Scientific Rationale And Innovations On A.M. Surge Management Through Chrono Therapeutics

World Health Organization - An estimated 1.28 billion adults aged 30-79 years worldwide have hypertension, most (two-thirds) living in low- and middle-income countries. The number of adults with hypertension increased from 594 million in 1975 to 1.13 billion in 2015, with the increase seen largely in low- and middle-income countries. 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% between 2010 and 2030.

Reference: https://www.who.int/news-room/fact-sheets/detail/hypertension

Early Morning BP surge, an increase in Blood Pressure over the transition from being asleep to awake exaggerates. During the early morning hours not only rapid rise in blood pressure but also cardiovascular events predominate. Thus, it appears that the early morning hours are the hours of highest cardiovascular risk and is the need of hour to deliver optimum amount of drug.

Diltiazem Hydrochloride (A Calcium channel blocker) produces antihypertensive effect by relaxation of vascular smooth muscle and Propranolol Hydrochloride (A Beta blocker) contributes to antihypertensive 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 undergoes a substantial Hepatic first pass effect and absolute bioavailability is only 40%, and 25% respectively. Hence the selected drug candidates in due consideration of disease pattern were encapsulated in a hardened gelatin shell and targeted to deliver in the colonic region, a potential site for the systemic absorption.

Dr. Vamsi Krishan Birupaneni, as part of his PhD thesis designed a Pulsatile release systems to undergo a lag-time of predetermined 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 5 hours is usually considered sufficient since transit time to reach colon is about 5 hours, which is relatively constant and hardly affected by the nature of formulation administered.

Dr. Vamsi Krishan has established 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, he optimized various process parameters of fluidized bed processors such as Inlet and outlet air temperatures, Atomization 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. A systematic evaluation of the designed pulsatile drug delivery system was carried out by Dr. Vamsi Krishan and his team with due consideration of Physico chemical properties of the components, establishment of invitro 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 hrs. and was prolonged over a period of 18 hrs. For Diltiazem hydrochloride formulations, a maximum

protection against adrenaline challenge was obtained at 12 hrs. And was prolonged over a period of 18 hrs. Against a 6 hrs. Maximum protection with an oral sustained formulations.

The dosage form can be administered at bedtime and will release the contents in the early morning hours when the risk of hypertension thus synchronizing release profile with chronobiologic antihypertensive therapy and deliver the drug at specific time as per pathophysiological needs of the disease, improve therapeutic efficacy. It embodies time controlled and site-specific drug delivery systems, subsequently optimizing therapeutic action and lessening side effects.

The research work was published in UGC approved journals, being cited and was an instrumental in few more research works carried out by other researchers. In addition 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 and meet the unmet needs of patients at affordable cost.

Dr. Vamsi Krishan was awarded as the 2nd best speaker for his profound skills on the Chrono-pharmaceutical drug delivery system at 3rd International conference held by Reignite conferences and his research work was acknowledged by Association of Pharmaceutical Teachers of India (APTI) in their Bulletin. Dr. Vamsi Krishan have been engaged in various inter disciplinary functions and handled various projects related to complex injectable, ophthalmic and Liposomes, awarded Quarterly technical awards at Organizational level.