“FORMULATION AND IN VITRO EVALUATION OF
HYDROGELS CONTAINING AN ANTI-HYPERTENSIVE
DRUG AS SUSTAINED DRUG DELIVERY SYSTEM”
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA.
BY
VENKATA ANUSHA MANTENA
DEPARTMENT OF PHARMACEUTICS
P.E.S COLLEGE OF PHARMACY
BANGALORE
2012
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR
DISSERTATION
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PRESENT ADDRESS
Name of the candidate and address VENKATA ANUSHA MANTENA
C/O P.E.S. COLLEGE OF PHARMACY,
50 FEET ROAD,
HANUMANTHA NAGAR,
BANGALORE-560050.
[email protected]
PERMANENT ADDRESS
ANUSHA. MANTENA
D/O MANTENA.ARJUNA RAJU,
D/NO:27-17-55/1, ASR NAGAR,
BHIMAVARAM,
WEST GODAVARI DIST, 534201(AP).
Name of the institution
P.E.S. COLLEGE OF PHARMACY
50 FEET ROAD,
HANUMANTHA NAGAR,
BANGALORE-560050.
Course of study and subject
MASTER OF PHARMACY IN
PHARMACEUTICS
6th September 2012
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Date of the admission
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Title of the topic:
“FORMULATION AND IN VITRO EVALUATION OF HYDROGELS
CONTAINING AN ANTI-HYPERTENSIVE DRUG AS SUSTAINED
DRUG DELIVERY SYSTEM”
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Brief resume of the intended work:
6.1 Need for the study:
The main objective of any drug delivery system is to provide a therapeutic
amount of drug to the proper site in the body to achieve the desired plasma drug
concentration. The sustained release dosage forms are becoming popular as these
have a number of advantages over conventional dosage forms like decreased
frequency of administration, less fluctuation in circulating blood levels, increased
patient compliance and more uniform effect. The main concept of sustained drug
delivery system are the use of system and techniques for altering and controlling the
absorption, blood levels metabolism, organ distribution and cellular uptake of
pharmacologically active agents. Hydrogels are a unique class of macromolecular
networks that can hold a large fraction of an aqueous solvent within their structures.
They are polymeric networks with three dimensional configurations capable of
imbibing high amounts of water or biological fluids. Their affinity to absorb water is
attributed to the presence of hydrophilic groups such as –OH,-CONH,-CONH2 and
SO3H in polymers forming hydrogel structures. Due to the contribution of these
groups and domines in network, the polymer is thus hydrated to different degrees
(more than 90% weight) depending on nature of aqueous environment and polymer
composition. They are insoluble due to the presence of chemical and/or physical
cross links such as entanglements. Their ability to swell, under physiological
conditions, makes them an ideal material for biomedical applications. It is also
possible to produce hydrogels containing a significant portion of hydrophobic
polymers, by blending or copolymerizing hydrophilic and hydrophobic polymers.
HYPERTENSION: (HTN) or high blood pressure is a cardiac chronic medical
condition in which the systemic arterial blood pressure is elevated. It is the opposite
of hypotension. Hypertension is classified as either primary (essential) hypertension
or secondary hypertension; About 90–95% of cases are categorized as "primary
hypertension," which means high blood pressure with no obvious medical cause. The
remaining 5–10% of cases (Secondary hypertension) are caused by other conditions
that affect the kidneys, arteries, heart or endocrine system.
The drug for study Losartan which is well absorbed from GIT and under goes
first pass metabolism with a total bioavailability of 33%. Out of the total
administered dose of Losartan approximately 14% of the drug is converted into
metabolite. The peak plasma concentration of the losartan and its metabolite is
achieved in 1 hour and 3-4 hours respectively.
The volume of distribution of losartan is 34 lts and its metabolite is 12 lts.
Most of the administered drug and its metabolite is plasma bound which cause
increase in plasma concentration on repeated daily dosing. The T1/2 of Losartan is
2hours and that of the metabolite is 6-9 hours. It is freely soluble in water, soluble in
alcohols, slightly soluble in common organic slovents such as acetonitrile, methyl
ethyl ketone.
6.2 REVIEW OF LITERATURE:

Pavithra TK has done the study to develop controlled release matrix tablets of
Losartan potassium by simplex lattice design and evaluating the relationship and
influence of different content levels of HPMC, Eudragit RSPO, Eudragit RLPO and
ethylcellulose, in order to achieve a zero-order release of Losartan potassium. Tablets
were prepared by wet granulation process. In-vitro drug release study revealed that
HPMC causes initial burst release of drug hence combining HPMC with Eudragit
sustained the action for 8hrs (95.92±0.57% release)review of the literature:.
