Formulation and development of ophthalmic in situ gel for the treatment ocular inflammation and infection using application of quality by design concept

Context: The conventional liquid ophthalmic delivery systems exhibit short pre-corneal residence time and the relative impermeability to the cornea which leads to poor ocular bioavailability.

Objective: The aim of this study was to apply quality by design (QbD) for development of dexamethasone sodium phosphate (DSP) and tobramycin sulfate (TS)-loaded thermoresponsive ophthalmic in situ gel containing Poloxamer 407 and hydroxyl propyl methyl cellulose (HPMC) K4M for prolonging the pre-corneal residence time, ocular bioavability and decreases the frequency of administration of dosage form. The material attributes and the critical quality attributes (CQA) of the in situ gel were identified. Central composite design (CCD) was adopted to optimize the formulation.

Materials and methods: The ophthalmic in situ forming gels were prepared by cold method. Materials attributes were the amount of Poloxamer 407 and HPMC and CQA identified were Gel strength, mucoadhesive index, gelation temperature and % of drug release of both drug.

Results and discussion: Optimized batch (F*) containing 16.75% poloxamer 407 and 0.54% HPMC K4M were exhibited all results in acceptable limits. Compared with the marketed formulation, optimized in situ gel showed delayed T_max, improved C_max and AUC in rabbit aqueous humor, suggesting the sustained drug release and better corneal penetration and absorption.

Conclusion: According to the study, it could be concluded that DSP and TS would be successfully formulated as in situ gelling mucoadhesive system for the treatment of steroid responsive eye infections with the properties of sustained drug release, prolonged ocular retention and improved corneal penetration.     

In vitro and in vivo evaluation of cubosomal in situ nasal gel containing resveratrol for brain targeting

The aim of this study was to enhance the delivery of resveratrol to the brain through the transnasal route by cubosomes. Cubosomes were prepared using glycerol monooleate and Lutrol F127 by probe sonication method. A 3² full factorial design was used for optimization of cubosomes and batch containing 4% w/v glycerol monooleate and 1.5% w/v of Lutrol F 127 was optimized. The selected cubosomal batch was cubical in shape, having mean particle size 161.5?±?0.12?nm. Entrapment efficiency was found to be 83.08% with zeta potential of –20.9?mV. In vitro release of cubosomal batch showed controlled release of drug profile (67%) up to 24?h. The optimized cubosomal dispersion was dispersed into gelling polymer (poloxamer 407) to form in situ gel for nasal use. The optimal cubosomal gel (containing 12% w/v poloxamer 407) had been subjected to ex-vivo permeation and in vivo biodistribution studies. It showed significantly higher transnasal permeation and better distribution to brain, when compared to the drug solution (i.n.) and drug solution (oral). Finally the cubosomal gel could be considered as a promising carrier for brain targeting of Resveratrol (Res) through transnasal route.     

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.     

In situ gelling formulation based on methylcellulose/pectin system for oral-sustained drug delivery to dysphagic patients

Background: Oral-sustained release gel formulations with suitable rheological properties have been proposed as a means of improving the compliance of dysphagic and geriatric patients who have difficulties with handling and swallowing oral dosage forms. Aim: We have modified the rheological and release properties of thermally reversible methylcellulose solutions by admixture with pectin, the gelation of which is ion-responsive, with the aim of formulating an in situ gelling vehicle suitable for oral-sustained drug delivery. Method: Gels formed by solutions containing methylcellulose (1.0–2.0%) and pectin (0.5–2.0%) were assessed for suitable gel strength, and in vitro and in vivo release of paracetamol. Results: Addition of 1.5% pectin to a 2.0% methylcellulose formulation containing 20% d-sorbitol and calcium ions in complexed form increased the gel strength and provided a formulation with a suitable viscosity for ease of swallowing by dysphagic patients. Gels formed in situ after oral administration of this formulation retained their integrity in the rat stomach for sufficient time for sustained release to be achieved. In vitro release of paracetamol from methylcellulose, pectin, and methylcellulose/pectin gels was diffusion-controlled. Plasma levels of paracetamol after oral administration to rats (gastric pH 2.6 and 5.5) of a solution including 2.0% methylcellulose/1.5% pectin showed improved sustained release compared with that from both 2.0% methylcellulose and 1.5% pectin solutions. Conclusions: The addition of suitable concentrations of pectin to methylcellulose solutions produces in situ gelling formulations with suitable viscosity for administration to dysphagic patients and improved sustained release characteristics.     

