Medicinal preparation for treating osteonecrosis and for treating patients at risk of osteonecrosis development

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

 

The scope to which the invention relates.

The present invention relates to new indications for a particular class of drugs. More specifically, the present invention relates to the use of bisphosphonates for the treatment of osteonecrosis and related disorders, such as cutting osteochondritis. Further, this invention relates to the use of bifosfonatami for the treatment of patients at risk of developing osteonecrosis.

Prerequisites to the creation of inventions

Osteonecrosis is a special clinical and pathological category, with many different causes and different pathogenesis. Although the violation was written many, are all factors in the etiology and pathogenesis currently remain unknown. Osteonecrosis can affect the site of a bone spontaneously in adults and children (Perthes disease), or be the result of a disease such as alcoholism, effects of glucocorticoids and/or cytotoxic drugs, exposure to a hyperbaric environment (caisson disease)ifracture, infections, haematological diseases, for example. At the present time there is no proven pharmacological tools for the treatment of osteonecrosis.

The consequences of this violation are serious because osteonecrosis usually affects n is a function of the joint and in most cases on the hip joint. With the defeat of the hip joint, the femoral head is sensitive to the destruction that leads to pain, inflexibility and long-term disability. The affected joint is further susceptible to deformation and osteoarthritis. Osteonecrosis with unknown etiology, affects a significant percentage of the population, including children. In particular, the incidence of Perthes disease (Legg-calve-Perthes disease) ranges from 8.5 to 21 per 100,000 children per yearii,iii,iv,v. The etiology of the disease remains unknown, but the total of the last direction of most of theories suggests that the hemorrhage of blood vessels leads to relative ischemia and osteonecrosis, which leads to resorption and destruction of necrotic epiphysis.vi,vii,viii

It is well known that Perthes disease leads to osteoarthritis. To 56 years in 40% of affected patients in one study performed a full surgical replacement of the hip. Is the subchondral bone destruction, as the head of the femur becomes weaker and more osteoporotic. It is not currently known effective medical treatment of Perthes disease. From mechanical influences, such as fastening, almost completely abandoned, because it is not proved that they alter the nature of the current violationix,x. Conventional wisdom dictates that the EU is and thigh of the child achieves a significant degree of deformation, surgery is indicated in order to position the femoral head in the best position in the joint, in an attempt to create a more spherical thigh, and, thus, to improve long-term prognosis. Some surgical tools designed for the prevention of destruction and aimed at saving state after the destruction and deformation of the thigh. Currently, surgical treatment has a limited or variable success.

There are other situations in which osteonecrosis of the femoral head is also evident in childhood. Mainly, the development of osteonecrosis affected children with malignant disease. Mattano et al showed that in 1409 children with acute lymphoblastic leukemia (ALL) percentage of developing osteonecrosis during the 3-year follow-up period is 9.3%xiv. In this study, the symptoms of pain and/or immobility were chronic in 84% of patients, and 24% had undergone orthopedic procedure and, in addition, 15% of prospective candidates for surgery in the future. In a subsequent study by the method of NMR imaging in 24 children with acute lymphoblastic leukemia Ojala et al documented osteonecrosis in 38%.

Osteonecrosis is also found in patients who recover after bone marrow transplantation, kidneys, lungs and liver. Children who have had a hip fracture, also mo is ut to suffer from osteonecrosis of the femoral head, as well as children with a sliding upper epiphysis of the femur. For these patients, the outcome is often poor, if they develop avascular necrosisxx. In a recent study of hip fracture in children avascular necrosis occurred in 40%xxi.

In adult patients coming progressive destruction of bone and cartilage of the joint, often coinciding with subchondral fracture. In a subsequent study of osteonecrosis of the femoral head, Ito et al found that 64% retained symptoms within six years, on average, further observationsxxii. People older can be a fast progressive destruction and deformity of the femoral head, in 66% of patients were observed progression to failure within a short period and 22% was fast resorption and destruction of the femoral headxxiii. For these elderly patients, carrying a full femoral arthroplasties surgery to remove the subsequent pain and immobility hip represents a substantial risk.

Surgical solutions for osteonecrosis include a decompression core for weakening intraosseous pressure and gain renewed blood supply; transplantation of bone or through the decompression core, either through joint (method type "hatch"); the graft is of vascularized bone and/or tissue; and redirectional osteotomy of the affected segment of the load. Also described local therapy for disease Perthes disease, operative or non-operative, in an attempt to restore the shape of the destroyed head of the femur. Also well described the use of external clamps or fasteners to unload the joint and prevent the destruction of the affected part. Surgical treatment of related diseases - dissecting osteochondritis usually involves the stabilization of a fragment of the subchondral bone, which is separated from the adjacent bone fixation device, with a change of the bone or without it, and drilled bone. Sometimes you want to remove this fragment.

Modern methods include the treatment of osteonecrosis of oxygen under high pressure, however, some authors have theoretically estimated that the bends is more likely to be a result of exposure to hyperbaric oxygen than nitrogenxxiv. Indeed, in a recent study in 20 children with osteonecrosis due to cytotoxic chemotherapy, there was no difference in subsequent MRI group receiving treatment with hyperbaric oxygen and control patientsxxv.

Despite the availability of such therapies, the prognosis for diseases such as osteonecrosis and rasselas the th osteochondritis is bad. After identifying the state of the destruction of diseased bone lasts from months to several years, leading to deformity and osteoarthritis of the corresponding joint.

Both conditions can lead to immobility of the patient and are costly for the individual and the society, mainly because osteonecrosis and, in particular, cutting osteochondritis often occur in young, healthy patients.

Complete replacement of the joint, often at a young age - related difficulties and short life expectancy, it is often necessary to relieve pain and suffering of these people. Pharmacological treatment, therefore, brings to these patients is of great benefit.

Any discussion of documents, acts, materials, devices, articles or the like, which have been specified in the present description, are presented solely for the purpose of providing context for the present invention. You should not assume that any or all of the data objects included in the prior art or were in the range of General knowledge in the technical field to which the present invention that existed in Australia before the priority date of each of the claims in this application.

