Formulation and evaluation of Pulsatile drug delivery system of salbutamol sulphate for the chronotherapy of asthma

1. “FORMULATION AND EVALUATION OF PULSATILE DRUG
DELIVERY SYSTEM OF SALBUTAMOL SULPHATE FOR THE
CHRONOTHERAPY OF ASTHMA”
M. PHARM DISSERTATION PROTOCOL
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA
BY
Chiranjibi Adhikari B. Pharm.
UNDER THE GUIDANCE OF
Dr. Gururaj S Kulkarni M. Pharm., Ph. D.,
Professor and HOD,
Department of Pharmaceutics,
Mallige College of Pharmacy.
#71, SILVEPURA, BANGALORE: 560 090

2. NEED FOR THE STUDY
• Certain diseases show predictable circadian
rhythms in their pathophysiology.
• In-vivo drug availability can be timed to match
rhythms of the diseases using chronotherapy
(medical treatment scheduled according to
biological clock) in order to optimize therapeutic
outcomes and minimize side effects.
• Solid oral pulsatile-release dosage forms are
highly promising over conventional controlled
release dosage forms when the constant drug
levels are not preferred but demand release of
drug after a time period of no drug release
i.e. lag time1, 2.

3. • Pulsatile drug delivery systems are designed to
deliver drug at predetermined time when the
disease displays its most morbid and mortal
state within a circadian cycle.
• Such systems elicit a sigmoidal drug release
profile with a lag time followed by a prompt
and quantified drug release.
• Time-controlled and site-specific single or
multiple unit pulsatile drug delivery systems
can be developed3, 4.

4. Advantages of Pulsatile drug delivery systems3,5
• Drug can be released as per the circadian rhythms of
body functions or diseases.
• Unnecessary exposure of the target organ to the drug
when therapeutic effect of the drug is not required can
be avoided.
• Extended daytime or night time activity.
• Drug loss by extensive first pass metabolism can be
prevented.
• Reduced dose size, dosage frequency and side effects.
• Protection of mucosa from irritating drugs.
• Overcome drug instability in gastric fluid.
• Improved therapeutic efficacy and better patient
compliance.
• Lower daily cost in therapy due to fewer dosage units.

5. • Pulsatile drug delivery systems draw increasing
interest because of the inherent suitability for
accomplishing chronotherapeutic goals, with a
number of widespread chronic diseases with
typical night or early-morning recurrence of
symptoms.
• E.g. bronchial asthma, rheumatoid arthritis,
angina pectoris, myocardial infraction, stroke,
sudden cardiac death, peptic ulcer and allergic
rhinitis.6

6. Chronobiological Behaviour of Asthma
• Asthma is a common chronic inflammatory
disease of the airways, characterized by
hyperresponsiveness to a variety of stimuli.
• Airway resistance, bronchoconstriction and
exacerbation of symptoms increase progressively
at night and early morning in asthmatic patients.7
• Lung function undergoes circadian changes. e.g.,
peak expiratory flow rate or forced volume in one
second is usually highest at 4 PM and lowest at 4
AM.8
• Approximately two-thirds of asthmatics suffer
from nocturnal asthma symptoms and the risk of
asthma attack is 100–fold greater during night
time sleep than during daytime activity.6

7. • This is driven by circadian changes in
epinephrine( bronchodilator), cortisol(anti-
inflammatory substance), Histamine (a
mediator of bronchoconstriction), melatonin
(sleep regulatory hormone), AMP, vagal tone, and
body temperature.7,9
• Histamine concentrations peak at a level that
coincided with the greatest degree of
bronchoconstriction at 4:00 am.2

8. • Pulsatile-release dosage form can potentially
treat the nocturnal asthma by releasing drug
after predetermined time-delay, provided that
the most appropriate drugs are administrated.
• The Pulsatile-release dosage form may be taken
at bedtime with a programmed start of drug
release in early morning hours when the risk of
asthmatic attacks is the greatest2, 7.

9. Salbutamol as an anti-asthmatic drug
• Salbutamol, also known as Albuterol, is short-acting,
selective Beta 2-adrenoceptor agonist (a
sympathomimetics bronchodilator).
• It opens up the medium and large airways in the lungs
and is used to treat asthma, exercise-induced
bronchospasm, and chronic obstructive pulmonary
disease.
• It relieves asthma by relaxing the bronchial smooth
muscle to produce immediate dilatation of the bronchi10,
11.
• Salbutamol Sulphate represents an appropriate and
effective therapeutic option for patients with wide range
of asthmatic symptoms and is popularly prescribed9, 12.

