International Journal of Drug Development and Research

Key words

Circadian rhythm; pulsatile drug delivery system; cardiovascular ailments; Diffucaps

INTRODUCTION

Now-a-days, the emphasis of pharmaceutical researchers is turned towards the development of more efficacious drug delivery systems with already existing molecule. Modified release dosage forms have a great importance in this regard. Such systems control the release pattern of drug, either with constant or variable rates drug is released with predetermined release rates. However, there are certain conditions for which such a release pattern is not suitable. These conditions demand release of drug after a lag time. This condition can be achieved by pulsatile drug delivery system which is defined as the rapid and transient release of certain amount of molecules within a short time period immediately after a predetermined off- release period i.e. lag time. A pulse has to be generated in such a way that a complete and rapid drug release is achieved after the lag time so as to match body’s circadian rhythms with the release of drugs1.

In this graph, it was aimed to achieve a sigmoid release pattern (Figure 1). The characteristic feature of the formulation was a well defined lag time followed by a drug pulse with the enclosed active quantity being released at once. Thus, the major challenge in the development of pulsatile drug delivery system is to achieve a rapid drug release after the lag time. Often, the drug is released over an extended period of time (patterns b & c in Figure. 1). A new concept of chronopharmaceutics has emerged, wherein research is devoted to the design and evaluate the drug delivery systems that release a therapeutic agent at a rhythm that ideally matches the biological requirement of a given disease therapy2.

The “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. These are:

Ultradian Rhythms

Shorter duration oscillations are termed as Ultradian Rhythms (more than one cycle per 24 h). E.g.90 minutes sleep cycle.

Infradian Rhythms

Oscillations that are longer than 24 hours are termed as Infradian Rhythms (less than one cycle per 24hours) e.g. Monthly Menstruation.

Circadian rhythms

Circadian rhythms are self-sustaining, endogenous oscillations that occur with a periodicity of about 24 Hours (Figure. 2).

These rhythms allow organism to anticipate and prepare for precise and regular environment changes. There are clear patterns of core body temperature, brain wave activity, hormone production, and other biological activities linked to this cycle. Some people function best in the morning while others have their peak in the noon or evening. If our normal rhythm is disrupted we tend to become anxious e.g. many people have difficulty in adjusting to swing-shift work schedules. In sleep wake cycle, an animal will settle into a 24 hour cycle activity and sleep even if deprived of light. Diurnal blood pressure fluctuations are super imposed by a 24-hour rhythm with lower levels during the night and higher in the day3, 17.

Advantage of pulsatile drug delivery system4, 5

•Due to its ability to release drug in a burst manner, it increases absorption and bioavailability at target site of absorption.

•Limit risk of mucosal irritation.

•Loss of drug by extensive first pass metabolism is prevented.

•Chronotherapy, programmed delayed release provides optimal treatment of diseases.

•No risk of dose dumping.

•Decreases drug interaction due to lower cytochrome P450 isoenzymes.

•Avoidance of undesirable side effects.

•Improved patient compliance.

•Flexibility in design

Disadvantage of pulsatile drug delivery system6

•Low drug loading capacity and incomplete release of drug.

•Higher cost of production.

•Large number of process variables.

•Lack of manufacturing reproducibility and efficacy.

•Batch manufacturing process.

•Unpredictable IVIVC.

•Need of advanced technology.

Need of Pulsatile drug delivery8

•Body function that follow circadian rhythms.

•When circadian rhythm is altered by the hormone such as rennin, aldosterone and cortisol etc level in blood.

•When rhythmic variation seen in acid secretion in stomach, gastric emptying, and gastrointestinal blood transfusion.

•Disease like bronchial asthma, myocardial infraction, angina pectoris, rheumatic disease, ulcer, and hypertension display time dependence.

•The lag time is essential for the drugs that undergo degradation in gastric acidic medium.

•It is possible to deliver the drugs to the distal part of GIT like colon targeting with pulsatile drug delivery.

•Drugs that undergo extensive first-pass metabolism are administered successfully as pulsatile drug delivery systems.

