Download tablet (ODT) - Rajiv Gandhi University of Health Sciences

Formulation and Evaluation of orally disintegrating systems-Oro Dispersible
tablet (ODT) of drugs used as therapeutically active Antihistamines.
M. Pharm dissertation protocol submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore – 560 041
By
Miss. SHIKHA SHARMA
Under the Guidance of
DR. KALYANI PRAKASAM
HOD and Professor
Department Of Pharmaceutics,
The Oxford College of Pharmacy,
No.6/9, 1st Cross, Begur Road,
Hongasandra, Bengaluru –560 068
Karnataka.
1
ANNNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1
Name and address of
candidate
Miss SHIKHA SHARMA
B-3,321,Tunghabahdra block, National games village,
Koramangala, Bengaluru , Karnataka
2
Name of institution
THE OXFORD COLLEGE OF PHARMACY,
No.6/9, 1st Cross, Begur Road,
Hongasandra, Bengaluru –560 068
Karnataka
3
Course of study and
subject
M. Pharm
(Pharmaceutics)
15-7-2011
4
Date of admission
5
Title of the project
Formulation and Evaluation of orally disintegrating
systems-Oro Dispersible
tablet (ODT) of drugs used as therapeutically active
Antihistamines.
2
6.0 BRIEF RESUME OF INTENDED WORK
6.1 Need For The Study:
Tablet is most popular among all dosage forms existing today because of convenience of self
administration, compactness and easy manufacturing. However, patients especially elderly find it
difficulty in swallowing tablets, capsules, fluids and thus do not comply with prescription which results
in high incidence of noncompliance and ineffective therapy
[1]
. Patient convenience and compliance
oriented research has resulted in bringing out many safer and newer drug delivery systems. Mouth
Fast disintegration or dissolving tablets are of such examples, for the reason of rapid disintegration or
dissolution in mouth with little amount of water or even with saliva
[2‐4].
Significance of this drug
delivery system includes administration without water, accuracy of dosage forms, ease of portability,
alternative to liquid dosage forms, ideal for pediatric and geriatric patients and rapid onset of action
[5‐7]
.
6.2 Objectives of the study
Mouth Fast Dissolving Tablets (MFDT’s) have emerged as an alternative to conventional oral
dosage forms to improve the patient compliance. Due to problem in swallowing ability with
age, the pediatric and geriatric patients complain of difficulty to take conventional solid dosage
forms . The MFDT’s are solid dosage forms that dissolve or disintegrate rapidly in the oral
cavity, which results in solution or suspension without the need of water. The main objective
of this work is to formulate and evaluate an antihistamine class of Drug( MFDT’s) using different
concentrations of superdisintegrants like croscarmellose sodium (CCS), crospovidone (CP),
sodium starch glycolate (SSG). Tablets will be prepared by direct compression method and evaluated
for hardness, friability, wetting time, disintegration time and percent drug release. FT-IR studies will
be done to ensure that there is no interaction between active ingredient and the excipients used in the
study.
3
6.3 REVIEW OF LITERATURE:1. Fast-dissolving tablets (FDT) of promethazine theoclate were prepared by direct-compression
method after incorporating superdisintegrants Ac-Di-Sol, Sodium Starch Glycolate (SSG), and
Crospovidone in different concentrations. Nine formulations having superdisintegrants at
different concentration levels were prepared to assess their efficiency and critical concentration
level. Different types of evaluation parameters for tablets were used. Tablets containing Ac- DiSol showed superior organoleptic properties, along with excellent in vitro and in vivo dispersion
time and drug release, as compared to other formulations. [8]
2. Fast-dissolving drug-delivery systems were first developed in the late 1970s as an alternative to
tablets,capsules, and syrups for pediatric and geriatric patients who experience difficulties
swallowing traditional oral soliddosage forms. In response to this need, a variety of orally
disintegrating tablet (ODT) formats were commercialized.Most ODT products were formulated
to dissolve in less than one minute when exposed to saliva to form a solution thatcould then be
more easily swallowed. Dissolvable oral thin films (OTFs) evolved over the past few years
from theconfection and oral care markets in the form of breath strips and became a novel and
widely accepted form byconsumers for delivering vitamins and personal care products.
