Development of Novel Nonaqueous Ethylcellulose Gel Matrices: Rheological and Mechanical Characterization

No HeadingPurpose. This study reports the rheological and mechanical characterization of novel non-aqueous ethylcellulose gel matrices intended for topical drug delivery. An attempt was also made to explain the molecular interaction within the gel systems from a molecular conformational approach.Methods. Nonaqueous gel matrices were prepared from three fine particle grades of ethylcellulose and propylene glycol dicaprylate/dicaprate. Continuous and oscillatory shear rheometry was performed using a cone-and-plate rheometer and mechanical characterization was performed using a universal tensile tester.Results. The gel matrices exhibited prominent viscoelastic behaviour, yield stress and thixotropy. Rheological and mechanical properties showed significant upward trends with increased polymeric chain length and polymer concentrations. Good linear correlations were obtained between rheological and mechanical properties. The solvent molecular conformation was found to play a role in affecting the formation of gel networks via intermolecular hydrogen bonding between ethylcellulose polymer chains.Conclusions. Ethylcellulose was successfully formulated as a nonaqueous gel with propylene glycol dicaprylate/dicaprate. The novel nonaqueous gel exhibited rheological profiles corresponding to a physically cross-linked three dimensional gel network, with suitable mechanical characteristics for use as a vehicle for topical drug delivery. Molecular conformation of the solvent was found to influence the molecular interactions associated with formation of ethylcellulose gel networks.     

Investigation of Wetting Behavior of Nonaqueous Ethylcellulose Gel Matrices Using Dynamic Contact Angle

PURPOSE: This study reports the development of a method based on dynamic contact angle to investigate the wetting behavior of non-aqueous ethylcellulose (EC) gel matrices intended for topical drug delivery. METHODS: Non-aqueous gel matrices were prepared from the three fine particle grades of EC and propylene glycol dicaprylate/dicaprate. Dynamic contact angle measurements of sessile drops of water and isopropylmyristate (IPM) on EC gel matrices were performed using a dynamic contact angle analyzer equipped with axisymmetric drop shape analysis of the sessile drop images. Gel density was determined by weighing known volumes of gel samples. RESULTS: The EC gel matrices were wetted by both water and IPM, with much higher wettability by the latter. Increased EC concentration and polymeric chain length decreased the extent and rate of wetting. Linear correlation was observed between wetting parameters and rheological as well as mechanical properties of EC gel matrices. CONCLUSIONS: The EC gel matrices exhibited both hydrophilic and lipophilic properties, with predominance of the latter. The extent and rate of wetting was governed by a balance of chemical and physical characteristics of the gel. EC gel matrices showed desirable wetting behavior in their function as a moisture-barrier, bioadhesive and vehicle for topical drug delivery.     

Design of minocycline-containing starch nanocapsules for topical delivery

Pharmaceutical research has been focussed on developing improved delivery systems while exploring new ways of using approved excipients. The present work investigated the potential of starch nanocapsules (StNC) as a topical delivery platform for hydrophilic antimicrobial drugs using minocycline hydrochloride (MH) as a model drug. Thus, a quality by design approach was used to assess the role of different factors that affect the main pharmaceutical properties of StNC prepared using an emulsification–solvent evaporation method. Full characterisation was performed in terms of particle size, encapsulation efficiency, morphology and physical stability at 5?±?3?°C. Results show the surfactant and lipid contents play a major role in StNC particle size distribution. The MH loading only promoted minor changes upon StNC properties. Formulations were stable without variations on physicochemical properties. All tested formulations presented a zeta-potential of +33.6?±?6.7?mV, indicating a good physical stability and evidencing that StNC are suitable nanocarriers for topical use.     

Novel Stability-Indicating RP-HPLC Method for the Simultaneous Estimation of Clindamycin Phosphate and Adapalene along with Preservatives in Topical Gel Formulations

A novel stability-indicating RP-HPLC method was developed for the simultaneous estimation of clindamycin phosphate (hydrophilic), adapalene (hydro-phobic), phenoxyethanol, and methylparaben in topical gel formulations. Optimum chromatographic separation among the analytes and stress-induced degradants peaks was achieved on the XBridge C18 (50 × 4.6 mm, 3.5 µm) column using a mobile phase consisting of a variable mixture of pH 2.50 ammonium hydrogen phosphate buffer, acetonitrile, and tetrahydrofuran with gradient elution. Detection was performed at 210 nm for phenoxyethanol, methylparaben, and clindamycin phosphate and 321 nm for adapalene. The method was optimized with a unique diluent selection for the extraction of clindamycin phosphate and adapalene from the gel matrix. The developed method was validated for method precision, specificity, LOD and LOQ, linearity, accuracy, robustness, and solution stability as per ICH guidelines. The proposed method can be employed for the quantification of clindamycin phosphate, adapalene, phenoxyethanol, and methylparaben in commercial topical gel formulations.     

