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1.
BMJ Open ; 9(7): e029083, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31350247

RESUMO

INTRODUCTION: Oxytocin, administered via injection, is recommended by WHO for the prevention and treatment of postpartum haemorrhage. However, the susceptibility of oxytocin injection to thermal degradation has led WHO and UNICEF to recommend cold-chain storage of all oxytocin products. Nevertheless, some oxytocin products supplied to the global market are labelled for storage at ≤25°C, often with a shorter shelf-life relative to products labelled for refrigeration. Differences in labelled storage requirements can lead to uncertainties among stakeholders around the relative stability of oxytocin products and specifically whether ≤25°C products are more resistant to degradation. Such confusion can potentially influence policies associated with procurement, distribution, storage and the use of oxytocin in resource-poor settings. OBJECTIVES: To compare the stability of oxytocin injection ampoules formulated for storage at ≤25°C with those labelled for refrigerated storage. DESIGN: Accelerated and temperature cycling stability studies were performed with oxytocin ampoules procured by the United Nations Population Fund (UNFPA) from four manufacturers. METHOD: Using oxytocin ampoules procured by UNFPA, accelerated stability (up to 120 days) and temperature cycling (up to 135 days between elevated and refrigerated temperatures) studies were performed at 30°C, 40°C and 50°C. Oxytocin content was quantified using a validated HPLC-UV method. RESULTS: All ampoules evaluated exhibited similar stability profiles under accelerated degradation conditions with the exception of one product formulated for ≤25°C storage, where the rate of degradation increased at 50°C relative to other formulations. Similar degradation trends at elevated temperatures were observed during temperature cycling, while no significant degradation was observed during refrigerated periods of the study. CONCLUSION: Oxytocin ampoules formulated for non-refrigerated storage demonstrated comparable stability to those labelled for refrigerated storage and should not be interpreted by stakeholders as offering a more stable alternative. Furthermore, these products should not be procured for use in territories with high ambient temperatures, where all oxytocin injection products should be supplied and stored under refrigerated conditions.


Assuntos
Armazenamento de Medicamentos/métodos , Ocitocina , Embalagem de Medicamentos , Estabilidade de Medicamentos , Temperatura
2.
J Pharm Sci ; 104(4): 1492-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25573540

RESUMO

Intravenously administered (i.v.) drug-cyclodextrin (CD) inclusion complexes are generally expected to dissociate rapidly and completely, such that the i.v. pharmacokinetic profile of a drug is unchanged in the presence of CD. The altered pharmacokinetics of a synthetic ozonide in rats has been attributed to an unusually high-binding affinity (2.3 × 10(6) M(-1) ) between the drug and sulfobutylether7 -ß-cyclodextrin (SBE7 -ß-CD) with further studies suggesting a significant binding contribution from the adamantane ring. This work investigated the binding affinity of three adamantane derivatives [amantadine (AMA), memantine (MEM) and rimantadine (RIM)] to SBE7 -ß-CD and the impact of complexation on their i.v. pharmacokinetics. In vitro studies defined the plasma protein binding, as well as the impact of SBE7 -ß-CD on erythrocyte partitioning of each compound. SBE7 -ß-CD binding constants for the compounds were within the typical range for drug-like molecules (10(2) -10(4) M(-1) ). The pharmacokinetics of AMA and MEM were unchanged; however, significant alteration of RIM plasma and urinary pharmacokinetics was observed when formulated with CD. In vitro studies suggested two factors contributing to the altered pharmacokinetics: (1) low plasma protein binding of RIM, and (2) decreased erythrocyte partitioning in the presence of high SBE7 -ß-CD concentrations. This work demonstrated the potential for typical drug-cyclodextrin interactions to alter drug plasma pharmacokinetics.


