Design of experiments assisted the development of inclusion complexes of ramipril using hydrophilic carriers for enhancement of solubility and dissolution rate

Abstract The goal of the present study was to develop inclusion complexes and polymers dispersions of ramipril prepared by physical mixing, kneading, co-evaporation, and solvent evaporation methods to enhance drug solubility and dissolution rate, and thereby to reduce drug dose and side effects using selected hydrophilic carriers such as β-CD, PVP-K25, PEG 4000, and HPMC K100M. The prepared formulations were characterized for solubility and in-vitro drug release studies. The systematic optimization of formulations was performed using I-Optimal experimental design by selecting factors such as type of carriers (X1), drug: carrier ratio (X2), and method of preparation (X3), and response variables including percent yield (Y1), solubility (Y2), Carr's index (Y3) and drug release in 30 min (Y4). Mathematical modeling was carried out using a quadratic polynomial model. The inclusion complex formulation (F27) was selected as an optimized batch by numerical desirability function and graphical optimization with the help of design space. The inclusion complex prepared by the co-evaporation method showed maximum drug solubility and released in pH 6.8 phosphate buffer compared to pure and other formulations. The inclusion complex is a feasible approach to improve the solubility, dissolution rate, bioavailability, and minimization of drugs' gastrointestinal toxicity upon oral administration of ramipril.

Inclusion complexes of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin with 2-hydroxypropyl-(-cyclodextrin: solubility and antimicrobial activity

The aim of the present study is to improve the solubility and antimicrobial activity of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin by formulating its inclusion complexes with 2-hydroxypropyl-ß-cyclodextrin in solution and in solid state. The phase solubility study was used to investigate the interactions between 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin and 2-hydroxypropyl-ß-cyclodextrin and to estimate the molar ratio between them. The structural characterization of binary systems (prepared by physical mixing, kneading and solvent evaporation methods) was analysed using the FTIR-ATM spectroscopy. The antimicrobial activity of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin and inclusion complexes prepared by solvent evaporation method was tested by the diffusion and dilution methods on various strains of microorganisms. The results of phase solubility studies showed that 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin formed the inclusion complexes with 2-hydroxypropyl-ß-cyclodextrin of AP type. The solubility of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin was increased 64.05-fold with 50% w/w of 2-hydroxypropyl-ß-cyclodextrin at 37 oC. The inclusion complexes in solid state, prepared by the solvent evaporation method, showed higher solubility in purified water and in phosphate buffer solutions in comparison with 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin alone. The inclusion complexes prepared by solvent evaporation method showed higher activity on Bacillus subtilis and Staphylococcus aureus compared to uncomplexed 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin due to improved aqueous solubility, thus increasing the amount of available 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin that crosses the bacterial membrane.

Inclusion complexes and self-assembled cyclodextrin aggregates for increasing the solubility of benzimidazoles

Albendazole and fenbendazole are imidazole derivatives that exhibit broad spectrum activity against parasites, but the low solubility of these drugs considerably reduces their effectiveness. Complexation of albendazole and fenbendazole with cyclodextrins (ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin) in both water and an aqueous solution of polyvinylpyrrolidone (PVP-k30) was studied to determine if it could increase the solubility and dissolution rate of the drugs. In an aqueous solution, ß-cyclodextrin increased the solubility of albendazole from 0.4188 to ~93.47 µg mL-1 (223×), and of fenbendazole from 0.1054 to 45.56 µg mL-1 (432×); hydroxypropyl-ß-cyclodextrin, on the other hand, increased solubility to ~443.06 µg mL-1 (1058×) for albendazole and ~159.36 µg mL-1 (1512×) for fenbendazole. The combination of hydroxypropyl-ß-cyclodextrin and polyvinylpyrrolidone enabled a solubility increase of 1412× (~591.22 µg mL-1) for albendazole and 1373× (~144.66 µg mL-1) for fenbendazole. The dissolution rate of the drugs was significantly increased in binary and ternary systems, with hydroxypropyl-ß-cyclodextrin proving to be more effective. The presence of the water-soluble PVP-k30 increased the dissolution rate and amorphization of the complexes. Analysis of the changes in displacement and the profile of the cyclodextrin bands in the 1H NMR spectra revealed a molecular interaction and pointed to an effective complexation in the drug/cyclodextrin systems. Monomeric forms and nanoclusters of cyclodextrins were observed in the drug/cyclodextrin systems, suggesting that the increase in solubility of the drugs in the presence of cyclodextrins should not be attributed only to the formation of inclusion complexes, but also to the formation of cyclodextrin aggregates

