Rectal formulation development

Both children and the elderly experience swallowing problems with oral formulations. A limited market already exists in pediatric therapeutics which addresses this problem. Although development of rectal formulations for the elderly has not been addressed extensively, with the expanding number of patients in this age group, the need for acceptable alternatives to oral dosing may increase efforts to develop rectal formulations. 

Chitosan has also been found to be beneficial in formulation development of delivery systems for local or systemic administration of drug through the rectal route. Chitosan microspheres encapsulating diclofenac sodium incorporated in hydrogels have been designed for efficient rectal administration [126]. Quaternized derivative of chitosan. 

Within the last 10, years several new compounds were launched in the field of non-steroidal antiinflammatory drugs (NSAIDs) with a clear focus on cyclooxygenase type 2 selective compounds. In the field of opioids on the other hand no new drugs have passed phase III clinical trials. In this field innovation has been achieved through new pharmaceutical formulations of known drugs such as transdermal systems, e.g. buprenorphine patch, transmucosal systems, e.g. fentanyl lollipop, or rectal delivery systems containing e.g. morphine. These were developed in order to reduce opioid side effects, but also to overcome pharmacokinetical limitations, in particular to prolong compliance and duration of action. 

Many drugs can now be delivered rectally instead of by parenteral injection (intravenous route) or oral administration. Generally, the rectal delivery route is particularly suitable for pediatric and elderly patients who experience difficulty ingesting medication or who are unconscious. However, rectal bioavailabilities tend to be lower than the corresponding values of oral administration. The nature of the drug formulation has been shown to be an essential determinant of the rectal absorption profiles. The development of novel absorption enhancers with potential efficacy without mucosal irritation (low toxicity) is very important. The delivery of peptide and protein drugs by the rectal route is currently being explored and seems to be feasible. 

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. 

When a child has febrile convulsions the decision to embark on continuous prophylaxis is serious for the child, and depends on an assessment of risk factors, e.g. age, nature and duration of the fits. Most children who have febrile convulsions do not develop epilepsy. Prolonged drug therapy, e.g. with phenytoin or phenobarbitone, has been shown to interfere with cognitive development, the effect persisting for months after the drug is withdrawn. Parents may be supplied with a specially formulated solution of diazepam for rectal administration (absorption from a suppository is too slow) for easy and early administration, and advised on managing fever, e.g. use paracetamol at the first hint of fever, and tepid sponging. 

In certain areas of the world, particularly some European countries and Japan, rectal dosage forms are somewhat more accepted by the patient population and, hence, development of rectal dosage forms has surpassed that in the United States. According to a survey in 1970, approximately 7.5% of all prescriptions in France were formulations intended for rectal administration.Even though a few countries may find rectal dosage forms more acceptable, these still represent a small area of the world-wide market share which can be assigned to rectal drug therapy. 

Artemisinin is an antimalarial constituent isolated from Qinghao. It is a sesquiterpene lactone with an endoper-oxide bridge, structurally distinct from other classes of antimalarial agents. Several derivatives of the original compound have proved effective in the treatment of Plasmodium falciparum malaria and are currently available in a variety of formulations artesunate (intravenous, rectal, oral), artelinate (oral), artemisinin (intravenous, rectal, oral), dihydroartemisinin (oral), artemether (intravenous, oral, rectal), and artemotil (intravenous). Artemisinic acid (qinghao acid), the precursor of artemisin, is present in the plant in a concentration up to 10 times that of artemisinin. Several semisjmthetic derivatives have been developed from dihydroartemisinin (1). 

Since poor bioavailability and a short half-life limit the pharmacological activity of artemisinin, several derivatives have been developed to address such disadvantages. A key compound among them is dihydroartemisinin, which serves not only as an intermediate, but is used as a drug by itself Reduction of the lactone is achieved under very mild conditions with sodium boranate in methanol at 0 °C. Esterification with succinic acid anhydride leads to artesunate, a water soluble compound, which is suitable for different routes of application (oral, rectal, intramuscular, and intravenous). Acetalisation of dihydroartemisinin with methanol produces artemether, which is soluble in lipids and can therefore be formulated for oral, rectal and intramuscular dosing. 

Drug overdose A 20-year-old man with ulcerative proctitis took a rectal suppository formulation of mesalazine 7500 mg orally and 7000 mg of the same formulation rectally [99 ]. He developed a headache, dizziness, nausea, and pain in the rectum. Colonoscopy showed diffuse hjrperemia and edema extending from the anal channel to the proximal rectal mucosa and a 1.5-cm... 

Methadone is a potent synthetic opioid analgesic, structurally unrelated to any of the opium-derived alkaloids. It is a highly lipophilic, basic drug (pKa 9.2) available as a hydrochloride powder formulation that can be reconstituted for oral, rectal, or parenteral administration. Methadone was developed in Germany in 1942 as a synthetic substitute for morphine, and has been approved and widely employed for opioid detoxification maintenance as well as acute and chronic pain management. 

As excipients, CDs have been widely used to cover the bitter taste of drugs, to increase their dissolution rates, to reduce irritation reactions and in low concentrations to suppress the haemolysis induced by some drugs [180]. Great effort has been made to develop CD-based drug formulations with different administrative routes, including parenteral, oral, pulmonary, nasal [181], transdermal, rectal [182] and ophthalmic [183] drug delivery [184]. 

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