Download RAJESH.R NARGUND COLLEGE OF PHARMACY

“FORMULATION AND DEVELOPMENT OF IMMEDIATE
RELEASE OF FIXED DOSE COMBINATION THERAPY FOR
PARKINSONISM DISEASE”
DISSERTATION PROTOCOL
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA.
BY
RAJESH.R
I Year M. PHARM,
DEPARTMENT OF PHARMACEUTICS,
NARGUND COLLEGE OF PHARMACY,
BANGALORE- 85. KARNATAKA.
(2010-2012)
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA.
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR PG DISSERTATION
1.
NAME OF THE
CANDIDATE &
ADDRESS (IN
BLOCK LETTERS)
RAJESH.R
NARGUND COLLEGE OF PHARMACY,
DATTATREYA NAGAR,2nd MAIN,
100 FT RING ROAD,BSK 3rd STAGE
BANGALORE-560085
2.
NAME OF THE
INSTITUTION
NARGUND COLLEGE OF PHARMACY,
DATTATREYA NAGAR,2nd MAIN,
100 FT RING ROAD,BSK 3rd STAGE
BANGALORE-560085
3.
COURSE OF STUDY
AND SUBJECT
MASTER OF PHARMACY IN
PHARMACEUTICS
4.
DATE OF
ADMISSION TO
COURSE
29th NOVEMBER 2010
5.
TITLE OF THE
TOPIC
“FORMULATION AND DEVELOPMENT OF
IMMEDIATE RELEASE OF FIXED DOSE
COMBINATION THERAPY FOR
PARKINSONISM DISEASE”
6.
BRIEF RESUME OF THE INTENDED WORK
6.1 NEED FOR THE STUDY
Parkinsonism is an extra pyramidal motor disorder characterized by rigidity, tremor and
hypokinesia with secondary manifestations like defective posture and gait, mask like face and
sialorrhoea, dementia may accompany. If untreated the symptoms progress over several years to
end stage disease in which the patient is rigid, unable to move, unable to breathe properly,
succumbs mostly to chest infections/embolism.
Parkinsons disease (PD) is a progressive regenerative disorder mostly affecting older people
first described by James Parkinson in 1870. The most consistent lesion in Parkinson disease is
degeneration of neurons in the substantial nigra pars compacta and the nigrostriatal tract
(Dopaminergic) .This results in deficiency of dopamine in the striatum which controls muscle tone
and co-ordinate movement and imbalance between dopaminergic (inhibitory) and cholinergic
(excitatory) system in the striatum occurs giving rise to the motor defect.
The cause of selective degeneration of nigrostriatal neurons is not precisely known but
appears to be multifactorial. The oxidation of dopamine by MAO – B and aldehyde dehydrogenase
generates hydroxyl free radical in the presence of ferrous iron. Normally these free radicals are
quenched by glutathione and other protective mechanisms. Age related and or otherwise acquired
defect in protective mechanism allows the free radical to damage lipid membranes and DNA
resulting in neuronal degeneration. Genetic pre-disposition may contribute to the vulnerability of
substantia nigra neurons.
Signs and Symptoms of Parkinson’s Disease
Parkinson’s disease is common movement disorder which is characterized by the following
primary motor symptoms:
• bradykinesia (slowed movement)
• muscle rigidity (stiffness)
• resting tremor (shaking; usually more pronounced on one side of the body)
• postural instability (poor balance)
Secondary symptoms can include:
• micrographia (small handwriting)
• dysarthria (soft, muffled speech)
• reduced arm swing on the affected side of the body
• short-stepped or shuffling gait
• reduced eye blinking and frequency of swallowing
• depression and anxiety
• sleep disorders
• low blood pressure
• constipation
• seborrhea (oily skin, dandruff)
STATISTICS OF PARKINSONISM IN INDIA:
As estimated seven to ten million people worldwide are living with parkinsonism
disease. Incidence of parkinson’s increases with age, but and estimated four of people with PD are
diagnoised before the age 50. Men are one and a half times more likely to have Parkinsons thean
women.
DIESASE CAN BE CONTROLLED BY USING THE FOLLOWING DRUGS :
Dopaminergic drugs for Parkinson's disease include:
o
Levodopa (Sinemet)
o
Levodopa is converted in the body to dopamine.
Dopamine Agonist Drugs for Parkinson's Disease
Several drugs mimic the effects of dopamine in the brain.
Dopamine agonists drugs for Parkinson's disease include:

Apomorphine (Apokyn)

Bromocriptine (Parlodel)

Pramipexole (Mirapex)

Ropinirole (Requip and Requip XL)

Rotigotine (Neupro)
Anticholinergic Drugs for Parkinson's Disease
These medications are often used in combination with other drugs. They decrease activity in areas
of the brain that have low dopamine levels.
Anticholinergic drugs for Parkinson's disease include:

Benztropine mesylate (Cogentin)

Trihexyphenidyl (Artane, Trihexy)
COMT Inhibitor Drugs for Parkinson's Disease.

