INTRODUCTION:

In the new technologies the released of drug in immediate or extended fashion. Depending on the disease condition the development of drug release technology is modified.^1,2 PDDS is also part of that development in which it delivers the drug according to chrono pharmacotherapy of disease. This situation necessitates the release of the medicine after a period of time has passed. This situation may be produced using a pulsatile delivery system, which is described as the quick and transitory release of a certain amount of molecule in a short time period following a pre-set off release period (lag time). A pulse must be developed in this manner that the medicine is released completely and quickly. After the lag period, the medicine is released in sync with the body's circadian cycle.³

Were,

A] After a lag interval, a sigmoidal release occurs.

B] After a lag time, the release is delayed.

C] After a lag time, there is a sustained release.

Figure 1. Drug release profile of pulsatile drug delivery system.(2)

A] Pulsatile delivery system

B] Conventional drug delivery system

C] Extended drug release.

Figure 2. Drug release profile with compare to other drug delivery system and pulsatile delivery system (3)

In this graph 1Following the lag time, indicate sigmoidal release This is how pulsatile medication delivery systems will look in the future. When a medicine is released after a lag period, the drug is released all at once.⁴

Chrono Pharmacology:

It is a branch of research concerned with optimizing medicinal effectiveness and minimizing side effects by scheduling drugs in respect to biological rhythms.⁵ The aim is to have a better knowledge of the periodic and thus predictable variations in medication’s desired effects and tolerance. Chrono pharmacology is the branch of medicine that studies how drugs affect people's biological clocks.⁶

Rhythms in Human Physiology:

Rhythms in Human physiology are self-sustaining cycles that are innately determined by the length of time between subsequent repetitionsunder normal conditions. Within 24 hours, 100 different measured human body markers show cyclic variations.⁶

In medicine, circadian rhythms are particularly essential. Circadian rhythms (circa about dies, day, or about 24 hour) A physiological day lasts around 25 hours. The environment, night and day social schedules, reset the clock every day. ⁶ The brain's circadian clock regulates daily physiological cycles such as sleep/wake, digestion, temperature, and hormones. Endogenous circadian rhythms are biological rhythms. Free-running rhythms result from a lack of external synchronizers. The duration of free-running rhythms varies per species and can be longer or less than 24 hours. Our internal clocks are determined by our genes. In mammals, the suprachiasmatic nucleus of the hypothalamus (SCN) houses an internal biological clock that sends time signals throughout the body.⁷ Circadian rhythms and annual/seasonal rhythms are controlled by it. To send out its time-of-day message, The SCN makes advantage of its autonomic nervous system connections, either by altering the endocrine glands' sensitivity or by directly influencing the endocrine output of the pineal gland (i.e., melatonin synthesis)

Rhythms of Different Systems:

· Respiratory system:

Greater bronchoconstriction at night due to increased parasympathetic tone, lower adrenaline and cortisol levels at midnight, and increased sensitivity to irritants and allergens at night.⁷

· Gastrointestinal tract:

Between 10 p.m. and 2 a.m., secretion of acid 2-3 times greater.⁸

· Cardiovascular system:

When comparing diastolic and systolic blood pressure, the amplitude of the 24-hour change is greater for diastolic blood pressure. At 9-11 a.m. and 6-7 p.m., blood pressure displays two peaks. Blood pressure drops (somewhat) in the afternoon and started decreasing at night.⁹

· Endocrine system:

Cortisol secretion is highest soon before awakening and lowest at mid-night in the morning. Growth hormone is at its highest during sleep. Early in the morning, testosterone peaks. 5-10 times increase in insulin Following the absorption of meals, the level rises.

· Plasma protein binding:

During nocturnal sleep, albumin and acid glycoprotein are at their lowest and highest levels, respectively. As a result, during night, medicines linked to plasma protein, such as lignocaine, carbamazepine, diazepam, valproic acid, and prednisolone, exhibit an increase in free fraction.