Diseases requiring pulsatile drug delivery

Circadian rhythm regulates many body functions in humans, viz., metabolism, behaviour, Physiology, sleep patterns, hormone production, etc. Asthma is one such disease where pulsatile drug delivery system can be useful. Circadian changes are seen in normal lung function, which reaches a low point in the early morning hours. . In peptic ulcer acid secretion is high in the afternoon and at night. In case of cardiovascular diseases, BP is at its lowest during the sleep cycle and rises steeply during the early morning period. Platelet agreeability is increased and fibrinolytic activity is decreased in the morning, leading to a state of relative hypercoagulability of the blood. Circadian increase in the blood sugar level after meal has been observed in Diabetes mellitus. Circadian variations seen in DOPA level in afternoon in case of Attention deficit syndrome7, 9, 10, 11.

Mechanism of drug release from pulsatile drug delivery system

The mechanism of drug release from PDDS can be occurring in the following ways12:

Diffusion

Water diffuses into the interior of the particle when particle come in contact with aqueous fluids in the gastrointestinal tract and resultant drug solutions diffuse across the release coat to the exterior.

Erosion

Some coatings designed to erode gradually with time, result in the release of drug contained within the particle.

Osmosis

An osmotic pressure can be built up within the interior of the particle when water allows entering under the right circumstances. The drug is forced out of the particle into the exterior through the coating.

METHODS OF DEVELOPMENT OF PULSATILE DRUG DELIVERY SYSTEM

Different approaches of pulsatile system are:

1. Time Controlled system

1.1 Pulsatile Delivery by Solubilisation or Erosion of layer

1.2 Pulsatile Delivery by Rupture of Membrane

1.3 Capsule Shaped Pulsatile Drug Delivery System

1.4 Pulsatile System Based On Osmosis

2. Internally stimuli induced system

2.1 Temperature–induced pulsatile release

2.1.1 Thermo responsive hydro gel systems

2.1.2 Thermo responsive polymeric micelle systems

2.2 Chemical stimuli induced pulsatile release

2.2.1 Glucose-responsive insulin release devices

2.2.2 PH sensitive drug delivery system

2.2.3 Inflammation-induced pulsatile release

2.2.4 Drug release from intelligent gels responding to antibody concentration

3. Externally Regulated System

3.1 Magnetic induces release

3.2 Ultrasound induces release

3.3. Electric field induces release

3.4 Light induces release

Multiparticulate System

Time Controlled system

Pulsatile Delivery by Solubilisation or Erosion of layer

In such systems the drug release is controlled by the dissolution or erosion of the outer coat which is applied on the core containing drug (Figure.3). The release of the active ingredient can be controlled by thickness and viscosity of the outer coat. The Time Clock system consists of a solid dosage form coated with lipid barriers containing carnauba wax and bees wax along with surfactants. Chronotropic system consists of a core containing drug reservoir coated by a hydrophilic polymer HPMC.System is composed of a drug-containing core and swells able polymeric coating of HPMC which slow the interaction with aqueous fluids4,8,9,11,13,14,15,16,17.

Pulsatile Delivery by Rupture of Membrane

These systems consist of an outer release controlling water insoluble but permeable coating subject to mechanically induced rupture phenomenon. The rupturing effect is achieved by coating the individual units with effervescent or swelling agents (Figure.4). Water permeation and mechanical resistance of the outer membrane are major factors affecting the lag time. The lag time can be varied by varying coating thickness or adding high amounts of lipophilic plasticizer in the outermost layer4, 8, 9,11,13,14,15,16,17.

Capsule Shaped Pulsatile Drug Delivery System

This dosage form consists of an insoluble capsule body containing drug and a release controlling plug (Soluble) is fitted between immediate release compartment and pulsed release compartment (Figure.5). The length of plug decides lag time. When it comes in contact with aqueous fluids, the cap rapidly dissolves thereby releasing the immediate release component followed by pulsed release component. Here the plug decides lag time which is inserted in to the body. A hydrostatic pressure generate inside the capsule that is why pulsatile drug delivery achieved4, 8, 9,11,13,14,15,16,17.

