Title : A novel Strontium Risedronate compound, a process for producing the strontium Resideronate and a pharmaceutical composition comprising the same
FIELD OF INVENTION;
The present invention relates to a novel Strontium Risedronate compound and salts thereof, a process for producing the same. The present invention further relates to a pharmaceutical composition comprising the strontium risendronate for the treatment of Osteoporosis and to reduce the risk of vertebral and bone fracture.
BACKGROUND OF THE INVENTION:
Risedronate sodium is an oral bisphosphonate that significantly reduces the risk of new vertebral fractures in postmenopausal women with established osteoporosis. It is also effective in the prevention of steroid - induced osteoporosis. Risedronate is very effective in the treatment of Paget's diseases. Risedronate sodium exists in three crystalline hydration states: anhydrous, monohydrate, Hemipenta hydrate.
Risedronate, a nitrogen-containing bisphosphonate, is indicated for the treatment and prevention of osteoporosis in postmenopausal women and in patients undergoing systemic glucocorticoid treatment for chronic inflammatory diseases. Localised to the bone following administration, risedronate targets the osteoclasts responsible for bone resorption and thereby normalises the bone remodelling process which is disrupted in osteoporosis. Consequently, risedronate increases or maintains bone mineral density (BMD) and reduces the incidence of vertebral and non-vertebral fractures in a clinical setting. In order to maximise bioavailability following oral administration, risedronate should be administered before food and following a period of fasting, with patients remaining upright for up to 30 minutes post-dosing. Failure to comply with dosage instructions may result in limited efficacy and an increased risk of side-effects. Risedronate is generally well tolerated with an adverse event profile resembling that of placebo. In contrast to some bisphosphonates, risedronate has a low propensity for causing

gasLruiiuesiinai imiauon, wnicn, coupiea wim its minimal drug interaction protile, may further promote patient concordance.
The US Patent No: 6,410,520 discloses [1-hydroxy -2(3-pyridinyl)ethylidine]bisphosphonic acid]monosodium salt.

Trade name: Actonel
Each Actonel tablet in the ACTONEL with CALCIUM co-package contains the equivalent of 35 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amoimts of monohydrate.
Route of administration: Tablet for Oral suspension.
Description: Risedronate sodium is a fine, white to off-white, odorless, crystalline powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents.
The European Patent No.: 186,405 (1986) to Procter & Gamble describes a pharmaceutical compositions containing geminal diphosphonates for treating or preventing diseases due to abnormal calcium and phosphate metabolism.

Strontium ranelate is used for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. It is the first dual-fianction antiosteoporotic treatment able to both increase bone formation and decrease bone resorption thereby rebalancing bone turnover in favour of bone formation.
Strontium ranelate is the alternate choice of therapy for postmenopausal osteoporosis, particularly for those unable to comply fully with bisphosphonate dosing instructions.
Strontium ranelate is indicated for the treatment of osteoporosis in postmenopausal women to reduce the risk of vertebral and hip fractures. The effects of strontium ranelate on bone closely resemble those of calcium, with which it shares a chemical group. Unlike other agents commonly used in the management of osteoporosis, strontium ranelate stimulates the formation of new bone tissue, as well as reducing bone resorption. In this manner, it redresses the bone remodelling process to favour bone formation. Formed by combining two stable strontium atoms with an organic moiety (ranelic acid), strontium ranelate localises almost exclusively to bone tissue following oral administration. Strontium ranelate prevents bone loss in ovariectomised rats, increases bone mass in osteopenic animals and increases bone strength in normal animals. Although relatively sparse, clinical studies conducted in postmenopausal women have revealed a dose-dependent increase in bone mineral density (BMD) of the lumbar spine and hip following up to 3 years of treatment. In women with osteoporosis, the risk of both vertebral and non-vertebral fracture was reduced by long-term treatment with strontium ranelate, with effects first evident after 1 year and sustained over 3 years. Data derived from clinical studies have shown strontium ranelate to be well tolerated, with an adverse event profile similar to that of placebo.
The US Patent No: 7,214,805 describes a process for the industrial synthesis of 5-[bis(carboxymethyl)amino]3-carboxymethyl-4-cyano-2-Thiophenocarboxylic acid di strontium
salt.