Companies with experience in the formulation of polymercoatings containing active
pharmaceutical ingredients (APIs) for transdermal drug delivery capitalized on theopportunity
to transition this technology to OTF formats. Today, OTFs are a proven and accepted
technology for thesystemic delivery of APIs for over-the-counter (OTC) medications and are in
the early- to mid-development stages for prescription drugs.[9]
3. A new fast-dissolving tablet (FDT) formulation of ebastine has been developed that dissolves
rapidly in the mouth without the need for water. The aim of the reported study was to evaluate
the preferences of allergic rhinitis patients who were given either a placebo version of ebastine
FDT or a placebo version of ebastine regular tablet (RT). Allergic rhinitis patients from
Germany, Italy and Mexico, who were regular consumers of oral antihistamines, were recruited
to a randomized, crossover study comparing placebo forms of ebastine FDT and ebastine RT.
Patients were interviewed at home and were given both a FDT and RT (10 and 20 mg doses
were used with a 1:1 ratio). Data on patient preferences were recorded and analyzed using
descriptive statistics. A total of 420 individuals participated (140 in each country), 70% with
intermittent and 24% with persistent allergic rhinitis. Using a rating scale of 0-10 and
comparing mean values, ebastine FDT was statistically significantly better than RT for:
4
sensation on dissolving (8.30 FDT vs 6.79 RT); taste it leaves in the mouth (8.10 FDT vs 6.60
RT); initial taste (8.07 FDT vs 6.63 RT); and texture (7.85 FDT vs 7.20 RT). Rapidity of
dissolution was rated 8.67 for FDT. With the same scale, RT rated statistically significantly
better than ebastine FDT for: appearance (7.46 RT vs 6.85 FDT); size (7.38 RT vs 7.06 FDT);
and shape (7.55 RT vs 7.24 FDT). General evaluation was statistically significantly better for
ebastine FDT (8.21 FDT vs 7.05 RT).. Ebastine FDT formulation is preferred to the RT by the
majority of allergic rhinitis patients, rating most highly for dissolution, taste and texture.[10]
4. The aim of this study was to prepare, using taste masked granules, rapidly disintegrating tablets
of chlorpheniramine maleate, a bitter drug. The taste masked granules were prepared using
aminoalkyl methacrylate copolymers (Eudragit E-100) by the extrusion method. In vitro release
profile obtained at pH 6.8 indicate that perceivable amount of drug will not be released in saliva
while high percent release (more than 80% in 30 min) would be obtained at acidic pH 1.2 of the
stomach. These taste masked granules were directly compressed into tablets using sodium
starch glycolate as a super-disintegrant. The prepared tablets containing the taste masked
granules having sufficient strength of 3.5 kg/cm were evaluated for taste by both
spectrophotometric method and through panel testing. Panel testing data collected from 20
healthy volunteers indicate successful formulation of oral fast disintegrating tablets which had
good taste and disintegrated in the oral cavity within 30s. One important innovation in this
direction is the development of fast dissolving/disintegrating oral dosage forms that dissolve or
disintegrate instantly upon contact with recipient's tongue or buccal mucosa. They have proved
to be ideal for geriatric and paediatric population, people suffering from dysphagia, clinical
conditions where water intake is limited and for drugs undergoing high first pass metabolism.
Chlorpheniramine maleate is widely used antihistaminic drug but it is very bitter. Therefore, to
provide this drug in a more accessible and patient compliant form, in the present study an
attempt has been made to mask its bitter taste and formulate it into mouth disintegrating
tablet.[11]
5. Recent advances in Novel Drug Delivery Systems (NDDS) aim for designing dosage
forms,convenient to be manufactured and administered, free of side effects, offering
immediate release and enhanced bioavailability, so as to achieve better patient
compliance. Though oral drug delivery systems, preferably, tablets are the most widely accepte
d dosage forms, for being compact, offering uniform dose and painless delivery. Yet, dysphagia
is the most common disadvantage of conventional tablets. This is seen to afflict nearly 35%
of the general population andassociated with a number of conditions, like parkinsonism,
5
mental disability, motion sickness, unconsciousness, unavailability of water etc. To overcome s
uch problems, certain innovative drug delivery systems, like ‘Mouth Dissolving Tablets’
(MDT) have beendeveloped. These are novel dosage forms which dissolve in saliva within a
few seconds, when put on tongue. Such MDTs can be administered anywhere and anytime,
withoutthe need of water and are thus quite suitable for children, elderly and mentallydisabled
patients. [12]
6. To evaluate patient perception of the onset of action and overall satisfaction with a fastdissolving tablet (FDT) formulation of ebastine in patients with intermittent or persistent
allergic rhinitis. This was a cross-sectional, multicenter, pharmacy-based survey involving adult
patients (>18 years) with allergic rhinitis who presented with a prescription for ebastine FDT.
