Formulation design and characterization of a non-ionic surfactant based vesicular system for the sustained delivery of a new chondroprotective agent

A diacereína é usada para o alívio sintomático e para a regeneração da cartilagem na osteoartrite. Devido aos efeitos adversos gastrointestinais, baixa solubilidade aquosa e biodisponibilidade, o seu uso clínico tem sido restrito. O objetivo do presente estudo foi melhorar o perfil de dissolução deste fármaco e obter liberação prolongada através do planejamento de um novo sistema de liberação designado de niossoma. Cinco formulações distintas de niossomas (F1 a F5) contendo tensoativos não iônicos (monoestearato de sorbitano) e colesterol, em diferentes proporções, de 5:5, 6:4, 7:3, 8:2 e 9:1, foram desenvolvidas através da técnica de evaporacão de fase reversa. Os tamanhos e índices de polidispersibilidade (PDI) obtidos variam entre 0,608 e 1,01 µm e entre 0,409 e 0,7781, respectivamente. Imagens de microscopia electrônica de varrimento (SEM) da formulação selecionada (F3) revelaram vesículas esféricas. Obteve-se encapsulação de 79,8% com a formulação F3 (7:3). Estudos de dissolução usando o método de diálise demonstraram padrão de liberacão prolongada para todas as formulações. A proporção de tensoativo e colesterol (7:3) na formulacão F3 prolongou o tempo de liberação do fármaco (T50%) até 10 horas. Estudos de modelação cinética demonstraram ordem de liberacão zero (R2=0,9834) e o expoente de liberação "n" do modelo de Korsmayer-Peppas (n=0.90) confirmou a liberação não-fickiana e anômala. Os resultados deste estudo sugerem que a diacereína pode ser encapsulada com sucesso no interior de niossomas, utilizando monostearato de sorbitano, o qual tem potencial para liberar, eficientemente, a diacereína no local de absorção.Diacerein is used for symptomatic relief and cartilage regeneration in osteoarthritis. Due to gastrointestinal side effects, poor aqueous solubility and low bioavailability, its clinical usage has been restricted. The objective of the present study was to enhance its dissolution profile and to attain sustained release by designing a novel delivery system based on niosomes. Five niosomal formulations (F1-F5) with non-ionic surfactant (sorbitan monostearate) and cholesterol in varying ratios of 5:5, 6:4, 7:3, 8:2 and 9:1 were developed by the reverse-phase evaporation technique. The size and polydispersivity index (PDI) were found in the range of 0.608 µm to 1.010 µm and 0.409 to 0.781, respectively. Scanning electron microscopy (SEM) of the selected formulation (F3) revealed spherical vesicles, and 79.8% entrapment was achieved with F3 (7:3). Dissolution studies using the dialysis method showed sustained release behaviour for all formulations. The optimized surfactant-to-cholesterol concentration (7:3) in formulation F3sustained the drug-release time (T50%) up to 10 hours. Kinetic modelling exhibited a zero-order release (R2=0.9834) and the release exponent 'n' of the Korsmayer-Peppas model (n=0.90) confirmed non-fickian and anomalous release. The results of this study suggest that diacerein can be successfully entrapped into niosomes using sorbitan monostearate and that these niosomes have the potential to deliver diacerein efficiently at the absorption site

Formulation and Evaluation of Levetiracetam Niosomes for Improved Anti-Convulsant Activity.

Niosomes or non-ionic surfactant vesicles are microscopic lamellar structures formed on admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether and cholesterol with subsequent hydration in aqueous media in Niosomes, the vesicles forming amphiphile is a non-ionic surfactant such as span-60 which is usually stabilised by addition of cholesterol and small amount of anionic surfactant such as dicetyl phosphate. Levetiracetam niosomal formulation was prepared by hand shaking method and it was evaluated for its entrapment efficiency, in-vitro drug diffusion profile, sterility tests and stability studies. The optimized formulation F2 and levetiracetam plain were evaluated for it’s anti-convulsant activity using flexion, extension, convulsion, stupor, recovery and death. The effects produced by the formulation (F2) in the mice were comparable with that of the in-vitro drug diffusion profile. Hence, the present study concluded that the anti-convulsant activity of levetiracetam formulation (F2) shows better activity than the levetiracetam plain

