An augmented delivery of the anticancer agent, curcumin, to the colon

This work describes the formulation aspects of an orally viable curcumin-containing mucoadhesive nanoparticulate system for management of colon cancer. Curcumin is documented to possess anticancer properties whilst modified citrus pectin yields a galactose functionality capable of inhibiting the growth and proliferation of colon cancer cells due to antagonism to galectin-3 (Gal-3). A successfully formulated curcumin containing chitosan-modified citrus pectinate nanoparticles (MCPCNPs) registered a z-average of 178 nm (± 0.896) and a positive surface charge of + 35.7 mV (± 1.41). The MCPCNPs presented high mucoadhesion propensity in the colonic region/ media and minimal at pH 1.2 (stomach). There was approximately 18 % curcumin release at pH 1.2 over 2 h and up to 68% release in the 33% (w/v) caecal medium over 24 h. The data obtained strongly suggests that the formulated MCPCNPs have the potential to be applied as an orally deliverable colon cancer formulation alternative in the treatment of colon cancer

Soliciting the Oral Route as a Logical Approach to Managing Colon Cancer

According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2018, colon cancer (CC) is the third most common cancer in men and second in women worldwide (Bray et al., 2018). Approximately 1.8 million new colon cancer cases were diagnosed globally in 2018, with nearly 881,000 resulting in deaths (Bray et al., 2018). The exact trigger of CC is still subject to debate but it is generally accepted that predisposing factors include genetics, diet and lifestyle. In any case, the chemical basis for cancer initiation cascade appears to be prompted by byproducts of aerobic metabolism such as reactive oxygen species (ROS). These are known to confer various levels of reactivity to biological tissues which may serve as trigger to cancer development (Finkel, 2011). This has been referred to as oxidative stress and is known to cause damage to lipids, proteins and importantly, DNA. On the other hand, ROS can also regulate other biological processes. It would seem therefore that a good balance in the levels of ROS is necessary within biological systems and any imbalance in this level serves as trigger for cancer. Most CCs develop slowly as polyps and eventually become malignant under uncontrolled growth that begins within the colonic mucosa and then spreads to the rest of the colon layers as a solid tumor. Fortunately, CC can be easily treated if detected early. Treatment and prognosis rely on the depth of the tumor, extent of lymph nodes involvement and metastasis to distant parts of the body (Ong and Schofield, 2016). Chemo- or radiotherapy may be used alone or in combination for long term treatment plans, whilst surgery may be required in severe cases. In radiotherapy, X-ray energy is irradiated to the suspected tumor from a linear accelerator that destroys cellular DNA and thus inhibits cell proliferation (Jong, 2017). On the other hand, chemotherapy relies on use of cytotoxic agents that inhibit cell growth (Wu et al., 2012) and may be administered prior to or after surgery. Chemotherapeutic agents commonly used in the management of CC include 5-fluorouracil (5-FU), irinotecan (CPT-11), leucovorin (l-LV), oxaliplatin (L-OHP), and capecitabine (Van Der Jeught et al., 2018). 5-FU was among the first synthesized anti-cancer drugs, however about 85% of parenterally administered 5-FU dose is metabolized within 15 min into inactive forms (Jordan, 2016). Thus, capecitabine, an orally administrated prodrug of 5-FU, is usually used instead due to the higher tumor response rate, ≈100% bioavailability and lower incidence of side effects (Miura et al., 2017). The majority of chemotherapeutic drugs are administered intravenously (i.v.), destined to accumulate within tumor regions. However, i.v. administration causes significant distribution in highly perfused organs (e.g., kidney, lung, etc.) compared to tumor sites. This untoward deployment of the i.v. administered chemotherapeutics may impair the functionality of said organs upon long-term exposure (Attili-Qadri et al., 2013; Patel, 2014). Thus, research focused on alternative modes of delivery of therapeutics is warranted. In this regard, soliciting the oral route for delivering anticancer agents in the management of CC seems logical because of the manifestation CC within the gastrointestinal tract (Sharma and Saltz, 2000; Date et al., 2016). Oral administration of therapeutics for CC enables localized deployment at tumor and hence improves its efficacy whilst at the same time reducing systemic toxicity. Furthermore, oral delivery route appropriate for the delivery of anticancer agents destined for the treatment of CC because it reduces stress and discomfort to patients, and offers flexibility in that, they can self-administer the medication and thus forgo hospital visits (Eek et al., 2016). Rectal administration presents a possibility for delivering drugs to the colon however therapy is ineffective if CC is widespread or in the event of local inflammation such as in Inflammatory Bowel Disease (IBD) (Hua, 2014). The unidirectional flow of colonic content is bound to void any device inserted rectally, which may also cause discomfort in patients

