Drug administration and Drug Delivery Systems
The oral route of drug administration is the most important method of administering drugs for systemic effects. The parentral route is not routinely used or not possible to self-administration of medication. The topical route of administration has only recently been employed to deliver drugs to the body for systemic effects. It is probable that at least 90 % of all drugs used to produce systemic effects are administered by the oral route. When a new drug is discovered, one of the first questions a pharmaceutical company asks is whether or not the drug can be effectively administered for its intended effect by the oral route. If it cannot, the drug is primarily relegated to administration in a hospital setting or physician’s office. Of drugs that are administered orally, solid oral dosage forms represent the preferred class of product. The reasons for this preference are well known1.Drug administration and Drug Delivery Systems
1.1 Novel Drug Delivery System:
Today, a pharmaceutical scientist is well versed with the fact that the overall action of a drug molecule is not merely dependent on its inherent therapeutic activity, rather on the efficiency of its delivery at the site of action. An increasing appreciation of the latter has led to the evolution and development of several drug delivery systems (DDS) aimed at performance enhancement of the potential drug molecules.
A review of the literature has revealed the recent several technical advancements have led to the development of various Novel Drug Delivery Systems (NDDS) that could revolutionize method of drug delivery and hence could provide definite therapeutic benefits 2.
Till date, remedies have been found for most of the diseases; but still research is going on inorder to improve the existing therapy. To bring a new drug molecule in the market, it involves a lot more than investment of time and money. In the pre GATT era the patents of drug molecules/formulations are expiring. The new way of patenting the drug is to use.
‘Novel Drug Delivery Systems’ i.e. NDDS with improved bioavailability (BA). To formulate a drug or to re-formulate it in a form of NDDS is not a Herculean task if one goes methodically and skillfully. This is where the formulation development studies play an important role.
1.2 Oral Controlled Drug Delivery:
Drug absorption at the desired rate means, first to reach the effective plasma level within an acceptable short time period; second, to avoid an overshoot in the case of rapidly absorbed drugs and third to maintain effective plasma levels over the desired time period. Although the intensity of pharmacological effect is related to the drug concentration at the site of action, which is in turn, related to the plasma drug concentration, an ideal situation is obtained when the concentration is continuously maintained between minimum effective and maximum safe levels (Therapeutic Index). Invariably, conventional drug dosage forms do not maintain the drug. Blood levels within the therapeutic range for an extended period of time. To achieve the same, a drug may be administered repetitively using a fixed dosing interval. This causes several potential problems as like saw tooth kinetics characterized by large peaks and troughs in the drug concentration-time curve (Fig.1), frequent dosing for drugs with short elimination half-life, and above all the patient noncompliance. Controlled release drug delievery systems(CRDDS) attempt to sustain drug blood concentration at relatively constant and effective levels in the body by spatial placement or temporal delivery. Thus CRDDS offer various advantages viz. reduce blood level fluctuations, minimize drug accumulation, employ less total drug, improve patient compliance, and minimize local and systemic side effects3-7.Drug administration and Drug Delivery Systems
Fig 1.1: Plasma level profiles following conventional and controlled release dosing
Modified release DDS, in general, can broadly divided into four categories:
‘ Delayed release
‘ Site specific release
‘ Receptor release
‘ Sustained release
a) Controlled release
b) Prolonged release
For the oral controlled administration of drug, several research and development activities have shown encouraging signs of progress in the development of programmable controlled release dosage forms as well as in the search for new approaches to overcome the potential problems associated with oral drug administration8.
