Cubosomal functionalized block copolymer platform for dual delivery of linagliptin and empagliflozin: Recent advances in synergistic strategies for maximizing control of high-risk type II diabetes.

A well-made chitosan-PVP block copolymer platform was equipped with highly ordered and uniform nano-channels. This highly adhesive block copolymer platform was designed to ensure the efficient co-delivery of two synergistic-acting hypoglycemic drugs. Linagliptin oral bioavailability is 30% due to poor permeability and intestinal degradation. Its pharmacokinetics shows a non-linear profile. Empagliflozin exhibited decreased permeability and decreased solubility in aqueous media between pH 1 and 7.5. Cubosomes were functionalized as a good microdomain to guest and improve the physicochemical characteristics of drug molecules with decreased permeability and solubility. Cubosomes loaded with linagliptin (linagliptin cubosomes (LCs)) and empagliflozin (empagliflozin cubosomes ECs) were separately prepared using the top-down method and optimized by applying 23 factorial design. Optimized cubosomal systems LCs (F3) and ECs (F4) were incorporated into a chitosan-PVP gel to obtain dual cubosome-loaded platforms (LECF) optimized through 22 factorial design. The permeation study from the optimized LECF (C1) ensured enhanced empagliflozin permeation alongside continued efflux for linagliptin, resolving potential risks due to its non-linear plasma profile. The in-vivo study revealed that AUC(0-∞) of linagliptin and empagliflozin was enhanced by 2- and threefold, respectively. Therefore, the chitosan-PVP block copolymer platform buccal application for the co-delivery of linagliptin and empagliflozin could contribute to enhanced clinical effectiveness in treating diabetes.

Architecting novel multilayer nanosponges for co-administration of two drugs managing high-risk type II diabetes mellitus patients suffering from cardiovascular diseases.

Nanosponges are porous solid nanoparticles composed of hyper-cross-linked polymers that serve as specific micro-domains designed for the co-encapsulation of two drugs with different chemical structures. Our goal was to engineer a novel assembly of multilayer nanosponges (MLNS) based on a layer-by-layer approach. This MLNS was engineered to incorporate two drugs (linagliptin and empagliflozin) in a new drug delivery route. Linagliptin has a low oral bioavailability due to intestinal degradation and low permeability. Its pharmacokinetics shows a non-linear profile which leads to a disproportionate increase in its effectiveness with increasing the dose frequency. Empagliflozin has a low permeability and is very slightly soluble in aqueous media between pH 1-7.5. MLNS could improve their bioavailability along with resolving possible risks due to the non-linear pharmacokinetics of linagliptin and maximizing its dose efficiency. 23 factorial design was used to optimize the novel systems. MLNS (F4) was chosen as the optimal system with an average diameter of 40 nm and the highest entrapment efficiency which accounts for 92.93 % ± 2.27 and 100.94 % ± 0.55 for linagliptin and empagliflozin respectively. Förster resonance energy transfer confirmed the formation of a multilayer structure in MLNS. The optimized system was incorporated within chitosan mucoadhesive buccal films which were optimized through 22factorial design. The permeation study from optimized MLNS-film (B4) ensured an improved empagliflozin permeation along with a controlled efflux for linagliptin, resolving possible risks due to the nonlinear plasma profile. The in-vivo study of MLNS-film (B4) revealed that AUC(0-∞)of linagliptin and empagliflozin was enhanced by two-fold and ten-fold, respectively. Therefore, the nano-buccal formulation for the co-delivered hypoglycemic drugs could contribute to improved clinical efficacy in the treatment of diabetes.

New intranasal cross-linked mosapride xyloglucan pluronics micelles (MOS-XPMs) for reflux esophagitis disease: In-vitro optimization and improved therapeutic efficacy.

