Gel vehicles are not inherently more irritating than creams

BACKGROUND: It has been thought that topical gels are inherently more irritating than topical creams. Nevertheless, the irritancies of topical products are potentially quite variable, and a priori assumptions about relative irritancy of gels versus creams may not be accurate. PURPOSE: To determine whether a metronidazole gel formulation is more or less irritating to the skin compared to metronidazole creams. METHODS: A total of 32 normal, healthy volunteers were tested using irritancy patches with 0.75% metronidazole gel and cream, 1% metronidazole cream, and petrolatum (used as the "negative control"). Blinded observers evaluated the application sites for signs of irritancy. A numerical score was assigned to these irritancy patch sites each day for 21 days, or until significant irritation developed, and cumulative irritancy scores were calculated for the study period. A mixed model of variance analysis was performed. RESULTS: After 21 days of evaluation, analysis of the mean cumulative irritancy scores for each of the agents used showed there to be no statistical difference in irritancy potential between the metronidazole gel and the metronidazole creams. However, the 1% metronidazole cream was significantly more irritating than petrolatum. CONCLUSION: There was no significant difference in the cumulative irritancy potential of cream and gel preparations of metronidazole. The irritancy of topical formulations for treating rosacea should be considered on a case by case basis.     

Effect of Mechanical Properties on the Release of Meloxicam from Poloxamer Gel Bases

Thermoreversible gel of meloxicam, efficient for the treatment of joint diseases, was aimed to prepare for night application available for chronotherapy in this study. Poloxamer 407 and 188 polymers were used at 20-30% w/w as a vehicle in combination with different additives (polyvinylmethylether maleic anhydride copolymer, hydroxypropyl methylcellulose, polyethylene glycol 400, dimethyl sulfoxide, sodium chloride). Characterisation of prepared gels was evaluated by viscosity and texture analysis, and the effect of formulation variables on the gel formulations were evaluated by in vitro drug release and erosion studies. Between the investigated gel bases, Poloxamer 407-hydroxypropyl methylcellulose gel was found to be ideal due to its gel strength (1.560±0.0135 N), viscosity (312.3±2.06 cP) and release characteristics. These promising results could be encouraging for further studies to make it an alternative to commercial dosage forms.     

Fluconazole-loaded solid lipid nanoparticles topical gel for treatment of pityriasis versicolor: formulation and clinical study

Solid lipid nanoparticles (SLNs) are very potential formulations for topical delivery of antifungal drugs. Hence, the purpose of this research was to formulate the well-known antifungal agent Fluconazole (FLZ)-loaded SLNs topical gel to improve its efficiency for treatment of Pityriasis Versicolor (PV). FLZ-SLNs were prepared by modified high shear homogenization and ultrasonication method using different concentration of solid lipid (Compritol 888 ATO, Precirol ATO5) and surfactant (Cremophor RH40, Poloxamer 407). The physicochemical properties and the in vitro release study for all FLZ-SLNs were investigated. Furthermore, the optimized FLZ-SLN formula was incorporated into gel using Carpobol 934. A randomized controlled clinical trial (RCT) of potential batches was carried out on 30 well diagnosed PV patients comparing to market product Candistan^® 1% cream. Follow up was done for 4?weeks by clinical and KOH examinations. The results showed that FlZ-SLNs were almost spherical shape having colloidal sizes with no aggregation. The drug entrapment efficiency ranged from 55.49% to 83.04%. The zeta potential values lie between ?21 and ?33?mV presenting good stability. FLZ showed prolonged in vitro release from SLNs dispersion and its Carbapol gel following Higuchi order equation. Clinical studies registered significant improvement (p?® cream.     

Influence of drug content,type of semi-solid vehicle and rheological properties on the skin penetration of the model drug fludrocortisone acetate

Throughout Europe, topical creams containing corticosteroids are diluted with various neutral cream bases to meet the specific needs of patients. Even though this practice has been common for years, its effect has not been thoroughly investigated and so the effectiveness of the diluted topical steroidal creams is difficult to predict. In the present study, the model drug fludrocortisone acetate was incorporated into three cream bases of different hydrophilicity that are commonly used in Austria. Different final drug concentrations were chosen for comparative studies. Additionally, a semi-solid preparation developed by our group was investigated for comparison. These formulations were tested in diffusion and tape stripping experiments. Diffusion cell studies showed that changes in drug concentration do not necessarily change the skin permeation behaviour in vitro. The tape stripping protocol was successfully optimised for investigation of semi-solid preparations to provide reproducible and accurate results despite the challenges of investigating semi-solid formulations. The results showed that tape stripping experiments are more suitable to elucidate subtle differences between formulations. The composition of the cream bases exhibited stronger effects on the skin penetration of the steroidal drug irrespective of its concentration than the rheological properties. No correlation between formulation viscosity and skin penetration was found.     

