“FORMULATION DEVELOPMENT AND EVALUATION OF ORODISPERSIBLE TABLETS OF ANTICONVULSANT DRUG LEVETIRACETAM”
DISSERTATION PROTOCOL
SUBMITTED TO
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA.
BY
PATEL KIRTANKUMAR VINODKUMAR
I Year M. PHARM,
DEPARTMENT OF PHARMACEUTICS,
NARGUNDCOLLEGE OF PHARMACY,
BANGALORE-85. KARNATAKA.
(2010-2012)
RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA.
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR pg DISSERTATION
1. / Name of the Candidate & Address (In block letters) / PATEL KIRTANKUMAR VINODKUMARNARGUND COLLEGE OF PHARMACY,
DATTATREYA NAGAR,2nd main,
100ft ring road,BSK 3rd stage
BANGALORE-560085
2. / Name of the Institution / NARGUNDCOLLEGE OF PHARMACY,
DATTATREYA NAGAR,2ndmain,
100ft ring road,BSK 3rd stage
BANGALORE-560085
3. / Course of Study and Subject / Master of pharmacy in
pharmaceutics
4. / Date of Admission to Course / 15th JUNE 2010
5. / Title of the Topic / “FORMULATION DEVELOPMENT AND EVALUATION OF ORODISPERSIBLE TABLETS OF ANTICONVULSANT DRUG LEVETIRACETAM”
6.
7. / BRIEF RESUME OF THE INTENDED WORK
6.1 NEED FOR THE STUDY
The aimof this research project is to prepare orodispersible tabletsof anticonvulsant drugby suitable methods and evaluate their in-vitroproperties. Some of the anticonvulsant drugs are levetiracetam, carbamazepine, gabapentine, primidone, lamotrigineetc.
Recently United States Pharmacopoeia (USP), Center for Drug Evaluation and Research (CDER), has approved Orally Disintegrating (OD) Tablet technology. USFDA defined OD tablet as “A solid dosage form containing medicinal substances, which disintegrate rapidly, usually within a matter of seconds, when placed upon the tongue”.
Oral dispersible tablets disintegrate and/or dissolve rapidly in the saliva without the need for water. Some tablets are designed to dissolve in saliva remarkably fast, within a few seconds, and are true oral-dissolving tablets, But others contain agents to enhance the rate of tablet disintegration in the oral cavity, and are more appropriately termed as oral-dispersible tablets, as they take up to a minute to completely disintegrate. Oral delivery is currently the gold standard in the pharmaceutical industry where it is regarded as the safest, most convenient and most economical method of drug delivery having the highest patient compliance.
The need for non-invasive delivery system continues due to patient’s poor acceptance and compliance with existing delivery regimens, limited market size for drug companies and drug uses, coupled with high cost of disease management. The current needs of the industry are improved solubility/stability, biological half-life and bioavailability enhancement of poorly absorbed drugs. Pharmaceutical marketing is another reason for the increase in availability of oral dispersible tablets.
Oral dispersible tablet form is designed to allow administration of an oral solid dosage form in the absence of water or fluid intake. Such tablets readily dissolve or disintegrate in the saliva generally within <60seconds. Oral dispersible tablets have been formulated for pediatric, geriatric and bedridden patients and for active patients who are busy and travelling and may not have access to water. Other groups that may experience problems using conventional oral dosage forms include the mentally ill, the developmentally disabled and patients who are uncooperative, on reduced liquid-intake.
Oral dispersible tablets are those when put on tongue disintegrate instantaneously releasing the drug that dissolves or disperses in the saliva. The faster the drug goes into solution, quicker the absorption and onset of clinical effect. Drugs from the oral dispersible tablets are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach and the bioavailability of the drug from this dosage form is significantly greater than those observed from conventional tablet dosage forms.
The basic approach in development of oral dispersible tablets is the use of superdisintegrants like cross linked carboxymethyl cellulose, sodium starch glycolate, polyvinylpyrollidone etc. which provide instantaneous disintegration of tablet after putting on tongue, thereby releasing the drug in the saliva.
Epilepsy is a chronic neurological disorder affecting 40 million people worldwide including 2.5 million people in the US. It is caused by abnormal, excessive electrical discharges of the nerve cells or neurons in the brain. Epilepsy is characterized by a tendency to haverecurrent seizures and defined by two or more unprovoked seizures. However, 20-30% of patients have either intractable or uncontrolled seizures or significant adverse side effects secondary to medication highlighting the ongoing need for the development of new antiepileptic drugs.
