scholarly journals Σύνθεση και χαρακτηρισμός πρωτότυπων ολιγομερών κυκλοδεξτρινών για μεταφορά φαρμάκων

2014 ◽  
Author(s):  
Μαλαματένια Μανουηλίδου
Keyword(s):  
Binding Capacity ◽  
Drug Carrier ◽  
Aqueous Solubility ◽  
Single Step ◽  
Drug Formulation ◽  
Water Soluble ◽  
Amide Bond ◽  
Mild Conditions ◽  
Order Of Magnitude ◽  
High Yields

Cyclodextrins (CDs) are cyclic hollow oligosaccharide molecules that form water solublehost-guest systems, with many applications in drug formulation and delivery. CDoligomers have been previously studied due to the interest towards smart hosts withenhanced molecular recognition and binding capacity as sensors, catalysts, enzymemimics, photoreactive systems, etc. The aim of this dissertation was to prepare αCDoligomers for drug inclusion and transport with criteria: (i) ease of preparation, inaqueous media, in short steps, under mild conditions and in good yields, (ii) to obtainoligomers with satisfactory aqueous solubility and full availability of the CD cavities (iv)to achieve multiple binding with strengths better or comparable to those of parent αCD.The copper catalyzed azide-alkyne cyclization (CuAAC) reaction was utilized to preparea new water soluble cyclodextrin trimer very efficiently. The trimer engulfed threemolecules of a model guest and satisfactorily solubilized the chemotherapeutictamoxifen citrate and its active metabolite, N-desmethyltamoxifen, increasing theirsolubility by >1 order of magnitude. Moreover, for the first time the bioorthogonalStaudinger Ligation was applied to prepare αCD-dimers. For this purpose, a doublyactive linker was specifically developed that enabled dimer preparation in a single step,in aqueous/organic media, under mild conditions and with high yields. The aboveprepared products were studied in detail by NMR spectroscopy and were found toadopt, by self-inclusion, a closed conformation in aqueous solution, which completelyopened up in the presence of a suitable guest, leaving the cavities fully available to formthe corresponding inclusion complexes. Titration and DOSY NMR experimentsconfirmed the above and showed that the dimeric species form slowly diffusingaggregates in water, that in the presence of the guest partially disperse. The StaudingerLigation could thus become the method of choice for preparing CD dimers.Solubilization of practically insoluble N-desmethyl-tamoxifen was also achieved to 0.3mM. Moreover, CD dimers prepared via amide bond formation were less efficient andrequired harsh conditions. Finally, SNO-αCD derivatives were prepared andcharacterized as bimodal NO and drug carrier systems.

scholarly journals Staudinger ligation towards cyclodextrin dimers in aqueous/organic media. Synthesis, conformations and guest-encapsulation ability

2014 ◽  
Vol 10 ◽  
pp. 774-783 ◽  
Author(s):  
Malamatenia D Manouilidou ◽  
Yannis G Lazarou ◽  
Irene M Mavridis ◽  
Konstantina Yannakopoulou
Keyword(s):  
Binding Capacity ◽  
Theoretical Calculations ◽  
Aqueous Media ◽  
Aqueous Solubility ◽  
Single Step ◽  
Organic Media ◽  
Azido Group ◽  
Staudinger Ligation ◽  
Mild Conditions ◽  
Narrow Side

β-Cyclodextrin (β-CD) dimers have been prepared using the bioorthogonal Staudinger ligation for the first time. In addition to a known linker, methyl 2-(diphenylphosphanyl)terephthalate, a doubly active linker was specifically developed that enabled connection of two β-CD units in a single step and in aqueous/organic media, under mild conditions and with good yields. A three-carbon spacer between the β-CD torus and the azido group was required for facile dimer formation. The products, as studied by NMR spectroscopy, were found to adopt closed conformations by intramolecular self-inclusion. On the other hand, association via intermolecular binding was also observed in aqueous solution, confirmed by DOSY NMR experiments. Despite self-inclusion, the β-CD cavities were capable of guest encapsulation, as shown by titration experiments: the binding constant with 1-adamantylamine was similar to that of natural β-CD. Theoretical calculations for isolated molecules (PM3 level of theory) and in the presence of solvent [water, PM3(COSMO)] as well as DFT calculations suggested that the compounds prefer to adopt conformations which bring the phenyl groups either inside the β-CD cavity (inclusion) or over its narrow side (vicinal). Thus, Staudinger ligation could be the method of choice for linking CDs exhibiting (i) ease of preparation in aqueous media, in short steps, under mild conditions and in good yields, (ii) satisfactory aqueous solubility and independent binding capacity of the cavities.