Gastrointestinal Delivery of APIs from Chitosan Nanoparticles

Successful clinical treatment outcomes rely on achieving optimal systemic delivery of therapeutics. The oral route of administering Active Pharmaceutical Ingredients (API) remains formidable because of ease to the patient and convenience. Yet, the gastrointestinal tract (GIT) poses several barriers that need to be surmounted prior to systemic availability, especially for Class IV type drugs. Drug delivery systems in the form of nanoparticles (NP), can be appropriately formulated to alter the physicochemical properties of APIs, thereby addressing constraints related to absorption from the GIT. Polymers offer amenability in the fabrication of NP due to their diversity. Chitosan has emerged as a strong contender in orally deliverable NP because it is biocompatible, biodegradable and muco-adhesive. Due to the positively charged amine moieties within chitosan (NH3+), interactions with the negatively charged sialic acid of mucin within the mucosa is possible, which favors delayed GI transit and epithelial uptake. This ultimately results in improved systemic bioavailability. Thus, we expect research in the use of chitosan in oral NP delivery to intensify as we transcend the frontier toward clinical testing of viable formulations

Lyophilized drug-loaded solid lipid nanoparticles formulated with beeswax and theobroma oil

Solid lipid nanoparticles (SLNs) have the potential to enhance the systemic availability of an active pharmaceutical ingredient (API) or reduce its toxicity through uptake of the SLNs from the gastrointestinal tract or controlled release of the API, respectively. In both aspects, the responses of the lipid matrix to external challenges is crucial. Here, we evaluate the effects of lyophilization on key responses of 1:1 beeswax–theobroma oil matrix SLNs using three model drugs: Amphotericin B (AMB), paracetamol (PAR), and sulfasalazine (SSZ). Fresh SLNs were stable with sizes ranging between 206.5–236.9 nm. Lyophilization and storage for 24 months (4–8 °C) caused a 1.6- and 1.5-fold increase in size, respectively, in all three SLNs. Zeta potential was >60 mV in fresh, stored, and lyophilized SLNs, indicating good colloidal stability. Drug release was not significantly affected by lyophilization up to 8 h. Drug release percentages at end time were 11.8 ± 0.4, 65.9 ± 0.04, and 31.4 ± 1.95% from fresh AMB-SLNs, PAR-SLNs, and SSZ-SLNs, respectively, and 11.4 ± 0.4, 76.04 ± 0.21, and 31.6 ± 0.33% from lyophilized SLNs, respectively. Thus, rate of release is dependent on API solubility (AMB < SSZ < PAR). Drug release from each matrix followed the Higuchi model and was not affected by lyophilization. The above SLNs show potential for use in delivering hydrophilic and lipophilic drugs

Antifungal and mucoadhesive properties of an orally administered chitosan-coated amphotericin B 1 nanostructured lipid carrier (NLC)

Surface - modified nanostructured lipid carriers (NLC) is a promising formulation to prolong the retention time of the therapeutic agent at the site of absorption. Chitosan-coated AmpB-loaded NLC (ChiAmpB NLC) were developed showing particle size of 394.4 ± 6.4 nm, encapsulation efficiency of 86.0 ± 0.3 % and a drug loading of 11.0 ± 0.1 %. ChiAmpB NLC showed biphasic release behaviour with no significant change in its physical properties upon exposure to conditions simulating the gastrointestinal tract. Compared to pure AmpB, ChiAmpB NLC observed not only a comparable antifungal behaviour but showed superior safety profiles, with two times lesser toxicity to the red blood cells and ten times safer to the HT-29 cell line. It was also successfully observed a translation of the in vitro mucoadhesion result to the ex vivo animal study in which ChiAmpB NLC results in higher percentage of retention in the small intestine compared to uncoated formulation. Together, the data strongly offered the possibility of having a non-toxic yet effective oral treatment for systemic fungal infections

Mucoadhesive chitosan-coated nanostructured lipid carriers for oral delivery of amphotericin B

This study describes the properties of an amphotericin B-containing mucoadhesive nanostructured lipid carrier (NLC), with the intent to maximize uptake within the gastrointestinal tract. We have reported previously that lipid nanoparticles can significantly improve the oral bioavailability of amphotericin B (AmpB). On the other hand, the aggregation state of AmpB within the NLC has been ascribed to some of the side effects resulting from IV administration. In the undissolved state, AmpB (UAmpB) exhibited the safer monomeric conformation in contrast to AmpB in the dissolved state (DAmpB), which was aggregated. Chitosan-coated NLC (ChiAmpB NLC) presented a slightly slower AmpB release profile as compared to the uncoated formulation, achieving 26.1 % release in 5 hours. Furthermore, the ChiAmpB NLC formulation appeared to prevent the expulsion of AmpB upon exposure to simulated gastrointestinal pH media, whereby up to 63.9 % of AmpB was retained in the NLC compared to 56.1 % in the uncoated formulation. The ChiAmpB NLC demonstrated mucoadhesive properties in pH 5.8 and 6.8. Thus, the ChiAmpB NLC formulation is well-primed for pharmacokinetic studies to investigate whether delayed gastrointestinal transit may be exploited to improve the systemic bioavailability of AmpB, whilst simultaneously addressing the side-effect concerns of AmpB

