PT1622629E - Controlled-release composition containing a strontium salt - Google Patents

Description

1

DESCRIPTION

" CONTROLLED RELEASE COMPOSITION CONTAINING A STROKING SALT " Field of the Invention The present application relates to a composition, which is in tablet form, for medical use and for once-daily administration, comprising at least one specific strontium salt, such as re-inked. The invention also relates to the tablet for said use for the treatment of a male subject suffering from diseases and conditions affecting the metabolism and / or structural integrity of the cartilage and / or bone. The invention also relates to the tablet, for said use, for the prevention of conditions affecting cartilage and / or bone in an individual and for use in the treatment and / or prophylaxis of secondary osteoporosis.

BACKGROUND OF THE INVENTION Osteoporosis is the most common form of bone metabolism in humans. It is a condition that affects a large number of people around the world and as the trend is for increasing the number of seniors in the coming decades, in most countries, the prevalence and impact of osteoporosis will also increase. The disease is pathologically characterized by an absolute reduction in the amount of bone mass and the structural quality of the bone and, clinically, by the increased susceptibility to fractures. In fact, osteoporosis is the leading cause of bone fractures in middle-aged and older women. 2

In general, there are two types of osteoporosis: primary and secondary. Secondary osteoporosis is the result of an identifiable disease process, treatments or therapeutic agents. However, approximately 90% of all cases of osteoporosis correspond to idiopathic primary osteoporosis. Primary osteoporosis includes postmenopausal osteoporosis, age-related osteoporosis (affecting most individuals over the age of 70-80), and idiopathic osteoporosis affecting middle-aged and younger men and women.

It is believed that the mechanism of bone loss in osteoporosis involves an imbalance in the process of bone remodeling. Bone remodeling occurs throughout life, renewing the skeleton and maintaining bone strength. This remodeling is mediated by specialized bone tissue cells, termed " osteoclasts " and " osteoblasts ". Osteoclasts (dissolution or bone resorption cells) are responsible for resorbing a portion of the bone within the bone matrix during the reabsorption process. After reabsorption, osteoblasts (bone-forming cells) arise after the osteoclasts, which then fill the reabsorbed portion with new bone. The formation of both types of cells, as well as their activity in bone are normally associated and well regulated, in order to maintain skeletal balance and structural integrity of bones. However, in people with osteoporosis, there is an imbalance in the bone remodeling process, resulting in bone loss at a faster rate than bone buildup. The single most important risk factor for osteoporosis is the estrogen deficiency that occurs naturally in menopause. The decrease in the production of endogenous estrogen 3 leads to a high metabolic activity in the bone tissue, where the increase in osteoclast-mediated bone resorption is superior to the more modest increase in bone formation, resulting in bone loss. The current number of people affected will increase at a rate higher than the rate of population growth due to the disproportionate increase in population in which there is an increase in the older segment of the population while the age of menopause begins constant. In recent decades, there has also been a substantial advance in the ability to predict and monitor osteoporosis, as well as improved bone mineral density (BMD) measurement methods and new biochemical markers specific for bone resorption and formation have been developed and made available for routine clinical use. New pharmaceutical agents for the treatment and / or prevention of osteoporosis have also been developed. Most of these treatments are based on the replacement of lost endogenous estrogen, either in the form of hormone replacement therapy (TSH) or selective estrogen receptor modulators (MSRE), or those in the class of compounds called bisphosphonates. MSRE and, especially, TSH can only be administered to female subjects, since the administration of estrogen and similar substances in male subjects will be associated with undesirable hormonal effects. In addition, even in women the use of MSREs and especially TSH is associated with significant side effects such as increased risk of cancer and cardiovascular disease, while bisphosphonates in addition to a potent anti-resorptive effect also decreases the formation of bone in a similar way, implying a loss of its therapeutic effect after a few years of treatment. Thus, there is a need for agents effective in the treatment and / or prophylaxis of osteoporosis. SORBERA L A; ET AL: " STRONTIUM RANELATE TREATMENT AND PREVENTION OF OSTEOPOROSIS BONE RESORPTION INHIBITOR BONE FORMATION STIMULANT ", DRUGS OF THE FUTURE, ES, Vol: 28, Nr: 4, 1 April 2003 (2003/04/01), pages 328 -335 discloses the use of a soluble strontium salt of an organic acid (strontium ranelate, a synthetic, unnatural amino acid, substituted with thiophene) for the treatment of osteoporosis. In the studies discussed in that document, PREVOS and STRATOS, strontium ranelate was administered once daily, see table 1, 1000 mg orally once per day. Said document further describes that strontium ranelate has good bioavailability. Said document is thus the closest prior art document.

Description of the invention The scope of the invention is limited by the appended claims. In a first aspect of the invention, it relates to a composition, which is in tablet form, for medical use and for once-daily administration, comprising at least one specific strontium salt, such as recidented. The composition is intended for once-daily administration. In a specific aspect of the invention, the strontium salt is characterized as having a solubility in water of about 200 g / L at most at room temperature and in a specific aspect, the strontium salt has a relatively low water solubility in physiological conditions (i.e., a solubility of less than 1 g / L at 40 ° C). 5

A second aspect of the invention relates to a pharmaceutical composition containing a strontium salt, wherein the composition is adapted to release the Sr salt such that the amplitude (difference between the peak and nadir) of the plasma concentration relative to the level of the peak should be less than about 40%, such as less than about 35%, less than about 30%, less than about 25%, less than about 20%, less about about 15% or less of about 10%, after administration of the composition to an individual once daily for a period of time of 7 days or more. In one preferred aspect, the time period corresponds to 7 days.

In one embodiment of the invention, the plasma concentration may range from about 16.2 ± 3 mg / L and 20.0 ± 2.3 mg / L, Sr, following administration of a pharmaceutical composition which comprises a daily dose of approximately 650 mg ionic strontium. It is contemplated that therapy with Sr salts would be significantly improved by reducing the frequency of administration. First, it is possible to reduce or minimize undesirable side effects and additionally it is possible to achieve a plasma level which is constant or substantially constant over an extended period of time, leading to a reduction in the amplitude between the peak and the values concentration of plasma concentration.

Thus, the patient will potentially have a more efficient treatment with a continuing treatment effect (e.g., a continuous anti-osteoporotic effect) over the treatment period.

An in vitro method suitable for determining whether a specific composition has suitable properties as regards the controlled release of Sr salt corresponds to an in vitro dissolution test as described in Ph. Eur. Thus, a controlled release composition , according to the invention, when tested in an in vitro dissolution test - strontium releases from pharmaceutical composition containing Sr salt, as follows: in the first 30 minutes of the test, at most about 10% P / P of the ion Sr; in the first 4 hours of the test, at most 70% P / P of the Sr ion is released; in the first 14 hours of the test, about 70% w / w or more of the ions are released. The tablet used in the invention may be a composition wherein the Sr salt is contained in a matrix which controls the release. The composition may also be coated with a controlled release coating which regulates the release of the compound containing

Some of the known strontium salts (e.g., strontium chloride, strontium hydroxide) have a high solubility in water (i.e. above 200 g / L in water and at an ambient temperature of 20-25 ° C). Regardless of their solubility in water, such strontium salts may be incorporated into a controlled release composition for once-daily administration. However, in a specific embodiment of the invention, the water solubility of the strontium salt is at most about 200 g / L, such as, for example, at most about 150 g / L, at most about 100 g / L, at most about 75 g / l, at most about 50 g / l, at most about 25 g / l, at most about 10 g / l, at most about 5 g / l at of about 2.5 g / L, or at most about 1 g / L, at room temperature (20-25 ° C). 7

In addition, the invention relates to such a composition, wherein the amount of Sr salt is adjusted so as to allow the composition to be suitable for administration once or twice daily.

As mentioned above, such a composition may be suitable for once-daily administration, for example at bedtime. It is known that bone resorption is superior at night than during the day, so administration of a quantity of Sr at bedtime may be favorable compared to administration of a similar amount of Sr in the morning. As shown in the examples herein, some strontium salts, i.e., those having a solubility in water of less than 200 g / L (as mentioned above) have a delayed appearance of the ionic strontium ion concentration peak, comparing, for example, to high solubility in water, strontium chloride. Accordingly, such salts are considered to be those suitable for use in the design of a controlled release pharmaceutical composition containing a strontium salt. The daily dose of strontium ion may be at least about 0.01 g, for example at least about 0.025 g, at least about 0.050 g, at least about 0.075 g, at least about 0.01 g, 1 g, at least about 0.2 g, at least about 0.3 g, at least about 0.4 g or at least 0.5 g or from about 0.01 to about 2 g, such as, for example, from 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 0.3 to about 1 g.

In a specific embodiment of the invention, it also relates to such composition, which comprises at least 0.5 g of Sr, defined as free ionic strontium, such as, for example, at least 0.6 g, at least 0.7 g, at least 0.8 g, at least 0.9 g, at least 1.0 g, at least 1.1 g, at least 1.2 g, at least 1.3 g, at least 1.4 g, at least 1.5 g, at least 1.6 g, at least 1.7 g, at least 1.8 g, at least 1.9 g or at least 2.0 g per day.

In addition, the invention relates to such a composition for use in a method for the treatment and / or prophylaxis of cartilage and / or bone disease and / or conditions resulting from cartilage dysregulation and / or bone metabolism in a mammal, such as, for example, an adult female human or male, adolescent or child, such as osteoporosis, osteoarthritis, osteopetrosis, osteopenia and Paget's disease, hypercalcemia, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, osteoarthritis, myositis ossificans, Bechterew's disease, malignant hypercalcemia, osteolytic lesions produced by bone metastasis, bone pain due to bone metastasis, bone loss due to sexual steroid hormone deficiency, bone abnormalities due to treatment with steroid hormones, bone abnormalities caused by cancer therapies, osteomalacia , Bechet's disease, hyperostosis, bone disease goals osteopenia induced osteoporosis or osteoporosis or osteoporosis induced by glucocorticoids or osteoporosis, osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis, for the improvement of fracture healing after traumatic or atraumatic fracture, for the improvement of implant stability and appropriate for maintenance or increase of the energy level, for the construction or strengthening of muscle tissues and for weight gain, the method comprising administering a single daily dose of a Sr salt comprising at least 0.7 g Sr, such as such as, for example, at least 0.8 g, at least 0.9 g, at least 1.0 g, at least 1.1 g, at least 1.2 g, at least 1.3 g, at least 1,4. g, at least 1.5 g, at least 1.6 g, at least 1.7 g, at least 1.8 g, at least 1.9 g or at least 2.0 g.

Strontium

Previous studies have shown that various strontium compounds modulate bone loss in osteoporosis when present at levels higher than that required for normal cell physiology. It is believed that the effect is due to a strontium-stimulating effect on pre-osteoblast cell replication and a direct or matrix-mediated inhibition of strontium osteoclast activity (Reginster, JY, Currpharm Des 2002: 8 (21): 1907-16). In other words, strontium acts as an anti-reabsorption agent and as an anabolic agent. Various strontium salts are known from the prior art, such as, for example, strontium ranelate (2- [N, N-di (carboxymethyl) amino] -3-cyano-4-carboxymethylthiophene-5 -carboxylic acid) described in EP-B 0 415 850. The portion of ranelate in the strontium compound derived from ranelic acid is unlikely to have any therapeutic effect alone for cartilage or bone conditions.

The strontium salts, as listed in the claims, may be in a composition, as described above. The salts may be in hydrate, anhydrous, solvate, polymorph, amorphous, crystalline, microcrystalline or in the polymeric form. In one embodiment of the invention, only non-radioactive isotopes of M. The organic acid may be selected from the group consisting of maleic acid, malonic acid, glutamic acid L- and D-, pyruvic acid, aspartic acid L- and D-, 10 alpha-ketoglutaric acid, pyruvic acid and succinic acid.

