Download 6.0 6.1 6.2 6.3 7.0 7.1 7.2 7.3 8.0 BRIEF RESUME OF THE

6.0
BRIEF RESUME OF THE INTENDED WORK:
6.1
NEED FOR THE STUDY:
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest
endocrine glands. The thyroid gland is found in the neck, below (inferior to) the thyroid cartilage(which
forms the laryngeal prominence, or "Adam's apple"). The isthmus (the bridge between the two lobes of
the thyroid) is located inferior to the cricoid cartilage.
The thyroid gland controls how quickly the body uses energy, makes proteins, and controls how
sensitive the body is to other hormones. It participates in these processes by producing thyroid hormones,
the principal ones being triiodothyronine (T3) and thyroxine (T4). These hormones regulate the rate of
metabolism and affect the growth and rate of function of many other systems in the body. T3 and T4 are
synthesized from both iodine and tyrosine. The thyroid also produces calcitonin, which plays a role in
calcium homeostasis.
Hormonal output from the thyroid is regulated by thyroid-stimulating hormone (TSH) produced
by the anterior pituitary, which itself is regulated by thyrotropin releasing hormone (TRH) produced by
the hypothalamus.
The thyroid gets its name from the Greek word for "shield", due to the shape of the related
thyroid cartilage. The most common problems of the thyroid gland consist of an overactive thyroid
gland, referred to as hyperthyroidism, and an underactive thyroid gland, referred to as hypothyroidism1.
Antithyroid drugs derived from thionamides, including methimazole and carbimazole, have
been widely used to treat patients with hyperthyroidism since 1940s. They are convenient, effective and
cheap. Side-effects of these drugs are few, and include skin rashes, urticaria, arthralgia and fever. The
symptoms are usually mild and transient. Leukopenia, which may occur in untreated patients with
thyrotoxicosis and in 1–5% of patients treated with antithyroid drugs, is usually benign and does not
increasee the risk of agranulocytosis and infection. Agranulocytosis (absolute neutrophil count, ANC
<500×106/l) is rare, and may develop in 0.2–0.5% of patients taking antithyroid drugs. It may occur
suddenly and explosively and may be complicated by severe infections in otherwise immunocompetent
patients2.
 To Reduce dosing frequency and to maintain the drug level at therapeutic concentration range by
formulating a controlled drug delivery system in the form of micropartticles using blend of
hydroxyl propyl methyl cellouse(HPMC) and ethyl cellulose(EC).
 Mixture of polymeric materials have good pharmaceutical and biological properties.These matrix
type of micro particles offer double benifits.Firstly molecular dispersion of drug in polymer
would dramatically improve drug dissolution rate by reducing particle size to minimum level.
 Secondly the presence of insoluble polymer in the micromatrix would modify the rate of drug
release.
REVIEW OF LITERATURE:
6.2
Sahoo SK, et al3 ., Microspheres of eudragit (RS 100 and RL 100) were prepared by solvent evaporation
method using an acetone/liquid paraffin system. Antithyroid drug was encapsulated into microspheres.
Magnesium stearate was used as droplet stabilizer and n-hexane was added to harden the micro spheres.
Encapsulation of the drug upto 67-91% was achieved. The prepared microspheres were characterized for
their micromeritic properties and drug loading, as well as FTIR, differential scanning colorimetry, X-ray
powder diffractrometry and scanning electron microscopy. The in-vitro release studies were performed
in pH 6.8 phosphate buffer. The best fit release kinetics was achieved with Higuchi plot followed by zero
order and first order.
Chiappetta DA, et al4 ., Antithyroid drug loaded micropartticles were prepared by double emulsion
solvent diffusion technique by using PH-sensitive Eudragit (E 100).By using this method 90% of
antithyroid drug can be loaded in the microparticles. The microspheres of antithyroid drug formulations
convenient in dose adjustment, ease of administration and improved organoleptic properties were
evaluated in blind randomized sensory experiments by ten healthy volunteers.The use of a w/o/o
emulsion system resulted in antithyroid drug loads around 90%.
David B, et al5 ., The present invention relates to an improved method of making drug delivery devices
for the controlled release of pharmacologically active agents and further, to drug delivery devices made
by h such method. More specifically, the present invention relates to a method of forming a film
comprising one or more biodegradable polymeric materials, one or more pharmacologically active
agents, and one or more biocompatible solvents. The film is then partially dried, rolled or otherwise
shaped, and then compressed. In this manner, the amount of pharmacologically active agent(s) that can
be incorporated into the drug delivery device is increased and the pharmacologically active agent(s)
is/are substantially homogeneously distributed throughout the drug delivery device. As a result, the
release characteristics of the pharmacologically active agent from the drug delivery device are enhanced.
