Chemical Delivery System Research Articles

In Vitro and In Vivo Evaluations of Dihydroquinoline- and Dihydroisoquinoline-based Targetor Moieties for Brain-specific Chemical Delivery Systems

Brain-targeted delivery of various drugs can be successfully achieved by chemical delivery systems (CDS) that contain a 1,4-dihydropyridine-based redox targetor moiety and undergo a sequential metabolism. However, the susceptibility of this moiety toward hydration in acidic media may limit the shelf-life of such compounds in aqueous formulation. Here, a systematic investigation of the chemical stability toward oxidation and hydration of ester and amide derivatives of 3-substituted 1,4-dihydropyridine, 1,4-dihydroquinoline, and 4-substituted 1,2-dihydroisoquinoline is reported, together with the in vitro stability and in vivo (rat) distribution of isoquinoline-based testosterone and hydrocortisone chemical delivery systems, which were selected as having the most suitable acid-resistant targetor moieties.

Delivery of Anti-Viral Nucleoside Analogues to the Central Nervous System

Delivery of anti-viral agents into the central nervous system (CNS) is clinically important. Direct brain infection by viral pathogens including herpes (HSV-I and II, VZV, and CMV) and AIDS virus (HIV-I and II) causes a progressive deterioration in mental function, and even death. Nucleoside analogues are a major source of clinically used anti-viral agents, although their delivery to the brain is severely limited by the presence of the blood-brain barrier and blood-cerebrospinal fluid barrier. Therefore, improvement of the delivery of these nucleoside analogues to the CNS has been investigated under various mechanisms, including metabolizing enzymes, endogenous cellular transport systems, conjugates, chemical delivery systems, and prodrugs. In this review, we will summarize the following topics: 1) Roles of hydrophobicity, protein binding, and the probenecid-sensitive transport system, in delivery of nucleoside analogues with anti-herpes or anti-HIV activity, to the CNS. 2) Role of brain tissue-localized purine metabolizing enzymes in the delivery of dideoxynucleosides with anti-HIV activity to the brain. 3) Chemical delivery systems for zidovudine (AZT) based on redox trapping within the brain. Keywords: Anti-Viral Nucleoside Analogues, Herpes, Hsv-1, II vzv, Cmv, Aids virus, Hiv-1, Blood-brain barrier, Blood-cerebrospinal fluid barrier

Ocular Preparations: The Formulation Approach

ABSTRACTThe main aim of pharmacotherapeutics is the attainment of an effective drug concentration at the intended site of action for a sufficient period of time to elicit the response. A major problem being faced in ocular therapeutics is the attainment of an optimal concentration at the site of action. Poor bioavailability of drugs from ocular dosage forms is mainly due to the tear production, non-productive absorption, transient residence time, and impermeability of corneal epithelium. This article reviews: the barriers that decrease the bioavailability of an ophthalmic drug; the objectives to be considered in producing optimal formulations; and the approaches being used to improve the corneal penetration of a drug molecule and delay its elimination from the eye. The focus of this review is on the recent developments in topical ocular drug delivery systems, the rationale for their use, their drug release mechanism, and the characteristic advantages and limitations of each system. In addition, the review attempts to give various analytical procedures including the animal models and other models required for bioavailability and pharmacokinetic studies. The latter can aid in the design and predictive evaluation of newer delivery systems.The dosage forms are divided into the ones which affect the precorneal parameters, and those that provide a controlled and continuous delivery to the pre- and intraocular tissues. The systems discussed include: (a) the commonly used dosage forms such as gels, viscosity imparting agents, ointments, and aqueous suspensions; (b) the newer concept of penetration enhancers, phase transition systems, use of cyclodextrins to increase solubility of various drugs, vesicular systems, and chemical delivery systems such as the prodrugs; (c) the developed and under-development controlled/continuous drug delivery systems including ocular inserts, collagen shields, ocular films, disposable contact lenses, and other new ophthalmic drug delivery systems; and (d) the newer trends directed towards a combination of drug delivery technologies for improving the therapeutic response of a non-efficacious drug. The fruitful resolution of the above-mentioned technological suggestions can result in a superior dosage form for both topical and intraocular ophthalmic application.

