PATEL HARDIK S by m73f69w



                SYNOPSIS FOR

                SUBMITTED TO


               PATEL HARDIK S.
                 I M. PHARM.

                        BANGALORE, KARNATAKA


1.    Name of the candidate and        PATEL HARDIK S.
      address (in block letters)       I M. PHARM.,
                                       DEPARTMENT OF PHARMACEUTICS,
                                       DAYANANDA SAGAR COLLEGE OF
                                       KUMARASWAMY LAYOUT,

                                       PERMANENT ADDRESS

                                       95, GURUKRUPA SOCIETY,
                                       NEAR G.E.B.,
                                       PATAN- DISTRICT,

2.    Name of the institute            Dayananda Sagar College of Pharmacy,
                                       Shavige Malleswara Hills,
                                       Kumaraswamy Layout,

3.    Course of study and subject      Master of Pharmacy in Pharmaceutics

4.    Date of admission to course      17th March 2008

5.    Title of the project:

6.   Brief resume of the intended work:

     6.1 Need of the study:

     The goal of designing sustained or controlled release matrix delivery systems is to
     maintain therapeutic blood or tissue levels of the drug for extended period of time,
     to reduce frequency of dosing or to increase the effectiveness of the drug by
     localizing at the site of action, reducing the dose required, or providing uniform
     drug delivery.

     Hydrophilic polymer matrix systems are widely used in oral controlled drug
     delivery because of their flexibility to obtain a desirable drug release profile, cost-
     effectiveness, and broad regulatory acceptance. The ability of the hydrophilic
     polymer matrices to release an entrapped drug in aqueous medium and to regulate
     the release of such drug by control of swelling and cross-linking makes them
     particularly suitable for controlled release applications. Sustained release can be
     achieved by formulating drugs as matrix tablets using hydroxypropylmethyl
     cellulose, sodium carboxymethyl cellulose and other swellable polymer. These
     matrices can be applied for the formulation of both hydrophilic and hydrophobic
     drugs and charged solutes.

     Fluoroquinolone antimicrobial agents are broad-spectrum antibacterial agents with
     excellent in vitro activity against gram-negative organisms and variable activity
     against gram positive cocci and anaerobes. Levofloxacin, the active component of
     the racemate ofloxacin, has been studied for a variety of clinical conditions
     including acute sinusitis, lower respiratory tract infections, uncomplicated skin and
     soft-tissue infections, and complicated urinary tract infections and has been shown
     to be effective against a variety of pathogens such as members of the family
     Enterobacteriaceae, Pseudomonas aeruginosa, and commonly isolated gram-
     positive organisms such as Staphylococcus aureus and Streptococcus pneumoniae.
     As a single isomer, levofloxacin appears to possess more potent microbiologic
     activity than other currently marketed quinolones, while it preserves the
pharmacokinetic and safety profiles of its racemic predecessor, ofloxacin.

So designing a sustained release formulation for the drug levofloxacin may
therapeutic concentration of drug in the blood and decrease the frequency of
dosing and also improve the efficacy of drug and patient compliance.

So in the present study, attempts will be made to formulate a sustained release
matrix tablet for the broad spectrum antimicrobial levofloxacin.
6.2 Review of literature

An attempt was made to develop sustained release matrix tablets of lithium
carbonate1 using different types and ratios of polymers including carbomer (CP),
sodium carboxymethylcellulose (Na CMC) and hydroxypropylmethylcellulose
(HPMC), to assess the release profiles and in vivo performance of the
formulations. The tablets were prepared by either direct compression (DC) or wet
granulation (WG). In vitro and in vivo studies were carried out to compare the
newly formulated sustained-release lithium carbonate tablets with sustained
release commercial tablets. The matrix tablets containing 15% CP reduces the
incidence of side effects often associated with high serum concentration of lithium
and blood level variations. Direct correlation between the dissolution profiles and
the relative bioavailability of the formulations could be observed.

