Solubilization and Wetting Effects of Bile Salts on the Dissolution of Steroids

The ability of sodium taurocholate to increase the initial dissolution rate of five steroids was studied in terms of effects on solubility, wetting, and diffusion coefficient. For all compounds, wetting effects predominated over solubilization effects at bile salt concentrations representative of the fasted state. For hydrocortisone, triamcinolone, betamethasone, and dexamethasone, this trend also continued at the higher bile salt concentrations typical of the fed state. Bile salts solubilized these compounds by a factor of two or less, and diffusivity changes were negligible at bile salt concentrations up to 30 mM. For the more lipophilic danazol, the wetting effects were small and of importance only at premicellar levels of bile salt. At higher concentrations, the increase in solubility was the predominant factor. Incorporation into micelles appeared to decrease the diffusivity slightly, but this was important only at bile salts concentrations of 15 mM or higher. In conclusion, it appears that even within a series of structurally related compounds the mechanism by which bile salts mediate increases in dissolution rate can differ considerably.     

Bile salt composition is secondary to bile salt concentration in determining hydrocortisone and progesterone solubility in intestinal mimetic fluids

Simulated intestinal fluids (SIFs) used to assay the solubility of orally administered drugs are typically based on a single bile salt; sodium taurocholate (STC). The aim of this study was to develop mimetic intestinal fluids with a closer similarity to physiological fluids than those reported to date by developing a mixed bile salt (MBS) system (STC, sodium glycodeoxycholate, sodium deoxycholate; 60:39:1) with different concentrations of lecithin, the preponderant intestinal phospholipid. Hydrocortisone and progesterone were used as model drugs to evaluate systematically the influence of SIF composition on solubility. Increasing total bile salt concentration from 0 to 30 mM increased hydrocortisone and progesterone solubility by 2- and ～25-fold, respectively. Accordingly, higher solubilities were measured in the fed-state compared to the fasted-state SIFs. Progesterone showed the greatest increases in solubility in STC and MBS systems (2-7-fold) compared to hydrocortisone (no significant change; P>0.05) as lecithin concentration was increased. Overall, MBS systems gave similar solubility profiles to STC. In conclusion, the addenda of MBS and lecithin were found to be secondary to the influence of BS concentration. These data provide a foundation for the design of more bio-similar media for pivotal decision-guiding assays in drug development and quality control settings.     

Canine Intestinal Contents vs. Simulated Media for the Assessment of Solubility of Two Weak Bases in the Human Small Intestinal Contents

Purpose This study was conducted to assess the relative usefulness of canine intestinal contents and simulated media in the prediction of solubility of two weak bases (dipyridamole and ketoconazole) in fasted and fed human intestinal aspirates that were collected under conditions simulating those in bioavailability/bioequivalence studies. Methods After administration of 250 mL of water or 500 mL of Ensure plus? [both containing 10 mg/mL polyethylene glycol (PEG) 4000 as nonabsorbable marker], intestinal aspirates were collected from the fourth part of the duodenum of 12 healthy adults and from the mid-jejunum of four Labradors. Pooled samples were analyzed for PEG, pH, buffer capacity, osmolality, surface tension, pepsin, total carbohydrates, total protein content, bile salts, phospholipids, and neutral lipids. The shake-flask method was used to measure the solubility of dipyridamole and ketoconazole in pooled human and canine intestinal contents and in fasted-state-simulating intestinal fluid (FaSSIF) and fed-state-simulating intestinal fluid (FeSSIF) containing various bile salts and pH-buffering agents. Results For both compounds, solubility in canine contents may be predictive of human intralumenal solubility in the fasting state but not in the fed state. The poor agreement of results in canine and human aspirates can be attributed to the higher bile salt content in canine bile. Solubility in FaSSIF containing a mixture of bile salts from crude bile predicted satisfactorily the intralumenal solubility of both drugs in the fasted state in humans. Solubility in FeSSIF, regardless of the identity of bile salts or of the buffering species, deviated from intralumenal values in the fed human aspirates by up to 40%. This was attributed to the lack of lipolytic products in FeSSIF, the higher bile salt content of FeSSIF, and the lower pH of FeSSIF. Conclusions FaSSIF containing a mixture of bile salts from crude bile, and FeSSIF containing lipolytic products and, perhaps, having lower bile salt content but slightly higher pH, should be more useful than canine intestinal aspirates for predicting intralumenal solubilities in humans.     

