ENCLOSURE I

6) BRIEF RESUME OF THE INTENDED WORK

6.1)

NEED FOR THE STUDY

Over the past three decades, various attempts have been made to develop gastro

retentive delivery systems (GRDS) such as floating systems, raft systems, expanding
systems, swelling systems, bioadhesive systems and low-density systems. These
systems can remain in the gastric region for several hours and hence significantly
prolong the gastric residence time of drugs. Prolonged gastric retention improves
bioavailability, reduces drug waste, and improves solubility for drugs that are less
soluble in a high pH environment1-3. It also helps to deliver the drug locally to the
stomach and proximal small intestines. Among various GRDS, hydrodynamically
balanced system (HBSTM) was first designed by Sheth and Tossounian in1975 4. These
systems are also called as floating drug delivery systems (FDDS) and classified as
effervescent and non-effervescent systems depending on the use of two formulation
variables. Both systems are used to boost up the gastric residence and the floatation
time in the gastro intestinal tract (GIT).
Effervescent systems of FDDS utilizes effervescent reaction between
carbonate/bicarbonate salts and citric/tartaric acid to liberate CO 2, which gets
entrapped in the jellified hydrocolloid layer of the system, thus decreasing its specific
gravity and making it float over chime. They may also contain matrices having
chambers of liquid components that gasify at body temperature. Whereas, noneffervescent systems of FDDS are prepared with gel forming hydrocolloids meant to
remain buoyant on stomach contents. A high level of (20 to 75 % w/w) one or more
highly swellable cellulose type of hydrocolloids like HEC, HPMC, NaCMC,
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polysacchacarides or matrix forming polymer such as polycarbonate, polycarbophil,

polyacrylates, polymethacrylate and polystyrene etc. are incorporated either in the
system. On coming in contact with gastric fluid, the hydrocolloid in the system
hydrates and forms a colloidal gel barrier around the gel surface. The air trapped by
the swollen polymer maintains a density less than unity or GI fluids and confers
buoyancy to the dosage forms5.
Nevirapine (NVP) is an antiretroviral drug that is currently used in the treatment
of human immunodeficiency virus type 1 (HIV-1) infections 6-7. The model drug
belongs to Biopharmaceutical Classification System (BCS) class II (low
solubility/high permeability), poses a challenge in achievement of optimal dissolution
kinetics from the dosage form. Drug release is a crucial and limiting step for oral drug
bioavailability, particularly for drugs with low gastrointestinal solubility and high
permeability8.
Floating drug delivery system is suitable for NVP as the absorption and
solubility of NVP is high at pH<3 9. It is also reported by various researchers that,
absorption rate of NVP was decreased from upper part to lower part of GIT and from
jejunum to descending colon10. Hence this work is planned to design non-effervescent
floating tablets of nevirapine using various swellable polymers and effectively
formulate into bioavailable drug products to enhance its bioavailability. Thus, noneffervescent floating tablets of nevirapine is anticipated to remain buoyant in the
gastric region for several hours and significantly prolong the gastric residence time of
drugs to enhance bioavailability.

ENCLOSURE II
6.2)

REVIEW OF LITERATURE
Getyala A et al11 prepared and evaluated noneffervescent floating drug

delivery (tablet dosage forms) of losartan potassium using polymers like Chitosan
and Karaya gum as matrix forming agents. Accurel() MP 1000 was used as floating
agent. The tablets were prepared by direct compression technique. FTIR, DSC studies
conformed that there was no incompatibility between the polymer and the drug. Tablet
showed zero lag time, continuance of buoyancy for >12 h. The tablet showed good in
vitro release. Drug release was through swelling and abided by the gellation
mechanism. In vivo X-ray studies depicted that tablets continued to float in the GIT
for 12 h. Accelerated stability showed that, tablets were stable for over 6 month. Thus
authors concluded that prepared non-effervescent floating tablet of Losartan
potassium could be used for the treatment of hypertension for more than 12 h with
single dose administration.
Garse H et al12 developed non-effervescent sustained release gastroretentive
floating tablets of labetalol hydrochloride prepared using various grades of HPMC
and poloxamer M127 as wetting agent. The tablets were evaluated for in vitro drug
release, floating time, floating lag time, swelling studies etc. The tablets formulated
with HPMC K4M CR and HPMC K15M CR along with poloxamer showed negligible
floating lag time with a total floating time over 12 hrs with complete release.
Formulation was optimized using Stat-Ease Design Expert 7.1 software. Optimized
batch was evaluated for the effect of change of osmolarity and pH on drug release,
floating and swelling behaviour.

