2. R.G.R. SIDDHANTHI COLLEGE OF PHARMACY
Under the guidance of
Ms. KOUSAR BEGUM
M.PHARM
PRESENTED BY
C. ADITYA
(13Y41R0014)
3.
4. ORAL CONTROLLED DRUG DELIVERY
SYSTEM
Oral route has been most popular & successfully used
route for controlled delivery of drugs.
Convenience & ease of administration.
Greater flexibility in dosage form design.
Ease of production & low cost of such a system.
5. An oral CDDS can be designed as:
• CONTINUOS RELEASE SYSTEM– It releases
drug continuously over an extended period of time.
• PULSATILE RELEASE SYSTEM– It is
characterized by a time period of no release followed
by a rapid & complete or extended drug release.
6. GASTRO RETENTIVE DRUG DELIVERY
SYSTEM
Gastro retentive drug delivery system
(GRDDS) is a site specific delivery system.
It delivers the drug either in stomach or in
intestine.
The drug delivery is obtained by retention of
dosage form in stomach and the drug is released
in a controlled manner to the specific site either
in stomach, duodenum or in intestine.
9. FLOATING DRUG DELIVERY
SYSTEM
Floating drug delivery systems (FDDS) or hydro
dynamically controlled systems are low-density
systems that have sufficient buoyancy to float over
the gastric contents and remain buoyant in the
stomach without affecting the gastric emptying rate
for a prolonged period of time. While the system is
floating on the gastric contents, the drug is
released slowly at the desired rate from the
system. After release of drug, the residual system
is emptied from the stomach. This results in an
increased GRT and a better control of the
fluctuations in plasma drug concentration.
10. TYPES OF FDDS
I) Non-Effervescent FDDS
Single Layer Floating Tablets
Bi-layer Floating Tablets
Alginate Beads
Hollow Microspheres
ii) Effervescent FDDS
Volatile liquid containing system
Gas-generating Systems
13. PULSATILE DRUG DELIVERY SYSTEM
Oral controlled drug delivery systems represent the
most popular form of controlled drug delivery
systems for the obvious advantages of oral route of
drug administration. Such systems release the drug
with constant or variable release rates. These
dosage forms offer many advantages, such as
nearly constant drug level at the site of action,
prevention of peak-valley fluctuations, reduction in
dose of drug, reduced dosage frequency, avoidance
of side effects, and improved patient compliance.
However, there are certain conditions for which
such a release pattern is not suitable.
14. In this context, the aim of the research was to achieve a so-
called sigmoidal release pattern (pattern A in Figure).The
characteristic feature of the formulation was a defined lag
time followed by a drug pulse with the enclosed active
quantity being released at once. Thus, the major challenge in
the development of pulsatile drug delivery system is to
achieve a rapid drug release after the lag time. Often, the drug
is released over an extended period of time (patterns B & C
in Figure)
Drug release profile of pulsatile
delivery system
15. METHODS OF PULSATILE DRUG DELIVERY
SINGLE UNIT SYSTEMS
CAPSULAR SYSTEM: Single unit systems
are mostly developed in capsule form. The lag
time is continued by a plug, which gets pushed
away by swelling or erosion, and the drug is
released as a pulse from the Insoluble capsule
body. e.g.: Pulsincap system.
MULTIPLE UNIT SYSTEMS
e.g.: Pellets.
17. NECESSITIES OF PULSATILE
DRUG DELIVERY SYSTEMS
First pass metabolism
Biological tolerance
Special chrono pharmacological needs
Local therapeutic need
Gastric irritation or drug instability in gastric fluid
18. Merits
• Predictable, reproducible and short gastric
residence time
• Less inter- and intra-subject variability
• Improve bioavailability
• Limited risk of local irritation
• No risk of dose dumping
• Flexibility in design
• Improve stability
19. Demerits
• Lack of manufacturing reproducibility and efficacy
• Large number of process variables
• Batch manufacturing process
20. FLOATING PULSATILE DRUG
DELIVERY SYSTEM
Floating approach has been used for gastric
retention of pulsatile dosage form.
