Dissertations / Theses on the topic 'Lipophilic drug'

The work presented in this thesis details the synthetic modification of the clinically important aminoglycoside antibiotics, neomycin B, paromomycin and tobramycin. We sought to modify aminoglycosides by attaching lipophilic groups, including fatty acids and steroids, with a view to improving the bacterial membrane permeability of these species, and ultimately their efficacy in the treatment of tuberculosis. Our initial synthetic strategy involved direct and specific functionalization of the singular primary hydroxyl group of the aminoglycoside antibiotic neomycin B, with lipophilic groups containing carboxylic acid functions via Mitsunobu esterification. Although, direct and selective Mitsunobu acylation of the primary hydroxyl group proved unsuccessful in the case of the pseudo tetrasaccharide neomycin B, the Mitsunobu reaction did however result in selective chemistry elsewhere in the molecule and this has been exploited for modification of the ido (ring IV) and streptamine (ring II) ring systems. Under carefully controlled conditions, the Mitsunobu reaction has been used for the selective dehydration of the ido ring, to give the talo epoxide, and, under more forcing Mitsunobu dehydration conditions, an aziridine function has been introduced into the streptamine moiety. Both the epoxide and the epoxide-aziridine neomycin building blocks were utilized as synthons in subsequent chemical transformations. Seventeen novel neomycin derivatives featuring modification of ring IV and/or ring II were obtained using this approach. Explicit structural elucidation of all the synthetic intermediates and the final products was achieved using high temperature NMR spectroscopy. Direct and specific functionalization of the singular primary hydroxyl group at the C5 position of the ribose ring (ring III) of neomycin B was achieved, via a procedure based in part on selective tripsylation of the C5III primary hydroxyl group of neomycin B reported previously, followed by subsequent displacement of the tripsyl group by azide. Terminal alkyne containing lipophilic esters were then successfully attached to the ribose residue of neomycin B via Cu(I)-mediated azide-alkyne coupling reaction. In addition to the isolation of two fortuitous, new and versatile synthons i.e. monoanhydro neomycin and bis-anhydro neomycin for modification of ring IV and ring II of neomycin, a third synthon based on neomycin framework, allowing stepwise modification of ring III and ring IV was designed and synthesized. This synthon features an epoxide function in the ido ring, and a protected amine function at the C5 position of the ribose ring. Examples of the stepwise use of this synthon for further synthetic modification of the neomycin framework were demonstrated. Fourteen novel neomycin derivatives featuring modification of ring III and /or ring IV were obtained and characterized. Regioselective Mitsunobu esterification of the single primary hydroxyl group of the pseudo trisaccharide tobramycin was utilized successfully to link a variety of hydrophobic esters with tobramycin. Nine lipophilic tobramycin derivatives with significant structural diversity were synthesised and characterized. In a preliminary study, the applicability of the Mitsunobu dehydration reaction for the regioselective formation of an epoxide ring in the ido moiety of the pseudo tetrasaccharide aminoglycoside antibiotic paromomycin system was confirmed. The regioselective ring-opening of the derived epoxide with azide at C3IV of paromomycin was also successfully demonstrated. In total, forty-two new potential aminoglycoside antibiotics have been synthesized and characterized.

