A quantitative approach to probe the dependence and correlation of food‐effect with aqueous solubility,dose/solubility ratio,and partition coefficient (Log P) for orally active drugs administered as immediate‐release formulations

The purpose of the present review was to systematically evaluate if aqueous solubility, dose/solubility ratio, and partition coefficient (Log P) could be used as useful parameters to quantitatively probe the dependence and correlation of in vivo food effects with these physicochemical properties of orally active drugs administered as immediate‐release (IR) formulations. Mean AUC data obtained under fasted and fed states of over 100 structurally diverse orally active drugs with different physicochemical properties were obtained from the primary literature. Correlations of AUC ratio (Fed/Fasted) with aqueous solubility, dose/solubility ratio, and Log P were derived and statistically evaluated by Pearson's correlation test (two‐tailed). A negative correlation was obtained between the logarithm of the aqueous solubility and the AUC ratio (r=?0.5982, N=93), whereas a positive correlation existed between AUC ratio and Log P (r=0.5147, N=110) and between AUC ratio and dose/solubility ratio (r=0.5511, N=87). All these correlations were significant (P<0.0001). Based on this study, the estimated range within which a drug is not expected to be significantly affected by food falls between 0.148–89.39 mg/ml for aqueous solubility and between 0.23–624 ml for the dose:solubility ratio. The corresponding range of Log P for expecting a lack of food‐effect lies between ?1.13 and 2.98. Quantitatively, the effect of food was most pronounced for lipophilic, poorly water‐soluble drugs (with only a few exceptions), irrespective of whether the drug is acidic, basic, or neutral. It is concluded that aqueous solubility, dose/solubility ratio, and partition coefficient can be used as useful parameters to probe the dependence and correlation of food‐effect with these physicochemical parameters for immediate‐release formulations. Drug Dev. Res. 65:55–75, 2005. © 2005 Wiley‐Liss, Inc.     

Chirality plays critical roles in enhancing the aqueous solubility of nocathiacin I by block copolymer micelles

Objectives Although drug solubilization by block copolymer micelles has been extensively studied, the rationale behind the choice of appropriate block copolymer micelles for various poorly water‐soluble drugs has been of relatively less concern. The objective of this study was to use methoxy‐poly(ethylene glycol)‐polylactate micelles (MPEG‐PLA) to solubilize glycosylated antibiotic nocathiacin I and to compare the effects of chirality on the enhancement of aqueous solubility. Methods Nocathiacin I‐loaded MPEG‐PLA micelles with opposite optical property in PLA were synthesized and characterized. The drug release profile, micelle stability and preliminary safety properties of MPEG‐PLA micelles were evaluated. Meanwhile, three other poorly water‐soluble chiral compound‐loaded micelles were also prepared and compared. Key findings The aqueous solubility of nocathiacin I was greatly enhanced by both l ‐ and d ‐copolymers, with the degree of enhancement appearing to depend on the chirality of the copolymers. Comparison of different chiral compounds confirmed the trend that aqueous solubility of chiral compounds can be more effectively enhanced by block copolymer micelles with specific stereochemical configuration. Conclusions The present study introduced chiral concept on the selection and preparation of block copolymer micelles for the enhancement of aqueous solubility of poorly water‐soluble drugs.     

Improvement of water solubility and in vitro dissolution rate of aceclofenac by complexation with β-cyclodextrin and hydroxypropyl-β-cyclodextrin

The present study deals with the inclusion complexation of aceclofenac with β-cyclodextrin by grinding, microwave and spray-drying techniques. A derivative of β-cyclodextrin, hydroxypropyl-β-cyclodextrin, was also subjected to the complexation process with aceclofenac by spray-drying technique. The samples were subjected to in-vitro dissolution studies, fourier transform infra-red spectroscopy, differential scanning calorimetry, nuclear magnetic resonance spectroscopy and x-ray diffraction studies. The in-vitro dissolution of aceclofenac-hydroxypropyl-β-cyclodextrin complex was faster as compared to the aceclofenac- β-cyclodextrin complex and aceclofenac alone. Spray-dried aceclofenac-β-cyclodextrin complex were subjected to anti-inflammatory and analgesic activity and showed significant anti-inflammatory and analgesic activity.     

Improvement in solubility and dissolution rate of flavonoids by complexation with beta-cyclodextrin

The inclusion into the beta-cyclodextrin is used to improve pharmacokinetic characteristics of hesperetin and naringenin. Solubility of hesperetin and naringenin with increasing concentrations of beta-cyclodextrin grows as long as the temperature increased. Stability constants were determined by the solubility method by Higuchi and Connors at different temperatures, and the thermodynamic parameters were calculated for inclusion complex formation in aqueous solution. The solid complexes were obtained in a molar ratio of 1:1 and their dissolution behavior at different pH was examined.     

