Combined drug therapy (CDT) is favoring for most of the treatment and the goal of the therapy is to decrease or reduce dose dependent adverse drug reactions and side effects. The present work an attempt to design bilayer tablets of Atorvastatin immediate release and Aspirin Pulsatile release for the treatment of cardiovascular diseases. Four formulations were prepared for immediate release layer of atorvastatin using different concentrations of Microcrystalline cellulose and Talc by direct compression method. For aspirin pulsatile release layer, the four formulations of core tablets were prepared using Microcrystalline cellulose, Talc. The different concentrations of Cross carmellose sodium and Sodium starch glycolate were selected as superdisintegrants in F1, F2 and F3, F4 formulations. Then the core tablets were coated with Eudragit S 100 as enteric polymer. Physico chemical parameters of bilayer tablets were performed and it has shown a good drug release profile. The work reveals that F3 formulation was the best formulation and they are the good candidate for lowering the risk of heart attack. Pattern like one layer of the formulation as immediate release to reduce the cholesterol level and the second layer to deliver the drug at right time and in right amount, to reduce the risk of heart attack. However stability studies and further clinical trials are needed to improve the tablet formulation by quality wise as well as efficacy wise.
3. CONTENTS
• Introduction
• Aim and Objectives
• Review of Literature
• Plan of work
• Materials and Methods
• Results and Discussion
• Summary and Conclusion
• Bibliography
21-Apr-18 3
4. INTRODUCTION
• Need of combination therapy
• Cardiovascular diseases
• Atorvastatin and aspirin
• Pulsatile delivery system (Chronotherapy)
• Bilayer tablets
21-Apr-18 4
6. AIMANDOBJECTIVES
21-Apr-18 6
Background and Significance of the study
Cardiovascular disease is one of the leading causes of death in the world
and one of the most significant factors for these diseases is total/high
density lipoprotein (HDL) cholesterol level. However, recent
developments have indicated that only taking the cholesterol level under
control is not sufficient for cardiovascular treatment. In line with this
need, researchers have found that use of some active agents in
combination provides a more effective treatment method.
7. • In the prior art, it is disclosed that cardiovascular diseases such as
atherosclerosis, heart attack, angina pectoris arise from increase in lipid
levels in blood; however, another factor called "thrombosis" plays an
important role in nervous system diseases accompanying these such as
stroke, paralysis. Thrombosis means obstruction of blood vessels in
consequence of formation of a blood clot in the blood vessels. This
obstruction may occur in any part of the body.
21-Apr-18 7
8. Due to the obstruction, blood flow through the target organ gets slower
and it may completely stop in advanced stages. Rarely, this clot
obstructs brain vessels and causes brain hemorrhage or obstruction of
heart veins, in other terms coronary infarction. Formation of thrombosis
in brain or blood veins going to the brain generally leads to fatal results.
To this respect, it is important to eliminate thrombosis and the factors
leading to thrombosis as well as lowering cholesterol level in blood in
the effective treatment of cardiac diseases.
21-Apr-18 8
9. • One of the drugs commonly used in the treatment and prevention of
thrombosis is aspirin. It is well known that aspirin use reduces the risk of
contracting cardiovascular diseases such as myocardial infarction and
similarly, statin group active agents are effective in prevention and
treatment of cardiovascular, cerebrovascular diseases. Use of aspirin and
statin group active agents in combination is known to decrease mortality
rates of cardiovascular diseases
21-Apr-18 9
10. Aim of the Study
• The main aim of the research work is the development of bilayer tablets
of atorvastatin immediate release and aspirin pulsatile release for the
treatment of cardiovascular diseases using newer excipient composition.