scholarly journals New renin inhibitors homologous with pepstatin

1981 ◽  
Vol 197 (2) ◽  
pp. 465-471 ◽  
Author(s):  
M Eid ◽  
G Evin ◽  
B Castro ◽  
J Menard ◽  
P Corvol
Keyword(s):  
Methyl Ester ◽  
Glutamic Acid ◽  
Water Soluble ◽  
Amino Acid Residues ◽  
Renin Inhibitors ◽  
C Terminus ◽  
Coupling Reagent ◽  
Order Of Magnitude ◽  
High Yields

Four homologues of pepstatin, the potent but poorly soluble inhibitor of aspartic proteinases, were synthesized by coupling to the C-terminus of the natural pentapeptide the following amino acid residues: L-arginine methyl ester, L-aspartic acid, L-glutamic acid and the dipeptide L-aspartyl-L-arginine. The peptide-coupling reagent we used, benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate, allowed us to obtain readily pure pepstatin homologues with high yields (60-83%). Pepstatylarginine methyl ester and pepstatylglutamic acid were about one order of magnitude more water-soluble than pepstatin. The four homologues and pepstatin were tested in vitro as inhibitors for highly purified pig and human renins acting on the N-acetyltetradecapeptide substrate. The 50% inhibitory concentrations (IC50) of the homologues were ranged from 0.01 to 1 microM against porcine renin at pH 6.0 (pepstatin IC50 approximately 0.32 microM) and from 5.8 to 41 microM against human renin at pH 6.5 (pepstatin IC 50 approximately 17 microM). By three different graphical methods we showed that pepstatin and the four homologues behaved as competitive inhibitors for porcine renin. The most potent inhibitors were pepstatylaspartic acid and pepstatylglutamic acid, with inhibitory constants respectively 2- and 10-fold smaller than that of pepstatin. By coupling glutamic acid to pepstatin, the ratio solubility/Ki was increased by two orders of magnitude.

Pharmaceutical Advances in Cyclodextrin Inclusion Complexes for Improved Bioavailability of Poorly-Soluble Drugs

2015 ◽  
Vol 8 (3) ◽  
pp. 2894-2905
Author(s):  
Ganesh Raosaheb Godge ◽  
Shivanand Hiremath ◽  
Bhakti Sonawale ◽  
Rani Shirsath
Keyword(s):  
Drug Delivery ◽  
Inclusion Complexes ◽  
Drug Carrier ◽  
Drug Formulation ◽  
Water Soluble ◽  
Formulation Development ◽  
Separation Processes ◽  
Pharmaceutical Application ◽  
Wide Range ◽  
Solubility Enhancers

Cyclodextrins (CDs) are commonly used in drug formulations as solubility enhancers because of their ability to form water-soluble inclusion complexes with poorly water-soluble drugs. Cyclodextrins are useful molecular chelating agents. The cyclodextrins have a wide range of applications in different areas of drug delivery and pharmaceutical industry due to their complexation ability and other versatile characteristics. Orally administered drugs completely absorb only when they show fair solubility in gastric medium and such drugs shows good bioavailability. The solubility and dissolution properties of drugs play an important role in the process of formulation development. The most common pharmaceutical application of cyclodextrin is to enhance the solubility, stability, safety and bioavailability of drug molecules. Cyclodextrins are cyclic oligosaccharides which have recently been recognized as useful pharmaceutical excipients. As a result of molecular complexation phenomena CDs are widely used in many industrial products, technologies and analytical methods. The negligible cytotoxic effects of CDs are an important attribute in applications such as drug carrier, food and flavors, cosmetics, packing, textiles, separation processes, environment protection, fermentation and catalysis. The objective of this review is to discuss and summarize some of the findings and applications of cyclodextrin and their derivatives indifferent areas of drug delivery. The paper also highlights important CD application in drug solubility and dissolution, bioavailability, safety and stability, their use as excipients in drug formulation, design of various novel delivery systems like liposome, microspheres, microcapsules, and nanoparticles. 

scholarly journals Synthesis and Anchoring of Antineoplastic Ferrocene and Phthalocyanine Derivatives on Water-Soluble Polymeric Drug Carriers Derived from Lysine and Aspartic Acid

2008 ◽  
Vol 2008 ◽  
pp. 1-10 ◽  
Author(s):  
M. David Maree ◽  
Eberhard W. Neuse ◽  
Elizabeth Erasmus ◽  
Jannie C. Swarts
Keyword(s):  
Aspartic Acid ◽  
Drug Carrier ◽  
Drug Carriers ◽  
Water Soluble ◽  
Amide Bond ◽  
Drug Conjugates ◽  
Synthetic Strategy ◽  
Coupling Reagent ◽  
Polymeric Drug ◽  
Derivatives Of

The general synthetic strategy towards water-soluble biodegradable drug carriers and the properties that they must have are discussed. The syntheses of water-soluble biodegradable copolymers of lysine and aspartic acid as potential drug-delivering devices, having amine-functionalised side chains are then described. Covalent anchoring of carboxylic acid derivatives of the antineoplastic ferrocene and photodynamically active phthalocyanine moieties to the amine-containing drug carrier copolymers under mild coupling conditions has been achieved utilising the coupling reagent O-benzotriazolyl-N,N,N′,N′-tetramethyluronium hexafluorophosphate to promote formation of the biodegradable amide bond. Even though the parent antineoplastic ferrocene and phthalocyanine derivatives are themselves insoluble in water at pH < 7, the new carrier-drug conjugates that were obtained are well water-soluble.

