INTRODUCTION:

Pulsatile drug delivery system works with chronotherapeutic agent which represents a pharmaceutical product that contains a dynamic element such a delivery system to deliver the drug at the time when it is needed. A pulsatile drug delivery system is characterized by a lag time that is an interval of no drug release followed by rapid or controlled or sustained drug release^[1]

In 1729, the first known experiment on biological rhythms was conducted by French astronomer Jean Jacques d’Ortous deMairan. Biological rhythms not only impact the function of physiology, but the pathophysiology of diseases. If symptoms of a disease became worse during the night or in the early morning the timing of drug administration and nature of the drug delivery system need careful consideration^[2].

Recent studies show that diseased have predictable cyclic rhythms and the timing of medication regimens can improve outcome in selected chronic conditions. “Chronopharmaceutics” consist of two words chronobiology and Pharmaceutics. Chronobiology is the study of biological rhythms and their mechanisms. There are three types of mechanical rhythms in our body, they are – Circadian, Ultradian, Infradian Circadian: “Circa” means about and “dies” means day Ultradian: Oscillation of shorter duration are termed as ultradian (more than one cycle per 24 h).

Infradian:

Oscillations that are longer than 24 h (less than one cycle per day)^[3].

Pulsed or pulsatile drug release is defined as the rapid and transient release of a certain amount of drug molecules within a short time-period immediately after a predetermined off-release period^[4]. It is characterized by two release phases, a first phase with no or little drug being released, followed by a second phase, during which the drug is released^[5].

These systems are beneficial for drugs having high first pass effect; drugs administered for diseases that follow chronopharmacological behavior, drugs having specific absorption site in GIT, targeting to colon, to increase the stability of dosage form and cases where night time dosing is required. Cardiovascular diseases, several functions (e.g. BP, heart rate, stroke volume, cardiac output, blood flow) of the cardiovascular system are subject to circadian rhythms. Recent studies have revealed that diseases have a predictable cyclic rhythm and that the timing of medication regimens can improve the outcome of a desired effect. This condition demands release of drug as a "pulse" after a time lag and such system has to be designed in a way that complete and rapid drug release should follow the lag time. Such systems are known as pulsatile drug delivery systems (PDDS)^[6].

Pulsatile drug delivery is of the chief types of the novel drug delivery system. It aims to release drugs on a planned pattern i.e. at suitable time and/or at proper site of action. There are many other modern systems which deliver the drug at predetermined rate with unremitting release like controlled release and sustained release but sometimes these kind of drug delivery show tolerance problem/dilemma for certain medication that is why pulsatile drug delivery is preferred to overcome this difficulty. Pulsatile drug delivery system is the one that follow circadian rhythm, an biological clock which is directly related to many physiological as well as pathological conditions of the body. There are many diseases which show circadian rhythm like heart attack, asthma, arthritis etc. that call for such a system that must show it’s effect at the exposure time of disease symptoms^[7].

The principle rationale for the use of pulsatile release is for the drugs where a constant drug release, i.e., a zero-order release is not desired. The release of the drug as a pulse after a lag time has to be designed in such a way that a complete and rapid drug release follows the lag time. Advantages of the pulsatile drug delivery system are reduced dose frequency; reduce side effects, drug targeting to specific site like colon and many more^[8].

Chronotherapy got attention in designing of Novel drug delivery system for treating diseases that rely on circadian rhythm. The term "Chrono "basically refers to the observation that every metabolic event undergoes rhythmic changes in time^[9]. Human body contains biological rhythm/biological clock. This rhythm occurs episodically in human body in accordance with systematic changes that takes place in environmental conditions. Genetic makeup dictates the internal clocks^[10].

Circadian Rhythm:

Rhythm that occurs in body within 24 hours is referred to as circadian rhythm. It rely on sleep wake cycle which is prejudiced by genetic makeup in our body. This in turn reflects the physiological functions of human body ^[11]. Certain disease conditions like hepatic and renal impairment, lung and cardiovascular diseases rely on circadian rhythm, which was supported by chronobiological studies. These studies revealed that all body functions are in coherence with circadian rhythm ^[12]. Certain disease like asthma, angina pectoris, hypertension rely on circadian rhythm where these disease shows peak symptoms at particular time in biological clock. To satisfy these conditions pulsatile drug delivery system was emerged where drug is released in a burst manner immediately after a pre-determined lagphase. It is a time and site specific drug delivery system^[13].

Concept of lag time in pulsatile drug delivery system:

Definition of lag time “Lag time is defined as the time between when a dosage form is placed into an aqueous environment and the time at which the active ingredient begins to get released from the dosage form.” A lag time of at least 0.5 hr or longer is considered to be important while a lag time of less than it is of little significance.

Lag times of more than 4 hrs are desired for delivery of drug into lower portion of small intestine while lag times between 0.5 and 4 hr are desirable in drug delivery in upper regions of gastrointestinal tract^[14].

Necessity for Pulsatile Drug Delivery System:

There are many conditions and diseases where sustained release formulations do not show good efficacy. In such cases pulsatile drug delivery is applicable.

1. First pass metabolism:

There are some drugs like beta blockers, and salicylamide, which show extensive first pass metabolism and require fast drug input to saturate metabolizing enzymes in order to minimize pre-systemic metabolism. Thus, a constant oral method of delivery would result in reduced oral bioavailability.

2. Biological tolerance:

Drug plasma profiles are often accompanied by a decline in the pharmacotherapeutic effect of the drug, e.g., biological tolerance of transdermal nitroglycerin, salbutamol sulphate.

3. Special chronopharmacological needs:

Many physiological actions and certain diseases are there which follow ‘circadian rhythm’(This word comes from Latin word “circa” means about and “dies” means day.) It has been recognized that many symptoms and onset of disease occur during specific time periods of the 24hour day, i.e. asthma and angina pectoris attacks are most frequently in the morning hours.

4. Local therapeutic need:

For the treatment of local disorders such as inflammatory bowel disease, inflammation with no loss due to absorption in the small intestine is highly desirable to achieve the therapeutic effect and to minimize side effects.

5. Gastric irritation or drug instability in gastric fluid:

Protection from gastric environment is essential for the drugs that undergo degradation in gastric acidic medium (e.g.: peptide drugs), irritate the gastric mucosa such as NSAIDS (Non-steroidal anti-inflammatory drugs) or induce nausea and vomiting ^[15-17].

Advantages and Drawbacks of Pulsatile Drug Delivery Systems:

Advantages:

· Predictable, reproducible and short gastric residence time

· Less inter- and intra-subject variability

· Improve bioavailability

· Reduced adverse effects and improved tolerability

· Limited risk of local irritation

· No risk of dose dumping

· Flexibility in design

· Improve stability

· Improve patient comfort and compliance

· Achieve a unique release pattern

· Extend patent protection, globalize product

· Overcome competition

Drawbacks:

· Lack of manufacturing reproducibility and efficacy

· Large number of process variables

· Multiple formulation steps

· Higher cost of production

· Need of advanced technology

· Trained/skilled personal needed for manufacturing^[18]

Following Diseases can be treated by Pulsatile Drug Delivery System:

Rheumatoid arthritis:

The chronological behavior of rheumatoid arthritis has been studied carefully. For example, there is circadian rhythm in the plasma concentration of C-reactive protein and interleukin-6 of the patient suffering from rheumatoid arthritis. The victims of rheumatoid arthritis feel more pain in morning but less in night while in osteoarthritis, the conditions are quite different. In osteoarthritis, pain is at its highest level in night which decreases during day time. Different NSAIDs are used to control the joint pain^[19-20].