· Liver enzymes:

In the middle of the (nocturnal) activity span, oxidative reactions reach a high. UDP-glucuronyl transferees catalyze more conjugation during activity than at rest. During the rest period, sulphate conjugation is faster than during activity.

Figure 3 Circadian Rhythm

Diseases and Chronotherapeutic:

24-hour cycle Up to now, the homeostatic hypothesis has guided the development of medication delivery methods. This notion is based on the idea that biological functions are consistent across time. Circadian rhythms have been identified for practically all human processes, including heart rate, blood pressure, body temperature, plasma concentrations of numerous hormones, stomach pH, and renal function, according to chronobiological research.¹¹The importance of rhythmic processes in the therapy of human illnesses has become clear. Circadian rhythms exist in pathological stages of disease, just as they do in physiological processes. Epidemiological studies have shown that there is a higher chance of illness symptoms at this time.¹²

In the therapy of a variety of disorders, the potential benefits of chronotherapeutic have been proven. Patients with allergic rhinitis, rheumatoid arthritis and associated disorders, asthma, cancer, cardiovascular disease, and peptic ulcer disease are all interested in learning more about how chronotherapy can help them.¹³ Patients with allergic rhinitis frequently report that their worst symptoms occur first thing in the morning. Patients taking a long-acting antihistamine at night instead of in the morning, as is typically suggested, may have better results in controlling morning pain.¹⁴

Diseases Required Pulsatile Delivery System:

1. Asthma

2. Peptic Ulcer

3. Cadiovascular Disease

4. Diebeties Mellitus

5. Hypercholestrolemia

6. Parkinson’s Disease

Asthma:

Asthma is common chronic inflammatory disease of the airways characterized by hyperresponsive to variety of stimuli. Resistant airway in asthmatic patients, bronchoconstriction and symptom aggravation grow gradually during the night and early morning. Circadian alterations in lung function occur. For example, expiratory flow rates are the highest at 4 p.m. and lowest at 4 a.m. Approximately two-third of asthmatics suffer from nocturnal asthma symptoms and risk of asthma attack greater during night time sleep as compare to day time activity. This is driven by circadian changes in epinephrine (Bronchodilator), cortisol (ant inflammatory substance), Histamine (amedator if bronchoconstriction) melatonin (sleep regulatory hormone) AMP, vagal tone and body temperature. At 4.00 a.m., histamine concentrations peaked at a level that corresponded to the greatest degree of bronchoconstriction.^16,17Pulsatile-release dosage form can potentially treat the nocturnal asthma by releasing drug after predetermine time delay, provided that most appropriate drugs are administrated. This dose type is given before bedtime, with medication release beginning in the early morning hours, when the risk of an asthmatic attack is highest.

Drug used in pulsatile delivery to treat nocturnal asthma:

Salbutamol:

Salbutamol is a fast-acting, highly selective Beta 2-adrenoceptor agonist with little cardiac adverse effects. This is used to treat asthma through relaxing the smooth muscle of the bronchial tubes causing the bronchi to dilate immediately.¹⁶ The 2-4 mg pill is radially absorbed from the oral route, with a 44 percent absolute bioavailability and a peak plasma concentration of 1-3 hours.

Salbutamol has a short biological half-life (3.8 to 6 hours), a high first-pass metabolism, and a restricted therapeutic window when taken orally. A pulsatile delivery device exposes salbutamol sulphate only when it is needed, potentially preventing undesirable systemic side effects and allowing a lower dose of life-saving medication to be used to treat night-time asthma.¹⁶

Montelukast:

Montelukast is a drug that can be used to treat asthma and allergic rhinitis. Montelukast belongs to the class of drugs known as leukotriene receptor antagonists. It acts by inhibiting the function of leukotriene D4 in the lungs, resulting in less inflammation and smooth muscle relaxation.¹⁷

Theophylline:

