Formulation Design of Fast Disintegrating Tablets Using Disintegrant Blends

In the present work, fast disintegrating tablets of prochlorperazine maleate were designed with a view to enhance patient compliance by direct compression method. In this method, crospovidone (up to 3% w/w) and croscarmellose sodium (up to 5% w/w) in combination were used as superdisintegrants. Since disintegrants complement each other, accelerating the disintegration process when used together. Estimation of prochlorperazine maleate in the prepared tablet formulations was carried out by extracting the drug with methanol and measuring the absorbance at 254.5nm. The prepared formulations were further evaluated for hardness, friability, drug content uniformity, in vitro dispersion time, wetting time and water absorption ratio. Based on in vitro dispersion time (approximately 12 s), one promising formulation was tested for in vitro drug release pattern in phosphate buffer pH 6.8 and short-term stability (at 40°/70% RH for 3 mo), drug-excipient interaction (IR spectroscopy) were studied. Among the formulations tested, formulation DCPC₄ containing 5% w/w of croscarmellose sodium and 3% w/w of crospovidone as superdisintegrant emerged as the overall best (t_50% 7.0 min) based on drug release characteristics in pH 6.8 phosphate buffer compared to commercial conventional tablet formulation (t_50% 17.4 min). Short-term stability studies on the promising formulation indicated that there were no significant changes in drug content and in vitro dispersion time (p<0.05).     

Effects of bile salts on gastrointestinal absorption of pravastatin

This study aimed to examine the effects of bile salts and formulations on the absorption through gastrointestinal tract of pravastatin, which has low bioavailability. Pravastatin sodium physical mixtures and solid dispersions were prepared using various bile salts. The physicochemical characteristics and permeation profiles were investigated using pravastatin sodium-bile salt physical mixtures and solid dispersions. Pravastatin in the physical mixture did not achieve amorphous state, whereas that in the solid dispersion was completely converted to amorphous state. The permeation enhancement factors ranged between 1.13 and 11.9 with the addition of bile salts, and the permeation flux of pravastatin sodium greatly increased as the sodium cholate (NaC) concentration increased from 5 to 10 mM. Pravastatin sodium permeation fluxes [μg/(cm(2) h)] from solid dispersions (drug-NaC = 1:49) (20.8 ± 2.7) were much higher than those from physical mixtures (4.7 ± 3.1) and commercial tablets (3.5 ± 1.2) (p < 0.05). The dissolution rates of pravastatin sodium from solid dispersions in pH 1.2 were much lower than those from physical mixtures and commercial products, whereas more than 97% of pravastatin sodium was dissolved at 5 min in pH 6.8. On the basis of the results, it was concluded that pravastatin sodium solid dispersions containing bile salts could enhance drug absorption.     

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。     

Effects of bile salts on the lovastatin pharmacokinetics following oral administration to rats

This study aimed to examine the effects of bile salts on pharmacokinetics of lovastatin, which has low bioavailability. Lovastatin solid dispersions were prepared using sodium deoxycholate (NaDC) and sodium glycholate (NaGC) at ratios of 1:19, 1:49, and 1:69. The formulated solid dispersions and control (commercial tablet) were administered to rats and plasma concentrations were determined by a validated LC-MS/MS method. Statistically significant differences were found in C_max, AUC_0–10, and AUC_0–∞ values among lovastatin formulations (p?<?0.05). NaDC-containing formulations revealed higher bioavailabilities than NaGC-containing solid dispersions at ratios of 1:19 and 1:49. Especially, NaDC-containing formulation at a ratio of 1:19 (NaDC19) showed the highest bioavailability. The AUC (both AUC_0–10 and AUC_0–∞) of NaDC19 was statistically higher than control and NaDC69 (p?<?0.05). The AUC values decreased as bile salt concentrations increased. Overall, formulations containing bile salts showed higher AUC values than control, even though all formulations did not show significantly higher AUC. In conclusion, the addition of bile salts to lovastatin could enhance drug bioavailabilities. However, too high concentrations of bile salts could decrease bioavailabilities of lovastatin.     