Three-dimensional ligand-based virtual screening methods have been used for many years in drug discovery, with a variable success depending on different factors, such as the complexity of the target system or the suitability of the molecular descriptors. New approaches are still necessary to cover the broad spectrum of relationships that a drug-like molecule may establish with the organism. In spite of the complexity of processes that modulate the activity of a drug, most tools are primarily focused on the use of shape or electrostatic descriptors. In contrast, since the importance of lipophilicity in pharmacodynamics and pharmacokinetics process, an exact representation of the 3D pattern of hydrophobic/hydrophilic regions can be a valuable guideline to enhance the molecular similarity studies. In this scenario, PharmScreen was conceived as a tool to exploit lipophilic 3D similarity. Exploiting the MST contributions to octanol/water partition coefficients, the capacity to perform correct molecular overlays and distinguish between active and inactive molecules is discussed. The overlap algorithm is validated against the AstraZeneca test, which comprises 121 experimentally derived sets of molecular overlays. The results point out the suitability of the MST-based hydrophobic parameters for generating molecular overlays, as correct predictions were obtained for 94%, 79%, and 54% of the molecules classified into easy, moderate, and hard sets, respectively. Moreover, the results point out that this accuracy is attained at a much lower degree of identity between the templates used by hydrophobic/HB fields and electrostatic/steric ones. On the other hand, the topological hydrophobic descriptors proposed are applied over 3D-QSAR models. In this context, the Miertus–Scrocco–Tomasi-derived hydrophobic descriptors have been shown to provide models for structure–activity relationships with a predictive accuracy comparable to traditional techniques based on electrostatic/steric parameters. The results reported support the assumption that lipophilicity, supplemented by HB acceptors/donors, provides a useful signature to enrich the information that can be retrieved from (i) molecular alignment and (ii) QSAR models, complementing the results obtained traditionally from electrostatic and steric properties. Taken together, lipophilicity is presented as a valuable alternative for the molecular similarity study. In addition, the applicability of our descriptors in structure-based methods has been explored in order to re-evaluate the complexes constituted by docking techniques (in our case, Glide). Since (de)solvation is fundamental for the establishment of the ligand-receptor complex, it can be expected that the docked ligands in the same pocket share lipophilic characteristics, even if there are several binding modes. However, approximations that affect solvation contribution are applied in the docking score functions, and by extension, some docking programs show problems performing VS especially in hydrophobic binding pockets. Specific binding typically requires the formation of key interactions between targets and ligands. Thus, 3D similarity relative to experimental binding modes could be sufficient to distinguish active compounds from decoys. In view of the results obtained the similarity descriptors proposed are introduced as a valid scoring function for discerning between active and inactive compounds. These findings support the usefulness of lipophilicity as driver descriptors in molecular similarity studies promoting their use in virtual screening campaigns considering LB approaches or in combination with SB. As conclusion, results obtained from the analysis of hydrophobic/hydrophilic descriptors presented in this thesis opens a new window to explore the vast chemical space, complementing the information derived from traditional descriptors in ligand- and structure-based approaches.
El fet d'assumir que molècules estructuralment semblants donaran lloc a activitats biològiques similars ha estat una idea àmpliament explotada en el disseny de fàrmacs. Aquesta premissa subjau en la majoria de les aplicacions pràctiques en recerca química i farmacèutica. No obstant això, el concepte de similitud molecular és subjectiu i la seva interpretació pot variar segons l’ús que se’n vulgui derivar. La quantificació d’aquesta mesura de semblança molecular depèn de la representació de les característiques químiques presents en l'estructura molecular mitjançant descriptors 1D, 2D o 3D, la ponderació d'aquests descriptors i l'expressió matemàtica de la funció de similitud. En l’àmbit de les característiques químiques utilitzades en els mètodes tridimensionals de similitud molecular, les propietats electrostàtiques i estèriques han estat dominants tradicionalment. Tanmateix, això oculta el paper fonamental exercit per altres contribucions a l'afinitat d'unió, com els canvis en la (de)solvatació del lligant i del receptor. Malgrat la seva rellevància, la lipofilicitat ocupa aparentment un paper secundari com a descriptor principal del reconeixement lligand-receptor. Sota aquesta premissa s’ha desenvolupat una eina de cribratge virtual 3D basada en lligands (PharmScreen) que explota les relacions de similitud entre topologies hidrofòbiques derivades del model continuo de solvatació Miertus – Scrocco – Tomasi (MST). Els estudis reportats al llarg d’aquesta tesis recolzen la utilitat de les contribucions atòmiques a la lipofilicitat com a descriptors fonamentals en estudis de similitud, complementant la informació derivada dels descriptors tradicional. PharmScreen es presenta, així, com una eina competitiva per aplicar en campanyes de cribratge virtual basada en lligand o en combinació amb tècniques basades en proteïna, obrint una nova finestra en l’ampli espai químic.