Improvement of solubility and oral bioavailability of rutin by complexation with 2-hydroxypropyl-beta-cyclodextrin

The object of this study was to enhance the solubility, dissolution rate, and oral bioavailability of rutin by complexation with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD). The interaction of rutin with cyclodextrins (CyDs) was evaluated by the solubility, and ultraviolet (UV) and circular dichroism (CD) spectrophotometries. The chemical and enzymatic stability of rutin was examined in an alkaline buffer solution and in rat small intestinal homogenates, respectively. Dissolution rates of rutin and its CyD complexes were measured by the dispersed amount method. In vivo absorption studies of rutin after oral administration via conventional tablet containing rutin alone or its beta-CyD complexes was performed on beagle dogs. The stability constants calculated from the phase solubility method increased in the order of HP-gamma-CyD < G2-beta-CyD < beta-CyD < HP-beta-CyD. Spectroscopic studies also revealed that HP-beta-CyD and beta-CyD formed a relatively more stable inclusion complex with rutin. The dissolution rates of rutin increased by the complexation with CyDs in the order of rutin alone < HP-beta-CyD < or = beta-CyD. HP-beta-CyD inhibited the hydrolysis of rutin in the alkaline buffer solution and the small intestinal homogenates of rats, suggesting that HP-beta-CyD may stabilize rutin in a gastrointestinal tract after oral administration. When the tablet containing rutin or its beta-CyD complexes was administered to beagle dogs, the plasma levels of homovanillic acid (HVA) (a major stable metabolite of rutin) after oral administration of HP-beta-CyD complex were much higher than in either that of rutin alone or in its beta-CyD complex. The in vivo absorption study suggests that HP-beta-CyD increased the oral bioavailability of rutin from the gastrointestinal tracts of beagle dogs because of the increase in solubility, faster dissolution rate, and gastrointestinal stability. HP-beta-CyD has a significant advantage with respect to providing high aqueous solubility while maintaining a lack of toxicity in oral pharmaceutical preparations of rutin.     

Improvement of water solubility and in vitro dissolution rate of gliclazide by complexation with beta-cyclodextrin

Inclusion complexes of gliclazide with beta-cyclodextrin were prepared using different two methods: neutralization and recrysstalization. Host-guest interactions were studied in the solid state by X-ray diffractometry and infrared spectroscopy. The stability constant between gliclazide and beta-cyclodextrin was calculated from the phase solubility diagram. It was found that the neutralization technique and a solid complex of gliclazide with beta-cyclodextrin in a molar ratio of 1.5:1 could be used to prepare the amorphous state of drug inclusion complexes. The dissolution rates of gliclazide from the inclusion complex made by neutralization was much faster than the pure drug, physical mixture of drug and cyclodextrin, recyristalization system and also comparable to the data reported in literature. Results of this report indicate that beta-cyclodextrin could be useful for the solid gliclazide formulations as it may results in a more rapid and uniform release of the drug.     

Improving glyburide solubility and dissolution by complexation with hydroxybutenyl‐β‐cyclodextrin

Objectives Glyburide, an important drug for type 2 diabetes, has extremely poor aqueous solubility and resulting low bioavailability. This study describes the ability of hydroxybutenyl‐β‐cyclodextrin (HBenBCD) to form complexes with glyburide, with enhanced solubility and dissolution rate in vitro. Method Glyburide and glyburide‐HBenBCD were evaluated in various test media known to simulate human gastrointestinal conditions in the fasted and fed states, respectively. Key findings At ～14 wt% drug load, in the presence of HBenBCD, an almost 400‐fold increase in glyburide aqueous solubility was observed. In the presence of HBenBCD, glyburide solubility was also significantly improved in all physiologically relevant test media. Subsequent dissolution experiments confirmed the solubility study results; the dissolution rate and total amount of drug released were significantly increased. Conclusions Complexation with HBenBCD may be an effective way to increase the bioavailability of glyburide.     

Prediction and improvement of protected peptide solubility in organic solvents*

A predictive method of solubility for protected peptide fragments of globular proteins was described. The solubility prediction was performed on the basis of both the randomness of peptide structures in a solid state and the existence of tertiary peptide bonds such as X-Pro and X-(Z)Y bonds, in which X and Y are arbitrary amino acid residues and Z is a suitable protecting group for the X-Y peptide bond. In order to predict the randomness, the coil conformational parameter, P_e, was utilized. Solubility prediction by this method was success fully applied to the two classes of protected peptides composed solely of hydrophobic and of various amino acid residues. The solubility test results also indicate that the protection of peptide bonds at suitable intervals is effective in achieving a remarkable improvement in the solubility of extraordinarily insoluble peptides. Lastly, the strategy for the selection of the coupling routes in the protein syntheses was proposed.     

