Development of dorzolamide hydrochloride in situ gel nanoemulsion for ocular delivery.

BACKGROUND: Several in situ gel-forming systems have been developed to prolong the precorneal residence time of a drug and to improve ocular bioavailability. Poloxamer 407 with its thermoreversible gelation and surface active properties was utilized to formulate a novel dorzolamide hydrochloride in situ gel nanoemulsion (NE) delivery system for ocular use. OBJECTIVE: Improvement of both ocular bioavailability and duration of action for dorzolamide hydrochloride was the aim of this study. METHODS: Physicochemical properties, in vitro drug release studies and biological evaluation of the prepared NEs were investigated. RESULTS: The optimum formulation of in situ gel NE consisted of Triacetin (7.80%), Poloxamer 407 (13.65%), Poloxamer 188 (3.41%), Miranol C2M (4.55%), and water (70.59%). Biological evaluation of the designed dorzolamide formulation on normotensive albino rabbits indicated that this formulation had better biological performance, faster onset of action, and prolonged effect relative to either drug solution or the market product. The formula showed a superior pharmacodynamic activity compared to the in situ gel dorzolamide eye drops. This indicated the effectiveness of the in situ gel properties of poloxamer 407, besides formulating the drug in an NE form for improving the therapeutic efficacy of the drug. CONCLUSION: These results demonstrate the superiority of in situ gel NE to conventional ocular eye drops and in situ gels to enhance ocular drug bioavailability.

Nanoemulsion as a potential ophthalmic delivery system for dorzolamide hydrochloride.

Dilutable nanoemulsions are potent drug delivery vehicles for ophthalmic use due to their numerous advantages as sustained effect and high ability of drug penetration into the deeper layers of the ocular structure and the aqueous humor. The aim of this article was to formulate the antiglaucoma drug dorzolamide hydrochloride as ocular nanoemulsion of high therapeutic efficacy and prolonged effect. Thirty-six systems consisting of different oils, surfactants, and cosurfactants were prepared and their pseudoternary-phase diagrams were constructed by water titration method. Seventeen dorzolamide hydrochloride nanoemulsions were prepared and evaluated for their physicochemical and drug release properties. These nanoemulsions showed acceptable physicochemical properties and exhibited slow drug release. Draize rabbit eye irritation test and histological examination were carried out for those preparations exhibiting superior properties and revealed that they were nonirritant. Biological evaluation of dorzolamide hydrochloride nanoemulsions on normotensive albino rabbits indicated that these products had higher therapeutic efficacy, faster onset of action, and prolonged effect relative to either drug solution or the market product. Formulation of dorzolamide hydrochloride in a nanoemulsion form offers, thus, a more intensive treatment of glaucoma, a decrease in the number of applications per day, and a better patient compliance compared to conventional eye drops.

Design and evaluation of chitosan films for transdermal delivery of glimepiride.

Glimepiride is a third generation oral antidiabetic sulphonylurea drug frequently prescribed to patients of type 2 diabetes. However, its oral therapy is encountered with bioavailability problems due to its poor solubility leading to irreproducible clinical response, in addition to adverse effects like dizziness and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy, the rationale of this study was to develop a transdermal delivery system for glimepiride. Chitosan polymer was utilized in developing transdermal films for glimepiride. Chitosan has film forming ability, bioadhesive and absorption enhancing properties. Aiming at optimizing the drug delivery and circumventing the skin barrier function, inclusion complexation of glimepiride with beta-cyclodextrin (beta-CyD) as well as the use of several conventional penetration enhancers were monitored for augmenting the drug flux. The physical and mechanical properties of the prepared films were investigated using tensile testing, IR spectroscopy and X-ray diffractometry. Release studies revealed adequate release rates from chitosan films. Permeation studies through full thickness rat abdominal skin were conducted. High flux values were obtained from films comprising a combination of the drug with limonene and ethanol as well as from films containing glimepiride-beta-CyD complex. In vivo studies on diabetic rats for selected formulae revealed a marked therapeutic efficacy sustained for about 48 hours. The above-mentioned results shed light on feasibility of utilizing chitosan as an effective, safe transdermal delivery system for glimepiride characterized by increased patient compliance and better control of the disease.

A transdermal delivery system for glipizide.

