Rectal Delivery System Research Articles

Advanced Technologies in Rectal Drug Delivery Systems: A Comprehensive Review of Recent Innovations and Future Prospects

Abstract: Rectal Drug Delivery System (RDDS) emerges as an alternative administration route due to the rectum's small surface area and limited enzyme activity, which contribute to efficient drug absorption. RDDS offers various advantages, such as reduced first-pass metabolism, rapid absorption of low molecular weight drugs, and the ability to accommodate large retention volumes and facilitate absorption via the lymphatic system. Moreover, RDDS is preferable for drugs with low stability, solubility, and permeability via oral administration, as well as effectively addressing concerns related to gastric irritation or degradation. This review delves into the factors influencing drug absorption in RDDS, including drug properties, formulation types, and physiological and pathology-associated considerations. It further explores conventional RDDS, including enemas, suppositories, tablets, gels, sprays, ointments, and creams, as well as novel approaches involving nanoparticles, liposomes, microspheres, and solid lipid nanoparticles (SLNs) in rectal dosage forms. Furthermore, the challenges and prospects of RDDS in treating rectal diseases are discussed. This review provides valuable insights into the potential of RDDS, highlighting the importance of continuous research and development in enhancing patient outcomes and advancing healthcare practices.

Basil seed mucilage as a bioadhesive polymer: Development of naproxen sodium microspheres and suppositories with in-vitro and ex-vivo studies

Background and purpose: The study explores basil seed mucilage as a bioadhesive carrier for naproxen sodium, demonstrating its ability to enhance solubility when administered rectally. The mucilage, derived from Ocimum basilicum seeds, showed bioadhesive properties and thermal stability, as confirmed by FTIR spectroscopy and X-ray diffraction analysis. Experimental approach: Microspheres were prepared using a double emulsion solvent evaporation technique, varying polymer ratios to optimize drug delivery. Key results: Particle size analysis revealed a range of 456±0.51 to 712±0.21 µm, with larger microspheres formed at higher mucilage concentrations due to increased viscosity. Encapsulation efficiency ranged from 45.01±0.25 % to 79.4±0.93 %, improving with higher basil/alginate ratios. The superior batch, OBM5, showed excellent mucoadhesive qualities in ex-vivo assays, attributed to the increased polymer content, facilitating interaction with rectal mucosa. SEM analysis of OBM5 indicated a spherical, monolithic structure conducive to free flow. Drug release was efficient, with OBM5 achieving 88.7±1.3 % after 7 hours, indicating a control­led release profile. Conclusion: Incorporated into polyethylene glycol (PEG) 4000 suppositories, suppose­tories were completely disintegrated in buffer solution within 25 minutes. The bioadhesive force of basil seed mucilage on rectal mucosa was significantly enhanced, reaching 6.44±0.58 g, correlating with mucilage concentration. These findings underscore the efficacy of basil seed mucilage as a bioadhesive biopolymer for rectal drug delivery systems.

Thermosensitive hydrogel with emodin-loaded triple-targeted nanoparticles for a rectal drug delivery system in the treatment of chronic non-bacterial prostatitis