Feasibility of poly (ε-caprolactone-co-DL-lactide) as a biodegradable material for in situ forming implants: evaluation of drug release and in vivo degradation

The purpose of this study was to evaluate the technical feasibility of poly (ε-caprolactone-co-DL-lactide), P (CL/DL-LA), for injectable in situ forming implants (ISFI). The ISFI was prepared by dissolving P (CL/DL-LA) in N-methyl-2-pyrrolidone (NMP), and Testosterone undecanoate (TU) was used as model drug. The effect of various polymer concentrations, molecular weights (Mws) and drug loads on the drug release from the TU-loaded ISFI systems was investigated in vitro. The release of TU-loaded ISFI was also evaluated in rats. In addition, a subcutaneous rabbit model was used to evaluate the degradation and foreign-body reaction of P (CL/DL-LA) ISFI. The use of higher concentration of P (CL/DL-LA) with higher molecule weight and larger CL:DL-LA monomer ratio for the TU-loaded ISFI gave a slower drug release. The ISFI of 80/20 P (CL/DL-LA) (Mw 61?753):NMP 20:80 with 16% TU formulation increased serum testosterone levels in rats over a period of three months. The in vivo degradation and biocompatibility study of ISFI shows that P (CL/DL-LA) degrades by a process of bulk degradation and that the foreign-body reaction of this biomaterial is relatively mild. In summary, our investigations demonstrate that in situ parenteral drug delivery systems can be obtained from P (CL/DL-LA) solutions.     

Preparation and evaluation of gel formulations for oral sustained delivery to dysphagic patients

Background: Oral sustained release gel formulations may provide a means of administering drugs to dysphagic and geriatric patients who have difficulties with handling and taking oral dosage forms. Aim: We have designed gel formulations for the oral administration of paracetamol with suitable rheological characteristics for ease of administration to patients with swallowing difficulties and sufficient integrity in the acidic environment of the stomach to achieve a sustained release of this drug. Method: Gels formed by gelatin, agar, gellan, pectin, and xyloglucan were assessed for suitable gel strength and in vitro and in vivo release characteristics. Results: Gellan (1.5%?w/v) and xyloglucan gels (1.5%?w/w) had acceptable gel strengths for ease of swallowing and retained their integrity in the rat stomach sufficiently well to sustain the release of paracetamol over a period of 6 hours. Comparison of 1.5%?xyloglucan gels with a commercially available preparation with identical paracetamol concentrations demonstrated improved sustained release properties of the xyloglucan gels. Conclusions: Gels formed by gellan and xyloglucan have suitable rheological and sustained release characteristics for potential use as vehicles for oral delivery of drugs to dysphagic patients.     

Thermoreversible mucoadhesive in situ nasal gel for treatment of Parkinson’s disease

Abstract

Parkinson’s disease is a degenerative disorder of the central nervous system (CNS). The most obvious symptoms are movement-related such as shaking, rigidity, slowness of movement and difficulty with walking, rigid muscular movements and difficulty in chewing and swallowing especially solid dosage forms. Ropinirole is an anti-Parkinson drug that has low oral bioavailability which is primarily due to first-pass metabolism. The objective of proposed work was to increase bioavailability of ropinirole and avoid patient discomfort by formulating thermoreversible in situ nasal gel. Thermoreversible nasal gels were prepared by cold method using Pluronic F-127 and hydroxy methyl propyl cellulose (HPMC K4M) as gelling agents. Formulations were evaluated for various parameters such as drug content, pH, gelling time, gelling temperature, gel strength, mucoadhesive force, ex vivo diffusion, histological studies and in vivo bioavailability. Formulations displayed gelation at nasal temperature and the gelation time was found to be less than mucociliary clearance time. The nasal residence time was seen to be increased due to mucoadhesion and increased gel strength. The nasal gel formulations showed ex vivo drug release between 56–100% in 5?h. Histological study of sheep nasal mucosa revealed that the gel had a protective effect on the mucosa unlike plain ropinirole which showed evidence of moderate cellular damage. A fivefold increase in bioavailability in brain was observed on nasal administration as compared to IV route. Thermoreversible in situ nasal gel was found to a promising drug delivery for Parkinsonian patients.     

