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DEVELOPMENT OF FAST DISSOLVING SUBLINGUAL WAFERS OF
PROMETHAZINE HYDROCHLORIDE.
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED
TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA
BY
INDRANIL GANGULY
Ι M.PHARM (2012-2013)
DEPARTMENT OF PHARMACEUTICS
M.S.RAMAIAH COLLEGE OF PHARMACY
BANGALORE - 560 054
KARNATAKA
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR P.G. DISSERTATION
Name of the Candidate
1. and Address
( (In block letters)
2.
Name of the Institution
3.
Course of Study and Subject
4.
Date of Admission to course
5.
Title of the Topic
Mr. INDRANIL GANGULY
S/o ARINDAM GANGULY
50, HARI GANGA BASAK ROAD,
AGARTALA,TRIPURA (WEST),
PIN- 799001
M.S.RAMAIAH COLLEGE OF
PHARMACY
M.S.R.NAGAR
M.S.R.I.T POST
BANGALORE-560 054.
MASTER OF PHARMACY
IN
PHARMACEUTICS
09/08/2012
“DEVELOPMENT OF FAST DISSOLVING SUBLINGUAL WAFERS
OF PROMETHAZINE HYDROCHLORIDE.”
1
6. BRIEF RESUME OF THE INTENDED WORK
6.1 NEED FOR THE STUDY
The oral route of administration is considered as the most widely accepted route. The
unique environment of the oral cavity offers its potential as a site for drug delivery. Because of its
rich blood supply and direct access to systemic circulation, the oral mucosal route is suitable for
drugs, which are susceptible to acid hydrolysis in the stomach or are extensively metabolized in the
liver. The target sites for local drug delivery in the oral cavity include the buccal cavity and
sublingual area.
Sublingual administration means placement of the dosage form under the tongue and the
drug reaches passes directly into the blood stream through ventral surface of the tongue and floor of
the mouth. The drug solutes are rapidly absorbed into the reticulated vein which lies underneath the
oral mucosa, and transported through the facial veins, internal jugular vein, and braciocephalic vein
and then drained in to the systemic circulation.1
The advantage of sublingual drug delivery is that the drug can be directly absorbed into the
systemic circulation bypassing first pass effect and avoiding pre-systemic elimination in the GI
tract. In addition, the thin sublingual mucosa (about 190 m compared to 500–800 m of the
buccal mucosa) and the abundance of blood supply at the sublingual region allows excellent drug
penetration (absorption) to achieve high plasma drug concentration with a rapid onset of action.2
Mouth dissolving formulations offer improved patient compliance as they enable oral
administration without the requirement of water or chewing. They are also known as fast
dissolving, rapid-dissolving, mouth-dissolving, fast melting, or orodispersible tablets and usually
disintegrate within 60 seconds when placed in the mouth. Such preparations are preferred by
patients with swallowing difficulties, including geriatrics, pediatrics, dysphagic, and bed ridden.
The active ingredients are absorbed through mucous membranes in the mouth and GIT and enter
the blood stream.
Tablet compression and lyophilization (Freeze drying) remain the two most popular
industrial approaches to manufacture mouth dissolving preparations.
The process of lyophilization involves the removal of solvent from a frozen drug solution or
suspension containing structure forming excipients. The principle involved is sublimation where a
solid is directly converted to the vapour phase without passing through the intermediate liquid
phase. Lyophilized or Freeze-dried products are porous with high hydration capacity and tend to
release their contents faster than products dried by other methods.
2
Some of the patented lyophilized ODT technologies include ZYDIS®, LYOC® and
QUICKSOLV®. 3
Motion sickness or kinetosis, also known as travel sickness is a very common disturbance
of the inner ear that is caused by repeated motion. Depending on the mode of travelling and cause it
can also be referred to as seasickness, car sickness, simulation sickness or airsickness. Motion
sickness can develop from the movement of a car, movement of a boat, or from turbulence in an
airplane. The symptoms of motion sickness are nausea, vomiting, dizziness, sweating, and a sense
of feeling unwell. These symptoms arise from the inner ear (labyrinth) due to changes in one's
sense of balance and equilibrium. Nausea, dizziness, fatigue and headache are the most common
symptoms of motion sickness. 4
A wide range of drugs have proven to be effective against nausea and vomiting. These
include anti- histamines, anti-cholinergics, dopamine receptor antagonists, 5 – HT3 receptor
antagonists and gastro-prokinetic agent.