BackgroundThe complex etiology and pathogenesis underlying Chronic Non-Bacterial Prostatitis (CNP), coupled with the existence of a Blood Prostate Barrier (BPB), contribute to a lack of specificity and poor penetration of most drugs. Emodin (EMO), a potential natural compound for CNP treatment, exhibits commendable anti-inflammatory, anti-oxidant, and anti-fibrosis properties but suffers from the same problems as other drugs.MethodsBy exploiting the recognition properties of lactoferrin (LF) receptors that target intestinal epithelial cells (NCM-460) and prostate epithelial cells (RWPE-1), a pathway is established for the transrectal absorption of EMO to effectively reach the prostate. Additionally, hyaluronic acid (HA) is employed, recognizing CD44 receptors which target macrophages within the inflamed prostate. This interaction facilitates the intraprostatic delivery of EMO, leading to its pronounced anti-inflammatory effects. A thermosensitive hydrogel (CS-Gel) prepared from chitosan (CS) and β-glycerophosphate disodium salt (β-GP) was used for rectal drug delivery with strong adhesion to achieve effective drug retention and sustained slow release. Thus, we developed a triple-targeted nanoparticle (NPs)/thermosensitive hydrogel (Gel) rectal drug delivery system. In this process, LF, with its positive charge, was utilized to load EMO through dialysis, producing LF@EMO-NPs. Subsequently, HA was employed to encapsulate EMO-loaded LF nanoparticles via electrostatic adsorption, yielding HA/LF@EMO-NPs. Finally, HA/LF@EMO-NPs lyophilized powder was added to CS-Gel (HA/LF@EMO-NPs Gel).ResultsCellular assays indicated that NCM-460 and RWPE-1 cells showed high uptake of both LF@EMO-NPs and HA/LF@EMO-NPs, while Raw 264.7 cells exhibited substantial uptake of HA/LF@EMO-NPs. For LPS-induced Raw 264.7 cells, HA/LF@EMO-NPs can reduce the inflammatory responses by modulating TLR4/NF-κB signaling pathways. Tissue imaging corroborated the capacity of HA/LF-modified formulations to breach the BPB, accumulating within the gland's lumen. Animal experiments showed that rectal administration of HA/LF@EMO-NPs Gel significantly reduced inflammatory cytokine expression, oxidative stress levels and fibrosis in the CNP rats, in addition to exerting anti-inflammatory effects by inhibiting the NF-κB signaling pathway without obvious toxicity.ConclusionThis triple-targeted NPs/Gel rectal delivery system with slow-release anti-inflammatory, anti-oxidant, and anti-fibrosis properties shows great potential for the effective treatment of CNP.Graphical

Research progress and innovation of drug delivery devices based on children's multidimensional demand for medication

Pediatric medication in China is characterized by a lack of child-specific drugs and insufficient types, specifications, dosage forms, and delivery devices. In recent years, new dosage forms with good compliance, such as inhalation preparation, rectal delivery system, and transdermal delivery system, have attracted more attention in pediatric medication. Because of the physiological characteristics of delicate viscera, difference in swallowing ability and psychological characteristics of fear of pain and aversion to bitter taste, it is particularly important to select suitable drug delivery route and drug delivery device according to children's physiological characteristics. With the help of the special drug delivery devices, traditional Chinese medicine and innovative Chinese medicine can be administered according to the expected design path, and drug delivery devices can ensure the accurate dose and improve the complia-nce to achieve the purpose of effective and safe drug delivery. It is also a way to realize the re-innovation of traditional Chinese medicine. The present study summarized the research progress in drug delivery devices for common drug delivery routes and new drug deli-very routes, put forward the innovative design idea of children's drug delivery devices according to the special needs of children, poin-ted out the compatibility of drug delivery devices and other problems in the current development, and prospected the application of intelligent information technology and additive manufacturing technology in drug delivery device innovation. This is expected to provide references for the development of innovative drugs and drug delivery devices suitable for children's multidimensional demand for medication.

Advancements in Rectal Drug Delivery Systems: Clinical Trials, and Patents Perspective

The rectal route is an effective route for the local and systemic delivery of active pharmaceutical ingredients. The environment of the rectum is relatively constant with low enzymatic activity and is favorable for drugs having poor oral absorption, extensive first-pass metabolism, gastric irritation, stability issues in the gastric environment, localized activity, and for drugs that cannot be administered by other routes. The present review addresses the rectal physiology, rectal diseases, and pharmaceutical factors influencing rectal delivery of drugs and discusses different rectal drug delivery systems including suppositories, suspensions, microspheres, nanoparticles, liposomes, tablets, and hydrogels. Clinical trials on various rectal drug delivery systems are presented in tabular form. Applications of different novel drug delivery carriers viz. nanoparticles, liposomes, solid lipid nanoparticles, microspheres, transferosomes, nano-niosomes, and nanomicelles have been discussed and demonstrated for their potential use in rectal administration. Various opportunities and challenges for rectal delivery including recent advancements and patented formulations for rectal drug delivery have also been included.

