FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"GASTRO-RETENTIVE DELIVERY OF MINERALS AND NUTRACEUTICALS"
2. APPLICANT (S):
(a) NAME: FDC Limited


(b)NATIONALITY: Indian company incorporated under the Companies Act 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.


Field of Invention:
The present invention relates to a novel pharmaceutical composition in the form of oral dosage form comprising the mineral (s) alone or in combination with vitamins and other nutraceuticals, wherein the delivery of minerals and nutraceutical substances is in gastrointestinal tract preferably at the site of absorption.
Background of the invention:
The minerals are a large class of nutrients, which are essential for versatile physiological functions. Minerals are classified into three categories such as macro minerals, microminerals and ultra trace elements, depending upon the quantity required for physiological and biochemical functions. A wide variety of minerals are essential for normal physiological functions, it includes but not restricted to iron, calcium, zinc, iodine, manganese, molybdenum, selenium, phosphorus, boron, nickel, lithium, antimony, sodium, potassium, chromium, magnesium, aluminum and lead.
Iron, an important mineral has diverse biological functions. This diverse biological function of Iron accounts for the wide ranging physiological imperfection. This imperfection is mainly due to Iron deficiency which commonly remains unrecognized. There are reports which indicate that most of maternal deaths are attributed to anaemia. Iron deficiency leads to lethargy, weakness, neuro-chemical abnormalities, impairment in learning ability. Calcium is the main constituent of hydroxyapatite, the principle mineral in bone and teeth. Calcium also plays an essential role in intracellular signaling and is therefore necessary for nerve and muscle function and blood clotting. Magnesium is present in all tissues including bones. It is required for normal energy metabolism and electrolyte balance. It is also needed for muscle and for bone and tooth structure. Although deficiencies of magnesium are rare, almost 20% of boys aged 11-14 years are at risk of lower intakes. Phosphorous is present in all plant and animal cells. 80% of phosphorous is present as a calcium salt in skeleton. Phosphorous is essential for bone and tooth structure, construction of cell membrane and energy metabolism. Sodium helps regulate body water content and electrolyte balance and is involved in energy utilization. Potassium is predominantly found in body fluids. The essential role of potassium is to maintain the water and electrolyte balance and proper functioning of cells especially nerves. Zinc is one of the important mineral that our body needs on a daily basis to


function normally, it contained mainly in bones, teeth, hair, skin, liver, muscle, leukocytes, and testes.
Molybdenum is involved in many enzyme processes, nerve function and protein metabolism. It is an essential constituent of two enzymes found in humans: xanthine oxidase, which is involved in uric acid formation and aldehyde oxidase which catalyzes the chemical oxidation of aldehydes. Selenium is associated with antioxidant properties and fat metabolism. It is important in body's continuing fight against cell damage caused by free radical. Manganese is important for growth, reproduction, formation of bones, and carbohydrate metabolism. Manganese aids in the metabolism of food, normal functioning of the nervous system, in the formation of the thyroxine hormone for the thyroid gland, and in the production of sex hormones. Manganese works as an antioxidant to help prevent cancer and heart disease. Chromium is an essential trace mineral that the body needs to grow properly and remain healthy. It is required during several biochemical reactions within the cells. It is important in the burning of carbohydrates and fats in the body, thus regulating blood glucose.
Almost all the minerals have their own physiological functions; if the quantity of minerals exceeds or reduces in body, it may lead to pathogenesis of diseases and cause severe damage to the body.
Dietary factors play an important role in the development of mineral deficiency. Although most habitually consumed diet contains adequate amount of minerals, absorption of minerals from diet sources are limited. Most of the minerals are absorbed in ionic state and hence the elements that remain bound to organic/inorganic molecules are not well absorbed. The fraction of ions absorbed at the mucosal surface, should undergo transportation from serosal membrane to blood. Though ions get better absorbed from small intestine, the large number of factors such as ionic charge, protein binding, ion-ion interaction, chelation with food etc determines the rate and extent of mineral absorption.
WO 2006/068729 describes the methods and composition for enhancing iron absorption. The said composition comprising one immediate release iron component and another iron component for controlled release profile. The method consists of vitamin C as an


