Journal of pharmaceutical sciences最新文献

Atomic layer coating (ALC) is an emerging, solvent-free technique to coat amorphous solid dispersion (ASD) particles with a nanolayer ceramic coating that has been shown to improve powder characteristics and limit drug crystallization. Herein, we evaluate the impact of aluminum oxide coatings with varying thickness and conformality on the release behavior of ritonavir/copovidone ASDs. Release performance of powders, neat tablets, and formulated tablets was studied. Confocal fluorescence microscopy (CFM) was used to visualize particle hydration and phase separation during immersion of the ASD in aqueous media. CFM revealed particle hydration requires defects for solvent penetration, but coatings, regardless of thickness, had minor impacts on powder dissolution provided defects were present. In tablets where less surface area is exposed to the dissolution media due to gel formation, slowed hydration kinetics resulted in phase separation of the drug from the polymer in coated samples, limiting release. Formulation with two superdisintegrants, crospovidone and croscarmellose sodium, as well as lactose achieved ∼90% release in less than 10 minutes, matching the uncoated ASD particles of the same formulation. This study highlights the importance of hydration rate, as well as the utility of confocal fluorescence microscopy to provide insight into release and phase behavior of ASDs.

Subvisible particle count is a biotherapeutics stability indicator widely used by pharmaceutical industries. A variety of stresses that biotherapeutics are exposed to during development can impact particle morphology. By classifying particle morphological differences, stresses that have been applied to monoclonal antibodies (mAbs) can be identified. This study aims to evaluate common biotherapeutic drug storage and shipment conditions that are known to impact protein aggregation. Two different studies were conducted to capture particle images using micro-flow imaging and to classify particles using a convolutional neural network. The first study evaluated particles produced in response to agitation, heat, and freeze-thaw stresses in one mAb formulated in five different formulations. The second study evaluated particles from two common drug containers, a high-density polyethylene bottle and a glass vial, in six mAbs exposed solely to agitation stress. An extension of this study was also conducted to evaluate the impact of sequential stress exposure compared to exposure to one stress alone, on particle morphology. Overall, the convolutional neural network was able to classify particles belonging to a particular formulation or container. These studies indicate that storage and shipping stresses can impact particle morphology according to formulation composition and mAb.

The refined Developability Classification System (rDCS) provides a comprehensive animal-free approach for assessing biopharmaceutical risks associated with developing oral formulations. This work demonstrates practical application of a recently advanced rDCS framework guiding formulation design for six diverse active pharmaceutical ingredients (APIs) and compares rDCS classifications with those of the Biopharmaceutics Classification System (BCS). While the BCS assigns five of the APIs to class II/IV, indicating potentially unfavorable biopharmaceutical attributes, the rDCS provides a more nuanced risk assessment. Both BCS and rDCS assign acetaminophen to class I at therapeutic doses. Voriconazole and lemborexant (both BCS II) are classified in rDCS class I at therapeutic doses, indicating suitability for development as conventional oral formulations. Fedratinib is classified as BCS IV but the rDCS indicates a stratified risk (class I, IIa or IIb), depending on the relevance of supersaturation/precipitation in vivo. Voxelotor and istradefylline (both BCS II) belong to rDCS class IIb, requiring solubility enhancement to achieve adequate oral bioavailability. Comparing the rDCS analysis with literature on development and pharmacokinetics demonstrates that the rDCS reliably supports oral formulation design over a wide range of API characteristics, thus providing a strong foundation for guiding development.

Administration of high-concentrated suspension formulations (i.e., solid particles dispersed in a liquid vehicle) can be limited due to their greater propensity for needle occlusion. The physical interaction between the solid phase (i.e., particles), the vehicle (i.e., flow field), and injection devices could result in the formation of particle bridging or filtering, posing a major risk in dose delivery accuracy and injectability. Here, given the limited understanding on how clogging initiates in syringe and needle delivery systems, we report an experimental approach to fully characterize the transient injection behavior of suspensions. In particular, we first established a custom fluorescence tagging and imaging technique with integrated force sensor to enable visual observation of local particle concentrations and plunger force monitoring throughout injection. Then, we investigated the effects of key formulation properties and device parameters including particle concentration and morphology, carrier viscosity, injection rate, needle and syringe sizes, and tissue backpressure on the incidence of suspension particle jamming and needle clogging. We performed systematic benchmark studies demonstrating that increasing needle inner diameter (ID) and particle density considerably reduced clogging risk, while increasing vehicle viscosity, particle size, and tissue backpressure significantly increased clogging. The experimental framework presented is amenable to quantifying clogging risk in drug-loaded particle suspensions and provides a guideline to make informed decisions on the tradeoffs between creating particles for pharmaceutical impact and feasibility of injection delivery.

