Formulation and Evaluation of Chronomodulated Drug Delivery System

Mukund G Tawar¹*, Satish V Shirolkar¹, Mahesh D Pawar², Nishant S Gandhi¹ and Nilesh B Deore¹

¹Pad. Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune-411018

²Microlabs Pvt. Ltd. Banglore.

ABSTRACT:

A pulsatile drug delivery system which is time dependent, consist of an effervescent core surrounded by consecutive layers of swelling and rupturable layers were prepared and evaluated. The cores comprising of the active agent Terbutaline sulphate (β₂ blocker) was prepared by direct compression method using different ratios of Microcrystalline cellulose, Osmotic agent and effervescent agent. The outer rupturable layer consists of Eudragit RS/RL (1:1) which surround the inner swelling layer comprising of Hydroxy propyl methyl cellulose E₅. The effect of various formulation and processing parameters were studied. The rupture and drug release studies were carried out using the USP paddle method at 50 rpm in 0.1 N HCl, and Phosphate buffer pH 6.8. The lag time of drug release was increased by increasing the rupturable layer and decreased by increasing the swelling layer level. The osmotic and the effervescent effect were involved in the drug release, as shown by the studies.

KEYWORDS: Nocturnal Asthma, Chronomudulated drug delivery, Terbutaline Sulphate, Swelling layer, Rupturable layer.

INTRODUCTION:

Nocturnal Asthma is a condition that is prevalent among two thirds of asthmatics i.e patient suffering from asthma. In this condition there is variable night time exacerbation of the asthma condition associated with increase in symptoms and need for medication. Symptoms typically occur between midnight and 8 am¹. It is convenient to take medication at midnight. So for this Nocturnal asthma, the treatment can be done by drugs such as Terbutaline sulphate (β₂ blocker) given in a pulsatile fashion, at a predetermined time/site rather than as a continuous delivery. With a delivery system capable of releasing drugs in a pulsatile fashion, drugs will follow a circadian rhythm This study is aimed to design and evaluate a Chronomudulated drug delivery system of Terbutaline sulphate for treatment of nocturnal asthma having an lag time of 6hrs, i.e. system taken at around bedtime 10 pm will release the drug at 4 am, when the asthma attacks are more prevalent^3-4.

MATERIALS AND METHODS:

Materials and reagents:

Terbutaline Sulphate, HPMC E5 and Eudragit RS/RL obtained as gift sample from Micro Laboratories Ltd Hosur.

Preparation of core tablets:

The core tablets containing Terbutaline Sulphate (5mg/tablet) were prepared using the following excipients: sodium chloride, microcrystalline cellulose, starch, sodium bicarbonate, lactose, Magnesium stearate, Talc. All excipients were mixed for 25 min and passed through a 125 mesh size sieve and directly compressed in to 200mg tablets using 8mm round concave punches on a rotary tablet machine using a force of 3000kg. Core tablets without sodium chloride and sodium bicarbonate were also prepared^{3-4, 7.}

Table no. 1-Fromulation of Batch C1 to C4

Ingredients (mg)	Formulation no.
Ingredients (mg)	C₁	C₂	C₃	C₄
Terbutaline sulphate	5	5	5	5
Sodium Chloride	60	40	20	-
Microcrystalline Cellulose	40	50	60	40
Starch	40	40	40	40
Sodium Bicarbonate	40	40	40	-
Lactose	11	21	31	110
Magnesium stearate	2	2	2	2
Talc	2	2	2	2

Development of pulsatile release tablets:

Pulsatile release tablets were prepared using an inner swelling layer comprising of HPMC E5 (15, 20 and 30 % w/w of tablet). This inner swelling layer was applied by direct compression. An outer polymeric layer consisting of Eudragit RS/RL (1:1, 6mg / cm²) dispersed in water/ethanol solution (60/40 v/v) using PEG 4000 (4.5% w/w of polymer content) as a plasticizer. The outer polymeric layer was incorporated by conventional pan coating. After finishing the coating process the tablets were then placed in an oven at 50o C for 2-3 hrs to remove the solvent⁷.

In vitro Dissolution study:

Using USP Paddle apparatus at 50 rpm and 37 0.5, the in vitro drug release from coated tablets was carried out. HCl (0.1N) and phosphate buffer (pH 6.8) was used as the dissolution medium. Tablets were subjected for 2h in HCl (0.1N) initially and then the media was changed to Phosphate buffer (6.8 pH). The samples were drawn out at regular intervals and analyzed by UV spectrophotometer at 278 nm for drug release study.