Mosapride belongs to class IV in Biopharmaceutics Classification System and is used in the treatment of reflux esophagitis. It exhibits poor bioavailability due to limited permeability, solubility and extensive first-pass metabolism. In this study, intranasal mosapride-loaded cross-linked xyloglucan Pluronic micelles (MOS-XPMs) was formulated and optimized to improve the low solubility & bioavailability of MOS. The solid dispersion technique using 23 full factorial design was applied. (MOS-XPMs) (F4) had the highest desirability value (0.952) and, therefore, it was selected as an optimal system. Xyloglucan cross-linked in the shell of Pluronic micelles offered improved stability and mucoadhesiveness to MOS-XPMs. 1H NMR spectra ensured the cross-linking of xyloglucan with Pluronic micelle shell and micelle stabilization. A Pharmacodynamic study revealed that MOS-XPMs showed 1.5-fold increase in duodenal and cecal motility compared to MOS suspension and 1.7-fold increase compared to the oral marketed product. The new MOS-XPMs were shown to be successful at improving the therapeutic efficacy of mosapride.

Stabilizing excipients for engineered clopidogrel bisulfate procubosome derived in situ cubosomes for enhanced intestinal dissolution: Stability and bioavailability considerations.

Clopidogrel bisulfate (CB) is a golden antiplatelet treatment, yet its benefits are limited by its low bioavailability (<50%) caused by poor intestinal solubility and absorption. The present study aims to improve CB intestinal solubility and absorption through developing a novel stable dry CB procubosomes tablets ready to disintegrate and re-disperse upon dilution in the GIT forming in situ CB cubosome nanoparticles while simultaneously overcome the poor stability of conventional cubosome dispersion at room temperature. Glyceryl monooleate based CB cubosome dispersion was prepared using Poloxamer 407 as surfactant, freeze dried using different stabilizing excipients (dextrose, mannitol and avicel) then compressed into procubosome tablets. The effect of excipient's physicochemical properties on the flowability, in vitro dissolution and stability at accelerated conditions (40 ±â€¯2 °C/75 ±â€¯5% RH) were evaluated. The prepared procubosomes exhibited an excipient type dependent dissolution profile where Avicel based procubosome tablet CF2 showed the highest in vitro dissolution profile among other excipients used during the freeze drying process. Upon transition to intestinal pH of 6.8 to mimic the drug absorption site, CF2 procubosome Avicel tablet, was able to preserve the enhanced CB release profile (99.6 ±â€¯6.92%) compared to commercial Plavix® where, CB dissolved % dropped dramatically to 79.1 ±â€¯2.45%. After storage for six months, CF2 retained the fresh tablet drug content of 98.5 ±â€¯5.82% and dissolution properties. Moreover, following oral administration in rabbits, CF2 showed higher relative bioavailability (153%) compared to commercial Plavix® with significant higher Cmax,shorter tmax, as well as enhanced antiplatelet activity.

Cubosomes as Oral Drug Delivery Systems: A Promising Approach for Enhancing the Release of Clopidogrel Bisulphate in the Intestine.

Clopidogrel bisulphate (CB) is a first line antiplatelet drug for treatment of myocardial infarction and stroke. Yet, its efficacy is limited by its poor solubility in intestinal pH, its main site of absorption. The main aim of this study is to enhance the intestinal release of CB by loading in cubosome nanoparticles. Glyceryl monooleate (GMO) based CB loaded cubosomes were prepared using a 33 factorial design to study the effect of polyvinyl alcohol (PVA), poloxamer 407 (PL407) concentrations and ratio of CB to the disperse phase on the average particle size, entrapment efficiency (%EE), in vitro release at 15 min (%Q15), and their morphology using transmission electron microscopy (TEM). The release of the optimized formula was compared in buffer transition media (pH 1.2 for 2 h then pH 6.8 for 6 h) to free drug to study the effect of the changing pH in the gastrointestinal tract (GIT) on CB release. The antihaemostatic properties of the optimized formula were compared to the commercial product Plavix® using bleeding time (BT) model in rabbits. The prepared cubosomes were in the nano range (115±6.47 to 248±4.63 nm) with high %EE (91.22±4.09% to 98.98±3.21%). The optimized formula showed significantly higher (p<0.05) CB release in intestinal pH and preserved the high% released (95.66±1.87%) in buffer transition release study compared to free drug (66.82±4.12%) as well as significantly (p<0.05) higher antihaemostatic properties with longer BT (628.47±6.12 s) compared to Plavix® (412.43±7.97 s). Thus, cubosomes proved to be a successful platform to enhance the intestinal release of CB and improve its absorption.

