Bisphosphonic acids intended for treatment and prevention of osteoporosis

FIELD: medicine.

SUBSTANCE: treatment or prevention of osteoporosis is ensured by introduction of a pharmaceutical composition containing approximately 150 mg of bisphosphonic acid. Treatment is administered once a month within one day. As bisphosphonic acid, risedronic acid is used preferentially.

EFFECT: invention allows improving clinical effectiveness and preventing by-effects in comparison with more frequent introduction of bisphosphononates.

6 cl, 1 tbl, 1 ex

The invention relates to the use of bisphosphonic acids, especially 1-hydroxy-3-(N-methyl-N-pentyl)aminopiperidin-1,1-bisphosphonate acid (ibandronic acid administered intravenously), or pharmaceutically acceptable salts of these acids in the composition of medicines for the preparation of drugs for the prevention or treatment of disorders characterized by pathologically increased bone resorption, especially for the prevention and treatment of osteoporosis.

The main function of the bones support the body, so they are often viewed simply as a building material. However, bone is a complex biomaterial adapted to a wide range of needs, incentives, and adverse impacts to which it is exposed. Internal prostheses replace bones and joints, but even highly advanced biomechanical internal prostheses do not actively respond to loads and environmental factors.

A number of diseases of humans and animals from mammals leads to disruption of bone resorption or associated with abnormal bone resorption. Such diseases include, but are not limited to, osteoporosis, Paget's disease (deforming fibrosa), destruction of the bone around the prosthesis or osteolysis, malignant hypercalcemia and metastatic lesions of bones. Of the listed diseases, the most common is osteoporosis, which is most common in women after menopause. Because osteoporosis and other diseases associated with bone destruction, are chronic, it is believed that the treatment should be prolonged.

Bisphosphonates, i.e. bisphosphonic acids or their pharmaceutically acceptable salts are synthetic analogs of natural pyrophosphate. Because of their pronounced affinity for the solid-phase calcium phosphate bisphosphonates strongly associated only with a mineral structure of bones. Pharmacologically active bisphosphonates are well known in the prior art, they are powerful inhibitors of bone resorption and therefore can be used for the treatment and prevention of diseases associated with impaired bone resorption, especially osteoporosis, Paget's disease, malignant hypercalcemia, metastatic and metabolic disorders of the bones.

As pharmaceutical agents bisphosphonates 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., each of which is referred to here by reference.

Pharmaceutical forms of bisphosphonates, currently presented on the market, intended for oral administration (tablets or capsules), or for intravenous injection or infusion (in the form of solutions). Admission to those who appenticeship doses of these drugs are well tolerated. However, representatives of the class of bisphosphonates irritate the skin and mucous membranes, and with consistent use in oral form can cause side effects, such as negative effects on the esophagus or gastrointestinal tract. For this reason, given the low bioavailability of bisphosphonates for oral use, in the present case of oral application method it is necessary to consider that the possible adverse effects for the patient.

The mechanism of action of bisphosphonates can be divided into two groups. Ibandronate belongs to more efficient nitrogen-containing bisphosphonate (R.G.G.Russell, M.J.Rogers in Bone 25 (1), 1999, s-106; M.J.Rogers and others in the Cancer 88 (12), Suppl., 2000, s-2978). Ibandronate is one of the most effective bisphosphonates, which are currently undergoing clinical testing as a medication for the treatment of osteoporosis and metastatic bone lesions. In animal experiments it was shown that ibandronate 2, 10, 50 and 500 times more effect on bone resorption than risedronate, alendronate, pamidronate and clodronate respectively (R.C.Mühlbauer etc. in J. Bone Miner. Res. 6, 1991, s-1011).

Ibandronate inhibits bone resorption without any deterioration of mineralization (R.C.Mühlbauer etc. in J. Bone Miner. Res. 6, 1991, s-1011). It was found that the inhibition of bone destruction occurs due to the reduction activestealth. In large doses ibandronate reduces the number of osteoclasts (R.C. Mühlbauer, etc. in J. Bone Miner. Res. 6,1991, s-1011).

As shown, bisphosphonates showed himself as a highly effective tool in the treatment of osteoporosis. However, because of a number of the limitations associated with low bioavailability for oral use and the possibility of gastro-intestinal disorders, it is obvious that the treatment/recovery of patients can achieve a better result by changing the mode, making it more convenient and flexible. Intermittent regimens, for example, once a week, which were previously described in the prior art do not allow to achieve the desired result in the treatment.

It was found that prevention or treatment of diseases for which characterized pathologically high bone resorption, for example, such diseases as osteoporosis, can be improved by monthly applications from 50 to 250 mg bisphosphonates or its pharmacologically acceptable salt, especially the monthly use of ibandronate, namely of ibandronic acid administered intravenously or its pharmaceutically acceptable salt.