Effects of three preparation technologies on the oral bioavailability of berberine α-hydroxy β-decanoylethyl sulfonate / 中成药

AIM To compare the effects of three preparation technologies on the oral bioavailability of HB (berberine α-hydroxy β-decanoylethyl sulfonate,houttuyn berberine).METHODS Solid dispersions,HP-β-CD inclusion complexes and nanosuspension freeze-dried powders were prepared.The suspensions of crude drug and these three preparations were intragastrically administered to SD rats,respectively.HPLC-MS/MS was adopted in the content determination of HB in plasma.then pharmacokinetics parameters were calculated.RESULTS Compared with the crude drug,three preparation technologies could significantly increase the Cmax value of this component (P ＜ 0.05),especially for HP-β-CD inclusion complexes (P ＜ 0.01).And HP-β-CD inclusion complexes demonstrated much higher AUC0-6h than the crude drug and the other two preparation technologies (P ＜ 0.05).CONCLUSION HP-β-CD inclusion complexes can effectively increase the oral bioavailability of HB.

Inclusion complex of amiodarone hydrochloride with cyclodextrins: preparation, characterization and dissolution rate evaluation

ABSTRACT This study aimed to improve the water solubility of amiodarone hydrochloride (AMH) via inclusion complexes with β-cyclodextrin, methyl-β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin. Inclusion complexes were developed by physical mixture, coevaporation, spray-drying and freeze-drying. Solid state analysis was performed using X-ray powder diffraction, differential scanning calorimetry and scanning electronic microscopy. Thermodynamic studies demonstrate that the inclusion complexes of drug into different cyclodextrins were an exothermic process that occurred spontaneously. Water solubility and drug dissolution rates were significantly increased after the formation of inclusion complexes with the cyclodextrins evaluated in relation to the physical mixture and pure drug. The present study provides useful information for the potential application of complexation with amiodarone HCl. This may be a good strategy for the development of solid pharmaceutical dosage forms.

Preparation and acute toxicity test of Bruceae Fructus oil and β-cyclodextrin polymer inclusion complexes / 中草药

Objective: To prepare Bruceae Fructus oil (BFO) β-cyclodextrin polymer (CDP) inclusion complexes (BFO-CDP-IC), and investigate its safety by acute toxicity test. Methods: BFO was extracted and CDP was prepared according to the literature, the IC of BFO with CDP (BFO-CDP) was prepared by homogenizing method and characterized by SEM, 1H-NMR, and FT-IR. The optimum preparation process was determined by single factor test and L9(34) orthogonal test. Entrapment efficiency (EE) was determined by HPLC. Acute toxicity of BFO-CDP-IC was assessed by determining the number of deaths of ICR mice over gavage treatment for 2 weeks. The commercial emulsion of BFO (BFOE) was used as a reference. Results: The extraction rate of BFO was 17.3%, the yield of CDP was 49.26%, and the degree of crosslinking was 8.47. The optimal conditions for preparation were as follows, ratio of BFO and CDP was 1:10, preparation temperature and time was 20℃ and 6 min, the amount of ether was 0.5 g. Additionally, the HPLC data showed that drug loading of complexes was 7.1%, and EE was 80%. In the acute toxicity test, the median lethal dose (LD50) of BFOE was 9.78 g/kg. In contrast, all mice treated with IC survived even at the highest dosage (15.36 g/kg). Conclusion: The prepared BFO-IC has high EE compared with commercially available BFOE, BFO-CDP polymer significantly decreased toxicity of BFO.

Preparation and Quality Control of Aspirin-β-cyclodextrin-PLGA Microspheres / 中国药房

OBJECTIVE:To prepare aspirin-β-cyclodextrin-PLGA microspheres,and control its quality. METHODS:Aspirin-β-cy-clodextrin inclusion complexes were firstly prepared,and then aspirin-β-cyclodextrin-PLGA microspheres were prepared by emul-sion-solvent evaporation method. The morphology and particle size of microspheres were detected,and entrapment efficiency and accu-mulative release rate were calculated. With entrapment efficiency as index,orthogonal test was adopted to optimize stirring speed,PVA concentration,PVA volume and feed ratio. RESULTS:The optimal formulation was as follows as stirring speed of 4 000 r/min,PVA concentration of 3%(g/100 ml),PVA volume of 30 ml,feed ratio of 1∶10. Prepared microspheres were round and smooth in appear-ance. Entrapment efficiency of the microspheres was (41.79 ± 1.09)%. The diameter were regular and ranged 0.5-127.5 μm. As drug-loaded microspheres degraded,the release of aspirin was slow and its accumulative release rate was 83%within 600 h. CONCLU-SIONS:Aspirin-β-cyclodextrin-PLGA microspheres are prepared successfully with regular morphology and good sustained-release.

