F O R M 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention: CONTROLLED RELEASE COMPOSITIONS OF VITAMIN C
2. Applicant(s)
(a) NAME: Rubicon Research Pvt. Ltd.
(b) NATIONALITY: An Indian Company
(c) ADDRESS: 221, Annexe Building, Goregaon Mulund Link Road,
Opposite Indira Container Yard, Off L.B.S. Marg,
Bhandup (West), Mumbai – 400 078, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be
performed.
1
The present invention relates to controlled release pharmaceutical compositions of
vitamin C and process for preparing such compositions. Particularly, the present
invention relates to controlled release pharmaceutical compositions comprising vitamin
C, at least one glyceryl ester, at least one cellulose ether and at least one
pharmaceutically acceptable excipient.
Field of the Invention
It is well known to those skilled in the art that the blood levels of drugs need to be
maintained above a minimum effective level and below its minimum toxic level in order to
obtain the desired therapeutic effects and to minimize side effects. Unfortunately for
some nutrients and vitamins, the pharmacokinetic properties (absorption, elimination and
metabolism) are such that they need to be administered three to four times a day or
ingested in several spaced doses throughout the day rather than a single large dose to
get the desired therapeutic effect. This kind of a dosing regimen is very inconvenient and
leads to reduction in patient compliance. Reduction of dosing regimen from three times a
day (tid) to twice daily (bid) to once a day results in increased convenience and comfort
and therefore increased patient compliance. One way of achieving this aim is by
administering the drug through controlled release formulations which provide uniform
release of a medicament at a controlled rate over a desired extended period of time and
so are of great benefit to both the patient and medical practitioner. Drug release which
can be controlled to a specific rate has some more advantages over conventional drug
delivery systems such as minimizing severity and frequency of local and systemic side
effects, maximizing the bioavailability, improving efficacy in treatment and avoiding the
fluctuations associated with the conventional immediate release formulations
administered three to four times a day.
Background of the Invention
Vitamin C (ascorbic acid) is a water-soluble vitamin, required for the synthesis of
collagen, an important structural component of blood vessels, tendons, ligaments, and
bone. Vitamin C also plays an important role in the synthesis of the neurotransmitter,
norepinephrine and helps in wound healing. It is needed for normal immune system
function and is a highly effective antioxidant. Even in small amounts vitamin C can
protect indispensable 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.
2
Unlike most mammals and other animals, humans do not have the ability to make their
own vitamin C and therefore must obtain vitamin C through diet. Vitamin C deficiency
usually results from a diet low in Vitamin C. Symptoms of Vitamin C deficiency include
tiredness, weakness, muscle and joint ache, soft gums, lowered resistance to infections.
Acute vitamin C deficiency leads to scurvy. If left untreated scurvy may prove fatal.
External supplementation with vitamin C is thus essential for prevention and treatment of
vitamin C deficiency.
Many immediate release dosage forms are available for vitamin C. Such conventional
immediate release formulations, once taken, release vitamin C rapidly resulting in high
concentrations of vitamin C in the stomach. High concentrations however result in
decreased absorption of vitamin C, resulting in lower bioavailability. As the dose is
increased there is reduction in absorption leading to lower bioavailability. Furthermore,
with immediate release formulations, the resulting high acidity also causes gastric
irritations in sensitive individuals. Additionally, when higher or constant levels of vitamin
C are required by the body, multiple dose administrations of immediate release
formulations to achieve constant release of the active over extended periods of time,
may result in patient and/or therapeutic incompliance.
Need thus exists for controlled release formulations of ascorbic acid which can alleviate
the above problems and provide desired bioavailability and patient compliance.
However, conventional controlled release formulations particularly based on use of
swelling/gelling polymers fail to provide the desired constant drug release characteristics
for an active agent such as vitamin C that has high aqueous solubility and is particularly
used in high doses. The failure is primarily due to a typical release profile that may be
obtained with these systems, which comprises of a high initial burst release and a
plateau with incomplete release towards end. High initial burst release is particularly
undesirable as it leads to poor in vivo performance, and may result in dose dumping
and/or poor local tolerability due to undesirable local effects of the active agent.