Promethazine hydrochloride is one of the most effective agents for treating motion sickness
and other balance disorders. Promethazine is also indicated for inducing light sedation and for
treating various allergic conditions. This drug is a first generation anti-histamine of the
phenothazines family. It mainly acts as a strong antagonist of the H1 receptor (antihistamine) and is
a moderate mACh receptor antagonist and hence it blocks the action of acetylcholine on the
receptors (anticholinergic effect). This explains its benefit in reducing the nausea experienced
during motion sickness.
Promethazine is well absorbed after oral and intramuscular doses. Peak plasma concentrations have
been seen after 2 to 3 hours after a dose by these routes. But its systemic bioavailability after oral
doses is very low (about 25%) which is mainly due to extensive first-pass metabolism in the liver.
Hence an alternative route of administration for this drug should be considered. Promethazine
undergoes extensive metabolism to promethazine sulfoxide and to N- dimethylpromethazine.
Promethazine has a half-life of 16-19 hours. It is excreted slowly via the urine and bile, chiefly as
metabolites.5
The objective of the present research work is to formulate and evaluate fast dissolving
sublingual wafers of Promethazine hydrochloride by lyophilization process to achieve a safe, rapid
and effective dosage form with enhanced drug dissolution and oral bio availability. The wafer will
be is instantly wetted by saliva when placed sublingually, following which the wafer will rapidly
hydrate and adhere onto the site of application. It will then rapidly disintegrate and dissolve (in less
3
than a minute), to release the medication for oro-mucosal absorption. Since Promethazine
hydrochloride is a bitter drug and taste masking will be attempted in order to overcome the bitter
taste by using various sweeteners and flavouring agents.
6.2 REVIEW OF LITERATURE
Literature survey was carried out on the proposed research work by referring various scientific
Research journals, Internet, Helinet facilities and Science direct.
 Shojaei AH, reviewed the suitability of the buccal mucosa as a route for systemic drug
delivery. The article discusses different buccal delivery systems along with the structure of
the
buccal
mucosa
and
the
different
experimental
methods
for
assessing
the
permeation/absorption of the buccal delivery systems.6
 Joshua S Boateng, et al. developed freeze-dried (lyophilized) wafers and solvent cast films
from Sodium alginate and Sodium Carboxymethylcellulose for mucosal surfaces including
wounds. The wafers were prepared by freeze drying and solvent evaporation method using
Paracetamol as the model drug. The freeze dried wafers showed greater drug loading, solvent
absorption capacity and moisture absorption than the corresponding solvent evaporated flims.7
 Joshua S Boateng, et al. prepared and compared the in vitro release properties of freeze dried
wafers and solvent evaporated films prepared from Sodium Carboxymethylcellulose.
Paracetamol was chosen as the model soluble drug. The drug release data fitted into different
kinetic models to find the best fit model (Korsmayer-Peppas) of drug release. The results
showed
that the rate of release of Paracetamol was faster from the wafers than the
corresponding films due to difference in physical structure.8
 Dixit RP, et al. reviewed the concept of Oral strip technology and its future potential. This
technology can be utilized for the administration of drugs to pediatric and geriatric patients.
Oral strip technology can be used for local action, rapid release products and for
buccoadhesive systems that are retained for longer period in the oral cavity.9
 Verena Garsuch, et al. prepared fast dissolving buccal wafers of caffeine and characterized
them using newly developed analytical and physio-chemical techniques. The wafers were
characterized by techniques such as scanning electron microscopy, near-infrared chemical
imaging, swelling analysis by thermo-mechanical method and dissolution studies using fiber
optic sensor system.10
4
 Sandeep Saini, et al. reviewed the importance of fast dissolving films. The article focuses on
the formulation of mouth dissolving films, their methods of manufacture and the quality
control tests. The article also compiles the recent advancements made regarding fast
dissolving films.11
 Ankit Baheti, et al. reviewed the role of the excipients such as bulking agents, buffering
agents, tonicity modifiers, antimicrobial agents, surfactants and co-solvents in the
lyophilization process. A list of ingredients used in the process along with their recommended
quantities was also discussed.12
 Marina Koland, et al. formulated fast dissolving films containing Ondansetron hydrochloride
for sublingual administration. The films were prepared from polymers such as Polyvinyl
Alcohol, polyvinylpyrrolidone, Carbopol 934P in different ratios by solvent casting method.