Pulmonary disease:

In the treatment of asthma, circadian rhythm plays a vital role. In the case of this disease, the airway resistance increases at night and reaches a low point in the early morning hours. The therapy of asthma has been suggested with corticosteroids, the ophylline and β₂ agonists^[21-22].

Hypercholesterolemia:

Many circadian alterations in lipid fraction in the normal as well as in patients, can cause the changes in the metabolism rhythm and in the blood coagulation system, thus carry out many complications. A circadian rhythm is followed in hepatic cholesterol synthesis which is generally high during day. Treatment with HMG Co reductase inhibitors has recommended that evening dosing was more effective than morning dosing^[23-25].

Diabetes mellitus:

The circadian changes of glucose and insulin in diabetes have been studied and their clinical importance in the case of insulin substitution in type 1 diabetes has been studied. The main aim of insulin therapy is to mimic the normal physiologic pattern of endogenous insulin secretion^[26-27].

Gastro-intestinal disorders:

The functions of gastro intestinal tract are affected by circadian rhythm. Gastric acid secretion is highest at night, so the disintegration, dissolution and absorption of drug is also slow at night. Therefore, for effective gastric ulcer prevention, once daily at bed timeH₂ antagonist has been suggested^[28].

Cardio-vascular diseases:

Many functions of cardio vascular system like blood pressure, cardiac output, stroke volume, blood flow of cardiovascular system are influenced by circadian rhythm. Blood pressure is lower during sleeping time and rises sharply during the early morning. Platelet aggregation is increased so the fibrinolytic activity is decreased in the morning, thus cause hypercoagulability of blood^[29-30].

Colonic delivery:

Colon is the most suitable site for drug absorption as low proteolytic enzyme activity is found there. It is good for delivering protein and peptide drugs. A Colon specific drug delivery prevents the drug release in stomach and small intestine, and affects an onset of drug release upon entry into colon. Time dependent delivery is a mean of targeting the drug after a pre-programmed time delay. The time is difficult to predict in advance, although a lag time of 5 hours is usually considered sufficient, given that small intestine transit time is relatively constant at 3 to 4 hours^[31].

Summary of some diseases which can be controlled by pulsatile drug delivery system is as given in table 1.

Table 1. Examples of diseases requiring pulsatile drug delivery [19-31]

Disease	Chronological Behavior	Drug Used
Peptic ulcer	acid secretion is high in afternoon and at night	H2 blockers
Asthma	Attacks during night and in morning hour	β2agonist, antihistaminics
Cardiovascular disease	BP is lowest in sleeping cycle and rises in early morning	Calcium channel blockers, ACE Inhibitors, ARBs
Arthritis	Pain in the morning and more pain in night	NSAIDs, Glucocorticoids
Diabetes mellitus	Increase in blood sugar level after meal	Sulfonylurea, Insulin, Biguanide
Hpercholesterolemia	Cholesterol synthesis is higher in night than during day time	HMG CoA reductase inhibitors

Types of Pulsatile Drug Delivery:

(1) Single unit system:

(a) Capsular system:

Single unit system is developed in capsule form. The lag time is maintained by a plug, which gets pushed away by swelling, and the drug is released as a pulse from the insoluble capsule body. e.g.: Pulsincap system^[32].

In this system a water insoluble body containing the drug is closed with a swellable hydrogel which is plugged at open end. Upon contact with, gastrointestinal fluid the plug swells and pushes itself out of the capsule after lag-time. For rapid release of water insoluble drug effervescent or disintegrating agents are also added.

Plug material is made up of swellable polymer (polymethacrylates), erodible compressed polymer (polyvinyl alcohol), congealed melted polymer (glyceryl mono oleate) and enzymatically controlled erodible polymer (pectin)^[33].

(b)Pulsatile delivery by osmosis:

This system consists of a capsule which is coated with a semi permeable membrane. Capsule contain insoluble plug consisting of osmotically active agent and the drug. This system indicates good in-vitro, in-vivo correlation in humans e.g. delivery of methylphenidate to school age children for the treatment of Attention Deficit Hyper activity Disorder (ADHD).

Fig 1: Design of port system

The programmable oral release technology (PORT system) is a good example of osmosis based pulsatile drug delivery. This consists of a gelatin capsule coated with a semi permeable membrane (e.g., cellulose acetate) covering an insoluble plug (e.g., lipidic) and an osmotically active agent along with the drug formulation. When in contact with the aqueous medium, water diffuses across the semipermeable membrane, resulting in increased inner pressure that ejects the plug after a lag time. The lag time is controlled by coating thickness^[34-35].

(c) Pulsatile delivery by solubilisation or erosion of membrane:

Fig 2: Schematic diagram of delivery systems with erodible coating layer.

In this system drug reservoir is surrounded with a soluble or erodible barrier layer that dissolves with time and the drug releases at once after the lag time e.g. Time Clock system. The Time Clock system consists of solid dosage form coated with lipid barriers such as carnauba wax and beeswax along with surfactants like polyoxyethylene sorbitan monooleate. The system contacts medium resulting in coat emulsification or erodes after the lag-time depending on the thickness of coat. The lag time of system is independent of the gastrointestinal motility, PH, enzyme and gastric residence^[36-39].

(d) Pulsatile delivery by rupture of membrane:

These systems are based up on a reservoir system coated with a rupturable membrane. The outer membrane ruptures due to the pressure developed by effervescent agents. Citric acid and sodium bicarbonate is added as effervescent mixture in tablet core coated with ethyl cellulose, when system comes in contact with water it produces carbon dioxide gas which exerts pressure and after lag time rupture the membrane and rapid release of drug occurs.

Fig. 3: Diagram of delivery systems with rupturable coating layer.

A reservoir system with a semi permeable coating is appropriate for the drugs with high first pass effect so in order to obtain in-vivo drug pattern similar to the administration of several immediate release doses. Cross carmellose sodium starch glycollate is used as swelling agent here which results in complete film rupture followed by rapid drug release. The lag time is controlled by composition of out erpolymeric membrane^[40-42].

(2) Multiple Unit Systems:

Multiparticulate systems are reservoir type of devices with a coating, which either ruptures or changes its permeability. Drug is coated over sugar seeds these granules may then be packaged in a capsule or compressed with additional excipients to form a tablet. The active pharmaceutical ingredient may also be blended or granulated with polymers before coating to provide an additional level of control. However, drug loading in this type of system is low due to higher need of excipients^[43-46].

(a) Pulsatile delivery by rupturable coating:

Similar to single unit system, the rupturing effect is achieved by coating the individual units with effervescent or swelling agents. Drug delivery was controlled by the rupture of the membrane. The timing of release was controlled by the thickness of coating and the amount of water soluble polymer to achieve the pulsed release. The swelling agent includes superdisintegrents like carboxy methylcellulose, sodium starch glycollate. Polymers like polyacrylic acid, polyethylene glycol etc. and tartaric acid and sodium bicarbonate that are used as effervescent agent^[47-50].

