Rectal fluid

Many physiological aspects affect drug absorption from the rectum (Table 7.1). Influential factors include the pH of the rectal contents, state of the mucus layer, volume and viscosity of rectal fluid, luminal pressure from the rectal wall on the dosage form, enzymatic and microbacterial degradation by rectal epithelium, presence of stools, and venous drainage differences within the rectosigmoid regions. 

Rectal fluid Volume pH Buffering ability Surface tension Viscosity Composition Luminal pressure from rectal wall... 

FIGURE 7.2 Process of the drug movement from rectal dosage vehicles to blood capillary in the rectum. The drug must be released from the base materials after liquefaction into the rectal fluid before drug is absorbed. 

Many reports have indicated the findings that the effects of CyDs on the rectal delivery of drugs depend markedly on vehicle type (hydrophilic or oleaginous), physicochemical properties of the complexes, and an existence of tertiary excipients such as viscous polymers. The enhancing effects of CyDs on the rectal absorption of lipophilic drugs are generally based on the improvement of the release from vehicles and the dissolution rates in rectal fluids, whereas those of CyDs on the rectal delivery of poorly absorbable drugs such as antibiotics, peptides,... 

The surface properties of a solid may significantly affect the drug when it reaches the interface between the vehicle and the rectal fluid. The amount of wetting. 

As discussed earlier, the pH of the rectal fluid can have a marked effect on the absorption of drugs from the rectum. Since the rectal fluid has a relatively low buffering capacity and the volume of the rectal fluid is small, it might be expected that the contents of the rectal dosage form largely control the pH of the rectum during administration. On this basis, one may be able to utilize the pH characteristics of the drug and incorporate suitable buffers and other excipients in the... 

IVIVCs are often indicated only for obtaining oral formulations. Various data have been presented in the cases of less-classical formulations such as intrauterine devices, chewing gums, ocular inserts, suppositories, etc. For example, for suppositories two main types of formulations exist one based on hydrophilic excipients and the second on lipophilic excipients. The first step is the dissolution of the mass. This means a fusion of the lipophilic base at human body temperature (36-39.5°C) or dissolution for the water-soluble base (even with a high melting point) in the rectal fluid. 

Medication is readily decomposed in gastric fluid but may be stable in rectal fluid First-pass effect of high-clearance drug may be partially avoided... 

Dmgs administered by the rectal route in suppositories are placed in intimate contact with the rectal mucosa, which behaves as a normal lipoidal barrier. The pH in the rectal cavity lies between 7.2 and 7.4, but the rectal fluids have little buffering capacity. As with topical medication, the formulation of the suppository can have marked effects on the activity of the drug. Factors such as retention of the suppository for a sufficient duration of time in the rectal cavity also influence the outcome of therapy the size and shape of the suppository and its melting point may also determine bioavailability. 

Non-ionic surfactants can be added to a fatty suppository base to enhance the release of poor water-soluble active substances [5b]. The results of studies on this subject, however, vary considerably. Often the in vitro release is improved, whereas the in vivo results are disappointing [8a]. This is partly caused by the formation of micelles in the rectal fluid and partly by the influence of the surfactant... 

If an active substance is practically insoluble in water (and therefore in the rectal fluid), the suppository will be ineffective. Certain excipients may increase the water solubility and, as a result, the absorption. A surfactant can be added... 

The active substance should have certain lipophilicity as well. If not, it will not pass the rectal lipoid membranes. On the other hand, a too high lipophilicity causes the active substance to be hardly released from a fatty base. For a systemic effect a good water-soluble active substance is preferred with sufficient lipophilicity at the pH of the rectal fluid to allow passage of the rectal membranes for absorption [8c]. 

Methadone is best incorporated in a macrogol base in the form of its hydrochloride salt, to obtain a good efficacy. Methadone hydrochloride (pKa 8.25) will be released from a fatty base, but at the rectal membrane methadone is converted to its unionised form. This lipophilic substance is so poorly soluble in the aqueous rectal fluid that it is not absorbed. By using a macrogol base (macrogol 1500 or PEG 1500), the solubility of the unionised methadone in the rectal fluid (now containing the macrogol as co-solvent) is improved [19, 20]. 

A macrogol base will mostly be chosen based on published data showing better release or absorption, or both. The advantage of water solubility and thus avoidance of the melting time is somewhat overestimated because the dissolution of macrogol in the rectal fluid takes time as well. Once the macrogol has been dissolved the active substance release is faster than from a fatty base because in the latter transport of the active substance from the fatty to the aqueous phase still has to take place. Moreover the active substance can dissolve in the rectal fluid simultaneously with the base. The base has considerable disadvantages however chemical incompatibilities and irritation. 

From a biopharmaceutical viewpoint, a large sized suppository may be advantageous. In principal, a larger volume spreads over a larger intestinal surface. As a result more active substance is released from the base, more active substance dissolves in the rectal fluid and the absorption is faster. This is especially important for substances that are poorly soluble in both fat and water, such as paracetamol. The release of active substance from the base in this case strongly depends on the extent of the interface between fat and rectal fluid available for active substance release. From a technological point of view a large size suppository must be... 

In enemas for a systemic effect, water as a vehicle has the great advantage of presenting only one liquid phase in the rectum, so no transition of the active substance from fat into rectal fluid is needed. The addition of co-solvents (see Sects. 

A water-insoluble active substance may be processed into an enema as a suspension. However, the dissolution rate may be insufficient for a systemic effect. If an active substance is too poorly soluble in water and thus in the rectal fluid, it cannot be absorbed at all. 

The pharmacist should have anticipated the bio-pharmaceutical consequences of the physico-chemical properties of oxcarbazepine. The drug is classified as a Class II substance for oral application. Logically, lack of adequate solubility is even more evident for the rectal administration as the volume of rectal fluid is limited (see Table 17.1). With an aqueous solubility of approximately 300 mg/L, the solubUity of the substance in the lipophilic base of the suppositories would certainly not be higher than 9.5 mg/mL (being a direct consequence of the value of the log P = 1.5 of oxcarbamazepine). This means that oxcarbazepine is not dissolved in the lipid but dispersed as crystals, which settle from the molten suppository once introduced in the rectal cavity. The amount of rectal liquid is limited and therefore a saturated solution will exist which involves only less than 1 mg dissolved oxcarbamazepine. Low solubility yields a low concentration and hence a low driving force for diffusion to occur. As a consequence, the rate of absorption is relatively low. This slow release may lead to hardly any uptake, due to defecation within several hours after insertion. 

According to Figure 14, the release of drugs from suppository bases is one of the important factors in the rectal absorption of the drugs, since the rectal fluid is small in volume and viscous compared to gastrointestinal fluid [119]. 

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