Thus, the present invention relates to the use of bisphosphonates acid or its pharmaceutically acceptable salts, especially of ibandronic acid administered intravenously or its pharmaceutically acceptable salts, for the por is for drinking, preparing medicines for the prevention or treatment of diseases, characterized by pathologically increased bone resorption, where the medicinal product

a) presents bisphosphonates acid or its pharmaceutically acceptable salt in an amount of about 50 to 250 mg, preferably from about 100 to 150 mg, and

b) is used orally for one month for one night or two, three days in a row.

Oral application of the drug in an amount not less than 120%, especially from 120 to 200% of the expected monthly doses for patients has the advantage that it is convenient and gives excellent results. "The expected dose" (100%) corresponds to the cumulative effective daily doses. Prior to the implementation of the programme of clinical research ibandronate was not known to any of the bisphosphonates, reducing the brittleness of the bones, which would have taken under the scheme, implying intervals more days when drugs were not used; effective were the only scheme of daily use. In the end it was completely unexpected that reduce bone fragility can be achieved when taking bisphosphonates once a month as a single dose or by the scheme, which consists in taking a few tablets.

Thus, the present invention relates to the use of bisphosphonic acids or their pharmaceutically acceptable salts, especially ibandronova key is lots or its pharmaceutically acceptable salts, for the preparation of drugs for prevention or treatment of diseases characterized by patalogichesky increased bone resorption, such as osteoporosis. According to the present invention, the drug includes at least 120% of the expected effective daily dose bisphosphonic acids or their pharmaceutically acceptable salts and applied monthly for one day or two, three days in a row.

The preferred embodiment of the present invention is the use of ibandronic acid administered intravenously or its pharmaceutically acceptable salts for the preparation of drugs for prevention or treatment of disorders characterized by pathologically increased bone resorption, where the medicinal product

a) presents ibandronova acid or its pharmaceutically acceptable salt in an amount of about from 100 to 150 mg and

b) is used orally for one month for one night or two, three days in a row.

The concept of "bisphosphonic acid" means substances that have two phosphonate groups bound photoaffinity ties with the Central (genialny) carbon atom. This R-C-P structure of the following formula (I). It should be noted that in the present description, the term "bisphosphonic acid"used in relation to therapeutic agents is e includes bisphosphonates, biphosphonate acid and bisphosphonic acids and salts and derivatives of these substances. Use special items when referring to a bisphosphonate or bisphosphonates do not purport to limit the scope of the present invention, if it is not stated specifically.

The term "pharmaceutically acceptable" in this case means that salts or chelating agents acceptable from the point of view of assessing their toxicity.

The term "pharmaceutically acceptable salt" refers to salts of ammonium, salts of alkali metals such as potassium and sodium (including mono, di - and trinitramine salt; they are preferred), salts of alkaline-earth metals such as calcium and magnesium, salts with organic bases, such as dicyclohexylamine salt, N-methyl-D - glucamine, and salts of amino acids such as arginine, lysine and the like.

The concept of "disease characterized by pathologically increased bone resorption" reflects a certain medical condition, the cause of which is set or not. Examples include osteoporosis after menopause, idiopathic juvenile osteoporosis, osteoporosis associated with Klinefelter syndrome, male osteoporosis, osteoporosis, due to the nature of power, osteoporosis associated with transplantation is lanov, osteoporosis associated with immobilization, osteoporosis, associated with inflammation and corticosteroids.

The term "within one month for one night or two, three days in a row" means the use of one to three tablets, proportionately or disproportionately dose for one day or two, three days in a row during one month, preferably for one day per month. In the present description the term "month" is used in accordance with the fact, as usually understood as the length of time duration approximately equal to four (4) weeks, 30 days or 1/12 part of the calendar year.

The term "drug" refers to a pharmaceutical composition. This refers to single or multiple patterns of use.

It is preferable to take the drug for one day per month. It is preferable to take the drug as a single dose, however, the present invention may use drugs as a set of sub-doses, which take two or three days in a row during the month.

Preferably, the drug involved is at least 100%, preferably from 120 to 200%, most preferably from 120 to 150% of the effective dose bisphosphonic acids or their pharmaceutically acceptable salts, more preferably bandoneonista or its pharmaceutically acceptable salts.

The concept of "effective dose" is from about 50 to 250 mg, more preferably from about 100 to 150 mg, bisphosphonates or its pharmaceutically acceptable salt, for example of ibandronic acid administered intravenously or its pharmaceutically acceptable salt. It is noted that the effective dose may be single or consist of several smaller doses (sub-doses). For example, if the effective dose is 150 mg, the drug can be taken as a single dose (1) 150 mg, two sub-doses (2) 75 mg, which take one day or two days in a row, or three sub-doses (3) 50 mg, which take one day, or two, three days in a row. If the effective dose is 100 mg, the drug can be taken one (1) dose of 100 mg, in the form of two sub-doses (2) 50 mg for one day or for two days in a row, preferably for two days in a row.

