FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
MODIFIED RELEASE COMPOSITION OF WATER SOLUBLE VITAMINS AND A PROCESS FOR ITS PREPARATION
OMNIACTIVE HEALTH TECHNOLOGIES LTD., an Indian Company, registered under the Indian Companies Act, 1956 having its registered office located at Rajan House, Appasaheb Marathe Marg, Prabhadevi,
Maharashtra, India 400025
The following specification particularly describes the invention and the manner in
which it is to be performed

Field of the invention:
The present invention relates to a modified release composition of water soluble vitamins and a process for its preparation. More particularly, the present invention provides an oral modified release composition containing Ascorbic acid, vegetable oil, non-swelling release retardant and optionally swelling release retardant, binders, fillers, lubricants which release at least 70% of Ascorbic acid in 6-10 hours and at least 80% in 8-12 hours. The composition is prepared in the form of granules, tablets, pellets, powder or capsules and is suitable for direct application as dietary supplements in the foodstuffs, pharmaceutical and commodities. This characteristic of the composition imparts high value addition for providing modified release dietary supplement for the wellbeing of healthy population in significantly cost-effective manner.
Background of the invention
Ascorbic acid, also known as Vitamin C, is a very important water-soluble vitamin. It is essential for preserving optimal health and it is used by the body for many purposes. Vitamin C promotes collagen biosynthesis, provides photo protection, causes melanin reduction, enhances the immunity (anti-virus effect), etc. Vitamin C is a highly effective antioxidant. Even in small amounts Vitamin C can protect indispensible molecules in the body, such as proteins, lipids (fats), carbohydrates, and nucleic acids (DNA and RNA) from damage by free radicals and reactive oxygen species that can be generated during normal metabolism as well as through exposure to toxins and pollutants. (Handbook of Vitamin C research: daily requirements, dietary sources and adverse effects 2009 PP. 185-211).
Ascorbic acid is an electron donor for enzymes involved in collagen hydroxylation, biosynthesis of carnitine and nor-epinephrine, tyrosine metabolism, and amidation of peptide hormones. Ascorbic acid (vitamin C) deficiency causes scurvy. The ability of vitamin C to donate electrons also makes it a potent water-soluble antioxidant that

readily scavenges free radicals such as molecular oxygen, superoxide, hydroxyl radical, and hypochlorous acid.
Ascorbic acid is a white solid and dissolves well in water to give mildly acidic solutions. In humans, an exogenous source of Ascorbic acid (vitamin c) is required for collagen formation and tissue repair. Ascorbic acid (vitamin c) is reversibly oxidized to dehydroascorbic acid (vitamin c) in the body. These two forms of the vitamin are believed to be important in oxidation-reduction reactions. This vitamin is involved in tyrosine metabolism, conversion of folic acid to folinic acid, carbohydrate metabolism, lipid synthesis, and proteins, iron metabolism, resistance to infections, and cellular respiration.
Ascorbic acid is an antioxidant needed for many different metabolic functions in the body, including repair and growth of tissue, healthy gums, and adrenal gland functions. However the body cannot manufacture vitamin C, and must be obtained from the diet or in the form of supplements.
The pharmacological study has shown that the absorption of Ascorbic acid depends on the amount of dietary intake. Dietary intake of 30 milligrams daily, results in the complete absorption of the Ascorbic acid from the lumen of the small intestine into the enterocytes. Maximum absorption of Ascorbic acid is attained by ingestion of several spaced doses throughout the day rather than by a single high dose. Further, modified-release composition gives better absorption than an equivalent dose that is immediately released. Intake of a single high dose of Ascorbic acid causes the body to reach its saturation stage delaying the further absorption which leads to the excretion of approximately 90% of the unabsorbed Ascorbic acid through urine. A time modified release composition of Ascorbic acid allows small amounts of Ascorbic acid to be released and utilized by the body over an extended period of time, allowing for more prolonged absorption. Modified release also minimizes stomach irritation in sensitive individuals. Emanual Cheraskin and his co-workers demonstrated that a sustained release multivitamin formulation enables large amount of Ascorbic acid to reach the

tissues than a non-sustained release formulation (Int J Vit Res 1969; 39: 407-415). Similarly, Taylor et al showed that the bioavailability of vitamin C (as ascorbate) was 50% higher in whole blood and 80% higher in plasma in a sustained release multivitamin (Int J Vit Nutr Res 1977; 467: 68-74).
Modified release formulations which provide for the uniform release of a medicament at a controlled rate over a desired extended period of time are of great benefit to both the patient and medical practitioner. Modified release of dietary supplements requires that the encapsulated material retain its biological activity or the activity of acceptable degradation products. Encapsulation of these molecules is commonly performed not only to retain and/or to slowly release them, but to provide a more stable environment for the encapsulated species.
Modified release composition offer numerous advantages compared to conventional dosage forms, which includes patient compliance, reduced dosing frequency, improved efficacy, better stability of the encapsulated substances, reduced toxicity, etc. Such systems often use macro molecules as carriers for the medicaments.
In view of the increasing research interest in the various health benefits of Ascorbic acid as can be seen above, there have been several approaches to commercially produce this vitamin. Numerous mechanisms have been employed for modified release formulations.
US3147187 discloses a composition in which biological active agent is dispersed within melt of water insoluble material or mixed with mixture of water insoluble and water soluble material. The said invention has limitation like the process melting of water insoluble material which may not be scalable and /or reproducible. Another disadvantage is that the heat sensitive ingredients are prone to degradation due to high temperature of molten mass.

