Gastric Emptying Of Dosage Forms

For the majority of cases, oral drug delivery is the cheapest and most convenient method of dosing. Unfortunately it is difficult to achieve a precise control of the plasma concentration-time profile, which shows marked intra- and inter-subject variation even under the rigidly controlled conditions of the clinical trial. In the unrestricted patient this is exaggerated by poor compliance and anything more complicated than a b.d. schedule is impractical. Daily patterns such as food intake, activity and posture are large contributors to inter- and intrasubject variation. The nature of food intake is not only specific to race and geographic location but unique for each person, and varies on a day-to-day basis. This factor probably produces the largest physiological variation in the behaviour of oral dose forms. The rate of gastric emptying, the presence of food or other drugs, the particular formulation of the drug (size, shape and rate of disintegration), and the vehicle carrying it all influence the absorption of the drug.

Once the dosage form has reached the stomach, it meets an highly variable environment in terms of food content and pH. The gastric emptying of tablets, pellets and liquids is highly dependent on the presence and amount of food in the stomach. Large tablets can either disintegrate in the stomach and empty with the digestible phase of the meal, or if they are designed to remain intact will be treated as indigestible material since they do not possess a significant calorific value. Large non-disintegrating capsules will empty with phase III of the MMC, and since ingestion is not synchronised to any particular part of the cycle, the emptying will appear erratic, occurring any time between a few minutes and 3 hours after administration.

When a large unit is given after a light meal (1500 kJ) the emptying becomes more predictable at around 2 to 3 hours. The meal serves to put the motility cycle into phase by initiating the fed pattern until the small calorific load has been passed to the duodenum. The next MMC then removes the tablet approximately 2 hours after the stomach has been cleared of the digestible components of the meal. Dosage forms are often administered to fasting subjects during pharmacokinetic studies in an attempt to reduce variability, but the effect of erratic emptying can affect the time of appearance of the drug in the plasma. However if the formulation is given with food to synchronise motility, the absorption of the drug can be influenced by the food. A possible solution is to give the drug with apple juice, which is a clear liquid, but has sufficient calories to synchronise gastric motility.

If a large single unit is given with a heavy meal (3600 kJ) and the subject is fed at regular intervals, the unit can remain in the stomach for longer than 8 hours due to prolonged suppression of the MMC. The only time at which the stomach can revert to the fasted pattern of motility is during the night when there is a sufficient interval between dinner and breakfast70. The length of the retention is proportional to the meal size. Thus when given with a meal of 650kJ, the mean residence time of a controlled release ibuprofen formulation was 2.0±0.9 h; when the size of the meal was increased to 3330 kJ, the mean residence time was in excess of 9±3 h. In the fasted state, the mean residence time was 1.0 ±0.4 h70.

The effect of administering a large non-disintegrating tablet (11x6 mm, density 1.4 g ml-1) with several different feeding regimens is shown in Figure 5.1671. It can clearly be seen that the continual intake of small meals throughout the day, such as is common in the Western world, can delay the emptying of the tablets for more than 10 hours. Increasing the calorific value of a liquid meal by nearly 4-fold did not produce a proportionate increase in gastric residence time, but a mixed meal with similar calorific value to the liquid meal a = on an empty stomach b = after a continental breakfast

(2200 kJ) c = after a breakfast + snack taken

2.5 h later d = after lunch (4000 kJ) e = after lunch + snack taken 2.5 h later f = after supper g = after breakfast + snack + lunch + snack + supper (at 2.5 h intervals)

Meal schedule

Figure 5.16 Gastric residence time of a large non-disintegrating unit (11x6 mm, density 1.4 g ml-1) with different feeding regimens.

nearly doubled the residence time of the tablet. The ingestion of snacks increased the gastric residence time of the tablet by about 1.5 hours, but as the original meal size increased the difference became less significant due to the greater variation in emptying.