absorption enhancer for iron but absorption enhancement for folic acid, vitamin B12 and other nutraceuticals and minerals has not been discussed.
US patent No 6521247 relates to nutraceuticals supplement which comprises two different iron compounds namely rapid dissolving iron compound and slow dissolving iron compound. The tablet is particularly used for the treatment of diseases and disorders associated with iron deficiency.
US patent application 20060134227 discusses the composition of nutritional or dietary supplement that promotes dietary iron absorption by co-administration of iron with organic acids. However, these formulations describes only the enhancement of iron absorption but not related with other minerals. It is therefore, essential to develop a system, which preferably improves the extent and reduce the rate of absorption of other minerals also.
US patent application No 20030190355 directed to the composition and method for enhancement of iron uptake by enhancing rate and extent of dissolution of iron components. The composition contains iron-providing materials which are released in gastrointestinal tract over a period of upto 24 h, but iron absorption is not uniform throughout gastrointestinal tract. Moreover, the maximum amount of iron gets absorbed in the proximal part of gastrointestinal tract. Release of iron in the distal parts of Gastrointestinal tract lead to lack of availability of drug release at the absorption site and hence provide inferior bioavailability. Gastroretentive drug delivery system for iron salts not only improve the iron absorption by slowly releasing iron at the site of the absorption but also avoids super saturation of iron at the site of the absorption.
Pharmaceutical compositions and method for preparation of tablets, capsules, medicated granules and oral solutions, used as nutritional supplements comprising of vital minerals and nutraceuticals such as oil soluble vitamins, water soluble vitamins and minerals such as zinc, selenium, iron and folic acid are known in the prior art, but bioavailability of minerals and nutraceuticals substances from said formulations have not been described and found to be rate limiting steps for its clinical efficacy.


Most of the mineral preparations available in market have been reported with poor and incomplete absorption and bioavailability and hence lead to clinical failure. In some cases such as iron therapy, administration of minerals results in adverse drug reaction such as constipation, loss of appetite, nausea, vomiting and metallic taste.
The design and development of therapeutically successful dosage forms for minerals is a challenging task and requires sound scientific justification. In past, variety of dosage forms have been developed to improve the bioavailability and therapeutic efficacy of minerals. However, only few systems are reported with desirable properties- Therefore, the present invention directed to the development of a novel system, which can improve the bioavailability of minerals by using technologies such as gastroretentive delivery systems, bio-adhesive systems, short term sustained release drug delivery systems, intestinal drug targeting, delayed immediate release system and delayed controlled release systems.
There is an urgent need to develop the formulation, which releases the nutraceuticals and minerals for the prolonged period of time at the site of absorption. The present invention relates to a novel pharmaceutical composition in the form of oral dosage form comprising the mineral (s) alone or in combination with vitamins and other nutraceuticals, wherein the delivery of minerals and nutraceutical substances is in gastro intestinal tract, preferably at the site of absorption with improved bioavailability.
Objective of the invention:
The primary objective of the present invention is to design a novel oral drug delivery system of mineral(s) alone or in combination with vitamins and nutraceuticals.
Further objective of the invention is to provide drug delivery system which releases said nutrients in controlled manner and also releases nutraceutical substances at the site of absorption.
Another objective of the present invention is to provide drug delivery system which not only improves absorption of nutraceuticals but also reduces side effects and toxicity.