Pulsatile System Based On Osmosis

In this System, a capsule coated with semi permeable membrane is employed (Figure. 6). There is an insoluble plug consisting of osmotically active agent and the drug formulation inside the capsule. This system divides the capsule interior into two compartments- one for the beneficial agent and the other for the osmotically active agent. Water diffuses across the semi permeable membrane when this cap comes into contact with GI fluids and it results in increased pressure inside that ejects the plug after a predetermined lag time. Thickness of the coating decides the lag time. E.g. Ritalin (methyl phenidate) used in the treatment of attention deficit hyper active disorder (ADHD) in children4,8,9,11,13,14,15,16,17.

Internally stimuli induced system

Temperature–induced pulsatile release:

Temperature is the most widely applied triggering signal for a variety of triggered or pulsatile drug delivery systems. The body temperature often deviates from the physiological temperature (370 C) in the presence of pathogens or pyrogens. This deviation from normal range acts as a stimulus that triggers the release of therapeutic agents from several temperature-responsive drug delivery systems. Various polymer properties, including the thermally reversible coil/globule transition of polymer molecules, swelling change of networks, glass transition and crystalline melting utilized by temperature induced triggered drug delivery systems3, 4, 10.

Thermo responsive hydro gel systems: Hydro gels that undergo reversible volume changes in response to changes in temperature are known as thermo sensitive gels. In thermo-responsive hydro gel systems, hydro gels undergo reversible volume changes in response to changes in temperature. These gels shrink at a transition temperature that is referred to the lower critical solution temperature (LCST) of the linear polymer. As it undergo volume change, this property can be utilised to obtain a squeezing hydro gel device by positioning hydro gel within a rigid capsule. The reversible volume change of temperature-sensitive hydro gels accomplish onoff release e.g. PIPAAm cross-linked gels (Figure. 7) showed thermo responsive, off-and-on swelling/deswelling phases and it swells below 320 C temperature, on the other side shrink above this temperature3,4,10.

Thermo responsive polymeric micelle systems:

Block copolymers were prepared by development of end functionalized PIPAAm (Figure. 8) with hydrophobic polymers, such as poly (butyl methacrylate) (PBMA), polystyrene (PST) etc. In aqueous solution, block copolymers formed micellar structure (with core shell structure) below PIPAAm's transition temperature. In this system, drug is released when polymer undergoes swelling or deswelling phase in response to chemical reaction with membrane, alteration of pH and Inflammation induce3, 4, 10.

The shell was constructed from thermo responsive PIPAAm, while the core comprised of hydrophobic polymer aggregates. The PIPAAm corona exhibited a change in its hydration/dehydration properties with changing temperature.

Chemical stimuli induced pulsatile release:

Glucose-responsive insulin release devices

These devices have been developed to respond with changes in glucose concentration in the blood. The hydro gels showed a glucose-responsive, sol–gel phase transition dependent upon the external glucose concentration. These devices also have pH sensitive hydro gel containing glucose oxidase immobilized in the hydro gel. When glucose concentration in the blood increases glucose oxidase converts glucose into gluconic acid which changes the pH of the system. This swelling of the polymer induced by this pH change which results in insulin release. Insulin by virtue of its action reduces blood glucose level and consequently gluconic acid level also gets decreased and system turns to the deswelling mode thereby decreasing the insulin release. Examples of the pH sensitive polymers include N, N- dimethylaminoethyl methacrylate, chitosan, polyol etc3, 7, 15, 16.

PH sensitive drug delivery system

This system contains two components- one is of immediate release type and second is pulsed release which releases the drug in response to change in pH. As different pH environment exist at different parts of the gastrointestinal tract so this advantage is utilised by pH dependent system. By selecting the appropriate pH dependent polymers, desired drug release can be achieved at specific location. Examples of pH dependent polymers are cellulose acetate phthalate, polyacrylates, and sodium carboxymethylcellulose. These polymers are used as enteric coating materials so as to provide release of drug in the small intestine3, 7, 15, 16.

