The present invention relates to a pharmaceutical composition for oral administration. More particularly, relates to such compositions in the form of controlled release system for delivery of active agents and the uses thereof in therapy.
BACKGROUND OF THE INVENTION
Controlled release formulation is important to improve therapeutic efficacy and to reduce the side effects. The controlled release formulations are convenient for patients as dosage frequency is reduced. The effective cost of the treatment is also reduced and hence it is useful in achieving low cost therapy. The industrial application is also an important factor which forces to use this technique of formulation of altered release beads and its evaluation so that it can be utilized for the production of low cost and highly effective treatments. Controlled release systems continue to be the most popular ones among all the drug delivery systems. It offers several advantages over the conventional systems like better plasma level profile, lower dose and less toxicity. Conventional single unit sustained release dosage forms could be disastrous if they fail to release the drug at the desired rate and in the desired amount, or if they release the entire amount of drug at once and cause dose dumping.
Sodium alginate (SA) is a naturally occurring biocompatible, biodegradable, bioadhesive biopolymer and is capable of rate and/or time-controlled drug release. Alginate microspheres have the advantage of controlling the drug release, prolonged drug residence time, thereby reduced dosing frequency, increased systemic bioavailability and improved patient compliance.
The present investigation includes the aim to prepare alginate microspheres by ionotropic gelation technique. The water based ionic cross-linking technique can provide characteristic advantage over conventional multi-particulate method which involves an "all-aqueous" system and avoids residual solvents in microspheres. L- arginine is well known for its potential to produce nitric oxide which is utilized

by enzymes in our body to regenerate cells or for the growth of cells and hence the liver regeneration activity which will be performed on formulated beads, will definitely be an important work in the course of this study.
The liver's ability to regenerate is known since ancient times and has been the subject of scientific study since the early 20th century. After a partial hepatectomy (removal of a section of the liver), liver cells reenter the cell cycle and replicate until the liver recovers its lost mass, within a precision of 10%. Various studies have shown that L-arginine helps in regeneration of liver cells. As metabolism of L-arginine to L-citruline produces NO which is proved to be essential for the regeneration of cells.
The following prior art is being reported:
Application number US40223792 relates to an oral formulation of arginine a-ketoglutarate is disclosed which formulation is comprised of arginine a-ketoglutarate and one or more excipient materials.
Application number CN133557664 relates to an auxiliary material for medicine production, and relates to a controlled-release medicine auxiliary material for improving the stability of a main medicine. The stability of the main medicine is remarkably improved, the preservation period of the medicine is prolonged, and meanwhile the effect of controlled-release is achieved. The auxiliary material is L-arginine-alpha-ketoglutarate, wherein L-arginine and alpha-ketoglutarate are reacted to prepare a salt in a ratio of 2 to 1; the weight ratio of L-arginine-alpha-ketoglutarate added into the medicine to the main medicine is (10: l)-(50:1).
Application number US39549762 relates to various controlled release pharmaceutical compositions that include an agent that enhances or modulates the endogenous production of nitric oxide in a mammal. Controlled release pharmaceutical compositions of L-arginine, its salts, peptides, and biological equivalents, together with methods of using the compositions are included. Also included are controlled release pharmaceutical compositions of botanical

extracts that modulate or enhance the production of nitric oxide, either alone or in combination with L-arginine or its biological equivalent.
Application number CN83411598 relates to The invention discloses a preparation method of sustained release Arginine for fishery. The procedure is carried out as follows. 1) preparation of Montmorillonite suspension slurry. 2) adsorption and ion exchange reaction between Montmorillonite and Arginine. 3) chelation reaction among montmorillonite, Arginine and copper. 4) washing, dehydration, baking and crushing.
Application number WO2002000212 relates to A sustained release formulation of L-arginine alone or in combination with an agent which enhances the biotransformation of L-arginine into NO is described herein. Figure 1A shows a schematic representation of proposed L-arginine dependent and independent pahtways.
Application number WO2001028538 relates to L-arginine, a derivative thereof or a pharmaceutically acceptable salt thereof for use as a laxative, for treatment of constipation and for clearing the rectum and/or the colon of a mammal. Composition suitable for topical administration to an area of the gastrointestinal tract are provided. Orally administered preparations comprising for example an enteric coating that dissolves at a desired location in the gastrointestinal tract; a controlled release formulation; a sustained release formulation; a targeted drug delivery system; or a combination thereof are also provided.
Application number WO2003094909 provides methods for the treatment and prevention of intermittent claudication or Alzheimer's disease in a subject, comprising administering to a subject a formulation comprising a precursor of NO, e.g., L-arginine and a formulation comprising an agonist of eNOS, e.g., and HMG-CoA reductase inhibitor, or a formulation comprising both L-arginine and an HMG-CoA reductase inhibitor. The invention further provides that the

