“FORMULATION AND EVALUATION OF PULSATILE DRUG DELIVERY SYSTEM OF SALBUTAMOL SULPHATE FOR THE CHRONOTHERAPY OF ASTHMA”

M. PHARM DISSERTATION PROTOCOLSUBMITTED 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

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.

• 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.

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.

• 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

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

• 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

• 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.

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.

• 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.

• 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.

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

• 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

• 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

• 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

• 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

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.

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.

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.

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.

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:

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.

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.

• 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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