As mentioned above, the strontium salt for the use according to the invention may be water soluble, having a solubility of at least 0.1 g / L, such as, for example, in the range of about 0 , 1 g / l to about 10 g / l, from about 0.2 g / l to about 5 g / l, at ambient temperature and exemplified by the salts listed above, i.e., in a specific aspect of the invention, the strontium salt has a solubility in water of at least 1 g / l, such as, for example, at least 5 g / l of at least 10 g / l of at least 20 g / at least 30 g / l of at least 40 g / l of at least 50 g / l of

at least 70 g / l of at least 80 g / l of at least 90 g / l or at least 100 g / l, measured at room temperature of 20-25 ° C. The daily dose of strontium may be at least about 0.01 g, such as, for example, at least about 0.025 g, at least about 0.050 g, at least about 0.075 g, at least about 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 g about 2 g, such as, for example, from about 0.1 to about 2 g, about 0.1 to about 1 g, from about 0.15 to about 0.5 g, about 0.3 to about 2 g or about 0.3 to about 1 g. Synthesis of strontium salts

This embodiment is not part of the invention. The organic strontium salts of carboxylic acid anions can be synthesized through a number of different pathways. A conventional method for the preparation of such organic salts of strontium is to use the reaction between the organic acid and strontium hydroxide in aqueous solution. This neutralization reaction of, for example, fumaric acid and strontium hydroxide salt follows the following scheme:

Sr2 + (aq) + 20H '(aq) + HOOCCHCHCOOH (aq) -> The suspension of the dissolved strontium fumarate can then be induced to precipitate by sublimation of the water and, subsequently, concentration of the salt. The crystals will slowly form and precipitate from the solution.

An alternative approach is to use the sodium or potassium salt of the appropriate carboxylic acid anion and strontium chloride. Like all organic strontium salts, it will be less soluble than the chloride salt which is highly soluble, the organic strontium salt will precipitate under these conditions, leaving NaCl and excess SrCl 2 in the solution. The equation below exemplifies this reaction scheme, using as an example the reaction between SrCl2 and sodium fumarate.

Sr2 + (aq) + 2C1 "(aq) + 2Na + (aq) + C4H2042" (aq) -►

Sr (OOCCHCHOO) (aq) + Cl " (aq) + Na + (aq)

The present inventors have discovered that different strontium salts require different synthetic routes and have identified for some strontium salts optimized synthesis and manufacturing processes. It has been found that the synthesis of strontium salts of the amino acids aspartate and glutamate (D- or L-) di-carboxylic forms is very difficult when following these conventional reaction pathways and generally results in low yields and purity of the crystalline salt obtained . In order to facilitate the large-scale production of strontium salts of pure dicarboxylic amino acids 12, in order to be able to have pharmaceutical use, according to the present invention, the present inventors have studied various routes of synthesis of these strontium salts in private. Thus, it has surprisingly been discovered that the synthesis of the well-defined and pure, strontium glutamate strontium in the form of hexahydrate is most convenient being performed with glutamate in the form of free acids and strontium hydroxide and requires high temperatures such as above temperatures of 80 ° C or more, preferably 100 ° C or up to 120 ° C or more preferred above 130 ° C (see example 7, where manufacturing processes for the synthesis of organic salts of strontium at an elevated temperature are described).

It has further been discovered that the addition of small volumes of alcohol can accelerate crystal formation of dissolved aqueous strontium organic salts. Examples of these procedures for the synthesis of organic salts of strontium with relevance for the treatment and / or prophylaxis of bone diseases are provided in the examples presented herein.

Pharmaceutical Compositions The invention also relates to pharmaceutical compositions of the tablet for said use, as described above, comprising at least one strontium compound. The pharmaceutical compositions according to the invention will normally further comprise one or more physiologically acceptable excipients, i.e., a therapeutically inert substance or a carrier. The carrier may be of a wide variety of forms, depending upon the dosage and route of administration desired. The pharmaceutical composition is designed to release the active substance in the gastrointestinal tract, i.e., in a preferred aspect, it is not intended for application or absorption through the mucosa of the oral route. The composition is a tablet such as, for example, conventional tablets, effervescent tablets, coated tablets, melt or sublingual tablets, tablets, powders, granules, granules, particulate matter, solid dispersions or solid solutions. The tablet may be coated with a coating which allows the release of at least part of the salt in the proximal portion of the small intestine, such as, for example, in the duodenum and / or the proximal jejunum, of at least 50% P / P , at least 60% P / P, at least 65% P / P, at least 70% P / P, at least 80% P / P or at least 90% P / P of the total value of the salt contained in the tablet. The tablet may have a shape which makes it easier and convenient for the patient to swallow. The tablet may, for example, be rounded or have a rod-like shape, with no sharp edges. Further, the tablet may be designed to be divided into two or more parts.

The pharmaceutical compositions may be prepared by any of the methods well known to a person skilled in the art of pharmaceutical formulations.

Pharmaceutically acceptable excipients may be, for example, fillers, binders, disintegrants, diluents, glidants, solvents, emulsifying agents, suspending agents, stabilizers, enhancers, flavors, colors, pH adjusting agents, retarding agents, wetting agents , surfactants, preservatives, antioxidants, etc. Details can be found in pharmaceutical manuals, such as, for example, Remington's Pharmaceutical Science or Pharmaceutical Excipient Handbook. In such cases, where the pharmaceutical composition is for a controlled release of the Sr-containing compound, it may also comprise release-controlling agents, such as, for example, material commonly used in the formulation of matrix tablets (e.g. cellulose such as hydroxypropylmethylcellulose and the like). Alternatively, the composition may be coated with a controlled release coating, such as an enteric coating or a film coating. A suitable coating may be a substantially water-insoluble, but water-permeable coating. The invention relates to a controlled release pharmaceutical composition for oral use, which consists of a tablet. The term " tablet " is intended to encompass tablets, coated tablets, matrix tablets, osmotic tablets and other forms known in the art. The term " multiparticulate " is intended to encompass a dosage form comprising a multiplicity of particles and / or granulates, all of which represent the desired dose and therapeutically useful. The particles are generally in diameter from about 50 microns to about 0.3 cm, with a preferred range of 100 μm to 1 mm. Multiparty forms represent an appropriate embodiment for use in dosage forms of dosage forms as they are adjustable according to the weight of an individual subject (e.g., a mammal, such as a human). Also disclosed is a process for the preparation of controlled or delayed release dosage forms of a strontium salt, for example comprising the steps of mixing or granulating the strontium salt together with one or more pharmaceutically acceptable excipients (selected from from the group consisting of fillers, binders, disintegrants, a release rate modifier, etc.), to give a powder mixture which can be processed, for example, in tablet pellets or tablets or pellets or tablets, which are supplied with a controlled release polymer coating, for the control of the release of the strontium salt.

In the case of the delayed release embodiment, the dosage form may have the same forms as described above, providing delivery of most of its strontium salt to regions of the distal gastrointestinal tract to the duodenum. A variety of embodiments relating to the dosage form and / or structures may be used in order to achieve this objective, i.e. multiparticulates, granules, pellets or other particulate dosage forms which can be processed into tablets.

The controlled release or delayed release dosage forms of this invention can be widely implemented.

Different embodiments include, for example, matrix systems, in which the strontium salt is embedded or dispersed in a matrix of another material which serves to retard the release of the active substance in the aqueous environment (i.e., the lumen fluid of the gastrointestinal tract). When the strontium salt is dispersed in such a matrix, the release of the drug occurs mainly from the surface of the matrix. 16

Thus, the active substance is released from the surface of the matrix after it has diffused through the matrix or when the surface of the composition wears off and thus exposes the active substance. In some embodiments, both mechanisms may operate simultaneously. The matrix systems may be large, i.e., tablet size (about 1 cm) or small (<0.3 cm). The system may be a single unit or multiple units, which are administered substantially simultaneously or may comprise a plurality of particles, referred to herein as multiparticulate. A multiparticulate may have various formulation applications. For example, a multiparticulate may be used as a powder for filling the capsule shell or used per se, for blending with food to increase palatability.

Slow hydration materials may also be used in order to provide a desired rate of release. The multiplicity of variables affecting the release of the active substance from matrices allows for flexibility in the design of compositions of different materials, sizes and release times. Examples of modifications of strontium ion release profiles are within the scope of this invention.

A specific embodiment of the invention relates to a multiparticulate matrix comprising a plurality of strontium salt-containing particles, wherein each particle comprises a mixture of the strontium salt with one or more suitable pharmaceutically acceptable excipients selected to form an array capable of limiting the rate of dissolution of the strontium salt in an aqueous medium. The matrix materials useful in this embodiment are generally water soluble materials, such as waxes, cellulose or other water insoluble polymers. If necessary, the matrix materials may be optionally formulated with water soluble materials, which may be used as binders or as permeation modifying agents. Matrix materials useful for the manufacture of such dosage forms include microcrystalline cellulose, such as Avicel (trade mark of FIVIC Corp., Philadelphia, PA), including series of microcrystalline cellulose, to which binding agents such as hydroxypropyl cellulose methyl, waxes such as paraffin, modified vegetable oils, carnauba wax, hydrogenated castor oil, beeswax and the like, as well as synthetic polymers such as polyvinyl chloride, polyvinyl acetate, vinyl acetate copolymers and ethylene, polystyrene and the like. Water-soluble binders or release-modifying agents, which may optionally be formulated into the matrix include water-soluble polymers, such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPIVI), methylcellulose, poly-N-vinyl pyrrolidinone (PVP), polyethylene oxide (PEO), polyvinyl alcohol (PVA), carrageenan xanthan gum and other natural and synthetic materials. In addition, materials that function as modifying agents include water-soluble materials, such as sugars or salts. Preferred water soluble materials include lactose, sucrose, glucose and mannitol, as well as HPC, HPMC and PVP.

A suitable process for the production of multiparticles for the matrix is an extrusion / sphering process. For this process, the active substance is mixed wet with a binder, extruded through a perforated plate or die and placed on a rotating disk. 18

Ideally, the extrudate breaks into fragments, which are rounded on round balls, spheroids or rods on a turntable.

Another preferred process for the production of matrix multiparticulates is the preparation of wax granules. In this process, a desired amount of the active substance is agitated with a wax to form a homogeneous mixture, which is cooled and then forced through a sieve to form granules. Suitable matrix materials are waxy substances, such as, for example, hydrogenated castor oil and carnauba wax and stearic alcohol.

Another process for the production of matrix multiparticulates involves the use of an organic solvent to assist in mixing the active substance with the matrix material. This technique can be used where it is desired to use a matrix material with an inadequate high melting point if the material were to be employed in a molten state would cause the active substance or polymeric material of the matrix to decompose. Alternatively, the active substance and the matrix material may be combined with a solvent to dissolve the matrix material and the resulting solution (which may contain solid particles of the drug) is, for example, spray-dried to obtain the dosage form particulate. This technique is preferred when the matrix material is a synthetic high molecular weight polymer such as any cellulose ether or cellulose ester. Solvents typically employed for ethanol, isopropanol, ethyl acetate and blending processes include acetone of two or more.

When formed, matrix multiparticulates may be mixed with compressible excipients such as lactose, microcrystalline cellulose, calcium phosphate and the like, and the blend is compressed to form a tablet. Disintegrators such as sodium starch glycolate or crosslinked polyvinylpyrrolidone are also usefully employed. Tablets prepared by this method disintegrate when placed in an aqueous medium (such as the gastrointestinal tract), thereby exposing the multiparticulate matrix, which liberates the strontium salt and / or the ionic form of free strontium from the composition.

Another embodiment of a matrix system is in the form of a hydrophilic matrix tablet containing the active substance and a hydrophilic polymer amount sufficient to provide a useful level of control over the dissolution of the strontium salt. Hydrophilic polymers useful for matrix formation include, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), polyethylene oxide, polyvinyl alcohol, xanthan gum, carbomer, carrageenans and zooglan. One suitable material is HPMC. Other similar hydrophilic polymers may also be employed. Using a low molecular weight polymer may increase the rate of dissolution. The rate of dissolution can also be controlled through the use of water-soluble additives, such as sugars, salts or soluble polymers. Examples of such additives are sugars, such as lactose, dextrose, cyclo-dextrose, sucrose, or mannitol, salts, such as NaCl, KCl, NaHC03, and water-soluble polymers such as PNVP or PVP, low weight molecular weight, HPC or HIVIPC or methyl cellulose. In general, increasing the fraction of the soluble material in the formulation may increase the rate of release. 20

A matrix tablet typically comprises about 20 to 90% by weight of the active substance and about 10 to 80% by weight of polymer.