McGinity JW, et al6 .,The microencapsulation process in which the removal of the hydrophobic polymer
solvent is achieved by evaporation has been widely reported in recent years for the preparation of
microspheres and microcapsules based on biodegradable polymers and copolymers of hydroxy acids.
The properties of biodegradable microspheres of poly(lactic acid) (PLA) and poly(lactic-co-glycolic
acid) (PLGA) have been extensively investigated. The encapsulation of highly water soluble compounds
including proteins and peptides presents formidable challenges to the researcher. The successful
encapsulation of such entities requires high drug loading in the microspheres, prevention of protein
degradation by the encapsulation method, and predictable release of the drug compound from the
microspheres. To achieve these goals, multiple emulsion techniques and other innovative modifications
have been made to the conventional solvent evaporation process.
Nicosia, et al7 .,The analysis of carbimazole tablets in The British Pharmacopoeia, 1993, includes a
quantitative thin layer chromatography (TLC) determination of methimazole. Repeated analysis of the
same samples did not give similar results. The repeatability and reproducibility of the method was
studied. It was proved that the residence time of the methimazole spot on the TLC plate is time
dependent.
G.G.Skellern, et al8 ., Carbimazole was administered to nine hyperthyroid patients, and blood samples
were taken at various time intervals for analysis of carbimazole, and it etabolite methimazole. A
technique was developed for the measurement of methimazole in serum using a High-Pressure Liquid
Chromatograph, which could detect nanogram quantities of this metabolite.After a single oral dose, the
patients' blood levels appeared to fall into two groups, either those with a maximum concentration of
methimazole between 30 and 60 min, or those whose maximum was 2 to 3 hours.The results would
suggest that there could be a correlation between the high level of methimazole in serum and the high
thyroxine concentration found in some patients.
Prakash K, et al9 ., The controlled release microcapsules were prepared by solvent evaporation method
using various cellulose polymers .The microcapsules were spherical and free flowing.The entrapment
efficiency was 76-86%.The release of drug from the microcapsules extended upto 8-12hrs.FTIR and
DSC thermograms showed that the microcapsules were stable and SEM showed that they are porus in
nature.Studies release kinetics can be done by fited to the zero order and Higuchi model.The release
kinetics data and charecterisation studies indicate that drug release from microcapsules was diffusion
controlled and the microcapsules were stable.
Kim BK, et al10 ., Microspheres containing antithyroid drugs were prepared by the emulsion solvent
evaporation method(o/o)using acyrlate methacrylate copolymers,Eudragit RL PO and Eudragit RS PO as
wall materials.Encapsulation efficiency was increased by using a acetonitrile and dichloromethane (1:1)
Solvent system.The microencapsulation efficiency ranged from 51.4-80.4%.The release rate of the
Eudragit RS PO microsphere was much lower than tnat Eudragit RL PO microspheres.The release
profile and encapsulation efficiencies depended strongly on the structure of the polymers used as wall
materials.
Singh RM, et al11 ., Antithyroid microcapsules were prepared by solvent evaporation method using ethyl
cellulose as a coating material. Influence of three solvents such as chloroform, dichloromethane and
ethylacetate on the drug release from hydroxybutyric acids microcapsules was studied. The
microcapsules were evaluated for size distribution, surface characteristics, drug content, wall thickness,
drug release characteristics. Drug release from microcapsules followed zero order kinetics and it is
influenced by the size of microcapsules and the solvent employed in the formulation.
Dehghana MHG, et al12 ., The microspheres of propylanhydrides and polyesters were prepared by
emulsion solvent evaporation method. Felodipine was successfully encapsulated into microspheres.
Docusate and stearicacid were used as surfactant/solubilizer.The maximum drug dissolution (24hrs) was
found tobe 96.66%.The drug release from these microspheres decreased with an increase in the amount
of polymer. The mean particle size diameter was between 19.5 to 30.5 micrometer, a significant increase
in particle size was observed with an increase in the amount of polymer. Inclusion of
surfactant/solubilizer docusate and stearic acid in the formulation significantly improved the dissolution.