"Bisphosphonic acids and their pharmaceutically acceptable salts" as pharmaceutical agents are described, for example, in patents US 4509612, US 4666895, US 4719203, US 4777163, US 5002937, US 4971958, US 4958839, EP-A 252504 and EP-A 252505, which are referred to in the present description by reference.

Methods of cooking bisphosphonic acids and their pharmaceutically acceptable salts can be found, for example, in US 3962432, US 4054598, US 4267108, US 4327039, US 4407761, US 4621077, US 4624947, US 4746654, US 4922077, US 4970335, US 5019651, US 4761406, US 4876248, J. Org. Chem. 32, 1967, s and EP-A 252504; they are presented in the present the invention in the form of links. Pharmaceutically acceptable salts bisphosphonic acids can also be used in the present invention. Examples of basic salts bisphosphonic acids are ammonium salts, alkali metal salts, such as potassium and sodium (including mono, di - and trinitramine salt; they are preferred), salts of alkaline-earth metals such as calcium and magnesium, salts with organic base, such as dicyclohexylamine salt, N-methyl-D-glucamine and salts of amino acids such as arginine, lysine, and so forth. Non-toxic, physiologically acceptable salts are preferred. Salt can be prepared by methods known in the prior art, for example as described in EP-A 252504 and US 4922077 referred to in the present description by reference.

Preferably, the drug contained from 100 to 150 mg of ibandronic acid administered intravenously or its pharmaceutically acceptable salt. It is preferable to take the drug as a single dose.

In the preferred embodiment of the present invention the term "bisphosphonate" corresponds to the substances with the General formula

where a and X are independently selected from the group consisting of hydrogen, hydroxyl, halogen, amino group, SH, phenyl, alkyl, mono - or dialkylamino group, mono - or dialkylaminoalkyl group, CNS group thioalkyl, thiophenyl, as well as fragments of the molecule aryl or heteroaryl selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazolyl and benzyl, where the optimum is the replacement of the aryl or heteroaryl-alkyl.

In the above chemical formula And may include X and X include And, thus, that two fragment molecules can form part of the same cyclic structure.

This also implies that the composition of the above chemical formula includes carbocyclic, aromatic and heteroaromatic structures for a and/or X substituents, for example, naphthyl, hinely, ethanolic, substituted and chlorophenylthio.

Preferred are structures in which a is selected from the group represented by hydrogen, hydroxyl and halogen, and X is selected from the group represented by alkyl, halogen, titaniam, thioalkyl and dialkylaminoalkyl.

More preferred are those in which a is selected from the group represented by hydrogen, hydroxyl and CL, and X is selected from the group represented by alkyl, CL, chlorophenylthio and dialkylaminoalkyl.

Preferred bisphosphonic acid or its pharmaceutically acceptable salt selected from the group represented by alendronate, cimatrone, clodronate, EB-1053, tiludronate, etidronate, ibandronate, incarnata, minodronate nerekonata, olpadronate, risedronate, peritoneum, pamidronate, zolendronate or their acceptable salts, such as monosodium monohydrate salt of ibandronic acid administered intravenously.

Ibandronic acid (1-hydroxy-3-(N-methyl-N-pentyl)aminopiperidin-1,1-bisphosphonic acid) or its physiologically compatible salts are particularly preferred, for example, monosodium monohydrate salt of ibandronic acid administered intravenously.

Bisphosphonates and their pharmaceutically acceptable salts can be used alone or in combination with other drugs affecting bone, as in fixed combinations, and in the form of individual drugs taken simultaneously; such drugs include hormones such as steroid hormones, such as estrogen; partial agonist of estrogen or combination estrogen-gestagen; calcitonin, or its analogs, or its derivatives, for example calcitonin parathyroid hormone (parathyroid hormon - PTH) salmon, eel or human, or equivalent, such as PTH (1-84), PTH (1-34), PTH (1-36), PTH (1-38), PTH (1-31)NH₂or PPTS 893; SERM (selective estrogen receptor modulator is a Selective Estrogen Receptor Modulator), such as raloxifene, lasofoxifene, TSE-434, FC1271, tibolone, vitamin D or similar. Such additional drugs affecting bone, can be used more often than a bisphosphonate.

Suitable pharmaceutical composition is known in the prior art and have been described, for example, in US 6143326 and US 6294196; in the present description, they are shown as links.

For the preparation of tablets, coated tablets, coated tablets or hard gelatin capsules of the substance according to the present invention can be mixed with pharmaceutically inert inorganic or organic excipients. Examples of suitable excipients for tablets, coated tablets or hard gelatin capsules can be lactose, corn starch or its derivatives, talc or stearic acid, or their salts.