• The objective of this present work was to design and develop an
optimized oral solid dosage form of double layer or bilayer formulation
especially for cardiovascular diseases using Aspirin and Atorvastatin
Calcium by direct compression method
21-Apr-18 10
11. REVIEWOF LITERATURE
21-Apr-18 11
AUTHORS TITLE PUBLICATION CONTENTUSED
Nawar M.Toma and
Yehia I.Khalil
Formulation and
Evaluation of Bilayer
Tablets Containing
Immediate Release
Aspirin Layer and
Floating Clopidogrel
Layer
Iraqi J Pharm Sci,
Vol.22(1) 2013
Aspirin and clopidogrel are considered the
most important oral platelets aggregation
inhibitors. So it is widely used for treatment
and prophylaxis of cardiovascular and
peripheral vascular diseases related to
platelets aggregation .In this study aspirin
and clopidogrel were formulated together as
floating bilayer tablet system.
Sanjay Dey, Sankha
Chattopadhyay
Formulation and
Evaluation of Fixed-
Dose Combination of
Bilayer Gastroretentive
Matrix Tablet
Containing Atorvastatin
as Fast-Release and
Atenolol as Sustained-
Release
BioMed Research
International
Volume 2014
The objective of the present study was to
develop bilayer tablets of atorvastatin and
atenolol that are characterized by initial
fastrelease
of atorvastatin in the stomach and comply
with the release requirements of sustained-
release of atenolol
12. 21-Apr-18 12
AUTHORS TITLE PUBLICATION CONTENTUSED
Patel Dipika,
Patel Vijay
Formulation
Development and
Evaluation of
Immediate Release
Tablets Containing
Atorvastatin
Calcium Drug
International Journal of
Pharmaceutical
Erudition May 2012,
2(1)
The present study is planned to develop amorphous
form of Atorvastatin Calcium into
immediate release tablets. Pre-formulation study and
drug excipients compatibility study was
done initially and the results obtained were directs
the way and method of formulation.
V.Kalvimoorthi,
N.Narasimhan
Formulation
development and
evaluation of
aspirin delayed
release tablets
International Journal of
Pharmaceutical
Sciences Review and
ResearchVolume 7,
Issue 1, March – April
2011
The main objective of this work was to formulation
development of the Aspirin delayed release tablets
and to understand thekinetics of drug release by
applying mathematical and model-dependent
approaches.
13. 21-Apr-18 13
AUTHORS TITLE PUBLICATION CONTENTUSED
Mohideen,
Jyothi, Pavani,
Formulation and
evaluation of bilayered
tablets of metformin
hydrochloride
And atorvastatin
calcium
International Journal of
Pharmaceutical Sciences
Review and Research
Volume 10, Issue 2,
September – October
2011
The objective of the study was to
develop a bilayer tablets consisting of
Atorvastatin calcium as an immediate
release layer and Metformin
hydrochloride as a sustained release
layer
Natarajan R.,
Abirami M.
Combination of aspirin,
clopidogrel bisulphate
and atorvastatin
calcium bilayer tablets
for heart diseases
Wjpps, Vol 5, Issue 2,
2016
Multilayered tablets possess various
benefits, like improves its efficacy and
safety by controlling the rate, time, and
place of release of drugs in the body and
the ability to prevent incompatibility
between drugs and excipients; and by
providing multiple release kinetics
mechanisms. The ternary combination is
used for atherosclerotic patients
suffering from various heart diseases.
14. DRUG PROFILE (Atorvastatin calcium)
Category: Cardiovascular agent
Description: White to off white amorphous powder
BCS classification: Class II (Low solubility, High permeability)
Solubility: Freely soluble in methanol and soluble in dimethylsulphoxide
(DMSO) and dimethyl formamide (DMF); insoluble in aqueous solution
with pH less than 4.0. It is very slightly soluble in distilled water,Phosphate
buffer (7.4) and acetonitrile; slightly soluble in ethanol. 20.4 ug/mL (pH
2.1), 1.23 mg/mL (pH 6.0)
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15. • Stability: Stable under ordinary conditions
• Partition Coefficient: The partition coefficient of atorvastatin and
calcium between octanol and water and was found to be 6.36
• pka: 4.46
• Storage: To be stored in well closed, away from heat and damp places
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16. Mechanism of action: Atorvastatin lowers plasma cholesterol and
lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol
synthesis in the liver and by increasing the number of hepatic LDL
receptors on the cell-surface to enhance uptake and catabolism of LDL;
atorvastatin also reduces LDL production and the number of LDL particles.