Tolcapone (Tasmar)

Entacapone (Comtan)
Additional Medications for Parkinson's Disease
Other drugs that may be used to treat Parkinson's disease include:


Amantadine (Symmetrel)
Rasagiline (Azilect)

Selegiline (Deprenyl, Eldepryl)

Levodopa, carbidopa, and entacapone combination (Stalevo)
DRUGS IN INDIAN MARKET WITH COMBINATION :

Sinemet (Carbidopa – Levodopa) Tablets.

Duodopa (levodopa/carbidopa intestinal gel.

Selegiline and Rasagiline Tablets

Entacapone and tolcapone

biperiden and orphenadrine or procyclidine
LEVODOPA ;
Levodopa has a specific effect in parkinsonism disease efficacy exceeding that of any
other drug used alone. It is inactive by itself but is the immediate precursor of the transmitter
dopamine .More than 95% of oral dose is decarboxylated in the peripheral tissue. About 1 – 2% of
administered levodopa crosses to the brain are taken up by the surviving dopaminergic neurons
converted to dopamine which is stored and released as a transmitter. Brains of parkinsonian
patients treated with levodopa till death had dopamine levels higher than those not treated.
CARBIDOPA AND BENSERAZIDE ;
These are extra cerebral dopa decarboxylase inhibitors, they do not penetrate blood
brain barrier and do not inhibit conversion of levodopa to dopamine in the brain .
BROMOCRIPTINE ;
It is an ergot derivative which acts as potent agonist on D2 but as partial agonist or
antagonist on D1 receptor. In parkinsonian symptoms occurs within half to one hour of an oral
dose and lasts for 6 – 10 hours..It is used only in late cases as a suppliment to levodopa starting
with low doses and gradually increasing as needed up to 5 to 10 mg thrice daily
ROPINIROLE AND PRAMIPEXOLE ;
These two are recently developed non – ergoline, selective D2 or oD3 receptor agonist .
Pramipexole has greater affinity for D3 receptors. Ropinirole is rapidly absorbed orally,40%
plasma proteins bound extensively metabolized eliminated with a terminal t1/2 of 6 hours .It is thus
linger acting than levodopa useful in the management of motor fluctuations.
SELEGILINE;
It is selective and irreversible MAO –B inhibitor .It predominates in the brain and blood
platelets, Selegiline alone has mild antiparkinsonian action. Adminstered with levodopa it prolongs
the action of levodopa, attenuates motor fluctuations and decreases varying of effect.
AMANTIDINE :
Developed as an antiviral drug for prophylaxis of influenza, it was found to benefit
parkinsonism.
TRIHEXPHENIDYL(BENZHEXOL)
It is the most commonly used drug. Start with the lowest dose in 2-3 divided portions per
day and gradually increase till side effects are tolerated.
. Benzhexol is an effective and the most commonly used drug among the synthetic atropine
substitutes.
6.2 REVIEW OF LITERATURE:
 To enhance dissolution and hence bioavailability of any drug from immediate release
tablets, disintegration is one of the important process. Few Super-disintegrants are available
commercially but due to the cost and expanding need of market, development of new
disintegrants is required. In the present investigation, we tried to judge the disintegration
efficiency of disintegrants by comparing various parameters such as disintegration time,
wetting time, maximal water uptake capacity and dissolution study of tablet. Disintegrants
powder properties like swelling and hydration capacity was compared. Various techniques
can be used to formulate immediate release tablets1.
 Direct compression, is one of the techniques that requires the incorporation of a
superdisintegrant into the formulation. Direct compression does not require the use of water
or heat during the formulation procedure and is very sensitive to changes in the type and
proportion of excipients and the compression forces, when used to achieve tablets of
suitable hardness without compromising the rapid disintegration characteristics. Recently,
immediate release tablets have gained prominence of being new drug delivery systems.2
 Most immediate release tablets are intended to disintegrate in the stomach, where the pH is
acidic. The objective of this article was to investigate the novel disintegrants and it’s
comparison with reported superdisintegrants in simulated gastric fluid and their efficiency
in promoting disintegration and dissolution of active ingredients from directly compressed