formulations used to treat or prevent intermittent claudication or Alzheimer's disease contain at least one controlled release agent. In a further embodiment, the production of NO is substantially uniform over a prolonged period of time.
Application number US173382674 relates to a controlled release biocidal salt of a first component comprises a cation of a N ester cationic biocidal molecule and a second component comprising an anion of a monomeric anionic molecule having insignificant biocidal activity. The salt is characterized such that when the salt is exposed to an aqueous medium, the salt partially dissolves thereby releasing biocidal ions in an amount sufficient to exceed the MIC or MBC of a target bacteria being controlled, and further characterized as leaving a residual reservoir of undissolved salt capable of releasing more biocidal ions as the salt is consumed or otherwise removed from the environment encompassing the target bacteria. The preferred cationic biocidal molecule comprises Na-lauroyl-L-arginine ethyl ester ("LAE").
Application number CN82681759 relates to calcium alginate/PAA-chitosan compound drug controlled-release microcapsule and making method. The microcapsule is double-component single-layer film compound one or double-component double-layer film compound one. It uses static combination, uses PAA-chitosan as film material, and uses high-pressure static liquid drop generator to make the microcapsule, using sodium alginate to decorate surface, the particle size even and controllable, within 200-1000 micro meter, and the particle surface glabrous.
Application number RU75887084 relates to microsphere with controlled release, which has covering layer and contains core, which contains exendin as active ingredient and biodegradable polymer, and covering layer, which covers core with covering material, exendin being exendin-4 (SEQ ID NO:2), biodegradable polymer represents polymer, selected from group, consisting of polylactide (PLA), polyglycolide (PGA), lactide and glycolide copolymer (PLGA),

polyorthoester, polyanhydride, polyhydroxybutyric acid, polycaprolactone and
polyalkylcarbonate; copolymer or simple mixture of two or more polymers,
selected from said group of polymers; copolymer of said polymer and
polyethylene glycol (PEG); or polymer-sugar complex, in which sugar is bound
5 with said polymer or said copolymer, covering material is selected from group,
consisting of essential amino acids, polypeptides and organic nitrogenous
compounds, essential amino acid being one or more, selected from group,
consisting of arginine, lysine and histidine; polypeptide represents L-Lys-L-Thr-
L-Thr-L-Lys-L-Ser; and organic nitrogenous compound is selected from group,
10 consisting of creatine, creatinine and urea, content of covering layer constitutes
from 0.01 to 5 wt fractions in terms per 100 wt fractions of microsphere.
OBJECTS OF THE INVENTION
Some of the objects of the present disclosure, which at least one embodiment
15 herein satisfies, are as follows.
It is an object of the present disclosure to ameliorate one or more problems of the
prior art or to at least provide a useful alternative
An object of the present disclosure is to provide a novel hepatoprotective oral
20 micro bead drug delivery system for controlled release of therapeutically active L-
Arginine for therapeutic use.
Another object of the present disclosure is to provide such a delivery system that
improved patient compliance and comfort.
Still another object of the present disclosure is to provide for such a composition
25 which is stable over time.
Another object of the present disclosure is to provide for better efficacy compared
to other conventional and controlled release dosage forms.
Still another object of the present disclosure is to provide for provide such a
dosage form that can be easily manufactured.
30 Still another object of the present disclosure is to provide for such a delivery
system that reduces the frequency of dosage administration.
6

