Maintain Drug Supersaturation Research Articles

Effect of hydrophilic additives on the dissolution and pharmacokinetic properties of itraconazole-enteric polymer hot-melt extruded amorphous solid dispersions

Hot-melt extrusion technology has been widely reported for producing amorphous solid dispersions of poorly water-soluble compounds. A number of studies revealed that enteric polymers containing ionizable groups are able to improve the physical stability and maintain drug supersaturation, thereby enhancing oral bioavailability. However, our previous studies found that itraconazole (ITZ)-enteric polymer amorphous solid dispersions are hydrophobic and poorly wettable. Moreover, drug release in an acidic environment (i.e. stomach) is very limited, indicating a narrow absorption window. In the present study, we investigated the effect of hydrophilic additives on the in vitro and in vivo performance of ITZ-enteric polymer amorphous solid dispersions. Incorporating Vitamin E TPGS into ITZ-HPMCAS amorphous solid dispersions significantly improved drug release in the acidic media. Surprisingly, a low concentration of Vitamin E TPGS also enhanced the degree of drug supersaturation in neutral pH media, which is unique as compared with other tested hydrophilic additives. This effect is not due to the solubilization of the surfactant. We further formulated the amorphous solid dispersions into tablet dosage forms and evaluated their performance in a bio-relevant dissolution media. Our optimized formulations exhibited drastically enhanced dissolution profiles as compared with the commercial ITZ product and ITZ amorphous solid dispersion without hydrophilic additive. In vivo study showed that Vitamin E TPGS induced rapid drug absorption after oral administration. Moreover, the elimination half-life of ITZ was prolonged due to the enzyme inhibition effect of Vitamin E TPGS.

An Insight into Different Stabilization Mechanisms of Phenytoin Derivatives Supersaturation by HPMC and PVP

In this study, we examined the stabilization mechanism of drug supersaturation by hypromellose (HPMC) and polyvinylpirrolidone (PVP). The poorly water-soluble drugs, phenytoin (diphenylhydantoin, DPH), and its synthesized derivatives monomethylphenytoin (MDPH) and dimethylphenytoin (DMDPH) were used. DPH supersaturation was efficiently maintained by both HPMC and PVP. HPMC maintained the supersaturation of MDPH and DMDPH in a similar manner to that of DPH, whereas the ability of PVP to maintain drug supersaturation increased as follows: DPH>MDPH>DMDPH. Caco-2 permeation studies and nuclear magnetic resonance measurements revealed that the permeability and molecular state of the drug in a HPMC solution barely changed. In fact, the solubilization of the drug into PVP changed its apparent permeability and molecular state. The drug solubilization efficiency by PVP was higher and followed the order: DPH>MDPH>DMDPH. The different drug solubilization efficiencies most likely result from the different strengths in the intermolecular interaction between the DPH derivatives and PVP. The difference in the stabilization mechanism of drug supersaturation by HPMC and PVP could determine whether the efficient maintenance of the drug supersaturation was dependent on the drug species. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2574–2582, 2015

Polymer incorporation method affects the physical stability of amorphous indomethacin in aqueous suspension

This study reports the potential of different polymers and polymer incorporation methods to inhibit crystallisation and maintain supersaturation of amorphous indomethacin (IND) in aqueous suspensions during storage. Three different polymers (poly(vinyl pyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC) and Soluplus® (SP)) were used and included in the suspensions either as a solid dispersion (SD) with IND or dissolved in the suspension medium prior to the addition of amorphous IND. The total concentrations of both IND and the polymer in the suspensions were kept the same for both methods of polymer incorporation. All the polymers (with both incorporation methods) inhibited crystallisation of the amorphous IND. The SDs were better than the predissolved polymer solutions at inhibiting crystallisation. The SDs were also better at maintaining drug supersaturation. SP showed a higher IND crystallisation inhibition and supersaturation potential than the other polymers. However, this depended on the method of addition. IND in SD with SP did not crystallise, nor did the SD generate any drug supersaturation, whereas IND in the corresponding predissolved SP solution crystallised (into the recently characterised η polymorphic form of the drug) but also led to a more than 20-fold higher IND solution concentration than that observed for crystalline IND. The ranking of the polymers with respect to crystallisation inhibition potential in SDs was SP≫PVP>HPMC. Overall, this study showed that both polymer type and polymer incorporation method strongly impact amorphous form stability and drug supersaturation in aqueous suspensions.