Solubility Enhancement of Poorly Soluble Drug Simvastatin by Solid Dispersion Technique

2016 ◽  
Vol 2 (2) ◽  
pp. 91-95
Author(s):  
Neelima Rani T ◽  
Pavani A ◽  
Sobhita Rani P ◽  
Srilakshmi N
Keyword(s):  
Dissolution Rate ◽  
Drug Carrier ◽  
Solid Dispersions ◽  
Aqueous Solubility ◽  
Onset Of Action ◽  
Kneading Method ◽  
Wetting Property ◽  
Poorly Soluble ◽  
Dispersion Technique ◽  
Low Solubility

This study aims to formulate solid dispersions (SDs) of Simvastatin (SIM) to improve the aqueous solubility, dissolution rate and to facilitate faster onset of action. Simvastatin is a BCS class II drug having low solubility & therefore low oral bioavailability. In the present study, SDs of simvastatin different drug-carrier ratios were prepared by kneading method. The results showed that simvastatin solubility & dissolution rate enhanced with polymer SSG in the ratio 1:7 due to increase in wetting property or possibly may be due to change in crystallinity of the drug.

Fenofibrate Solid Dispersion for Improving Oral Bioavailability: Preparation, and Characterization and in vivo Evaluation

2020 ◽  
Vol 13 (5) ◽  
pp. 5102-5109
Author(s):  
Venu Madhav K ◽  
Somnath De ◽  
Chandra Shekar Bonagiri ◽  
Sridhar Babu Gummadi
Keyword(s):  
Oral Bioavailability ◽  
Oral Delivery ◽  
Solid Dispersions ◽  
In Vitro Release ◽  
Aqueous Solubility ◽  
Water Soluble ◽  
Scanning Calorimetry ◽  
In Vivo Evaluation

Fenofibrate (FN) is used in the treatment of hypercholesterolemia. It shows poor dissolution and poor oral bioavailability after oral administration due to high liphophilicity and low aqueous solubility. Hence, solid dispersions (SDs) of FN (FN-SDs) were develop that might enhance the dissolution and subsequently oral bioavailability. FN-SDs were prepared by solvent casting method using different carriers (PEG 4000, PEG 6000, β cyclodextrin and HP β cyclodextrin) in different proportions (0.25%, 0.5%, 0.75% and 1% w/v). FN-SDs were evaluated solubility, assay and in vitro release studies for the optimization of SD formulation. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) analysis was performed for crystalline and morphology analysis, respectively. Further, optimized FN-SD formulation evaluated for pharmacokinetic performance in Wistar rats, in vivo in comparison with FN suspension.  From the results, FN-SD3 and FN-SD6 have showed 102.9 ±1.3% and 105.5±3.1% drug release, respectively in 2 h. DSC and PXRD studies revealed that conversion of crystalline to amorphous nature of FN from FT-SD formulation. SEM studies revealed the change in the orientation of FN when incorporated in SDs. The oral bioavailability FN-SD3 and FN-SD6 formulations exhibited 2.5-folds and 3.1-folds improvement when compared to FN suspension as control. Overall, SD of FN could be considered as an alternative dosage form for the enhancement of oral delivery of poorly water-soluble FN.

Self Microemulsifying Nutraceutical and Drug Delivery Systems

2014 ◽  
Vol 7 (3) ◽  
pp. 2520-2528 ◽  
Author(s):  
Vikrant P Wankhade ◽  
Nivedita S Kale ◽  
K.K Tapar
Keyword(s):  
Drug Delivery ◽  
Drug Delivery System ◽  
Delivery System ◽  
Ternary Phase Diagram ◽  
Aqueous Solubility ◽  
Oral Formulation ◽  
Water Soluble ◽  
Drug Dissolution ◽  
The Novel ◽  
Peristaltic Movement

Many chemical entities and nutraceuticals are poor water soluble and show high lipophilicity. It’s difficult to formulate them into oral formulation because of its low aqueous solubility which ultimately affects bioavailability. To enhance the bioavailability of such drugs compounds, self microemulsifying drug delivery system is the reliable drug delivery system. In this system the drug is incorporated in the isotropic system and formulated as unit dosage form. Self microemulsifying drug delivery system is the novel emulsified system composed of anhydrous isotropic mixture of oils, surfactant, and co solvent and sometimes co surfactant. Drug is directly dispersed into the entire gastro intestinal tract with continuous peristaltic movement and drug is available in the solution form of microemulsion, absorbed through lymphatic system and bypasses the dissolution step. Hence they increase the patient compliance. The excipients are selected on basis of construction of ternary phase diagram. Self micro-emulsifying drug delivery system is very useful for drug in which drug dissolution is rate limiting step. This review describes the novel approaches and evaluation parameters of the self microemulsifying drug delivery system towards different classic drugs, proteins-peptides, and nutraceuticals in various oral microemulsion compositions and microstructures.

