Content Introduction Criteria of Drugs for PDDS Different Approaches Fabrication Recent Advancement Marketed Preparations Conclusion References
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)
What and Why PDDS ? ? ? 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. NOON HIGH ALERTNESS BEST COORDINATIONHIGHEST TESTOSTERONE SECRETION FASTEST REACTION TIME BOWEL MOVEMENT LIKELYMELATONIN SECRETION STOPS GREATEST CVS EFFICIENCY & MUSCLE STRENGTH SHARPEST RISE IN BP HIGHEST BLOOD PRESSURE HIGHEST BODY TEMP LOWEST BODY TEMP MELATONIN SECRETION STARTS DEEPEST SLEEP BOWEL MOVEMENT SUPPRESSED MIDNIGHT Circadian
Necessity of PDDS 1. Chronopharmacotherapy of diseases which shows circadian rhythms in their pathophysiology. 1. asthmatic attacks during early morning 2. heart attacks in the middle of the night 3. morning stiffness in arthritis 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 targetting 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)
Advantages1. Extended daytime or nighttime activity2. Reduced side effects3. Reduced dosage frequency4. Reduction in dose size5. Improved patient compliance6. Lower daily cost to patient due to fewer dosage units are required by the patient in therapy.7. Drug adapts to suit circadian rhythms of body functions or diseases.8. Drug targeting to specific site like colon.9. Protection of mucosa from irritating drugs.10.Drug loss is prevented by extensive first pass metabolism
Different ApproachesA. PREPLANNED SYSTEMS I. Pulsatile system based on capsule II. Pulsatile system based on osmosis III. Drug delivery system with erodible or soluble layer IV. Drug delivery system with rupturable layerB. STIMULI INDUCED PULSATILE SYSTEMS I. Temperature induced system II. Chemically induced System III. Externally stimuli System
A. PREPLANNED SYSTEMS I. Pulsatile system based on capsule 1. PULSINCAP®The Pulsincap® system (Scherer DDS, Ltd) is an example of such asystem that is made up of a water insoluble capsule body filled withdrug formulation (McNeil et al., 1990, Wilding et al., 1992 and Saegeret al. 2004). The body is closed at the open end with a swellablehydrogel plug.The length of plug decides lag time.The plug material consists of insoluble but permeable and swellablepolymers (eg, polymethacrylates), erodible compressed polymers(eg, hydroxypropylmethyl cellulose, polyvinyl alcohol,polyethylene oxide) (Krögel et al., 1998), congealed meltedpolymers (eg, saturated polyglycolated glycerides, glycerylmonooleate), and enzymatically controlled erodible polymer (eg,pectin, agar) (Krögel et al., 1999).
Advantages :• Well tolerated in animals and healthy volunteers, and therewere no reports of gastro-intestinal irritation (Saeger et al.,2004).Disadvantages :• Potential problem of variable gastric residence time, which wasovercome by enteric coating the system to allow its dissolutiononly in the higher pH region of small intestine (Binns et al., 1996)
Development and evaluation of pulsatile drug delivery system using novel polymerThe 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.
II. Pulsatile System Based On OsmosisOsmotic system consists of capsule coated with the semipermiablemembrane.In this system for development of osmotic pressuredifferent techniques are used.Case 1: Osmotic system containing insoluble plug (eg. PORTsystem)Case 2: Osmotic system based on expandable orificetechnology, Linkwitz et al.elastomer (eg. Styrene-butadiene copolymer)Case 3: Osmotic capsule containing micropores, Niwa et al
Fig. Drug release mechanism from Port CapsuleStep1: Cap dissolves off. immediately or modified release dose isreleased.Step 2: Energy source is activated by controlled permeation of GIfluid.Step 3: Time-release plug is expelled.Step 4: Pulse or Sustained release of second dose.