优选精制蛇毒酶凝胶剂基质组成及制备工艺

目的室温条件下优选精制蛇毒酶凝胶剂基质组成及制备工艺。方法以凝胶剂的稳定性及外观性状为考察指标,以卡波姆-940、氮酮、丙三醇-丙二醇和吐温-80为可变因素,选用L9(34)表进行正交实验。结果最优的基质组成是:卡波姆-940 2.0g,氮酮1.0g,丙三醇-丙二醇为7g∶3g,吐温-80 1.5g。结论按该法制备的凝胶剂符合中国药典2005年版软膏剂的有关规定。     

The effect of additives on the availability of atropine in transdermal therapeutic systems]

The present paper investigates the effect of 13 liquid and semisolid additives on the pharmaceutical availability of atropine from dermal silicone matrices. The hydrophobic additives isopropylmyristate, linseed oil, methylsilicone oil, olive oil, liquid paraffin, the tensides Abil B 8842, Spans 20, 40, 60, Tweens 40 and 80, and the hydrophilic additives polyethylene glycol 200 and 400 were employed for the study. The additives were incorporated into the silicone matrices in the amount of 5%. The paper aimed to replace polyethylene glycol, used in dermal silicone matrices at present, with a different additive. When using liquid or semisolid additives, a 2 to 3.5-fold increase in pharmaceutical availability of atropine in contrast to the control sample was achieved. The highest values of pharmaceutical availability were obtained with the use of isopropylmyristate, polyethylene glycol 400, olive and linseed oils, and Span 20. The paper discusses the effect of the individual additives on the mechanism of release of atropine from silicone matrices.     

Dynamic rheology as a quantitative method for real-time tracking of excipient solvation in non-aqueous hydroxypropylcellulose topical gels

This article describes a method to quantitatively track the solvation of HPC in a non-aqueous solvent system during topical gel manufacture. Where visual observation and microscopy could not establish a trend, straight-forward rheological profiling demonstrated a correlation between increased solvation of hydroxypropyl cellulose polymer (viscosity modifier) and decreased tan δ, indicating the formation of a viscoelastic gel network over time during processing. This correlation serves as a valuable tool for process optimization and HPC solvation tracking in non-aqueous topical gel formulations.     

Characterization of spreadability of nonaqueous ethylcellulose gel matrices using dynamic contact angle

This study reports the characterization of spreadability of nonaqueous ethylcellulose (EC) gel matrices intended for topical drug delivery using a newly developed method based on dynamic contact angle. EC solutions were prepared using three grades of EC and propylene glycol dicaprylate/dicaprate. Dynamic contact angles of sessile drops of EC solutions on silicone elastomer were measured using a dynamic contact angle analyzer equipped with axisymmetric drop shape analysis-profile. Roughness of silicone elastomer, viscosity of EC solutions and compressibility of semisolid EC gels were determined by the atomic force microscope, cone-and-plate rheometer and tensile tester, respectively. The silicone elastomer employed as a substrate was demonstrated to have similar hydrophilic/lipophilic properties as the human skin. Spreadability of EC solutions was dependent on EC concentration, polymeric chain length and polydispersity. EC gel spreadability was governed by viscosity and the extent of gel-substrate interaction. From the apparent contact angle values, most EC gel formulations tested were found to be moderately spreadable. Linear correlation observed between spreading parameter and compressibility of EC gel verified the applicability of dynamic contact angle to characterize EC gel spreadability. Thus, the feasibility of employing dynamic contact angle as an alternative technique to measure gel spreadability was demonstrated. The spreadability demonstrated by EC gel would facilitate application on the skin indicating its potential usefulness as a topical dosage form.     

