pulsatile drug delivery systems

Pulsatile Drug Delivery System (PDDS):

Pulsatile Drug Delivery System (PDDS) Prepared By : Sagar Vekariya Guided By : Mrs. Parul K. Patel Dr. Rishad Jivani

Content:

Content Introduction Criteria of Drugs for PDDS Different Approaches Fabrication Recent Advancement Marketed Preparations Conclusion References

1. Introduction:

1. Introduction Why conventional dosage forms??? Advantages (Material, Manufacturing, Technology, Patient complience) Why modified/ controlled dosage forms?? Advantages over conventional dosage forms ( Chronic Treatment, Patient complience, cost of over all treatment)

Slide 4:

What and Why PDDS ? ? ? BEST COORDINATION FASTEST REACTION TIME GREATEST CVS EFFICIENCY & MUSCLE STRENGTH HIGHEST BLOOD PRESSURE HIGHEST BODY TEMP MELATONIN SECRETION STARTS BOWEL MOVEMENT SUPPRESSED MIDNIGHT DEEPEST SLEEP LOWEST BODY TEMP SHARPEST RISE IN BP MELATONIN SECRETION STOPS BOWEL MOVEMENT LIKELY HIGHEST TESTOSTERONE SECRETION HIGH ALERTNESS NOON Circadian Rhythm 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.

Slide 5:

Chronopharmacotherapy of diseases which shows circadian rhythms in their pathophysiology . asthmatic attacks during early morning heart attacks in the middle of the night morning stiffness in arthritis Avoiding the first pass metabolism e.g. protein and peptides For which the tolerance is rapidly exists (e.g. Salbutamol sulphate ) For targetting specific site in intestine e.g. colon ( e.g Sulfasalazine ) For time programmed administration of hormone and drugs, For drugs having the short half life ( e.g ß-blockers) Necessity of PDDS

Slide 6:

Advantages Extended daytime or nighttime activity Reduced side effects Reduced dosage frequency Reduction in dose size Improved patient compliance Lower daily cost to patient due to fewer dosage units are required by the patient in therapy. Drug adapts to suit circadian rhythms of body functions or diseases. Drug targeting to specific site like colon. Protection of mucosa from irritating drugs. Drug loss is prevented by extensive first pass metabolism

Different Approaches:

Different Approaches A. PREPLANNED SYSTEMS Pulsatile system based on capsule Pulsatile system based on osmosis Drug delivery system with erodible or soluble layer Drug delivery system with rupturable layer B. STIMULI INDUCED PULSATILE SYSTEMS Temperature induced system Chemically induced System Externally stimuli System

A. PREPLANNED SYSTEMS:

A. PREPLANNED SYSTEMS Pulsatile system based on capsule PULSINCAP ® The Pulsincap ® system (Scherer DDS, Ltd) is an example of such a system that is made up of a water insoluble capsule body filled with drug formulation (McNeil et al., 1990, Wilding et al., 1992 and Saeger et al. 2004). The body is closed at the open end with a swellable hydrogel plug . The length of plug decides lag time. The plug material consists of insoluble but permeable and swellable polymers ( eg , polymethacrylates ) , erodible compressed polymers ( eg , hydroxypropylmethyl cellulose, polyvinyl alcohol, polyethylene oxide) (Krögel et al., 1998), congealed melted polymers ( eg , saturated polyglycolated glycerides , glyceryl monooleate ) , and enzymatically controlled erodible polymer ( eg , pectin, agar) ( Krögel et al., 1999).