Das MK, et al13 ., Microencapsulation of Diltiazem HCL by ionotropic external gelatine technique was
done due its low entrapment efficiency limits. The prepared microspheres were characterized by
incorporation efficiency, particle size, invitro release behaviour. The drug loaded microspheres show 6393% incorporation efficiency, scanning electron microscopy (FTIR) and differential scanning
calorimetry (Dsc). Sustained
release for the microspheres can be done by changing alginate
concentrations and polymer compositions.
Raosaheb NS, et al14 ., The main aim is to develop a controlled release formulation is to reduce the
frequent dosing. Risks associated with conventional dosage forms like tablets and capsules namely
variations in gastric emptying and dose dumping, can be minimized by use of multiparticulate systems
such as pellets and microspheres. Cefiximie microspheres were prepared by solvent evaporation method.
Microspheres are subjected to SCM studies(50-200micrometer), drug entrapment analysis(78.27%w/w)
and drug release kinetic studies. Results of study indicate that microspheres have superior performance
then the pellets for controlled release.
J.R.Wall et al15., Studies of in vitro immuno reactivity to propylthiouracil (PTU), methimazole (MMI),
and carbimazole (CARB), as assessed by peripheral blood lymphocyte transformation and 2 antibody
tests, were carried out in 12 patients with Graves’ hyperthyroidism who had developed agranulocytosis
during treatment with PTU (11 patients) or CARB (1 patient) from 1 week to 10 yr earlier. Significant
lymphocyte transformation responses to antithyroid drugs (stimulation indices > mean ± 2 SD for normal
subjects) were found in 5 of 6 patients tested, in 1 patient to PTU only, in 3 patients to MMI only, and in
1 patient to both PTU and MMI, but in none of 10 patients currently being treated with PTU who did not
develop agranulocytosis. Circulating antibodies causing neutrophil agglutination in the presence of
antithyroid drugs were demonstrated, using the indirect Coombs test, in 5 of 7 patients tested, in 2
patients to PTU only, in 3 patients to CARB only and in 1 patient (the only one tested with MMI) to PTU
and MMI. Lymphocyte transformation and antibody tests to PTU were both carried out in 6 patients. Of
these, both tests were positive in one patient, both negative in 3 patients, and 1 negative and 1 positive in
2 patients. In the 1 patient in whom both tests were carried out with CARB (patient 3), tests were
negative, whereas in the 1 patient in whom both tests were carried out with MMI (patient 3), 1 test was
positive, whereas the other was negative. Thus, in patients in whom both tests were carried out using the
same drug, correlation between lymphocyte transformation responses and the detection of neutrophil
antibodies was found in 5 of 6 cases. Antibodies reactive with neutrophils were also detected in 2 of the
5 patients tested using an enzyme-linked immunosorbent assay. In this test antibodies to PTU or MMI
were not demonstrated.
Christopher A.S.Pegg et al16., Thyroid autoantibody synthesis was investigated in cultures of
lymphocytes isolated from several sources, including thyroid and lymph nodes from patients with
hyperthyroid Graves' disease treated preoperatively with carbimazole or propranolol. The ability of
thyroid lymphocytes to secrete immunoglobulins, including thyroid microsomal or thyroglobulin
autoantibodies, was markedly reduced in lymphocyte suspensions obtained from patients treated with
carbimazole compared with suspensions from patients treated with propranolol. This effect (which was
greater in individuals treated with carbimazole for longer periods) was attributable to a significant
reduction in the number of viable lymphocytes present after the 14-day culture interval. In contrast, the
type of preoperative therapy had little effect on cultures of lymphocytes obtained from lymph nodes
draining the thyroid. Although it is not yet clear whether carbimazole exerts its effects in vivo by direct
immunosuppression or indirectly by altering the thyroid microenvironment, our observations indicate
that the fall in serum levels of thyroid autoantibodies that occurs during carbimazole therapy is related to
an effect of the drug on lymphocytes within the thyroid.
OBJECTIVES OF THE STUDY:
6.3
The objectives of the present study are following:
1. To prepare controlled release antithyroid drug by solvent evaporation method.
2. To study the prepared formulations for drug excipient compatibility by FTIR and DSC, Surface
morphology by SEM.