Characterization of fasted-state human intestinal fluids collected from duodenum and jejunum

The solubility of drugs in the gastrointestinal tract is very challenging to simulate with artificial media due to the high complexity of human intestinal fluid (HIF). In particular, bile salt composition, pH and buffer capacity are very important characteristics of HIF, since they determine the solubility of drugs in-vivo. In this study, we have measured the concentrations of individual bile salts in human intestinal fluids (n=6) collected from two different locations (duodenum and jejunum) in the fasted state. Total bile salt concentrations ranged from 570 to 5,137 microM in the duodenum and from 829 to 5,470 microM in the jejunum. The following rank order of relative bile salt concentration in duodenum was observed: taurocholic acid > glycocholate >or= glycochenodeoxycholate > glycodeoxycholate > taurochenodeoxycholate > taurodeoxycholate. Cholic acid, tauroursodeoxycholate, chenodeoxycholic acid, and deoxycholic acid represented less than 1% of bile salts present in the samples. Ursodeoxycholate could not be detected in HIF. No statistically significant difference between bile salt composition of duodenal and jejunal aspirates was observed. The buffer capacity of HIF was compared with other media commonly used for solubility/dissolution determinations, indicating a relatively low buffer capacity of HIF (4-13 mmol L(-1)/pH). This low buffer capacity was reflected in the change in pH (between 4 and 9.5) that occurred in HIF after addition of model compounds covering a broad pK(a) range. Interindividual variability in pH, buffer capacity and bile salt contents of HIF will contribute to differences in the rate and extent of absorption of compounds for which dissolution/solubility is the rate limiting step. The variability observed warrants further research to explore the impact of intraluminal conditions on drug solubility.     

Evaluation of Various Dissolution Media for Predicting In Vivo Performance of Class I and II Drugs

Purpose. In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. Methods. Dissolution behavior of two class I drugs, i,e, acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIF_sp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. Results. Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGF_sp) within 30 minutes, 70% dissolution in 2 hours under fed state simulated upper jejunal conditions but only 6% dissolution in 2 hours under fasted state conditions. Conclusions. As predicted, dissolution of class II drugs proved to be in general much more dependent on the medium than class I drugs. With the array of compendial and physiological media available, it should be possible to design a suitable set of tests to predict the in vivo dissolution of both class I and II drugs from immediate release formulations.     

The Effects of Food on the Dissolution of Poorly Soluble Drugs in Human and in Model Small Intestinal Fluids

Purpose This study was conducted to determine the effect of food on drug solubility and dissolution rate in simulated and real human intestinal fluids (HIF). Methods Dissolution rate obtained via the rotating disk method and saturation solubility studies were carried out in fed and fasted state HIF, fed dog (DIF), and simulated (FeSSIF) intestinal fluid for six aprotic low solubility drugs. The intestinal fluids were characterized with respect to physical–chemical characteristics and contents. Results Fed HIF provided a 3.5- to 30-times higher solubility compared to fasted HIF and FeSSIF, whereas fed DIF corresponded well (difference of less than 30%) to fed HIF. The increased solubility of food could mainly be attributed to dietary lipids and bile acids. The dissolution rate was also 2 to 7 times higher in fed HIF than fasted HIF. This was well predicted by both DIF and FeSSIF (difference of less than 30%). Conclusions Intestinal solubility is higher in fed state compared to fasted state. However, the dissolution rate does not increase to the same extent. Dog seems to be a good model for man with respect to dissolution in the small intestine after intake of a meal, whereas FeSSIF is a poorer means of determining intestinal saturation solubility in the fed state.     