Pharmaceutical compositions may also contain preservatives, agents that promote dissolution, stabilizers, moisturizers, emulsifiers, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, the agents to provide coverage or antioxidants. They may also contain other therapeutically valuable agents. Preferred is a pharmaceutical composition, presented in the form of a tablet with a film coating, the core of which contains from 50 to 200 mg bisphosphonates acid or its pharmaceutically acceptable salt, as described above, and one or more pharmaceutically acceptable excipient selected from the group consisting of lactose, polyvinylpyrrolidone, microcrystalline cellulose, crosspovidone, stearic acid, silicon dioxide; tablet core contains od is n or more pharmaceutically acceptable excipient, selected from the group containing hypromellose, titanium dioxide, talc and polyethylene glycol 6000. Such compositions are known in this field and, for example, described in US 6143326 and US 6294196.

Another aspect of the present invention is a method of treating, reducing the symptoms of diseases or prevention of disorders characterized by pathologically increased bone resorption. The method consists in the fact that mammals prescribe the effective amount bisphosphonates acid or its pharmaceutically acceptable salts. Particularly the present invention relates to a method of treatment or lowering the manifestations of disorders characterized by pathologically increased bone resorption; the method consists in the oral use of an effective amount of bisphosphonate acid or its pharmaceutically acceptable salt, approximately from 50 to 250 mg bisphosphonates acid or its pharmaceutically acceptable salt is used for one or two, three consecutive days per month. As mentioned above, an effective amount bisphosphonates acid or its pharmaceutically acceptable salt can be taken as a single dose or as several smaller doses (sub-doses).

Preferably according to the method, which consists in taking from about 50 to 250 mg, more preferably from about 100 to 150 mg, bisphosphonates is whether its pharmaceutically acceptable salt, within one or two or three consecutive days per month. Although the method involves the administration of the medicine in the form of several sub-doses, the most preferred is the use of a single dose. Examples of the application dose of the drug in the form of several sub-doses are as follows: if the effective dose is 150 mg, it can be taken as two sub-doses (2) 75 mg per day or for two days in a row, or three sub-doses (3) 50 mg for one day or for two, three days in a row; if the effective dose is 100 mg it can be taken as two sub-doses (2) 50 mg one day or two consecutive days, preferably for two days in a row. Preferred bisphosphonates is ibandronic acid or its pharmaceutically acceptable salt such as monosodium monohydrate salt of ibandronic acid administered intravenously.

Preferably according to the method of the present invention bisphosphonic acid selected from the group represented by alendronate, cimatrone, clodronate, EB-1053, tiludronate, etidronate, ibandronate, incarnata, minodronate, nerekonata, olpadronate, risedronate, peritoneum, pamidronate, zolendronate or their pharmaceutically acceptable salts. More preferably, the selected bisphosphonates acid was ibandronate or its pharmaceutically acceptable salt, for example of Manager the t monosodium salt of ibandronic acid administered intravenously.

The invention is further illustrated by example.

The pharmaceutical composition

As an example, consider the composition of the tablets weighing 50 mg of the Composition and method of preparing such tablets are known in the prior art and shown, for example, in US 6143326 and US 6294196.

Other compositions can be prepared by calculating the content of ingredients based on the number bisphosphonates acid such as monosodium monohydrate salt of ibandronic acid administered intravenously.

1. A method of treating or preventing osteoporosis, comprising a first treatment by oral administration to a subject in need of such treatment, the first dose in one day pharmaceutical composition comprising about 150 mg bisphosphonates acid or of such number of its pharmaceutically acceptable salts, which is equivalent to about 150 mg of the specified bisphosphonates acid, and the continuation of this treatment by oral administration once a month for one day a pharmaceutical composition comprising about 150 mg bisphosphonates acid or of such number of its pharmaceutically acceptable salts, which is equivalent to about 150 mg bisphosphonates acid.

2. The method according to claim 1, wherein the pharmaceutical composition comprises about 150 mg of risedronate key is lots or such number of its pharmaceutically acceptable salts, which is equivalent to about 150 mg of risedronate acid.

3. The method according to claim 1, in which the mentioned pharmaceutical composition is a solid pharmaceutical composition.

4. The method according to claim 2, in which the mentioned pharmaceutical composition is a solid pharmaceutical composition.

5. A method of treating or preventing osteoporosis, comprising oral administration to a subject in need of such treatment, once a month a pharmaceutical composition comprising about 150 mg of risedronate acid or of such number of its pharmaceutically acceptable salts, which is equivalent to about 150 mg of risedronate acid.

6. The method according to claim 5, in which the pharmaceutical composition comprises about 150 mg of risedronate acid or its pharmaceutically acceptable salt, which is equivalent to about 150 mg of risedronate acid.