Unravelling Micro and Nano vesicular System in Intranasal Drug Delivery for Epilepsy.

Epilepsy is one of the major neurological disorders, affecting about 50 million people globally. Oral, intravenous, and rectal delivery systems are available for the management of epileptic seizures. However, intranasal delivery serves beneficial for delivering anti-epileptic drugs owing to the advantages it offers. Various approaches have been developed over the years aiming to attain either a safer or faster brain delivery; a nasal delivery system proposes significant outcomes. The non-invasiveness and high vascularity contribute to the high permeability of the nasal mucosa, allowing rapid drug absorption. This review highlights some of the promising novel approaches delivering antiepileptic drugs efficiently employing the nasal route. The method includes a collection of data from different search engines like PubMed, ScienceDirect, SciFinder for obtaining appropriate and relevant literature regarding epilepsy, intranasal delivery of antiepileptic agents, and novel therapeutics. The present review underlines the majority of work related to intranasal delivery in the treatment of epilepsy, aiming to draw the attention of the researchers towards the easiest and efficient ways of formulation for the delivery of antiepileptics during seizures. This review intends to provide understanding about the delivery aspects of anti-epileptic drugs, the benefits of intranasal delivery, and the novel approaches employed for the treatment of epilepsy.

Formulation of oxybutynin chloride microparticle-loaded suppositories: in vitro characterization and in vivo pharmacokinetic study

BackgroundOxybutynin chloride (OXC) is used to treat overactive urinary bladder. OXC is metabolized in the liver to N-desethyloxybutynin, which is mainly responsible for the anticholinergic side effects of OXC. Conventional oxybutynin suppositories formulated earlier have shown most common side effects, such as dry mouth, constipation and serious anticholinergic reaction. Hence the present research work deals with the formulation and characterization of OXC microparticle-loaded mucoadhesive suppositories which may remain adhered in the lower rectum and avoid first pass metabolism. The emulsification–ionic gelation method is employed to prepare OXC microparticles. Two formulation factors at three levels, i.e. polymer concentration and stirring speed, were selected. Sodium alginate (concentration 1–2%) and 1% w/v Carbopol 971P were used to prepare OXC microparticles. OXC microparticles were evaluated for various parameters such as production yield, entrapment efficiency, mucoadhesive strength, shape, size, zeta potential, Fourier Transform Infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, in vitro dissolution studies and stability studies. Suppositories loaded with OXC microparticles were prepared by the fusion method using Poloxamer 188 and propylene glycol and evaluated for various parameters like weight variation, disintegration time, in vitro dissolution study, stability study and pharmacokinetic study.ResultsResults of in vitro characterization revealed that optimized batch of OXC loaded microparticles exhibited production yield 94.024% entrapment efficiency 95.378% and mucoadhesion strength 95.544%, particle size range 764.04–894.13 µm, zeta potential − 14.5 mV, with 0.946 desirability. Consequences of DSC and XRPD evaluation shown that drug was effectively entrapped inside the microparticles. In vitro release studies revealed improvement in drug dissolution as a consequence of its entrapment into microparticles. SEM results showed that micelles were sphere-shaped. On rectal administration of OXC microparticles loaded suppository in male Sprague–Dawley Rats, the relative bioavailability was found 173.72%.ConclusionIn vivo study elicits rapid increase in absorption of drug from microparticles loaded suppository when compared with the oral formulation and drug loaded suppository in rats. OXC microparticles loaded suppository is novel and promising drug delivery system for rectal administration and may avoid anticholinergic side effects of hepatic metabolite, N-desethyloxybutynin. These rectal drug delivery systems will be advantageous for efficient absorption of drugs and to avoid first pass metabolism.

Development of Stable Nano-Sized Transfersomes as a Rectal Colloid for Enhanced Delivery of Cannabidiol.

