Delivery of long-acting injectable antivirals: best approaches and recent advances.

PURPOSE OF REVIEW: Treatment of chronic disease in a manner that promotes compliance and patient adherence has necessitated the consideration for drug delivery approaches that reduce the burden of regimens requiring daily treatment. Long-acting injectable (LAI) products have been developed in many disease areas and are now being exploited for the treatment of infectious disease, most notably HIV. RECENT FINDINGS: Research published over the past 3 years has shown that LAI nanosuspensions of nonnucleoside reverse transcriptase inhibitors and integrase inhibitors provide extended exposure to the active drug over a period of days to weeks. Some of these candidates are currently in clinical study and are highly anticipated medications for the prevention of HIV. SUMMARY: LAIs represent a growing need in the treatment of chronic infections. To date, the approach has been most successfully applied in the treatment of HIV, but could certainly be expanded into other diseases like tuberculosis. Most importantly, LAIs can provide a means to help prevent the emergence of resistance which may be attributed to lack of compliance to regimens requiring daily, oral administration.

Making the leap from daily oral dosing to long-acting injectables: lessons from the antipsychotics.

There are now long-acting versions of six antipsychotic drugs on the U.S. market, and with them, five unique combinations of molecular form and delivery strategy long-acting-injectable-antipsychotics (LAIAs) show evidence of reduced relapses of schizophrenia, but their introduction has been slow, taking at least nine years after the approval of each oral drug. Oily solutions of lipophilic prodrugs were the first to enter the LAIA market, but they relied on esterification of a hydroxyl handle that was lost with the emergence of the atypical antipsychotics. A review of the literature and patents shows that companies tested many different approaches before reaching the currently marketed versions, including aqueous suspensions of poorly soluble salts, polymeric microspheres, and new approaches to making prodrugs. Yet, very little has been published to support faster development of safe long-acting injectables (LAIs). This review introduces some of the critical considerations in creating an LAI; then it analyzes the existing products and discusses areas where further research is needed. The available literature suggests that lipophilic prodrugs may be inherently safer than poorly soluble salts as LAIs. Other areas needing additional study include (1) the range of physical properties acceptable for LAIs and the effect of prodrug tail length in achieving them, and (2) the role of physiological responses at the injection site in the release of drug from a depot.

Prodrugs of pioglitazone for extended-release (XR) injectable formulations.

N-Acyloxymethyl derivatives of pioglitazone (PIO) have been prepared and characterized as model candidates for extended-release injectable formulations. All PIO derivatives prepared are crystalline solids as determined by powder X-ray diffraction, and the solubility in aqueous media is below 1 µM at 37 °C. The melting points steadily increase from 55 °C, for the hexanoyloxymethyl derivative, to 85 °C, for the palmitoyloxymethyl derivative; inversely, the solubilities in ethyl oleate decrease as a function of increasing acyl chain length. The butyroyloxymethyl ester has a higher melting point and a lower solubility in ethyl oleate than expected from the trend. The (13)C solid-state NMR spectra of the PIO homologues between the hexanoyloxymethyl derivative and stearoyloxymethyl derivative suggest a common structural motif with the acyl chains exchanging between two distinct conformations, and the rate of exchange is slower for longer chain derivatives. The butyroyloxymethyl derivative is efficiently converted to PIO in in vitro rat plasma with a half-life of <2 min at 37 (o) C, while the rate of enzymatic cleavage in rat plasma decreases as the ester chain length increases for the longer acyloxymethyl derivatives. The concentration of PIO in plasma increases rapidly, or "spikes," in the hours following intramuscular (IM) injection of either the HCl salt or the butyroyloxymethyl derivative. In contrast, the more lipophilic palmitoyloxymethyl derivative provides slow growth in the PIO concentration over the first day to reach levels that remain steady for 2 weeks. On the basis of its in vivo pharmacokinetic profile, as well as material and solubility properties, the PIO palmitoyloxymethyl derivative has potential as a once-monthly injectable medication to treat diabetes.