US8034363 describes the method of preparation of modified release compositions of Ascorbic acid phosphate and absorbable polymers. In this application the novel controlled release compositions of Ascorbic acid phosphate (AZP) are prepared by drying AZP powder and melt blending the AZP powder with pre-dried biocompatible, absorbable aliphatic polyester polymer. The melt blended AZP/polymer composition may then be further melt processed into the form of the desired medical device or component including, but not limited to fibers, rods, screws, staples, suture anchors, films and the like.
US3062720 describes composition in which granules or tablets containing biological active agents are coated with water insoluble material such as wax or synthetic resin. This process is tedious, expensive and requires special equipment. Moreover for preparing this formulation, a special jacketed equipment or vessel is required for melting of waxes and this increases the cost as well as the number of steps involved and imparts high temperature and thus makes the manufacturing process more tedious and troublesome.
US7422758 discloses the therapeutic composition in the form of a beadlet which is suitable for oral administration and provides immediate and sustained release of therapeutic material. Beadlets are prepared by an Extruded-Spheronization method which comprises an inner core containing at least one medicament e.g. a slow release vitamin, an outer layer containing at least one medicament e.g. a fast release vitamin and a controlled release coating between the inner core and the outer layer which coating controls the release of the inner core medicament. Moreover for preparing this formulation, a special extruder-spheronizer is required and this increases both the cost and the number of steps, in the manufacturing process.
WO2007040997 relates to pharmaceutical dosage forms comprising: an absorption window active agent; a controlled release component comprising enteric-coated

controlled release beads, wherein the enteric-coated release beads comprise at least two pH- sensitive polymer layers. The controlled-release dosage forms provide good bioavailability of absorption window active agents. Current invention leads to high cost with tedious process and it might not be possible to get reproducible profile. The disadvantage of this technology is the use of very high cost equipments like fluidized bed processer equipped with bottom spray facility and the process is very complicated and tedious. Moreover using this process is expensive considering the cost of Ascorbic acid which itself is a commodity.
US20090181084 describes an oral fast-disintegrating tablet including tiny particles of slowly-releasable Ascorbic acid. The composition comprises of many tiny particles of Ascorbic acid, and fast-disintegrating ingredient of Ascorbic acid and other agents mixed with those tiny particles, which are dispersedly mixed with and surrounded by the fast-disintegrating ingredient. The polymers viz: Hydroxypropyl methyl cellulose phthalate and cellulose acetate phthalate are used in high proportion (i.e. 40-80%) which is not acceptable for manufacturing dietary supplements.
CN102579318 discloses a stable vitamin C sustained release preparation and a preparation method thereof. The vitamin C sustained release preparation comprises vitamin C, an antioxidant synergist and a metal ion chelating agent.
RU2008110884 provides a controlled release formulation of Vitamin C with reduced initial burst release, which comprises a combination of non-polymeric release retardant and pH independent non-swelling release retardants.
US6491948 discloses orally administered compositions comprising two redox systems: reduced Ascorbic acid in a sustained release form and oxidized isoquercetin with an increased concentration of reduced vitamin C over a prolonged time in the brain.

JP2000105 describes the composition of sustained release tablets free from variability of release rate affected by pH in digestive tube, enzyme, etc., and free from adhesion to mucosa of esophagus and digestive tube comprising a drug and fine water-insoluble cellulosic polymer.
CH668362 discloses a composition containing one or more active with one or more additive in which at least one additive being a swelling agent. The swelling agent is vegetable mucilage derived from Plantago ovata.
KR860002197 invention relates to compositions and processes for making suitable controlled release dosage compressed forms of biologically active agents such as drugs, nutrients, pesticides, other biocides and fragrances.
US6087393 discloses method of stabilizing free 1-ascorbic acid from oxidation by dispersing the free 1-ascorbic acid in a mixed glycol carrier and a solution containing the Ascorbic acid in the mixed glycol solution.
US7101563 relates to compositions of Ascorbic acid for topical application, this composition comprises pulverized L-ascorbic acid in a substantially non-aqueous carrier having a pH greater than that of skin, and preferably not less than approximately 5.5 and not greater than approximately 7.5.
US5750I23 describes the cosmetic composition in which Ascorbic acid (Vitamin C) is stabilized by dimethyl isosorbide in a pharmaceutically acceptable carrier. Among the preferred carriers are polyols such as polyethylene glycol, propylene glycol and mixtures thereof.
None of the above prior art discloses a simple, low cost and easy process for manufacturing modified release composition of Ascorbic acid. The process itself by

design should take care of stability aspect of the composition resulting in more uniform and prolonged-release of Ascorbic acid. Thus, there is a need to provide a novel modified release composition of Ascorbic acid and a method for manufacturing considering the various aspects,
Ascorbic acid has high water solubility and 70-90% of Ascorbic acid is absorbed by the body and metabolized by hepatic clearance. Some Ascorbic acid is metabolized to inactive compounds including Ascorbic acid-2-sulfate and oxalic acid. Due to high water solubility of Ascorbic acid (more than 1 mg/ ml of water), high dosing is recommended and this property makes this molecule un-suitable for the preparation of modified release compositions in low-weight dosage forms which can be easily swallowed by human beings. The available release retardants known in the prior art have particular disadvantage of usage in higher amount due to high water solubility of Ascorbic acid which results in higher weight dosage forms and thus poses difficulty in swallowing of higher weight and size tablets. The use of higher amount of conventional release retardants also has direct impact on increased cost of the dosage form.
Ascorbic acid is also a very unstable molecule and degradation starts upon exposure to air, light, heat, moisture, metal ions, oxygen, and base, and it easily decomposes into biologically inactive compounds such as 2,3-diketo-L-gulonic acid, oxalic acid, L-threonic acid, L-xylonic acid and L-lyxonic acid. This makes its use very limited in the field of pharmaceuticals, nutraceutical/dietary, dermatological and cosmetics.
From above, it is clear that presently there is a need in this art for a low weight, stable, cheaper and effective Ascorbic acid modified release composition using excipients approved for use in long term administration having E-number/ GRAS status that ensure safety of healthy human beings for long term administration. The reason for this situation is the high water solubility and instability of Ascorbic acid which makes it unsuitable for preparation of low-weight dosage forms which can be easily swallowed

