Rectal Drug Delivery to Paediatric Population

Despite its unpopularity, the rectal route of paediatric drug administration remains of interest especially in pre-school children as it can overcome some drug delivery challenges with oral and parenteral routes. Few studies have been conducted on the use and acceptability of traditional rectal dosage forms (i.e., suppositories, enemas and gels) in different parts of the world. It showed that barrier to adoption could be linked with poor knowledge, little information and understanding of this administration modality. Reformulation for the rectal delivery of drugs intended for oral and/or parenteral administration that do not reach their full potential, was explored by a study at University College London. The top 3 candidates were Azithromycin, Amodiaquine and Raltegravir. Little rectal delivery innovation has occurred but topics such as acceptability and use of rectal drug delivery; types of rectal dosage forms and reformulation considerations are discussed presently in order to raise awareness around the need to modernise rectal dosage forms this to achieve the full potential for successful reformulation.

The bioavailability of cytarabine in dogs with meningoencephalitis of unknown etiology through iontophoresis and rectal delivery

Background: Cytarabine (CA) is used to treat dogs with meningoencephalitis of unknown etiology (MUE) by subcutaneous or intravenous administration. Aim: The objective was to investigate transdermal iontophoresis and rectal administration as alternative routes of CA delivery. Methods: Two client-owned dogs with MUE were studied. The ActivaPatch® IONTOGOTM 12.0 iontophoresis drug delivery system delivered 200 mg/m2 CA transdermally. Blood samples were collected by sparse sampling technique after initiation of the device. At another visit, 100 mg/m2 CA was administered rectally. Blood samples were collected by sparse sampling technique after administration. Plasma CA concentrations were measured by high-pressure liquid chromatography. Results: The concentration of plasma CA after transdermal and rectal administration was below the limits of quantification (0.1 μg/ml) in all samples suggesting inadequate bioavailability with transdermal and rectal administration. Conclusion: Transdermal and rectal CA administration are not reasonable alternative routes of delivery.

Oral, but not rectal delivery of epigallocatechin-3-gallate alleviates colitis by regulating the gut microbiota, oxidative stress, inflammation, and barrier integrity

Background: Alteration of the gut microbiota may contribute to the development of inflammatory bowel diseases (IBDs). Epigallocatechin-3-gallate (EGCG), a major bioactive constituent of green tea, is known to be beneficial in IBDs alleviation. However, it is unclear whether EGCG attenuates IBDs through direct improvement of gastrointestinal function or indirect alteration of the structure and function of the gut microbiota.Results: We first investigated the therapeutic effects of EGCG on disease severity, oxidative stress, inflammation, barrier function, and gut microbiota in murine colitis model, and further demonstrate it via EGCG pre-supplementation. We revealed that, oral, but not rectal, delivery of EGCG alleviated the severity of colitis through attenuation of anti-oxidative and anti-inflammatory response. Mucin-secreting goblet cell number, barrier function gene expression levels, and the integrity of tight junctions in the colon were also enhanced by oral EGCG. Additionally, we observed distinct EGCG-mediated alternation in the gut microbiome, as highlighted by increased Akkermansia abundance and butyrate production. Furthermore, we revealed that prophylactic oral application of EGCG for 21 days prior to the onset of dextran sodium sulfate (DSS)-induced colitis also ameliorated colonic damage, oxidative stress, and inflammatory response. Prophylactic EGCG significantly enriched Akkermansia, Faecalibaculum, and Bifidobacterium and enhanced acetate, propionate and butyrate production in DSS-treated mice. Moreover, scores of differential microbes, in particular Akkermansia, showed a strong positive correlation with short-chain fatty acids (SCFAs) and antioxidant enzyme levels in both the plasma and colon, but a negative association with inflammatory cytokines and malondialdehyde.Conclusions: EGCG is capable of treating DSS-induced colitis both therapeutically and prophylactically by inducing a pronounced anti-oxidative and anti-inflammatory response. Attenuation of colitis by oral, but not rectal administration of, EGCG suggests an intimate involvement of the gut microbiota. Increased Akkermansia and subsequent protective SCFAs production may be largely responsible for the anti-inflammatory and anti-oxidative function of EGCG, leading to restoration of intestinal epithelial homeostasis of the host. These findings provide novel insights into EGCG-mediated remission of IBDs and the rationale for devising more effective therapeutic strategies for IBDs.

Expert design and desirability function approach for the development of diazepam thermally sensitive rectal gel

Aim: The aim of the present work was to develop an in situ thermosensitive rectal gel for diazepam by using Expert-design for improving three factors and a three-level process was formed by using a cold method. Methods & materials: Response surface design was utilized to investigate the effect of independent variables like sodium chloride (NaCl, X1), poloxamer 407 (F-127, X2) and diazepam (X3), on different dependent variables such as gelation temperature, mucoadhesive strength, drug content, along with permeation and stability. Results: The obtained results revealed that the addition of diazepam enhanced the gelation temperature of hydrogel while it decreased the gel strength and mucoadhesive force. Conclusion: It is suggested that in situ hydrogels may be suitable candidates for rectal delivery.

Evaluation of a Methylcellulose and Hyaluronic Acid Hydrogel as a Vehicle for Rectal Delivery of Biologics

Biologics have changed the management of Inflammatory Bowel Disease (IBD), but there are concerns regarding unexpected systemic toxicity and loss of therapeutic response following administration by injection. Local delivery of biologics directly to the inflamed mucosa via rectal enema administration addresses the problems associated with systemic administration. Hydrogels are potentially useful delivery vehicles enabling rectal administration of biologics. Here, we prepared a hydrogel system based on methylcellulose (MC) and hyaluronic acid (HA), which possesses mucosal healing properties, incorporating a model macromolecular drug, namely (fluorescently-labeled) bovine serum albumin (BSA). The BSA-loaded MCHA hydrogel showed temperature-dependent gelation (liquid-like at 20 °C and gel-like at 37 °C) and shear thinning behavior, with these being important and desirable characteristics for rectal application (enabling easy application and retention). BSA release from the MCHA system at 37 °C was linear, with 50% of the loaded drug released within 2 h. The system demonstrated acceptable toxicity towards intestinal (colon) Caco-2 epithelial cells, even at high concentrations. Importantly, application of the BSA-loaded MCHA hydrogel to polarized Caco-2 monolayers, with or without an exemplar absorption enhancer, resulted in transintestinal permeability of BSA. The study therefore indicates that the MCHA hydrogel shows potential for topical (rectal) delivery of biologics in IBD.