tablets of metoclopramide HCl. Gellan gum (GG) is a linear anionic polysaccharide,
biodegradable polymer obtained from Pseudomonos elodea consisting of a linear
tetrasaccharide repeat structure and used as a food additive. Agar (AG) is the dried
gelatinous substance obtained from Gelidium amansii (Gelidanceae) and several other
species of red algae like, Gracilaria (Gracilariaceae) and Pterocadia (Gelidaceae). Both
were reported earlier as disintegrant.3
 TAG has better disintegration efficiency than AG Same procedure was adopted for to
enhance disintegrant efficiency to GG.4
 Adamas was founded in 2004 to address vexing global health problems such as Parkinson’s
disease and dementia, and infectious diseases such as influenza. Adamas uses proven
technologies to create precisely calibrated fixed‐dose regimens in controlled release
combinations that overcome the limitations of monotherapy and conventional formulations.
The company has three product candidates in development: ADS‐8902, its proprietary
triple combination antiviral drug (TCAD) therapy for flu, ADS‐5101, a proprietary
once‐daily extended release (ER) formulation of amantadine hydrochloride for the
symptomatic treatment of Parkinson’s disease and other disorders, and ADS‐8703, a
proprietary fixed‐dose combination for the symptomatic treatment of dementia.5
 World Health Organization(WHO) guidelines recommend a combination of two nucleoside
reverse transcriptase inhibitors (NRTI) and one non-nucleoside reverse transcriptase
inhibitor (NNRTI) as a first-line regimen in resource-poor settings to treat HIV-1 infection.
Currently, only one WHO prequalified combination of NRTI/NNRTI is available as a fixeddose combination, combining Efaverinz, Emitriptazine, Teofovir DF, and its use has been
shown to be effective. This study shows how to formulate the bi-layered tablets of
combination drugs Efavirenz, Lamivudine, Tenofovir DF by using sodium laurly sulfate as
dissolution medium for providing sink condition and in this sodium Lauryl sulfate as non
ionic surfactant as wetting agent in Efavirenz layer increase the Solubility of drug. These
three drugs use for treatment of HIV. I called as anti-retroviral drugs in combined form for
avoiding drug resistance, overdose, side effects, improve efficiency of drug line therapy.
The use of three drugs in same formulation shows synergism effect to increase drug action.
Bilayer layer tablets are preferred when the release profiles of the drugs are different from
one another. Bi-layer tablet is suitable for sequential release of two drugs in combination,
separate two incompatible substances.6
 Compression is becoming more prevalent across the pharmaceutical industry as the number
of FDC.S increases. The aim of this work develop robust formulation followed by separating
as two layer two avoid incompatibility between the drugs by bilayer formulation form.7
 Libermann HAetal., Formulated Multi layer tablets are made by compressing different
granulations fed into the die in succession, one on top of another in layers, and have the
appearance of a sandwich, because, the edges of each layer are exposed. Each layer comes
from a separate feed frame with individual weight control. Rotary tablet presses can be set up
for two or three layers. Incompatible substances can be separated by formulating them in
separate layers as a two layer tablets or separating the two layers by a third layer of an inert
substance as a barrier below the two. Two layer tablets may be designed for sustain release,
one layer for the immediate release of the drug and second layer for extended release thus
maintaining a prolonged blood level. Layers may be colored differently to identify the
product. The weight of each layer can be accurately controlled in contrast to putting one drug
of a combination product in a sugar coating (Libermann HA et al., 1990).8
 Oral route of drug administration is perhaps the most appealing route for the delivery of
drugs. The various dosage forms administered orally, the tablet is one of the most preferred
dosage forms because of its ease of manufacturing, convenience administration, accurate
dosing, stability compared with oral liquids, and because it is more tamperproof than
