Pulsatile drug delivery system

novel drug delivery

1. PULSATILE DRUG DELIVERY SYSTEMS:

2. Introduction Applications of PDDS Approaches Advantages and limitations: Recent advancement Marketed products Conclusion References CONTENT:-

3. 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. INTRODUCTION :-

4. It is a chronopharmacotherapy designed according to the circadian rhythm of body. It is a type of INTELLIGENT DRUG DELIVERY SYSTEM : capable of adjusting drug release rates in response to a physiological need. Types: Open loop control systems : also known as pulsed or externally regulated systems.The externally controlled devices apply external triggers for pulsed delievery of drugs such as magnetism,ultrasound and electrical effect. It includes the following: Magnetically modulated pulsatile systems Ultrasonically modulated pulsatile systems

5. Electrically modulated pulsatile systems Thermosensitive drug delivery systems. 2. closed loop controlled systems : They are also known as self regulated systems in which release rate of drug is controlled by feedback information, without any external intervention. It includes the following: PH responsive drug delivery Glucose-responsive insulin delivery Inflammation-induced pulsatile release

6. APPLICATIONS :- Diseases that require PDDS:

7. DISEASE CHRONOLOGICAL BEHAVIOUR DRUGS USED Peptic ulcer Acid secretion is high in the afternoon and at night. H2 blockers Asthma Precipitation of attacks during night or at early morning. Β2 agonist, Antihistamines Cardiovascular diseases BP is at its lowest during the sleep cycle and rises steeply during the early morning Nitroglycerin, calcium channel, blocker, ACE inhibitors 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

8. Avoiding the first pass metabolism e.g. protein and peptides. Drugs for which the tolerance rapidly exists, e.g.: salbutamol sulphate. For time programmed administration of hormone and drugs. For drugs having the short half life, e.g.: β -blockers. For targeting specific site in intestine e.g. colon, e.g.: sulfasalazine.

9. VARIOUS APPROACHES OF PDDS :- Different approaches of pulsatile system are broadly divided as follows: 1. Time controlled systems: Capsule based system, System based on osmosis, Solubilization or erosion, With rupturable coating layer. 2. Internal stimuli induced: Temperature induced, Chemical stimuli induced. 3. Externally regulated: Magnetically induced, Ultrasonic induced, Electrically induced, Light induced. 4. Multiparticulate . 5. System for vaccine and hormone products.

10. Capsule shaped pulsatile drug release : 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. This dosage form consists of an insoluble capsule body containing a drug and swellable and degradable plugs made of substances such as hydrophilic polymers or lipids. The lag time can be controlled by manipulating the dimension and the position of the plug. Polymers used for designing of the hydro gel plug includes: Insoluble but permeable and swellable polymers(e.g., polymethacrylate) Erodible compressed polymers (e.g., hydroxypropylmethyl cellulose, polyvinyl alcohol, Polyethylene oxide) 1.TIME CONTROLLED SYSTEMS :-

11. Congealed melted polymers (e.g., saturated polyglycolated glycerides, glyceryl monoleate) Enzymatically controlled erodible polymer (e.g., pectin ). Schematic diagram of drug release from capsule: On contact with aqueous fluids, the cap rapidly dissolves thereby releasing the immediate release component followed by pulsed release component. The length of plug decides lag time.

12. System based on osmosis: It consists of a capsule coated with a semipermiable 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 semipermiable 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. E.g.: the port system.

13. Solubilization or erosion systems: In such systems, the core containing drug is coated with the soluble or erodible polymer as outer coat and drug release is controlled by the dissolution or erosion of the outer coat. Time dependent release of the drug can be obtained by optimizing the thickness of the outer coat as shown in fig: e.g. The Time Clock system and the chronotropic system .

14. System with rupturable coating membrane: In place of swelling or eroding, these systems are dependent 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 swelling, disintegrants, effervescent excipients, or osmotic pressure. Water permeation and mechanical resistance of the outer membrane are major factors affecting the lag time. E.g.: Buflomedil HCl is used for treatment of peripheral arterial disease.