by human beings. Commercial availability of such a cost effective and low weight dosage form would help in establishing the potential health benefits of Ascorbic acid as dietary supplements.
Based on the above needs and during experimentation, it was surprisingly found that the use of vegetable oil in the composition increases the stability of pulverized Ascorbic acid via coating on the surface of Ascorbic acid and thus makes it more hydrophobic and prevents moisture and oxygen uptake by Ascorbic acid. Therefore, vegetable oil used in the instant invention acts as an efficient protecting and retarding agent synergistically along with the non swelling and/or swelling release retardant.
The present invention particularly makes use of vegetable oils containing tocopherol. Tocopherol is a naturally occurring antioxidant which prevents oxidation of the molecules and increases the stability. Thus, use of vegetable oils containing tocopherol is useful for controlling the release of the active compound and protecting Ascorbic acid from degradation.
The term "pulverized" as used herein means reducing the particle size of Ascorbic acid by a know process or method of particle size reduction. For example, the pulverization of Ascorbic acid can be done by milling, grinding, micronization or other particle size reduction methods known in the art.
The instant invention uses pulverized Ascorbic acid having particle size D90 of less than 200 microns. The smaller particle size gives more uniform, consistent and reproducible release profile of Ascorbic acid when subjected to dissolution testing methods as described in compendial monographs e.g. USP, IP, BP, JP etc.

Objectives of the present invention
The main objective of the present invention is to provide an oral modified release composition of Ascorbic acid, in combination with vegetable oil, non-swelling and/ or swelling release retardant, which releases at least 70% of Ascorbic acid in 6-10 hours and at least 80% of Ascorbic acid in 8-12 hours.
Another objective of the present invention is to provide the desired controlled release dissolution profile in the dissolution media.
Yet another objective of the present invention is to provide modified release composition of pulverized Ascorbic acid with particle size D90 of less than 200 microns, comprising a combination of non-swelling and/or swelling release retardant along with vegetable oil and in the form of granules that can be directly compressed into suitable size tablets and/or can be directly filled into suitable size two piece capsules.
Still another objective of the present invention is to provide low-weight and size dosage forms which can be easily swallowed by human beings.
Yet another objective of the present invention is to provide a stable, cheaper and effective Ascorbic acid modified release composition using excipients approved for use in long term administration having E-number/ GRAS status that ensures safety of human beings for long term administration.
Still another objective of the present invention is to prepare the composition by using lesser amounts of conventional release retard ants.
Yet another objective of the present invention is to provide a process for the preparation of Ascorbic acid modified release composition.

Summary of the invention
The composition of the present invention is described herein below which is illustrative as shown in the examples and should not be construed to limit the scope of the present invention in any manner whatsoever.
Accordingly, the present invention provides an oral modified release composition which comprises:
a. Pulverized Ascorbic acid with particle size D90 of less than 200 microns;
b. at least one vegetable oil that contains natural tocopherol;
c. at least one non swelling release retardant; and
d. optionally swelling release retardants, binders, fillers, lubricants or mixture thereof.
The said composition is in the form of tablet, pellets, powder, capsule or granules characterized in that at least 70% of Ascorbic acid is released in 6-10 hours and at least 80% of Ascorbic acid in 8-12 hours.
The present invention also provides a process for the preparation of modified release composition of Ascorbic acid which comprises the following steps:
a. Mixing of Ascorbic acid and vegetable oil along with stabilizer and anti-caking
agent;
b. Melting of non-swellable release controlling agents and mixing of this melted
solution with a suitable binder in presence of a suitable organic solvent;
c. Granulation of the dry mix obtained in step 'a' by using solution of step 'b';
d. Drying the granules obtained in step 'c';
e. Sizing of the granules by passing through 20 mesh ASTM;
f. Blending of the granules of step 'e' with fillers and lubricants;
g. Compressing of the granules of step 'f into suitable size tablets using a suitable
tablet press;

h. Optionally filling of granules of step 'f 'into two piece hard gelatin capsules or into sachets.
Ascorbic acid used is in the range of 25% to 80% w/w of composition.
The stabilizer is selected from citric acid, tartaric acid, disodium EDTA or mixtures thereof, preferably citric acid.
The anti-caking agent is selected from magnesium stearate, colloidal silicon dioxide, talc, sodium stearyl fumarate or mixtures thereof, preferably colloidal silicon dioxide. The binders are selected from
The organic solvent is selected from isopropyl alcohol, ethyl alcohol, acetone or mixtures thereof, preferably isopropyl alcohol.
The fillers are selected from microcrystalline cellulose, starch, modified starch, lactose or mixtures thereof, preferably microcrystalline cellulose.
The lubricants are selected from magnesium stearate, colloidal silicon dioxide, talc, sodium stearyl fumarate or mixtures thereof, preferably magnesium stearate.
The vegetable oils used in the present invention are selected from Sunflower oil, Safflower Oil, Corn Oil, Almond oil, Palm oil, Soyabean oil, Wheat germ oils or mixtures thereof.
The term release retardant as used in this is any excipient that can retard the release of an active compound and includes polymers, waxes, fatty acids etc.

The term swelling release retardants used in the invention swell in physiological medium by absorbing water; it may thereby form a gel. It may also absorb other liquids and swell.
The swellable excipients used in this invention are selected from group of cellulose ether for example hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose; hydroxyalkyl alkylcelluloses, such as, hydroxyethyl methyl cellulose and hydroxypropyl methylcellulose; carboxyalkylcellulose esters; other natural, semi-synthetic, or synthetic di-, oligo- and polysaccharides such as galactomannans, tragacanth, agar, guar gum, and polyfructans; methacrylate copolymers; polyvinylalcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinylalcohol and polyvinylpyrrolidone; polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, preferably cellulose ether derivatives such as hydroxypropyl methylcellulose and hydroxypropyl cellulose, most preferred hydroxypropyl methylcellulose.
The term non swelling release retardants used in this invention are the retardants which do not swell but they control the release of actives in physiological media. The non-swelling release retardants are selected from the group of polymeric release retardants and non polymeric release retardants such as fatty acids, long chain monohydric alcohols, waxes etc for example polyvinyl alcohol, polyvinyl acetate, mixture of polyvinyl acetate and polyvinyl pyrrolidone, polymethacrylic acid derivatives, cellulose derivatives such as ethyl cellulose.
Examples of non-swelling non-polymeric release retardants include, but are not limited to, esters, hydrogenated oils, natural waxes, synthetic waxes, hydrocarbons, fatty alcohols, fatty acids, monoglycerides, diglycerides, triglycerides and mixtures thereof.