Biorelevant dissolution media: aggregation of amphiphiles and solubility of estradiol

Biorelevant dissolution media containing bile salt and lecithin at concentrations appropriate for fed and fasted state are useful when testing oral solid formulations of poorly water-soluble drugs. Dilution of amphiphile solutions affects the aggregation state of the amphiphiles because bile salt is partitioned between the aqueous phase and the aggregates. The aim of the investigation was to study the effect of dilution on the size distribution of aggregates and its effect on the solubilization capacity. Clear buffered solutions of four intestinal amphiphiles (sodium glycocholate, lecithin, monoolein, and oleic acid) and a combination of these were prepared at high bile salt concentration. Micelles in the glycocholate solutions decreased in size when diluted. The addition of insoluble amphiphiles led to bigger micelles with no clear correlation between size of the micelles and amphiphile concentration. Dilution of the two- and four component media caused enlargement of the mixed micelles and formation of vesicles. The solubility of estradiol in the buffer solution was increased with addition of the amphiphiles. A good correlation (R(2) = 0.987) was found between estradiol solubility and mass concentration of the amphiphiles. The results demonstrate that, in the case of estradiol, the concentration of amphiphiles rather than the aggregation state determines the solubilization capacity of the medium.     

Advances in the design of fasted state simulating intestinal fluids: FaSSIF-V3

Biorelevant media are commonly used to simulate the physiological composition of human intestinal fluids (HIF) in in vitro solubility and dissolution investigations. In comparison with the surfactant solutions or blank buffers, these media are able to better reflect the physiological solubility and dissolution behavior of poorly soluble active pharmaceutical ingredients (APIs). The aim of this investigation was to review the composition of FaSSIF and FaSSIF-V2 according to recently summarized data about the physiological composition of fasted state human intestinal fluid and propose an updated version, FaSSIF-V3. Furthermore the surface tension was considered as a possible surrogate parameter to gauge the physiological correctness of new versions of biorelevant media.Various prototypes of FaSSIF-V3 were prepared with each of the following five bile salts: taurocholate (TC), glycocholate (GC), tauroursodeoxycholate (TUDC), taurochenodeoxycholate (TCDC) and glycochenodeoxycholate (GCDC) as well as replacing lecithin with its hydrolysis products, lysolecithin and sodium oleate. Two additional media consisting of a mixture of glycocholate (GC) and taurocholate (TG), with or without 0.2 mM cholesterol, were also investigated.Solubilities of ten model compounds in various prototypes of FaSSIF-V3 were measured using HPLC-UV and compared to the solubilities in the existing biorelevant media (FaSSIF and FaSSIF-V2), fasted HIF, blank buffer and a 0.5% sodium dodecyl sulfate (SDS) solution. Additionally, the influence on the surface tension properties of various combinations of bile salts, phospholipids and their hydrolysis products and cholesterol in these media was investigated and an attempt was made to calculate the CMC of the various generations of FaSSIF.The results demonstrated that the amount and the type of phospholipids as well as the type of bile salt had a significant influence on the solubility and surface tension in the various FaSSIF-V3 prototypes and existing biorelevant media. In contrast to results with biorelevant media, it was demonstrated that blank buffers generally underestimate and SDS solutions highly overestimate the physiological relevant solubilities of all investigated APIs.The prototype containing FaSSIF-V3-GC/TC_Chol was able to better reflect the solubilities of the most investigated APIs in fasted HIF than the existing media, and it also matched the physiological surface tension reported for the fasted human gut, and was designated FaSSIF-V3.     

