Effect of functional excipients on the dissolution and membrane permeation of furosemide formulated into multiple-unit pellet system (MUPS) tablets.

The effect of functional excipients (i.e. chitosan, sodium lauryl sulphate, NaHCO3, and CaCO3) formulated in multiple-unit pellet system (MUPS) tablets has been investigated on the dissolution and permeability of furosemide, a BCS class IV compound. Spherical beads were produced and compressed into MUPS tablets. MUPS tablet formulations were evaluated for hardness, disintegration, mass variation, friability, and dissolution (pH 1.2, pH 4.6, and pH 7.4). Ex vivo permeability studies were conducted across excised pig tissues (pyloric antrum and duodenal region) on selected experimental MUPS tablet formulations. Histological analysis was conducted on the tissues after exposure to selected experimental MUPS tablet formulations. Dissolution results in the 0.1 M HCl (pH 1.2) showed the highest effect of the excipients on furosemide release. Dissolution parameters showed increased dissolution of furosemide for the MUPS tablet formulations containing functional excipients: a 4.5-10-fold increase in the AUC values, the %max showed a 60-70% increase and up to a 19-fold increase in DRi was seen. Permeability results revealed a 2.5-fold higher cumulative percentage transport for selected formulations. The results proved that functional excipients incorporated into beads, compressed into MUPS tablet formulations increased furosemide release as well as permeation across excised intestinal tissues.

Sceletium tortuosum: A review on its phytochemistry, pharmacokinetics, biological, pre-clinical and clinical activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Sceletium tortuosum (L.) N.E.Br., the most sought after and widely researched species in the genus Sceletium is a succulent forb endemic to South Africa. Traditionally, this medicinal plant is mainly masticated or smoked and used for the relief of toothache, abdominal pain, as a mood-elevator, analgesic, hypnotic, anxiolytic, thirst and hunger suppressant, and for its intoxicating/euphoric effects. Sceletium tortuosum is currently of widespread scientific interest due to its clinical potential in treating anxiety and depression, relieving stress in healthy individuals, and enhancing cognitive functions. These pharmacological actions are attributed to its phytochemical constituents referred to as mesembrine-type alkaloids. AIM OF THE REVIEW: The aim of this review was to comprehensively summarize and critically evaluate recent research advances on the phytochemistry, pharmacokinetics, biological, pre-clinical and clinical activities of the medicinal plant S. tortuosum. Additionally, current ongoing research and future perspectives are also discussed. METHODS: All relevant scientific articles, books, MSc and Ph.D. dissertations on botany, behavioral pharmacology, traditional uses, and phytochemistry of S. tortuosum were retrieved from different databases (including Science Direct, PubMed, Google Scholar, Scopus and Web of Science). For pharmacokinetics and pharmacological effects of S. tortuosum, the focus fell on relevant publications published between 2009 and 2021. RESULTS: Twenty-five alkaloids belonging to four structural classes viz: mesembrine, Sceletium A4, joubertiamine, and tortuosamine, have been identified from S. tortuosum, of which the mesembrine class is predominant. The crude extracts and commercially available standardized extracts of S. tortuosum have displayed a wide spectrum of biological activities (e.g. antimalarial, anti-oxidant, neuromodulatory, immunomodulatory, anti-HIV, neuroprotection) in in vitro or in vivo studies. While the plant has been studied in clinical populations, this has only been in healthy subjects, so that further study in pathological states remains to be done. Nevertheless, the aforementioned studies have demonstrated that S. tortuosum has potential for enhancing cognitive function and managing anxiety and depression. CONCLUSION: As an important South African medicinal plant, S. tortuosum has garnered many research advances on its phytochemistry and biological activities over the last decade. These scientific studies have shown that S. tortuosum has various bioactivities. The findings have further established the link between the phytochemistry and pharmacological application, and support the traditional use of S. tortuosum in the indigenous medicine of South Africa.

