FIELD OF INVENTION:

The present invention generally relates to pharmaceutical compositions. More particularly, the present invention relates to a pharmaceutical composition to increase the bioavailability of iron and calcium by coating with a mucoadhesive polymer.

BACKGROUND OF THE INVENTION:

Iron is the most important mineral in our body as iron form complexes with molecular oxygen in haemoglobin which is a common oxygen transporter. Although, in the general population, a healthy balanced diet should largely obviate the need for vitamin and mineral supplementation, pregnancy and lactation create extra nutritional demands which make supplementation advisable. Expansion in red cell volume, increased demands of the developing foetus and placenta and blood loss during delivery are few of the reasons for the increased occurrence of anaemia among pregnant women. Iron supplementation is generally recommended for women at particular risk of iron deficiency. There are many oral compositions available to meet the need of iron. And most of the existing oral preparations containing iron show poor bioavailability and side effects leading to discontinuation of therapy. Common adverse drug reactions found with the conventional preparations are mainly gastrointestinal intolerance like nausea, vomiting, constipation, diarrhoea, epigastric pain etc. Discontinuation rates of therapy are high due to the above mentioned side effects and unpleasant taste of some oral iron preparations. Most of these side effects are attributed to the fraction of iron that remains unabsorbed following ingestion and remains localised in the intestinal lumen.

Iron shows good solubility at acidic pH of the stomach. Dietary Iron is converted in to ionic Fe + ready for absorption at acidic pH of the stomach. Amount of dietary non-haem iron converting to ionic iron increases with increase in gastric residence time of the food. Numerous studies have conclusively demonstrated that iron absorption is more efficient in the duodenal and proximal segments than in the distal segment of the small intestine due to large number of transferrin receptors found in duodenum. Most of the ionic iron is absorbed from the duodenum by transferrin receptor mediated endocytosis. Once they cross duodenum the absorbable ferric or ferrous form of iron is hydrolysed, due to higher pH at post-duodenal small intestine, to form insoluble ferric hydroxide. Insoluble iron forms do not show any absorption. Some authors have attributed these side-effects to the irritation of the GI mucosa by the catalysis of free radicals from non-transferrin bound free iron.

Calcium is another mineral which is essential for a pregnant woman. A Cochrane systematic review has reported the benefit of calcium supplementation during pregnancy in reducing the incidence of hypertensive disorders and preterm labour. The effect on pre-eclampsia is greater for women with low baseline calcium intake. Here, arises a salient need for an external supplement in the form of a pharmaceutical composition. Calcium deficiency due to inadequate intake of calcium or its poor intestinal absorption also causes osteoporosis and other skeletal diseases.

Calcium oral preparations do not show any side effects but has low bioavailability. Calcium which is present in food is in the form of a complex with other dietary constituents. First these complexes has to be broken down and then calcium is released in a soluble and ionised form, which is absorbed into the body. The solubility of calcium complexes is increased by the presence of gastric juice. In the duodenum and upper jejunum, calcium is mainly absorbed by an active vitamin D dependent transcellular process whereas in the ileum the dominant process is vitamin D independent paracellular diffusion. Absorption by the other parts of the intestine is almost nil, mainly due to the precipitation of calcium due to the alkalinity produced by the bile.

There are many methods discussed in existing art for increasing the absorption of nutrients.
United States Patent Publication Number 20080193531 to Marc S. Hermelin et a/.entitled "compositions for improving gastrointestinal nutrient and drug absorption" relates to compositions and methods for improving the absorption of nutrients and/or drugs in the gastrointestinal tract of a subject. Here, proton pump inhibitor is used to increase the pH that might have an impact on bioavailability of iron. Since PPIs (Proton Pump Inhibitor) significantly increases the pH for a long period of time (i.e.) throughout day which might negatively impact the bioavailability of iron in the duodenum. It may prolong the time required to treat iron deficiency including side effects like constipation.

WIPO Patent Publication Number 2008127669 to Claire Dulieu et al. entitled "Bilayer lyophilized pharmaceutical compositions and methods of making and using same" relates to a bilayer lyophilized pharmaceutical composition aimed for oral, transoral or transmucosal absorption in bucal region.

United States Patent Publication Number 20090004281 to Tien Nghiem et al entitled "multiparticulate osmotic delivery system" relates to a multiparticulate osmotic delivery system for a modified release of at least one drug. The composition includes a core that includes at least one drug in combination with at least one pharmaceutically acceptable recipient. The composition further includes an osmotic subcoat surrounding the core, and a modified release overcoat surrounding the osmotic subcoated core.
United States Patent Number 8,734,855 to Guosong Liu et al. entitled "Slow release magnesium composition and uses thereof" relates to compositions that contain magnesium and threonate, or a threonate precursor molecule, formulated for extended or modified release to provide physiological concentrations over a desired time period.

