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“FORMULATION DEVELOPMENT AND EVALUATION OF TASTEMASKING EFFICIENCY OF PEDIATRIC FORMULATIONS USING
SYNTHETIC AND NATURAL SOURCES”
M. PHARM DISSERTATION PROTOCOL
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA
By
SEMBETI NAVEEN KUMAR
B.PHARM
Under the guidance of
Dr. K. V. SANDHYA,
PROFESSOR & HOD,
DEPT. OF PHARMACEUTICS.
Under the Co-guidance of
Ms. D. AGILANDESWARI,
ASST. PROFESSOR,
DEPT. OF PHARMACEUTICS.
DEPARTMENT OF PHARMACEUTICS,
T. JOHN COLLEGE OF PHARMACY, GOTTIGERE,
BANGALORE – 83,
KARNATAKA
2012-2013
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA
BANGALORE
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1.
Name of the Candidate and
Address (in block letters)
2.
Name of the Institution
3.
Course of Study and Subject
SEMBETI NAVEEN KUMAR
B-11-296/6, SUHASINI NAGAR, BUCHIREDDY
PALEM, S.P.S.R, NELLORE DISTRICT,
ANDRAPRADESH.
T. JOHN COLLEGE OF PHARMACY,
GOTTIGERE,
BANGALORE – 83
KARNATAKA
M. PHARM.
(PHARMACEUTICS)
4.
5.
Date of Admission to Course
Title of the Topic.
05-09-2012
‘FORMULATION DEVELOPMENT AND
EVALUATION OF TASTE-MASKING EFFICIENCY
OF PEDIATRIC FORMULATIONS USING
SYNTHETIC AND NATURAL SOURCES’
6. BRIEF RESUME OF THE INTENDED WORK
6.1 Need for the Study:
In earlier days it was believed that the drugs having bitter taste are more
efficient as well as more curable. This concept has been reversed with development of
numerous formulation techniques. In recent era oral administration of bitter drugs with
an acceptable degree of palatability becomes key issue for the health care providers,
especially for pediatric and geriatric patients. Palatability is the combination of sensory
perceptions including taste and smell and to a lesser extent texture, appearance and
temperature of the products. Taste transduction involves the interaction of molecule with
taste receptor cells, which reside in specific structures known, as TASTE BUDS.
The function of taste buds is to relay information about the taste of the molecule
to the central nervous system. Each taste type affects the receptor cells through distinct
mechanisms. The transduction of most bitter and sweet compounds is mediated by G
protein gustducin while for salty and sour, is done by ion channels. Dissociation of
gustducin into alpha and beta subunit decreases cAMP level and activate phospholipase
C, which generates second messenger IP3 and DAG. This complex cascade of bio
chemical events results in taste cells sending a signal to the brain that is interpreted as
bitter and unpleasant. Thus preventing interaction between active molecule and taste bud
could mask bitter taste.
Numbers of therapeutically active herbal and synthetic molecules are having
bitter taste. The unpleasant and unacceptable taste can be modified using below
mentioned suitable techniques. Since last two decades’ large numbers of industrially
viable techniques, are very well explored for the taste masking of bitter drugs1,2.
Based upon the recent theory that taste cells can interpret and process all the
different stimuli, a method of diminishing the overall response to one stimulus would be
to introduce a second stimulus. This is based upon the assumption that differences
among responses to stimuli are not so much a distinction between firing and non-firing
of the neurons, but instead the difference in the amount of firing. This theory is the basis
for the current research being presented in this paper: the ability to transform the
responses of certain stimuli by introducing other stimuli. Effective blocking of the taste
receptors can be accomplished by either coating the surface pore or competing within
the channel themselves to reduce the net effect of the bitter stimuli firings. While the
introduction of competing stimuli is part of the masking system, specific flavours and
sweetness profiles are essential to complete the experience and produce a pleasant taste
for the consumer3-5.
There are number of factors that are taken into consideration during the tastemasking formulation like,
i.
Extent of the bitter taste of the active component,
ii.
total dose of the drug,
iii.
drug particulate shape and size distribution,
iv.
Solubility and ionic characteristics of drug,
v.
formulations characteristics in terms of disintegration and dissolution
rate,
vi.
desired release rate and bioavailability and
vii.
type of dosage form6-11
Taste masking has always been the integral part of formulation especially for
pediatric formulations. During almost last three decades advanced novel formulation
techniques have been utilized to improve the aesthetics of the final products. Some of
the techniques adopted for taste masking are as follows.