Floating-pulsatile concept was applied to increase
the gastric residence of the dosage form.
A combination of floating and pulsatile principles of
drug delivery system would have the advantage that
a drug can be released in upper GI tract after a
defined time period of no drug release.
21. Advantages
Retention of drug delivery system in stomach
prolongs overall.
Acidic substance like aspirin cause irritation on
the stomach wall when come into contact with
it hence floating pulsatile formulation may be
useful for administration of aspirin and other
similar drugs.
It has application also local drug delivery to the
stomach and proximal small intestine e.g.,
ranitidine for nocturnal acid breakthrough.
No risk of dose dumping.
22. Disadvantages
Drug which are irritant to gastric mucosa is also
not desirable or suitable.
The dosage form should be administered with
full glass of water(200-250ml).
Manufacturing this type of dosage form
requires multiple formulation steps, higher cost
of production, need of advance technology,and
trained or skilled personnel needed form
manufacturing.
24. TYPES
Time Controlling Floating Pulsatile Drug
Delivery
Reservoir System with Eroding Polymer or
Soluble Barrier Coating
Reservoir systems with ruputurable coating
Capsule shape system provided with release
controlling plug
Release controlling plug
Multi particulate drug delivery system
25. DESIGN OF FLOATING PULSATILE DRUG
DELIVERY SYSTEM
The purpose of designing by which the drug is
released from dosage form depends on the type of
coating;
insoluble coating under all physiological
conditions,
pH-dependent coating whose solubility changes
dramatically at some point in GI tract,
slowly erodible coating.
The method of application and processing
conditions may influence the porosity of the
coating and consequently the release mechanism.
28. AIM:
To formulate and evaluate the Dofetilide controlled
release tablets for pulsatile drug delivery system by using
various grades of HPMC Polymers.
OBJECTIVES:
To study the effect of Drug polymer ratio or concentration of
polymer on drug release.
To study the effect of Sodium bicarbonate on floating lag
time and on drug release.
To study the effect of polymer, polymer grades on the
parameters like duration of buoyancy and drug release.
To study the effect of hardness on floating lag time.
29.
30. To determine the kinetics and mechanism of drug release.
To determine the in-vitro drug release studies.
To compare the different grades of HPMC Polymers with
Dofetilide.
To achieve the above objectives the experimental work was
framed as below.
Formulation of floating core tablets of Dofetilide.
Formulation of Dofetilide effervescent floating tablets with
HPMC K 4 M, HPMC K 15 M, HPMC K 100 M.
Formulation of Dofetilide effervescent floating tablets using
of combination of polymers i.e., eudragit s100, eudragit l100.
Determination of effect of sodium bicarbonate concentration
on floating lag time and drug release.
31. Evaluation of effervescent floating core tablets of
Dofetilide.
Construction of calibration curve of Dofetilide in 0.1 N
HCl.
To evaluate prepared formulations for floating lag time
and total floating time.
To evaluate prepared core tablets for various physical
parameters like Weight variation, Thickness, Hardness
& Friability.
To determine content uniformity of effervescent
floating tablets.
To carry out swelling studies of the formulations.
Determination of in vitro drug release from the
formulations in 0.1 HCl for 10 hours.
32. In vitro release data was fitted into various kinetic models
for suggesting the suitable mechanism of drug release.
Selection of the best batch of tablets based on the in-vitro
release data.(optimized formulations-Coating of the
optimized formulations of core floating tablets of Dofetilide
with polymer solution.
Selection of the best batch of tablets based on the in-vitro
release data.
To determine content uniformity of effervescent floating
tablets.
To carry out swelling studies of the formulations.
Determination of in vitro drug release from the formulations
in 0.1 HCl for 10 hours.
In vitro release data was fitted into various kinetic models
for suggesting the suitable mechanism of drug release
33. Selection of the best batch of tablets based on the in-vitro
release data.(optimized formulations-Coating of the
optimized formulations of core floating tablets of
Dofetilide with polymer solution.