Solid Dispersion Formulations by FDM 3D Printing—A Review

Additive manufacturing (AM) is revolutionizing the way medicines are designed, manufactured, and utilized. Perhaps, AM appears to be ideal for the fit-for-purpose manufacturing of medicines in contrast to the several disadvantages associated with the conventional fit-for-all mass production that accounts for less than 50% of pharmacotherapeutic treatment/management of diseases especially among children and elderly patients, as well as patients with special needs. In this review, we discuss the current trends in the application of additive manufacturing to prepare personalized dosage forms on-demand focusing the attention on the relevance of coupling solid dispersion with FDM 3D printing. Combining the two technologies could offer many advantages such as to improve the solubility, dissolution, and oral bioavailability of poorly soluble drugs in tandem with the concept of precision medicine and personalized dosing and to address the dilemma of commercial availability of FDM filaments loaded with Class II and/or Class IV drugs. However, thermal treatment especially for heat-sensitive drugs, regulatory, and ethical obligations in terms of quality control and quality assurance remain points of concern. Hence, a concerted effort is needed between the scientific community, the pharmaceutical industries, the regulatory agencies, the clinicians and clinical pharmacists, and the end-users to address these concerns

Practicality of 3D Printed Personalized Medicines in Therapeutics

Technological advances in science over the past century have paved the way for remedial treatment outcomes in various diseases. Pharmacogenomic predispositions, the emergence of multidrug resistance, medication and formulation errors contribute significantly to patient mortality. The concept of "personalized" or "precision" medicines provides a window to addressing these issues and hence reducing mortality. The emergence of three-dimensional printing of medicines over the past decades has generated interests in therapeutics and dispensing, whereby the provisions of personalized medicines can be built within the framework of producing medicines at dispensaries or pharmacies. This plan is a good replacement of the fit-for-all modality in conventional therapeutics, where clinicians are constrained to prescribe pre-formulated dose units available on the market. However, three-dimension printing of personalized medicines faces several hurdles, but these are not insurmountable. In this review, we explore the relevance of personalized medicines in therapeutics and how three-dimensional printing makes a good fit in current gaps within conventional therapeutics in order to secure an effective implementation of personalized medicines. We also explore the deployment of three-dimensional printing of personalized medicines based on practical, legal and regulatory provisions. Copyright 2021 Amekyeh, Tarlochan and Billa.Scopu

Multiboronic acid-conjugated chitosan scaffolds with glucose selectivity to insulin release

The principal challenge for the use of boronic acids (BA) as glucose sensors is their lack of specificity for glucose. We examined the selectivity of and insulin release from two boronic acids- (2-formyl-3-thienylboronic acid (FTBA) and 4-formylphenylboronic acid (FPBA)) conjugated chitosan scaffolds to glucose and fructose. Adsorption of glucose to BA: chitosan conjugates was dose-dependent up to 1:1 at 35 and 42% for FPBA and FTBA respectively but the FTBA conjugates adsorbed more glucose and fructose at respective FPBA ratios. The affinity of both BA conjugates to glucose decreased with increase in BA ratio. On the other hand, the affinity of both BA conjugates for fructose decreased from ratio 1:1 to 2:1 then rose again at 3:1. Insulin release from FPBA nanoparticles (FPBAINP) and FTBA nanoparticles (FTBAINP) were both concentration-dependent within glyceamically relevant values (1–3 mg/ml glucose and 0.002 mg/ml fructose). Furthermore, the total amounts of insulin released from FPBAINP in both the media were higher than from FTBAINP. Both FPBAINP and FTBAINP have the potential for development as a glucose-selective insulin delivery system in physiological settings

Pharmacokinetics and tissue distribution of an orally administered mucoadhesive chitosan-coated amphotericin B-Loaded nanostructured lipid carrier (NLC) in rats

© 2019 Informa UK Limited, trading as Taylor & Francis Group. Oral delivery of amphotericin B (AmpB) is desirable because it provides a more patient-friendly mode of administration compared to the current delivery approach akin with the marketed AmpB formulations. The goal of the study was to investigate the pharmacokinetics and tissue distribution of orally administered chitosan-coated AmpB-loaded nanostructured lipid carriers (ChiAmpB NLC) administered to Sprague Dawley rats at a dose of 15 mg/kg. Orally administered ChiAmpB NLC resulted in a two-fold increase in the area under the curve (AUC0-∞) compared to the uncoated AmpB NLC and marketed Amphotret®. This enhanced bioavailability of AmpB suggests prolonged transit and retention of ChiAmpB NLC within the small intestine through mucoadhesion and subsequent absorption by the lymphatic pathway. The results show that mean absorption and residence times (MAT & MRT) were significantly higher from ChiAmpB NLC compared to the other two formulations, attesting to the mucoadhesive effect. The ChiAmpB NLC presented a lower nephrotic accumulation with preferential deposition in liver and spleen. Thus, the limitations of current marketed IV formulations of AmpB are potentially addressed with the ChiAmpB NLC in addition to utilizing this approach for targeting internal organs in visceral leishmaniasis