Sceletium tortuosum: A review on its phytochemistry, pharmacokinetics, biological and clinical activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Sceletium tortuosum (L.) N.E.Br, the most sought after and widely researched species in the genus Sceletium is a succulent forb endemic to South Africa. Traditionally, this medicinal plant is mainly masticated or smoked and used for the relief of toothache, abdominal pain, and as a mood-elevator, analgesic, hypnotic, anxiolytic, thirst and hunger suppressant, and for its intoxicating/euphoric effects. Sceletium tortuosum is currently of widespread scientific interest due to its clinical potential in treating anxiety and depression, relieving stress in healthy individuals, and enhancing cognitive functions. These pharmacological actions are attributed to its phytochemical constituents referred to as mesembrine-type alkaloids. AIM OF THE REVIEW: The aim of this review was to comprehensively summarize and critically evaluate recent research advances on the phytochemistry, pharmacokinetics, biological and clinical activities of the medicinal plant S. tortuosum. Additionally, current ongoing research and future perspectives are also discussed. METHODS: All relevant scientific articles, books, MSc and Ph.D. dissertations on botany, behavioral pharmacology, traditional uses, and phytochemistry of S. tortuosum were retrieved from different databases (including Science Direct, PubMed, Google Scholar, Scopus and Web of Science). For pharmacokinetics and pharmacological effects of S. tortuosum, the focus fell on relevant publications published between 2009 and 2021. RESULTS: Twenty-five alkaloids belonging to four structural classes viz: mesembrine, Sceletium A4, joubertiamine, and tortuosamine, have been identified from S. tortuosum, of which the mesembrine class is predominant. The crude extracts and commercially available standardized extracts of S. tortuosum have displayed a wide spectrum of biological activities (e.g. antimalarial, anti-oxidant, immunomodulatory, anti-HIV, neuroprotection, enhancement of cognitive function) in in vitro or in vivo studies. This plant has not yet been studied in a clinical population, but has potential for enhancing cognitive function, and managing anxiety and depression. CONCLUSION: As an important South African medicinal plant, S. tortuosum has garnered many research advances on its phytochemistry and biological activities over the last decade. These scientific studies have shown that S. tortuosum has various bioactivities. The findings have further established the link between the phytochemistry and pharmacological application, and support the traditional use of S. tortuosum in the indigenous medicine of South Africa.

In vitro transport of the steroidal glycoside P57 from Hoodia gordonii across excised porcine intestinal and buccal tissue.

Hoodia gordonii was traditionally used by the Khoisan people as a thirst and appetite suppressant and is currently commercially available as a popular weight-loss supplement. The perceived active ingredient isolated from this plant is a steroidal glycoside named P57. This study aimed at investigating the in vitro transport of P57 across excised porcine intestinal and buccal mucosa in a Sweetana-Grass diffusion apparatus. For both the intestinal and buccal experiments, the transport of pure P57 was compared to that obtained from a crude plant extract. Bi-directional transport experiments were conducted across the intestinal tissue in two different media namely Krebs-Ringer bicarbonate buffer and simulated intestinal fluid. Apical-to-basolateral transport experiments were conducted across the buccal tissue in two different media namely Krebs-Ringer bicarbonate buffer and artificial saliva. Apparent permeability coefficient (P(app)) and flux values were calculated and analysed by means of a one-way repeated analysis of variance (ANOVA) to determine if differences were significant (p≤0.05). The transport of pure P57 across intestinal tissue was significantly higher in the secretory direction than in the absorptive direction indicating efflux by membrane transporters. Much higher intestinal transport was obtained for P57 in both directions when applied in the form of a crude extract, possibly due to inhibition of efflux as indicated by lower secretory transport compared to absorptive transport. For the buccal tissue, no transport was obtained for the pure P57, while relatively high transport was obtained when applied in the form of a crude extract. Furthermore, the intestinal transport of P57 was significantly decreased when the crude extract was prepared in simulated intestinal fluid compared to when it was prepared in buffer. On the other hand, buccal transport was higher in artificial saliva than in buffer. It is therefore evident that the transport of P57 across mucosal tissues is significantly affected on exposure to conditions simulating the in vivo situation.

Impact of traditional medicinal plant extracts on antiretroviral drug absorption.