Estratégias utilizadas para o incremento da solubilidade do fármaco antiretroviral classe II: Efavirenz / Strategies used to improve the solubility of a class ii antiretroviral drug: Efavirenz

O efavirenz (EFZ) é considerado um dos fármacos anti- HIV mais utilizados, porém, como a grande maioria dos antirretrovirais, é classificado como fármaco de classe II, segundo o Sistema de Classificação Biofarmacêutica (SCB), por apresentar baixa solubilidade e alta permeabilidade. É bem conhecido que a solubilidade aquosa de um fármaco constitui requisito prévio à absorção e, assim, se faz uma das mais importantes barreiras à eficácia do medicamento. Desta forma, o aumento, através de tecnologias farmacêuticas, da dissolução aquosa e, conseqüentemente, da biodisponibilidade de fármacos pouco solúveis em água é considerado como um dos mais desafiantes aspectos no desenvolvimento moderno de fármacos. Este trabalho tem como objetivo realizar um levantamento da literatura cientifica e discussão sobre as principais técnicas aplicadas no melhoramento da dissolução do EFZ, dentre elas: dispersões sólidas, complexos de inclusão, sistemas multicomponentes e sistemas particulados nos últimos 10 anos (2004 ? 2014). Após levantamento bibliográfico, verificou-se maior número de publicações empregando a técnica de dispersões sólidas, provavelmente, porque a mesma é considerada uma técnica simples e de baixo custo. Desta forma, ficou claro que há grande interesse, por parte dos pesquisadores, de desenvolver métodos eficientes e econômicos que visam o melhoramento da dissolução aquosa deste fármaco e que o desenvolvimento de dispersões sólidas é, sem dúvida, uma solução interessante.(AU)

Efavirenz (EFZ) is considered one of the most used anti-HIV drugs. However, like the others anti-retroviral drugs, it is classified as a class II drug, according to the Biopharmaceutics Classification System (BCS), due to its low solubility and high permeability. It is well-known that the aqueous solubility of a drug is the prerequisite for its absorption and becomes one of the major barriers to the effectiveness of it. Thus, the improvement of the aqueous dissolution and, therefore, the bioavailability of drugs that are poorly soluble in water, is pursued by the pharmaceutical technology, once they are challenging aspects in the modern drug development. This paper aims, besides discussing, to perform a systematic review of the scientific literature regarding the main techniques applied in improving the dissolution of EFZ, including: solid dispersions, inclusion complexes, systems and multicomponent particulate systems; in the last 10 years (2004-2014). A greater number of publications using the technique of solid dispersions (SD) were found, probably because it is considered a simple and inexpensive technique. Therefore it is clear that there is great interest from researchers to develop efficient and economical methods aimed at improving the aqueous dissolution of EFZ and that the development of SD is, with no doubt, an interesting solution.(AU)

Multicomponent complex formation between pyrimethamine, cyclodextrins and water-soluble polymers

The combined effect of hydroxypropyl-β-cyclodextrin (HPβCD) and polyvinylpyrrolidone (PVP) or sodium carboxymethylcellulose (CMC) on the solubility of pyrimethamine (PYR) was studied. Equimolar PYR-HPβCD solid systems, in the presence or the absence of 0.25 percent (w/v) PVP or 0.10 percent (w/v) CMC were prepared by coevaporation or freeze-drying, and characterized by differential scanning calorimetry, X-ray diffraction analysis and dissolution profile. Phase-solubility analysis was used to investigate the interactions in aqueous solution between PYR and HPβCD, in the absence or presence of polymers, which showed a linear increase of PYR solubility depending on the concentration of HPβCD. The presence of polymer did not alter the stoichiometry of the complexes. DSC results were indicative of complexation, due to the loss of the characteristic endothermic peak of PYR. X-ray diffraction analysis confirmed the DSC results. Binary and ternary complexes showed higher dissolution rate when compared with the pure drug.