10. • Oral Salbutamol tablets are mainly required for
the treatment of asthma in resource limited
settings as inhaled Salbutamol tends to be
unavailable or unaffordable13.
• The drug (2, 4 mg tablet) is rapidly absorbed
from oral route and absolute bioavailability is
44% with peak plasma concentration at 1-3
hrs14.
• However, oral Salbutamol has short biological
half-life (3.8 - 6 hours), high first pass
metabolism and narrow therapeutic window15,
16.

11. • Fine tremor, nervous tension, headache, muscles
cramp and palpitations are the common side-
effects17.
• High doses or prolonged use may cause
hypokalaemia15.
• This makes it necessary to formulate Salbutamol
tablets by using a chronopharmaceutical
approach.
• Pulsatile drug delivery system exposes Salbutamol
Sulphate only when it is actually required that
could prevent unwanted systemic side effect and
subsequently a lower dose of life saving drug may
be sufficient to treat nocturnal asthma11.

12. REVIEW OF LITERATURE
• Sajan J, Cinu T.A, Chacko A.J, Litty J, Jaseeda T.
reviewed about chronotherapeutic treatment in
which in vivo drug availability is timed to match
rhythms of disease, in order to optimise
therapeutic outcomes and minimise side effects. It
was based on the observation that there is an
inter-dependent relationship between peak-to-
trough rhythmic activity in disease symptoms and
risk factors, pharmacologic sensitivity, and
pharmacokinetics of many drugs. They added that
various technologies such as time-controlled,
pulsed, triggered and programmed drug delivery
devices have been developed and extensively
studied for chronopharmaceutical drug delivery.2

13. • Sarda R.R., Niture J.T., Kendre D.G., Satpute K.L.
optimized the chronomodulated dosage form of
Salbutamol sulphate for Asthma using full factorial
design. The combination of polymers HPMC K4M and
Eudragit RSPO was selected for the study based on lag
time and release characteristics. HPMC K4M was found
to retard the release of drug which was attributed to
high viscosity of the polymer. Swelling of HPMC K4M
increased the diffusion path length and its gelling nature
holded the coat intact. Permiability of other polymer
Eudragit RSPO was found to be less and had less
influence on the drug release. But, Eudragit RSPO was
necessary for brusting of tablets as it was less intact in
the HPMC K4M network. It was found that formulation
was time dependent and inner core tablet burst due to
pressure generated in it by Crosscarmellose Sodium
after following predetermined lag time.15

14. • Sadaphal K. P., Thakare V. M., Gandhi B. R.,
Tekade B. W. prepared and evaluated pulsatile
drug delivery system of theophylline to mimic
the cicardian rhythm of the Asthma. The design
consisted of a rapid release core tablet and a
controlled release coating layer. A combination
of Isopropyl Alcohol (70%) and Acetone (30%)
was used as solvent for Eudragit S100 coating
and was found that the coated drug was
satisfactory in terms of release of the drug after
a lag time of 6 hrs. From the study it has been
concluded that the lag time can be controlled by
adjusting the thickness of coating layer as well
as the superdisintegrant concentration.16

15. • N. Kanaka Durga Devi, B. Sai Mrudula, A. Prameela
Rani formulated and evaluated one pulse drug delivery
system of Montelukast Sodium based on press coated
tablet preparation. Primojel, Ac-di-sol and polyplasdone
were selected as swelling polymers in the core tablet and
barrier layer formulations consisted of Xanthan gum,
Ethyl cellulose, and Tamarind seed polysaccharide.
Formulation with 7.5% polyplasdone was optimized as
the best immediate release core tablet or burst release of
the drug. The lag time was maintained by press coating
the core tablets with barrier layer. Barrier layer with
Xanthan gum, EC T10, Mannitol, and TSP in 5, 15, 65
and15% w/w respectively could resist the RPM
pressures as well as pH differences and was found to
show single pulse drug delivery with considerable drug
release for 2 hours after maintaining the pre expected 5
½ hours lag time.17