ETHNOPHARMACOLOGICAL RELEVANCE: [corrected] Traditional herbal medicines are often used for the treatment of different diseases in developing countries, especially in the rural areas where a lack of an efficient primary health care system is usually experienced. Many patients infected with the human immunodeficiency virus are taking traditional herbal medicines in conjunction with their modern antiretroviral medication and drug-herb interactions can occur in these cases. AIM OF THE STUDY: To investigate the effect of water extracts of two traditional medicinal plants, Hypoxis hemerocallidea and Sutherlandia frutescens as well as l-canavanine (a constituent of Sutherlandia frutescens) on the transport of nevirapine across human intestinal epithelial cells. MATERIALS AND METHODS: Nevirapine transport in the apical to basolateral and basolateral to apical directions across Caco-2 cell monolayers was determined alone (normal control) and in the presence of verapamil (positive control), water extracts of Hypoxis hemerocallidea and Sutherlandia frutescens and an aqueous solution of l-canavanine. The cumulative transport and apparent permeability coefficient (P(app)) values were calculated and compared. RESULTS: Nevirapine alone was substantially effluxed in the basolateral to apical direction across the intestinal epithelial cell monolayers, which was statistically significantly (p < or = 0.05) decreased by addition of verapamil, Hypoxis hemerocallidea extract and the l-canavinine solution. The effect of Sutherlandia frutescens on nevirapine transport was not statistically significantly different from the control. CONCLUSIONS: Hypoxis hemerocallidea and l-canavanine interact with the efflux of nevirapine across intestinal epithelial cells and therefore can potentially increase the bioavailability of this antiretroviral drug when taken concomitantly.

Chitosan-polycarbophil complexes in swellable matrix systems for controlled drug release.

A prerequisite for progress in the design of novel drug delivery systems is the development of excipients that are capable of fulfilling multifunctional roles such as controlling the release of the drug according to the therapeutic needs. Although several polymers have been utilised in the development of specialised drug delivery systems, their scope in dosage form design can be enlarged through combining different polymers. When a polymer is cross-linked or complexed with an oppositely charged polyelectrolyte, a three-dimensional network is formed in which the drug can be incorporated to control its release. The swelling properties and release kinetics of two model drugs with different water solubilities (i.e. diltiazem and ibuprofen) from monolithic matrix tablets consisting of an interpolyelectrolyte complex between chitosan and polycarbophil are reported. Matrix tablets consisting of this polymeric complex without drug or excipients exhibited extremely high swelling properties that are completely reversible upon drying. The drug release from matrix systems with different formulations depended on the concentration of the chitosan-polycarbophil interpolyelectrolyte complex and approached zero order release kinetics for both model drugs. The chitosan-polycarbophil interpolyelectrolyte complex has demonstrated a high potential as an excipient for the production of swellable matrix systems with controlled drug release properties.

Development of an analytical method for the evaluation of N,N-dimethylformamide in dosage form design.

N,N-Dimethylformamide (DMF) is a well-known chemical entity that is extensively used for pharmaceutical, biomedical and chemical applications. Previous research identified the need for the development of an effective dosage form for the systemic delivery of DMF due to its unique antiviral properties. For purposes of quality control and evaluation during pharmaceutical product development, development of an analytical method was required. A gas chromatographic (GC) method was developed with a flame-ionization detector (FID) on a carbowax packed glass column. 2-Methoxyethanol was used as internal standard. The analytical method proved to be capable of separating DMF and 2-methoxyethanol adequately within a relatively short runtime of 2.5 min. The analytical method described was primarily developed for use in dissolution studies of DMF containing delivery systems. Various physicochemical properties of candidate internal standard materials were correlated with the observed retention times of these compounds. The best correlation (r2 = 0.8077) was obtained between the boiling point and the retention time of the compounds for the current application. The boiling point of an internal standard candidate material may thereforebe useful in predicting the retention time of that compound under similar conditions.

Targeting receptors, transporters and site of absorption to improve oral drug delivery.