Chemical Structure:


Si^

Molecular weight: 513.491
Trade name: Protos
Protos 2g sachets contain 2g strontium ranelate as a yellow powder.
Route of administration: Granules for oral suspension.
Description: Strontium ranelate is a yellowish-white non-hygroscopic powder. It crystallizes
as a monohydrate form but one water molecule is particularly labile and this leads to a
compound containing either 8 or 9 water molecules per strontium ranelate molecule. Strontium
ranelate is slightly soluble in purified water (3.7mg/mL at saturation point) and practically
insoluble in organic solvents (eg, methanol).
Strontium is a metallic element widely distributed, although in minute amounts, and found in various compounds, seawater, marine plants, and food. It is also found in bones and teeth, but it is not known if it is essential for them, and, as it stands, strontium has no nutritive value. It is the radioactive form that is the health concern.
With a half-life of twenty-eight years, strontium-90 is easily passed on in the food chain ~ animals eat the grass, and people eat the products from these animals.

First discovered in 1790 by a Scots-Irish chemist, Adair Crawford, strontium was found to be a distinct mineral species in with the barium crystals common in the area of the Scottish town of Strontian. Since then, the mineral has remained in relative obscurity, except for a few patent medicines that had nothing to do with bone health.
Strontium has recently been re-discovered as being an essential substance in helping to prevent osteoporosis and the only one that has the ability to regenerate, preserve, and even restore bone growth.
Strontium was found to be vital to a healthy skeletal system. It was report that a lack of strontium in the diet caused defective mineralization of the bones and teeth in lab animals, suggested that mammals need the mineral for normal skeletal development and suffer from a deficiency if they do not obtain it in their food - just as they would if their diets lack calcium, magnesium, or zinc.
The hint that made researchers take strontium more seriously was the fact that 99% of the mineral is concentrated in the skeletal system. Researchers then began adding it to the animal's diet and found that the bony "dentin" tissue in their teeth increased. They also noted that healthy teeth contained more strontium than those with cavities. In addition, people living in areas where Strontium was higher in the drinking water had fewer incidents of dental caries - a finding that was subsequently reinforced by more studies over the next few decades.
Bone is a living tissue -just like any other in the body. It grows and it wears down. Although it seems unchanging after full growth is attained, in reality, bone is in a continual process of remodeling and renewal. Old bone is torn down by cells called osteoclasts and is resorbed by another special class of bone cells called osteoblasts, which then builds up replacement tissue. This constant balance of resorption and new bone formation allows for continual replacement of old, stressed, and/or damaged tissue with new and healthy bone. It also allows the body to adjust its skeletal structure when it is subjected to new or changing stresses.
Over the years, the body naturally wears down. This is especially true of the skeletal system. Arthritis and osteoporosis become more common with age. It is especially apparent in