Systems as discussed in US patent application US20080248107A1 attempt to overcome
the above problem associated with the use of swelling polymers, by developing a nonswelling
system based on the use of non-polymeric release retardant and pH
independent non-swelling release retardant. However, due to the use of non-swelling
3
excipients as release retardants, these non-swelling dosage forms have a tendency to
pass through the gastrointestinal tract at a faster rate, even before the complete release
and absorption of the vitamin occurs in the gastrointestinal tract.
Thus, controlled release systems of vitamin C can show either undesirable initial burst
release or incomplete absorption of vitamin C in gastrointestinal tract. A need therefore
exists to develop controlled release compositions of vitamin C, devoid of limitations
discussed above and having reduced initial burst release, enhanced bioavailability,
therapeutic effectiveness and substantially complete release of vitamin C.
The present inventors after thorough research found that the above desired features can
be achieved by employing at least one glyceryl ester and at least one cellulose ether.
The use of glyceryl esters and cellulose ethers provides a sustained release dosage
form of vitamin C, which releases drug with reduced initial burst and substantially
complete release of vitamin C in gastrointestinal tract at a controlled rate for a
considerable period of time. The process employed is simple, reproducible and
amenable to large scale manufacture using conventional equipment.
The present invention relates to controlled release compositions comprising vitamin C, at
least one glyceryl ester, at least one cellulose ether, and at least one pharmaceutically
acceptable excipient. The controlled release compositions of the present invention
provide reduced initial burst release with controlled and substantially complete release of
vitamin C.
Summary of the Invention
The present inventors have addressed the need of developing a controlled release
dosage form of Vitamin C providing reduced initial burst release and substantially
complete release of vitamin C. It was surprisingly found that the substantially complete
release of vitamin C for a longer period of time at a desired release rate along with
reduced initial burst release was achieved by using at least one glyceryl ester and at
least one cellulose ether.
Detailed Description of the Invention
In one embodiment, the controlled release compositions of the present invention
comprise vitamin C, at least one glyceryl ester, at least one cellulose ether; and at least
one pharmaceutically acceptable excipient.
4
The term "composition" or "formulation" or "dosage form" has been employed
interchangeably for the purpose of the present invention and mean that it is a
pharmaceutical composition which is suitable for administration to a subject. For the
purpose of the present invention the terms "controlled release" or "sustained release" or
"extended release" have been used interchangeably and mean that the dosage form is
designed to release vitamin C over an extended period of time e.g. from about 1 to about
24 hours; from about 2 to about 24 hours; from about 2 hours to about 20 hours; from
about 4 to about 16 hours; from about 4 to about 12 hours; so that therapeutically
beneficial levels of vitamin C are maintained over an extended period of time, e.g. from
about 2 to about 24 hours; from about 4 to about 24 hours; from about 4 to about 20
hours; from about 4 to about 16 hours; from about 4 to about 12 hours. The subject can
be an animal, preferably a mammal, more preferably a human.
“Reduced initial burst release” in accordance with the present invention means the
reduction in release of vitamin C from the dosage form at initial time points. The release
of vitamin C from the dosage form in first hour according to present invention is less than
35% and preferably less than 30% when measured by an in-vitro dissolution test in 0.1N
HCl. In one embodiment, in-vitro dissolution test in 0.1N HCl is done using dissolution
apparatus II with 900 ml media at 75 rpm.
“Substantially complete release of active” in accordance with the present invention
means the release of vitamin C from the dosage form is more than 75%, preferably 80%
at 8 hours when measured by an in-vitro dissolution in 0.1N HCl. In one embodiment, invitro
dissolution test in 0.1N HCl is done using dissolution apparatus II with 900 ml media
at 75 rpm.
The Active Agent
The active agent in the present invention is Vitamin C. The term vitamin C applies to
substances that possess antiascorbutic activity. The terms vitamin C, ascorbic acid and
ascorbate are commonly used interchangeably. Generally a prophylactic dosage of 2.5
to 6 grams of various forms of vitamin C daily is recommended. Up to 15 grams daily
may be required when attempting to eliminate or halt the progression of diseases.