Current cannabidiol (CBD) formulations are challenged with unpredictable release and absorption. Rational design of a rectal colloid delivery system can provide a practical alternative. In this study the inherent physiochemical properties of transferosomes were harnessed for the development of a nano-sized transfersomes to yield more stable release, absorption, and bioavailability of CBD as a rectal colloid. Transfersomes composed of soya lecithin, cholesterol, and polysorbate 80 were synthesized via thin film evaporation and characterized for size, entrapment efficiency (%), morphology, CBD release, ex vivo permeation, and physicochemical stability. The optimized formulation for rectal delivery entrapped up to 80.0 ± 0.077% of CBD with a hydrodynamic particle size of 130 nm, a PDI value of 0.285, and zeta potential of −15.97 mV. The morphological investigation via SEM and TEM revealed that the transfersomes were spherical and unilamellar vesicles coinciding with the enhanced ex vivo permeation across the excised rat colorectal membrane. Furthermore, transfersomes improved the stability of the encapsulated CBD for up to 6 months at room temperature and showed significant promise that the transfersomes promoted rectal tissue permeation with superior stability and afforded tunable release kinetics of CBD as a botanical therapeutic with inherent poor bioavailability.

A KPV-binding double-network hydrogel restores gut mucosal barrier in an inflamed colon

Ulcerative colitis (UC) usually occurs in the superficial mucosa of the colorectum. Here, a double-network hydrogel (PMSP) was constructed from maleimided γ-polyglutamic acid and thiolated γ-polyglutamic acid through crosslinking of thiol-maleimide and self-oxidized thiols. PMSP with a negative charge specifically adhered to the inflamed mucosa with positively charged proteins rather than to the healthy mucosa. PMSP exhibited good mechanical strength with storage modulus (G′) of 17.6 Pa and a linear viscoelastic region (LVR) of 107.2% strain. Moreover, PMSP showed a stronger bio-adhesive force toward the inflamed tissue-mimicking substrate than toward its healthy counterpart. In vivo imaging confirmed that PMSP specifically adhered to the inflamed colonic mucosa of rats with TNBS-induced UC. KPV (Lys-Pro-Val) as a model drug was easily captured by PMSP through electrostatic interactions, thus retaining its bioactivity for a longer time under high temperature conditions. Moreover, the alleviating effect of KPV on rats with TNBS-induced colitis was significantly improved by PMSP after intracolonic administration. The epithelial barrier of the colon also effectively recovered following PMSP-KPV treatment. PMSP-KPV also modulated the gut flora, markedly augmenting the abundance of beneficial microorganisms in gut homeostasis. The mechanism by which PMSP-KPV induces a therapeutic effect may be associated with the inhibition of oxidative stress. Conclusively, the PMSP hydrogel seems to be a promising rectal delivery system for the therapy of UC. Statement of significanceUlcerative colitis (UC) is a chronic and relapsing disease of the gastrointestinal tract. A key therapeutic approach to treat UC is to repair the mucosal barriers. Here, a double-network hydrogel (PMSP) was constructed from maleimided and thiolated γ-polyglutamic acid through crosslinking of thiol-maleimide and self-oxidized thiols. The negatively charged PMSP specifically adhered to the inflamed colon rather than its healthy counterpart and was retained for a longer time. KPV as a model drug was easily captured by PMSP, which provided better stability to KPV when exposed to high temperature of 50 °C. The epithelial mucosal barrier of the colon was effectively recovered by the rectal administration of PMSP-KPV to rats with TNBS-induced UC. Moreover, PMSP-KPV modulated the gut flora of colitic rats, markedly augmenting the abundance of beneficial microorganisms. Conclusively, PMSP seems to be a promising rectal delivery system for UC therapy.

