Nicholas Bodor

Neural network studies: Part 3. Prediction of partition coefficients

Abstract In a previous paper (N. Bodor, A. Harget and M.-J. Huang, J. Am. Chem. Soc., 113 (1991) 9480) we demonstrated the utility of a neural network approach in the estimation of the aqueous solubility of organic compounds. This approach has now been extended to the prediction of partition coefficients. A training set of AM1 calculated properties and experimental values for 302 compounds was used and, after training, the neural network was tested for its ability to predict the partition coefficients of 21 compounds not included in the training set. We also tested six more compounds with molecular properties out of the training set property range. A comparison was made with the results obtained from a previous study which had used a regression analysis approach (N. Bodor and M.-J. Huang, J. Pharm. Sci., 81 (1992) 272). The neural network results compared favorably with those given by the regression analysis approach, both for the training set and for the new compounds.

Soft drug design: general principles and recent applications.

Soft drug design represents a new approach aimed to design safer drugs with an increased therapeutic index by integrating metabolism considerations into the drug design process. Soft drugs are new therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their therapeutic effect. Hence, they are obtained by building into the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified. In an attempt to systematize and summarize the related work done in a number of laboratories, including ours, the present review presents an overview of the general soft drug design principles and provides a variety of specific examples to illustrate the concepts. A number of already marketed drugs, such as esmolol, remifentanil, or loteprednol etabonate, resulted from the successful application of such design principles. Many other promising drug candidates are currently under investigation in a variety of fields including possible soft antimicrobials, anticholinergics, corticosteroids, β‐blockers, analgetics, ACE inhibitors, antiarrhythmics, and others. Whenever possible, pharmacokinetic and pharmacodynamic properties are briefly summarized and compared to those of other compounds used in the same field.

Use of 2-hydroxypropyl-beta-cyclodextrin as a solubilizing and stabilizing excipient for protein drugs.

A chemically modified, amorphous β-cyclodextrin, namely, 2-hydroxypropyl-β-cyclodextrin (HPCD), was examined as a solubilizing and stabilizing agent for protein drugs. The aqueous solubility of ovine growth hormone at pH 7.4 was increased through the use of HPCD. This effect was manifested by higher UV transparency at 600 nm. Interleukin-2 (IL-2) is rendered insoluble upon lyophilization in the absence of stabilizers. Use of aqueous HPCD provides a clear solution, as indicated by fluorometric light scattering, and inhibits aggregate formation, as shown by ultracentrifugation and Western blot analyses. In addition, there were no major conformational changes of IL-2 in HPCD formulation as indicated by fourth-derivative ultraviolet spectroscopy. Finally, IL-2 retained 100% of its biopotency when prepared in HPCD solutions. Aggregation of insulin was also suppressed by HPCD. These data, as well as the i.v. safety of HPCD and its well-characterized chemical composition, suggest that this starch derivative may be a potentially useful excipient for protein drugs intended for parenteral use.

An intravenous toxicity study of 2-hydroxypropyl-β-cyclodextrin, a useful drug solubilizer, in rats and monkeys

Abstract The subacute and subchronic intravenous (i.v.) toxicity of 2-hydroxypropyl-β-cyclodextrin (HPCD) was examined in Sprague-Dawley rats and cynomolgus monkeys. After either 14 or 90 days of alternate day dosing with either saline or 200 mg/kg HPCD, no toxicologically meaningful differences were observed in the following parameters: body weight, body weight gain, food consumption, hematology, clinical chemistry, organ weights, organ to brain weight ratio, organ to body weight ratio and macroscopic and microscopic histopathology. Subsequent to these studies, an acute high-dose study was performed in cynomolgus monkeys which indicated that a single i.v. dose of HPCD as high as 10 g/kg was not lethal.

Recent advances in the brain targeting of neuropharmaceuticals by chemical delivery systems

Brain-targeted chemical delivery systems represent a general and systematic method that can provide localized and sustained release for a variety of therapeutic agents including neuropeptides. By using a sequential metabolism approach, they exploit the specific trafficking properties of the blood-brain barrier and provide site-specific or site-enhanced delivery. After a brief description of the design principles, the present article reviews a number of specific delivery examples (zidovudine, ganciclovir, lomustine benzylpenicillin, estradiol, enkephalin, TRH, kyotorphin), together with representative synthetic routes, physicochemical properties, metabolic pathways, and pharmacological data. A reevaluated correlation for more than 60 drugs between previously published in vivo cerebrovascular permeability data and octanol/water partition coefficients is also included since it may be useful in characterizing the properties of the blood-brain barrier, including active transport by P-glycoprotein.

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.

Soft drugs--10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate.

An improved synthesis of loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene 17 beta-carboxylate) was achieved. The design of the new type of glucocorticoid was based on the soft drug concept. The relative binding affinities of loteprednol and its putative metabolites (PJ90 and PJ91) to rat lung type II glucocorticoid receptor were determined in a competitive binding experiment with [3H]triamicinolone acetonide. The medium contained cortienic acid (10(-5) M) in order to block transcortin binding sites. Loteprednol etabonate exhibited a binding affinity which was 4.3 times that of dexamethasone, both compounds having a Hill factor close to 1 whereas PJ90 and PJ91 did not show any affinity to the receptor. Loteprednol etabonate was compared to betamethasone 17 alpha-valerate in a vasoconstriction test which was performed on the forearm skin of human volunteers. The results showed that loteprednol etabonate has good skin-permeation properties and strong glucocorticoid activity.

Ophthalmic drug design based on the metabolic activity of the eye: soft drugs and chemical delivery systems.

Despite its apparent easy accessibility, the eye is, in fact, well protected against the absorption of foreign materials, including therapeutic agents, by the eyelids, by the tearflow, and by the permeability barriers imposed by the cornea on one side and the blood-retinal barrier on the other. Most existing ophthalmic drugs were adapted from other therapeutic applications and were not specifically developed for the treatment of eye diseases; hence, they are not well suited to provide eye-specific effects without causing systemic side effects. A real breakthrough in the area of ophthalmic therapeutics can be achieved only by specifically designing new drugs for ophthalmic applications to incorporate the possibility of eye targeting into their chemical structure. Possibilities provided along these lines by designing chemical delivery systems (CDSs) and soft drugs within the framework of retrometabolic drug design are reviewed here. Both are general concept applicable in almost any therapeutic area. This review will concentrate on \-adrenergic agonists and anti-inflammatory corticosteroids, where clinical results obtained with new chemical entities, such as betaxoxime, adaprolol, loteprednol etabonate, and etiprednol dicloacetate, exist to support the advantages of such metabolism-focused, ophthalmic-specific drug design approaches.

Redox Drug Delivery Systems for Targeting Drugs to the Brain

Drug targeting to specific receptors or specific organs has been one of the main objectives of the medicinal and pharmaceutical chemists from the beginning of the century. However, only in the past 15 years or so have there been any promising developments in achieving this goal. The term “site-specific drug delivery” covers targeting to receptors or organs or any other specific part of the body to which we wish to deliver the drug exclusively. The site-specific delivery of drugs is indeed a very attractive goal because this provides one of the most significant potential ways to improve the therapeutic index (TI) of the drugs.’ When a drug is delivered preferentially to the site of the action by virtue of this desired differential distribution, it will spare the rest of the body; thus, it will significantly reduce the overall toxicity while maintaining its therapeutic benefits. At the present time, there are three basically different approaches for site-specific drug delivery. The first, the physical or mechanical approach, is based on effectively formulating a drug in a delivery device, which by virtue of its physical localization will allow differential release of the drug. The site specificity thus is due to exclusively producing higher drug concentrations wherever the device is localized, while the drug concentration in the rest of the body is very much diminished due to the simple dilution factor. The limitations of this approach are clearly due to the fact that many desired target sites are simply not available for the physical approach. In addition, often the distributional differences due to the dilution effect may not be sufficient to produce significant improvement in the TI. The second basic approach is the biological one, according to which a drug is potentially targeted by a biological carrier that would have specific affinity for certain receptor sites, organs or other biological targets. This kind of approach, such as using monoclonal antibodydrug conjugates, erythrocyte carriers, or macromolecular product carriers (such as liposomes) has been the subject of many investigations. The limitations of this approach are primarily problems presented by stoichiometry, controlling the processes related to releasing the drugs from the biological carriers, as well as biological incompatibility of the carriers. The third approach is the chemical approach, the use of the site-specific chemical delivery systems (CDSs),’.’ which provide a wide variety of possibilities for siteenhanced or site-specific delivery. The CDS is produced by chemical reactions (at least

Hydroxymethyl and acyloxymethyl prodrugs of theophylline: enhanced delivery of polar drugs through skin

Abstract A series of 7-acyloxymethyl prodrugs of theophylline has been prepared by the acylation of 7-(hydroxymethyl)theophylline and by the alkylation of theophylline with an acyloxymethyl halide. The lipid solubilities of all the prodrugs were markedly improved over that of theophylline but, in addition, the succinamate and the glycinate derivatives exhibited increased water solubilities. As a result, prodrugs which exhibited partition coefficients between 0.03 and 16.7 were obtained. Selected acyloxymethyl prodrugs as well as 7-(hydroxymethyl)theophylline were effective in increasing the delivery of theophylline through hairless mouse skin by 3.5–5 times that of theophylline. Several of the prodrugs, when applied topically to normal and hairless mice, inhibited DNA synthesis in the skins of the mice after they had undergone UV irradiation.