Dali Shukla

Lipid – An emerging platform for oral delivery of drugs with poor bioavailability

The sole objective of pharmaceutical science is to design successful dosage forms which fulfill the therapeutic needs of the patients effectively. Development of new drug entities is posing real challenge to formulators, particularly due to their poor aqueous solubility which in turn is also a major factor responsible for their poor oral bioavailability. Lipids as carriers, in their various forms, have the potential of providing endless opportunities in the area of drug delivery due to their ability to enhance gastrointestinal solubilization and absorption via selective lymphatic uptake of poorly bioavailable drugs. These properties can be harvested to improve the therapeutic efficacy of the drugs with low bioavailability, as well as to reduce their effective dose requirement. The present communication embodies an in-depth discussion on the role of lipids (both endogenous and exogenous) in bioavailability enhancement of poorly soluble drugs, mechanisms involved therein, approaches in the design of lipid-based oral drug delivery systems with particular emphasis on solid dosage forms, understanding of morphological characteristics of lipids upon digestion, in vitro lipid digestion models, in vivo studies and in vitro-in vivo correlation.

Assessment of solubilization characteristics of different surfactants for carvedilol phosphate as a function of pH.

The effect of surfactants on the solubility of a new phosphate salt of carvedilol was investigated at different biorelevent pH to evaluate their solubilization capacity. Solutions of different classes of surfactants viz., anionic-sodium dodecyl sulfate (SDS) and sodium taurocholate (STC), cationic-cetyltrimethylammonium bromide (CTAB) and non-ionic-Tween 80 (T80) were prepared in the concentration range of 5-35 mmol dm(-3) in buffer solutions of pH 1.2, 3.0, 4.5, 5.8, 6.8 and 7.2. The solubility data were used to calculate the solubilization characteristics viz. molar solubilization capacity, water micelle partition coefficient, free energy of solubilization and binding constant. Solubility enhancement in basic pH was in following order: CTAB>T80>SDS>STC. CTAB and T80 showed remarkable solubility enhancement in acidic pH as well. Among the anionic surfactants, solubility in acidic medium was retarded except at pH 1.2 in case of SDS. Cationic and non-ionic surfactants were found to be suitable for enhancing the solubility of CP which can be employed for maintaining the in vitro sink condition in the basic dissolution medium. While anionic surfactants showed solubility retardant behavior which may be exploited in increasing the drug entrapment efficiency of a colloidal drug delivery system formulated by emulsification technique.

Lipid-based oral multiparticulate formulations – advantages, technological advances and industrial applications

Introduction: Lipid-based formulations have emerged as potential dosage forms to harvest effectively the therapeutic benefits of existing lipophilic molecules and new chemical entities. Compared with existing excipients, lipids by virtue of their unique physicochemical properties and resemblance to in vivo components demonstrate the extra advantage of improving the bioavailability of lipophilic and highly metabolizable drugs. Moreover, if used as the major excipient, lipids can reduce the required dose and even the toxicity of drugs with poor aqueous solubility. Areas covered: This review deals with the importance of multiparticulate systems in drug delivery, the therapeutic and manufacturing advantages of lipids as excipients, and the technological advances made so far in utilizing lipids for multiparticulate dosage forms, with emphasis on their application and success on an industrial scale. Lipids are being widely formulated into different multiparticulate dosage forms using innovative modifications of conventional equipment with relative ease, using methods such as melt-granulation, adsorption on solid support, spray-cooling, melt-extrusion/spheronization, freeze-pelletization, pastillation, and so on. Expert opinion: There is still a need to design new simple dosage forms and to upgrade existing manufacturing technology, in order to open up new avenues in drug delivery, for preparing patent non-infringing formulations of existing drug products, and to help patients receive treatment at an affordable cost.