Marketed Technologies of Pulsatile Drug Delivery System:

There are many recent marketed technologies which have been developed for pulsatile release of drug from dosage forms such as Pulsincap TM, Diffucap®, three-dimensional printing®, CODAS®, OROS®, IPDAS®, GEOCLOCK®, Ritalina®, Uniphyl®, Opana®ER.48-50 Some of them are discussed below:

Pulsincap TM technology:

Pulsincap was developed by R.R. Scherer International Corporation (Michigan). This device consists of a non-disintegrating half capsule body sealed at the open end with a hydrogel plug that is covered by a water-soluble cap. The whole unit is coated with an enteric polymer to avoid the problem of variable gastric emptying. When this capsule comes in contact with the dissolution fluid, it swells, and after a lag time, the plug pushes itself outside the capsule and rapidly releases the drug^[51].

Fig 4: Design of Pulsincap system

DIFFUCAPS® Technology:

pH variations in GI tract affect the solubility and absorption of certain drugs and cause a problem in the development of a sustained or controlled release formula. Diffucaps® is a multiparticulate bead system consists of multiple layers of drug, excipients and release-controlling polymers. The beads contain a layer of organic acid or alkaline buffer to control the solubility of a drug by creating an optimal pH microenvironment for drugs that exhibit poor solubility in intestinal pH, in environments with pH greater than 8.0 or in physiological fluids. Diffucaps® beads are <1.5 mm in diameter and can be filled into capsules or compressed into orally disintegrating tablets. In addition, for patients who experience difficulty in swallowing tablets or capsules, Diffucaps® products are produced in capsules that allow the capsules to be opened and the contents used as a sprinkle on foods, providing a flexible dosage form^[52].

CODAS® (chronotherapeutic oral drug absorption system):

In some cases, immediate release of drug is unwanted. Adelay of drug action may be required for a variety of reasons. Chronotherapy is an example of when drug release may be programmed to occur after a prolonged interval following administration. CODAS technology is designed for bedtime dosing, incorporating a 4- to 5-hdelay in drug delivery. These pellet-filled capsules provide for extended release of the drug in the GI tract. This delay is produced by the use of non-enteric release-controlling polymer to drug loaded beads. The release-controlling polymer is a combination of water soluble and water insoluble polymers. As water from the gastrointestinal tract comes into contact with the polymer-coated beads, the water soluble polymer slowly dissolves, and the drug diffuses through the resulting pores in the coating. The water insoluble polymer continues to act as a barrier, maintaining the controlled release of the drug^[53].

OROS® technology:

OROS delivery system is suitable for poorly water soluble drugs. The push-pull system is comprised of a bilayer or trilayer tablet core consisting of one push layer and one or more drug layers. The drug layer contains the poorly soluble drugs, osmotic agents and a suspending agent. A semipermeable membrane surrounds the tablet core. A variety of OROS® systems (ALZA Corp.) have been developed: Procardia XL®, Ditropan XL® and Concerta®are notable examples. L-OROSTM technology was developed by Alza to overcome the drug solubility issue. These formulations include self-emulsifying liquid carrier formulations (SEF) that allow a drug to be more readily absorbed through the gastrointestinal membrane and blood stream. The SEF in L-OROS systems consists of drugs in non-aqueous liquid carriers formulated to give either a solution or a nanosuspension. As a drug in solution is released in the GI tract, it forms very small droplets (<100nm), increasing the drugs solubility, thereby enhancing bioavailability^[54].

IPDAS® (Intestinal Protective Drug Absorption System):

This novel drug delivery system is appropriate forGI irritant drugs such as NSAIDs. The IPDAS® technology contains numerous high-density, controlled-release beads, which are compressed into a tablet form. Once an IPDAS® tablet is ingested, it disintegrates and disperses beads containing a drug in the stomach, which subsequently passes into the duodenum and then to GIT in a controlled independent of the feeding state. Release is controlled by the polymer system used to coat the beads formed in the extruded/spheronised multiparticulates. ‘Elan Drug Technologies’ prepared naproxen formulation, Naprelan®. Although naproxen, as the free acid or the sodium salt, has reliable pharmacokinetic characteristics with once-daily dosing but the GI irritant and ulcerogenic potential associated with a large bolus dose of naproxen prevents safe use of an immediate-release form. In addition, the desired pharmacodynamics activity of a once-daily dosage form of naproxen requires rapidly available naproxen for a prompt onset of analgesic activity as well as a prolonged phase of absorption to provide 24-h analgesic/anti-inflammatory activity. The prepared IPDAS system entitled Naprelan®has a proven onset of pain relief within 30 min that lasts up to 24 h and has been shown to be well-tolerated with reduced gastric irritancy^[55].

Geoclock®:

Skye Pharma developed a new oral drug delivery technology, Geoclock®, in the form of chronotherapy-focused press-coated tablets. These tablets have an active drug inside an outer tablet layer which is made of a mixture of hydrophobic wax and brittle material to get a pH-independent lag time prior to core drug delivery at a predetermined release rate. The dry coating method aids the timed release of both slow release and immediate release active cores by releasing the inner tablet first, after which time, the surrounding outer shell gradually disintegrates. Lodotra TM formulated tablet from this technique, which, once ingested, did not release the active ingredient prednisone, until approximately four hours later. This allows a patient to swallow the tablet at 10 pm before going to sleep, with the dose of prednisone not being released until 2 am and reaching maximum plasma levels at 4 am, which is regarded as the optimal timing to relieve the stiffness and pain on waking in the early hours of the morning^[56].

Fig 5: Drug release profile of pulsatile drug delivery systems

Pulsatile Drug Delivery Systems of Losartan:

Losartan is a selective, competitive angiotensin II (receptor type 1 (AT1)) antagonist, reducing the end organ responses to angiotensin II. Reduction in blood pressure occurs independently on the status of the renin-angiotensin system. Losartan is well absorbed after oral intake and bioavailability of about 33% and plasma half-life ranging from1.5 to 2.5hours. It does not have the adverse effect of dry cough. Losartan may be used to treat hypertension, isolated systolic hypertension, left ventricular hypertrophy and diabetic nephropathy. It may also be used as an alternative agent for the treatment of systolic dysfunction, myocardial infarction, coronary artery disease, and heart failure^[57].

Based on the concept of pulsatile release, some formulations are already prepared by different techniques. Natural as well as synthetic polymers are of great use in pulsatile formulation as they contribute a lot to extend the drug release as release retardants.

Ashwini MS et al. designed pulsatile capsule of losartan involves the preparation of cross linked hard gelatin capsules by using formaldehyde, then the drug diluent mixture were prepared and loaded in, which was separated by using hydrogel plugs of different polymers of different viscosities. Prepared formulations were subjected to evaluation of various parameters like weight variation, percentage drug content, in vitro drug release and stability studies^[58].

