JP2007523916A - Strontium-containing compounds for the prevention or treatment of necrotic bone conditions - Google Patents

Abstract

Effective doses of the strontium-containing compound (a) are reduced to osteonecrotic bone diseases such as idiopathic or secondary osteonecrosis, avascular osteonecrosis, glucocorticoid-induced bone ischemia / osteonecrosis, Leg-Calve-Pertes disease and A method of treating and / or preventing the osteonecrotic bone disease in a mammal comprising administering to the mammal in need of treatment and / or prevention of femoral head necrosis. Treated with a therapeutic agent (b) comprising administering a strontium compound (a) in combination with a therapeutic agent (b) known or suspected to induce apoptosis and / or necrosis of bone cells Treating and / or treating osteonecrotic bone diseases such as idiopathic or secondary osteonecrosis, avascular osteonecrosis, glucocorticoid-induced bone ischemia / osteonecrosis and femoral head necrosis in a mammal being or being treated How to prevent.
[Selection figure] None

Description

The present invention relates to methods for the treatment and / or prevention of necrotic bone conditions, and pharmaceutical compositions used for such treatment.

BACKGROUND OF THE INVENTION Necrotic bone conditions such as idiopathic or secondary osteonecrosis, avascular osteonecrosis, glucocorticoid induced bone ischemia / osteonecrosis, leg-calve-pertez disease and femur Bone head necrosis is a severe debilitating condition. These conditions may be associated with medical interventions such as high dose glucocorticoid therapy and various treatments for HIV / AIDS, or in susceptible individuals, or other diseases such as Cushing's disease, storage disease ( It may rise spontaneously as a result of eg Gaucher disease), abnormal hemochromatosis (eg sickle cell disease), pancreatitis, decompressive condition or trauma (eg dislocation or fracture).

  Osteonecrosis is characterized by distinct histopathological features that appear on radiographs or bone scans. Diagnostic methods for its identification have recently been improved by the introduction of new sensitive high resolution MRI and other imaging techniques, but effective therapeutic agents or medicines for the prevention and / or treatment of this condition No intervention has been developed.

  Although some pathological situations can induce osteonecrotic conditions, among the most common clinical situations, the use of high-dose glucocorticoids and apoptosis-inducing compounds, such as high doses administered to HIV-infected patients There is antiretroviral treatment.

  Although most skeletal sites can be affected by osteonecrosis, this condition is most commonly found in the femoral head bone below the hip joint surface. The remaining medical intervention choice is orthopedic surgery, where the necrotic bone area and affected joint structures are removed and replaced with appropriate implants. For example, in some patients with juvenile necrotizing bone disease or patients with severe medical conditions, this type of plastic surgery is a major problem and can be used for the prevention and / or treatment of necrotic bone conditions. There is an unmet medical need for new medical treatments.

SUMMARY OF THE INVENTION Accordingly, the present invention relates to osteonecrotic bone diseases such as idiopathic or secondary osteonecrosis, avascular osteonecrosis, glucocorticoid-induced bone ischemia / osteonecrosis, leg-carve-pertes disease and femoral head. A method for the treatment and / or prevention of osteonecrotic bone disease in a mammal in need of treatment and / or prevention of necrosis, the method comprising administering an effective dose of a strontium-containing compound (a) to the mammal Including doing.

  As noted above, one of the common causes of osteonecrotic bone disease is known or suspected to induce osteocyte apoptosis and / or necrosis, thereby leading to osteonecrotic bone disease Treatment with a therapeutic agent. Thus, the present invention relates to osteonecrotic bone in a mammal being treated or treated with a therapeutic agent (b) known or suspected to induce apoptosis and / or necrosis of bone cells. The invention relates to a method for treating and / or preventing diseases such as idiopathic or secondary osteonecrosis, avascular osteonecrosis, glucocorticoid-induced bone ischemia / osteonecrosis and femoral head necrosis, said method comprising a strontium compound (a) In combination with (b).

  The invention also relates to a pharmaceutical composition for use in the treatment and / or prevention of osteonecrotic bone conditions.

Detailed Description of the Invention Osteonecrosis is distinguished from most other metabolic bone diseases in that the pathophysiology of the disease involves the modulation of vascular factors and skeletal metabolism other than those found, for example, in osteoporosis. It has been reported that certain osteoporosis therapies, such as the administration of bisphosphonates, may actually be associated with an increased risk of developing osteonecrosis (Robinson NA and Yeo JF. Ann Acad Med Singapore. 2004; 33 (4 Suppl): 48-9; Greenberg, MS. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004; 98: 259-60). Thus, not all commonly used osteoporosis therapies are considered useful in the treatment of osteonecrosis.

  However, the inventors have demonstrated the therapeutic effect of non-radioactive strontium salts in a model of osteonecrosis, and thus administration of non-radioactive strontium-containing compounds is indeed an osteonecrotic bone disease such as idiopathic or secondary. Novel for the prevention and treatment of the disease in mammals in need of prevention and treatment of traumatic osteonecrosis, avascular osteonecrosis, glucocorticoid-induced bone ischemia / osteonecrosis, leg-carve-perthes disease and femoral head necrosis Can be an important approach.