Thesis (Ph.D.)--University of Florida, 2004.
Typescript. Title from title page of source document. Document formatted into pages; contains 139 pages. Includes Vita. Includes bibliographical references.

A study to develop novel lipophilic metal ion complexes based on dihydrocholesterol was undertaken. Steroid ligands functionalised at the 2- and 3- positions were synthesized as possible bidentate ligands for complexation of metal ions. Condensation of 5α-cholestan-3-one with ethyl formate in the presence of base gave 2-hydroxymethylene-5α-cholestan-3-one, and 2- acetyl-5α-cholestan-3-one was obtained by the reaction between 3- trimethylsilyloxy-5α-cholest-2-ene and acetyl chloride. Attempts to synthesize 2,3-dioximino-5α-cholestane from 5α-cholestan-3-one and 2α-hydroxy-5α-cholestan-3-one were unsuccessful. Likewise 2- methylene-5α-cholestan-3-one, which was expected to lead to other bidentate ligands, could not be prepared satisfactorily from 5α-cholestan- 3-one or 3-trimethylsilyloxy-5α-cholest-2-ene.

The purpose of this study was to evaluate the stability of vitamin K1 oral liquids in Sterile Water for Injection when stored in amber glass bottles and amber plastic syringes under refrigerated conditions. Four 100-mL batches of vitamin K1 in Sterile Water for Injection were prepared in amber glass bottles to protect from light. One of the batches was divided into 1-mL aliquots, using amber plastic oral syringes, and capped. The prepared bottles and syringes were stored in a laboratory refrigerator. On each day of sampling, 1-mL aliquots were removed from each bottle and mixed with an equal volume of ethanol. Likewise, the contents of sample syringes were mixed with ethanol to achieve an assay concentration of 0.5 mg/mL. Recovery of vitamin K1 in the compounded samples was quantified against a United States Pharmacopeia reference standard. Quantification was achieved using a stability-indicating high-performance liquid chromatography with ultraviolent light detection method. Product stability is defined as 90% to 110% of the initial concentration. The percent recovery in the Sterile Water for Injection preparations in glass bottles remained above 90% for the 105-day duration of the study, but some samples stored in amber plastic syringes fell below 90% on day 21. Furthermore, a statistically significant difference (2-way ANOVA, P < 0.0001) emerged between syringes at day 0 and day 30, and this trend continued through the day 60, 90, and 105 samples. The only statistically significant difference found within the bottle-stored samples occurred on day 105 (versus zero, P = 0.0465), but the recovery on day 105 still exceeded 90%. Vitamin K1 in Sterile Water for Injection, stored in a refrigerated amber glass bottle, is stable for 105 days. This preparation can also be stored in amber plastic syringes, but this decreases the beyond-use date to 14 days.

碩士
台北醫學院
醫學研究所
89
The influence of an erbium:YAG laser on the transdermal delivery of drugs across skin was studied in vitro. Indomethacin and nalbuphine, which have the same molecular weight, were selected as model lipophilic and hydrophilic drugs respectively, to compare skin permeation by laser treatment. The results indicate a significant increase in the permeation of indomethacin and nalbuphine across skin pretreated with an erbium:YAG laser. The laser had a greater effect on the permeation of hydrophilic molecules which usually possess low permeability. The laser intensity and its spot size were found to play an important role in controlling transdermal delivery of drugs. Permeation of the hydrophilic drug increased following an increase of laser energy. On the other hand, a different result was observed for the lipophilic drug transported across laser-treated skin. The stratum corneum (SC) layer in skin could be partly ablated by the erbium:YAG laser. The barrier function of the SC may also be modulated by a lower intensity of the laser without affecting the viability and structure of the epidermis/dermis as determined by histological observations. However, ultrastructural alteration of the epidermis/dermis may be caused by laser treatment. Use of an erbium:YAG laser is a good method for enhancing transdermal absorption of both lipophilic and hydrophilic drugs, because it allows precise control of SC removal, and this ablation of SC can be reversible to the original normal status.

