FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION (See section 10 and role 13)
l.TITLE OF THE INVENTION:
"AN IMPROVED FORMULATION FOR BENZIMIDAZOLES"
2. APPLICANT(S)
(a) NAME : TITAN LABORATORIES PVT. LTD.
(b) NATIONALITY : Indian (An Indian company incorporated under the
Companies Act, 1956)
(c) ADDRESS : TITAN LABORATORIES PVT. LTD.
102 TITAN HOUSE, M.P.VAIDYA MARG, 60 FEET ROAD, GHATKOPAR -EAST, MUMBAI - 400 077 MAHARASHTRA INDIA
3. PREAMBLE TO THE DESCRffTION:
COMPLETE
The following specification describes invention The following specification particularly describes the invention and the manner in which it is to be performed

Field of Invention:
The invention relates to an improved formulation for benzimidazoles. More specifically, the invention relates to formulations for benzimidazole which mitigate the effect of magnesium deficiency related to long-term use of benzimidazoles and method for manufacturing thereof.
Background of Invention:
Benzimidazoles are most effective drugs available to reduce gastric acid secretions. They are often the first choice of treatment for acidic disorders of gastric tract. The mode of action involves immediate reduction of acid content in stomach thereby reducing excess acidity.
The reduction in acidity is a result of irreversible blocking of the rTTK* Proton pumps present in the canaliculi of the parietal gastric cells, hence these molecules are also referred to as "Proton Pump Inhibitors" or abbreviated as "PPIs".
The effectiveness and the patient compliance received by this set of drugs and its generally "safe" profile have led to extensive use of benzimidazoles for acid control. At times, depending on the age or medical condition, a prolonged use is prescribed especially in case of geriatric persons and even more so in patients who are vulnerable to gastrointestinal bleeding or ulcers.

The reduction of acid content is also helpful in healing gastric ulcers, which may be caused by NSAID treatment; hence Benzimidazole-NSAID combinations have been marketed. These combinations have shown a better efficacy of treatment, particularly in case of chronic term of treatment. Said combination was first described in US 6365184 of AstraZeneca AB.
There are compelling evidences available throughout the scientific literature and community at large which suggest that such prolonged use of benzimidazoles does show certain adverse effects. The most recent of adverse reactions to be reported are those relating to reduction of Bone Mineral Density (BMD). Certain epidemiological studies for instance, Yang et al. (2006), Vestergaard et al. (2006), Yang (2008), Corley et al. (2010) and Mariko et al. (2010) have proved, beyond doubt, that prolonged use of benzimidazole does affect the bone density thereby making them frailer and more prone to fractures, specifically those situated in hip, wrist or spine.
On further literature survey it was observed that the probable cause for frailty of bones is reduced calcium absorption, which might occur due to reduction of gastric acid (Yang, 2008), as effected by benzimidazole therapy.
It is well known that calcium is essential for maintaining body health. Calcium has multiple functions in human body, for instance, construction and maintenance of bones and teeth, clotting of blood and maintaining blood pressure, neural

transmissions etc. The most abundant source of calcium in human body is the skeleton itself. The skeleton serves as a bank of minerals for the body. The body can borrow from the skeletal stores when blood calcium levels deplete and return calcium to bones when calcium levels replenish, as needed. The deficiency can be consequence of reduced calcium absorption from food through stomach. This, as already pointed out, can be result of reduced acidity of stomach as a result of benzimidazole treatment.
With a view of treating this side effect, Sundhardas, Renjit, in his International Patent Application No. WO 2008/085728 dated 26th December, 2008 had proposed unit dosage form containing combination of Vitamin D, Calcium supplement and a benzimidazole. Therefore, this Patent Application relates only to treatment of Calcium deficiency.
This Calcium deficiency is typically treated by giving calcium supplements, as seen from above. However, according to an article published at http://www.mgwater.com/calmagab.shtml. authored by Nan Kathryn Fuchs, Ph.D., and published around 2002, suggests that Magnesium is also an essential component playing a major role in calcium absorption and thereby showing an enhanced effect in maintaining bone health, thereby treating any bone related disorder including osteoporosis.
Further, it was hypothesized by Carpenter et ai in there article titled "A Randomized Controlled Study of Effects of Dietary Magnesium Oxide