  Previous studies have shown that various strontium compounds modulate bone loss in osteoporosis. In vitro studies show that strontium has a direct stimulatory effect on pre-osteoblastic cell division and maturation and direct or matrix-mediated inhibition of osteoclast activity (Reginster, JY, Curr Pharm Des 2002: 8 (21): 1907-16). In other words, in vitro data indicate that strontium acts as both an absorption inhibitor and an anabolic agent. Various strontium salts from the prior art, such as strontium lactate, strontium chloride and strontium ranelate described in EP-B 0415850 (2- [N, N-di (carboxymethyl) amino] -3-cyano-4-carboxymethyl The strontium salt of thiophene-5-carboxylic acid) is known. Other known strontium salts are, for example, strontium tartrate, strontium lactate, strontium phosphate, strontium carbonate, strontium nitrate and strontium sulfate.

  Bone consists mainly of an organic matrix containing type I collagen and an inorganic phase containing calcium phosphate and calcium carbonate. Bone matrix proteins are synthesized by osteoblasts. The formation of the organic bone matrix then serves as a scaffold for the precipitation of the inorganic calcium salt of the bone mineral matrix, giving the bone its structural strength. Bone degradation is mediated almost exclusively by multinucleated osteoclasts, which secrete the acids responsible for the lysis of the inorganic bone matrix and the enzymes responsible for the degradation of organic bone matrix proteins.

  Usually, bone resorption and bone formation are closely related. Thus, for example, when bone resorption is reduced by bone resorption inhibitors such as bisphosphonates, bone formation is also reduced to about the same extent. Conversely, when bone formation is increased by, for example, anabolic treatment, such as the hormone PTH, osteoclast recruitment and activity are also up-regulated. Strontium has been reported to have the ability to decouple the process of bone formation and resorption and thus maintain a net positive bone balance. This is due to the combined action of strontium ions that reduce bone resorption and increase or stabilize bone formation.

  According to our observations, the anabolic effect of strontium on bone appears to be particularly suitable for the treatment of osteonecrotic damage. This is because this property allows strontium to promote new mineralized bone in-growth into necrotic damage leading to state repair.

  In addition to this advantageous effect of strontium, the inventors have surprisingly found that strontium ions have an anti-apoptotic effect on bone cells. This effect can protect the cells from certain forms of apoptosis-inducing conditions, such as high doses of glucocorticoid therapy or systemic administration of pro-apoptotic agents, such as antiretroviral or anti-malignant tumor therapy. Since many of the necrotic bone conditions can be associated with apoptosis of bone cells and / or osteoblasts, administration of a compound having an anti-apoptotic effect may be of therapeutic value in the treatment and / or prevention of such conditions. Thus, for necrotic bone conditions induced by administration of therapeutic agents as described above, administration of a strontium-containing compound prevents osteoclast apoptosis and / or necrosis, and consequently, osteonecrotic bone disease. And, if necrotic bone damage caused by apoptosis / necrosis of bone cells has already occurred, it can have a dual effect of promoting new bone ingrowth.

  An effective amount of a strontium-containing compound (a) for a mammal in need of or already undergoing treatment with a therapeutic agent known or suspected to induce apoptosis and / or necrosis of bone cells Would be of great value as part of the same treatment regimen as the administration of therapeutic agent (b).

  Thus, the present invention relates to osteonecrotic bone in a mammal being treated or treated with a therapeutic agent (b) known or suspected to induce apoptosis and / or necrosis of bone cells. The invention relates to a method for treating and / or preventing diseases such as idiopathic or secondary osteonecrosis, avascular osteonecrosis, glucocorticoid-induced bone ischemia / osteonecrosis and femoral head necrosis, said method comprising a strontium compound (a) An effective dose of in combination with (b).

The present inventors provide a prophylactic and / or therapeutic treatment in that administration of a strontium-containing compound (a) in combination with a therapeutic agent (b) can achieve one or more of the following advantageous effects: It has been found that it has special value.
i) Incidence of osteonecrotic bone disease in patients treated with the combination of (a) and (b) compared to patients treated with (b) alone at the same dose as (b) in combination therapy Or a reduction in the incidence or severity of osteonecrotic bone disease whose severity is reduced by at least 5%, such as at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, and / or
ii) In patients treated with the combination of (a) and (b), related to the disease or condition in the patient as compared to (b) alone treated with the same dose as (b) in the combination therapy Any clinically relevant findings, such as bone pain, joint pain, immobility, dysfunction, frequency and / or severity of side effects defined as weight loss or bone mineral density (BMD) loss, at least 5%, for example at least (B) a reduction in the frequency and / or severity of side effects that is reduced by 10%, at least 20%, at least 30%, at least 40%, or at least 50%.

  As described above, glucocorticoid at a high dose is one of the therapeutic agents (b) known to induce osteonecrotic bone disease due to osteocyte apoptosis. Glucocorticoids and other related steroid hormones are given at high doses to modulate the immune system response in several clinical situations such as organ or bone marrow transplantation, inflammation and / or autoimmune diseases and chronic prolonged inflammatory conditions. It is done. Of bone marrow transplant recipients, the incidence of avascular osteonecrosis is estimated to exceed 8% in 5 years (Socie G et al., Br J Haematol. 1994: 86 (3): 624-628. ). Thus, therapeutic agent (b) can be a glucocorticoid and / or another steroid hormone.

