Download proforma for registration of subjects for dissertation

RAJIV GANDHI
UNIVERSITY OF HEALTH SCIENCES, KARNATAKA.
4th ‘T’ Block, Jayanagar, BANGALORE - 560 027
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1.
Name of the Candidate and Address
PRIYA SHARMA
25/24,Geeta Apartment ,
B.B Sengupta Road,
Behala Chowrasta ,Kolkata
Pin:- 700034.
Name of the Institution
Al-Ameen College of Pharmacy,
Hosur Road, Bangalore – 560 027.
3.
Course of Study and Subject
M. Pharm – Pharmaceutics.
4.
Date of Admission
2.
09th June 2009.
Title of the Topic:
5.
“Design And Development Of Mouth Dissolving Tablets (MDT) of Selected
Cephalosporin”.
1
Brief resume of the intended work:
6.1 – Need for the study:Cephalosporins are class of β-lactam antibiotics originally derived from Acremonium, which was
previously known as “cephalosporium”. Cephalosporins are bactericidal and have the same mode of
action as other β-lactam antibiotics (penicillin) but are less susceptible to penicillinases. Cephalosporins
disrupt the synthesis of the
peptidoglycan
layer of bacterial cell walls. The peptidoglycan layer is
important for cell wall structural integrity. The final transpeptidation step in the synthesis of the
peptidoglycan is facilitated by transpeptidases
known as penicillin binding protein (PBP) site. PBPs
bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the
peptidoglycan. β- lactam antibiotics mimic this site and competitively inhibit PBP cross linking of
peptidoglycan.
Bacteria that are susceptible to Cephalexin include Staphylococcus aureas, Streptococcus pneumonia,
Haemophilus influenza, E. coli and several others. Cephalexin is most commonly used to treat infections
caused by the bacteria; such as :-respiratory tract infection, pneumonia, bronchitis, strep throat, or
tonsillitis, bone infection (osteomyelitis), middle ear infection(otitis media), sinus infection(sinusitis),
urinary tract infection, irritation to the prostate( prostatitis),skin infection such as cellulitis, folliculitis, or
impetigo. Cephalosporins are commonly used for surgical prophylaxis. They are most diverse class of
antibiotics; they are grouped into “generation” by their antimicrobial properties. Each newer generation
has broad spectrum of activity than the one before.1
Cephalexin has highly soluble and low permeable, falls under biopharmaceutical classification system
(BCS) class III and approved by FDA in 1971. Cephalexin is a semi-synthetic first generation having
activity against gram positive bacteria like Staphylococcus aureas and Streptococci, which are the most
frequent causes of the community acquired skin and soft tissues infections. Cephalexin is also have
action
against gram negative bacilli like E .Coli and Klebsiella species which commonly causes
community acquired urinary tract infections (UTI). Because of its activity against E.coli, it has also been
used as the one of the alternative antimicrobials in treating urinary tract infection in children and in
pregnant women. It is also recommended as prophylaxis for infective endocarditis during oral procedures
in person with penicillin hypersensitivity. 2
Cephalexin is administered orally, is acid stable and rapidly absorbed by the gastro intestinal tract.
The serum half- life of Cephalexin is 0.5-1.2 h in adults with normal renal function. The serum half-life
of the drug is 5 h in neonates and 2.5 h in children 3-12 months of age. Approximately 70-90% of a
single 250 or 500 mg oral dose is excreted within 8-12hrs in adults with normal renal function.
2
The usual adult dosage of cephalexin is 250 mg every 6 h. For Streptococcal pharyngitis, skin infections,
or uncomplicated cystitis in patients older than 15 yrs of age, 500 mg of cephalexin may be given every
12 h. A minimum 10 days of therapy is recommended in infections caused by Streptococcus pyogenes.
Pediatric Dosage: - The usual dosage of Cephalexin for children is 25 – 50 mg daily. Although the daily