A study investigated the possibility of developing once-daily sustained release
matrix tablets of nicorandil2. The tablets were prepared by wet granulation method.
Ethanolic solutions of ethylcellulose (EC), Eudragit RL-100, Eudragit RS-100, and
polyvinylpyrrolidone were used as granulating agents along with hydrophilic
matrix    materials    like   hydroxypropylmethylcellulose       (HPMC),      sodium
carboxymethylcellulose, and sodium alginate. The tablets were subjected to
thickness, diameter, weight variation test, drug content, hardness, friability, and
in vitro release studies. All the tablet formulations showed acceptable
pharmacotechnical properties and complied with in-house specifications for tested
parameters. The results of dissolution studies indicated that formulation F-I (drug-
to-HPMC, 1:4; ethanol as granulating agent) could extend the drug release upto
24 hours. In the further formulation development process, F-IX (drug-to-HPMC,
1:4; EC 4% wt/vol as granulating agent), the most successful formulation of the
study, exhibited satisfactory drug release in the initial hours, and the total release
pattern was very close to the theoretical release profile.
A study described the pharmacokinetics of levofloxacin3 by a linear two
compartment open model with first order elimination. Plasma concentrations in
healthy volunteers reach a mean peak drug plasma concentration (Cmax) of
approximately 2.8 and 5.2 mg/L within 1 to 2 hours after oral administration of
levofloxacin 250 and 500mg tablets, respectively. The bioavailability of oral
levofloxacin approaches 100% and is little affected by the administration with
food. Oral absorption is very rapid and complete, with little difference in the serum
concentration-time profiles following 500mg oral or intravenous (infused over
60 minutes) doses. Levofloxacin is widely distributed throughout the body, with a
mean volume of distribution of 1.1 L/kg, and penetrates well into most body
tissues and fluids. Drug concentrations in tissues and fluids are generally greater
than those observed in plasma, but penetration into the cerebrospinal fluid is
relatively poor (concentrations approximately 16% of simultaneous plasma
values). Levofloxacin is approximately 24 to 38% bound to serum plasma proteins
(primarily albumin); serum protein binding is independent of serum drug
concentrations. The plasma elimination half-life ranges from 6 to 8 hours in
individuals with normal renal function. Approximately 80% of levofloxacin is
eliminated as unchanged drug in the urine. Levofloxacin pharmacokinetics are not
appreciably affected by age, gender or race when differences in renal function, and
body mass and composition are taken into account.

An attempt was made to formulate and evaluate hydrophilic matrix tablets of
diltiazem hydrochloride4 to achieve a controlled and sustained drug release. Matrix
tablets of diltiazem hydrochloride were prepared using polymers like hyroxy
propyl methyl cellulose (HPMC K15, HPMC K4), sodium carboxy methyl
cellulose (SCMC) and Guar gum, and different diluents like lactose, starch,
microcrystalline cellulose. All the batches were evaluated for thickness, weight
variation, hardness, drug content uniformity and in vitro drug release
characteristics as per USP XXIV monograph. The drug release rates from matrix
tablets were compared with marketed SR formulations. Matrix erosion and
swelling studies were also carried out. The release kinetics and mechanism of drug
release by regression coefficient analysis and Peppas exponential release model
equation were also investigated. SCMC matrix tablets showed more hydration and
erosion than other matrix tablets. Tablets having HPMC K15 gave more sustained
release than other hydrophilic polymers studied and it was comparable with
marketed SR tablets. Amount of HPMC K15 and presence of different diluents
significantly affected the drug release. It was observed that all the fabricated
tablets delivered the drug following Higuchi diffusion mechanism.

A once in daily sustained release matrix tablet of ibuprofen5 was developed using
hydroxypropyl methylcellulose as release controlling factor and to evaluate drug
release parameters as per various release kinetic models. In order to achieve
required sustained release profile, tablets were directly compressed using Avicel
pH 101 and magnesium stearate. The formulated tablets were also characterized
for physical and chemical parameters and results were found in acceptable limits.
Different dissolution models were applied to drug release data in order to evaluate
release mechanisms and kinetics. Criteria for selecting the most appropriate model
were based on linearity (coefficient of correlation). The drug release data fit well
to the Higuchi expression. Drug release mechanism was found as a complex
mixture of diffusion, swelling and erosion.