Amphiphilogels as drug carriers: effects of drug incorporation on the gel and on the active drug

Amphiphilogels (a subset of organogels) are being studied as drug carriers in our laboratories. In this paper, the effects of drug incorporation on the drugs and the gels are discussed. Amphiphilogels were prepared by heating a mixture of the gelator (sorbitan monostearate or sorbitan monopalmitate) and the liquid (e.g. Tweens or liquid Spans) to form a solution/dispersion, which was cooled to the gel state. Drugs were dissolved by heating a mixture of the drug and the gel and cooling the resulting solution. Hydrophilic gels (composed of hydrophilic Tweens as the liquid) were more effective solvents than hydrophobic ones (composed of hydrophobic Span 20 or 80 liquids). The latter's solvent capacity could, however, be increased by the inclusion of co-solvents, such as propylene glycol and ethanol. Drug incorporation at 10% w/w did not cause any detrimental changes in gel stability, while the drug's release rate was dependent on its concentration and on the nature of the gel's liquid component (which influences drug solubility), but not on gelator concentration or on the method of drug incorporation. This study shows the importance of the nature of the gels' liquid component and the possibility of using hydrophilic amphiphilogels as solvents for poorly water-soluble drugs.     

Preparation and Evaluation of Soft Gellan Gum Gel Containing Paracetamol

The objective of this study was to develop soft paracetamol gel using gellan gum as a gelling agent and sodium citrate as a source of cation. Different batches were prepared using three different concentrations of gellan gum (0.1, 0.3, and 0.5%), each with two different sodium citrate concentrations (0.3 and 0.5%). The consistency of the paracetamol gel was dependent on the concentration of gellan gum, sodium citrate and co-solute. The results of dissolution study of soft gel containing 0.3% gellan gum and 0.3% sodium citrate revealed that paracetamol was completely released in 30 min. Polyethylene glycol 400 worked as a solubilizer for paracetamol. All the gels possessed acceptable sensory characteristics when evaluated by human volunteers. Short term stability study carried out for four weeks at different temperatures revealed no considerable changes in performance characteristics of developed optimized formulation.     

硝苯地平亲水凝胶骨架缓释片剂的研究

硝苯地平亲水凝胶骨架缓释片是采用ＨＰＭＣ，ＰＥＧ等辅料压制而成．体外释放度实验给出，１２ｈ累积释放量＞７０％，其释放行为符合Ｈｉｇｕｃｈｉ时间平方根方程．稳定性因素实验结果显示：本品在高温（８０℃）高湿（ＲＨ９３％）条件下较稳定，但光照（３０００ＬＸ）使含量明显降低．     

Stability of 5-aminolevulinic acid in novel non-aqueous gel and patch-type systems intended for topical application

Aminolevulinic acid (ALA) stability within topical formulations intended for photodynamic therapy (PDT) is poor due to dimerisation to pyrazine-2,5-dipropionic acid (PY). Most strategies to improve stability use low pH vehicles, which can cause cutaneous irritancy. To overcome this problem, a novel approach is investigated that uses a non-aqueous vehicle to retard proton-induced charge separation across the 4-carbonyl group on ALA and lessen nucleophilic attack that leads to condensation dimerisation. Bioadhesive anhydrous vehicles based on methylvinylether-maleic anhydride copolymer patches and poly(ethyleneglycol) or glycerol thickened poly(acrylic acid) gels were formulated. ALA stability fell below pharmaceutically acceptable levels after 6 months, with bioadhesive patches stored at 5 degrees C demonstrating the best stability by maintaining 86.2% of their original loading. Glycerol-based gels maintained 40.2% in similar conditions. However, ALA loss did not correspond to expected increases in PY, indicating the presence of another degradative process that prevented dimerisation. Nuclear magnetic resonance (NMR) analysis was inconclusive in respect of the mechanism observed in the patch system, but showed clearly that an esterification reaction involving ALA and both glycerol and poly(ethyleneglycol) was occurring. This was especially marked in the glycerol gels, where only 2.21% of the total expected PY was detected after 204 days at 5 degrees C. Non-specific esterase hydrolysis demonstrated that ALA was recoverable from the gel systems, further supporting esterified binding within the gel matrices. It is conceivable that skin esterases could duplicate this finding upon topical application of the gel and convert these derivatives back to ALA in situ, provided skin penetration is not affected adversely.     