21-Apr-18 16
17. Table 1: Pharmacokinetics Parameters
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Sl.no Parameters Results
1 Oral absorption > 90%
2 Presystemic metabolism >80%
3 Plasma protein binding >98%
4 Volume of distribution 565L
5 Distribution in blood (Blood cells: plasma) 0.25
6 Plasma half life 14hr
18. Therapeutic Uses: Atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme
A (HMG-CoA) reductase inhibitor (a statin), is a lipid regulating drug with
actions on plasma lipids similar to those of simvastatin. It is used to reduce
LDL-cholesterol, Apo lipoprotein B, and triglycerides, and to increase
HDL-cholesterol in the treatment of hyperlipidemias, including
hypercholesterolemia’s and combined (mixed) hyperlipidemia (type IIa or
IIb hyperlipoproteinaemias), hypertriglyceridemia (type IV), and
dysbetalipoproteinaemia (type III)
21-Apr-18 18
19. • ADR: The commonest adverse effects of therapy with Atorvastatin and
other statins are gastrointestinal disturbances. Other adverse effects
reported include headache, skin rashes, dizziness, blurred vision,
insomnia, and dysgeusia.
• Contraindications: If the patient becomes pregnant while taking this
drug, therapy should be discontinued and the patient apprised of the
potential hazard to the fetus.
21-Apr-18 19
20. Aspirin
• Category: Antiplatelet Agent, Salicylate, Platelet Aggregation Inhibitor
• Description: Aspirin, an acetyl derivative of salicylic acid, is a white,
crystalline, weakly acidic substance, with a melting point of 136 °C (277
°F),[3] and a boiling point of 140 °C (284 °F).[126] Its acid dissociation
constant (pKa) is 3.5 at 25 °C (77 °F).
21-Apr-18 20
21. • BCS classification: Class II (Low solubility, High permeability)
• Solubility: Aspirin is a weak acid that is only slightly soluble in water.
Aspirin is soluble in organic solvents such as ethanol, DMSO, dimethyl
formamide.
• Stability: In aqueous solutions, aspirin is most stable at a pH of 2-3, less
stable at a pH of 4-8, and least stable at a pH less than 2 or greater than
8. Partition Coefficient: The partition coefficient of aspirin is 5 in ethanol
with respect to water.
21-Apr-18 21
22. • pka: 3.5
Mechanism of action:
• involves inhibition of platelet activation and aggregation.
• Aspirin blocks the formation of COX-dependent vasoconstrictors
endothelial dysfunction in atherosclerosis.
• Improve vasodilatation, reduce thrombosis, and inhibit progression of
atherosclerosis. Aspirin reduces the inflammatory response in patients
with coronary artery disease and may inhibit thrombosis the progression
of atherosclerosis by protecting low-density lipoprotein from oxidation
21-Apr-18 22
24. 21-Apr-18 24
ADR: EENT: tinnitus. GI: GI bleeding, dyspepsia, epigastric
distress, nausea, abdominal pain, anorexia, hepatotoxicity,
vomiting. Hemat: anemia, hemolysis. Derm: rash, urticaria.
Misc: allergic reactions including anaphylaxis and laryngeal
edema.