Assuntos
Amantadina/farmacocinética , Memantina/farmacocinética , Rimantadina/farmacocinética , beta-Ciclodextrinas/administração & dosagem , Amantadina/administração & dosagem , Amantadina/sangue , Amantadina/urina , Animais , Interações Medicamentosas , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Injeções Intravenosas , Masculino , Memantina/administração & dosagem , Memantina/sangue , Memantina/urina , Modelos Biológicos , Ligação Proteica , Ratos Sprague-Dawley , Rimantadina/administração & dosagem , Rimantadina/sangue , Rimantadina/urina , beta-Ciclodextrinas/sangue
3.
J Pharm Sci ; 104(4): 1561-2, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25583633

RESUMO

The utility of cyclodextrin (CD) complexation in improving apparent solubility of drugs in parenteral formulations is well established. Administration of these formulations delivers CD directly into the systemic circulation, and it may be necessary to demonstrate unaltered in vivo disposition of a drug coadministered with a CD. Crucial to the undertaking of such a study is the need for bioanalytical assays in which CD presence does not impact drug quantitation. This is of particular importance when assessing the potential impact of in vivo CD complexation on the urinary excretion of a drug, as CDs are predominantly eliminated via glomerular filtration, and hence are present in urine at significantly higher concentration than would be present in blood and plasma. Of 23 publications (in the past 30 years) describing preclinical and clinical assessment of drug pharmacokinetics after i.v. administration of CD-enabled formulations, only two reports clearly stated that the presence of CD had no impact on assay performance. In this work, we describe the simple process involved in (1) predicting the maximum concentrations of a modified CD, sulfobutylether7 -ß-CD (SBE7 -ß-CD), in plasma and urine samples from preclinical studies, and (2) evaluating the impact of SBE7 -ß-CD on the quantitative liquid chromatography-mass spectrometry analysis of rimantadine.


Assuntos
Cromatografia Líquida , Excipientes/administração & dosagem , Excipientes/farmacocinética , Espectrometria de Massas , Rimantadina/farmacocinética , Tecnologia Farmacêutica/métodos , beta-Ciclodextrinas/farmacocinética , Administração Intravenosa , Animais , Calibragem , Química Farmacêutica , Cromatografia Líquida/normas , Excipientes/metabolismo , Espectrometria de Massas/normas , Modelos Biológicos , Ratos , Padrões de Referência , Reprodutibilidade dos Testes , Rimantadina/administração & dosagem , Rimantadina/sangue , Rimantadina/química , Rimantadina/urina , Tecnologia Farmacêutica/normas , beta-Ciclodextrinas/administração & dosagem , beta-Ciclodextrinas/sangue , beta-Ciclodextrinas/química , beta-Ciclodextrinas/urina
4.
PLoS One ; 8(12): e82965, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24376618

RESUMO

Oxytocin is recommended by the World Health Organisation as the most effective uterotonic for the prevention and treatment of postpartum haemorrhage. The requirement for parenteral administration by trained healthcare providers and the need for the drug solution to be maintained under cold-chain storage limit the use of oxytocin in the developing world. In this study, a spray-dried ultrafine formulation of oxytocin was developed with an optimal particle size diameter (1-5 µm) to facilitate aerosolised delivery via the lungs. A powder formulation of oxytocin, using mannitol, glycine and leucine as carriers, was prepared with a volume-based median particle diameter of 1.9 µm. Oxytocin content in the formulation was assayed using high-performance liquid chromatography-mass spectroscopy and was found to be unchanged after spray-drying. Ex vivo contractility studies utilising human and ovine uterine tissue indicated no difference in the bioactivity of oxytocin before and after spray-drying. Uterine electromyographic (EMG) activity in postpartum ewes following pulmonary (in vivo) administration of oxytocin closely mimicked that observed immediately postpartum (0-12 h following normal vaginal delivery of the lamb). In comparison to the intramuscular injection, pulmonary administration of an oxytocin dry powder formulation to postpartum ewes resulted in generally similar EMG responses, however a more rapid onset of uterine EMG activity was observed following pulmonary administration (129 ± 18 s) than intramuscular injection (275 ± 22 s). This is the first study to demonstrate the potential for oxytocin to elicit uterine activity after systemic absorption as an aerosolised powder from the lungs. Aerosolised oxytocin has the potential to provide a stable and easy to administer delivery system for effective prevention and treatment of postpartum haemorrhage in resource-poor settings in the developing world.