Still another object of the present disclosure is to provide for drug loading and drug release prolongation.
Yet another object of the present disclosure is to provide for a composition with
desirable characteristics like favorable size of beads along with flowability,
5 slipperiness, easy swallowability, moisture retention, taste masking improved
drug delivery, drug entrapment and drug loading.
Yet another object of the present disclosure is to provide for a composition capable of hepatoprotection.
Other objects and advantages of the present disclosure will be more apparent from
10 the following description, which is not intended to limit the scope of the present
disclosure.
SUMMARY OF THE INVENTION
The following presents a simplified summary of the invention in order to provide
15 a basic understanding of some aspects of the invention. This summary is not an
extensive overview of the present invention. It is not intended to identify the key/critical elements of the invention or to delineate the scope of the invention. Its sole purpose is to present some concept of the invention in a simplified form as a prelude to a more detailed description of the invention presented later.
20
Oral drug delivery systems can be divided into immediate release and modified release systems. Immediate release dosage forms are those which disintegrate rapidly and get dissolved to exhibit instant drug release. Immediate release may be provided by way of an appropriate pharmaceutically acceptable diluents or
25 carrier, which does not prolong, to an appreciable extent, the rate of drug release
and/or absorption cause fast increased and decreased absorption of drug. This absorption pattern leads to reduction or loss in drug effectiveness or increased incidence of side effects. Administration of the immediate released drug delivery system requires to be administered frequently therefore it is necessary to
30 compensate the decrease in drug plasma concentration due to metabolism and
excretion.
7

I. It is an embodiment of the present invention that the pharmaceutical
controlled release composition comprises L-Arginine, Sodium alginate,
Calcium chloride, Xanthan, Bentonite and Aminoalkyl methacrylate
copolymer.
5 2. It is an embodiment of the present invention that the composition produces
beads in a very narrow size range, the standard deviation being less than 0.5 mm.
3. It is an embodiment of the present invention that the composition to provide a
novel hepatoprotective oral micro bead drug delivery system for controlled
10 release of therapeutically active L-Arginine for therapeutic use.
4. It is an embodiment of the present invention that the composition is to provide such a delivery system that improved patient compliance and comfort.
5. It is an embodiment of the present invention that the composition is to provide for such a composition which is stable over time.
15 6. It is an embodiment of the present invention that the composition is to provide
for better efficacy compared to other conventional and controlled release dosage forms. 7. It is an embodiment of the present invention that the composition is to provide for provide such a dosage form that can be easily manufactured.
20 8. It is an embodiment of the present invention that the composition is to provide
for such a delivery system that reduces the frequency of dosage administration. 9. It is an embodiment of the present invention that the composition is to provide for drug loading and drug release prolongation.
25 10. It is an embodiment of the present invention that the composition is to provide
for a composition with desirable characteristics like favorable size of beads along with flowability, slipperiness, easy swallowability, moisture retention, taste masking improved drug delivery, drug entrapment and drug loading.
II. It is an embodiment of the present invention that the composition is to provide
30 for a composition capable of hepatoprotection.
12. It is an embodiment of the present invention that the process of preparation of controlled release formulation comprises
8

a. mixing sodium alginate in a small amount of distilled water;
b. adding L-Arginine, Xanthan, Bentonite and Aminoalkyl methacrylate
copolymer into sodium alginate solution with stirring;
c. preparing separately calcium chloride (4, 6 and 8%w/v) solution by
5 dissolving in water.
d. adding drug containing sodium alginate solution drop wise into
calcium alginate solution leading to formation of beads.
The said composition provides favorable size to the beads along with flowability, slipperiness, easy swallowability, retains moisture for longer duration. The
10 composition is a taste masked preparation. The preparation has improved drug
delivery, drug entrapment and drug loading with first order release.
The process involved is a simple process. In fact it is an easy one step process of mixing the ingredient in particular order to achieve the solution. The components of the composition are carefully selected after due experimentation in the
15 particular concentration so as to provide for all the desirable characteristics in a
single formulation.
DETAILED DESCRIPTION OF THE INVENTION
The following description is of exemplary embodiments only and is not intended
20 to limit the scope, applicability or configuration of the invention in any way.
Rather, the following description provides a convenient illustration for implementing exemplary embodiments of the invention. Various changes to the described embodiments may be made in the function and arrangement of the elements described without departing from the scope of the invention. 25
Oral drug delivery systems can be divided into immediate release and modified
release systems. Immediate release dosage forms are those which disintegrate
rapidly and get dissolved to exhibit instant drug release. Immediate release may
be provided by way of an appropriate pharmaceutically acceptable diluents or
30 carrier, which does not prolong, to an appreciable extent, the rate of drug release
and/or absorption cause fast increased and decreased absorption of drug. This
9