 Narayani RK studied the collagen-poly(HEMA) hydrogels for the controlled delivery
of methotrexate and cisplatin and found that release of anticancer drug is possible
to modulate by applying different types of crosslinking methods.2
 Satish CS et al have prepared gelatin-poly(methacrylic acid) interpenetrating
polymeric network hydrogels as a pH sensitive delivery system for Glipezide and
have shown sustained release over a period of 12 hour. The release of drug was
found to depend on pH, crosslinking agent concentration and methacrylic acid
content in the IPN.3
 George M have prepared a pH sensitive alginate-guar gum hydrogel for the controlled
delivery of protein drugs. The study found that the entrapment efficiency of beads
increased with increase in amounts of Guar gum and glutaraldehyde concentration
and concluded that freeze-dried alginate-Guar gum hydrogel could be considered as
a potent candidate for a protein delivery matrix to the intestine via oral route.4

Jain SK et al have designed, developed and evaluated chitosan hydrogel beads for
targeted drug delivery to colon. The results of release studies indicated that
Eudragit S100-coated chitosan beads offer a high degree of protection from
protection from premature drug release in simulated upper GIT conditions. Eudragit
S100-coated chitosan beads delivered most of the drug load in the colon, an
environment rich in bacterial enzymes that degrade the chitosan and allow drug
release to occur at the desired site.5
 Senela S et al designed a formulation containing chitosan for local delivery of
chlorhexidine gluconate (Chx) to the oral cavity. Gels (at 1 or 2% concentration) or
film forms of chitosan were prepared containing 0.1 or 0.2% Chx and their in vitro
release properties were studied. No significant difference was observed in release
when concentration of Chx was increased from 0.1 to 0.2% indicating that gel
formulations would enable application of Chx at lower concentrations. Release of
Chx from gels was maintained for 3 h. No lag-time was observed in release of Chx
from either gels or films and highest antifungal activity was obtained with 2%
chitosan gel containing 0.1% Chx with a MIC value of 0.25 mg gel/cm3.6
 Liu J et al studied release of theophylline (TPH) from three types of blend
hydrogels. Release profiles of TPH from various types of hydrogels were
determined by UV–vis absorption measurement at 272 nm. Experimental results
showed that the releases of TPH from these hydrogels were dependent upon the
composition of the hydrogel, the type of component, the possible interactions
between two component polymers, as well as external temperature. Blend of gelatin
with a polysaccharide polymer (agar or κ-carrageenan) always resulted in a slower
release than using gelatin itself. When a 1:1 (i.e. 5:5) ratio (in weight) of gelatin to
agar (or κ-carrageenan) was used, the release was much slower than using either
gelatin or agar (or κ-carrageenan). When the different blend ratios (9:1, 7:3, and
5:5) of gelatin to agar (or κ-carrageenan) were used, the slowest release was always
obtained from the ratio of 5:5. The effect of temperature on the release of TPH was
also studied. The release rate increased with increasing temperature.7
 Hsiue GH et al have prepared pilocarpine trapped in a matrix diffusion-controlled
drug delivery system using hydrophilic inserts of Poly(2-hydroxyethyl methacrylate)
(pHEMA) to ensure an increased bioavailability of pilocarpine and prolong the
length of time in which the medication remains in the eyes of the test subjects. The
physical and chemical properties of pilocarpine were investigated to elucidate the
mechanism of drug-polymer interaction and the effect on drug release behavior of
controlled release polymeric devices. The carbonyl group of pilocarpine and the
hydroxy group of pHEMA form the hydrogen bonding. The effective drug release
time increased with the increase of the cross-linking density. Results showed that the
drug release ability can continue for 24 h such that the concentration of pilocarpine
maintained an effective dose. Moreover, the in vivo animal experiment confirmed
that the polymer film effectively reduced the intraocular pressure.8
 Colinet et al developed of new pH-sensitive, amphiphilic and biocompatible
hydrogels based on alginate-g-PCL, cross-linked with calcium ions to form beads,
prepared for controlled delivery of poorly water-soluble drug. They observed
swelling profiles of these hydrogels and found that they swell slightly (10–14%) in a
simulated gastric fluid (pH 1.2), and strongly (700–1300% before disintegration) in
a simulated intestinal fluid(SIF) (pH 6.8). In both media, rate of swelling were lower
for beads based on amphiphilic derivatives than for alginate/Ca2+ ones due to the
hydrophobic PCL grafts. A model drug, theophylline, was entrapped into these
hydrogels and release studies were carried out and found that release of TPH from
