A Synopsis
On
“FORMULATION, CHARACHTERIZATION AND
EVALUATION OF SITE SPECIFIC DRUG DELIVERY
SYSTEM (S)
OF ANTICANCER DRUG”
Under Supervision of-
Supervisor
Co-Supervisor
Prof. R.K.Khar
Dr. S.K. Prajapati
Ex-Head & Ex-Dean
Department of Pharmaceutics,
Faculty of Pharmacy,
Jamia Hamdard (Hamdard University),
New Delhi
Head & Reader
Institute of Pharmacy,
Bundelkhand University,
Jhansi (U.P.)
Submitted by
Rishikesh Gupta
M.Pharm.
Specialization of the proposed research work:Pharmaceutics (Pharmacy)
Aims and objectives of present research works:1. To prepare novel floating drug delivery systems containing anti-cancer drugs to
optimize and rationalize the delivery.
2. To do comparative studies on prepared dosage forms for various relevant process
and formulation parameters in order to find out the potential delivery system.
Name and Signature of Candidate
CONTENTS
Chapter
Page No.
1. Introduction
02-05
2. Literature Review
06-09
3. Research Envisaged
10
4. Plan of work
11-12
5. References
13-15
INTRODUCTION
The gastric emptying time (GET) and the variation in the pH in the different
segments of gastrointestinal tract (GIT) are the major challenges in the development of
oral controlled release drug delivery systems. Various attempts have been made to
enhance the residence time of the dosage form within the stomach. Gastroretentive
system can remain in the gastric region for several hours and hence significantly prolong
the gastric residence time of drug in the GIT. The prolongation of gastric residence time
(GRT) of delivery system could be achieved by the mechanism of mucoadhesion,
simultaneous administration of pharmacological agents that delay the gastric emptying.
One of the methods for enhancement of GRT is based on the mechanism of
floatation. Wherein the delivery systems are less dense than the gastric fluid. Floating
single dosage form, also called hydro dynamically balanced systems (HBS), have been
extensively studied.
Floating systems, first described by Davis in 1968, are low-density systems that
have sufficient buoyancy to float over the gastric contents and remain in the stomach for a
prolonged period. The system floats over the gastric contents, releasing the drug slowly at
the desired rate, which not only results in increased GRT but also reduces fluctuation in
plasma drug concentration.
FLOATING SYSTEM:
These have a bulk density lower than the gastric content. They remain buoyant in
the stomach for a prolonged period of time, with the potential for continuous release of
drug. Eventually, the residual system is emptied from the stomach. Gastric emptying is
much more rapid in the fasting state and floating systems rely heavily on the presence of
food to retard emptying and provide sufficient liquid for effective buoyancy.
Floating systems can be classified as effervescent and non-effervescent
systems.
Effervescent Systems: Floatation of a drug delivery system in the stomach can be
achieved by incorporating a floating chamber filled with air, or an inert gas. Gas can be
introduced into the floating chamber by the volatilization of an organic solvent (e.g., ether
or cyclopentane) or by the CO2 produced as a result of an effervescent reaction between
organic acids and carbonate–bicarbonate salts.
Non-effervescent Systems: Non-effervescent systems incorporate a high level (20–75%
w/w)
of
one
or
more
gel-forming,
highly
swellable,
cellulosic
hydrocolloids,
polysaccharides, or matrix-forming polymers into tablets or capsules. Upon coming into
contact with gastric fluid, these gel formers hydrate to form a colloidal gel barrier that
controls the rate of fluid penetration into the device and subsequent drug release. The air
trapped by the swollen polymer lowers the density of and confers buoyancy to the dosage
form.
Stomach cancer is the second leading cause of the death. Stomach cancer can be cured
if the tumor is found early and completely removed surgically. However, the disease is
often not diagnosed until it has already spread (metastasized) to other tissues and
organs. Outcomes are very poor for patients with advanced stomach cancer that cannot
be surgically removed.
There are two factors that play a major role in the development of stomach cancer;
Infection with Helicobacter pylori bacteria and the type of diet.
The earliest sign of both non-cancerous (benign) and cancerous (malignant) stomach
tumor is microscopic internal bleeding, which is usually only detected by tests that is
based on stool examination for blood content. The patient may also feel tired if this
bleeding causes the loss of too many healthy red blood cells (anemia).