15. In these systems, the release of the drug takes place after stimulation by any biological factor like temperature, or any other chemical stimuli. Many of the polymeric delivery systems experience phase transitions and demonstrate marked swelling deswelling changes in response to environmental changes including solvent composition ionic strength, temperature, electric fields, and light. TEMPERATURE INDUCED SYSTEMS : This deviation sometimes can act as a stimulus that triggers the release of therapeutic agents from several temperature responsive drug delivery systems for diseases accompanying fever. The temperature induced pulsatile/triggered drug delivery systems utilize various polymer properties, including the thermally reversible coil/globule transition of polymer molecules swelling change of networks, glass transition and crystalline melting . 2 . INTERNAL STIMULI INDUCED SYSTEMS :-

16. Thermo responsive hydrogel systems: Thermo-responsive hydrogel systems employ hydrogels which 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. Thermo-sensitive hydrosensitive hydrogels have a certain chemical attraction for water, and therefore they absorb water and swell at temperatures below the transition temperature whereas they shrink or deswell at temperatures above the transition temperature by expelling water. Thermally responsive hydrogels and membranes have been extensively exploited as platforms for the pulsatile drug delivery.

17. Thermo responsive polymeric micelle systems: In this type, the gel system tightly stores targeted drug in the micelles and rapidly releases controlled amount of the drug by switching on–off of external stimuli such as temperature or infrared laser beam. E.g. 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 .

18. Chemical stimuli induced systems: In these systems, there is release of the drug after stimulation by any biological factor like enzyme, pH or any other chemical stimuli. PH sensitive drug delivery systems: This type of PDDS contains two components. The first is fast release type while the other is pulsed release which releases the drug in response to change in pH. In case of pH dependent system, advantage has been taken of the fact that there exists different pH environment at different parts of the gastrointestinal tract. By selecting the pH dependent polymers drug release at specific location can be obtained.

19. Examples of pH dependent polymers include 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 intestine. E.g: Eudragit in colon targeted systems.

20. Glucose-responsive insulin release devices: In a glucose-rich environment, such as the bloodstream after a meal, the oxidation of glucose to gluconic acid catalyzed by glucose oxidase can lower the pH to approximately 5.8. This pH change induces swelling of the polymer 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 etc .

21. Inflammation induced pulsatile release : On receiving any physical or chemical stress, such as injury, fracture etc., inflammation take place at the injured sites. During inflammation, hydroxyl radicals are produced from these inflammation-responsive cells. Degradation via hydroxyl radicals however, is usually dominant and rapid when Hyaluronic Acid gel 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 delievery systems.

22. Drug release from intelligent gels responding to antibody concentration : There are numerous kinds of bioactive compounds which exist in the body. Recently, novel gels were developed which responded to the change in concentration of bioactive compounds to alter their swelling/deswelling characteristics. Special attention was given to antigen-antibody complex formation as the cross-linking units in the gel, since such interaction is very specific. Utilizing the difference in association constants between polymerized antibodies and naturally derived antibodies towards specific antigens, reversible gel swelling/deswelling and drug permeation changes occurs.

23. Enzymatically- activated liposome: Drug loaded liposomes was incorporated into microcapsules of alginate hydrogels. Liposomes inside the microcapsules were coated with phospholipase A2 to achieve a pulsatile release of drug molecules. Phospholipase A2 was shown to accumulate at the water/liposome interfaces and remove an acyl group from the phospholipids in the liposome. Destabilized liposomes release their drug molecules, thus allowing drug release to be regulated by the rate determining microcapsule membrane. Drawback: destabilization due to the absorption of plasma proteins on the lipid bilayer and have thus limited the application of these formulations.

