Kuwait Pharmacy Bulletin DRUG INFORMATION FOR THE HEALTH PROFESSIONAL Vol 20 No 3 Autumn 2016 ISSN 1028-0480 Pulsatile drug delivery system Introduction rhythm in terms of their daily activity. Better absorption and bioavailability in compari- Traditional drug delivery system, or TDDS, is the son to TDDS and sustained release, because of classical method of delivering a drug to the body complete release of the drug from the formulation. without controlling the rate or time of drug release. Ability to target specific organs or tissues increas- On the other hand, modified drug delivery sys- es the bioavailability of poorly bioavailable drugs. tem, or MDDS, is a more recent method to intro- Drug frequency and dose used in PDDS is lower duce a drug into the body with the adjustment of than in TDDS. This will reduce side effects and time, rate, and site of medication liberation. An will increase patient compliance and decrease the important type of MDDS is pulsatile drug delivery cost. systems, PDDS, in which the drug is released from First pass metabolism can be avoided, leading to its formulation after a pre-determined off-release less drug-drug interactions. period or into a specific body site under certain Risk of local GI irritation is lowered. conditions. This period is called lag time and de- No risk of dose dumping effect. fined as the time needed to release a drug from the Reduced chance of developing biological toler- dosage form after placing it in an aqueous environ- ance. ment. In an ideal pulsatile drug delivery system, Reduced intra- and inter-patient variability. the drug is released completely and rapidly after a Many solid dosage forms have been successfully lag time; however, drug release can be in a sus- made as PDDS, including tablets, capsules, micro- tained or delayed fashion. spheres, and pellets. Certain diseases such as arthritis, cardiovascular diseases, peptic ulcer and hypercholesterolemia can be targeted by PDDS. Disadvantages These are good targets for PDDS due to their unique daily rhythmic activity, and the pulsatile Low medication loading limit and incomplete dis- release of the drugs mimics the activity patterns of charge of medication these disorders. For instance, colon-specific release Higher expense of formulation has been achieved by PDDS to manage irritable Huge number of procedure variables bowel disease. Absence of creation reproducibility and efficacy Many pharmaceutical companies have become Erratic in vitro-in vivo correlation more interested in PDDS, which follows the same Complex equipment needed in manufacturing [7] physiological release pattern of the endocrine sys- tem. Moreover, many physiological functions are Classification affected by the body’s rhythm, including gastric and urinary pH, GI motility, blood pressure and PDDS can be classi- body temperature[1]. In addition, some conditions fied based on their follow a certain rhythm in their activity, and con- target release, includ- stant release of the drug is not suitable for these ing time-controlled, In this issue conditions because of increased side effects. PDDS site-specific or stimuli target these conditions only when they are active, Pulsatile drug delivery 1 -induced systems in Test your knowledge 8 minimising side effects. which the drug is re- Topical issues 9 leased under gastroin- In the news 11 Advantages (2-6) Special feature– Islamic 13 testinal pH or enzy- contribution to medicine matic control, and News from FoP 15 Best option for conditions that follow a circadian externally regulated New drug approvals 16 2 Kuwait Pharmacy Bulletin Autumn 2016 systems where the active components are liberated B. Intestinal enzymes dependent release in response to irradiation, ultrasound, magnetism Many bacterial species present in the colon undergo and electrical effect. The other classification de- vitamin K synthesis, releasing some enzymes, and pends on the technology used to prepare PDDS, immunity function. Sulfasalazine is a pro-drug con- consisting of both single and multiple unit systems. sisting of sulfapyridine and meselamine, which is the active moiety. Sulfasalazine is the first pro-drug Classification based on target release that utilises bacterial enzymes called azoreductases which break the azo bond between sulfapyridine and Time-controlled pulsatile release mesalamine in the colon in order to exert their phar- macological action in patients with rheumatoid ar- Time-controlled pulsatile release dosage forms are thritis or irritable bowel syndrome. Many side ef- used to liberate the medication after a pre- fects have been experienced by patients due to the determined lag time. This delayed release is not presence of sulfapyridine in the formulation, so affected by gastric pH, enzymes or motility. How- newer dosage forms have replaced it with dextran, ever, it is influenced by the delivery system, in pectin or other natural polysaccharides [2]. which the active agent is released by different C. GI transit time/pressure