Yusrida Darwis

Advanced drug delivery to the lymphatic system: lipid-based nanoformulations

The delivery of drugs and bioactive compounds via the lymphatic system is complex and dependent on the physiological uniqueness of the system. The lymphatic route plays an important role in transporting extracellular fluid to maintain homeostasis and in transferring immune cells to injury sites, and is able to avoid first-pass metabolism, thus acting as a bypass route for compounds with lower bioavailability, ie, those undergoing more hepatic metabolism. The lymphatic route also provides an option for the delivery of therapeutic molecules, such as drugs to treat cancer and human immunodeficiency virus, which can travel through the lymphatic system. Lymphatic imaging is useful in evaluating disease states and treatment plans for progressive diseases of the lymph system. Novel lipid-based nanoformulations, such as solid lipid nanoparticles and nanostructured lipid carriers, have unique characteristics that make them promising candidates for lymphatic delivery. These formulations are superior to colloidal carrier systems because they have controlled release properties and provide better chemical stability for drug molecules. However, multiple factors regulate the lymphatic delivery of drugs. Prior to lymphatic uptake, lipid-based nanoformulations are required to undergo interstitial hindrance that modulates drug delivery. Therefore, uptake and distribution of lipid-based nanoformulations by the lymphatic system depends on factors such as particle size, surface charge, molecular weight, and hydrophobicity. Types of lipid and concentration of the emulsifier are also important factors affecting drug delivery via the lymphatic system. All of these factors can cause changes in intermolecular interactions between the lipid nanoparticle matrix and the incorporated drug, which in turn affects uptake of drug into the lymphatic system. Two lipid-based nanoformulations, ie, solid lipid nanoparticles and nanostructured lipid carriers, have been administered via multiple routes (subcutaneous, pulmonary, and intestinal) for targeting of the lymphatic system. This paper provides a detailed review of novel lipid-based nanoformulations and their lymphatic delivery via different routes, as well as the in vivo and in vitro models used to study drug transport in the lymphatic system. Physicochemical properties that influence lymphatic delivery as well as the advantages of lipid-based nanoformulations for lymphatic delivery are also discussed.

Development and characterization of polymeric microspheres for controlled release protein loaded drug delivery system

The aim of the present work was to investigate the preparation of microspheres as potential drug carriers for proteins, intended for controlled release formulation. The hydrophilic bovine serum albumin was chosen as a model protein to be encapsulated within poly(D,L-lactide-co-glycolide) (50:50) microspheres using a w/o/w double emulsion solvent evaporation method. Different parameters influencing the particle size, entrapment efficiency and in vitro release profiles were investigated. The microspheres prepared with different molecular weight and hydrophilicity of poly(D,L-lactide-co-glycolide) polymers were non porous, smooth surfaced and spherical in structure under scanning electron microscope with a mean particle size ranging from 3.98 to 8.74 μm. The protein loading efficiency varied from 40 to 71% of the theoretical amount incorporated. The in vitro release profile of bovine serum albumin from microspheres presented two phases, initial burst release phase due to the protein adsorbed on the microsphere surface, followed by slower and continuous release phase corresponding to the protein entrapped in polymer matrix. The release rate was fairly constant after an initial burst release. Consequently, these microspheres can be proposed as new controlled release protein delivery system.

Rehydrated sterically stabilized phospholipid nanomicelles of budesonide for nebulization: physicochemical characterization and in vitro, in vivo evaluations

Background Inhaled corticosteroids provide unique systems for local treatment of asthma or chronic obstructive pulmonary disease. However, the use of poorly soluble drugs for nebulization has been inadequate, and many patients rely on large doses to achieve optimal control of their disease. Theoretically, nanotechnology with a sustained-release formulation may provide a favorable therapeutic index. The aim of this study was to determine the feasibility of using sterically stabilized phospholipid nanomicelles of budesonide for pulmonary delivery via nebulization. Methods PEG5000-DSPE polymeric micelles containing budesonide (BUD-SSMs) were prepared by the coprecipitation and reconstitution method, and the physicochemical and pharmacodynamic characteristics of BUD-SSMs were investigated. Results The optimal concentration of solubilized budesonide at 5 mM PEG5000-DSPE was 605.71 ± 6.38 μg/mL, with a single-sized peak population determined by photon correlation spectroscopy and a particle size distribution of 21.51 ± 1.5 nm. The zeta potential of BUD-SSMs was −28.43 ± 1.98 mV. The percent entrapment efficiency, percent yield, and percent drug loading of the lyophilized formulations were 100.13% ± 1.09%, 97.98% ± 1.95%, and 2.01% ± 0.02%, respectively. Budesonide was found to be amorphous by differential scanning calorimetry, and had no chemical interaction with PEGylated polymer according to Fourier transform infrared spectroscopy. Transmission electron microscopic images of BUD-SSMs revealed spherical nanoparticles. BUD-SSMs exhibited prolonged dissolution behavior compared with Pulmicort Respules® (P < 0.05). Aerodynamic characteristics indicated significantly higher deposition in the lungs compared with Pulmicort Respules®. The mass median aerodynamic, geometric standard deviation, percent emitted dose, and the fine particle fraction were 2.83 ± 0.08 μm, 2.33 ± 0.04 μm, 59.13% ± 0.19%, and 52.31% ± 0.25%, respectively. Intratracheal administration of BUD-SSMs 23 hours before challenge (1 mg/kg) in an asthmatic/chronic obstructive pulmonary disease rat model led to a significant reduction in inflammatory cell counts (76.94 ± 5.11) in bronchoalveolar lavage fluid compared with administration of Pulmicort Respules® (25.06 ± 6.91). Conclusion The BUD-SSMs system might be advantageous for asthma or chronic obstructive pulmonary disease and other inflammatory airway diseases.