24. This system is not self-operated, but instead requires externally generated environmental changes to initiate drug delivery. These can include magnetic fields, ultrasound , electric field, light, and mechanical force . Magnetically induced systems: The use of an oscillating magnetic field to modulate the rates of drug release from polymer matrix was one of the old methodologies. Magnetic carriers receive their magnetic response to a magnetic field from incorporated materials such as Magnetite, Iron, Nickel, Cobalt etc . For biomedical applications, magnetic carriers must be water-based, biocompatible, non-toxic and non-immunogenic mechanistic approach based on magnetic attraction is the slowing down of oral drugs in the gastrointestinal system. This is possible by filling an additional magnetic component into capsules or tablets. EXTERNALLY REGULATED PULSATILE RELEASE SYSTEM:-

25. The speed of travel through the stomach and intestines can then be slowed down at specific positions by an external magnet, thus changing the timing and/ or extent of drug absorption into stomach or intestines. Schematic representation:

26. Electric field induced system: Electrically responsive delivery systems are prepared from polyelectrolytes (polymers which contain relatively high concentration of ionisable groups along the backbone chain) and are thus, pH-responsive as well as electro-responsive. Under the influence of electric field,electroresponsive hydrogels generally bend, depending on the shape of the gel which lies parallel to the electrodes whereas deswelling occurs when the hydrogel lies perpendicular to the electrodes. E.g.: poly(acrylamide-grafted-xanthan gum ) hydrogel for transdermal delivery of ketoprofen.

27. Ultrasound induced release systems: Ultrasound is mostly used as an enhancer for the improvement of drug permeation through biological barriers, such as skin. Ultrasound devices are used to achieve up to a 27-fold increase in the release of 5-fluorouracil from an ethylene and vinyl acetate matrix. Increasing the strength of the ultrasound resulted in a proportional increase in the amount of 5-fluorouracil released.

28. Light induced release systems: Light-sensitive hydrogels have potential applications in developing optical switches , display units, and opthalmic drug delivery devices. The interaction between light and material can be used to modulate drug delivery . When hydrogel absorb the light and convert it to heat, raising the temperature of composite hydrogel above its LCST, hydrogel collapses and result in an increased rate of release of soluble drug held within the matrix .

29. Such systems are: Reservoir systems with rupturable polymeric Coatings. Reservoir systems with soluble or eroding polymer coatings. Floating multiparticulate pulsatile systems. The purpose of designing multiparticulate dosage form is to develop a reliable formulation that has all the advantages of a single unit formulation and yet devoid of the danger of alteration in drug release profile and formulation behaviour due to unit to unit variation. MULTIPARTICULATE SYSTEMS:-

30. The system consists of uniform spheroidal beads of 1-2mm in diameter containing drug & excipients and is coated with product specific controlled release polymers and drug releases by erosion or diffusion. 5. SYSTEM FOR VACCINE AND HORMONE PRODUCTS:- Vaccines are traditionally administered as an initial shot of an antigen followed by repeated booster shots to produce protective immunity. PDDS offer the possibility of single-shot vaccines if initial booster release of the antigen can be achieved from one system in which timing of booster release is controlled. GnRH for synthesis and secretion of luteinizing hormone and follicle stimulating hormone in cows.

31. 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. RECENT ADVANCEMENTS:-

32. Magnetic Nanocomposite Hydrogel: Nanocomposites were synthesized by incorporation of super paramagnetic 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 . Banner’s VersetrolTM Technology: In this technology drug is incorporated in lipophilic or hydrophilic matrix and that is than incorporated in soft gelatin capsule shell. By applying combination of lipophilic and hydrophilic matrices desire release profile can be achieved. TMDS (Time Multiple Action Delivery system) Technology: It 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.

33. COMMERCIAL PRODUCTS:- NAME ACTIVE INGREDIENT DISEASE MECHANISM PULSYS® Amoxicillin Pharyngitis/tonsillitis Time controlled system UNIPHYL® Theophylline Asthma Externally regulated system RITALIN β Methyl phenidate Attention deficit hyperactive disorder Osmotically regulated system CODAS® Verapamil HCl Hypertension Multiparticular pH dependent system DIFFUCAPS® Verapamil HCl Propanolol HCl Hypertension Multiparticulate system

34. CONCLUSION:- It is known that sustained and controlled release products provide a desired therapeutic effect, but fall for diseases following biological rhythms. 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. 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

35. REFERENCE:- Encyclopedia of controlled drug delivery, volume:2, by Edith Mathiowitz; pg no:446 to 457. Handbook of pharmaceutical controlled release technology; edited by Donald L.Wise; pg.no: 67 to 81. Internet source.