Enhancement of Solubility and Dissolution Rate of Poorly Water Soluble Drug using Cosolvency and Solid Dispersion Techniques

1970 ◽  
Vol 1 (4) ◽  
pp. 349-356
Author(s):  
Meka Lingam ◽  
Vobalaboina Venkateswarlu
Keyword(s):  
Dissolution Rate ◽  
Solid Dispersions ◽  
Physicochemical Characterization ◽  
Aqueous Solubility ◽  
Water Soluble ◽  
Scanning Calorimetry ◽  
Peg 400 ◽  
Water Soluble Drug ◽  
Poorly Water Soluble ◽  
Poorly Water Soluble Drug

The low aqueous solubility of celecoxib (CB) and thus its low bioavailability is a problem.    Thus, it is suggested to improve the solubility using cosolvency and solid dispersions techniques. Pure CB has solubility of 6.26±0.23µg/ml in water but increased solubility of CB was observed with increasing concentration of cosolvents like PEG 400, ethanol and propylene glycol. Highest solubility (791.06±15.57mg/ml) was observed with cosolvency technique containing the mixture of composition 10:80:10%v/v of water: PEG 400: ethanol. SDs with different polymers like PVP, PEG were prepared and subjected to physicochemical characterization using Fourier-transform infrared (FTIR) spectroscopy, X-ray diffractometry (XRD), differential scanning calorimetry (DSC), solubility and dissolution studies. These studies reveals that CB exists mainly in amorphous form in prepared solid dispersions of PVP, PEG4000 and PEG6000 further it can also be confirmed by solubility and dissolution rate studies. Solid dispersions of PV5 and PV9 have shown highest saturation solubility and dissolution rate

Amorphous and Crystalline Particulates: Challenges and Perspectives in Drug Delivery

2017 ◽  
Vol 23 (3) ◽  
pp. 350-361 ◽  
Author(s):  
Hisham Al-Obaidi ◽  
Mridul Majumder ◽  
Fiza Bari
Keyword(s):  
Crystal Engineering ◽  
Drug Carrier ◽  
Solid Dispersions ◽  
Chemical Properties ◽  
Pharmaceutical Product ◽  
Water Soluble ◽  
Amorphous Form ◽  
Physico Chemical ◽  
Water Soluble Drugs ◽  
Amorphous Drug

Crystalline and amorphous dispersions have been the focus of academic and industrial research due to their potential role in formulating poorly water-soluble drugs. This review looks at the progress made starting with crystalline carriers in the form of eutectics moving towards more complex crystalline mixtures. It also covers using glassy polymers to maintain the drug as amorphous exhibiting higher energy and entropy. However, the amorphous form tends to recrystallize on storage, which limits the benefits of this approach. Specific interactions between the drug and the polymer may retard this spontaneous conversion of the amorphous drug. Some studies have shown that it is possible to maintain the drug in the amorphous form for extended periods of time. For the drug and the polymer to form a stable mixture they have to be miscible on a molecular basis. Another form of solid dispersions is pharmaceutical co-crystals, for which research has focused on understanding the chemistry, crystal engineering and physico-chemical properties. USFDA has issued a guidance in April 2013 suggesting that the co-crystals as a pharmaceutical product may be a reality; but just not yet! While some of the research is still oriented towards application of these carriers, understanding the mechanism by which drug-carrier miscibility occurs is also covered. Within this context is the use of thermodynamic models such as Flory-Huggins model with some examples of studies used to predict miscibility.

scholarly journals Electrochemical multicomponent synthesis of 4-selanylpyrazoles under catalyst- and chemical-oxidant-free conditions

2021 ◽  
Author(s):  
Yan Wu ◽  
Jin-Yang Chen ◽  
Jing Ning ◽  
Xue Jiang ◽  
Jie Deng ◽  
...  
Keyword(s):  
Multicomponent Reaction ◽  
Raw Materials ◽  
Multicomponent Synthesis ◽  
Mild Conditions ◽  
Simple Protocol ◽  
High Yields

An electrochemical multicomponent reaction was established under catalyst-, chemical-oxidant-free and mild conditions, which provides an eco-friendly and simple protocol for constructing 4-selanylpyrazoles from easily available raw materials with high yields.

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