Bojja R et al. formulated drug delivery system based on an insoluble capsule body filled with Losartan potassium microspheres and sealed with hydrogel plug. The microspheres were prepared by Emulsification internal gelation method. Microspheres containing Losartan potassium were prepared employing sodium alginate alone and in combination with xanthan gum and guar gum, BaCO₃as crosslinking agent. The homogeneous polymer(s) solution was prepared in distilled water stirred magnetically with gentle heat. The drug and cross-linking agent were added to the polymer solution and mixed thoroughly by stirring magnetically to form a viscous dispersion which was then extruded through a syringe with a needle of size no. 23 into light liquid paraffin containing 1.5% Tween 80w/v and 0.2%v/v glacial acetic acid being kept under magnetic stirring at 100 rpm. The microspheres were retained in the light liquid paraffin for 30 min to produce rigid discrete particles. They were collected by decantation and the product thus separated was washed with chloroform to remove the traces of paraffin oil. These microspheres were characterized for size analysis, flow properties, % Drug Content, % Entrapment efficiency^[59].

Latha K et al. prepared the press-coated tablets (PCT) containing losartan potassium in the inner core were made by compression-coating with hydroxyl propyl methyl cellulose (HPMC 100KM) alone and mixed with micro crystalline cellulose (MCC) as the outer layer in different ratios. The HPMC 100KM and MCC were accurately weighed. A solution of 7.5% PVP in hydro alcoholic mixture of iso propyl alcohol and water in the ratio of 70:30 was used to wet mass the HPMC 100KM and MCC. The wet mass was pressed through a sieve of 710μm aperture size and dried for 2 hrs at 450C in a hot air oven. The dried mass was again screened through a sieve of 500μm aperture size. Talc and magnesium stearate were added to the dried granules and passed through a sieve of 500μm aperture size and blended for 2 minutes. Half the amount of polymer granules was placed inside the die to make a powder bed. The core tablet was placed at the center on the polymer bed while the remaining half of the polymer granules was filled into the die. The content was compressed at a constant compression force with a rotary compression machine. The effect of the outer layer on the lag time of drug release was investigated. The parameters determined were tablet tensile strength, friability, drug content and in vitro dissolution. Fourier trans form infra red spectroscopy (FTIR) and powder X-ray diffractometry (PXRD) to investigate any drug/excipient modifications/interactions^[60].

Shivhare UD et al. formulated the core tablets which were prepared by using wet granulation containing a superdisintegrant. Eudragit S100 and Eudragit L100 were used as pH dependent polymers for coating of tablets. All the ingredients were accurately weighed and sieved through sieve No. 60. To mix the ingredients thoroughly, losartan potassium, micro-crystalline cellulose and cross carmellose sodium were blended in mortar and pestle for 15 min. then passed through sieve #85. Blend was mixed in polybag for 10 min and mixture was granulated with granulating fluid prepared by dissolving binding agent polyvinyl pyrroli done (PVP K-30) in Isopropyl alcohol. The wet mass was then passed through sieve #16 and the granules obtained were dried at 60°C for 30-45 min. The dried granules were sized with sieve #22 and finally granules were blended with magnesium stearate and talc as lubricant and glidant respectively. Granules were compressed on tablet punching machine. A pre weighed sample of sufficient number of core tablets was placed in a conventional coating pan and the coating solution (solution of Eudragit S100 and Eudragit L100) was sprayed manually onto the surface of the tumbling tablets with a spray gun and were dried in an oven at 50-52°C for minimum 6 h for removal of residual solvent. Tablets were evaluated for various pre and post compression such as compressibility index, Hausners ratio, hardness, friability, weight variation, thickness, drug contentand drug release^[61].

Bajpai M et al. used direct compression method using 7 mm concave punch with single station tablet compression machine to develop pulsatile release tablet with lag time of 5-6 h and fast drug release there after so two types of core tablets were prepared, one containing superdisintegrant crosspovi done (C) and other containing effervescent agent (E) for producing burst release from final coated tablet. Optimized formulation containing effervescent agent contained 50 mg losartan potassium, effervescent agent (NaHCO₃: citric acid, 1:0.76), sodium chloride and microcrystalline cellulose (15.66% w/w each based on total core weight) as filler, talc and magnesium stearate (1% w/w each based on total core weight) as lubricant and glidant. Optimized batch containing crosspovidone contained 50 mg losartan potassium, 12% crosspovidone, 27.66% lactose, 16.66% starch and 1% each talc and magnesium stearate in 120 mg tablet. Three types of granules were prepared by using three different polymers i.e. sodium carboxymethyl cellulose (NaCMC), HPMC K4M, and HPMC E50. Granules were formed by simple mixing of polymer with 5% w/v alcoholic solution of polyvinyl pyrollidone K30 to form dough. The formed dough was passed through sieve, dried and resieved through sieve no. 20. Finally mixed with talc and magnesium stearate. In addition to above polymers hydroxypropyl cellulose was directly used (without granulation) for compression coating because of its directly compressible character.

Two hundred milligrams of prepared granules was used for shell formation in each tablet. Press coating of tablet was performed. Half the amount of powder from 200 mg was filled into the die to form a powder bed. In center core, tablet formulation is placed. Over this remaining half of the granules was filled into die and contents were compressed using concave punches of 10 mm diameter. Tablets were evaluated for hardness, disintegration time, weight variation, thickness, drug content and drug release ^[62].

Sravani SL et al. developed microspheres formulations which were prepared by emulsion solvent evaporation. The effect of various formulation and processing factors on microspheres characteristics were investigated by changing polymer: drug ratio. Weighed amount of Losartan potassium and polymer in 1:1 ratio were dissolved in 10ml of chloroform. The homogeneous drug and polymer organic solution was then slowly added in a thin stream to 100ml of liquid paraffin containing 1% surfactant (span 80) with constant stirring for 1h. The resulting microspheres were separated by filtration and washed with petroleum ether. The microspheres finally air dried over a period of 12 hr and stored in a desiccator. In case of 1:1.5and 1:2 core:coat ratios, the corresponding polymer get varied respectively.

Capsule Bodies were separated from cap, 25 ml of 15% (v/v) formaldehyde was taken into desiccators and a pinch of potassium permanganate was added to it, to generate formalin vapours. The wire mesh containing the empty bodies of capsule was then exposed to formaldehyde vapours. The reaction was carried out for 12 h after which the bodies were removed and dried at 50⁰C for 30 min to ensure completion of reaction between gelatin and formaldehyde vapours.

Plug for sealing the capsule body was prepared by compressing equal amount of equal amount of HPMC K100: lactose, carbapol: lactose, sodium carboxy methyl cellulose (Na CMC): lactose, and Methyl Cellulose: lactose using 7 mm punches and dies on rotary tablet press.

The microspheres were evaluated for Hausners ratio, Average particle size, encapsulation efficiency, drug content and drug release^[63].

Madgulkar A et al. presented research work to develop release modulated beads of losartan potassium complexed with anion exchange resin, Duolite AP143 (cholestyramine). Chitosan was selected as a hydrophilic polymer for the formation of beads which could sustain the release of the drug up to 12 h, along with drug resin complex (DRC). Chitosan beads were prepared using an in-liquid curing method by inotropic cross-linking or interpolymer linkage with sodium tripolyphosphate (TPP).