1. Taste masking by amino acids, sweeteners, flavors and proteins
2. Taste-masking by Increase in viscosity
3. Taste masking using Lipids
4. Taste masking using anesthetic agents and taste potentiators
5. Taste masking using anesthetic agents and taste potentiators
6. Taste masking with effervescent formulations
7. Taste masking by Prodrug formulation of the drug
8. Coating Techniques
9. Taste masking by solid dispersion
10. Taste masking using inclusion complex
11. Taste masking by Ion exchange resin
12. Nanotechnology based taste masking techniques
i.
Microencapsulation
ii.
Liposomes and multiple emulsions
The use of a number of drugs including antibiotics which have undesirable tastes has
been increasing12. The objective of the work is to develop efficient method to mask the
taste of a bitter antibiotic by adopting various techniques using synthetic and natural
sources which would be suitable for pediatric patients.
6.2 Review of Literature:
Momin et al (2012)13 Taste masking is the main factor in the development of the
dosage form. It opens the doors for new inventions and patents. Many techniques have
been developed which not only improve the taste of molecule but also the formulation
and performance of the molecule. The main objective of present review is to explore
different method, technologies and evaluations to mask the obnoxious taste of drugs, so
that patients can use these drugs without hesitation of taste.
Kayumba et al (2011)14 developed a taste-masked quinine sulphate dosage form
as a flexible pediatric formulation tool. Pellets were produced as they offer more
flexibility to body weight dose adaptation and therefore represent an alternative to tablet
breaking in pediatrics. Quinine sulphate pellets were produced via extrusionspheronisation. His observations correlated well with the bitterness score of the
formulations determined via the Astree electronic tongue and its Bitterness Prediction
Module, showing that 20% (w/w) Eudragit E PO was required to obtain a homogeneous
film and to delay quinine sulphate release sufficiently to mask the bitterness after drug
administration. In acid medium immediate quinine sulphate release was obtained.
Tripathi et al (2011)15 explained that taste is an important parameter in case of
drugs administering orally. Taste masking becomes a prerequisite for bitter drugs to
improve the patient compliance especially in the pediatric and geriatric population. The
problem of bitter taste of drug in pediatric formulations is a challenge to the formulators
in the present scenario. Masking the bitter taste of drugs is a potential tool for the
improvement of patient compliance which intern decides the commercial success of the
product. Two approaches are commonly utilized to overcome the bad taste of the drug.
The first includes reduction of drug solubility in the saliva and second approach is to
alter the ability of the drug to interact with taste receptor.
Chiapetta Singh A et al (2011)16 developed Indinavir pediatric anti-HIV/AIDS
formulations enabling convenient dose adjustment, ease of oral administration, and
improved organoleptic properties by means of the generation of drug-loaded
microparticles made of a polymer that is insoluble under intake conditions and dissolves
fast in the stomach in order to completely release the active agent. His work explored
the
production
of
indinavir-containing microparticles
based
on
a
common
pharmaceutical excipient as a means for the improvement of medicines of drugs
involved in the treatment of HIV/AIDS. For systems containing about 15% drug, taste
studies confirmed the acceptability of the formulation. In pediatric regimes, this
composition would require an acceptable amount of formulation (0.7–1.5 g).
Sharma D et al (2012)17 worked on a novel approach for the improvement of
organoleptic properties of pharmaceutical substances. They used different types of
“Taste Masking Techniques” such as coating of drugs, microencapsulation, multiple
emulsion, viscosity modifiers, ion exchange resins...etc. They also used sugars, flavours,
sweeteners, lipoproteins, adsorbents in the above techniques. These techniques were
found to enhance the bioavailability and performance of the drug dosage form.
Kruthi et al (2012)18 worked on orodispersible tablets of the bitter drug
Drotaverine HCL, used in the treatment of paedriatic and geriatric patients. The bitter
taste of the drug was masked by using techniques such as melt granulation and kneading
method. The carriers used include glyceryl Behenate - (compritol 888 ATO), glyceryl
pamito stearate (precirol ATO 5) & sucrose fatty acid ester (D 1811).
Sona PS et al (2011)19 worked on taste masking of bitter taste of Diclofenac
Sodium and formulated an orally disintegrating tablet (ODT).They employed various
physical & chemical methods that prevented the drug substance from interacting with
the taste buds. They used veegum (magnesium aluminium silicate) as the taste masking
agent and sodium starch glycolate and croscarmellose sodium as superdisintegrants.