不同添加剂对双氯芬酸钾凝胶剂稳定性的影响

目的 研究不同添加刑对双氯芬酸钾凝胶剂稳定性的影响。方法 制备凝胶刑过程中加入不问添加刑，考察制剂稳定性。结果 丙二醇、0．5％吐温-80有利于凝胶刑的稳定性，甘油、并丙醇、1．0％吐温-80容易使双氯芬酸钾从凝胶剂中析出。结论 不同添加剂对双氯芬酸钾凝胶荆稳定性有不同的影响，合适的添加刑有利于凝胶剂的稳定。     

Protein–Solvent Interactions in Pharmaceutical Formulations

The stability of proteins is affected by a variety of solvent additives. Sugars, certain amino acids and salts, and polyhydric alcohols stabilize proteins in solution and during freeze-thawing. Urea and guanidine hydrochloride destabilize proteins under either condition. These effects can be explained from the preferential interactions of the cosolvents with the proteins; i.e., the protein stabilizers are preferentially excluded from the proteins, while the destabilizers bind to them. There is a class of compounds, such as polyethylene glycol and 2-methyl-2,4-pentanediol, that destabilize proteins at high temperature but stabilize them during freeze-thawing. Such effects can be accounted for by their preferential exclusion from the native proteins determined at room temperature and from their hydrophobic character, which depends on temperature. During freeze-drying, only a few sugars appear to be effective in protecting proteins from inactivation, as most other stabilizers cannot exert their action on proteins without water. The stabilization is due to hydrogen bonding between the sugars and the dried proteins, the sugars acting as water substitute. Understanding the mechanism of the effects of solvent additives on the protein stability should aid in the development of a suitable formulation for protein.     

新型缓释骨架材料聚氧化乙烯与HPMC凝胶层结构的差异比较

比较聚氧化乙烯(PEO)和羟丙甲纤维素(HPMC)缓释骨架片吸水膨胀后凝胶层结构的差异,探讨PEO作为新型骨架材料的优势。通过考察PEO和HPMC骨架片在不同释放时间点的吸水性和膨胀性,解释凝胶层结构的差异。PEO分子量型号对骨架片凝胶层结构和凝胶层厚度有显著影响,但考察的三种型号HPMC骨架片其凝胶层结构和凝胶层厚度无显著性差异。结果显示,PEO是一种优良的亲水骨架材料,相对于HPMC而言,具有更强的调节释药行为的能力。     

Effect of HLB of additives on the properties and drug release from the glyceryl monooleate matrices.

Glyceryl monooleate (GMO) is an amphiphilic surfactant, which as such can solubilize hydrophilic, lipophilic and amphiphilic drug molecules in its different polarity regions. Addition of additives with different polarities in GMO leads to change in phase behavior and related properties of GMO. Effect of the additives with different hydrophilic lipophilic balance (HLB; 1.5, 3, 4, 5, 7, 10 and 11) in GMO matrices on its phase transformation, rheological properties, mechanical properties, wetting and release behavior was investigated. Polarizing light microscopy showed that the GMO matrices incorporated with lower HLB additive (1.5, 3, 4 and 5) form cubic phase at higher rate while lamellar phase was prominent for matrices with additive of HLB 7, 10 and 11. The diametrical crushing strength and viscosity was decreased with increased HLB of additive. Lower HLB additives enhanced contact angle as compared to plain matrices and high HLB additives induced change in solid-liquid interface from hydrophobic to hydrophilic leading to decline in contact angle. Percent swelling of matrices was increased linearly with increase in HLB of additives. Tensiometric method was used for determination of bioadhesive strength of hydrated matrices and it was observed that matrices with additives of HLB 10 presented highest bioadhesion due to higher rate of hydration and formation of lamellar phase. As the HLB of additives in matrix increased, release was shifted from anomalous (non-Fickian) diffusion and/or partially erosion-controlled release to Fickian diffusion. Initial lag was observed for drug released from matrices with additive of HLB 1.5, 3, 4 and 5. Thus incorporation of the additives of different HLB changed molecular packing, which significantly affected drug release pattern.     