A Survey on Mucoadhesive Thermoreversible Drug Delivery System with special Emphasis on Recto-Anal Region for the Treatment of Internal Hemorrhoids

The concept of combination of thermo reversibility and mucoadhesion has achieved a much valuable interest in various fields of pharmaceutics. Mucoadhesive drug delivery systems interact with the mucus layer covering the mucosal epithelial surface, and mucin molecules and increase the residence time of the dosage form at the site of absorption. Thermoreversible gels are the hydrogels that are liquids at room temperature but undergo gelation when in contact with body fluids or change in pH. A major problem faced by conventional formulation in various routes of administration viz. nasal, ocular, vaginal, rectal, etc is drainage of instilled formulation, poor patient compliance as in the case of vaginal and rectal delivery system. Also, blurred vision and irritation to mucosa is observed in the case of ocular and nasal delivery respectively. The drainage of the formulation results in inaccurate dose delivery thus decreasing the bioavailability of the drug which demands an increase in the frequency of the administration. To overcome these limitations, there is need of novel delivery system such as thermoreversible mucoadhesive insitu gel which provides an ease of administration and improved patient compliance as these smart delivery system is free flowing liquid at ambient temperature and gels at physiological temperature which is higher than the LCST (low critical solution temperature) of thermoreversible polymer. The combined effect of mucoadhesion and thermoreversible property will enhance prolongation of residence time of dosage form and the accuracy of the dose in body cavity respectively, leading to increased bioavailability of the drug. This review focuses on benefits of mucoadhesive thermoreversible system of drug delivery through rectum for the treatment of internal hemorrhoids.

Achievements in Thermosensitive Gelling Systems for Rectal Administration.

Rectal drug delivery is an effective alternative to oral and parenteral treatments. This route allows for both local and systemic drug therapy. Traditional rectal dosage formulations have historically been used for localised treatments, including laxatives, hemorrhoid therapy and antipyretics. However, this form of drug dosage often feels alien and uncomfortable to a patient, encouraging refusal. The limitations of conventional solid suppositories can be overcome by creating a thermosensitive liquid suppository. Unfortunately, there are currently only a few studies describing their use in therapy. However, recent trends indicate an increase in the development of this modern therapeutic system. This review introduces a novel rectal drug delivery system with the goal of summarising recent developments in thermosensitive liquid suppositories for analgesic, anticancer, antiemetic, antihypertensive, psychiatric, antiallergic, anaesthetic, antimalarial drugs and insulin. The report also presents the impact of various types of components and their concentration on the properties of this rectal dosage form. Further research into such formulations is certainly needed in order to meet the high demand for modern, efficient rectal gelling systems. Continued research and development in this field would undoubtedly further reveal the hidden potential of rectal drug delivery systems.

Mucoadhesive-to-penetrating controllable peptosomes-in-microspheres co-loaded with anti-miR-31 oligonucleotide and Curcumin for targeted colorectal cancer therapy.

Background: Accumulating evidences indicate that nanomedicines greatly decrease the side effects and enhance the efficacy of colorectal cancer (CRC) treatment. In particular, the use of rectal delivery of nanomedicines, with advantages such as fast therapeutic effects and a diminishing hepatic first-pass effect, is currently emerging.Method: We established a CRC targeted delivery system, in which α-lactalbumin peptosomes (PSs) co-loaded with a microRNA (miR)-31 inhibitor (miR-31i) and curcumin (Cur) were encapsuslated in thiolated TEMPO oxidized Konjac glucomannan (sOKGM) microspheres, referred as sOKGM-PS-miR-31i/Cur. The CRC targeting capability, drug release profiles, mucoadhesive-to-penetrating properties and therapeutic efficacy of sOKGM-PS-miR-31i/Cur delivery system were evaluated in colorectal cancer cells and azoxymethane-dextran sodium (AOM-DSS) induced tumor models.Results: sOKGM-PS-miR-31i/Cur delivery system were stable in the harsh gastrointestinal environment after rectal or oral administration; and were also mucoadhesive due to disulfide bond interactions with the colonic mucus layer, resulting in an enhanced drug retention and local bioavailability in the colon. Concomitantly, the released PS-miR-31i/Cur PSs from the microsphere was mucus-penetrating, efficiently passing through the colonic mucus layer, and allowed Cur and miR-31i specifically target to colon tumor cells with the guide of CD133 targeting peptides. Consequently, rectal delivery of sOKGM-PS-miR-31i/Cur microspheres suppressed tumor growth in an azoxymethane-dextran sodium sulfate (AOM-DSS)-induced tumor model.Conclusion: sOKGM-PS-miR-31i/Cur microspheres are effective rectal delivery system with combined advantages of mucoadhesive and mucus-penetrating properties, representing a potent and viable therapeutic approach for CRC.