Controlled drug delivery system
Most solid dosage forms are designed to release their medication to the body for
absorption rapidly and completely, where as some dosage forms are designed to release
the drug slowly for more prolonged drug release and sustained drug action. The termcontrolled release implies that the release of drug from the dosage form occurs in a
planned, predictable, and slower than normal fashion.
In general, controlled delivery attempts to:
Delayed release
Sustained release
Site specific targeting and Receptor targeting
Delayed release system are those that use repetitive intermittent design of a drug from
one or more immediate release units incorporated into a single dosage form i.e. repeat
action tablets, capsules and enteric coated where timed release is achieved by a barrier
coating.
Sustained releases systems include any drug delivery systems that achieve slow release
of drug over extended period of time. This system is successful at maintaining constant
drug level in the target tissue or cell; it is considered as controlled release system.
Site specific and receptor targeting refers to targeting of a drug directly to a certain
biological location. In the cases of site specific release, the target is adjacent to or in the
diseased organ or tissues. For receptor release, the target is the particular receptor for a
drug within an organ or tissue. Both these system are considered to be controlled drug
system.
TARGETED DRUG DELIVERY SYSTEM:
The objective of drug targeting is to achieve a desired pharmacological response at a
selected site without undesirable interaction at other sites. At present drug targeting is
achieved by following two approaches:
Involves chemical modification of the parent compound to a derivative, which is activated
only at target site.
Utilizes carriers such as liposomes, microspheres, nanoparticles, antibodies, cellular
carriers (erythrocytes and lymphocytes), and macromolecules to direct the drug to its site
of action.
The Prodrug approach which involves an inactive derivative of the parent compound
(prodrug) that is activated predictably in-vivo to the active drug species. However, with
few exceptions, it cannot achieve site-specific delivery.
Chemical Delivery System approach involves the transformation of the active drug by
synthetic means into an inactive derivative, which when placed in the body, will undergo
several predictable enzymatic transformations principally at its site of action. This
approach has proven to be successful in local delivery of drug to the eye, brain, and
testes.
Advantages of TDDS:
Specific targeting of the drug to the colon is recognized to have several therapeutic
advantages. Drugs that are destroyed by the acidic environment of the stomach or
metabolized by pancreatic enzymes are only slightly effective in the colon. Treatment of
colonic diseases such as ulcerative colitis, Crohn's disease and colorectal cancer is more
effective with the direct delivery of drugs to the colon The features of the colon that makes
it suitable for targeting of various drugs including proteins and peptides are-:
Its lower metabolic activities.
Longer residence time (20-30hrs.)
Responsiveness to absorption enhancers.
Targeting opportunities offered by colonic bacterial enzymes.
Transmucosal and membrane potential difference that is significant in the absorption of
the ionized and unionized drugs, and possibility that bulk water absorption in this region
may provide scope for solvent drug.
LITERATURE REVIEW
1. Kawashima, et al. prepared multiple-unit hollow microspheres by emulsion solvent
diffusion technique. Microballoons were floatable in-vitro for 12 hours when immersed
in
aqueous
media
Radiographical
studies
proved
that
microballoons
orally
administered to humans were dispersed in the upper part of stomach and retained
there for 3 hours against peristaltic movements.
2. Joseph, et al. developed a floating dosage form of piroxicam based on hollow
polycarbonate microspheres. The microspheres were prepared by the solvent
evaporation technique. Pharmacokinetic analysis was derived from plasma
concentration vs. time plot and revealed that the bioavailability from the piroxicam
microspheres alone was 1.4 times that of the free drug and 4.8 times that of a dosage
form consisting of microspheres plus the loading dose was capable of sustained
delivery of the drug over a prolonged period.
3. Sato, et al. prepared hollow microspheres by the emulsion solvent diffusion method
using enteric acrylic polymers with the drug in a mixture of dichloromethane and
ethanol. The optimum loading amount of riboflavin in the microballoon was found to
impart ideal floatable properties to the microballoons. On the other hand, little
entrapment was observed for aspirin due to the low distribution coefficient; however,
entrapment improved to some extent upon reduction of the pH of the process.
4. El-Kamel, et al. prepared floating microparticles of ketoprofen, by emulsion solvent
diffusion technique. Four different ratios of Eudragit S-100 with Eudragit RL were used.
The formulation containing 1:1 ratio of the two above mentioned polymers exhibited
high percentage of floating particles in all the examined media as evidenced by the
percentage of particles floated at different time intervals.