The Effects of Bile Salts and Lipids on the Physicochemical Behavior of Gemfibrozil

Physicochemical effects caused by intestinal fluids on drugs in the gastrointestinal (GI) tract can be a contributing factor in food induced changes in bioavailability. To identify physicochemical properties of gemfibrozil that may be altered by endogenous and dietary lipids, in vitro studies were conducted in model systems approximating the conditions of the upper GI tract. Factors examined include pH, solubility in bile salt micellar and mixed micellar systems with monoolein and lecithin, effect of fatty acids, dissolution, wetting, and partitioning in triglyceride dispersions. Gemfibrozil was solubilized by glycocholate solutions in a manner typical of other lipids and a three-fold increase in solubility was observed over physiologic concentrations. Addition of increasing amounts of swelling amphiphiles (monoolein, lecithin) to glycocholate solutions resulted in a linear increase in solubility. Fatty acid salts had no effect on gemfibrozil solubilization by micellar solutions. The dissolution rate of gemfibrozil increased slightly in the presence of glycocholate relative to buffer, however, addition of monoolein increased the dissolution rate three-fold. In triglyceride dispersions of mixtures of lipids, monoolein increased the fraction of drug in the micellar sub-phase, whereas fatty acid reduced it. The results indicate that in the conditions of the fed state gemfibrozil solubility and dissolution could be substantially increased relative to the conditions in the fasted state.Presented in the part at the 8th Annual Meeting of the American Association of Pharmaceutical Scientists, Lake Buena Vista, Florida, November 14–18, 1993.     

孟鲁司特钠咀嚼片体外溶出研究

目的 研究孟鲁司特钠咀嚼片体外溶出行为及其影响因素,为该品种新剂型开发和仿制药一致性评价提供参考。方法 考察pH、胆盐、表面活性剂等因素对孟鲁司特钠咀嚼片溶出的影响。结果 孟鲁司特钠在pH 7.5的介质中,随着胆盐浓度的增加,溶解度明显上升;孟鲁司特钠咀嚼片在pH 1.0盐酸溶液、pH 4.0醋酸盐溶液、pH 6.8磷酸盐溶液的溶出过程中,会迅速析出形成混悬液,而0.5%十二烷基硫酸钠水溶液会抑制其析出。结论 孟鲁司特钠咀嚼片的体外溶出受pH、胆盐、表面活性剂的影响较大,可以为其新型给药系统的开发和质量一致性评价提供参考。     

When Interactions Between Bile Salts and Cyclodextrin Cause a Negative Food Effect: Dynamic Dissolution/Permeation Studies with Itraconazole (Sporanox®) and Biomimetic Media

The marketed oral solution of itraconazole (Sporanox®) contains 40% (259.2 mM) of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The obvious role of HP-β-CD is to solubilize itraconazole and to overcome its poor aqueous solubility that restricts its absorption.In this study, we investigated the biorelevance of in vitro experiments by the influence of biomimetic media (containing bile salts and phospholipids) on the predicted itraconazole absorption from the commercial HP-β-CD-based Sporanox® solution. We performed phase-solubility studies of itraconazole and dynamic 2-step-dissolution/permeation studies using a biomimetic artificial barrier, Sporanox® solution, and fasted state simulated intestinal fluid (FaSSIF_V1).Both FaSSIF_V1 and HP-β-CD increased the apparent solubility of itraconazole when used individually. In combination, their solubility-enhancing effects were not additive probably due to the competition of bile salts with itraconazole for the hydrophobic cavity of HP-β-CD. Our combined dissolution/permeation experiments indicated the occurrence of a transient supersaturation from Sporanox® upon two-step dissolution. Through systematic variation of bile salt concentrations in the biomimetic media, it was observed that the extent and the duration of supersaturation depend on the concentrations of bile salts: supersaturation was rather stable in the absence of bile salts and phospholipids. The higher the bile salt concentration, the faster the collapse of the transient supersaturation occurred, an effect which is nicely mirrored by reduced in vitro permeation across the barrier. This is an indication of a negative food effect, which in fact correlates well with what earlier had been observed in clinical studies for Sporanox® solution.In essence, we could demonstrate that in vitro two-stage dissolution/permeation experiments using an artificial barrier and selected biomimetic media may predict the negative effects of the latter on cyclodextrin-based drug formulations like Sporanox® Oral Solution and, at the same time, provide a deeper mechanistic insight.     

