Improved initial burst of estradiol organogel as long-term in situ drug delivery implant: formulation,in vitro and in vivo characterization

Objective: The present investigation was aimed at optimizing of estradiol (E2) loaded l-amino acid derivatives organogel formulations resulting in improved the high initial release problems and sustained release of E2.

Methods: The visco-elastic properties of blank organogels were measured by rheometer. The E2 organogel formulations were optimized using a central composite design. Also, the effect of gelator structure and composition of the gel formulations on release behavior (in vitro and in vivo) had been studied.

Results: The change of the gelator structure could affect significantly the stiffness of the implants. The release behavior of gel without N-Methyl-2-pyrrolidinone (NMP) was controlled by gel corrosion only. While the drug release of the gel with NMP was controlled by both corrosion and diffusion. The high initial release problems of the organogels were improved by optimizing the formulations. The system consisting by N-Lauroyl l-lysine methyl ester (LLM) derivative in the oil indicated the lowest initial drug release, showed a much lower blood drug level and maintained a steady state for nearly 1 month.

Conclusion: Organogels based on l-lysine methyl ester derivative were ideal carriers for long-term parenteral administration of E2.     

In situ forming implants for the delivery of metronidazole to periodontal pockets: formulation and drug release studies

This study was performed to obtain prolonged drug release with biodegradable in situ forming implants for the local delivery of metronidazole to periodontal pockets. The effect of polymer type (capped and uncapped PLGA), solvent type (water-miscible and water-immiscible) and the polymer/drug ratio on in vitro drug release studies were investigated. In situ implants with sustained metronidazole release and low initial burst consisted of capped PLGA and N-methyl-2-pyrolidone as solvent. Mucoadhesive polymers were incorporated into the in situ implants in order to modify the properties of the delivery systems towards longer residence times in vivo. Addition of the polymers changed the adhesiveness and increased the viscosity and drug release of the formulations. However, sustained drug release over 10 days was achievable. Biodegradable in situ forming implants are therefore an attractive delivery system to achieve prolonged release of metronidazole at periodontal therapy.     

A novel honokiol liposome: formulation,pharmacokinetics, and antitumor studies

Abstract

It is necessary to discover a novel antitumor liposome with prolonged circulation time, high efficacy, and low cost. Here, we reported a liposomal honokiol (HNK) prepared with a new type of excipient, Kolliphor HS15, which was termed as HS15-LP-HNK. In addition, we employed PEGylated liposomal honokiol (PEG-LP-HNK) as positive control. The HS15-LP-HNK was prepared by thin-film hydration method. It was near-spherical morphology with an average size of 80.62?±?0.72?nm (PDI = 0.234?±?0.007) and a mean zeta potential of ?3.91?±?0.06?mv. In vivo studies exhibited no significant difference between HS15-LP-HNK and PEG-LP-HNK. The pharmacokinetic and biodistribution results showed that HS15-LP-HNK could improve the bioavailability and increase tumor accumulation of honokiol. Furthermore, HS15-LP-HNK could enhance antitumor efficacy of honokiol with low toxicity. In summary, HS15-LP-HNK is promising in tumor targeted drug delivery system.     

The characterization,pharmacokinetic, and tissue distribution studies of TPGS-modified artesunate liposome in rats

Objective: The objective of this study (ARS-TPGS-Lipo) was to enhance the stability, encapsulation efficiency (EE), improve AUC, circulation time and liver targeting of ARS-TPGS-Lipo.

Methods: ARS-TPGS-Lipo was prepared by thin-film dispersion method and characterized by TEM. The EE, in vitro release and stability of ARS-TPGS-Lipo were detected by HPLC and UV. In addition to the safety evaluation, the pharmacokinetics and tissue distribution studies were also carried out after i.v. administration.

