Novel drug delivery system for early morning surge management through chrono therapeutics

As per the World Health Organization (WHO), an estimated 1.28 billion adults aged 30-79 years worldwide have hypertension, and most (two-thirds) live in Low- and Middle-Income Countries (LMICs). The number of adults with hypertension increased from 594 million in 1975 to 1.13 billion in 2015, with the increase seen largely in LMICs. Hypertension is a major cause of premature death worldwide. One of the global targets for non-communicable diseases is to reduce the prevalence of hypertension by 33 per cent between 2010 and 2030.

Hypertensive patients often experience an early morning BP surge, measured as an increase in blood pressure over the transition from being asleep to awakening. It has been observed that during the early morning hours, there is a rapid rise in blood pressure as well as cardiovascular events. Thus, it appears that since the early morning hours are the hours of the highest cardiovascular risk, it is crucial to deliver an optimum amount of medication during this time.

Shortcomings of current medication

Diltiazem hydrochloride (a calcium channel blocker) produces an anti-hypertensive effect by relaxation of vascular smooth muscle and propranolol hydrochloride (a beta blocker) contributes to the anti-hypertensive effect due to decreased cardiac output, diminution of tonic sympathetic nerve outflow and inhibition of renin release by the kidneys.

However, upon oral administration of an immediate release formulation, both drugs undergo a substantial hepatic first pass effect and absolute bioavailability is only 40 per cent, and 25 per cent respectively.

The solution

Hence, after due consideration of the disease pattern, the selected drug candidates were encapsulated in a hardened gelatin shell and targetted to deliver in the colonic region, a potential site for systemic absorption.

As part of PhD thesis, I and my mentors Dr Chandu Baburao and Dr V Sai Kishore designed a pulsatile release system to undergo a lag-time of pre-determined span of no release, followed by a rapid and complete release of loaded drugs. The approach is based on the principle of delaying the time of drug release until the system transits from mouth to colon. A lag-time of five hours is usually considered sufficient since transit time to reach colon is about five hours, which is relatively constant and hardly affected by the nature of formulation administered.

As part of my doctoral research, I established the rationale for the selection of polymers that are highly compatible with colon, such as Eudragit NM 30 D, Eudragit RL 30 D and Eudragit FS 30 D by performing all the pre-formulation studies.

As part of formulation of drug pellets by Wurster technique and encapsulating in the hardened gelatin capsule, I optimised various process parameters of fluidised bed processors such as inlet and outlet air temperatures, atomisation air pressure, and blower speed and spray rate and, as a whole, have good propensity of scaling up the formulation to satisfy the futuristic purpose.

Evaluation of the solution

A systematic evaluation of the designed pulsatile drug delivery system was carried out by my team with due consideration of Physico-chemical properties of the components, establishment of in-vitro release profile of pulsatile capsule, stability of the dosage form in line with ICH guidelines and determined pharmacokinetic and pharmacodynamics parameters on healthy rabbits.

In agreement with pharmacokinetic data and pharmacodynamics evaluations on rabbits, with pulsatile formulations of propranolol hydrochloride formulations, maximum ß-blockade was obtained at 12.0 hours, and was prolonged over a period of 18 hours. For diltiazem hydrochloride formulations, a maximum protection against adrenaline challenge was obtained at 12 hours, and was prolonged over a period of 18 hours, against a six hours maximum protection with oral sustained formulations.

Advantages of the solution

The dosage form can be administered at bedtime and will release the contents in the early morning hours when the risk of hypertension is the highest. This, thus, synchronises release profile with chronobiologic anti-hypertensive therapy and delivers the drug at specific time as per pathophysiological needs of the disease, improving therapeutic efficacy. It embodies time-controlled and site-specific drug delivery systems, subsequently optimising therapeutic action and lessening side effects.

The research work was published in UGC-approved journals, is being cited, and was instrumental in few more research works carried out by other researchers. In addition, it has been exhibited at several national and international platforms like ICMBPS-22, Reignite international conference, UCG-Dubai and highly appreciated due to the scope of usage of current delivery system to other therapies like cancer, arthritis and asthma to meet the unmet needs of patients at affordable cost.

Application in industry after fine tuning the formulation and scale up etc….

The research work demonstrated the development of new drug delivery system with the drug already available in the market. So, selected drug safety is well-known and gives quick dosage approval process and accelerates drug/dosage availability for patients.

Cheaper and more effective therapeutic drugs to patient. Reduced new dosage development timelines and decrease in the spending on product/process design which is burden for development of new dosage forms.

This product can be quickly scaled up and can be commercialised with minimum efforts.