The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, Its molecular formula is C8H14N2O2 and its molecular weight is 170.21. Levetiracetam is chemically unrelated to existing anticonvulsant drugs (AEDs).
Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste.
It is very soluble in water (104.0 g/100 mL). It is freely soluble in chloroform (65.3 g/100 mL)
and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in
acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed
as g/100 mL solvent.)
Mechanism Of Action
The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown.
The antiepileptic activity of levetiracetam was assessed in a number of animal models of
epileptic seizures. Levetiracetam did not inhibit single seizures induced by maximal stimulation
with electrical current or different chemoconvulsants and showed only minimal activity in
Submaximalstimulation and in threshold tests. Protection was observed, however,
against secondarily generalized activity from focal seizures induced by pilocarpine and
kainicacid, two chemoconvulsants that induce seizures that mimic some features of human
complex partial seizures with secondary generalization. Levetiracetam also displayed inhibitory
properties in the kindling model in rats, another model of human complex partial seizures, both
during kindling development and in the fully kindled state. The predictive value of these animal
models for specific types of human epilepsy are uncertain.
Challenges in the development of orodispersible tablets
Rapid disintegration of tablet in the oral cavity.
Compatible with taste masking technology.
Retaining drug properties.
Avoid increase in tablet size.
Have sufficient mechanical strength.
Minimum or no residue in mouth.
Protection from atmospheric parameters such as moisture, temperature etc.
Good package design.
6.2 REVIEW OF LITERATURE:
Gohel M.et al,presented thatthough the tablet is the most widely used dosage form because of its convenience in terms of self–administration, compactness and ease in manufacturing, geriatric and pediatric patients experience difficulty in swallowing conventional tablets, which leads to poor patient compliance. To overcome this weakness they have developed an innovative drug delivery system known as orally dispersible tablets (ODTs). These are novel type of tablets which disintegrate /dissolve/disperse in saliva.1
Abdelbary G.et al,demonstrated the use of the texture analyser in the in-vitro determination of the disintegration behaviour of different rapid disintegrating tablet (RDT) was successful, convenient and precise. Further they have shown the new operating structure for a better simulation of the in-vivo conditions, where the use of the perforated grid on which the tablet is placed minimises the operating error that might occur when using an adhesive tape. This structure mimics the situation in the patient’s mouth.2
Sammour OA. et al,presented that the basic approach used in the development of the ODTs is the use of superdisintegrants.3
Biradar SS.et aldemonstrated the ingredients which are used in the formulation of ODTs should allow quick release of the drug, resulting in faster dissolution. This includes both the active ingredients and the excipients. These excipients are balance the properties of the active ingredients in ODTs. This demands a thorough understanding of the chemistry of these excipients to prevent interaction with the active ingredients.4
Venkatesh DP.et al,reported the utility of ion exchange resins in the taste masking of ambroxol hydrochloride and the formulation of taste masked oro-dispersible tablets of ambroxol hydrochloride.5
Kumaresan C. demonstrated different ways for the formulation of the oral dispersible tablets and how the product performance depends on the drug suitability and excipients selection in the delivery system. He described the ideal characteristics of the drug and excipients required to be employed in the formulation of oral dispersible tablets and taste masking methods and manufacturing methods.6
Swamy PV.et al,developed orodispersible tablets of carbamazepinewith a view to enhance patientcompliance by direct compression method using 3² full factorial designs. Crospovidone (2-10% w/w) was used as superdisintegrant and microcrystallinecellulose (0-30% w/w) was used as diluent, along with directly compressible mannitol to enhance mouth feel. The tablets were evaluated for hardness, friability, thickness, drug content uniformity, in vitro dispersiontime, wetting time and water absorption ratio. Based on in vitro dispersion time (approximately 10 s).The formulation containing 2% w/w crospovidone and 30%w/w microcrystallinecellulose was found to be promising and tested for in vitro drug release pattern (in pH 6.8 phosphate buffer), short-term stability (at 40º/75 % RH for 3 w) anddrug-excipient interaction. This formulation showed four-fold faster drug release (t25%) compared to the conventional commercial tablet formulation. Short-term stability studies on the formulation indicated that there is no significant change in drug content and in vitro dispersion time (p < 0.05).7
Bandari Set al presented a complete overview on the formulation of orodispersible tablets right from the formulation aspects to the packaging of the orodispersible tablets. They also included various methods by which the orodispersible tablets can be formulated like8:
1) Lyophilization or Freeze-drying.
2) Moulding.
3) Cotton candy process.
4) Spray drying.
5) Mass extrusion.