5
The compositions of the present invention may also include other forms of Vitamin C
such as, but not limited to, natural or synthetic vitamin C, mineral salts of ascorbic acid,
Acerola Vitamin C, Rose hip Vitamin C, Vitamin C with bioflavonoids, reduced acidity
Vitamin C, Non-acid Vitamin C etc. or any combinations thereof. In one embodiment, the
active agent may be present in any suitable form, such as, but not limited to, particle,
powder, crystal, granules or coated granules. In another embodiment of the present
invention, one or a combination of more than one forms of vitamin C may also be
employed. In a further embodiment, the amount of vitamin C is present in the
compositions of the present invention in an amount of about 10% to about 95% by
weight of the composition. In another embodiment, Vitamin C is present in the
compositions of the present invention in an amount of about 25% to about 75% by
weight of the composition. In one embodiment, vitamin C is present in an amount of
about 100 mg to 1000 mg. In another embodiment, vitamin C is present in an amount of
about 500 mg.
In a further embodiment, the compositions of the present invention comprise at least one
glyceryl ester and at least one cellulose ether.
The controlled release compositions of the present invention of vitamin C further
comprise at least one glyceryl ester. Without being bound by any theory it is believed
that one or more glyceryl esters may be employed in the compositions of the present
invention to create a hydrophobic environment around the active agent which may cause
certain reduction in the release of the active agent.
Glyceryl esters
Glyceryl esters are a type of waxes. They are esters formed from a fatty acid having from
about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl
groups of glycerol is substituted by a fatty acid. They may also be a monoglyceryl esters,
diglyceryl esters, or triglyceryl esters (glycerides) and derivatives thereof formed from a
fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or
more of the hydroxyl groups of glycerol are substituted by a fatty acid. Glycerides
employed in the present invention include, but are not limited to, glyceryl monostearate,
glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl
monopalmitate, glyceryl palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl
6
monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl
monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate,
glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl
monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate,
polyglyceryl diisostearate, lauroyl macrogolglycerides, oleoyl macrogolglycerides,
stearoyl macrogolglycerides, glyceryl tricaprylate, glyceryl monooleate, glyceryl
monolaurate, and combinations thereof. In one embodiment the glyceryl esters
employed include, but are not limited to, Compritol® (Glyceryl behenate), Gelucire®
(Macrogolglycerides Lauriques), Precirol® (Glyceryl Palmitostearate), Plurol®
diisostearique (Polyglyceryl Diisostearate), Geleol® (Glyceryl Stearate), and mixtures
thereof.
In another embodiment, the glyceryl ester employed in the composition of the present
invention is glyceryl behenate.
The amount of glyceryl ester employed in the formulation of the present invention may
vary depending upon the degree of controlled release desired. In one embodiment,
glyceryl ester is present in the formulation in an amount of about 0.5% to about 90%,
preferably from about 1% to about 85%, and more preferably from about 1.5% to about
80%, by weight of the composition.
The controlled release dosage forms of the present invention in addition to vitamin C and
at least one glyceryl esters further comprises at least one cellulose ether. Cellulose
ethers help in regulating the rate of release of vitamin C from the composition for a
longer period of time.
Cellulose ethers
In one embodiment, cellulose ethers are polymers derived from cellulose. Cellulose
ethers that may be employed in the composition of the present invention include, but are
not limited to, methylcellulose, methylhydroxyethylcellulose, hydroxypropyl cellulose,
hydroxypropyl ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose,
hydroxyethyl carboxymethylcellulose, carboxy methylcellulose, carboxymethyl
hydroxyethylcellulose, hydroxyethyl methy cellulose, sodium carboxymethylcellulose and
calcium carboxymethylcellulose, their derivatives and combinations thereof. In one
embodiment, cellulose ether employed in the present invention is hydroxypropyl
methylcellulose. In one embodiment, cellulose ethers of different viscosities ranging
7
from about 50 centipoise to about 5,00,000 centipoise as a 2% aqueous solution at 20°C
may be employed in the compositions of the present invention. In a further embodiment,
cellulose ethers of different viscosities ranging from about 10,000 centipoise to about
3,00,000 centipoise as a 2% aqueous solution at 20°C may be employed in the
compositions of the present invention.
The cellulose ether may be present in the dosage form of the present invention in an
amount of about 2% to about 90% by weight of the dosage form. In one embodiment, the
cellulose ether may be present in the dosage form of the present invention in an amount
of about 5% to about 80% by weight of the dosage form. In another embodiment, the
cellulose ether may be present in the dosage form of the present invention in an amount
of about 10% to about 70% by weight of the dosage form.