Assuntos
Sistemas de Liberação de Medicamentos , Ocitócicos/uso terapêutico , Ocitocina/uso terapêutico , Hemorragia Pós-Parto/prevenção & controle , Útero/efeitos dos fármacos , Administração por Inalação , Animais , Dessecação , Países em Desenvolvimento , Eletromiografia , Excipientes , Feminino , Glicina , Humanos , Leucina , Pulmão , Manitol , Tamanho da Partícula , Hemorragia Pós-Parto/fisiopatologia , Período Pós-Parto , Pós , Gravidez , Carneiro Doméstico , Útero/fisiologia
6.
ChemMedChem ; 8(2): 242-55, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23303535

RESUMO

Chemogenomics methods seek to characterize the interaction between drugs and biological systems and are an important guide for the selection of screening compounds. The acid/base character of drugs has a profound influence on their affinity for the receptor, on their absorption, distribution, metabolism, excretion and toxicity (ADMET) profile and the way the drug can be formulated. In particular, the charge state of a molecule greatly influences its lipophilicity and biopharmaceutical characteristics. This study investigates the acid/base profile of human small-molecule drugs, chemogenomics datasets and screening compounds including a natural products set. We estimate the acid-ionization constant (pK(a)) values of these compounds and determine the identity of the ionizable functional groups in each set. We find substantial differences in acid/base profiles of the chemogenomic classes. In many cases, these differences can be linked to the nature of the target binding site and the corresponding functional groups needed for recognition of the ligand. Clear differences are also observed between the acid/base characteristics of drugs and screening compounds. For example, the proportion of drugs containing a carboxylic acid was 20 %, in stark contrast to a value of 2.4 % for the screening set sample. The proportion of aliphatic amines was 27 % for drugs and only 3.4 % for screening compounds. This suggests that there is a mismatch between commercially available screening compounds and the compounds that are likely to interact with a given chemogenomic target family. Our analysis provides a guide for the selection of screening compounds to better target specific chemogenomic families with regard to the overall balance of acids, bases and pK(a) distributions.


Assuntos
Produtos Biológicos/química , Descoberta de Drogas/métodos , Íons/química , Preparações Farmacêuticas/química , Bibliotecas de Moléculas Pequenas/química , Ácidos/química , Bases de Dados de Produtos Farmacêuticos , Humanos
7.
Mol Inform ; 32(5-6): 505-15, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27481668

RESUMO

Human small molecule metabolites (the human metabolome) are a set of compounds that interact with at least one macromolecule in the biosphere. This study investigates the acid/base profile of the human metabolome, natural products and drugs, together with an analysis of their physicochemical properties. Ionisation constants (pKa values) are estimated for each compound and the identity of the ionisable functional groups in each set is determined. The acid/base and physicochemical property profile of the lipid component of the metabolome differed considerably to the other datasets. In contrast, the acid/base properties of non-lipid metabolites were found to be similar to both drugs and natural products. While the non-lipid metabolites have lower average ClogP values and more hydrogen bond donors than the other datasets, the distribution of physicochemical property values overlapped considerably with the drug dataset. Considering also that the non-lipid metabolites are of biochemical interest, their characteristics have great potential to influence the selection of screening compounds for drug discovery.

8.
Chem Soc Rev ; 42(2): 485-96, 2013 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-23099561

RESUMO

While drug discovery scientists take heed of various guidelines concerning drug-like character, the influence of acid/base properties often remains under-scrutinised. Ionisation constants (pK(a) values) are fundamental to the variability of the biopharmaceutical characteristics of drugs and to underlying parameters such as logD and solubility. pK(a) values affect physicochemical properties such as aqueous solubility, which in turn influences drug formulation approaches. More importantly, absorption, distribution, metabolism, excretion and toxicity (ADMET) are profoundly affected by the charge state of compounds under varying pH conditions. Consideration of pK(a) values in conjunction with other molecular properties is of great significance and has the potential to be used to further improve the efficiency of drug discovery. Given the recent low annual output of new drugs from pharmaceutical companies, this review will provide a timely reminder of an important molecular property that influences clinical success.


Assuntos
Descoberta de Drogas/métodos , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Farmacocinética , Solubilidade
9.
J Pharm Sci ; 101(9): 3347-59, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22623044

RESUMO

Interaction of colistin and colistin methanesulfonate (CMS) with liposomes has been studied with the view to understanding the limitations to the use of liposomes as a more effective delivery system for pulmonary inhalation of this important class of antibiotic. Thus, in this study, liposomes containing colistin or CMS were prepared and characterized with respect to colloidal behavior and drug encapsulation and release. Association of anionic CMS with liposomes induced negative charge on the particles. However, degradation of the CMS to form cationic colistin over time was directly correlated with charge reversal and particle aggregation. The rate of degradation of CMS was significantly more rapid when associated with the liposome bilayer than when compared with the same concentration in aqueous solution. Colistin liposomes carried positive charge and were stable. Encapsulation efficiency for colistin was approximately 50%, decreasing with increasing concentration of colistin. Colistin was rapidly released from liposomes on dilution. Although the studies indicate limited utility of colistin or CMS liposomes for long duration controlled-release applications, colistin liposomes were highly stable and may present a potential opportunity for coformulation of colistin with a second antibiotic to colocalize the two drugs after pulmonary delivery.