碩士
國立成功大學
化學工程學系
104
This study reports embeddable polycarbonate-co-polyoxalate (PCOX) microneedles (MNs) containing crosslinked gelatin microspheres (MPs) as a dual- drug transdermal delivery system for hydrophilic and hydrophobic drugs. In this system, hydrophobic model drugs, rhodamine 6G (Rh6G), was encapsulated within the MNs; whereas hydrophilic model drugs, nile blue, was loaded within the MPs. PCOX MNs were mounted to the top of a dissolvable poly(N- vinylpyrrolidone)/poly(vinyl alcohol) (PVP/PVA) supporting array, providing mechanical strength to fully insert the MNs into the skin. When inserted into the skin, the supporting array can be quickly dissolved by interstitial fluid, leaving the MNs within the skin for sustained drug delivery without requiring a transdermal patch. The gelatin MPs quickly swell to release nile blue because of contact with skin’s water. Such swelling will cause the MN disintegration, thus accelerating Rh6G release from the MNs. The gelatin MPs was prepared by utilizing W/O emulsion polymerization and then crosslinked with genipin solution for 6 h. When contact with water for 90 s, the diameter of the crosslinked MPs can swell to ~2 times their initial diameter (n = 10). The MNs were then prepared by filling a MN mold with nile blue-loaded MPs. These MNs have sufficient mechanical strength to be inserted into porcine and rat skins at a depth of 700~1000 μm. In vitro drug release study showed that nile blue can be quickly released from the MNs (~80% at Day 14). At Day 50, 100% of Rh6G was released from the group with MPs, whereas there is only 75% of Rh6G release from their counterpart. This indicated that MP swelling indeed enhances drug release from the MNs. Such release behavior can be also observed from the in vivo drug release study. These results demonstrated that the embeddable PCOX MNs with gelatin MPs, which enable to simultaneously release hydrophilic and hydrophobic drugs into the skin in a sustained manner, may be a new generation of transdermal delivery system.

M.Sc.
Despite several decades of extensive research and development in pharmaceutical chemistry, the poor solubility of lipophilic compounds in aqueous media remains a major barrier to their absorption, bioavailability and clinical efficacy. This poor solubility is also a problem in other areas such as the flavour and fragrance industry. In cosmetics, for example, poor aqueous solubility and instability of oily compounds causes problems in formulation and fragrance stability. One approach to overcome these difficulties is to encapsulate oily compounds in biocompatible materials. As a drug delivery system such an approach is attractive if the size of the capsule is reduced to the micrometer or nanometer scale. Naturally occurring polysaccharides like sodium alginate (NaALG) and chitosan (CS) are generally regarded as safe (GRAS) for use in human use and have therefore gained much attention recently. As a drug delivery system, this polymer matrix can be used to prevent drug degradation in the gastro intestinal tract (GIT) and often provides controlled release of the encapsulant. Cyclodextrins (CDs) on the other hand offer an alternative approach. These cyclic oligosaccharides have the ability to form non-covalent inclusion complexes with a range of organic compounds, and in so doing alter their physiochemical properties such as solubility. This study was aimed at exploring these concepts by using ALG and CS as an entrapment matrix for an essential oil, tagette oil (used as a model oily drug) that is insoluble in aqueous media. Alginate/chitosan (ALG/CS) nanoparticles were prepared in a 3-step procedure; emulsification of tagette oil in aqueous Na-ALG solution, followed by ionotropic pre-gelation of the ALG core with CaCl2 and further crosslinking with CS. Morphology and particle size measurements were performed by scanning and transmission electron microscopy (SEM and TEM), and Malvern Zetasizer.