Ethosomal nanocarriers: the impact of constituents and formulation techniques on ethosomal properties, in vivo studies, and clinical trials

Ethosomal systems are novel lipid vesicular carriers containing a relatively high percentage of ethanol. These nanocarriers are especially designed for the efficient delivery of therapeutic agents with different physicochemical properties into deep skin layers and across the skin. Ethosomes have undergone extensive research since they were invented in 1996; new compounds were added to their initial formula, which led to the production of new types of ethosomal systems. Different preparation techniques are used in the preparation of these novel carriers. For ease of application and stability, ethosomal dispersions are incorporated into gels, patches, and creams. Highly diverse in vivo models are used to evaluate their efficacy in dermal/transdermal delivery, in addition to clinical trials. This article provides a detailed review of the ethosomal systems and categorizes them on the basis of their constituents to classical ethosomes, binary ethosomes, and transethosomes. The differences among these systems are discussed from several perspectives, including the formulation, size, ζ-potential (zeta potential), entrapment efficiency, skin-permeation properties, and stability. This paper gives a detailed review on the effects of ethosomal system constituents, preparation methods, and their significant roles in determining the final properties of these nanocarriers. Furthermore, the novel pharmaceutical dosage forms of ethosomal gels, patches, and creams are highlighted. The article also provides detailed information regarding the in vivo studies and clinical trials conducted for the evaluation of these vesicular systems.

Solubilization of beclomethasone dipropionate in sterically stabilized phospholipid nanomicelles (SSMs): physicochemical and in vitro evaluations

Background The local treatment of lung disorders such as asthma and chronic obstructive pulmonary disease via pulmonary drug delivery offers many advantages over oral or intravenous routes of administration. This is because direct deposition of a drug at the diseased site increases local drug concentrations, which improves the pulmonary receptor occupancy and reduces the overall dose required, therefore reducing the side effects that result from high drug doses. From a clinical point of view, although jet nebulizers have been used for aerosol delivery of water-soluble compounds and micronized suspensions, their use with hydrophobic drugs has been inadequate. Aim: To evaluate the feasibility of sterically stabilized phospholipid nanomicelles (SSMs) loaded with beclomethasone dipropionate (BDP) as a carrier for pulmonary delivery. Methods 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 5000) polymeric micelles containing BDP (BDP-SSMs) were prepared by the coprecipitation and reconstitution method, and the physicochemical and in vitro characteristics of BDP-SSMs were investigated. Results BDP-SSMs were successfully prepared with a content uniformity and reproducibility suitable for pulmonary administration. The maximum solubility of BDP in SSMs was approximately 1300 times its actual solubility. The particle size and zeta potential of BDP-SSMs were 19.89 ± 0.67 nm and −28.03 ± 2.05 mV, respectively. The SSMs system slowed down the release of BDP and all of the aerodynamic values of the aerosolized rehydrated BDP-SSMs were not only acceptable but indicated a significant level of deposition in the lungs. Conclusion The SSM system might be an effective way of improving the therapeutic index of nebulized, poorly soluble corticosteroids.