Development of the loratadine gel for enhanced transdermal delivery

Background: The oral administration of loratadine, an antihistamine, can have a variety of adverse side effects, such as headache, fatigue, and nausea, because of the transient high blood concentration. To avoid these effects, loratadine can be administered using a transdermal drug delivery system. Method: This study examined the effects of the drug concentration on drug release from prepared hydroxypropyl methylcellulose gels using a synthetic cellulose membrane at 37°C. The drug concentrations tested were 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% (w/w). The effect of temperature on drug release from the 0.3% loratadine gels was evaluated at 27°C, 32°C, 37°C, and 42°C. Various types of penetration enhancers, such as glycols, glycerides, propylene glycol derivatives, nonionic surfactants, and fatty acids, were incorporated in the gel formulation to increase the level of drug permeation. Results: The rate of drug release increased with increasing drug concentration or temperature. The activation energy for the release of the drug was 5.714 kcal/mol for 0.3% loratadine gel. Among all the enhancers used in this study, polyoxyethylene 2-stearyl ether showed the best enhancing effect. The enhancement factor of the loratadine gel containing the polyoxyethylene 2-stearyl ether was 2.03 compared with that of the loratadine system containing no enhancer. Conclusions: These results suggest that the topical gel formulation of loratadine containing a penetration enhancer could be developed to enhance the penetration of loratadine.     

Development of modified in situ gelling oral liquid sustained release formulation of dextromethorphan

Context: Alternative strategies are being employed to develop liquid oral sustained release formulation. These included ion exchange resin, sustained release suspensions and in situ gelling systems. The later mainly utilizes alginate solutions that form gels upon contact with calcium which may be administered separately or included in the alginate solution as citrate complex. This complex liberates calcium in the stomach with subsequent gellation. The formed gel can break after gastric emptying leading to dose dumping.

Objective: Development of modified in situ gelling system which sustain dextromethorphan release in the stomach and intestine.

Methods: Solutions containing alginate with calcium chloride and sodium citrate were initially prepared to select the formulation sustaining the release in the stomach. The best formulation was combined with chitosan. All formulations were characterized with respect to flow, gelling capacity, gelling strength and drug release.

Results: Increasing the concentration of alginate increased the gelling capacity and strength and reduced the rate of drug release in gastric conditions with 2% w/v alginate being the best formulation. However, these formulations failed to sustain the release in the intestinal conditions. Incorporation of chitosan with alginate increased the gelling capacity and strength and reduced the rate of drug release compared to alginate only system. The effect was optimum in formulation containing 1.5% w/v chitosan. The sustained release pattern was maintained both in the gastric and intestinal conditions and was comparable to that obtained from the marketed product.

Conclusion: Alginate-chitosan based in situ gelling system is promising for developing liquid oral sustained release.     

Thermosensitive bioadhesive gels for the vaginal delivery of sildenafil citrate: in vitro characterization and clinical evaluation in women using clomiphene citrate for induction of ovulation

Objective: The objective of this study is to develop and characterize in situ thermosensitive gels for the vaginal administration of sildenafil as a potential treatment of endometrial thinning occurring as a result of using clomiphene citrate for ovulation induction in women with type II eugonadotrophic anovulation. While sildenafil has shown promising results in the treatment of infertility in women, the lack of vaginal pharmaceutical preparation and the side effects associated with oral sildenafil limit its clinical effectiveness.

Methods: Sildenafil citrate in situ forming gels were prepared using different grades of Pluronic^® (PF-68 and PF-127). Mucoadhesive polymers as sodium alginate and hydroxyethyl cellulose were added to the gels in different concentrations and the effect on gel properties was studied. The formulations were evaluated in terms of viscosity, gelation temperature (T_sol-gel), mucoadhesion properties, and in vitro drug release characteristics. Selected formulations were evaluated in women with clomiphene citrate failure due to thin endometrium (Clinicaltrial.gov identifier NCT02766725).

Results: The T_sol-gel decreased with increasing PF-127 concentration and it was modulated by addition of PF-68 to be within the acceptable range of 28–37?°C. Increasing Pluronic® concentration increased gel viscosity and mucoadhesive force but decreased drug release rate. Clinical results showed that the in situ sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow with no reported side effects. Further, these results were achieved at lower frequency and duration of drug administration.

Conclusion: Sildenafil thermosensitive vaginal gels might result in improved potential of pregnancy in anovulatory patients with clomiphene citrate failure due to thin endometrium.     