  Examples of other therapeutic agents known or suspected to have a role in inducing apoptosis / necrosis of bone cells and consequently leading to osteonecrotic bone disease are antiretroviral compounds such as efavirenz (Sustiva® Trademark)), zidovudine (retrovir (registered trademark)), lamivudine (epivir (registered trademark)), abacavir (Ziagen (registered trademark)), sarcitabine (hivid (registered trademark)), didanosine (videx (registered trademark)), Stavudine (Zerit (registered trademark)), Tenofovir Disoproxil fumarate (Billiard (registered trademark)), Emtricitabine (Emtriva (registered trademark)), Phosamprenavir (Rexiva (registered trademark)), Nevirapine (Vilamun ( Registered trademark)), Delavirdine (Rescrypter (registered trademark)), Capabililine, Enfubi Tide (Fuseon (registered trademark)), Saquinavir (Inbilase (registered trademark), Fort Base (registered trademark)), Ritonavir (Norbia (registered trademark)), Indinavir (Crixiban (registered trademark)), Tipranavir, Amdoxovir, Elbucitabine, Atazanavir (Reyataz (registered trademark)), nelfinavir (biraccept (registered trademark)), amprenavir (agenase (registered trademark)), PRO-542, TMC-114, TMC-125, BMS-56190, DPC-0830.

  Other pro-apoptotic therapies associated with osteonecrosis are cytostatic and neoplastic agents used for cancer prevention and treatment.

  Some of the therapeutic agents used to treat osteoporosis are also known to induce osteonecrosis. One example of such a class of therapeutic agents is bisphosphonates.

  In certain embodiments of the invention, the strontium-containing compound (a) and the therapeutic agent (b) are administered as separate compositions. Administration of (a) and (b) is directed to the type of therapeutic agent (b), the therapeutic regimen of (b), the nature of the disease to which (b) is administered and the bone cells of the mammal receiving (b) ( Depending on the influence of b), it can be performed simultaneously or sequentially.

  In certain situations, the therapeutic agent (b) is known to induce apoptosis and / or necrosis of bone cells and is administered according to the normal treatment regimen of (b) for the particular disease to which (b) is administered. Is done. In such circumstances, the strontium-containing compound (a) can be administered prior to or concurrently with (b). Where (a) is administered prior to (b), administration of (a) can occur for example hours, days or weeks or prior to administration of (b).

  For example, in the case of high dose glucocorticoid therapy for autoimmune diseases such as systemic lupus erythematosus (SLE), the administration of strontium compound (a) can be started simultaneously with the high dose glucocorticoid (b). In cases where glucocorticoid treatment can be performed first, for example in the treatment of patients undergoing kidney transplantation, the strontium compound (a) is administered prior to the glucocorticoid (b), for example 1 month, 2 weeks or 1 week or more. Can be administered before.

In another situation, it is only speculated that the therapeutic agent (b) induces apoptosis and / or necrosis of bone cells. In this situation, administration of the strontium-containing compound may not be initiated until the effect of (b) on bone cells can be demonstrated. Thus, in such circumstances, administration of (a) can begin with a substantial time delay of, for example, days or weeks from the start of administration of (b).
An example of this is osteonecrosis associated with antiretroviral therapy (b) in HIV, where the length of treatment period is an important risk factor for the occurrence of osteonecrosis. Treatment with the strontium compound (a) can be started up to 5 years after treatment with antiretroviral therapy (b) is started.

  Even if the strontium-containing compound (a) and the therapeutic agent (b) are administered sequentially, for example during a time interval of several hours, days, weeks, months or years, they are part of the same treatment. It is considered to be.

Administration of the strontium-containing compound (a) can be performed one or more times per day, for example 2 to 5 times per day. Administration can also be performed one or more times per week, for example 1 to 3 times per week.
Depending on the total daily or weekly dose of (a) required, the strontium compound (a) can be administered one day or, for example, as many times as (b) per week, or (a) Or, for example, it can be administered less than (b) per week or more than (b) per day or per week. Even if (a) and (b) are not administered the same number of times per day or for example per week, they are considered to be part of the same treatment.

  Administration of the strontium-containing compound (a) can be by enteral or parenteral routes or by topical administration. In a specific embodiment of the invention, administration is by the oral route.

In a specific method according to the invention, the strontium-containing compound (a) and the therapeutic agent (b) are administered as a single composition.
Regardless of the method used to treat and / or prevent osteonecrotic bone condition, i.e., whether the strontium compound is administered alone or in combination therapy with therapeutic agent (b) as described above The following is true:
The strontium compound (a) is selected from the group consisting of strontium salts of organic or inorganic acids, the salt being in hydrate, anhydride, solvate, polymorph, amorphous, crystalline, microcrystalline or polymeric form possible. In certain embodiments of the invention, only non-radioactive isotopes of strontium are used.

  The inorganic acids that make strontium salts are boric acid, bromous acid, carbonic acid, chloric acid, diphosphoric acid, disulfuric acid, dithionic acid, dithionic acid, thunder acid, hydroazide acid, hydrobromic acid, hydrogen chloride Acid, hydrofluoric acid, hydroiodic acid, hydrogen sulfide, hypophosphoric acid, hypophosphorous acid, iodic acid, iodic acid, metaboric acid, metaphosphoric acid, metaphosphorous acid, metasilicic acid, nitric acid, nitrous acid, Select from the group consisting of orthophosphoric acid, orthophosphorous acid, orthosilicic acid, phosphoric acid, phosphinic acid, phosphonic acid, phosphorous acid, pyrophosphorous acid, selenic acid, sulfonic acid, sulfuric acid, sulfurous acid, thiocyanic acid and thiosulfuric acid be able to.