Revealing facts behind spray dried solid dispersion technology used for solubility enhancement

Poor solubility and bioavailability of an existing or newly synthesized drug always pose challenge in the development of efficient pharmaceutical formulation. Numerous technologies can be used to improve the solubility and among them amorphous solid dispersion based spray drying technology can be successfully useful for development of product from lab scale to commercial scale with a wide range of powder characteristics. Current review deals with the importance of spray drying technology in drug delivery, basically for solubility and bioavailability enhancement. Role of additives, selection of polymer, effect of process and formulation parameters, scale up optimization, and IVIVC have been covered to gain the interest of readers about the technology. Design of experiment (DoE) to optimize the spray drying process has been covered in the review. A lot more research work is required to evaluate spray drying as a technology for screening the right polymer for solid dispersion, especially to overcome the issue related to drug re-crystallization and to achieve a stable product both in vitro and in vivo. Based on the recent FDA recommendation, the need of the hour is also to adopt Quality by Design approach in the manufacturing process to carefully optimize the spray drying technology for its smooth transfer from lab scale to commercial scale.

Doxofylline: a promising methylxanthine derivative for the treatment of asthma and chronic obstructive pulmonary disease

Background: Doxofylline, a methylxanthine derivative, has recently drawn attention because of its better safety profile and similar efficacy over the most widely prescribed analogue, theophylline, indicated for asthma and chronic obstructive pulmonary disease. Objective: This article attempts to discuss the pharmacodynamics/pharmacokinetics and clinical efficacy of doxofylline. Method: An extensive search in three electronic databases (Unbound Medline, Pubmed and Sciencedirect) and internet search engines (Scirus and Google Scholar) were used to identify the clinical studies on doxofylline. The literature search was carried out without time constraints to ensure maximum coverage of existing literature on doxofylline. Results/conclusion: In a relatively large number of comparative studies, doxofylline is indicated to have less affinity for α1 and α2 receptors than theophylline. Unlike theophylline, doxofylline does not antagonize calcium channels, nor does it interfere with the influx of calcium into the cells, which probably reduces the cardiac side effects. Moreover, it does not affect sleep rhythm, gastric secretions, heart rate and rhythm and CNS functioning. Numerous reports available regarding the better tolerability of doxofylline than theophylline prove it as a potential bronchodilator with promising pharmacological behavior. However, despite its superior safety and clinical efficacy, the potential of doxofylline has not been fully exploited.

Utilization of adsorption technique in the development of oral delivery system of lipid based nanoparticles.

The objective of the present study was to employ suitable adsorbent with free flowing characteristics for improving the stability and physical properties of solid lipid nanoparticles (SLN) for oral administration. Stearic acid based nanoparticles of carvedilol phosphate were fabricated by solvent emulsification evaporation technique in sodium taurocholate solution prepared in pH 7.2 buffers (I-KH2PO4/NaOH or II-NaH2PO4/Na2HPO4) with 1% polyvinyl alcohol. Nanoparticles were then adsorbed by passing the nanodispersion through a Neusilin US2 (adsorbent) column. Interestingly, scanning electron microscopy revealed round deformed and even collapsed nanoparticles in Buffer-I and discrete spherical to ellipsoidal nanoparticles in Buffer-II which indicates the inability of nanoemulsion to crystallize and form SLN in Buffer-I. The successful formation of SLN in Buffer-II was confirmed by differential scanning calorimetry and X-ray diffraction. The retention of SLN from the nanodispersion by adsorption on the adsorbent imparted good flow property and resulted in a marked stability improvement of the formulation in terms of drug retention efficiency and release profile as compared to the simple nanosuspension. In conclusion, the adsorbent technology would be instrumental in imparting additional features to the existing conventional colloidal system for pharmaceutical application which would ease the process of capsule filling at industrial scale, simplify the handling of formulations by patients and can significantly improve the shelf life of the product for a longer period of time as compared to liquid formulations.