An Open Comparative Clinical Evaluation on “Sagana Vatham” (Cervical Spondylosis) with siddha herbal formulation drug “Kurunthotti Kashayam”(Internal), “Azhinjil Thylam”(External) and “Varmam Therapy

The aim of the study is to compare and evaluate the safety and efficacy of Kurunthotti Kashayam (Int) and Azhinjil Thylam (Ext), and Varmam therapy intervention for saganavatham. The study consisted of four parts namely, 1. Analytical testing as per AYUSH protocol. 2. Toxicity studies – Acute and Sub-acute toxicity studies as per OECD guidelines.(423&407). 3. Pharmacological studies- Anti inflammatory and analgesic activity 4. Clinical trial into three groups The analytical testing as per AYUSH protocol for evaluating Kurunthotti Kashayam chooranam was done at Indian Institute of Technology exemplified that the polyherbal formulation Kurunthotti Kashayam has no heavy metals as per ICPOES, and FT-IR analysis for functional group present in the drug. Phytochemical screening revealed the presence of Flavanoids, proteins, amino acids, alkaloids, tannins, hydroquinone derivatives in methanolic and acetone extract. Terpenes were estimated in chloroform extract. The drug namely Kurunthotti Kashayam was prepared and tested for toxicity studies, pharmacological studies at C L Baid Metha College of pharmacy. Acute and repeat dose oral toxicity study of Kurunthotti Kashayam revealed that the drug was safe. Histopathological studies have shown that the drug has no toxic effects in the vital organs. Analgesic activity of Kurunthotti Kashayam in wistar albino rats in acetic acid induced writhing test indicated that kurunthotti kashayam had shown dose dependent activity against standard diclofenac sodium . In vivo anti inflammatory activity of the test drug in wistar albino rats using carageenan induced paw edema method revealed that the drug has anti inflammatory activity with reference drug indomethacin. The study was approved by the Institutional Ethical Committee (IEC). The clinical trial is also registered in Clinical Trial Registry of India (CTRI). The comparative study of Kurunthotti kashayan alone (Group1), Kurunthotti kashayam and azinjil thylam (Group 2) and Kurunthotti kashayam, Azhinjil thailam with Varmam therapy (Group 3) was done in three groups each comprising 20 patients. The inferences were made. All three groups shown statistically significant improvement. Primary outcome was assessed by Visual Analog Scale (Universal Pain Assessment Scale). Secondary outcome i.e reduction in clinical parameters was also assessed. Among the three groups Group 3 shown better improvement than the other two groups. Statistical analysis was performed to assess the significance of the clinical trial

Formulation, Characterization and Evaluation of Ketoconazole Niosomal Gel for the Treatment of Cutaneous Leishmaniasis