The effect of meal size on the gastric emptying times of single units is extremely important, especially for enteric coated preparations since this is the main factor influencing the onset of drug release from enteric coated tablets72. The definition of a "large" tablet is still not known for humans. Tablets of between 3 and 7 mm empty similarly from the stomach after light, medium and heavy meals, and it is the calorific value of the meal and not the size which influences the emptying significantly73.

The gastric emptying rates of multiparticulate dosage forms are not as severely affected by the presence or absence of food as are large single units. The gastric emptying of encapsulated pellets from the fasted stomach depends upon the nature of the capsule, the speed at which it disintegrates and the degree of dispersion of the pellets in the low volume of gastric contents available74. It has been proposed that dispersion of the capsule contents occurs into the mucus, followed by clearance at the normal mucus turnover rate, so that the emptying of pellets from the fasted stomach was a random event with the pellets emptying as a series of boluses. When pellets are administered with a meal, they tend to empty in a similar fashion to the digestible component of the meal (Figure 5.17).

The discrimination of the emptying of dosage forms produced by the presence of food can clearly be seen in a study in which a large non-disintegrating single unit (an osmotic pump device) and a pellet formulation were administered together (Figure 5.18). When administered with the light breakfast, in the majority of subjects, the single unit had emptied by 2 hours amidst the pellets; however the heavy breakfast greatly delayed the gastric emptying of the single unit to more than 9 hours. The emptying of the pellets was also prolonged by the heavier meal, but not to the same extent as the single unit75.

Figure 5.16 Gastric residence time of a large non-disintegrating unit (11x6 mm, density 1.4 g ml-1) with different feeding regimens.

Mody Gastric Emptying
Figure 5.17 The gastric emptying of multiparticulates in a hard gelatin capsule taken either "with a meal or dispersed within a meal

Time of dosing relative to a meal

Often patients are instructed to take their medication "with a meal", but instructions are never precise and this can be interpreted by the patient as taking the medication immediately before, midway through or just after the food. After dosing with a capsule containing pellets during or 10 minutes after a meal, pellets tend to remain in the upper half of the stomach. In these cases, the gastric emptying pattern is approximately linear with time. If the capsule is taken 10 minutes prior to a meal, the pellets empty faster following an exponential pattern (Figure 5.19)76.

Figure 5.18 The effect of meal size on the emptying of single units (Osmets®) and multip articulates. Note that at 12 h four of the large units were still in the stomach, however, the released drug had emptied from the stomach

Anti-reflux agents provide an example of how certain medications, particularly those which float on the gastric contents, are affected by time of dosing relative to a meal. Ingestion of an anti-reflux agent prior to meal causes it to empty before the food, and in addition it does not form the floating raft which is required for its action77. However, the anti-reflux agent does float when administered 30 minutes after a meal and hence its emptying is delayed with respect to the food. The gastric residence of floating formulations can be prolonged by frequent intake of meals27 since ingestion of subsequent meals will delay the emptying of both the original meal and the formulation78.

Retention of formulations in the stomach

There are several advantages in the use of formulations which remain in the stomach. For example, improvement in local delivery of drug to treat infections such as Helicobacter pylori, or prolonging the exposure of the upper small intestine to high concentrations of drug. This also may be advantageous for drugs which are acid soluble. Gastroretentive dosage forms will significantly extend the period of time over which drugs may be released, and thus prolong dosing intervals and increase patient compliance.

Many systems have been reported in the literature and the majority rely on floatation mechanisms to produce gastric retention. The prolonged gastric emptying of these formulations relies entirely on the presence of food in the stomach and they are generally emptied either at the end of the digestive phase, or with the MMC if they are large.

A hydrodynamically balanced system (HBS) was the first low-density formulation to be described. It is simply a capsule containing a mixture of drug, gel-forming hydrophilic polymer and excipients such as hydrophobic fatty materials. Upon contact with gastric fluid the capsule shell dissolves and the drug-hydrocolloid mixture absorbs water and swells to form a soft-gelatinous barrier. As the outer layer is eroded, a new layer is continually formed and the drug is released by diffusion through the hydrated layer79. To improve buoyancy and drug release the formulation was modified by the addition of a second layer of HPMC. Flotation of the HBS was visualised in volunteers using endoscopy80.