Results: The size, PDI, zeta potential, and EE of ARS-TPGS-Lipo were 126.7?±?9.9?nm, 0.182?±?0.016, ?10.1?±?1.43?mV, and 78.8?±?1.89%, respectively. ARS-TPGS-Lipo showed the slow-release effect in vitro release experiments. The AUC of ARS in the ARS-TPGS-Lipo group was 7.51 times higher than in the ARS group after i.v. administration and the circulation time was significantly prolonged. The tissue distribution results showed the components of artesunate and its metabolism DHA of the ARS-TPGS-Lipo group were much higher in liver than the ARS-Lipo group.

Conclusion: ARS-TPGS-Lipo was prepared successfully, which had the smaller vesicles size with a better PDI, better stability, higher EE, and slow-release. The results of safety evaluation indicated that ARS-TPGS-Lipo had no hematotoxicity and hepatorenal toxicity. The pharmacokinetic studies indicated ARS-TPGS-Lipo had higher AUC, longer circulation time and better liver targeting.     

Temperature-responsive, Pluronic-g-poly(acrylic acid) copolymers in situ gels for ophthalmic drug delivery: rheology, in vitro drug release, and in vivo resident property

To prolong the precorneal resident time and improve ocular bioavailability of the drug, Pluronic-g-poly(acrylic acid) copolymers were studied as a temperature-responsive in situ gelling vehicle for an ophthalmic drug delivery system. The rheological properties and in vitro drug release of Pluronic-g-PAA copolymer gels, as well as the in vivo resident properties of such in situ gel ophthalmic formulations, were investigated. The rheogram and in vitro drug release studies indicated that the drug release rates decreased as acrylic acid/Pluronic molar ratio and copolymer solution concentration increased. It was also shown that the drug concentration had no obvious effect on drug release. The release rates of drug from such copolymer gels were mainly dependent on the gel dissolution. In vivo resident experiments showed the drug resident time and the total resident amount increased by 4-fold and 1.2-fold for in situ gel compared with eye drops. These in vivo experimental results, along with the rheological properties and in vitro drug release studies, demonstrated that in situ gels containing Pluronic-g-PAA copolymer may significantly prolong the drug resident time and thus improve bioavailability. The results showed that the Pluronic-g-PAA copolymer can be a promising in situ gelling vehicle for ophthalmic drug delivery.     

Preparation and evaluation of in situ gelling ophthalmic drug delivery system for methazolamide

Purpose: In this study, a thermosensitive in situ gelling vehicle was prepared to increase the precorneal resident time and the bioavailability of methazolamide (MTA). Method: Poloxamer analogs were used as the gelling agents, and the in situ gel was obtained by using a cold method. The gelation temperature, rheological properties, in vitro release as well as in vivo evaluation (the elimination of MTA in aqueous humor and intraocular-lowering effect) of the optimized formulations were investigated. Results: The optimum concentrations of poloxamer analogs for the in situ gel-forming delivery system were 21% (w/w) poloxamer 407 and 10% (w/w) poloxamer P188. This formulation was able to flow freely under nonphysiological conditions and underwent sol–gel transition in the cul-de-sac upon placement into the eye. In vitro release studies demonstrated a diffusion-controlled release of MTA from the poloxamer solutions over a period of 10 hours. In vivo evaluation indicated that the poloxamer solutions had a better ability to retain drug than MTA eyedrops did. Conclusion: These results suggested that in situ gelling ophthalmic drug delivery system may hold some promise in ocular MTA delivery.     

Inhalable liposomes of Glycyrrhiza glabra extract for use in tuberculosis: formulation,in vitro characterization,in vivo lung deposition,and in vivo pharmacodynamic studies

Objective: The current study involves the development of liposomal dry powder for inhalation (LDPI) containing licorice extract (LE) for use in tuberculosis.

Significance: The current epidemiology of tuberculosis along with the increasing emergence of resistant forms of tuberculosis necessitates the need for developing alternative efficacious medicines for treatment. Licorice is a medicinal herb with reported activity against Mycobacterium tuberculosis.

Methods: Liposomes with LE were prepared by thin film hydration technique and freeze dried to obtain LDPI. The comprehensive in vitro and in vivo characterization of the LDPI formulation was carried out.