Formulation and evaluation of diclofenac sodium buccoadhesive discs

Twenty diclofenac sodium buccoadhesive discs containing Cp974p, polycarbophil, PEO, SCMC-medium viscosity (SCMC-MV), SCMC-ultrahigh viscosity (SCMC-UHV) or their combinations were prepared. These buccoadhesive discs were evaluated for release pattern, swelling capacity, surface pH, mucoadhesion performance, and in vitro permeation of diclofenac sodium through buccal membranes. In vivo testing of mucoadhesion time, strength of adhesion, irritation, bitterness due to drug swallowing and disc disintegration in the buccal cavity were also performed. Drug bioavailability of a selected diclofenac sodium buccoadhesive product was then compared with that of Voltarin 100 SR tablet. The percentage relative bioavailability of diclofenac sodium from the selected buccoadhesive disc 50 mg was found to be 141.31%.     

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.     

Enhancing Skin Permeation of Biphenylacetic Acid (BPA) Using Salt Formation with Organic and Alkali Metal Bases

In the present study, a series of organic and alkali metal salts of biphenylacetic acid (BPA) have been prepared and evaluated in vitro for percutaneous drug delivery. The physicochemical properties of BPA salts were determined using solubility measurements, DSC, and IR. The DSC thermogram and FTIR spectra confirmed the salt formation with organic and alkali metal bases. Among the series, salts with organic amines (ethanolamine, diethanolamine, triethanolamine, and diethylamine) had lowered melting points while the alkali metal salt (sodium) had a higher melting point than BPA. The in vitro study showed that salt formation improves the physicochemical properties of BPA, leading to improved permeability through the skin. Amongst all the prepared salts, ethanolamine salt (1b) showed 7.2- and 5.4-fold higher skin permeation than the parent drug at pH 7.4 and 5.0, respectively, using rat skin.     

Plantago ovata Mucilage in the Design of Fast Disintegrating Tablets

In the present work, fast disintegrating tablets of prochlorperazine maleate were designed with a view to enhance patient compliance by direct compression method. In this method mucilage of Plantago ovata and crospovidone were used as superdisintegrants (2-8% w/w) along with microcrystalline cellulose (20-60% w/w) and directly compressible mannitol (Pearlitol SD 200) to enhance mouth feel. The prepared batches of tablets were evaluated for hardness, friability, drug content uniformity, wetting time, water absorption ratio and in vitro dispersion time. Based on in vitro dispersion time (approximately 8 s), the two formulations were tested for the in vitro drug release pattern (in pH 6.8 phosphate buffer), short-term stability (at 40°/75% relative humidity for 3 mo) and drug-excipient interaction (IR spectroscopy). Among the two promising formulations, the formulation prepared by using 8% w/w of Plantago ovata mucilage and 60% w/w of microcrystalline cellulose emerged as the overall best formulation (t_50% 3.3 min) based on the in vitro drug release characteristics compared to conventional commercial tablets formulation (t_50% 17.4 min). Short-term stability studies on the formulations indicated that there are no significant changes in drug content and in vitro dispersion time (p<0.05).     

Hybrid drug delivery system for oropharyngeal,cervical and colorectal cancer – in vitro and in vivo evaluation

The present investigation was designed with the intention to formulate a versatile 5-fluorouracil(5-FU) matrix tablet surpassing issues associated with current conventional chemotherapeutic drug delivery systems. The novel 5-FU matrix tablet fulfills therapeutic needs by engineering matrix tablets utilizing chitosan–sodium alginate interpolyelectrolyte complex (IPEC). IPEC was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The matrix tablets were formulated utilizing IPEC alone and in combination with chitosan, sodium alginate and sodium deoxycholate as permeation enhancer. Pharmaceutical properties, swelling studies, in vitro dissolution and diffusion studies, mucoadhesive studies and in vivo studies were performed for formulated 5-FU. The selected chitosan–sodium alginate IPEC offers pH independent 5-FU release in comparison to alone or physical mixture of chitosan and sodium alginate. Furthermore, novel matrix tablets demonstrated significantly higher bioadhesive properties with controlled 5-FU release without the initial burst effect and also demonstrated a higher permeation of 5-FU. To conclude, the developed novel 5-FU matrix tablets pave way as an excellent alternative for cancer treatment which could potentially minimize the dose dependent side effects and provide better patient compliance.     