Postprandial Changes in Solubilizing Capacity of Human Intestinal Fluids for BCS Class II Drugs

Purpose  To explore the effect of the nutritional state on the solubilizing properties of human intestinal fluids (HIF) on a time-after-food administration basis. Methods  HIF were collected in fractions of 30 min from five volunteers in the fasted, fed and fat-enriched fed state. In vitro solubility of five BCS class II drugs (danazol, diazepam, nifedipine, ketoconazole, indomethacin) was assessed in the intestinal fractions and simulated intestinal fluids. Results  Solubilities in intestinal fractions were characterized by high time- and subject-dependent variability. For the non-ionized drugs, solubility in early intestinal fractions was higher in both fed states compared to the fasted state, and in the fat-enriched fed state compared to the fed state. Solubility in simulated intestinal fluids did not sufficiently predict the solubilizing capacity of the early postprandial phase. Solubility in HIF was shown to be determined by a complex interplay of various intraluminal parameters. For the ionized drugs, pH played a significant role for indomethacin (R ² = 0.86); for the partly ionized ketoconazole other intraluminal parameters were also important. Conclusions  Solubilizing capacity of HIF in the fed state is strongly time-dependent. Intraluminal dissolution may, therefore, vary with drug arrival time in the small intestine and constitute a source of variability in intestinal drug absorption.     

Impact of Swelling of Spray Dried Dispersions in Dissolution Media on their Dissolution: An Investigation Based on UV Imaging

Impact of SDD-dissolution medium interactions on the swelling and dissolution of spray dried dispersions (SDDs) was investigated using UV imaging by monitoring SDD swelling in situ, along with correlating of the swelling with the micro-dissolution and intrinsic dissolution of SDDs. SDDs of ketoconazole or indomethacin with three polymers: polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were prepared for the study. Dissolution media employed for assessing swelling and dissolution include water, acetate buffer, phosphate buffer, fasted state simulated intestinal fluid (FaSSIF), and fed state simulated intestinal fluid (FeSSIF), in which influence of polymers and drugs together with the physical-chemical properties of dissolution media (pH, and the presence of sodium taurocholate and lecithin) on SDD swelling and dissolution was evaluated. It appears that hydrophilic and hydrophobic properties of polymers can significantly impact SDD swelling and thus the dissolution. Furthermore, properties of dissolution media such as pH as well as presence of bile salts and lecithin seems to affect SDD swelling and dissolution as well. Throughout the text, thermodynamic swelling of polymers was used to interpret SDD dissolution behavior. Finally, practical implication of polymer swelling on dissolution was discussed.     

Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women

Purpose. To chemically characterize the fluids available for drug dissolution in the upper gastrointestinal tract during the fasted state in humans, and to examine variations and potential gender differences regarding the physico-chemical properties of these fluids. Methods. Twenty-four healthy volunteers, 12 females and 12 males, were intubated, and fluids from the stomach and upper jejunum were collected separately. Bulk pH, osmolality, electrolytes and total concentrations of bile acids and proteins were assessed. To study intraindividual variations, eleven of the individuals were studied on more than one occasion. Results. The stomach and upper jejunal fluids varied significantly in all the measured entities, except the total concentration of proteins. The intraindividual variability was pronounced in some of the individuals, both in the stomach and the upper jejunum. We did not, however, observe any gender differences. Conclusions. This study demonstrates the complex nature of the fluids available for drug dissolution in the stomach and the upper small intestine in humans. The results can be used when designing a more physiological in vitro dissolution media representative for the fasted state. When designing such a medium, we suggest that gender differences not be taken into account.     