Results: The particle size of liposomes was around 210?nm with drug entrapment of almost 75%. Transmission electron microscopy revealed spherical shape of liposome vesicles. The flow properties of the LDPI were within acceptable limits. Anderson Cascade Impactor studies showed the mean median aerodynamic diameter, geometric standard deviation and fine particle fraction of the LDPI to be 4.29?µm, 1.23, and 54.68%, respectively. In vivo lung deposition studies of LDPI in mice showed that almost 46% of the drug administered reaches the lungs and 16% of administered drug is retained in the lungs after 24?hours of administration. The in vivo pharmacodynamic evaluation of the LDPI showed significant reduction in bacterial counts in lungs as well as spleen of TB-infected mice.

Conclusions: LE LDPI thus has a promising potential to be explored as an effective anti-tubercular medicine or as an adjunct to existing anti-tubercular drugs.     

Oral liquid in situ gelling methylcellulose/alginate formulations for sustained drug delivery to dysphagic patients

Background: Elderly patients with swallowing dysfunction may benefit from the oral administration of liquid dosage forms with in situ gelling properties.

Aim: We have designed in situ gelling liquid dosage formulations composed of mixtures of methylcellulose, which has thermally reversible gelation properties and sodium alginate, the gelation of which is ion-responsive, with suitable rheological characteristics for ease of administration to dysphagic patients and suitable integrity in the stomach to achieve a sustained release of drug.

Method: The rheological and gelation characteristics of solutions containing methylcellulose (2.0%) and sodium alginate (0.25–1.0%) were assessed for their suitability for administration to dysphagic patients. The gel strength and in vitro and in vivo release characteristics of gels formed by selected formulations were compared using paracetamol as a model drug.

Results: Mixtures of 2.0% methylcellulose and 0.5% alginate containing 20% d-sorbitol were of suitable viscosity for ease of swallowing by dysphagic patients and formed gels at temperatures between ambient and body temperature allowing administration in liquid form and in situ gelation in the stomach. In vitro release of paracetamol from 2.0% methylcellulose/0.5% alginate gels was diffusion-controlled at pH 1.2 and 6.8. Measurement of plasma levels of paracetamol after oral administration to rats of a 2.0% methylcellulose/0.5% alginate formulation showed improved sustained release compared to that from 2.0% methylcellulose and 0.5% alginate solutions and from an aqueous solution of paracetamol.

Conclusions: Solutions of mixtures of methylcellulose and alginate in appropriate proportions are of suitable consistency for administration to dysphagic patients and form gels in situ with sustained release characteristics.     

Single non-ionic surfactant based self-nanoemulsifying drug delivery systems: formulation,characterization, cytotoxicity and permeability enhancement study

Single non-ionic surfactant based self-nanoemulsifying drug delivery system (SNEDDS) was formulated and characterised for poor water soluble drug, Atorvastatin calcium. Capmul MCM oil showing highest solubility for Atorvastatin calcium was selected as oil phase. Self-nanoemulsifying capacity of Cremophor RH 40, Cremophor EL, Tween 20, Tween 60, Tween 80 and Labrasol were tested for the selected oil. In vitro dissolution studies were performed and were characterized by t85% and dissolution efficiency (DE). Cytotoxicity of the formulations and permeation enhancement of the drug across caco-2 cell monolayer was assessed. Capmul MCM was found to be better nanoemulsified in decreasing order of Cremophor RH 40 > Cremophor EL > Tween 20 > Tween 60 > Tween 80. Values of droplet size (range 11–83 nm), polydispersity index (range 0.07–0.65); zeta potential (range ?3.97 to ?19.0) and cloud point (60–85°C) before and after drug loading proves the uniformity and stability of the formulations. SNEDDS formulated with Tween 20 surfactant showed enhanced dissolution with t85% and DE values at 10 min and 78.70, respectively. None of the formulation showed cytotoxicity at the concentration tested. Tween 20 based SNEDDS enhanced permeation of the drug as compared with pure drug across cell lines. It can be concluded that SNEDDS can be formulated by using single non-ionic surfactant system for enhance dissolution and absorption of poorly soluble drug, Atorvastatin calcium.     

