Formulation and Evaluation of Chrono Modulated Pulsatile Drug Delivery System of Doxofylline

1. FORMULATIONAND EVALUATION OF CHRONOMODULATED
PULSATILEDRUG DELIVERY SYSTEMOF DOXOFYLLINE
UNDER THE GUIDENCE OF:
Mrs.G.SREE LAKSHMI, M.Pharm
PRESENTED BY:
J.AKHIL RAJA (13AD1R0021)

2. CONTENTS
INTRODUCTION
NECESSITIES & ADVANTAGES
Pathophysiology of asthma
Drug profile
Aim & objectives
PLAN OF WORK
literATURE REVIEW
METHODOLOGY
Evaluation parameters
RESULTS &DISCUSSIONS
CONCLUSION
REFERENCES

3. INTRODUCTION TO PULSATILE DRUG DELIVERY SYSTEM
 It is defined as the rapid and transient release of drug
molecules within a short time-period immediately after a
predetermined off-release period.
 these are developed to deliver drug according to circadian
behavior of diseases.
 Intelligent drug delivery system capable of adjusting drug
release rates in response to a physiological need.
 Ecofriendly.

4. NECESSITY OF PULSATILE DRUG DELIVERY SYSTEM
 Protection from gastric environment.
 First-pass metabolism can be overcome.
 Biological tolerance.
 Local therapeutic need.
 Special chronopharmacological needs

5. ADVANTAGES OF formulated drug in PDDS
 Drug targeting to specific site.
 Drug loss is prevented by extensive first pass
metabolism.
 Improved bioavailability, stability, patient comfort.
 Extended day time or night time activity.
 Reduces dose of drug without decrease in therapeutic
activity.
 Lower daily cost to patient due to fewer dosage units
are required by the patient in therapy.
 Limited risk of local irritation.

6. LIMITATIONS
 Trained/skilled personal needed for manufacturing.
 Multiple manufacturing steps and large number of
process variables.
 Incomplete release.
 In-vivo variability in single unit PDDS.

7. Pathophysiology of asthma
o It is a common pulmonary condition defined by chronic
inflammation of respiratory tubes, inflamed airways react to
environmental triggers such as smoke, dust, or pollen. The
airways narrow and produce excess mucus, making it difficult
to breath.

8. The timing of human biological rhythms is synchronized to the rotation of the Earth, and is
influenced by numerous external and internal time cues. These stimuli are known as 'zeitgebers'
(German for 'time giver'). Light is the most important and potent zeitgeber.

9. IUPAC Name: 7-(1, 3-Dioxolan -2-ylmethyl)-1,3-dimethylpurine-2,6-
dione
Chemical Formula: C11H14N 4O4
Molecular weight: 266.25 g/mol
CLINICAL PHARMACOLOGY:
Mechanism of Action: Unrelated to HDAC inhibition, PDE inhibition
or adenosine receptor antagonism.
Pharmacodynamics: Doxofylline is a theophylline derivative. Similarly,
its mechanism of action is related to the inhibition of phosphodiesterase
activities, resulting in bronchodilating effects.
Pharmacokinetics:
Absorption: 62.6%
Protein binding: 48%
Metabolism: Hepatic
Half life: 1.8 hrs
Route of elimination: Renal
Uses: It has anti tussive and bronchodilator effects, and acts as
a phosphodiesterase inhibitor. It is used in the treatment of asthma.

10. AIM&OBJECTIVES
Aim:
 This study attempts to formulate and evaluate a time controlled
Chrono modulated drug delivery system of Doxofylline for the
treatment of asthma. It was aimed to have a lag time of six hours i.e.,
the system is taken at the bed time and expected to release the drug
after a period of six hr when the asthma attacks are more prevalent.
 The ultimate aim of this proposal is to design a new
chronotherapeutic system for Doxofylline with high potential
benefits in treating nocturnal asthma. Chrono modulated delivery can
be achieved mainly with drug containing cores, which are covered
with release controlling layers. The core serves as reservoir, and the
release controlling layers protect the core from the environment e.g.,
water, acidic pH, and enzymes until the drug is released after a
predetermined lag phase. The coatings can erode/dissolve, rupture or
alter their permeability at the required time.