III. Drug delivery system with erodible or soluble layer• In such systems the drug release is controlled by the dissolutionor erosion of the outer coat which is applied on the corecontaining drug.• Time dependent release of the active ingredient can be obtainedby optimizing the thickness of the outer coat 1. Chronotropic® system 2. Time Clock® system 3. Multilayered Tablet1. Chronotropic® system consists of a drug containing core coated byhydroxypropylmethyl cellulose (HPMC), a hydrophilic swellablepolymer, which is responsible for a lag phase in the onset ofrelease (Gazzania et al., 1994 and 1995). variability in gastric emptying time can be overcome, and a
2. Time Clock® system Consists of a solid dosage form coated with lipidic barrierscontaining carnauba wax and bees‟ wax along withsurfactants, such as span 80 (Pozzi et al., 1992 and Wilding etal., 1994). After a lag time proportional to the thickness of the film, thiscoat erodes or emulsifies in the aqueous environment, and thecore is then available for dispersion. The lag time increased with increasing coating thickness Wax + Drug Core Surfactant
3. Multilayered TabletA release pattern with two pulses was obtained from a three-layeredtablet containing two drug containing layers separated by a drug-freegellable polymeric barrier layer (Conte et al., 1989 and 1992) Multilayered Tableta. Initial rapid release drug layerb. Drug – free gellable polymeric barrier layerc. Second pulse generating drug layerd. Impermeable ethyl cellulose layer (3 – sided)
IV. Drug delivery system with rupturable layerThese systems consist of an outer release controlling waterinsoluble but permeable coating subject to mechanically inducedrupture phenomenon. Ethyl cellulose Bicarbonate coating + Citric acid + Drug Rupturable polymer layer Superdisintegrating agent + Drug
Process and Formulation Variables Affecting the Performance of a Rupturable Capsule‐Based Drug Delivery System with Pulsatile Drug Release 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 SYSTEMSI. Temperature induced system Thermo-responsive hydrogel systems have been developed forpulsatile release. In these systems the polymer undergoes swelling or deswellingphase in response to the temperature which modulate drugrelease in swollen state. Eg. 1) Y.H. Bae et al developed indomethacin pulsatile releasepattern in the temperature ranges between 20oC and 30oC byusing reversible swelling properties of copolymers of N-isopropylacrylamide and butyrylacrylamide.2) Kataoka et al developed the thermosensitive polymeric micellesas drug carrier to treat the cancer. They used endfunctionalizedpoly(N-isopropylacrylamide) (PIPAAm) to prepare corona of themicelle which showed hydration and dehydration behavior withchanging temperature.
I. Chemical induced system There has been much interest in the development of stimuli-sensitive delivery systems that release a therapeutic agent inpresence of specific enzyme or protein. One prominent application of this technology has beendevelopment of a system that can autonomously release insulin inresponse to elevated blood glucose levels.1. pH dependent system GLUCOSE GLUCONIC ACID Glucose oxidase immobilized on cross linked polyacrylamide INSULIN N, N- diethylaminoethyl methacrylate and 2-hydroxypropyl methacrylate (DEA-HPMA) formed the barrier membrane
III. Externally stimuli System For releasing the drug in a pulsatile manner, another way can bethe externally regulated systems in which drug release isprogrammed by external stimuli like magnetism, ultrasound,electrical effect and irradiation.a) Magnetically Stimulatedb) Ultrasonically Stimulatedc) Photo Stimulatedd) Electrically Stimulated
Evaluation Parameters ◦ Hardness ◦ Friability ◦ Weight uniformity ◦ Swelling index ◦ Thickness of layer ◦ Drug release profile ◦ Coating uniformity
Recent Advancement inPDDS1. 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.
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‟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
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
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
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
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.
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.
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 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.
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.
References1. Ramesh D. Parmar, et al. “Pulsatile Drug Delivery Systems: An Overview”, International Journal of Pharmaceutical Sciences and Nanotechnology, Volume 2, Issue 3, Oct – Dec 2009.2. JIGAR D. PATEL, et al. “PULSATILE DRUG DELIVERY SYSTEM: AN "USER-FRIENDLY" DOSAGE FORM”, JPRHC, Volume 2, Issue 2, April 2010, 204-215.3. Roland A. Bodmeier, et al. “Drug Delivery: Pulsatile Systems”4. Recent Techniques For Oral Time Controlled Pulsatile Technology, The Internet Journal of Third World Medicine™ ISSN: 1539-4646