**7. Rectal route**

Rectal delivery of drugs is sometimes necessary if other routes of delivery are not applicable. This method offers some advantages such as rapid absorption of many low molecular weight drugs, partial avoidance of the first-pass metabolism, potential absorption into the lymphatic system, retention of large volumes, etc. This method is also beneficial considering the low amount of proteases compared to other parts of the GIT. This route allows both local and systemic delivery of drugs. Local delivery of drugs can be used to treat constipation, hemorrhoids, inflammation, hyperkalemia, etc. Systemic delivery of drugs can be used to treat pain, fever, nausea and vomiting, migraines, and sedation. Controlled absorption enhancement can also be achieved via this route due to the constant condition of the rectal environment. However, this method also has limitations, including limited absorption surface area, dissolution problem due to low fluid content, drug metabolism, etc. [170]. Several drugs such as insulin and pentagastrin have been successfully delivered via this route. Some rectal delivery systems are described below.

#### **7.1 Absorption enhancers**

Since the bioavailability of the peptide is low via the rectal route, various absorption enhances such as enamines, salicylate and its derivatives, surfactants, micelles, etc., have been investigated. It has been shown that enamine derivatives enhanced rectal absorption of CMZ (a hydrophilic antibiotic) [171]. Salicylate and its derivatives enhance rectal absorption of insulin, heparin, gastrin, and pentagastrin [172].

### **7.2 Protease inhibitors**

Protease inhibitors reduce the degradation of various proteins and peptides due to the inhibition of proteases at the absorption site. Therefore, the use of protease inhibitors is one of the promising approaches for delivering protein or peptide therapeutics. Protease inhibitors (e.g., bacitracin, aprotinin, bestatin, trypsin inhibitor, puromycin, etc.) has been shown to enhance rectal absorption of protein and peptide therapeutics [173].