dosage may be given in 2 equally divided doses at 12 h intervals for the treatment of streptococcal
pharyngitis in patients older than 1 yr of age or for the treatment of skin infections in the children. A
minimum of 10 days of therapy is recommended in infections caused by Streptococcus pyogenes. For
the treatment of otitis media, dosage of 75-100 mg/kg daily in 4 divided doses. Prophylaxis of Bacterial
Endocarditis: - Adults should receive a single dose of 2g and pediatric patients should receive a single
50 mg/kg administered 1 hr prior to the procedure. Dosage in Renal impairment :-In patients with
impaired renal function, the initial dose of Cephalexin may be the same as in patients with normal renal
functions; subsequent doses must be modified in response to the degree of renal impairment, severity
of infections and serum concentration of the drug. The drug has been administered in 250 mg doses at 12
to 24 h intervals in adult with creatinine clearances less than 5 ml/min. 250 mg doses every 12 h in
adults with creatinine clearances of 5-10 ml/min, and 500 mg doses every 8-12 h in adults with creatinine
clearances of 11-40 ml/min.3
The concept of mouth dissolving tablets emerges from the desire to provide patient with more
conventional means of taking their medicines. Many patients find difficult to swallow tablets and hard
gelatin capsules and do not take their medicines as prescribed. Dysphagia is seen to affect nearly 35% of
the general population. Many elderly persons will have difficulties in taking the conventional dosage
form because of their hand tremors and dysphagia. Swallowing problems are also common in children’s
because of there under developed muscular or nervous system.4
The technologies utilized for fabrication of mouth dissolving tablets include lyophillization, molding,
direct compression, cotton candy process; spray drying; sublimation mass extrusion, Nanonization and
quick dissolve film formation. The use of super disintegrate like is the basic approach in the development
of the mouth dissolving tablets (MDTs). Disintegrates play an important role in the disintegration and
dissolution of the mouth dissolving tablets. Examples are sodium starch glycolate, crospovidone,
microcrystalline cellulose and pregelantized starch.
The advantage of mouth dissolving tablets are that it shows convenience and patient compliance,
administration to patients who cannot swallow such as disabled bed ridden patients, useful for pediatric,
geriatric and psychiatric patients, useful during travelling where water may not be available, acceptable
taste and pleasant mouth feel, possibility of loading high dose of drug, most rapid drug absorption
3
through pre gastric absorption from the mouth, pharynx and
oesophagus, easily disintegrate and
dissolve in oral cavity hence rapid onset of action and increase in bioavailability, provide advantage of
liquid medication in the form of solid preparation.5
The demand for mouth dissolving tablets (MDTs) has thus been growing during the last decade,
particularly for children and the elderly who have difficulty in swallowing tablets and capsules. These
dosage forms are placed in the mouth, allowed to disperse or dissolve in the saliva, and then swallowed
without the need for water. The advantage of this convenient administration has encouraged both
academia and industry to generate new fast disintegrating formulations and technological approaches in
this field.
Thus there is a need to design and formulate a dosage form of the widely prescribed cephalosporin for
children and elderly. In the present study an approach is made to design, develop and evaluate mouth
dissolving tablet of a selected cephalosporin prepared by using super disintegrants by direct compression
or wet granulation technique; further effervescent method will also be evaluated for optimising the
treatment of bacterial infections.
4
6.2 REVIEW OF LITERATURE