absorption pattern leads to reduction or loss in drug effectiveness or increased
incidence of side effects. Administration of the immediate released drug delivery
system requires to be administered frequently therefore it is necessary to
compensate the decrease in drug plasma concentration due to metabolism and
5 excretion.
Modified release systems (controlled/sustained/extended/modified release dosage
form) have been developed to improve the pharmacokinetic profiles of active
pharmaceutical ingredients, patient compliance, as well as reducing dosing
10 frequency and side effects.
Oral modified release drug delivery systems are most commonly used for
Delayed release (e.g., by using an enteric coating);
Extended release (e.g., zero-order, first-order, biphasic release, etc.);
Programmed release (e.g., pulsatile, triggered, etc.) and
15 Site specific or timed release (e.g., for colonic delivery or gastric retention).
Controlled/sustained/extended/modified release dosage form are the alternative terms used to describe the controlled released drug delivery system developed with predictability and reproducibility in the drug release kinetics. Delayed
20 release dosage forms are the oral dosage forms which prevent immediate
disintegration and release the active ingredient(s) into the body. Oral extended release dosage forms offer the opportunity to provide constant or nearly constant drug plasma levels over an extended period of time following administration Extended release dosage forms include single-unit, such as tablets or capsules,
25 and multiple-unit dosage forms, such as mini-tablets, pellets, beads or granules,
either as coated (reservoir) or matrix devices.
Primary aim of oral control drug delivery systems is designed to achieve more
predictable and increased bioavailability. Now a day hundreds of the drugs are
30 available in market as oral DDS because of improved patient’s compliance and
ease of administration. Hence most of the pharmaceutical researches are focused
10

on development of oral controlled DDS. Oral controlled DDS have advantage of
single dose for the whole duration of treatment and it delivers the active drug
directly at the specific site. Scientists have succeeded to develop a system and it
encourages the scientists to develop control release systems. Controlled release
5 DDS includes any drug delivery system that achieves slow release of drug over a
prolonged/extended period of time. Advantages of modified released DDS compared to conventional DDS are as:
1. Therapeutic advantage: Reduction in drug plasma level fluctuations by
10 maintenance of a steady plasma level of the drug over a prolonged time period can
be obtained.
2. Reduction in adverse effects: A drug plasma level is maintained and
shows improvement in tolerability within a narrow therapeutic window with no
sharp peaks hence it greatly reduces the chances of side effects.
15 3. Improved Patient compliance: Patient compliance can be improved by oral
modified DDS in case of long-term treatment of chronic disease because of reduced dosing frequency.
4. Reduced total dose and healthcare cost: It requires use of less amount of
total drug to treat the diseased condition hence total cost of therapy could be lower
20 as compared to immediate-release product with reduced side effects.
EXAMPLES
EXAMPLE 1: PRELIMINARY STUDIES
25 General Composition of L-arginine beads for Initial Studies

Ingredients (%) FC1 FC 2 FC 3 FC4 FC5 FC6 FC7
L-Arginine 1 1 1 1 1 1 1
Sodium alginate 3 3 3 3 3 3 3
11