A brief statement of the substance of the invention

In the first aspect, the present invention is in medical environments is TBE, selected from the group consisting of at least one biphosphonate used for the treatment of osteonecrosis.

In the second aspect, the present invention is pharmaceutical agent selected from the group consisting of at least one biphosphonate used for the treatment of dissecting osteochondritis.

In the third aspect, the invention consists in a method of treatment of a patient with osteonecrosis and/or dissect osteochondritis, this method includes a step of introducing patient drug selected from the group consisting of at least one biphosphonate.

In the fourth aspect, the invention consists in a method of prevention of osteonecrosis and/or dissecting osteochondritis and any complications associated with these diseases in patients with risk of any of these diseases, this method includes a step of introduction of patient drug selected from the group consisting of at least one biphosphonate.

In the fifth aspect, the invention lies in the use of drugs selected from the group consisting of at least one biphosphonate, for the manufacture of a medicinal product for the treatment of osteonecrosis.

In the sixth aspect, the invention lies in the use of medicinal environments is TBA, selected from the group consisting of at least one biphosphonate for the manufacture of a medicinal product for the treatment of dissecting osteochondritis.

In the seventh aspect, the invention lies in the use of drugs selected from the group consisting of at least one biphosphonate for the manufacture of a medicinal product, suitable for prevention of the introduction of the patient to the risk of osteonecrosis and/or dissecting osteochondritis.

In the eighth aspect, the present invention is pharmaceutical agent selected from the group consisting of at least one biphosphonate used to prevent destruction or chondrolysis cartilage associated with osteonecrosis and/or dissect osteochondritis.

In the ninth aspect, the present invention is a method of preventing the destruction or chondrolysis cartilage associated with osteonecrosis and/or dissect osteochondritis, including the stage of introduction of patient drug selected from the group consisting of at least one biphosphonate.

Selected bisphosphonate preferably operates at least at reducing or preventing severe deformation and/or destruction of bone and cartilage and enables the formation of new bone TC is no Bologov cases when this drug is administered prophylactically to a patient with risk or osteonecrosis, or dissecting osteochondritis, such prophylactic administration preferably has an impact on the creation of a depot therapeutically effective biphosphonate within the patient's body, thereby minimizing the destruction and deformation of bones and promoting the formation of new bone tissue and supporting bone structure, if there is osteonecrosis.

In a preferred embodiment of the invention, the drug can be administered intravenously. Alternatively, the drug can be administered orally. In addition, the drug can be injected subcutaneously, intramuscularly, transdermal, local or any other way in which it can realize therapeutic effect. Next, we examine the application of this drug locally at the target site. For example, this drug can be introduced locally during surgical operations regarding osteonecrosis.

In the embodiment of the invention, where the medicine is applied locally, as part of the transaction, the drug can be applied directly superimposed on the surface of the bone, or as part of a local si is the topic of shipping drugs. Local delivery system drug may be in the form of a substitute bone graft or filler, or autogenic or allogenic bone graft. The bone graft substitute or extender may contain calcium sulfate, calcium carbonate, Tris calcium hydroxyapatite or other components containing calcium, separately or in combination. Substitute bone graft filler, autograft or allograft may also contain additional mixing with an effective amount of biphosphonate, the carrier medium such as collagen, gelatin, glycerin, propylene glycol, gum, polyglycolic acid (PGA), poly-l lactic acid (PLLA), poly (d-l lactic acid (PLLA), porous silicone, or any other absorbable biocompatible environment, in the form or a liquid for injection, gel, putty or cement, or in the form of a moldable fluid, cement, putty, gel, flexible sheets, grids or sponge or other easy methods. It may also include any combination of the above and any binding agent. Biphosphonate and media separately can also be used for local delivery of the drug. In addition to the initial local or systemic introduction may or may not be useful to the system put in place is giving.

The media may contain nutrients needed by the cells involved in bone formation, or other cells, and preferably biodegradable. Optionally, the carrier may contain gene products, known for participating in the reconstruction of bone. Examples of suitable gene products include, but are not limited to, bone morphogenic protein-7 (OP-1), BMP-2 and -4, other bone morphogenic proteins, transforming growth factor beta, fibroblast growth factor (basic or acidic), insulin-like growth factor -1 or -2, osteocalcin or other known biologically active proteins, polypeptides or gene products. This method should have a beneficial synergistic effect - biphosphonate, stabilizing the structure of the skeleton and growth factors, potentially stimulating increased vascularization and new bone formation by introducing only biphosphonate. In addition, this combination may be more effective than only these gene products of growth factors, because the new bone formed in the result of the actions of growth factors, will be better preserved when using biphosphonate.

The transport medium may also contain blood products containing growth factors or cells, "light layer of a blood clot" (e.g. AGF™), aspirate bone marrow and cultured osteoblast cells or their precursors, or poly potent stem cells. The carrier may also contain cells, transfetsirovannyh genes of bone formation, for example by using adenoviral vector, so that they sverkhekspressiya genes involved in the restoration of bone tissue, leading to increased bone formation. And in this case, such a combination therapy may be synergistic, biphosphonate stabilizing skeletal structure, cells and stimulating the growth of new bone tissue formation by introducing only biphosphonate.

Several combinations of cells, the gene products of growth factors, nutrients, transport environment and substitute bone graft can be effective when mixing at least one biphosphonates.

In another embodiment, the drug is a zoledronic acid (zoledronate) {1-hydroxy-2-[(1H-imidazol-1-yl)ethyliden]bebopalula acid}. On the other hand, this drug can be pamidronate {3-amino-1-hydroxypropylamino bebopalula acid}, alendronate {4-amino-1-hydroxybutylidene bebopalula acid}, etidronate {1-hydroxyethylidene bebopalula acid}, clodronate {dihlormetilen bebopalula acid}, risedronate {2-(3-pyridinyl)-1-hydroxyethylidene bebopalula acid}, tiludronate {chloro-4-finaltime the ilidene bebopalula acid}, ibandronate {1-hydroxy-3(methylpentylamino)-propylidene bebopalula acid}, encadrant {cycloheptyl-amino-methylene bebopalula acid}, minodronate {[1-hydroxy-2-(imidazo[l,2-a]pyridine-3-yl)ethylidene]bebopalula acid}, olpadronate {(3-dimethylamino-1-hydroxypropylamino)bebopalula acid}, meridional (6-amino-1-hydroxybenzylidene-1,1-bebopalula acid), EB-1053 1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bebopalula acid, or any other therapeutically effective biphosphonate or its pharmaceutically acceptable salts or esters.