Feasibility of obtaining in situ nanocapsules through modified self-microemulsifying drug delivery systems. A new manufacturing approach for oral route administration

Nanocapsules (NCs) are submicron-sized core shell systems which present important advantages such as improvement of drug efficacy and bioavailability, prevention of drug degradation, and provision of controlled-release delivery. The available methods for NC production require expensive recovery and purification steps which compromised the morphology of NCs. Industrial applications of NCs have been avoided due to the aforementioned issues. In this study, we developed a new method based on a modified self-microemulsifying drug delivery system (SMEDDS) for in situ NCs production within the gastrointestinal tract. This new methodology does not require purification and recovery steps and can preserve the morphology and the functionality of NCs. The in situ formed NCs of Eudragit^® RL PO were compared with nanospheres (NEs) in order to obtain evidence of their core-shell structure. NCs presented a spherical morphology with a size of 126.2?±?13.1?nm, an ibuprofen encapsulation efficiency of 31.3% and a zeta-potential of 37.4?mV. Additionally, NC density and release profile (zero order) showed physical evidence of the feasibility of NCs in situ creation.     

Elastic liposomal formulation for sustained delivery of antimigraine drug: in vitro characterization and biological evaluation

The aim of this study was to prepare and characterize a topical formulation for sustained delivery of rizatriptan. Elastic liposomal formulation of rizatriptan was prepared and characterized for different characteristics by evaluating in vitro and in vivo parameters. The in vivo performance of optimized formulation was evaluated for antimigraine activity in mice using morphine withdrawal-induced hyperalgesia. The in vitro skin permeation study across rat skin suggested carrier-mediated transdermal permeation for different elastic liposomal formulation to range between 18.1 +/- 0.6 and 42.7 +/- 2.3 microg/h/cm(2), which was approximately 8-19 times higher than that obtained using drug solution. The amount of drug deposited was 10-fold higher for elastic liposome (39.9 +/- 3.2%) than using drug solution (3.8 +/- 1%); similarly the biological activity of optimized elastic liposome formulation was found to be threefold higher than the drug solution. On the basis of the results, it can be concluded that the elastic liposomal formulation provided sustained action of rizatriptan due to depot formation in the deeper layer of skin.     

Injectable PLA-based in situ forming implants for controlled release of Ivermectin a BCS Class II drug: solvent selection based on physico-chemical characterization

In situ forming implants (ISI) prepared from biodegradable polymers such as poly(d,l-lactide) (PLA) and biocompatible solvents can be used to obtain sustained drug release after parenteral administration. The aim of this work was to study the effect of several biocompatible solvents with different physico-chemical properties on the release of ivermectin (IVM), an antiparasitic BCS II drug, from in situ forming PLA-based implants. The solvents evaluated were N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone (2P), triacetine (TA) and benzyl benzoate (BB). Hansen’s solubility parameters of solvents were used to explain polymer/solvent interactions leading to different rheological behaviours. The stability of the polymer and drug in the solvents were also evaluated by size exclusion and high performance liquid chromatography, respectively. The two major factors determining the rate of IVM release from ISI were miscibility of the solvent with water and the viscosity of the polymer solutions. In general, the release rate increased with increasing water miscibility of the solvent and decreasing viscosity in the following order NMP>2P>TA>BB. Scanning electron microscopy revealed a relationship between the rate of IVM release and the surface porosity of the implants, release being higher as implant porosity increased. Finally, drug and polymer stability in the solvents followed the same trends, increasing when polymer-solvent affinities and water content in solvents decreased. IVM degradation was accelerated by the acid environment generated by the degradation of the polymer but the drug did not affect PLA stability.     