Drugs that are easily absorbed from the gastrointestinal tract (GIT) and having a short half-life are eliminated quickly from the blood circulation. To avoid this problem, the oral controlled release (CR) formulations have been developed as these will release the drug slowly into the GIT and maintain a constant drug concentration in the serum for a longer period of time1. Oral controlled release dosage forms (CRDFs) are being developed for the past three decades due to their advantages. The design of oral controlled drug delivery systems (CDDS) should primarily be aimed at achieving more predictable and increased bioavailability of drugs. Orally administered
controlled release dosage forms suffer from mainly two adversities:
1.3 Gastroretentive drug delivery system (GRDDS) :
Recent scientific and patent literature shows increased interest in academics and industrial research groups regarding the novel dosage forms that can be retained in the stomach for a prolonged and predictable period of time. One of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the GI tract is to control the gastric residence time (GRT), using gastroretentive drug delivery system (GRDDS) that will provide us with new and important therapeutic options8. A major constraint in oral controlled drug delivery is that not all drug candidates are absorbed uniformly throughout the GIT. Some drugs are absorbed in a particular portion of the GIT only or are absorbed to a different extent in various segments of the GIT. Such drugs are said to have an absorption window, which identifies the drug’s primary region of absorption in the GIT 11Drug administration and Drug Delivery Systems
Figure1. 2: (a) Conventional drug delivery system (b) GRDDS
An absorption window exists because of physiological, physicochemical, or biochemical factors. Drugs having site-specific absorption are difficult to design as oral CRDDS because only the drug released in the region preceding and in close vicinity to the absorption window is available for absorption. After crossing the absorption window, the released drug goes waste with negligible or no absorption (Fig.2a). This phenomenon drastically decreases the time available for drug absorption after its release and jeopardize the success of the delivery system. The GRDDS can improve the controlled delivery of the drugs which exhibit an absorption window by continuously releasing the drug for a prolonged period before it reaches its absorption site, thus ensuring its optimal bioavailability (Fig.2b) 12.
Pharmaceutical aspects of gastroretentive drug delivery system (GRDDS) :
In designing GRDDS, the following characteristics should be sought: convenient intake, retention in the stomach according to clinical demand; ability to load substantial amount of drugs with different physicochemical properties and release them in controlled manner; complete degradation, preferable in the stomach13 .Gastric retention will provide advantages such as the delivery of drug with narrow absorption window in the small intestinal region. Also longer residence time in the stomach could be advantages for local action in the upper part of small intestine; e. g. in the treatment of peptic ulcer disease, further more improved bioavailability is expected for drug that absorbed readily upon release in the GI tract.
1.4 Physiology of Stomach:
The shape of the normal stomach is generally like letter ‘J’. Sometimes the long axis may be slanting from left to right or it may be even horizontal. The junction of the esophageal mucosa with that of the stomach is abrupt. The oesophago-cardiac line of junction is irregular or zigzag and is often referred as the ‘Z’ or ‘ZZ’ line. At the pylorus, the mucous membrane of the stomach makes junction with that of duodenum. The capacity of the average stomach is about 1.12-1.7 lts. The stomach can be subdivided into three parts- the fundus, the body and the pylorus.Drug administration and Drug Delivery Systems
Figure 1.3: Stomach anatomy
Each of these contains a particular type of gland. The cardiac area is the zone,1 to 4 cm wide that guards the esophageal orifice, also known as cardiac Fundus Body Pylorus sphincter. The fundic area is the largest area of stomach accounting for 60-80 % of total mucosal surface, interposed between the cardiac and the pyloric areas. The lower part of the fundic area is separated from the pylorus by a sharp angle on the lesser curvature called the incisura angularis. The junction of the pyloric and fundic area is not sharply demarcated and is frequently known as transitional zone.
The pylorus is limited on the left by the incisura and on the right by the pyloric sphincter. The circular fibres of pyloric sphincter guards against back flow of small intestinal contents into the stomach. The pyloric area is about 15 % of the total gastric mucosal area. It is subdivided into two parts: (a) the pyloric antrum which is short, comparatively wider, proximal chamber and (b) the pyloric canal which is narrow tubular passage about 3 cm long, ending in the pyloric sphincter (Fig.3).
Histologically, stomach consists of the same four layers but with characteristic differences. The outer serous coat consists of peritoneum. The muscular coat consists of three layers: the outer longitudinal, the middle circular and the inner oblique layer. Next comes the submucous coat, and then come the layer of muscular is mucosae and a supporting stroma of connective tissue. This layer of muscle also contains of an outer longitudinal and an inner circular layer. Finally comes mucous membrane which is thrown out into the large folds called rugae when the stomach is empty and these folds tend to disappear when distended14.
