Absorption of drugs rectal

Reproduced from C. D. F. Muir, Clinical Aspects of Inhaled Particles, Heinemann, London, 1972. 

In the treatment of nasal symptoms the patient adjusts the dose so that, perhaps, the theoretical bases of droplet and particle retention are less vital. Although formulation of the nasal drops, or sprays from plastic squeeze-bottles must obviously influence the efficiency of medication, little work has in the past been carried out relating formulation to the effect of intranasal medicines. Microsphere delivery systems have received some attention, however, with special interest being directed to bioadhesive microspheres. 

The once traditional suppository base, cocoa butter (theobroma oil) is a variable natural product which undergoes a polymorphic transition on heating. It is primarily a triglyceride. Four polymorphic forms exist y, m.p. 18.9°C a, m.p. 23°C / , m.p. 28°C and the stable /i form, m.p. 34.5°C. Heating above 38°C converts the fat to a metastable mixture solidifying at 15-17°C instead of 25°C, and this subsequently melts at 24°C instead of at dl-dS C. Reconversion to the stable yS-form takes 1-4 days depending on storage conditions. 

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. 

The rectum is the terminal 15-19 cm of the large intestine. The mucous membrane of the rectal ampulla, with which suppositories and other rectal medications come into contact, is made up of a layer of cylindrical epithelial cells, without villi. 

---

Rectal absorption of drugs from aqueous or alcoholic solutions is generally much faster than from suppositories. Non-surfactant adjuvants, such as salicylates, increase rectal absorption of water-soluble drugs and also of high molecular weight compounds, such as insulin, heparin, and gastrin. 

The inclusion of a surfactant in the suppository formulation may enhance the rectal absorption of drugs. The effect has been attributed to the formation of mixed micelles. It has been suggested that the presence of the micelle facilitates the incorporation of the lipid component of the mixed micelle into the biological membrane. This lipid then enhances the fluidity and permeability of the membrane to the poorly absorbed drug. It appears that the colorectal mucous membrane is more sensitive to the effects of mixed micelles than the gastrointestinal membrane of the small intestine. 

Rectal absorption of drugs may be slow and unpredictable in the neonatal period, although it is a useful route when other methods are not available. The relative bioavailability may also be influenced by the rate of hepatic metabolism. The absorption of drugs from the rectum is also influenced by the rate of expulsion. Infants have a greater number of rectal contractions than adults (Di Lorenzo et al, 1995), which may enhance the expulsion of the dose and reduce absorption of drugs such as paracetamol (van Lingen et ah, 1999). 

Sodium salicylate has been found to enhance rectal absorption of drugs [309] but contrary to the action of some surfactants the absorption promotion was not found to be the result of a permanent change in the rectal mucosa. 

K Kakemi, T Arita, S Muranishi. Absorption and excretion of drugs. XXVII. Effect of nonionic surface-active agents on rectal absorption of sulfonamides. Chem Pllarm Bull 13 976-985, 1965. 

The absorption of drugs from the rectal [32] cavity has been studied in some detail. Muranishi et al. [34] have shown that a significant increase in the absorption and lymphatic uptake of soluble and colloidal macromolecules can be achieved by pretreating the rectal mucosal membrane with lipid-nonionic surfactant mixed micelles. They found no evidence of serious damage of the mucosal membrane. Davis [30] suggested that the vaginal cavity could be an effective delivery site for certain pharmaceuticals, such as calcitonin, used for the treatment of postmenopausal osteoporosis. 

Rectal Administration Rectal administration of a drug may be applied when the patient is unable to take the drug orally and some other routes are impractical. The drug administered via the rectum is absorbed and partially bypasses the liver. However, the absorption of drugs may be unreliable in certain cases. 

Schmitt M, Guentert TW. Influence of the hydrophilicity of suppository bases on rectal absorption of carprofen, a lipophilic nonsteroidal anti-inflammatory drug. J Pharm Sci 1990 79(4) 359-363. 

Lysergic acid is a well known component especially as its amide derviative - lysergic acid diethyl amide (LSD) - to be considered in the next section on CNS drugs. Today ergotamine can be used in the treatment of chronic migraine headache although its side effects do not make it an appropriate prophylactic. It is usually compounded with caffeine and administered orally, by inhalation or suppository. The caffeine increases oral and rectal absorption of the ergotamine. Oral dose is 2 mg at onset and 2 mg at 30 minute intervals up to 6 mg with no more than 10 mg administered per week. 

In the past two decades, many studies have tested adjuvants that act by either permeabilizing the rectal mucosa or inhibiting drug degradation. Oral and rectal routes of drug administration are unsuitable for adequate absorption of various compounds with a peptide or protein structure and of several hydrophilic antibiotics. The use of absorption enhancers, e.g., salicylates, enamines, surfactants, and straight-chain fatty acids, has gained wide interest... 

Watanabe, Y., et al. 1992. Absorption enhancement of polypeptide drugs by cyclodextrins. I. Enhanced rectal absorption of insulin from hollow-type suppositories containing insulin and cyclodextrins in rabbits. Chem Pharm Bull 40 3042. 

Miyake, M., et al. 2004. Development of suppository formulation safely improving rectal absorption of rebamipide, a poorly absorpbable drug, by utilizing sodium laurate and taurine. J Control Rel 99 63. 

In this chapter, we especially focus on the strategies for enhancement of rectal absorption of various drugs including peptides and proteins from rectal mucosa using pharmaceutically useful excipients, cyclodextrins (CyDs), and the other absorption enhancers. 

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,... 

However, some negative effects of the combination of CyDs and polysaccharide on the rectal drug delivery were reported. Lin et al. [38] demonstrated that the mixture of (3-CyD and hydroxypropylmethylcellulose (HPMC) markedly reduced the in vivo bioavailability of acetaminophen from both aqueous solution and hydrogels. Not only the lower partition coefficient but also the higher hydrophilic property of the (3-CyD complex and the higher viscosity of HPMC hydrogel matrix might be responsible for the decrease in the in vitro permeation rate and depression of in vivo rectal absorption of acetaminophen. 

Morimoto, K., T. Iwamoto, and K. Morisaka. 1987. Possible mechanisms for the enhancement of rectal absorption of hydrophilic drugs and polypeptides by aqueous polyacrylic acid gel. J Pharmacohiodyn 10 85. 

Sekine, M., et al. 1985. Improvement of bioavailability of poorly absorbed drugs. V. Effect of surfactants on the promoting effect of medium chain glyceride for the rectal absorption of (3-lactam antibiotics in rats and dogs. J Pharmacobiodyn 8 653. 

---