Theophylline is a methylated xanthine class of medication used to treat respiratory illnesses such as COPD and asthma. It's a bronchodilator and nonselective phosphodiesterase inhibitor that improves respiratory muscle performance and mucociliary clearance. Theophylline's broncho dilating effect makes it effective in the long-term treatment of bronchial asthma.¹⁸

Peptic Ulcer:

Peptic ulcer is the erosion in lumen of stomach. The human stomach is capable of secreting hydrochloric acid in concentration that create a greater than 2-million-fold gradient in hydrogen ion concentration between the gastric lumen and tissue vascular compartment. Under the fasting condition acid is secreted in relatively low amount to maintain an intragastric pH of approximately 1.5. This slow level rate termed as basal acid secretion. The rate of basal acid secretion is highest between 9pm and midnight.¹⁹

Meals are often accompanied with an increase in acid secretion and a brief rise in intragastric pH because to the meal's buffering impact. Thus, during a day time. Intragastric pH changes over the day, particularly during mealtimes. Intragastric pH remains low during the night-time hours when there is no food present. Based on the Circadian rhythm, the secretion of gastric acid is higher in the early morning or late at night, so our goal is to give the medicine late at night and only then receive the right outcome. This condition is well treated by pulsatile delivery that provide a drug after required lag time.¹⁹

Drugs used in pulsatile delivery to treat peptic ulcer

Lansoprazole:

Lansoprazole is an antiulcer medication that belongs to the proton pump inhibitor class. Lansoprazole is a benzimidazole sulfoxide derivative that inhibits gastric acid output for a long time. Lansoprazole is used for the treatment of duodenal or gastric ulcers, gastroesophageal reflux disease, and zollinger-ellison syndrome. Lansoprazole, which can be targeted to the colon in a pH and time dependent manner, can be used to control medication levels in synchrony with nocturnal acid secretion's circadian rhythm.²⁰ A pulsatile 'Tablet in Capsule' dosage form containing lansoprazole taken at bedtime with a programmed start of drug release early in the morning hours can prevent a sharp increase in the incidence of high gastric acid secretion, especially during the early morning hours, when the risk of peptic ulcer is highest.

Rabeprazole:

Rabeprazole is medication that decrease stomach acid. It used to treat peptic ulcer, gastroesophageal reflux disease and excess stomach acid secretion. The effectiveness is similar to other proton pump inhibitors. Rabeprazole's bioavailability is approximately 52%, meaning that 52% of orally administered dose is expected to enter systemic circulation (the bloodstream). Rabeprazole is 97 percent protein bound once it reaches the bloodstream. Rabeprazole has a biological half-life of around one hour in humans. After a single orally given dosage, rabeprazole reaches its maximal level in human plasma in around 3.5 hours. Oral absorption is unaffected by the dosage given.²¹

Cardiovascular Disease:

Cardiovascular functions such as heart rate and blood pressure show 24 h variation. Since the majority of these illnesses can result in fatal or severe results, the incidence of cardiovascular disease such as acute myocardial infarction, strokes, and arrhythmia shows obvious diurnal variation. Cardiovascular medicine chrono pharmacology and chronotherapy: Implications for coronary heart disease prevention and treatment²²

Various Cardiovascular Disease:

1) Blood pressure/Hypertension:

Blood Pressure is well known to exhibit 24 h variation with a peak in the morning. Throughout the day and night, blood pressure varies. The oscillations might last anywhere from seconds to minutes, or they can last a long time from day to night and season to season. The diurnal shifts associated with the sleep-wake cycle are the most easily noticed and important blood pressure variations²² The pattern of blood pressure measurements acquired from a typical circadian rhythm during the sleep-wake cycle. During awake hours, the pressure rises, then plateaus for several hours until reaching a peak early in the morning.

2) Acute myocardial infraction (AMI):

The AMI Occurs in mostly early morning. A number of physiological functions. Throughout the day and night, blood pressure varies. The oscillations might last anywhere from seconds to several minutes, or they can last a long time from day to night and season to season. The diurnal shifts associated with the sleep-wake cycle are the most easily noticed and important blood pressure variations. The pattern of blood pressure measurements acquired from a typical circadian rhythm during the sleep-wake cycle. Continuous blood pressure monitoring throughout the day and night showed a trend with minimum systolic and diastolic pressure values between midnight and 4 a.m. In during waking time, the pressure rises, then plateaus for several hours before reaching maximum levels early in the morning.