menopausal women when the hormone estrogen suppresses the resorption process, causing a dramatic increase in bone loss. However, this process does not just suddenly appear in women at menopause. It actually begins in both men and women at an early age.
Strontium causes baby osteoblasts to multiply more quickly. There is also a notable increase in the synthesis of DNA in these cells. With all the new osteoblasts on hand, bone tissue cultures exposed to strontium synthesize more bone matrix (the mineral-enriched collagen that forms the foundation of bone tissue). Strontium also appears to draw extra calcium into bones.
Until recently, it has been thought that, because of its chemical similarity to calcium, strontium could replace it somewhat in various body processes, including replacing a small proportion of the calcium in such calcified tissues as bones and teeth. However, this theory is now being ruled out since the amount of calcium appears to have no effect on these parameters or from ranelic acid, the inert acid salt to which strontium has been bound in many of the more recent clinical trials.
Instead, researchers are seeing that there is a receptor in osteoblasts which responds specifically to strontium and is unaffected by calcium, aluminum, or any other metallic element. This would be consistent with the understanding that while calcium is necessary for building new bone, it does not stimulate that growth - although an abundance of calcium does help to suppress bone teardown.
Strontium also appears to prevent the resorption caused by excessive parathyroid hormone and, unlike the bisphosphate drugs, does not kill existing osteoclasts. Instead, it slows the rate at which immature osteoclasts develop. The Osteoblasts continually build new bone tissue while Osteoclasts continually tear down old bone cells. This increases mineral density and bone strength without increasing brittleness or having any negative impact on bone quality .
Subsequent studies indicate that Strontium supplements increase bone mass and, the more that is taken, the greater the bone mass that is gained.
Even more striking were the results in women's hip bones. Despite the calcium and vitamin D3 supplements that these women had been taking, those who did not take Strontium as well.

actually suffered a bone density loss in their hips of 0.57% each year of the study. By contrast, those who had added Strontium to their regime gained bone mass in their hips. In addition, those taking strontium suffered 56% fewer new vertebral deformities compared with those taking only calcium and vitamin D3.
Although most of the recent studies have been focusing on osteoporosis patients, this mineral has also been found to benefit bone structure and function in those who have the following conditions:
• Bone lesions from metastatic bone carcinoma, degenerative weight loss, or liver disease
• Morquio's disease (also known as mucopolysaccharidosis type IV - a. genetic disorder that leads to a buildup of keratin sulfate in the bones, ultimately causing vertebral fractures and bone deformations)
• Milkman's disease (osteomalacia marked by multiple pseudofractures)
• Gushing's syndrome (a hormonal disorder caused by high levels of the hormone Cortisol and sometimes called hypercortisolism)
• Nutritional osteoporosis
• Childhood rachitic bone deformities caused by Rickets
• Male osteoporosis
It is now known that, almost always, strontium and calcium are found together in natural plant foods. Plants, animals, and humans absorb and store these two minerals in similar fashion. Data compiled from ancient bones have revealed that carnivores had lower bone strontium/calcium ratios than herbivores. This also makes sense since it is now known that the more protein that is consumed, the more calcium that is leeched from the body.
If taken properly, both minerals play a key role in bone health. However, some studies suggest that strontium may not be effective and indeed may be counterproductive, if the calcium intake is not adequate.

It is also important to take strontium at a different time than the calcium supplement. This is because calcium and strontium use the same pathways for absorption in the intestinal tract. By taking them together, absorption will be dramatically reduced.
Bone loss accelerates suddenly in menopausal women because the drop in estrogen levels causes an increase in the resorption (teardown) of existing bone. Age-related bone loss is also caused by a decrease in the formation of new bone tissue.
Strontium is a mineral found along with calcium in most foods. Research has long suggested that it may be an essential nutrient required for the normal development, structure, function, and health of the skeletal system. Clinical trials going back into the 1940s have supported this conclusion, but recent studies have provided evidence that it can offer unique nutritional support against loss of bone structure and function.
Human clinical trials also support Strontium's ability to both support new bone formation and prevent excessive resorption.
Early clinical trials' results led researchers to speculate that Strontium increased osteoblast activity.
Bone biopsies from a small pilot trial revealed an astounding 172.4% increase in new bone formation after six months of Strontium supplementation.
The bone-building activity of osteoblasts can be measured using bone-specific alkaline phosphatase, while crosslinked N-telopeptide (NTx) and C-telopeptide (CTx) mark the degradation of bone collagen by ravaging osteoclasts. The use of these tests in large clinical trials has confirmed that Strontium supplements decrease bone resorption and also stimulate bone-building osteoblast activity and new bone formation in women with osteoporosis.
There are several therapies currently available designed to slow down the effects of bone loss such as:
• bisphosphonates
• HRTs (hormone replacement therapies)

