Formulation of Medicated Chewing Gum Containing Sceletium tortuosum and Process Optimization Utilizing the SeDeM Diagram Expert System.

Sceletium tortuosum is one of the most promising medicinal plant species for treating anxiety and depression. Traditionally, aerial parts are chewed (masticatory herbal medicine) providing fast relief and rendering the masticatory route for delivery, ideal. This study intended formulating novel medicated chewing gum containing S. tortuosum to alleviate depression and anxiety. S. tortuosum extract was formulated into directly compressed medicated chewing gum (MCG) containing different Health-in-Gum® (HIG) bases through process optimization with the SeDeM Diagram Expert System. Physical properties of MCGs were characterized, and specialized drug release studies performed. According to the manufacturer, only HIG-03 was specifically developed for direct compression; however, the SeDeM System was successfully applied to all HIG-bases investigated. HIG-01 and HIG-04 are also considered useful in direct compression as no considerable differences in these MCG formulations' physical properties were recognized. Inclusion of a lubricant, however, is deemed essential, and MCG comprising HIG-01, most suited for direct compression. Dissolution experiments found only two alkaloids used as markers, mesembrine and mesembrenone, were released in quantifiable concentrations regardless formulation constituents. Novel directly compressed MCG-containing S. tortuosum extract was successfully formulated by which the biologically active phytochemicals of S. tortuosum can be scientifically delivered through the traditionally applied mastication method.

Characterization of solid lipid dispersions prepared by hot fusion containing a double-fixed dose combination of artemether and lumefantrine.

OBJECTIVE: The World Health Organization has called for the development of novel drug delivery systems to combat malaria - the fourth most prevalent cause of death globally. The plausibility of utilizing hot fusion to prepare solid lipid dispersions containing the prescribed first-line, double-fixed dose combination (artemether and lumefantrine), proposed for inclusion in directly compressed lipid matrix tablets, was investigated. Significance: Currently, no anti-malarial product is commercially available that employs lipid technology in a solid oral dosage form that contains this double-fixed dose combination. Through developing lipid matrix tablets, the stability, solubility and subsequent bioavailability of these drugs could be significantly enhanced in the presence of lipids or oils. METHODS: Hot fusion encompasses encompassed melt mixing of a selected lipid base and the dispersion of the active ingredient(s) therein below their glass transition temperatures. Solid-state characterization, particle size analysis and pharmacotechnical properties were evaluated, with particular focus given to powder flowability. RESULTS: Stearic acid in a 0.5:1 lipid:drug ratio demonstrated the best powder flow properties of the investigated solid lipid dispersion for inclusion into prospective lipid-matrix tablets duly based on an increase in overall particle size, a more spherical particle shape and improved powder flow properties compared to the individual active ingredients. CONCLUSION: Good powder flow is critical for powders destined for inclusion into tablets - especially when employing direct compression as method of manufacture - in this case, lipid matrix tablets, which have demonstrated huge promise as a prospective dosage form for future use in malarial treatment.

Topical Delivery of Artemisone, Clofazimine and Decoquinate Encapsulated in Vesicles and Their In vitro Efficacy Against Mycobacterium tuberculosis.

Vesicles are widely investigated as carrier systems for active pharmaceutical ingredients (APIs). For topical delivery, they are especially effective since they create a "depot-effect" thereby concentrating the APIs in the skin. Artemisone, clofazimine and decoquinate were selected as a combination therapy for the topical treatment of cutaneous tuberculosis. Delivering APIs into the skin presents various challenges. However, utilising niosomes, liposomes and transferosomes as carrier systems may circumvent these challenges. Vesicles containing 1% of each of the three selected APIs were prepared using the thin-film hydration method. Isothermal calorimetry, differential scanning calorimetry and hot-stage microscopy indicated no to minimal incompatibility between the APIs and the vesicle components. Encapsulation efficiency was higher than 85% for all vesicle dispersions. Vesicle stability decreased and size increased with an increase in API concentration; and ultimately, niosomes were found the least stable of the different vesicle types. Skin diffusion studies were subsequently conducted for 12 h on black human female skin utilising vertical Franz diffusion cells. Transferosomes and niosomes delivered the highest average concentrations of clofazimine and decoquinate into the skin, whereas artemisone was not detected and no APIs were present in the receptor phase. Finally, efficacy against tuberculosis was tested against the Mycobacterium tuberculosis H37Rv laboratory strain. All the dispersions depicted some activity, surprisingly even the blank vesicles portrayed activity. However, the highest percentage inhibition (52%) against TB was obtained with niosomes containing 1% clofazimine.