Formulation,Characterization, and In Vitro Evaluation of Bioadhesive Gels Containing 5-Fluorouracil

The objective of this study was to prepare and evaluate in vitro the bioadhesive gels of 5-Fluorouracil (FU) for the treatment of oropharyngeal cancer. In preformulation study, the physicochemical interactions between FU and polymers were investigated by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectrophotometry, and differential scanning calorimetry (DSC). According to FTIR, XRD, and DSC studies, the drug did not show any evidence of an interaction with the polymers used and was present in an unchanged state. The gel formulations containing FU were prepared by using Poloxamer 407, HPMC K 15 M, and Gantrez® S-97 (polymethylvinylether-co-maleic anhydride). The formulations contained Poloxamer 407 (16–18% w/w) either alone or in combination with HPMC K 15 M and Gantrez® S-97. The bioadhesiveness of the gels was found to increase with increasing proportion of HPMC K 15 M and Gantrez® S-97. In vitro release studies indicated that release could be sustained up to 8 hr. The permeability coefficients (Kp) of gel across cellulose membrane and buccal mucosal membrane were 1.06 × 10^?4 cm/s and 3.94 × 10^?5 cm/s, respectively, and differed significantly (p < 0.05). Increasing temperature increased the drug release by increasing drug diffusion despite increase in viscosity. The pH of the release medium showed a very slight effect on the release of FU. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer–Peppas model and the drug release kinetics primarily as non-Fickian diffusion.     

Development and physical characterization of a periodontal bioadhesive gel of metronidazole

To develop a localized drug delivery system that offers prolonged administration of metronidazole into the periodontal pocket, muccoadhesive gel formulations containing 5% w/w metronidazole were prepared using the bioadhesive polymers: carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpirrolidone, and carbopol. Increased concentrations of the polymers decreased the drug release rate and enhanced syringeability, yield value, and adhesiveness but decreased the spreadability. The bioadhesive properties of the gels were affected by pH and Ca 2+ concentration. The gel containing 20% hydroxyethylcellulose, 20% polyvinylpirrolidone, and 1% carbopol exhibited zero-order drug release kinetics and suitable physical properties for drug delivery to the periodontal pocket.     

Development and Physical Characterization of a Periodontal Bioadhesive Gel of Metronidazole

To develop a localized drug delivery system that offers prolonged administration of metronidazole into the periodontal pocket, muccoadhesive gel formulations containing 5% w/w metronidazole were prepared using the bioadhesive polymers: carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, polyvinylpirrolidone, and carbopol. Increased concentrations of the polymers decreased the drug release rate and enhanced syringeability, yield value, and adhesiveness but decreased the spreadability. The bioadhesive properties of the gels were affected by pH and Ca 2+ concentration. The gel containing 20% hydroxyethylcellulose, 20% polyvinylpirrolidone, and 1% carbopol exhibited zero-order drug release kinetics and suitable physical properties for drug delivery to the periodontal pocket.     

Transdermal delivery of meloxicam using niosomal hydrogels: in vitro and pharmacodynamic evaluation

Abstract

Non-ionic surfactant vesicles were prepared using Span-60 and cholesterol in the mass ratios of 1:1, 2:1, 1:2 and 3:1 for transdermal delivery of an anti-inflammatory drug meloxicam (MXM). The drug encapsulation efficiencies and particle size were observed in the range of 32.9–80.7% and 56.5–133.4?nm, respectively. Three different gel bases were also prepared using Poloxamer-407, Chitosan and Carbopol-934 as polymers to study the performance of the in vitro release of the drug. Prepared gels were also converted into niosomal gels. In vitro release characteristics of MXM from different gels were carried out using dialysis membrane in phosphate buffer (pH 7.4). The poloxamer-407 gel or niosomal poloxamer-407 gel showed the superior drug release over the other formulations. The release data were treated with various mathematical models to assess the relevant parameters. The results showed that the release of MXM from the prepared gels and niosomal gels followed Higuchi’s diffusion model. The flux of MXM was found to be independent on the viscosity of the formulations. The anti-inflammatory effects of MXM from different niosomal gel formulations were evaluated using carrageenan-induced rat paw edema method, which showed superiority of niosomal gels over conventional gels.     