NTRODUCTION:Novel drug delivery system aims to provide a therapeutic amount of drug to the appropriate site in the body to accomplish promptly and then maintain the desired drug concentration. The drug delivery system should deliver the drug at a rate controlled by the necessity of the body over a specified term of treatment. The two important aspects of idealized drug delivery are as follows; 1. Spatial drug delivery: Targeting a drug to a particular organ or tissue. 2. Temporal drug delivery: the drug delivery rate to a target tissue is controlled. Novel drug delivery systems are designed to achieve a continuous delivery of drugs AIM OF WORK: The aim of the present study is 1. To formulate Ketoconazole niosomal gel drug delivery system using various non -ionic surfactants and cholesterol to enhance its therapeutic efficacy by controlled release. 2. To provide an efficient dosage form by targeting it to the macrophages for the treatment of Cutaneous Leishmaniasis.PLAN OF WORK:The present work was designed and planned as follows: 1. Drug excipients compatibility studies- FT- IR study 2. Determination of λmax of Ketoconazole in phosphate buffered saline pH 7.4 3. Calibration curve of the drug in phosphate buffered saline pH 7.4 4. Preformulation studies and optimization of process related variables using niosomes prepared in different molar ratios of non- ionic surfactant (Span 40) and constant molar ratio of cholesterol (25 μmol) by thin film hydration technique. Effect of hydration time, Effect of capacity and rotational speed of evaporator flask Effect of Sonication time, Effect of osmotic shock, Formulation of Ketoconazole niosomes using optimized process parameters using various molar ratios of different non- ionic surfactants keeping cholesterol constant at 25 μmol. Evaluation of Ketoconazole niosomes, Drug content, Entrapment efficiency by centrifugation method, In- vitro drug release study of niosomal formulations and Ketoconazole drug solution in phosphate buffered saline pH 7.4 using dialysis membrane, In- vitro release kinetics, Selection of best ratio and preparation of Ketoconazole niosomal gel using various non- ionic surfactants (Span 20, Span 40 and Span 60). Determination of particle size distribution using Malvern zeta analyzer. Morphological studies using Optical microscopy and Scanning electron microscopy(SEM). at predictable and reproducible kinetics over an extended period of time in the circulation. The potential advantages of this concept include minimization of drug related side effects due to controlled therapeutic blood levels instead of oscillating blood levels, improved patient compliance due to reduced frequency of dosing and the reduction of the total dose of drug administered. Hence, the combination of both sustained release and control release properties in a delivery system would further enhance therapeutic efficacy SUMMARY:1.The purpose of this research was to prepare Ketoconazole loaded niosomes for sustained release of drug and incorporate it in to topical gel delivery system to reduce the side effects by site specific targeting.2.Thin film hydration technique was employed to produce niosomes using non ionic surfactants and cholesterol.3.The process related parameters were optimized such as hydration time (60 minutes), sonication time (10minutes), osmotic shock, rotational speed of the evaporator flask (initially 100 rpm, later 150 rpm).4Cholesterol used as a membrane additive, acts as a stabilizer as well as fluidity buffer to improve the stability of the vesicles.5.The formulations were prepared using different non- ionic surfactants by varying the surfactant concentration (Span 20, Span 40 and Span 60) and keeping the cholesterol concentration fixed.6.The formulated niosomes were characterized for entrapment efficiency.CONCLUSION:It is concluded that the thin film hydration technique is a useful method for the successful incorporation of poorly water soluble drug Ketoconazole into niosomes with high entrapment efficiency. The prolonged release of the drug from the niosome suggests that the frequency of administration and adverse effects significantly thereby improving the patient compliance. The administration of drug as gel type formulation enhances its penetration across the stratum corneum and the reduced size and its vesicular structure not only improved its localization in the stratum spinosum in which the infected macrophages reside and also its uptake by the infected macrophages

Formulation and Evaluation of Etoricoxib Niosomal Topical Gel.

The past decade, advanced drug delivery research and development has surged ahead of others in formulation research. The emergence of novel technology and the growing capabilities of proteomics, genomics and combinatorial chemistry have provided scientists with new technologies. The niosomal formulations were successfully prepared by thin film hydration technique using cholesterol and Span20, 40, 60, 80 Tween 60, 80 and Brij-52 as non-ionic surfactant. The presence of cholesterol made the niosomes more stable with high entrapment efficiency and retention properties. The highest entrapment efficiency was observed with span60 and it may be concluded that the entrapment efficiency may be improved using surfactant with decrease HLB value and highest phase transition temperature

Sustainable release of propranolol hydrochloride laden with biconjugated-ufasomes chitosan hydrogel attenuates cisplatin-induced sciatic nerve damage in in vitro/in vivo evaluation