Dissolution/Permeation of Albendazole in the Presence of Cyclodextrin and Bile Salts: A Mechanistic In Vitro Study into Factors Governing Oral Bioavailability

We aimed to understand the impact of the interplay between bile salts and cyclodextrins on the dissolution-permeation of poorly soluble drug compounds with a moderate-strong binding constant to cyclodextrin. Phase diagrams were prepared on the chosen model compound albendazole in phosphate buffer, fasted state simulated intestinal fluid (FaSSIF), and a modified fed state simulated intestinal fluid (FeSSIF_mod) with (2-hydroxypropyl)-beta-cyclodextrin (HP-β-CD) concentrations of up to 10 % (m/m). Then we investigated the dissolution/permeation interplay of albendazole dissolved/suspended in the different media through a biomimetic barrier on a 96-well in vitro model. The apparent solubility of albendazole was enhanced by HP-β-CD and FaSSIF/FeSSIF_mod separately. However, when albendazole was dissolved in HP-β-CD and biomimetic media together, the solubility was significantly lower than the predicted additive solubility from the solubilizing effects. It is postulated that this is due to the sodium taurocholate from the biomimetic media displacing albendazole from the hydrophobic cavity of HP-β-CD. In the permeation experiments, the highest permeation was observed at cyclodextrin concentrations able to solubilize close to the total dose of albendazole without a major surplus of solubilization capacity. Furthermore, an over-proportional permeation enhancement was observed when both, cyclodextrin and biomimetic media were present. These results indicate that the interplay between bile salts and cyclodextrins can enhance the free (molecularly dissolved) fraction of drug in solution to a greater extent than could be obtained with one of the solubilizing components alone. In conclusion, at carefully selected cyclodextrin-concentrations in combination with biomimetic media, obviously, a transient supersaturation is induced, which is made responsible for the observed major permeation enhancement.     

Preparation and Evaluation of Orodispersible Tablets of Pheniramine Maleate by Effervescent Method

In the present work, orodispersible tablets of pheniramine maleate were designed with a view to enhance patient compliance by effervescent method. In the effervescent method, mixture of sodium bicarbonate and tartaric acid (each of 12% w/w concentration) were used along with super disintegrants, i.e., pregelatinized starch, sodium starch glycolate, croscarmellose sodium and crospovidone. The prepared batches of tablets were evaluated for hardness, friability, drug content uniformity and in vitro dispersion time. Based on in vitro dispersion time (approximately 60 s), three formulations were tested for in vitro drug release pattern (in pH 6.8 phosphate buffer), short-term stability (at 40±2°/75±5% RH for 3 mo) and drug-excipient interaction (IR spectroscopy). Among three promising formulations, formulation ECP₄ containing 4% w/w crospovidone and mixture of sodium bicarbonate and tartaric acid (each of 12% w/w) emerged as the overall best formulation (t_70% = 1.65 min) based on the in vitro drug release characteristics compared to commercial conventional tablet formulation. Short-term stability studies on the formulations indicated no significant changes in the drug content and in vitro dispersion time (P < 0.05).     

Dissolution and Permeation Properties of Naproxen From Solid-State Systems With Chitosan