6) Direct compression
Yamamoto Y.et al, demonstrated the relation between powder characteristics and disintegration time of tablets in the mouth (DTM). It was revealed that a high bulk density results in a short DTM. Tablets producing a DTM less than 60s were obtained when the powder bulk density was greater than 0.5g/mL. They have also demonstrated that the tablets with a short DTM value tend to possess low hardness. However, the use of high-compressibility excipients in the formulation increased the hardness to values greater than 3kg.9
Ranch KM.et al,suggested another approach used in developing ODTs is maximizing pore structure of the tablets. Vacuum drying and freeze-drying techniques have been tried by researchers to maximize the pore structure of tablet matrix containing subliming agent.10
Radke RS.et al, demonstrated thatin ODTs faster the drug in the solution, quicker the absorption and onset of clinical effect. Some drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down in to the stomach.11
Shukla D.et al, presented that the fast dissolving property of the ODTs is attributed to quick ingress of water into tablet matrix resulting in rapid disintegration. Hence , the basic approaches to develop ODTs include:
1) Maximizing the porous structure of the tablet matrix
2) Incorporating the appropriate disintegrating agent/agents
3) Using highly water-soluble excipients in the formulation.
So far, several techniques have been developed on the basis of different principles. The resulting dosage forms vary on grounds like mechanical strength of the final product, drug and dosage form stability, mouth feel, taste, disintegration time, rate of dissolution and absorption from saliva, swallowability and overall bioavailability.12
Patel B.et al, demonstrated that formulation methods like Sublimation method in which a subliming material camphor is added , Effervescent method in which effervescent substances like sodium bicarbonate is added, Super disintegration addition method in which superdisintegrants like croscarmellose sodium, crosspovidone are added are used in the formulation of oral dispersible tablets of Cinnarizine.13
Singh J.et al, prepared the tablets were made by non-aqueous wet granulation using crospovidone and mannitol. A 22 factorial design was used to investigate the amount of crospovidone and tastemasking, soothening hydrophilic agent (mannitol), as independent variables, and disintegration time as dependent response. Formulated orodispersible tablets were evaluated for weight variation, friability, disintegration time, drug content, wetting time, water absorption ratio and in vitro drug release.
The results showed that the presence of a superdisintegrant and mannitol is desirablefor orodispersion. All the formulations satisfied the limits of orodispersion with a dispersiontime of less than 60 sec. For example, formulation which contain crospovidon 5%w/w and mannitol 44% showed a disintegration time of 32.1sec, crushing strength of 4.93 kg/cm2, drug content of 98.5% and fast drug release rate of 99.5% within 30 min, as compared with the conventional tablet (49.5%).It is feasible to formulate orodispersible tablets of meloxican with acceptabledisintegration time, rapid drug release and good hardness, which could be amenable to replication on an industrial scale.14
ADVANTAGES OF ORAL DISPERSIBLE TABLET
Administration to the patients with dysphagia (difficulty in swallowing) such as the elderly, stroke victims, bedridden patients, patients affected by renal failure & patients who refuse to swallow such as pediatric, geriatric & psychiatric patients.
Rapid drug therapy intervention.
Requires no water.
Overcome unacceptable taste of the drug due to taste masking agents.
Convenient for administration and patient compliant for disabled, bedridden patients for people who travel a lot and busy people, who do not always have access to water.
Good chemical stability.
Free from need of measuring, an essential drawback in liquids. Good mouth feel property helps to change the perception of medication as bitter pill particularly in pediatric patients.
The risk of chocking or suffocation during oral administration of conventional formulations due to physical obstruction is avoided, thus providing improved safety.
6.3OBJECTIVES OF THE STUDY:
The main objective of the present study was undertaken for formulation and evaluation
of oral dispersible tablets by adopting following steps.
Step I: Development of suitable analytical method for the estimation of the Drugs.
Step II: Preformulation studies, Drug-excipients compatibility studies for selection
of excipients.
StepIII: Preparation of the formulation of oral dispersible tablets of levetiracetam using
two or more methods.
StepIV: Evaluation of the prepared formulation by different physicochemical
characterization studies such as
Weight Variation
Hardness
Friability
Content uniformity
Wetting time
Water absorption ratio
Disintegration time
Dissolution rate
Step V: Stability study of the most satisfactory formulation.
MATERIALS AND METHOD
MATERIALS:
Some of the commonly used antiepileptic drugs:-
- Levetiracetam, carbamazepine, gabapentine, primidone, lamotrigine etc.
Crospovidone, Cross carmellose sodium, Sodium starch glycolate, Acrylic acid derivatives, Sodium Alginate,L-HPC, NS-300, ECG-505, L-HPC etc
Flavoring agents:-
Lemon Oil, clove oil etc.