Propylene glycol or PEG 400 were used as plasticizers and Mannitol or Sodium Saccharin as
sweeteners were also included. The prepared formulations showed satisfactory result when
subjected to various physio-chemical tests such as uniformity of weight, thickness, surface
pH, folding endurance, uniformity of drug content, swelling index, bioadhesive strength and
tensile strength. The formulations were also subjected to evaluation of in vitro drug release by
using USP Dissolution Apparatus. Ex vivo drug release and permeation studies were also
carried out using porcine membrane as the model. All the formulations showed 81-88 %
release within 7 minutes.13
 Sangeetha S, et al. reviewed the suitability of mucosa as a potential site for drug administration.
The article focusses on various transmucosal routes of drug delivery such as buccal, nasal,
rectal, vaginal drug delivery.14
 Frank Kofi Bedu-Addo, discussed the fundamentals of lyophilization and provides case studies
about the development of lyophilised products and its importance in the biophysical
characterisation in formulation process.15

Priyank Patel, et al. reviewed the different sublingual dosage forms, advantages, factors
affecting sublingual absorption, pharmacology of Ondansetron, methods of preparation and
various in vitro and in vivo evaluation parameters of sublingual tablet of ondansetron.16
 Longsheng Hu, et al. studied the effect of chemical enhancers and iontophoresis on the in vitro
transbuccal delivery of Ondansetron HCl using porcine buccal tissue. The chemical enhancers
used were dodecyl 2-(N, N-dimethyl amino) propionate (DDAIP), its HCl salt dodecyl-2-(N, Ndimethylamino)
propionate
hydrochloride
(DDAIP
HCl),
N-(4-bromobenzoyl)-
S,Sdimethyliminosulfurane (Br-iminosulfurane), and azone. The study demonstrated that
anodal iontophoresis at 0.1, 0.2 and 0.3mA current intensity significantly increased transbuccal
5
delivery of the drug 3.3-fold, 5.2-fold and 7.1-fold respectively compared to control. A light
microscopy study showed that treatment with chemical enhancers and iontophoresis did not
cause major morphological changes in the buccal tissue.17
 Isaac Ayensu, et al. developed lyophilized aqueous gels of the polymer incorporating varying
concentrations of glycerol as plasticizer and
D-mannitol
as cryoprotectant. The different
formulations were characterized by their physico-mechanical properties. The optimised
formulation was loaded with bovine serum albumin and lyophilised with or without annealing.
Differential scanning calorimetry were used to determine the appropriate lyophilisation cycle
by evaluating thermal events before lyophilisation and possible phase separation of bovine
serum albumin after lyophilisation. Texture analysis was employed to investigate the in vitro
mucoadhesive properties in tensile mode, residual moisture content by thermo-gravimetric
analysis while hydration capacity and drug release studies were performed. Microscopic
architecture and crystallinity were examined using scanning electron microscopy and X-ray
diffractometry respectively. The results showed the potential of employing lyophilised chitosan
wafers for buccal mucosa delivery of protein based drugs.18
 Kavitha K, et al. developed oral fast dissolving tablets of Promethazine HCl by direct
compression method using camphor as subliming agent. Sodium Starch Glycolate,
Croscarmellose Sodium and Tulsion 414 were used as superdisintegrants. The prepared
formulations were evaluated for weight variation, hardness, friability, drug content,
disintegration time, wetting time and in vitro dissolution. The tablets showed a disintegration
time of less than 60 seconds.19
 Sachin B. Mahamuni, et al. prepared fast dissolving tablets of Promethazine HCl using taste
masked granules. The granules were prepared using gastro erodible aminoalkyl methacrylate
copolymers (Eudragit E-100) by extrusion method. Fast dissolving tablets were prepared by
direct compression using taste-masked granules and a mixture of excipients containing
optimized level of Microcrystalline cellulose and Starch. The effect of various
superdisintegrants Crospovidone, Sodium Starch Glycolate, Croscarmellose sodium was also
studied. The prepared tablets were evaluated for taste, crushing strength, disintegration time and
dissolution. Evaluation of taste masked granule of PM HCl was confirmed by UV
spectrophotometric method as well as sensory evaluation study. The dissolution rate was
significantly improved with tablets formulated with taste masked granules of PM HCl as
compared with unmasked granules. This could be accounted to the effect of Eudragit E-100 on
the dissolution profile of PM HCl and also aiding in masking the bitter taste.20
6
6.3 OBJECTIVES OF THE STUDY
The present research work has been aimed for:
 Formulation of fast dissolving Promethazine hydrochloride oral wafers by lyophilization
method, using ideal polymers.