The purpose of this study was to investigate the influence of different types of chitosan and of the preparation technique of the drug–polymer combination in improving the dissolution and permeation abilities of naproxen, a very poorly water-soluble anti-inflammatory drug. Drug–chitosan systems were prepared by simple physical mixing, kneading, cogrinding, or coevaporation using five types of chitosan (base and glutamate or hydrochloride salts, both at two different molecular weights). The products were tested for drug-dissolution behavior and for permeation properties through both Caco-2 cell monolayers and artificial lipophilic membranes. All combinations with chitosan base were significantly (p < .01) more effective in enhancing drug-dissolution rate than those with both its salts, probably in virtue of its higher amorphizing effect toward the drug, as observed in solid-state studies. A different rank order was found in permeation experiments in which chitosan glutamate was the most powerful partner in improving the drug-apparent permeability (p < .01), followed by the hydrochloride salt (p < .05), whereas no significant effect was obtained with chitosan base. Cogrinding was the most powerful technique in promoting both dissolution and permeation properties of the drug, thus pointing out the importance of the preparation method in obtaining efficacious drug-carrier systems. Finally, the good correspondence between permeation experiments with Caco-2 cells and those with the artificial lipophilic membrane indicated the suitability of this latter in preformulation studies for a rapid screening of the best carrier and the most efficient drug-carrier preparation method for improving the biopharmaceutical properties of drugs.     

Enhancement of dissolution of nystatin from buccoadhesive tablets containing various surfactants and a solid dispersion formulation

Nystatin is commonly employed to treat fungal infections in the mouth. It is not absorbed via the stomach and it will therefore not treat fungal infections in any part of the body other than the mouth. Nystatin buccoadhesive tablets release the drug very slowly due to the poor solubility of nystatin in water and also the presence of polymers with mucoadhesive properties. Therefore, the aim of the present study was to improve drug release from buccoadhesive tablets, while retaining adequate mucoadhesive properties. To this end, a solid dispersion of nystatin: lactose (1:3) was prepared and mixed with xanthan. The effects of hydrophilic surfactants such as cremophor RH40 and Tween 80 on drug release and mucoadhesive properties of nystatin tablets were also investigated as were swelling and erosion indices and strength of bioadhesion in vitro to a biological membrane. The interaction between nystatin and lactose in solid dispersion formulation was investigated by XRPD, FT-IR and DSC. The results showed that a solid dispersion formulation and mucoadhesive tablets containing surfactants led to faster drug release than their simple physical mixtures. Drug release was also faster from a solid dispersion compared to tablets containing surfactants. Swelling and erosion results showed that tablets made of a solid dispersion swelled and eroded faster than a physical mixture formulation. The presence of surfactant slightly increased the degree of swelling and erosion of buccoadhesive tablets.     

Oramucosal Delivery of LHRH: Pharmacokinetic Studies of Controlled and Enhanced Transmucosal Permeation

ABSTRACT

Several transmucosal therapeutic systems (TmTs) were developed to study the enhanced/controlled delivery of luteinizing hormone-releasing hormone (LHRH) through oral mucosae for prolonged periods. TmTs is a track field-shaped bilayer mucoadhesive device consisting of fast-release and sustained-release layers. In vivo evaluations were performed in beagle dogs, and pharmacokinetic profiles were monitored to characterize the transmucosal permeation kinetics of LHRH delivered by the various TmTs formulations containing a stabilizer, cetylpyridinium chloride, and a permeation enhancer, such as bile salts, to enhance the stability and permeability of LHRH. The plasma LHRH concentrations were observed to reach the plateau level within 30 min and were maintained for 2 hr following application of TmTs, in contrast to a rapid elimination profile observed after IV administration. Addition of 5% bile salt into the fast-release layer was observed to produce an enhancement in the absorption rate, higher plateau plasma levels, and greater systemic bioavailability. Addition of pH modifiers was noted to affect the bile salt enhanced transmucosal delivery of LHRH. To prolong the plasma LHRH level, several loading doses of LHRH were incorporated into the sustained-release layer. The plasma levels were sustained and the area under the curve (AUC) values were found to be linearly dependent upon the combined loading doses of LHRH in the fast-release and sustained-release layers. Mucosal irritation was also measured, using buccal mucosa, and results were observed to be low and reversible for the single application. The results indicated that TmTs is relatively safe and capable of achieving enhanced and controlled transmucosal delivery of peptide drugs.     

Badam gum: a natural polymer in mucoadhesive drug delivery. Design,optimization, and biopharmaceutical evaluation of badam gum-based metoprolol succinate buccoadhesive tablets

Context: Applicability of natural polymers in pharmaceutical drug delivery.