Slide 10:

Advantages : Well tolerated in animals and healthy volunteers, and there were no reports of gastro-intestinal irritation ( Saeger et al., 2004). Disadvantages : Potential problem of variable gastric residence time , which was overcome by enteric coating the system to allow its dissolution only in the higher pH region of small intestine ( Binns et al., 1996)

Slide 11:

Development and evaluation of pulsatile drug delivery system using novel polymer by Avinash R Tekade , Surendra G Gattani The aim of the present investigation was to develop a pulsatile drug delivery system based on an insoluble capsule body filled with theophylline microspheres and sealed with a swellable novel polymer plug isolated from the endosperm of seeds of higher plant Delonix regia family- Fabaceae . Theophylline microspheres were prepared by solvent evaporation method using Eudragit S 100. The swellable plugs of varying thickness and hardness were prepared by direct compression, which were then placed in the capsule opening. The drug delivery system was designed to deliver the drug at such a time when it was needed most to offer convenience to the chronic patients of asthma . Formulated dosage forms were evaluated for an in vitro drug release study, which showed that the release might be consistent with a release time expected to deliver the drug to the colon depending on the thickness and hardness of the hydrogel plug. Thus, thickness and hardness of the novel polymeric plug plays an important role in controlling the drug release from the formulated drug delivery system.

Slide 12:

II. Pulsatile System Based On Osmosis Osmotic system consists of capsule coated with the semipermiable membrane.In this system for development of osmotic pressure different techniques are used. Case 1: Osmotic system containing insoluble plug ( eg . PORT system) Case 2: Osmotic system based on expandable orifice technology , Linkwitz et al. elastomer ( eg . Styrene-butadiene copolymer) Case 3: Osmotic capsule containing micropore s , Niwa et al

Slide 13:

Step1: Cap dissolves off. immediately or modified release dose is released. Step 2: Energy source is activated by controlled permeation of GI fluid. Step 3: Time-release plug is expelled. Step 4: Pulse or Sustained release of second dose. Fig. Drug release mechanism from Port Capsule

Slide 14:

III. Drug delivery system with erodible or soluble 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. Time dependent release of the active ingredient can be obtained by optimizing the thickness of the outer coat Chronotropic ® system Time Clock ® system Multilayered Tablet Chronotropic ® system consists of a drug containing core coated by hydroxypropylmethyl cellulose (HPMC), a hydrophilic swellable polymer , which is responsible for a lag phase in the onset of release ( Gazzania et al., 1994 and 1995). variability in gastric emptying time can be overcome, and a colon- specific release can be obtained by additional entric coating.

Slide 15:

Chronotropic ® system

Slide 16:

2 . Time Clock ® system Consists of a solid dosage form coated with lipidic barriers containing carnauba wax and bees’ wax along with surfactants , such as span 80 ( Pozzi et al., 1992 and Wilding et al., 1994). After a lag time proportional to the thickness of the film , this coat erodes or emulsifies in the aqueous environment, and the core is then available for dispersion. The lag time increased with increasing coating thickness Drug Core Wax + Surfactant

Slide 17:

3. Multilayered Tablet 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 (Conte et al., 1989 and 1992) Multilayered Tablet Initial rapid release drug layer Drug – free gellable polymeric barrier layer Second pulse generating drug layer Impermeable ethyl cellulose layer (3 – sided)

Slide 18:

IV. Drug delivery system with rupturable layer These systems consist of an outer release controlling water insoluble but permeable coating subject to mechanically induced rupture phenomenon. Bicarbonate + Citric acid + Drug Ethyl cellulose coating Rupturable polymer layer Superdisintegrating agent + Drug

Slide 19:

Process and Formulation Variables Affecting the Performance of a Rupturable Capsule‐Based Drug Delivery System with Pulsatile Drug Release A. Dashevsky , T. Bussemer , A. Mohamad and R. Bodmeier The objective of this study was to optimize several process and formulation parameters, which influence the performance of a rupturable , pulsatile drug delivery system. The system consisted of a drug‐containing hard gelatin capsule , a swelling layer of croscarmellose (Ac‐Di‐Sol®) and a binder, and an outer ethylcellulose coating . Polyvinyl pyrrolidone ( Kollidon 90F) was superior to HPMC and HPC as a binder for the swelling layer with regard to binding (adherence to capsule) and disintegration properties of the swelling layer. The capsule‐to‐capsule uniformity in the amount of swelling layer and outer ethylcellulose coating, which significantly affected the lag time prior to rupture of the capsule, was optimized by decreasing the batch size, and by increasing the rotational pan speed and the distance between the spray nozzle and the product bed. The type of baffles used in the coating pan also affected the layering uniformity . Fully‐filled hard gelatin capsules had a shorter lag time with a higher reproducibility compared to only half‐filled capsules, because the swelling pressure was directed primarily to the outer ethylcellulose coating and not to the inner capsule core. Stability studies revealed that the lag time of the capsules was stable over a 240‐day period when the moisture content was kept unchanged.