Selection of the best batch of tablets based on the in-vitro
release data.
34.
35. Naqash J.Sethi et.al.,2017
Atrial fibrillation is the most common arrhythmia of
the heart with a prevalence of approximately 2% in the
western world. Atrial flutter, another arrhythmia,
occurs less often with an incidence of approximately
200,000 new patients per year in the USA. Patients
with atrial fibrillation and atrial flutter have an
increased risk of death and morbidities. The
management of atrial fibrillation and atrial flutter is
often based on interventions aiming at either a rhythm
control strategy or a rate control strategy. The evidence
on the comparable effects of these strategies is unclear.
This protocol for a systematic review aims at
identifying the best overall treatment strategy for atrial
fibrillation and atrial flutter.
36. Crassandra maynard et.al.,2016
The Side Effects of Drugs Annuals form a series of
volumes in which the adverse effects of drugs and
relevant related material are surveyed. Relevant
material may include hypersensitivity reactions,
interactions and pertinent pharmacogenomic aspects.
The series supplements the contents of Meyler's Side
Effects of Drugs: The International Encyclopedia of
Adverse Drug Reactions and Interactions. This is a
review of the literature published from January 2015
to December 2015 on adverse reactions to positive
inotropic drugs and drugs used in dysrhythmias
covering cardiac glycosides, amiodarone, dofetilide,
dronedarone, and flecainide.
37. Mary H. Parker et.al.,2015
A role for oral antiarrhythmic drugs (AADs) remains in
clinical practice for patients with atrial and ventricular
arrhythmias in spite of advances in nonpharmacologic
therapy. Pharmacists play a vital role in the appropriate
use of AAD dosing, administration, adverse effects,
interactions, and monitoring. Pharmacists who are
involved in providing care to patients with cardiac
arrhythmias must remain updated regarding the efficacy
and safety of the most commonly used AADs. This
review will address key issues for appropriate initiation
and maintenance of commonly selected Vaughan-
Williams Class Ic and III agents in the outpatient
setting.
38. Giuseppe Stabile et.al.,2014
Antiarrhythmic drugs (AADs) are often used after ablation
for atrial fibrillation (AF); the drugs employed vary, but most
common are the drugs that were unsuccessful prior to
ablation since it seems that the efficacy of AADs might
substantially increase after catheter ablation of AF. AADs
reduce early recurrences of atrial tachyarrhythmias after AF
catheter ablation, whereas they did not prevent arrhythmia
recurrences occurring later. Several upstream therapies
(angiotensin-converting enzyme inhibitors, angiotensin
receptor blockers, statins, corticosteroids and colchicine)
have been tested with conflicting results. To date, there is no
sufficient evidence to support the use of any upstream
therapy after AF catheter ablation. Larger registries and
controlled clinical trials in well-defined patient groups and
with well-defined outcome parameters are required to further
elucidate the role of AADs after AF ablation.
39. UPENDRA C. GALGATTE et.al.,2013
In chronopharmacotherapy, drug administration is
synchronized with circadian rhythms. The present study was
based on objective whether drug delivery would provide a
maximum drug release approximately in 6 h after taken orally
at bedtime. Methods: The strategy adopted for tablet
formulation include preparation of core tablet by direct
compression containing drug, ranitidine hydrochloride (RH),
which was coated with ethyl cellulose (EC N10) and
hydroxypropyl methylcellulose (HPMC E15) followed by
coating of HPMC E15 and sodium bicarbonate for generation
of effervescence which was further coated by eudragit RL 100
for effervescence entrapment to produce density
40.
41. INTRODUCTION
TO
PULSATILE DRUG
DELIVERY SYSTEM
COLLECTION OF DRUG AND
EXCIPIENTS
COLLECTION OF
MATERIAL
LITERATURE
REVIEW
COLLECTION OF EQUIPMENT
PREFORMULATION
STUDIES
EVALUATION
PREPARATION OF
EFFERVESCENT
DOFETILIDE TABLETS
T
RESULTS
DISCUSSION
42.