Supplementation on Bone Mineral Content in Healthy Girls", published in 2006, that the Mg-deficiency may contribute to suboptimal attainment of bone mass during adolescent. It was observed during this study that Mg supplementation regimen was well tolerated with optimal compliance, and resulted in a favorable incremental gain of bone mineral content (BMC) at the hip in premenarchal girls
Required Magnesium is readily absorbed form various foods, in the intestine. Alike calcium, even magnesium requires acidic environment for absorption. Therefore, during benzimidazole treatment, even absorption of magnesium is drastically decreased due to lack of acid environment in the gastrointestinal tract.
a Safety notification published by FDA in March, 2011 inveterate that these observations were result of prolonged treatment term of dosage of benzimidazoles, typically of about 180 days, would result in sever Magnesium deficiency. Such a deficiency has been associated with muscle spasm (tetany), irregular heartbeat (arrhythmias), and convulsions (seizures) among others. This observation was confirmed by a study carried out by Epstein, Martin et al (N Engl J Med 355; 17; October 26, 2006), whereby serum levels of Magnesium during benzimidazole treatment were studied. The study revealed that Magnesium serum levels dropped below the normal range, which is of 0.70 - 1.00 mmol/liter. Similar observation was more authoritatively confirmed by Cundy, T. et al in their article titled "Severe hypomagnesaemia in long-term users of proton-pump inhibitors" (Clin Endocrinol (Oxf). 2008 Aug;69(2):338-41. Epub 2008 Jan 2).

Epstein Martin et al further suggested that the Magnesium supplementation might facilitate maintaining normal magnesium levels.
Calcium supplementation along with benzimidazole regime is known in art, considering the GI tract environment and prior arts and role of Magnesium in Calcium absorption inventors hereby propose a formulation for supplementation of benzimidazole therapy with dietary Magnesium source.
Therefore inventors hereby propose a novel combination of at least one benzimidazole and at least one dietary Magnesium source which functions as source of dietary Magnesium thereby treating the side effects caused by reduced acidity of gastric canal to absorb Magnesium.
Summary of Invention:
The invention, therefore, provides a novel, combination containing at least one benzimidazole and at least one dietary Magnesium source.
In another aspect, the invention provides an oral formulation for treatment of magnesium deficiency, wherein the formulation comprises therapeutically effective amount of at least one benzimidazole and a therapeutically effective amount of at least one Mg-salt.
In another aspect, the invention provides a process for manufacturing the pharmaceutical formulation of invention.

In further aspect, the invention provides a method of treatment of benzimidazole induced Magnesium deficiency.
Detailed Description of Invention:
The invention will now be discussed in details with reference to certain specific and preferred embodiments along with examples.
Benzimidazoles have long been used as antacid drugs and have achieved a seat of honor as forerunner for treatment of acidity. The main action of these compounds inhibition of the H+/K+ Proton pumps which are located in the canaliculi of the parietal gastric cells lining the intestine. The benzimidazoles effectively control acidity by paring the H+ production to almost a halt.
It has been observed that acid which is dispensed in stomach serves more functions than the well-known function of digestion. It has been observed that the acid is essential for proper digestion and assimilation of inorganic ion such as Ca+2 and Mg2+, Zn2+, Iron and vitamin B12 and vitamin C and p-carotene.
A decreased acid production limits or constricts Mg2+ ion absorption, which is, generally, the consequence of reduced stomach acidity by use of benzimidazole. Depleted Mg2+-ion is particularly relevant since, this deficiency can lead to heart arrhythmias also it can be cause of anxiety, restless leg syndrome, insomnia and

muscle pain. Apart from these adverse effects, Magnesium plays an important role in at least 300 fundamental enzymatic reactions which may be concluding in some other disorders.
Magnesium helps with formation of bone and teeth and assists the absorption of calcium and potassium. While calcium stimulates the muscles, magnesium is used to relax the muscles. It is further needed for cellular metabolism and the production of energy. It is required for cardiac muscle toning and controlling blood pressure.
Together with vitamin B12, it may prevent calcium oxalate kidney stones. It helps prevent depression, dizziness, muscle twitching, and pre-menstrual syndrome. It can help prevent the calcification of soft tissue and may help prevent cardiovascular disease, osteoporosis, and certain forms of cancer, and it may reduce cholesterol levels.
Magnesium assists the parathyroid gland to process vitamin D, and a shortage here can cause absorption problems with calcium. And, for these very reasons Magnesium is of vital importance in our health.
It was observed by M. T. Kuipers et al in their review article titled "Hypomagnesaemia due to use of proton pump inhibitors - a review" the oral magnesium supplements have shown an ameliorating effect on hypomagnesaemia