Tumor-selective lipopolyplex encapsulated small active RNA hampers colorectal cancer growth invitro and in orthotopic murine.

Small active RNA (saRNA)-induced gene activation (RNAa) is a novel strategy to treat cancer. Our previous work proved that the p21-saRNA-322 successfully hindered colorectal cancer growth by activating p21 gene. However, the barrier for successful saRNA therapy is lack of efficient drug delivery. In the present study, a rectal delivery system entitled p21-saRNA-322 encapsulated tumor-selective lipopolyplex (TSLPP-p21-saRNA-322) which consist of PEI/p21-saRNA-322 polyplex core and hyaluronan (HA) modulated lipid shell was developed to treat colorectal cancer. Our results showed that this system maintained at the rectum for more than 6h and preferentially accumulated at tumor site. CD44 knock down experiment instructed that the superb cellular uptake of TSLPP-p21-saRNA-322 attributed to HA-CD44 recognition. An orthotopic model of bio-luminescence human colorectal cancer in mice was developed using microsurgery and TSLPP-p21-saRNA-322 demonstrated a superior antitumor efficacy invitro and invivo. Our results provide preclinical proof-of-concept for a novel method to treat colorectal cancer by rectal administration of TSLPP formulated p21-saRNA-322.

Silk-elastinlike protein polymers enhance the efficacy of a therapeutic glycosaminoglycan for prophylactic treatment of radiation-induced proctitis

Radiation-induced proctitis (RIP) is the most common clinical adverse effect for patients receiving radiotherapy as part of the standard course of treatment for ovarian, prostate, colon, and bladder cancers. RIP limits radiation dosage, interrupts treatment, and lowers patients' quality of life. A prophylactic treatment that protects the gastrointestinal tract from deleterious effects of radiotherapy will significantly improve patient quality of life and may allow for higher and more regular doses of radiation therapy. Semi-synthetic glycosaminoglycan (GAG), generated from the sulfation of hyaluronic acid, are anti-inflammatory but have difficulty achieving therapeutic levels in many tissues. To enhance the delivery of GAG, we created an in situ gelling rectal delivery system using silk-elastinlike protein polymers (SELPs). Using solutions of SELP 815K (which contains 6 repeats of blocks comprised of 8 silk-like units, 15 elastin-like units, and 1 lysine-substituted elastin-like unit) with GAG GM-0111, we created an injectable delivery platform that transitioned in <5min from a liquid at room temperature to a hydrogel at body temperature. The hydrogels released 50% of their payload within 30min and enhanced the accumulation of GAG in the rectum compared to traditional enema-based delivery. Using a murine model of radiation-induced proctitis, the prophylactic delivery of a single dose of GAG from a SELP matrix administered prior to irradiation significantly reduced radiation-induced pain after 3, 7, and 21days by 53±4%, 47±10%, and 12±6%, respectively. Matrix-mediated delivery of GAG by SELP represents an innovative method for more effective treatment of RIP and promises to improve quality of life of cancer patients by allowing higher radiotherapy doses with improved safety.