• j>JiKJvis i^seiective estrogen receptor modulators,), and
• Calcitonin
Existing drugs for treating osteoporosis, as well as calcium and vitamin D supplements, work by reducing bone resorption. But they do not support the formation of new bone.
These drugs and nutrients increase the mineralization of bone, but they do not help the body to build new bone tissue. The resulting bone is less prone to fracture, but is not the same as youthful, healthy bone.
Unlike the range of side-effects that accompany bisphosphonates and other antiresorptive drugs, no side-effects have ever been reported that could be attributed to Strontium. People experienced no symptomatic or chemical or physiological signs of toxicity after taking Strontium supplements for as long as four years, at two and a half times the dose of elemental Strontium that's used in today's clinical trials.
Most of the existing drugs are anti-resorptive agents which work by slowing down runaway bone resorption. Calcium and vitamin D supplements also have anti-resorptive action that keeps the body's stores of these nutrients at levels high enough so that calcium will not leech out of the bones by the parathyroid hormone. These, however, DO NOT increase the body's ability to build new bone. They just keep old bone from being destroyed.
Despite what a bone mineral density (BMD) test may show, bone mass continues to fall even while a person is on such drugs as bisphosphonates or any other antiresorptive drug. All that an increase in the readings of the DEXA machines indicates is that there is an increase in the mineralization of the bone tissue left, but does not show the continual decline in the amount of bone tissue - leaving everyone with a false sense of security.
More importantly, conventional osteoporosis treatments are one-sided and half-way measures. Although these drugs are effective in treating one part of the bone-loss problem (excessive bone resorption), they fail to address the cause; that is, a decline in bone formation.

To address the disease process of osteoporosis fully, the present invention aims at providing an agent that will not only prevent bone resorption but will also boost the body's declining ability to create new bone tissue.
SUMMARY OF THE INVENTION :
The objective of the present invention is to provide a novel compound that will prevent the resorption and to correct the error of the body's bone-building capacity.
Accordingly the present invention provides a novel Strontium Risedronate compound represented by a formula (I)
0 PH O
HO—P—C—P—O


HO

O

^^ (I)
or its pharmaceutical salts thereof.
The further objective of the present invention is to provide a process for producing a novel Strontium Risedronate compound.
It is still further objective of the present invention to provide a pharmaceutical composition comprising Strontium Risedronate for the treatment of Osteoporosis.
The present invention further encompasses a method of treatment of Osteoporosis comprising the step of administrating to a subject in need of such treatment, a safe and effective amount of Strontium Risedronate.

DETAILED DESCRIPTION OF THE INVENTION :
The Strontium Risedronate compound of the present invention is composed of two atoms of stable strontium (an element with properties similar to calciimi) mid one molecule of Risedronic acid. It has a dual effect on bone metabolism, increasing bone formation and decreasing bone resorption. It is used for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures.
Strontium risedronate of the present invention is off white to white crystalline powder, insoluble in organic solvents (like Acetone, Methanol, Ethanol, Chloroform, Ethylene dichloride etc) and very sparingly soluble in water. Chemical Formula: CyHgNOTPz.Sr^^
The present invention further relates to a novel process for producing Strontium Risedronate wherein it is prepared by reacting Risedronic acid with strontium hydroxide in water media at 95 -100°C.
CTHHNFZOT + Sr(OH)2 ► C7H9NP207Sr + 2 H2O
Risedronic acid strontium hydroxide Risedronate strontium water
Another aspect of the present invention is a pharmaceutical composition or medicament comprising Strontium risedronate and pharmaceutical acceptable excipients. Any known excipients may be used.
Another aspect of the present invention is a method of treatment or preventing postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures by administrating

the elective amount of the Strontium risedronate according to the present invention . In particular, it increases bone formation and decreases bone resorption. The mode of administration may be oral or any other modes of administration.
The following non-limiting example illustrate the process according to the present invention :
Example:
Input Raw Materials