alginate beads in low pH solutions was significantly reduced compared to
alginate/Ca2+ beads, and these systems were able to protect effectively drug from
acidic environment. The rapid disruption of alginate-g-PCL/Ca2+ beads in intestinal
media resulted in a final burst release of drugs.9
 Zahedi P have studied the physicochemical parameters affecting the formation of
solid molecular dispersions of poorly water-soluble drugs in poly(2-hydroxyethyl
methacrylate) (PHEMA) hydrogels and effect of storage humidity levels on their
physical stability. They prepared samples using different drugs like diclofenac
sodium, piroxicam and naproxen as model drugs. These were characterized by X-ray
diffraction (XRD), differential scanning calorimetry (DSC) and Fourier transform
infrared spectroscopy (FTIR), as well as changes in the physical state during storage
under different humidity conditions. The threshold drug loading level of about 30%
exists in these solid molecular dispersions, above which amorphous to crystalline
transition may occur. Presence of hydrogen bonding between the polymer and the
drug improves the compatibility between the drug and the polymer and a decreased
mobility in the glassy polymer so retard the crystallization below the loading
threshold. An increase in dissolution rate was observed from the polymeric solid
molecular dispersion when compared with crystalline pure drug. These
physicochemical results indicated that solid molecular dispersions based on PHEMA
hydrogels can effectively enhance the dissolution and used in improving the oral
bioavailability of poorly water-soluble drugs.10
 Jennifer J et al characterized thermoresponsive hydrogels (liquids at room
temperature, gels at body temperature) as a novel drug delivery. They synthesized
thermoresponsive hydrogels using poly(N-isopropylacrylamide) (PNIPAAm), crosslinked with poly(ethylene glycol) diacrylate (PEG-DA) and Proteins were
encapsulated into the hydrogels, including bovine serum albumin (BSA),
immunoglobulin G (IgG), bevacizumab and ranibiumab. Cross-linked PNIPAAm
hydrogel exhibited a fast and reversible phase change with alteration in temperature.
The rate of protein release was examined as a function of cross-link density. Release
profiles of the proteins showed an initial burst of release within 48 hours, and then a
steady state was reached, which sustained for approximately 3 weeks. They found
that hydrogels with less cross-linking showed faster release and yielded a more
pliable gel for intra vitreal injection via small-gauge needles and gel was able to
encapsulate and release various proteins for long duration of time.11
 Garcia DM et al have prepared a pH-sensible poly(2-hydroxyetyl methacrylate-comethacrylic acid) hydrogels for controlled release of Timolol melate and evaluated
the influence of Hydrogel composition and pH in the swelling and Timolol malate
release at 37oC. The results showed that as methacrylic(MAA) content in the
Hydrogel increased its swelling was higher because of the hydrophilic character of
monomer. Diffusion coefficients were higher as the MAA content in hydrogel
increased. The pH increase caused a higher ionization of the polymer network and
so, a higher swelling and faster release of drug.12
 Jafari S have formulated Acrylic acid and Methacrylic acid Hydrogels with
Polyethylene Glycol and have studied the swelling and complex formation which
indicated that at higher pH, the acrylic acid hydrogels were having higher degree of
swelling than methacrylic acid hydrogels .Further it was found that Methacrylic acid
hydrogels can form strong complexes with polyethylene glycol than acrylic acid
hydrogels and that acidic pH promotes the complex formation but with a lower
degree of swelling.13
•Satish CS have prepared and evaluated swelling and in vito release of insulin from
semi-interpenetrating polymeric networks of poly(vinyl alcohol) and poly(methacrylic
acid).The swelling studies showed that the hydrogels swelled in pH 7.4 more
compared to pH 2.0. The release of insulin was maximum in pH 7.4 and less than 5 %
release was seen in acidic pH.14
6.3Main objectives of the study:
The objectives of the present study are as follows:
1.
To design and develop hydrogels containing an anti hypertensive drug.
2.
To carry out swelling studies and determine equilibrium swelling index.
3.
To carry out the in vitro drug release profile of the formulations.
4.
To study the effect of polymer composition on hydrogel swelling and release behavior.
5.
To carry out the stability studies of the selected formulations.
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Materials and methods:
7.1 Source of data:
The data will be obtained from the literature survey and internet source. The data will be
obtained from the experimental work, which includes formulation of sustained release solid
oral dosage forms by using different polymers, evaluation of drug content and stability studies.