Glipizide is one of the most commonly prescribed drugs for treatment of type 2 diabetes. Oral therapy with glipizide comprises problems of bioavailability fluctuations and may be associated with severe hypoglycaemia and gastric disturbances. As a potential for convenient, safe and effective antidiabetic therapy, the rationale of this study was to develop a transdermal delivery system for glipizide. For this purpose, inclusion complexes of the drug in beta-cyclodextrin (beta-CyD), dimethyl-beta-cyclodextrin (DM-beta-CyD), hydroxypropyl-beta-cyclodextrin (HP-beta-CyD), and hydroxypropyl-gamma-cyclodextrin (HP-gamma-CyD) were prepared. Several percutaneous formulations of the drug and the prepared complexes in different bases (o/w emulsion, polyethylene glycol, carboxymethyl cellulose and Carbopol) were developed. Release studies revealed an improved release of the drug from formulations containing glipizide-CyD complexes. Ex vivo permeation studies through full thickness rat abdominal skin were conducted, whereby the effect of several conventional penetration enhancers (propylene glycol [PG], oleic acid, urea, dimethyl sulfoxide, menthol, limonene and cineole) was monitored. Highest flux was obtained from ointments prepared with Carbopol gel base containing a combination of PG and oleic acid as well as ointments prepared in the same base utilizing glipizide-DM-beta-CyD complex and urea. In vivo studies on diabetic male Wistar rats revealed a marked therapeutic efficacy sustained for about 48 hours. In this respect, two formulations showed best biological performance. In the first formulation, the drug was incorporated in Carbopol gel base in the presence of 20% PG together with 15% oleic acid. The second was prepared by incorporating glipizide-DM-beta-CyD complex in Carbopol gel base in presence of 15% urea. The glucose tolerance test showed suppression of hyperglycaemia induced in glucose-loaded rats. The above-mentioned results might shed a strong beam of light on the feasibility of using glipizide in a transdermal delivery system for treatment of type 2 diabetes with the aim of improving both patient compliance and pathophysiology of the disease.

Implication of inclusion complexation of glimepiride in cyclodextrin-polymer systems on its dissolution, stability and therapeutic efficacy.

The effect of complexation of glimepiride, a poorly water-soluble antidiabetic drug, with beta-cyclodextrin and its derivatives (HP-beta-CyD and SBE-beta-CyD) in presence of different concentrations of water-soluble polymers (HPMC, PVP, PEG 4000 and PEG 6000) on the dissolution rate of the drug has been investigated. The results revealed that the dissolution rate of the drug from these ternary systems is highly dependent on polymer type and concentration. The dissolution rate of the drug from ternary systems containing PEG 4000 or PEG 6000 seems to be generally higher than from systems containing HPMC or PVP. An optimum increase in the dissolution rate of the drug was observed at a polymer concentration of 5% for PEG 4000 or PEG 6000 and at 20% concentration of HPMC or PVP. The dissolution rate of the drug from the ternary system glimepiride-HP-beta-CyD-5% PEG 4000 was high compared to the other systems. Tablets containing the drug or its equivalent amount of this ternary system were prepared and subjected to accelerated stability testing at 40 degrees C/75% R.H. to investigate the effect of storage on the chemical stability as well as therapeutic efficacy of the tablets. The results revealed stability of the tablets and consistent therapeutic efficacy on storage.

Formulation and biological evaluation of glimepiride-cyclodextrin-polymer systems.

Glimepiride is one of the third generation sulfonylureas used for treatment of type 2 diabetes. Poor aqueous solubility and slow dissolution rate of the drug lead to irreproducible clinical response or therapeutic failure in some cases due to subtherapeutic plasma drug levels. Consequently, the rationale of this study was to improve the biological performance of this drug through enhancing its solubility and dissolution rate. Inclusion complexes of glimepiride in beta-cyclodextrin (beta-CyD), hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and sulfobutylether-beta-cyclodextrin (SBE-beta-CyD), with or without water soluble polymers were prepared by the kneading method. Binary systems were characterized by thermogravimetric analysis, IR spectroscopy and X-ray diffractometry. Phase solubility diagrams revealed increase in solubility of the drug upon cyclodextrin addition, showing A(p) type plot indicating high order complexation. All the ternary systems containing beta-CyD or HP-beta-CyD showed higher dissolution efficiency compared to the corresponding binary systems. The hypoglycemic effect of the most rapidly dissolving ternary system of glimepiride-HP-beta-CyD-PEG 4000 was evaluated after oral administration in diabetic rats by measuring blood glucose levels. The results indicated that this ternary system improves significantly the therapeutic efficacy of the drug. In conclusion, the association of water soluble polymers with glimepiride-CyD systems leads to great enhancement in dissolution rate, increased duration of action and improvement of therapeutic efficacy of the drug.

Discrepancy among dissolution rates of commercial tables as a function of the dissolution method. Part 7: Aspirin.

The dissolution rate of fifteen batches of commercial aspirin tablets manufactured by five leading pharmaceutical companies was determined by closed and open dissolution systems. The most consistent results were those obtained by the USP method. Inter-batch as well as inter-brand variations were found to be more evidently detected and evaluated by adopting the USP and beaker methods, respectively. The bioavailability of these products was assessed in human subjects according to a cross-over design system. The following pharmacokinetic parameters for the drug were computed, viz., maximum excretion rate, elimination rate constant, half-life time, area under excretion rate versus time curve and total amount of drug excreted during 24 h following administration of a single oral dose. Based on the values of the correlation coefficient of the in vitro results obtained by different methods with the in vivo results, the beaker method appears to correlate best with the area under excretion rate versus time curve and total amount of drug excreted. Thus, determination of the dissolution rate of aspirin tablets by the beaker method can be considered as a reliable tool for predicting the in vivo performance of the preparation.