Drug-polymer-water interaction and its implication for the dissolution performance of amorphous solid dispersions.

The in vitro dissolution mechanism of an amorphous solid dispersion (ASD) remains elusive and highly individualized, yet rational design of ASDs with optimal performance and prediction of their in vitro/in vivo performance are very much desirable in the pharmaceutical industry. To this end, we carried out comprehensive investigation of various ASD systems of griseofulvin, felodipine, and ketoconazole, in PVP-VA or HPMC-AS at different drug loading. Physiochemical properties and processes related to drug-polymer-water interaction, including the drug crystallization tendency in aqueous medium, drug-polymer interaction before and after moisture exposure, supersaturation of drug in the presence of polymer, polymer dissolution kinetics, etc., were characterized and correlated with the dissolution performance of ASDs at different dose and different drug/polymer ratio. It was observed that ketoconazole/HPMC-AS ASD outperformed all other ASDs in various dissolution conditions, which was attributed to the drug's low crystallization tendency, the strong ketoconazole/HPMC-AS interaction and the robustness of this interaction against water disruption, the dissolution rate and the availability of HPMC-AS in solution, and the ability of HPMC-AS in maintaining ketoconazole supersaturation. It was demonstrated that all these properties have implications for the dissolution performance of various ASD systems, and further quantification of them could be used as potential predictors for in vitro dissolution of ASDs. For all ASDs investigated, HPMC-AS systems performed better than, or at least comparably with, their PVP-VA counterparts, regardless of the drug loading or dose. This observation cannot be solely attributed to the ability of HPMC-AS in maintaining drug supersaturation. We also conclude that, for fast crystallizers without strong drug-polymer interaction, the only feasible option to improve dissolution might be to lower the dose and the drug loading in the ASD. In this study, we implemented an ASD/water Flory-Huggins parameter plot, which might assist in revealing the physical nature of the drug-polymer interaction. We also introduced supersaturation parameter and dissolution performance parameter as two quantitative measurements to compare the abilities of polymers in maintaining drug supersaturation, and the dissolution performance of various solid dispersions, respectively.

Maintenance of Supersaturation II: Indomethacin Crystal Growth Kinetics Versus Degree of Supersaturation

This study compares the kinetics of crystal growth of indomethacin from supersaturated suspensions at varying degrees of supersaturation (2 ≤ S ≥ 9) in the presence of seed crystals of the γ-form of indomethacin, the lowest energy polymorph. At high S (6 ≤ S ≥ 9), the crystal growth was first order with rate coefficients (kG ) that were nearly constant and consistent with the value predicted for bulk-diffusion control. At lower S (<6), kG values were significantly smaller, decreasing approximately linearly with a decrease in S. The decline in kG at low S was attributed to a prolonged period during the initial stages of crystal growth in which surface integration was rate limiting. The apparent solubility of indomethacin after crystal growth for 3 days increased by ∼1.6-fold at both low (S = 2) and high (S = 6) degrees of supersaturation suggesting that a higher energy surface layer was deposited on the γ-form seed crystals during crystal growth. When growth experiments were repeated at low S in the presence of indomethacin seed crystals isolated from a previous crystal growth experiment (i.e., seed crystals having higher energy surface), kG matched the higher values observed for bulk diffusion-controlled crystal growth. Crystal growth experiments were also conducted at S < 1.6 using a constant infusion of an indomethacin solution in the presence of γ-form seed crystals to obtain kG under conditions where deposition of a higher energy surface could not occur. At these conditions, the smaller value of kG indicative of surface integration control was again observed and the apparent solubility of indomethacin after crystal growth matched that of the γ-form. A quantitative mechanistic understanding of the crystal growth kinetics of indomethacin derived from experiments at high and low S may be useful in future studies aimed at understanding the inhibitory effects of pharmaceutical excipients on the crystal growth of poorly soluble compounds and their utility in maintaining drug supersaturation during oral absorption.