Cellulose acetate microspheres as floating depot systems to increase gastric retention of antidiabetic drug: formulation, characterization and in vitro-in vivo evaluation

Gastric emptying is a complex process that is highly variable and makes the in vivo performance of drug delivery systems uncertain. In order to avoid this variability, efforts have been made to increase the retention time of the drug delivery systems for more than 12 hours utilizing floating or hydrodynamically controlled drug delivery systems. The objective of this investigation was to develop a floating, depot-forming drug delivery system for an antidiabetic drug based on microparticulate technology to maintain constant plasma drug concentrations over a prolonged period of time for effective control of blood sugar levels. Formulations were optimized using cellulose acetate as the polymer and evaluated in vitro for physicochemical characteristics and drug release in phosphate buffered saline (pH 7.4), and evaluated in vivo in healthy male albino mice. The shape and the surface morphology of the prepared microspheres were characterized by optical microscopy and scanning electron microscopy. In vitro drug release studies were performed and drug release kinetics were calculated using the linear regression method. Effects of stirring rate during preparation and polymer concentration on the size of microspheres and drug release were observed. The prepared microspheres exhibited prolonged drug release (more than 10 hours) and remained buoyant for over 10 hours. Spherical and smooth-surfaced microspheres with encapsulation efficiency ranging from 73% to 98% were obtained. The release rate decreased and the mean particle size increased at higher polymer concentrations. Stirring speed affected the morphology of the microspheres. This investigation revealed that upon administration, the biocompatible depot-forming polymeric microspheres controlled the drug release and plasma sugar levels more efficiently than plain orally given drug. These formulations, with their reduced frequency of administration and better control over drug disposition, may provide an economic benefit to the user compared with products currently available for diabetes control.     

Impact of surfactant selection on the formulation and characterization of microparticles for pulmonary drug delivery

The effect of suspension stabilizers, internal aqueous phase volume and polymer amount were investigated for the production of protein loaded poly(d,l?lactide-co-glycolide) (PLGA) microparticles suitable for pulmonary drug delivery. PLGA microparticles were produced adopting water-in-oil-in-water (W/O/W) solvent evaporation technique and were investigated for surface morphology, particle size, encapsulation efficiency (EE%) and in-vitro release profile. Porous surface morphologies with a narrow size distribution were observed when employing 0.5?ml internal aqueous phase; 23.04?µm (±0.98), 15.05?µm (±0.27) and 22.89?µm (±0.41) for PVA, Tween 80 and oleic acid. Porous microparticles exhibited increased size and reduction in EE% with increasing internal aqueous phase, with non-porous microparticles produced when adopting 2.0?ml internal aqueous phase. The selection of stabilizer influences the size of the pores formed thus offers potential for the aerodynamic properties of the microparticles to be manipulated to achieve suitable aerosolization characteristics for pulmonary delivery of proteins.     

Positively and negatively charged liposomes as carriers for transdermal delivery of sumatriptan: in vitro characterization

Background: The influence of liposome composition, lamellarity, preparation method, and charge on the encapsulation efficiency, size, polydispersity, and surface charge of sumatriptan liposomes was studied. For this purpose, we studied multilamellar, unilamellar, and frozen and thawed liposomes. Positively or negatively charged liposomes were obtained using both phosphatidylcholine and cholesterol, in combination with stearylamine or dicetylphosphate. Liposomal formulations were characterized by confocal laser scanning microscopy and optical microscopy for vesicle formation, morphology, and lamellarity by dynamic laser light scattering for size distribution and polydispersity, and electrophoretic mobility for zeta potential determination. To obtain more information about the sumatriptan encapsulation, dynamic dialysis technique was employed. The sumatriptan amount was quantified by high-performance liquid chromatography. Results: Overall obtained results showed that liposomes may be interesting carriers for sumatriptan succinate. Statistical analysis evidenced that the preparation method does not affect the evaluated characterization parameters. However, the presence of charge inducer agents modified these characteristics. Highest loading efficiency of sumatriptan was exhibited for positively charged liposomes containing 6.58:10.34:3.73 mmolar ratio for phosphatidylcholine : cholesterol : stearylamine. The mean size was affected by the charge inducer, being smaller in positively charged liposomes. Logically, surface charge of liposomes varied as a function of the employed charged agent. Also, interesting results were obtained when vesicles were loaded with sumatriptan, showing a statistical significance between all pairs, comparing the formulations with and without drug. Conclusion: Results obtained revealed that the presence of sumatriptan into the vesicles has a different behavior in negatively and positively charged liposomes.     