Calcium chloride 4 4 4 4 4 4 4
Xanthan - 1.2 0.6 1 0.5
Bentonite - 0.6 1 0.5 1
Aminoalkyl methacrylate copolymer - 5 5 5
Water (upto) 100 100 100 100 100 100 100
During preliminary studies, various formulations were prepared using different ratios of the ingredients. It was done to aid in choosing the suitable coating agent.
5 EXAMPLE 2 PREPARATION OF ALGINATE BEADS
The beads were prepared by using ionic gelation method. Sodium Alginate (SA) solutions (4%, 6% and 8% w/v) were prepared by dissolving 4, 6 and 8g of SA in a small amount of distilled water using mortar pestle. When smooth solution was formed, the volume was made up to 100mL. L-Arginine, Xanthan, Bentonite and Aminoalkyl
10 methacrylate copolymer was added into each SA solution with 15 min stirring on
magnetic stirrer to form a smooth solution; calcium chloride (CC) (4, 6 and 8%w/v) was dissolved Water. This solution was stirred for further 30 min. The bubble free drug containing SA solution (200mL) was then added drop wise (1mL/m) using through 21 gauge needle fitted with 10 mL glass syringe into 100 mL solution of CC solution. This
15 resulted in the formation of beads.

Ingredients (%) Quantity %
L-Arginine 0.1-5
Sodium alginate 2-10
Calcium chloride 1-10
Xanthan 0.5-8
12

Bentonite

0.1-8

Aminoalkyl methacrylate 1-20 copolymer
EXAMPLE 3 FLOW PROPERTIES, BEADS SIZE AND UNIFORMITY
Alginate beads of the uniform size, shape and density were formulated by keeping
various factors constant viz. falling rate of drops, stirring rate, viscosity as well as
5 distance between gelation media and syringe. Any change in these factors may
result in non-homogenous and non-uniform beads.
Microspheres were found to be discrete, spherical, free flowing and of monolithic
matrix type. The microspheres were uniform in size for each batch. By observing
the surface of beads closely small cracks were observed that are may be caused by
10 partial collapsing of the polymer network during dehydration. In contrast, ethanol
drying caused significant improvement in maintaining the spherical shape as well as decrement of the cracks on the surface. The size variation in bead size is very narrow which is very unique to the invention.
15 EXAMPLE 4: DRUG ENTRAPMENT EFFICIENCY (DEE)
Accurately weighed amount of beads (100 mg) were suspended in 50mL of
standard phosphate buffer of pH 6.8±0.1 and kept for 24 h. On the next day, it was
stirred for 5 m and then filtered. After suitable dissolution, the drug content in the
filtrate was determined by HPLC.
20 Efficiency of drug entrapment was calculated in terms of percentage drug
entrapment (%DEE) as per the following equation:
Actual amount of drug loaded
%DEE= X100
Theoretical amount of drug loaded
25 EXAMPLE 5: IN-VITRO DRUG RELEASE STUDY
In-vitro release studies were carried out on formulated beads using USP XXIV dissolution test apparatus-I. Accurately weighed quantity of beads was suspended
13

in pH 1.2 gastric media. This medium was stirred at 120 rpm and maintained at
37±0.1°C. The formulated beads were tested for drug release for 2 h in 0.1 N HCl.
The dissolution medium was replaced with phosphate buffer pH 6.8±0.1 and
tested for drug release for next 10 h. Samples were withdrawn at appropriate
5 intervals from both media and replaced by fresh media. The amount of L-arginine
was determined by HPLC equipped with UV-detector at 210 nm. The release studies were conducted in triplicate. The results of in-vitro release data were fitted into various release equations and kinetic models.
10 EXAMPLE 6: STABILITY STUDIES
Optimised formulation was also subjected to accelerated stability studies to determine the changes in BS, SI, DEE and release profile on storage. The stability studies were carried out at 40±2°C/75±5% relative humidity (RH) for 6 months (zone II conditions as per ICH Q1 guidelines) in an environment chamber (Jindal
15 S.M. Scientific 216, New Delhi). The samples were withdrawn periodically and
evaluated.
Characterization of formulated L-arginine beads for preliminary study