A study examined the possibility of preparing sustained release pellets of
ofloxacin6. The pellets were subjected to a coating process with methacrylic acid
copolymers to produce sustained release characteristics. The pellets with different
coatings were investigated by release tests in vitro. Finally, pellets with the best
coating suspension were subjected to a multiple doses pharmacokinetic study. The
in vitro release profiles showed that pellets coated with Eudragit NE30D and
Eudragit L30D55, at a ratio of 1:8 (w/w) and a coating level of 8% with diethyl
phthalate plasticizer equivalent to 10% of solid material in the coating suspension
were suitable for sustained release. In the bioavailability study, the principal
pharmacokinetic parameters showed there were differences between the sustained
release pellets and the conventional ofloxacin capsules. The relative bioavailability
of ofloxacin sustained release pellets compared with conventional ofloxacin
capsules was 116.35 ± 33.31%. All the statistics indicated that the preparation has
a sustained release effect with many advantages over conventional preparations.

An attempt was made to produce a quick/slow biphasic delivery system for
ibuprofen7. A dual-component tablet made of a sustained release tableted core and
an immediate release tableted coat was prepared by direct compression. Both the
core and the coat contained a model drug, ibuprofen. The sustained release effect
was achieved with a polymer, hydroxypropyl methylcellulose (HPMC) or
ethylcellulose to modulate the release of the drug. The in vitro release studies
showed the desired biphasic release behavior, depending on the composition of the
matrix tablet. And it was concluded that the HPMC core was suitable for providing
a constant and controlled release for a long period of time.

A study investigated the use of sodium alginate for the preparation of hydrophilic
matrix tablets intended for prolonged drug release using ketoprofen8 as a model
drug. The matrix tablets were prepared by direct compression using sodium
alginate, calcium gluconate, and hydroxypropylmethylcellulose (HPMC) in
different combinations and ratios. In vitro release tests and erosion studies of the
matrix tablets were carried out in USP phosphate buffer (pH 7.4). Matrices
consisting of sodium alginate alone or in combination with 10% and 20% of
HPMC give a prolonged drug release at a fairly constant rate. Incorporation of
different ratios of calcium gluconate leads to an enhancement of the release rate
from the matrices and to the loss of the constant release rate of the drug. Only the
matrices containing the highest quantity of HPMC (20%) maintained their capacity
to release ketoprofen for a prolonged time.

A sustained release matrix tablet was developed for highly water soluble tramadol
hydrochloride9 using natural gums (xanthan and guar gum) as cost effective,
nontoxic, easily available, and suitable hydrophilic matrix systems compared with
the   extensively    investigated   hydrophilic    matrices    (ie,   hydroxypropyl
methylcellulose (HPMC)/carboxymethyl cellulose (CMC) with respect to in vitro
drug release rate) and hydration rate of the polymers. Matrix tablets of tramadol
were produced by direct compression method. The tablets were evaluated for
physical characteristics. The dissolution test was performed in the phosphate
buffer media (pH 7.4) up to 8 hours. Tablets with only xanthum gum had the
highest mean dissolution time, the least dissolution efficiency (8%), and released
the drug following a zero order model via swelling, diffusion, and erosion
mechanisms. Guar gum alone could not efficiently control the drug release, while
xanthum and all combinations of natural gums with HPMC could retard tramadol
HCl release.