DRC was prepared by a single batch process. The purified ion-exchange resin particles were dispersed in a drug solution with a net weight ratio of 1:1 in the pH range of 6–7 and stirred for 4 h, room temperature. The DRC was separated by filtration and dried in a hot air oven at 50°C.

Drug-loaded beads were prepared by droplet extrusion/ ionic cross-linking of the chitosan solution containing DRC into sodium TPP aqueous solution. Chitosan solution of 2% w/v was prepared by dissolving chitosan in acetic acid (2% v/v), then DRC was dispersed uniformly in this solution with gentle stirring. The bubbles in the mixed system were eliminated by sonication. Then, it was dropped using a 22-gauge needle into a gently stirred aqueous solution of TPP at a flow rate 1 ml/min. Beads were formed instantaneously due to the electrostatic attraction between NH3⁺on chitosan and PO4^-on TPP. The solidified beads were filtered and rinsed thoroughly with distilled water to remove traces of TPP and dried.

The dried beads were studied for Average particle size, surface morphology by Scanning Electron Microscopy (SEM), swelling behavior, encapsulation efficiency and drug release^[64].

Nagaraja G et al. prepared microspheres by solvent evaporation method in which Losartan potassium was added to the polymer solution (Eudragit L-100 and S-100 in 1:2 ratios were dissolved in 10 ml of acetone) and mixed thoroughly. This organic phase was slowly poured at 15^oC into liquid paraffin (100 ml) containing 1%w/w of Span-80 with stirring at 1000 rpm to form a smooth emulsion. Thereafter, it was allowed to attain room temperature and stirring was continued until residual acetone evaporated and smooth-walled, rigid and discrete microcapsules were formed. The microcapsules were collected by decantation and the product was washed with n-Hexane, four times and dried at room temperature for 3 hrs.

Bodies were separated from the caps. 25 ml of 15% v/v formaldehyde was taken into desiccator and a pinch of potassium permanganate was added to it, to generate formalin vapors. The wire mesh containing the bodies of the capsule was then exposed to formaldehyde vapors. The desiccator was tightly closed. The reaction was carried out for 12 hrs after which the bodies were removed and dried at 50^oC for 30 minutes to ensure completion of reaction between gelatin and formaldehyde vapors.

Formaldehyde treated hard gelatin capsules were chosen for the formulation. The bodies and caps were separated manually. Microcapsules equivalent to 150 mg of the Losartan potassium were accurately weighed and filled into the treated bodies by hand filling. The capsules containing the microcapsules were then plugged with different grades like hydroxyl propyl methylcellulose at different concentration like HPMC K4M, HPMC E15, and HPMC E50–20, 30, 40 mg. The joint of the capsule body and cap was sealed with a small amount of the 5% ethyl cellulose ethanolic solution. The sealed capsules were completely coated with 5% Cellulose Acetate Phthalate (CAP) to prevent variable gastric emptying.

The microspheres were studied for Average particle size, surface morphology by SEM, encapsulation efficiency,% Yield, Carr’s Index, Hausner’s ratio, and drug release^[65].

Murthy TE et al. prepared modified released tablets for losartan potassium by wet granulation technique by using natural (Guar gum, Xanthan, Gum karaya, Gum kondagogu, Olibanum) and modified [CMGG (Carboxy methylated guar gum), CMGG-I (Carboxy methylated guar gum-Iodine), BG-C (Borax Guar gum- Cross linked), BG-F (Borax Guar gum- Films)] gums as release retardant polymers^[66].

The summary of previous work done on pulsatile drug delivery of Losartan is given in Table 2.

CONCLUSION:

Pulsatile drug delivery system has been realized as extremely useful system in various scientific areas. Over the years, many methodologies have been employed for developing pulsatile drug delivery system like controlled PDDS which is often made up of rupturable or erodible polymer coating layer. Extended release formulations and immediate release formulation are not efficient in treating the diseases especially diseases with chronological pathopysiology, for which, pulsatile drug delivery is beneficial. The drug is delivering in this system when its actual concentration is needed as per chronological need. Pulsatile release systems must be promising in the future with the virtue of delivering drug at the right time, right place and in right amounts so that the patients suffering from chronic problems like arthritis, asthma, hypertension etc. can be benefitted. The future holds a lot of promises in pulsatile drug delivery system and by further study this will be developed as novel and efficient approach. Circadian rhythm of the body is an important concept for understanding the optimum need of drug in the body. Thus, designing of proper pulsatile drug delivery will enhance the patient compliance, optimum drug delivery to the target side andminimizing the undesired effects. The etiology of the dreaded diseases like hypertension, cardiac arrest, asthma etc. can be linked to the release of the specific drugs through these systems. Reviewed studies of PDDS with reference to Losartan and Captopril shows that pulsatile drug delivery system would definitely contribute in the betterment of the therapy for the hypertension.

AUTHOR’S CONTRIBUTION:

All the authors have contributed equally in the collection of data and to assemble information in writing of the manuscript.

ACKNOWLEDGMENTS:

Author thanks Prof. Syed Waseem Akhtar, Hon. Chancellor and Prof. Aqil Ahmad, Hon. Vice Chancellor for providing excellent research facility in the university. The university has provided a manuscript communication number for further communication (IU/RandD/2018-MCN000473).

CONFLICT OF INTEREST:

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

REFERENCES:

1. Vaniprasanna Tubati et al. An Over View of Chronotherapeutic Drug Delivery Systems Based on Floating Pulsatile Concept. Journal of Advances in Medical and Pharmaceutical. 2016, 7(3):1-18.

2. Singh HN, Saxena S, Singh S, Yadav AK. Pulsatile Drug Delivery System: Drugs used in the Pulsatile Formulations. Research Journal of Pharmaceutical Dosage Forms and Technology. 2013, 5(3):115-121.

3. Dhengale AA, Darekar AB, Saudagar RB. A Review: Pulsatile Drug Delivery System. Research Journal of Pharmaceutical Dosage Forms and Technology. 2016, 8(3): 221-227.

4. Patil IS, Patil OA, Mandake GC, Nitalikar MM. Development and Evaluation of Telmisartan Pulsatile Drug Delivery by using Response Surface Methodology. Asian Journal of Pharmaceutical Research. 2018, 8(4): 205-14.

5. Baghel P, Roy A, Chandrakar S, Bahadur S. Pulsatile Drug Delivery System: A Promising Delivery System. Research Journal of Pharmaceutical Dosage Forms and Technology. 2013, 5(3): 111-114.

6. Guo ZX, Qiu MC. Losartan down regulates the expression of transforming growth factor beta type I and type II receptors in kidney of diabetic rat. Zhonghua NeiKe ZaZhi. 2003, 42(6): 403-8.

7. Lemmer B. Chronopharmacokinetics: Implications for drug treatment. Journal of Pharmacy and Pharmacology. 1999, 51: 887-890.

8. Sukanya M, Saikishore V, Shanmukha PY, Srikanth K. Novel Approaches for Pulsatile Drug Delivery System. Research Journal of Pharmaceutical Dosage Forms and Technology.2012, 4(4): 197-201.

9. Trivedi RV et al. Chronotherapy: A concept, pauperism and approches. International Journal of Pharmaceutical Development and Technology. 2011, 1(1):1-10

10. Sudhamani T et al. Chronotherapeutic floating pulsatile drug delivery: An approach for time specific and site specification absorption of drugs. Research Journal of Pharmaceutical Technology. 2011, 4(5): 685-690.