Inflammation-induced pulsatile release

Any physical or chemical stress, such as injury, fracture etc. cause inflammation at the injured sites. The inflamed responsive cells produce hydroxyl radicals .Yui and co-workers focused on the inflammatory induced hydroxyl radicals and designed drug delivery systems, which responded to the hydroxyl radicals and degraded in a limited manner. They used hyaluronic acid (HA) which is specifically degraded by the hyaluronidase or free radicals. Degradation of HA via the hyaluronidase is very low in a normal state of health. Degradation via hydroxyl radicals however, is usually dominant and rapid when HA is injected at inflammatory sites. Thus, it is possible to treat patients with inflammatory diseases like rheumatoid arthritis; using anti inflammatory drug incorporated HA gels as new implantable drug delivery systems5, 7,10,11,13.

Drug release from intelligent gels responding to antibody concentration

In the human body numerous kinds of bioactive compounds are exist. The change in concentration of these bioactive compounds can be detected by recently developed novel gels to alter their swelling/deswelling characteristics. Antigenantibody complex formation is of great importance as the cross-linking units in the gel due to such specific interaction. Reversible gel swelling/deswelling and drug permeation changes occurs by the utilization of the difference in association constants between polymerized antibodies and naturally derived antibodies towards specific antigens5,7,10,11,13.

Externally Regulated System

Magnetic induces release

Magnetically regulated system contains magnetic beads in the implant. Magnetic steel beads were engrafted in an ethylene and vinyl acetate (EVAc) copolymer matrix that was loaded with bovine serum albumin as a model drug. The beads oscillate within the matrix on exposure to the magnetic field, alternatively creating compressive and tensile forces.

This in turn acts as a pump to push more amount of the active solute out of the matrix 1, 2,3,16.

Ultrasound induces release

Ultrasound is used as an enhancer for the improvement of drug permeation through a biological barrier, such as skin, lungs, intestinal controlled drug delivery e.g. Miyazaki et al. used ultrasound to achieve up to a 27-fold increase in the release of 5-fluorouracil from an ethylene and vinyl acetate (EVAc) matrix. As degradation of biodegradable matrix was enhanced by ultrasonic exposure, the rate of drug release also increased. Increasing the strength of the ultrasound resulted in a proportional increase in the amount of 5- fluorouracil released1, 2,3,16.

Electric field induces release

As these devices use polyelectrolyte thus are pHresponsive as well as electro responsive. Polyelectrolyte contains polymers with comparatively high concentration of ionisable groups along the backbone chain. For chronotherapy, several technologies are required such as microelectronics and micromachining and potential etc. These technologies also include iontophoresis, iontophoresis and infusion pumps. Under the influence of electric field, electro-responsive hydro gels generally bend, depending on the shape of the gel which lies parallel to the electrodes whereas deswelling occurs when the hydro gel lies perpendicular to the electrodes 1, 2,3,15

Light induces release

In this system drug delivery is regulated by the interaction between light and material and can be achieved by combining a material that absorbs light at a desired wavelength and a material that uses energy from the absorbed light to regulate drug delivery. A new class of optically active nanoparticles is developed such as Gold nanoshells which comprise of a thin layer of gold surrounding a core. Required composite material can be obtained by implanting the nano shells in a NIPAAm-co-AAM hydro gel. A nanoshell when absorb the near-infrared light and convert it to heat and then temperature of composite hydro gel is raised above its lower critical solution temperature (LCST). Finally, hydro gel collapses and these results in an enhanced rate of release of soluble drug held within the matrix 1, 3, 14, 10.

Multiparticulate System

These systems consist of reservoir with either rupturable or altered permeability coating and most commonly housed in Capsular body. The purpose of designing Multiparticulate dosage form is to develop a reliable formulation that has all the advantages of a single unit formulation. A rupturable pulsatile drug delivery system consists of three components: (a) drug core (b) swelling layer comprising of a superdisintegrant and a binder (c) an insoluble water permeable polymeric coating 3, 4,8,15.