dependent release mechanisms depending on the type of barrier coat- ing [8]. Different parts of the GI tract have different transit times. Gastric transit time is not constant between In formal techniques, water-soluble coatings individuals, and it depends on the type of diet, mo- were used in order to achieve slow dissolution in bility, diseases and drugs. However, it can be uti- the intestine to liberate the active ingredient. An- lised to deliver the drug to the large intestine after a other technique is to surround an osmotic agent lag time of around 5-6 h. In addition to transit time, and drug molecules by a water-permeable but in- soluble coat. Once the tablet reaches the GI tract, the difference in the pressure of different regions in water diffuses gradually through the coat into the the GI tract can also be useful to achieve site specif- core, where the osmotic agent swells until the coat ic drug delivery. A good example is the use of ethyl bursts to liberate drug molecules. In addition to cellulose coated dosage forms [11]. The molecular these two techniques, a water-impermeable film weight of ethyl cellulose can be controlled in order with a controlled opening can be used to enclose to withstand gastric and small intesinal pressure. High molecular weight results in higher resistance the active ingredient. As water from GI tract enters to GI pressure. In comparison to other GI regions, the tablet through this opening, core release occurs the pressure in the colon is the highest and ethyl cel- once the film bursts [9]. lulose will rupture in the colon, achieving colon spe- cific delivery [12]. Stimuli or site specific delivery system D. Inflammation-induced pulsatile release A. Gastrointestinal pH dependent release Numerous mediators such as hydroxyl radicals are Different sites of the GI tract have different pH released from immune cells during inflamation,. conditions. One example of a pH dependent release Hyaluronic acid is a drug that is degraded by these is enteric coated oral dosage forms. Enteric coating radicals and also by hyaluronidase enzymes, to exert usually consists of weakly acidic polymers that the anti-nflammatory action. Hyaluronic acid is of- maintain their non-ionized form at gastric pH; ten indicated to be injected into the affected joint in however they are ionized at intestinal pH and patients with rheumatoid arthritis[11]. therefore soluble in the intestine [9]. One formula- tion example is theophylline, which is designed to E. Antibody dependent release relieve symptoms of nocturnal asthma. The inner Intelligent gels were developed to release the drug core consists of micro-encapsulated theophylline in response to antibody concentration. They are able coated with eudragit L-100 and S-200, which are to change their swelling/de-swelling properties by pH sensitive co-polymers. This core is capped by a which drug permeation changes. The basic design is hydrogel plug followed by an insoluble hard gela- to incorporate polymerized antigen-antibody com- tin and a soluble cap. The whole dosage form is plex in the gel network, and in the presence of the enteric coated in order to achieve pH dependent same free antigen, the antibody in the antigen- release [10]. antibody complex will bind to the free antigen lead- ing to gel swelling and subsequently drug release [11]. Vol 20, No 3 Drug Information For The Health Professional 3 F. Glucose-responsive insulin release devices A novel device that consists of a pH sensitive hy- drogel incorporating glucose oxidase and insulin has been used to replace insulin injections. At high blood glucose levels, glucose will be converted to gluconic acid by glucose oxidase. The acidity of gluconic acid causes swelling of the hydrogel, leading to release of the integrated insulin [11]. Externally regulated systems The advantages of using an external stimulus in- clude choosing the dose, duration and time of drug release. External stimuli used in pulsatile release systems involve electric and magnetic field, as well as ultrasound. A. Electric field Preparations using this technique usually contain polyelectrolytes, so they are responding to pH Fig 1. Pulsincap® design [16] changes and electric field. On application of exter- nal electric field to a hydrogel that contains poly- electrolytes, hydroxyl ions will be generated at the swells slowly during a defined lag time and pushes cathode, and the local pH will increase. This leads itself outside the capsule to release the drug [16]. to hydrogel erosion and drug release [13]. B. Osmotic based dosage forms B. Magnetic field Various preparations of PDDS, such as PORT sys- Magnetically induced pulsatile release system con- tem, rely on osmosis to release drugs. The PORT sists of magnetic beads incorporated in a dosage system is composed of drug molecules mixed with form, and external magnetic field. The basic mech- an osmotically active agent and capped with an in- anism of this approach is to control the movement soluble plug.