Theoretical Insights into the Formation, Structure, and Energetics of Some Cyclodextrin Complexes

To investigate the physicochemical aspects relevant for the formation of various cyclodextrin inclusion complexes and to search for corresponding general structure–complex-stability relationships, stability data of 1 : 1 complexes for 179, 310, and 51 guest molecules with unsubstituted α-, β-, and γ-cyclodextrin were collected. Statistical analysis using structure-based parameters such as molecular size, hydrophobicity, rotatable bonds, electronic properties, and the presence or absence of more than 150 various functional or structural moieties were performed. The complexation thermodynamics could be well described within the framework of our recently introduced molecular size-based model for nonassociative liquids. With increasing guest size, 1 : 1 complex stability, as measured by ln K or Δ G0, increases linearly up to a size limit characteristic for each CD, and the corresponding slopes and intercepts are in agreement with those predicted by the model. For larger structures, values level off and are scattered around an average value depending on shape, goodness of fit, and possibly lipophilicity and some specific effects (e.g. such as those caused by presence of phenol functionality). The complexation between β-cyclodextrin and certain large steroidal guest molecules, especially a brain-targeted estradiol chemical delivery systems (E2-CDS) that is under clinical development, was investigated in details based on fully relaxed semiempirical AM1 quantum chemical calculations. A deformation index (DI) of the CD ring computed using these fully optimized host-guest geometries could be used to characterize the conformational change of the guest.

Thin film atomic layer deposition equipment for semiconductor processing

Atomic layer deposition (ALD) of ultrathin high-K dielectric films has recently penetrated research and development lines of several major memory and logic manufacturers due to the promise of unprecedented control of thickness, uniformity, quality and material properties. LYNX-ALD technology from Genus, currently at beta phase, was designed around the anticipation that future ultrathin materials are likely to be binary, ternary or quaternary alloys or nanolaminate composites. A unique chemical delivery system enables synergy between traditional, production-proven low pressure chemical vapor deposition (LPCVD) technology and atomic layer deposition (ALD) controlled by sequential surface reactions. Source chemicals from gas, liquid or solid precursors are delivered to impinge on reactive surfaces where self-limiting surface reactions yield film growth with layer-by-layer control. Surfaces are made reactive by the self-limiting reactions, by surface species manipulation, or both. The substrate is exposed to one reactant at a time to suppress possible chemical vapor deposition (CVD) contribution to the film. Precisely controlled composite materials with multiple-component dielectric and metal–nitride films can be deposited by ALD techniques. The research community has demonstrated these capabilities during the past decade. Accordingly, ALD equipment for semiconductor processing is unanimously in high demand. However, mainstream device manufacturers still criticize ALD to be non-viable for Semiconductor device processing. This article presents a broad set of data proving feasibility of ALD technology for semiconductor device processing.

Retrometabolic drug design--novel aspects, future directions.

A brief overview of the general, retrometabolic drug design principles, including soft drug and chemical delivery system design, is presented. Selected recent developments within these fields are also summarized, including results related to the design of soft bufuralol and amiodarone analogues, to the airway activity of loteprednol etabonate, a soft corticosteroid, and to the brain targeted delivery of some neuropeptides.

Synthesis and biological investigations of 5-substituted pyrimidine nucleosides coupled to a dihydropyridine/pyridinium salt redox chemical delivery system.