induced by benzimidazole treatment. Other than Kuipers et al (2009), there are myriad theoretical evidences which suggest that oral supplementation of Magnesium has an ability to cure Benzimidazole induced hypomagnesaemia.
Accordingly, the invention describes a combination of a therapeutically effective amount of at least one benzimidazole and a therapeutically effective amount of at least one dietary magnesium salt in a single dosage form.
For the purpose of this invention the term "benzimidazole" or "proton pump inhibitor" or "PPI" refers to Omeprazole (EP005129); Lansoprazole (EP174726); Pantoprazole (EP166287); Rabeprazole (EP268956) or any pharmaceutically acceptable salt thereof. The term also related to any enantiomer of aforementioned benzimidazoles or any pharmaceutically acceptable salts, solvates or polymorphs etc. thereof.
For the purpose of this invention the term "dietary Magnesium source" would include, but not limited to, chelates, complexes, salts or any therapeutically acceptable Magnesium sources etc. the dietary Magnesium source are preferably Magnesium salts.
For the purpose of this invention the term "Magnesium salt" would relate to Magnesium Oxide, Magnesium Chloride, Magnesium Hydroxide, Magnesium sulfate, Magnesium carbonate, Magnesium Citrate, Magnesium Lactate and any

other therapeutically acceptable salt or solvate of Magnesium which can be generally prescribed as source of dietary Magnesium, preferably Magnesium Oxide.
In an embodiment, the formulation of invention further comprises additional pharmaceutically acceptable excipients not limited to binders, fillers, tonicity agents and etcetera.
In an additional embodiment, the formulation for invention can be in administered as suspension, solution, syrup, powder for suspension, tablets, multiunit pellet system, capsules, granules etcetera or the combinations or variations of above formulations like tablet-in-capsules, mini-tablets, granules-in-capsule. Any of the formulations may be coated, if desired, using techniques known in art.
In optional embodiment, the formulation of the invention may also contain a sweetening agent, taste-masking agent, emulsifiers, tabletting aids, lubricants, anti-tacking agents and the like.
The formulation of invention can be manufactured by any of the known manufacturing techniques. The methods for preparation of such formulation would include, but are not limited to, granulation either wet or dry, extrusion-spheronization, drug-layering, slugging etc.

Mg-salts have been used by formulators as buffer or pH modifying agent at much lower quantities of the order of few milligrams. A higher quantity of Magnesium is required to be used as dietary supplement. Recommended Dietary Allowance of Magnesium is placed at an order of 420 mg/day for adult human males and 320 mg/day for adult human females, therefore each dose should contain around 200 mg of Magnesium Oxide. Since this quantity is well beyond what is conventionally used, it was imperative that an experimental verification be carried out to determine the robustness of the formulation.
In an embodiment of the invention, the pharmaceutical formulation contains a therapeutically effective amount of benzimidazole, and therapeutically effective amount of dietary Magnesium source. In the said formulation, said benzimidazole may be selected from omeprazole, lansoprazole, rabeprazole and pantoprazole.
In a specific embodiment, the dietary Magnesium source is an organic or inorganic Magnesium salt, preferably inorganic magnesium salt. The inorganic magnesium salt is, preferably, Magnesium Oxide.
The formulation of invention, optionally, further contains sweetening agent, taste-masking agent, emulsifiers, tabletting aids, lubricants, anti-tacking agents.
In an embodiment, the formulation may be devised in form of suspension, solution, syrup, powder for suspension, tablets, multiunit pellet system, capsules, granules

or combinations thereof, preferably the formulation is formulated in form of a suspension or powder for suspension.
In further embodiment, the invention provides a process for preparation of the formulation of invention.
EXAMPLES Experimental Data:
Experiments were carried out to determine the effect of Magnesium Oxide Concentration on the pH, owing to reason that benzimidazoles, are generally, unstable at acidic pH which is generally encountered in stomach and are stable at neutral to alkaline pH, preferably at a pH of 10.5. This pH is, in commercially available formulations, maintained by use of Sodium hydrogen carbonate (NaHCOj).
In below experiments the inventors have demonstrated that MgO on its own has a capacity to maintain the optimal pH. The experimental results are presented in Table 1.
Table 1:

S.No. Expt-1 Expt-2 Expt-3 Expt-4 Expt-5 Expt-6
Initial pH of acidic medium HC1 : 2.00 pH 2.00 pH 2.00 pH 2.00 pH 2.00 pH 2.00 pH 2.00 pH
Volume of acidic medium taken: 15ml 65ml 100ml 100ml 100ml 100ml

Quantity of API (E) taken: 20mg 20mg 20mg 40mg 40mg 40mg
Quantity of NaHC03 taken: 500mg 500mg 500mg 500mg 500mg -
Quantity of MgO(Light)taken: - - 200mg 200mg

Time (in min.) Expt-1 Expt-2 Expt-3 Expt-4 Expt-5 Expt-6
pH values
5 7.8 8.05 7.82 7.19 9.32 10.28
10 7.88 8.1 7.9 7.21 9.68 10.34
J5 7.89 8.15 7.95 7,34 9.75 10,36
30 7.9 8.19 8.08 7.87 9.88 10.38
45 8.02 8.25 8.17 7.97 10 10.39
Observations:
1. Presence of 500mg of NaHC03 with differing volume of acid (Expt 1-3) does not have a significant change in the pH values over a specified time interval. The pH range maintained is between 7 and 8. Although there is neutralization pH maintained is more towards neutral environment.
2. In Expt-4 also increase in API quantity does not affect the pH window.
3. In Expt-5 addition of MgO does have an effect on the pH value. In presence of both NaHC03 500mg and MgO 200mg the pH shift is more towards the alkaline values.
4. In Expt-6 addition of MgO 200mg alone maintains the pH range of 10 to 10.5.
5. In all the examples irrespective of the alkalizer used pH is being maintained in the required neutral to alkaline range over a time period of 45 minutes.

Conclusion:
Since most of the PPI's are stable in a neutral to alkaline environment the above experiments would serve as a measure for addition of the alkaline agent namely NaHC03 and MgO either used alone or in a combination.
The invention will now be described by reference to the following examples, in Table 2 which are merely illustrative and are not to be construed as a limitation of the scope of the present invention Table 2 :

Ingredients Composition

1 2 3
Esomeprazole Magnesium 23.64 23.64 23.64
Sucralose 200.00 300.00 200.00
Sucrose 847.43 599.26 —
PG Sugar ~ — 847.43
Magnesium oxide 200.00 200.00 200.00
NaHC03 — 1000.00 —
Xanthan gum 5.00 3.00 5.00
Titanium dioxide 0.50 0.10 0.50
Flavour 4.00 2.0 4.0
Mannitol 847.43 ~
Total 2128.00 2128.00 2128.00

Procedure:
1. Weigh the ingredients through specified sieves.
2. Sift the ingredients through specified sieves.
3. Mix to form a homogeneous blend.
4. Dispense in sachets.

We Claim,
1. A pharmaceutical formulation for treatment of benzimidazole induced
hypomagnesaemia comprising
a. a therapeutically effective quantity of Benzimidazole, and
b. a therapeutically effective quantity of dietary Magnesium source.
2. The pharmaceutical formulation of Claim 1, wherein the benzimidazole is selected form omeprazole, lansoprazole, rabeprazole and pantoprazole.
3. The pharmaceutical formulation of Claim 1, wherein the dietary Magnesium source is a Magnesium salt.
4. The pharmaceutical formulation of Claims 1 and 3, wherein the Magnesium salt is organic or inorganic.
5. The pharmaceutical formulation of Claim 4, wherein the Magnesium salt is an inorganic salt.
6. The pharmaceutical formulation of Claim 6, wherein the inorganic Magnesium salt is Magnesium Oxide.
7. The pharmaceutical formulation of Claim 1, wherein the formulation further optionally comprises pharmaceutically acceptable and compatible sweetening agent, taste-masking agent, emulsifiers, tabletting aids, lubricants, anti-tacking agents.

8. The pharmaceutical formulation of Claim 1, wherein the formulation can be formulated in form of suspension, solution, syrup, powder for suspension, tablets, multiunit pellet system, capsules, granules or combinations thereof.
9. The pharmaceutical formulation of Claim 8, wherein the formulation is in form of a suspension or powder for suspension.
10. The process for preparation of pharmaceutical formulation of Claim 1.