Penetration enhancing effects of selected natural oils utilized in topical dosage forms.

CONTEXT: Various natural products, including oils, have been utilized as penetration enhancers due to their "safety profiles". These oils contain fatty acids promoting skin permeability through lipid fluidization within the stratum corneum; and might therefore be able to effectively enhance transdermal drug delivery. OBJECTIVE: We investigated possible penetration enhancing properties of selected oils, utilizing flurbiprofen as marker compound in emulgel formulations. The formulations were compared to a liquid paraffin emulgel and a hydrogel to establish any significant penetration enhancing effects. METHODS: Gas chromatographic analysis of the natural oils was performed at ambient temperature to determine the fatty acid composition in each selected natural oils. Franz cell diffusion studies and tape stripping methods were employed to study delivery of the marker into, and through the skin. RESULTS: The following rank order for the emulgel flux-values was obtained: Hydrogel >>>> olive oil >> liquid paraffin >> coconut oil > grape seed oil >> Avocado oil ≥ Crocodile oil >> Emu oil. DISCUSSION: Results suggested that oils containing predominantly mono-unsaturated oleic acid, on average increased the flux of the marker to a larger extent than oils containing an almost even mixture of both mono- and poly-unsaturated fatty acids. Oils comprising saturated fatty acids (SFAs) with alkyl chains between C12 and C14, increased the marker flux to a higher extent than oils containing C16-C18 SFAs. Effects observed for branched fatty acids, however, did not vary significantly from effects for unbranched fatty acids with the same carbon chain length. CONCLUSION: Natural oils possess penetration enhancing effects.

Effect of moisture content, temperature and exposure time on the physical stability of chitosan powder and tablets.

CONTEXT: Chitosan does not rank highly regarding its employment as tablet filler due to certain limitations. Undesirable properties that limit its utilization as excipient in solid dosage forms include its hydration propensity that negatively affects tablet stability, strength and disintegration. OBJECTIVE: The objective of this study was to investigate the physical stability of chitosan powder, mixtures, granules and tablets under accelerated conditions such as elevated temperatures and humidity over different periods of time. METHODS: Selected physico-chemical properties of pure chitosan powder, physical mixtures of chitosan with Kollidon® VA64 (BASF, Ludwigshafen, Germany), chitosan granules, as well as tablets were evaluated under conditions of elevated humidity and temperature. RESULTS AND DISCUSSION: The physical stability of chitosan tablets exhibited sensitivity towards varying exposure conditions. It was furthermore evident that the presence of moisture (sorbed water) had a marked influence on the physical stability of chitosan powder and tablets. It was evident that the presence of Kollidon® VA64 as well as the method of inclusion of this binder influenced the properties of chitosan tablets. The physical stability of chitosan powder deteriorated to a greater extent compared to that of the chitosan tablets, which were subjected to the same conditions. CONCLUSION: It is recommended that tablets containing chitosan should be stored at a temperature not exceeding 25 °C as well as at a relatively low humidity (<60%) to prevent deterioration of physical properties. Direct compression of chitosan granules which contained 5%w/w Kollidon® VA64 produced the best formulation in terms of physical stability at the different conditions.

The Science of Selecting Excipients for Dermal Self-Emulsifying Drug Delivery Systems.

Self-emulsification is considered a formulation technique that has proven capacity to improve oral drug delivery of poorly soluble drugs by advancing both solubility and bioavailability. The capacity of these formulations to produce emulsions after moderate agitation and dilution by means of water phase addition provides a simplified method to improve delivery of lipophilic drugs, where prolonged drug dissolution in the aqueous environment of the gastro-intestinal (GI) tract is known as the rate-limiting step rendering decreased drug absorption. Additionally, spontaneous emulsification has been reported as an innovative topical drug delivery system that enables successful crossing of mucus membranes as well as skin. The ease of formulation generated by the spontaneous emulsification technique itself is intriguing due to the simplified production procedure and unlimited upscaling possibilities. However, spontaneous emulsification depends solely on selecting excipients that complement each other in order to create a vehicle aimed at optimizing drug delivery. If excipients are not compatible or unable to spontaneously transpire into emulsions once exposed to mild agitation, no self-emulsification will be achieved. Therefore, the generalized view of excipients as inert bystanders facilitating delivery of an active compound cannot be accepted when selecting excipients needed to produce self-emulsifying drug delivery systems (SEDDSs). Hence, this review describes the excipients needed to generate dermal SEDDSs as well as self-double-emulsifying drug delivery systems (SDEDDSs); how to consider combinations that complement the incorporated drug(s); and an overview of using natural excipients as thickening agents and skin penetration enhancers.