The syntheses, antiviral activities, and partition coefficients (P) of 3'-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-coupled nucleosides are described. These novel compounds were designed in an effort to enhance the lipophilicity, and thereby the delivery to the CNS, without compromising the anti-HSV-1 activity of the parental nucleosides. We have previously reported the synthesis of 3'-O-(1-methyl-1,4-dihydropyridyl-3- carbonyl) analogs of 5-iodo-(5), 5-vinyl-(6), and (E)-5-(2-iodovinyl)-2'-deoxyuridines (7). We now report the synthesis of 5-iodo-3'-O-(1-methyl-1,4-dihydropyridyl-3- carbonyl)-5'-O-acetyl-2'-deoxyuridine (15) and 3'-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2'-deoxyuridine (17). Quarternization of the 3'-O-(3-pyridylcarbonyl) compounds (10,12) using iodomethane afforded the corresponding 1-methyl pyridinium salts (13,14) which were reduced with sodium dithionite to yield the corresponding 3'-O-1-methyl-1,4-dihydropyridyl-3-carbonyl compounds (15,16). The deprotection of 3'-O-(1-methyl-1,4-dihydropyridyl- 3-carbonyl)-5'-O-t-butyldimethylsilyl-2'-deoxyuridine (16) with Bu4N+F- afforded 3'-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-2'-deoxyuridine (17). Compounds 5-7 and 15 were evaluated for their antiviral activity in vitro against HSV-1, HSV-2, HCMV, and VZV, and were found to retain anti-HSV-1, HSV-2 and VZV activity as compared to their parental nucleosides (1-3). In addition, the cellular toxicity of 3'-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)-coupled compounds (5-7 and 15) was found to be lower than the parent nucleosides. The lipophilicity of compounds (5-7,15,17) are enhanced substantially, compared to the parent nucleosides, as indicated by an increase in corresponding P values (1-octanol-water) upon replacement of the C-3' hydroxyl by 1-methyl-1,4-dihydropyridyl-3-carbonyl moiety.

Design, in vitro stability, and ocular hypotensive activity of t-butalone chemical delivery systems

The objective of this work was to synthesize two bioreversible diacyl derivatives of t-butalone (chemical delivery systems), determine their chemical and in vitro stability, and investigate their potential use as topical antiglaucoma agents. The stability of these compounds was determined in isotonic phosphate buffers (pH range 5–8) and in selected biological media, including human whole blood, rabbit and rat blood, and the anterior segment tissues of rabbit. The ocular hypotensive activity of these compounds in unrestrained, normotensive albino rabbits was determined with a pneumatonometer. The two compounds were stable at lower pH. The stability decreased as the pH increased, suggesting their lability to base-catalyzed hydrolysis. These compounds exhibited significant differences in the hydrolytic rates in the whole blood among species examined (rat > rabbit > human). The observed rates of disappearance in different ocular tissues were indicative of relative enzyme activity in these media (iris-ciliary body > cornea > aqueous humor). The two compounds exhibited a significant ocular hypotensive activity (P < 0.01) at 2% dose level. The peak activity was found between 2 and 4 h, and the activity was maintained for 4.5 to 7 h. The dipivalyl derivative of t-butalone exhibited more pronounced decrease in intraocular pressure than that of diisovaleryl derivative. The present study suggests the possible use of diacyl derivatives of t-butalone as ocular hypotensive agents. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1026–1033, 2001

Novel Site‐Specific Chemical Delivery System as a Potential Mydriatic Agent: Formation of Phenylephrine in the Iris‐Ciliary Body from Phenylephrone Chemical Delivery Systems

The objective of this study was to test the three novel ester derivatives of phenylephrone (isovaleryl, phenylacetyl, and pivalyl esters) as potential site‐specific chemical delivery systems. The mydriatic effect and ocular distribution/metabolism of these compounds were studied by topical application to the eyes of normal rabbits. It was assumed that a reduction–hydrolysis sequence could produce the active phenylephrine in the iris‐ciliary body tissues. All the derivatives showed a more pronounced mydriatic effect than that of phenylephrine, whereas phenylephrone was completely devoid of any mydriatic activity. Phenylacetyl ester was the most potent drug, with short duration of action, and showed maximum activity in the presence of 0.01% benzalkonium chloride without causing any visible irritation to the rabbit eye. Administration of the novel compounds to the eyes of the rabbits showed no traces of phenylephrine in the systemic circulation, contrary to topical administration of phenylephrine. Phenylephrone was detected in different compartments of the eye, whereas phenylephrine was present only in the iris‐ciliary body tissues following administration of phenylacetyl ester. The conversion of phenylephrone esters to the active drug, phenylephrine, and thus their subsequent activity was dependent on the physicochemical characteristics of the drugs. The results suggest the potential use of phenylacetyl ester as a potent short‐term mydriatic agent without systemic side effects. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:12–22, 2001.