A suitable matrix tablet comprises, by weight, about 50% to about 80% of the active substance, about 15% to about 35% HPMC, about 0% to about 35% lactose, about 0% to about 15% PVP, 0% to about 20% microcrystalline cellulose and about 0.25% to about 2% magnesium stearate.

Matrix systems, as a class, often exhibit non-constant release of the drug from the matrix. This result may be a consequence of the diffusive mechanism of drug release and modifications in the geometry may be used to achieve a more constant rate of drug release, as detailed below.

In another embodiment, a matrix tablet may be coated with an impermeable coating and an orifice (e.g., a circular bore or a rectangular aperture is provided, whereby the contents of the tablet are released.

In a suitable embodiment, a tablet or a capsule is coated with an impermeable material on part of its surface, for example on one or both sides of the tablet or on the radial surface of the tablet. The dosage form may be coated with a coating which modulates the release of the active substance. By &quot; waterproof material &quot; is meant a material having sufficient thickness and impermeability to the active substance so that there is no significant transport thereof through the material during the required drug release time interval (i.e. from several hours to about one day) . Such a coating can be obtained by selecting a coating material with a sufficiently low diffusion coefficient for the active substance and applying it sufficiently dense.

For these embodiments of the invention, the materials for forming the impermeable coating include substantially all materials in which the diffusion coefficient of the active substance is suitable. Preferred coating materials include film forming polymers and waxes. Especially preferred are thermoplastic polymers, such as polyethylene-co-vinyl acetate, polyvinyl chloride, ethylcellulose and cellulose acetate. These materials exhibit the desired low permeation rate of the active substance when applied as coatings.

Another controlled release matrix system comprises the active substance dispersed in a hydrogel matrix. This embodiment differs from the hydrophilic matrix tablet discussed above, wherein the hydrogel, in this embodiment, is not a compressed tablet of erodible granular material, but a network of a monolithic polymer. As is known in the prior art, a hydrogel is a network of a water expandable polymer. Hydrogels are preferred materials for matrix devices because they can absorb or can be constructed to contain a large volume of water, thereby allowing diffusion of the solvated drug into the matrix.

The drug diffusion coefficients in hydrogels are characteristically high and for highly expandable gels in water, the diffusion coefficient of the drug in the gel may approach the value in pure water. This high diffusion coefficient allows for practical release rates from relatively large devices (i.e., the microparticles form is not required). Preferred materials include hydrophilic vinyl and acrylic polymers, polysaccharides, such as calcium alginate, and polyethylene oxide. Those which are especially suitable are poly-2-hydroxyethyl methacrylate, polyacrylic acid, polymethacrylic acid, poly-N-vinyl pyrrolidinone, polyvinyl alcohol and copolymers thereof and with hydrophobic monomers such as methyl ethacrylate, acetate vinyl and the like. Also preferred are hydrophilic polyurethanes, which contain many polyethylene oxide units. Other preferred materials include hydrogels comprising interpenetrating polymer nets, which may be formed by addition or by condensation polymerization, the individual monomer components may comprise hydrophilic and hydrophobic groups.

Other coating materials include cellulose, cellulose acetate and cellulose acetate butyrate. The polymer may be applied as a solution in an organic solvent or as an aqueous dispersion or latex. The coating operation may be conducted in standard equipment, such as a fluid bed coater, Wurster coater or a rotary bed coater. If desired, the permeability of the coating can be adjusted by mixing two or more materials. A particularly useful process or adapting the porosity of the coating comprises adding a predetermined amount of a finely divided water-soluble material such as water-soluble sugars or salts or polymers to a solution or dispersion (for example , an aqueous latex) of the membrane forming polymer to be used. When the dosage form is ingested in the aqueous medium of the gastrointestinal tract, these water soluble membrane additives are leached out of the membrane, leaving pores which facilitate the release of the drug. The membrane coating may also be modified by the addition of plasticizers, as is known in the art.

Specific examples of the amounts of the administered compounds are mentioned above. However, it will be understood that the amount of the compounds actually administered will be determined by a physician, considering relevant circumstances including the condition being treated, the choice of compounds to be administered, the age, weight and response of the particular patient, the severity of the patient's symptoms and / or signs and the chosen route of administration. While, the present compounds are preferably administered orally, the compounds may also be administered by any other suitable route.

Men's Treatment

Contrary to popular belief, osteoporosis is not just a disease of women. Men are not as resistant to osteoporosis as previously thought, and the age-related increase in fractures observed in women is also evident in men. One of the main reasons why osteoporosis is not as common in men as in women is the largest skeleton of men. Other factors include shorter life expectancy, late onset and slow progression of bone mass loss in men, and the absence of rapid bone loss affecting women as a result of cessation of endogenous estrogen production at menopause. 24

However, as knowledge of the pathophysiology of the disease has increased in recent years, it has been recognized that male osteoporosis represents a major public health problem. In the United States of America, up to 5 million men suffer from osteoporosis and the number is increasing. Nearly 30-40% of patients develop the so-called &quot; idiopathic &quot; at a young age, in the absence of any detectable cause, while others have several obvious secondary reasons for bone loss, including excess glucocorticoids, hypogonadism, alcohol abuse, smoking, renal tubular disease with wasted calcium or other diseases of the liver or of the intestine.

Thus, the invention relates to a tablet for use as claimed, for the treatment and / or prophylaxis of a disease in the cartilage and / or bone and / or conditions resulting from a dysregulation in the metabolism of cartilage and / or bone in a such as, for example, osteoporosis, osteoarthritis, osteopetrosis, osteopenia and Paget's disease, malignant hypercalcemia, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, osteodystrophy, myositis ossificans, Bechterew's disease, malignant hypercalcemia, lesions osteolytic disorders produced by bone metastasis, bone pain due to bone metastasis, bone loss due to sexual steroid hormone deficiency, bone abnormalities due to treatment with steroid hormones, bone abnormalities caused by cancer therapies, osteomalacia, Bechet's disease, hyperostosis, metastatic bone disease , osteopenia induced by immobilization or osteoporosis or osteo glucocorticoid-induced pain or osteoporosis, pseudoglioma osteoporosis syndrome, idiopathic juvenile osteoporosis, for the improvement of fracture healing after traumatic or atraumatic fracture, to improve implant stability and appropriate for maintenance or increase of energy level, for the construction or strengthening of muscle tissues and for weight gain, the method comprising administering a salt in Sr amount and a frequency which can give a daily dose of about 0.25 to about 1.5 g Sr 2 + free ionic , such as, for example, from about 0.30 g to about 1.5 g, from about 0.40 g to about 1.40 g, from about 0.50 g to about 1.30 g, from about 0.60 g to about 1.20 g, from about 0.60 g to about 1.0 g, or from about 0.60 g of about of 0.8 g. Sr salt is administered orally and is contained in a pharmaceutical composition as defined above.

Prophylaxis

Some of the drugs currently used for the treatment of diseases and conditions affecting the metabolism and / or structural integrity of bone and / or cartilage may have a therapeutic effect on the disease, however, at the same time, many of the medications used are associated with severe side effects. An example of a group of pharmacological substances with serious side effects is bisphosphonates, which appear to have detrimental side effects, such as, for example, potential inhibition of bone formation, as well as reabsorption and malabsorption through oral administration . In addition, they are known to cause gastrointestinal irritation and have an extremely long half-life in the bone. Therefore, the individual in need of treatment should have minimal exposure to such compounds. Accordingly, said pharmacological substances are not suitable for prophylactic treatment.

As there are no known side effects associated with the administration of strontium at doses suitable for prophylaxis, strontium will probably be very useful for the prevention of cartilage and / or bone conditions. Accordingly, the invention relates to a tablet for the use as claimed, and to a method for the treatment and / or prophylaxis of cartilage and / or bone disease and / or conditions, resulting from dysregulation in cartilage metabolism and / or bone in a mammal, such as, for example, an adult female human or male, adolescent or child, such as, for example, osteoporosis, osteoarthritis, osteopetrosis, osteopenia and Paget's disease, malignant hypercalcemia, periodontal disease , hyperparathyroidism, periarticular erosions in rheumatoid arthritis, osteodystrophy, ossificating myositis, Bechterew's disease, malignant hypercalcemia, osteolytic lesions produced by bone metastasis, bone pain due to bone metastasis, bone loss due to sexual steroid hormone deficiency, bone anomalies due to treatment steroid hormones, bone abnormalities caused by cancer therapies, osteomalacia, Bechet's disease, h iperostosis, metastatic bone disease, osteopenia induced osteoporosis or osteoporosis or osteoporosis induced by glucocorticoids or osteoporosis, osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis, for the improvement of fracture healing after traumatic or atraumatic fracture, suitable for improving the stability of the implant and for maintaining or increasing the energy level, for the construction or strengthening of muscle tissues and for weight gain, the method comprising administering a compound containing M. Measurement of BMD, bone mineral density, or other forms of radiographic evaluation of bones or joints may be used to establish or confirm a diagnosis of diseases and conditions affecting the metabolism and / or structural integrity of cartilage and / or bone, such as, for example, osteoporosis and osteopenia. The BMD value may also be used to determine whether a prophylactic treatment should be initiated. There are several techniques that are available for the measurement of BMD non-invasively. Bone densitometry is the best method available to diagnose osteoporosis and osteopenia and other bone diseases and to identify individuals at risk of developing bone disease. In bone densitometry the amount of bone mineral present is measured, which is an important factor in bone strength. Traditional methods of densitometry are based on X-ray absorptiometry, such as, for example, dual-energy x-ray absorptiometry, simple energy x-ray absorptiometry and radiographic absorptiometry. In addition to these approaches, qualitative computed tomography, which uses a CT scan, can be used to calculate BMD. Another method of bone densitometry is quantitative ultrasound, which is relatively inexpensive, portable and radiation free. In this case, the part of the bone to be measured is positioned between two ultrasound transducers and the bone mass is determined by the transmission of sound waves passing through the bone; the less they get thicker the bone.

In order to normalize the values of different densitometers and to obtain a value that can be easily used in the diagnosis, the value of BMD can be used to calculate the values designated by T-score and Z-score. The T-score value is considered the most clinically relevant value and describes the relative BMD of the individual for the average BMD for normal young adults, women or men, 28 respectively, expressing the difference as a number of standard deviations (SDs). In the female case, if an individual's T-score is less than 1 SD, below the average of normal young adult females, BMD is considered normal. For each SD below the mean bone mass of normal young adult females, the risk of fracture increases by about 1.5 to 3 times and below 2 SDs, increases exponentially. The Z-score compares the BMD of the subject with the average BMD for the male or female, with the same age as the individual. However, among older adults, low BMD is common, so compared to the same age, norms can be misleading, that is, an 80-year-old can have a Z-score, which compares favorably with controls of the same age, however, as the average of the patients in this age group, the individual may be at risk of suffering fracture (s).

In a method used in the invention for the prevention of a condition in the cartilage and / or bone, individuals who are at risk of developing such a condition can be identified by calculating the T-score of the individuals. Thus, the present invention relates to a method wherein the subject is female with a bone mineral density, BMD, of greater than 1 SD below the average for female adults.

In another method the Z-score is calculated, i.e., the present invention relates to a tablet for use as claimed in a prophylactic method, wherein the subject is female having a below-BMD value for women of same age. If the woman belongs to an age group where the average female subjects may have a high risk of bone fracture, a prophylactic treatment may be considered, although the female individual has a BMD equal to or greater than the mean value for women of the same age. The invention also relates to a tablet for use as claimed in a prophylactic method as described above, wherein the subject is male, with a BMD greater than 1 SD, below the average adult male.