Nanotransfersomes-loaded thermosensitive in situ gel as a rectal delivery system of tizanidine HCl: preparation, in vitro and in vivo performance

The purpose of the current study was to develop tizanidine HCl (TIZ; a myotonolytic agent used for treatment of spasticity) loaded nanotransfersomes intended for rectal administration, aiming to bypass the hepatic first-pass metabolism. TIZ-loaded nanotransfersomes were prepared by thin-film hydration method followed by characterization for various parameters including entrapment efficiency, vesicle diameter, in vitro release and ex vivo permeation studies. Transfersomal formulation composed of phosphatidylcholine and Tween 80 at a weight ratio of (85:15) gave a satisfactory results. It exhibited encapsulation efficiency of 52.39%, mean diameter of 150.33 nm, controlled drug release over 8 h and good permeation characteristics. Optimum formula was then incorporated into Pluronic-based thermoreversible gel using hydroxypropyl methylcellulose (HPMC) as a mucoadhesive polymer. Pharmacokinetic study was performed by rectal administration of transfersomes-loaded in situ gel to rabbits and compared with oral drug solution and rectal TIZ in situ gel. The pharmacokinetic study revealed that the transfersomal formulation successively enhanced the bioavailability of TIZ by about 2.18-fold and increased t1/2 to about 10 h as compared to oral solution. It can be concluded that encapsulation of TIZ into nanotransfersomes can achieve a dual purpose of prolonged TIZ release and enhanced bioavailability and so may be considered as a promising drug delivery system for the treatment of spasticity.

In situ delivery of thermosensitive gel-mediated 5-fluorouracil microemulsion for the treatment of colorectal cancer.

In situ administration of 5-fluorouracil (5FU) “thermosensitive” gel effectively reduced systemic side effects in treating colon rectal cancer; however, the penetration efficacy of the formulation was considerably low due to the poor lipid solubility of 5FU. The aim of this study was to develop thermosensitive gel-mediated 5FU water-in-oil microemulsion (TG-5FU-ME) for improving the infiltration of 5FU. An in vitro release test showed that TG-5FU-ME sustained the drug’s release up to 10 hours. TG-5FU-ME exhibited good stability, and the microemulsion entrapped did not show any change in morphology and 5FU content during the 4-month storage. Transportation test in the Caco-2 cell monolayer showed that TG-5FU-ME had a permeability 6.3 times higher than that of 5FU thermosensitive gel, and the intracellular uptake of 5FU increased by 5.4-fold compared to that of 5FU thermosensitive gel. In vivo tissue distribution analysis exhibited that the TG-5FU-ME group had drug levels in rectal tissue and mesenteric lymph nodes, which were significantly higher than those of 5FU thermosensitive gel group, with very low blood levels of 5FU in both groups. Furthermore, TG-5FU-ME was not associated with detectable morphological damage to the rectal tissue. Conclusively, TG-5FU-ME might be an efficient rectal delivery system to treat colorectal cancer.

Enteral siRNA delivery technique for therapeutic gene silencing in the liver via the lymphatic route.

An efficient targeting delivery technology is needed for functional oligonucleotides to exert their potential effect on the target gene without an adverse effect in vivo. Development of enteral delivery systems for nucleic acids is a major challenge because of their large molecular size and instability. Here, we describe a new enteral delivery technique that enables small interfering RNA (siRNA) selectively delivered to the liver to silence its target Apolipoprotein B gene expression. A nuclease-resistant synthetic siRNA was conjugated with α-tochopherol and administered as lipid nanoparticle to the large intestine of the mice in a postprandial state. The selective transport into the liver, effective gene silence, and consequently significant reduction in serum low density lipoprotein-cholesterol level, were demonstrated. The chylomicron-mediated pathway via the lymphatic route was suggested as major mechanism. This unique approach may provide a basis for developing oral and rectal delivery systems for nucleic acids targeting liver.

Pharmacokinetics and anti-hypertensive effect of metoprolol tartrate rectal delivery system

The main aim of this work was to develop rectal suppositories for better delivery of metoprolol tartrate (MT). The various bases used were fatty, water soluble and emulsion bases. The physical properties of the prepared suppositories were characterized such as weight variation, hardness, disintegration time, melting range and the drug content uniformity. The in vitro release of MT from the prepared suppositories was carried out. The evaluation of the pharmacological effects of MT on the blood pressure and heart rate of the healthy rabbits after the rectal administration compared to the oral tablets was studied. Moreover, the formulation with the highest in vitro release and the highest pharmacological effects would be selected for a further pharmacokinetics study compared to the oral tablets. The results revealed that the emulsion bases gave the highest rate of the drug release than the other bases used. The reduction effect of the emulsion MT suppository base on the blood pressure and heart rate was found to be faster and greater than that administered orally. The selected emulsion suppository base (F11) showed a significant increase in the AUC (1.88-fold) in rabbits as compared to the oral tablets. From the above results we can conclude that rectal route can serve as an efficient alternative route to the oral one for systemic delivery of MT which may be due to the avoidance of first-pass effect in the liver.

