Trends in prevalence, treatment use, and disease burden in patients with eosinophilic granulomatosis with polyangiitis in Japan: real-world database analysis.

OBJECTIVES: Report the prevalence of eosinophilic granulomatosis with polyangiitis (EGPA) and describe oral corticosteroid (OCS) use and disease burden before and after mepolizumab approval in 2018 for EGPA in Japan. METHODS: Two retrospective studies (GSK IDs: 218083; 218084) used two databases: 1) the JMDC insurer database (Japanese health insurer claims) was used to report annual EGPA prevalence and OCS use in mepolizumab-treated patients; 2) Medical Data Vision database was used to report annual treatment use, OCS dose, relapses, and healthcare resource utilization (HCRU) in patients with EGPA. RESULTS: EGPA prevalence (95% confidence interval) increased from 4.2 (0.1, 23.4) in 2005 to 58.6 (53.2, 64.5) per 1,000,000 in 2020. Median OCS dose (mg/day) decreased from a range of 4.8-7.7 during 2010-2017 to 4.5-4.8 during 2018-2020 (lowest dose in 2020). The proportion of patients with prednisolone-equivalent daily OCS dose >10 mg decreased from 2017 (11.9%) to 2020 (10.3%), while the median dose halved. The proportion of patients with EGPA relapses (64.3% to 41.6%) and hospitalisation (27.8% to 23.6%) decreased from 2010 to 2020. CONCLUSIONS: EGPA prevalence increased between 2005 and 2020. With the introduction of mepolizumab for EGPA in 2018, real-world OCS use, relapses and HCRU decreased.

A strategic review on the involvement of receptors, transcription factors and hormones in acne pathogenesis.

Acne vulgaris is a very common pilosebaceous inflammatory disease occurring primarily on the face and also rare on the upper arms, trunk, and back, which is caused by Propionibacterium, Staphylococcus, Corynebacterium, and other species. Pathophysiology of acne comprises of irregular keratinocyte proliferation, differentiation, increased sebum output, bacterial antigens and cytokines induced inflammatory response. Treatment of acne requires proper knowledge on the pathophysiology then only the clinician can come out with a proper therapeutic dosage regimen. Understanding the pathophysiology not only includes the mechanism but also involvement of receptors. Thus, this review is framed in such a way that the authors have focused on the disease acne vulgaris, pathophysiology, transcription factors viz. the Forkhead Box O1 (FoxO1) Transcription Factor, hormones like androgens and receptors such as Histamine receptors, Retinoic receptor, Fibroblast growth factor receptors, Toll like receptor, Androgen receptor, Liver X-receptor, Melanocortin receptor, Peroxisome proliferator-activated receptor and epidermal growth factor receptors involvement in the progression of acne vulgaris.

In vitro characterization studies of self-microemulsified bosentan systems.

CONTEXT: Bosentan is a poorly soluble drug and pose challenges in designing of drug delivery systems. OBJECTIVE: The objective of this study is to enhance the solubility, dissolution and shelf-life of bosentan by formulating it as S-SMEDDS capsules. MATERIALS AND METHODS: Solubility of bosentan was tested in various liquid vehicles such as oils (rice bran and sunflower), surfactants (span 20 and tween 80) and co-surfactants (PEG 400 and propylene glycol) and microemulsions were developed. Bosentan was incorporated into appropriate microemulsion systems which were previously identified from pseudo ternary phase diagrams. Bosentan-loaded SMEDDS were evaluated for drug content, drug release, zeta potential, and droplet size. The selected liquid SMEDDS were converted into solid SMEDDS by employing adsorption and melt granulation. Solid SMEDDS were characterized for micromeritics and evaluated for drug content, drug release, and shelf-life. RESULTS: Isotropic systems R5, R13, S5, and S13 with submicron droplet size had exhibited 85.45, 94.12, 81.67, and 96.64% drug release, respectively. Solid SMEDDS of MR13 and AS13 formulations with rapid reconstitution ability, exhibited 84.85 and 86.74% of on par drug release. The formulations were physicochemically intact for 1.02 and 1.56 years. DISCUSSION: Liquid SMEDDS composed with PEG400 had displayed optimal characters. Solid SMEDDS had high-dissolution profiles than bosentan due to modification in the crystalline structure of drug upon microemulsification. CONCLUSION: Thus, solid SMEDDS addressed the solubility, dissolution, and stability issues of bosentan and becomes an alternate for clinical convenience.

Solid self microemulsification of Atorvastatin using hydrophilic carriers: a design.