In addition, the invention also relates to a tablet for use as claimed in a method wherein the subject is male having a BMD below the average for adult males for men of the same age. If the subject belongs to an age group in which the male average may have a higher risk of bone fracture, it may be considered a prophylactic treatment, although the male individual has a BMD equal to or greater than the mean value for men of the same age. The invention also relates to a tablet for use as claimed in a prophylactic method, wherein the subject is 20 years or older, such as, for example, 25 years or more, 30 years or more, 35 years or more, 40 years or more, 45 years or older or 50 years or older, female. Another way of assessing bone and cartilage status is provided through dynamic biochemical markers that reflect the turning in cartilage or bone. In comparison to BMD or other similar static measurements, which provide a measure of the current state of the bone and / or cartilage, a particular biomarker may provide a measure of the tipping current of the tissue from which the marker is derived. This provides a dynamic control of the therapeutic effects and also allows for a prediction of the progression of the disease or condition affecting the turning of the bone and / or cartilage. As an example, it has been shown in a number of studies that a specific bone resorption marker, C-telopeptide-derived fragments of type I collagen, CTX, provides an independent BMD indicator of subsequent fracture risk, with similar potency to BMD measurements by itself. In addition, the fracture risk measurement provided by CTX measurements is an additive to the measurement provided by BMD determinations and thus individuals with both low and high BMP bone turnover as indicated by elevated CTX levels are more at risk of bone fracture compared to individuals with only high BMD or reduced CTX. Similar data were obtained with a specific marker of cartilage, fragments derived from collagen type II, CTX-II.

Thus, individuals at risk of developing pathological deterioration of bone and / or cartilage can be defined by measuring bone-specific biomarkers or cartilage metabolism. Similar to BMD measurements, biomarkers measurements may be expressed in T-scores or Z-scores related to the relevant reference populations or the values may simply be expressed in relation to the predefined levels. The invention also relates to a tablet for use as claimed in a prophylactic method as described above, wherein the subject is male with a biomarker level of a bone resorption marker, such as CTX or NTX, for a further than 1 SD above the average adult male.

Additionally, the invention also relates to a tablet for use as claimed in a method wherein the male subject with a bone resorption marker 31 such as CTX or NTX, above the average for a male adult of the same age. If the male person belongs to an age group, in which the average male individual may have a higher risk of bone fracture, it may be considered a prophylactic treatment, although the male individual has a marker for resorption bone, such as CTX or NTX, below the mean levels of the respective marker for men of the same age. The invention also relates to a tablet for use as claimed in a prophylactic method, wherein the subject is aged 20 years or more, such as, for example, 25 years or more, 30 years or more, 35 years or more, 40 years or more, 45 years or older, or 50 years or more, female.

Furthermore, the invention relates to a combined use of BMD measurement and one or more biomarkers for the definition and / or prediction of individuals at risk for progression of a disease or condition affecting bone and / or cartilage turning. Estrogen plays an important role in bone health because estrogen protects bones by preventing the skeletal system from elevating bone turnover, which results in an imbalance between bone formation and resorption and subsequent skeletal deterioration. When the level of estrogen decreases after menopause, more bone is reabsorbed relative to what is built. Women who do not take any medication to prevent bone loss can lose up to 3% to 5% of their bone mass in each of the five years after menopause and, for example, at 70 years of age, bones can weigh 30% to 50% less than before menopause. 32

Thus, although, at the beginning of menopause, a woman may have a level of BMD and / or a specific biomarkers of bone and / or cartilage turning within the normal range (i.e., as defined by the T-Score ), it may be beneficial to initiate a treatment for the prevention of the development of a bone condition in the future. Thus, the invention relates to a tablet for use as claimed in a method as described above, wherein the subject is a peri-menopausal woman or a woman at a recent onset of menopause.

Additionally, the invention relates to a tablet for use as claimed in a method wherein the subject is a woman with menopause for at least 6 months or more. The invention also relates to a tablet for use as claimed in a method for the prophylaxis of a cartilage and / or bone condition in males, wherein the subject is aged 20 years or more, such as, for example, 25 years or more , Age 30 or over, age 35 or over, age 40 or over, age 45 or over, age 50 or over, age 55 or over, age 60 or over, age 65 or older, or age 70 or older.

Secondary osteoporosis

Although 90% of all cases of osteoporosis are idiopathic primary osteoporosis, there is also a need for the prevention and / or treatment of secondary osteoporosis, which is the result of an identifiable process of the disease or agent. Accordingly, the invention relates to a tablet for use as claimed in a method for the treatment and / or prevention of secondary osteoporosis in a subject, method 33 comprises administering an effective amount of a Sr salt to the subject. Secondary osteoporosis can be induced by diseases of the endocrine system and / or metabolic causes such as hypogonadism, hypercortisolism, hyperprolactinemia, anorexia nervosa, mastocytosis, porphyria, type 1 diabetes mellitus, primary or secondary hyperparathyroidism, hyperthyroidism, acromegaly, Cushing's syndrome, acidosis, Guacher's disease, hemochromatosis, androgenic insensitivity and pregnancy. Secondary osteoporosis can also be induced by nutritional conditions such as, for example, malabsorption, malnutrition, chronic liver disease, vitamin D deficiency, calcium deficiency, resection of parts of the gastrointestinal tract (eg gastrectomy), smoking and alcohol abuse. Administration of certain drugs may also lead to secondary osteoporosis. Examples of such pharmacological substances are, for example, corticosteroids (including inhaled corticosteroids), heparin, antiepileptic drugs (for example, phenytoin), hormone analogue releasing gonadotrophin, loop diuretics, phenobarbital, anti-neoplastic / immunosuppressive agents ( for example, methotrexate and cyclosporine), thyroid hormones, depo-medroxyprogesterone acetate, calcineurin-calmodulin phosphatase inhibitors such as, for example, Tacrolimus and aromatase inhibitors such as Formestane, Exemestane, Aminoglutethimide, Fadrozole, Rogletimide, Anastrozole, Letrozole and Vorozole.

A collagen metabolism with connective tissue disorders and / or diseases may also be the cause of secondary osteoporosis. Examples of such disorders are, for example, osteogenesis imperfecta, homocysteine, rickets, Ehlers-Danlos syndrome and Marfan syndrome.

Bone marrow diseases such as, for example, myeloma, leukemia, and thalassemia may also be the cause of secondary osteoporosis. Further, rheumatological / inflammatory diseases, such as, for example, systemic lupus erythematosus, ankylosing spondylitis and rheumatoid arthritis may also cause secondary osteoporosis.

In children and adolescents, secondary causes of osteoporosis include juvenile arthritis, juvenile rheumatoid arthritis, juvenile chronic arthritis, childhood cancer, neuromuscular diseases such as cerebral palsy, spina bifida and muscular dystrophy, familial dysautonomia, fibrous dysplasia, juvenile Paget disease (osteoprotegerin deficiency ), familial idiopathic bone pain and isolated hyperphosphatemia. Other potential causes of secondary osteoporosis in children and adolescents are excessive exercise, amenorrhea, dermatomyositis, asthma, inflammatory bowel disease such as Crohn's disease and muscular dystrophy.

Other general causes of secondary osteoporosis may include hypophosphatase, immobilization, cystic fibrosis, renal insufficiency, hypercalciuria, chronic obstructive pulmonary disease, mastocytosis, depression, spinal cord injury, sarcoidosis, malignant disease, lymphoplasmacytic lymphoma, organ or surgical transplantation, as well as male chemical sterilization (including, but not limited to the use of anti-androgens and / or hormone analogue releasing gonadotropin). 35

Prophylaxis of secondary osteoporosis

As mentioned above, some drugs may be the cause of secondary osteoporosis.

In order to prevent the development of secondary drug induced osteoporosis in a patient, it may be beneficial to administer a prophylactic amount of Sr as part of the same treatment regimen as administration of the drug.

Thus, the invention relates to a tablet for use as claimed in a method for preventing secondary osteoporosis in a subject induced by drugs, the method comprises administering to the subject a prophylactic amount of a Sr salt prior to, during or after treatment of the individual with the pharmacological substance that induces osteoporosis. Administration may take place substantially concurrently with the administration of the osteoporosis-inducing drug, and the Sr salt and the osteoporosis-inducing drug may be contained in the same pharmaceutical composition.

Accordingly, the invention relates to a tablet for use as claimed comprising a Sr salt and a pharmacological substance inducing osteoporosis together with a pharmaceutically acceptable excipient. The Sr salt and the drug may also be administered simultaneously, in separate co-administered compositions. When two separate formulations are being coadministered, each formulation, especially those for oral use, may be color coded or otherwise labeled, readily identifiable so as to avoid confusion, either by the individual or by the physician. 36

Other aspects of the invention

In some embodiments of the invention, the inventors have discovered that it is preferred that the ranelate, if present, is present in an amount of less than 5% w / w of the total amount of strontium. Also disclosed is a kit used for better healing of the fracture following a traumatic or atraumatic fracture, and the fracture may be, for example, one of the following: fracture of the distal end of the radius, such as, for example, Colle fracture or a fracture Smiths, a femoral fracture, such as a proximal femur such as a cervical fracture, trochanteric fracture, or a subtrochanteric fracture. The improvement of healing of a fracture can be defined in terms of reducing the time a patient will require gypsum, reducing cure time as defined in a radiograph, reducing the time to fracture stability, improving the formation of the callus as seen by radiography, the reduction in the time before the onset of callus formation when viewed by radiography and / or reduction in time to recover full or near complete mobility or the level of physical activity.

Further embodiments of the invention are set forth in the appended claims. The details and particularities described above and below and related to the compounds and the compositions according to the invention apply mutatis mutandis to other aspects of the invention. 37

Picture's description

Figure 1. X-ray diffractogram of strontium hexahydrate glutamate crystals prepared by the method as described in example 7.

Figure 2. X-ray diffractogram of strontium malonate crystals prepared by the method as described in example 7. The strontium malonate salt was not previously characterized and comprises a novel crystallographic structure, however it is perceptible from the stable baseline and of the diffraction peaks with a well-defined spacing, that the crystal form of the malonate salt is homogeneous and pure.

Figure 3. The results of the optimization experiments for strontium glutamate synthesis described in table 6. The influence on strontium glutamate synthesis yield was investigated by varying four parameters. (Yields over 100% indicate incomplete drying).

Figure 4: Lot of serum strontium concentrations measured in rats, which received a single dose of strontium, as indicated at the top of each panel. The data points represent the mean and the standard deviation for each measurement point. Pre-doses represent the corresponding samples, obtained from animals treated with vehicle alone. The invention is further illustrated by the examples which are not intended to limit the invention, however. 38

Examples

Example 1 (Reference) General method for the preparation of crystalline strontium salts by precipitation from dissolved strontium chloride and sodium salts dissolved from the appropriate carboxylic anions

In a 100 mL volume glass beaker, 5 g of sodium salt of the carboxylic acid was dissolved in a small volume of water, which was heated slightly to not more than 30-50 ° C. The final volume was 25-50 mL. In another beaker, 10 g of SrCl 2 (SrCl 2 hexahydrate, Sigma-Aldrich 43,966-5) were dissolved in 100 mL of water. The latter solution was slowly decanted into the first dissolved sodium salt solution. The transfer continued observation of the onset of cloud formation, which resulted in a total volume of 50-100 mL. The solution was allowed to stand at room temperature (22-24 ° C) for several days until a significant amount of crystallized precipitate of the organic strontium salt appeared. The reaction that occurs is exemplified by the reaction between the strontium ions and sodium fumarate (reaction schemes (a) and (b)):

(Aq) + H 2 (aq) + H 2 O (aq) + H 2 O (aq) + H 2 O (aq) + H 2 (aq) ) (B)

In order to accelerate the crystallization, it was addition of small volumes of ethanol, such 50-60% v / v induces an acceleration one verified that as 5-10% v / v significant a that of the precipitation of the desired strontium salt. The addition of ethanol is of particular importance in the synthesis of strontium salts with solubility greater than 2 g / L at room temperature (22-24 ° C) and thus will provide a substantial advantage for the synthesis of strontium salts of L-aspartate, L-glutamate and lactate. In order to achieve the desired product within a short period, it was essential to observe an initial crystallization or initial penumbra in the solution from the first stage.