Assuntos
Antibacterianos/química , Colistina/análogos & derivados , Colistina/química , Lipídeos/química , Administração por Inalação , Antibacterianos/administração & dosagem , Química Farmacêutica , Colesterol/química , Colistina/administração & dosagem , Coloides , Preparações de Ação Retardada , Estabilidade de Medicamentos , Cinética , Lipossomos , Fosfatidilcolinas/química , Propriedades de Superfície , Tecnologia Farmacêutica/métodos
10.
J Phys Chem B ; 114(14): 4836-40, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20302384

RESUMO

Colistin is an amphiphilic antibiotic that has re-emerged into clinical use due to the increasing prevalence of difficult-to-treat Gram-negative infections. The existence of self-assembling colloids in solutions of colistin and its derivative prodrug, colistin methanesulfonate (CMS), was investigated. Colistin and CMS reduced the air-water interfacial tension, and dynamic light scattering (DLS) studies showed the existence of 2.07 +/- 0.3 nm aggregates above 1.5 mM for colistin and of 1.98 +/- 0.36 nm aggregates for CMS above 3.5 mM (mean +/- SD). Above the respective critical micelle concentrations (CMC) the solubility of azithromycin, a hydrophobic antibiotic, increased approximately linearly with increasing surfactant concentration (5:1 mol ratio colistin:azithromycin), suggestive of hydrophobic domains within the micellar cores. Rapid conversion of CMS to colistin occurred below the CMC (60% over 48 h), while conversion above the CMC was less than 1%. The formation of colistin and CMS micelles demonstrated in this study is the proposed mechanism for solubilization of azithromycin and the concentration-dependent stability of CMS.


Assuntos
Antibacterianos/química , Azitromicina/química , Colistina/análogos & derivados , Colistina/química , Pró-Fármacos , Tensoativos/química , Antibacterianos/metabolismo , Azitromicina/metabolismo , Micelas , Soluções
11.
J Pharm Sci ; 99(7): 2999-3008, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20091817

RESUMO

Chlorpromazine is an antipsychotic agent with poor aqueous solubility. Complexation with SBE(7)-beta-CD can aid intravenous delivery through increasing the apparent solubility of chlorpromazine. However, chlorpromazine has also been known to self-associate. This self-association can influence its capacity to interact with other chemical species, such as cyclodextrins. This study aimed to characterise the self-association and cyclodextrin binding properties of chlorpromazine, and the effect on pharmacokinetic parameters in rats when dosed with a SBE(7)-beta-CD containing formulation. Pharmacokinetic studies of chlorpromazine in the presence and absence of SBE(7)-beta-CD were undertaken in rats. The binding constant of SBE(7)-beta-CD and chlorpromazine was studied relative to chlorpromazine concentration via fluorescence. The self-association of chlorpromazine was studied by fluorescence and UV-visible spectrophotometry. Urinary excretion of intact chlorpromazine increased in the presence of SBE(7)-beta-CD. The SBE(7)-beta-CD binding constant of chlorpromazine is highly concentration dependent and the variation can be attributed to the self-association of chlorpromazine. The apparent binding constant of chlorpromazine is highest at pharmacologically relevant concentrations, providing an explanation for the significant increase in renal chlorpromazine excretion observed in rats.