capsules. The bioavailability of drug is dependent on in vivo disintegration, dissolution and
various physiological factors. In recent years, scientists have focused their attention on the
formulation of quickly disintegrating tablets.9,10
 The task of developing rapidly disintegrating tablets is accomplished by using a suitable
diluents and superdisintegrant. The domperidone is selected as the model drug which comes
under anti-emetic class. Domperidone is gastrointestinal emptying (delayed) adjunct;
peristaltic stimulant: The gastroprokinetic properties of domperidone are related to its
peripheral dopamine receptor blocking properties. Domperidone facilitates gastric emptying
and decreases small bowel transit time by increasing esophageal and gastric peristalsis and by
lowering esophageal sphincter pressure. Antiemetic: The antiemetic properties of
Domperidone are related to its dopamine receptor blocking activity at both the chemoreceptor
trigger zone and at the gastric level. Domperidone is optimized suits for preparation of MDT
as it has longer half life and in case of vomiting it required quick release.11,12
 Vacuum and Freeze-drying techniques have been tried by researchers to maximize the pore
structure of tablet matrix. Freeze drying yields a fragile and hygroscopic product. Therefore,
it was decided to adopt the vacuum-drying technique in the present investigation. Vacuum
drying was adopted after addition of a subliming agent to increase porosity of the tablets. It is
likely that a porous hydrophilic matrix will easily pick up the disintegrating medium and
break quickly.13-18
 A32 full factorial design is applied for the optimization of the fast dissolving tablets of
the Domperidone. The concentration of Superdisintegrants (Crospovidone) and amount of
sublimating agent (Camphor) were taken as independent variable. The dependent variables
selected are disintegration time and friability to find out effect of independent variables on
dependent variables.19-22
6.3 OBJECTIVES OF THE STUDY:
The aim of the present work is to formulate and evaluate the fast Immediate release tablet
of Parkinsonian Disease.
 In this study, an attempt will be made to develop an Immediate release tablet of
Parkinsonian Disease.
 Absorption of drug is from the oral cavity into the systemic circulation thus it will bypass
the hepatic circulation and metabolism or by incorporation of the buffers for increasing the
stability of the drug.
 The stability of Parkinsonian drugs in aqueous solution is pH dependent; the rate of
degradation increases with decreasing pH. So there is a need to increase their stability.
 To decrease the dose of parkinsonian.
 To increase patient convenience and compliance.
 To compare the various formulations using different excipients and choosing the best
formulation as per ICH guidelines.
7.
MATERIALS AND METHOD
MATERIALS:
1. Some of the commonly used AntiParkinsonian Drugs:o Levodopa, Carbidopa, Ropinirole, Amantidine, Pramipexole etc.
2. Super disintegrants:o Crospovidone, Cross carmellose sodium, Sodium starch glycolate, Acrylic
acid derivatives, Sodium Alginate,L-HPC, NS-300, ECG-505, L-HPC etc
3. Flavoring agents:o lemon Oil, Clofibrate, Isosorbide 5-mononitrate etc
4. Colouring agents:o Sunset yellow, Orange etc.
5. Sweetning agents:o Aspartame, Sodium saccharine, Sucrose, Mannitol etc.
6. Effervesent Mixture:o Sodium bicarbonate, Citric acid, Tartaric acid, Sodium Salt of Alginic acid,
etc.
METHODS:
Some of the commonly methods which are planned to be used for the formulation of the
Immediate Release of Anti-Parkinsonian drugs are:
o Lyophilization or Freeze-drying.
o Vaccum Drying.
o Spray drying.
o Mass extrusion.
o Compaction.
o Direct compression.
7.1 SOURCE OF DATA:
1. Library: Nargund college of pharmacy.
2. e-library: Nargund college of pharmacy.
3. Official books ( IP, BP, USP, EP).
4. RGUHS Library, Bangalore.
5. International and national Pharmaceutical abstracts etc.
A. 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
B. Internet Browsing.
 www.sciencedirect.com
 www.google.com
 www.pubmed.com
 www.pharmainfo.net
 www.pharmasm.com
7.2 METHODS OF DATA COLLECTION:
1. Literature survey using internet and scientific journals.
2. Experimental studies which includes:
 The formulation evaluated for the compatibility studies using thermal