Examples of esters, such as glyceryl esters include, but are not limited to, glyceryl monostearate, glyceryl palmitostearate; acetylated glycerol monostearate, sorbitan monostearate, and cetyl palmitate, glyceryl behenate magnesium stearate and calcium stearate and mixtures thereof.
Examples of waxes include, but are not limited to spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, and mixtures thereof.
Examples of fatty alcohols, i.e. higher molecular weight nonvolatile alcohols that have from about 14 to about 31 carbon atoms include, but are not limited to, cetyl alcohol, cetylstearyl alcohol, stearyl alcohol, lauryl alcohol and mixture thereof.
Examples of fatty acids which may have from about 10 to about 22 carbon atoms include, but are not limited to, stearic acid, edecanoic acid; palmitic acid, lauric acid, and myristic acid and mixture thereof.
The following examples are given by the way of illustration of the present invention and therefore should not be construed to limit the scope of the present invention.
Ascorbic acid modified release composition is prepared using vegetable oils which contain tocopherol along with other food grade excipients. The following examples provide detailed formula for preparation of Ascorbic acid modified release granules which can be directly compressed into suitable size tablets and/or directly filled into suitable size two piece capsules or into sachets.

Process for the preparation of Ascorbic Acid tablets Method I:
a. Pulverization/ Milling of Ascorbic acid:
Ascorbic acid was pulverized and/or milled using multi-mill/Air jet mill and passed through 80 mesh ASTM to get particle size of D90 below 200 microns.
b. Granulation:
Sifted Ascorbic acid, citric acid, and vegetable oil selected from the group of Sunflower oil, Safflower oil, Corn oil and/or Soyabean oil and polymer (Hydroxy propyl methyl cellulose, Ethyl cellulose) and colloidal silicon dioxide were blended in a planetary mixture for 10 minutes with intermittent racking. The dry mix was granulated in a planetary mixture or rapid mixer granulator using Povidone solution (dissolved in to required quantity of isopropyl alcohol). Wet granules were dried at suitable temperature around 60°C, sized through 20 mesh ASTM and blended with magnesium stearate and microcrystalline cellulose.
c. Compression:
The lubricated granules were compressed in to 1000 mg tablet weight using 10 station single rotary B-tooling tablet compression machine (using 19* 10mm biconcave punch plain on both sides). The thickness of the tablet was in the range of 5-6.5 mm and hardness was in the range of 8-15 Kg/cm .
Following tables represent different compositions of Ascorbic acid tablets prepared by the above given process by using different vegetable oils containing natural tocopherol.

Example 1
SrNo. Ingredients % w/w
Composition Composition Composition Composition
1 2 3 4
1 Ascorbic acid 70.00 70.00 70.00 70.00
2 Citric acid 1.00 1.00 1.00 1.00
3 Sunflower oil 0.10 0.50 1.00 2.00
4 Hydroxy propyl methyl cellulose 20.00 20.00 20.00 20.00
5 Povidone 2.00 2.00 2.00 2.00
6 Colloidal silicon dioxide 2.50 2.50 2.50 2.50
7 Magnesium Stearate 2.00 2.00 2.00 2.00
8 Microcrystalline cellulose 2.40 2.00 1.50 0.50
9 Isopropyl alcohol 10.00 10.00 10.00 10.00
Example 2
SRNo. Ingredients %w/w
Composition Composition Composition Composition
5 6 7 8
1 Ascorbic acid 70.00 70.00 70.00 70.00
2 Citric acid 1.00 1.00 1.00 1.00
3 Safflower Oil 0.10 0.50 1.00 2.00
4 Hydroxy propyl methyl cellulose 20.00 20.00 20.00 20.00
5 Povidone 2.00 2.00 2.00 2.00
6 Colloidal silicon dioxide 2.50 2.50 2.50 2.50
7 Magnesium stearate 2.00 2.00 2.00 2.00
8 Microcrystalline cellulose 2.40 2.00 1.50 0.50
9 Isopropyl alcohol 10.00 10.00 10.00 10.00

Example 3
SRNo. Ingredients %w/w
Composition Composition Composition Composition
9 10 11 12
1 Ascorbic Acid 70.00 70.00 70.00 70.00
2 Citric Acid 1.00 1.00 1.00 1.00
3 Corn Oil 0.10 0.50 1.00 2.00
4 Hydroxy Propyl Methyl Cellulose 20.00 20.00 20.00 20.00
5 Povidone 2.00 2.00 2.00 2.00
6 Colloidal silicon dioxide 2.50 2.50 2.50 2.50
7 Magnesium Stearate 2.00 2.00 2.00 2.00
8 Microcrystalline Cellulose 2.40 2.00 1.50 0.50
9 Isopropyl alcohol 10.00 10.00 10.00 10.00
Example 4
SRNo. Ingredients %w/w
Composition Composition Composition Composition
13 14 15 16
1 Ascorbic Acid 70.00 70.00 70.00 70.00
2 Citric Acid 1.00 1.00 1.00 1.00
3 Soyabean Oil 0.10 0.50 1.00 2.00
4 Hydroxy Propyl Methyl Cellulose 20.00 20.00 20.00 20.00
5 Povidone 2.00 2.00 2.00 2.00
6 Colloidal silicon dioxide 2.50 2.50 2.50 2.50
7 Magnesium Stearate 2.00 2.00 2.00 2.00
8 Microcrystalline Cellulose 2.40 2.00 1.50 0.50
9 Isopropyl alcohol 10.00 10.00 10.00 10.00