Peripheral nerve injuries significantly impact patients’ quality of life and poor functional recovery. Chitosan–ufasomes (CTS–UFAs) exhibit biomimetic features, making them a viable choice for developing novel transdermal delivery for neural repair. This study aimed to investigate the role of CTS–UFAs loaded with the propranolol HCl (PRO) as a model drug in enhancing sciatica in cisplatin-induced sciatic nerve damage in rats. Hence, PRO–UFAs were primed, embedding either span 20 or 60 together with oleic acid and cholesterol using a thin-film hydration process based on full factorial design (2(4)). The influence of formulation factors on UFAs’ physicochemical characteristics and the optimum formulation selection were investigated using Design-Expert(®) software. Based on the optimal UFA formulation, PRO–CTS–UFAs were constructed and characterized using transmission electron microscopy, stability studies, and ex vivo permeation. In vivo trials on rats with a sciatic nerve injury tested the efficacy of PRO–CTS–UFA and PRO–UFA transdermal hydrogels, PRO solution, compared to normal rats. Additionally, oxidative stress and specific apoptotic biomarkers were assessed, supported by a sciatic nerve histopathological study. PRO–UFAs and PRO–CTS–UFAs disclosed entrapment efficiency of 82.72 ± 2.33% and 85.32 ± 2.65%, a particle size of 317.22 ± 6.43 and 336.12 ± 4.9 nm, ζ potential of −62.06 ± 0.07 and 65.24 ± 0.10 mV, and accumulatively released 70.95 ± 8.14% and 64.03 ± 1.9% PRO within 6 h, respectively. Moreover, PRO–CTS–UFAs significantly restored sciatic nerve structure, inhibited the cisplatin-dependent increase in peripheral myelin 22 gene expression and MDA levels, and further re-established sciatic nerve GSH and CAT content. Furthermore, they elicited MBP re-expression, BCL-2 mild expression, and inhibited TNF-α expression. Briefly, our findings proposed that CTS–UFAs are promising to enhance PRO transdermal delivery to manage sciatic nerve damage

Fabrication and characterization of ciprofloxacin loaded niosomes for transtympanic delivery

Ciprofloxacin (CPH) is a broad-spectrum antibiotic used to treat bone, joint, and skin infections. It is commercially available as an extended-release tablet and as a cream dosage form. CPH is a bactericidal active pharmaceutical ingredient (API) of the fluoroquinolone drug class. It inhibits deoxyribonucleic acid (DNA) replication by inhibiting bacterial DNA topoisomerase and DNA gyrase enzymes. Common adverse effects include nausea, vomiting, unusual fatigue, pale skin, and may increase the risk of tendinitis, which could be a major concern. CPH is, according to the Biopharmaceutics Classification System (BCS), classified as a BCS class IV drug exhibiting low oral bioavailability, low solubility, and intestinal permeability. CPH was chosen as a good candidate for the study because of its stability in solutions, its low molecular weight (331.4 g/mol), and its moderate lipophilicity (log P = 0.28) [16]. The use of conventional ear drops in the ear is effective, avoids hepatic first metabolism and extensive protein binding and may reduce adverse effects as a low dose may be used to achieve a therapeutic effect. However, conventional ear drops and oral antibiotics have a long onset of action and have to be taken/applied in short intervals. For convenience and assurance of a long residence time in the ear, CPH may be delivered by using a niosomal formulation, a liquid at room temperature, to allow administration into the ear without the need to constantly apply the ear drops for long periods of time. A simple, rapid, precise, accurate, reproducible, and specific reversed-phase high-performance liquid chromatography (RP-HPLC) method using ultraviolet (UV) detection for the quantitation of CPH was developed and optimized using a central composite design (CCD). The method was validated using International Conference on Harmonisation (ICH) guidelines and was found to be linear, precise, accurate, and specific for the analysis of CPH. Since the method is specific, it was used to quantify CPH in commercial and experimental formulations and monitor CPH released during in-vitro release testing. The compatibility of CPH and potential excipients was investigated during preformulation studies using Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC) to identify and select suitable excipients for use during formulation development activities. No apparent interactions were evident between CPH, and the excipients tested. The probe sonication method was used to manufacture CPH loaded niosomes using different surfactants/surfactant combinations, and a combination of Tween® 80: sodium lauryl sulfate (SLS) was found to be the best composition in terms of both entrapment efficiency and Zeta potential. The limits for the independent input variables used for the manufacture included amplitude, sonication time, and amount of cholesterol were determined. Design of experiments (DOE) was used to design the study. The input variables investigated included amplitude, amount of cholesterol, and sonication time. The output or responses monitored included Zeta potential, vesicle size, polydispersity index (PDI), and entrapment efficiency. Non-ionic surfactant systems are predominantly stabilized by steric stabilization, and there is only a minor electrostatic element from adsorbed hydroxyl ions. With the inclusion of SLS it is to be expected that Zeta potential will be a contributing factor. DOE using Box-Behnken design (BBD) and response surface methodology (RSM) in addition to Artificial Neural Networks (ANN) were used for the optimization of the formulation. The optimized formulation had a composition of 1 g cholesterol, 1 g of Tween® 80, 1 g of SLS and was prepared at an amplitude of 11.294 % with a sonication time of 3.304 minutes. The formulation exhibited zero-order release kinetics and had an average pH of 7.45. The formulation was stored at 4 ℃ and 25 ℃ and was assessed for vesicle size, entrapment efficiency, Zeta potential, colour, lamellarity, and PDI every 7 days for 4 weeks. The lead formulation stored at 4 ℃ was more stable than the formulation at 25 ℃ in terms of entrapment efficiency, PDI and vesicle size during the 4-week period. CPH loaded niosomes for transtympanic delivery in the treatment of otitis media were developed and optimized. The technology exhibits sustained release of CPH and has the potential for further development and optimization.Thesis (MSc) -- Faculty of Pharmacy, Pharmacy, 202