Development of In Situ Gelling and Bio Adhesive 5-Fluorouracil Enema

In this study, a novel 5-Fluorouracil (5-FU) enema with good bio adhesion and temperature sensitivity was developed using in situ gelling technology. The preparation was formulated as a free-flowing liquid before use, while a layer of gel film was quickly formed when administered in the rectum, with a large contact surface area. It also demonstrated good biocompatibility, appropriate gel strength and bio adhesive force with excellent adhesion to rectal mucosa and prolonged action time, allowing more effective drug absorption and diffusion to surrounding tissues. Poloxamer 407 and poloxamer 188 were applied to adjust the gelling temperature. With the addition of carbopol and polycarbophil (bio adhesive substances), the solubility of 5-FU and gel strength increased, the temperature of gelation and the surface area of drug contact on mucous epithelium decreased. Decreased adhesive force between the preparation and the mucous membrane of the rectum was demonstrated with improving carbopol and polycarbophil’s concentration. In vitro release demonstrated that 5-FU in situ gelling enema with different bases had a rapid and almost complete drug release. We used an optimized formulation of P407/P188/polycarbophil/5-FU (17/2.5/0.2/1.0) for animal experiments. The result showed that the drug evenly covered the surface of the rectum and there was no leakage in 6 hours. The in situ gelling enema showed significantly higher rectal tissue levels of 5-FU compared with suppository and intravenous administration, indicating that 5-FU could be well absorbed due to the enlarged releasing area, longer retention time and larger amount of dissolved active ingredients. Systemically, 5-FU levels in the enema group were similar to those in the suppository group and significantly lower than the intravenous group. The enema was not associated with morphological damage to rectal tissue. These results suggest that the bio adhesive and in situ gelling enema could be a more effective rectal delivery system of 5-FU.

Docetaxel-Loaded Thermosensitive and Bioadhesive Nanomicelles as a Rectal Drug Delivery System for Enhanced Chemotherapeutic Effect

To investigate the potential of thermosensitive and biadhesive nanomicelles in improving the bioavailability of docetaxel (DCT) and its chemotherapeutic effect. DCT-loaded nanomicelles were prepared by emulsufication and characterized in terms of physico-chemical and visco-elastic parameters. The optimzed formulation was evaluated for in vivo localization, pharmacokinetic and anti-tumor efficacy. The hydrodynamic size of DCT-loaded nanomicelles was approximately 13 nm and the nanomicelles exhibited a sufficient gelation strength (9250 mPa·s) and bioadhesive force (2100 dyn/cm²) to be retained in the upper part of rectum. We observed a high rectal bioavailability of 29% DCT compared to that following oral administration in rats, as it successfully evaded the multidrug efflux transporters and hepatic first-pass metabolism. Plasma concentration around ∼50 ng/mL was maintained throughout the study period (12 h) while Taxotere® attained subtherapeutic range within 4 h of drug administration. Results also revealed that the rectally administered DCT-loaded nanomicelles exhibited a significant anti-tumor effect (200 mm³) with a reduced toxicity profile when compared to orally administered DCT (950 mm³). Furthermore, histological study showed that the rectal mucosa was completely intact with no signs of irritation upon treatment with DCT-loaded nanomicelles. Taken together, our novel thermosensitive and biadhesive nanomicelles demonstrated the ability to improve the bioavailability and chemotherapeutic potential of DCT in vivo. To the best of our knowledge, this is the first report describing the rectal delivery of DCT-loaded nanomicelles.