Example 5
SRNo. Ingredients %w/w
Composition Composition Composition Composition
17 18 19 20
1 Ascorbic Acid 70.00 70.00 70.00 70.00
2 Citric Acid 1.00 1.00 1.00 1.00
3 Sunflower Oil 0.10 0.50 1.00 2.00
4 Ethyl cellulose 20.00 20.00 20.00 20.00
5 Povidone 2.00 2.00 2.00 2.00
6 Colloidal silicon dioxide 2.50 2.50 2.50 2.50
7 Magnesium Stearate 2.00 2.00 2.00 2.00
8 Microcrystalline Cellulose 2.40 2.00 1.50 0.50
9 Isopropyl alcohol 10.00 10.00 10.00 10.00
Example 6
SRNo. Ingredients %w/w
Composition Composition Composition Composition
21 22 23 24
1 Ascorbic Acid 70.00 70.00 70.00 70.00
2 Citric Acid 1.00 1.00 1.00 1.00
3 Safflower Oil 0.10 0.50 1.00 2.00
4 Ethyl cellulose 20.00 20.00 20.00 20.00
5 Povidone 2.00 2.00 2.00 2.00
6 Colloidal silicon dioxide 2.50 2.50 2.50 2.50
7 Magnesium Stearate 2.00 2.00 2.00 2.00
8 Microcrystalline Cellulose 2.40 2.00 1.50 0.50
9 Isopropyl alcohol 10.00 10.00 10.00 10.00

Example 7
SRNo. Ingredients %w/w
Composition Composition Composition Composition
25 26 27 28
1 Ascorbic Acid 70.00 70.00 70.00 70.00
2 Citric Acid 1.00 1.00 1.00 1.00
3 Corn Oil 0.10 0.50 1.00 2.00
4 Ethyl cellulose 20.00 20.00 20.00 20.00
5 Povidone 2.00 2.00 2.00 2.00
6 Colloidal silicon dioxide 2.50 2.50 2.50 2.50
7 Magnesium Stearate 2.00 2.00 2.00 2.00
8 Microcrystalline Cellulose 2.40 2.00 1.50 0.50
9 Isopropyl alcohol 10.00 10.00 10.00 10.00
Example 8
SRNo. Ingredients %w/w
Composition Composition Composition Composition
29 30 31 32
1 Ascorbic Acid 70.00 70.00 70.00 70.00
2 Citric Acid 1.00 1.00 1.00 1.00
3 Soyabean oil 0.10 0.50 1.00 2.00
4 Ethyl cellulose 20.00 20.00 20.00 20.00
5 Povidone 2.00 2.00 2.00 2.00
6 Colloidal silicon dioxide 2.50 2.50 2.50 2.50
7 Magnesium Stearate 2.00 2.00 2.00 2.00
8 Microcrystalline Cellulose 2.40 2.00 1.50 0.50
9 Isopropyl alcohol 10.00 10.00 10.00 10.00

Process for the preparation of Ascorbic Acid tablets Method II:
a. Pulverization/Milling of Ascorbic acid:
Ascorbic acid was pulverized and/or milled using multi-mill/Air jet mill and passed through 80 mesh ASTM to get particle size of D90 below 200 microns.
b. Granulation:
Sifted Ascorbic acid, citric acid, and vegetable oil selected from the group of Sunflower oil, Safflower oil, Corn oil and/or Soyabean oil and colloidal silicon dioxide were blended in planetary mixture for 10 minutes with intermittent racking. Cetyl alcohol, Stearic acid and/or glyceryl monostearate was melted at 70°C. Povidone solution (dissolved in to required quantity of isopropyl alcohol) was added into Cetyl alcohol, Stearic acid with glyceryl monosterate melt. Dry mix was granulated using this solution to get desire granules. Wet granules were dried at 45°C, in to fluidized bed dryer, sized through 20 mesh ASTM and blended with magnesium stearate and microcrystalline cellulose.
c. Compression:
The lubricated granules were compressed in to 1000 mg tablet weight using 10 station single rotary B-tooling tablet compression machine (using 19* 10mm biconcave punch plain on both sides). The thickness of the tablet was in the range of 5-6.5 mm and hardness was in the range of 8-15 Kg/cm2.
Following tables represent different compositions of Ascorbic acid tablets prepared by the above given process by using different vegetable oils containing natural tocopherol.

Example 9
SRNo. Ingredients %w/w
Composition Composition Composition Composition
33 34 35 36
1. Ascorbic Acid 70.00 70.00 70.00 70.00
2. Citric Acid 1.00 1.00 1.00 1.00
3. Sunflower oil 0.5 1.00 1.50 5.00
4. Glyceryl monostearate 15.00 15.00 15.00 15.00
5. Stearic acid 5.00 5.00 5.00 5.00
6. Povidone 2.00 2.00 2.00 2.00
7. Colloidal silicon dioxide 2.50 2.50 2.50 1.00
8. Magnesium Stearate 2.00 2.00 2.00 1.00
9. Microcrystalline Cellulose 2.00 1.50 1.00 -
10. Isopropyl alcohol 10.00 10.00 10.00 10.00
Example 10
SRNo. Ingredients %w/w
Composition Composition Composition Composition
37 38 39 40
1. Ascorbic Acid 70.00 70.00 70.00 70.00
2. Citric Acid 1.00 1.00 1.00 1.00
3. Sunflower oil 0.5 1.00 1.50 5.00
4. Cetyl alcohol 2.00 2.00 2.00 2.00
5. Stearic acid 18.00 18.00 18.00 18.00
6. Povidone 2.00 2.00 2.00 2.00
7. Colloidal silicon dioxide 2.50 2.50 2.50 1.00
8. Magnesium Stearate 2.00 2.00 2.00 1.00
9. Microcrystalline Cellulose 2.00 1.50 1.00
10. Isopropyl alcohol 10.00 10.00 10.00 10.00

In-vitro drug dissolution studies:
The modified release compositions of Ascorbic acid obtained by the above mentioned methods were subjected to in vitro drug release studies in 900 ml purified water using USP type II dissolution apparatus with 50 rotation speed and temperature 37±0.5°C. The result of the study is shown in the following tables:

Table 1
Time (hr) % Cumulative Ascorbic acid Release
Composition 1 Composition 2 Composition 3 Composition 4
0.25 15 16 11 16
1 25 24 22 27
2 53 57 53 59
4 73 75 75 74
6 95 89 88 82
8 98 95 92 90
12 98 100 96 100
Table 2
Time (hr) % Cumulative Ascorbic acid Release
Composition 5 Composition 6 Composition 7 Composition 8
0.25 19 15 11 12
1 29 25 22 20
2 55 51 52 50
4 79 78 75 73
6 85 88 80 85
8 96 92 88 89
12 101 100 100 97
Table 3
Time (hr) % Cumulative Ascorbic acid Release
Composition 9 Composition 10 Composition 11 Composition 12
0.25 20 18 15 14
1 30 28 21 26
2 56 52 49 40
4 78 61 58 63
6 88 81 72 69
8 92 89 81 80
12 100 100 97 96

Table 4
Time (hr) % Cumulative Ascorbic acid Release i
0.25 Composition 13
13 Composition 14
15 Composition 15
20 Composition 16
12
1 30 35 41 39
2 50 55 62 54
4 67 64 66 63
6 79 75 72 72
8 88 85 88 83
12 100 101 100 94
Table 5
Time (hr) % Cumulative Ascorbic acid Release i
0.25 Composition 17 19 Composition 18
21 Composition 19
20 Composition 20
12
1 35 38 34 31
2 58 52 49 45
4 65 63 61 55
6 79 75 73 72
8 84 88 85 81
12 100 99 96 95
Table 6
Time (hr) Cumulative Ascorbic acid Release
0.25 Composition 21
12 Composition 22
15 Composition 23
12 Composition 24
14
1 38 35 36 32
2 61 68 65 60
4 69 75 72 69
6 79 82 83 78
8 89 92 92 85
12 101 100 101 98

Table 7
Time (hr) % Cumulative Ascorbic acid Release
Composition 25 Composition 26 Composition 27 Composition 2$
0.25 17 18 15 13
1 41 36 35 32
2 65 55 52 59
4 . 71 69 65 68
6 82 79 75 75
8 92 88 86 88
12 101 100 99 102
Table 8
Time (hr) '/o Cumulative Ascorbic acid Release
Composition 29 Composition 30 Composition 31 Composition 32
0.25 18 18 19 18
1 36 35 34 34
2 52 54 45 47
4 73 68 62 65
6 73 77 74 73
8 89 88 81 81
12 102 98 88 98
Table 9
Time (hr) % Cumulative Ascorbic acid Release
Composition 33 Composition 34 Composition 35 Composition 36
0.25 20 22 15 15
1 38 35 27 24
2 59 55 49 51
4 78 71 65 66
6 85 86 77 74
8 92 89 83 81
12 101 99 96 98

Table 10
Time (hr) % Cumulative Ascorbic acid Release
Composition 37 Composition 38 Composition 39 Composition 40
0.25 17 18 18 17
1 35 35 35 31
2 49 48 49 42
4 65 64 67 60
6 78 74 76 76
8 87 77 81 83
12 92 92 95 91
The comparative dissolution studies were also carried out along with some of the extended release compositions of Ascorbic acid available in the market. The data shown below in Table 11 is the percent cumulative release of Ascorbic acid obtained from these marketed samples.

Table 11
Time (hr) % Cumulative Ascorbic acid Release

Sunkist Timed Release (Mfg by:
WIN
Pharmaceuticals
INC, USA) C Max (Mfg by:
Douglas
Laboratories INC,
USA) NATURAL
FACTORS
VITAMIN C
(mfg by Natural
Factor, Canada) NATROL EASY -C TIME
RELEASE (Mfg by Natrol Inc.
USA)
0.25 9 15 7 10
1 34 44 30 69
2 64 72 53 112
4 95 107 88 -
6 99 - 110 -
Conclusion:
Dissolution profile of Ascorbic acid represented in above tables (Table: 1-10) indicate that the combination of vegetable oils with non swelling and/or swelling release retardants reduces the dissolution of Ascorbic acid. Also combination of vegetable oil

with non-swellable polymeric and /or non-polymeric release retardants (Examples 5-10) synergistically reduces the release of Ascorbic acid as compared to the combination with swellable release retardants (Examples 1-5). The combination of vegetable oil containing natural tocopherol along with non-swellable polymeric and/or non-polymeric release retardant increases the hydrophobic environment of drug matrix and prevents the permeation of dissolution media in to the matrix. The composition also exhibits significant delay in the release profile when compared with other marketed samples (Table: 11) thus providing desired sustained release properties which in turn assures in-vivo prolonged release of Ascorbic acid. The dissolution profile of procured marketed products shows erratic/in-consistent, rapid release/dissolution of Ascorbic acid instead of release in sustained manner. In most of the products the drug is completely released within 2-6 hours of time, which may lead to dose dumping.
The above results clearly demonstrate the superiority of the composition of the present invention.
Stability Studies:
Accelerated stability studies were performed to establish within short period of time the intrinsic stability of modified release composition of Ascorbic acid and to help predict what can be expected during the formal long term stability study. Modified release compositions of Ascorbic acid in the form of tablets were charged for stability studies at 40 ±2°C, 75±5% RH for 3 months period, In this study the composition was analyzed at interval of one month for a period of three months for various parameters, which includes assay and dissolution profile of Ascorbic acid.

Following tables show the stability data of different compositions.

Table 1
% Cumulative Ascorbic acid Release of Composition 1-4
Composition 1 Composition 2 Composition 3 Composition 4
Time (hr) 1M 2M 3M 1M 2M 3M 1M 2M 3M 1M 2M 3M
0.25 20 25 27 29 30 25 11 10 8 15 20 18
1 29 35 39 36 35 35 22 25 19 35 25 22
2 59 61 65 62 61 59 53 49 50 55 60 58
4 78 81 82 82 88 85 75 65 69 62 75 73
6 85 89 90 91 95 95 88 71 75 79 83 81
8 91 95 95 96 97 99 92 82 88 85 95 92
12 98 102 99 101 102 100 96 95 100 99 100 99
% Assay 99 98 99 97 98 100 99 96 97 98 100 98
Table 2 ease of Composition
% Cumulala ive Ascorbic acid Re
5-9
Time (hr) Coi 1M n position 5 Composition 6 Composition 7 Composition 8