Novel site‐specific chemical delivery system as a potential mydriatic agent: Formation of phenylephrine in the iris‐ciliary body from phenylephrone chemical delivery systems

Novel site‐specific chemical delivery system as a potential mydriatic agent: Formation of phenylephrine in the iris‐ciliary body from phenylephrone chemical delivery systems

Intraocular Pressure-Lowering Activity and In Vivo Disposition of Dipivalyl Terbutalone in Rabbits

The ocular hypotensive activity and in vivo disposition of dipivalyl terbutalone, a chemical delivery system for terbutaline, were investigated in the albino rabbit model. The dose–response relationship was assessed at drug concentrations ranging from 0.5 to 4% in normal saline. Intraocular pressure (IOP)-lowering activity of dipivalyl terbutalone was compared with epinephrine in equal concentrations. The in vivo disposition was investigated after topical administration of dipivalyl terbutalone at 4% dose level for which two metabolic products, terbutaline, and terbutalone, were monitored in different anterior segment tissues/fluid of albino rabbits, including corneal and iris–ciliary body homogenates and aqueous humor. The instillation of 0.5, 1, 2, and 4% solutions (1 drop of 50 μL) significantly decreased the IOP of normotensive rabbits in a dose-dependant manner. At the highest dose, the maximum reduction (5.6 ± 0.65 mm Hg) was observed at 3 h. In a comparative efficacy study, dipivalyl terbutalone was found to be more effective than epinephrine. In the in vivo distribution after the topical administration of dipivalyl terbutalone, terbutaline was found only in the iris–ciliary body, whereas terbutalone was found in all parts of the eye studied. This work suggests the potential use of dipivalyl terbutalone as an antiglaucoma agent, representing a new chemical delivery system for terbutaline.

ChemInform Abstract: Targeting Drugs to the Brain by Redox Chemical Delivery Systems

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Chemical defense: aquatic beetle (Dineutes hornii) vs. fish (Micropterus salmoides).

Captive largemouth bass (Micropterus salmoides) reject the gyrinid beetle, Dineutes hornii. They also reject edible items (mealworms) treated by topical addition of the norsesquiterpene gyrinidal, the principal component of the defensive secretion of the beetle. The bass' oral tolerance of gyrinidal varies broadly as a function of the gyrinidal dosage and the state of satiation of the fish. When taking a D. hornii or a gyrinidal-treated mealworm in the mouth, the fish subjects the item to an intensive oral flushing behavior, seemingly intended to rid the item of gyrinidal. The duration of oral flushing is itself a function of the gyrinidal dosage and the state of satiation of the bass. To counter oral flushing, D. hornii emits its secretion as a slow trickle. Duration of emission is slightly longer (1.5 min) than the time (1.3 min) invested by the bass in flushing a D. hornii before rejecting the beetle. We postulate that flush resistance may be a general feature of defensive chemical delivery systems in aquatic prey, given that oral flushing may be a common strategy of fish.

Lactitol-based poly(ether polyol) hydrogels for controlled release chemical and drug delivery systems.

The hydroxyl groups of lactitol were propoxylated to produce poly(ether polyol) (LPEP). The average pK(a) value of hydroxyl groups of the polyol was 1.63. Cross-linked hydrogels were synthesized by esterification with chlorinated poly(ethylene glycol) bis(carboxymethyl) ether (PEGBCOCl). The swelling ratio decreased with increasing cross-linking ratio (PEGBCOCl:LPEP) from 2:1 to 4:1 in the hydrogels and was sensitive to temperature change between 25 and 55 degrees C and concentrations of salt and glucose. The swelling ratio did not change significantly with pH in the range of 4-9. The release profiles of a model active agent, acetylsalicylic acid, from the hydrogels showed that the diffusional release rate had a half-order dependence on time, and the diffusivity decreased with increasing cross-linking ratio. This work demonstrated that LPEP-based hydrogels can be used for controlled delivery of drugs and agrochemicals and the release rates can be controlled with the cross-linking ratio of the hydrogel.