Via a telephone interview, patients were asked to evaluate the characteristics of ebastine FDT in
comparison with their previous experience with other antihistamines. 100 patients with allergic
rhinitis were included in the study (41 had intermittent disease, 57 persistent disease and two
with unknown disease states). Patients rated ebastine FDT very highly (mean scores: 4.5-4.7
out of a possible 5) for all characteristics related to convenience, such as easy to take, easy to
carry around in a bag or pocket, suitable for taking anytime/anywhere, and convenient to use. A
total of 85% of patients perceived ebastine FDTs onset of action to be fast or very fast, and 77%
indicated that it acted faster than their usual antihistamine. A total of 96% were satisfied or very
satisfied with ebastine FDT and 98% were interested in using the drug again. Patients with
rhinitis rate ebastine FDT very highly in terms of its formulation, convenience of use and its
rapid onset of action. These characteristics resulted in a high level of individual satisfaction
with the new formulation and a clear preference by the majority of patients to use ebastine FDT
in the future.[13]
7. In recent decades, a variety of pharmaceutical research has been conducted to develop new
dosage forms. Among the dosage forms developed to facilitate ease of medication, the rapid
disintegrating tablet (RDT) is one of the most widely employed commercial products. As our
society is becoming increasingly aged, the development of Fast- or mouth dissolving tablets
have been formulated for pediatric, geriatric, and bedridden patients and for active patients who
are busy and traveling and may not have access to water. Such formulations provide an
opportunity for product line extension in the many elderly persons will have difficulties in
taking conventional oral dosage forms because of hand tremors and dysphagia. Swallowing
problems also are common in young individuals because of their underdeveloped muscular and
nervous systems. Other groups that may experience problems using conventional oral dosage
6
forms include the mentally ill, the developmentally disabled, and patients who are
uncooperative, on reduced liquid-intake plans, or are nauseated. In some cases such as motion
sickness, sudden episodes of allergic attack or coughing, and an unavailability of water,
swallowing conventional tablets may be difficult. This paper summarizes the formulation
methods and drug formulation coming in market.[14]
8. The present work aimed at preparing quick release films of levocetirizine dihydrochloride with
the purpose of developing a dosage form for a very quick onset of action, managing severe
conditions of allergies, enhancement of bioavailability, and is very convenient for
administration, without the problem of swallowing and using water. These films can be
prepared by using polymers such as hydroxypropyl methylcellulose (HPMC) and polyvinyl
alcohol (PVA), as either single polymer or in combination of two, by a solvent casting method.
They were evaluated for physical characteristics and gave satisfactory results. The formulations
were subjected to disintegration, in vitro drug release tests, and in vivo studies on rats. A
marked increase in the dissolution rate was exhibited by fast-dissolving films of levocetirizine
dihydrochloride containing HPMC as a polymer, when compared to conventional tablets. The
haloperidol-induced catalepsy, milk-induced leukocytosis, and nasal provocation in vivo studies
in rats proved that the fast-dissolving films of levocetirizine dihydrochloride produced a faster
onset of action compared to the conventional tablets. Fast dissolving films of levocetirizine
dihydrochloride can be considered suitable for clinical use in the treatment of allergic rhinitis
and other conditions of allergies, where a quicker onset of action for a dosage form is desirable
along with the convenience of administration.[15]
9. In recent times, a variety of pharmaceutical research has been conducted to develop novel drug
delivery system. Among them delivery developed to facilitate ease of medication, the fast
disintegrating tablet (FDT) is one of the most widely employed commercial products. As our
society is becoming increasingly aged, the development of Fast- or mouth dissolving tablets
have been formulated for pediatric, geriatric, and bedridden patients and for active patients who
are busy and traveling and may not have access to water. Such development provide an
opportunity for product line extension in the many aged persons will have difficulties in taking
conventional oral dosage forms (viz., solutions, suspensions, tablets, and capsules) because of
hand tremors and dysphasia. Swallowing problems also are common in children individuals.
Other groups that may experience problems using conventional oral dosage forms include the
mentally retarded, the developmentally disabled, and patients who are uncooperative, on
reduced liquid-intake plans, or are nauseated. In some cases such as motion sickness, allergic
7
attack or coughing, and unavailability of water, swallowing conventional tablets may be
difficult. This paper summarizes the formulation methods of mouth dissolving tablet. [16]
10. Over the past three decades, rapid disintegrating tablets have gained considerable attention as a
preferred alternative to conventional tablets and capsules due to better patient compliance.
Generally, elderly people experience difficulty in swallowing the conventional dosage forms
(tablets, capsules,solutions and suspensions) because of tremors of extremities and dysphasia.