11. Evans RM, Marain C. Taking your medication: A question of timing. American Medical Association 1996, 3-8.

12. Li JJ. Circardian variation in myocardial ischemia: The possible mechanisms involving in this phenomenon. Med Hypotheses. 2003, 61(2): 240-243.

13. Nainwal Nidhi, Chronotherapeutics: A chronopharmaceutical approach to drug delivery in the treatment of asthma. Journal of Controlled Release. 2012, 163(3):353-360.

14. Saigal Nitin, Baboota Sanjula, Ahuja Alka, Ali Javed. Site specific chronotherapeutic drug delivery system: A patent review. Recent patents on drug delivery and formulation. 2009: 64-70.

15. Tangri P, Khurana S. Pulsatile drug delivery systems: Methods and advances. International Journal of Drug Formulation and Research. 2011, 2(3):100-114.

16. Bhandawalkar K, et al. Recent trends in pulsatile drug delivery systems: A review. International Journal of Institutional Pharmacy and Life Sciences. 2002, 2(3): 167-185.

17. Singh NP, Ganarajan G, Kothiyal P. Pulsatile drug delivery system: a review. World Journal Pharmacy Pharmaceutical Sciences.2016, 5:479-491.

18. Dalvadia H, Patelb JK. Chronpharmaceutics, pulsatile drug delivery system as current trend. Asian journal of pharmaceutical sciences. 2010, 5(5):204-30.

19. Herold M, Günther R. Circadian rhythm of C-reactive protein in patients with rheumatoid arthritis. Progress in clinical and biological research. 1987, 227:271-9.

20. Martin RJ, Banks SS. Chronobiology of asthma. American Journal of Respiratory Critical Care Medicine.1998; 158:1002–1007.

21. Arkinstall WW. Review of the North American experience with evening administration of Uniphyl tablets, a once daily theophylline. The American Journal of Medicine. 1994, 85(1): 521–524.

22. Bogin RM, Ballard RD. The treatment of nocturnal asthma with pulsed release albuterol. Chest.1992, 102: 362-366.

23. Khamidov N, Zaslavskaia RM, Arustamian GS. The daily dynamics of blood lipids in elderly subjects with hypertension. Laboratornoedelo.1990, (11):47-50.

24. Hulcher FH, Reynolds J, Rose JC. Circadian rhythm of HMG-CoA reductase and insulin in African green monkeys. Biochemistry international. 1985;10 (2):177-85.

25. Mayer D. The circadian rhythm of synthesis and catabolism of cholesterol. Archives of toxicology.1976, 36(2-4): 267–276

26. Rigas AN, Bittles AH, Hadden DR, Montgomery DA. Circadian variation of glucose, insulin, and free fatty acids during long-term use of oral hypoglycemic agents in diabetes mellitus. British Medical Journal. 1968, 4(5622): 25-8.

27. Cincotta AH, Meier AH. Circadian rhythms of lipogenic and hypoglycaemic responses to insulin in the golden hamster (Mesocricetus auratus).Journal of endocrinology. 1984, 103(2):141-6.

28. Humphries TJ, Root JK, Hufnagel K. Successful drug specific chronotherapy with the H₂ blocker famotidine in the symptomatic relief of gastro esophageal reflux disease. Annals of the New York Academy of Sciences. 1991, 618(1):517.

29. Lemmer B. Cardiovascular chronobiology and chronopharmacology. Biological Rhythms in Clinical and Laboratory Medicine. 1992, 2:418-427.

30. Tofler GH et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. New England Journal of Medicine. 1987,, 316(24):1514-8.

31. Libo Y, James L, Joseph A. Colonic-specific drug delivery: new approaches and Invitro/invivo evaluation. International Journal of Pharmacy. 2002;235:1-15.

32. Reddy JR et al. Pulsatile Drug Delivery System. Journal of Pharmaceutical Science and Research. 2009; 1(4): 109-115.

33. Ueda T et al. Development of Novel Drug Delivery System, Time Controlled Explosion System (TES). I. Concept and design. Journal of drug targeting. 1994;2(2):133-40.

34. Baker R.W. Controlled release delivery system by an osmotic bursting mechanism. US Patent. 1976; 3,952,741.

35. Schultz P, Kleinebudde P. A new multiparticulate delayed release system: Part I: dissolution properties and release mechanism. Journal of controlled release. 1997;47(2):181-9.

36. Morita R, Hunda Y, Takahashi R. Development of Oral Controlled Release Preparation; I. Design of SCAR and Its Release Controlling Factor. Journal of Controlled Release. 2000:279-309.

37. Gennaro AR, ed. Remington: The Science and Practice of Pharmacy. 20th ed. USA: Lippincott. Williams and Wilkins.2000; 20: 903-905.

38. Das NG, Das SK. Controlled release of oral dosage forms. Pharmaceutical technology. 2003; 15:10-7.

39. Ashford M, Fell JT, Attwood D, Sharma H, Woodhead PJ. An in vivo investigation into the suitability of pH dependent polymers for colonic targeting. International Journal of Pharmaceutics. 1993; 95(1-3):193-9.

40. Evans DF et al. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut. 1988;29(8):1035-41.

41. Gurny R, Junginger HE, Peppas NA. Pulsatile drug delivery (current applications and future trends). Paperback APV. Stuttgart, Germany. 1993.

42. Ibekwe VC, Kendall RA, Basit AW. Drug delivery to the colon. The Drug Delivery Companies Report, Spring/Summer, Pharmaventures Ltd. 2004.

43. Takaya T et al. Development of a colon delivery capsule and the pharmacological activity of recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) in beagle dogs. Journal of pharmacy and pharmacology. 1995;47(6):474-8.

44. Bussemer T, Otto I, Bodmeier R. Pulsatile drug delivery systems. Critical Review. The Drug Carrier System. 200;18(5): 433-58.

45. Daumesnil R. Marketing Considerations for multiparticulate drug delivery systems. Drugs and the pharmaceutical sciences. 1994; 65:457-74.

46. Schultz P, Tho I, Kleinebudde P. A new multiparticulate delayed release system.: Part II: coating formulation and properties of free films. Journal of controlled release. 1997;47 (2):191-9.

47. Chen CM. Multiparticulate Pulsatile Drug Delivery System. US Patent No. 5,508,040; 1996.

48. Schultz P, Kleinebudde P. A new multiparticulate delayed release system. Part I: Dissolution properties and release mechanism. Journal of controlled release.1997; 47: 181-189.

49. Sungthongjeen S, Puttipipatkhachorn S, Paeratakul O, Dashevsky A, Bodmeier R. Development of pulsatile release tablets with swelling and rupturable layers. Journal of controlled release. 2004;95(2):147-59.

50. Survase S, Kumar N. Pulsatile Drug Delivery Current Scenario. CRIPS 2007; 8(2): 27-33.

51. MacNeil ME, Rashid A, Stevens HN. Dispensing device.World Patent 1990; 9009168.

52. Roy P, Shahiwala A. Multiparticulate formulation approach to pulsatile drug delivery: current perspectives. Journal of controlled release. 2009;134(2):74-80.