SOME NOVEL MULTIPARTICULATE DRUG TECHNOLOGIES

PRODAS Technology (Programmable Oral Drug Absorption System)

PRODAS technology is a combination of both Multiparticulate and hydrophilic matrix tablet technologies in which a number of minitablets gathered in a hard gelatine capsule. The minitablets produced by direct compression of granules having active ingredients. As it combines the advantages of tabletting technology within a capsule so it may be immediate release, delayed-release and/or controlled-release drug delivery systems in single dosage form 12,18,19,20.

OROS Technology (Osmotic-controlled Release Oral delivery System)

This technology depends on osmotic pressure to give pre-programmed, controlled drug delivery to the gastrointestinal tract. The system is composed of two compartments—the drug vessel and the osmotic engine cap. When the system comes in contact with an aqueous medium, water permeates into the osmotic engine cap through rate-controlling membrane (Figure. 9). Hydration of the osmotic engine leads to its expansion, which exerts a driving force against the ridge of the drug vessel. The two compartments separate from each other by sliding apart. After disengaging, the open mouth of the drug vessel is exposed to the fluid environment. Essential entire dose get delivered by Chronoset. The vessel is made of water-impermeable ethylene-co-vinyl acetate copolymer (EVA) and the cap is made of proprietary water-permeable blends of polycaprolactone (TONE) and flux enhancers 12,.

Available marketed products

• Alpress LP (prazosin)

• Covera-HS (verapamil)

• Procardia XL (nifedipine)

CODAS Technology (Chronotherapeutic Oral Drug Absorption System)

This technology is designed to delay drug release for a predetermined time to tune therapy to the body’s circadian rhythms. Again, the technology is based on polymer coated Multiparticulate. The release controlling coating is a blend of water soluble and water insoluble polymers. When water from the gastrointestinal tract get in touch with the polymer coated beads, the water soluble polymer gradually 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 drug. 18, 19

Marketed Preparation

Verelan PM XL capsule API- Verapamil HCl

DIFFUCAPS Technology

DIFFUCAPS technology delivers drugs into the body in a circadian release manner. Diffucaps technology in its simplistic form involves the preparation of 12, 18, 20, 21.

(1) Core of Inert particles surrounded by drug layer.

(2) Customized release (CR) beads by coating immediate release (IR) particles with one or more functional dissolution rate (release) controlling polymers or waxes (outermost layer in Figure 10).

(3) One or more functional polymer coated Diffucaps bead populations get combine into hard gelatine or Hydroxypropyl Methylcellulose (HPMC) capsules.

A layer of organic acid or alkaline buffer surrounds the beads to direct solubility of a poorly soluble drug by creating an optimal pH microenvironment (Figure 11). Every Diffucaps bead has an inert core enclosed by drug as well as coated with a functional polymer membrane to control the rate of drug release. The active core may be produced by granulating and milling and/or by extrusion and spheronization of API.This technology is particularly suitable for drugs that conventionally need multiple daily doses or drugs require customized release formulations. Diffucaps can also be combined with other proprietary Pharmaceutical Technologies to optimize drug delivery12, 20.

Marketed preparation

• Innopran XL Tablets Verapamil HCl

• Zofran Tablets Ondansetron HCl dihydrate

SODAS Technology (Spheroidal Oral Drug Absorption System)

SODAS is a Multiparticulate technology that enables the production of customized dosage forms and responds directly to individual drug candidate needs. The drug loaded beads are coated with controlled release polymers (water soluble and insoluble, pH dependent or independent) to form a release rate controlling membrane. Then, the beads are filled into hard gelatine capsules for ease of administration 18,19,20,21.

RECENT ADVANCES IN THE PULSATILE DRUG DELIVERY SYSTEM

At present, pulsatile drug delivery systems have great importance in various disease conditions specifically in diabetes where dose is suggested at different time intervals. The sub-systems, multi-particulate systems (e.g. pellets) offer various advantages over single unit. The release profile of pellets can be of any type like time dependent, pH dependent, micro flora activated system. Great interest is taken in site and time specific oral drug delivery to improve therapeutic efficacy. Gastro retentive drug delivery system is a suggestion to prolong gastric residence time, thereby targeting site-specific drug release in upper gastrointestinal (GI) tract. Floating drug delivery system (FDDS) and bio adhesive drug delivery are widely used techniques for gastro retention. Various pulsatile technologies have been developed on the basis of methodologies as discussed previously.