Yet another objective of the present invention is to provide the drug release in proximal part of gastrointestinal tract using any one or combination of the systems such as gastroretentive delivery systems, bio-adhesive systems, short term sustained release drug delivery systems, intestinal drug targeting, delayed immediate release systems and delayed controlled release systems.
It is an objective of the invention that the proposed drug delivery system belongs to any one or more solid oral dosage forms with dosing frequency of either once daily or twice daily administration.
Summary of the invention:
The present invention relates to a novel pharmaceutical composition in the form of oral dosage form comprising the mineral (s) alone or in combination with vitamins and other nutraceuticals, wherein the delivery of nutraceutical substances is in gastro intestinal tract preferably at the site of absorption.
Detailed description of the invention:
The present invention describes controlled delivery of mineral(s) alone or in combination with vitamins and nutraceuticals by using one or more technologies, including but not limited to gastroretentive delivery system, bio-adhesive system, delayed release system or short term sustained release system.
Gastroretentive drug delivery systems are designed to improve the gastric residence time of drug and/or dosage form and hence increase the contact time of the drug at the site of absorption. Drugs with intermittent half life, which are having good absorption in proximal part of gastroretentive tract are ideal candidates for development of gastroretentive dosage forms. A wide variety of approaches are available to fabricate the gastroretentive drug delivery system as follows
• Bio-adhesive drug delivery systems
• Floating drug delivery systems
• High density drug delivery systems
• Expandable drug delivery systems
• Short term sustained release systems


The above mentioned technologies have been extensively used to design single oral unit dosage forms which include tablets, pellets, capsules, powders, granules and films, multi layer tablets like bi and tri layer, and multi particulate systems like mini pellets, beads, mini tablets. The present invention relates to the development of gastro retentive delivery system using the above mentioned approaches with mineral (s) alone or in combination with vitamins and other nutraceuticals.
Examples:
Example 1

Sodium Feredetate 231mg
Cyanocobalamin 0.015mg
Folic acid 1.5mg
Carbopol l00mg
Microcrystalline Cellulose 47 mg
Magnesium Stearate 4mg
Colloidal silicon dioxide 2mg
Accurate weighed quantities of active and inactive ingredients except magnesium stearate and colloidal silicon dioxide are pass through ASTM sieve no 30. The powder blend was granulated using IPA as a wet granulating liquid by rapid mixture granulator for 30 mins. The obtained wet mass was sieved through ASTM sieve no. 8 and air dried at 55°C for 1 hr. dried granules are sized by using ASTM sieve no. 30 and fines were collected. Fines were geometrically mixed with folic acid, cyanocobalamin and colloidal silicon dioxide. The obtained fine mass was mixed with the granules. Granules were lubricated with magnesium stearate and compressed using 12mm punches.


Example 2

Active Layer
Sodium Feredetate 231mg
Cyanocobalamin 0.015mg
Folic acid 1-5mg
Hydroxypropyl methylcellulose 40 mg
Macrocrystalline Cellulose 83 mg
Magnesium Stearate 6mg
Colloidal silicon dioxide 4mg
Bioadhesive layer
Sodium CMC 80 mg
Carbopol 40 mg
Lactose 75 mg
Magnesium stearate 3mg
Colloidal silicondioxide 2mg
Accurate weighed quantities of active and inactive ingredients except magnesium stearate and colloidal silicon dioxide are pass through ASTM sieve no 30. The powder blend was granulated using IPA as a wet granulating liquid by rapid mixture granulator for 30mins. The obtained wet mass was sieved through ASTM sieve no. 8 and air dried at 55°C for 1 hr. dried granules are sized by using ASTM sieve no. 30 and fines were collected. Fines were geometrically mixed with folic acid, cyanocobalamin and colloidal silicon dioxide. The obtained fine mass was mixed with the granules. Granules were lubricated with magnesium stearate and compressed Bioadhesive layer.
Accurately weighed quantities of sodium CMC and carbopol were sieved through ASTM sieve no. 60. Accurately weighed quantities of lactose and colloidal silicon dioxide were sieved through ASTM sieve no. 30. Both the powder blend were mixed using planatory mixer for the period of 30mins. The obtained powdered blend was lubricated with required quantity of magnesium stearate and compressed.


Blend of active and bioadhesive layers has been compressed using bilayer tablet compression machine. The targeted compression force and hardness of both layers was maintained. Prepared tablets were evaluated for its pharmaceutical characterization such as hardness, weight variation, thickness, content uniformality, and invitro dissolution and exvivo bioadhesive strength.

Dr. P. Aruna Sree
Agent for the Applicant