Gastric histiocytoma dog emptying of dosage forms – drug delivery

For the majority of cases, oral drug delivery is the cheapest and most convenient method histiocytoma dog removal cost of dosing. Unfortunately it is difficult to achieve a precise control of histiocytoma dog removal cost the plasma concentration-time profile, which shows marked intra- and inter-subject variation even under the rigidly controlled conditions of the histiocytoma dog removal cost clinical trial. In the unrestricted patient this is exaggerated by poor compliance histiocytoma dog removal cost 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 histiocytoma dog removal cost 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 histiocytoma dog removal cost 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 histiocytoma dog removal cost the drug.

Once the dosage form has reached the stomach, it meets an highly variable environment in terms of food histiocytoma dog removal cost content and ph. The gastric emptying of tablets, pellets and liquids is highly dependent on the presence and histiocytoma dog removal cost amount of food in the stomach. Large tablets can either disintegrate in the stomach and empty histiocytoma dog removal cost with the digestible phase of the meal, or if they are designed to remain intact will be histiocytoma dog removal cost treated as indigestible material since they do not possess a histiocytoma dog removal cost 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 histiocytoma dog removal cost of the cycle, the emptying will appear erratic, occurring any time between a few minutes and 3 hours histiocytoma dog removal cost after administration.

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

If a large single unit is given with a heavy histiocytoma dog removal cost meal (3600 kj) and the subject is fed at regular intervals, the unit can remain in the stomach for longer than histiocytoma dog removal cost 8 hours due to prolonged suppression of the MMC. The only time at which the stomach can revert to histiocytoma dog removal cost the fasted pattern of motility is during the night when histiocytoma dog removal cost there is a sufficient interval between dinner and breakfast70. The length of the retention is proportional to the meal histiocytoma dog removal cost size. Thus when given with a meal of 650kj, the mean residence time of a controlled release ibuprofen formulation histiocytoma dog removal cost was 2.0±0.9 h; when the size of the meal was increased to 3330 histiocytoma dog removal cost 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 (11×6 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 histiocytoma dog removal cost small meals throughout the day, such as is common in the western world, can delay the emptying of the tablets for more than histiocytoma dog removal cost 10 hours. Increasing the calorific value of a liquid meal by nearly histiocytoma dog removal cost 4-fold did not produce a proportionate increase in gastric residence histiocytoma dog removal cost time, but a mixed meal with similar calorific value to the histiocytoma dog removal cost liquid meal a = on an empty stomach b = after a continental breakfast

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

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

The discrimination of the emptying of dosage forms produced by histiocytoma dog removal cost the presence of food can clearly be seen in a histiocytoma dog removal cost 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 histiocytoma dog removal cost pellets; however the heavy breakfast greatly delayed the gastric emptying of histiocytoma dog removal cost the single unit to more than 9 hours. The emptying of the pellets was also prolonged by the histiocytoma dog removal cost heavier meal, but not to the same extent as the single unit75.

Often patients are instructed to take their medication with a histiocytoma dog removal cost meal, but instructions are never precise and this can be interpreted histiocytoma dog removal cost 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 histiocytoma dog removal cost minutes after a meal, pellets tend to remain in the upper half of the histiocytoma dog removal cost stomach. In these cases, the gastric emptying pattern is approximately linear with time. If the capsule is taken 10 minutes prior to a histiocytoma dog removal cost 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 histiocytoma dog removal cost single units (osmets®) and multip articulates. Note that at 12 h four of the large units histiocytoma dog removal cost 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 histiocytoma dog removal cost the food, and in addition it does not form the floating raft histiocytoma dog removal cost which is required for its action77. However, the anti-reflux agent does float when administered 30 minutes after a histiocytoma dog removal cost meal and hence its emptying is delayed with respect to histiocytoma dog removal cost the food. The gastric residence of floating formulations can be prolonged by histiocytoma dog removal cost frequent intake of meals27 since ingestion of subsequent meals will histiocytoma dog removal cost delay the emptying of both the original meal and the histiocytoma dog removal cost formulation78. Retention of formulations in the stomach

There are several advantages in the use of formulations which histiocytoma dog removal cost remain in the stomach. For example, improvement in local delivery of drug to treat infections such histiocytoma dog removal cost as helicobacter pylori, or prolonging the exposure of the upper small intestine to histiocytoma dog removal cost high concentrations of drug. This also may be advantageous for drugs which are acid histiocytoma dog removal cost soluble. Gastroretentive dosage forms will significantly extend the period of time histiocytoma dog removal cost 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 histiocytoma dog removal cost majority rely on floatation mechanisms to produce gastric retention. The prolonged gastric emptying of these formulations relies entirely on histiocytoma dog removal cost the presence of food in the stomach and they are histiocytoma dog removal cost 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 histiocytoma dog removal cost 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 histiocytoma dog removal cost released by diffusion through the hydrated layer79. To improve buoyancy and drug release the formulation was modified histiocytoma dog removal cost by the addition of a second layer of HPMC. Flotation of the HBS was visualised in volunteers using endoscopy80.

In order to improve buoyancy, an important strategy has been to incorporate gas producing agents histiocytoma dog removal cost such as sodium bicarbonate within the formulation. The systems may be composed of single or multiple layers histiocytoma dog removal cost 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 histiocytoma dog removal cost a semipermeable membrane. Another approach has been to start with a buoyant core histiocytoma dog removal cost e.G. An empty hard gelatin capsule, polystyrene foam or concave tablet shell81.

In vivo studies have shown that gastrically retained dose forms histiocytoma dog removal cost can produce up to 25% increase in bioavailability for agents such as riboflavin82, but others report no effect for drugs such as acetaminophen histiocytoma dog removal cost in fasted or fed states83. Floating formulations can be a disadvantage for some drugs such histiocytoma dog removal cost 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 histiocytoma dog removal cost for retaining dose forms in the stomach. The rationale behind this approach is that a dense object histiocytoma dog removal cost will fall through food and sit at the bottom of histiocytoma dog removal cost 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 histiocytoma dog removal cost of 1.03 and 1.61 g cm3 88. A number of subsequent studies have also failed to find histiocytoma dog removal cost an effect of formulation density until very high densities are histiocytoma dog removal cost reached e.G. 2.8 g cm-3 89. In this case gastric emptying can be significantly prolonged in histiocytoma dog removal cost both fasted and fed subjects, but small intestinal transit time is unaffected.

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

The gastric retention of solid dosage forms may also be histiocytoma dog removal cost achieved by mucoadhesion, in which case the dosage form will adhere to the histiocytoma dog removal cost 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 histiocytoma dog removal cost and the main problem appears to be that these polymers histiocytoma dog removal cost are such good adhesives that they stick to anything they histiocytoma dog removal cost come into contact with. Hence they will stick to the gelatin released from the histiocytoma dog removal cost 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 histiocytoma dog removal cost stick to the epithelial mucus.

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