After precipitation, the solution was filtered on a Buchner funnel using a suction flask and the crystals were washed in small volumes of ethanol. The crystals of some of the salts were very soluble, so, in order to improve the yield of the crystals, the solution was allowed to stand for longer, such as at least 30-60 min. Repeated crystallization resulted in yields of approximately 50%. The strontium salts of L-aspartate and lactate were very soluble, with solubility greater than 25 g / L in water and at room temperature. Lactate and strontium salt L-glutamate were precipitated from solutions with an excess of strontium chloride and large crystals of lactate salt were achieved by slow evaporation of the solvent.

Example 2 (Reference) General method for the preparation of crystalline salts by neutralization of the carboxylic acids with strontium hydroxide

A small amount of an appropriate organic acid (0.75-3 g, see table below) was dissolved in water by heating at temperatures between 30 ° C-50 ° C. Then, strontium hydroxide (Sigma Aldrich, Sr (OH) 28H20, MW 265.71, CAS No. 1311-10-0, approx 10 g / L) was added slowly. Thereafter, a magnetic stirrer was added and heating and gentle (i.e., 30-50 ° C) agitation of the suspension was started. After some time, the solution is cleared and all the solid material is dissolved. Heating is maintained and after three hours of incubation, the solution is filtered while still hot, on a Buchner funnel. Very small amounts of impurities were left in the filter. The filtrate was subsequently allowed to cool to ambient temperature overnight, which resulted in the growth of fine powdered crystals of the desired strontium salt. Further purifications of the salts can be performed by re-crystallizations (Table 2).

Strontium salt (free acid used): Sr (OH) 2 * 8H20 Free acid Amount Retained Recovery * Melting Solubility Crystal structure Fumarate 1.0404 g 1.40 g 0.999 g 99% &gt; 380 ° C Yes No Cetylglutaric 2 2.017 g 1.441 g 0.828 g 72% &gt; 380 ° C Yes No Succinate 2.098 g 1.177 g 0.958 g 92% 230 ° C Yes Yes L-Ascorbate 3 2.094 g 1.805 g 2.005 g 15%> 380 ° C Yes No L-glutamate 2.017 g 1.453 g 0.175 g 15% &gt; 380 ° C Yes Yes Citrate 2.057 g 1.918 g 1.123 g 48% &gt; 380 ° C Yes Yes D-aspartate 2.190 g 1.316 g 0.167 g 14% &gt; 380 ° C None None Tartrate 2.070 g 1.502 g 2.005 g 129% &gt; 380 ° C Yes Yes 41

Table 2: Starting reagent values used for the synthesis of organic strontium salt and recoveries in the synthesis of eight specific organic strontium salts following the general reaction pathway with the free acid forms of the anion and strontium hydroxide.

Notes *) Recovery calculated as% of strontium content, in Sr (OH) 2 * 8H20. 1) Fumaric acid is insoluble in water and ethanol is added to the suspension until complete solubilisation is achieved. Synthesis is continued with this material. 2) The strontium-AKG salts have a slight brownish appearance. 3) In addition to the indicated amounts of strontium hydroxide and L-ascorbate, 4.087g of additional SrCl2 * 6H20 are solubilized in water and added to the reaction mixture.

Example 3

Determinations of the solubility of organic strontium salts Synthesis of strontium salts The great majority of the strontium salts can be obtained by reacting the sodium salt of the organic acid with the strontium chloride following the general method of synthesis described in example A. However, strontium citrate, strontium tartrate, strontium succinate and α-ketoglutarate strontium for the solubility studies were obtained by synthesis from the free acid forms of the carboxylic acid and strontium hydroxide as described in example 2. Strontium glutamate was obtained as described in example 4, using an incubation temperature of 100 ° C to obtain pure and homogeneous crystals of strontium hexahydrate glutamate. Detailed solubility studies were performed with the strontium salts listed in Table 3 below:

Strontium salt MW% Sr Sr-ranelate (* 7H20) + 639.6 27.4 SrCl2 (* 6H20) + 266.632.9 Sr-Fumarate (* 6H20) + 309.7 28.3 Sr- glutamate (* 6H20) 340.7 25.7 Sr-Î ± -ketoglutarate (* 6H20) 339, 725.8 Sr-aspartate (* 3H20) 272.7 32.1 Sr-succinate (* 6H20) 311.78 , 1 Sr-ascorbate (* 6H20) + 545, 816, 1 Sr-malenate (* 6H20) 309, 7 28.3 Sr-malonate (* 1H20) 207.72 42.2 Sr-pyruvate (* 6H20) 369 , 7β, 7β-tartrate (* 6H₂O) + 343, 725.5 Sr-citrate (* 6H₂O) + 749, 11, 1 + Reference compounds

Table 3: Summary of the strontium salts used in the solubility study. MW indicates the molecular weight of the salt in crystalline and homogeneous form with the indicated amount of crystalline water and% Sr indicates the molar percentage of strontium constituting this crystalline form. The solubility of strontium salts of organic carboxylic acids was measured in water. The solubility of these salts was also measured as a function of temperature. This was done by incubating the saturated solutions of the salts in incubators, with controlled temperature. In addition, the solubility of the salts was studied in pure distilled water, as well as buffered solutions of 0.05M ammonium carbonate, with a physiological pH of 7.5.

Buffered solutions were immersed in a temperature controlled water bath at room temperature (22-24 ° C), at 30 ° C or at 40 ° C. The test tubes were shaken and the solutions were subsequently incubated in a 24 hour constant temperature incubator. In order to eliminate any influence of remnant strontium chloride, in solubility determination, all the precipitate was collected at the bottom of the test tubes and solutions above the precipitate were carefully removed and replaced with fresh solutions. After replacing the solutions, the test tubes were agitated again and allowed to stand for a further 24 hours. From these solutions, the dissolved proportions of the strontium salt were collected in 1 ml volumes, at the specified temperature. The solutions were diluted to 50 mL prior to analysis by flame atomic absorption spectrometry (F-AAS). Prior to the subsequent series of sampling the solutions were equilibrated at the following temperature for 24 hours.

Analysis of strontium by flame atomic absorption spectrometry F-AAS and ICP-MS 44

Two methods were used for the quantification of strontium in solutions: flame atomic absorption spectrometry (F-AAS) and the most sensitive inductively coupled plasma mass spectrometry (ICP-MS). For most studies, the F-AAS method had sufficient sensitivity.

Prior to the analysis of synthesized organic strontium salts, the solubility in water of some commercially available strontium salts was determined by the F-AAS method to verify the accuracy of the measurements and compare the results obtained with the reference values for the solubility of the salts. The following strontium salts were obtained: Sr-oxalate (Aldrich 57,416-3) SrS04 (Aldrich 45,129-0) SrHP04 (Aldrich 48,042-2) and SrCl2 (Aldrich 43,966-5). The solubilities were studied as described above and the strontium content in the saturated solutions determined as described below.

Some of the very soluble strontium salts were additionally diluted prior to F-AAS analysis. Measurements were performed using a Perkin-Elmer 2100 equipped with a hydrogen lamp for background signal correction. Strontium was measured at an aperture of 0.2 nm, the wavelength was 460.8 nm operated at an energy of 58 and a current of 8 mA.

The solutions with very low strontium content (ie, from strontium carbonate solubility) were analyzed by the inductively coupled plasma mass spectrometry (ICP-MS) method. This analysis was performed using a Perkin Elmer Elan 5000 system equipped with a cross flow nebulizer. The power was set at 1000 W and the argon gas flow was 12 L / min and 0.8 L / min of the torch and plasma gas, respectively. The determined solubility for the commercially available strontium salts was in good agreement with the reference values. For most studies, the F-AAS method had sufficient sensitivity. Table 4 shows the solubilities of strontium chloride, phosphate, carbonate, oxalate and sulfate in water at 22 ° C. It is evident that the values determined, experimentally, are in agreement with the indicated reference values for these salts. The main divergence between the reference values and the experiment was obtained for the strontium chloride, where a lower solubility was obtained and strontium carbonate, where a significantly higher solubility was found. Since the solubility of strontium carbonate is very low, it was necessary to apply ICP-MS for the determination of Sr content in the supernatants of these experiments. In addition, the solubility of this salt will be dependent on the carbon dioxide content of the ambient air, which was not controlled in the present test, providing a possible explanation for the differences between the determined solubility and the reference value.

Salt Method Measurement g / L Expected value 18Â ° C (g / L) SrCl2 F-AAS 240 538 SrHP03 F-AAS 0.5 - SrS04 F-AAS 0.1 Âμl SrC204 F- 05 SrC03 ICP-MS 0.00009 0.011

Table 4: Solubility of commercially available strontium salts in water at room temperature (22-24 ° C), determined as described in example 3. The expected values refer to the values quoted in the scientific or reference literature, such as &quot; Beilstein compendium &quot;.

Temperature and influence of pH on the solubility of the organic strontium salt

For most of the organic strontium salts listed in Table 2, temperature changes in the range 20-40øC have only little influence on solubility (Table 5). However, for strontium L-glutamate, the temperature has a significant influence on solubility in the range of 20 ° C to 40 ° C. The solubility of this salt increased more than triple in the range studied, unlike most other salts. It is noted that solubility under physiological conditions (37 ° C) is of relevance for the pharmaceutical use of the substances, and therefore, the surprising increase in the solubility of strontium glutamate at a higher temperature may have therapeutic implications of high potential. The solubility of the strontium salts in buffered ammonium carbonate solution at pH 7.5 was generally higher than the solubility determined in pure water (Table 5). However, there are some notable exceptions, such as strontium maleate, with a lower solubility in buffered solution. Thus, it was found more relevant to compare the solubility of the strontium salts by comparing the values obtained in water, as shown in table 5.

Relative Solubility

The water solubilities of the organic strontium salts at ambient temperature and 40øC are listed in Table 5. The L-aspartate and lactate strontium salts had solubilities greater than 50 g / L, determination of the solubility with the experimental procedures used.

The results correspond to observations during the synthesis experiments, where citrate, fumerate and tartrate precipitated, instantly when synthesized by the production processes described in examples 1 and 2. This is indicative of poor solubility of such strontium salts, such as is evident by the low solubility of these salts over the other organic strontium salts, both at 22 ° C and 40 ° C. The glutamate salt had a higher solubility than the other salts, especially at a temperature of 40 ° C. During the synthesis of this salt, it was necessary to add alcohol to the solution to initiate crystal growth, indicative of a relatively high water solubility. The other strontium salts studied only precipitated after evaporation of the solvent for a few days at room temperature, however, addition of alcohol was not necessary to initiate crystal formation and precipitation.

Strontium salt Solubility at room temperature (22-24 ° C) (m / L) Solubility at 40 ° C (mg / L) Anion In water pH 7.5 In water pH 7.5 Malonate * * 1474 2816 1441 2127 L-glutamate ** 2111 3022 7093 7195 L-aspartate ** 4200 7900 Pyruvate * 2204 1946 1929 1829 oethoglutarate * * 1316 2252 3534 3809 48

Fumerate ** + 571 1215 444 977 Maleate ** 3002 1680 2527 1457 Tartrate ** + 883 1831 1028 1400 Ranelate **** + 760 890 1450 1970 Succinate * * 1137 926 1116 2233 Citrate *** + 107 388 147 430 + Reference compounds

Table 5. Relative solubility of strontium salts studied in buffered water solutions at pH 7.5 at 40 ° C and at room temperature (22-24 ° C) as determined by F-AAS. *) mono carboxylic acid **) dicarboxylic acid ***) tri-carboxylic acid ****) Quattro-carboxylic acid

Example 4

Preparation of strontium glutamate hexahydrate by synthesis at 100 ° C

Initially, a suspension of glutamic acid (white) is prepared by adding 100 ml of millipore water to 14.703 g (0.1 mol) of solid L-glutamic acid (Sigma Aldrich, C5 H9 NO4, MW 187.14 g / mole , CAS No. 142-47-2, lot No. 426560/1, fillingo code 43003336) in a 250 ml beaker. To this suspension was added 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). Then, a magnetic stirrer was added and agitation was started, as well as the run-up to the boiling point of the suspension. The final suspension is also white in color and agitation is maintained by maintaining a mean rotation rate of the stirring apparatus. In order to prevent the entry of carbon dioxide into the solution, the beaker was covered with a glass cover.