6.3 Objective of the study:
The objective of the study is to develop a sustained release matrix tablet for
levofloxacin, which are expected to
    Maintain the therapeutic drug concentration in the blood for a prolonged
       period of time.
    Improve bioavailability.
    Reduce the frequencies of drug administration.
    Improve the efficacy of the drug.
    Reduce the dose related side effects.
    Improve patient compliance.
Plan of work
The work will be executed as follows
    Preformulation studies
    Formulation of different batches of sustained release matrix tablets
    Evaluation of formulated tablets as per Pharmacopoeial standards
           o Physicochemical characterization
           o Uniformity of drug content
           o In-vitro drug release studies
    In vitro antibacterial activity of the selected formulation
7.   Materials and methods
     7.1 Source of data:
     Official Pharmacopoeia, Standard books, Pharmaceutics databases, internet, etc.
     7.2 Method of collection of the data (including sampling procedure, if any):
     The pharmacological details of the drug will be collected from various standard
     books, journals and other sources like research literature databases such as
     Medline, Science direct, etc.
     Experimental data will be collected from the evaluation of designed formulation
     and then subjecting the formulation to different studies such as preformulation,
     drug content, release profile, stability studies, etc.
     The outline of such methods that would be adopted includes;
          1. Preformulation studies standard to development of matrix tablets.
          2. Selection of excipients and rate control polymers of the formulations and
             fixing their ranges to be used.
          3. Development of tablets based on studies in step 1 and 2.
          4. Optimization of the formulations.
     7.3. Does it require any investigation or interventions to be conducted or
     patients or other humans or animals? If so please describe briefly:
     7.4. Has ethical clearance been obtained from your institute in case of 7.3
     Not Applicable
8.   List of references:
     1. Emami J, Tavakoli N, Movahedian A, In vitro- in vivo evaluation of sustained
     release lithium carbonate matrix tablets: Influence of hydrophilic matrix materials.
     J. Res. Med. Sci. 2004; 2: 89-96.

     2. Reddy KR, Mutalik S, Reddy S, Once-daily sustained release matrix tablets of
     nicorandil: Formulation and in vitro evaluation. AAPS PharmSciTech. 2003;4:E61.

     3. Fish DN, Chow AT, The clinical pharmacokinetics of levofloxacin. Clin
     Pharmacokinet. 1997;32:101-119.
4. Mishra B, Bansal A, Sankar C, Development and in vitro evaluation of
hydrophilic matrix tablets of diltiazem hydrochloride. Acta Pharmaceutica Turcica

5. Lopes CM, Lobo JM, Pinto JF, Costa PC, Compressed matrix core tablet as a
quick/slow dual-component delivery system containing ibuprofen. AAPSPharm
SciTech. 2007;8: E76

6. Cui Y, Zhang Y, Tang X, In vitro and in vivo evaluation of ofloxacin sustained
release pellets. Int J Pharm. 2008;360:47-52.

7. Sarfraz MK, Rehman NU, Mohsin S, Naproxen release from sustained release
matrix system and effect of cellulose derivatives. Pak. J. Pharm. Sci. 2006;19:
8. Giunchedi P, Gavini E, Moretti MDL, Pirisino G, Evaluation of alginate
compressed matrices as prolonged drug delivery systems. AAPS PharmSciTech.

9. Varshosaz J, Tavakoli N, Kheirolahi F, Use of hydrophilic natural gums in
formulation of sustained-release matrix tablets of tramadol hydrochloride. AAPS
Pharm.Sci.Tech. 2006;7:E24.
9.   Signature of the candidate
                                     PATEL HARDIK S.

10. Remarks of the guide:            Recommended for research and submission
                                     of dissertation.

11. Name and Designation (in block
    11.1. Guide                      Dr. ARSHIA SHARIFF,
                                     PROFESSOR & HEAD,
                                     Department of Pharmaceutics,
                                     Dayananda Sagar College of Pharmacy,
                                     Kumaraswamy Layout,

     11.2. Signature
     11.3. Co-guide if any           Not applicable
     11.4. Signature
     11.5. Head of the department    Dr. ARSHIA SHARIFF,
                                     PROFESSOR & HEAD,
                                     Department of Pharmaceutics,
                                     Dayananda Sagar College of Pharmacy,
                                     Kumaraswamy Layout,
    11.6. Signature
12. 12.1. Remarks of the principal   DR. V. MURUGAN,
                                     Dayananda Sagar College of Pharmacy,
                                     Kumaraswamy Layout,

     12.2 Signature

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