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21-Apr-18 1
DESIGNOF DUALRELEASEDRUGDELIVERYSYSTEMOF
ASPIRINANDATORVASTATINFORCARDIOVASCULARDISEASES
In partial fulfillment of the requirement for KUHS for the award of degree of
BACHELOR OF PHARMACY
by
Fathima.M (Reg.No.140090479), Mohamed Ashique.S Reg.No.140090484
Under the guidance of
Asst. Prof. Reshma Fathima.K M.pharm.
GRACE COLLEGE OF PHARMACY,PALAKKAD
April 2018
21-Apr-18 2
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
INTRODUCTION
• Need of combination therapy
• Cardiovascular diseases
• Atorvastatin and aspirin
• Pulsatile delivery system (Chronotherapy)
• Bilayer tablets
21-Apr-18 4
21-Apr-18 5
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.
• 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
 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
• 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
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
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
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.
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.
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)
21-Apr-18 14
• 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
21-Apr-18 15
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
Table 1: Pharmacokinetics Parameters
21-Apr-18 17
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
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
• 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
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
• 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
• 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
21-Apr-18 23
Bioavailability:
80-100%
Cmax:
1.323μg/ml
tmax:
1-3hr
Protein
binding: 80-
90%
Onset time:
5-30minutes
Elimination
half life: 2-
4.5hr
volume of distribution is 0.1–0.2 L/kg.
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
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
MATERIALS ANDMETHODS
 Aspirin and atorvastatin( Yarrow chem products Mumbai)
 MCC (Yarrow chem products Mumbai)
 Crosscarmellose sodium (Yarrow chem products Mumbai)
 Sodium starch glycolate (Yarrow chem products Mumbai)
 Talc(Yarrow chem products Mumbai)
 Eudragit S 100 (Yarrow chem products Mumbai)
 PEG ( Poly ethylene Glycol) (SDFCL Sd fine chem Ltd)
 Titanium dioxide (Prowess Lab chemicals Pallappuram. P.O ottapalam)
21-Apr-18 26
Instruments used
 Rotary punching machine (Rimek, Ahmedabad)
 Disintegration Apparatus (Electrolab, Mumbai)
 Dissolution Apparatus (Electrolab, Mumbai)
 Hardness tester (Monsanto Apparatus)
 Roche Friabilator
 FT-IR (Shimadzu, Japan)
 UV- spectrophotometer (Shimadzu, Japan)
21-Apr-18 27
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
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
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
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
21-Apr-18 32
Photographs of the preparedbilayer tablets
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
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
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
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.
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
Sl.no Ingredients F1(mg) F2(mg) F3(mg) F4(mg)
Immediate release layer
1 Atorvastatin 10 10 10 10
2 Microcrystalline cellulose 138 137 136 135
3 Talc 2 3 4 5
4 Total weight 150 150 150 150
Pulsatile release layer
5 Aspirin 75 75 75 75
6 Microcrystalline cellulose 100 100 100 100
7 Cross carmellose sodium 1.5 2 - -
8 Sodium starch glycolate - - 1.5 2
9 Talc 2 2 2 2
10 Total weight 180 180 180 18021-Apr-18 38
Table: 5 Composition of Immediate release tablets of Atorvastatin Pulsatile release tablets of Aspirin
Table 6 - Precompression parameters of Atorvastatin and aspirin formulation
21-Apr-18 39
S.No Parameters F1 F2 F3 F4
Atorvastatin powder blend
1 Bulk
density(g/cm3)
0.59 0.57 0.58 0.55
2 Tapped
density(g/cm3)
0.68 0.64 0.66 0.64
3 Carrs Index (%) 13.23 10.93 12.12 14.06
4 Hausner’s ratio 1.15 1.12 1.13 1.16
5 Angle of repose 30.13 30.04 27.16 30.35
Aspirin powder blend
1 Bulk
density(g/cm3)
0.57 0.58 0.61 0.62
2 Tapped
density(g/cm3)
0.69 0.66 0.68 0.69
3 Carrs Index (%) 17.3 12.21 10.29 10.14
4 Hausner’s ratio 1.21 1.13 1.11 1.11
5 Angle of repose 31.23 30.54 29.25 31.28
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
Table 8 - Weight Variation data for bilayer tablets
S No Weight Variation(mg)
F1 F2 F3 F4
1 334 335 330 350
2 335 315 325 321
3 337 335 331 328
4 338 330 328 329
5 342 332 334 335
6 332 342 339 342
7 318 345 320 358
8 334 343 320 329
9 319 352 322 322
10 337 339 331 338
Remarks Passes Passes Passes Passes
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
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
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
21-Apr-18 45
S.No Medium Time(hr) % drug release
F1 F2 F3 F4
Atorvastatin immediate release layer
1
0.1N HCl
0 0 0 0 0
2 0.5 24.52 20.52 23.96 17.52
3 1.0 55.91 54.12 49.53 24.82
4 1.5 70.15 68.19 68.29 42.58
5 2.0 92.15 89.29 90.25 72.96
Aspirin Pulsatile release layer
6 0.1N HCl 1 3.9 4.28 4.17 5.28
7 2 4.12 4.56 4.82 6.96
8 6.8 pH
phosphate
buffer
3 4.18 5.20 4.96 7.89
9 4 5.20 5.45 5.14 9.25
10 5 6.12 6.23 5.25 10.45
11 6 72.23 85.25 97.79 92.25
Table 12: Comparative In-Vitro Release of Bilayer Tablets of Aspirin and
Atorvastatin
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
Bilayer tablet of aspirin and
atorvastatin
SUMMARY AND CONCLUSION
Atorvastatin
immediate
release layer
Aspirin pulsatile
layer
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
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
21-Apr-18 53

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Bilayer Tablets of Aspirin and Atorvastatin

  • 2. DESIGNOF DUALRELEASEDRUGDELIVERYSYSTEMOF ASPIRINANDATORVASTATINFORCARDIOVASCULARDISEASES In partial fulfillment of the requirement for KUHS for the award of degree of BACHELOR OF PHARMACY by Fathima.M (Reg.No.140090479), Mohamed Ashique.S Reg.No.140090484 Under the guidance of Asst. Prof. Reshma Fathima.K M.pharm. GRACE COLLEGE OF PHARMACY,PALAKKAD April 2018 21-Apr-18 2
  • 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) 21-Apr-18 14
  • 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 21-Apr-18 15
  • 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 21-Apr-18 17 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
  • 23. 21-Apr-18 23 Bioavailability: 80-100% Cmax: 1.323μg/ml tmax: 1-3hr Protein binding: 80- 90% Onset time: 5-30minutes Elimination half life: 2- 4.5hr volume of distribution is 0.1–0.2 L/kg.