After a few minutes of boiling and stirring, the solution is clarified and all the solid material is dissolved. The boiling was maintained and more water was added, when necessary, as to replenish the water lost through its boiling. After three hours of boiling, the solution was filtered on a Buchner funnel while boiling continued. Very small amounts of impurities were left in the filter. The filtrate was subsequently allowed to cool to room temperature, allowing the growth of fine powder crystals of strontium glutamate hexahydrate. Precipitation of the final product proceeded in the filtrate in one hour. The product was filtered and dried at 110 ° C in an oven for 1/2 hour followed by drying of 12 hours in a desiccator over orange silica. Prior to analysis by x-ray crystallography and by FAAS, the salts were ground in a mortar until a fine powder was obtained. The total yield of strontium glutamate hexahydrate was about 98%, prior to recrystallization, and most impurities consisted of traces of reactants and of strontium carbonate. This yield is significantly higher than the yield obtained by synthesis under standard conditions where only 15% was obtained (see example B). Thus, the high temperature synthesis method, as described in the present patent, provides a significant gain in yield and a reduction in the synthesis time, obtaining a strontium glutamate salt with a higher purity. The product was unequivocally identified as strontium glutamate hexahydrate by X-ray crystallography and by comparing the results with the literature data. 50

Further improvements in the synthesis may include degassing, with nitrogen or with argon, water and all aqueous solutions, which prevents contact with the carbon dioxide which may eventually lead to the formation of strontium carbonate impurities. Additionally, one skilled in the art will readily be able to adapt the following procedure to one under an inert gas atmosphere.

Example 5

Preparation of strontium aspartate trihydrate by synthesis at 100 ° C

Initially, a suspension of aspartic acid (white color) is prepared by adding 100 ml of millipore water to 13.311 g (0.1 mol) of solid L-aspartic acid (Fluka, C 5 H 9 NO 4, MW 133.11 g / mol, CAS No. 56-84-8, lot 432866/1, filling code 52603495) into a 250 mL beaker. To this suspension was added 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). Then, a magnetic stirrer was added and stirring was started, as well as heating to the boiling point of the slurry. In the final suspension, also white, stirring was maintained by maintaining a mean rotation rate of the stirring apparatus. In order to avoid the entry of carbon dioxide into solution, the beaker was covered by a glass cover.

After a few minutes of boiling and stirring, the solution is clarified and all the solid material is dissolved. Boiling was maintained and additional water was added, when necessary, to replenish the water lost by boiling. After three hours of boiling, the solution was filtered on a Buchner funnel, while boiling proceeded. Very small amounts of impurities were left in the filter. The filtrate was subsequently allowed to cool to room temperature, resulting in the growth of fine powder crystals of strontium aspartate trihydrate. Precipitation of the final product proceeded in the filtrate in one hour. The product was filtered and dried at 110øC in a furnace for 1/2 hour, followed by drying for 12 hours in a desiccator over orange silica. Prior to analysis by x-ray crystallography and by FAAS, the salts were ground in a mortar until a fine powder was obtained. The total yield of strontium aspartate trihydrate was approximately 98% prior to recrystallization and most impurities consisted of traces of reactants and strontium carbonate. This yield is significantly higher than the yield obtained by synthesis under standard conditions, where only 14% was obtained (see example 2). Thus, the high temperature synthesis method, as described in the present patent, provides a significant gain in yield and a reduction in the synthesis time, resulting in a higher purity strontium aspartate salt. The product was unequivocally identified as strontium aspartate trihydrate by x-ray crystallography and by comparing the data with the results from the Cambridge Crystallography database.

Further improvements in the synthesis may include the degassing, with nitrogen or argon, of water and all aqueous solutions, preventing contact with the carbon dioxide which may eventually lead to the formation of strontium carbonate impurities. Additionally, one skilled in the art will readily be able to adapt the following procedure to one under an inert gas atmosphere. 52

Example 6

Preparation of strontium malonate monohydrate by synthesis at 100 ° C

Initially, a suspension of malonic acid (white color) is prepared by the addition of 100 ml of millipore water in 10,406 g (0.1 mol) of solid malonic acid (Fluka, MW 104.06 g / mole, CAS No. 141- 82-2, lot 449503/1, filling code 44903076) into a 250 ml beaker. To this suspension was added 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). Thereafter, a magnetic stirrer was added and stirring was started, as well as heating to the boiling point of the slurry. The final suspension is also white in color and agitation was maintained by maintaining a mean rotation rate of the stirring apparatus. In order to avoid the entry of carbon dioxide into the solution, the glass was covered by a glass cover.

After a few minutes of boiling and stirring, the solution is clarified and all the solid material dissolved. Boiling was maintained and additional water was added, when necessary, to restore the water lost to boiling. After three hours of boiling, the solution was filtered on a Buchner funnel while still boiling. Very small amounts of impurities were left in the filter. The filtrate was subsequently allowed to cool to room temperature, resulting in the growth of finely powdered strontium malonate crystals. Precipitation of the final product proceeded rapidly during filtration and most of the product was obtained in the filter (without heating). Briefly, the precipitation progressed in the filtrate. The product was filtered and dried at 110 ° C in a furnace for 1/2 hour, followed by drying for 12 hours in a desiccator on orange silica. Prior to analysis by x-ray crystallography and by FAAS, the salts were ground in a mortar until a fine powder was formed. The total yield of strontium malonate was about 98%, prior to recrystallization, and most impurities consisted of traces of reactants and strontium carbonate. The product was unequivocally identified as strontium malonate by x-ray crystallography and by comparing the data with the results from the Cambridge Crystallography Database.

Further improvements in the synthesis may include the degassing, with nitrogen or argon, of water and all aqueous solutions, thus preventing contact with the carbon dioxide which may eventually lead to the formation of strontium carbonate impurities. Additionally, one skilled in the art will readily be able to adapt the following procedure to one under an inert gas atmosphere.

Example 7

Methods of manufacturing water soluble strontium salts of dicarboxylic acids using temperatures above 100 ° C

According to methods previously developed, and described in Examples 2-6, the synthesis of strontium salts of organic dicarboxylic acids and especially strontium salts of amino acids can be difficult to produce on a larger scale (e.g. &gt; 1kg) , due to the low yields and the difficulties of separating the desired reaction products from the contaminants. Strontium carbonate salts are of particular interest, since they form as impurities when the reaction occurs in atmospheric air, which contains normal levels of carbon dioxide. It has been described in Examples 4-6 that the total yield of the product depends on the temperature and the time of synthesis when the strontium salts of dicarboxylic acids are made from the free acid form of the anion and strontium hydroxide. For the reaction to be complete, the mixture of the appropriate amino acid and strontium hydroxide requires boiling in water for three hours, allowing sufficient time for the strontium in the reaction mixture to react with the carbon dioxide in the air. In this example methods of improving the synthesis are described, providing optimized reaction conditions, wherein the temperature is raised above 100øC in a closed vessel, and where the reaction times are significantly reduced. The present example provides representative data for the optimization of conditions for the synthesis of strontium glutamate in an autoclave system. Strontium glutamate is used as an example, but the optimizations described in the example are also applicable in the synthesis of other strontium salts, where the exact reaction conditions can be optimized, as described in this example. Reaction temperatures should be maintained below the melting point or below the decomposition temperature of the organic anion radical of the desired strontium salt. As an example, the malonic acid decomposes at 132-134 ° C and therefore the synthesis of strontium malonate should be performed at temperatures below 132 ° C. Strontium L-glutamate was used as a strontium model compound in the optimization experiments. The purity of the product was monitored by comparison with the crystallographic data and by measuring the strontium content. Ideally, the strontium content is 25.7% in strontium L-glutamate hexahydrate, which is the product formed in these studies. Other soluble strontium salts may be prepared by similar methods in high yield and purity.

Experimental

Preparation of solutions: A suspension of glutamic acid (white) is prepared by the addition of 100 ml of millipore water in 14,703 g (0.1 mol) of solid L-glutamic acid (Sigma Aldrich, C5 H9 NO4, MW 187.14 g / mol, CAS No. 142-47-2, lot No. 426560/1, filling code 43003336) in a 250 mL beaker. To this suspension was added 22.257 g, 26.571 g or 31.885 (0.08 mole, 0.1 mole or 0.12 mole) of solid strontium hydroxide (Sigma Aldrich, Sr (OH) 2 · 8H 2 O, MW 265.71 , CAS No. 1311-10-0).

Optimization Experiments

After the preparation of the salts, nine optimization experiments were performed according to the definitions in table 6.

Experience N °. Temp. (%) Autoclave pressure (bar)% Yield% SR (ASA) 1 125 15 0.8 50 1.55 94 25 2 124 30 1 75 1 112 22 3 124 60 1.2 100 1, 6 121 21 4 127 15 0.8 100 1.2 118 22 5 132 30 1 50 1.55 120 25 6 132 60 1.2 75 1, 6 50 22 7 134 15 0.8 75 LO LO V \ -1 108 24 8 134 30 1 100 LO LO V \ -1 76 14 9 132 60 1.2 50 LO LO * &gt;. \ -1 82 24 56

Table 6. Parameters and main results of the optimization procedure for the synthesis of strontium glutamate. Pressure was monitored but not used in the optimization process. The strontium content (% Sr) was measured by FAAS, however, it is not used as a quality parameter. The yield (%) was applied as a quality parameter.

Procedure 1. The calculated amount of acid was weighed and transferred to a BlueCap autoclave vial and Millipore water was added. The vial was closed and stirred so as to obtain a slurry of fine granulate. 2. The calculated amount of strontium hydroxide octahydrate was weighed and added to the acid solution of step (1) and the vial was vigorously vortexed until all material was transformed into fine-grained powder. 3. The vial was placed in the autoclave and the temperature was set. There was no further stirring in the autoclave. 4. At a temp. = 100 ° C, the autoclave valve was closed and time was started. 5. During the autoclave treatment, the actual temperature and pressure were monitored. 6. After the end of the autoclaving time as soon as possible, the steam is allowed to escape, taking into account the safety precautions. 7. At a temperature of approximately 110 ° C, the autoclave was opened and the solution was recovered. Once again the flask was shaken to obtain a high degree of mixing. 8. After treatment in the autoclave, the solution was immediately hot filtered on a Buchner funnel, leaving only traces of carbonate in the filter. The product precipitated from the solution during cooling to room temperature. 9. After precipitation, the product was filtered and dried in an oven for 1/2 hour at 110 ° C. It was then dried in a desiccator over orange silica gel. Finally, the product was triturated in a mortar until a fine powder was obtained. 10. The product was weighed after milling and calculated total yield.

Preparation of strontium malonate according to the invention

In order to confirm the applicability of the high temperature synthesis method to other strontium salts, besides strontium L-glutamate, strontium malonate was prepared. Basically, the reaction conditions encountered for the preparation of strontium L-glutamate were employed. A suspension of malonic acid (white color) is prepared by adding 100 ml of millipore water to 10.41 g (0.1 mol) of solid malonic acid (Fluka 63290, MW 104.1) in a 250 ml beaker. To this suspension was added 22.257 g, 26.571 g or 31.885 g (0.08 mol, 0.1 mol or 0.12 mol) of solid strontium hydroxide (Sigma

Aldrich, Sr (OH) 2 * 8H 2 O, 265.71 MW, CAS no. 1311-10-0). The reaction procedure described above was followed and the temperature was maintained below 130øC to avoid malonic acid decomposition, while the reaction time was maintained for 15 min.

Strontium content (% Sr): 58

A 0.2 g sample was dissolved in 100 mL of 0.1 M HNO3 prepared in Millipore water. This solution was further diluted by a factor of 500 with a 1% KCl solution and the strontium content was determined by FAAS. Measurements were performed using a Perkin-Elmer 2100 equipped with a hydrogen lamp for correction of the background signal. Strontium was measured at an aperture of 0.2 nm, the 460.8 nm wavelength operated at an energy of 58 and a current of 8 mA.