The compositions of the present invention typically may also include other
pharmaceutically acceptable excipients such as, but not limited to, binders, fillers,
lubricants, diluents, granulating aids, disintegrants, glidants, colorants, flavorants,
surfactants, pH adjusters, anti- adherents and the like. As is well known to those skilled
in the art, pharmaceutical excipients are routinely incorporated into solid dosage forms.
This is done to ease the manufacturing process as well as to improve the performance of
the dosage form.
The present invention may include one or more diluents including, but not limited to,
lactose, lactose monohydrate, sugar, dextrate, dextrate hydrated, dextrins, fructose,
lactitol, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as
calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium
sulfate, wood cellulose and microcrystalline cellulose and the like, or mixtures thereof.
The diluents may be incorporated in the compositions of the present invention in an
amount of from about 1% to about 90% by weight. In another embodiment, the diluent
may be present in an amount of about 2 % to about 80% by weight.
Examples of suitable binders employed in the dosage form include, but are not limited to,
starch, microcrystalline cellulose, highly dispersed silica, mannitol, lactose, polyethylene
glycol, polyvinylpyrrolidone, vinyl copolymers, copovidone, polymethacrylic acid
derivative, natural or synthetic gums and the like or mixtures thereof. In one embodiment
the binders employed in the compositions of the present invention is polyvinyl
pyrrolidone or copovidone, or combinations thereof. Binders may be incorporated into
8
the system in an amount of about 0.1% to about 30% by weight of the dosage form. In
another embodiment, the binder may be incorporated in an amount of about 1 % to
about 20% by weight of dosage form. In a further embodiment, the binder may be
present in an amount of about 2% to about 15% by weight of the dosage form. In a
further embodiment, the binder may be present in an amount of about 0.5% to about
10% by weight of the dosage form. In a further embodiment, the binder may be present
in an amount of about 0.1 % to about 7.5% by weight of the dosage form.
Examples of suitable lubricants employed in the dosage form include, but are not limited
to, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, polyethylene
glycol, colloidal silicon dioxide, sodium stearyl fumarate, carnauba wax and the like and
mixtures thereof. Lubricants may be employed in an amount of from about 0.2 to about
10% by weight of the dosage form. In another embodiment, lubricants may be employed
in an amount of from about 0.5 to about 5% by weight of the dosage form.
Compositions of the present invention may optionally also include a glidant such as, but
not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof. Antiadherents
employed in the dosage form include, but are not limited to, talc, magnesium
stearate or finely divided silica, and the like or mixtures thereof. Disintegrants that may
be employed include, but are not limited to natural, modified or pregelatinized starch,
crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted
hydroxypropyl cellulose, calcium silicate and the like or mixtures thereof. Examples of
surfactants that may be employed include, but are not limited to, sodium docusate,
glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester,
sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, and the like or mixtures
thereof. pH adjusters that may be employed include, but are not limited to, sodium
citrate, magnesium oxide, citric acid and the like or mixtures thereof. One or more
flavorants employed, include, but are not limited to, mint flavor, orange flavor, lemon
flavors, strawberry aroma, vanilla flavor, raspberry aroma, cherry flavor, tutty frutty flavor,
magnasweet 135, key lime flavor, grape flavor, trusil art 511815, fruit extracts and the
like or mixtures thereof. Suitable sweeteners include, but are not limited to, sucralose,
aspartame, acesulfame, sodium saccharine and the like or mixtures thereof. One or
more colorants employed, include, but are not limited to, titanium dioxide, dyes, lake
pigments or natural colors and the like or mixtures thereof.
9
Compositions of the present invention may optionally include one or more polymeric or
non-polymeric materials that may additionally aid in controlling the release rate of active
from the composition. Such excipients include polyethylene oxides of molecular weight
100,000-7,000,000 Daltons(Polyox®), polyvinyl alcohols (MW: 20,000-200,000 Daltons),
substituted copolymers of polyvinyl acetate and polyvinylpyrrolidone like Kollidon® VA64
and Kollidon® SR, sodium alginate, carrageenan, xanthan gum individually or in
combination of ceratonia, locust bean gum or veegum, guar gum, gellan gum,
methylcellulose and chitosan, ethylcellulose, dextrates, dextrins, eudragit® (RL and RS
grade), cellulose acetate, cellulose acetate trimellitate, cellulose acetate butyrate,
cellulose acetate propionate, cetostearyl alcohol, cetyl alcohol, lecithin, medium chain
triglycerides, eudragit® RSPO, eudragit® RLPO, stearic acid, stearyl alcohol,
hydrogenated vegetable oil, carnauba wax, microcrystalline wax and beeswax.