  • 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
  • 26. MATERIALS ANDMETHODS  Aspirin and atorvastatin( Yarrow chem products Mumbai)  MCC (Yarrow chem products Mumbai)  Crosscarmellose sodium (Yarrow chem products Mumbai)  Sodium starch glycolate (Yarrow chem products Mumbai)  Talc(Yarrow chem products Mumbai)  Eudragit S 100 (Yarrow chem products Mumbai)  PEG ( Poly ethylene Glycol) (SDFCL Sd fine chem Ltd)  Titanium dioxide (Prowess Lab chemicals Pallappuram. P.O ottapalam) 21-Apr-18 26
  • 27. Instruments used  Rotary punching machine (Rimek, Ahmedabad)  Disintegration Apparatus (Electrolab, Mumbai)  Dissolution Apparatus (Electrolab, Mumbai)  Hardness tester (Monsanto Apparatus)  Roche Friabilator  FT-IR (Shimadzu, Japan)  UV- spectrophotometer (Shimadzu, Japan) 21-Apr-18 27
  • 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
  • 32. 21-Apr-18 32 Photographs of the preparedbilayer tablets
  • 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
  • 38. Sl.no Ingredients F1(mg) F2(mg) F3(mg) F4(mg) Immediate release layer 1 Atorvastatin 10 10 10 10 2 Microcrystalline cellulose 138 137 136 135 3 Talc 2 3 4 5 4 Total weight 150 150 150 150 Pulsatile release layer 5 Aspirin 75 75 75 75 6 Microcrystalline cellulose 100 100 100 100 7 Cross carmellose sodium 1.5 2 - - 8 Sodium starch glycolate - - 1.5 2 9 Talc 2 2 2 2 10 Total weight 180 180 180 18021-Apr-18 38 Table: 5 Composition of Immediate release tablets of Atorvastatin Pulsatile release tablets of Aspirin
  • 39. Table 6 - Precompression parameters of Atorvastatin and aspirin formulation 21-Apr-18 39 S.No Parameters F1 F2 F3 F4 Atorvastatin powder blend 1 Bulk density(g/cm3) 0.59 0.57 0.58 0.55 2 Tapped density(g/cm3) 0.68 0.64 0.66 0.64 3 Carrs Index (%) 13.23 10.93 12.12 14.06 4 Hausner’s ratio 1.15 1.12 1.13 1.16 5 Angle of repose 30.13 30.04 27.16 30.35 Aspirin powder blend 1 Bulk density(g/cm3) 0.57 0.58 0.61 0.62 2 Tapped density(g/cm3) 0.69 0.66 0.68 0.69 3 Carrs Index (%) 17.3 12.21 10.29 10.14 4 Hausner’s ratio 1.21 1.13 1.11 1.11 5 Angle of repose 31.23 30.54 29.25 31.28
  • 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
  • 41. Table 8 - Weight Variation data for bilayer tablets S No Weight Variation(mg) F1 F2 F3 F4 1 334 335 330 350 2 335 315 325 321 3 337 335 331 328 4 338 330 328 329 5 342 332 334 335 6 332 342 339 342 7 318 345 320 358 8 334 343 320 329 9 319 352 322 322 10 337 339 331 338 Remarks Passes Passes Passes Passes
  • 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
  • 45. 21-Apr-18 45 S.No Medium Time(hr) % drug release F1 F2 F3 F4 Atorvastatin immediate release layer 1 0.1N HCl 0 0 0 0 0 2 0.5 24.52 20.52 23.96 17.52 3 1.0 55.91 54.12 49.53 24.82 4 1.5 70.15 68.19 68.29 42.58 5 2.0 92.15 89.29 90.25 72.96 Aspirin Pulsatile release layer 6 0.1N HCl 1 3.9 4.28 4.17 5.28 7 2 4.12 4.56 4.82 6.96 8 6.8 pH phosphate buffer 3 4.18 5.20 4.96 7.89 9 4 5.20 5.45 5.14 9.25 10 5 6.12 6.23 5.25 10.45 11 6 72.23 85.25 97.79 92.25 Table 12: Comparative In-Vitro Release of Bilayer Tablets of Aspirin and Atorvastatin
  • 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
  • 47. Bilayer tablet of aspirin and atorvastatin SUMMARY AND CONCLUSION
  • 48.
  • 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