X-ray crystallography The second purity check was performed by X-ray crystallography powder using a Huber G670 diffractometer. A diffractogram feature of strontium glutamate is shown in Fig. An X-ray diffractogram of strontium malonate obtained by the high temperature synthesis method disclosed in the present example is shown in Fig. 2. The double peak on the low angle side of the peak of maximum intensity is an artifact of the instrument.

Results and discussion

In Table 4, it is observed that some of the synthesis conditions resulted in a relatively low yield and in the low purity strontium glutamate, as is verified by the molar% of strontium in the reaction product. Experiment # 8 was produced in relatively low yield and did not contain the expected, 25.7% strontium, which was also confirmed by x-ray analysis. Despite this unexpected result, in general, the results of the optimization experiments are close to the expected products. The incomplete reaction provides a product of very low strontium content, while the formation of strontium carbonate, during synthesis, provides too high a strontium content. The conditions employed in Experiments 1 and 5 allowed a strontium content of 59 according to the expected value. Note that, although also apparent, the product of Experiment No. 6 was produced in a low yield, containing an amount of strontium corresponding to the expected value.

By studying the influence of individual parameters on total yield (Table 6 and Figure 3), it becomes clear that temperature, autoclave time and acid-base ratio are important factors for the synthesis, while the total volume is less important. A yield of more than 100%, which is observed under the experimental conditions 2, 3, 4, 5 and 7 causes incomplete drying, however this effect is almost eliminated when the average values obtained are considered, as in fig. 3. Thus, the maximum yield was obtained using a high temperature (133øC), a short autoclave time (15 min) and an excess of strontium hydroxide. Therefore, the temperature proves to be more important than the time, but its importance is comparable to the base ratio for the acid. However, great care must be taken not to exceed the decomposition temperature in the synthesis of other strontium salts, which for, for example, the malonate is 132-134 ° C. A 10th optimization control experiment was performed in order to confirm the maximum yield of the optimization experiments.

An additional experiment was also carried out to confirm the applicability of the high temperature synthesis method for the preparation of other organic salts of strontium in addition to strontium L-glutamate. Strontium malonate has been chosen since this salt can be considered especially difficult to prepare under conditions of high temperatures due to the low dissociation temperature of the malonic acid anion. However, as shown in Figure 2, pure and well-defined crystalline strontium malonate 60 can be readily obtained. The crystalline structure of the compound has not been completely determined, as it is a novel structure not described above, but the data show that the high temperature method is likely to be applicable to many other organic strontium salts.

Further improvements in synthesis include the introduction of an inert atmosphere under the conditions of the synthesis as well as the degassing of all solutions by nitrogen gas or argon so as to reduce the formation of strontium carbonate.

Conclusion The optimization of the experiments shows that it is possible to synthesize strontium glutamate in high yields, raising the temperature to values above 100 ° C and using a short time (15 min) in the autoclave. In addition, a 20% excess of strontium hydroxide also improves overall yield without compromising the purity of the synthesized strontium salt. A drying, slightly more vigorous than the silica gel orange should be applied as a drying process, so as to obtain the product completely dry. Examples of more effective drying agents are concentrated sulfuric acid or calcium oxide, but also conventional lyophilization or other mechanical treatments can be applied for this procedure.

Example 8 (Reference)

Pharmacokinetic properties of organic strontium salts with low solubility 61 The aim of this study was to evaluate the bioavailability of an organic strontium salt with low solubility (strontium citrate) as compared to strontium chloride and strontium ranelate. Bioavailability was assessed by determining the serum strontium concentration at regular intervals over a 24 hour period and by calculating AUC. The experiment was performed on Wistar rats from the HanTacrWH (GALAS) strain of Taconic M & B A / S, Ejby, DK-4623 Lille Skensved, Denmark. At the beginning of the acclimatization period, the rats were approximately 9 weeks old with a weight of about 200-250 g. The animals were housed in a room with filtered air at a temperature of 21 ° C ± 3 ° C and a relative humidity of 55% ± 15% and a ventilation system providing 10 air changes per hour. The room lighting was performed to provide a cycle of 12 hours of light and 12 hours of dark. The mice were fed a complete rodent sediment diet &quot; Altromin 1314 &quot; (Chr. Petersen A / S, DK-4100 Ringsted, Denmark). The rats had free access to bottles of domestic grade water acidified with hydrochloric acid to pH 2.5 so as to avoid microbial growth.

Rats were randomly assigned to four groups of nine treated animals as indicated in the table below. The groups, dose levels, and number of animals are listed in table 7 below:

Dose1 (mg / kg) Group Salt of Strontium MW% Sr Equivalent Dose1 (amounts in mg) Animal Vehicle No. Vehicle Control (0.5% CMC) - - - 1-900 B Sr-ranelate (* 7H20) 639, 6 27.4 500 = 137mg Sr ++ 10-18 416 C SrCl2 (* 6H20) 266.6 6.99mg Sr ++ = 416 19-27 390 D Sr-citrate (* 6H20) 749.135.113mg Sr ++ = 390 28-36

Table 7: The four treatment groups of pharmacokinetic experience. The doses administered to each group are listed in the first column and the salt content, MW and Sr, in the middle columns. The doses are adjusted to provide an equimolar dose of strontium at 500 mg / kg strontium ranelate (heptahydrate) (group B). The test article was administered once per oral gavage, according to the most recent body weight data. The control group was dosed with the vehicle alone (0.5% carboxymethyl cellulose, CMC). The vehicle was prepared with deionized water for all treatment groups, including controls. Test substances (strontium salts) were dissolved / suspended in a volume corresponding to 5 ml / kg body weight. In order to keep the compounds in suspension, the formulations were maintained on a magnetic stirrer prior to and during administration. Blood samples for determination of strontium absorption and bioavailability

On the day of treatment (Day 1), blood samples were collected from all animals. Blood samples were collected from three animals per group, in the following phases: pre-treatment, and 30 min, 1, 1.5, 2, 4, 8 and 24 hours post-treatment, so that in three animals of each group had samples collected at moments 0, 1.5 and 6 hours, three other rats at the times of 0.5, 2, 8 hours and the remaining three animals in the group had samples collected at 1, 4 and 24 hours.

Approximately 0.5-0.6 mL of blood was obtained at each time point from the orbital venous plexus in serum tubes. The blood was maintained at room temperature for 30 to 60 minutes and until centrifugation (10 min, 1270G, 20øC). Serum was transferred to Nunc cryogenic tubes (Nunc, Denmark) and frozen at -18 ° C for further analysis of the strontium content by graphite chamber atomic absorption spectrometry (GF-AAS).

Concentration spectrometry with concentrated graphite chamber (GF-AAS) HC1 was added to the serum samples to a final concentration of 0.2% HCl and the samples were then subjected to analysis using a Perkin-Elmer 2100 equipped with a lamp of hydrogen for correction of the background signal. Strontium was measured at an aperture of 0.2 nm, wavelength of 460.8 nm, operated at an energy of 58 and a current of 8 mA.

Results of the pharmacokinetic study of strontium salt absorption

In Figure 4, the serum concentration measured in the three groups treated with strontium salts is plotted as a function of time after the administration of the compounds. It is evident that the administration of strontium salts results in a rapid and highly significant increase in serum strontium concentrations. Comparing the pharmacokinetic properties of different salts, it is evident that both the highly soluble strontium chloride as well as the relatively poorly soluble strontium ranelate (see example 3) are absorbed rapidly, reaching a maximum serum concentration after about 2 hours . In contrast to strontium citrate the lower solubility reaches the maximum serum concentration with a slower kinetic rate and with a maximum concentration reached after about 6-8 hours. In addition, the serum strontium concentration, in the time interval of 0-8 hours, after administration of strontium citrate appears to be more stable.

When the AUC calculations were performed the general course of curves, as evidenced by the mean values of Fig. 4, was best described by the response model / pharmacokinetic curves in a specially developed mathematical model. At the initial stage, it is assumed that strontium is not metabolized but simply transferred from the stomach / upper digestive tract of the mouse to the epithelial cells through an active transport mechanism. In addition, without metabolism, the strontium ion is transferred from the stomach / upper digestive tract, where it is simultaneously released into the blood vessels.

Only during the circulation of strontium through the veins, strontium is dispersed and metabolized by the body tissues. This credible but simplified description includes a two strand ion strontium uptake mechanism, following the oral administrations of strontium ions, probably corresponding to two fastening mechanisms, a rapidly activated active mechanism, and an active passive transport mechanism along the length of the digestive tract. After the dose of strontium was administered to rats, a characteristic time of absorption was found at t = 12 min. The maximum serum strontium content was observed after approximately 30 min. The characteristic time value of 12 min. is interpreted as the duration that the strontium ions can be taken by the active mechanism of transport of the intestinal lumen and secreted into the circulation. The strontium transfer time between the stomach and the blood vessels is initiated almost instantaneously, while the transfer time between the intestines and the blood vessels proceeds at a later stage, which depends on the type of salt studied. However, for all salts, after about 1750 min. (29 hours) the levels of strontium are close to the natural level, which corresponds to the pre-dose level.

The model calculations were applied to determine the areas under the curve, which are shown in table 7. The standard deviations of the AUC values correspond to the general uncertainty about the measurements of Fig. 4, and their amplitude do not allow significant discrimination between the salts.

Salt Anion Sr AUC mg / L.min STDDEV mg / L.min Chloride 7300 2000 Citrate 8900 4700 Vehicle 168 67 Ranelate 5800 1700

Table 7. Determination of the area under the curve according to (AUC) and the model calculations.

These effects of the retarded strontium absorption observed with strontium citrate may improve the pharmacological properties of strontium. Strontium citrate resulted in a high level of bioavailability, assessed from the AUC curve (Table 7), although the differences for the other treatment groups did not reach statistical significance. Late realization of Cmax may be an advantage for the use of the strontium compound for the treatment of diseases and conditions affecting bone metabolism. In such cases, it is often advantageous to administer the compound at night before bed as it would allow the compound to act overnight when bone resorption occurs at a higher rate.

In addition, administration prior to bedtime minimizes potential calcium interference in the normal diet, administration of the pharmaceutical preparation of the strontium salt will be done after the last meal. This is in contrast to daytime administration when the calcium content of normal meals has a potential to interfere with and reduce the absorption of strontium. Gradual increase in serum strontium concentration for 4-8 hours after compound administration, which work well with compound administration at night and appears well suited to maximize the therapeutic effect of the strontium compound on bone metabolism.