Dhoka MV et al, (2011)20 worked on the taste masking of
Cefpodoxime
Proxetil , a 3rd generation broad spectrum β- Lactam cephalosporin class of antibiotic
administered orally in paediatric and adult patients and is extremely bitter in taste.
Floating microspheres of cefpodoxime proxetil with eudragit E100 plus HPMC and
Eudragit E100 plus PEG were prepared by the emulsion solvent diffusion method to
mask the bitter taste of an antibiotic. The effect of different polymers with different
drug–polymer ratios on the taste masking and the characteristics of the microspheres
were investigated. It was found that Eudragit E100 masked the taste but retarded the
drug release whereas combination of Eudragit E100 with PEG and with HPMC showed
the better result for masking the unpleasant taste of Cefpodoxime Proxetil with floating
ability as well as provide good drug release.
6.3 Objectives of the Study:
The present study is planned with the following objectives:
 Preformulation studies of the drug and polymers, drug-excipient compatibility by
DSC, X-ray diffraction, FTIR methods.
 To develop suitable analytical method for the estimation of the drugs.
 Taste masking of the method using suitable polymers and methods.
 Evaluation studies
 Formulation of suitable dosage form like suspensions, solution of the tastemasked drug
 Evaluation of the prepared suspension formulation by different physicochemical
characterization studies such as viscosity, sedimentation volume, Rheological
parameters & stability studies.
 The optimal formulation(s) would be subjected for accelerated studies as per ICH
guidelines.
7.
MATERIALS AND METHODS:
Drug
: Antibiotics
Polymers & Excipients
:
Alginates,
Methylcellulose,
Hydroxyethylcellulose,
Carboxymethylcellulose, Sodium Carboxymethylcellulose, Microcrystalline cellulose,
Acacia, Tragacanth, Xanthan gum, Bentonite, Carbomer, Carageenan, Powdered
cellulose, Gelatin…etc.
7.1 Source of Data:
1) Review of literature from:
a. Journals: such as
- Indian Journal of Pharmacy & Pharmaceutical Science
- International Journal of Pharmaceutical.
- International Research Journal of Pharmacy.
- Journal of Global Pharma Technology.
- International Journal of Applied Pharmaceutics.
- International Journal of Drug Delivery.
b. Internet browsing.
2) e-Library: T. John college of Pharmacy.
7.2 Methods of collection of data (including sampling procedures, if any)
1. Laboratory studies which include, preformulation studies, formulation and
evaluation studies such as amount of drug released rate kinetics &stability
studies etc.
2. Data of physiochemical properties of the drug and polymers used such as
solubility in various solvents, pH will be collected through literature search.
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 ---8.
REFERENCES:
1. Shah PP and Mashru RC. Development and evaluation of Artemether taste masked
rapid disintegrating tablets with improved dissolution using solid dispersion
technique. AAPS Pharm SciTech. 2008; 9: 494–500.
2.
Strickley RG and Dahl TC. Pediatric drugs - a review of commercially available
oral formulations.J Pharm Sci. 2008; 97(5): 1731-774.
3. Sohi H, Sultana Y and Khar RK. Taste masking technologies in oral
pharmaceuticals: recent developments and approaches. Drug Dev Ind Pharm. 2004;
30(5) : 429-48.
4. Cerea M. A novel powder coating process for attaining taste masking and moisture
protective films applied to tablets. Int J Pharm. 2004; 27: 127-39.
. 5. Al-Omran MF, Al-Suwayeh SA, El-Helw AM, Saleh SI.
Taste masking of
diclofenac sodium using microencapsulation. J Microencapsul, 2002; 19(1): 4552.
6. Bora D, Borude P, Bhise K. Taste masking by spray-drying technique. Pharm Sci
Tech. 2008; 9(4): 1159-64.
1. Xu J, Bovet LL, Zhao K. Taste masking microspheres for orally Disintegrating
tablets. Int J Pharm. 2008; 359(1-2): 63-9.
2. Bhise K, Shaikh S, Bora D. Taste mask, design and evaluation of an oral
formulation using ion exchange resin as drug carrier. Pharm Sci Tech. 2008;
9(2): 557-62.