ACCU-BREAK Technology

This technology is designed to easily divisible tablets in exact smaller doses, thus dosage adjustment become easy. In ACCU-T-CR Trilayer tablets, tablet contains a controlled-release (CR) medication and/or immediate release (IR) component. It gets separated by a drug-free break layer which allows the CR dose to be divided into exact half doses 18.

TMDS Technology

The Time Multiple Action Delivery System provides control release rate of multiple ingredients within a single tablet 18.

GEOCLOCK Technology

In this technology, chronotherapy focused presscoated tablets are used in which an active drug remain surrounded by an outer tablet layer consists of a mixture of hydrophobic wax and brittle material. In this way a pH independent lag time is obtained. E.g. LODOTRA – used in rheumatoid arthritis 18.

DUREDAS Technology (Dual Release Drug Absorption System)

In this technology, a bilayer tablet was manufactured. One layer of the tablets provided with immediate release action and second layer with sustained release action 19.

KV/24

In this technology, one or more drug compounds remain encapsulated to express release of drug in a pre-determined fashion. Prior to coating with one or more polymers, a neutral core is coated with a drug substance to achieve a once-a day release profile. The drug can be combined in two ways, one with the neutral core second incorporated into the coating process 20.

INNOHERB

In this technology, pellets are coated inside of the capsule. Desired active herbal compound converted into micro pellets or small beads. The coating of these carried out by semi permeable membrane to improve stability and mask taste/smell 20.

IPDAS Technology (Intestinal Protective Drug Absorption System)

In this, the beads with high density drug are compressed to form controlled release tablets. It is particularly suitable for tablet that cause gastroirritation and disintegrates rapidly. The release is controlled by the nature of the drug-containing bead matrix or its semi-permeable membrane coating. It is extruded and spheronised Multiparticulate based technology. Initially, it was developed for a proprietary formulation of naproxen with fast onset of action to relief pain over a 24-hour period which is marketed in the US and Canada under the trade name Naprelan. 18,19,20,21

ORBEXA Technology

In this multi particulate system, high drug is loaded and product is subjected to granulation. After granulation/extrusion and spheronization, functional polymer membranes are used to coat the resultant beads for additional release rate control and may be filled into capsules. This technology can be used for sensitive drugs such as proteins. 18, 20, 21

CURRENT SCENARIO AND FUTURE SCOPE

Now a day's, in the field of drug delivery, more focused is done on the potential of systems that are able to release drugs after a programmable lag phase i.e. in a pulsatile mode. Beside these systems, multiparticulate systems (e.g. pellets) offer several advantages over single unit .In addition to this, there are no risk of dose dumping, flexibility of blending units with different release patterns, as well as short and reproducible gastric residence time.

The future of chronotherapeutics and delivering drugs in a pulsatile manner seems to be quite promising as in certain diseases states. It exhibit several advantages over the traditional zero or first order drug delivery mechanism. Time controlled or site specific single or multiple units are obtained by pulsatile drug delivery techniques. Pulsatile release (time site or specific) most often is achieved by using different polymers in coating layers or by changing the coating thickness.

CONCLUSIONS

Although sustained and controlled drug delivery systems have acquired a lot of success and application in field of Pharmacy. These systems are not able to deliver drug according to circadian behaviour of diseases but pulsatile systems have importance in this regard. Due to their high efficiency and lack of undesirable adverse effects to the whole body, the stimuli-responsive feature of these systems is useful for treatment of patients. But major drawbacks arise from the biological variations among individuals. The basic parameters in the design of polymer based pulsatile systems are the biocompatibility and the toxicity of the polymers used. It can be concluded that Pulsatile drug delivery system provide a unique way of delivering drugs possessing chronopharmacological behaviour, extensive first pass metabolism, necessity of night time dosing, or absorption window in GIT.Pulsatile drug delivery system shall be promising in future.

Conflict of Interest

NIL

Source of Support

NONE

Tables at a glance

Table 1 Table 2 Table 3

Figures at a glance

Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11

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