Evaluation of topical econazole nitrate formulations with potential for treating Raynaud’s phenomenon

The purpose of this work was to design and characterize a topical formulation of econazole nitrate (EN) with potential for treating Raynaud’s phenomenon (RP). Four topical dosage forms (F1_topical solution, F2_HPMC or hydroxypropyl methylcellulose dispersion, F3_VersaBase^® cream, and F4_{_}Lipoderm^® Activemax? Cream) containing 3% w/w EN were prepared and characterized for drug content, pH, viscosity, spreadability, drug crystallinity, stability, and in vitro permeation using Franz cells across pig ear skin, and results were compared to the 1% marketed EN cream. All four formulations had acceptable physical and visual characteristics required for topical application, with 3% w/w EN. The order of amount of drug permeated from highest to lowest was F2 (10.27%) > F4 (2.47%) > F1 (2.28%) > F3 (1.47%) > marketed formulation (0.22%). Formulation F2 showed better penetration of the drug into the stratum corneum, epidermis, and dermis layers. The drug concentration in the stratum corneum and epidermis was approximately 10–20 times higher with F2 compared to the marketed formulation. All formulations were found to be stable for up to 6 months. All four EN formulations were found to be better than the 1% marketed cream. Formulation F2_{_}HPMC dispersion could be further explored as a treatment option for RP.     

Formulation and evaluation of novel controlled release of topical pluronic lecithin organogel of mefenamic acid

In the present study, pluronic lecithin based organogels (PLO gels) were formulated as topical carrier for controlled delivery of mefenamic acid. Ten organogel formulations were prepared by a method employing lecithin as lipophilic phase and pluronic F-127 as hydrophilic phase in varying concentrations to study various parameters using in vitro diffusion study and in vivo studies. All formulations were found to be off-white, homogenous, and reluctant to be washed easily and have pH value within the range of 5.56–5.80 which is nonirritant. Polymer concentration increased in formulations of F1 to F5 (lecithin) and F6 to F10 (pluronic) resulted in decrease of the gelation temperature, increase of viscosity and reduction of spreadability of gels having polymer tendency to form rigid 3D network. Organogels with higher viscosity were found to be more stable and retard the drug release from the gel. The formulations of F2 and F3 were selected for kinetic studies and stability studies, as they found to have all physical parameters within acceptable limits, highest percent drug content and exhibited highest drug release in eight hours. The order of drug release from various formulations was found to be F2?>?F3?>?F10?>?F4?>?F1?>?F9?>?F8?>?F5?>?F7?>?F6. The optimized formulation F2 was found to follow zero order rate kinetics showing controlled release of the drug from the formulations. In vivo anti-inflammatory activity of optimized mefenamic acid organogel (F2) against a standard marketed preparation (Volini gel) was found satisfactory and significant.     

Enhanced Transdermal Delivery of Diazepam by Submicron Emulsion (SME) Creams

Diazepam, a lipophilic drug with CNS activity, serves here as a model to investigate the efficacy of SubMicron Emulsion (SME) as a novel transdermal vehicle. Diazepam was formulated in various topical regular creams and SubMicron Emulsion creams of different compositions. The different formulations were applied topically and protection against Pentamethylenetetrazole induced convulsive effects in mice was monitored. The efficacy of Diazepam applied topically in emulsion creams strongly depends on the oil droplet size and to a lesser degree - on the formulation composition and the oil type. Processing medium-chain-triglyceride (MCT) emulsion with a high-pressure homogenizer causes a drastic reduction in the droplet size, thereby significantly increasing the transdermal activity of Diazepam. In this case both the high-pressure homogenization and the presence of lecithin, an efficient dispersant, contribute to the effective droplet size reduction of below 1 micron, usually between 100–300 nm. The SubMicron Emulsions as vehicles for transdermal delivery of Diazepam generate significant systemic activity of the drug as compared with regular creams or ointments. Transdermal delivery of Diazepam via SME formulations is very effective, and the activity may reach the range of parenteral delivery. A single application of Diazepam in SME cream to mice skin provides pronounced transdermal drug delivery and prolonged protective activity up to 6 hours.     

In Vitro Release of Hydrocortisone from Topical Preparations and Automated Procedure

The in vitro drug release profile of hydrocortisone (HC) from creams, ointments, and lotions has been determined using an automated procedure. A diffusion cell system and commercially available synthetic membranes were utilized for the studies. The use of a synthetic membrane obviates the problems associated with using skin membranes. Uniform creams and ointment samples for determining the release rate profile were prepared by using the teflon mask. Automated sampling avoids operator artifacts. The automated technique developed for determining the in vitro release rate profile of the drug from creams, ointments, and lotions using a diffusion-cell system appears to be a reasonable and practical procedure for assuring batch-to-batch uniformity of topical drug products.     