Although the oral route of drug administration is the most acceptable way of self-medication with a high degree of patient compliance, the intestinal absorption of many drugs is severely hampered by different biological barriers. These barriers comprise of biochemical and physical components. The biochemical barrier includes enzymatic degradation in the gastrointestinal lumen, brush border and in the cytoplasm of the epithelial cells as well as efflux transporters that pump drug molecules from inside the epithelial cell back to the gastrointestinal lumen. The physical barrier consists of the epithelial cell membranes, tight junctions and mucus layer. Different strategies have been applied to improve the absorption of drugs after oral administration, which range from chemical modification of drug molecules and formulation technologies to the targeting of receptors, transporters and specialized cells such as the gut-associated lymphoid tissues. This review focuses specifically on the targeting of receptor-mediated endocytosis, transporters and the absorption-site as methods of optimizing intestinal drug absorption. Intestinal epithelial cells express several nutrient transporters that can be targeted by modifying the drug molecule in such a way that it is recognized as a substrate. Receptor-mediated endocytosis is a transport mechanism that can be targeted for instance by linking a receptor substrate to the drug molecule of interest. Many formulation strategies exist for enhancing drug absorption of which one is to deliver drugs at a specific site in the gastrointestinal tract where optimum drug absorption takes place.

Low molecular weight quaternised chitosan (11): in vitro assessment of absorption enhancing properties.

N-Trimethyl chitosan chloride (TMC; high molecular weight) and N-trimethyl chitosan oligosaccharide (TMO; low molecular weight) with different degrees of quaternisation were synthesised and evaluated for their absorption enhancing properties across mucosal epithelia. These quaternised chitosan derivatives (0.0625% w/v-0.5% w/v) showed a significant decrease in the transepithelial electrical resistance (TEER) of cultured rabbit tracheal epithelial cell monolayers as compared to the control. The degree of quaternisation and concentration of the compounds influenced the extent of the reduction in TEER. Higher degrees of quaternisation and an increase in the concentration of the compound were associated with a more pronounced reduction in the TEER. The TMO derivatives seemed to be more effective in lowering the TEER of tracheal cell monolayers as compared to the TMC polymers. Ciliary beat frequency (CBF) is the main defence mechanism of the respiratory tract and is therefore a useful parameter in evaluating the toxicity of nasally administered drugs and additives. The effect of the synthesised chitosan derivatives on the CBF of human nasal epithelial cells at pH 7.4 was determined by a method based on an analogue contrast enhancement technique. The TMO oligomers exhibited lower inhibition of the CBF of human nasal epithelial cells compared to that of the TMC polymers. It was proposed that this reduced effect on the CBF is due to the lower viscosity and molecular weight of TMO. However, no acute toxicity was found with any of the synthesised chitosan derivatives by means of the CBF tests conducted in this study.

N-trimethyl chitosan chloride: optimum degree of quaternization for drug absorption enhancement across epithelial cells.

N-trimethyl chitosan chloride (TMC) is a polycation that enhances drug transport across epithelia by opening tight junctions. The degree of quaternization of TMC determines the number of positive charges available on the molecule for interactions with the negatively charged sites on the epithelial membrane and thereby influences its drug absorption-enhancing properties. The effects of six different TMC polymers (degree of quarternization between 12% and 59%) on the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers and on the transport of hydrophilic and macromolecular model compounds across Caco-2 cells were determined. All the TMC polymers were able to decrease the TEER markedly in a slightly acidic environment (pH 6.2). However, only TMC polymers with higher degrees of quaternization (> 22%) were able to reduce the TEER in a neutral environment (pH 7.4). The maximum reduction in TEER (47.34 +/- 6.0% at a concentration of 0.5% w/v and pH 7.4) was reached with TMC with a degree of quaternization of 48%, and this effect did not increase further with higher degrees of quaternization of TMC. In agreement with the TEER results, the transport of model compounds across Caco-2 cell monolayers increased with an increase in the degree of quaternization of TMC. However, the transport reached a maximum for TMC with a degree of quaternization of 48% (25.3% of the initial dose for [14C]mannitol and 15.2% of the initial dose for [14C]PEG 4000), and this effect did not increase further with higher degrees of quaternization of TMC. Therefore, the increase in the effects of TMC on intestinal epithelia did not directly correlate up to the maximum quaternization degree of this polymer, but reached an optimum value already at an intermediate degree of quaternization (ca. 48%).