In one embodiment, osteonecrosis or cutting osteochondritis strikes the head of the femur, the distal end of the femur, the proximal end of the tibia, talus, navicular or the other tarsal bones, the head of the metatarsal bone, the head of the humerus or proximal end of the humerus, the humeral head or distal end of the humerus, radial head bone, scaphoid, semilunar, or other bone of the wrist. It is believed, however, that this disease can affect any bone or joint of the body.

In the following embodiment, osteonecrosis found in children diagnosed with Perthes disease (Legg-calve-Perthes disease).

In another embodiment of the invention OST Necros or osteochondritis may be of unknown etiology.

In the following embodiment of the invention osteonecrosis or cutting osteochondritis may develop secondarily. For example only, osteonecrosis or cutting osteochondritis may develop secondary disease, such as Gaucher disease, sickle cell anemia or other hematologic disorders, renal failure, liver failure, endocrine disorders, HIV and related syndromes, leukemia or other malignant disease, primary bone dysplasia, connective tissue disease, autoimmune disorders or immunosuppression.

Osteonecrosis or cutting osteochondritis may develop in response to exposure to substances known high risk of developing osteonecrosis, including, but not limited to, corticosteroids (glucocorticoids), cyclosporine, or other immunosuppressive drugs, cytotoxic drugs for the treatment of malignant diseases or rheumatoid arthritis abuse of prohibited chemical substances, abuse of alcohol and/or Smoking.

Osteonecrosis or cutting osteochondritis may develop due to bone marrow transplantation or organ transplantation.

In another embodiment of the invention osteonecrosis or ressaca the speaker osteochondritis may be associated with trauma, such as a fracture. The fracture may be a fracture of the femoral head, neck or Mineralny fracture of the femur, fracture of the head or neck of the radial bone, the head of the humerus, fracture of talus or other tarsal bones, fracture of the humeral head, neck or fracture pozhalovati shoulder joint, fracture of the scaphoid, semilunar, or other bones of the wrist. On the other hand, the fracture may be some other bones.

Osteonecrosis or cutting osteochondritis may be associated with damage other than fracture, such as dislocation or subluxation.

The drug can be introduced to the patient intraoperatively with osteonecrosis or cutting osteochondritis. Surgical treatment may include decompression of the heart transplant bone vascularizing bone transplant or tissue graft or a technique of transplantation of bone tissue type, "Luke", osteoplasty or chondroplasty, osteotomy or external fixation.

In cases, this drug is selected from the group consisting of at least one biphosphonate administered prophylactically, this drug can be administered to the patient previously suffering from osteonecrosis in one area, and therefore, with a high risk of developing osteonecrosis is in another area. In this case, known osteonecrosis can affect the head of the femur, the distal end of the femur, the proximal end of the tibia, talus, or other tarsal bone, the head of the metatarsal bone, the head of the humerus or proximal end of the humerus, the humeral head or distal end of the humerus, radial head bone, scaphoid, semilunar, or other bone of the wrist.

In the following embodiment of the invention, the medicine can be injected prophylactically to a patient with a fracture, if there is a high risk that the fracture leads to osteonecrosis. The fracture may be a fracture of the femoral head, neck or Mineralny fracture of the hip, slipped epiphysis of the head of the humerus or other bone epiphysis, fracture of the head or neck of the radial bone, the head of the humerus, fracture of the talus other tarsal bones, fracture of the humeral head, neck or pozhalovati shoulder joint, fracture of the scaphoid, semilunar, or other bones of the wrist. On the other hand, prophylactic treatment may be initiated in a patient with damage, which is not a fracture, such as dislocation or subluxation, if there is a risk that this damage leads to osteonecrosis, such as traumat the economic dislocation of the hip or traumatic dislocation of the shoulder.

In another embodiment, this drug can be injected prophylactically to a patient who teach, going to conduct or have conducted an operation to cause osteonecrosis. In this embodiment, the operation may include the correction of congenital or acquired hip dislocation, osteotomy about any joint, plastic surgery on the bone, the decompression core or transplantation of bone tissue vascularized bone tissue or soft tissue transplantation, a technique of transplantation of bone tissue type "hatch" for the treatment of osteonecrosis.

Additional indications for preventive treatment can be when osteonecrosis or cutting osteochondritis develops secondary disease, such as Gaucher disease, sickle cell anemia or other hematologic disturbance, renal insufficiency, hepatic insufficiency, endocrine disturbance, HIV and associated syndromes, leukemia or other malignant disease, primary bone dysplasia, a disease of connective tissue, autoimmune disease or immunosuppression.

The patient who spend preventive treatment could be exposed to substances known fact that they are a high risk factor for osteonecrosis, including, but n is limited to the corticosteroids (glucocorticoids), cyclosporine and other immunosuppressants, cytotoxic drugs for the treatment of malignant diseases or rheumatoid arthritis abuse of illegal substances, alcohol and/or Smoking.

In another embodiment of the invention, the patient may be at high risk of developing osteonecrosis or dissecting osteochondritis in the bone marrow transplantation or transplantation of an organ.

In the following embodiment, the drug of the present invention may be introduced simultaneously with the treatment program radiation therapy.

Biphosphonate can be zoledronate acid (zoledronate), or any pharmaceutically acceptable salt, or a complex ester. Preferably, zoledronic acid is administered parenterally and preferably at a dose of about 0.25 mg to 12 mg for an adult patient, or from about 0.005 mg/kg to 0.5 mg/kg for a child approximately every three months. However, provided that zoledronic acid can enter the time in four weeks, six weeks or every two months. In addition, zoledronic acid can be entered in one dose and subsequent dose to enter as needed.