Contraindications:
Hypersensitivity to aspirin or other salicylates; Cross-
sensitivity with other NSAIDs may exist (less with non
aspirin salicylates
Indication: Aspirin is used in the treatment of a number of
conditions, including fever, pain, rheumatic fever, and
inflammatory diseases, such as rheumatoid arthritis,
pericarditis, and Kawasaki disease. Lower doses of aspirin
have also been shown to reduce the risk of death from a
heart attack, or the risk of stroke in some circumstances
25. PLAN OF WORK
Preformulation study (compatibility and flowability study)
Construction of standard curve of Atorvastatin and Aspirin
Design of bilayer tablets of Atorvastatin and Aspirin
Evaluation of bilayer tablets of Atorvastatin and Aspirin
21-Apr-18 25
28. Methodology
• Compatibility Study using FTIR
• Design of Immediate release tablets of Atorvastatin and Pulsatile release
tablets of Aspirin
• Preparation of the bilayer tablets
Preparation of Atorvastatin immediate release layer
Preparation of Aspirin Pulsatile release layer (core tablet)
Preparation of coated tablets of Aspirin
21-Apr-18 28
29. Schematic Presentation for Compression of Bi-Layer Tablet
• Filling of first layer.
• Compression of first layer.
• Ejection of upper punch.
• Filling of second layer.
21-Apr-18 29
30. Evaluation of Bilayer tablets of Aspirin and Atorvastatin
• Preparation of Standard curve of Atorvastatin in 0.1N HCl
• Preparation of standard curve of Aspirin in 0.1N HCl
• Preparation of Standard curve of Aspirin in pH 6.8 phosphate buffer
Pre compression parameters
• Angle of repose
• Bulk and tapped density
• Hausner ratio
• Compressibility index
21-Apr-18 30
31. Post compression parameters
Hardness test
Friability test
Weight variation test
Drug content Uniformity
In Vitro Drug Release Studies
21-Apr-18
31
Dissolution parameters
Medium: 0.1 N HCl (pH1.2), Phosphate buffer pH 6.8
Apparatus: USP, XXIII-type 2 Paddle
RPM: 50
Temperature: 37±0.5ºC
Volume: 900ml
33. RESULTS ANDDISCUSSIONS
Preparation of standard plot for Atorvastatin in 0.1N HCl
Table 2 - Calibration curve for Atorvastatin
21-Apr-18 33
Concentration(µg/ml) Absorbance
0 0
5 0.242
10 0.464
15 0.679
20 0.888
25 1.09
Calibration curve of Atorvastatin
34. Preparation of standard plot for Aspirin in 0.1N HCl
Table 3 - Calibration curve for Aspirin
21-Apr-18 34
Concentration(µg/ml) Absorbance
0 0
5 0.192
10 0.38
15 0.565
20 0.752
25 0.912
35. Preparation of standard plot for atorvastatin in pH 6.8 phosphate
buffer
Table 4 - Calibration curve for atorvastatin
21-Apr-18 35
Concentration (µg/ml) Absorbance
0 0
5 0.02
10 0.036
15 0.058
20 0.075
25 0.098
36. Compatibility studies by FTIR
21-Apr-18 36
• FT-IR spectrum was used to study the possible interaction between
Aspirin and excipient, Atorvastatin and excipients
• The results of the study indicates FT-IR spectrum of Drug and excipients
did not differed with major peaks of pantoprazole sodium.ie ; all the
major peaks of the drug appeared on the blend indicate that there is no
possible interaction between drug and excipients.