The enhancement of isoflavones water solubility by complexation with modified cyclodextrins: a spectroscopic investigation with implications in the pharmaceutical analysis

The improvement of isoflavones bioavailability by complexation with chemically modified cyclodextrins (CyDs) has been exploited to analyse the drug/macrocycle binding affinity by a conventional method with new useful measures. Genistein (Gen) and daidzein (Daidz) were investigated in aqueous medium and in presence an amount of (2-hydroxypropyl)-beta-cyclodextrin (HP-beta-CyD) at different host/guest molar ratios. The solubility in pure water, approximately 3 x 10(-6)M for Gen and approximately 10 x 10(-6)M for Daidz, was obtained by distributing the of guest molecule between water and the organic solvent. The stoichiometric ratios and stability constants describing the extent of formation of the complexes have been determined by phase-solubility UV-vis measurements and confirmed by circular dichroism data. These results have implications in the determination of the carrier's capacity for the complexation of the drug in water solution.     

Improvement of the bitter taste of drugs by complexation with cyclodextrins: applications, evaluations and mechanisms

Drugs having bitter tastes cause low patient compliance. Many taste-masking techniques such as physical barrier coatings, chemical modification and sensory masking have been developed. Among chemical modification, the inclusion complexation of drugs with cyclodextrins (CyDs) can provide the effective bitter taste-masking effects without complicated formulation and/or delayed dissolution of drugs. Herein, we describe some quantitative methods to evaluate the taste-masking effects of CyD complexes with drugs in solution and the solid state. In addition, we introduce the recent applications of CyDs to excipients for taste masking against various bitter-taste drugs, as well as discuss the possible mechanisms for the taste-masking effect of CyD complexation.     

Improvement of protein loading and modulation of protein release from poly(lactide-co-glycolide) microspheres by complexation of proteins with polyanions

A novel method was proposed to incorporate and modulate protein release from poly(lactide-co-glycolide) (PLGA) microspheres by a modified w/o/w emulsion solvent evaporation technique with poly(methacrylic acid) (PMAA)/insulin complex suspension as the inner aqueous phase instead of the neat protein solution. It was found that a reversible, water-insoluble complex could be formed between PMAA and insulin by electrostatic interactions. A great increase in insulin entrapment efficiency was observed as the PMAA/insulin complex was adopted to prepare PLGA microspheres. A large number of the complex particles adsorbed at the surface of the microspheres, resulting in the more rapid insulin release. The complexation and microencapsulation processes have little effect on insulin bioactivity, which was revealed by examination of the plasma glucose levels of the diabetic rats administrated with the microspheres.     

Improvement of solubility,dissolution and stability profile of artemether solid dispersions and self emulsified solid dispersions by solvent evaporation method

Abstract

The purpose of this study was to investigate changes in the water solubility of artemether; a poorly soluble drug used for the treatment of malaria. Different solid dispersions (SDs) of artemether were prepared using artemether and polyethylene glycol 6000 at ratio 12:88 (Group 1), self-emulsified solid dispersions (SESDs) containing artemether, polyethylene glycol 6000, cremophor-A-25, olive oil, hydroxypropylmethylcellulose and transcutol in the ratio 12:75:5:4:2:2, respectively (Group 2). SESDs were also prepared by substituting cremophor-A-25 in Group 2 with poloxamer 188 (noted as Group 3). Each of these preparations was formulated using physical mixing and the solvent evaporation method. Aqueous solubility of artemether improved 11-, 95- and 102-fold, while dissolution (in simulated gastric fluid) increased 3-, 13- and 14-fold, for formulation groups 1, 2 and 3, respectively. X-ray diffraction patterns of SDs indicated a decrease in peak intensities at 10° implying reduced artemether crystallinity. Scanning electron micrographs invariably revealed embedment of artemether by various excipients and a glassy appearance for solvent evaporated mixtures for all three formulation Groups. Our findings indicate improved hydrophilic interactions for drug particles yield greater solubility and dissolution in the following order for artemether formulating methods: solvent evaporation mixtures?>?physical mixtures?>?pure artemether.     