53. Troy M. Timing drug availability with therapeutic need. Speciality pharma. 2004; 2:44-7.

54. Bhatt Ashvin D, Pethe AM. Lipid Technology-A Promising Drug Delivery System For Poorly Water Soluble Drugs. International Journal of Pharma Research and Development. 2010; 1:1-11.

55. Verma RK, Garg S. Drug delivery technologies and future directions. Pharmaceutical Technology. 2001; 25(2):1-4.

56. Jain D, Raturi R, Jain V, Bansal P, Singh R. Recent technologies in pulsatile drug delivery systems. Biomatter. 2011 Jul 1; 1(1):57-65.

57. Nayakulu BR, Kumar NR, Kumar CK, Abhilash PR. Formulation and evaluation of floating matrix tablet of Losartan for gastroretentive drug delivery. Asian Journal of Pharmacy and Technology. 2016;6(2):85-90.

58. Ashwini MS, Ahmed MG. Design and evaluation of Pulsatile drug delivery of Losartan Potassium. Dhaka University Journal of Pharmaceutical Sciences. 2013;12(2):119-23.

59. Bojja R, Satyanandam R. Design and Development of Pulsincap for Chronopharmaceutical Drug Delivery of Losartan Potassium. Asian Journal of Pharmaceutical Research and Development. 2014; 2(3):78-86.

60. Latha K et al. Development of an Optimized Losartan Potassium Press-Coated Tablets for Chronotherapeutic Drug Delivery. Tropical Journal of Pharmaceutical Research. 2011; 10(5): 551-558.

61. Shivhare UD, Kakade VN. Formulation and Evaluation of Pulsatile Drug Delivery System of Losartan Potassium by Factorial Design. International Journal of pharmaceutical Sciences and Nanotechnology. 2013;5 (4):1895-1901.

62. Bajpai M et al. Design and In Vitro Evaluation of Compression-coated Pulsatile Release Tablets of Losartan Potassium. Indian Journal of Pharmaceutical Sciences. 2012;74(2): 101–106.

63. Sravani SL, Saikishore V, Saikrishna MV. Design and Characterization of Pulsatile Drug Delivery of Losartan Potassium. Indo American Journal of Pharmaceutical Sciences. 2017; 4(3):706-712.

64. Madgulkar A, Bhalekar M, Swami M. In Vitro and In Vivo Studies on Chitosan Beads of Losartan Duolite AP143 Complex, Optimized by Using Statistical Experimental Design. American Association of Pharmaceutical Scientists. 2009;10(3):743-751.

65. Nagaraja G et al. Design and evaluation of time programmed pulsincap system for chronotherapeutic delivery of losartan potassium. Journal of Chemical and Pharmaceutical Research. 2013;5(6):76-87.

66. Murthy TE, Madalasa AL. Design and Development of Oral Modified Release Formulations for Losartan Potassium with Natural and Modified Gums. Research Journal of Pharmaceutical Dosage Forms and Technology. 2018;10(3):149-56.

67. Noman MA, Albooryhi M, Sayf AA, Kadi HO. In-vitro evaluation of captopril tablets present in Yemen markets. Research Journal of Pharmaceutical Dosage Forms and Technology. 2012;4(2):124-7.

68. Gadad AP et al. Design and characterization of hollow/porous floating beads of captopril for pulsatile drug delivery. Asian Journal of Pharmaceutics. 2012:137-143.

69. Thampi NK et al. Formulation, Optimization and Evaluation of Floating Pulsatile Beads of Captopril. World Journal of Pharmacy and Pharmaceutical Sciences. 2017; 6(6):1619-1637.

70. Meka L et al. Preparation of a Matrix Type Multiple-Unit Gastro Retentive Floating Drug Delivery System for Captopril Based on Gas Formation Technique: In Vitro Evaluation. AAPS Pharm Sci Tech. 2008;9(2):612.

71. Kapoor D, Patel R et al. Formulation, Optimization and Evaluation of Floating Microspheres of Captopril. Asian Journal of Biomedical and Pharmaceutical Sciences. 2012;2(9) :1-10.

72. Thadkala K, Prathyusha R, Raju A et al. Formulation Development, Optimization and Characterization of Floating Beads of Captopril. International Journal of Pharmaceutical Research and Allied Sciences. 2013; 2(2):32-46.

73. Basawaraj S. Patil, et at. Formulation and in-vitro evaluation of Captopril floating matrix tablets. Journal of Pharmacy Research. 2012; 5 (2).803-806

Received on 02.03.2019 Modified on 27.03.2019

Research J. Pharm. and Tech. 2019; 12(7):3175-3188.