Colouring agents:-
Sunset yellow, Orangeetc.
Sweetning agents:-
Aspartame, Sodium saccharine, Sucrose, Mannitol etc.
Effervesent Substances:-
Sodium bicarbonate, Citric acid, Tartaric acid.
METHODS:
Some of the commonly used methodswhich are planned for the formulation of the
orodispersible tablets of anticonvulsant drugs are:
Lyophilization or Freeze-drying.
Moulding.
Cotton candy process.
Spray drying.
Mass extrusion.
Compaction.
Direct compression.
7.1 SOURCE OF DATA:
Library: Nargund College of pharmacy.
E-library: Nargund College of pharmacy.
Official books(IP,BP,USPand EP).
RGUHS Library, Bangalore.
International and national Pharmaceutical abstracts etc.
Journals & articles :
- Asian Journal of Pharmaceutics.
- International Journal of Pharmaceutics.
- Journal of Controlled Release.
- European Journal of Pharmaceutics.
- Journal of Antimicrobial Chemotherapy
- Asian Journal of Pharmaceutical and Clinical Research
- European Heart Journal
7.2 METHODS OF DATA COLLECTION:
Literature survey using internet and scientific journals.
Experimental studies which includes:
The formulation evaluated for the compatibility studies using FTIR etc.
Evaluating the pre-formulation parameters like bulk density, tapped density,
Carr`s index etc.
Formulation development and evaluation.
Granular properties, tablet properties and in-vitro dissolution studies for the
developed formulation.
UV/Vis Spectrophotometeric, HPLC etc. for the estimation of drug in in-vitro . dissolution samples.
7.3 Does the study require any investigation or intervention to be conducted on patients or
other human or animals?
-NO-
7.4Has ethical clearance been obtained from your institute?
-NOT APPLICABLE
8. LIST OF REFERENCES
1) Gohel M, Patel M,Amin A, Agrawal R, Dave R and Bariya N. Formulation
Design and Optimization of Mouth Dissolve Tablets of Nimesulide
Using Vacuum Drying Technique. AAPS PharmSciTech. 2004; 5(3) Article
36:1-6.
2) Abdelbary G, Eouani C, Prinderre P, Joachim J, Reynier JP, Piccerelle Ph.
Determination of the in vivo disintegration profile of rapidly disintegration tablets and
correlation with oral disintegration. International Journal of Pharmaceutics 2005;292:
29-41.
3) Sammour OA, Hammad MA, Megrab NA and Zidan AS. Formulation and
Optimization of Mouth Dissolve Tablets Containing Rofecoxib Solid Dispersion.
AAPS PharmSciTech 2006; 7(2) Article 55: E1-E9.
4) Biradar SS, Bhagavati ST. and Kuppasad IJ. Fast Dissolving Drug Delivery
Systems. The Internet journal of pharmacology. 2006:4(2).
5) VenkateshDP, Geetha Rao CG. Formulation of taste masked oro-dispersible
Tablets of ambroxol hydrochloride. Asian Journal Of Pharmaceutics.
2008-Dec; 261-4.
6) Kumaresan C. Orally Disintegrating Tablet-Rapid Disintegration, Sweet Taste, And
target Release Profile. 2008 Sep;6(5).
7) Swamy PV, Shahidulla SM, Shirsand SB, Hiremath SN, Younus Ali MD.
Orodispersible tablets of carbamazepine prepared by direct compression method
using 32 full factorial design. Dhaka Univ. J. Pharm. Sci. 2008 june; 7(1): 1-5.
8) Bandari S, Mittapalli RK, Gannu R, Rao YM. Orodispersible tablets: An overview.
Asian Journal of Pharmaceutics 2008 Jan.
9) Yamamoto Y, Fujii M, Watanabe K, Tsukamoto M, et al. Effect of powder
characteristics on oral tablet disintegration. International Journal of Pharmaceutics
2009; 365:116-20.
10) Ranch KM, Koli AR. Formulation, Design and Optimization of Orodispersible
Tablets of Atenolol. International journal of pharma Tech Research.
2009-Dec; 1(4):1559-63.
11) Radke RS, Jadhav JK. and Chajeed MR. Formulation And Evaluation Of
Orodispersible Tablets Of Baclofan. International Journal of ChemTech Research
CODEN (USA). 2009 July-Sept; l (3):517-21.
12) Shukla D, Chakraborty S, Singh S. and Mishra B. Mouth Dissolving Tablets 1: