Final pulsatile dds copy

PULSATILE DRUG DELIVERY SYSTEM

PRESENTED BY:

A. ABHINAV REDDYM.PHARM I YEAR PHARMACEUTICS

R.No.256212886001

GUIDED BY:

Mrs. YASMIN BEGUM

(Ph.D)

CONTENTS

• Introduction and definition• Necessity of PDDS• Advantages and limitations• Classification• Circadian rhythms in occurance & severity of disease• Evaluation parameters• Recent advances• Conclusion

INTRODUCTION

• Pulsatile drug delivery systems (PDDS) are gaining importance as they deliver a drug at time and site specific manner resulting in improved therapeutic efficacy as well as compliance.

• Chronopharmacotherapy designed according to the circadian rhythm of the body

• Ecofriendly• Intelligent drug delivery system capable of adjusting

drug release rates in response to a physiological need.

DEFINITION:Pulsatile drug delivery system is defined as the rapid and transient release of certain amount of drug molecules within a short time period immediately after a predetermined off-release period, i.e., lag time.

Pulsatile drug delivery aims to release drug on programmed pattern i.e. at appropriate time and at appropriate site of action. In various diseases in which we can recommend the pulsatile drug delivery system such as duodenal ulcer, cardiovascular diseases, arthritis, asthma, diabetes, neurological disorder, cancer, hypertension and hypercholesterolemia etc.

Drug release profile of pulsatile DDS

1. Chronopharmacotherapy diseasesi. Asthmatic attacks during early morningii. Heart attacks in the middle of the nightiii. Morning stiffness in arthritisiv. Peptic ulcer during afternoon & night

2. Avoiding the first pass metabolism e.g. protein and peptides

3. For which the tolerance is rapidly exists (e.g. Salbutamol sulphate)

4. For targeting specific site in intestine e.g. colon (e.g .Sulfasalazine)

5. For time programmed administration of hormone and drugs

6. For drugs having the short half life (e.g. ß-blockers)

NECESSITY OF PDDS

ADVANTAGES• Extended daytime or nighttime activity• Reduced dose size, dosage frequency• Drug targeting to specific site. • Drug loss is prevented by extensive first pass metabolism .• Predictable, reproducible and short gastric residence time• Less inter- and intra-subject variability• Improved bioavailability, stability, patient comfort and compliance• Reduced adverse effects and improved tolerability• Limited risk of local irritation• No risk of dose dumping• Flexibility in design• Achieve a unique release pattern• Extend patent protection, globalize product, and overcome competition

LIMITATIONS

• 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

Classification

A . Time controlled:

Single unit pulsatile systems:

1.Capsule based systems: Single-unit systems are mostly developed in capsule form. The lag time is controlled by a plug, which gets pushed away  by swelling or erosion, and the drug is released as a “Pulse”  from the insoluble capsule body.

The lag time can be controlled by manipulating the dimension and the position of the plug. Polymers used for designing of the hydrogel plug1) Insoluble but permeable and swellable polymers(e.g., polymethacrylate)

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2)Erodible compressed polymers (e.g., hydroxypropylmethyl cellulose, polyvinyl alcohol, Polyethylene oxide)

3)Congealed melted polymers (e.g., saturated polyglycolated glycerides, glyceryl monooleate)

4) Enzymatically controlled erodible polymer (e.g., pectin).

2.Capsular system based on Osmosis

a. PORT system:

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It consists of a capsule coated with a semipermeable membrane. Inside the capsule was an insoluble plug consisting of Osmotically active agent and the drug formulation.

When this capsule came in contact with the dissolution fluid, the semipermeable membrane allowed the entry of water, which caused the pressure to develop and the insoluble plug expelled after a lag time. Such a system was utilized to deliver methylphenidate used in the treatment of attention deficit hyperactivity disorder as the pulsatile port system. This system avoided second time dosing, which was beneficial for school children during daytime.

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b. Pulsatile system with Erodble or soluble barrier coatings:Most of the pulsatile drug delivery systems are reservoir devices coated with a barrier layer. This barrier erodes or dissolves after a specific lag period, and the drug is subsequently released rapidly from reservoir core. The lag time depends on the thickness of the coating layer.

1 . The chronotropic system:

The Chronotropic® system consists of a drug-containing core coated by hydrophilic swellable hydroxypropylmethyl cellulose (HPMC), which is responsible for a lag phase in the onset of release. In addition, through the application of an outer gastric-resistant enteric film, the variability in gastric emptying time can be overcome, and a colon-specific release can be obtained, relying on the relative reproducibility of small intestinal transit time. The lag time is controlled by the thickness and the viscosity grades of HPMC. The system is suitable for both tablets and capsules.

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2. ‘TIME CLOCK’ System:

The lag time could be controlled by varying the thickness of the film. After the lag time, i.e., the time required for rehydration, the core immediately releases the drug. This system has shown reproducible results in vitro and in vivo.

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3.Compressed Tablets: Compression coating can involve direct compression of both the core and the coat, obviating needs for separate coating process and use of coating solutions. The outer tablet of the compression-coated tablet provides the initial dose, rapidly disintegrating in the stomach and the inner layer is formulated with components that are insoluble in gastric media but are released in the intestinal environment. Materials such as hydrophilic cellulose derivates can be used. Compression is easy on laboratory scale. The major drawbacks of the technique are that relatively large amounts of coating materials are needed and it is difficult to position the cores correctly.

Press-coated pulsatile drug delivery systems:

1.Press-coated pulsatile drug delivery systems can be used to protect hygroscopic, light-sensitive, oxygen labile or acid-labile drugs.

2. Press-coated pulsatile drug delivery systems are relatively simple and cheap.

3. These systems can involve direct compression of both the core and the coat.

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4. Materials Such as hydrophobic, hydrophilic can be used in press-coated pulsatile drug delivery system.

5. Press-coated pulsatile drug delivery systems involve compression which is easy on laboratory scale.

6. Press-coated pulsatile formulations release drug after “lag-time”.

7. Press-coated pulsatile drug delivery formulations can be used to separate incompatible drugs from each other or to achieve sustained release.

4. Multilayered Tablets:

A release pattern with two pulses was obtained from a three layered tablet containing two drug containing layers separated by a drug-free gellable polymeric barrier layer.

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C.Pulsatile system with rupturable coating:

These systems depend on the disintegration of the coating for the release of drug. The pressure necessary for the rupture of the coating can be achieved by the effervescent excipients, swelling agents, or osmotic pressure. An effervescent mixture of citric acid and sodium bicarbonate was incorporated in a tablet core coated with ethyl cellulose. The carbon dioxide developed after penetration of water into the core resulted in a pulsatile release of drug after rupture of the coating. The release may depend on the mechanical properties of the coating layer.

1)Pulsatile system based on rupturable coating:

E.g. Time –controlled Explosion system (TCES):

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This is a multiparticulate system in which drug is coated on non-pareil sugar seeds followed by a swellable layer and an insoluble top layer.The swelling agents used include Superdisintegrants like sodium carboxymethyl cellulose, sodium starch glycollate, L hydroxypropyl cellulose. Polymers like polyvinyl acetate, polyacrylic acid, polyethylene  glycol, etc.

2) Osmotic based rupturable coating system:

This system is based on a combination of osmotic and swelling effects. The core containing the drug, a low bulk density solid and/or liquid lipid material (eg, mineral oil) and a disintegrant was prepared. This core was then coated with cellulose acetate. Upon immersion in aqueous medium, water penetrates the core displacing lipid material. After the depletion of lipid material, internal pressure increases until a critical stress is reached, which results in rupture of coating.

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Multiple unit

a. Pulsatile delivery by change in membrane permeability:

The permeability and water uptake of acrylic polymers with quaternary ammonium groups can be influenced by the presence of different counter-ions in the medium.Several delivery systems based on this ion exchange have been developed. Eudragit RS 30D is reported to be a polymer of choice for this purpose. It typically contains positively polarized quaternary ammonium group in the polymer side chain, which is always accompanied by negative hydrochloride counter-ions. The ammonium group being hydrophilic facilitates the interaction of polymer with water, thereby changing its permeability and allowing water to permeate the active core in a controlled manner. This property is essential to achieve a precisely defined lag time.

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b. Rupturable coating system:• Similar to single unit system , the rupturing effect is achieved by coating the individual units with effervescent/swelling agents.• This drug delivery system comprising of a plurality of particles that are divided into several individual delivery units, each having its own distinct composition.• Drug delivery was controlled by the rupture of the membrane.• This timing of release was controlled by the thickness of coating & the amount of water soluble polymer to achieve the pulsed release.• The individual particles had same composition of internal core, but the thickness of the external coating layer varied.

DELIVERY SYSTEM WITH RUPTURABLE LAYERS

B. STIMULI INDUCED PULSATILE SYSTEMS

I. Temperature induced system

Thermo-responsive hydrogel systems have been developed for pulsatile release. In these systems the polymer undergoes swelling or deswelling phase in response to the temperature which modulate drug release in swollen state. Eg.

1) Y.H. Bae et al developed indomethacin pulsatile release pattern in the temperature ranges between 20oC and 30oC by using reversible swelling properties of copolymers of N-isopropylacrylamide and butyrylacrylamide.

2) Kataoka et al developed the thermosensitive polymeric micelles as drug carrier to treat the cancer. They used endfunctionalized poly(N-isopropylacrylamide) (PIPAAm) to prepare corona of the micelle which showed hydration and dehydration behavior with changing temperature.

I. Chemical induced system

There has been much interest in the development of stimuli-sensitive delivery systems that release a therapeutic agent in presence of specific enzyme or protein. One prominent application of this technology has been development of a system that can autonomously release insulin in response to elevated blood glucose levels.

1. pH dependent system

INSULIN

Glucose oxidase immobilized on cross linked polyacrylamide

N, N- diethylaminoethyl methacrylate and 2-hydroxypropyl methacrylate (DEA-HPMA) formed the barrier membrane

GLUCOSE GLUCONIC ACID

C. Externally stimuli System

For releasing the drug in a pulsatile manner, another way can be the externally regulated systems in which drug release is programmed by external stimuli like magnetism, ultrasound, electrical effect and irradiation. a) Magnetically Stimulatedb) Ultrasonically Stimulatedc) Photo Stimulatedd) Electrically Stimulated

a. Magentically stimulated:• Drug molecules and magentic beads are uniformly distributed

within a solid polymeric matrix in magentically triggered systems . Although drugs released by diffusion whenthe device is exposed to fluids , a much higher release rates obtained in the presence of an external oscillating magnetic field.

• MECHANISM: The two principle parameters controllingthe release rates in these systems are the magnetic field characteristics and the mechanical properties of polymer matrix.

b. Ultrasonically stimulated:• Release rates of substances can be repeatedly modulated at will from a position external to the delivery system by ultrasonic irridation.Both bioerodible & nonerodible polymer were used as drug carriers matrices . Both the polymer erosion & drug release rates were enhanced when the bioerodible samples were exposed to ultrasound.• MECHANISM: It was proposed that cavitation &

acoustic streaming are responsible for the augmented degradation &release of bioerodible polymers .

c. Photo stimulated: The interaction between light and material can be used To modulate drug delivery. This can be accomplished by combining a material that uses energy from the absorbed light to modulate drug delivery. MECHANISM: Photoresponsive gels reversibly change their physical or chemical properties up on photoradiation. A photoresponsive polymer consists of a photoreceptor ,usually a photochromic chromophore, & a functional part. The optical signals captured by the photochromic molecules the then the isomerisation of the chromophores in the photoreceptor converts it to a chemical signal.

d. Electrically stimulated: An electric field as an external stimulus has advantages such as availability of equipment, which allows precise control with regards to the magnitude of the current, duration of electric pulses, interval between pulses etc. Electrically responsive delivery systems are prepared from polyelectrolytes and are thus pH- responsive as well as electro responsive. Under the influence of electric field, electro responsive hydrogels generally deswell, swell or erode. This rapid drug release was attributed to the electrostatic force, squeezing effect, and electro-osmosis of the gel. Complete on-off drug release was achieved, as no drug release was apparent without the application of electric current

Evaluation Parameters

– Hardness– Friability– Weight variation– Swelling index– Determination of Lag time– Disintegration time– Uniformity of drug content– Dissolution studies

WEIGHT VARIATION:• The Pharmacopoeial limits for deviation for tablets of more than 250 mg are ± 5%.The average percentage deviation for all tablet formulations was found to be within the specified limits and hence all formulations complied with the test for weight variation.

UNIFORMITY OF DRUG CONTENT:• Good uniformity in drug content was found within and among the different types of tablet formulations. The values ranged from 97±1.12 % to 101±1.023 % of labelled amount. Hence the tablet prepared passes the pharmacopoeial limit.