Assuntos
Antipsicóticos/química , Antipsicóticos/farmacocinética , Clorpromazina/química , Clorpromazina/farmacocinética , Ciclodextrinas/química , Animais , Masculino , Micelas , Ratos , Ratos Sprague-Dawley
12.
Antimicrob Agents Chemother ; 53(8): 3496-500, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19487440

RESUMO

Peroxide antimalarials, including artemisinin, are important for the treatment of multidrug-resistant malaria. These peroxides are known to react with iron or heme to produce reactive intermediates that are thought to be responsible for their antimalarial activities. This study investigated the potential interaction of selected peroxide antimalarials with oxyhemoglobin, the most abundant form of iron in the human body. The observed stability of artemisinin derivatives and 1,2,4-trioxolanes in the presence of oxyhemoglobin was in contrast to previous reports in the literature. Spectroscopic analysis of hemoglobin found it to be unstable under the conditions used for previous studies, and it appears likely that the artemisinin reactivity reported in these studies may be attributed to free heme released by protein denaturation. The stability of peroxide antimalarials with intact oxyhemoglobin, and reactivity with free heme, may explain the selective toxicity of these antimalarials toward infected, but not healthy, erythrocytes.


Assuntos
Antimaláricos/química , Artemisininas/química , Hemoglobinas/química , Peróxidos/química , Estabilidade de Medicamentos , Humanos , Estrutura Molecular , Espectrofotometria
13.
Bioconjug Chem ; 19(4): 940-50, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18333604

RESUMO

Gene therapy by delivery of nonviral expression vectors is highly desirable, due to their safety, stability, and suitability for production as bulk pharmaceuticals. However, low transfection efficiency remains a limiting factor in application on nonviral gene delivery. Despite recent advances in the field, there are still major obstacles to overcome. In an attempt to construct more efficient nonviral gene delivery vectors, we have designed a series of novel lipopeptide transfection agents, consisting of an alkyl chain, one cysteine, 1 to 4 histidine and 1 to 3 lysine residues. The lipopeptides were designed to facilitate dimerization (by way of the cysteine residues), DNA binding at neutral pH (making use of charged lysine residues), and endosomal escape (by way of weakly basic histidine residues). DNA/lipopeptide complexes were evaluated for their biophysical properties and transfection efficiencies. The number and identity of amino acids incorporated in the lipopeptide construct affected their DNA/lipopeptide complex forming capacity. As the number of lysine residues in the lipopeptide increased, the DNA complexes formed became more stable, had higher zeta potential (particle surface charge), and produced smaller mean particle sizes (typically 110 nm at a charge ratio of 5.0 and 240 nm at a charge ratio of 1.0). The effect of inclusion of histidines in the lipopeptide moiety had the opposite effect on complex formation to lysine, but was necessary for high transfection efficiency. In vitro transfection studies in COS-7 cells revealed that the efficiency of gene delivery of the luciferase encoding plasmid, pCMV-Luc, mediated by all the lipopeptides, was much higher than poly(L-lysine) (PLL), which has no endosomal escape system, and in two cases was slightly higher than that of branched polyethylenimine (PEI). Lipopeptides with at least two lysine residues and at least one histidine residue produced spontaneous transfection complexes with plasmid DNA, indicating that endosomal escape was achieved by incorporation of histidine residues. These low molecular weight peptides can be readily synthesized and purified and offer new insights into the mechanism of action of transfection complexes.


Assuntos
Lipoproteínas/metabolismo , Transfecção/métodos , Animais , Células COS , Chlorocebus aethiops , DNA/metabolismo , Desoxirribonucleases/metabolismo , Endossomos/metabolismo , Transfecção/instrumentação
14.
Antimicrob Agents Chemother ; 52(4): 1291-6, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18268087

RESUMO

The reaction of spiro- and dispiro-1,2,4-trioxolane antimalarials with heme has been investigated to provide further insight into the mechanism of action for this important class of antimalarials. A series of trioxolanes with various antimalarial potencies was found to be unreactive in the presence of Fe(III) hemin, but all were rapidly degraded by reduced Fe(II) heme. The major reaction product from the heme-mediated degradation of biologically active trioxolanes was an alkylated heme adduct resulting from addition of a radical intermediate. Under standardized reaction conditions, a correlation (R2 = 0.88) was found between the extent of heme alkylation and in vitro antimalarial activity, suggesting that heme alkylation may be related to the mechanism of action for these trioxolanes. Significantly less heme alkylation was observed for the clinically utilized artemisinin derivatives compared to the equipotent trioxolanes included in this study.