In another embodiment, zoledronic acid can enter injecting the dose of about 2 mg, about 4 mg, about 6 mg, or about 8 mg for adult patients, or approximately 0.025 mg/kg, about 0.05 mg/kg, about 0.075 mg/kg or about 0.1 mg/kg for a child approximately every three months. Zoledronic acid can enter parenterally in a dose of about 2 mg, about 4 mg, about 6 mg or about 8 mg for adult patients, or approximately 0.025 mg/kg, about 0.05 mg/kg, about 0.075 mg/kg or about 0.1 mg/kg child approximately every six months. In another embodiment, zoledronic acid can enter parenterally in a dose of about 2 mg, about 4 mg, about 6 mg or about 8 mg for adult patients, or approximately 0.025 mg/kg, about 0.05 mg/kg, about 0.075 mg/kg or about 0.1 mg/kg for a child approximately every twelve months. In another embodiment, zoledronic acid can enter parenterally in a dose of about 2 mg, about 4 mg, about 6 mg or about 8 mg for adult patients, or approximately 0.025 mg/kg, about 0.05 mg/kg, about 0.075 mg/kg or about 0.1 mg/kg for a child, as a single dose. Alternatively, zoledronic acid can be administered orally.

In another embodiment, biphosphonate represents pamidronate or any pharmaceutically acceptable salt or ester. Preferably, pamidronate administered parenteral the but and preferably at a dose of from about 15 to 90 mg approximately every one to three months for an adult patient or 0.25 mg/kg to 3.0 mg/kg every one to three months for a child. In the following embodiment, pamidronate, you can enter parenterally in a dose of about 15 mg, about 30 mg, about 60 mg, or 90 mg every one to three months for an adult patient or 0.25 mg/kg, about 0.5 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg, or about 3.0 mg/kg every one to three months for a child. In another embodiment, the pamidronate is administered parenterally at a dose of about 15 mg, about 30 mg to about 60 mg, or 90 mg approximately every six months for an adult patient or 0.25 mg/kg, about 0.5 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg, or about 3.0 mg/kg approximately every six months for a child. In another embodiment, the pamidronate is administered parenterally at a dose of about 15 mg, about 30 mg, about 60 mg, or 90 mg approximately every twelve months in an adult patient or 0.25 mg/kg, about 0.5 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg, or about 3.0 mg/kg approximately every twelve months for a child. In another embodiment, the pamidronate is administered parenterally at a dose of about 15 mg, about 30 mg, about 60 mg, or 90 mg for adult patient or 0.25 mg/kg, about 0.5 mg/kg, about 1.0 mg/kg, about 2.0 mg/kg, or about 3.0 mg/kg for a child in a single dose.

In another embodiment, biphosphonate depict is to place an alendronate or any pharmaceutically acceptable salt or ester. Preferably, alendronate administered orally and preferably at a dose of from about 2.5 mg to about 50 mg per day or from about 10 mg to 300 mg per week for an adult patient. For a child preferred dose for oral administration is from about 0.05 mg/kg to 1.0 mg/kg / day or from about 0.2 mg/kg to 6.0 mg/kg per week. Alendronate can be administered orally in a dose of about 5 mg, about 10 mg, about 20 mg or about 40 mg per day or about 35 mg, about 70 mg, about 140 mg, or about 280 mg per week for an adult. Child alendronate can be administered orally in a dose of about 0.1 mg/kg, about 0.2 mg/kg, about 0.4 mg/kg, or about 0.8 mg/kg / day, or about 0.8 mg/kg, about 1.5 mg/kg, about 3.0 mg/kg, or about 5.0 mg/kg per week. Alternatively, alendronate is administered parenterally and preferably at a dose of about 0.25 mg to 30 mg approximately every one to three months, or in a single dose.

In the following embodiment, biphosphonate represents risedronate or any pharmaceutically acceptable salt, or ester. Preferably, risedronate administered orally and preferably at a dose of from about 2.5 mg to about 60 mg per day or from about 10 mg to 300 mg per week for an adult patient, or from about 0.05 mg/kg to 1.0 mg/kg / day or from about 0.25 mg/kg to 7.0 mg/kg for children is. Risedronate can be administered orally in a dose of about 2.5 mg, about 5 mg, about 10 mg or about 30 mg per day, or about 15 mg, about 30 mg, about 60 mg, or about 210 mg per week for an adult patient or for a child of about 0.05 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.5 mg/kg / day, or about 0.25 mg/kg, about 0.5 mg/kg, about 1.5 mg/kg, about 2.5 mg/kg per week. Alternatively, risedronate can be administered intravenously.

In the following embodiment, biphosphonate is a ibandronic acid or any pharmaceutically acceptable salt or ester. Preferably, ibandronate administered parenterally and preferably at a dose of about 0.25 mg to 30 mg, and more preferably in a dose of from about 2 mg to 10 mg approximately every one to three months, or in a single dose.

In another embodiment, ibandronate administered orally at a dose of about 2.5 mg, about 5 mg, about 10 mg or about 30 mg per day, or about 15 mg, about 30 mg, about 60 mg, or about 210 mg per week for an adult patient or for a child of about 0.05 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.5 mg/kg / day, or about 0.25 mg/kg, or about 0.5 mg/kg, about 1.0 mg/kg, or about 2.5 mg/kg per week.

In another embodiment, biphosphonate is encadrant or Liu is th pharmaceutically acceptable salt, or its ester. Preferably, encadrant administered parenteral and preferably at a dose of about 0.25 mg to 30 mg, more preferably about 10 mg for an adult patient or for a child from about 0.005 mg/kg to 0.6 mg/kg, more preferably from about 0.025 mg/kg to 0.25 mg/kg approximately every one to three months, or in a single dose.