Fabrication and in vitro evaluation of bidirectional release and stability studies of mucoadhesive donut-shaped captopril tablets

Objective: To obtain controlled release of captopril in the stomach, coated, mucoadhesive donut-shaped tablets were designed.

Materials and methods: Donut-shaped tablet were made of different ratios of diluents to polymer or combination of polymers by direct compression method. Top and bottom portions of the tablet were coated with water-insoluble polymer followed by mucoadhesive coating. Time of water penetration, measurement of tensile strength, mucoadhesion studies (static ex vivo and ex vivo wash-off) were taken into account for characterization of respective films. In vitro study has been performed at different dissolution mediums. Optimized batches were also prepared by wet granulation. Stability studies of optimized batches have been performed.

Results: The results of time of water penetration and tensile strength indicated positive response against water impermeation. Mucoadhesive studies showed that film thickness of 0.12?mm was good for retention of tablet at stomach. At pH 1.2, optimized batch of tablet made with hydroxypropyl methyl cellulose (HPMC) E15 as binder showed 80% w/w drug release within 4–5?h with maximum average release of 97.49% w/w. Similarly, maximum average releases of 96.36% w/w and 95.47% w/w were obtained with nearly same dissolution patterns using combination of HPMC E5 and HPMC E50 and sodium salt of carboxy methyl cellulose (NaCMC) 500–600 cPs instead of HPMC E15. The release profiles in the distilled water and pH 4.5 followed the above pattern except deviation at pH 6.8. Stability studies were not positive for all combinations.

Conclusion: Coated, mucoadhesive donut-shaped tablet is good for controlled release of drug in the stomach.     

Development of meloxicam in situ implant formulation by quality by design principle

Objective: The focus of this study was to develop and optimize in situ implant formulation of meloxicam by quality by design (QbD) principle for long-term management of musculoskeletal inflammatory disorders.

Methods: The formulation was optimized by Box–Behnken design with polylactide-co-glycolide (PLGA) level (X₁), N-methyl pyrrolidone level (X₂) and PLGA intrinsic viscosity (X₃) as the independent variables and initial burst release of drug (Y₁), cumulative release (Y₂), and dissolution efficiency (Y₃) as the dependent variables. The formulation was physicochemically characterized by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy and powder X-ray diffraction (PXRD). Pharmacokinetic studies of the optimized formulation were performed on Sprague--Dawley rats.

Results: Y₁ was significantly affected by X₂ and X₃. Y₂ was affected by X₁ and X₃ while Y₃ was affected by all three independent variables employed in the formulations. Responses for the optimized formulation were in close agreement with the values predicted by the model. SEM photomicrographs indicated uniform gel formulation. No chemical interaction between the components of formulation was observed by FT-IR and meloxicam was found to be present in the amorphous form in the gel matrix as revealed by PXRD. The maximum plasma concentration (C_max), time to achieve C_max and area under plasma concentration curve were significantly different from those of the solution formulation used as the control. Plasma concentration of meloxicam was maintained above its IC₅₀ concentration required for COX-2 inhibition for 23 days.

Conclusion: Meloxicam in situ implant may provide long-term management of inflammatory conditions with improved patient compliance and better therapeutic index.     

Injectable thermosensitive hydrogel based on chitosan and quaternized chitosan and the biomedical properties

A novel injectable thermosensitive hydrogel (CS–HTCC/α β-GP) was successfully designed and prepared using chitosan (CS), quaternized chitosan (HTCC) and α,β-glycerophosphate (α,β-GP) without any additional chemical stimulus. The gelation point of CS–HTCC/α β-GP can be set at a temperature close to normal body temperature or other temperature above 25°C. The transition process can be controlled by adjusting the weight ratio of CS to HTCC, or different final concentration of α,β-GP. The optimum formulation is (CS + HTCC) (2% w/v), CS/HTCC (5/1 w/w) and α,β-GP 8.33% or 9.09% (w/v), where the sol–gel transition time was 3 min at 37°C. The drug released over 3 h from the CS–HTCC/α,β-GP thermosensitive hydrogel in artificial saliva pH 6.8. In addition, CS–HTCC/α,β-GP thermosensitive hydrogel exhibited stronger antibacterial activity towards two periodontal pathogens (Porphyromonas gingivalis, P.g and Prevotella intermedia, P.i). CS–HTCC/α, β-GP thermosensitive hydrogel was a considerable candidate as a local drug delivery system for periodontal treatment.     