Effect of inner swelling layer:

Core tablets were coated with 15%, 20%, 25%, and 30% of HPMC E5 as inner swelling layer and subjected to dissolution study. The outer polymer layer of Eudragit (RL/RS 1:1) remained the same. Effect of this swelling layer on lag time of drug release was studied using UV spectrophotometer⁶.

Effect of outer polymer layer concentration:

The core tablets were coated with different conc. of Eudragit RL/RS (1:1) i.e. 4%, 6%, 8%, 10% w/w (inner swelling layer remained the same) to study its effect on lag time².

Effect of paddle speed on the lag time and release characteristics:

Coated tablets were subjected to in vitro dissolution study at different paddle speeds (50 and 100 rpm). Other conditions remained the same as described. Effect of paddle speed on release behaviour and lag time was observed and analyzed using a spectrophotometer.

RESULTS AND DISCUSSION:

As the numbers of hydrophilic quaternary ammonium groups present in Eudragit RL were much higher as compared to RS, faster drug release was observed from it. Water influx was through the semi permeable rupturable outer coating which leads to the expansion and erosion of an intermediate layer, which ultimately resulted in rupture of the outer coating. Thickness of the swelling layer was the critical parameter which influenced the rupture of outer coating.

The presence of an osmotic agent helped in drawing water towards the tablet which resulted in shortening of lag time. The tablets with sodium bicarbonate in their core showed slightly lower lag time due to the generation of carbon dioxide, which resulted in building up of pressure inside the core and helped in early rupturing of the outer of the outer polymeric layer.

Fig1: In vitro Dissolution behaviour of developed pulsatile drug delivery system.

Fig2: Effect of outer coating on % water uptake and lag time of developed pulsed release tablet. Eudragit outer coating levels used was 4 mg/cm2(─♦─), 6 mg/cm2 (─■─), 8 mg/cm2 (─▲─) and 10 mg/cm2 (─●─).

The water uptake capacity and drug release before the rupture of tablet was dependent on outer acrylate polymer coating. The lag time increased with increased outer coating level. A fast and complete release was observed at 4 and 6 mg/cm² Eudragit coating level. With higher coating level (8 and 10 mg/cm²) of Eudragit, a slower release was observed after lag time, due to lower degree of rupturing.

Fig 3:- Effect of inner swelling layer concentration on the lag time of the time dependent release tablet

Inner swelling layer concentration were, 30%w/w (─♦─), 25%w/w (─■─) and20%w/w (─▲─)

Table No.-2 Formulation of Different Batches

Ingredients (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9 (optimized batch)
Terbutaline sulphate	5	5	5	5	5	5	5	5	5
Sodium chloride	20	20	20	20	20	20	20	20	20
Microcrystalline cellulose	60	60	60	60	60	60	60	60	60
Starch	40	40	40	40	40	40	40	40	40
Sodium bicarbonate	40	40	40	40	40	40	40	40	40
Lactose	31	31	31	31	31	31	31	31	31
Mg stearate	2	2	2	2	2	2	2	2	2
Talc	2	2	2	2	2	2	2	2	2
HPMC E5	15% w/w	20% w/w	25% w/w	30% w/w	25% w/w	25% w/w	25% w/w	25% w/w	25%w/w
Eudragit (RL/RS)	6% w/w	6% w/w	6% w/w	6% w/w	4% w/w	6% w/w	8% w/w	10% w/w	8%w/w

Fig. 4: Effect of paddle rotation (rpm) of dissolution apparatus on the lag time and release profile of pulsed release tablet. Paddle rotation 50 rpm (─♦─) and 100 rpm (─■─).

The lag time of tablet decreased with increasing level of swelling layer. As the amount of swelling agent (HPMC E₅) increased, it exerted more pressure over the outer layer resulting in rapid rupturing of the tablet. After breaking of the outer layer the drug release from the time dependent release tablet with 10% w/w HPMC E₅ layer was lower compared to that from the tablet with 20% w/w HPMC E₅layer. Increase in inner swelling layer concentration (30% w/w) resulted in early burst of tablet.

CONCLUSION:

A Chronomudulated drug delivery system for Terbutaline sulphate for the treatment of nocturnal asthma was successfully developed. The optimized formulation F9 was found to be satisfactory in terms of release of the drug after a lag time of 6 h. The dosage form can be taken at bed time and will release the contents in the early hours of morning when the asthmatic attacks are more prevalent. The release of the drug was sharp and complete after the lag time, which is necessary for any pulsatile drug delivery system.

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Received on 09.01.2010

Accepted on 20.02.2010

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(1): Jan. –Feb. 2010, 100-102