Objective: The objective of the present investigation was to evaluate the applicability of badam gum (BG) obtained from Terminalia catappa LINN, belongs to the family combretaceae as a buccoadhesive polymer using metoprolol succinate as a model drug.

Methods: Tablets were prepared by wet granulation technique. Compression coating technique was employed for the preparation of unidirectional release buccal tablets using cellulose acetate as an impermeable backing layer.

Results: Muco/buccoadhesive properties of the BG were increased with the increase in the concentration of polymer which was evident form the detachment force measurement, ex vivo residence time, and swelling studies. MBG 2 was found to be the optimized formulation based on drug dissolution studies and bioadhesion studies. FTIR and DSC studies performed on the optimized formulation indicated no drug–polymer interaction. MBG 2 was found to be stable after accelerated stability testing for 6 months as per ICH guidelines. Pharmacokinetic studies of the optimized formulation were performed in six healthy human volunteers in comparison with that of the commercial extended release oral tablet GUDPRESS XL-25 by estimating pharmacokinetic parameters and mean residence time (MRT). It was found that there is a significant increase in the bioavailability of metoprolol succinate from BG formulation which was evident from the high AUC and MRT values compared with the commercial formulation.

Conclusion: The above results clearly indicated that badam gum can be used as a mucoadhesive polymer for buccal drug delivery.     

Formulation and physicochemical characterisation of buccoadhesive films containing ketorolac

Ketorolac tromethamine, the non-steroidal anti-inflammatory drug, was formulated onto buccoadhesive films to overcome the limitations in the currently available dosage and routes of administration which in sequence will increase patients’ compliance. Films were cast from organic and aqueous solvents using various bioadhesive polymers namely: sodium carboxymethyl cellulose (Na-CMC), hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC) and Carbopol 934. The prepared films were subjected to investigations for their physical and mechanical properties, swelling behaviors, in vitro bioadhesion, drug permeation via bovine buccal mucosa and in vitro drug release. These properties were found to vary significantly depending on the preparation methods, the type of the polymers and the ratio of addition of both plasticizer (i.e. polyethylene glycol) and film forming agent (ethyl cellulose and polyvinylpyrolidene). Formula number K10 containing carbopol 0.5% and HPMC 0.5% was found to be the best film as it shows good adhesion, acceptable pH, and gives a reasonable ketrolac release (about 85-90% at 6 h). In addition, this film was subjected to in vitro and in vivo release. The obtained results indicate that the concentration of ketorolac in the oral cavity was maintained above 4.0 μg/mL for a period of at least 6 h. This film shows promising results for using the ketrolac buccoadhesive route of administration topically and systemically, and thus it will be subjected to clinical evaluation in future work.     

Improvement of oxaprozin solubility and permeability by the combined use of cyclodextrin, chitosan, and bile components

The effect of the combined use of randomly methylated β-cyclodextrin (RAMEB), chitosan (CS), and bile components (dehydrocholic (DHCA) or ursodeoxycholic (UDCA) acids and their sodium salts) on solubility and permeability through Caco-2 cells of oxaprozin (a very poorly water-soluble non-steroidal anti-inflammatory drug) has been investigated. Addition of CS, bile acids, and their sodium salts increased the RAMEB solubilizing power of 4, 2, and 5 times, respectively. Drug-RAMEB-CS co-ground systems showed very higher dissolution rate than corresponding drug-RAMEB systems. Addition of bile components further improved drug dissolution rate. The CS presence enabled a significant increase in drug permeability through Caco-2 cells with respect to drug-RAMEB systems. Moreover, CS and NaDHC showed a synergistic enhancer effect, enabling a 1.4-fold permeability increase in comparison with systems without bile salt. However, unexpectedly, no significant differences were found between physical mixtures and co-ground products, indicating that drug permeation improvement was due to the intrinsic enhancer effect of the carriers and not to drug-carrier interactions brought about by co-grinding, as instead found in dissolution rate studies. The combined use of RAMEB, CS, and NaDHC could be exploited to develop effective oral dosage forms of oxaprozin, with increased drug solubility and permeability, and then improved bioavailability.     