Organic acids are acetic acid, C ₂ H ₅ COOH, C ₃ H ₇ COOH, C ₄ H ₉ COOH, (COOH) ₂ , CH ₂ (COOH) ₂ , C ₂ H ₄ (COOH) ₂ , C ₃ H ₆ ( COOH) ₂ , C ₄ H ₈ (COOH) ₂ , C ₅ H ₁₀ (COOH) ₂ , fumaric acid, maleic acid, malonic acid, lactic acid, citric acid, tartaric acid, oxalic acid, ascorbic acid, benzoic acid, salicylic acid, pyruvin Acid, L- and D-aspartic acid, phthalic acid, carboxylic acid, formic acid, methanesulfonic acid, ethanesulfonic acid, camphoric acid, gluconic acid, L- and D-glutamic acid, trifluoroacetic acid, ranelic acid, 2,3,5,6-tetrabromobenzoic acid, 2,3,5,6-tetrachlorobenzoic acid, 2,3,6-tribromobenzoic acid, 2,3,6-trichlorobenzoic acid, 2,4-dichloro Benzoic acid, 2,4-dihydroxybenzoic acid, 2,6-dinitrobenzoic acid, 3,4-dimethoxybenzoic acid, abietic acid, acetoacetic acid, acetone dicarboxylic acid, aconitic acid, acrylic acid Adipic acid, alanine, α-ketoglutaric acid, anthranilic acid, benzylic acid, arachidic acid, arginine, aspartic acid, aspartic acid, azelaic acid, behenic acid, benzenesulfonic acid, β-hydroxybutyric acid, brassic acid, capric acid, chloroacrylic acid , Cinnamic acid, citraconic acid, crotonic acid, cyclopentane-1,2-dicarboxylic acid, cyclopentanecarboxylic acid, cystathionine, lanelic acid, decanoic acid, erucic acid, ethylenediaminetetraacetic acid, fulvic acid, fumaric acid, gallic acid, glutacone Acid, glutamic acid, glutamine, glutaric acid, gulonic acid, glycine, heptanoic acid, hexanoic acid, histidine, humic acid, hydroxystearic acid, isoleucine, isophthalic acid, itaconic acid, lanthionine, lauric acid (dodecanoic acid), leucine, levulin , Linoleic acid (cis, cis-9,12-octadecadienoic acid), lysine, malic acid, m-chlorobenzoic acid, melicic acid, mesaconic acid, methacrylic acid, monochloroacetic acid, myristic acid, (tetradecanoic acid), Nonanoic acid, norvaline, octanoic acid, oleic acid (cis-9-octadecanoic acid), ornithine, oxaloacetic acid, palmitic acid (hexadecanoic acid), p-aminobenzoic acid, p-chlorobenzoic acid, petrothelic acid, phenylacetic acid, phenylalanine P-hydroxybenzoic acid, pimelic acid, propiolic acid, propionic acid, proline, serine, p-tert-butylbenzoic acid, p-toluenesulfonic acid, threonine, tryptophan, tyrosine, pyruvic acid, sarcosine, sebacic acid, serine, Sorbic acid, stearic acid (octadecanoic acid), suberic acid, succinic acid, terephthalic acid, It can be selected from the group consisting of trollic acid, threonine, thyronine, tricarbaric acid, trichloroacetic acid, trimellitic acid, trimesic acid, tyrosine, ulmic acid, valine and cyclohexanecarboxylic acid.

  Any acid that the US Food and Drug Administration (FDA) finds safe for use in an orally ingested composition can be used in the present invention. In certain embodiments of the invention, the acid can be a monoprotic acid or a diprotic acid. In another embodiment of the invention, the acid can be either L-type or D-type or any mixture thereof.

  Specific examples of strontium salts for use according to the invention are strontium chloride, strontium chloride hexahydrate, strontium citrate, strontium malonate, strontium succinate, strontium fumarate, strontium ascorbate, L and / or D Strontium aspartate of any type, strontium glutamate, strontium alpha-ketoglutarate, strontium pyruvate, strontium tartrate, strontium glutarate, strontium maleate, strontium methanesulfonate, strontium of any type L and / or D Benzene sulfonate, strontium ranelate and mixtures thereof.

  In a specific embodiment of the invention, the strontium salt is composed of strontium ions complexed with a dicarboxylic organic acid. Such salts can also be salts of amines or amino acids or mixtures thereof. The strontium salt of the dicarboxylic acid is selected such that the dicarboxylic acid portion of the composition has a higher solubility constant for strontium ions compared to calcium ions under physiological conditions. Thus, the dissolved salt provides a solution with preferential binding of free calcium ions, which promotes intestinal absorption of strontium ions, thus improving the therapeutic effect and / or in osteonecrotic conditions It may provide the advantage of reducing the required dosage required to achieve a prophylactic and / or therapeutic effect.

  The daily dose of ionic strontium is at least about 0.01 g, such as at least about 0.025 g, at least about 0.050 g, at least about 0.075 g, at least about 0.1 g, at least about 0.2 g, at least about 0.3 g, at least about 0.4. g or at least about 0.5 g, or about 0.01 to about 2 g, such as about 0.1 to about 2 g, about 0.1 to about 1 g, about 0.15 to about 0.5 g, about 0.3 to about 2 g, or about 1 to about 2 g. It can be.