Shukla D,
Chakraborty S,
Singh S,
Mishra
B,
presents a detailed review regarding
technological advances made so far in the area of evaluation of mouth dissolving tablets with
respect to special characteristics of these unique dosage forms.6

Nagar M. and Yana A.V prepared a cinnarizine orodispersable tablets: A chitosan based fast
mouth dissolving tablets to enhance the disintegration and dissolution of the drug in oral cavity
and hence better patient compliance and effective therapy in case of children and elderly
patients.7

Akesiripong S, Rattanajamtri C, Janwittayanuchi W. Compare the bioavailability studies of two
brands of Cephalexin Monohydrate capsules of 500mg
were performed in twelve health Thai
male volunteers. A Cross over study was selected, using a single dose of 500mg capsules of both
the brands. Plasma concentration of cephalexin was determined by HPLC technique. Relevant
pharmacokinetics parameters were analyzed and compared between the two brand names. Results
revealed that AUC, Amax and tmax obtained from concentration time profiles of both the
products, were not significantly different (p>0.1).8

Cardenas J, Quinn EL, Rooker G, Bavinger J, Pohlod D evaluated single -dose of Cephalexin
therapy for Acute Bacterial urinary tract infection and Acute Urethral syndrome with Bladder
Bacteriuria. They investigated the efficacy of the single dose therapy with 3g of Cephalexin was
evaluated in 129 women with symptoms of acute uncomplicated lower urinary tract infections. Of
91patients with significant Bacteriuria, 61(67%) were cured of their original infection. The cure
rates of (87%) for our younger patients, those less than 25yrs of age, was better than that(46%) of
our patients over 40years of age(P less than 0.0001). Patients with infection that were negative in
antibody -coated bacteria test were cured at a significantly higher rate than those with infections
that were positive in antibody- coated bacteria test(71% versus 19%; P=0.003).Those patients
with infection caused by cephalexin-susceptible organisms were cured at a rate similar to that for
patients with infection caused by the cephalexin resistant organism (68%versus50%;P=0.52).The
cure rate for the suburban patients was 90% versus 45% for inner city patients(P=0.008).Of the
28 women with acute urethral syndrome due to low level bacteriuria, 27 were cured.9

. Smith EK, William JD has used Cephalexin monohydrate in chronic bacteriuria and acute
5
urinary infections. One hundred and eighty strains of bacteria causing urinary tract infection were
tested for sensitivity to Cephalexin using a tube dilution technique. Approximately 70per cent of
strains were inhibited by 10mcg. Cephalexin per ml. or less. Cephalexin was used to treat two
groups of patients with urinary tract infection. The first group had chronic Bacteriuria and the
second group had acute urinary tract infections. Two weeks after treatment 61 percent of the first
group of patient and 87percent of the second group of patients were cleared of their infections.
Six weeks after the start of the therapy 59percent of the patients with chronic Bacteriuria who
were cleared of infection at 2 weeks were still clear. None of the patients who had acute
infections had replased.10

Gower PE use the small doses of Cephalexin (125mg) in the management of recurrent urinary
tract infection in women”. They investigated entered into the double blind trial to investigate the
prevention of the recurrence of the invention. Cephalexin 12.5mg was compared with placebo.
During a 6months follow up period 13 to 25 women given the placebo had a recurrence of
bacteriuria, while only one patient had replased while taking Cephalexin. The results shows that
the Cephalexin 125 mg nod is an efficient prophylactic for urinary infection and is well tolerated
by patients.11

Lautre G, Baker LW have given cephalexin therapy of soft tissue infection. Thirty patients with a
soft tissue and some with bone infection were treated with Cephalexin. Twenty seven cases
respond satisfactory, while two cases have a
un- satisfactory response. In ten of the cases a
Penicillin- resistant pathogenic organism was isolated. Five patients had Gram negative and five
mixed infections. The drug was well tolerated and no side effects directly attributable to the drug
were noted. Cephalexin appears to be very useful additional antibacterial agents assessed on
clinical criteria, particularly incase due to penicillin–resistant, Gram–negative or mixed
infections.12

Mendey A.P. Compared Pivmecillinam and Cephalexin in acute uncomplicated urinary ract
infection. The clinical and bacteriological efficacy of a three day course of Pivmecillinam, 200
mg three times daily, was compared with that of a 7-day course of Cephalexin, 250mg four times
daily, 216 patients with bacteriologically confirmed, acute, uncomplicated, urinary tract infection.
Both treatments were similarly effective. Clinical cure or improvement was obtained
6
in 95.3% of patients give Pivmecillinam and 93.6% of patients given Cephalexin. Bacteriological
success was achieved in 89.7% and 81.7% taking pivmecillinam or Cephalexin respectively.
Eradication rates of Escherichia coli were 90.1% for pivmecillinam and 80.6% for Cephalexin.
Both treatments were well tolerated. This study has confirmed that a 3-day course of
pivmecillinam is effective and well tolerated in uncomplicated cystitis.13

Omaima A, Sammour, Mohammed A. Hammad, Nagia A. Megrab, and Ahmed S.Zidan
formulated and optimize the mouth dissolve tablets containing Rofecoxib solid dispersion to
increase the solubility and dissolution rate of Rofecoxib by the preparation of its solid dispersion
with polyvinyl pyrrolidone K30 (PVP K30) using solvent evaporation method. This investigation
demonstrated the potential of experimental design in understanding the effect of the formulation
variables on the quality of mouth dissolving tablets containing solid dispersions of a hydrophobic
drug.14