特比萘芬乳凝胶的制备及质量评价

目的:制备特比萘芬乳凝胶并对其质量进行评价。方法:以溶解度为指标筛选乳化剂和油相,以不同微乳体系的三元相图筛选油相、乳化剂和助乳化剂的用量,采用直接溶胀法制备乳凝胶,并对其含量、体外经皮渗透性、皮肤刺激性、稳定性进行考察。结果:乳凝胶的最优处方(100 g)为丙二醇辛酸酯14.0 g、聚氧乙烯-35-蓖麻油40.0 g、丙二醇2.0 g。制备的特比萘芬乳凝胶含量合格,12 h的体外累积渗透量为(1 283.7±33.5)μg/cm2,皮肤刺激反应评分24 h为0.1、48 h为0(无刺激),稳定性各项指标无明显变化。结论:该制剂制备处方合理,质量可控。     

Hydrophilic gels containing chlorophyllin-loaded liposomes: development and stability evaluation

The aim of this study was to develop and characterize hydrophilic gels containing chlorophyllin(CHL)-loaded liposomes as well as to evaluate their stability. Two different CHL-loaded liposome dispersions using non-hydrogenated and hydrogenated soybean lecithin were prepared, characterized for their particle size, polydispersity index and trapping efficiency and incorporated in Carbopol 940 NF hydrogel. The gels obtained were analyzed for flow properties, pH values and CHL content. The control liposome-free gel was obtained by incorporating the CHL solution in the hydrogel. The stability of the gels was evaluated in terms of rheological properties, pH values and CHL content during 6 months' storage at 20 +/- 2 degrees C. Suitable gel formulations for topical use were obtained revealing shear-thinning plastic flow behaviour without significant thixotropy during the whole period of examination. High yield values of the samples during the whole period indicated a long-term stability of the gel formulations. The gel formulations expressed a mild acid value acceptable for topical preparations. After 6 months' storage the CHL content was highest in the gel containing non-hydrogenated lecithin liposomes, followed by the gel containing hydrogenated lecithin liposomes and liposome-free gel, indicating that the encapsulation of CHL in liposomes led to a greater stability of CHL.     

Investigating critical effects of variegated lubricants,glidants and hydrophilic additives on lag time of press coated ethylcellulose tablets

The research envisaged focuses on vital impacts of variegated lubricants, glidants and hydrophilic additives on lag time of press coated ethylcellulose (EC) tablets using prednisone as a model drug. Several lubricants and glidants such as magnesium stearate, colloidal SiO₂, sodium stearyl fumarate, talc, stearic acid, polyethylene glycol (6000) and glyceryl behenate were investigated to understand their effects on lag time by changing their concentrations in outer coat. Further, the effects of hydrophilic additives on lag time were examined for hydroxypropylmethylcellulose (E5), hydroxypropylcellulose (EF and SSL), povidone (K30), copovidone, polyethylene glycol (4000), lactose and mannitol. In vitro drug release testing revealed that each selected lubricant/glidant, if present even at concentration of 0.25% w/w, significantly reduced the lag time of press coated tablets. Specifically, colloidal SiO₂ and/or magnesium stearate were detrimental while other lubricants/glidants were relatively less injurious. Among hydrophilic additives, freely water soluble fillers had utmost influence in lag time, whereas, comparatively less impact was observed with polymeric binders. Concisely, glidant and lubricant should be chosen to have minimal impact on lag time and further judicious selection of hydrophilic additives should be exercised for modulating lag time of pulsatile release formulations.     

Studies on the In-vitro Percutaneous Penetration of Indomethacin from Gel Systems in Hairless Mice

The influence of co-solvents on the in-vitro percutaneous penetration of indomethacin from gel systems was studied using a simplex lattice experimental design. Gel formulations were prepared by gelling the vehicle mixture of water, either alcohol or isopropanol and either propylene glycol or PEG 400 with 1% w/w Carbomer 940. Hairless mouse skin was employed as the barrier in a Franz-type diffusion cell. The penetration rates at steady state for seven formulations were fitted to a polynomial equation based on this simple lattice method and a three-dimensional plot was constructed. The formulation having the maximal penetration rate was determined to be the vehicle with a solvent ratio of water: alcohol: propylene glycol equal to 15:33:52, and which possessed a solubility parameter of 15 and a drug solubility of around 10 mg mL^?1. When the solubility parameter of the vehicle was > 15, the drug solubility increased. However, the penetration rate decreased with an increasing solubility parameter. For those vehicles with a solubility parameter < 15, both the drug solubility and the penetration rate decreased with a decrease in the solubility parameter. There was shown to be an approximately 20-fold increase in the relative enhancement factor when using both alcohol and isopropanol, but only a threefold increase for both propylene glycol and PEG 400, when compared with water.