ISSN:8756-3320    

DOI:10.1089/jop.1994.10.1

年代:1994

数据来源: MAL

摘要:

ABSTRACTThere are two major novelmetabolism-based drug design conceptswhich have significant advantages when used in the design of safe, specific ophthalmic drugs. One is based onpredictable enzymatic activationprocesses by enzymes found exclusively or preferentially at the site of action--in this case, within the eye, primarily in the iris-ciliary body. The second majorretrometabolic designtechnique involvessoft drug approaches. Among the various soft drug design strategies, it was found that the "inactive metabolite" and the "soft analog" approaches are the most useful for designing safe and selective ophthalmic drugs. In the first case, the design process starts with a known (or predicted) inactive metabolite (Mi) of the drug (D). This Miis then structurally modified in the "chemical activation" stage to the soft drug (SD), which is isosteric and/or isoelectronic with D to produce activity at the target receptors, similar to that of D. By design, however, SD is also subject to a facile, predictable (generally hydrolytic) metabolism leading in one step to the starting inactive Mi. As this deactivation takes places everywhere in the body, the desired activities are produced virtually exclusively at the target site at or near the place of application. Successful use of this general concept has led tosoft β-blockers as safe antiglaucoma agents,soft anticholinergics as short acting mydriatic agents, andsoft corticosteroids asa type of novel,safe anti-inflammatoryagents, which due to their unique design, do not elevate intraocular pressure IOP and do not produce other systemic and local side effects

ISSN:8756-3320    

DOI:10.1089/jop.1994.10.3

年代:1994

数据来源: MAL

摘要:

ABSTRACTFor patients with conditions requiring chronic rather than acute therapy, the advantages of collagen shields in providing high and sustained levels of drugs and/or lubricants to the cornea are outweighed by the difficulty of insertion of the shield and the problem of blurred vision. We have developed a delivery system in which collagen pieces suspended in a viscous vehicle can be instilled into the lower forniceal space, thereby simplifying application and reducing blurring of vision. The collagen pieces (Collasomes) can be formulated with various constituents such as antibiotics or cyclosporine, or with chemical alterations such as the inclusion of a lipid (Lacrisomes) for the treatment of dry eyes. In the normal eyes of volunteers, Collasomes hydrated in a solution of sodium fluorescein and suspended in a methylcellulose vehicle as a model for delivery of water-soluble drugs produced fluorescein concentrations 17 to 42 times higher in the cornea and 6 to 8 times higher in the aqueous humor, compared with fluorescein-containing vehicle alone. In a preliminary controlled study, 76% of patients with moderately severe keratoconjunctivitis sicca (KCS) preferred Lacrisomes to the vehicle control because of a more soothing effect and longer duration of comfort. All preparations were well tolerated by all study subjects. Current studies involve improving drug delivery by chemically modifying the collagen molecule to slow diffusion of the drug from the Collasome matrix, as well as varying the amount of cetyl alcohol and combining it with modified collagen in Lacrisomes to maximize comfort in patients with dry eyes.

ISSN:8756-3320    

DOI:10.1089/jop.1994.10.17

年代:1994

数据来源: MAL

摘要:

ABSTRACTMicroparticulates are drug-containing small polymeric particles (erodible, non-erodible or ion-exchange resins) that are suspended in a liquid carrier medium. Upon administration of particle suspension in the eye, the particles reside at the delivery site (cul-de-sac, sub conjunctiva or vitreous cavity) and the drug is released from the particles through diffusion, chemical reaction, polymer degradation, or ion-exchange mechanism. Several distinct approaches have been used to formulate drugs in microparticulate dosage form for intraocular and topical application. These include erodible microparticulates, swelling mucoadhesive particulates, pH responsive microparticulates, nanoparticles/latex systems, ion-exchange resins, etc. Injection of bioerodible microparticulates in the vitreous for treating infections of posterior segment and the release of acceptable levels of drug up to two weeks has been demonstrated. Both corneal and non-corneal routes of drug entry in the eye from topical instillations are postulated. Thein vitroandin vivostudies have shown that this dosage form holds great promise for sustained drug release in the eye. However, several formulation challenges, including production of stable suspensions, uniform dose per unit volume, efficient drug entrapment, reproducible and large scale manufacturing, uniform particle size, etc., have to be addressed. Fruitful resolution of technological challenges will result in a superior dosage form for both topical and intraocular ophthalmic application. Recent developments and future challenges of microparticulate ophthalmic drug delivery system are discussed in this review.