A new self-emulsifying formulation of mefenamic acid with enhanced drug dissolution

To enhance the dissolution of poorly soluble mefenamic acid, self-emulsifying formulation (SEF), composing of oil, surfactant and co-surfactant, was formulated. Among the oils and surfactants studied, Imwitor^® 742, Tween^® 60, Cremophore^® EL and Transcutol^® HP were selected as they showed maximal solubility to mefenamic acid. The ternary phase diagram was constructed to find optimal concentration that provided the highest drug loading. The droplet size after dispersion and drug dissolution of selected formulations were investigated. The results showed that the formulation containing Imwitor^® 742, Tween^® 60 and Transcutol^® HP (10:30:60) can encapsulate high amount of mefenamic acid. The dissolution study demonstrated that, in the medium containing surfactant, nearly 100% of mefenamic acid were dissolved from SEF within 5 min while 80% of drugs were dissolved from the commercial product in 45 min. In phosphate buffer (without surfactant), 80% of drug were dissolved from the developed SEF within 5 min while only about 13% of drug were dissolved in 45 min, from the commercial product. The results suggested that the SEF can enhance the dissolution of poorly soluble drug and has a potential to enhance drug absorption and improve bioavailability of drug.     

Calendar

The aim of our study was to prepare clomiphene citrate gel formulations that possess appropriate mechanical properties, stay on the vaginal mucosa for a long period of time, and provide sustained drug release for the local treatment of human papilloma virus infections. In this respect, 1% CLM gels including polyacrylic acid (PAA) polymers such as Carbopol® 934P (C934P), Carbopol® 971P (C971P), Carbopol® 974P (C974P) in various concentrations, and their conjugates containing thiol groups were prepared. Polyacrylic acid-cysteine (PAA-Cys) conjugates were synthesized in laboratory conditions. Mechanical properties of the gels such as hardness, compressibility, elasticity, adhesiveness, and cohesiveness were measured by TA-XTPlus texture analyzer and the vaginal mucoadhesion of formulations was investigated by mucoadhesion test. Based on obtained data, gel formulations containing C934P and its conjugate had appropriate hardness and compressibility to be applied to the vaginal mucosa and highest elasticity to show good spreadability and highest cohesion to prevent the disintegration of gel in the vagina. The mucoadhesion of the gels changed significantly depending on the polymer type and concentration (p < 0.05). The addition of conjugates containing thiol groups caused an increase in mucoadhesion (p < 0.05). The gels containing C934P-Cys showed highest adhesiveness and mucoadhesion due to the highest amount of thiol groups. A significant decrease was observed in the drug release of gel formulations as the polymer concentration increased (p < 0.05). The increase in the drug release related to the conjugate addition was not statistically significant (p > 0.05). A change in the amount of CLM was not observed in all formulations at the end of the stability test.     

Design,Preparation and Evaluation of HPMC-Based PAA or SA Freeze-Dried Scaffolds for Vaginal Delivery of Fluconazole

Purpose

Aim of this work was preparation of bioadhesive gel formulations based on Hydroxypropyl methylcellulose (HPMC), Poly(acrylic acid) (PAA) or Sodium alginate (SA) loaded with anise/fluconazole β-cyclodextrin inclusion complexes in 1:2 and 1:3 ratios intended for vaginal applications.

Methods

Freeze-drying method was effectively utilized and superporous morphology was obtained. The superporous morphology of the lyophilized gels, dynamic water vapor sorption measurements, drug release kinetics studies and their antimicrobial activities are presented.

Results

HPMC content influences especially the sorption/desorption behaviour of HPMC-based PAA gels and the morphology of the gel formulations with fluconazole/β-cyclodextrin inclusion complexes, due to the interactions among the gel networks absorbing water molecules. It was found that fluconazole release kinetics correspond to quasi-Fickian, Fickian diffusion and non-Fickian mechanisms for the studied hydrogels. The tested vaginal formulations with β-cyclodextrin inclusion complexes exhibited selectivity toward S. aureus ATCC 25923 and all tested Candida strains in comparison with the gel formulation without β-cyclodextrin.

Conclusions

The fluconazole/β cyclodextrin inclusion complexes ensure a controlled release of fluconazole over a few days, the highest amount of drug release (92%) being observed after 43 h. These bioadhesive gel formulations could be very promising topical alternative for treatment of vaginal fungal infections.

     

Correlation Between Rheological Properties and <Emphasis Type="Italic">In Vitro</Emphasis> Drug Release from Penetration Enhancer-Loaded Carbopol® Gels

Purpose

The aim of this study was to investigate the effect of commonly used penetration enhancers on the viscoelastic properties and in vitro drug release from topical gel formulations.