When the strontium-containing compound is strontium malonate, it can be administered at a dosage equivalent to about 0.1 to about 10 grams per day calculated as an anhydrous salt. More specifically, the salt is about 0.2 to about 8 g per day, for example about 0.4 to about 5 g per day, about 0.6 to about 3 g per day, about 0.7 to about 3 g per day, calculated as an anhydrous salt. It can be administered at a dose corresponding to about 2 g.
If another strontium salt is used, one skilled in the art can calculate the total daily dose of strontium salt, depending on the desired daily dose of counterion and ionic strontium.

As described above, administration of the strontium-containing compound (a) can be performed one or more times per day, for example 2-5 times per day. Administration can be performed one or more times per week, for example 1 to 3 times per week.
Administration of (a) can be by enteral or parenteral route or topical administration. In preferred embodiments, administration is by the oral route.

  The mammal to be treated in the method according to the invention can be a human or a domestic animal, such as a cat, dog, horse, cow or sheep. In a preferred embodiment, the subject to be treated is a human, for example a human female or male, an adult, an adolescent or a child.

  Mammals in need of treatment are treated with bone-based imaging techniques such as X-ray, ultrasound, magnetic resonance imaging, and / or using specific biochemical markers of bone replacement. It can be identified and / or monitored by assessing alternation changes.

  The details and specific examples described above apply mutatis mutandis to the following.

  In addition to the methods described above, the present invention relates to the use of a strontium-containing compound (a) for osteonecrotic bone conditions in mammals such as idiopathic or secondary osteonecrosis, avascular osteonecrosis, glucocorticoid-induced bone collapse. It also relates to the use for the manufacture of a medicament for the treatment and / or prevention of blood / bone necrosis, leg-carve-perthes disease and femoral head necrosis.

  The present invention also relates to the use of the strontium-containing compound (a) and the therapeutic agent (b) for the manufacture of a medicament for treating and / or preventing osteonecrotic bone conditions in mammals, wherein b) is known or presumed to induce osteocyte apoptosis and / or necrosis leading to osteonecrotic bone condition.

Further, the present invention relates to a strontium-containing compound (a), a therapeutic agent (b) known or suspected to induce apoptosis and / or necrosis of bone cells and lead to an osteonecrotic bone state, In particular to pharmaceutical compositions comprising one or more pharmaceutically acceptable excipients, ie therapeutically inert substances or carriers.
The above carriers can take a wide variety of forms depending on the desired dosage form and route of administration.
Pharmaceutically acceptable excipients include, for example, fillers, binders, disintegrants, diluents, glidants, solvents, emulsifiers, suspending agents, stabilizers, enhancers, flavors, colorants, pH It can be a conditioning agent, a retarding agent, a wetting agent, a surfactant, a preservative, an antioxidant, and the like. Details can be found in pharmaceutical handbooks such as Remington's Pharmaceutical Science or Pharmaceutical Excipient Handbook.

  Specific examples of the amount of compound administered are described above. However, the amount of compound actually administered will be related to the condition being treated, the choice of compound to be administered, the age, weight and response of the individual patient, the severity of the patient's symptoms and the chosen route of administration. It is understood that it is decided by the doctor in consideration of the situation. While it is preferred that the compositions of the invention be administered orally, the compound can be administered by any other suitable route.

  The pharmaceutical composition according to the present invention may be in the form of a solid, semi-solid or liquid composition. In certain embodiments of the invention, the pharmaceutical composition may be in the form of a tablet. The tablet is at least 50% w / w, at least 60% w / w, at least 65% of the total amount of salt, e.g. the salt contained in the tablet, proximal to the small intestine, e.g. in the duodenum and / or proximal jejunum. It may be coated with a coating that allows release of% w / w, at least 70% w / w, at least 80% w / w or at least 90% w / w.

  In another embodiment of the invention, the compound is fully or predominantly soluble in the ventricle, eg at least 50% w / w, at least 60% w / w, at least 65% of the total amount of salt contained in the tablet. % w / w, at least 70% w / w, at least 80% w / w or at least 90% w / w.

  The tablet may have a shape that the patient can easily and properly swallow. Thus, the tablets may have a round or spindle shape, for example without sharp edges. Further, the tablet can be designed to be divided into two or more parts.

The semi-solid form of the composition can be a paste, gel or hydrogel.
The liquid form of the composition can be a solution, an emulsion including a nanoemulsion, a suspension, a dispersion, a liposome composition, a spray, a mixture, a syrup or an elixir.
Other suitable dosage forms of the pharmaceutical composition according to the invention may be capsules, sachets, troches, devices and the like.

  The pharmaceutical composition can be manufactured using any method known to those skilled in the art of pharmaceutical formulation.

  The present invention also relates to a kit comprising two or more components, wherein the first component comprises a strontium-containing compound (a) and the second component induces osteoclast apoptosis and / or necrosis to induce osteonecrosis A therapeutic agent (b) known or suspected to lead to a sexual bone condition.

  It may be advantageous for a method, pharmaceutical composition or kit according to the invention to contain one or more further active substances. One or more additional active substances may have a therapeutic and / or prophylactic effect against osteonecrotic bone disease, eg osteonecrosis. The term “active substance having therapeutic and / or prophylactic effect on osteonecrotic bone disease” refers to certain medical outcomes, such as a reduced incidence of osteonecrosis, bone pain associated with osteonecrotic injury Active substances capable of achieving a reduction in bone marrow, increased bone density, and / or improved bone healing or prevention of fractures in subjects at risk of developing an osteonecrotic condition. Examples of such substances are bone resorption inhibitors and anabolic agents. However, one or more active substances having other effects other than those described above may also be included in the method or pharmaceutical composition of the present invention. Such active substances are for example pain relievers (analgesics), anti-inflammatory drugs, antiretroviral drugs, antineoplastic drugs, disease modifying antirheumatic drugs or other antirheumatic drugs. possible.