11. Objectives:
 Following specific objectives are proposed:
 Step-1: To design and fabricate using suitable technology.
 Step-2: To develop suitable analytical method for the estimation
of the drug.
 Step-3: To evaluate all the excipients for compatibility study.
 Step-4: To evaluate the powder mix for precompression
characteristic and tableting characteristics.
 Step-5: To compress the formulation according to compatibility
study.
 Step-6: To evaluate post compression parameters like thickness,
hardness, friability, weight variation and content uniformity etc.
 Step-7: Optimization of formulation parameters using
appropriate methods

12. PLAN OF WORK
 Literature survey
 Selection of materials &
methodology
 Pre-formulation studies on
Doxofylline
 Calibration Curve development
Preformulation studies
 Bulk density
 Tapped density
 Carr’s Index/compressibility
index
 Hausner ratio
Formulation development
1. Product Development
2. Evaluation of Doxofylline
tablets
 Thickness
 Hardness of the tablet
 Weight variation
 Friability
 Drug content uniformity
(Assay)
 In vitro release studies
(Dissolution)
 Accelerated stability studies
Results and Discussion
Summary and Conclusion

13. LITERATURE REVIEW
Chetan . R et al., Pulsatile Drug Delivery Systems are gaining a lot of
interest as they deliver the drug at the right place at the right time and in
the right amount, thus providing spatial and temporal delivery and
increasing patient compliance. These systems are designed according to
the circadian rhythm of the body. The principle rationale for the use of
pulsatile release of the drugs is where a constant drug release is not
desired. A pulse has to be designed in such a way that a complete and
rapid drug release is achieved after the lag time. Various systems like
capsular systems, osmotic systems, single- and multiple-unit systems
based on the use of soluble or erodible polymer coating and use of
rupturable membranes have been dealt with in the article. It summarizes
the latest technological developments, formulation parameters, and
release profiles of these systems. These systems are beneficial for the
drugs having chronopharmacological behavior where night time dosing
is required, such as anti-arrhythmic and anti-asthmatic. Current review
article discussed the reasons for development of pulsatile drug delivery
system, types of the disease in which pulsatile release is required,
classification, advantages, limitation, and future aspects of pulsatile drug
delivery system.

14. Sumit Patil et. al ., The objective of this study was to develop and
evaluate a press-coated pulsatile drug delivery system intended for
treatment of early morning stiffness and symptomatic relief from pain in
patients with rheumatoid arthritis. The formulation involved press
coating of a rupturable coat around a rapidly disintegrating core tablet of
aceclofenac. A three-factor, two-level, full factorial design was used to
investigate the influence of amount of glyceryl behenate, amount of
sodium chloride in the coating composition, and the coating level on the
responses, ie, lag time to release and amount of aceclofenac released in
450 minutes.
Anamika Singh et. al ., Pulsatile drug delivery systems are developed to
deliver drug according to circadian behavior of diseases. This means that
these systems will deliver drug at time when disease display it’s most
morbid and mortal state within a circadian cycle (24 hrs.). The product
follow a sigmoidal drug release profile characterized by a time period of
no release (lag time) followed by a rapid and complete drug release.

15. Devdhawala Mehul G et al ., Chrono therapeutics drug delivery system
is useful in the treatment of disease, in which drug availability is timed to
match rhythms of disease, in order to optimize therapeutic effect and
minimize side effects. The specific time that patients take their
medication is very important as it has significant impact on success of
treatment. If symptoms of a disease display circadian variation, drug
release should also vary over time.
Mayur Desai et. al ., A tablet system consisting of cores coated with two
layers of swelling and rupturable coatings was prepared and evaluated as
time controlled chronomodulated tablet. Cores containing Montelukast
sodium as model drug were prepared by direct compression and then
coated sequentially with an inner swelling layer containing a HPMC E 5
and an outer rupturable layer of Eudragit RL/RS (1:1). A three-factor,
two-level, full factorial design was used to investigate the influence of
amount of HPMC E 5 and Eudragit RL/RS (1:1) on the responses, i.e.,
lag time to release and time required for 80% of drug to releases. The
dissolution tests were studied using the USP paddle method at 50 rpm in
0.1 N HCL for 2 hr and than in phosphate buffer pH 6.8. The results
obtain from present study suggest that swelling come reputable coating
approach gives desire drug release after lag time.