analysis such as DSC, TGA and XRD techniques.
 Formulation development and evaluation.
 Granular properties, tablet properties and in-vitro dissolution studies for the
developed formulation.
 Spectrophotometeric, HPLC, FTIR methods etc for the estimation of drug
and for analysis of in-vitro dissolution samples.
 Statistical analysis of all the results.
7.3 Does the study require any investigation or intervention to be conducted on patients or
other human or animals?
-NO-
7.4 Has ethical clearance been obtained from your institute?
-NOT APPLICABLE
8.
LIST OF REFERENCES
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Current status of tablet disintegration: http://www.pharmainfo.net. Accessed 2006
July.
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in Different pH Media on the Dissolution of Hydrochlorothiazide from Directly
Compressed Tablets: AAPS pharmscitech.2005 May;E120-6.
Augsburger LL, Brzecko AW, Shah U, Hahm HA, Characterization and
functionality of super disintegrants: Encyclopedia of Pharmaceutical Technology
New York, NY: Marcel Dekker Inc; 2002; 2623-38.
Akihiko I, Masayasu S, Development of oral dosage form for elderly patients: use
of agar as base of rapidly disintegrating tablets. Chem.Pharm bull. 1996;45:2132-6.
ADAMAS PHARMACEUTICALS RAISES $40 MILLION IN SERIES D
FINANCING Appoints George M. Rehm and David L. Mahoney to Board of
Directors.
Nagaraju.R, and Rajesh.K, Formulation and Evaluation of Bilayer Sustained
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Remya P.N, Formulation and Evaluation of Bilayer Tablets of Ibuprofen and
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S. Mohideen1, T.Satyanarayana, P. Suresh Kumar, S. Navneetha Krishnan1,
R. Mahalaxmi, S. Pavani, Brown’s college of Pharmacy, Khammam, Andhra
Pradesh, India.Department of Pharmaceutics, Manipal College of Pharmaceutical
sciences, Manipal, Karnataka,India.
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Chang R, Guo X, Burnside B and Couch R, A review of fast dissolving tablets.
PharmTech North Am. 2000 DEC; 52-8.
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compressed tablets rapidly disintegrating in the oral cavity. Chem Pharm Bull.1996;
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Tripathi KD, Essential of Medical Pharmacology, Jaypee Publisher Ltd, 2008.
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Kanthleen Parfitt: Martindale, The Complete Drug Reference. The Royal
Pharmaceutical Society. Pharmaceutical Press. 1999.Thirty second Edition.
Omaima AS, Mohammed AH, Nagia AM and Ahmed SZ, Formulation and
optimisation of mouth dissolve tablets containing rofecoxib solid dispersion.
AAPS Pharm Sci Tech 2006; 7: 55.
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 Pharm Sci Tech 2004; 5: 36.
Suresh S, Pandit V and Joshi HP, Preparation and evaluation of mouth dissolving
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Heinemann H and Rothe W,Preparation of porous tablets. US patent 388026,1975.
Knistch A, Hagen E and Munz HD, Production of porous tablets.US patent
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Roser BJ and Blair J, Rapidly soluble oral dosage forms, methods of making the
same and composition thereof.US patent 576961,1998.
Ahmed IS and Fatahalla FA ,Pilot study of relative bioavailability of two oral
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Ketoprofen tablet using freeze-drying in blister technique. Drug Develop Ind
Pharm 2006; 32:437-42.
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tablets by Lyophilization using hydrochlorothiazide as a model drug. Int J Pharm
1997; 152: 215-225.
Remon JP and Corveleyn S, Freeze-dried rapidly disintegrating tablets. 2000,US
patent 6010719.
9.
SIGNATURE OF THE
CANDIDATE
10.
REMARKS OF THE GUIDE
11.
NAME AND DESIGNATION OF
11.1 GUIDE
SIGNATURE
11.3 CO-GUIDE
SIGNATURE
11.4 HEAD OF THE DEPT.
(RAJESH.R)
RECOMMENDED FOR DISSERTATION WORK.
Dr. GOPAL MURALIDHARAN
PROFESSOR
DEPT. OF PHARMACEUTICS
NARGUND COLLEGE OF PHARMACY
MR. T. KRISHNA MURTHY
TEAM LEADER,
STRIDES ARCOLAB LIMITED
Dr. C.S.R LAKSHMI
PROFESSOR AND HEAD
DEPT. OF PHARMACEUTICS
NARGUND COLLEGE OF PHARMACY,
SIGNATURE
12.
REMARKS OF THE
PRINCIPAL
FORWARDED AND RECOMMENDED FOR
FAVORABLE CONSIDERATION.
SIGNATURE
PROF. DAYANAND. S. PURANIK
PRINCIPAL