Methods

Three penetration enhancers, diethylene glycol monoethyl ether (Transcutol^®-P, TC), propylene glycol (PG), and 70 % ethanol were selected in this study. The non-steroidal anti-inflammatory drug diclofenac sodium (DNa) was used as a model drug. DNa gels were prepared using the gelling agent Carbopol^® 971P with or without different concentrations of the three penetration enhancers. Each gel formulation was characterized in terms of its viscoelastic properties (elastic or storage modulus G′ and viscous or loss modulus G″) using a controlled stress rheometer (CSR) and in vitro release using Franz diffusion cells.

Results

DNa gels containing TC, PG, and ethanol demonstrated a significant decrease in the viscoelastic properties compared to gels containing no penetration enhancers, and an enhancement in drug release. Gels containing TC at the highest tested concentration (40 %) exhibited the lowest viscoelastic properties and showed the highest enhancement in drug release. Both TC and ethanol showed a concentration-dependent effect in promoting steady-state flux values for DNa, unlike PG. DNa release kinetics from all gels followed super case II transport as fitted by the Korsmeyer–Peppas model.

Conclusions

Our results provide valuable insights into the mechanisms by which different penetration enhancers can modulate drug release from topical gels by altering the rheological properties of the gelling agent.

     

Formulation and stability study of chlorpheniramine maleate nasal gel

Nasal administration has been of special interest in the last decade due to its feasibility and relative high bioavailability compared to the oral rout of administration. Our study aimed to develop a nasal gel formulation for an antihistaminic drug, Chlorpheniramine maleate (CPM), which suffers from poor oral bioavailability (25–45%) due to its first-pass metabolism in the liver. Different formulations of CPM nasal gels were prepared using different polymers in different concentrations, these gels were evaluated for their in vitro (physico-chemical properties, release, permeability and stability) to select the best formulation which subject to in vivo tests including mucociliary clearance and bioavailability, both in comparison to the solution and commercial tablet Allergyl^®.     

Comparison of pharmaceutical properties of topical non-steroidal anti-inflammatory drug preparations on quality of life

To compare the effects of different pharmaceutical properties of commercially available topical nonsteroidal antiinflammatory drugs (NSAIDs) on the quality of life, we administered a questionnaire to 65 healthy volunteers. We investigated five creams, five gels, and four solutions of topical NSAID preparations in this study. The survey was conducted to clarify the relationship of their answers and pharmaceutical properties of the topical NSAID preparations. Questions addressed spreadability, smell, viscosity, and comfort level of the topical NSAID preparations. Among the five creams, Napageln had lower spreadability, less smell, and greater viscosity than the other preparations. Because of its easy spreadability, weak smell, and low viscosity, the volunteers favored Sector cream among the cream preparations. Among the five gel preparations, Inteban had less spreadability, stronger smell, and higher viscosity than the other preparations. The volunteers favored Epatec over the other gel preparations. All four solutions had the odor of menthol and other artificial ingredients, except for Napageln. These findings indicate that information on the pharmaceutical properties of commercially available topical NSAID preparations will be helpful to physicians and pharmacists in conducting medical treatment and prescribing.     

Formulation and Evaluation of Cefixime Trihydrate Matrix Tablets Using HPMC,Sodium CMC,Ethyl Cellulose

The objective of the present work is to design sustained release matrix tablets of cefixime trihydrate by incorporating drug in a matrix made up of release retardant polymers, which prolong drug release leading to minimization of the peak and valley effect in the plasma and provide patient convenience. The effect of combination of polymers on parameters like release pattern, release mechanism of the drug were studied. Total nine formulations each containing 200 mg of drug were prepared by direct compression method. The formulations F-1, F-2, F-3 were prepared with a 1:1 drug to polymer ratio using hydroxypropyl methylcellulose, carboxymethyl cellulose sodium and ethyl cellulose. F-4 was prepared with a 1:1 ratio of hydroxypropyl methylcellulose, carboxymethyl cellulose sodium, F-5 as prepared with a 1:1 ratio of hydroxypropyl methylcellulose and ethyl cellulose, F-6 was prepared with a 1:1 ratio of carboxymethyl cellulose sodium and ethyl cellulose, F-7, F-8, F-9 were prepared by using polymers hydroxypropyl methylcellulose, carboxymethyl cellulose sodium and ethyl cellulose in the ratios of 0.5:0.5:1, 0.5:1:0.5, and 1:0.5:0.5. Designed matrix tablets were evaluated for various pre-compression and post-compression parameters. Formulation F-5 showed 102.15 % release at the end of 12 h and it is selected as the best formulation. All Formulations followed zero order with non-Fickian diffusion method.