CONTEXT: Atorvastatin has a limited advantage to formulate oral dosage forms. OBJECTIVE: To enhance the solubility of Atorvastatin and to design the suitable solid self-microemulsifying drug delivery systems (S-SMEDDS) Materials and methods: The clear and transparent self-microemulsifying drug delivery system (SMEDDS) were formulated using coconut oil and isopropyl myristate as lipid phases; Tween 80 as surfactant; PEG 400 and glycerin as co-surfactant at 2:1, 3:1, 1:2 and 1:3 ratio. The pseudo ternary phase diagrams were constructed to identify the microemulsion region. The SMEDDS were evaluated for zeta potential, poly dispersity index, globule size, pH, viscosity and drug release. The solid SMEDDS were developed by employing adsorption and melt granulation methods. The S-SMEDDS were evaluated for micromeritics, morphology, solid state property, reconstitution ability, drug release and stability. RESULTS: The micro formulations formed with particle size of 25 nm had shown a 3-folds rise in drug release. The solid SMEDDS had reconstituted to a good microemulsion rapidly in 1-3 min, with a release of 94.62% at the end of 30 min and behaved as immediate releasing capsules. Their shelf-life was found to be 1.3 years. DISCUSSION: The 1:3 ratio SMEDDS had shown more drug release owing to their less particle size. The solid SMEDDS had shown an increased dissolution profiles than atorvastatin. The solid state of the drug had changed in formulation inferring their enhanced solubility. CONCLUSION: The solid form of atorvastatin liquid SMEDDS had been formulated successfully with enhanced shelf life and solubility.

Receptors and ligands role in colon physiology and pathology.

Colonic diseases are more prevalent during the past decade. Colorectal cancer, ulcerative colitis, Crohn's disease, diverticulitis, irritable bowel syndrome are the major reported colonic diseases. Innovative strategies are defensible in order to advance the efficacy of colonic disease treatment. During the past decade there has been an extensive advance in the understanding of receptor signaling both from a clinical as well as a preclinical perspective. A sound knowledge on molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in colorectal cancer therapy and inflammatory pathways in the ulcerative colitis. Receptor signaling has been involved in these pathways. To understand the receptor ligand interaction, one must have the basic knowledge regarding those receptors and ligands. This review summarizes the existing knowledge of the expression and function of various receptors and ligands in the colonic tissue. It also covers their role in the physiological processes and pathological conditions of colon.

Process, Physicochemical Characterization and In-Vitro Assessment of Albendazole Microcrystals.

Purpose: Albendazole is a poorly soluble drug which limits its oral bioavailability. The study was focussed to enhance the solubility by in-situ micronization. Methods: Albendazole microcrystals were prepared by solvent change method using gum karaya and hupu gum as stabilizing agents and the effect of each stabilizer on the prepared microcrystals were studied. FT-IR, DSC, XRD and SEM analysis were performed as a part of characterization studies. The formulations were evaluated for micromeritics, solubility and drug release. The microcrystals that had shown optimized properties were filled into suitable capsules. Results: The formulations showed reduction in particle size with uniform size distribution and three folds increase in drug release. The microcrystals had shown more than 100-folds increase in solubility compared to pure drug. Surface energy, enthalpy and crystalline nature of microcrystals were found to be reduced. Microcrystals containing gum karaya had shown more drug release. The filled-in capsules also showed increase in drug release rate. The solubility enhancement of albendazole microcrystals was mainly due to the surface adsorption of the stabilizing agents that led to reduction in surface energy and crystalline nature as substantiated by the DSC and XRD studies. The type of stabilizing agent had significant effect on dissolution rate. High affinity of albendazole with gum karaya led to faster drug release profiles. Conclusion: The study proved that in-situ micronization is an effective technique to enhance the solubility and dissolution rate of poorly soluble drugs like albendazole.

Chronopharmacokinetic Evaluation of Budesonide Multiparticulate Systems.