The Development of Dermal Self-Double-Emulsifying Drug Delivery Systems: Preformulation Studies as the Keys to Success.

Self-emulsifying drug delivery systems (SEDDSs) are lipid-based systems that are superior to other lipid-based oral drug delivery systems in terms of providing drug protection against the gastrointestinal (GI) environment, inhibition of drug efflux as mediated by P-glycoprotein, enhanced lymphatic drug uptake, improved control over plasma concentration profiles of drugs, enhanced stability, and drug loading efficiency. Interest in dermal spontaneous emulsions has increased, given that systems have been reported to deliver drugs across mucus membranes, as well as the outermost layer of the skin into the underlying layers. The background and development of a double spontaneous emulsion incorporating four anti-tubercular drugs, clofazimine (CFZ), isoniazid (INH), pyrazinamide (PZY), and rifampicin (RIF), are described here. Our methods involved examination of oil miscibility, the construction of pseudoternary phase diagrams, the determination of self-emulsification performance and the emulsion stability index of primary emulsions (PEs), solubility, and isothermal micro calorimetry compatibility and examination of emulsions via microscopy. Overall, the potential of self-double-emulsifying drug delivery systems (SDEDDSs) as a dermal drug delivery vehicle is now demonstrated. The key to success here is the conduct of preformulation studies to enable the development of dermal SDEDDSs. To our knowledge, this work represents the first successful example of the production of SDEDDSs capable of incorporating four individual drugs.

Development of a HPLC Method for Analysis of a Combination of Clofazimine, Isoniazid, Pyrazinamide, and Rifampicin Incorporated into a Dermal Self-Double-Emulsifying Drug Delivery System.

We describe the development and validation of a new high performance liquid chromatography (HPLC) method for analysis of a combination of the first-line anti-tubercular drugs isoniazid, pyrazinamide, and rifampicin together with clofazimine. This is a unique challenge since clofazimine and rifampicin are relatively highly lipophilic drugs, whereas isoniazid and pyrazinamide are considerably more hydrophilic. Thus, clear separation of peaks and quantification of four individual drugs can present difficulties during the development of an analytical method. Detection was established at two wavelengths-254 nm for isoniazid and pyrazinamide and 320 nm for clofazimine and rifampicin. Gradient elution was employed using 0.1% aqueous formic acid (A) and acetonitrile (B); clear separation of the four drugs was achieved within 10 min. A linear relationship was indicated by a correlation coefficient (r2) of 0.9999 for each anti-tubercular drug, respectively. The limit of detection (LOD) for the individual drugs was 0.70 µg/mL (isoniazid), 0.30 µg/mL (pyrazinamide), 0.20 µg/mL (rifampicin) and 0.20 µg/mL (clofazimine). Precision experiments rendered a mean recovery percentage of 101.25% (isoniazid), 98.70% (pyrazinamide), 99.68% (rifampicin) and 97.14% (clofazimine). This HPLC method was validated and is reliable, repeatable, and accurate for the purpose of conducting simultaneous HPLC analyses of the four anti-tubercular drugs.

Adapting Clofazimine for Treatment of Cutaneous Tuberculosis by Using Self-Double-Emulsifying Drug Delivery Systems.

Although chemotherapeutic treatment regimens are currently available, and considerable effort has been lavished on the development of new drugs for the treatment of tuberculosis (TB), the disease remains deeply intractable and widespread. This is due not only to the nature of the life cycle and extraordinarily disseminated habitat of the causative pathogen, principally Mycobacterium tuberculosis (Mtb), in humans and the multi-drug resistance of Mtb to current drugs, but especially also to the difficulty of enabling universal treatment of individuals, immunocompromised or otherwise, in widely differing socio-economic environments. For the purpose of globally eliminating TB by 2035, the World Health Organization (WHO) introduced the "End-TB" initiative by employing interventions focusing on high impact, integrated and patient-centered approaches, such as individualized therapy. However, the extraordinary shortfall in stipulated aims, for example in actual treatment and in TB preventative treatments during the period 2018-2022, latterly and greatly exacerbated by the COVID-19 pandemic, means that even greater pressure is now placed on enhancing our scientific understanding of the disease, repurposing or repositioning old drugs and developing new drugs as well as evolving innovative treatment methods. In the specific context of multidrug resistant Mtb, it is furthermore noted that the incidence of extra-pulmonary TB (EPTB) has significantly increased. This review focusses on the potential of utilizing self-double-emulsifying drug delivery systems (SDEDDSs) as topical drug delivery systems for the dermal route of administration to aid in treatment of cutaneous TB (CTB) and other mycobacterial infections as a prelude to evaluating related systems for more effective treatment of CTB and other mycobacterial infections at large. As a starting point, we consider here the possibility of adapting the highly lipophilic riminophenazine clofazimine, with its potential for treatment of multi-drug resistant TB, for this purpose. Additionally, recently reported synergism achieved by adding clofazimine to first-line TB regimens signifies the need to consider clofazimine. Thus, the biological effects and pharmacology of clofazimine are reviewed. The potential of plant-based oils acting as emulsifiers, skin penetration enhancers as well as these materials behaving as anti-microbial components for transporting the incorporated drug are also discussed.