Enhanced active liposomal loading of a poorly soluble ionizable drug using supersaturated drug solutions

Nanoparticulate drug carriers such as liposomal drug delivery systems are of considerable interest in cancer therapy because of their ability to passively accumulate in solid tumors. For liposomes to have practical utility for antitumor therapy in patients, however, optimization of drug loading, retention, and release kinetics are necessary. Active loading is the preferred method for optimizing loading of ionizable drugs in liposomes as measured by drug-to-lipid ratios, but the extremely low aqueous solubilities of many anticancer drug candidates may limit the external driving force, thus slowing liposomal uptake during active loading. This report demonstrates the advantages of maintaining drug supersaturation during active loading. A novel method was developed for creating and maintaining supersaturation of a poorly soluble camptothecin analogue, AR-67 (7-t‐butyldimethylsilyl‐10-hydroxycamptothecin), using a low concentration of a cyclodextrin (sulfobutylether-β-cyclodextrin) to inhibit crystallization over a 48h period. Active loading into liposomes containing high concentrations of entrapped sodium or calcium acetate was monitored using drug solutions at varying degrees of supersaturation. Liposomal uptake rates increased linearly with the degree of supersaturation of drug in the external loading solution. A mathematical model was developed to predict the rate and extent of drug loading versus time, taking into account the chemical equilibria inside and outside of the vesicles and the transport kinetics of various permeable species across the lipid bilayer and the dialysis membrane. Intraliposomal sink conditions were maintained by the high internal pH caused by the efflux of acetic acid and exchange with AR-67, which undergoes lactone ring-opening, ionization, and membrane binding in the interior of the vesicles. The highest drug to lipid ratio achieved was 0.17 from a supersaturated solution at a total drug concentration of 0.6mg/ml. The rate and extent of loading was similar when a different intraliposomal metal cation (sodium) was used instead of calcium. The proposed method may have general application in overcoming the formulation challenges associated with the liposomal delivery of poorly soluble, ionizable anticancer agents.

Utility of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) for Initiation and Maintenance of Drug Supersaturation in the GI Milieu

To identify materials and processes which effect supersaturation of the GI milieu for low solubility drugs in order to increase oral bioavailability. A variety of small and polymeric molecules were screened for their ability to inhibit drug precipitation in supersaturated solutions. The best polymeric materials were utilized to create spray-dried dispersions (SDDs) of drug and polymer, and these were tested for drug form and homogeneity. Dispersions were tested in vitro for their ability to achieve and maintain drug supersaturation, for a variety of drug structures. Of the 41 materials tested, HPMCAS was the most effective at maintaining drug supersaturation. Drug/HPMCAS SDDs were consistently more effective at achieving and maintaining drug supersaturation in vitro than were SDDs prepared with other polymers. Drug/HPMCAS SDDs were effective in vitro for eight low solubility drugs of widely varying structure. Drug/HPMCAS SDDs were more effective at achieving and maintaining supersaturation than were rotoevaporated Drug/HPMCAS dispersions or physical mixtures of Drug and HPMCAS. The degree of achievable drug supersaturation increased with increasing polymer content in the SDD. The drug in Drug /HPMCAS SDDs was amorphous, and the dispersions were demonstrated to have a single glass transition and were thus homogeneous. HPMCAS has been identified as a uniquely effective polymer for use in SDDs of low solubility drugs, with broad applicability across a variety of drug structures and properties.