Brain-targeted chemical delivery of [Leu2, Pip3]-TRH: synthesis and biological evaluation

A chemical targeting system for [Leu2, Pip3]-TRH (Gln,Leu,Pip) was synthesized in order to allow its specific delivery to the central nervous system (CNS). Sequential metabolism of the obtained ‘packaged’ chemical delivery system, (CDS), DHT-Pro-Pro-Gln-Leu-Pip-OCh, should yield a ‘locked-in’ precursor following the oxidative conversion of the dihydrotrigonellyl (DHT) to the trigonellyl (T+) moiety, followed by removal of the cholesteryl function and cleavage of the T+-Pro-Pro by prolyl endopeptidase. The antagonism of barbiturate-induced sleeping time was used to assess the activity of the CDS. The sleeping time after administration of vehicle and [Leu2]-TRH was 100.5±6.3min, and 78.2±4.7min, respectively. The [Leu2, Pip3]-TRH-CDS showed a significant decrease in sleeping time (58.2±3.4 min) compared to the vehicle or [Leu2]-TRH. These results indicate successful brain delivery of the precursor construct, and an effective release of the active GlnLeuPip in the brain.

Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery.

Propofol (2,6-diisopropylphenol) is becoming the intravenous anesthetic of choice for ambulatory surgery in outpatients. It is extensively metabolized, with most of the administered dose appearing in the urine as glucuronide conjugates. Favorable operating conditions and rapid recovery are claimed as the main advantages in using propofol, whereas disadvantages include a relatively high incidence of apnea, and blood pressure reductions. Besides a literature summary of the pharmacodynamics, pharmacokinetics, toxicology, and clinical use, this review provides a deeper discussion on the current understanding of mechanism of action and structure-activity relationships, and recent findings on drug delivery technologies as applied to the improvement of propofol formulations. The action of propofol involves a positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABAA receptors. Recent results from recombinant human GABAA receptor experiments and findings from the work exploring the effects at other receptors (e.g., glycine, nicotinic, and M1 muscarinic receptors) are reviewed. Studies showing its antiepileptic and anxiolytic properties are also discussed. The structure-activity relationships (SAR) of series of alkylphenols and p-X-substituted congeners have been reinvestigated. Interestingly, unlike the other congeners tested sofar, p-iodo-2,6-diisopropylphenol displayed anticonvulsant and anticonflict effects, but not sedative-hypnotic and anesthetic properties. Due to its high lipid-solubility, propofol was initially formulated as a solution with the surfactant Cremophor EL, but the occurrence of pain on injection and anaphylactoid reactions prompted to search for alternative formulations. Results from using cyclodextrins, water-soluble prodrugs, and adopting Bodor's approach to the site-specific chemical delivery system (CDS), as well as the advantages provided by computer-controlled infusion systems, are examined in some detail.

Permeability of Chemical Delivery Systems Across Rabbit Corneal (SIRC) Cell Line and Isolated Corneas: A Comparative Study