Formulation and in vivo evaluation of ondansetron orally disintegrating tablets using different superdisintegrants

The aim of this study was to formulate cost effective taste-masked orally disintegrating tablets of ondansetron, a bitter drug using different superdisintegrants by a wet granulation technique. Microcrystalline cellulose (Avicel) as a diluent and disintegrant in addition to aspartame as a sweetener were used in all formulations. The prepared tablets were evaluated for weight variation, thickness, hardness, friability, drug content, water content, in vitro disintegration time and in vitro drug release. The tablets’ hardness was maintained in the range of 2–3 kg and friability was <1% for all batches. All tablet formulations disintegrated rapidly in vitro within 5.83 to 33.0 sec. The optimized formulation containing 15% Polyplasdone XL-10 released more than 90% of drug within 5 min and the release was comparable to that of a commercial product. In human volunteers, optimized formulation was found to have a pleasant taste and mouth feel and they disintegrated in the oral cavity within 12 sec. The stability results were also satisfactory. A pharmacokinetic study with the optimized formulation was performed in comparison with a reference (Zofer MD 8®) and they were found to be bioequivalent. In conclusion, a cost effective ondansetron orally disintegrating tablet was successfully prepared with acceptable hardness, desirable taste and rapid disintegration in the oral cavity.

Preparation, characterization, and in vivo evaluation of insulin-loaded PLA-PEG microspheres for controlled parenteral drug delivery.

Aim: The aim of this study was to prepare insulin-loaded poly(lactic acid)–polyethylene glycol microspheres that could control insulin release at least for 1 week and evaluate their in vivo performance in a streptozotocin-induced diabetic rat model. Methods: The microspheres were prepared using a water-in-oil-in-water double emulsion solvent evaporation technique. Different formulation variables influencing the yield, particle size, entrapment efficiency, and in vitro release profiles were investigated. The pharmacokinetic study of optimized formulation was performed with single dose in comparison with multiple dose of Humulin® 30/70 as a reference product in streptozotocin-induced diabetic rats. Results: The optimized formulation of insulin microspheres was nonporous, smooth-surfaced, and spherical in structure under scanning electron microscope with a mean particle size of 3.07 ×μm and entrapment efficiency of 42.74% of the theoretical amount incorporated. The in vitro insulin release profiles was characterized by a bimodal behavior with an initial burst release because of the insulin adsorbed on the microsphere surface, followed by slower and continuous release corresponding to the insulin entrapped in polymer matrix. Conclusions: The optimized formulation and reference were comparable in the extent of absorption. Consequently, these microspheres can be proposed as new controlled parenteral delivery system.

Validated high performance liquid chromatography (HPLC) method for the determination of sumatriptan in rabbit plasma: Application to pharmacokinetic study

A new, sensitive and specific isocratic reverse phase-high performance liquid chromatography (RPHPLC) method with fluorescence detection was developed and validated for the determination of sumatriptan in rabbit plasma using sulpiride as an internal standard (IS). Sumatriptan was extracted from plasma by a liquid-liquid extraction with a mixture of tert-butyl methyl ether, dichloromethane and ethyl acetate (2:2:3, v/v). Chromatographic separation of the analyte and internal standard was achieved on a Phenomenex C4 (250 × 4.6 mm, 5 µm) analytical column maintained at 40°C. The mobile phase was composed of 25 mM ammonium acetate (pH 6.5) and acetonitrile (85:15, v/v), pumped isocratically at a flow rate of 0.9 ml/min. Column eluent was monitored at excitation and emission wavelengths of 225 and 350 nm. The calibration curve was linear over a concentration range of 1 to 300 ng/ml (r 2 = 0.9999) with a limit of quantification, 1 ng/ml. The intra-day and inter-day precision and accuracy were between 2.24 and 4.28% and -1.10 and 2.86%, respectively. The mean recoveries of sumatriptan and sulpiride were 89.92 and 91.03%, respectively. Sumatriptan containing plasma samples were stable at -20°C for 14 days. The validated method was successfully applied for pharmacokinetic study after a single oral administration of sumatriptan (50 mg) to rabbits.

Incorporation of Beclomethasone Dipropionate into Polyethylene Glycol‐Diacyl Lipid Micelles as a Pulmonary Delivery System

Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics Preclinical Research Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics Clinical Development Phases I‐III Regulatory, Quality, Manufacturing Postmarketing Phase IV

Prerequisite Characteristics of Nanocarriers Favoring Oral Insulin Delivery: Nanogels as an Opportunity

Extensive research has been carried out for developing nanocarriers to overcome the major barriers preventing success in oral insulin therapy, which includes (a) identification of in vivo barriers, (b) incorporation of prerequisite characteristics into single nanocarrier, and (c) exclusion of the use of additional potentially toxic chemicals as enzyme inhibitors or permeation enhancers. The present review identifies the prerequisite characteristics of single nanocarrier that could avoid major hindrance being faced in oral insulin delivery. An effort is made to discuss the involvement of prerequisite characters to overcome the major hurdles, which prevent the success in oral insulin delivery. GRAPHICAL ABSTRACT