Solidification of Self-Emulsifying Drug Delivery Systems as a Novel Approach to the Management of Uncomplicated Malaria.

Malaria affects millions of people annually, especially in third-world countries. The mainstay of treatment is oral anti-malarial drugs and vaccination. An increase in resistant strains of malaria parasites to most of the current anti-malarial drugs adds to the global burden. Moreover, existing and new anti-malarial drugs are hampered by significantly poor aqueous solubility and low permeability, resulting in low oral bioavailability and patient noncompliance. Lipid formulations are commonly used to increase solubility and efficacy and decrease toxicity. The present review discusses the findings from studies focusing on specialised oral lipophilic drug delivery systems, including self-emulsifying drug delivery systems (SEDDSs). SEDDSs facilitate the spontaneous formation of liquid emulsions that effectively solubilise the incorporated drugs into the gastrointestinal tract and thereby improve the absorption of poorly-soluble anti-malaria drugs. However, traditional SEDDSs are normally in liquid dosage forms, which are delivered orally to the site of absorption, and are hampered by poor stability. This paper discusses novel solidification techniques that can easily and economically be up-scaled due to already existing industrial equipment that could be utilised. This method could, furthermore, improve product stability and patient compliance. The possible impact that solid oral SEDDSs can play in the fight against malaria is highlighted.

Investigating In Vitro and Ex Vivo Properties of Artemether/Lumefantrine Double-Fixed Dose Combination Lipid Matrix Tablets Prepared by Hot Fusion.

Highly lipophilic antimalarial drugs, artemether and lumefantrine, whilst an effective fixed-dose combination treatment to lower the malarial disease burden, are therapeutically hindered by low aqueous solubility and varied bioavailability. This work investigates the plausibility of directly compressed lipid matrix tablets, their role as lipid-based formulations and their future standing as drug delivery systems. Lipid matrix tablets were manufactured from solid lipid dispersions in various lipid:drug ratios employing hot fusion-the melt mixing of highly lipophilic drugs with polymer(s). Sequential biorelevant dissolution media, multiple mathematical models and ex vivo analysis utilizing porcine tissue samples were employed to assess drug release kinetics and more accurately predict in vitro performance. Directly compressed stearic acid tablets in a 0.5:1 lipid:drug ratio were deemed optimal within investigated parameters. Biorelevant media was of immense value for artemether release analysis, with formulation SA0.5C1 (Stearic Acid:double fixed dose in a 0.5:1 ratio (i.e., Stearic acid 70 mg + Lumefantrine 120 mg + Artemether 20 mg); CombiLac® as filler (q.s.); and 1% w/w magnesium stearate) yielding a higher percentage of artemether release (97.21%) than the commercially available product, Coartem® (86.12%). However, dissolution media lacked the specificity to detect lumefantrine. Nonetheless, stearic acid lipid:drug ratios governed drug release mechanisms. This work demonstrates the successful utilization of lipids as pharmaceutical excipients, particularly in the formulation of lipid matrix tablets to augment the dissolution of highly lipophilic drugs, and could thus potentially improve current malarial treatment regimens.

Anti-Melanoma Activities of Artemisone and Prenylated Amino-Artemisinins in Combination With Known Anticancer Drugs.

The most frequently occurring cancers are those of the skin, with melanoma being the leading cause of death due to skin cancer. Breakthroughs in chemotherapy have been achieved in certain cases, though only marginal advances have been made in treatment of metastatic melanoma. Strategies aimed at inducing redox dysregulation by use of reactive oxygen species (ROS) inducers present a promising approach to cancer chemotherapy. Here we use a rational combination of an oxidant drug combined with a redox or pro-oxidant drug to optimize the cytotoxic effect. Thus we demonstrate for the first time enhanced activity of the amino-artemisinin artemisone and novel prenylated piperazine derivatives derived from dihydroartemisinin as the oxidant component, and elesclomol-Cu(II) as the redox component, against human malignant melanoma cells A375 in vitro. The combinations caused a dose dependent decrease in cell numbers and increase in apoptosis. The results indicate that oxidant-redox drug combinations have considerable potential and warrant further investigation.