  Specific examples of active substances that can be used in the method or pharmaceutical composition according to the invention are calcium-α-ketoglutarate, calcium and / or its salts, vitamin D, for example vitamin D3 and / or functional equivalents of vitamin D3, Glucagon-like peptide-2, glucagon-like peptide-2 releasing composition, non-steroidal anti-inflammatory drug, pain relieving agent, tumor necrosis factor α (TNF-α) inhibitor, inhibitor of IL-15 release or function, IL-1 An inhibitor of release or function.

  The following examples are intended to illustrate the invention without limiting it.

Example Example 1
The effect of strontium malonate in an osteonecrotic animal model The fundamental reason for this study was to assess the ability of strontium to act as a therapeutic and bone growth-promoting (anabolic-promoting) agent in an osteonecrotic animal model . In this model, syngeneic necrotic bone grafts were implanted into the thighs of recipient rats. The necrotic graft was broken down during which new bone ingrowth occurred. At the end of the experiment, structural grafts were collected and analyzed by histology to quantify both the degradation of the necrotic graft and the ingrowth of new bone. Necrotic graft insertion may be followed by treatment with anabolic and / or absorption inhibitors and the effects monitored after the end of the experiment. This rat model has been previously described (Astrand J, Aspenberg P. BMC Musculoskelet Disord. 2002; 3 (1): 19).

Methods and Materials Compounds (active strontium test article: Sr-malonate, 189.6 g / mol; placebo substance, calcium malonate, 142.1 g / mol) were suspended in drinking water for rats. The salt is produced in a 1.6 g / l solution, which is close to saturation (22-25 ° C.). Therefore, long stirring was necessary to completely dissolve the substance. A new batch of drinking water was refreshed weekly for the duration of the experiment. When not in use, the solution was stored in a sealed container at room temperature. Preliminary experiments showed that each animal drank 60-90 ml / 24 h and the approximate daily strontium dose was 120 mg strontium malonate (equal to ionic strontium 55.4 mg).

  The study was conducted in 20 male Sprague-Dawley rats, Taconic M & B, Lille Skensved, Denmark, weighing 350 g (equivalent to 9-10 weeks of age). The animals were acclimatized for 2 weeks prior to the start of the experiment, and thus were about 12 weeks of age at the time of transplantation of the necrotic bone graft (week 0).

  The study consisted of two groups of 10 rats each. Rats were randomly assigned to groups prior to the start of the study. In a previous study using therapeutic intervention in this model of osteonecrosis (Astrand J, Aspenberg P. BMC Musculoskelet Disord. 2002; 3 (1): 19), the study lasted 6 weeks. At week 0, these rats were subjected to surgery in which a necrotic bone graft from a female Sprague-Dawley rat was inserted with a cancellous (trabecular) bone graft. Bone grafts were excised from female rats after necropsy and frozen at -80 ° C. to kill all cells in the bone graft. The graft was then placed in a titanium chamber placed in the tibia of the right hind limb with a complete anesthesia operation. Treatment with strontium malonate or control (calcium malonate) was started at week 0. Food and water containing the suspended test substance were ad libitum. Rats were euthanized after 6 weeks and the titanium chamber containing the necrotic bone graft was removed and processed for histological evaluation.

  Carefully removed from the titanium chamber, the implant was decalcified in 10% formic acid, 2% formaldehyde for 14 days. The decalcified skeletal tissue was embedded in paraffin and cut into 1 μm sections parallel to the long axis of the graft. Subsequently, each section was stained with hematoxylin and eosin and visually scored for the appearance of necrotic graft degradation and new bone ingrowth.

result
All 20 animals completed the 6-week study period and could be used for histological analysis. Histological analysis showed that soft tissue invaded the graft in all rats. The new bone formed a bone ingrowth frontier. The main parameter of the analysis was the measurement of this ingrowth distance. The two groups of animals showed considerable differences in the extent of new bone ingrowth. The strontium malonate treatment group had an average ingrowth of 3.43 (± 1.35 (SD)) mm compared to an average ingrowth of 2.24 (± 1.00) p = 0.038. This indicates that strontium malonate has a considerable anabolic effect, thus indicating the potential use of this compound in both prevention and treatment of osteonecrosis.

The strontium malonate used in the examples herein is prepared as described below.
Preparation of strontium malonate anhydride by synthesis at 100 ° C First, a suspension of malonic acid (white), 100 mL of Millipore water and solid malonic acid (Fluka, MW 104.06 g / mol, CAS no. 141-82 -2, lot. No. 449503/1, filling code 44903076) Prepared by adding 10.406 g (0.1 mol) in a 250 mL beaker. To this suspension, 26.571 g (0.1 mol) of solid strontium hydroxide (Sigma Aldrich, Sr (OH) ₂ * 8H ₂ O, MW 265.71, CAS no. 1311-10-0) was added. A magnetic stir bar was then added and stirring and heating were started to the boiling point of the suspension. The final suspension was also white and stirring was continued by maintaining a moderate rotation of the stirring device. The beaker was covered with a cover glass to prevent carbon dioxide from entering the solution.