Characterization and evaluation of β-glucan formulations as injectable implants for protein and peptide delivery

Context: Injectable implants are biodegradable, syringeable formulations that are injected as liquids, but form a gel inside the body due to a change in pH, ions or temperature.

Objective: To investigate the effect of polymer concentration, pH, ions and temperature on the gel formation of β-glucan, a natural cell-wall polysaccharide derived from barley, with particular emphasis on two-phase system formation after addition of dextran or PEG.

Materials and methods: Oscillation viscometry was used to evaluate the gel character by measuring flow index (N), storage (G′) and loss (G″) moduli. Two-phase systems were further characterized for hardness and syringeability using a texture analyzer. Finally, in vitro release characteristics were determined using Franz diffusion cells.

Results: Oscillation viscometry revealed that only addition of dextran or PEG resulted in distinct gel formation. This was seen by a decrease in N after polymer addition. Moreover, hardness (in g) of the gels increased significantly (p?<?0.001) from 3.65?±?0.43 to 34.30?±?8.90 (dextran) and 805.80?±?5.30 (PEG) 24?h after polymer addition. In vitro release profiles showed significantly (p?<?0.05) reduced AUC_{0–8 h}, k and percentage of drug released from two-phase systems compared to β-glucan dispersions, with the PEG system resulting in the lowest amount released over 8?h (15.1?±?1.6%).

Discussion: The unfavorable mixing enthalpy and higher water affinity of PEG resulted in the formation of a dense β-glucan gel.

Conclusion: 1.5% (w/w) β-glucan combined with PEG at a ratio of 1:3 seemed to be the most promising injectable formulation with respect to fastest gel formation, increased hardness and sustained release.     

A novel ion-activated in situ gelling ophthalmic delivery system based on κ-carrageenan for acyclovir

The aim of this study was to prepare and evaluate ion-activated in situ gel ophthalmic drug delivery system based on κ-carrageenan (KC), using acyclovir as a model drug, hydroxypropyl methylcellulose (HPMC) as the viscosity agent and hydroxypropyl-β-cyclodextrin (HP-β-CD) as the penetration enhancer. The two ternary phase diagrams exhibited the effect of K⁺ and Ca²⁺ on the sol-to-gel transition, which turned out that KC was more sensitive to K⁺. The optimal ophthalmic matrix (prepared from KC and HPMC) was optimized with in vitro drug release test. The apparent permeability coefficient of acyclovir under 2% HP-β-CD was found to have dramatically increased (2.16-ploid) than that of conventional eye drops (p?in situ gel based on KC significantly delayed drug release and its bioavailability could be improved in comparison with the conventional eye drops. Hence, it has the potential to be a novel kind of ocular drug delivery system.     

A novel vehicle for local protein delivery to the inner ear: injectable and biodegradable thermosensitive hydrogel loaded with PLGA nanoparticles

Delivery of biomacromolecular drugs into the inner ear is challenging, mainly because of their inherent instability as well as physiological and anatomical barriers. Therefore, protein-friendly, hydrogel-based delivery systems following local administration are being developed for inner ear therapy. Herein, biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing interferon α-2?b (IFN α-2?b) were loaded in chitosan/glycerophosphate (CS/GP)-based thermosensitive hydrogel for IFN delivery by intratympanic injection. The injectable hydrogel possessed a physiological pH and formed semi-solid gel at 37?°C, with good swelling and deswelling properties. The CS/GP hydrogel could slowly degrade as visualized by scanning electron microscopy (SEM). The presence of NPs in CS/GP gel largely influenced in vitro drug release. In the guinea pig cochlea, a 1.5- to 3-fold increase in the drug exposure time of NPs-CS/GP was found than those of the solution, NPs and IFN-loaded hydrogel. Most importantly, a prolonged residence time was attained without obvious histological changes in the inner ear. This biodegradable, injectable, and thermosensitive NPs-CS/GP system may allow longer delivery of protein drugs to the inner ear, thus may be a potential novel vehicle for inner ear therapy.     

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.     