ISSN:8756-3320    

DOI:10.1089/jop.1994.10.29

年代:1994

数据来源: MAL

摘要:

ABSTRACTPoor bioavailability of ophthalmic solutions caused by dilution and drainage from the eye can be overcome by usingin situ-forming ophthalmic drug delivery systems prepared from polymers that exhibit reversible phase transitions. Joshi et al. (1), have demonstrated that aqueous compositions that reversibly gel in response to simultaneous variations in at least two physical parameters, such as temperature, pH, and ionic strength, can be formed by appropriate combinations of macromolecular polymers which exhibit reversible gelation properties. In the present study, the rheological characterization of such a system, prepared by a combination of Carbopol®(C) and methyl cellulose (MC), was carried out at two different pH (4.0 and 7.4) and temperatures (25 and 37°C) by rotational cone and plate viscometry. The shear stress (τ) vs. shear rate (D) flow curves of the aqueous polymer solutions indicated a pseudoplastic behavior, with a yield point. An increase in pH from 4.0 to 7.4, or temperature from 25 to 37°C, resulted in an increase in viscosity (η), τ, and yield point, the magnitude of changes being highest when both the parameters were altered simultaneously. An increase in concentration of either C or MC, or an increase in MC molecular weight results in an increase in η, τ, and yield point. Among the compositions studied, a solution containing 1.5% MC 0.3% C was found to have low η, and formed a strong gel under simulated physiological conditions. Such a system can be formulated as drug containing liquid suitable for administration by instillation into the eye, which upon exposure to physiological conditions will shift to the gel (semi-solid) phase, thus increasing the precorneal residence time of the delivery system and enhancing ocular bioavai

ISSN:8756-3320    

DOI:10.1089/jop.1994.10.47

年代:1994

数据来源: MAL

摘要:

ABSTRACTA new novel delivery system for ophthalmic drugs was developed using an antiglaucoma agent Betaxolol Hydrochloride as a model. The new delivery system involved both the binding and release of drug from ion exchange resin particles. Betaxolol was studied in-vitro via a release model analysis. The ocular comfort of Betaxolol was greatly enhanced by reducing the availability of free drug molecules in the precorneal tear film. The amount of resin concentration was selected to obtain optimum binding of the drug. The zeta potential of suspended particles was adjusted to produce flocculated suspension. Drug resin particles were then incorporated into the structured vehicle, containing Carbomer 934P as a polymer, to enhance the physical stability and ease of resuspendability of the product. This delivery system also optimized the bioavailability of Betaxolol, reducing the total drug concentration in half to 0.25% Betaxolol in 0.25% BETOPTIC S Ophthalmic Suspension as compared with 0.5% Betaxolol in BETOPTIC 0.5% Sterile Ophthalmic Solution dosage form. Increased comfort of 0.25% BETOPTIC S Ophthalmic Suspension, as well as its bioequivalency data in animal models (rabbits), was confirmed in actual clinical trials of the product 0.25% BETOPTIC S Ophthalmic Suspension. The 0.25% BETOPTIC S Ophthalmic Suspension product has been approved by FDA and is marketed in U. S. since February 1990. The 0.25% BETOPTIC S Ophthalmic Suspension formulation has an increased bioavailability (equivalent to BETOPTIC 0.5% Sterile Ophthalmic Solution at half the concentration of drug); and pharmaceutically, is an elegant suspension product which settles slowly providing uniform dosage and increased ocular comfort.

ISSN:8756-3320    

DOI:10.1089/jop.1994.10.57

年代:1994

数据来源: MAL

摘要:

ABSTRACTIontophoresis has been utilized in the field of ophthalmology for many years. Present application of this technique has diminished considerably and few clinicians are currently familiar with its use. This review aims to educate the reader regarding the essential features of this procedure and to discuss the past and future role of iontophoresis in ocular drug delivery.