DOI: 10.5958/0974-360X.2019.00535.3

Dosage Form	Polymers and Excipients	Method	Result
Capsule	HPMC, Sodium CMC, Lactose	Crosslinking of hard gelatin capsule shell with formaldehyde followed by drug and excipients loading by hand filling which is separated by hydrogel.	Release studies revealed that the capsules plugged with polymer HPMC showed better pulsatile release of drug over a period of 8 to 10 hours. FTIR studies indicated that there was no chemical interaction between the drug and excipients used. The percentage drug content was from 98.75 -100.25. The stability studies showed no change in the physical changes and appearance at room temperature andat 40°/75 RH.
Microspheres	BaCO₃, Sodium alginate, guar gum and Xanthan gum	Emulsification internal gelation	Microspheres containing Sod. Alginate+Xanthum Gum + Drug showed best result i.e 12 hours (5^thhour to 17^thhour) sustained action compared to other formulations. FTIR studies revealed that there was no change or shifting of characteristic peaks in drug loaded microspheres suggested no significant drug polymer interaction which indicates the stable nature of the drug in all formulations. % Yield= 88%-93%. Encapsulation efficiency=94.3-98.6 % Drug content=19.6-10.4% Particle size= 625.34-718.68μm.
Tablet	HPMC, PVP K30, CCS, MCC, Talc, Magnesium striate	Wet granulation	Formulation with HPMC+MCC (30:70) +drug showed a predetermined lag time of 6 h prior to burst release of the drug from tablet. Friability values (%) was 0.42 ± 0.05. Tensile strength was 1.06 ± 1.2 % Drug content was 99.1 ±1.5 FTIR spectra showed the characteristic peaks separated for both the drug and excipient. The powder x-ray diffraction patterns of the drug and polymer (HPMC 100KM) that Losartan potassium showed distinct characteristic crystalline peaks at angles of 11.5, 14.5, 19.5 On the other hand, HPMC 100KM showed no characteristic peaks which indicates that it is amorphous
Tablet	EudragitL100, Eudragit S100, PVP K30, MCC, Talc, Magnesium striate	Wet granulation	The formulation with Eudragit L100 andEudragit S100(1:2) exhibited best lag time of 5.5 hours and drug release 95.23% for 12 hours. The drug content was uniform (97.7 ± 0.032 to ± 0.053) Hardness (kg/cm²) = 4.5-5.3 Friability (%) = 0.43-0.99 Weight Variation(mg)=106-110 Thickness(mm)=2.3-3.3 Compressibility Index=7.5-13.2 Hausner’s ratio=0.87-0.92
Tablet	HPMC K4M, HPMC E50, HPC, effervescent agent (NaHCO₃, citric acid, 1:0.76), sodium chloride, cross povidide, microcrystalline cellulose, talc and magnesium stearate	Direct Compression	Formulation containing effervescent agent in core and coated with hydroxypropyl cellulose (HPC) provide lag time of 4.5 h with 73% drug release in 6 hours. Drug Content=99.3 ±0.31 Thickness(mm)=2.50-2.58 Hardness(kg/cm²) =1±0.2 Disintegration time (With superdisintegrant) = 4±0.40 min. Disintegration time (With effervescent agent) = 0.95±0.40 min
Microspheres	Eudragit RLPO and Eudragit RSPO, HPMC K100, lactose, carbapol, Na CMC and Methyl Cellulose	Emulsion solvent evaporation technique	Microspheres prepared with HPMC K100 +Lactose in 1:2 ratio has shown lag time of 5 hours and prolonged release for a period of 12 hours. % Drug Content=32.41-48.56 % Encapsulation efficiency=96.46-98.22 Average Particle Size=5.22.17-588.24 μm Hausner’s Ratio=1.180-1.188 Angle of repose=26.10-27.64
Beads	Chitosan, acetic acid, Tripolyphosphate (TPP), Duolite (Resin)	Ionotropic Crosslinking method	Studies revealed that as the concentration of chitosan and TPP was increased, entrapment efficiency and the drug release were found to increase. % Entrapment efficiency=79-92 Degree of Swelling=410% SEM= SEM studies demonstrate the morphology of beads. Beads were spherical with roughness on the surface. DSC= DSC studies confirm the complexation of losartan potassium with Duolite AP143, as each chemical entity shows its characteristic DSC curve.
Microcapsules	HPMC K4M, HPMC E15, HPMC E50, Cellulose Acetate Pthalate (CAP), Span 80, Paraffin,n-hexane	Solvent evaporation	% release for formulation having 1:2 ratio of drug and HPMC K4M was found to be 98.45% at the end of 12th hrs after maintaining lag time of 5 hours. % Yield=79.93-91.26 Particle Size Analysis=135-655μm Hausner’s ratio=1.19-1.30 Carr’s Index=15.71-19.11 Entrapment Efficiency=68.93-80.12 SEM= Particles were rough surfaced spherical, smooth and discrete.
Tablet	Modified natural gums e.g. Carboxy methylated guar gum, Carboxy methylated guar gum-Iodine	wet granulation method	The formulation with borax guar gum exhibited beat results. Drug content (%) =99.2±0.24 Hardness (kg/cm²) = 4±0.12 Friability (%) =0.275-0.019 Weight Variation (mg)= 213.6±1.14 Thickness (mm)=3.27±0.03

Dosage Form	Polymers and Excipients	Method	Result
Beads	Methoxy Pectin, Guar Gum, Calcium chloride, acetic acid, sodium bicarbonate	Ionotropic Gelation Technique	The formulation containing 1:3 ratio of methoxy pectin: Guar gum with comparatively higher amount of sodium bicarbonate showed drug showed 96.7% drug release for 8 hours after maintain 6 hour lag time. Particle Size=0.946-1.124mm %Entrapment efficiency=62.92-83.10 Bulk Density(g/cc) =0.72-1.73 % Bead Porosity=28.34-38.41 Floating Ability= 6-12 hours
Beads	Sodium alginate, acetic acid, sodiumbicarbonate, calcium chloride	Ionotropic Gelation Technique	The results of invitro drug release in both acidic and phosphate buffer showed minimum% cumulative drug release of 11.13% at 6th hr in acidic buffer and sudden release of 96.49% drug in phosphate buffer within 1 hr. Entrapment efficiency= 97.59% FTIR=It shows that no incompatibility is present between the drug and excipients. DSC= Symmetric peak at 109⁰C before the corresponding melting point of Captopril, is observed with no significant baseline changes implies that the sample is pure and the heat capacity of the sample does not change along the process. SEM= Particle surface was rough, spherical in shape and discrete. Buoyancy study= 6 hrs floating time was observed.
Tablet	MCC, HPMC K100, Ethyl Cellulose, Eudragit, PEG (Poly Ethylene Glycol), Sodium bicarbonate	Direct Compression Technique	The formulation containing Eudragit as gas entrapment polymeric membrane showed highest buoyancy over a period of 12 hours and highest release. Friability=0.4±0.08%; % Compressibility= 14.43-0.30 Angle of Repose(degrees)=28.01±1.44; Hausner’s ratio=1.17±0.14 Floating Ability= 12 hours SEM=Surface of effervescent layered units coated with polymers was smoothest. DSC=In the mixture of drug and excipients melting endotherm of drug was well preserved with slight changes in terms of broadening or shifting towards the lower temperature. It has been reported that the quantity of material used, especially in drug–excipient mixtures, affects the peak shape and enthalpy. Thus, it was concluded that captopril is compatible with all the excipients used in the formulation.
Floating microspheres	HPMCK4, Ethyl Cellulose, Tween 80, Dichloromethane, Ethanol, Liquidparaffin	Non-aqueous Solvent Evaporation method	It was observed that as the concentration of HPMC K 4 M increased, the % cumulative release of captopril decreased. Formulation with 3:1 ratio of drug and polymers with 600 rpm speed showed 85.52% buoyancyand 97.5% drug release. % Yield=48.21-86.09 Particle size= 49.3-96.0 mm Buoyancy (%) = 68.13-88.33 Hausner’s ratio = 5.19-10.1 Angle of Repose(degrees)=0.62-0.78 Bulk Density(gm/cc³) = 0.652-0.84 SEM= Microspheres showed a hollow spherical structure with a smooth surface morphology. DSC=It has been observed that there is no chemical interaction between captopril and the polymer used.
Floating Beads	Sodium alginate, Carbopol934P, Arachis Oil	1-Ionotropic Gelation Method (Without arachis oil), 2-Emulsion Gelation Method (with Arachis oil)	Floating beads made from emulsion gelation method showed higher entrapment efficiency and better buoyancy as compared to beads made by ionotropic gelation method. Arachis oil containing beads gave the release upto 12 hours after maintaining 6 hr. lag time. Particle size=1.27-1.38mm % Yield=31.6-98.5 %Entrapment efficiency=26.18-87.32 Buoyancy=65-100% SEM=The surface of the oil-entrapped alginate microspheres was rough and showed small pores containing oil droplets dispersed all over the structure. FTIR=The absorption peak values were matching with the peak values obtained for pure drug sample captopril and polymers carbopol and sodium alginate
Floating Matrix Tablets	HPMC K4M, Talc, Sodium carbonate, Magnesium stearate	Direct Compression Method	The matrix tablets containing HPMCK4M and sodium bicarbonate showed drug showed 97.47% drug release. Thickness= 4.55 ± 0.03mm. Weight Variation(mg)= 250 ± 0.85 Drug Content (%) =99.55 ± 1.47 Friability (%) =0.59 ± 0.02 Hardness (kg/cm2) = 5.0 ± 0.62 Swelling index (%) =39.20 ± 0.38 Floating Ability = >12 hours