Performance comparison of a co-crystal of carbamazepine with marketed product.

The carbamazepine: saccharin co-crystal (1) was studied in terms of a series of attributes, including suitability for multi-gram scale-up, propensity for crystal polymorphism, physical stability, in vitro dissolution and oral bioavailability, with the goal of comparing 1 with the marketed form of carbamazepine (Tegretol). Preparation of 1 was achieved on a 30g scale with a conventional cooling crystallization process from alcohol solution without seeding. The compound is not overtly polymorphic. This finding is in contrast to the form diversity of pure carbamazepine, which has four known polymorphs and a host of solvates, including a dihydrate, which is the stable form in the presence of water. Physical and chemical stability of the co-crystal is also shown to be quantitatively similar to the pure drug in the marketed product (Tegretol). Finally, comparison of oral bioavailability of 1 with Tegretol tablets in dogs shows the co-crystal to be a viable alternative to the anhydrous polymorph in formulated solid oral products. The balance of properties and performance of 1 as a model co-crystal is discussed.

Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations.

Biopharmaceutical evaluation of crystalline celecoxib salts in novel solid formulations, which were designed to simultaneously facilitate dissolution and inhibit precipitation in vitro, showed fast and complete absorption in beagle dogs at doses up to 7.5 mg/kg orally. In contrast, 5 mg/kg celecoxib in the form of Celebrex(R) showed approximately 40% absolute bioavailability in a cross-over experiment. An in vitro-in vivo correlation was observed in dog, and a threshold level of in vitro dissolution needed to maximize in vivo performance was highlighted. Oral bioavailability was limited in the absence of excipient combinations that delayed precipitation of celecoxib free acid as the salt neutralized in the GI fluid. Formulations of crystal forms having high energy (a 'spring'), thus transiently increasing solubility in aqueous solution relative to the free acid, combined with excipients functioning as precipitation inhibitors ('parachutes') were shown to provide both enhanced dissolution and high oral bioavailability.

High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids.

The concepts of high-throughput (HT) screening and combinatorial synthesis have been integrated into the pharmaceutical discovery process, but are not yet commonplace in the pharmaceutical development arena. Emerging strategies to speed pharmaceutical development and capture solid form diversity of pharmaceutical substances have resulted in the emergence of HT crystallization technologies. The primary type of diversity often refers to polymorphs, which are different crystal forms of the same chemical composition. However, diverse salt forms, co-crystals, hydrates and solvates are also amenable to study in HT crystallization systems. The impact of form diversity encompasses issues of stability and bioavailability, as well as development considerations such as process definition, formulation design, patent protection and regulatory control. This review highlights the opportunities and challenges of HT crystallization technologies as they apply to pharmaceutical research and development.

Celecoxib:nicotinamide dissociation: using excipients to capture the cocrystal's potential.

The cocrystal of celecoxib and nicotinamide (Cel:Nic) was crystallized from chloroform in a 1:1 ratio, and the structure has been solved from powder X-ray diffraction data. The dissolution and solubility of Cel:Nic are medium dependent and can be attributed to differences in conversion of Cel:Nic to celecoxib polymorphs I and III (Cel-I and Cel-III). The presence of low concentrations of surfactants facilitates the rapid conversion of neat Cel:Nic to large aggregates of Cel-III that dissolve more slowly than commercial Cel-III into 1% SDS solution. In contrast, combinations of Cel:Nic with both 1-10% solid SDS and PVP wet rapidly and convert to a mixture of amorphous celecoxib and a micron-sized crystalline celecoxib form IV (Cel-IV), which has recently been shown to be up to 4-fold more bioavailable than marketed Cel-III. More than 90% of the suspended material dissolves within 2 min at 37 degrees C when transferred to 1% SDS solution. This example highlights the importance of exploring the form conversion of cocrystals in aqueous media prior to pharmacokinetic studies, and illustrates the potential of simple formulations to overcome the limitations caused by rapid dissociation of cocrystals and recrystallization of poorly soluble forms in aqueous media.