43. DRUG PROFILE
Drug Name : DOFETILIDE
IUPAC Name : N-[4-(2 {[2(4methanesulfonamidophenyl)
- ethyl](methyl) amino} ethoxy )
phenyl]methanesulfonamide
Synonyms : Tikosyn, Dofetilidum, Dofetilide, Dofetilida.
Solubility : It is very slightly soluble in water and propan-
2-ol and is soluble in 0.1M aqueous sodium
hydroxide, acetone, and aqueous 0.1M
hydrochloric acid.
45. Pharmaco dynamics:Dofetilide is an antiarrhythmic
drug with Class III (cardiac action potential duration
prolonging) properties and is indicated for the
maintenance of normal sinus rhythm. Dofetilide
increases the monophasic action potential duration in a
predictable, concentration-dependent manner, primarily
due to delayed repolarization.
Mechanism of action: The mechanism of action of
Dofetilide is a blockade of the cardiac ion channel
carrying the rapid component of the delayed rectifier
potassium current, IKr. This inhibition of potassium
channels results in a prolongation of action potential
duration.
46. Adverse Effects: Dizziness, headache, symptoms of
respiratory tract infection (eg, cough, mild fever,
sneezing, sore throat), Severe allergic reactions (rash;
hives; itching; difficulty breathing; tightness in the chest;
swelling of the mouth, face, lips, throat, or tongue;
unusual hoarseness)
Clinical use: In the suppression of atrial fibrillation in
individuals with LV dysfunction, It has clinical
advantages over other class III antiarrythmics in
chemical cardioversion of atrial fibrillation, and
maintenance of sinus rhythm
Storage: It is stored at room temperature, between 59
and 86 degrees F (15 and 30 degrees C). Store away
from heat, moisture, and light.
49. Name of the material Source
Dofetilide AURABINDO PHARMA PVT LTD
HPMC K4 M Merck Specialities Pvt Ltd, Mumbai, India
HPMC K15 M Merck Specialities Pvt Ltd, Mumbai, India
HPMC K 100 M Merck Specialities Pvt Ltd, Mumbai, India
Sodium bicarbonate Merck Specialities Pvt Ltd, Mumbai, India
Magnesium stearate Merck Specialities Pvt Ltd, Mumbai, India
Micro crystalline cellulose Merck Specialities Pvt Ltd, Mumbai, India
Talc Merck Specialities Pvt Ltd, Mumbai, India
MATERIALS
50. EQUIPMENT
Name of the Equipment Manufacturer
Weighing Balance Wensar
Tablet Compression Machine
(Multistation)
Karnavati.
Hardness tester Monsanto hardness tester
Vernier callipers Mitutoyo, Japan.
Roche Friabilator Labindia, Mumbai, India
Dissolution Apparatus Labindia, Mumbai, India
UV-Visible Spectrophotometer Labindia, Mumbai, India
pH meter Labindia, Mumbai, India
FT-IR Spectrophotometer
Per kin Elmer, United States of
America.
51.
52. Analytical method development:
a) Determination of absorption maxima:
b) Preparation calibration curve
Drug – Excipient compatibility studies:
a) Fourier Transform Infrared (FTIR) spectroscopy
b) Pre-formulation parameters
53. Angle of repose:
Tan θ = h / r
Tan θ = Angle of repose,
h = Height of the cone,
r = Radius of the cone base
Angle of Repose Nature of Flow
<25 Excellent
25-30 Good
30-40 Passable
>40 Very poor
Angle of Repose values (as per USP)
54. Bulk density:
Bulk Density = M / Vo
Where, M = weight of sample
Vo = apparent volume of powder
Tapped density:
Tap= M / V
Where, Tap= Tapped Density
M = Weight of sample
V= Tapped volume of powder
55. Measures of powder compressibility:
Carr’s Index = [(tap - b) / tap] × 100
Where, b = Bulk Density
Tap = Tapped Density
Carr’s index Properties
5 – 15 Excellent
12 – 16 Good
18 – 21 Fair to Passable
2 – 35 Poor
33 – 38 Very Poor
>40 Very Very Poor
Carr’s index value (as per USP)
56. Formulation development of Tablets
Procedure:
Dofetilide and all other ingredients were
individually passed through sieve no #60.