In-vitro cytotoxicity of various Siphonochilus aethiopicus (Schweinf.) B.L. Burtt extracts in combination with selected tableting excipients.

OBJECTIVES: To investigate the cytotoxic potential of S. aethiopicus extracts in combination with chitosan and Pharmacel® 101, on two cell lines. METHODS: Extracts were chemically characterised utilising UPLC-Q-TOF/MS, followed by determination of cell viability and membrane integrity. KEY FINDINGS: Ethanol (EtOH) and diethyl ether (DiEt) extracts contained significant quantities of all chosen biomarker molecules; however, only two were scarcely quantifiable in aqueous extracts. Aqueous extracts did not induce any cytotoxic effects, whereas EtOH and DiEt extracts caused concentration-dependent decreases in cell viability and membrane integrity loss in both cell lines. Ensuing exposure to EtOH extracts at 50, 100 and 150 µg/ml, HepG2 cells were considered 15.5%, 12.5% and 32.8% apoptotic, whereas DiEt extracts caused 4.5%, 13.5% and 33.9% apoptotic cells. Exposure to EtOH and DiEt extracts at 50 µg/ml ensued in 20.2% and 21.3% apoptosis in Caco-2 cells; 100 µg/ml induced apoptosis in 19.9% and 10.3% of Caco-2 cells; whereas exposure to 150 µg/ml EtOH extracts caused 12.6% apoptosis compared to 11.7% induced by the DiEt extract. CONCLUSIONS: None of the excipients caused any significantly altered cellular effects, indicating little chance for physicochemical interactions. Aqueous extracts did not possess any cytotoxic properties. However, it is clear that organic extracts caused apoptotic and necrotic cell death.

Formulation and evaluation of selected transmucosal dosage forms containing a double fixed-dose of acyclovir and ketoconazole.

Viral and fungal dermatological manifestations are often the first and only sign of HIV/AIDS. They are cosmetically disfiguring and threaten the quality of life, but can be treated by acyclovir and ketoconazole, correspondingly. This study attempted the formulation of stable, double fixed-dose acyclovir and ketoconazole novel transmucosal dosage forms, which are able to provide an efficient flux for both compounds. A cream, gel and lip balm formulation containing both drugs were formulated that can be applied to mucosal tissue. Compatibility experiments between acyclovir and ketoconazole were conducted. A six month stability study was performed on the formulations which included visual appearance; mass variation; assay of the drugs; pH; viscosity; zeta potential; and particle size distribution. Flow-through diffusion tests, utilizing vaginal porcine mucosal specimens, were conducted to determine in vitro permeation. No physicochemical interactions exist between the actives. Stability testing revealed that the formulations could be considered stable and may easily be stored at 25°C/60% RH. The following rank order could be established for the average cumulative acyclovir amount that permeated the mucosa: Acitop®≥gel>cream>lip balm; and for the average cumulative ketoconazole amount: lip balm>>>Ketazol®>gel>cream. Both drugs depicted release rates that obeyed the Higuchi model, affirming release from a matrix system. Stable transmucosal dosage forms containing a double fixed-dose of acyclovir and ketoconazole; and targeting mucosal tissue could thus be prepared. These formulations were able to provide an efficient flux for both compounds.

Impact of traditional African medicine on drug metabolism and transport.

INTRODUCTION: Africa is a continent of rich plant biodiversity with many indigenous plants having a long history of being used for medicinal purposes. A considerable number of patients consult traditional healers in African countries for their primary health-care needs. As Western medicines become more available through governmental programmes to treat diseases such as infections with HIV/AIDS, patients are faced with an increased potential of herb-drug interactions. AREAS COVERED: Several medicinal herbs indigenous to Africa are discussed in terms of their effects on pharmacokinetics of allopathic drugs through modulation of enzymes and active transporters. Clinically relevant herb-drug interactions obtained from in vivo studies are discussed, with data from in vitro studies also included to ensure a complete review. EXPERT OPINION: Traditional herbal medicines are often used under a false sense of security because of the perception that it is safe due to its natural origin. The potential for interactions between herbal and allopathic drugs is often neglected. Data on clinically relevant herb-drug interactions from clinical trials can be used to educate health-care workers and patients, contributing to improved therapeutic outcomes.