BACKGROUND: Poor oral absorption of budesonide limits the design of its solid oral dosage form. With this context, multiparticulate pulsatile system of budesonide for chronotherapy of nocturnal asthma was aimed in this study. METHODS: Initially, solid dispersions of budesonide (BD) using sodium starch glycolate (SSG) and guar gum (GG) were developed and characterized. Uniform sized non-pareil seeds (~400 µm) were coated with solid dispersions to obtain immediate (BMP) and controlled release pellets by solution layering technique. Rationale of selection of BD in this research was based on recent patents such as diltiazem HCl (US5914134) and multipar-ticulate systems (US5017381). Pulsatile drug release pellets (BMPP) of BD were obtained by coating the controlled release pellets with Eudragit L100 and RS 100. Pellets were assessed by saturation sol-ubility, FTIR, DSC, micromeritic, SEM, drug content, drug release, pharmacokinetic and stability studies. RESULTS: Solubility of BD was increased by 22 folds due to inter-particle distribution of BD and polymers in solid dispersions. No changes in characteristic functional groups of BD had indicated the compatibility of drug with polymers as noticed in FTIR and DSC. Fluidized bed processor enabled the production of spherical and uniformly distributed pellets with optimum angle of repose (12-19°) and friability (<1%). Solution layering technique employed in preparation of pellets had facilitated with moderately high BD content (91.5-99.6%) and 100% drug release at the end of 12hr. The pulsatile release pellets (BMPP) produced 6hr lag phase followed by 12hr controlled release. Promised pharmacokinetics was resulted as Cmax of 380ng/ml for BMP-2 and 162ng/ml for BMPP-5 and Tmax of 5 hr for BMP-2 and 12hr for BMPP-5. Increased pharmacokinetics was the direct results of increased solubility of BD due to application of solid dispersion and solution layering on pellets. CONCLUSIONS: Chronopharmacokinetics of BD were achieved with the help of Eudragit coatings on pellets. The BMP and BMPP formulations were found to be reasonably stable over a period of time. Thus, optimal chronopharmacokinetics of BD was achieved successfully by multiparticulate pulsatile technology.

Cubosomes as targeted drug delivery systems - a biopharmaceutical approach.

Cubosomes are reversed bicontinuous cubic phases and possess unique physicochemical properties. These special systems are receiving much attention for the delivery of various hydrophilic, hydrophobic and amphiphilic drugs with enhanced bioavailability and high loading capacity. A wide variety of drugs are applicable for cubosome formulation for various routes of delivery. The lipids used in cubosome formulation are more stable and offer stability to the formulation during shelf-life. The article reviews about the back ground, techniques of cubosome preparation such as high pressure homogenization, probe ultrasonication and automated cubosome preparation; and also methods of cubosomes preparation such as top down, bottom up and other methods with pictorial presentation. This article emphasizes the phase transition and also targeted approaches of cubosomes. The characterization studies for cubosomes such as cryo transmission electron microscopy, differential scanning calorimetry and scanning electron microscopy followed by in-vitro and in-vivo evaluation studies of cubosomes were explained with appropriate examples. Recent applications of cubosomes were explained with reference to flurbiprofen, odorranalectin, diazepam and dexamethasone. The advantages, disadvantages and limitations of cubosomal technology were emphasized.

In-vitro assessment and pharmacodynamics of nimesulide incorporated Aloe vera transemulgel.

The aim of the investigation was to prepare nimesulide emulsion for incorporation in Aloe vera gel base to formulate 'nimesulide - Aloe vera transemulgel' (NAE) and to carryout in-vitro assessment and in-vivo anti-inflammatory studies of the product. Although the use of nimesulide is banned for oral administration, due to its potential for inducing hepatotoxicity and thrombocytopenia, the use of nimesulide for topical delivery is prominent in the treatment of many inflammatory conditions including rheumatoid arthritis. The drug loading capacity of transdermal gels is low for hydrophobic drugs such as nimesulide. Nimesulide can be effectively incorporated into emulgels (a combination of emulsion and gel). Aloe vera has a mild anti-inflammatory effect and in the present study Aloe vera gel was formulated and used as a gel base to prepare NAE. The emulgels thus prepared were evaluated for viscosity, pH, in-vitro permeation, stability and skin irritation test. In-vivo anti-inflammatory studies were performed using carrageenan induced hind paw edema method in Wistar rats. The results were compared with that of commercial nimesulide gel (CNG). From the in-vitro studies, effective permeation of nimesulide from NAE (53.04 %) was observed compared to CNG (44.72 %) at 30 min indicating better drug release from NAE. Topical application of the emulgel found no skin irritation. Stability studies proved the integrity of the formulation. The percentage of inhibition of edema was highest for the prepared NAE (67.4 % inhibition after 240 min) compared to CNG (59.6 %). From our results, it was concluded that the Aloe vera gel acts as an effective gel base to prepare nimesulide emulgel with high drug loading capacity (86.4 % drug content) compared to CNG (70.5 % drug content) with significant anti-inflammatory effect.

Assessment of hupu gum for its carrier property in the design and evaluation of solid mixtures of poorly water soluble drug - rofecoxib.