Suresh .S ,.Pandit.V
and
Joshi H.P prepared and evaluated mouth dissolving tablet of
Salbutamol Sulphate by using sublimable ingredients .Selection of filler also had an important
role in deciding the disintegration time .Thus attempt was made to improve the onset of action
of bronchodilator used commonly in the treatment of asthma.15

Dobetti .L reviewed fast melting tablets in which general technologies for the production of fast
melting tablets like freeze drying, molding and direct compression were described. 16

Gohel M, Patel M, Amin A, Agrawal R, Dave R, Bariya N formulated design and optimize
mouth dissolve tablets of nimesulide using vacuum drying technique. Granules containing
nimesulide, camphor, crospovidone, and lactose were prepared by wet granulation technique.
Camphor was sublimed from the dried granules by exposure to vacuum. The porous granules
were then compressed. The tablets were evaluated for percentage friability, wetting time, and
disintegration time. Sublimation of camphor from tablets resulted in superior tablets as compared
with the tablets prepared from granules that were exposed to vacuum.17

Elo J, Ahava K compared Cephalexin with Ampicillin has been studied in 92 children with
urinary tract infection. In 26 patients more than one UTI was treated, the total number of
infections treated being 118, 59 with cephalexin and 59 with ampicillin. After cephalexin
treatment 49 cases (84.5%) gave pathogen free urinary samples compared to 37 cases(62.7%)
after ampicillin. Escherichia coli was absent in the post –treatment urine samples of 33
7
patients out of 36(91.6%) treated with cephalexin and in 22 out of 40 patients (55.0%) treated
with ampicillin. No side effects to cephalexin was reported compared to an incidence of 15% in
patients receiving ampicillin.18

Kumar ND, Raju SA, Shirsand SB, Para MS, Rampure MV prepared a fast dissolving tablet of
fexofenadine HCL by effervescent method to enhance the patient compliance. Three super
disintegrates viz., crospovidone, croscarmellose sodium and sodium starch glycolate along with
the sodium bicarbonate and anhydrous citric acid in different ratios and directly compressible
mannitol (Pearlitol SD200) to enhance mouth feel. The prepared batches were evaluated for
hardness, friability, drug content uniformity, and in vitro dispersion time. Based on the dispersion
time(approx 20sec), three formulations were tested for in vitro drug release pattern in pH6.8
phosphate buffer, short-term stability at 40 ˚/75% RH for 3 months and drug excipient interaction
(IR spectroscopy). Among the three promising formulations, the formulation ECP 3 containing
18% w/w of anhydrous citric acid emerged as the best (t50% 4 min) based on the in vitro drug
release characteristics compared to conventional commercial tablet formulation(t50% 15min).
Short- term stability studies on the formulations indicated that there are no significant changes in
drug content and in vitro dispersion time (P< 0.05).19
6.3 OBJECTIVE OF STUDY:Design and Development of mouth dissolving tablets(MDT) of the selected Cephalosporin.
SPECIFIC OBJECTIVE:
To evaluate different methods of preparation of mouth dissolving tablet and select suitable
method.

To develop optimum formulation of mouth dissolving tablets of cephalexin.

Selection of mouth dissolving tablet formulation of Cephalexin.

To evaluate the selected mouths dissolving tablet formulation and compare it with available
marketed formulation.
7.0 Materials and Methods
7.1 Source of Data:
I. Review of Literature from
8
a. Journals - such as

Advanced Drug Delivery Reviews.

International Journal of Pharmaceutical Sciences.

Drug Development and Industrial Pharmacy.

Journal of Antimicrobial Chemotherapy.

Pub med.

Science Direct.

Journal of infection.