Tretinoin-loaded liposomal formulations: from lab to comparative clinical study in acne patients.

Topical tretinoin is the most commonly used retinoid for acne. However, its irritative potential on the applied area and the barrier properties of the stratum corneum limit its use. The objective of the present study was to formulate tretinoin liposomal gel to obtain a formula with lower skin irritation potential and greater clinical effect. A statistical 2(4) factorial design was adopted. Sixteen formulae prepared and were properly evaluated. A candidate formula (F13G) prepared with 0.025% tretinoin, phospholipid- cholesterol-dicetylphosphate (9:1:0.01) and incorporated in 1% carbopol gel was selected for skin irritation test. Clinical study was conducted on acne patients and compared to marketed product. All liposomes formulations were spherical in shape. The addition of cholesterol in the film hydration method significantly decreased the vesicle size, and increased the percentage of incorporation efficiency at (p < 0.05). The presence of dicetylphosphate significantly increased drug release but did not affect the percentage of incorporation efficiency and vesicle size. The results of the clinical study in acne patients revealed that F13G showed significantly higher efficacy when compared to marketed product (p < 0.05).

Leflunomide biodegradable microspheres intended for intra-articular administration: Development, anti-inflammatory activity and histopathological studies.

Leflunomide, the disease-modifying anti-rheumatic drug was formulated as microspheres for prolonged drug release in the form of intraarticular injection. Eight formulations were developed using three biodegradable PDLG polymers (lactide/glycolide copolymer) and polycaprolactone (PLC) at two drug:polymer ratios (1:2 and 1:4). Solvent evaporation method was employed using polyvinyl alcohol or hydropxypropyl methylcellulose as stabilizers. Formulations were assessed for encapsulation efficiency, yield, particle size, release pattern and SEM. F6 (PDLG 5010), with appropriate particle size and prolonged drug release, was chosen for in-vivo studies using arthritis induced rats, which were intrarticularly injected with F6 or took oral Avara(®). Nuclear factor-kappa B measurements and histopathologic studies were conducted. There was significant reduction of inflammation caused by both F6 and oral Avara(®). Histopathologic studies showed minimal infiltration by chronic inflammatory cells and no angiogenesis in F6 compared to Avara(®). Results also revealed biocompatibility of the polymer used.

Bioenhanced sublingual tablet of drug with limited permeability using novel surfactant binder and microencapsulated polysorbate: In vitro/in vivo evaluation.

Formulation of sublingual tablets of drugs with limited permeability poses a great challenge due to their poor absorption. In this study, bioenhanced sublingual tablets (BESTs) of zolmitriptan were prepared using novel surfactant binder (Pluronic® p123/Syloid® mixture) to enhance tablet disintegration and dissolution. Microencapsulated polysorbate 80 (Sepitrap™ 80) were included in the composition of BESTs to enhance the drug transport through the sublingual mucosa. Tablets were evaluated for in vitro/in vivo disintegration, in vitro dissolution and ex vivo permeation. Solubility studies confirmed that phosphate buffer; pH 6.8 could be used as dissolution medium for sublingual tablets of zolmitriptan. BEST-5 containing Pluronic® p123/Syloid® mixture and Sepitrap™ 80 exhibited the shortest in vitro/in vivo disintegration times (<30s), the highest dissolution at early time dissolution points and the highest enhancement of drug transport through mucosal membrane. The in vivo pharmacokinetic study using human volunteers showed a significant increase in the rate and extent of sublingual absorption with less variations of Tmax after sublingual administration of both BEST-5 and Zomig-ZMT ODT. Our results proposed that Pluronic® p123/Syloid® mixture and Sepitrap™ 80 could be promising for the development of sublingual tablets for rapid onset of action of drugs with limited permeability.