Rapid disintegrating drug delivery systems may offer asolution for these problems. Oral
delivery is currently the gold standard in the pharmaceutical industry where it is regarded asthe
safest, most convenient and most economical method of drug delivery having the highest
patient compliance .Rapid disintegrating tablets (RDT) are useful in patients, such aspediatric,
geriatric, bedridden, or developmentally disabled, who may face difficulty in swallowing
conventional tablets or capsulesand liquid orals or syrup, leading to ineffective therapy, with
persistent nausea, sudden episodes of allergic attack, or coughing for those who have an active
life style. The objective of this articleis to review the development of RDTs, challenges in
formulation ,new RDT technologies and evaluation methodologies,
suitability of drug
candidates, and future prospects.[17]
11. An orally disintegrating tablet or orodispersible tablet (ODT) is a drug dosage form available
for a limited amount of over-the-counter (OTC) and prescription medications. ODTs differ
from traditional tablets in that they are designed to be dissolved on the tongue rather than
swallowed whole. The ODT serves as an alternative dosage form for patients who experience
dysphasia (difficulty in swallowing) or for where compliance is a known issue and therefore an
easier dosage form to take ensures that medication is taken. Common among all age groups,
dysphasia is observed in about 35% of the general population, as well as up to 60% of the
elderly institutionalized population and 18-22% of all patients in long-term care facilities.
During the last decade, ODTs have become available in a variety of therapeutic markets, both
OTC and by prescription. An additional reason to use ODTs is the convenience of a tablet that
can be taken without water.[18]
12. Orally disintegrating systems have carved a niche amongst the oral drug delivery systems due
to the highest patients compliance especially the geriatrics and pediatrics and patients suffering
from dysphagia, motion sickness, repeated emesis and mental disorders prefer them because
they cannot swallow large quantity of water. Further, drugs exhibiting satisfactory absorption
from the oral mucosa or intended for immediate pharmacological action can be advantageously
formulated in these dosage forms. However, the requirements of formulating these dosage
8
forms with mechanical strength sufficient to with stand the rigors of handling and capable of
disintegrating within a few seconds on contact with saliva are inextricable. A variety of dosage
forms like tablets, films, chewing gums, microparticles, nanoparticles etc. have been developed
for enhancing the performance of orally disintegrating systems. Advancements in the
technology for manufacturing these systems include the use of freeze drying, cotton candy,
melt, direct compression etc and wet granulation processes. For Taste masking of active
ingredients Fluid bed coating, agglomeration, pelletization etc methods have proven useful. It is
important to note that although, freeze dried and effervescent disintegrating systems rapidly
disintegrate in contact with fluids, they do not generally exhibit the required mechanical
strength. Similarly, the candy process cannot be used for thermolabile drugs. This article
attempts at discussing the patents relating to orally disintegrating systems with respect to the
use of different formulation ingredients and technologies.[19]
7.0 MATERIALS AND METHODS:
Materials:
Antihistamine compound will obtained as gift sample from a Pharmaceutical company.. Pearlitol® SD
200, a directly compressible vehicle, Crospovidone (CP), Croscarmellose Sodium (CS), Sodium
starchGlycolate (SSG) will be purchased from, Nihal traders, Hyderabad, aspartame and peppermint
flavor will be from Himedia, Mumbai, colloidal silicon dioxide (Aerosil®) and talc from Span Pharma
Private Limited (Hyderabad, India).
Method of preparation- :
Formulation of different batches.
Mouth fast dissolving tablets (MFDT’s) will be prepared by direct compression method according
to a specific set of Formulations. All the ingredients will be passed through mesh # 40 except
Magnesium stearate. Magnesium stearate will be passed through mesh # 60. Drug, pearlitol SD 200
and super disintegrant will be mixed by taking small portion of each in ascending order and blended
to
get a uniform mixture in a mortar. The other ingredients are to be weighed and mixed in geometrical
order and tablets will be compressed using 8mm round flat punches on a Tablet Compressiom machine.
Batch of 100 tablets each of 200mg weight will be prepared .as per the specific master formula.
9
7.1 Source of the data:
The data required for the work will be collected from different books, Journal and articles available
in the Library of The Oxford college college of Pharmacy, Journals available at Jgate – Helinet of the
Rajiv Gandhi University of Health sciences Website and through various internet sources.
7.2 Method of collection of data:
Evaluation of Tablets
[20-23]
FT-IR spectrum to check for the Compatibility of the Formulation blend.