Formulation and evaluation of mucoadhesive buccal patch of acyclovir utilizing inclusion phenomenon

Mucoadhesive buccal patch releasing drug in the oral cavity at a predetermined rate may present distinct advantages over traditional dosage forms, such as tablets, gels and solutions. A buccal patch for systemic administration of acyclovir in the oral cavity was developed using polymers hydroxy propyl methyl cellulose (K4M), hydroxy propyl methyl cellulose (K15M), sodium carboxy methyl cellulose and poly vinyl pyrolidone (K30), plasticizer poly ethylene glycol (400) and a backing membrane of Eudragit (RL100). The films were evaluated in terms of swelling, residence time, mucoadhesion, release, and organoleptic properties. The optimized films showed lower release as compared to controlled drug delivery systems. Hence, an inclusion complex of acyclovir was prepared with hydrophilic polymer hydroxylpropyl beta-cyclodextrin in the molar ratio of 1:1. The inclusion complex was characterized by optical microscopy, FAB mass spectroscopy, and FTIR spectroscopy. Patches formulated with the acyclovir inclusion complex were evaluated along the same lines as those containing acyclovir alone. The in vitro release data revealed a substantial increase from 64.35 percent to 88.15 percent in the case of PS I and PS II batches, respectively, confirming the successful use of inclusion complexes for the formulation of buccal patch of acyclovir.

Mucoadesivos bucais liberadores de fármacos para a cavidade oral com taxa de liberação pré-determinada podem apresentar distintas vantagens em relação às formas farmacêuticas convencionais como comprimidos, géis e soluções. Neste trabalho, um adesivo bucal para administração sistêmica de aciclovir através da cavidade oral foi desenvolvido empregando-se os polímeros hidroxipropilmetil celulose (K4M), hidroxipropilmetil celulose (K15M), carboximetil celulose sódica e polivinil pirrolidona (K30), polietilenoglicol plastificado (400) e uma membrana suporte de Eudragit (RL100). Os filmes obtidos foram avaliados em termos de intumescimento, tempo de residência, mucoadesão, liberação e propriedades organolépticas. Os filmes otimizados apresentaram liberação mais lenta em comparação a outros sistemas de liberação controlada. Desta maneira, um complexo de inclusão de aciclovir foi preparado com o polímero hidrofílico hidroxipropil beta-ciclodextrina em proporções molares 1:1. O complexo de inclusão foi caracterizado por microscopia ótica, espectrometria de massas FAB e espectroscopia FTIR. Os adesivos formulados com o complexo de inclusão de aciclovir foram avaliados em paralelo com adesivos contendo aciclovir isolado. Os dados de liberação in vitro revelaram um aumento substancial, de 64,34 por cento para 88,15 por cento, nos lotes PS I e PS II, respectivamente, confirmando o sucesso do uso de complexos de inclusão para a formulação de adesivos bucais de aciclovir.

Study on Transdermal Penetration of Loratadine Inclusion Complexes Gels in Vitro / 中国药房

0.05).The value of J of negative group was(6.180?0.214) ?g?cm-2?h-1,while there was significant difference between trial group and negative group(P

Inclusion effect of isoandrographolide-?-cyclodextrin / 中草药

Objective To study the inclusion effect of isoandrographolide-?-cyclodextrin by method of UV,IR,and 1H-NMR.Methods The inclusion compound of isoandrographolide-?-cyclodextrin was prepared by saturated solution method assist microwave,equilibrium constants of inclusion complexes and molar ratio of isoandrogapholide-?-cyclodextrin were determined by the UV.The inclusion compound and their molar ratio were confirmed by IR and 1H-NMR.Results The isoandrographolide and ?-cyclodextrin formed inclusion compound.The equilibrium constants of inclusion complexes were 140.845 L/mol and the molar ratio was 1∶1.Conclusion The isoandrographolide could be inclused by ?-cyclodextrin and the inclusion effect is better.

Characterization of Rhodiola crenulata/?-cyclodextrin complex / 中成药

AIM:To characterize the inclusion complex of volatile oil of Rhodiola crenulata/?-cyclodextrin. METHODS: Some analytical methods,such as DTA,IR,GC,TLC were apllied to the investigation before and after the inclusion. RESULTS: The difference between the inclusion and physical mixture in differential thermal(analysis,) infrared spectra,gas chromatogram and thin layer chromatogram. CONCLUSION: The inclusion of Rhodiola crenulata volatile oil has the characteristic of intramolecular inclusion.