DISINTEGRATION TIME:• As per the requirements of pulsatile tablets the core tablet should give rapid and transient release. The tablets prepared by using lactose as diluents give disintegration time from 191 to 663 second, where as the tablets prepared by using microcrystalline cellulose shows disintegration time between 221 to 10-15 second. Where Sodium starch glycolate was used as superdisintegrant in both case. The studies showed that the tablet hardness affects the disintegration time, harder the tablet more the disintegration time.

HARDNESS TEST:• The hardness of these tablets should be ranges from 4-5 gives best disintegration results being in its own limits.

DETERMINATION OF LAG TIME(t10):The dissolution profile shows increase in the lag time with increase in the percent weight gain. The weight gain directly increases the coating thickness so the lag time too. The aim of the study was to develop a tablet which will be protected from gastric environment and will release the drug rapidly in the intestine after 5-6 hours of administration. So the above batches showed increase in lag time from 147 to 438 minutes with respect to their coating level. The lag time was determined while performing the dissolution test.

Friability: The friability of 10 tablets will determine using Roche friabilator. This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches in each revolution. Preweighed sample of tablets will place in the friabilator and will subject to 100 revolutions. Tablets will dedust using a soft muslin cloth and reweigh.

SWELLING INDEX:• Five tablets will weighed individually (W1) and placed in a suitable buffer(0.1 N HCL, phosphate buffer ph 6.8) for a hour and then after excess surface water will removed carefully with filter paper. The swollen tablet will then reweighed (W2) and the swelling index (SI) will be calculated using the following formula.

Swelling Index SI=[(W2-W1)/W1]×100

DISSOULTION STUDIES:• The dissolution studies were carried out in 0.1N HCl (900 ml) at 37 ± 0.5oCusing USP dissolution apparatus type II. Aliquots of dissolution medium were withdrawn at predetermined time interval and content of MT was determined by using UV spectrophotometer.

Circadian rhythms in occurance & severity of disease

• The symptom intensity of many medical conditions & the occurance of life-threatening medical emergencies exhibit rather precise timings.

• Gout, gall bladder & peptic ulcer – attacks most frequent at night.

• Rhematiod arthritis – more intense overnight/ in the morning.• Depression – most severe in the morning.• Perforated & bleeding ulcer – most common occurs in

afternoon.

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Asthma:• Symptoms of asthma occur 50-100 times more often at night than during the day.• Many circadiandependent factors appear to contribute to the worsening of nocturnal astmatic symptoms.• For example cortisol levels were highest at the time of awakening & lowest in the middle of the night . And histamine concentrations peaked at a level that coincided with the greatest degree of bronchoconstriction at 4:00 am.

PAIN:•Pain threshold does not follow the same pattern in all tissues.• The sensitivity threshold of the gingiva to a cold stimulus was maximal at 18:00 h & reached a peak at 3:00 h. • Tooth sensitivity was lowest between 15:00 & 18:00 h, with a peak in pain intensity at 8:00 h.• Morphine peak maximal at 9:00 h & was the least at 15:00 h in patients undergoing elective surgery.• The peak demand for morphine occurred in the early morning & was lowest during the night in post-operative gynecologic patients.

Arthritis:• Patients with osteoarthritis tend to have less pain in the morning & more at night .• Rheumatoid arthritis , have pain that usually peaks in the morning & decreases throughout the day.• Chronotherapy for all arthritis using NSAIDs such as Ibuprofen.( should be timed to ensure that the highest blood levels of the drug coincide with peak pain)• For osteoarthritis sufferers , optimal time for NSAIDs such as Ibuprofen would be around noon/mid-afternoon.• The same drug would be more effective for people with rheumatoid patients when taken after the evening meal.

Cardiac vascular diseases:• Several functions of CVS are subject to circadian rhythms.• Platelet aggregability is increased & fibrinolytic activity is decreased in the morning leading to relative hyper –coaggulability of blood.• Cardiac events also occur with a circadian pattern .• Numerous studies have shown an increase in the incidence of early morning myocardial infraction, sudden cardiac death, stroke .• BP is at its lowest during the sleep cycle & rises steeply during the early morning awakening period.

• Hypertension patients will have same circadian rhythm as that of normotensive persons , although hypertensive patients have an upward shift in the profile .• hypertensive patients have quite amarked rise in BP upon awakening called “the morning surge”. ( increases can be 3mm Hg/hr (systolic) & 2mm Hg/hr (diastolic) for first 4-6 hrs after awakening up)• This due to increase of catecholamine concentration in the early morning .