Tadros MI13 studied gastroretentive controlled-release drug delivery system

containing ciprofloxacin hydrochloride. Ten tablet formulations were designed using
hydroxypropylmethylcellulose (HPMC K15M) and/or sodium alginate (Na alginate)
as release-retarding polymer(s) and sodium bicarbonate (NaHCO(3)) or calcium
carbonate (CaCO(3)) as a gas former. Swelling ability, floating behaviour, adhesion
period and drug release studies were conducted in 0.1 N HCl (pH 1.2). Drug release
profiles of all formulae followed non-Fickian diffusion. Statistical analyses of data
revealed that tablets containing HPMC K15M (21.42%, w/w), Na alginate (7.14%,
w/w) and NaHCO(3) (20%, w/w) (formula F7) or CaCO(3) (20%, w/w) (formula
F10) were promising systems exhibiting excellent floating properties, extended
adhesion periods and sustained drug release characteristics. Both formulae were
stored at 40 degrees C/75% RH for 3months according to ICH guidelines. Formula
F10 showed better physical stability. Abdominal X-ray imaging of formula F10,
loaded with barium sulfate, in six healthy volunteers revealed a mean gastric retention
period of 5.50+/-0.77h.
Bomma R et al14 prepared and evaluated floating matrix tablets of norfloxacin
to prolong gastric residence time, leading to an increase in drug bioavailability.
Tablets were prepared by the wet granulation technique, using polymers such as
hydroxypropyl methylcellulose (HPMC K4M, HPMC K100M) and xanthan gum.
Tablets were evaluated for hardness, thickness, friability, and mass variation, drug
content and floating properties and in vitro drug release characteristics for 9 h. The
tablets exhibited controlled and prolonged drug release profiles while floating over
the dissolution medium. Non-Fickian diffusion was confirmed as the drug release
mechanism from these tablets, indicating that water diffusion and polymer
rearrangement played an essential role in drug release. The best formulation (F4) was
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selected based on in vitro characteristics and was used in vivo radiographic studies by
incorporating BaSO4. These studies revealed that the tablets remained in the stomach
for 180 +/- 30 min in fasting human volunteers and indicated that gastric retention
time was increased by the floating principle, which was considered desirable for the
absorption window drugs.
Garg R and Gupta GD15 studied floating (effervescent and noneffervescent)
tablets of acyclovir as model drug for prolongation of gastric residence time. Floating
effervescent tablets were formulated by various materials like hydroxypropyl
methylcellulose K 4M, K 15M, psyllium husk, swelling agent as crospovidone and
microcrystalline cellulose and gas generating agent like sodium bicarbonate and citric
acid and evaluated for floating properties, swelling characteristics and in vitro drug
release studies. Floating noneffervescent tablets were prepared by polypropylene
foam powder and different matrix forming polymers like HPMC K 4M, Carbopol
934P, xanthan gum and sodium alginate. In vitro drug release studies were performed
and drug release kinetics evaluated using the linear regression method was found to
follow both the Higuchi and the Korsmeyer and Peppas equation. The drug release
mechanism was found fickian type in most of the formulations.
Ravala JA et al16 investigated of the effects of formulation and processing
parameters on a floating matrix controlled drug delivery system consisting of a poly
(styrene-divinyl benzene) copolymer low density powder, a matrix-forming
polymer(s), drug (Ranitidine hydrochloride), and diluents (optional). The tablets were
prepared by the direct compression technique, using hydrophilic matrix polymers
HPMC K4M, HPMC K15M, HPMC K100M, sodium alginate, psyllum, sesbania
gum, guar gum, and gum acacia, with or without low density copolymer. Tablets were