白芍水提物及芍药苷改善环磷酰胺致白细胞减少的对比研究

目的对比观察白芍水提物及芍药苷对环磷酰胺(CTX)致小鼠白细胞减少症的影响。方法给小鼠连续灌胃10d,第6和第7天腹腔注射高剂量CTX造成外周血白细胞减少。比较各给药组和模型组小鼠体质量、外周血白细胞数量、股骨中骨髓有核细胞数及肝、脾、胸腺造血免疫器官脏器系数。结果连续2d腹腔注射CTX 100mg.kg-1,可见小鼠外周血白细胞数、骨髓有核细胞数均显著减少(P<0.01),肝脏、脾脏和胸腺系数均明显降低(P<0.01)。白芍水提物及芍药苷均使小鼠外周血白细胞数、骨髓有核细胞数显著增多,脾脏系数明显升高。用药期间各组小鼠体质量无明显差异。结论白芍水提物及芍药苷对CTX所致小鼠白细胞减少和骨髓细胞减少均有升高作用,可提高CTX减少的小鼠脾脏系数。     

Enhancement of solubility and dissolution rate of poorly water-soluble naproxen by complexation with 2-hydroxypropyl-β-cyclodextrin

The solubility and dissolution rate of naproxen (NPX) complexed with 2-hydroxypropyl-β-cyclodextrin (2-HPβCD) using coprecipitation, evaporation, freeze-drying and kneading method were investigated. Solubility of NPX linearly increased (correlation coefficient, 0.995) as 2-HP-βCD concentration increased, resulting in A_L type phase solubility curve. Inclusion complexes prepared by four different methods were compared by differential scanning calorimetry (DSC). The NPX showed sharp endothermic peak around 156°C but inclusion complexes by evaporation, freeze-drying and kneading method showed very broad peak without distinct phase transition temperature. In contrast, inclusion complex prepared by coprecipitation method resulted in detectable peak around 156°C which is similar to NPX, suggesting incomplete formation of inclusion complex. Dissolution rate of inclusion complexes prepared by evaporation, freeze-drying and kneading except coprecipitation method was largely enhanced in the simulated gastric and intestinal fluid when compared to NPX powder and commercial NAXEN^® tablet. However, about 65% of NPX in gastric fluid still remained unreleased but most of NPX dissolved within 5 min in intestinal fluid. In case of inclusion complex prepared by coprecipitation method, formation of inclusion complex appeared to be incomplete, resulting in no marked enhancement of dissolution rate. From these findings, inclusion complexes of poorly water-soluble NPX with 2-HPβCD were useful to increase solubility and dissolution rate, resulting in enhancement of bioavailability and minimization of gastrointestinal toxicity of drug upon oral administration of inclusion complex.     

Enhancement of solubility,dissolution release profile and reduction in ulcerogenicity of piroxicam by inclusion complex with skimmed milk

Abstract

Context: Piroxicam (PXM), a non-steroidal anti-inflammatory drug which is poorly soluble in water and ulcerogenic. Milk has been used against the gastric disturbances caused by non-steroidal anti-inflammatory drugs. In this study, skimmed milk (SKM) is used as the carrier for inclusion complex (IC) due to its surface active agent and amino acid content.

Purpose: To enhance the solubility, dissolution rate and prevent ulcerogenicity of PXM though IC with SKM.

Methods: IC of PXM were prepared with SKM by solvent evaporation method using rota evaporator and were evaluated for solubility, dissolution, solid state characterization, drug excipient interaction, rat intestinal permeation, ulcerogenicity and histopathological studies.

Results: Solubility of PXM was enhanced 2.5 times with IC. The dissolution release and amount of PXM permeated through rat small intestine was enhanced significantly with IC. Decreases in the gastric lesion index values of IC were observed than physical mixture (PM) and free PXM. The histopathological studies revealed significant reduction in ulceration in rat stomach after treatment with IC.

Conclusion: It is concluded that SKM is a good carrier to prepare IC of PXM for oral administration.     

Inhibition of thrombocyte aggregation by oral motapizone and other drugs

Summary Ten healthy subjects took single oral doses of placebo, 8.8±1.8 mg motapizone, 40±13 mg captopril, 25 mg dihydralazine, 20 mg nifedipine and 4.5±1.1 mg prazosin in random order, and, as the last preparation 500 mg acetylsalicylic acid. Thrombocyte aggregation induced ex-vivo with collagen, ADP and adrenaline was measured before and after 60 min.Immediately before each dose, the threshold concentration of each agent was determined in each subject, i.e. the concentration producing about 90% of maximal aggregation. After the preparation had been taken, aggregation was induced with 1-, 2- and 4-times the threshold concentration.Both motapizone and also acetylsalicylic acid caused marked inhibition of aggregation at up to 4-times the threshold concentration; the dose ratio was about 1:50. Motapizone produced greater inhibition of the aggregation induced by ADP and acetylsalicylic acid than of that due to collagen. The inhibitory actions after captopril, dihydralazine, nifedipine and prazosin were weak and did not significantly differ from placebo.     