Delivery of nanocarrier-loaded hydrophobic drugs via the airways

BACKGROUND AND PURPOSE: Systemic delivery of hydrophobic therapeutics represents substantial formulation challenges impeding optimal benefits due to side effects and sub-therapeutic drug levels at the target site consequently leading to progression of multi-drug resistance. This thesis describes three distinct novel nanotechnology-based strategies with desirable aerosolization characteristics for delivery via the airways, aimed at enhancing the therapeutic efficacy of hydrophobic drugs for pulmonary and neurological disorders. METHODS: The first approach involved the development of dry powder microparticles for pulmonary delivery of antifungal amphotericin B nanocomplexes, prepared by co-grinding the drug with ascorbic acid. Nanocomplexes developed were characterized for molecular interactions by FT-IR, size, zeta potential, morphology, in vitro aerodynamic behavior and antifungal activity. The second strategy entailed design of liposomes co-encapsulating rifampicin and ibuprofen using Design of Experiment, targeted to the mannose and/or scavenger receptors on the alveolar macrophages where TB infection resides. Spray dried microparticles were characterized for in vitro aerodynamic behavior and macrophage uptake using the flow cytometer in RAW 264.7 cells. The third approach involved the development of Kolliphor® HS 15 micelles incorporating neuroprotective agents CNB001 or curcumin and Kolliphor® TPGS micelles encapsulating curcumin for the treatment of neurodegeneration and neuroblastoma respectively. Nasal delivery of these micellar systems was intended for brain targeting. Micelles were characterized for size, charge, aerosol droplet size distribution, drug release, morphology and in vitro cellular studies on SH-SY5Y cells. RESULTS: Successful development of nanocarrier-based systems with a high encapsulation efficiency greater than 80% for all the systems was achieved, with particle size desirable for the end-use. Spray dried microparticles of amphotericin B nanocomplexes with L-leucine showed a high fine particle fraction of around 58% signifying likely deposition in the peripheral airways, to the areas of fungal infection. There was no loss of antifungal activity against Candida spp on complexation of amphotericin B. Microparticles of liposomes encapsulating antitubercular drugs showed good aerosolization, and up to 65% fine particle fraction on addition of L-leucine could be achieved. An enhanced in vitro cellular uptake was evident for negative-charged liposomes targeted to the scavenger receptors and the mannosylated liposomes targeted to the mannose receptors on the macrophage cell line RAW 264.7. Finally, Kolliphor® micelles encapsulating CNB001 or curcumin showed desired aerosol droplet size for delivery to the posterior nasal olfactory epithelium with median size of 42.75-54.86 μm when aerosolized by the Nasal™ Mucosal Atomization Device. The formulations intended for neuroprotection showed improved cellular viability, reduction in reactive oxygen species and nuclear morphology in the in vitro Parkinson’s model. CONCLUSION: The nanotechnology-based formulations combined with administration to or through the airways using commercially available delivery devices, represent a highly attractive formulation strategy for delivery of hydrophobic agents to the target site at a therapeutic level to combat issues of multi-drug resistance