3. Agresti C and Liang JF. Specific interactions between Diphenhydramine and
alpha-helical poly (glutamic acid)--a new ion-pairing complex for taste masking
and pH-controlled
Diphenhydramine release. Eur J Pharm Biopharm. 2008;
70(1): 226-33.
4. Uchida T, Tanigake A and Miyanaga Y. Evaluation of the bitterness of
antibiotics using a taste sensor. J Pharm Pharmacol, 2003; 55(11): 1479-485.
5. Li L, Naini V and Ahmed SU. Utilization of a modified special-cubic design
and an electronic tongue for bitterness masking formulation optimization. J
Pharm Sci, 2007; 96(10): 2723-734.
6. Abhijeet Y. Patil, Pravin K. Bhoyar. Jagdish R. Baheti, Satish M. Kardel,
Chandrakant T. Karanjekar and Dhanashri B. Nagulwar. Design and
Optimization of Ambroxol Hcl Microparticles for bitter taste masking. World
Journal of Pharmacy and Pharmaceutical Sciences. 2012; 1(1): 368-75.
7. Munira Momin*, Sudha Rathod and Swapan Kar. Taste masking techniques for
bitter drugs-an overview.International Journal of Pharmacy and Technology.
2012; 4(2): 2100-118.
8. Kayumba P C, Huyghebaert N, Cordella C, Ntawukuliryayo J D, Vervact C and
Remon J P. Quinine sulphate pellets for flexible pediatric drug dosing:
Formulation Development and Evaluation of taste-masking efficiency using
electronic tongue. European Journal of Pharmaceutics and Biopharmaceutics.
2007;
9. Aditi Tripathi, Dipika Parmar, Upendra Patel, Ghanshyam Patel, Dhiren
Daslaniya and Bhavin Bhimani. Taste Masking: A Novel Approach for Bitter
and Obnoxious Drugs.Journal of Pharmaceutical Science and Bioscientific
Research. 2011; 1(3): 136-42.
10. Diego
A
Chiappetta, Ángel
M
Carcaboso, Carlos
Bregni, Modesto
Rubio, Guillermo Bramuglia and Alejandro Sosnik. Indinavir-Loaded pHsensitive microparticles for taste masking: Toward Extemporaneous Pediatric
Anti-HIV/AIDS Liquid Formulations with improved patient compliance. AAPS
PharmSciTech. 2009; 10(1): 1-6.
11. Sharma S and Lewis S. Taste Masking Technologies: A Review, Int J Pharm
Pharm Sci. 2010; 2(2): 6-13.
12. Kruthi M, Rani AS and Kumar KS. Development and Evaluation of Taste
Masked Orodispersible Tablets of Drotaverine HCL. International e-Journal of
Pharmaceutical Sciences. 2012; 1(1): 1-17.
13. Sona P S and Muthulingam C. Formulation and Evaluation of Taste Masked
Orally Disintegrating Tablets of Diclofenac sodium. International Journal of
Pharm Tech Research. 2011; 3(2): 819-826.
14. Dhoka MV, Nimbalkar1 UA and Pande A. Preparation of Cefpodoxime Proxetil
Polymeric Microspheres by the Emulsion Solvent Diffusion Method for Taste
Masking. International Journal Of Pharmtech Research. 2011; 3(1): 411-419.
9.
SIGNATURE OF CANDIDATE
[Mr. SEMBETI NAVEEN KUMAR]
10 REMARKS OF GUIDE
RECOMMENDED
WORK.
11 NAME AND DESIGNATION OF
(IN BLOCK LETTERS)
11.1 GUIDE.
FOR
DISSERTATION
Dr. K. V. SANDHYA, M.Pharm., Ph.D.
PROFESSOR & HOD,
DEPT. OF PHARMACEUTICS,
T. JOHN COLLEGE OF PHARMACY,
GOTTIGERE, BANGALORE.
11.2 SIGNATURE OF THE
GUIDE
11.3
HEAD OF THE
DEPARTMENT.
Dr. K. V. SANDHYA, M.Pharm., Ph.D.
PROFESSOR & HOD,
DEPT. OF PHARMACEUTICS,
T. JOHN COLLEGE OF PHARMACY,
GOTTIGERE, BANGALORE.
11.4
12 12.1
12.2
SIGNATURE OF THE HOD
REMARKS OF THE
PRINCIPAL.
SIGNATURE OF THE
PRINCIPAL.
FORWARDED AND RECOMMENDED FOR
DISSERTATION WORK.