16. S.NO INGREDIANTS D1 D2 D3 D4 D5
1 DOXOFYLLINE(DRUG) 10mg 10mg 10mg 10mg 10mg
2 MAGNESIUM STEARATE(LUBRICANT) 2mg 2mg 2mg 2mg 2mg
3 EUDRAGIT(POLYMER) 50mg - 25
mg
- -
4 SODIUM ALGINATE(POLYMER) - 50mg - - -
5 HPMC(POLYMER) - - 25mg
50mg
-
6 XANTHANE GUM(POLYMER) - - - -
50mg
8 SODIUM STARCH
GLYCOLATE(DISINTEGTANT)
2mg 2mg 2mg 2mg 2mg
9 MCC(BINDER) 33mg 33mg 33mg 33mg 33mg
10 PVP(FILLER) 1mg 1mg 1mg 1mg 1mg
11 TALC (GLIDANT) 2mg 2mg 2mg 2mg 2mg
LISTS OF QUANTITIES OF INGREDIANTS

17. METHODOLOGY
preparation of core tablet
Mix the weighed quantities of sodium starch glycolate, pvp, mcc
sieve through mesh 44
add drug + lubricant + glidant and mix thoroughly
Punch it by passing it through punching machine which possess
6mm dye

18. FORMULATION OF COATED TABLETS
Fill half of the dye cavity with polymer
Place core tablet
Fill the remaining cavity with polymer
Compress it

19. EVALUATION PARAMETERS
PRE compression PARAMETERS
A) BULK DENSITY
Bulk density = weight of sample taken /volume noted
B) TAPPED DENSITY
Tapped density = W/Vf
C) COMPRESSIBILITY INDEX
tapped density – bulk density
Compressibility Index = ----------------------------- . 100
tapped density
D) HAUSNER RATIO
tapped density
Hausner ratio = -----------------------
bulk density

20. E) ANGLE OF REPOSE
Angle of repose = tan = h/r
 = tan-1 h/r
Where
• h = height of pile
• r = radius of the base of the pile
•  = angle of repose

21. POST COMPRESSION PARAMETERS
A) WEIGHT VARIATION TEST
average.wt – individual.wt
Weight variation= ------------------------------ ---- .100
average.wt
B)
B) THICKNESS
Twenty tablets were randomly selected form each batch and there thickness wa
measured by using vernier caliper. Thickness of three tablets from each batch
was measured and mean was calculated.
Percentage deviation allowed under weight variation test
Average weight of tablet (X mg) Percentage deviation allowed
130 mg or less
130mg to 324 mg
more than 324 mg
10%
7.5%
5%

22. C) HARDNESS
Hardness indicates the ability of a tablet to withstand mechanical
shocks while handling. The hardness of the tablets was
determined using Monsanto hardness tester. It is expressed in
kg/cm. Three tablets were randomly picked and hardness of the
tablets were determined.
D) FRIABILITY
% F = {1-(Wo/W)} ×100
Where,
• % F = friability in percentage
• Wo = Initial weight of tablet
• W = weight of tablets after revolution
(Range not more then 1%)

23. E) CONTENT UNIFORMITY
Twenty tablets from each batch were powdered and weighed accurately
equivalent to 100 mg Doxofylline. Dissolve the weighed quantity of
powder into 100 ml of 0.1 N NaOH solution by stirring it for 15 min. 1
ml of solution was pipette out into 10 ml volumetric flask and make up
the volume with distilled water. Immediately analyze the drug by taking
absorbance at nm using reagent blank.
F) IN-VITRO DRUG RELEASE STUDIES
In-Vitro drug release studies were carried out using Tablet dissolution test
apparatus USP II at 50 rpm. The dissolution medium consisted of 900 ml
of Standard buffer pH 6.8 period of time. Temperature maintained at
375.The sample of 5ml was withdrawn at predetermined time intervals
and an equivalent amount of fresh dissolution fluid equilibrated at the
same temperature was replaced. From that 5 ml sample, 1 ml sample was
withdrawn and placed in a 10 ml volumetric flask, and make the volume
with buffer . The diluted samples were assayed at nm against reagent
blank.