evaluated for in vitro release characteristics for 8 h in 0.1 mol/L HCl at 37C. The
release rate was modified by varying the type of matrix-forming polymer, the tablet
geometry (radius), and the addition of water-soluble or water-insoluble diluents. At
the same time, different concentrations of low-density copolymer were taken to
examine any differences in the floating lag-time of the formulation. The similarity
factor, floating lag-time, and t50 and t90 were used as parameters for selection of the
best batch. The tablet eroded/swelled upon contact with the release medium, and the
relative importance of drug diffusion, polymer swelling and tablet erosion on the
resulting release patterns varied significantly with the type of matrix forming polymer.
The highly porous copolymer provided a low density and, thus, excellent in vitro
floating behaviour of the tablets at a concentration of 15% (w/w). It was conclude that
floating behaviour of the low-density drug delivery systems could be successfully
combined with accurate control and prolongation of the drug release patterns.
Chen YC et al17 developed gastroretentive drug delivery systems (GRDDSs)
by combining floating and swelling. Floating tablets of losartan were formulated with
hydroxyethylcellulose (HEC), chitosan (CS) and sodium bicarbonate (SB) for
evaluating floating capacity and swelling characteristics. Results demonstrated that
formulations at HEC:CS ratio of 5:5 containing CS, both the floating lag time and
floating duration were optimal and reached the preferred swelling effect and sustain
for 24h. Adding SB improved the floating capabilities for all ratios of HEC:CS, but
reduced the swelling ability for those formulations containing a higher portion of low
viscosity grade CS. Sustained release profiles for losartan in those formulations were
achievable, using all viscosity grades of CS at all examined HEC:CS ratios; however,
it is more adjustable at different HEC:CS ratios when using a lower viscosity grade of
CS. Optimized GRDDS formulations for losartan composed of an equivalent ratio of
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HEC to CS with 20mg SB resulted in the tablets floating for more than 16 h and an
adjustable sustained release profile.
Negi JS et al18 developed and evaluated non-effervescent floating matrix
tablets using Euryale ferox seeds powder (EFSP). Different matrix tablets were
prepared using hydroxy propyl methyl cellulose (HPMC) K4M, ciprofloxacin HCl
and EFSP. The effects of various formulation variables were investigated on in
vitro drug release and in vitro floating behaviour of the matrix tablets. With increase
in EFSP proportion in the matrix tablets, improvement in buoyancy was observed.
Drug release from matrix tablets was reduced in the presence of EFSP particles. Most
of the formulations were best fitted with Korsmeyer-Peppas and zero-order release
kinetics.
Patel P et al19 developed sustained release non-effervescent floating matrix
tablet of captopril with a view of prolonging gastric retention time as well as avoiding
intestinal degradation. The tablets were prepared using hydrophilic matrix like HPMC
K15MCR and HPMC K100MCR alone and in combination by wet granulation
method. Isopropyl alcohol (IPA) or alcoholic solutions of PVP K-30 or ethyl cellulose
(EC) are used as wetting agents. The tablets prepared with HPMC K15MCR and
HPMC K100MCR alone and in combination could not control the drug release
pattern. Incorporation of hydrophobic polymer EC in granulation fluid showed good
drug release pattern. In vitro drug release, in vitro buoyancy and swelling behaviour
remained unaffected by change in pH and osmolarity. The formulation was stable at
40C/75% RH for three months. It was concluded that stable sustained release
floating gastroretentive tablets of drug with no floating lag time, floating time greater
than 24 h and desired drug release pattern could be successfully prepared.

6.3)

ENCLOSURE III
OBJECTIVES OF THE STUDY: The proposed work is planned with the
following objectives,
To formulate and evaluate non-effervescent floating tablets of
nevirapine using various swellable or low density polymers.
To prolong the gastric residence time for continuous release of drug.
To reduce fluctuation in plasma drug concentration after oral
administration.
To increase the drug bioavailability after oral administration.
To reduce undesirable adverse effects with improved patient
compliance and acceptance.

ENCLOSURE IV
7) MATERIALS AND METHODS
7.1) SOURCE OF DATA:
The primary data will be collected by conducting various experiments and
investigations in the laboratory and recording the observations. The secondary data
will be collected by various national and international journals like Indian Journal of
Pharmaceutical Sciences, European Journal of Pharmaceutical Sciences, Journal of
Controlled Release, International Journal of Pharmaceutics, Drug Development and
Industrial Pharmacy, etc. Then, various pharmacy books, Pharmacopoeias and
professional websites like Helinet, Pubmed etc. will be referred.

ENCLOSURE V

7.2) MATERIALS
Drug: Nevirapine
Polymers: Swelling agent/Gel forming polymer like hydroxypropyl methyl cellulose
(HPMC) HPMC K100, HPMC K4, HPMC K15, hydroxyethyl cellulose (HEC),
hydroxypropyl cellulose (HPC), sodium carboxy methyl cellulose (NaCMC),
carbopol or natural gums such as xantam gum, gaur gum and karaya gum or chitosan,
low density polymers or any other suitable polymers.
7.3) METHODS: Non-effervescent floating tablets of nevirapine will be formulated
by suitable techniques such as wet granulation or dry granulation direct compression
method using various swellable or low density polymers or any other suitable
polymers.