5. Sopimath, et al. prepared hollow microsphers of cellulose acetate loaded with four
cardiovascular drugs (nifedipine [NFD], nicardapine hydrochloride [NCD], verapamil
hydrochloride [VRP], and dipyridamole [DIP]) by solvent diffusion- evaporation method.
Here, they used ethyl acetate less toxic as solvent and concluded that the release of
drug was controlled for more than 8 hours.
6. Fell, et al. prepared floating alginate beads incorporating amoxicillin. The beads were
produced by drop wise addition of alginate into calcium chloride solution, followed by
removal of gel beads and freeze-drying. The beads containing the dissolved drug
remained buoyant for 20 hours and high drug-loading levels were achieved.
7. Illum, and Ping. developed microspheres that released the active agent in the
stomach environment over a prolonged period of time. The outer layer was
composed of bioadhesive (chitosan). The microspheres were prepared by spray
drying an oil/water or water/oil emulsion of the active agent, the water-insoluble
polymer, and the cationic polymer.
8. Yang, et al. prepared microspheres with microballoons inside for floating drug delivery
systems from xanthan gum and gelatin by water-in-oil method with theophylline as
model drug. They concluded that with increasing the amount of gelatin, the percentage
yield and drug encapsulation efficiency decreased. The drug release rate also
decreased with increasing gelatin content.
9. Shrivastava, et al. developed floating microspheres by the solvent evaporation method
using polymers hydroxypropylmethylcellulose, ethyl cellulose and dichloromethane,
ethanol as solvent. And concluded that microspheres of different size and drug content
could be obtained by varying the formulation variables.
10. Jain, et al. prepared novel calcium silicate based microspheres of repaglinide for
gastroretentive floating microspheres by using calcium silicate as porous carrier,
repaglinide as oral hypoglycemic agent and Eudragit S 100 as polymer. And studied
the effect of different formulation and process variables on the internal and external
practical morphology, micromeritic properties, in-vitro floating behavior, physical state
of incorporated drug, drug loading and in-vitro release studies; and concluded that the
incorporation of the porous calcium silicate in the microspheres proved to be an
effective method to achieve the desired release behavior and buoyancy.
11. Zheng, et al. prepared floating–bioadhesive microparticles containing clarithromycin for
eradication of Helicobacter pylori by combined method of emulsion/evaporation and
internal/ion gelation using ethyl cellulose and chitosan as polymers; and concluded that
clarithromycin contained in CAEMS was released in sustained manner in-vitro.
12. Soppimath, et al studied the effect of coexcipients on drug release and floating
property of nifedipine hollow microspheres. These microspheres were prepared by
solvent diffusion-evaporation technique. It was concluded that the release of nifedipine
was enhanced by the addition of coexcipients.
13. Sahoo, et al. developed floating microspheres of ciprofloxacin hydrochloride by cross
linking technique by dripping. It was concluded that the enhanced buoyancy and
controlled release properties of sodium bicarbonate containing microspheres made
them an excellent candidate for floating drug dosage forms.
14. Shishu, et al. developed multiparticulate alginate floating beads of 5-flurouracil for
stomach specific drug delivery and concluded that the floating type gastroretentive
dosage forms of 5-FU showed better response in comparison to other dosage form.
15. Manoj, et al. developed an oral floating matrix tablet of diltiazem hydrochloride using
Methocel K 100M CR and Compritol 888 as polymers and concluded that the
combination of Methocel K 100M CR and Compritol 888 ATO has resulted in minimal
variation in drug release.
16. Patel, et al. prepared floating granules of Ranitidine hydrochloride by using Gelucire
43/01 and concluded that the hydrophobic lipid Gelucire 43/01 is an effective carrier
for the design of multiple floating drug delivery system of highly water soluble drugs.
Research Envisaged
Mostly the drugs for treatment of stomach cancer are given via parentral route. The
major problem associated with such delivery is that alongwith cancerous cell, even
normal cell are exposed to the drug, resulting in severe side effects. The present work is
aimed at development of site specific floating controlled release drug delivery system to
affect localized drug delivery of anti-cancer drug for the treatment of stomach cancer.
There is no such a system available in the market till date for support the work. The study
shall encompass development & Characterization of different novel drug delivery system
bearing anticancer drug(s) for localized site specific delivery.
PLAN OF WORK
The study shall be carried out on the following lines:
1. Pre-formulation studies of selected drug:
a) Identification & characterization of the drug.
b) Physicochemical properties (i.e. melting point, Solubility, Partition coefficient
etc.)
c) Drug & polymer compatibility study.