There are no reports about the pharmaceutical applications of hupu gum (HG). Hence the present study was undertaken to test its suitability in the dissolution enhancement of poorly water soluble drug. Rofecoxib (RFB) was taken as model drug. For comparison solid mixtures were prepared with carriers such as poly vinyl pyrrolidone (PVP), sodium starch glycollate (SSG) and guar gum (GG). Physical mixing (PM), co-grinding (CG), kneading (KT) and solvent evaporation (SE) techniques were used to prepare the solid mixtures, using all the carriers in different carrier and drug ratios. The solid mixtures were characterized by powder X-ray diffraction (XRD) and Fourier-transformed infrared spectroscopy (FTIR). There was a significant improvement in the dissolution rate of solid mixtures of HG, when compared with the solid mixtures of other carriers. There was an increase in dissolution rate with increase in concentration of HG upto 1:1 ratio of carrier and drug. No drug-carrier interaction was found by FTIR studies. XRD studies indicated reduction in crystallinity of the drug with increase in HG concentration. Hence HG could be a useful carrier for the dissolution enhancement of poorly water soluble drugs.

Microemulsions based transdermal drug delivery systems.

Since the discovery of microemulsions by Jack H Schulman, there has been huge progress made in applying microemulsion systems in plethora of research and industrial process. Microemulsions are optically isotropic systems consisting of water, oil and amphiphile. These systems are beneficial due to their thermodynamic stability, optical clarity, ease of preparation, higher diffusion and absorption rates. Moreover, it has been reported that the ingredients of microemulsion can effectively overcome the diffusion barrier and penetrate through the stratum corneum of the skin. Hence it becomes promising for both transdermal and dermal drug delivery. However, low viscosity of microemulsion restrains its applicability in pharmaceutical industry. To overcome the above drawback, the low viscous microemulsions were added to viscous gel bases to potentiate its applications as topical drug delivery systems so that various drug related toxic effects and erratic drug absorption can be avoided. The present review deals with the microemulsions, various techniques involved in the development of organic nanoparticles. The review emphasized on microemulsion based systems such as hydrogels and organogels. The physicochemical characteristics, mechanical properties, rheological and stability principles involved in microemulsion based viscous gels were also explored.

A perspective overview on lipospheres as lipid carrier systems.

Both hydrophilic and lipophilic therapeutics can be delivered successfully into deep and peripheral tissues such as cerebrospinal fluid and central nervous system by encapsulating them with crystalline lipids as lipospheres. The advent of lipospheres was meant to deliver both therapeutic moieties with enhanced efficacy and added stability to reach out intended tissue areas. Although extensive information is available on physicochemical, analytical and biopharmaceutical aspects of lipospheres, there was no specific order pertaining to critical composition and rationale of component selection available for academic and pilot scale processing of lipospheres. With the interest of compiling key points in a typical formulation of lipid lipospheres, this article was intrigued to discuss melt method, co-solvent, microemulsion, super critical fluid, spray drying and spray congealing techniques that were employed to scale up lipospheres. The selection criteria for both the drugs and lipids in liposphere formulations were demonstrated here. The quality assessment with variables like loading capacity and entrapment efficiency was explained. A note on preliminary screening factors to determine the liposphere formation such as liposphere dimensions with morphological scenario was detailed in this article. This article also includes the stability and storage issues with reference to photolysis. The marked differential in enhancing solubility and permeability characteristics of Class II and IV drug candidates by liposphere delivery systems with an evident of in vivo outcomes were emphasized.

Formulation and pharmacodynamic evaluation of glibenclamide incorporated niosomal gel.

OBJECTIVE: The research aims to formulate and develop the controlled release profile of glibenclamide by encapsulating glibenclamide into niosomes followed by incorporation into an aqueous gel base. MATERIALS AND METHODS: Glibenclamide incorporated niosomes were prepared by a modified ether injection technique using Span 20/Span 80 and cholesterol. The prepared niosomes were evaluated for chemical incompatibility by FT-IR, morphology, vesicle dimension, encapsulation efficiency, in-vitro diffusion and drug release kinetics. Niosomal gels were prepared by incorporating the optimized niosomes into a gel base containing Carbopol 934 and evaluated for viscosity, in-vitro diffusion and in-vivo pharmacodynamic activity. RESULTS AND DISCUSSION: The results indicated that relationship between the amount of Span and niosomal vesicular diameter was inversely proportional. Microscopic images have illustrated the sphere shape vesicles. The cumulative percentage of drug release from niosomal suspension was observed in the order GN-4>GN-2>GN- 6>GN-5>GN-3>GN-1. Glibenclamide gel showed highest percentage drug release when compared to niosomal gel. Invivo study revealed that the glibenclamide incorporated niosomal gel formulation; GNG-1 is more efficient in lowering blood glucose levels in experimental animals. CONCLUSION: The niosomal gel of glibenclamide had released the drug in well controlled manner which is supported by pharmacodynamic activity with evidence of consistent lowering of blood glucose levels.