Drug used in pulsatile delivery to treat cardiovascular disease:

Lisinopril:

Lisinopril is a drug of the angiotensin-converting enzyme (ACE) inhibitor class that is primarily used in the treatment of hypertension, congestive heart failure, and heart attacks. It is also used in preventing the renal and retinal complications of diabetes. The drug has a half-life of 12 hrs. This drug belongs to BCS Class III, having good water solubility.²³ Lisinopril is slowly and incompletely absorbed after oral administration with a bioavailability of 25–30%. The objective of the present study was to improve gastric retention, so consequently, the bioavailability of the drug. The distribution is expected to happen in a burst, that is, all at once after a lag period. The goal of developing an acceptable formulation is to deliver the medicine at the proper time, which is early in the morning.

Propranolol:

Propranolol is a competitive antagonist at beta adrenoceptors that is nonselective. It has a high affinity for both beta-1 and beta-2 receptors, but has a lower affinity for the beta-3 subtype. Despite its quick absorption after oral treatment, propranolol has such a limited bioavailability due to considerable first-pass metabolism. Liver metabolism eliminates propranolol, which is strongly bound to plasma proteins.

Metoprolol:

Metoprolol is β1 selective adrenergic receptor blocking agent used in the management of hypertension, angina pectoris, cardiac arrhythmias, myocardial infarction, heart failure, hyperthyroidism and in the prophylactic treatment of migraine.²⁵ Because the half-life of the medicine is relatively short (about 4-6 hours) and drug administration is necessary every 4-6 hours in the normal course of therapy, sustained release/control release formulations are warranted for prolonging activity and improving patient compliance.

Atenolol:

Atenolol is a β1-receptor antagonist that is widely used in the therapyof diverse CVD such as angina pectoris, cardiac arrhythmia, and systematic HTN. In atenolol, the stereogeniccenter resides at the N-N-dimethyl propoxy side chain, resulting in the existence of enantiomeric pair. S-Atenolol is the S-enantiomer of (±)-atenolol, the eutomer, which alone is responsible for the β-adrenoceptor blockingactivity. The S-enantiomer has been found to lack the reported side effect of a lowered heart rate sometimes encountered with the racemate.

Diabetes mellitus:

In the management of diabetes, the target is to maintain the patient in normoglycemia. Since the time of day, patient activities, and medication timing can all affect the risk of blood glucose peaks and troughs, chrono pharmacological elements are extremely important in the management of diabetes mellitus, Shift workers are known to have greater incidences of diabetes and obesity, poor glucose control, and cardiovascular disease and death. The 24-hour circadian clock is crucial for glucose tolerance.²⁶ A human study discovered that when eating and sleeping cycles are not in sync with the internal body clock, blood sugar homeostasis and, in particular, glucose tolerance is significantly affected.

Drug used in pulsatiledelivery to treat Diabetes mellitus.

Glipizide:

Glipizide is belonging to class of sulfonylureas. Oral sulfonylurea act through insulin release by inhibiting the k_ATPchannel of the pancreatic B-cell. Glipizide is an oral rapid and short acting anti-diabetic drug. The biological half-life of Glipizide is 3.4 to 0.7 hrs. to avoid multi dosing of drug pulsatile delivery system helpful to produce therapeutical effect at required time period.²⁷

Hypercholesterolemia:

Hypercholesterolemia is a presence of high level of cholesterol in blood. High cholesterol can limit blood flow, increasing the risk of a heart attack or stroke. Cholesterol synthesis is generally high at night time as compare to daylight due to the activity of rate limiting enzyme HMG COA is higher at night. Diurnal cholesterol synthesis can account for up to 30-40% of total daily cholesterol synthesis. To treat this condition of high cholesterol synthesis at night HMG COA refuse inhibitors are used. Studies with HMG COA reductase inhibitor suggest that evening dosing is more effective than morning dosing.²⁸