In another embodiment, encadrant administered orally at a dose of about 2.5 mg, about 5 mg, about 10 mg or about 30 mg per day, or about 15 mg, about 30 mg, about 60 mg, or about 210 mg per week for an adult patient or for a child of about 0.05 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.5 mg/kg / day, or about 0.25 mg/kg, or about 0.5 mg/kg, about 1.0 mg/kg, or approximately 2.5 mg/kg per week.

In another embodiment, biphosphonate is minodronate or any pharmaceutically acceptable salt, or ester. Preferably, minodronate injected from 0.25 mg to about 30 mg approximately every one to three months, or in a single dose. More preferably, minodronate administered parenteral and, preferably, at a dose of about 0.25 mg to 12 mg for an adult patient, or from about 0.005 mg/kg to 0.5 mg/kg for a child approximately every three months. In another embodiment, minodronate you can enter parenterale at a dose of about 2 mg, about 4 mg, about 6 mg or about 8 mg for adult patients, or approximately 0.025 mg/kg, about 0.05 mg/kg, about 0.075 mg/kg or about 0.1 mg/kg for a child approximately every three months. Minodronate you can enter parenterally in a dose of about 2 mg, about 4 mg, about 6 mg or about 8 mg for adult patients, or approximately 0.025 mg/kg, about 0.05 mg/kg, about 0.075 mg/kg or about 0.1 mg/kg for a child approximately every six months.

In another embodiment, minodronate you can enter parenterally in a dose of about 2 mg, about 4 mg, about 6 mg or about 8 mg for adult patients, or approximately 0.025 mg/kg, about 0.05 mg/kg, about 0.075 mg/kg or about 0.1 mg/kg for a child approximately every twelve months. In another embodiment, minodronate you can enter parenterally in a dose of about 2 mg, about 4 mg, about 6 mg or about 8 mg for adult patients, or approximately 0.025 mg/kg, about 0.05 mg/kg, about 0.075 mg/kg or about 0.1 mg/kg for a child in a single dose. Alternatively, minodronate can be administered orally.

In another embodiment, biphosphonate is clodronate or any pharmaceutically acceptable salt or ester. Clodronate may be administered orally in the dose range from about 400 mg to 2400 mg / d is ery adult or for a child up to 50 mg/kg to 250 mg/kg or injected at doses ranging from 150 mg to 300 mg or for a child from 1 mg/kg to 5 mg/kg, repeated daily for 2 to 5 days, and repeat, if necessary, if possible every six months.

In another embodiment, biphosphonate represents etidronate or any pharmaceutically acceptable salt, or ester. Etidronate can be administered orally in the dose range from about 100 to 400 mg (5 to 20 mg/kg / day) or for a child from 5 to 20 mg/kg / day.

In another embodiment, biphosphonate is tiludronate or any pharmaceutically acceptable salt or ester. Tiludronate may be administered orally in the dose range from about 400 mg per day for an adult or for a child from 5 to 20 mg/kg / day.

In another embodiment, biphosphonate is olpadronate or any pharmaceutically acceptable salt or ester. Olpadronate can be administered orally in a dose range of about 50-400 mg per day for an adult or for a child from 0.1 mg/kg to 10 mg/kg or intravenously at doses ranging from 1 mg to 20 mg or for a child from 0.1 mg/kg to 0.5 mg/kg every one to three months.

In another embodiment, biphosphonate is meridional or any pharmaceutically acceptable salt, is whether it ether. In another embodiment, meridional administered in parenteral dosage range from 10 mg to 100 mg for an adult or for a child from 0.1 to 2 mg/kg intravenously every one to three months.

In another embodiment, this drug is an EB-1053.

Brief description of drawings

Only to bring the example, the preferred embodiment of the invention described with reference to the accompanying figures:

Figure 1 represents the General formula for a class of bifosfonatami.

Figa and 2B are x-rays of patients diagnosed with Perthes disease.

Figure 3 is a series of x-rays characteristic of the proximal femur of rats of Example 1.

Figure 4 is a series of x-ray images of the proximal femur of each rat of Example 1.

Figure 5 presents a series of TC 99 scanogram bones to demonstrate recovery vessels in the proximal femur of each rat of Example 1.

6 is a series nedeklarirovanny histological preparations Von Kossa, showing the preservation of the shape of the bone of the proximal femur of rats of Example 1.

7 is a series of histological preparations stained with toluidine blue, showing the preservation of articular cartilage in rats of Example 1.

Fights series fluorescent histological preparations, demonstrate the activity of osteogenesis in the proximal areas of the thighs groups of rats of Example 1.

The preferred embodiment of the invention

This invention relates to the use of biphosphonate following formula depicted in figure 1, where R1and R2different to provide different efficiency and other properties of biphosphonate. The present invention relates to a new pharmacological treatment of osteonecrosis, including osteonecrosis, striking bone and cartilage, adjacent to the joint. With the introduction of a therapeutically effective dose of at least one biphosphonate, such as zoledronicaa acid, the destruction of dead bone tissue can be slowed down due to the reduction of osteoclastic activity, while increasing the mineralization of new bone tissue can accelerate the repair process of new bone superior mechanical integrity, thus reducing the size of any fracture of the affected bone and cartilage. This minimizes the risk of deformation of the joint or cartilage and further reduces the risk of pain and the development of osteoarthritis.

It is known that bisphosphonates remain therapeutically effective for a long time. Essentially, in the return of blood flow to a dead site, as confirmed by stenogramma the affected bone, dead bone tissue begins to capture any recirculating biphosphonate. Bisphosphonates then begin to have a protective and reparative action, thus delaying the destruction of dead bone tissue, while the mineralized new bone tissue is formed as a result of treatment with bisphosphonates. Highly mineralized new bone tissue improves the mechanical integrity of the affected joint.