2M 3M 1M 2M 3M 1M 2M 3M 1M 2M 3M
0.25 18 25 21 15 12 15 10 16 15 12 10 8
1 31 36 31 28 25 28 22 28 22 22 18 18
2 48 58 49 45 49 45 56 48 45 56 49 45
4 61 69 66 68 68 56 78 69 65 78 73 69
6 72 78 75 75 78 71 88 78 72 86 82 78
8 88 88 89 89 88 86 95 91 88 93 93 83
12 98 99 98 99 96 99 100 99 95 99 99 96
% Assay 99 98 99 98 97 99 99 98 98 99 98 97

Table 3
% Cumulative Ascorbic acid Release of Composition 9-12
Composition 9 Composition 10 Composition 11 Composition 12
Time (hr) 1M 2M 3M 1M 2M 3M 1M 2M 3M 1M 2M 3M
0.25 19 18 22 19 18 15 18 16 16 15 14 16
1 33 36 38 28 24 26 23 21 21 28 26 30
2 55 56 59 48 46 45 53 49 52 42 49 55
4 75 73 68 62 65 66 63 61 65 61 65 69
6 88 86 79 85 86 83 76 73 75 71 78 89
8 92 93 92 93 93 91 88 85 88 86 89 95
12 100 100 100 100 100 96 99 97 99 96 100 101
% Assay 100 99 97 98 99 97 98 99 99 98 99 98
% Cumulati Table 4


ve Ascorbic acid Release of Composition 13-16
Composition 13 Composition 14 Composition 15 Composition 16
Time (hr) 1M 2 M 3M 1M 2M 3M 1M 2M 3M 1M 2M 3M
0.25 15 10 11 17 15 13 18 15 13 11 15 12
1 33 32 32 35 32 28 38 41 38 35 38 35
2 55 49 45 58 58 48 55 58 60 51 55 49
4 71 65 62 69 71 67 68 69 69 65 69 68
6 82 76 77 78 79 78 75 78 88 71 80 78
8 91 89 89 88 90 89 90 89 93 85 88 88
12 100 98 99 100 99 99 100 98 100 96 99 95
%
Assay 98 99 97 99 99 97 99 98 100 98 100 99

Table 5
% Cumulative Ascorbic acid Release of Composition 17-20
Composition 17 Composition 18 Composition 19 Composition 20
Time
(hr) 1M 2M 3M 1M 2M 3M 1M 2M 3M 1M 2M 3M
0.25 17 15 12 18 15 12 18 12 11 11 10 9
1 32 31 30 36 32 28 38 29 29 33 32 28
2 55 48 49 55 49 48 49 45 46 49 44 46
4 63 65 62 61 65 62 63 68 58 58 58 60
6 76 77 78 77 77 73 71 75 76 79 70 73
8 82 86 86 86 83 88 88 85 86 86 85 88
12
% Assay 98 97 99 96 98 99 96 99 99 95 97 99 97 96 99

99 98 97 98 98 97 98 97 99

Table 6
% Cumulative Ascorbic acid Release of Composition 21-24
Composition 21 Composition 22 Composition 23 Composition 24
Time (hr) 1M 2M 3M 1M 2M 3M 1M 2M 3M 1M 2M 3M
0.25 11 10 9 14 18 13 11 12 10 10 18 14
1 36 32 27 31 36 32 36 36 32 28 32 36
2 58 49 47 64 65 56 61 59 49 59 65 59
4 62 59 58 71 77 70 73 70 61 66 76 68
6 77 80 78 82 82 81 80 83 76 71 84 81
8 89 86 88 96 90 93 95 93 86 86 89 90
12 97 96 99 100 99 100 100 99 95 96 99 100
%
Assay 98 99 99 98 98 97 98 97 99 100 98 99

Table 7
% Cumulative Ascorbic acid Release of Composition 25-28
Composition 25 Composition 26 Composition 27 Composition 28
Time 1M 2M 3M 1M 2M 3M 1M 2M 3M 1M 2M 3M
(hr)
0.25 13 12 9 16 15 13 12 10 12 14 10 10
1 36 28 28 33 30 26 25 28 35 33 30 32
2 53 48 49 58 62 55 56 55 56 58 53 48
4 68 69 65 63 70 68 65 68 70 67 68 65
6 72 78 75 72 80 76 74 71 75 73 76 72
8 82 89 88 86 89 85 82 89 92 89 92 88
12 99 100 95 98 99 95 99 98 100 99 100 101
%
Assay 99 98 99 99 98 99 99 98 98 100 98 98
Table 8
% Cumulative Ascorbic acid Release of Composition 29-32 32
Composition 29 Composition 30 Composition 31 Composition

Time (hr) 1M 2M 3M 1M 2M 3M 1M 2M 3M 1M 2M 3M
0.25 15 11 10 17 15 13 15 18 13 15 11 11
1 32 29 32 33 28 27 31 36 27 31 27 31
2 54 52 55 58 61 60 42 61 53 44 36 40
4 64 65 68 69 70 69 60 72 67 59 60 62
6 78 78 79 82 83 78 71 85 75 71 73 78
8 89 89 88 90 88 85 89 93 87 85 81 86
12 99 99 100 100 96 95 95 100 96 99 95 97
% Assay 100 98 99 99 97 99 98 99 100 100 99 100