Formulation code %Yield Bead Size (mm) Swelling Index (%) DEE (%)


pH 1.2 pH 6.8
FC 1 45±0.12 1.153±0.23 43±0.43 278±0.92 41.00±0.31
FC2 76±1.52 1.182±0.42 79±0.99 269±3/05 61.46±0.71
FC3 79±2.01 1236±0.21 85±1.03 275±1.32 63.73±0.33
FC4 83±0.23 1.543±0.11 90±2.48 282±1.18 66.18±0.14
FC5 78±0.98 1.237±0.28 83±0.09 279±1.72 66.97±1.2
FC6 82±1.02 1.286±0.03 89±1.07 288±0.11 70.57±0.58
FC7 84±2.31 1.388±0.30 97±3.13 301±1.20 71.58±0.84
14

EXAMPLE 7: HEPATO-PROTECTIVE STUDY
Hepatoprotective study of L-arginine was determined as follows:
Paracetamol-induced liver damage in rats: Animals studies were carried out using
5 Wistar albino rats (150-180 g) of either sex. The animals were obtained from the
animal house, Indian Veterinary Research institute (IVRI), Bareilly, India. The animals were kept in standard laboratory conditions and having free access to food and water. The animal experiment protocol was approved by IAEC. The rats were randomly distributed in five groups (six rats in each group):
10 Group I (control group) received normal diet.
Group II: The animals of this group received paracetamol 2000 mg/kg of b.w. in distilled water to induce hepato-toxicity for 7 days. During the procedure no other treatment was given to this group which severed as positive control. Test preparations were administered after induction of hepatotoxicity for 7 days.
15 Group III i.e. group was received paracetamol 2000 mg/kg (1 ml tween/kg b.w.)
of body weight in 1mL of distilled water. After confirmation of hepatotoxicity, animals were treated orally with F1 (100 mg/kg of b.w.).
Group IV received paracetamol 2000 mg/kg of body weight in 1ml of distilled water. After confirmation of hepatotoxicity, animals were treated orally with F3
20 (equivalent to 100 mg/kg of b.w.).
Group V was given Paracetamol 2000 mg/kg of body weight in 1mL of distilled water. After confirmation of hepatotoxicity, animals were treated orally with F6 (equivalent to 100 mg/kg of b.w.). Prepared formulations were administered by oral route using plastic catheter.
25
Biochemical studies
The blood (3mL) as obtained from all animals by puncturing retro-orbital plexus. The blood samples were allowed to clot for 45 m at room temperature. Serum was separated by centrifugation at 2500 rpm at 30°C for 15 m and utilized for the
30 estimation of various bio-chemical parameters namely SGPT.
15

Estimation of Transaminase
Serum Glutamate Pyruvate Transaminase (SGPT)
The SGPT catalyzes the transfer of amino group from L - Alanine to L -
Ketogluatarate with the formation of Pyruvate and Glutamate. The Pyruvate so
5 formed is allowed to react with 2, 4 DNPH to produce 2: 4
dinitrophenylhydrazone derivative which is brown coloured in alkaline medium. The absorbance of this hydrozone derivative is correlated to SGPT activity by plotting a calibration curve between Pyruvate.
10 Serum Glutamate Oxaloacetate Transaminase (SGOT)
SGOT catalyzes transfer of amino group from L- Aspartate to L - Ketoglutarate with formation of Oxaloacetate and glutamate. The Oxaloacetate so formed, is allowed to react with 2, 4, DNPH to form 2, 4 dinitrophenylhydrazone derivative which is brown coloured in alkaline medium. The absorbance of this hydrazone
15 derivative is correlated to SGOT activity by plotting a calibration curve using
pyruvate standard.
Estimation of Serum Alkaline Phosphatase (SALP)
Serum SALP hydrolyzes phenyl phosphate into phenol and disodium hydrogen
20 phosphate at pH 10.0. The phenol so formed acts with 4-amino antipyrine in
alkaline medium in presence of oxidizing agent potassium ferricyanide to form a red colored complex whose absorbance is proportionate to the enzyme activity.
Estimation of Total Bilirubin
25 Bilirubin reacts with diazoties sulfanilic acid in acidic medium to form
azobilirubin, a purple coloured complex whose absorbance is proportional to bilirubin concentration. Assessment of total bilirubin (direct and Indirect) by diazotization method is carried out in the presence o f an activator. Direct bilirubin, being water soluble is allowed to react with diazotized sulfuric acid in
30 the absence of an activator.
16