In other studies suggested that zoledronicaa acid inhibits angiogenesis in the range of doses used in this studyxxviand thus it is not expected that her property is useful for the treatment of osteonecrosis. Previous results of the authors of the invention, showing that the introduction of zoledronate acid lead to the strengthening of education, mineralization and strength of callus distraction when rabbits are not consistent with these observationsxxvii. This is based on the understanding that angiogenesis is an important factor in osteogenesis. The hypothesis used for the creation of this experiment were based on the knowledge that the treatment bifosfonatami can lead to antiresorptive and preosteoblast effects. Positive effects of bifosfonatami on osteoblasts is now widely known, they do not act only on the OST is clusty xxviii,xxix. Thus, treatment bifosfonatami can provide a solution to the problem of susceptibility to fractures, osteonecrosis, such as the femoral neck, the neck of the talus or scaphoid bone, increasing bone formation and preventing the destruction from osteonecrosis.

The example presented in Figure 2. Radiograph (A) shows the hip joint 7 year old boy diagnosed with Perthes disease for six months before was made by x-rays. Radiograph (B) shows the hip joint of another boy with a diagnosis of Perthes disease in the twelve months to x-rays. You can see these typical signs of underlying disease progression disease. The epiphysis (growing the head of the femur) 10 is clearly dead. Highly mineralized bone tissue in recruitireland.com the epiphysis is resorbed in response to various endogenous mediators, such that violated its mechanical integrity and she collapses. Along with the resorption of necrotic bone resorption occurs metatithemi bone 11 (bone in the diaphysis and especially the area adjacent to the epiphyseal or growth plate), mostly the same mediators. This eliminates structural support for the growth of the plate 12, which soon collapses and becomes destructuring is Anna, limiting the growth and repair of the femoral head 10. The formation of new bone in the lateral surface of the femoral head 10 poor quality, small mechanical integrity. She is slowly being squeezed out of the joint, eventually giving a saddle-like shape of the femoral head 10.

The introduction of a therapeutically effective amount of biphosphonate will slow resorption and destroy dead bone tissue, limit resorption metatithemi bone and stimulate high content of minerals in the new bone formed in the side of the epiphysis. To prevent the destruction of dead bone tissue and increasing the mechanical integrity of the new bone will retain more spherical shape of the femoral head. Because the prognosis for the disease Perthes disease depends on servicesthe of the femoral headxxxsuch introduction of a therapeutically effective dose of biphosphonate probably significantly improves outcomes for patients with Perthes disease.

Example 1

The following example describes the process by which there may be effects of bifosfonatami on dead bone.

Model was used traumatic osteonecrosis of 24 female rats, Wistar (Wistar) at the age of 14 weeks. The animals were observed for a period of six weeks is after surgery, aimed at the disruption of the blood supply of the femoral head. Was selected six-week period of time, as this is the period of time for which, as you know, is the destruction of the femoral head in this model. Animals were treated in accordance with ethical standards.

Rats were randomly distributed into 3 groups of 4 individuals according to the scheme below. Individuals in the control group receive only injections of saline (S) subcutaneously. Animals, subsequently receiving treatment that received saline only preoperative and zoledronic acid (ZA) (Novartis) 0.1 mg/kg, from commercial companies, was administered by subcutaneous injection in postoperative 1 and 4 weeks. Animals receiving treatment before and after surgery, received zoledronic acid 0.1 mg/kg in all three time.

A similar operation was conducted by each rat in zero time. Before anesthesia, all animals were weighed with high accuracy. Animals were kept warm during surgery and recovery period. Anesthesia was performed with a mixture of Ketamine (Ketamine) 75 mg/kg and Xylazine (Xylazine) 10 mg/kg of the Drug was mixed in the same syringe immediately before injection and was administered 0.2 ml per 100 g body weight intramuscularly. Introduction occurred during the 5-10 minutes.

After preparation of a sterile solution and shave the right lower limb was made open access to the hip joint. Opened the capsule and the head of the right femur freed from the acetabulum. The round ligament was cut, disrupting the blood supply from this source. The entire neck of the femur freed from soft tissue resurfacing wikilove seam. It ruined the lateral epiphyseal artery and any other vessel supplying the femoral head through the neck.

The animals were given feed and water without restrictions and were placed in cages in groups of 4 individuals.

4 and 5 week spent double fluorescent labelling: in week 4, was administered intraperitoneally injected 30 mg/kg demeclocycline and in week 5, administered intraperitoneally injected 20 mg/kg of calcein. An hour before selection was subcutaneously injected 70 MBq Tc99 MDP for holding scintigraphy bone samples.

After selection, took the right and left proximal sites of the femur and fixed in 4% paraformaldehyde. Radiographs were made in pairs for high-quality film using a Faxitron x-ray system Shielded Cabinet (Hewlett Packard, McMinnville, OR). X-rays were converted into digital form and analyzed using the Bioquant image analysis (R&M Biometrics Inc., Nashville, TN), which is connected with a digital tablet (GTCO CalComp, Inc., Columbia, MD). Registered is the site of a bone, the height and width of the femoral head and compared with the opposite side. Scintigraphic scans were done using a 4 mm long. BMD and BMC were measured by using a scanner pDEXA Sabre (Norland, Ft Atkinson WI).

The samples were immersed in the resin and did nedeklarirovanny slice. Coronal sections (6 μm) were done through the femoral head. Sections were stained with von Kossa to determine the amount and structure of bone beams. For unpainted samples used fluorescent microscopy to visualize fluorescent tags and evaluation of bone formation.

One control rat died and not been replaced, for the analysis remained the 23 pairs of the proximal femur.

Results

Typical radiographs are shown in Figure 3. Full series of radiographs of each of the proximal femur are presented in Figure 4. In this figure, the top row refers to a group receiving saline, the second number refers to the group receiving postoperative treatment, and the third number refers to a group receiving treatment before and after surgery. The right femur were operated, and the leftists were not.

Morphologically, the bone structure is well preserved in the group receiving postoperative treatment, not counting some resorption of the femoral neck. In the group receiving treatment before and after surgery, is olovka thighs preserved almost completely.