Free versus liposome-entrapped streptomycin sulfate in treatment of infections caused by Salmonella enteritidis.

Streptomycin sulfate liposomes were prepared by the vortex dispersion method. The liposomes were formulated from a mixture of L-alpha-dipalmitoyl phosphatidyl choline (DPPC), cholesterol with or without (neutral) a charge inducing agent. Two phospholipid molar ratios were considered, namely, DPPC cholesterol 7:2 and 7:4. The amount of streptomycin sulfate entrapped was estimated, microbiologically, and found to range from 0.080 to 1.323% of the initial amount of drug used for preparation of liposomes, depending on the surface charge of the liposomal vesicles. Particle size analysis, measured by the coulter counter, showed a mean particle diameter ranging from 4.417-8.424 microns. Drug targeting experiments were done using Swiss mice as the experimental animals. The in-vivo results indicated that the streptomycin sulfate concentration targeted to the liver and spleen by the liposome encapsulated drug was 2-3 times that exhibited by the free drug. This effect occurred after one day of liposome injection, but it decreased over time from one to seven days. The amount of streptomycin sulfate targeted to the lung, by the liposome formulation 7:2:1 was more than that exhibited by the free drug. This is true only after 7 d from injection. On the other hand, the liposomes of molar ratio 7:4:1 showed much less effect even when compared to the free drug. The survival rate experiments indicated a definite protection against Salmonella enteritidis, exhibited by the liposome-encapsulated streptomycin compared to the free drug.

Effect of urea on the activity of certain ophthalmic drugs in man.

The role displayed by urea (2-10%) solutions, on the miotic and mydriatic activities of pilocarpine hydrochloride and homatropine hydrobromide respectively, was investigated on the human eye. At different concentrations, urea exerts no effect on the miotic activity of pilocarpine, whereas in the case of homatropine a negative effect is experienced. For the parameters, area under pupil diameter--time curve (AUC) and maximum pupillary response (MPR), a linear relationship exists between response to homatropine and urea concentration. However, the dependency is more pronounced in conjunction with the MPR parameter.

On the diffusion of chloramphenicol from oleaginous ointment bases.

The rate of diffusion of chloramphenicol from oleaginous ointment bases was investigated. It was found that the rate of diffusion of the drug from beeswax is markedly higher than that from hard paraffin. Cetrimide, whether present in the waxy base or in the aqueous diffusion medium, enhances markedly the rate of diffusion of chloramphenicol. The effect of cetrimide is, however, more pronounced in the case of hard paraffin. Incorporation of triolein in the waxy bases markedly increases the diffusion of the drug. This was correlated to changes in certain rheological parameters of the bases in presence of triolein.

A paper chromatographic method for separation and determination of synephrine in injectable solutions.

A new analytical method using ascending paper chromatographic technique was developed for identification and quantitative determination of residual synephrine in fresh and deteriorated samples. This method was found to be stability indicating; one to five degradation products have been successfully separated from drug samples subjected to accelerated stability testing at 60 degrees C for 3 months.

Interaction between thiamine hydrochloride and lipoic acid.

An interaction between thiamine hydrochloride and DL-alpha-lipoic acid in aqueous solution was depicted. Evidence is presented through spectrophotometric as well as vapour pressure measurements to show that thiamine hydrochloride and DL-alpha-lipoic acid form a single 1:1 complex. The stability constant and the molar extinction coefficient of the complex (at 244 nm) were determined at 25 degrees C and found to be 3.1-10(4) and 970, respectively. Vapour pressure measurements at 60 degrees C reveal that more or less complete dissociation of the complete takes place at this temperature.

Studies on the stability of injectable solutions of some phenothiazines. Part 1: Effects of pH and buffer systems.

The stability of phenothiazines is affected by the pH-value of the solution. At the pH-values of maximum stability, triflupromazine hydrochloride and chlorpromazine hydrochloride are more stable than promazine hydrochloride. The stability of chlorpromazine hydrochloride in the Sörensen's phosphate buffer is slightly higher than that in the McIlvaine's citric acid-phosphate buffer system. On the other hand, the stbility of promazine hydrochloride and triflupromazine hydrochloride in the latter buffer system is slightly higher than that in the former one.

Studies on the stability of injectable solutions of some phenothiazines. Part 2: Effect of chelating agents and antioxidants.

Chelating agents (disodium EDTA, DTPA, HEDTA and NTA) exhibit a stabilizing action towards phenothiazines to different extents. This could be correlated to the stability constants of their metal chelates as well as to the dependency of these constants on the pH-value of the solution. Antioxidants (sodium bisulphite, sodium dithionite, and sodium metabisulphite) also exert a stabilizing effect which could be correlated--in the first place--to the pH-value of the solution. The sulphur content of the antioxidant might also be relevant to such an effect.