Intestinal paracellular permeation enhancement with quaternised chitosan: in situ and in vitro evaluation.

Previous studies have shown that N-trimethyl chitosan chloride (TMC) is a potent absorption enhancer for hydrophilic and macromolecular compounds across mucosal surfaces. TMC proved to be effective in neutral and basic pH environments where the absorption enhancing ability of chitosan is severely hampered by its insolubility in these environments. The absorption enhancing characteristics of TMC polymers with different degrees of quaternisation were investigated in vitro and in situ to identify the most effective polymer in a neutral pH environment. Different degrees of quaternisation were obtained by varying the number and duration of the reaction steps in the synthesis process of TMC. The TMC polymers were characterised with 1H-NMR spectroscopy and the degrees of quaternisation were between 22.1 and 48.8%. Everted intestinal sacs (rats) were used to determine the effect of the polymers (0.0625-0.5% w/v) on the permeation of the hydrophilic model compound, [14C]mannitol, at a pH value of 7.4. A single pass intestinal perfusion method was also used to evaluate the permeation enhancing properties of the TMC polymers under the same conditions. The results obtained from both methods clearly showed a pronounced enhancement of [14C]mannitol permeation when administered with the different TMC polymers. It was shown that the permeation enhancing effects depend on the degree of quaternisation of TMC. In both models the best permeation enhancing results were obtained with the highest degree of quaternisation of TMC (48.8%) at a concentration of 0.5% w/v.

Effect of the degree of quaternisation of N-trimethyl chitosan chloride on absorption enhancement: in vivo evaluation in rat nasal epithelia.

Five TMC polymers with different degrees of quaternisation (12-59%) were synthesised and administered together with [14C]-mannitol in the nasal route of rats at a pH of 6.20 and 7.40, respectively. All the TMC polymers increased the nasal absorption of [14C]-mannitol significantly at pH 6.20, but only TMC polymers with higher degrees of quaternisation (>36%) were able to increase the absorption of this hydrophilic model compound at pH 7.40. The absorption of [14C]-mannitol at pH 7.40 increased with an increase in the degree of quaternisation of TMC until a maximum absorption value was reached with TMC with a degree of quaternisation of 48%. The absorption of [14C]-mannitol did not increase further, even when TMC with a higher degree of quaternisation (59%) was used. This can probably be explained by steric effects caused by the attached methyl groups and changes in the flexibility of the TMC molecules with an increase in the degree of quaternisation above an optimum value for absorption enhancement in a neutral environment. It was concluded that the degree of quaternisation of TMC plays an important role in the absorption enhancement properties of this polymer across nasal epithelia in a neutral environment.

Effect of the type of base and number of reaction steps on the degree of quaternization and molecular weight of N-trimethyl chitosan chloride.

N-Trimethyl chitosan chloride (TMC), a chemically modified derivative of chitosan, is the first chitosan derivative shown to be an effective absorption enhancer for peptide and protein drugs across mucosal epithelia. TMC is synthesized by reductive methylation with methyl iodide in the presence of a strong base such as sodium hydroxide. In this reaction, the primary amino group on the C-2 position of chitosan is changed to a quaternary amino group. The charge density, as determined by the degree of quaternization, and probably also the molecular weight of TMC are important factors that influence the absorption enhancement effect and toxicity of this polymer. The molecular weight of the starting polymer decreases during the synthesis procedure due to factors such as the strong alkaline environment and elevated experimental temperatures. This study investigated the effects of two different bases, sodium hydroxide and dimethyl amino pyridine, together with a varying number and duration of reaction steps, on the degradation and the degree of quaternization of TMC polymers. 1H-NMR (nuclear magnetic resonance) spectra showed a major increase in the degree of quaternization (21%-59%) of TMC with an increase in the number of reaction steps when sodium hydroxide was used as the base. Intrinsic viscosity values indicated that the use of dimethyl amino pyridine did not cause polymer degradation to the same extent as sodium hydroxide, but that the degree of quaternization of TMC stayed low (7.3%-9.6%) even when the number of reaction steps was increased. A combination of the two bases did not reduce polymer degradation, while the degree of quaternization was limited to relatively low values (12.5%-34.4%).