from zero to 5; j denotes a number from zero to 2; and the sum is

The invention relates to the derivatives of pyridazine General formula I, in which R1represents phenyl or pyridyloxy group which may be substituted by 1-3 substituents selected from halogen and lower alkoxygroup; R2represents a phenyl group which may be substituted at the 4th position of the lower alkoxygroup, lower alkylthiol, lower alkylsulfonyl or lower alkylsulfonyl group and in other positions 1 or 2 substituents selected from halogen atoms, lower CNS groups, lower alkylthio, lower alkylsulfonyl groups and lower alkylsulfonyl groups;3represents a hydrogen atom; a lower CNS group; halogenated lower alkyl group; a lower cycloalkyl group; phenyl, pyridyloxy or fenoxaprop, which may be substituted by 1-3 substituents selected from halogen atoms, lower alkyl groups, lower CNS groups, carboxyl groups, lower alkoxycarbonyl groups, nitro, amino, lower alkylamino and lower alkylthio; unsubstituted or substituted lower alkyl group piperidino, piperidinyl, piperazine derivatives or morpholinopropan; unsubstituted or zameshannuu lower alkylamino group piperazinylcarbonyl group; A represents a linear or branched lower alkylenes or lower alkynylamino group having 1-6 carbon atoms; or And can mean single bond when R3represents the lower cycloalkyl or halogenated lower alkyl group; X represents an oxygen atom or a sulfur atom; provided that the following combinations are excluded: R1and R2represent 4 metoksifenilny, X represents an oxygen atom, a represents a single bond, and R3represents a hydrogen atom or 2-chloraniline group; or their salts

The invention relates to the field of medicine and relates to a treatment for abnormal bone metabolism

The invention relates to medicine, namely to traumatology and orthopedics, and can be used for the treatment of fistulous forms of chronic osteomyelitis with the presence of small sequestrum
The invention relates to medicine, surgery and can be used for the treatment of osteomyelitis

The invention relates to new thiazole derivative of the formula (I) in which R1denotes a group of formula (a)-(d), where R2denotes a group of formula (II), R3denotes hydrogen, alkyl, cycloalkyl, and so on; R4denotes alkyl, phenyl, heteroaryl; R5and R6each independently of one another denote hydrogen, heteroaryl; R7and R8each independently of one another denotes hydrogen, or R7and R8together with the N atoms to which they are linked, form a 5-6-membered heterocycle; R9denotes hydrogen, alkyl, cycloalkyl; R10denotes phenyl, benzyl, and so on; And denotes a carbonyl or sulfonyl; In denotes hydrogen; and m each represents zero or a positive number from zero to 2, but not equal to zero when R1denotes-NH2; b denotes a number from zero to 4; C, d, f, g, k, l and m each independently of one another denotes zero or 1, so that each of the C, f and g cannot simultaneously denote zero and thus m does not denote zero when f or g represents 1; q represents zero or 1, and each k and l also denotes zero, when i denotes zero; e denotes a number from zero to 3; h represents a number from zero to 5; j denotes a number from zero to 2; and the sum is

The invention relates to medicine, specifically to pharmacology, and relates to a composition for neoplasms of collagen containing calcium hydroxide, two or more atomic alcohol and fatty oil of vegetable or animal origin, and, if necessary, pharmaceutically acceptable excipients, and also relates to the preparation of compositions, in the preparation of drugs for stimulation of tumor collagen in vivo

The invention relates to compounds of the formula a-b-D-E-F-G, where the values of the radicals presented in the description in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts

The invention relates to compounds of the formula R1-Y-A-B-D-E-F-G, where a represents-NR2-N= CR2- In means (C1-C8)-alcander, D is-O-, -CO-NR2- E means a 6-membered aromatic ring system, F has the values specified for D, G means-C(R4)(R5)(C(R6)(R7))p-(CH2)q-R10, Y represents a simple bond, R1means 4-10-membered mono - or polycyclic aromatic or nonaromatic ring system, which optionally may contain 1-4 atom N, R2means N, R8OR9; R4, R5, R6, R7denote, independently of one another, H, R8N(R2R9, R8OC(O)N(R2R9, R8means H or (C5-C14)-aryl-(C1-C8)-alcander, R9simple link, R10means C(O)R11, R11IT means, p, q independently from each other 0 or 1, in all their stereoisomeric forms and mixtures thereof in all ratios, and their physiologically acceptable salts
The invention relates to food processing and pharmaceutical industries
Drug // 2238730
The invention relates to medicine, namely to medicines broad-spectrum
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