Modified pulsincap of ibuprofen--a novel approach for chronotherapy.

The aim of the present work was to develop colon specific drug delivery system for ibuprofen using natural polymers as carriers. We have investigated colon specific, pulsatile device to achieve time and site specific release of ibuprofen based on chronopharmaceutical considerations. The basic design consists of an insoluble hard gelatin capsule body, filled with ibuprofen surface solid dispersions and sealed with guar gum hydrogel plug. The entire capsule was coated with ethyl cellulose, so that the variability in gastric emptying time can be overcome and a colon specific release can be achieved. Surface solid dispersions (SSDs) of ibuprofen were prepared using natural polymers such as Guar gum (GG), Hupu gum (HG) and Xanthan gum (XG) in the weight ratios of 1:0.5, 1:1 and 1:2 by using solvent evaporation method. Physicochemical properties of the prepared SSD were characterized by FTIR and DSC. Optimized SSD were obtained by practical yield, drug content, solubility and dissolution studies and were selected for further fabrication of pulsincaps. Guar gum was used as hydrogel plug material to maintain a suitable lag period. The prepared pulsincaps were evaluated for in-vitro release. Pulsincap formulated with Ibuprofen-Hupu gum (PF3) at 1:2 ratio of surface solid dispersions showed highest drug release over the period of 12 hr and release was found to be Higuchi model kinetics. The present research study results have confirmed that the modified pulsincap of ibuprofen is a suitable device for the time dependent and site specific delivery to the colon segment of GIT.

In vitro and in vivo assessment of piroxicam incorporated Aloe vera transgel.

BACKGROUND: The aim of the study was to develop piroxicam-Aloe vera gel (PAG) formulation and make a pharmacodynamic evaluation of the formulation. MATERIALS AND METHODS: The gel was prepared by using carbopol 934 as gelling agent and methyl paraben as a preservative in an Aloe vera gel base. The formulated gel was also evaluated for physicochemical parameters like pH, viscosity, drug content, and in vitro diffusion assessment. Pharmacodynamic activity of the formulation was evaluated in Wistar albino rats. The formulated gel was compared with that of similar marketed gel (commercial piroxicam gel (CPG)) against the same parameters. RESULTS: From in vitro studies, an effective drug release from PAG was observed to be 68.17% when compared with that of the CPG (62.71%) at 180 min indicating better drug release from the gel formulated in this study. Percentage inhibition of edema was greater for the preparation of PAG (29.57 mean percent inhibition after 60 min) compared to marketed gel which exhibited 18.3% after 60 min. CONCLUSION: It was concluded from the results that the Aloe vera gel acts as an effective gel base to prepare piroxicam gel with high drug loading capacity and improved anti-inflammatory effect. From the statistical analysis the formulation of PAG showed better release than the CPG at p < 0.05 level of significance.

Anatomical, biochemical and physiological considerations of the colon in design and development of novel drug delivery systems.

The colon is composed of four distinct layers such as serosa, muscularis externa, sub mucosa and mucosa. There exists a difference in the anatomy, neural and blood supply and absorption characteristics as the length of the colon is traversed. At birth the mucosal surface of the colon is similar to that of the small intestine but rapid changes occur with the loss of the villi leaving flat mucosa with deep crypts. The existence of receptors like muscarinic M3, cholecystokinin1, Eph, Erb B, estrogen (α, ß), gastrin releasing peptide, killer Ig like receptor, lymphocyte-endothelial receptor, notch, pregnane X, substance P and peroxisome proliferator-activated γ receptor can be utilized as a promising approach for targeting. The inner compact firm mucus is impervious to bacteria, making it a defensive barrier for the colossal bacterial load. The mucus thus provides innate immunity to maintain the homeostasis in colon. The physiological properties of the colon such as pH, transit time, luminal pressure of the colon, and the presence of microbial flora localized in the colon are utilized in the drug design. The drug delivery systems exploit enteric coating and biodegradable polymers to reach colon in an intact form by surpassing the barriers in the stomach and small intestine. The presence of azo-reductase, glucuronidase, dextranase, pectinase, glycosidase, polysaccharidase made it feasible to design prodrug and enzyme based drug delivery. Drug designing methodologies in colon specific drug delivery include pH- based systems, enzymedepended systems, timed- release systems and pressure/osmotically release systems.