The dosage form of present invention is a solid dosage form such as, but not limited to,
tablet, granule, spheroid, bead, pellet, tablets within a capsule or capsule. In one
embodiment, the solid dosage form is a tablet. In another embodiment, the tablet may
vary in shape such as oval, triangle, almond, peanut, parallelogram, pentagonal,
hexagonal, and trapezoidal. In another embodiment, the tablet dosage form may be
monolithic or multilayered. In still another embodiment, the tablet dosage form may be
matrix type or multiparticulate type. In another embodiment, the dosage form of the
present invention is not non-swelling.
In one of the embodiment of the present invention, the dosage form may be optionally
coated. In further embodiment controlled release composition of the present invention
wherein the composition is coated with a coating system comprising at least one
polymer, at least one sweetener and at least one flavourant. Surface coating may be
employed for aesthetic purposes or for dimensionally stabilizing the compressed dosage
form. In one embodiment, the surface coating may comprise one or more coating layers.
In one embodiment, the dosage form may be coated with at least one polymeric seal
coating layer and a flavor and colour coating thereupon. The coating may be carried out
using any conventional technique employing conventional ingredients suitable for oral
use. In one embodiment, the coating may be applied to obtain 1% to 15% weight gain. A
surface coating can, for example, be in the form of a film using conventional polymers
including, but not limited to, hydroxypropyl methyl cellulose, hydroxypropyl cellulose,
carboxymethyl cellulose, polyvinyl alcohol, polymethacrylates and the like, and
combinations thereof.
10
The controlled release composition according to the present invention achieves release
of vitamin C over an extended period of time, thereby extending the duration of drug
action over that achieved by conventional delivery. In one embodiment, the compositions
of the present invention allow for controlled release of Vitamin C over an extended or
prolonged or considerable period of time of at least 4 hour period following oral
administration. In another embodiment, the compositions of the present invention allow
for controlled release of Vitamin C over an extended or prolonged or considerable period
of time of at least 6 hour period following oral administration. In a further embodiment,
the compositions of the present invention allow for controlled release of Vitamin C over
an extended or prolonged or considerable period of time of at least 8 hour period
following oral administration. In one embodiment, the compositions of the present
invention allow for controlled release of Vitamin C over a period an extended or
prolonged or considerable period of time of about 4 hours to about 24 hours following
oral administration. In another embodiment, the compositions of the present invention
allow for controlled release of Vitamin C over a period of about 4 hours to about 12 hours
following oral administration. In one embodiment, the composition of the present
invention maintains a drug concentration in the blood within the therapeutic range for 4
hours or more. In another embodiment, the composition of the present invention
maintains a drug concentration in the blood within the therapeutic range for 8 hours or
more. In one embodiment, the composition of the present invention maintains a drug
concentration in the blood within the therapeutic range from about 4 hours to about 24
hours. In another embodiment, the composition of the present invention maintains a drug
concentration in the blood within the therapeutic range from about 4 hours to about 18
hours. In a further embodiment, the composition of the present invention maintains a
drug concentration in the blood within the therapeutic range from about 4 hours to about
16 hours. In one embodiment, the composition of the present invention maintains a drug
concentration in the blood within the therapeutic range from about 4 hours to about 12
hours.
The formulations in accordance with the present invention may be manufactured using
conventional techniques of common tableting methods known in the art such as direct
compression, wet granulation, dry granulation and extrusion/ melt granulation. In one
embodiment, the dosage form of the present invention can be prepared by direct
compression or granulation techniques. Direct compression technique involves
11
compression of active agent and at least one glyceryl esters and cellulose ethers after
mixing them for a definite time period with other excipients.
In another embodiment, wet granulation or dry granulation or melt granulation methods
can be used. In case of melt granulation, the glyceryl ester is melted and the active
agent is added and mixed with the molten mass effectively, allowed to solidify and thus
producing drug granules. In another embodiment, the active agent is granulated using
molten glyceryl esters. In some cases, both active agent and glyceryl behenate may be
melted together and cooled to room temperature. In case of wet granulation active agent
is blended with a binder and granulation is carried out using a solvent. Alternatively a
blend of active agent and other inactive excipients is granulated using a binder solution.