3. To carryout invitro dissolution studies.
4. To carryout stability studies for optimised formulation.
5. To characterise the prepared microparticles for micromeritic properties.
6. To carryout invitro release studies and compared with commercially available preparation.
EVALUATION
1. Drug polymer compatibility studies by FTIR / DSC.
2. Surface morphology by SEM.
3. Drug loading capacity microencapsulation.
4. Invitro drug release studies.
7.0
MATERIALS AND METHODS:
Method of preparation:
Solvent evaporation method, Emulsion polymerisation, Phase separation, Double emulsion solvent
diffusion etc.,
MATERIALS
Drug :
Antithyroid drugs like carbimazole, methimazole, propylthiouracil etc.,
Polymers: Ethylcellulose, Eudragit, HPMC etc.,
Solvent and other excipients
7.1
SOURCE OF DATA:
1. Review of literatures from:
a. Journals - such as
 Indian Journal of Pharmaceutical Sciences.
 European Journal of Pharmaceutical Sciences.
 Asian Journal of Pharmaceutics.
 International Journal of Pharmaceutics.
 Drug development and Industrial pharmacy.
 Indian Drugs.
 Journal of Pharmaceutical Research.
 AAPS journal.
b.World Wide Web.
7.2
DOES THE STUDY REQUIRES ANY INVESTIGATIONS TO BE CONDUCTED ON PATIENT OR
OTHER HUMAN OR ANIMALS?
“NO”
7.3
HAS ETHICAL CLEARENCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.5??
“NOT APPLI CABLE”
8.0
LIST OF REFERENCES:
1. Wikipedia,
The
free
Encyclopedia.
Antithyroid.
[online].
Available
from
URL;
http://en.Wikipedia.org/wiki/Antithyroid drug.
2. Bartalena L, Bogazzi F, Martino E. Adverse effects of thyroid hormone preparations and antithyroid
drugs. Drug Safety 1996; 15:53–63. Medline Web of Science.
3. Sahoo SK, Mallick AA, Barik BB,Senapati PC.Formulation and in vitro evaluation of eudragit
microspheres, Tropical J Pharmaceutical Research 2005;4(1):369-75.
4. Chiappetta DA, Angel M,Carboso, Bregni C, Rubio M, Bramuglia G, pH-sensitive microparticles for
taste masking: AAPS PharmaSciTech2009;10(1):1-6.
5. David B Master; Drug Delivery Devices Comprising Biodegradable Protein For The Controlled
Release Of Pharmacologically Active Agents And Method Of Making The Drug Delivery Devices Patent 6342250 Filed dated:9/25/1998.
6. McGinity JW, O’Donnell PB.Preparation of microspheres by the solvent evaporation technique.Drug
Dynamics Institute, College of Pharmacy, The University of Texas at Austin, Austin, TX, 787121074, USA.
7. Pharmaceutical Quality Control, State Genaral Laboratory, Ministory of Health, 1451 Nicosia,
Cyprus Received 14 April 1997;Available online 4 March 1999.
8. Plasma concentrations of methimazole, a metabolite of carbimazole, in hyperthyroid patients G. G.
Skellern, J. B. Stenlake, W. D. Williams, and D. G. McLarty.
9. Prakash K, Raju PN, Shanta KK, Lakshmi MN. Preparation and characterization of microcapsules
using various cellulose polymers. Tropical J Pharmaceutical Research 2007;6(4):841-7.
10. Kim BK, Hwang SJ, Park JB, Park HJ. Preparation and characterization of drug loaded
polymethcrylate microspheres by an emulsion solvent evaporation method. J Microencapsulation
2002;19(6):811-22.
11. Singh RM, Singh GN, Gupta.P. Mathur SC. Formulation and evaluation of ethylcellulose coated
microcapsules:Influence of Solvents.Indian Drugs 2008;45(5):372-75.
12. Dehghana MHG, Mouzam MI. Improved dissolution of felodipine from ethylcellulose microspheres.
Indian Drugs 2008;45(2):115-8.
13. Das MK, Maurya DP. Microencapsulation of water-soluble drug by emulsification-internal gelation
technique Educ Res 2009;43(1):28-38.
14. Raosaheb NS, Narayan BA. Development and evaluation of once a day oral controlled
multiparticulate drug delivery system of Cefiximie trihydrate.Indian J Pharm Educ Res 2008;42(3).
15. J.R.Wall, S.L.Fang,T.Kuroki, S.H.Ingabar and L.E.Braverman Department of Medicine, University
of Massachusetts Medical School Worchester.
16. Sandra M. McLachlan, Christopher A.S.PEGG, Marian C.Atherton, Shirley Middleton, Eric
T.Young, Fred Clark and Bernard Rees Smith.