Polymer Carriers

Another agent that has benefited from liposome encapsulation is 4-hydroxy-L-proline (cHyp), which has been examined for its ability to prevent bleomycin-induced pulmonary fibrosis. Poiani et al. encapsulated cHyp in liposomes composed of DPPC cholesterol stearylamine, 14 7 4, and administered them to rats by intratracheal instillation 104 . They found that liposomal cHyp suppressed collagen accumulation in bleomycin-induced pulmonary fibrosis and exhibited prolonged residence in the lungs with...

Prodrug Systems

One of the first prodrugs on the market that used colonic enzymatic biodegradation as its active principle was sulfasalazine (salazosulfapyridine). More modern successor products are olsalazine, balsalazine, and ipsalazine 50 , all of them used for the treatment of inflammatory bowel diseases and containing two molecules linked by an azo bond (Figure 2). The prodrugs pass the stomach and the small intestine unchanged and unabsorbed. Reaching the cecum, they are reduced and cleaved by specific...

Liver Cirrhosis or Fibrosis

Liver cirrhosis is among the top 10 causes of death in the Western world. The disease occurs after chronic damage to hepatic cells, mainly hepatocytes, which can be caused by viral hepatitis, chronic alcohol abuse or toxic injury, biliary disease, and metabolic liver disorders 64 . Liver cirrhosis is characterized by an abnormal deposition of connective tissue in the liver, which hampers the normal functions of the liver. Other features of the disease are general tissue damage, chronic...

In Vivo Testing

A radiotelemetric method has been described to test the disintegration property of a tablet 58 . A tablet containing a citrate buffer was coated with hydroxypropyl methylcellulose phthalate and then placed in a Heidelberg capsule that also contained a pH-electrode (Figure 8). An antenna is strapped around the midriff of the dog to detect the output from the Heidelberg capsule. Figure 8 Schematic for attachment of the enteric-coated tablet to the Heidelberg pH detector capsule (From Ref. 58)....

Info

Figure 3 Lung and liver glucocorticoid receptor occupancy after intratracheal administration of 100 lg kg triamcinolone acetonide phosphate solution (TAP, A), liposomal preparation of triamcinolone acetonide (B) and intratracheal administration of 200 nm TAP liposomes (C, intermediate release liposomes) and 800 nm TAP liposomes (D, slow release liposomes). Data taken from Ref. 69. Figure 3 Lung and liver glucocorticoid receptor occupancy after intratracheal administration of 100 lg kg...

Principles Of Retrometabolic Drug Design

As we have often argued, metabolic considerations should be an integral part of any drug design process. Rational drug design can be accomplished only by incorporating metabolic considerations into the design process from the very beginning. Retrometabolic approaches represent a novel, systematic method to accomplish this goal. By combining structure-activity relationships (SAR) with structure-metabolism relationships (SMR), they allow the design of safe, localized compounds. As illustrated by...

Lipid Digestion And Absorption And The Preabsorptive Phase

Lipids, unlike many excipients, whether present in food or as discreet pharmaceutical additives, are processed both chemically and physically within the GIT before absorption and transport into the portal blood (or mesenteric lymph). Indeed, most of the effects mediated by formulation-based lipids or the lipid content of food are mediated by means of the products of lipid digestion molecules that may exhibit very different physicochemical and physiological properties when compared with the...

Preface

A book on the subject of drug targeting could not possibly omit Paul Ehrlich's theory of the magic bullet. It was on the occasion of attending Der Freisch tz, a romatic opera by the German composer Carl Maria von Weber, that he coined his famous phrase. As the story goes, the young hunter apprentice (to ensure success in the imminent shooting competition that would award him the degree of master shooter) draws up a pact with the Devil, who promises three ''free shots'' (whence Der Freisch tz)...

In vivo

Figure 3 Gel-state versus liquid-state application of vesicles prepared from dilauryl-phosphatidylcholine and septaoxyethylene alkylethers or distearylphosphatidylcholine and cholesterol hemisuccinate. A cross-section of rat skin visualized with confocal laser scanning microscopy after 6 h application. The dye used was fluorescein-phosphatidyl ethanol amine. The vesicles were applied onto rat skin in vivo. tion of soy lecithin liposomes (liquid-state vesicles) using OsO4 staining and fixation....

Soft Drugs

Soft drugs are active isosteric-isoelectronic analogues of a lead compound, but they are deactivated in a predictable and controllable way after achieving their therapeutic role 21, 24-29 . They are designed to be rapidly metabolized into inactive species and, hence, to simplify the transformation-distribution-activity profile of the lead. Consequently, soft drugs are new therapeutic agents obtained by building in the molecule, in addition to the activity, the most desired way in which the...

Drug Albumin Conjugates

After a suitable carrier for the cell type of interest is developed, drugs can be coupled to this carrier either directly or through a spacer molecule. The bond between the carrier and the drug has to be stable in plasma but biodegradable when the drug has reached the target site. Spacer molecules used for drug targeting purposes are (endo- or exo-) peptidase-sensitive spacers, esterase-sensitive spacers, and acid-sensitive spacers 149, 150 . Acid-sensitive spacers are quite relevant, because...

Stability of Polymers

Stability of the polymers at usual storage conditions depends on their molecular structure. Several studies have documented that methacrylic acid copolymers are the most stable polymers as bulk and finished dosage form (Figure 3) 24 . The limiting factor of stability of the polymers is their ester function, which tends to hydrolyze. This happens more easily with cellulose phthalates than with metha-crylic acid copolymers. All polymers tend to lose carboxylic functional groups when they are...

Coating Processes

Enteric film coatings are usually applied as a simple single-layer film coat, although in some instances it may be necessary to apply multiple-layer film coatings. Coating formulations usually contain the enteric polymer, a plasticizer if necessary, pigments, and sometimes also a glidant to prevent sticking of the film coatings during the manufacturing process. Colorants might be added to the enteric film coating formulations directly or be applied in a separate coating layer. By use of...

References

Vaupel, Anatomie, Physiologie, Pathophysiologie des Menschen, Gastrointestinal Tract and Digestion, Scientific Publishers, Stuttgart, 1991. 2. T. T. Kararli, Gastrointestinal absorption of drugs, Crit. Rev. Ther. Drug Carrier Systems 6 39-86 (1989). 3. G. T. MacFarlane, and J. H. Cummings, The colonic flora, fermentation and large bowel digestion function, Chapter 4, The Large Intestine Physiology, Pathophysiology and Disease (S. F. Phillips, J. H. Pemberton, and...

Chemical Delivery Systems

Chemical delivery systems (CDSs), positioned on the other side of the retrometa-bolic drug design loop, represent novel and systematic ways of targeting active biological molecules to specific target sites or organs on the basis of predictable enzymatic activation. In principle, chemical drug delivery systems should include any drug targeting system that requires a chemical reaction to produce it. Consequently, they should include those systems where there is a covalent link between the drug...

Modified Albumins

Albumin may be substituted with sugars, charged molecules, and (cyclic) pep-tides to obtain specificity for a certain cell type. The combination of receptor density on cells and the degree of substitution of receptor ligands on the albumin core protein greatly determines the cell-specific accumulation. To date, a set of carriers to all cell types of the liver is available (Table 4). Targeting to hepatocytes is well established. Modification of albumin with at least 13 sugar moieties of lactose...

Bio Distribution Studies of the Carrier

The in vivo behavior of a carrier is an essential issue in the concept of drug targeting to determine the pharmacological effects and side effects of therapeutic compounds. A number of experimental methods are available to examine this issue. Organ distribution studies can be performed to determine quantitatively the total amount of carriers present in the target organ compared with the other organs 94, 213, 214 . Usually, the carrier is radioactively labeled to allow detection in vivo. The...

Introduction

One of the most important goals of pharmaceutical research and development is targeted drug delivery, defined as optimization of the therapeutic index by localizing the pharmacological activity of the drug to the site of action. It is important to distinguish this broad definition as the ability to achieve a desired pharmacological response at a selected site without undesired interaction at other sites from a narrower definition of the basic targeting concept. Within this narrower definition,...

Contents

Part I PHYSICAL TARGETING APPROACHES 1. Enteric Targeting Through Enteric Coating 1 Bianca Brogmann and Thomas E. Beckert 2. New Experimental Coating Material for Colon-Specific 3. Pharmacokinetic Considerations in the Design of Pulmonary Drug Delivery Systems for Glucocorticoids 51 4. Lipid-Based Formulations for Oral Administration Opportunities for Bioavailability Enhancement and Lipoprotein Targeting of Lipophilic Drugs 85 Christopher J. H. Porter and William N. Charman 5. Topical...

Contributors

Bauer Pharmaceutical Technology Department, Freiburg Materials Research Center, Freiburg, Germany Thomas E. Beckert Technical Customer Service Pharma Polymers, Rohm GmbH, Darmstadt, Germany Leonie Beljaars Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Exploration, Groningen, The Netherlands Nicholas Bodor Center for Drug Discovery, University of Florida, Gainesville, Florida Joke A. Bouwstra Leiden Amsterdam Center for Drug Research, Leiden University,...

Smedds

A In a previous study in male beagle dogs the absolute BA of Hf HCl was 8.6 5.3 79 . Source Ref. 80. a In a previous study in male beagle dogs the absolute BA of Hf HCl was 8.6 5.3 79 . Source Ref. 80. mercially available tablet formulation 250 mg Hf HCl in fasted beagles was 8.6 5.3 79 . The capacity of dispersed lipid-based formulations to enhance the bioavailability of Hf is further supported by a recent study in fasted beagles in which the absolute oral bioavailability of crystalline Hf...

What Are Ggs Drug

The natural function of the skin is to protect the body against loss of endogenous substances such as water and against undesired influences from exogenous substances in the environment. The main barrier for diffusion of molecules across the skin resides in its outermost layer, the stratum corneum SC 1 . The SC consists of keratin-filled dead cells, the corneocytes, which are entirely surrounded by crystalline lamellar lipid regions Figure 1 . The cell boundary of the corneocytes consists of a...