Flurbiprofen-loaded niosomes-in-gel system improves the ocular bioavailability of flurbiprofen in the aqueous humor

The present work aimed to prolong the contact time of flurbiprofen (FBP) in the ocular tissue to improve the drug anti-inflammatory activity. Different niosome systems were fabricated adopting thin-film hydration technique and using the nonionic surfactant Span 60. The morphology of the prepared niosomes was characterized by scanning electron microscopy (SEM). Physical characterization by differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy were conducted for the optimized formula (F5) that was selected on the basis of percent entrapment efficiency, vesicular size and total lipid content. F5 was formulated as 1% w/w Carpobol 934 gel. Pharmacokinetic parameters of FBP were investigated following ocular administration of F5-loaded gel system, F5 niosome dispersion or the corresponding FBP ocular drops to albino rabbits dispersion. Anti-inflamatory effect of F5-loaded carbopol gel was investigated by histopathological examination of the corneal tissue before and after the treatment of inflamed rabbit eye with the system. Results showed that cholesterol content, surfactant type. and total lipid contents had an apparent impact on the vesicle size of the formulated niosomes. Physical characterization revealed reduced drug crystallinity and incidence of interaction with other niosome contents. F5-loaded gel showed higher C_max, area under the curve (AUC_0–12), and thus higher ocular bioavailability than those of the corresponding FBP ocular solution. F5-loaded gel showed a promising rapid anti-inflammatory effect in the inflamed rabbit eye. These findings will eradicate the necessity for frequent ocular drug instillation and thus, improve patient compliance.     

Pharmacodynamic and pharmacokinetic investigation of cyclodextrin-mediated asenapine maleate in situ nasal gel for improved bioavailability

Asenapine maleate (AM) is used in the treatment of schizophrenia. Its oral and sublingual bioavailability is <2% and 35%, respectively, due to first pass metabolism and poor solubility. To avoid first pass metabolism and to enhance solubility at all nasal pH conditions, thermo-responsive in situ nasal gel containing asenapine maleate-hydroxyl propyl β cyclodextrin inclusion complex (AM-HPβCD) was prepared in the present study. Inclusion complex (1:1 molar ratio) was characterized using UV spectroscopy, FITR and XRD techniques. Selected formulation (F8b) contained a thermo-sensitive polymer poloxamer 407 which formed gel at 23%w/v concentration and a mucoadhesive polymer PVP K 30 (0.3%w/v) in temperature range of 29–34?°c. It was analyzed for pH, clarity, gelation temperature, mucoadhesive strength, gel strength and rheological parameters using Anton paar compact rheometer. This formulation was subjected to in vitro drug diffusion study using the Franz diffusion cell. Maximum % drug diffusion was obtained at the end of 120?min (99.1?±?0.44%w/v). Dissolution in simulated nasal fluid was 92.33?±?0.15%w/v at the end of 120?min. Locomotor activity was improved with nasal gel containing AM-HPβCD as compared to AM and AM-HPβCD oral solution in rats. C_max for nasal gel was found to be more (9?ng/ml) as compared to AM-HPβCD (5.5?ng/mL) and oral standard solution (2?ng/ml). T_max was found to be 1.5?h. AUC and thus bioavailability in rats by nasal route was increased by 2.5 fold.     

Antitumor activity of TNF-α after intratumoral injection using an in situ thermosensitive hydrogel

Local drug delivery strategies based on nanoparticles, gels, polymeric films, rods and wafers are increasingly used in cancer chemotherapy in order to enhance therapeutic effect and reduce systemic toxicity. Herein, a biodegradable and biocompatible in situ thermosensitive hydrogel was designed and employed to deliver tumor necrosis factor-α (TNF-α) locally by intratumoral injection. The triblock copolymer was synthesized by ring-opening polymerization (ROP) of β-butyrolactone (β-BL) and lactide (LA) in bulk using polyethylene glycol (PEG) as an initiator and Sn(Oct)₂ as the catalyst, the polymer was characterized by NMR, gel permeation chromatography and differential scanning calorimetry. Blood and tumor pharmacokinetics and in vivo antitumor activity of TNF-α after intratumoral administration in hydrogel or solution with the same dose were evaluated on S180 tumor-bearing mice. Compared with TNF-α solution, TNF-α hydrogel exhibited a longer T_1/2 (4-fold) and higher AUC_tumor (19-fold), but C_max was lower (0.5-fold), which means that the hydrogel formulation improved the efficacy with a lower systhemic exposure than the solution formation. In addition, TNF-α hydrogel improved the antitumor activity and survival due to lower systemic exposure than the solution. These results demonstrate that the in situ thermosensitive hydrogel-based local delivery system by intratumoral injection is well suited for the administration of TNF-α.