Such granules are then blended with other excipients. Alternatively a blend of active
agent and other inactive excipients is granulated using a binder solution. In a further
embodiment, dry granulation process may employ a roller compaction process. The
composition of the present invention is easy to scale up as it involves processes
routinely carried out in pharmaceutical industry.
The preparation of the controlled release composition of the present invention is simple
and non-demanding with respect to energy and time. The method of preparation and
choice of pharmaceutical excipients employed in the compositions of the present
invention, described herein, also ensure very good stability and the desired physical
properties of the dosage form as well as the required dissolution profile.
In one embodiment, the invention also relates to controlled release compositions
comprising at least one second active agent in addition to vitamin C. The second active
agent that may be employed in the compositions of the present invention include, but are
not limited to, one or more pharmaceutically active agents. In another embodiment, the
second active agent that may be employed in the compositions of the present invention
include, but are not limited to, vitamins or minerals and the like or combinations thereof.
Suitable vitamins include, but are not limited to, vitamin A, beta carotene, vitamin D3
(cholecalcipherol), vitamin E (tocopherol acetate), vitamin B1 (thiamine), vitamin B2
(riboflavin), nicotinamide, vitamin B5 (panthothenic acid), vitamin B6 (pyridoxine), folic
acid, vitamin B12 (cyanocobalamin), vitamin K1 and biotin. Acceptable minerals include,
but are not limited to, calcium salts, such as calcium carbonate, calcium phosphate, or
calcium glycerophosphate, magnesium salts, such as magnesium phosphate or
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magnesium oxide, zinc salts, such as zinc citrate trihydrate, selenium salts such as
sodium selenate, potassium iodide, manganese salts, such as manganese sulphate,
molybdate salts such as sodium molybdate, chromium salts such as chromium chloride,
sodium chloride and potassium chloride. In another embodiment, the second active
agent that may be employed with vitamin C is zinc citrate trihydrate.
While the invention has been described with reference to exemplary embodiments, it will
be understood by those skilled in the art that various changes may be made and
equivalents may be substituted for elements thereof without departing from the scope of
the invention. In addition, many modifications may be made to adapt a particular
situation or material to the teachings without departing from the essential scope thereof.
Therefore, it is intended that the invention not be limited to the particular embodiment
disclosed as the best mode contemplated for carrying out this invention, but that the
invention will include all embodiments falling within the scope of the appended claims.
The invention is further illustrated by the following examples, which are for illustrative
purposes and should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Example 1: Controlled release Vitamin C tablets
Table 1: Composition of vitamin C controlled release tablets
Ingredients mg/unit
Ascorbic acid 500
Glyceryl behenate 75
Microcrystalline cellulose 85
Polyvinylpyrrolidone 32
Hydroxypropylmethylcellulose 150
Magnesium Stearate 8
Total 850
Procedure: Weighed quantity of ascorbic acid was mixed with glyceryl behenate and
microcrystalline cellulose and was passed through 40 mesh sieve and mixed for a period
of 15 min at slow speed. The blend was further mixed at about 70°C for 15 – 20 minutes
and the mass was cooled to 45°C and dried. The treated ascorbic acid was passed
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through oscillator granulator using 20-mesh sieve and blended with
hydroxypropylethylcellulose and polyvinylpyrrolidone for 10 min. The blend was
lubricated using magnesium stearate. The lubricated blend was then compressed into
tablets.
Example 2: Controlled release Vitamin C tablets
Table 2: Composition of vitamin C controlled release tablets
Ingredients mg/unit
Ascorbic acid 500
Glyceryl palmitostearate 50
Microcrystalline cellulose 90
Polyvinylpyrrolidone 25
Hydroxypropylethylcellulose 125
Magnesium Stearate 10
Total 800
Procedure: Weighed quantity of ascorbic acid was granulated using molten glyceryl
palmitostearate and the granules were mixed with microcrystalline cellulose,
polyvinylpyrrolidone and hydroxypropylmethylcellulose. This blend thus obtained was
lubricated using magnesium stearate and the lubricated blend was compressed to get
the tablets.