WIPO Patent Publication Number 2012093980 to Mahmut Bilgic entitled "Improved risedronate formulation" relates to highly bioavailable formulations comprising risedronate and/or a pharmaceutically suitable derivative for prevention and treatment of bone loss and diseases associated with bone loss.

Though the existing prior art discuss about improving the bioavailability of nutrients supplementation, these compositions stay in the duodenum for short period of time leading to poor bioavailability and may give side effects resulting in discontinuation of therapy. To overcome the short comings of the existing prior art, the present invention provides a pharmaceutical composition in oral form in a sachet which provides enhanced bioavailable iron and calcium to human body by coating the mineral particles with a polymer having mucoadhesion property.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a pharmaceutical composition to increase the bioavailability of iron and calcium which is provided in oral dosage forms.

The present invention provides an instant orange juice powder in a sachet fortified with more bioavailable, safe and targeted delivery of iron and calcium in the form of mucoadhesive microparticles in pregnant women, growing children and elderly men and women. The iron and calcium particles are coated with a mucoadhesive polymer using coating techniques such as spray drying, solvent evaporation technique and coacervation methods. The polymer improves the absorption of iron and calcium as it increases the residence time at the site of highest absorption as the formulation has the mucoadhesive property.

In one embodiment of the present invention, the mucoadhesive polymer coated iron and calcium microparticles are incorporated in instant orange juice powder along with ascorbic acid, vitamin D and folic acid in a sachet.
In another embodiment of the present invention, the mucoadhesive polymer coated iron and calcium microparticles are incorporated in instant orange juice powder along with ascorbic acid and vitamin D in a sachet.

In yet another embodiment of the present invention, the mucoadhesive polymer coated iron microparticles are incorporated in instant orange juice powder along with ascorbic acid and folic acid in a sachet.

In still another embodiment of the present invention, the mucoadhesive polymer coated iron microparticles are incorporated in instant orange juice powder along with ascorbic acid in a sachet.

In still another embodiment of the present invention, the mucoadhesive polymer coated calcium microparticles are incorporated in instant orange juice powder along with Vitamin D and Folic acid in a sachet.

In still another embodiment of the present invention, the mucoadhesive polymer coated calcium microparticles are incorporated in instant orange juice powder along with Vitamin D in a sachet.
The objectives and advantages of the present invention will become more evident from the following detailed description when taken in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS:

The objective of the present invention will now be described in more detail with reference to the accompanying drawings, in which:

FIG. 1 shows Scanning Electron Microscopy (SEM) image of iron microspheres;

FIG. 2 shows Scanning Electron Microscopy (SEM) image of calcium microspheres; and

FIG. 3 shows adhesion profiles of mucoadhesive polymer coated iron and calcium microparticles.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to pharmaceutical compositions and oral dosage forms of iron and calcium. The composition provides increased bioavailability of iron and calcium. The present invention is mainly developed with an idea to overcome the extra nutritional demands that occur during pregnancy and lactation.

According to the present invention, the iron and calcium particles are coated with a mucoadhesive polymer using coating techniques such as spray drying, solvent evaporation technique and coacervation methods, wherein the mucoadhesive polymer improves the absorption of iron and calcium as its mucoadhesive property helps to retain the particles in the duodenum for increased absorption. Mucoadhesion is the state in which two materials, at least one biological in nature, are held together for an extended period of time by interfacial forces. It is also defined as the ability of a synthetic or biological material to adhere to a biological tissue for an extended period of time.
In an embodiment of the present invention, the mucoadhesive polymer coated iron and calcium microparticles are incorporated in instant orange juice powder along with ascorbic acid, vitamin D and folic acid in a sachet. Incorporation of the ascorbic acid improves the solubility of non-haem iron by promoting acid conditions in the stomach, improving the solubility of iron; reducing solubilised ferric iron (Fe3+) to ferrous iron (Fe +), making it unavailable to form insoluble ferric hydroxides which are not absorbed; and combining with iron to form a soluble complex, which is maintained in the alkaline environment of the small intestine aiding transport across the mucosal membrane.

In another embodiment of the present invention, the mucoadhesive polymer coated iron and calcium microparticles are incorporated in instant orange juice powder along with ascorbic acid and vitamin D in a sachet.