1.5 Gastric Emptying:
The GIT is always in a state of continuous motility. The process of gastric emptying occurs both during fasting and fed states; however, the pattern of motility differs markedly in the two states. In the fasted state, it is characterized by an interdigestive series of electrical events which cycle both through the stomach and small intestine every 2-3 h. This activity is called the interdigestive myoelectric circle or migrating myoelectric complex (MMC), which is often divided into four consecutive phases13.Drug administration and Drug Delivery Systems
Figure1.4: Typical motility patterns in fasting state12
A complete cycle of these 4 phases, as illustrated in Fig. 4, has an average duration of 90-120 minutes. Any CRDDS designed to stay during the fasted state should be capable of resisting the house-keeping action of phase III, if one intends to prolong the GI retention time. The bioadhesive properties added to the GI drug delivery system must be capable of adhering to the mucosal membrane strongly enough to withstand the shear forces produced in this phase15.
The gastroretentive technology of solid dosage forms is thus mainly dependent on the coincidence between dosing time and phase III MMC occurrence. Dosage forms such as tablets, capsules and particles have demonstrated a transit pattern similar to that of nutrients. These forms taken orally in the fasted state empty within 90 min. In fed state, these will have to await the MMC activity occurring at the end of digestion to be cleared from stomach in association with the Phase III cleansing contractions. It is thus the pylorus, and, more particularly, the small diameter of the gastric lumen at the gastroduodenal junction, that has remarkable function of performing the selective retention of the solid particles, depending on their size16.
1.5.1. Factors Affecting Gastric Retention 10, 12:
Gastric residence time of an oral dosage form is affected by several factors. The pH of the stomach in fasting state is ~1.5 to 2.0 and in fed state is 2.0 to 4.0. A large volume of water administered with an oral dosage form raises the pH of stomach contents from 6.0 to 9.0. Stomach doesn’t get time to produce sufficient acid when the liquid empties the stomach; hence generally basic drugs have a better chance of dissolving in fed state than in a fasting state.
To pass through the pyloric valve into the small intestine the particle size should be in the range of 1 to 2 mm.. In the case of elderly persons gastric emptying is slowed down. Generally females have slower gastric emptying rates than males. Stress increases gastric emptying rates while depression slows it down. Studies have revealed that gastric emptying of a dosage form in the fed state can also be influenced by its size. Small-size tablets leave the stomach during the digestive phase while the large-size tablets are emptied during the housekeeping waves. The effect of size of floating and nonfloating dosage forms on gastric emptying and concluded that the floating units remained buoyant on gastric fluids12. These are less likely to be expelled from the stomach compared with the nonfloating units, which lie in the antrum region and are propelled by the peristaltic waves.Drug administration and Drug Delivery Systems
It has been demonstrated using radiolabeled technique that there is a difference between gastric emptying times of a liquid, digestible solid, and indigestible solid. It was suggested that the emptying of large (91 mm) indigestible objects from stomach was dependent upon interdigestive
migrating myoelectric complex. Indigestible solids larger than the pyloric opening are propelled back and several phases of myoelectric activity take place when the pyloric opening increases in size during the housekeeping wave and allows the sweeping of the indigestible solids. Size and shape of dosage unit also affect the gastric emptying. Garg and Sharma15 reported that tetrahedron- and ring-shaped devices have a better gastric residence time as compared with other shapes. The diameter of the dosage unit is also equally important as a formulation parameter. Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm.
Floating units away from the gastroduodenal junction are protected from the peristaltic waves during digestive phase while the nonfloating forms which stay close to the pylorus and are subjected to propelling and retropelling waves of the digestive phase.Drug administration and Drug Delivery Systems It is also observed that of the floating and nonfloating units, the floating units had a longer gastric residence time for small and medium units while no significant difference was seen between the 2 types of large unit dosage forms. When subjects are kept in the supine position it was observed that the floating forms could only prolong their stay because of their size; otherwise the buoyancy remained no longer an advantage for gastric retention. A comparison was made to study the affect of fed and non-fed stages on gastric emptying. For this study all subjects remaining in an upright position were given a light breakfast and another similar group was fed with a succession of meals given at normal time intervals. It was concluded that as meals were given at the time when the previous digestive phase had not completed, the floating form buoyant in the stomach could retain its position for another digestive phase as it was carried by the peristaltic waves in the upper part of the stomach10.Drug administration and Drug Delivery Systems
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