7.2 Method of collection of data (including sampling procedures if any):
The data will be collected from prepared formulations subjected to different evaluation
techniques, estimation of drug content, in-vitro drug release and stability studies.
7.3 Does the study require any investigation or interventions to be
Conducted on patients or other humans or animals?
- NO –
7.4 Has ethical clearance been obtained from your institution in case of 7.3 ?
- Not applicable –
8.
LIST OF REFERENCES:
1. Pavithra T.K; P, Harshitha R, Panneer K, Renuka S, Prakash R, B;, Narendra C.
Formulation and Evaluation of Hydrogel Based Oral Controlled Drug Delivery System
for Antihypertensive Drug. Journal of Pharmaceutical Science and Technology.
2010;2(8).
2. Narayani R, Rao KP. Collagen-poly (HEMA) hydrogels for the controlled delivery of
methotrexate and cisplatin. Int J Pharm. 1996;138:121-4.
3. Gupta NV, Satish CS, Shivakumar HG. Preparation and characterization of Gelatinpoly(methacrylic acid) Interpenetrating Polymeric network hydrogels as pH sensitive
Delivery system for Glipizide. Indian J Pharm sci. 2007;64-8.
4. George M, Abraham TE. pH sensitive alginate-guar gum hydrogel for the controlled
delivery of protein drug. Int J Pharm. 2007;335:123-9.
5. Jain SK, Jain A, Gupta Y, Ahirwar M. Design and development of hydrogel beads for
targeted drug delivery to the colon. AAPS Pharm Sci Tech. 2007;8:E1-E8.
6. Senela S, lkincia G, Kasa S, Yousefi Radb A, Sargonc MF, Hincala AA. Chitosan films
and hydrogels of Chlorhexidine gluconate for oral mucosal delivery. Int J Pharm.
2000;193(2):197-203.
7. Jianhong L, Shiqi L, Lin L, Erjia L. Release of theophylline from polymer blend
hydrogels. Int J Pharm. 2005;298(1):117-25.
8. Hsiue GH, Guu JA, Cheng CC. Poly(2-hydroxyethyl methacrylate) film as a drug
delivery system for Pilocarpine. Biomaterials. 2001;22:1763-9.
9. Colinet I, Dulong V, Mocanu G, Picton L, Le Cerf D. New amphiphilic and pHsensitive hydrogel for controlled release of a model poorly water-soluble drug. Eur J
Pharm Biopharm. 2009;73:345-50.
10. Zahedi P, Lee PI. Solid molecular dispersions of poorly water-soluble drugs in poly(2hydroxyethyl methacrylate) hydrogels. Eur J Pharm Biopharm. 2007;63(3):320-8.
11. Jennifer J, Derwent K, William F, Mieler MD. Thremoresponsive Hydrogels a new
Ocular Drug Delivery platform to the posterior segment of the eye. Trans Am
Ophthalmol Soc. 2008;106:206-14.
12. Garcia DM, Escobar JL, Noa Y, Bada N, Hernaez E, Katime I. Timolol maleate release
from pH-sensible poly(2-hydroxyethyl methacrylate-co-methacrylic acid) hydrogels.
Eur Polym J. 2004;40:1683-90.
13. Jafari S, Modarress H. A study on swelling and complex formation of Acrylic Acid and
Methacrylic Acid Hydrogels with Polyethylene Glycol. Iran Polym J. 2005;14(10):86370.
14. Satish CS, Shivakumar HG. Dynamic swelling and in vitro release of insulin from semi
interpenetrating polymeric networks of poly(vinyl alcohol) and poly(methacrylic acid).
Indian J Pharm Sci. 2007;68:133-40.
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Signature of the candidate:
(ANUSHA.MV)
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Remarks of the guide:
RECOMMENDED.
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Name And Designation of:
11.1 Guide
Dr. SATISH C.S.
Professor,
Department of Pharmaceutics,
P.E.S. College of Pharmacy,
Bangalore-560050.
11.2 Signature
11.3 Co-Guide
NOT APPLICABLE
11.4 Signature
11.5 Head of the department
Dr. SATISH C.S.
Professor& HOD,
Department of Pharmaceutics,
P.E.S. College of Pharmacy,
Bangalore -560050.
11.6 Signature
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12.1 Remarks of the Chairman and Principal:
Prof. Dr. S. MOHAN,
Principal,
P.E.S. College of Pharmacy,
Bangalore-560050.
12.2 Signature :