Dissolution media simulating the intralumenal composition of the small intestine: physiological issues and practical aspects

The objective of this study was to test various aspects of dissolution media simulating the intralumenal composition of the small intestine, including the suitability of the osmolality-adjusting agents and of the buffers, the substitution of crude sodium taurocholate (from ox bile) for pure sodium taurocholate and the substitution of partially hydrolysed soybean phosphatidylcholine for egg phosphatidylcholine. It was concluded that biorelevant media should contain sodium as the major cation species to better reflect the physiology. However, the use of non-physiologically relevant buffers is inevitable, especially for simulation of the fed state in the small intestine. The buffers used may affect the solubility product of weakly basic compounds with pK(a)(s) higher than about 5, the solubility of extremely highly lipophilic compounds due to salting in/out properties of the anion of the buffer and the stability of the dissolving compound. It is prudent in relevant situations to run an additional dissolution test in a modified fed state simulated intestinal fluid (FeSSIF) (or fasted state simulated intestinal fluid (FaSSIF), where applicable) containing alternative buffer species. Although a mixture of bile salts is physiologically more relevant than pure sodium taurocholate, this issue seems to be of practical importance in only a few cases. Adequate simulations in these cases will probably require the use of a number of pure substances and could substantially increase the cost of the test. Finally, unless the drug is extremely lipophilic (ca. logP> 5), egg phosphatidylcholine can be substituted by partially hydrolysed soybean phosphatidylcholine.     

Forecasting the In Vivo Performance of Four Low Solubility Drugs from Their In Vitro Dissolution Data

Purpose. To assess the usefulness of biorelevant dissolution tests in predicting food and formulation effects on the absorption of four poorly soluble, lipophilic drugs. Methods. Dissolution was studied with USP Apparatus II in water, milk, SIF_sp, FaSSIF, and FeSSIF. The in vitro dissolution data were compared on a rank order basis with existing in vivo data for the tested products under fasted and fed state conditions. Results. All drugs/formulations showed more complete dissolution in bile salt/lecithin containing media and in milk than in water and SIF_sp (USP 23). Comparisons of the in vitro dissolution data in biorelevant media with in vivo data showed that in all cases it was possible to forecast food effects and differences in absorption between products of the same drug with the physiologically relevant media (FaSSIF, FeSSIF and milk). Differences between products (both in vitro or in vivo) were less pronounced than differences due to media composition (in vitro) or dosing conditions (in vivo). Conclusions. Although biorelevant dissolution tests still have issues which will require further refinement, they offer a promisingin vitro tool for forecasting the in vivo performance of poorly soluble drugs.     

Crystallization from Supersaturated Solutions: Role of Lecithin and Composite Simulated Intestinal Fluid

Purpose

The overall purpose of this study was to understand the impact of different biorelevant media types on solubility and crystallization from supersaturated solutions of model compounds (atazanavir, ritonavir, tacrolimus and cilnidipine). The first aim was to understand the influence of the lecithin content in FaSSIF. As the human intestinal fluids (HIFs) contain a variety of bile salts in addition to sodium taurocholate (STC), the second aim was to understand the role of these bile salts (in the presence of lecithin) on solubility and crystallization from supersaturated solutions,

Methods

To study the impact of lecithin, media with 3 mM STC concentration but varying lecithin concentration were prepared. To test the impact of different bile salts, a new biorelevant medium (Composite-SIF) with a composition simulating that found in the fasted HIF was prepared. The crystalline and amorphous solubility was determined in these media. Diffusive flux measurements were performed to determine the true supersaturation ratio at the amorphous solubility of the compounds in various media. Nucleation induction times from supersaturated solutions were measured at an initial concentration equal to the amorphous solubility (equivalent supersaturation) of the compound in the given medium.

Results

It was observed that, with an increase in lecithin content at constant STC concentration (3 mM), the amorphous solubility of atazanavir increased and crystallization was accelerated. However, the crystalline solubility remained fairly constant. Solubility values were higher in FaSSIF compared to Composite-SIF. Longer nucleation induction times were observed for atazanavir, ritonavir and tacrolimus in Composite-SIF compared to FaSSIF at equivalent supersaturation ratios.

Conclusions

This study shows that variations in the composition of SIF can lead to differences in the solubility and crystallization tendency of drug molecules, both of which are critical when evaluating supersaturating systems.