Non-ionic surfactant based vesicular drug delivery system for topical delivery of caffeine for treatment of cellulite: design,formulation, characterization,histological anti-cellulite activity,and pharmacokinetic evaluation

Cellulite is a common topographical alteration where skin acquires an orange peel or mattress appearance with alterations in adipose tissue and microcirculation. This work aims to develop and evaluate a topical niosomal gel formulae with good permeation to reach the subcutaneous fat layer. Several caffeine niosomal dispersions were prepared and incorporated into gel formulae using Carbopol 940 polymer, chemical penetration enhancers, and iontophoresis, then the prepared gels were applied onto the skin of rats and anticellulite activity of caffeine from the prepared gels compared to that of the commercial product Cellu Destock^® was evaluated by histological study of the skin and measurement of plasma level of caffeine passing through the skin using liquid chromatography (LC/MS–MS). Results of histology revealed reduction of size and thickness of fatty layer of rat skin in the following order: FVII?>?FXIV?>?Cellu Destock^®?>?FVII?+?Iontophoresis?>?FXIV?+?Iontophoresis. Pharmacokinetic results of caffeine in plasma revealed that C_max, T_max, and AUC_0–12h decreased in the following order: FXIV?>?FVII?>?Cellu Destock^®. These results conclude that incorporation of caffeine niosomal dispersion into gel matrix with penetration enhancers and iontophoresis resulted in improvement in penetration of caffeine through the skin into the underlying fatty layer in treatment of cellulite.     

Development of acetazolamide-loaded,pH-triggered polymeric nanoparticulate in situ gel for sustained ocular delivery: in vitro. ex vivo evaluation and pharmacodynamic study

The objective of research was to develop a novel pH-triggered polymeric nanoparticulate in situ gel (NP-ISG) for ophthalmic delivery of acetazolamide (ACZ) to enhance the conjunctival permeation and precorneal residence time of the formulation by overcoming the limitations of protective ocular barriers. Nanoparticles (NP1--NP12) were developed by nanoprecipitation method and evaluated for pharmacotechnical characteristics including transmission electron microscopy. The optimized formulation, NP10 was dispersed in carbopol 934?P to form nanoparticulate in situ gels (NP-ISG1--NP-ISG5). NP-ISG5 was selected as optimized formulation on the basis of gelation ability and residence time. Ex vivo transcorneal permeation study exhibited significantly higher ACZ permeation from NP-ISG5 (74.50?±?2.20?mg/cm²) and NP10 (93.5?±?2.25?mg/cm²) than eye drops (20.08?±?3.12?mg/cm²) and ACZ suspension (16.03?±?2.14). Modified Draize test with zero score indicated nonirritant property of NP-ISG5. Corneal toxicity study revealed no visual signs of tissue damage. Further, NP-ISG5 when tested for hypotensive effect on intraocular pressure (IOP) in rabbits revealed that NP-ISG5 caused significant decrease in IOP (p?in vitro efficacy, safety and patient compliance.     

原位复合聚芳硫醚砜/多壁碳纳米管复合材料的制备及性能初探

采用原位复合法制备了聚芳硫醚砜/多壁碳纳米管(MWCNTs)复合材料,先将酸化前后的多壁碳纳米管与聚芳硫醚砜各自进行原位复合,发现未酸化处理的碳纳米管在聚芳硫醚砜基体中的相容性很差,在基体内部不能有效地分散;此外,还发现随着碳纳米管添加量的增加,其体积电阻率由1013.9Ω.m降到104.3Ω.m,同时其热稳定性也随之逐渐升高。