In yet another embodiment of the present invention, the mucoadhesive polymer coated iron microparticles are incorporated in instant orange juice powder along with ascorbic acid and folic acid in a sachet.
In still another embodiment of the present invention, the mucoadhesive polymer coated iron microparticles are incorporated in instant orange juice powder along with ascorbic acid in a sachet.
In still another embodiment of the present invention, the mucoadhesive polymer coated calcium microparticles are incorporated in instant orange juice powder along with Vitamin D and Folic acid in a sachet.

In still another embodiment of the present invention, the mucoadhesive polymer coated calcium microparticles are incorporated in instant orange juice powder along with Vitamin D in a sachet.

In still another embodiment of the present invention, the iron particle used is a ferrous salt of iron selected from a group consisting of carbonyl iron, ferrous sulphate, ferrous bisglycinate, ferrous gluconate, ferrous fumarate and ferrous carbonate ferrous succinate, which has a particle size of 0.1 to 100 urn. It is further coated with mucoadhesive polymers from a group consisting of polyacrylic acid, chitosan, poly carbomer, methylcellulose, ethylcellulose, hydroxylpropyl cellulose, hydroxy propyl methylcellulose, sodium carboxy methylcellulose, carbomers, polycarbophil, poly (hydroxyethyl methylacrylate), poly (ethylene oxide), poly (vinyl pyrrolidone), poly (vinyl alcohol), tragacanth, sodium alginate, karaya gum, guar gum, xanthan gum, lectin, soluble starch, gelatin, pectin and chitosan, using spray drying technique to form coated microparticles. The microparticles are also coated using other coating techniques. These polymers are having mucoadhesive property. Mucoadhesive coating retains the microparticles in the acidic environment of the stomach. Increasing gastric residence time increases gastric absorption of iron from the duodenum. Further ascorbic acid is added along with the mucoadhesive polymer coated iron particles so as to increase the solubility of non-haem iron. Ascorbic acid promotes the acid condition in the stomach that increases the solubility of iron. Ferric iron (Fe3+) is reduced to ferrous iron (Fe2+), making it unavailable to form insoluble ferric hydroxides which are not absorbed. Ferrous iron combined with iron to form a soluble complex, which is maintained in the alkaline environment of the small intestine aiding transport across the mucosal membrane.
In still another embodiment of the present invention, the calcium particle used is selected from a group consisting of calcium citrate malate, calcium oxalate, tri calcium phosphate, calcium citrate, calcium citrate, calcium lactate, calcium carbonate, calcium phosphate, calcium lactate citrate, calcium gluconate, calcium bis-glycinate and calcium lactate malate which has a particle size of 0.1 to 100 urn, that is coated with the mucoadhesive polymers such as polyacrylic acid, chitosan, poly carbomer, methylcellulose, ethylcellulose, hydroxyl propyl cellulose, hydroxy propyl methylcellulose, sodium carboxy methylcellulose, carbomers, polycarbophil, poly (hydroxyethyl methylacrylate), poly (ethylene oxide), poly (vinyl pyrrolidone), poly (vinyl alcohol), tragacanth, sodium alginate, karaya gum, guar gum, xanthan gum, lectin, soluble starch, gelatin, pectin and chitosan. Coating of mucoadhesive polymers forms microencapsulated calcium particles that increases the gastric retention. Slowly calcium particles owing to its solubility in acidic media dissolves and releases from the polymer matrix coating by diffusion. Increasing gastric residence time increases gastric absorption of calcium. Further, the incorporation of vitamin D increases the absorption of calcium from duodenum.
In still another embodiment of the present invention, orange juice flavoured iron and calcium are to be consumed as a powder without water. This will further enhances the mucoadhesion resulting in better bioavailability.

In still another embodiment, other flavours such as vanilla, chocolate, coffee, cocoa, citrus oil, including lemon, orange, grape, lime, grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth can also be used.

In still another embodiment of the present invention, to complement the addition of ascorbic acid, the composition containing iron particles is presented in the form of instant powder in the sachet. As powders show more stability and ease of handling and ambient storage unlike liquid canned or packed juices.

After the preparation, the particles were characterised using scanning electron microscopy. The mucoadhesion properties of the coated particles were compared with that of free particles. Mucoadhesion test provides information on how long the particles are going to stay adhered to the mucosa. If the coated particles are going to be more adherent; the absorption of the particle is going to be more and hence less side effects.