Duodenal Ulcer:• In peptic ulcer patients , gastric acid secretion is highest during the night .• Supression of nocturnal acid is an important factor in duodenal ulcer healing.• Therefore , for active duodenal ulcer , once daily at bed time is the recommended dosage regimen for H2 antagonists .• At night time , when gastric motility & emptying are slower , drug disintegration , dissolution & absorption may be slower .

Cancer:• Chemotherapy may be more effective & less toxic if cancer drugs are administered at carefully selected times that take advantages of tumor cell cycles while less toxic to normal tissue.• The rhythmic circadian changes in tumor blood flow & cancer growth are relevant.• Normal human bone marrow DNA synthesis peaks around noon, DNA synthesis in malignant lymphoma cells peaks near mid night.• By treament at mid night , more tumor cell kill could be achieved with some dose of S-phase active cytotoxic therapy & with relativity little bone marrow damage.

Hypercholesterolemia:• A circadian rhythm occurs during hepatic cholesterol synthesis. This rhythm varies according to individuals. Indeed , there is a large variation in plasma mevalonate concentrations between individuals .• Therefore cholesterol synthesis is generally higher during the night than during day light.• The maximal production occurs early in the morning i.e., 12 h after the last meal.• Studies with HMG Co A reductase inhibitors have suggested that evening dosing was more effective than morning dosing.

Diabetes:• The circadian variations of glucose & insulin in diabetes have been extensively studied.• The goal of insulin therapy is to mimic the normal physiologic pattern of endogenous insulin secretion in healthy individuals , with continuous basal secretion as well as meal stimulated secretion.• Providing basal insulin exogenously to patients with diabetes inhibits hepatic glucose production.• Exogenous administration of meal time doses promotes peripheral glucose up take as well as reducing hepatic glucose release.

Diseases that require pulsatile drug delivery

Disease Chronological behavior Drugs used

Peptic ulcer Acid secretion is high in the afternoon and at night.

H2blockers

Attention deficit syndrome Increase in DOPA level in afternoon

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Cardiovascular diseases BP is at its lowest during the sleep cycle and rises steeply during the early morning

Nitroglycerin, calcium channel,blocker, ACE inhibitors

Asthma Precipitation of attacks during night or at early morning.

Β2 agonist, Antihistamines

Arthritis Level of pain increases at night

NSAIDs, Glucocorticoids

Diabetes mellitus Increase in the blood sugar level after meal

Sulfonylurea, Insulin

Hypercholesterolemia Cholesterol synthesis is generally higher during night than day time.

HMG CoA reductase, Inhibitors

RECENT ADVANCES:I.ACCU-BREAK TECHNOLOGY ( Accu-Break Pharm., USA )

ACCU-BREAK tablets are designed to

provide physicians and patients with easily divisible tablets that when divided, result in exact smaller doses, thus facilitating ease of dosage adjustment.

Accu-Break Technology is divided in to 2 types ACCU-B Technology & ACCU-T Technology.

In ACCU-T-CR Trilayer tablets, the controlled release technology is used to further enhance treatment options. Tablet contains a CR medication at either end separated by a drug-free break layer, allowing the CR dose to be divided into exact half doses.

Additionally, an IR component can be added to CR tablets to add even more treatment options and potential product capabilities.

II. SODAS® Technology• SODAS® (Spheroidal Oral Drug Absorption System) is

Elan’s Multiparticulate drug delivery system. Based on the production of controlled release beads, the SODAS® technology is characterized by its inherent flexibility, enabling the production of customized dosage forms that respond directly to individual drug candidate needs.

• Elan’s SODAS® Technology is based on the production of uniform spherical beads of 1-2 mm in diameter containing drug plus excipients and coated with product specific controlled release polymers.

• The most recent regulatory approvals for a SODAS® based system occurring with the launch of once-daily oral dosage forms of Avinza™, Ritalin® LA and Focalin® XR.

III. IPDAS® Technology

• The Intestinal Protective Drug Absorption System (IPDAS® Technology) is a high density multiparticulate tablet technology, intended for use with GI irritant compounds.

• Once an IPDAS® tablet is ingested, it rapidly disintegrates and disperses beads containing a drug in the stomach, which subsequently pass into the duodenum and along the gastrointestinal tract in a controlled and gradual manner, independent of the feeding state.