Example 3: Controlled release Vitamin C tablets
Table 3: Composition of Vitamin C tablets
Ingredients mg/unit
Ascorbic acid 500
Microcrystalline cellulose 95
Glyceryl behenate 25
Povidone 35
Hydroxy propyl methyl cellulose (Methocel K 100 M) 135
Magnesium stearate 10
Total (Core tablet weight) 800
Seal coating
Hypromellose 40
Isopropyl alcohol q.s
14
Purified water q.s
Seal coated tablet weight 840
Final coating
Polyvinyl alcohol (orange color) 23
Orange flavor 0.4
Sucralose 1.6
Purified water q.s.
Total coated tablet weight 865
Procedure: Ascorbic acid was mixed with glyceryl behenate and microcrystalline
cellulose and granulated with povidone solution. The granules were blended with
hydroxypropyl methylcellulose and the blend was mixed with magnesium stearate and
compressed into tablets. The tablets were further coated with seal coat and final coat.
The controlled release tablets of ascorbic acid exhibited desired release profile in 0.1N
HCl using dissolution apparatus II with 900 ml media at 75 rpm.
Time (Hrs) % Release
0 0.0
1 25.0
2 46.7
4 68.9
8 90.2
12 96.5
Example 4: Controlled release Vitamin C and elemental zinc tablets
Table 4: Composition of Vitamin C and elemental zinc tablets
Ingredients mg/tablet
Ascorbic acid 500
Glyceryl behenate 35
Microcrystalline cellulose 95
Povidone 35
Hydroxypropyl methyl cellulose
(Methocel K 100 M)
125
Magnesium stearate 10
Total (Core tablet weight) 800
15
Zinc coating
Zinc citrate trihydrate 15
Polyvinyl pyrrolidone 15
Glycerin 5
Purified water q.s
Seal Coating
Hypromellose 40
IPA q.s
Purified water q.s
Final coating
Polyvinyl alcohol (orange color) 23
Orange flavor 0.4
Sucralose 1.6
Purified water q.s
Total Coated tablet weight 900
Procedure: Ascorbic acid was mixed with glyceryl behenate and microcrystalline
cellulose and granulated with granulating agent povidone solution. The granules were
blended with hydroxypropyl methyl cellulose and the blend was mixed with magnesium
stearate and compressed into tablets. The tablets were further coated with a zinc and
hypromellose. Controlled release tablets of ascorbic acid exhibited desired release
profile.
16
CLAIMS
We claim:
1) A controlled release pharmaceutical composition comprising vitamin C, at least one
glyceryl ester, at least one cellulose ether, and at least one pharmaceutically acceptable
excipient.
2) The composition of claim 1 wherein the vitamin C is natural or synthetic ascorbic acid,
mineral salts of ascorbic acid, acerola vitamin C, rose hip vitamin C, vitamin C with
bioflavonoids, reduced acidity vitamin C, non-acid vitamin C, metabolites, isomers and
mixtures thereof; said vitamin C being present in an amount of about 10% to about 95%
by weight of the composition.
3) The composition of claim 1 wherein the glyceryl ester is glyceryl monooleate, glyceryl
monostearate, glyceryl monolaurate, glyceryl distearate, glyceryl tristearate, glyceryl
tricaprylate, glyceryl behenate, glyceryl dibehenate, and mixtures thereof; said glyceryl
ester being present in an amount of about 0.5% to about 90% by weight of the
composition.
4) The composition of claim 1 wherein the cellulose ether is methylcellulose,
methylhydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose,
hydroxyethyl carboxymethylcellulose, carboxy methylcellulose, carboxymethyl
hydroxyethylcellulose, and mixtures thereof; said cellulose ether being present in an
amount of about 2% to about 80% by weight of the composition.
5) The composition of claim 1 wherein the pharmaceutically acceptable excipient is diluent,
lubricant, granulating agent, colorant, flavorant, sweetener, surfactant, pH adjuster, antiadherent,
glidant or combinations thereof.
6) The composition of claim 1 wherein the composition provides in-vitro release of about 4
hours or more.
7) The composition of claim 1 wherein the composition is in the form of a tablet.
8) The composition of claim 1 wherein the composition is further coated with a coating
system comprising at least one polymer.
9) A controlled release pharmaceutical composition comprising granules comprising vitamin
C and glyceryl behenate dispersed in a matrix comprising hydroxypropyl methylcellulose
and at least one pharmaceutically acceptable excipient.

10) The composition of claim 1, wherein the controlled release pharmaceutical composition further comprises an additional active agent in an immediate or sustained release manner.