S.No Raw Materials Qty
1 Risedronic acid (Pure) 10 gm
2 Strontium Hydroxide 9.65 gm
3 DM Water 50+50 ml
Steps involved in the preparation of Strontium Risedronate:
1. Pure Risedronic acid and DM Water of 50 ml is charged at RT
2. The aqueous mixtures is stirred for 10 min at RT
3. Strontium Hydroxide is added to aqueous mixtures and charged at RT
4. The reaction mixture is stirred for 1 hour at RT until the material becomes thick
5. Further 50 ml of DM Water is added to the mixture and heated to a temperature of about 95-100°C.
6. Further, the heated reaction mixture is stirred for 4-5 hours at 95-100°C and cooled to RT

7. Finally, the reaction mixture is filtered and separated using known techniques, in a known manner. The separated substance is washed with DM Water to obtain a pure form of mono strontium salt of risedronate.

The Strontium resideronate according to the present invention has the following properties.
The following tests were carried out to determine the properties of the mono strontium salt of risedronate of the present invention.
1. Strontium % by [IPOCA] result is:- 23.68% theoretically it is 23.64% It is an evident that one mole of strontium is reacted with one mole of Risedronic acid

2. X-RD: As per X-RD spectrum it is crystalline powder only .
3. DSC : peak on set temperature is not obtained up to 400°C. This indicates it is pure salt.
4. IR : -CH, C-0, stretching present in IR spectrum. This indicates it is an organic salt.
EXPERIMENTAL DATA /EFFICACY TEST:
Most osteoporosis treatments have proven efficacy in reducing the risk of vertebral fractures, whereas evidence is less straightforward for prevention of non-vertebral fractures. Conclusions as to the efficacy of a treatment should be based primarily on analyses of the intention to treat (IFT) population rather than on exploratory subgroup analyses; however, non-vertebral anti-fracture efficacy has been largely derived by post-hoc subgroup analyses. This review and meta-analysis was perfonned to assess non-vertebral anti-fracture efficacy of several osteoporosis therapies, including a more stringent assessment of the ITT populations. Data on non-vertebral anti-fracture efficacy, a defined endpoint of the ITT mialyses and confirmed by radiographs, were obtained from randomized, placebo-controlled, phase 111 clinical trials of at lea.st .3-year duration. Meta-analyses were performed for the two bisphosphonates, alendronate and risedronate. Relative risks (RR), 95% confidence intervals (CI) and statistical significance for active treatment compared with placebo were calculated. Eleven clinical trials met the criteria for review, three of which .showed statistically significant (P < 0.05) non-vertebral anti-fracture efficacy in the ITT population: two trials with risedronate and one trial with strontium. A meta-analysis showed significant reductions in the relative risk of non-vertebral fracture for both alendronate (RR=0.86; 95% CI: 0.76-0.97, P=0.012) and risedronate (RR=0.81; 95% CI: 0.71-0.92, P=0.001). Risedronate and strontium ranelate were the only treatments to show non-vertebral anti-fracture efficacy in this robust assessment of anti-fracture efficacy of osteoporosis therapy using ITT populations in trials of 3 years or more in duration. Risedronate was the only agent shown to demonstrate efficacy in more than one trial. Meta-analysis showed that both alendronate and risedronate provide non-vertebral anti-fracture efficacy.
This clearly demonstrates that the combination of Risedronate and Strontium is very effective against Oestoporosis and bone deformities.

We claim:
1. A compound of Formula I

or a pharmaceutical salts thereof
2. A process for producing a compound of formula I, comprising the step of reacting
risedronic acid and strontium hydroxide in an aqueous medium at a temperature in the range of
about 95 to about 100°C.
3. A pharmaceutical composition comprising a compound of formula I as claimed in claim 1, and a pharmaceutically acceptable excipients, for the treatment of Osteoporosis.
4. A method of treatment of Osteoporosis comprising the step of administrating to a subject in need thereof, a medicament having a compound of formula I as claimed in claim 1.