  After a few minutes of boiling and stirring, the solution clarified and all solids dissolved. Additional water was added as needed to maintain boiling and replace water loss due to boiling. After boiling for 3 hours, the solution was filtered through a Buchner funnel while boiling. A very small amount of impurities remained on the filter paper. Subsequently, when the filtrate was cooled to room temperature, fine powder crystals of strontium malonate grew. The final product precipitation proceeded rapidly during filtration and the majority of the product was found in the filter paper (unheated). Precipitation proceeded in the filtrate only in rare cases. The product was filtered and dried in an oven at 110 ° C. for 30 minutes, then dried on silica orange in a desiccator for 12 hours. Prior to analysis by X-ray crystallography and flame atomic absorption spectroscopy (F-AAS), the salt was ground into a fine powder in a mortar.

  The overall yield of strontium malonate was approximately 98% before recrystallization, and the majority of impurities consisted of reagents and strontium carbonate reminisces. The product was clearly identified as strontium malonate (anhydride) by comparison of the data with results from X-ray crystallography and the Cambridge crystallography database.

In a further improvement of the synthesis, anhydrous strontium malonate was produced on a 10 kg scale in the process according to the invention to show the applicability of the process for large scale synthesis. 15.80 kg of Sr (OH) ₂ * 8H ₂ O was dissolved in 63.2 l of pure water and heated to 95-100 ° C. 5.63 kg of malonic acid was dissolved in 4.1 l of pure water, filtered, and then 1.4 l of water was further added to heat the solution to 95-100 ° C. The two solutions were mixed in a closed reaction vessel under an inert nitrogen atmosphere and stirred at reflux for 20 minutes. Subsequently, heating was stopped and the solution was allowed to cool to 40-50 ° C. over 2-4 hours, during which time strontium malonate was precipitated. The precipitate was filtered and the salt was further washed with 13.2 l of water and then completely dried in vacuo at a temperature of 70 ° C. 9.4 kg of anhydrous high purity strontium malonate was obtained as a homogeneous microcrystalline white powder, corresponding to a yield of 94%. The product was clearly identified as strontium malonate (anhydride) by comparison of the data with results from X-ray crystallography and the Cambridge crystallography database.

The tablet used in the method according to the present invention can be produced as follows.
Formulation of Strontium Malonate into Tablets Strontium malonate can be formulated for pharmaceutical use in convenient tablets for oral administration. Tablets should be manufactured using microcrystalline strontium malonate prepared as described above. For the manufacture of tablets, the following procedure can be performed, which gives about 12000 tablets.
3600 g of strontium malonate prepared as described above is mixed with 180 g of Avicel PH102 (microcrystalline cellulose) Ph. Eur. After mixing, 144 g Polyvidone A Ph. Eur. And 450 g pure water Ph. Eur. Are added to the mixture.

  The weight of the mixture is adjusted (theoretical weight 3924 g). After the mixing process is complete, the granulated material is screened through a 1.2 mm pore size mesh and dried at 40 ° C. in a tray in a suitable drying oven. Add anhydrous colloidal silica (Aerosil 200) Ph. Eur 23 g, Avicel PH102 (microcrystalline cellulose) Ph. Eur 284 g and magnesium stearate Ph. Eur 23 g to the granules. Mix thoroughly and screen the material through a screen with a pore size of 0.7 mm. This material is put on a tablet press.

9 mm white round tablets (φ9 mm) without score lines are produced, each containing the following ingredients:
Strontium malonate 300 mg
Microcrystalline cellulose Ph.Eur. 43.5 mg
Polyvidone Ph.Eur. 12 mg
Anhydrous colloidal silica Ph.Eur. 2.25 mg
Magnesium stearate Ph.Eur. 2.25 mg

  In a pharmaceutical application where a 1.2 g dose of strontium malonate is administered, four tablets can be administered to a subject in need. By using a tablet press with a larger press head, one skilled in the art can produce larger tablets containing more of the listed ingredients in the same relative amounts.

Claims (23)