Head of femur in the group receiving saline, were less in percentage than neoperabelnoy hand, as measured by the system of Bioquant image analysis (table I). Head of femur operated group receiving saline decreased to 63% in comparison with the opposite side (the non-operated hip). This result was significantly reduced when comparing two groups receiving treatment with neoperabelnoy control group receiving saline (p<0,01, ANOVA). The greatest preservation of the femoral head was in the group that received treatment before and after surgery (85%)and in the group receiving treatment after surgery (79%), but the head is much better preserved than in the control (p<0.01, checking on student test).

Table I

Results
Neopalimovsky controlOperated controlReceived treatment afterBefore and after
XR region head (reverse %)-637985
BMD (g/cm2)0,110,070,110,12
0,0170,0060,0120,015

DEXA scans showed a significant increase (P<0,01, ANOVA) in the head of the femur BMD and BMC in the groups receiving treatment, compared with control groups, with conservation values neopoznannogo control or close to it. (Table II). In previous experiments of the inventors, it was found that the strength is highly correlated with BMC, reduced by one third in the group receiving saline. As shown in Figure 5, bone scintigraphy showed complete revascularization, the operated area causes increased absorption compared to the non-operated area in all cases. In this figure the upper row corresponds to a group receiving saline, the second row corresponds to the group receiving subsequent treatment, and the third row corresponds to a group receiving treatment before and after surgery. The right femur were operated, and the left is not.

Histology showed preservation of bone structures in both groups receiving treatment, while in the operated control group was observed resorption significant portion of the epiphysis, and he was wide and flat (6).

In the groups receiving treatment, also better preserved articular cartilage. (Fig 7). In rats receiving treatment before and posleoperatsi, when staining toluidine blue, visible thick articular cartilage corresponding to further cartilage growth, but delayed ossification after avascular damage. Articular cartilage looked equivalent in the sample group who received treatment after surgery, and neoperabelnoy group, the worst in the control, where the cartilage was thin and had a lot of plagioclase zones.

Tagging tetracycline showed recovery of bone formation in week 4 in all groups (Fig). Bone formation was intense in the operated control group, (top right), did not restore the massive resorption in six weeks. Bone formation in the femoral head bone in the group receiving postoperative treatment was similar to that in neoperabelnoy the control group (bottom left). In animals receiving treatment before and after surgery (bottom right), bone formation was clearly expressed, but to a lesser extent, between 4 and 5 weeks, with a very small number of surfaces on which are formed bone tissue with a high density. No confirmation bone formation in the samples of the epiphyses of the operated animals.

Discussion

Application zoledronate acid reduced the fracture of epiphysis (antiresorptive effect), and also made it possible for bone formation and mineralization, the actuator is appropriate to viable saved epiphysis. In the groups receiving the treatment, also proved the preservation of articular cartilage.

Cervical femoral bones were partially rezorbirovanny in the group receiving postoperative treatment. It is assumed that this happens a week before the introduction of zoledronate acid because it is not observed in the group receiving treatment before and after surgery.

Specialists in this field would understand what can be done numerous variations and/or modifications of the present invention, as shown in some embodiments, implementation, without straying from the inventive concept or scope of the claims, as described in General terms. These options for implementation, thus, are considered in all respects as illustrative and not restrictive.

1. Drug comprising an effective amount of biphosphonate used for the treatment of osteonecrosis and/or dissecting osteochondritis.

2. The drug according to claim 1, characterized in that biphosphonate represents zoledronic acid or any pharmaceutically acceptable salt, hydroxide or ester.

3. The drug according to claim 1, characterized in that biphosphonate selected from the group consisting of pamidronate, alendronate, etidronate, clodronate, risedronate, " is Renata, ibandronate, incarnate, minodronate, olpadronate, meridionale, EB-1053, or any pharmaceutically acceptable salt, hydroxide or complex ester.

4. The drug according to any one of the preceding paragraphs, characterized in that is used for the treatment of osteonecrosis or dissecting osteochondritis, striking the head of the femur, the distal end of the femur, the proximal end of the tibia, talus, or other tarsal bone, the head of the metatarsal bone, the head of the shoulder or the proximal end of the humerus, the humeral head or distal end of the humerus, radial head bone, scaphoid, semilunar, or other bone of the wrist.

5. The drug according to any one of the preceding paragraphs, characterized in that is used for the treatment of osteonecrosis in the possession of a child diagnosed with Perthes disease.

6. The drug according to any one of the preceding paragraphs, characterized in that is used prophylactically to prevent osteonecrosis, and/or dissecting osteochondritis, and/or any complications associated with these diseases.

7. The drug according to any one of the preceding paragraphs, characterized in that it is administered intravenously, orally, subcutaneously, intramuscular, transdermal or topically to a patient or Loka is Ino to the target area in the specified patient.

8. The drug according to any one of the preceding paragraphs, characterized in that it further comprises a suitable carrier.

9. The drug of claim 8, wherein the carrier includes a bone graft substitute or extender, or autogenic or allogenic bone graft.

10. The drug according to claim 2, characterized in that biphosphonate represents zoledronic acid or any pharmaceutically acceptable salt, hydroxide or ester in a unit dose of from 0.25 to 12 mg

11. The drug according to claim 3, characterized in that biphosphonate selected from the group consisting of pamidronate in a unit dose of from 15 to 90 mg of alendronate in a unit dose of from 2.5 to 50 mg, risedronate in a unit dose of from 2.5 to 60 mg, ibandronate in a unit dose of from 0.25 to 30 mg, incarnate in a unit dose of from 0.25 to 30 mg, minodronate in a unit dose of from 0.25 to 30 mg, clodronate in a single dose of 200 to 2400 mg of etidronate in a unit dose of from 100 to 800 mg, tiludronate in a single dose from 200 to 800 mg, olpadronate in a single dose of 50 to 400 mg, meridionale in a unit dose of from 10 to 100 mg or any of their pharmaceutically acceptable salts, hydroxide or complex ester.

12. The method of treatment or prophylaxis of a patient with osteonecrosis and/or dissect osteochondritis or at risk of developing any of the listed the diseases, includes introduction to the patient an effective amount of a medicinal product, including biphosphonate.