Liver weight
Liver was carefully excised and washed in ice cold normal saline solution and
pressed between filter paper pads and weighed. A portion of liver (one animal of
each group) was preserved in 10% neutral formalin for histopathology.
5
Histopathological Studies
On the eight day surviving animals from each group were sacrificed by
decapitation and the histopathological techniques. The liver was carefully
dissected out, extraneous tissue was cleaned of and then wet weights were noted.
10 The part of the liver was fixed in formalin and processed for microtome
sectioning at 5 micron thickness, stained with haematoxylin and eosin. The
damaged produced in the liver structure in the form of degeneration, necrosis and
fibrosis was graded.
Groups SGPT(I SGOT(IU/ SALP(IU/ Total Liver
bilirubi weight
U/L) L) L) n (mg/100g
(mg/dL m body
) weight)
Normal
Paracetamol; (2000mg/kg)
F1 + Paracetamol (2000 mg/kg)
F3 + Paracetamol (2000mg/kg)
F6 + Paracetamol (2000mg/kg) 81.17 ±
6.20 354.92. ± 1.65 161.74±6. 21 0.45±0. 20 3.635±0.1 34

262.11. ± 2.65 456.12. ± 4.19 482.41 ± 6.29 2.29 ± 0.85 4.75±0.11

92 .04± 4.77 393.65. ± 4.45 336.25 ± 5.33 0.47 ± 0.21 4.005±0.1 05

77.97± 4.13 374.28. ± 4.58 328.69 ±
5.35 0.42 ± 0.19 3.57±0.26

84.44±
5.22 388.72 ± 4.38 323.85 ± 4.48 0.32 ± 0.13 3.86±1.02
1
17

Statistical Analysis
To achieve a meaningful conclusion, the data were analyzed by standard statistical procedures. Average and standard errors were calculated at different days after treatment and also in different treatment groups, for each of the parameter studied. In order to investigate the effect of days of treatment (0 -7 days) as well as the effect of the treatment groups on different biochemical constituents and enzymes one way ANOVA was carried out. Whenever an effect was found to be significant the critical difference (CD) test were carried out in order to compare the subclass means for significance. All experiments were repeated for three times. Results are reported as means ± SEM.
Evaluation Parameter Results

Lag Time (Sec) 86±1.33
pH 7.4±0.2
Drug Content (%) 100±0.81
Cumulative Drug Release (12 hours) (%) 49.66± 0.63
Cumulative Drug Release (24 hours) (%) 92.77±0.28
Kinetic data value (r2) coefficient of regression 0.9973
Kinetic model fit First order
While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art 25 from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.

Claim,

A pharmaceutical controlled release composition comprising L-Arginine,
Sodium alginate, Calcium chloride, Xanthan, Bentonite and Aminoalkyl
methacrylate copolymer.
A pharmaceutical controlled release composition as claimed in claim 1,
wherein the composition produces beads have a size range variation of less
than 0.5mm.
A pharmaceutical controlled release composition as claimed in claim 1,
wherein the composition is stable over six months.
A pharmaceutical controlled release composition as claimed in claim 1,
wherein the composition demonstrates improved efficacy.
A pharmaceutical controlled release composition as claimed in claim 1,
wherein the composition has favorable size of beads, flowability, slipperiness,
easy swallowability, moisture retention, taste masking, drug delivery, drug
entrapment and drug loading.
A process of preparation of controlled release composition which comprises of
L-Arginine, Sodium alginate, Calcium chloride, Xanthan, Bentonite and
Aminoalkyl methacrylate copolymer thereof, characterized in that; said
process of preparation comprises of following steps;
mixing sodium alginate in a small amount of distilled water;
adding L-Arginine, Xanthan, Bentonite and Aminoalkyl methacrylate
copolymer into sodium alginate solution with stirring;
preparing separately calcium chloride (4, 6 and 8%w/v) solution by
dissolving in water.
adding drug containing sodium alginate solution drop wise into
calcium alginate solution leading to formation of beads.