B. STIMULI INDUCED PULSATILE SYSTEMS:

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 20 o C and 30 o C 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.

Slide 21:

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

Slide 22:

III. 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. Magnetically Stimulated Ultrasonically Stimulated Photo Stimulated Electrically Stimulated

Evaluation Parameters:

Evaluation Parameters Hardness Friability Weight uniformity Swelling index Thickness of layer Drug release profile Coating uniformity

Recent Advancement in PDDS:

Recent Advancement in PDDS ACCU-BREAK™ Technology Accu-Break Pharmaceuticals, Inc. and Azopharma Product Development Group, Inc. Accu-Break tablets are manufactured on commercially available multilayer compression equipment. Accu-Break™ Technology is divided in to two types ACCU-B™ Technology and ACCU-T™ Technology.

Slide 25:

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.

Slide 26:

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.

Slide 27:

IV. CODAS™ Technology 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.

Slide 28:

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.

Slide 29:

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.

Slide 30:

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.

Slide 31:

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.

Slide 32:

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.

Slide 33:

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.

Slide 34:

XII. IntelliMatrixTM Technology IntelliPharmacetical is a pharmaceutical technology development company with a suite of proprietary tablet technologies. IntelliMatrixTM drug delivery platform is unique composition of several different ‘intelligent’ polymers such as hydroxy ethylcellulose and a channel former as Lactose. XIII. 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.

Slide 35:

XIV. Banner’s VersetrolTM Technology VersetrolTM Technology is novel innovative technology that provides time controlled release for wide range of drug. In this technology drug is incorporated in lipophilic or hydrophilic matrix and that is than incorporated in soft gelatin capsule shell. This technology is versatile because depending on physiochemical properties of drug either emulsion or suspension can be developed. For lipophilic drugs suspension formulation is preferred while for hydrophilic drugs emulsion form is utilized. By applying combination of lipophilic and hydrophilic matrices desire release profile can be achieved.

Slide 36:

XV. Magnetic Nanocomposite Hydrogel Magnetic nanocomposite of temperature responsive hydrogel was used as remote controlled pulsatile drug delivery. Nanocomposites were synthesized by incorporation of superparamagnetic Fe 3 O 4 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.

Slide 37:

Marketed Products :

Conclusion:

Conclusion It can be concluded that pulsatile drug delivery systems offer a solution for delivery of drugs exhibiting chronopharmacological behavior, extensive first-pass metabolism, necessity of night-time dosing, or absorption window in GIT. A variety of systems based on single or multiple units are developed for pulsatile release of drug. One major challenge will be to obtain a better understanding of the influence of the biological environment on the release performance of pulsatile delivery systems in order to develop simple systems based on approved excipients with a good in vitro-in vivo correlation.

References:

References Ramesh D. Parmar , et al. “ Pulsatile Drug Delivery Systems: An Overview” , International Journal of Pharmaceutical Sciences and Nanotechnology, Volume 2, Issue 3, Oct – Dec 2009. JIGAR D. PATEL, et al. “ PULSATILE DRUG DELIVERY SYSTEM: AN "USER-FRIENDLY" DOSAGE FORM” , JPRHC, Volume 2, Issue 2, April 2010, 204-215. Roland A. Bodmeier , et al. “Drug Delivery: Pulsatile Systems” Recent Techniques For Oral Time Controlled Pulsatile Technology, The Internet Journal of Third World Medicine™ ISSN: 1539-4646