Lisbon, August 29, 2013

Claims (38)

A medical tablet for oral administration once a day comprising at least one strontium salt of an organic acid, wherein the organic acid is selected from the group consisting of alpha-ketoglutaric acid, L-and D-aspartic acid, L- and D-glumatic acid, maleic acid, malonic acid [CH 2 (COOH) 2], pyruvic acid, succinic acid [C 2 H 4 (COOH) 2] and one or more physiologically acceptable excipients, wherein the amount of the strontium salt is adjusted so that the composition is administered once daily. A tablet for use according to claim 1, wherein the water solubility of the strontium salt is at most 200 g / L or at most 150 g / L, at most 100 g / L, at most 75 g / L, not more than 50 g / l, at most 25 g / l, at most 10 g / l, at most 5 g / l, at most 2,5 g / l or at most 1 g / l at room temperature (20-25 ° C). A tablet for use according to claim 1 or 2, wherein the water solubility of the strontium salt is at least 0.1 g / L or in a range from 0.1 g / L to 10 g / L , from 0.2 g / L to 5 g / L, at room temperature (20-25 ° C). A tablet for use according to claim 1, wherein the water solubility of the strontium salt is at least 1 g / L or at least 5 g / L, at least 10 g / l, at least 20 g / L, at least 30 g / L, at least 40 g / L, at least 50 g / L, at least 60 g / L, at least 70 g / L, at least 40 g / / L or at least 100 g / L, at room temperature (20-25 ° C). A tablet for use according to any one of the preceding claims for once-daily bedtime administration. A tablet for use according to any one of the preceding claims, comprising at least 0.01 g of strontium (calculated as ionic strontium) or at least 0.025 g, at least 0.050 g, at least 0.075 g, at least 0 , 1 g, at least 0.2 g, at least 0.3 g, at least 0.4 g or at least 0.5 g or 0.01 to 2 g, or 0.1 to 2 g, of 0.1 to 1 g, 0.15 to 0.5 g, 0.3 to 2 g or 0.3 to 1 g. A tablet for use according to any of claims 1-5, comprising at least 0.5 g of strontium (calculated as ionic strontium) or at least 0.6 g, at least 0.7 g, at least 0. 8 g, at least 0.9 g, at least 1.0 g, at least 1.1 g, at least 1.2 g, at least 1.3 g, at least 1.4 g, at least 1.5 g g, at least 1.6 g, at least 1.7 g, at least 1.8 g, at least 1.9 g or at least 2.0 g. A tablet for use according to any one of the preceding claims, in the form of a matrix tablet. A tablet for use according to claim 8 comprising 20 to 90% w / w of the active substance and 10 to 80% v / v of polymer. A tablet for use according to any one of the preceding claims, wherein the Sr salt is released from the composition such that the amplitude (difference between the peak and nadir) of the plasma concentration relative to the level of the peak should be less than 40% or less than 35%, less than 30%, less than 25%, less than 20%, less than 15% or less than 10%, after administration of the composition to an individual, once a day for at least 30 days or at least 21 days, at least 14 days, at least 7 days, such as 7 days. A tablet for use according to any of the preceding claims, wherein the composition, when tested in an in vitro dissolution test, releases strontium ions from the strontium salt-containing composition, as follows: in the first 30 minutes of the test, at most 10% w / w of Sr ion is released; in the first 4 hours of the test, at most 70% w / w of the Sr ion is released; in the first 14 hours of the test 70% w / w or more of the Sr ion is released. A tablet for use according to any one of the preceding claims, wherein the Sr salt is contained in a matrix which controls the release. A tablet for use according to any one of the preceding claims, wherein the composition is coated with a controlled release coating which regulates the salt release of the salt A tablet for use according to any one of the preceding claims, wherein the salt is a hydrate, anhydrous, solvate, polymorph, amorphous, crystalline, microcrystalline or in the polymeric form. A tablet for use according to any one of the preceding claims, wherein the strontium salt is selected from the group consisting of strontium succinate, strontium malonate, strontium maleate, strontium L- and D-glutamate, L and strontium D-aspartate, strontium pyruvate, strontium alpha-ketoglutarate and mixtures thereof. At least one strontium salt of an organic acid, wherein the organic acid is selected from the group consisting of alpha-ketoglutaric acid, L- and D-aspartic acid, L- and D-glumatic acid, maleic acid, malonic acid [C 2 H 4 (COOH) 2] and physiologically acceptable excipients for medical use to be administered as a tablet for oral administration once daily for the prophylaxis of a condition affecting and / or bone or for the treatment and / or prophylaxis of a disease and / or condition of the cartilage and / or bone, resulting in dysregulation of cartilage and / or bone metabolism in a mammal. 17. At least one strontium salt for use according to claim 15 for use in preventing in a subject from a disease and / or condition of the cartilage and / or bone, resulting in dysregulation of cartilage and / or bone metabolism in a mammal, such as, for example, an adult female human or male, adolescent or child, such as osteoporosis, osteoarthritis, osteopetrosis, osteopenia and Paget's disease, malignant hypercalcemia, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis , osteodystrophy, myositis ossificans, Bechterew's disease, malignant hypercalcemia, osteolytic lesions produced by bone metastasis, bone pain due to bone metastasis, bone loss due to sexual steroid hormone deficiency, bone abnormalities due to treatment with steroid hormones, bone abnormalities caused by cancer therapy, osteomalacia, Bechet's disease, hyperostosis, osteopenia induced by immobilization or osteoporosis or osteoporosis induced by glucocorticoids or osteoporosis, osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis, for use in improving fracture healing after traumatic or atraumatic fracture and appropriate for maintaining or raising the level for building or strengthening muscle tissues and for weight gain, wherein a tablet of one or more strontium salts of an organic acid, wherein the organic acid is selected from the group consisting of alpha-ketoglutaric acid, L-and D-aspartic acid, L- and D-glumatic acid, maleic acid, malonic acid [0 (COOH) 2], pyruvic acid, succinic acid [C 2 H 4 (COOH) 2] and one or more physiologically acceptable excipients, for to be administered once daily. 18. At least one strontium salt for use according to claim 16 for use in the treatment and / or prophylaxis of a disease and / or condition of the cartilage and / or bone, resulting in dysregulation of cartilage and / or bone metabolism in mammal, such as, for example, an adult female human or male, adolescent or child, such as, for example, osteoporosis, osteoarthritis, osteopetrosis, osteopenia and Paget's disease, hypercalcemia, periodontal disease, hyperparathyroidism, rheumatoid arthritis, osteodystrophy, ossificating myositis, Bechterew's disease, malignant hypercalcemia, osteolytic lesions produced by bone metastasis, bone pain due to bone metastasis, bone loss due to sexual steroid hormone deficiency, bone abnormalities due to treatment with steroid hormones, Bone anomalies caused by cancer therapy, osteomalacia, Bechet's disease, hyperostosis, osteopenia induced osteoporosis or osteoporosis or osteoporosis induced by glucocorticoids or osteoporosis, osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis, for use in improving healing of fractures following traumatic or atraumatic fracture and appropriate for maintaining or raising the level for building or strengthening muscle tissues and for weight gain, wherein a tablet of one or more strontium salts of an organic acid, wherein the organic acid is selected from the group consisting of alpha-ketoglutaric acid, L-and D-aspartic acid, L- and D-glumatic acid, maleic acid, malonic acid [CH 2 (COOH) 2], pyruvic acid, succinic acid [C 2 H 4 (COOH) 2] and one or more physiologically acceptable excipients, for comprising at least 0.5 g of strontium (calculated as strontium ion), such as, for example, at least 0.6 g, at least 0.9 g, at least 1.0 g, at least 1.1 g, at least 1.2 g, at least 1.3 g, at least 1 g , 4. g, at least 1.5 g, at least 1.6 g, at least 1.7 g, at least 1.8 g, at least 1.9 g or at least 2.0 g. 19. At least one strontium salt for use according to claim 16 for use in the treatment and / or prophylaxis of a disease and / or condition of the cartilage and / or bone, resulting in dysregulation of cartilage and / or bone metabolism in such as, for example, an adult female human or male, adolescent or child, such as osteoporosis, osteoarthritis, osteopetrosis, osteopenia and Paget's disease, malignant hypercalcemia, periodontal disease, hyperparathyroidism, periarticular erosions osteoarthritis, osteodystrophy, ossificating myositis, Bechterew's disease, malignant hypercalcemia, osteolytic lesions produced by bone metastasis, bone pain due to bone metastasis, bone loss due to sexual steroid hormone deficiency, bone abnormalities due to treatment with steroid hormones, Bone anomalies caused by cancer therapy, osteomalacia, Bechet's disease, hyperostosis, osteopenia induced by immobilization or osteoporosis or osteoporosis induced by glucocorticoids or osteoporosis, osteoporosis pseudoglioma syndrome, idiopathic juvenile osteoporosis, for use in improving fracture healing after traumatic or atraumatic fracture and appropriate for maintaining or raising the level for building or strengthening muscle tissues and for weight gain, wherein a tablet of one or more strontium salts of an organic acid, wherein the organic acid is selected from the group consisting of alpha-ketoglutaric acid, L-and D-aspartic acid, L- and D-glumatic acid, maleic acid, malonic acid [CH 2 (COOH) 2], pyruvic acid, succinic acid [C 2 H 4 (COOH) 2] and one or more physiologically acceptable excipients, for medical use comprising once daily administration wherein the amount providing a daily dose of 0.25 g to 1.5 g of Sr 2 + free, or from 0.30 g to about 1.5 g, from 0.40 g to 1.40 g, from 0.50 g to 1.30 g, from 0.60 g to 1.20 g, from 0.70 g to 1.10 g or 0.80 g to 1.00 g. 20. The at least one strontium salt for use according to any one of claims 16-19, wherein the strontium salt is the malonate salt. 21. The at least one strontium salt for use according to any one of claims 16-20, wherein the tablet is for oral administration. 22. The at least one strontium salt for use according to any one of claims 16-21, wherein the tablets are defined in any one of claims 1-7, 9-15. 23. At least one strontium salt for use according to claim 17, wherein the individual is female with a bone mineral density, BMD, of greater than 1 SD below the young adult female female. 24. At least one strontium salt for use according to claim 17, wherein the individual is female with a BMD below the adult female mean for women of the same age group. 25. At least one strontium salt for use according to claim 17, wherein the individual is male with a BMD of greater than 1 SD, below the male young adult mean. 26. The at least one strontium salt for use according to claim 17, wherein the individual is male with a BMD below the male adult mean for men of the same age group. 9 27. The at least one strontium salt for use according to claim 17, wherein the subject is female having a level of a specific bone resorption biomarker of more than 1 SD above the young adult average feminine 28. The at least one strontium salt for use according to claim 17, wherein the subject is female with a level of a specific bone resorption biomarker above the adult female mean for women of the same age. 29. At least one strontium salt for use according to claim 17, wherein the subject is male with a specific level of a bone resorption biomarker of more than 1 SD, above the young adult male average. 30. The at least one strontium salt for use according to claim 17, wherein the subject is male with a specific level of a bone resorption biomarker above the male adult mean for men of the same age. At least one strontium salt for use according to claims 17, 23, 24 for the treatment of a woman of 20 years or older or 25 years or more, 30 years of age or over, 35 years of age or over, 40 years or older, 45 years or older or 50 years or older. 32. At least one strontium salt for use according to claim 17, 23, 24, 17-28, 31 for use in the treatment of a woman who is approximately the same age as the onset age of menopause. 10 33. At least one strontium salt for use according to claim 17, 23, 24, 17-28, 31, wherein the subject is a woman having about 6 months or more beyond the onset of menopause. 34. At least one strontium salt for use according to claims 17, 25-26, 29-30 for the treatment of a man of 50 years or more or 25 years or more, 30 years or more, 35 years or more, age 40 or over, age 45 or over, age 50 or over, age 55 or over, age 60 or over, age 65 or older, or age 70 or older. 35. At least one strontium salt for use according to claims 17 and 23-34, wherein the daily dose of strontium administered is at least 0.01 g strontium, or at least 0.025 g, at least 0.050 g , at least 0.075 g, at least 0.1 g, at least 0.2 g, at least 0.3 g, at least 0.4 g or at least 0.5 g or 0.01 to 2 g, or 0.1 to 2 g, 0.1 to 1 g, 0.15 to 0.5 g, 0.3 to 2 g or 0.3 to 1 g. 36. At least one strontium salt for use according to claim 16 in the treatment and / or prevention of secondary osteoporosis in a subject, wherein an effective amount of one or more strontium salts of an organic acid, wherein the acid organic acid is selected from the group consisting of alpha-ketoglutaric acid, L- and D-aspartic acid, L- and D-glumatic acid, maleic acid, malonic acid [CH 2 (COOH) 2], pyruvic acid, succinic acid [C 2 H 4 (COOH ) 2] and one or more physiologically acceptable excipients, for medical use, comprising once daily administration in the subject. 11 37. At least one strontium salt for use according to claim 36, wherein the secondary osteoporosis is induced by, for example, endocrine diseases, metabolic causes, nutritional conditions, drug substances and / or disorders of collagen metabolism. A strontium salt for use according to claim 16 for use in preventing drug induced secondary osteoporosis in a patient comprising administering to the subject a prophylactic amount of one or more strontium salts of an organic acid , wherein the organic acid is selected from the group consisting of alpha-ketoglutaric acid, L- and D-aspartic acid, L- and D-glumatic acid, maleic acid, malonic acid [CH 2 (COOH) 2], pyruvic acid, succinic acid [C 2 H 4 (COOH) 2] and one or more physiologically acceptable excipients for medical use prior to, during or after treatment of the subject with the substance of the drug which induces secondary osteoporosis. Lisbon, August 29, 2013