Drug used in pulsatile delivery to treat Hypercholesterolemia

Fluvastatin:

Fluvastatin sodium is an antilipemic agent that competitively inhibits HMG-CoA reductase. It's part of a class of drugs known as statins, and it's used to lower cholesterol levels in the bloodstream and prevent heart attacks and strokes. Its short biological half-life is 3 hrs. and low bioavailability makes it an appropriate candidate for pulsatile delivery system. Fluvastatin pulsatiledelivery is characterized by proportioning medication concentration in the early morning hours when free cholesterol levels are higher. It may be given before night and is capable of releasing drug after a predetermined time delay.²⁹

Pravastatin:

Pravastatin is belonging to class of medication know as statin. This are the cholesterol lowering agent used to preventing cardiovascular disease at high risk and treating abnormal lipid conditions. Pravastatin inhibits function of HMG-COA reductase. The half-life of drug 1-3 hrs. It's recommended to use only after other measures, such as diet, exercises and weight reduction have not improved cholesterol level. The use of pravastatin is generally weaker as compare to other statin but for a pulsatiledelivery system they have an ideal approach due to its pharmacokinetics and minimum side effect.³⁰

Parkinson's disease:

The loss of voluntary muscle movement is known as akinesia. It's most commonly associated with Parkinson's disease as a symptom (PD). Morning akinesia in Parkinson’s disease Dopamine neurotransmission control is frequently disrupted, which leads to movement problems. Parkinson's disease (PD) is a movement illness caused by progressive dopamine neuron loss and is related with faulty dopamine neurotransmission control. In order to replace the lost dopamine PD motor symptoms is currently treated with oral levodopa (L-DOPA, a precursor of dopamine), which must be emptied from the stomach and absorbed in the proximal small intestine. Levodopa is converted into dopamine in the brain, and stored in the neurons until needed by the body for movement. It remains the single most effective agent in the management of Parkinson's symptoms.³¹

Drug used in pulsatile delivery to treat morning akinesia:

Levodopa and dopa decarboxylase inhibitor:

Pharmaceutical composition that addresses short-comings of current formulations comprising levodopaand DOPA decarboxylase inhibitors; by providing a composition that enables timed pulsatile release of these compounds. Providing a delayed burst release of a DOPA decarboxylase inhibitor such as carbidopa and a delayed burst release of levodopa after a predetermined lag time, preferably separated in time whereby the DOPA decarboxylase inhibitor is released before levodopa, provides a means for the management of morning akinesia in patients with Parkinson's disease.³¹

With pulsatile delivery, the patient may improve the night time sleeping pattern and be efficiently relieved from a complete disabling state in the morning. Furthermore, such a composition can be taken together with existing marketed immediate and controlled release levodopa products, to provide a full day dose coverage for most patients with Parkinson's disease.

It is an aspect to provide a pulsatile release pharmaceutical composition comprising levodopa and a DOPA decarboxylase inhibitor, and a pulsatile release component providing for a predetermined lag time followed by a pulse release of said levodopa and said DOPA decarboxylase inhibitor.

CONCLUSION:

The development of a pulsatiledelivery system that can effectively treat diseases with non-constant dose therapy has made significant progress. Due to high patient compliance, convenience of administration, and versatility in formulations, oral medication delivery is currently the most preferred route of drug delivery. Hypertension, osteoarthritis, peptic ulcer, asthma, and other circadian disorders necessitate chrono pharmacotherapy. The methods described in this article are based on attempts made over the last decade to achieve Pulsatile release for a variety of diseases.

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Received on 11.05.2022 Modified on 10.06.2022

Asian J. Res. Pharm. Sci. 2022; 12(4):329-334.

DOI: 10.52711/2231-5659.2022.00056