 Evaluation of formulated wafers using different parameters like surface pH, swelling
studies, drug content, wafer thickness, folding endurance of the wafer, in-vitro bio-adhesive
studies, in-vitro drug release studies, ex-vivo permeation studies etc.
 Compatibility studies between the drug and carrier by FTIR and DSC.
 Statistical analysis of all the results.
 To conduct stability studies as per the ICH guidelines and predict the shelf life of the dosage
form.
7. MATERIALS AND METHOD
7.1 SOURCE OF DATA
1. Library and E- library of M.S. Ramaiah College of Pharmacy.
2. The data will be collected from official books such as (IP, BP and USP).
3. Internet source.
4. RGUHS Library, Bangalore (J-Gate Helinet).
5. Micromedex® Health care series. Drug Information Centre: M.S. Ramaiah
College of Pharmacy.
6. International and National Pharmaceutical journals.
7. Lab based studies.
7.2 MATERIALS
 Drug: Anti-emetic drug: Promethazine hydrochloride
 Polymers like Hydroxypropyl Methylcellulose, Hydroxypropyl Cellulose, Sodium
Carboxymethylcellulose, Pullulan, Polyvinyl Alcohol, etc.
 Plasticizers like Glycerol, Polyethylene Glycol, Dibutyl Phthalate, Castor oil etc.
 Organoleptic additives like coloring, flavoring and sweetening agents.
All the chemicals, excipients and solvents used will be of laboratory grade/analytical grade
and procured from reliable sources.
7
7.3 METHODS OF DATA COLLECTION
Data will be collected from the experimental work which includes:
1) PRE-LABORATORY WORK
The drug, solvents and excipients required for the formulation and evaluation wafers will
be procured from reputed chemical suppliers like Merck, Ranbaxy, Qualigens, Himedia etc.
2) LABORATORY WORK
Preformulation studies
 The drug-polymer compatibility determination using thermal analysis such as FTIR and
DSC techniques.
 Plot of standard calibration curve for pure drug Promethazine hydrochloride
Formulation studies
 Formulation of lyophilized wafers of Promethazine hydrochloride using ideal polymer
blends in varied combination ratios by suitable methods.
Evaluation studies
 Evaluation of the formulated wafers using different parameters like Surface pH,
Swelling studies, drug content, thickness, Folding endurance, in-vitro Bioadhesive
studies, ex-vivo Permeation studies.
 In-vitro drug release and kinetics studies of the dosage forms.
 Stability studies of the optimized formulation as per the ICH guidelines and to predict
the shelf life.
7.4
DOES
THE
STUDY
REQUIRE
ANY
INVESTIGATION
OR
INTERVENTION TO BE CONDUCTED ON PATIENTS OR OTHER
HUMAN OR ANIMALS?
-NO8
7.5 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR
INSTITUTE?
-NOT APPLICABLE-
8. LIST OF REFERENCES
1. K Patel Nibha, SS Pancholi. An Overview on: Sublingual Route for Systemic Drug
Delivery. Int J Res Pharm Biomed Sci.2012; 3 (2):913- 923.
2. Ziya Bayrak, et al. Formulation of Zolmitriptan sublingual tablets prepared by direct
compression with different polymers: In vitro and in vivo evaluation. Eur J Pharm
Biopharm.2011; 78:499–505.
3. Saniket Fuzele, Derek Moe, Ehab Hamed. ODT technology – LYOC (lyophilized wafer):
an orally disintegrating tablet technology. Drug Dev Del. March 2012:1-5
4. URL: http://www.medicinenet.com/motion_sickness/article.htm [Cited on Jan 5, 2013].
5. Sean C Sweetman (Eds.) Martindale-The complete drug reference.36th edition.
Pharmaceutical Press: Great Britain. 2009; 588-589.
6. Amir H Shojaei. Buccal mucosa as a route for systemic drug delivery: a review. J Pharm
Pharma Sci.1998; 1 (1):15-30.