Weight variation:
Thickness Variation
Hardness or crushing strength
Friability
Water Absorption Ratio (R)
Wetting Time
Drug content uniformity.[24]
Mouth feel
In Vitro Disintegration Time
Dissolution study
Stability studies:
10
7.3
DOES THE STUDY REQUIRE ANY INVESTIGATION TO BE CONDUCTED ON PATIENT
OR OTHER HUMANS OR ANIMALS?
“No”
7.4
HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN
CASE OF 7.3
“NA ”
11
8
LIST OF REFERENCES:-
[1] Seager H. J.Pharm.Pharmacol.1998;50(4):375‐382.
[2] Habib W, Khankari R, Hontz J. Drug carrier systems. 2000;17(1):61‐72.
[3] Chang RK, Guo X, Bumside BA, Couch RA. Pharm. Tech 2000;24(6):52‐58.
[4] Sunada H, Yonezawa Y, Danoj K. Drug Dev. Ind. Pharm. 1999;25(5):571‐581.
[5] Reddy LH, Ghosh B, Rajneesh. Indian J. Pharm. Sci. 2002;64(4):1‐3.
[6] Bradoo R, Shahani S, Poojary SM, Deewan B, Sudharshan S. JAMA India. 2001;4(10):27‐31.
[7] Mishra DN, Bindal M, Singh SK, Kumar SGV. Indian Drugs. 2005;42(10):685‐687.
[8] Sharma S, Gupta GD. Department of Pharmaceutics. Formulation and characterization of fastdissolving tablet of promethazine theoclate. Asian journal of pharmaceutics. 2008;2(1):70-72.
[9] Arya A, Chandra A, Sharma V, Pathak K. Fast Dissolving Oral Films: An Innovative Drug
Delivery System and Dosage Form. Int. J. of chem. Tech. 2010 Jan;2(1):576-583.
[10] Roger A, Fortea J, Mora S, Artes M. Ebastine fast-dissolving tablets versus regular tablets:
acceptability and preference in patients with allergic rhinitis. Expert Review of Clinical Pharmacology
2008 May;1(3):381-389.
[11] Shishu, Ashika B, Singh T. Preparation of tablets rapidly disintegrating in saliva containing bitter
taste-masked granules by compression method. Int. J. of .Pharm Sci. 2007;69(1):80-84.
[12] Kaur T, Gill B, Kumar S, Gupta GD. Mouth dissolving tablets: a novel approach to drug delivery.
International Journal of Current Pharmaceutical Research. 2011;3(1).
[13] Roger A, Josep F, Sheila M et al. Patient assessment of onset of action and overall satisfaction
with ebastine fast-dissolving tablets in allergic rhinitis. Expert Review of Pharmacoeconomics and
Outcomes Research. 2008 Aug;8(4):337-342.
[14] Gupta A. Recent trends of fast dissolving tablet - an overview of formulation technology. IJPBA.
2010
[15] Prabhu P, Malli R, Koland M, Vijaynarayana K, D'Souza U, Harish NM, et al. Formulation and
evaluation of fast dissolving films of levocitirizine dihydrochloride. Int. J. of Pharm investigation.
2011;1(2):99-104.
[16] Dutta S, Kumar P. Formulation of fast disintegrating tablets. Int. J. of Drug Formulation & Res.
2011 Jan;2(1).
[17] Khan T, Nazim S, Shaikh S, Shaikh A, Khairnar A, Ahmed A. An approach for rapid
disintegrating tablet: a review. Int. J of Pharm research and development. 2011;3(03).
12
[18] Thakur RR, Kashi M. An unlimited scope for novel formulations as orally disintegrating systems:
Present and future prospects. J. Appl. Pharm Sci. 2011;1(01):13-19.
[19] Goel H, Rai P, Rana V, Tiwary AK. Orally Disintegrating Systems: Innovations in Formulation
and Technology. Recent Patents on Drug Delivery & Formulation. 2008 Nov;2(3):258-274.
[20] YX Bi, M Sunanda; Y Yonezawa; K Danjo. Drug Dev Ind. Pharm.1999; 25(5):571-81.
[21] Avari NG, Bhalekar M. Indian Drugs.2004;41(1):19-23.
[22] United states pharmacopoeia XXIV-NF XIX, Asian edition, USP convention Inc. 2000:19411943.
[23] N Vaja Divyesh kumar; M Patel Maulik; T Joshi Ujjwal; M Patel Jaykishan. J. Chem.
Pharm. Res.2010;2(5):307-312
[24] AFM El Walily, MA Korany, A El Gindy and MF Bedair. J. of Pharm. and
Biomedical Analysis.1998;17(3):435-442.
13
14