ENCLOSURE V
7.4) METHOD OF COLLECTION OF DATA:
Experimental data from the developing non-effervescent floating tablets of
nevirapine shall be collected by evaluating for the following,
A) Preformulation studies:
1. Melting point study.
2. Drug-polymer interaction studies by FTIR and DSC.
B) Pre-compressional parameters:
1. Bulk density
2. Tapped density
3. Angle of repose
4. Compressibility index

5. Hausner ratio and Carrs Index.

C) Post compressional parameters: (Evaluation of tablets)
1. Shape of tablet
2. Tablet dimensions
3. Weight variation test
4. Hardness test
5. Friability test
6. Content uniformity test
7. Swelling studies
8. In vitro evaluation of floating properties of tablets
9. In vitro drug release studies using USP dissolution apparatus
10. The in vitro data shall be analyzed statistically and drug release
kinetics shall be studied.

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ENCLOSURE VI
8) LIST OF REFERENCES:
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floating dosage form for furosemide. J Pharm Sci 1994;83:239-245.
2. Deshpande AA, Rhodes CT, Shah NH, Malick AW. Controlled release drug
delivery systems for prolonged gastric residence: an overview. Drug Dev Ind
Pharm 1996;22:531-539.
3. Whitehead L, Fell JT, Collett JH, Sharma HL, Smith AM. Floating dosage
forms: an in-vivo study demonstrating prolonged gastric retention. J Control
Rel 1998;55:3-12.
4. Sheth PR and Tossounian J. The Hydrodynamically Balanced System (Hbs):
A Novel Drug Delivery System for Oral Use. Informa healthcare
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5. Vyas SP and Roop K Khar. Gastroretentive Systems: In Controlled Drug
Delivery, Concepts & Advances, Vallabh Prakashan, Delhi (2012); pp 196217.
6. Nelson M, Waters L, John L. Non-nucleoside reverse transcriptase inhibitors:
a review. Int J Clin Pract 2007;61(1):105-118.
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Indian J Pharm Sci 2006;68(1):1-6.
8. Kasim NA, et al. Molecular properties of WHO essential drugs and
provisional biopharmaceutical classification. Mol Pharm 2004;1(1):85-96.
9. Hawi A, Bell G. Preformulation studies of nevirapine, a reverse transcriptase
inhibitor. Pharm Res 1994;11:236.
10. Sreeraj Macha, Chan-Loi Yong et.al. Assessment of Nevirapine Bioavailability
from targeted sites in the Human Gastro intestinal Tract. J clin Pharmacol
2009;49(12):1417-1425.
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11. Getyala A, Gangadharappa HV, Prasad MS, Reddy MP, Kumar TM.
Formulation and evaluation of non-effervescent floating tablets of losartan
potassium. Curr Drug Deliv 2013;10(5):620-629.
12. Garse H, Vij M, Yamgar M, Kadam V, Hirlekar R. Formulation and evaluation
of a gastroretentive dosage form of labetalol hydrochloride. Arch Pharm Res
2010;33(3):405-410.
13. Tadros MI. Controlled-release effervescent floating matrix tablets of
ciprofloxacin hydrochloride: development, optimization and in vitro-in vivo
evaluation in healthy human volunteers. Eur J Pharm Biopharm 2010;74(2):
332-339.
14. Bomma R, Swamy Naidu RA, Yamsani MR, Veerabrahma K. Development
and evaluation of gastroretentive norfloxacin floating tablets. Acta Pharm
2009;59(2):211-221.
15. Garg R, Gupta GD. Preparation and evaluation of gastroretentive floating
tablets of acyclovir. Curr Drug Deliv 2009;6(5):437-43.
16. Ravala JA, Patela JK, Naihong Lib, Patela MM. Ranitidine hydrochloride
floating matrix tablets based on low density powder: effects of formulation
and processing parameters on drug release. Asian J Pharma Sci 2007;2(4):130142.
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profiling

of

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drug

delivery

systems

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improved floating and swelling capabilities. Int J Pharm 2013;441(1-2):162-9.

18. Negi JS, Jugran V, Kasliwal N. Development of non-effervescent floating
matrix tablets based on Euryale ferox seeds. Asian J Pharm 2011;5(2): 93-100.
19. Patel P, Dand N, Somwanshi A, Kadam VG, Hirlekar RS. Design and
Evaluation of a Sustained Release Gastroretentive Dosage Form of Captopril:
A Technical Note. AAPS PharmSciTech 2008; 9(3):836839.

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