7. Joshua S Boateng, Anthony D Auffret, Kerr H Matthews, Michael J Humphrey, Howard
N.E Stevens, Gillian M Eccleston. Characterisation of freeze-dried wafers and solvent
evaporated films as potential drug delivery systems to mucosal surfaces. Int J Pharm. 2010;
389: 24-31.
8. Joshua S Boateng, Anthony D Auffret, Kerr H Matthews, Michael J Humphrey, Howard
N.E Stevens, Gillian M Eccleston. In-vitro drug release studies of polymeric freeze-dried
wafers and solvent-cast films using Paracetamol as a model soluble drug. Int J Pharm.2009;
378: 66-72.
9. Dixit R P, Puthil S P Oral strip technology: overview and future potential. J Control
Release. 2009; 139: 94-107.
10. Verena Garsuch, Jorg Breitkreutz. Novel analytical methods for characterization of oral
wafers. Eur J Pharm Biopharm. 2009; 73:195-201.
9
11. Sandeep Saini, Arun Nanda, Monika Hooda, Komal. Fast dissolving flims (FDF):
innovative drug delivery system. Pharmacologyonline.2011; 2: 919-928.
12. Ankit Baheti, Lokesh Kumar, Arvind K Bansal. Excipients used in lyophilisation of small
molecules. © IPEC- Americas Inc, J. Excipients and Food Chem. 2010; 1 (1): 41-54.
13. Marina Koland, VP Sandeep, R Narayana Charyulu. Fast dissolving sublingual films of
ondansetron hydrochloride: Effect of additives on in-vitro drug release and mucosal
permeation. J Young Pharmacists. 2010; 2(3): 216-22.
14. S Venkatesh, D Nagaswami, PN Krishan, R Saraswathi. Mucosa as a route of systemic drug
delivery. Res J Pharm Bio and Chem Sci. 2010; 1, 3: 178-187.
15. Frank Kofi Bendu-Ado. Understanding lyophilisation formulation development. Pharm
Tech. 2004: 10-18.
16. Priyank Patel, Sandip Makwana, Urvish Jobanputra, Mihir Ravat, Ankit Ajmera, Mandev
Patel. Sublingual route for the systemic delivery of Ondansetron. Int J Drug Dev Res.2011;
3(4): 36-44.
17. Longsheng Hu, Bassam B. Damajb, Richard Martinb, Bozena B. Michniak-Kohn. Enhanced
in vitro transbuccal drug delivery of Ondansetron HCl. Int J Pharm. 2011; 404: 66–74.
18. Isaac Ayensu, John C. Mitchell, Joshua S. Boateng. Development and physico-mechanical
characterisation of lyophilised chitosan wafers as potential protein drug delivery systems
via the buccal mucosa. Colloids and Surfaces B: Biointerfaces. 2012; 91(1): 258-265.
19. Kavitha K., Sandeep D. S., Mehaboob Yadawad, More Mangesh. Formulation and
Evaluation of Oral Fast Dissolving Tablets of Promethazine HCl by Sublimation Method.
Int J PharmTech Res.2011; 3(2): 660-663.
20. Sachin B. Mahamuni, Sadhana R. Shahi, Nandakishor V. Shinde, Gaurav R. Agrawal.
Formulation and evaluation of fast dissolving tablets of Promethazine HCl with masked
bitter taste. Int J Pharm Res Dev. 2009; 7:1-18.
10
9.
SIGNATURE OF THE CANDIDATE
10.
REMARKS OF THE GUIDE
11.
NAME AND DESIGNATION OF
11.1 GUIDE
Recommended for Approval
Mrs. SINDHU ABRAHAM, M. Pharm
Lecturer
Dept. of Pharmaceutics
M.S. Ramaiah College of Pharmacy,
Bangalore-560 054.
11.2 SIGNATURE
11.3 CO-GUIDE
NOT APPLICABLE
11.4 SIGNATURE
11.5 HEAD OF THE DEPT.
Dr. S.BHARATH, M. Pharm, Ph.D., ACCR
Professor and Head
Dept. of Pharmaceutics
M.S. Ramaiah College of Pharmacy,
Bangalore-560 054.
11.6 SIGNATURE
12.
12.1 REMARKS OF THE PRINCIPAL
Forwarded for Approval
12.2 SIGNATURE
11