  Effective dosages of the strontium-containing compound (a) are adjusted to osteonecrotic bone diseases such as idiopathic or secondary osteonecrosis, avascular osteonecrosis, glucocorticoid-induced bone ischemia / osteonecrosis, Leg-Calve-Pertes disease and A method of treating and / or preventing the osteonecrotic bone disease in a mammal comprising administering to the mammal in need of treatment and / or prevention of femoral head necrosis.   The daily dose of strontium is at least about 0.01 g, such as at least about 0.025 g, at least about 0.050 g, at least about 0.075 g, at least about 0.1 g, at least about 0.2 g, at least about 0.3 g, at least about 0.4 g or at least About 0.5 g, or about 0.01 to about 2 g, such as about 0.1 to about 2 g, about 0.1 to about 1 g, about 0.15 to about 0.5 g, about 0.3 to about 2 g, or about 0.5 to about 2 g. Item 2. The method according to Item 1.   The method according to claim 1 or 2, wherein the administration is performed one or more times per day.   4. The method according to claim 3, wherein the administration is performed 2 to 5 times per day.   The method according to any one of claims 1 to 4, wherein the administration is by enteral or parenteral route or by topical administration.   6. The method of claim 5, wherein administration is by the oral route.   Treated with a therapeutic agent (b) comprising administering a strontium compound (a) in combination with a therapeutic agent (b) known or suspected to induce apoptosis and / or necrosis of bone cells Treatment of osteonecrotic bone diseases in mammals being or being treated, such as idiopathic or secondary osteonecrosis, avascular osteonecrosis, glucocorticoid-induced bone ischemia / osteonecrosis and femoral head necrosis and / or How to prevent.   8. The method according to claim 7, wherein apoptosis and / or necrosis of bone cells leads to osteonecrotic bone disease. Administration of the strontium-containing compound (a) and the therapeutic agent (b) includes:
i) Incidence of osteonecrotic bone disease in patients treated with the combination of (a) and (b) compared to patients treated with (b) alone at the same dose as (b) in combination therapy Or a reduction in the incidence or severity of osteonecrotic bone disease whose severity is reduced by at least 5%, such as at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%;
ii) In patients treated with the combination of (a) and (b), related to the disease or condition in the patient as compared to (b) alone treated with the same dose as (b) in the combination therapy Any clinically relevant findings, such as bone pain, joint pain, immobility, dysfunction, frequency and / or severity of side effects defined as weight loss or bone mineral density (BMD) loss, at least 5%, for example at least 9. A method according to claim 7 or 8, which leads to at least one of a reduction in the frequency and / or severity of side effects of (b) which is reduced by 10%, at least 20%, at least 30%, at least 40% or at least 50%. .   The method according to any one of claims 7 to 9, wherein the therapeutic agent (b) is glucocorticoid and / or another steroid hormone.   The therapeutic agent (b) is an antiretroviral compound such as efavirenz (Sastiva®), zidovudine (Retrovir®), lamivudine (Epivir®), abacavir (Ziagen®), Sarcitabine (Hivid (registered trademark)), didanosine (Videx (registered trademark)), stavudine (Zerit (registered trademark)), tenofovir disoproxil fumarate (Billiard (registered trademark)), emtricitabine (emtriva (registered trademark)) )), Fosamprenavir (Rexiva®), Nevirapine (Viramune®), Delavirdine (Rescrypter®), Capabilbilin, Enfuvirtide (Fuseon®), Saquinavir ( Inbilase (registered trademark), Fort Base (registered trademark)), ritonavir (no A (registered trademark)), indinavir (crixiban (registered trademark)), tipranavir, amdoxovir, elbucitabine, atazanavir (relayats (registered trademark)), nelfinavir (biraccept (registered trademark)), and amprenavir (registered trademark)) The method according to claim 7, PRO-542, TMC-114, TMC-125, BMS-56190, DPC-0830.   The method according to any one of claims 7 to 9, wherein the therapeutic agent (b) is a bisphosphonate.   The daily dose of strontium is at least about 0.01 g, such as at least about 0.025 g, at least about 0.050 g, at least about 0.075 g, at least about 0.1 g, at least about 0.2 g, at least about 0.3 g, at least about 0.4 g or At least about 0.5 g or about 0.01 to about 2 g, such as about 0.1 to about 2 g, about 0.1 to about 1 g, about 0.15 to about 0.5 g, about 0.3 to about 2 g, or about 1 to about 2 g. Item 13. The method according to any one of Items 7 to 12.   14. The method according to any one of claims 7 to 13, wherein (a) and (b) are administered as a single composition.   14. The method according to any one of claims 7 to 13, wherein (a) and (b) are administered as separate compositions.   The method according to any one of claims 7 to 15, wherein the administration of (a) and (b) is performed simultaneously or sequentially.   The method according to any one of claims 1 to 16, wherein the strontium-containing compound (a) is selected from the group consisting of strontium salts of organic or inorganic acids.   18. The method of claim 17, wherein the salt is a hydrate, anhydride, solvate, polymorph, amorphous form, crystalline form, microcrystalline form or polymer form.   The salt is strontium chloride, strontium carbonate, strontium citrate, strontium malonate, strontium succinate, strontium fumarate, strontium ascorbate, strontium pyruvate, strontium L-glutamate, strontium D-glutamate, strontium L-aspartate Strontium D-aspartate, strontium α-ketoglutarate, strontium lactate, strontium tartrate, strontium glutarate, strontium maleate, strontium methanesulfonate, strontium benzenesulfonate, strontium ranelate and mixtures thereof The method according to any one of claims 1 to 18.   Osteonecrotic bone condition in mammals such as idiopathic or secondary osteonecrosis, avascular osteonecrosis, glucocorticoid-induced bone ischemia / osteonecrosis, Leg-Calve-Perthes disease and femur of strontium-containing compound (a) Use for the manufacture of a medicament for treating and / or preventing osteonecrosis of the bone.   Osteonecrosis in mammals with strontium-containing compounds (a) and therapeutic agents (b) known or suspected to induce osteonecrotic bone conditions by inducing apoptosis and / or necrosis of bone cells Use for the manufacture of a medicament for treating and / or preventing a bone condition.   A strontium-containing compound (a) and a therapeutic agent (b) known or suspected to induce osteonecrotic bone condition by inducing apoptosis and / or necrosis of bone cells and optionally 1 or A pharmaceutical composition comprising more pharmaceutically acceptable excipients.   A therapeutic agent known or suspected that the first component comprises a strontium-containing compound (a) and the second component induces osteocyte apoptosis and / or necrosis leading to osteonecrotic bone condition ( A kit comprising 2 or more components comprising b).