Supramolecular behavior of the amphiphilic drug (2R)-2-ethylchromane-2-carboxylic acid arginine salt (a novel PPARalpha/gamma dual agonist).

PURPOSE: This study was conducted to evaluate the aggregation properties of an amphiphilic drug. METHODS: Aggregation of the drug was studied by various methods including phase-contrast and polarized microscopy, spectrophotometry, surface tensiometry, atomic force microscopy, and dynamic light scattering. Lymph-cannulated rats were used to assess fractions of drug that were absorbed into lymphatics. RESULTS: During the pharmaceutical development of an alpha/gamma dual PPAR agonist, a derivative of a chromane-2-carboxylic acid (compound 1), it was discovered that the compound was able to form various aggregates in aqueous media from pH 6.5 to 7.1, whereas aggregating predominantly into micelles at higher pH values. Critical micelle concentrations seemed to be quite low, about 0.25 mM (0.17 mg/mL) in deionized water as determined by spectrophotometric (dye) and surface tensiometry (du Nuoy) methods. Aggregation of compound 1 into large supramolecular aggregates was visualized via phase-contrast microscopy and atomic force microscopy. The observed aggregates ranged from 250 nm to greater than 10 microm in size. Formation of liquid crystalline phases was observed by polarized microscopy as the material was gradually hydrated with water. Lymph studies in rats indicated that up to 6.9% of the orally administered dose of compound 1 in pH 6.5 buffer appeared in lymph, suggesting that supramolecular aggregation may also occur in vivo leading to partitioning between the portal and the lymph routes. CONCLUSIONS: The aforementioned supramolecular aggregation was found to have a profound effect on the pharmaceutical development of the drug and potentially on in vivo absorption of the drug.

Solid-state nuclear magnetic resonance determination of the physical form of BHA on common pharmaceutical excipients.

PURPOSE: The purpose of this study was to evaluate the physical form of 2-tert-butyl-4-methoxy-phenol (BHA) following wet granulation onto common pharmaceutical excipients. METHODS: A 13C label was incorporated into the methoxy group of BHA, the major isomer in synthetic butylated hydroxyanisole. Solutions of the labeled BHA were used to load the labeled BHA onto common pharmaceutical excipients. After air drying under ambient conditions, the mixtures were examined by 13C MAS and CP/MAS nuclear magnetic resonance (NMR) spectroscopy to evaluate the physical form of the BHA. RESULTS: The data suggested that BHA could exist as either a crystalline or an amorphous component and that amorphous material was either bound to excipients or relatively mobile during the time of the NMR experiment. At 0.1% loading, BHA appeared to be amorphous and mobile in the freshly prepared blends. At 0.5% loading, BHA was shown to be amorphous on microcrystalline cellulose (MCC) and hydroxypropylmethylcellulose (HPMC) while remaining crystalline on lactose, mannitol, calcium phosphate dihydrate, and croscarmellose sodium. CONCLUSIONS: Solid-state NMR spectroscopy has been used to probe the physical forms of 13C-labeled BHA granulated onto common pharmaceutical excipients. The techniques described in this paper may be applied to help explain stability changes in formulations containing BHA.

Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids.

Cocrystals of the poorly soluble antifungal drug cis-itraconazole (1) with 1,4-dicarboxylic acids have been prepared. The crystal structure of the succinic acid cocrystal with 1 was determined to be a trimer by single-crystal X-ray. The trimer is comprised of two molecules of 1 oriented in antiparallel fashion to form a pocket with a triazole at either end. The extended succinic acid molecule fills the pocket, bridging the triazole groups through hydrogen-bonding interactions rather than interacting with the more basic piperazine nitrogens. The solubility and dissolution rate of some of the cocrystals are approximately the same as those of the amorphous drug in the commercial formulation and are much higher than those for the crystalline free base. The results suggest that cocrystals of drug molecules have the possibility of achieving the higher oral bioavailability common for amorphous forms of water-insoluble drugs while maintaining the long-term chemical and physical stability that crystal forms provide.