J –gate@Helinet.
b. Internet Browsing.
www.google.com.
www.wikipedia.com.
7.2 - Method of collection of data:
1. From Literature
2. Preformulation studies including preliminary stability studies.
3. Formulation of mouth dissolving tablets by different method
4. Evaluation of mouth dissolving tablets by different methods.
a) Drug content estimation.
b) Fourier
transforms infrared spectroscopy (FTIR).
c) In-vitro disintegration studies
d) In-vitro dissolution studies.
e) Differential Scanning Calorimetry (DSC).
5. Compare with marketed formulation of selected Cephalosporins drugs.
7.3 - Does the study require any investigations or interventions to be conducted on patients or other
humans or animals? If so, Please describe briefly.
NO
7.4 – Has ethical clearance been obtained from your Institution in case of 7.3?
NOT APPLICABLE
9
8.0
Bibliography
1. http://er.wikipedia.org/wiki/cephalosporin. [cited 2009 Nov15].
2. http://en.wikipedia.org/wiki/BiopharmaceuticsClassificationSystem. [cited 2009 Nov 20].
3. AHFS Drug information 2001. Bethesda, Maryland. Authority of the board of the American society
of health- system pharmacists; 2001:230-1.
4. http://www.farmavita.net/content/view/1094/84/ [cited 2009 Nov16].
5. www.pharmainfo.net/reviews/manufacturing technologies-MDT [cited 2009 Nov18 ].
6. Shukla D, Chakraborty S, Singh S, Mishra B. Mouth dissolving tablets II : An Overview of
Evaluation Techniques. Sci Pharm 2009;77: 327-41.
7. Nagar M, Yadav AV. Cinnarizine orodispersable tablets: A chitosan based fast mouth dissolving
technology. PharmTech 2009; 1: 1079-91.
8.
http://pharmacy.hcu.ac.th/text/cephal.htm.(cited 2009 Nov 19).
9. Cardenas J, Quinn EN , Rooker G, Bavinger J, Pohlod D. Single- dose cephalexin therapy for
acute bacterial urinary tract infections and acute urethral syndrome with bladder bacteriuria. Jt
Antimicrob Chemother 1986; 29: 383-9.
10. Smith KE William JD .The use of cephalexin monohydrate in chronic bacteriuria and acute urinary
tract infection. Br J Urol 2008; 42(5):522-28.
11. Gower PE. The use of small doses of cephalexin (125 mg) in the management of recurrent urinary
tract infection in women. J Antimicrob Chemother1975; 1: 93-8.
12. Lautre G, Baker LW. Cephalexin theraphy of soft tissues infection. A Medical Journal.1972;837-39.
13. Mendey AP. Comparison of pivmecillinam and cephalexin in acute uncomplicated urinary tract
infection. Int J Antimicrob Agents. 2000;13:183-7.
14. Omaima AS, Mohammed AH, Nagia AM, Ahmed SZ. Formulation and optimization of mouth
dissolve tablets containing rofecoxib solid dispersion. AAPS PharmSciTech. 2006;7(2):1-9.
15. Suresh S, Pandit V Joshi HP. Preparation and evaluation of mouth dissolving tablets of salbutamol
sulphate. Indian J Pharm Sci. 2007;69(3):467-69.
16. http://pharmtech.findpharma.com/pharmtech/data/articlestandard//pharmtech/512001/5137/article.pdf
[cited 2009 Nov 21).
10
17. Gohel M, Patel M, Amin A, Agrawal R, Dave R, Bariya N. Formulation design and optimization of
mouth dissolve tablets of nimesulide using vacuum drying technique. AAPS PharmSciTech
2004;5(3):1-5.
18. Elo J, Ahava k. Cephalexin compared with ampicillin in urinary tract infections in children. J
Antimicrob Chemother. 1975:85-92.
19. Kumar ND, Raju SA, Shirsand SB, Para MS, Rampure MV. Fast dissolving tablets of fenofenadine
HCL by effervescent method. Indian J Pharm Sci. 2009:71:116-19.
11
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Signature of the candidate:
10
Remarks of the Guide:
11
Name and Designation of:
(PRIYA SHARMA)
Recommended
11.1 Institutional Guide:
Dr. (Mrs.) SARASIJA SURESH
Professor and Head,
Department of pharmaceutics.
Al-Ameen College of Pharmacy
Bangalore- 560027
11.2 Signature:
11.3 Head of the Department:
Dr. (Mrs.) SARASIJA SURESH
Professor and Head
Department of pharmaceutics
Al-Ameen College of Pharmacy
11.4 Signature
12
12.1 Remarks of the Chairman and
Principal
Forwarded to the University for scrutiny
12.2 Signature
Prof. B. G. SHIVANANDA
Principal
Al-Ameen College of Pharmacy,
Hosur Road, Bangalore – 560 027.
12