Assuntos
Alquilação , Antimaláricos/farmacologia , Heme/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Compostos de Espiro/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/metabolismo , Artemisininas/farmacologia , Humanos , Cinética , Testes de Sensibilidade Parasitária/métodos , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Relação Estrutura-Atividade
15.
J Pharm Sci ; 96(11): 2945-56, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17549767

RESUMO

The iron-mediated reactivity of various dispiro-1,2,4-trioxolanes was determined by automated kinetic analysis under standard reaction conditions. The active antimalarial compounds underwent peroxide bond cleavage by Fe(II) resulting in products indicative of carbon-centered radical formation. The rate of reaction was heavily influenced by the presence of spiro-substituted adamantane and cyclohexane rings, and was also significantly affected by cyclohexane ring substitution. Steric hindrance around the peroxide oxygen atoms appeared to be the major determinant of reaction rate, however polar substituents also affected reactivity by an independent mechanism. A wide range of reaction rates was observed within this class of peroxide antimalarials, however iron-mediated reactivity did not directly correlate with in vitro antimalarial activity.


Assuntos
Antimaláricos/química , Compostos Ferrosos/química , Compostos Heterocíclicos com 1 Anel/química , Compostos de Espiro/química , Adamantano/análogos & derivados , Adamantano/química , Animais , Antimaláricos/farmacologia , Cristalografia por Raios X , Cicloexanos/química , Compostos Heterocíclicos com 1 Anel/farmacologia , Cinética , Modelos Moleculares , Plasmodium falciparum/efeitos dos fármacos , Compostos de Espiro/farmacologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-22469139
18.
Artigo em Inglês | MEDLINE | ID: mdl-22469140
19.
J Pharm Sci ; 95(4): 737-47, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16435367

RESUMO

Chemical stability of a new class of ozonide (1,2,4 trioxolanes) antimalarial compounds was investigated. The effects of pH, ionic strength, dielectric constant and cyclodextrin-complexation on the chemical stability and degradation product formation of selected compounds were examined. The mechanism of degradation in aqueous solution was probed using (18)O-labelled water and kinetic solvent isotope effect studies. The effect of stereochemistry was investigated using selected pairs of stereoisomers. The degradation of the ozonides in aqueous solution followed apparent first-order kinetics, with no effect of ionic strength and no indication of any direct involvement of water in the degradation mechanism. All major degradation products were identified and mass balance was confirmed. Stereochemistry had a significant effect on degradation rate; trans isomers degrading approximately four-fold faster than the corresponding cis isomers. The degradation rates were essentially independent of pH above pH 2; however, an additional specific acid catalysed pathway was dominant below pH 2. Solvent dielectric constant had a significant effect on the degradation rate. It is proposed that the degradation observed in aqueous solution occurred through a concerted heterolytic scission of the central ozonide ring, with chemical substituents on the cyclohexyl ring having only a minor influence on degradation rate.


Assuntos
Antimaláricos/química , Compostos Heterocíclicos/química , Ozônio/química , Ciclodextrinas/química , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Cinética , Peróxidos/química , Estereoisomerismo , Água/química
20.
J Pharm Sci ; 95(2): 256-67, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16374851

RESUMO

The pharmacokinetic profile and renal clearance of a novel synthetic ozonide antimalarial (1) was found to be significantly altered when intravenously administered to rats as a cyclodextrin-based formulation (0.1 M Captisol, a sulfobutylether beta-cyclodextrin derivative (SBE(7)-beta-CD)) compared to a cyclodextrin-free isotonic buffered glucose formulation. There was an 8.5-fold decrease in the steady-state blood volume of distribution, a 6.6-fold decrease in the mean residence time and a greater than 200-fold increase in renal clearance of 1 when administered in the cyclodextrin formulation. Analysis of the whole blood and plasma concentration profiles revealed an essentially constant blood to plasma ratio when 1 was administered in the cyclodextrin-free formulation, whereas this ratio changed as a function of time when administered in the presence of the cyclodextrin derivative. It is postulated that the observed differences were due to a very strong complexation interaction between 1 and the cyclodextrin, resulting in a slow dissociation of the complex in vivo, and altered distribution and excretion profiles. Preliminary studies using isothermal titration calorimetry (ITC) indicated that the association constant for the 1/Captisol complex was approximately two orders of magnitude higher than reported for typical drug/cyclodextrin complexes.


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacocinética , Ciclodextrinas/química , Ciclodextrinas/metabolismo , Ozônio/química , Animais , Antimaláricos/urina , Calorimetria , Injeções Intravenosas , Masculino , Conformação Molecular , Preparações Farmacêuticas , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Fatores de Tempo
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