• Release of active ingredient from the multiparticulates occurs through a process of diffusion through the polymeric membrane. micromatrix of polymer/active ingredient formed in the extruded/spheronized multiparticulates.

• Naprelan®, which is marketed in the United States and Canada, employs the IPDAS® technology. This innovative formulation of naproxen sodium.

IV.CODAS TECHNOLOGY ( Elan corp., Patent No US6500459 )

Elan’s drug delivery technology can be tailored to release drug after a predetermined delay.

The CODAS™ drug delivery system enables a delayed onset of drug release, resulting in a drug release profile that more accurately compliments circadian patterns.

Elan’s Verelan® PM represents a commercialized product using the CODAS™ technology. The Verelan® PM formulation was designed to begin releasing Verapamil approximately four to five hours post ingestion. This delay is introduced by the level of release-controlling polymer applied to the drug-loaded beads.

V. PRODAS® Technology• Programmable Oral Drug Absorption System (PRODAS®

Technology) is a multiparticulate technology, which is unique in that it combines the benefits of tabletting technology within a capsule.

• The PRODAS® delivery system is presented as a number of minitablets combined in a hard gelatin capsule. Very flexible, the PRODAS® technology can be used to pre-program the release rate of a drug. It is possible to incorporate many different minitablets, each one formulated individually and programmed to release drug at different sites within the gastro-intestinal tract. It is also possible to incorporate minitablets of different sizes so that high drug loading is possible.

VI. TMDS Technology• TMDS (Time Multiple Action Delivery system) Technology

provide control release rate of multiple ingredient within single tablet in programme manner. TMDS Technology allows for more than one active ingredient in a single tablet formulation provide multiple release profile over extended period of time.

VII. DMDS Technology• DMDS (Dividable Multiple Action Delivery System) is designed

to provide greater dosing flexibility that improve product efficacy and reduces side effects. Traditional controlled release tablet often lose their controlled release mechanism of delivery once it broken. But DMDS technology allows tablet to be broken down in half so that each respective portion of the tablet will achieve exactly the same release profile as the whole tablet. This allows the patient and physician to adjust the dosing regimen according to the clinical needs without compromising efficacy.

VIII. PMDS Technology

• PMDS (Programmed Multiple-action Delivery System) technology is designed to provide for the multi-phasic delivery of any active ingredient in a more controlled fashion as compared to typical controlled release technologies.

• This technology allows us to overcome one of the technical challenges in the development of multi-particulate dosage forms – achieving acceptable uniformity and reproducibility of a product with a variety of release rates. It is designed to provide greater dosing flexibility that improves product efficacy and may reduce side effects.

IX. GEOCLOCK® Technology• SkyePharma developed a new oral drug delivery

technology, Geoclock®; that allows the preparation of chronotherapy-focused press-coated tablets.

• Geoclock® tablets have an active drug inside an outer tablet layer consisting of a mixture of hydrophobic wax and brittle material in order to obtain a pH-independent lag time prior to core drug delivery at a predetermined release rate. This dry coating approach is designed to allow the timed release of both slow release and immediate release active cores by releasing the inner table first after which time the surrounding outer shell gradually disintegrates.

• Using this novel technology, SkyePharma has been developing Lodotra™, a rheumathoid arthritis drug, on behalf of Nitec Pharma. Lodotra™ will deliver the active pharmaceutical ingredient at the most suitable time of day to treat the disease.

X. GEOMATRIX™ Technology• The Geomatrix™ technology is applied to achieve

customised levels of controlled release of specific drugs and can achieve simultaneous release of two different drugs and different rates from a single tablet.

• The controlled release is achieved by constructing a multilayered tablet made of two basic key components; 1) hydrophilic polymers such as hydroxypropyl methycellulose (HPMC) and 2) surface controlling barrier layers.

• SkyePharma manufactures several Geomatrix™ products for its partners, which include Sular® for Sciele, ZYFLO CR™ for Critical Therapeutics, Coruno® for Therabel, diclofenac-ratiopharm® uno for ratiopharm and Madopar DR® for Roche.

XI. PULSYS™ Technology• MiddleBrook™ (Earlier known as Advancis

Pharmaceuticals) Pharmaceuticals developed PULSYS™, an oral drug delivery technology that enables once daily pulsatile dosing. The PULSYS™ dosage form is a compressed tablet that contains pellets designed to release drug at different regions in the gastro-intestinal tract in a pulsatile manner.