     

Physiological parameters of the gastrointestinal fluid impact the dissolution behavior of the BCS class IIa drug valsartan

Abstract

The objective of this study was to investigate the effect of the physiological parameters (pH, buffer capacity, and ionic strength) of the gastrointestinal (GI) fluid on the dissolution behavior of the class II weakly acidic (BCS class IIa) drug valsartan. A series of in vitro dissolution studies was carried out on Diovan^® immediate release tablets using media that cover the physiological range of pH (1.2–7.8), buffer capacity (0–0.047?M/ΔpH), and ionic strength (0–0.4?mol/L) of the GI fluid during fasted and fed states using the conventional USP II apparatus. Valsartan exhibited pH- and buffer capacity-dependent dissolution behavior, where valsartan release was slow and incomplete in media simulating gastric fluid with low pH, and fast and complete in media simulating intestinal fluid with high pH. In addition, the rate of valsartan release increased with increasing the buffer capacity of the dissolution medium. In water and NaCl solutions, valsartan release was incomplete and the dissolution profiles were similar regardless of the ionic strength of the medium, indicating an ionic strength-independent dissolution behavior. These results highlight the significant effect of the physiological parameters of the GI fluid on the dissolution behavior of BCS class IIa drugs.     

Oral bioavailability of ketoprofen in suspension and solution formulations in rats: the influence of poloxamer 188

Objectives The aim of the current study was to investigate the effect of poloxamer 188 (P‐188) on the bioavailability of the BCS class 2 drug ketoprofen in vivo. Methods Aqueous suspension and solution formulations of ketoprofen with and without P‐188 were orally administered to fasted male Wistar rats. The intrinsic dissolution rate and solubility of ketoprofen in simulated intestinal fluid, in both the presence and absence of P‐188, was measured. Key findings The AUC and C_max were found to be significantly enhanced when ketoprofen was administered as suspension and P‐188 was present in the formulation (Susp P‐188) as compared to the surfactant‐free formulation (～4‐fold higher AUC, 7‐fold higher C_max). While drug solubility appeared to be almost unaffected by P‐188, a significantly faster dissolution was observed. In addition, the influence of P‐188 on the drug absorption process was investigated by comparison of solution formulations with and without P‐188. Conclusions The in‐vivo performance of these solutions, a pure buffer solution and a P‐188‐containing buffer solution showed no significant difference, suggesting that the increase in bioavailability for Susp P‐188 was primarily a consequence of the dissolution rate‐enhancing effect.     

Regiospecific Intestinal Absorption of the HIV Protease Inhibitor L-735,524 in Beagle Dogs

Purpose. To evaluate regional intestinal absorption and the feasibility of sustained release dosage form development for an HIV protease inhibitor, L-735,524. Methods. L-735,524 free base or sulfate salt was administered orally as suspension, solution or in solid dosage forms to fasted or fed Beagle dogs. Delayed-release dosage forms with slow or fast in vitro dissolution rates were evaluated in vivo to assess plasma concentration profiles. In addition, drug was administered directly into the jejunum or colon of animals, and drug concentrations determined in portal circulation to characterize absorption from these sites. Results. L-735,524 sulfate was well absorbed orally from a solution or capsule formulation if fasted animals' stomachs were preacidified with citric acid solution. A free base suspension, delivered in divided doses to fed animals, was also well absorbed. Prototype extended release dosage forms of L-735,524 produced a reduction in peak plasma levels but failed to prolong absorption and extend plasma concentrations compared to an immediate release capsule. Administration of L-735,524 sulfate solution (pH<3) as bolus solution or by infusion into the jejunum resulted in rapid but incomplete absorption compared to oral gavage. The free base suspension (pH 6.5) delivered into jejunal or colonic regions did not produce measurable systemic plasma concentrations. Conclusions. Extended release formulations did not prolong absorption of L-735,524 in dogs. Optimal L-735,524 absorption was dependent on solubility in an acidic environment in the duodenum.