Inclusion complexation of metronidazole benzoate with β-cyclodextrin and its depression of anhydrate-hydrate transition in aqueous suspensions

Metronidazole benzoate was found to form an inclusion complex with β-cyelodextrin (β-CyD) in aqueous solution and in the solid phase. A phase solubility diagram was obtained and an apparent 1:1 formation complex constant of 1.3 × 10³ M^?1 was determined. A microcrystalline inclusion complex was isolated and shown to have the stoichiometric composition of 1:1.5 (drug: β-CyD). By inclusion complexation of the metronidazole ester with β-CyD the phase transition of the clinically used anhydrous form of the compound to the monohydrate occurring in aqueous suspensions was inhibited as was the marked crystal growth resulting from the phase transition. Besides increasing the physical stability of metronidazole benzoate suspensions the complexation with β-CyD protected the drug against photochemical degradation and decreased the rate of hydrolysis.     

水和非水毛细管电泳-电导检测法分离测定水杨酸类药物

目的建立水和非水毛细管电泳-电导法分离水杨酸类药物。方法用未涂层石英毛细管柱(55 cm×50 μm),以10 mmol·L^-1 Tris-30 mmol·L^-1 H₃BO₃(pH 8.0)为运行缓冲液,分离电压为24 kV,进样时间10 s,电导检测法。结果在非水实验条件下,水杨酸(SA)、乙酰水杨酸(ASA)和磺基水杨酸(SSA)得到很好的分离。SA,ASA和SSA的线性范围分别为0.05～100 mg·L^-1,5.0～250 mg·L^-1,0.08～100 mg·L^-1,r均大于0.995。结论应用于阿斯匹林制剂中水杨酸和乙酰水杨酸含量的测定,结果令人满意。与水介质相比,乙醇介质具有更高的灵敏度和分离效率。     

Effect of cationic amphiphilic drugs on the hydrolysis of acidic and neutral phospholipids by liver lysosomal phospholipase A

Rat liver lysosomal phospholipase A hydrolyzes both acidic and neutral phospholipids. Numerous cationic amphiphilic drugs including imipramine, propranolol, 4,4'-bis(diethylaminoethoxy)-alpha, beta- diethyldiphenylethane and chloropromazine inhibit phospholipase A. Cationic amphiphilic drugs bind readily to acidic phospholipids but much less readily to neutral phospholipids. Formation of drug-lipid complexes is thought to be an important mechanism involved in the inhibition of lysosomal phospholipases. Therefore, we studied the effects of four cationic amphiphilic inhibitors on lysosomal phospholipase A using one acidic and two neutral phospholipid substrates. The concentration of the drugs required to produce 50% inhibition was much higher when phosphatidylinositol was used as substrate. The degradation of phosphatidylethanolamine and phosphatidylcholine was more readily inhibited by these agents than that of phosphatidylinositol. In drug-induced lipidosis, the predominance of acidic phospholipids may be due to redirection of phospholipid metabolism towards the formation of acidic phospholipids with a resultant increased delivery of these lipids to lysosomes. Based on our results, it does not appear to be due to decreased enzymatic hydrolysis of drug-acidic phospholipid complexes, at least when pure phospholipid substrates are used. Lysosomal storage of both acidic and neutral phospholipids appears to be caused by inhibition of lysosomal phospholipase action in view of the probable high intralysosomal levels of these agents.     

HPLC法测定盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯的平衡溶解度和脂水分配系数

目的:测定盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯在乙醇、乙腈、丙酮、乙酸乙酯等溶剂中的平衡溶解度以及在正辛醇-水和正辛醇-缓冲液体系中的表观油水分配系数。方法:采用HPLC法测定盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯的浓度,采用摇瓶法测定其表观油水分配系数。结果:25℃时盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯在乙醇、乙腈、丙酮、乙酸乙酯中的平衡溶解度分别为31.36,141.50,575.77,598.68 g.L-1。pH=4时此目的化合物的平衡溶解度最小,而表观油水分配系数最大。结论:盐酸吲哚美辛2-[2-(6-甲氧基-2-萘基)吗啉基]乙酯的平衡溶解度及油水分配系数与介质的pH有关。其水溶性较差,脂溶性好。