All the ingredients were mixed thoroughly by
triturating up to 15 min.
The powder mixture was lubricated with talc.
The tablets were prepared by using direct
compression method.
58. Evaluation of post compression
parameters for prepared Tablets
Weight variation test:
% Deviation = (Individual weight – Average weight / Average weight) × 100
Average weight of tablet
(mg) (I.P)
Average weight of tablet
(mg) (U.S.P)
Maximum percentage
difference allowed
Less than 80 Less than 130 10
80-250 130-324 7.5
More than More than 324 5
Pharmacopoeial specifications for tablet weight variation
59. Hardness:
Thickness:
Friability:
% Friability = [ ( W1-W2) / W] × 100
Where, W1 = Initial weight of three tablets
W2 = Weight of the three tablets after testing
60. Determination of drug content:
In-vitro Buoyancy studies: The in vitro
buoyancy was determined by floating lag time, and
total floating time. (As per the method described by
Rosa et al) The tablets were placed in a 100ml
beaker containing 0.1N HCl. The time required for
the tablet to rise to the surface and float was
determined as floating lag time (FLT) and duration
of time the tablet constantly floats on the
dissolution medium was noted as Total Floating
Time respectively (TFT).
61. In-vitro drug release studies:
Dissolution parameters:
Apparatus -- USP-II,
Paddle Method
Dissolution Medium -- 0.1 N HCl
RPM -- 75
Sampling intervals (hrs) --
0.5,1,2,3,4,5,6,7,8,10,11,12
Temperature -- 37°c + 0.5°c
62. Application of Release Rate Kinetics
To Dissolution Data
Zero order release rate kinetics: To study the zero–
order release kinetics the release rate data ar e fitted
to the following equation.
F = Ko t
Where, ‘F’ is the drug release at time‘t’, and ‘Ko’ is
the zero order release rate constant. The plot of %
drug release versus time is linear.
63. First order release rate kinetics: The release rate data
are fitted to the following equation
Log (100-F) = kt
A plot of log cumulative percent of drug remaining to be
released vs. time is plotted then it gives first order
release.
64. Higuchi release model: To study the Higuchi
release kinetics, the release rate data were fitted to
the following equation.
F = k t1/2
Where, ‘k’ is the Higuchi constant.
Hixson-Crowell release model:
(100-Qt)1/3= 1001/3– KHC.t
Where, k is the Hixson-Crowell rate constant.
65.
66. Analytical Method Concentration
[µg/ml]
Absorption
0 0
2 0.172
4 0.310
6 0.438
8 0.563
10 0.719
Observations for graph of Dofetilide in 0.1N HCl (271 nm)
y = 0.0699x + 0.0173
R² = 0.9974
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0 5 10 15
Abs
Abs
Linear (Abs)
Standard graph of Dofetilide in 0.1N HCl
77. In the present research work gastro retentive floating matrix
formulation of formulation by using various hydrophilic
polymers.
Initially analytical method development was done for the
drug molecule. Absorption maxima was determined based on
that calibration curve was developed by using different
concentrations.
Gas generating agent sodium bicarbonate concentration was
optimized. Then the formulation was developed by using
different concentrations of polymers of various grades of
HPMC.
The formulation blend was subjected to various pre
formualation studies, flow properties and all the formulations
were found to be good indicating that the powder blend has
good flow properties.
78. Among all the formulations the formulations prepared by
using HPMC K 4 M and HPMC K 100 M were unable to
produce desired drug release, they were unable to retard
drug release up to 12 hours.
The formulations prepared with HPMC K 15 M retarded
the drug release up to 12 hours in the concentration of 75
mg (F3). Hence they were not considered.
The optimized formulation dissolution data was subjected
to release kinetics, from the release kinetics data it was
evident that the formulation followed First order
mechanism of drug release.