Pharmaceutical Particulates and Membranes for Delivery of Drugs and Bioactive Molecules

This book is a collection of papers published in the Special Issue of Pharmaceutics, entitled "Pharmaceutical Particulates and Membranes for Delivery of Drugs and Bioactive Molecules". A drug release profile is a consequential factor for nanoparticle application, directly related to drug stability and therapeutic results, as well as formulation development. Pharmaceutical particulates of different sizes and shapes (e.g., liposomes, oil-in-water emulsions, polymeric nano- and microspheres, metallic nanoparticles (NPs) such as gold, silver and iron oxide crystals, and core-shell hybrid NPs) offer many diagnostic and therapeutic applications. Membranes are also extensively utilized in many applications. They are especially beneficial to the distribution of macromolecular drugs and biopharmaceutical drugs (peptides, proteins, antibodies, oligonucleotides, plasmids, and viruses) with physicochemical and pharmacokinetic vulnerability. The delivery of drugs and bioactive molecules using particulates and membranes has gained a great deal of attention for various applications, such as the treatment of secondary infections, cancer treatment, skin regeneration, orthopaedic applications, and antimicrobial drug delivery. In addition, several production techniques have been utilized for the fabrication of particulates and membranes in the last decade, which include lyophilisation, micro-emulsion, nano-spray dryer, nano-electrospinning, slip casting and 3D printers. Therefore, pharmaceutical particulates and membranes possess excellent prospects to deliver drugs and bioactive molecules with the potential to improve new delivery strategies like sustained and controlled release

Advanced Engineering of Contact Lens Coatings using Electrohydrodynamic Atomization

While the eye presents numerous opportunities for drug delivery (DD); there are many challenges met by conventional methods. Despite the exponential growth in research to overcome these downfalls and achieve sustained and controlled DD, the anatomical characteristics of the eye still pose formulation challenges. The research presented in this thesis utilises Electrohydrodynamic Atomization (EHDA) to engineer novel coatings for ocular contact lenses. EDHA was selected to develop coatings for the delivery of timolol maleate (TM); with the intention of achieving sustained drug release for treatment of glaucoma. The work presented here is a proof-of-concept; showing the versatility of a promising technique by applying it to a DD remit within which EHDA has not yet been fully exploited: Ocular Drug Delivery (ODD). The first step was to identify a suitable polymeric matrix to act as the vehicle/carrier and see the effects of different polymers on the in vitro release of TM and ex vivo TM permeation. Hereafter, based on the results of this work, 4 different PEs were incorporated to attempt to enhance TM release and permeation through the cornea. Further modification of the formulations saw the effect of integrating chitosan on the release of TM from the electrically atomised coatings. Characterisation of the atomised coatings at each stage demonstrated highly stable matrices, which possessed extremely advantageous morphologies and sizes (within the nanometre range). All coatings also demonstrated adequate to high encapsulation efficiencies (EEs) (>64%) with the highest EE being 99.7%. In vitro release (i.e. cumulative percentage release) steadily increased upon introduction of additives to the base polymeric formulations yielding different release profiles; ranging from biphasic profiles to triphasic profiles. Ex vivo analysis and biological compatibility testing also presented promising results. The use of EHDA has not yet been explored in depth within the ocular research remit. It has shown great potential in the work presented here; engineering on demand lens coatings capable of sustaining both TM release and TM permeation