Bumadizone calcium dihydrate microspheres compressed tablets for colon targeting: formulation, optimization and in vivo evaluation in rabbits.

The objective of this study was the development of a colon-targeted microspheres which were compressed into tablets containing the non-steroidal anti-inflammatory bumadizone calcium hemihydrate. [corrected]. A 3(2) full factorial design was adopted for the evaluation of the prepared microspheres. The effect of two independent variables namely polymer type (Eudragit RS100, ethyl cellulose and cellulose acetate butyrate), and drug: polymer ratio (1:1, 9:1 and 18:1) was studied on the entrapment efficiency and in vitro drug release for 12 h. Colon targeting aims to minimize the release of the drug off target area (pH 1.2 and 6.8) and to maximize the release of the drug in target area (pH 7.4). Candidate formulae were compressed into core tablets and colon targeting was achieved using the enzyme-dependent polymer (pectin) as coat in three different concentrations 50, 75 and 90%. Candidate formula F15 (microspheres prepared using BDZ:CAB in a ratio of 18:1 and compressed into tablets using 50% pectin and 50% Avicel in the coat) was able to adequately modulate drug release avoiding drug release in the gastric ambient, and reaching the colonic targeting where 99.7% release was achieved within 12 h following zero-order model. In vivo studies showed that F15 achieved significant decrease in myeloperoxidase activity and inflammation with delayed Tmax (4 h) and lower Cmax (2700 ng/ml) when compared to marketed product.

Formulation of tretinoin-loaded topical proniosomes for treatment of acne: in-vitro characterization, skin irritation test and comparative clinical study.

Tretinoin (TRT) is a widely used retinoid for the topical treatment of acne, photo-aged skin, psoriasis and skin cancer which makes it a good candidate for topical formulation. Yet side effects, like redness, swelling, peeling, blistering and, erythema, in addition to its high lipophilicity make this challenging. Therefore, the aim of this study was the development of TRT-loaded proniosomes to improve the drug efficacy and to increase user acceptability and compliance by reducing its side effects. Nine formulae were prepared according to 3(2) factorial design and were evaluated for their morphology, vesicle size, entrapment efficiency (EE %), and% of drug released after 5 h. Hydrogel of the candidate formula, N8G (proniosomes prepared with 0.025% TRT, and Span60: cholesterol molar ratio of 3:1 and incorporated in 1% carbopol gel) was developed and evaluated for skin irritation test and clinical study in acne patients compared to marketed product. Candidate formula showed higher efficacy and very low irritation potential when compared to marketed product in human volunteers.

Formulation of a novel oxybenzone-loaded nanostructured lipid carriers (NLCs).

The objective of the current study was to formulate oxybenzone into nanostructured lipid carriers (NLCs) to enhance its sunscreening efficacy and safety. NLCs of oxybenzone were prepared by the solvent diffusion method. A complete 2(3) factorial design was used for the evaluation of the prepared oxybenzone NLCs. The study design involves the investigation of the effect of three independent variables namely liquid lipid type (Miglyol 812 and oleic acid), liquid lipid concentration (15% and 30%), and oxybenzone concentration (5% and 10% with respect to total lipids) on the particle size (p.s.) , the entrapment efficiency (EE%) and the in vitro drug release after 8 h. The prepared NLCs were spherical in overall shape and were below 0.8 microm. Miglyol 812 and 30% liquid lipid were found to significantly decrease the p.s. and increase the EE% when compared to oleic acid and 15% liquid lipid. Increasing oxybenzone concentration increased significantly the p.s. but did not affect the EE%. NLCs prepared using Miglyol 812, 15% liquid lipid, and 10% oxybenzone showed slower drug release when compared to those prepared using oleic acid, 30% liquid lipid, and 5% oxybenzone, respectively. The candidate oxybenzone-loaded NLC dispersion was then formulated into gel. The incorporation of oxybenzone into NLCs greatly increased the in vitro sun protection factor and erythemal UVA protection factor of oxybenzone more than six- and eightfold, respectively, while providing the advantage of overcoming side effects of free oxybenzone as evidenced by very low irritation potential.