The purpose of this study was to investigate the corneal permeability of phenylephrone chemical delivery systems (CDS) across isolated cornea and to evaluate the utility of the SIRC cell line (epithelial cells originating from rabbit cornea) as an in vitro model for predicting the ocular permeability. The effect of benzalkonium chloride (BAC) on the drug permeability through SIRC cell layers was also studied. The transport of phenylephrone CDS across the isolated cornea of the albino rabbit was measured at various pH values using a two-chamber glass diffusion cell, and the results were compared with the reported permeability values across SIRC cells of rabbit origin. Corneal membranes showed lower flux values for compounds, especially for hydrophilic compounds, than the SIRC cell line. A significant correlation was observed between the permeability coefficients through corneal membranes and SIRC cells. When the pH of the transport medium was increased, the permeability coefficients increased and lag times decreased in both in vitro models. Furthermore, both in vitro models showed significant correlation between permeability coefficients and lipophilicities of the drugs. The three esters, having higher lipophilic characteristics, showed higher permeability than phenylephrine HCl. The phenylacetyl ester of phenylephrone showed a three-fold increase in penetration across SIRC cell layers in the presence of 0.01% BAC. These results suggest that the use of SIRC cell layers can reasonably predict the permeability of ophthalmic drugs across corneal membranes.

Targeting drugs to the brain by redox chemical delivery systems.

Chemical delivery systems (CDSs) based on the redox conversion of a lipophilic dihydropyridine to an ionic, lipid-insoluble pyridinium salt have been developed to improve the access of therapeutic agents to the central nervous system. A dihydropyridinium-type CDS or a redox analog of the drug is sufficiently lipophilic to enter the brain by passive transport, then undergoes an enzymatic oxidation to an ionic pyridinium compound, which promotes retention in the CNS. At the same time, peripheral elimination of the entity is accelerated due to facile conversion of the CDS in the body. This review discusses chemical, physicochemical, biochemical, and biological aspects in relation to the principles and practical implementation of the redox brain-targeting approach to various classes of drugs. Representative examples to the brain-enhanced delivery of neurotransmitters, steroids, anticonvulsants, antibiotics, antiviral, anticancer and antidementia agents, and neuropeptides and their analogs are presented in detail. In vivo and in vitro studies and preliminary clinical data of several novel derivatives have been promising, which could lead to a practical use of the redox CDSs after proper pharmaceutical development. The investigations accentuate the need for considering physicochemical, metabolic, and pharmacokinetic properties in designing of carrier systems that are able to target drugs into the central nervous system.

Analytical Verification of Waterborne Chemical Treatment Regimensin Hatchery Raceways

Abstract Chemical therapy for control and prevention of fish diseases is a necessary and common practice in aquaculture. Many factors affect the accuracy of a chemical treatment application, such as the functioning of the chemical delivery system, calculation of chemical quantities to be delivered, water temperature, geometry of the culture unit, inlet-outlet structure, the influence of aerators, wind movement, and measurement of water volumes and flow rates. Three separate trials were conducted at the Osceola Fish Hatchery, a facility of the Wisconsin Department of Natural Resources, evaluating the accuracy of flow-through hydrogen peroxide treatments applied to 1, 3, or 9 raceways that were connected in series. Raceways were treated with 50 or 75 μL/L of hydrogen peroxide for 30 min. Chemical concentrations were determined titrimetrically. The target treatment regimen was not realized in any of the applications. Chemical concentrations dropped and exposure times increased with each additional raceway tr...

Recent advances in retrometabolic design approaches

The retrometabolic drug design approaches simultaneously incorporate structure activity (SAR) and structure metabolism (SMR) relationships in the design process. Two major approaches were developed, the chemical delivery systems (CDS), which allow chemical–enzymatic targeting of drugs via strategic sequential enzymatic activation of the inactive CDSs. On the opposite end of the retrometabolic design loop are the soft drugs (SD), which are designed to have highly improved therapeutic indeces by controlling their metabolism, after they achieve their therapeutic role. One of the most successful SD class is the ‘inactive metabolite approach’, where the design starts from an inactive metabolite of a drug. Its strategic manipulation yields an isosteric/isoelectronic drug analog, which is enzymatically deactivated to the very inactive metabolite at the desired compartment and with controlled rate. Overall, retrometabolic approaches represent a complex collection of chemical–enzymatic means for the design of safer drugs and for their controlled release. Most recent advances involve FDA approval of a soft steroid, as well as the first successful brain targeting of various neuropeptides and their brain-targeted analogs.