24. G) STABILITY STUDIES
 Stability of pharmaceutical product may be defined as the capability
of a particular formulation in a specific container/closure system to
remain within its physical, chemical, microbiological therapeutic and
toxicological specification.
 These stability data involves selected parameters that taken together
from the stability profile. Pharmaceutical products are expected to
meet their specification for identifying purity, quality and strength
throughout their defined storage period at specific storage condition
The success of an effective formulation can be evaluated only through
stability studies. The purpose of stability testing is to obtain a stable
product which assures its safety and efficacy up to the end of shelf life at
defined storage conditions and peak profile. The prepared Matrix tablets
of Doxofylline swere placed on plastic tubes containing desiccant and
stored at ambient conditions, such as at room temperature, 40±2oc and
refrigerator 2-8oc for a period of 30 days.

25. RESULTS & DISCUSSIONS
S.
no
Bulk
density
Tapped
density
Compressibility
index
Hausner
ratio
ANGLE OF
REPOSE(0)
F1 0.497 0.637 16.97 1.231 29.70
F2 0.503 0.642 16.65 1.236 29.22
F3 0.501 0.638 15.47 1.243 30.70
F4 0.497 0.642 15.58 1.241 30.10
F5 0.520 0.632 17.72 1.215 31.2
Characterization of Formulation

26. Each value represents the mean ± standard deviation
(n = 3)
S. No Weight
variation
(mg)*
Thickness
(mm)*
Hardness
(kg/cm2)*
Friability
(%)
Drug
content
(%)
F1 203 2.73 2.45 0.04 6.72 0.27 0.54 96.82
F2 204 2.31 2.42 0.05 6.75 0.28 0.53 98.41
F3 203 2.55 2.45 0.08 6.93 0.28 0.55 98.76
F4 205 1.77 2.52 0.06 6.72 0.23 0.59 97.20
F5 202 1.58 2.55 0.04 6.64 0.14 0.61 97.74

27. Dissolution Profile of batch no. F1 to F5
S. NO Time in hours (cumulative % drug release)
1 2 3 4 5 6 7 8
F1 12.79 29.43 43.63 57.56 65.23 78.64 87.40 96.65
F2 17.53 31.60 40.14 51.17 63.20 71.85 82.51 95.67
F3 19.53 27.32 36.69 50.72 69.50 76.61 88.68 97.21
F4 12.08 25.61 31.47 42.30 49.13 55.74 62.54 68.56
F5 33.02 52.22 66.52 74.17 85.92 94.04 95.5 96.0

28. SUMMARY AND CONCLUSION
In this study pulsatile tablets were prepared, which consist of two parts,
the core tablet and its outer polymeric part. Core tablets of Doxofylline
were formulated by conducting different trials using ingridients
mentioned in the formulated table. . The trial F3 was optimized which
contains sodium starch glycolate 4mg as super disintegrant, because as
it shows lower disintegration time and good dissolution profile. Core
tablets were press coated using various polymers like HPMC K15M,
Eudragit L 100 and Eudragit S 100. Remaining 4 formulations coated
by different polymers. Among all these F3 shows better results so F3 is
optimized according to results obtained. Due to presence of
combination of polymers it provided the lag time of about 5hours
which may be due to the pH dependent nature of the polymers which
predominantly ruptures at higher pH. A drug delivery system with a lag
time of around 5 hours and pulsatile properties was successfully
developed.

29. The aim of the study was to develop a pulsatile drug delivery system of
Doxofylline for the management of Asthma. The Chrono therapeutic
drug delivery system of doxofylline was prepared which provided
desired lag time thus it can be taken at bedtime such that the drug will be
released in the morning hours i.e. at the time of symptoms and useful for
chronopharmaceutics of Asthma.
The results indicated that amount of polymer in the formulation affects
the drug release rate. The drug release was high-pitched and full after
the lag time, which is mandatory for a pulsatile drug delivery system.
Thus, the formulated pulsatile tablets will deliver the drug permitting to
the need of the patient so as to give the highest therapeutic benefit of
treatment.

30. REFFERENCE
• Encyclopedia of controlled drug delivery, volume:2,
by Edith Mathiowitz; pg no:446 to 457.
• Handbook of pharmaceutical controlled release
technology; edited by Donald L.Wise; pg.no: 67 to 81
• Internet source

31. THANK YOU