ISSN:8756-3320    

DOI:10.1089/jop.1994.10.69

年代:1994

数据来源: MAL

摘要:

ABSTRACTA series of polyanionic natural or semi-synthetic polymers (polygalacturonic acid, hyaluronic acid, carboxymethylamylose, carboxymethylchitin, chondroitin sulfate, heparan sulfate and mesoglycan) were evaluated as potential mucoadhesive carriers for ophthalmic drugs. Solutions containing cyclopentolate (CY) or pilocarpine (PI) as salts (or polyanionic complexes) with the acidic polymers, all showing a low viscosity, were tested for miotic (resp. mydriatic) activity in albino rabbits. In the case of some polymeric complexes, small but significant increases of the areas under the activity vs. time curves (AUC) over reference cyclopentolate hydrochloride (CYHCl) or pilocarpine nitrate (PINO3) vehicles, and significant AUC decreases after removal of precorneal mucin by treatment with N-acetylcysteine were observed. A correlation was found between these data, considered indicative of the occurrence of a mucoadhesive interaction "in vivo", and "in vitro" viscometric data expressing the polymers-mucin force of interaction. The advantages and limitations of the mucoadhesive non-viscous approach in the formulation of ophthalmic vehicles are presented and discussed.

ISSN:8756-3320    

DOI:10.1089/jop.1994.10.83

年代:1994

数据来源: MAL

摘要:

ABSTRACTBecause of rapid developments in biotechnology, numerous peptides are now available for clinical treatment of various diseases. In order to avoid parenteral injections, alternative routes of drug administration have been investigated. Among them, the ocular route seemed to be the most feasible one because a) it could deliver precise doses of drugs just like injections; b) it was much easier and less expensive to administer eyedrops than an injection; c) the rate of systemic absorption through the ocular route was as fast as an injection; d) eye tissues were much less sensitive to the development of immunological reactions than other tissues; e) the drug absorbedviathe ocular route would avoid the first passage through hepatic circulation to reach the sites of action before liver metabolism; and f) no tolerance and ocular side effects could be detected after long-term (three months) daily administration of insulin eyedrops.

ISSN:8756-3320    

DOI:10.1089/jop.1994.10.93

年代:1994

数据来源: MAL

摘要:

ABSTRACTInsulin administered in eyedrop from with a surfactant agent has been shown to be clinically effective in treating diabetes in animal models. Concentrations of insulin as high as 100 U/ml in saline were shown to produce no detectable clinical toxicity to human eyes in single-dose administration. We sought to investigate the local toxicity of insulin in human eyes during long-term, multidose administration. A prospective, randomized, placebo controlled, double-masked study was conducted involving eight healthy volunteers. Subjects were given 50 μl sterile saline containing 100 U/ml crystalline porcine insulin randomized to one eye and 50 μl placebo (sterile saline) to the fellow eye administered twice daily for 8 weeks. Subjective ocular irritation and visual acuity and objective assessment of the eyelids, conjunctiva, cornea, anterior chamber, crystalline lens, pupil size, and intraocular pressure were evaluated. Blood D-glucose levels were monitored to assess glycemic levels. There was no statistically significant difference (p>0.05) observed between insulin-treated and placebo-treated eyes. Eyedrops containing insulin were subjectively as comfortable and objectively as clinically innocuous as sterile saline alone. The results of this study demonstrate that insulin (100 U/ml) in saline is nontoxic to the human eye after long-term, multi-dose exposure. Topical administration of insulin combined with an absorption-promoting agent may be a practical and feasible alternative to multiple daily subcutaneous injections or implanted pump devices currently used in the long-term treatment of diabetes mellitus if a nonirritating absorption-promoting agent can be identified. Further studies are warranted to determine the toxicity and efficacy of these absorption-promoting agents in humans and to develop an eyedrop formulation that maximizes safety, efficacy and compliance in patients with diabetes mellitu

ISSN:8756-3320    

DOI:10.1089/jop.1994.10.101

年代:1994

数据来源: MAL