Cyclodextrin formulation of dorzolamide and its distribution in the eye after topical administration

Sigurđsson, Hákon Hrafn; Stefánsson, Einar; Gudmundsdottir, Elinborg; Eysteinsson, Þór; Þorsteinsdóttir, Margrét; Loftsson, Þorsteinn

doi:10.1016/j.jconrel.2004.10.004

Cited by 72 publications

(49 citation statements)

References 25 publications

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“…Dorzolamide hydrochloride was synthesized in the 1980s (12) and was shown to be about 20 times more potent than the carbonic anhydrase inhibitor acetazolamide with regard to the inhibition of carbonic anhydrase isoenzyme II (13), which is thought that this isoenzyme plays a major role in aqueous humor secretion (14). The pK a values of dorzolamide hydrochloride are 6.35 and 8.5 (15) and its apparent partition coefficient is 1.96 for the n-octanol/pH 7.4 buffer system (16).…”

Section: Introductionmentioning

confidence: 99%

“…The concentration of dorzolamide HCl in Trusopt® is 2.2%, corresponding to 2.0% of the free base, pH 5.65. Hydroxyethyl cellulose is used to increase the viscosity of Trusopt® eye drops to 100 cps; this increased viscosity leads to increased corneal contact time and, consequently, to increased bioavailability (15). However, the relatively low pH and high viscosity have been shown to generate local irritation after topical administration of the eye drops (18).…”

Section: Introductionmentioning

confidence: 99%

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Nanoemulsion as a Potential Ophthalmic Delivery System for Dorzolamide Hydrochloride

et al. 2009

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Abstract. 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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nanoemulsion as a Potential Ophthalmic Delivery System for Dorzolamide Hydrochloride

et al. 2009

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“…As can be seen in Figure 4, DIOP obtained with commercial preparation Trusopt was significantly higher than that obtained with all tested ophthalmic solutions with significantly longer duration of action. This finding could be attributed to the relatively high viscosity (100 cps) [Sigurdsson et al, 2005] that increases the contact period of the Trusopt with the ocular absorbing surface and decreases the rate of tear washing out of the administered drops regardless of the observed and reported [Sigurdsson et al, 2005] ocular reddening and irritation. Figure 5 shows the DIOP measurements of the second set of ophthalmic solutions containing different concentrations (0-1.5%) of the viscosity increasing agent HPMC using formulation SE3 from the first set of ophthalmic solutions, since it has shown the highest in vitro permeability characteristics.…”

Section: In Vivo Iop Lowering Effectsmentioning

confidence: 99%

“…1) is a carbonic anhydrase inhibitor first synthesized in the 1980s [Maren, 1995] and became available as topical eye drop solution (Trusopt s ) in 1995. The concentration of dorzolamide HCl in Trusopt is 2.2% (w/v), corresponding to 2.0% of the free base, at pH 5.65 [Sigurdsson et al, 2005]. DZD was shown to be about 20 times more potent CAI, with regard to isoenzyme II, than acetazolamide topical activity [Sugrue, 1996].…”

Section: Introductionmentioning

confidence: 99%

Effects of (−)‐carveol and HPMC on the in vitro ocular transport and the in vivo intraocular pressure lowering effects of dorzolamide formulations in normotensive New Zealand rabbits

Afouna

Khedr

Al-Marzoqi

2009

Drug Development Research

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The objective of the current study was to maximize the ocular bioavailability of the carbonic anhydrase inhibitor, dorzolamide hydrochloride (DZD) via (a) enhancement of DZD corneal transport using terpene enhancers, (b) reducing pre-corneal loss of the installed dose via increased formulation viscosity, and (c) assessment of the in vivo intraocular pressure (IOP) lowering effects of test formulations using rabbit. DZD was formulated as a 2% ophthalmic solution containing different concentrations of HPMC as a viscosity improving agent (VIA), and (À)-carveol as a corneal penetration enhancer. The transport of DZD from test formulations was quantitatively determined using in vitro diffusion experiments, the permeability parameters were mathematically calculated, and the in vivo IOP lowering effects were assessed using a Tono-Pen XL s tonometer. The results revealed a good correlation between the in vitro permeability parameters and the in vivo DIOP. The magnitude of the DZD-IOP lowering effects and durations of actions for DZD formulations were dependent on (a) the concentration of (À)-carveol, and (b) the contact period with ocular tissue which was found to be a single-valued function of the HPMC as VIA. Drug Dev Res 70 : 191-198, 2009.