Amorphous solid dispersion (ASD) tablets based on hydrophilic polymer carriers may encounter disintegration challenges. In this work, the effect of different formulation composition variables on the ASD tablet disintegration performance was systematically studied. GDC-0334: copovidone (PVPVA) 60: 40 ASD prepared by spray drying was selected as the model ASD system. The effects of ASD loading, filler type and ratio, disintegrant type and level were then investigated using tablets made by direct compression process. Tablet disintegration time increased with the increase of ASD loading, especially when ASD loading exceeded 50 %. At the same tablet solid fraction, when lactose was used as the soluble filler, faster tablet disintegration was observed compared to the tablets with mannitol as the soluble filler. Among the three tested disintegrants, croscarmellose sodium performed the best in facilitating the ASD tablet disintegration, followed by sodium starch glycolate, and crospovidone was the poorest. When croscarmellose sodium was used as the disintegrant, 5 % level was sufficient to enable ASD tablet disintegration at 60 % ASD loading and further increase of croscarmellose sodium level to 8 % did not provide additional benefit. Water uptake experiments were performed on selected tablets and the results demonstrated a positive correlation with tablet disintegration time, indicating water penetration is a major contributing step for the disintegration of our ASD tablets. Overall, this work provides a rationale for excipient selection and insights into building a platform formulation approach for developing immediate-release ASD tablets.

The stabilization of protein therapeutics against aggregation is crucial for maintaining their efficacy and safety. This study investigated the synergistic effects of cyclodextrins (CDs) and electrolytes at high concentrations on the stabilization of immunoglobulin G (IgG), insulin, and adeno-associated virus (AAV) vectors. The effects of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) combined with various electrolytes were evaluated using human plasma-derived IgG as a model protein. The HP-β-CD and L(+)-arginine hydrochloride combination synergistically increased the onset temperature of protein aggregation and inhibited the formation of soluble and insoluble aggregates during long-term storage. Notably, this synergistic effect was not observed when sucrose was used instead of HP-β-CD. Similar synergistic effects were observed with insulin and AAV vectors. The findings suggest that the stabilization mechanism could potentially involve enhanced interactions between HP-β-CD and IgG, preventing protein-protein interactions. However, the combination did not synergistically improve the solubility of free aromatic amino acids, including tyrosine and tryptophan. This study highlights the potential of using the combination of CDs and electrolytes as a promising formulation strategy for stabilizing complex protein therapeutics. Further studies are needed to elucidate the underlying mechanisms and generalize the approach to other proteins with varying physicochemical properties.

Antibody-drug conjugates (ADCs) are revolutionizing cancer treatment by specific targeting of the cancer cells thereby improving the therapeutic window of the drugs. Nevertheless, they are not free from unwanted toxicities mainly resulting from non-specific targeting and release of the payload. Therefore, the dosing regimen must be optimized through integrated analysis of the risk-benefit profile, to maximize the therapeutic potential. Exposure-response (E-R) analysis is one of the most widely used tools for risk-benefit assessment and it plays a pivotal role in dose optimization of ADCs. However, compared to conventional E-R analysis, ADCs pose unique challenges since they feature properties of both small molecules and antibodies. In this article, we review the E-R analyses that have formed the key basis of dose justification for each of the 12 ADCs approved in the USA. We discuss the multiple analytes and exposure metrics that can be utilized for such analysis and their relevance for safety and efficacy of the treatment. For the endpoints used for the E-R analysis, we were able to uncover commonalities across different ADCs for both safety and efficacy. Additionally, we discuss dose optimization strategies for ADCs which are now a critical component in clinical development of oncology drugs.

With an increasing number of Biopharmaceutical Classification System (BCS) II/IV pipeline compounds, solubilizing and supersaturating formulation strategies are becoming prevalent. Beyond formulation and solid form strategies, prodrugs are also employed to overcome solubility-limited absorption of poorly water-soluble compounds. Prodrugs can potentially yield supersaturated systems upon conversion to the parent drug intraluminally and thus enhance absorption. However, supersaturation also increases the driving force for crystallization, resulting in low solution concentrations, which can potentially negate the advantage of prodrugs. In this work, two unique solubility-enhancing prodrugs, phosphate and glycine esters, were investigated for a rapidly crystallizing parent drug. Ex vivo absorption studies using rat tissue and in vivo studies in dogs were performed. Conversion rate of the phosphate prodrug to the parent was dependent on the milieu and increased ∼24-fold in the presence of intestinal contents as medium and tissue relative to neat buffer. In contrast, conversion of the glycine prodrug was minimal under any conditions tested, suggesting that the conversion occurs after absorption into the enterocytes. Phosphate prodrug showed a non-linear increase in parent drug absorptive flux across rat intestinal tissue with concentration when intestinal contents were used as donor media. This was attributed to rapid conversion and high supersaturation of the parent drug which subsequently resulted in crystallization at high doses in the donor chamber. Glycine prodrug did not undergo complete conversion at high doses and was absorbed unchanged on the basolateral side, indicating saturation of the converting enzymes in the enterocytes. The combined flux (parent drug and glycine) showed a linear increase with dose and crystallization was not observed. Under physiological conditions, glycine prodrug that is absorbed unchanged from the intestine can potentially undergo complete conversion in hepatocytes after absorption and make the parent drug systemically available. Thus, glycine prodrug provided overall higher absorption compared to phosphate prodrug. The observed flux levels for both the prodrugs were higher compared to the parent drug alone, highlighting an advantage to use of a prodrug strategy to improve absorption of such compounds. Oral dosing in a dog PK study revealed that the bioavailability using the phosphate prodrug was ∼50% whereas, it was ∼100% with glycine prodrug, supporting the in vitro observations.