16. • Patel T., Ananthapur M., Sabitha J.S., Tribedi S.,
Mathappan R., Prasanth V.V. formulated and evaluated
an oral, pulsatile drug delivery system to achieve time
release of salbutamol sulphate, based on
chronopharmaceutical approach for the treatment of
nocturnal asthma. A core tablets was prepared by direct
compression method and coated with an inner swellable
layer containing 30 % HPMC E5. The entire device was
enteric coated with 5% cellulose acetate phthalate. In
vitro release profiles during the first four hours there
was no drug release and in between 5 to 6 hrs
immediate release was observed. Increasing the level of
the rupturable layer (CAP) increased mechanical
strength and retarded the water uptake and thus
prolonged the lag time. The lag time of the pulsatile
tablets decreased with increasing amounts HPMC E5 in
the inner coating layer.11

17. OBJECTIVES OF THE STUDY
– To develop a time controlled pulsatile oral
tablets of Salbutamol Sulphate using suitable
polymers and other excipients.
– Incorporation of drug in the core, to be released
promptly at the time of asthmatic risk.
– Optimization of the coating composition and
coating thickness to acquire lag time of 4-6
hours.
– To study the in-vitro drug release kinetics of the
prepared formulation.
– Accelerated stability studies of selected
formulations as per ICH Guidelines.

18. MATERIALS AND METHODS
• Drug – Salbutamol sulphate.
• Polymers - Hydroxypropyl methylcellulose,
Hydroxypropyl cellulose, Ethyl Cellulose, Cellulose
Acetate phthalate, Sodium Alginate, Carbomer,
Carbopol, Eudragit, etc.
• Super disintegrants - Crospovidone, Cross
carmellose sodium, Sodium starch glycolate, etc.
• Binders - Microcrystalline Cellulose, Polyvinyl
pyrrolidone, etc.
• Glidants - Magnesiun Stearate, Spray-dried
Lactose,etc.
• Surfactants - Sodium Lauryl Sulphat,
polyoxyetylen esorbitan monopleate, etc.

19. METHODS
Pulsatile-release drug delivery system will be
prepared using any of the following methods:
1. Delivery systems with soluble or erodible
membranes-The outer coat barrier erodes or
dissolves after specific time period and drug on
the core is subsequently released from such drug
delivery systems. Lag time prior to drug release
will be obtained by optimizing the coating
composition and coating thickness. Through the
application of an outer gastric-resistant enteric
film, the variability in gastric emptying time can
be overcome, and a colon-specific release can be
obtained4, 6.

20. 2. Delivery system with repturable coating-
• These systems consist of an outer water insoluble
but permeable coating subject to mechanically
induced rupture phenomenon.
• The rupturing effect is achieved by effervescent
excipients, swelling agents, or osmotic pressure in
the tablet core.
• The lag time can be varied by varying coating
thickness or adding high amounts of lipophilic
plasticizer in the outermost layer.
• This system can be successfully designed for
delivery of drugs that exhibit extensive first-pass
metabolism3, 6.

21. Designing of the above release systems
comprises of the following steps:
I) Preparation of Core Tablets:
• Dry blending or wet granulating of a drug,
super disintegrant, and pharmaceutically
acceptable excipients.
• Compressing the blends/ granules into a
tablet core using appropriate tooling.
II) Coating over the tablet core:

22. Any of the following Coating system may be applied:-
a) Press Coating Method: Initially half the quantity
of coating polymer is placed in the die cavity, and
then the core tablet is carefully positioned in the
center of die cavity. The remaining half quantity of
the polymer is filled in the die, and the content is
compressed using tablet compression machine21.
b) Pan Coating Method: The polymer along with
pharmaceutically acceptable coating additives are
dissolved in suitable solvent, and then the coating is
applied on the core of tablet in a pan by spraying
solution of polymer27.

23. Method of Collection of Data
• Identification of drug.
• Drug-excipients compatibility study.
• Preformulation studies of the core powder blend like bulk
density, tap density, Hausner’s ratio, Carr’s index, angle of
repose, etc.
• Formulation of core tablets using different compositions and
study of in-process parameters of like weight variation,
hardness, thickness, friability, disintegration, drug content,
drug content uniformity, etc.
• Development of coated tablet with different quantity of
coating materials and evaluation for various parameters like
general appearance, weight variation, thickness, lag time, in-
vitro drug release, etc.
• The data so obtained will be subjected for statistical analysis.
• Accelerated stability studies of the selected formulation as
per ICH guidelines.

24. • Does the study require any investigation or
intervention to be conducted on patients or other
humans or animals? If so, please mention briefly.
 NO.
• Has ethical clearance been obtained from your
institution in case of 7.3?
 NOT APPLICABLE.

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