The invention is further demonstrated by the following illustrative examples.
Example 1:

Preparation of micro particles:
The present invention is about coating iron and calcium particles with mucoadhesive polymers. Ferrous sulphate is dissolved in 5 mL of water and 1500 mg of the polymer HPMC is dissolved in 20 mL of chloroform. These two solutions are mixed to form a primary emulsion using a probe sonicator. The primary emulsion is injected into 90 mL of liquid paraffin and 10 mL of n-hexane at room temperature to form micro particles. These microspheres floating in the solvent are collected by decantation. These microspheres are dried overnight and kept for lyophilisation for 24 hrs.
Example 2
Preparation of micro particles by Coacervation:

0.4 g of HPMC is dissolved in 10 mL of isopropanol. 0.133 g of calcium carbonate is also added in small quantities to the polymer solution. The solution is stirred well using magnetic stirrer at a temperature of 40 C. Isopropanol is added in small quantities upto 45 mL and the temperature is raised from 40 C-85 C. Stirring is continued and the temperature is reduced to room temperature. 45 mL of a non solvent (PEG) is added in successive doses. And the curing agent is added to the solution at an amount of 100-125 mL in every 30 minutes for 6 times under mechanical agitation at an rpm of 1200. Microspheres were cured by stirring at a temperature less than 25 C for 2 to 4 hours. The solution was kept for settling and the micorparticles were obtained after decanting and kept for lyophilisation for 24 hours.

FIG.l and FIG. 2 illustrate the Scanning Electron Microscopy (SEM) of iron and calcium microspheres respectively. The prepared iron microspheres are spherical particles of approximately about 1178 Jim size. The calcium microspheres produced are slightly clustered in appearance, but contains uniformly distributed spherical particles of approximately 20 Jim. The mucadhesion property of iron and calcium particles is compared with iron and calcium coated with mucoadhesive polymer, using a known technique.

The mucoadhesion test has been conducted as follows. Around 0.5 grams of hot agar and 0.1 gram of mucin solution in phosphate buffer has been cast on a glass plate and left to gel at 4 C for 3 hours. The iron/calcium microparticles and iron/calcium coated with a mucoadhesive polymer were placed on top of the gel and they started moving downward after keeping the glass slide in a vertical position. The displacement in cm was measured and is inversely proportional to the adhesion potential. As prepared iron/caclium particles coated with the polymer HPMC has been compared with that of free iron/calcium particles for mucoadhesion properties.

Referring to FIG. 3 shows large displacement for ferrous sulphate. In the first hour itself ferrous sulphate particles have started moving and by seventh hour it is reaching the maximum displacement. As compared to ferrous sulphate, mucoadhesive polymer coated micro particles of ferrous sulphate started to move by second hour and it is reaching a small displacement of 1.5 cm by nine hours. For mucoahdesive polymer coated calcium micorparticles, there was no displacement observed even after nine hours.

While the foregoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof, those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiment, method, and examples herein. The invention should therefore not be limited by the above described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention as claimed.

CLAIM:

1. An oral pharmaceutical composition for improving bioavailability of iron and calcium microparticles, the composition comprising: mucoadhesive polymer coated iron and calcium microparticles, and optionally, comprising at least one nutrient selected from the group consisting of ascorbic acid, vitamin D, folic acid or any combination thereof.

2. The composition according to claim 1, wherein said iron has a particle size of about 0.1 to 1500 urn.

3. The composition according to claim 1, wherein said calcium has a particle size of about 0.1 to 100 urn.

4. The composition according to claim 1, wherein said iron particle is selected from a group consisting of carbonyl iron, ferrous sulphate, ferrous bisglycinate, ferrous gluconate, ferrous fumarate, ferrous carbonate and ferrous succinate.

5. The composition according to claim 1, wherein said calcium particle is selected from a group consisting of calcium citrate malate, calcium oxalate, tri calcium phosphate, calcium citrate, calcium lactate, calcium carbonate, calcium phosphate, calcium lactate citrate, calcium gluconate, calcium bis-glycinate and calcium lactate malate.

6. The composition according to claim 1, wherein said mucoadhesive polymer is selected from a group consisting of polyacrylic acid, chitosan, poly carbomer, methylcellulose, ethylcellulose, hydroxyl propyl cellulose, hydroxy propyl methylcellulose, sodium carboxy methylcellulose, carbomers, polycarbophil, poly (hydroxyethyl methylacrylate), poly (ethylene oxide), poly (vinyl pyrrolidone), poly (vinyl alcohol), tragacanth, sodium alginate, Karaya gum, guar gum, xanthan gum, lectin, soluble starch, gelatin, pectin and chitosan.

7. The composition according to claim 1, further comprises a flavor base.

8. The composition according to claim 7, wherein said flavor is orange.

9. The composition according to claim 7, wherein said flavor is selected from a group consisting of vanilla, chocolate, coffee, cocoa, citrus oil, lemon, orange, grape, lime, grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple and apricot.

10. The composition according to claim 1, is in the form of a sachet.

11. The composition according to claim 1, is formulated into an oral preparation for consuming without water.