2. Selection/Development of spectroscopic method of analysis for the estimation of
drug in formulations and biological fluids.
3. Design and development of targeted drug delivery system and optimization of
process variables.
4. Characterization of targeted drug delivery system.
5. Stability studies
6. In-vivo studies
Instrument Used
 UV Spectrophotometer,
 Single pan balance,
 Electronic balance,
 pH-meter,
 Hot Air oven,
 Optical Microscope,
 Fourior transform Infra-red (FTIR),
 High Performance Liquid Chromatography (HPLC),
 Magnetic stirrer with hot plate,
 Digital dissolution rate test apparatus,
 Lab Incubator,

Melting point apparatus,

Tray Dryer,
REFERENCES
1. Naggar VF, El-Kamel AH, Sokar MS, Al Gamal SS. Preparation and
evaluation of ketoprofen floating drug delivery system. Int j Pharm 2001; 220:
13-21.
2. Arora Sweta, Ali Jwed, Ahuja Alka, Khar RK,and Baboota Sanjula. Floating
Drug Delivery System: A Review, AAPS PharmaSciTech 2005; 6,: Article 47.
3. Rednick AB, Tucker SJ. Sustained release bolus for animal husbandry. US
patent No. 3 507 952; 1970.
4. Singh BN, Kim KH. Floating Drug Delivery Systems: An Approach to Oral
Controlled Drug Delivery via Gastric Retention. J Contrl Release 2000; 63:
235–259.
5. Kawashima Y., Niwa T., Takeuchi H., Hino T., Ito Y., Preparation of multiple
unit hollow microspheres (microballoons) with acrylic resins containing
tranilast and their drug release characteristics (in vivo).J. Controlled Release.
1991, 16, 279-290.
6. Illum L., Ping H., Gastroretentive controlled release microspheres for
improved drug delivery. US patent 6 207 197. March 27, 2001.
7. Sopimath K.S., Kulkarni A.R., Aminabhavi T.M., Development of Hollow
microspheres as floating controlled release system for cardiovascular drugs:
Preparation and release characteristic, Drug Dev. Ind. Phar., 27, 2001, 507515.
8. Joseph N.J., Laxmi S., Jayakrishnan A., A floating type oral dosage from for
piroxicam based on hollow microspheres: in-vitro and in-vivo evaluation in
rabbits. J. Controlled Release, 2002. 79, 71-79.
9. Sato Y., Kawasima Y., Takeuchi H., Yamamoto H., Eur, J. Pharm. Biopharm.,
55, 2003, 297-304.
10. Jain S.K., Awasthi A.M., Jain N.K.,Agrawal G.P., Calcium silicate based
microspheres of repaglinide for gastroretentive floating drug delivery:
Preparation and in-vitro characterization, J. Controlled Release, 107, 2005,
300-309.
11. Zheng J., Liu C., Bao D., Zhao Y., Ma X., Preparation and evaluation of
floating-bioadhesive microparticles containing
clarithromycin or the
eradication of Helicobacter pylori, J. App. Poly. Sci., 102, 2006, 2226-2232.
12. Sopimath K. S., Aminabhi T.M., Agnihotri S.A., Mallikarjuna N., Kulkarni
P.V.,Effect of coexcipients on drug release and floating property of nifedipine
hollow microspheres: A Novel Gastro Retentive Drug Delivery System, J.
App. Poly. Sci., 100, 2006, 486-494.
13. Sahoo S.K., Mohapatra S., Dhal S.K., Behera B.C., Barik B.B., Formulation of
floating microspheres ciprofloxacin hydrochloride by cross-linking technique.,
The Indian Pharmacist, 6, 2007, 65-68.
14. Patel Dashrath M., Patel Natvarlal M., Patel Viral F., Bhatt Darshini A.,.
Floating Granules of Ranitidine Hydrochloride-Gelucir 43/01: Formulation
Optimization Using Factorial design., AAPS Pharmascitech, 2007, 8, Article
30.
15. Manoj N., Gambhire, Kshitij W., Ambade, Kurmi Sushma D., Kadam Vilasrao
J., Jadhav Kisan R., Development and In Vitro Evaluation of an oral floating
Matrix tablet Formulation of Diltiazam hydrochloride., AAPS Pharmascitech,
2007,8, Article 73.
16. Shishu, Gupta N., Aggarwal N., Stomach-specific drug delivery of 5-flurouracil
using floating alginate beads., AAPS Pharmascitech, 2007,8, Article 48.