CHAPTER 1INTRODUCTIONTremendousadvancements in science and technology have been aimed at human welfare. Recentdevelopments in the area of healthcare have focused upon reducing the morbiditystatus and decreasing the mortality rates. In this field, medicines have beenused since antiquity, and now humans have with them most modern techniques,capable of combating diseases which were main cause of death.
Despiteof the search for the ultra-modern techniques of drug delivery for the purposeof diagnosis or treatment, conventional form of drug delivery has stillretained its position in the market. Discovery of nanoparticles, dendrimers,vesicular systems, carbon nanotubes has been done but the delivery of drug inthe form of a tablet still remains the most popular. Oral route of drug deliveryis found to be most common, even in today world, because of the variousadvantages served by the oral route of drug delivery 1.
More than 90% of thedrugs that are known to produce systemic effects are delivered by the oralroute 2. In the dosage forms administered orally, solid dosage forms, exampletablets and capsules, are the most preferred class of products. A few of theiradvantages are:1) Ease ofadministration of the medication to the patient.2) Possibility ofvarying properties achieved while preparation of solid dosage forms.3) Variationpossible in terms of the dose, size, and organoleptic properties.
4) Decreased costof production, as well as cheaper medication costs.5) Overallincreased patient compliance 3.Tabletsare the most widely used dosage forms and are available broadly under twocategories, immediate release and modified release dosage forms. Thisclassification is based on the type of the absorption profile of the drug andthe time at which the absorption of the drug takes place. The oral route inmajority of cases provides the drug release at a predetermined, predictable andcontrolled rates 2, 3. But at many a times, variations in the drug absorptionhas been seen due to various factors, and also this route suffers variousphysiological problems.1) Non predictablegastric emptying time, that differs from patient to patient, and also upon thephysiological condition of the body.
2) Thegastro-intestinal transit time that varies with the type of diet taken, and thetime of taking the medication.3) The presence ofabsorption window in the upper small intestine, which is responsible forabsorption of a large number of drugs.4) Inability tocontrol the release of the drug from the dosage forms in the desired region ofthe gastro-intestinal tract.5) Drugs which areabsorbed only from the stomach, drugs unstable in the intestinal pH, and drugsacting locally in the stomach need special formulations 4.Inorder to overcome the various disadvantages, and help the easy and effectiveadministration of the special class drugs, a novel approach of drug delivery,the gastro-retentive drug delivery systems has been developed. This dosage formhas been developed with the objective that after the delivery, the dosage formshall be retained in the gastric region, and thus it can easily release thedrug in a controlled and sustained manner. Also the drug can now becontinuously supplied to the area of absorption, absorption window from whichthey can be easily absorbed 5.
1.1 Emergence of Gastro-Retentive Dosage Forms Theprimary aim of any delivery system at the present time is to provide a steadyplasma concentration of the drug for a suitable time period. The drugs whichhave comparatively shorter half-lives suffer a disadvantage that they areeliminated quickly from the body and thus they need frequent dosing. Repeatedadministration of drug is not always possible for the patient and also is notfeasible which leads to the failure of the therapy. Thus there was a need todevelop drug delivery systems which could provide drug release over an extendedperiod of time and can be, at the same time, administered orally 6. Gastroretentive drug delivery systems is a novel approach in which the drugs areretained in the stomach region of the gastro-intestinal tract, thus prolongingthe action or in other words, providing a sustained release of the drugs in thestomach region. The need of the gastro-retentive drug delivery approach wasfelt for:1) The drugs whichare unstable at higher pH, degrade at the intestinal region are to be kept inthe acidic surroundings, till they release their whole drug, Eg.
Ranitidine HCLand metronidazole. Thus their retention is important for the stability issues.2) The drugs whichare meant to provide a local action at the gastric region, for example, protonpump inhibitors, for the treatment of the gastric ulcers, have to be present inthe stomach area for their action. Thus their retention is important.3) The drugs whichget absorbed from a narrow absorption window, generally from the upper part ofthe small intestine, or the duodenal region, Eg. Metformin, Furosemide,Ciprofloxacin, Baclofen.
These drugs have to be supplied in a given limiteddose in a continuous manner at the absorption site for effectivebioavailability. This can only be achieved through gastro-retention.4) The drugs whichare less soluble in the intestinal area, example Cinnarazine, Verapamil,Diazepam, their solubility can also be increased by the retention process inthe stomach region.
7 1.2 Advantages of the Gastro-Retentive Drug Delivery Systems:Gastro-retentivedrug dosage forms offer some potential advantages in area of drug delivery ofvarious classes of drugs. Some of them are:1) Overall improved bioavailability of drugs: Drugs with limited absorption in the intestinalregion or the ones that absorb more in gastric region. 2) Reduced drug wastage: Drugs which had to be earlier administered inhigher dose due to various stability or solubility issues now can also beadministered in lower dosage.3) Improved solubility profile: Drugs like Papaverine and Domperidone that areless soluble in the higher pH of the intestine regions, are now be easilyfabricated.4) Local action and therapy: Drugs administered for the purpose of providing a localaction at the gastric area such as antacids, or that administered for thetreatment of the gastric ulcers, are readily absorbed and show enhancedactivity.
For example, eradication of the H.pylori from the sub-mucosal regionin case of esophagitis 4, 6, 7.5) Reduced dosing for drugs: Drugs which are of shorter half-life andeliminated quickly from body are to be taken repeatedly. With gastricretention, a sustained action can be achieved and dosing can be reduced.6) Less fluctuations in drug concentration: gastro-retention provide less fluctuations in thedrug concentrations and thus the adverse effects which are related to theconcentration, can be relieved. This proves to be advantageous in cases wherethe drug has a narrow therapeutic index. Also this helps in the betterselective-receptor activation.
5,8 1.3 Disadvantages of the Gastro-Retentive Drug DosageForms: 9Besidesoffering a large number of advantages for various classes of drugs, thegastro-retentive drug delivery systems also have a variety of disadvantages:1) Drugs disruptive to the stomach: there are some drugs where the gastro-retention isundesirable, for instance Aspirin and other non-steroidal anti-inflammatorydrugs are known to cause lesions and burns.2) Drugs unstable in stomach region: Drugs causing irritation to the stomach lining anddrugs may degrade in the low pH of the stomach need not be formulated asgastro-retentive dosage forms 6.3) Drugs with uniform absorption: There are drugs which show uniform absorptionthroughout the gastro-intestinal tract, for example, Isosorbide Dinitrate. Sothere is no need for gastro retention in such cases as well.
4) Stomach fluid volume: For the purpose of floating, there is need ofadequate amount of fluid in the stomach which is not always possible.5) Drug administration: The floating systems need to be taken with atleast 200-250ml of water. The administration of such a volume is not possiblemaximum times. 1.4 Conventional Dosage Forms versus Gastro-RetentiveSystems: 10 S.NO CHARACTERISTICS CONVENTIONAL GASTRO-RETENTIVE 1 Patient compliance Comparatively less More compliance 2 Toxicity cases More chances Less chances 3 Dose dumping Increased cases less cases 4 Drugs unstable in gastric environment Less suitable More advantages 5 Drugs less soluble in intestinal pH Variable absorption Effective absorption 6 Drugs with narrow absorption window Less bioavailability Increased bioavailability 7 Drugs acting locally in stomach Variable action Improved action