Table 9
% Cumulative Ascorbic acid Release of Composition 33-36
Composition 33 Composition 34 Composition 35 Composition 36
Time (hr) 1M 2M 3M 1M 2M 3M 1M 2M 3M 1M 2M 3M
0.25 17 20 15 21 18 15 13 12 12 12 10 13
1 33 38 31 31 28 22 27 30 36 24 33 38
2 58 62 53 56 55 53 45 48 55 55 48 59
4 73 70 62 69 66 69 61 62 69 69 69 68
6 81 85 78 80 78 75 75 76 78 75 78 79
8 90 92 85 85 83 82 82 85 89 88 89 92
12 98 100 95 99 97 99 96 96 100 98 99 100
% Assay 100 100 99 99 100 99 99 100 99 99 98 99
Table 10
% Cumulative Ascorbic acid Rele ase of Composition 37-40
Composition 37 Composition 38 Composition 39 Composition 40
Time (hr) 1M 2M 3M 1M 2M 3M 1M 2M 3M 1M 2M 3M
0.25 15 33 13 13 10 13 20 18 15 25 15 12
1 39 36 32 31 28 29 41 38 29 33 35 28
2 58 52 49 53 49 53 59 62 58 46 48 45
4 71 63 63 69 65 71 69 73 71 65 65 58
6 82 75 78 77 79 80 79 82 82 79 80 78
8 90 86 83 86 88 91 90 90 93 88 89 89
12 99 96 98 96 95 100 99 98 100 98 95 96
% Assay 99 98 99 100 99 100 99 97 98 98 99 99

Results of stability studies:
The stability data demonstrates no significant drop in the assay which indicates that the vegetable oil containing tocopherol plays a critical role in stabilization of Ascorbic acid. It forms a protective coating over the pulverized Ascorbic acid and retains its activity. The dissolution profile of Ascorbic acid compositions did not change over the period of time (3 months at accelerated conditions) which indicates that the vegetable oil along with non-swelling and/or swelling release retardants maintains the hydrophobic nature of matrix system during stability.
Advantages of the present invention
The present invention provides an oral modified release composition of Ascorbic acid which releases at least 70% of Ascorbic acid in 6-10 hours and at least 80% of Ascorbic acid in 8-12 hours.
The said composition is in the form of tablets, capsules, powder, pellet or granules.
The granules obtained can be directly compressed into suitable size tablets and/or can be directly filled into suitable size two piece capsules or into sachets.
The present invention provides low-weight and size dosage forms which can be easily swallowed by human beings.
The present invention provides a stable, cheaper and effective Ascorbic acid modified release formulation using excipients approved for use in long term administration having E-number/ GRAS status that ensures safety of human beings for long term administration.
The composition is prepared by using lesser amounts of conventional release retardants.

The present invention provides a stable modified release composition of Ascorbic acid which is protected from harmful effects of oxygen, moisture and light.
The present invention also provides a modified release composition of Ascorbic acid using pulverized Ascorbic acid thus facilitating uniform and reproducible dissolution release profile.

We claim
1. An oral modified release composition of Ascorbic acid which comprises:
a. pulverized Ascorbic acid with particle size of D90 below 200 microns;
b. at least one vegetable oil that contains natural tocopherol;
c. at least one non swelling release retardant; and
d. optionally swelling release retardant, binders, fillers, lubricants or mixture thereof.
2. The oral modified release composition of Ascorbic acid as claimed in claim 1, wherein the said composition is in the form of tablets, capsules, pellets, powder or granules.
3. The oral modified release composition of Ascorbic acid as claimed in claim 1, wherein the said composition releases at least 70% of Ascorbic acid in 6-10 hours and at least 80% of Ascorbic acid in 8-12 hours.
4. The oral modified release composition of Ascorbic acid as claimed in claim 1, wherein the composition contains 25% to 80% w/w of composition of Ascorbic acid.
5. The oral modified release composition of Ascorbic acid as claimed in claim 1, wherein the vegetable oil is selected from Sunflower oil, Safflower Oil, Corn oil, Almond oil, Palm oil, Peanut oil, Wheat germ oil or mixtures thereof.
6. The composition as claimed in claim 1, wherein the vegetable oil used is in the range of 0.01 to 5.0 % w/w of composition.
7. The oral modified release composition as claimed in claim 1, wherein the non-swelling release retardant is selected from the group of waxes, long chain monohydric alcohols, fatty alcohol, esters, fatty acids or mixture of thereof.

8. The oral modified release composition as claimed in claim 1, wherein the said non-swelling release retardant is present in the range of 2% to 30% w/w of the composition.
9. The oral modified release composition as claimed in claim 1, wherein the said swellable release retardant is selected from the group of cellulose ether, preferably cellulose ether derivatives such as hydroxypropyl methylcellulose and hydroxypropyl cellulose, most preferred hydroxypropyl methylcellulose or mixture of thereof.

10. The oral modified release composition as claimed in claim 1, wherein the said swellable release retardant is present in the range of 2% to 30% w/w of the composition.
11. A process for the preparation of modified release composition of Ascorbic acid, which comprises:
a. Mixing of Ascorbic acid and vegetable oil along with stabilizer and anti-caking
agent;
b. Melting of non-swell able release controlling agents and mixing of this melted
solution with a suitable binder in presence of a suitable organic solvent;
c. Granulation of the dry mix obtained in step 'a' by using solution of step 'b';
d. Drying the granules obtained in step 'c';
e. Sizing of the granules by passing through 20 mesh ASTM;
f. Blending of the granules of step 'e' with fillers and lubricants;
g. Compressing of the granules of step 'f into suitable size tablets using a suitable
tablet press;
h. Optionally filling of granules of step 'f 'into two piece hard gelatin capsules or into sachets.
12. The process as claimed in claim 11, wherein the stabilizer is selected from citric
acid, tartaric acid, disodium EDTA or mixtures thereof, preferably citric acid.

13. The process as claimed in claim 11, wherein the anti-caking agent is selected from
magnesium stearate, colloidal silicon dioxide, talc, sodium stearyl fumarate or mixtures
thereof, preferably colloidal silicon dioxide.
14. The process as claimed in claim 11, wherein the binder is selected from
hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, tragacanth,
agar, guar gum, polyvinylpyrrolidone or mixtures thereof.
15. The process as claimed in claim 11, wherein the organic solvent is selected from isopropyl alcohol, ethyl alcohol, acetone or mixtures thereof, preferably isopropyl alcohol.
16. The process as claimed in claim 11, wherein the fillers are selected from microcrystalline cellulose, starch, modified starch, lactose or mixtures thereof, preferably microcrystalline cellulose.
17. The process as claimed in claim 11, wherein the lubricants are selected from magnesium stearate, colloidal silicon dioxide, talc, sodium stearyl fumarate or mixtures thereof, preferably magnesium stearate.