A Systematic Quantitative Evaluation of Permeation Enhancement Window: Transdermal Permeation Enhancing Dynamics Establishment and Molecular Mechanisms Characterization of Permeation Enhancer

At present, transdermal permeation enhancing dynamics studies on permeation enhancers are still limited. In this study, these dynamics were established based on the content of enhancer Plurol Oleique CC in skin (C_POCC) and the increment of drug permeation amount (ΔQ). A new concept deemed “permeation enhancement window” (ΔC_POCC), comprised of a threshold dose (C^thr), maximal dose (C^max) and permeation enhancement efficiency (Eff) was used to evaluate the enhancement effect of POCC for different drugs. According to results of FT-IR, ATR-FTIR and DSC analyses, the higher CPOCC of patches containing acidic drugs vs. basic drugs resulted from their stronger interaction with pressure-sensitive adhesives, leading to more free POCC and a greater disturbing effect on stratum corneum (SC) lipids. Below C^thr, a longer lag phase for acidic drugs resulted from more POCC required to compete with ceramide. When CPOCC exceeded C^max by about 400 μg/g, plateau phases for all drugs were reached due to the upper limit of SC lipid fluidity, as confirmed by SAXS and Raman imaging. In summary, the differences in the permeation enhancement window for the test drugs resulted from the varied interaction strengths among POCC, drugs and adhesives, as well as changeable SC lipid fluidity.     

A photophysical study on the role of bile salt hydrophobicity in solubilizing amphotericin B aggregates

Amphotericin B (AmB) is a highly effective antifungal agent and finds utility against a broad spectrum of fungal species. Bile salts are biocompatible biosurfactants, widely used as drug delivery media for many hydrophobic drugs. AmB in the colloidal suspension of sodium deoxycholate (NaDC) is a well-known commercial formulation of AmB. In the present work, the association of AmB with three bile salts, namely sodium cholate, sodium taurodeoxycholate and sodium taurocholate is studied using the photophysical properties of AmB. Selective excitation of monomeric AmB (λ_ex 414 nm, λ_em 560 nm) and dimeric AmB (λ_ex 335 nm, λ_em 472 nm) reveal that with increasing concentration of bile salts, the higher aggregates in water disaggregate to form both monomeric and dimeric forms of AmB. This is seen to be a general trend in all the bile salts studied. Results of steady state fluorescence anisotropy and fluorescence lifetimes studies suggest that the interaction between AmB (hydrophobic heptaene face) and bile salts (hydrophobic steroidal face) is essentially hydrophobic. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4153–4160, 2009     

In Situ Artificial Membrane Permeation Assay under Hydrodynamic Control: Permeability-pH Profiles of Warfarin and Verapamil

Purpose

To investigate the permeation of two ionisable drug molecules, warfarin and verapamil, across artificial membranes. For the first time since the introduction of the parallel artificial membrane permeation assay (PAMPA) in 1998, in situ permeation-time profiles of drug molecules are studied.

Methods

The method employs a rotating-diffusion cell where the donor and acceptor compartments are separated by a lipid-impregnated artificial membrane. The permeation of the solute is investigated under well-defined hydrodynamic conditions with control over the unstirred water layer. The flux of the permeating molecule is analysed in situ using UV spectrophotometry.

Results

In situ permeation-time profiles are obtained under hydrodynamic control and used to determine permeability coefficients. An advanced analytical transport model is derived to account for the membrane retention, two-way flux and pH gradient between the two compartments. Moreover, a numerical permeation model was developed to rationalise the time-dependent permeation profiles. The membrane permeability, intrinsic permeability and unstirred water permeability coefficients of two drug molecules are obtained from two independent methods, hydrodynamic extrapolation and pH profiling, and the results are compared.

Conclusions

Both warfarin and verapamil exhibit high permeability values, which is consistent with the high fraction absorbed in human. Our results demonstrate that a considerable lag-time, varying with the solute lipophilicity and stirring rate, exists in membrane permeation and leads to incorrect compound ranking if it is not treated properly. Comparison of the permeability data as a function of pH and stirring rate suggests that some transport of the ionized molecules occurs, most likely via ion-pairing.