Clinical updates on carvedilol: a first choice β-blocker in the treatment of cardiovascular diseases

Importance of the field: Carvedilol, a non-selective β-blocker, has recently drawn attention because of its therapeutic benefits over other prescribed analogues for the treatment of cardiovascular diseases (CVDs). Areas covered in this review: The present review attempts to present the clinical efficacy of carvedilol in comparison to other available β-blockers. The literature search was carried out in three electronic databases (Unbound Medline, Pubmed and Sciencedirect) and internet search engines (Scirus and Google Scholar) without time constraints to ensure maximum literature coverage. What the reader will gain: A relatively large number of comparative studies have revealed that carvedilol has advantage over traditional β-blockers with respect to hemodynamic and metabolic effects, due to its unique non-selective α-/β-adrenoceptor affinity. Such results indicate its safe and effective therapeutic application particularly in patients with complicated CVDs, even in pediatric and geriatric patients. Take home message: The therapeutic profile of carvedilol indicates its suitability for treatment of complicated CVDs than other non-selective β-blockers. However, there is a limitation in terms of its dose due to its low bioavailability (∼ 25%). Therefore, there is still need for bioavailability enhancement and dose reduction to further improve the therapeutic efficacy of the drug.

Evaluation of in vivo behavior of controlled and pulsatile release pastilles using pharmacokinetic and γ-scintigraphic techniques

Objective: To evaluate the in vivo behavior of controlled and pulsatile release pastilles for chronic treatment of asthma and chronic obstructive pulmonary disease (COPD) and for the chronotherapeutic management of nocturnal asthma, respectively. Research design & methods: The prepared immediate release and controlled release pastilles were subjected to in vivo pharmacokinetic studies in rats. Whereas, pulsatile release formulation was subjected to γ-scintigraphic study in rats to study the gastrointestinal transit of the formulations and its results were correlated with the previous pharmacokinetic data. Results: The in vivo pharmacokinetic study of controlled release pastille formulation showed significant decrease in Cmax with increase in tmax, which indicates that the effect of dosage form would last for longer duration. Thus, the prepared formulation can be useful for the chronic treatment of asthma and COPD. The γ-scintigraphic study and pharmacokinetic data indicated that the pastilles coated with the enteric coat and the additional floating coat were effective in significantly delaying the in vivo drug release (by 4–5 h) required for the chronotherapeutic treatment of nocturnal asthma. Conclusion: This study opens a new alternative to the conventional tablet or capsule dosage form for the development of both immediate and modified release drug delivery systems.

Effective in-vivo utilization of lipid-based nanoparticles as drug carrier for carvedilol phosphate.

Objectives  Lipid nanoparticles as carrier for oral drug administration improve gastrointestinal solubility of poorly soluble drugs and thus enhance bioavailability. However, basic drugs may undergo rapid dissolution from such solid dispersions in the stomach and precipitate in the intestine due to their higher solubility in acidic medium. Therefore, the objective of this work was to study the enhancement in bioavailability of carvedilol phosphate (basic drug) by providing an alkaline gastric environment to drug‐loaded solid lipid nanoparticles.

In vitro and in vivo evaluation of multilayered pastilles for chronotherapeutic management of nocturnal asthma

Objective: The present work was undertaken with an objective to design a multilayered dosage form of doxofylline, using pastillation technology, for the chronotherapeutic management of nocturnal asthma. Research design & methods: Pastilles consisting of the drug, polyethylene glycol and colloidal silicon dioxide, were generated using an in-house laboratory-scale pastillation device. The pastilles were further coated with enteric polymers and a floating layer, using conventional coater. The pastilles were subjected to physicochemical analysis, morphological characterization, in vitro drug release studies and in vivo pharmacokinetic studies in rats. Results: It was observed that colloidal silicon dioxide was instrumental in improving the contact angle of the pastilles. The uncoated pastilles released the drug immediately, while the enteric-coated (10% w/w) pastilles were found to have sufficient acid resistance when the coat is applied with 5% (v/v) triethyl citrate as plasticizer. The in vivo blood serum profile indicated that the pastilles coated with the enteric coat and the additional floating coat were effective in significantly delaying the in vivo drug release required for the chronotherapeutic treatment of nocturnal asthma. Conclusion: The present work opens a new alternative to the conventional tablet or capsule dosage form for the development of both immediate-release and modified-release drug delivery systems.