Figure 5.19 The effect on emptying of dosing time of a multiparticulate with respect to a meal

Figure 5.19 The effect on emptying of dosing time of a multiparticulate with respect to a meal

In order to improve buoyancy, an important strategy has been to incorporate gas producing agents such as sodium bicarbonate within the formulation. The systems may be composed of single or multiple layers and the gas-generation agent can be incorporated into any of the layers. Alternatively, ion-exchange resin can be loaded with bicarbonate and coated with a semipermeable membrane. Another approach has been to start with a buoyant core e.g. an empty hard gelatin capsule, polystyrene foam or concave tablet shell81.

In vivo studies have shown that gastrically retained dose forms can produce up to 25% increase in bioavailability for agents such as riboflavin82, but others report no effect for drugs such as acetaminophen in fasted or fed states83. Floating formulations can be a disadvantage for some drugs such as amoxycillin trihydrate, which show a reduction in bioavailability compared to conventional systems84.

In contrast to floating systems, high density systems also have been investigated as a method for retaining dose forms in the stomach. The rationale behind this approach is that a dense object will fall through food and sit at the bottom of the greater curvature away from antral mixing. These devices have been used to great effect in animals, particularly ruminants, and early work in humans appeared promising at first. The studies reported that increasing the density of a multi-particulate dose form from 1 to 1.6 gcm-3 significantly increased the transit time in ileostomy subjects85. Unfortunately the results were later found not to be reproducible86. No differences in transit were found for pellets of 0.94 and 1.96 g cm3 87 or for single units with densities of 1.03 and 1.61 g cm3 88. A number of subsequent studies have also failed to find an effect of formulation density until very high densities are reached e.g. 2.8 g cm-3 89. In this case gastric emptying can be significantly prolonged in both fasted and fed subjects, but small intestinal transit time is unaffected.

Studies conducted in dogs have demonstrated that spheres empty from the fed stomach as a function of their diameter, their density and the viscosity of the gastric contents90. The smaller the diameter (between 1 and 5 mm), the faster the spheres emptied; however spheres smaller than 1 mm did not empty any faster than 1 mm spheres. Spheres which were more or less dense than water emptied more slowly than the same size spheres with unit density. The explanation given for this is that the lighter spheres floated and the heavier spheres sank and so moved out of the central aqueous stream. Increasing the viscosity of the gastric contents caused even large dense spheres to empty more quickly, possibly because it retarded the layering of the spheres to the base of the stomach. This phenomenon has been observed in human subjects dosed with different density pellets. Pellets which floated on or sank to the base of the stomach emptied more slowly then pellets of a similar density to food. When the light and heavy pellets were administered with a small meal, their emptying was similar to that seen with pellets of a similar density to food when administered with a large meal (Figure 5.20). This suggests that the light and heavy pellets are not caught up in the antral flow.

The gastric retention of solid dosage forms may also be achieved by mucoadhesion, in which case the dosage form will adhere to the mucosal surface of the stomach wall. Once attached, it will remain there until mucus turnover sloughs it off. The mucoadhesives which have been tried are polycarbophil and Carbopol®. Studies in animals and humans have produced rather disappointing results and the main problem appears to be that these polymers are such good adhesives that they stick to anything they come into contact with. Hence they will stick to the gelatin released from the capsules in which they were dosed, or to water-soluble proteins present in the stomach, and also sloughed mucus. This non-specific adhesion severely reduces the amount of bioadhesive available to stick to the epithelial mucus.

Earlier studies conducted in dogs used slurries of polycarbophil particulates (1-3 mm in diameter) at doses of 30 and 90 g13. The meal containing the 90 g polycarbophil slurry demonstrated a decreased rate of gastric emptying. At autopsy, the particles were shown not

Fraction 80 Remaining in Stomach 60

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Responses

  • Geremia
    Does dosing drug with food normalize gastric emptying and intestinal transit time?
    7 months ago
  • ivana
    Does gastric emptying affect enteric coated tablet?
    29 days ago

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