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“…Modified CDs, such as randomly methylated b-cyclodextrin (RM b-CD) have gained increasing popularity due to its improved water solubility and less toxicity as compared with the natural b-cyclodextrin. [8][9][10] One of the approaches for modulating the release of drugs from a delivery system and changing the release kinetics over a period of time is to use blends of hydrophilic and hydrophobic polymers.…”

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confidence: 99%

Single and Multi-Layered Nanofibers for Rapid and Controlled Drug Delivery

Azarbayjani

Chan

2010

Chem. Pharm. Bull.

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143Polymeric drug delivery systems are able to improve therapeutic efficacy, reduce toxicity, and can be designed to control and prolong drug release by adjusting the degradation rate of the polymer.1,2) Poly vinyl alcohol (PVA) is a biodegradable, hydrophilic polymer with distinct properties such as high degree of swelling, inherent non-toxicity and good biocompatibility. 3,4) Aliphatic polyesters such as poly (D,L-lactide) (PLA) and its copolymers with glycolic acid (PLGA) are biodegradable and biocompatible polymers with remarkably broad applications in sustained drug delivery. 5-7)Cyclodextrins (CDs) are a group of cyclic oligosaccharides. They are able to form inclusion complexes with lipophilic guest molecules which have been shown to improve aqueous solubility, dissolution rate and bioavailability of lipophilic drugs without decreasing the intrinsic ability of the lipophilic drug molecule to penetrate the biological membranes. Modified CDs, such as randomly methylated b-cyclodextrin (RM b-CD) have gained increasing popularity due to its improved water solubility and less toxicity as compared with the natural b-cyclodextrin. 8-10)One of the approaches for modulating the release of drugs from a delivery system and changing the release kinetics over a period of time is to use blends of hydrophilic and hydrophobic polymers. 11)Electrospinning utilizes high voltage source to produce nanoscale and microscale polymeric fibers with high surface area-to-volume ratio and porosity. 1,12,13) When the electrostatic charge exceeds the surface tension of the solution, the fiber jet travels from the syringe nozzle to the electrically charged ground collector and allows the solvent to evaporate, thus leading to the deposition of the non-woven solid polymer fiber on the surface of the metallic target collector. Multi-layered nanofiber mat is obtained by sequentially electrospinning the second polymer solution on the same target collector as the first polymer. This strategy helps to compensate the limitation of the individual polymers while the inherent advantage of both the polymers can be obtained in a single fiber mat. [14][15][16][17] The aim of this work is the preparation of haloperidol loaded nanofiber via electrospinning of hydrophobic, PLA and PLGA, and hydrophilic polymers, PVA and RM b-CD. We intend to demonstrate that multi-component/multilayered polymeric mixture influence the physical and biological properties of electrospun fibers. The nanofiber morphology, structure, diameter of the polymeric nanofiber mats were investigated by field emission scanning electron microscopy (FESEM), and fourier transform infrared (FT-IR) measurements. The release characteristics of haloperidol from the drug-loaded fiber mats were investigated. ExperimentalMaterials PLA (R 203H with inherent viscosity of 0.34 dl/g), PLGA (73 : 27 and 48 : 52) RG 503, RG 755S with inherent viscosity of 0.63 dl/g and 0.52 dl/g were a kind gift from Boehringer Ingelheim (Ingelheim, Germany). PVA Mw 70000-100000 and haloperidol were purchased from S...

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Cyclodextrin formulation of dorzolamide and its distribution in the eye after topical administration

Cited by 72 publications

References 25 publications

Nanoemulsion as a Potential Ophthalmic Delivery System for Dorzolamide Hydrochloride

Nanoemulsion as a Potential Ophthalmic Delivery System for Dorzolamide Hydrochloride

Effects of (−)‐carveol and HPMC on the in vitro ocular transport and the in vivo intraocular pressure lowering effects of dorzolamide formulations in normotensive New Zealand rabbits

Single and Multi-Layered Nanofibers for Rapid and Controlled Drug Delivery

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