13. The method according to item 12, characterized in that biphosphonate represents zoledronic acid or any pharmaceutically acceptable salt, or ester.

14. The method according to item 12, characterized in that biphosphonate selected from the group consisting of pamidronate, alendronate, etidronate, clodronate, risedronate, tiludronate, ibandronate, incarnate, minodronate, olpadronate, meridionale, EB-1053 or any pharmaceutically acceptable salt, hydroxide or complex ester.

15. The method according to any of PP-14, characterized in that the medicinal product is administered to the patient intravenously, orally, subcutaneously, intramuscular, transdermal or local, or locally in the target treatment site.

16. The method according to item 15, wherein the drug is administered locally to the target treatment site before, during or after the procedure decompression core, transplantation or bone transplantation vascularized bone.

17. The method according to item 15, wherein the drug is administered locally to the target treatment site in conjunction with the local delivery system.

18. The method according to 17, wherein the local delivery system is a bone substitute TRANS is landata or filler, or autogenic or allogenic bone graft.

19. The method according to item 13, wherein biphosphonate zoledronic acid or any pharmaceutically acceptable salt, hydroxide or ester is administered in parenteral doses ranging from 0.25 to 12 mg for an adult patient or 0.005 to 0.5 mg/kg for a child every three months.

20. The method according to item 13, wherein zoledronic acid or any pharmaceutically acceptable salt, hydroxide or ester is administered four weeks, six weeks or every two months.

21. The method according to item 13, wherein biphosphonate zoledronic acid or any pharmaceutically acceptable salt, hydroxide or ester is administered every twelve months.

22. The method according to item 13, characterized in that zoledronic acid is administered in parenteral single dose.

23. The method according to claim 4, characterized in that biphosphonate represents pamidronate or any pharmaceutically acceptable salt, a hydroxide or an ester, administered in parenteral dose range from 15 to 90 mg every one to six months adult patient or from 0.25 to 3.0 mg/kg every one to six months the child.

24. The method according to 14, characterized in that biphosphonate represents alendronate or any pharmaceutically acceptable salt, a hydroxide or an ester, administered orally in the range of the Ohe doses ranging from 2.5 to 50 mg / day or 10 to 300 mg per week, for adult patients, and from 0.05 to 1.0 mg/kg / day, or from 0.2 to 6.0 mg/kg per week for a child.

25. The method according to 14, wherein the alendronate is administered in parenteral dosage range from 0.25 to 30 mg every one to three months, or in a single dose.

26. The method according to 14, characterized in that biphosphonate represents risedronate, or any pharmaceutically acceptable salt, a hydroxide or an ester, administered orally in doses ranging from 2.5 to 60 mg / day or 10 to 300 mg per week for an adult patient, or from 0.05 to 1.0 mg/kg / day, or from 0.25 to 7.0 mg/kg per week the child.

27. The method according to 14, characterized in that biphosphonate is a ibandronic acid or any pharmaceutically acceptable salt, a hydroxide or an ester, administered in parenteral dosage range from 0.25 to 30 mg every one to three months, or in a single dose.

28. The method according to 14, characterized in that ibandronate administered orally in doses ranging from 2.5 to 30 mg per day, or 15 to 210 mg per week for an adult patient or from 0.05 to 0.5 mg/kg / day, or from 0.25 to 2.5 mg/kg per week the child.

29. The method according to 14, characterized in that biphosphonate is encadrant, or any pharmaceutically acceptable salt, a hydroxide or an ester, administered in parenteral dosage range from 0.25 to 30 mg for an adult patient or 0.005 to 0.6 mg/kg child, where the specified dose is administered every one to three months, or in a single dose.

30. The method according to 14, otlichuy is the, that biphosphonate is minodronate, or any pharmaceutically acceptable salt, a hydroxide or an ester, administered in parenteral dosage range from 0.25 to 30 mg every one to three months, or in a single dose.

31. The method according to 14, characterized in that biphosphonate is clodronate, or any pharmaceutically acceptable salt, a hydroxide or an ester, administered orally in doses ranging from 400 to 2400 mg per day or administered intravenously in doses ranging from 150 to 300 mg daily for 2 to 5 days.

32. The method according to 14, characterized in that biphosphonate represents etidronate, or any pharmaceutically acceptable salt, a hydroxide or an ester, administered orally in doses ranging from 100 to 400 mg per day or from 5 to 20 mg/kg / day child.

33. The method according to 14, characterized in that biphosphonate is tiludronate, or any pharmaceutically acceptable salt, a hydroxide or an ester, administered orally at a dose of 400 mg per day for an adult, or from 5 to 20 mg/kg / day child.

34. The method according to 14, characterized in that biphosphonate is olpadronate, or any pharmaceutically acceptable salt, a hydroxide or an ester, administered orally in doses ranging from 50 to 400 mg per day for an adult, or from 1 to 10 mg/kg child, or intravenous every one to three months is in the range of doses from 1 to 20 mg adult or from 0.1 to 0.5 mg/kg in the child.

35. The method according to 14, characterized in that biphosphonate is meridional, or any pharmaceutically acceptable salt, a hydroxide or an ester, administered parenterally in doses ranging from 10 to 100 mg for an adult.

36. The use of the drug, comprising an effective amount of biphosphonate, for producing a medicinal product for the treatment of osteonecrosis and/or dissecting osteochondritis or suitable for prevention of the introduction of the patient to the risk of osteonecrosis and/or dissecting osteochondritis.

37. Drug comprising an effective amount of biphosphonate used to prevent destruction or chondrolysis cartilage associated with osteonecrosis and/or dissect osteochondritis.

38. A method of preventing the destruction or chondrolysis cartilage associated with osteonecrosis and/or dissect osteochondritis, including the introduction of patient drug selected from the group comprising an effective amount of biphosphonate.

Priorities for items:

06.02.2001 - claims 1 to 7, 13, 15-19, 25, 27-33, 35-36, 42-44;

03.04.2001 - PP-12, 20-24;

13.12.2001 - PP, 26, 34, 37-41.



 

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