37. 21-Apr-18
37
FTIR spectrum of Aspirin FTIR spectrum of Aspirin, MCC, CCS,SSG, Eudragit S 100
FTIR spectrum of Atorvastatin, MCC, TalcFTIR spectrum of Atorvastatin
40. Weight Variation test
Table 7: Specification for weight variation of tablets as per IP
21-Apr-18 40
Average weight of tablet (mg) % Deviation
125 or less ±10
125-250 ±7.5
250 mg or more ±5
42. S. No Hardness (kg/cm2)
F1 F2 F3 F4
1 6.5 7.0 6.5 6.0
2 7.0 6.5 6.0 6.5
3 7.5 7.0 6.5 7.0
21-Apr-18 42
Table 9: Hardness for Bilayer tablets of Aspirin and Atorvastatin
The hardness of the tablet was determined by
Monsanto hardness tester. It was found in the range
of 6-7 kg/ Cm2. The results were given in table 9. The
batch F3 was showed satisfactory hardness
43. Friability test
Table 10 - Friability study of Tablets
21-Apr-18 43
Batch code Friability (%)
F1 0.56
F2 0.62
F3 0.43
F4 0.48
Friability test was done by Roche
friabilator. Friability of all tablets were in
the acceptable range (<1%). Results
were given in the table 10. The results
showed that all the tablets prepared is in
the acceptable range. The batch F3
showed 0.49% of weight loss
44. Table 11- Drug content estimation of Bilayer tablets of Aspirin and
Atorvastatin
21-Apr-18 44
Batch Code Drug Content of
Atorvastatin layer
(%)
Drug Content of Aspirin layer (%)
F1 76.89 79.25
F2 79.44 81.23
F3 93.27 94.45
F4 84.23 89.48
46. 21-Apr-18 46
The bilayer tablet formulations were prepared and evaluated with an aim of
immediate release of Atorvastatin and Pulsatile release of Aspirin. The compatibility
study of drug and polymer compositions was studies by FT-IR. The IR spectrum of
drug and polymer shown, the major characteristics of absorption bands of excipients
with negligible difference of absorption band values. So, FT-IR spectra shows there is
no change in nature and position of absorption band indicating no chemical reaction
between Aspirin and Atorvastatin Calcium and excipient combinations
A physical combination of the excipients with the aspirin
was probably responsible for the pulsatile release
characteristics of Aspirin. The physical characteristics of
tablets were evaluated such as bulk characterization, angle
of repose, weight variation, hardness and friability
In Atorvastatin immediate release layer F1 formulation
showed that maximum drug was released at 2 hr in 0.1 N
HCl. At the same time, F3 formulation also showing 90%
drug release. In Aspirin Pulsatile release layer, all
formulations showed that limited release in 0.1 N HCl. After
5 hrs, there was a sudden release of drug, Eudragit S 100
maintained a lag time of 5hrs and the drug was released
after 5hrs. The F3 formulation showing maximum drug
release (97%) at 6 hr in pH 6.8 phosphate buffer
DISCUSSION
51. Combined drug therapy (CDT) is favoring for most of the treatment and the goal of the therapy is to decrease
or reduce dose dependent adverse drug reactions and side effects. The present work an attempt to design
bilayer tablets of Atorvastatin immediate release and Aspirin Pulsatile release for the treatment of
cardiovascular diseases. Four formulations were prepared for immediate release layer of atorvastatin using
different concentrations of Microcrystalline cellulose and Talc by direct compression method. For aspirin
pulsatile release layer, the four formulations of core tablets were prepared using Microcrystalline cellulose,
Talc. The different concentrations of Cross carmellose sodium and Sodium starch glycolate were selected as
superdisintegrants in F1, F2 and F3, F4 formulations. Then the core tablets were coated with Eudragit S 100 as
enteric polymer. Physico chemical parameters of bilayer tablets were performed and it has shown a good drug
release profile. The work reveals that F3 formulation was the best formulation and they are the good candidate
for lowering the risk of heart attack. Pattern like one layer of the formulation as immediate release to reduce
the cholesterol level and the second layer to deliver the drug at right time and in right amount, to reduce the
risk of heart attack. However stability studies and further clinical trials are needed to improve the tablet
formulation by quality wise as well as efficacy wise
52. 21-Apr-18 52
BIBLIOGRAPHY
1. S. Mohideen, B. Jyothi [2011], “Formulation and Evaluation of Bilayered Tablets of
Metformin Hydrochloride and Atorvastatin Calcium”, International Journal of
Pharmaceutical Sciences Review and Research, 10(2), page no: 130-134.
2. Mohammad Zameeruddin, Kishor R. Rajmalle [2014], “Formulation and Evaluation of
Immediate Release Tablet Containing Atorvastatin Solid Dispersion”, wjpps, 3(8), page no:
1925-1941.
3. Reshma Fathima K, Sivakumar R [2018], “Design of Pulsatile Tablets of Pantoprazole
Sodium: Factorial Design Approach”, Saudi journal of medical and pharmaceutical sciences,
page no:333-339