• PULSYS™ Technology’s Moxatag™ tablet contain Amoxicillin is designed to deliver amoxicillin at lower dose over a short duration therapy in once daily formulation. Advancis have also demonstrated that by preclinical studies which improved bactericidal effect for amoxicillin when deliver in pulsatile manner as compared to standard dosing regimen even against resistant bacteria.

XII. Eurand’s pulsatile and chrono release System • Eurand’s Time controlled pulsatile release system

is capable of providing one or more rapid release pulses at predetermined lag times, such as when chronotherapy is required, and at specific sites, such as for absorption along the GI tract.

• Eurand has created a circadian rhythm release (CRR) dosage form for a cardiovascular drug, Propranolol hydrochloride, with a four-hour delay in release after oral administration. Administered at bedtime, Propranolol is released after the initial delay such that maximum plasma level occurs in the early morning hours, when the Patient is most at risk.

Xlll. Magnetic Nanocomposite Hydrogel

• Magnetic nanocomposite of temperature responsive hydrogel was used as remote controlled pulsatile drug delivery. Nanocomposites were synthesized by incorporation of superparamagnetic Fe3O4 particles in negative temperature sensitive poly (N-isopropylacrylamide) hydrogels. High frequency alternating magnetic field was applied to produce on demand pulsatile drug release from nanocomposite hydrogel. Nanocomposite hydrogel temperature increase above LCTS so, result in to accelerated collapse of gel. Hence Nanocomposites hydrogel are one type of On-Off device where drug release can be turn on by application of alternative magnteic field.

1. ACCU-BREAK Technology2. Aqualon CMC EZ Technology3. Banner’s Versetrol Technology4. CODAS Technology5. COLAL Technology6. Covera-HS Technology7. Diffutab Technology8. DMDS Technology9. EGALET Technology10. Eurand Minitabs Technology11. Eurand’s Diffucaps mult. system12. Eurand’s Pulsatile & Chrono release

system13. Geoclock Technology14. Geomatrix Technology15. IntelliMatrix Technology16. IPDAS Technology

17. Magnetic Nanocomposite Hydrogel

18. Opana ER Technology19. Orbexa Technology20. OROS Technology21. OSDrC Technology22. PMDS Technology23. Ritalina Technology24. Port Technology25. PRODAS Technology26. Pulsincap Technology27. PULSYS Technology28. SODAS Technology29. Syncro Dose Technology30. 3D printing31. TMDS Technology32. Uniphyl Technology

RECENT ADVANCES

Marketed Products :

 CONCLUSION There is a constant need for new delivery systems that can

provide increased therapeutic benefits to the patients. Pulsatile drug delivery is one such system that, by delivering

drug at the right time, right place, and in right amounts, holds good promises of benefit to the patients suffering from chronic problems like arthritis, asthma, hypertension, etc.

PDDS can effectively release drug according to body's circadian clock giving release of drug after a specified time lag.

With increase in technological advancement and better design parameters hurdles can be overcome in the near future and more number of patients will be greatly benefited by these systems.

REFERENCES• Meenu Rajput, Ritika Sharma, Sunil Kumar, Pulsatile Drug Delivery System: A

Review, ijrpbs, ISSN: 2229-3701, Vol. 3,118-124, (1) Jan – Mar 2012.• Dhirendra C. Patel*, Ritesh B. Patel, Gargi B. Patel, Pulsatile Drug Delivery System,IJPRS,

vol-1 (5): November, 2012], ISSN No: 2278-9464.

• S. R. Tajane*, B. B. Kholwal, S. S. Suryawanshi and K. N. Tarkase ,• CURRENT TRENDS IN PULSATILE DRUG DELIVERY SYSTEMS , IJPSR, 2012; Vol. 3(2): 358-

366 , ISSN: 0975-8232 .• JIGAR D. PATEL, et al. “PULSATILE DRUG DELIVERY SYSTEM: AN "USER-FRIENDLY" DOSAGE

FORM”, JPRHC, Volume 2, Issue 2, April 2010, 204-215.• Vikram S. Chhabra “ The Essentials Of Chronopharmacotherapeutics” vol 4:1-8 issue

4,2012, ISSN- 0975-1491.

• Sadaphal K.P.1*, Formulation and evaluation of pulsatile drug delivery system for chronobiological disorder: Asthma , International Journal of Drug Delivery 3 (2011) 348-356.