AAPS PharmSciTech最新文献

In pharmaceutical manufacturing, equipment is often used for multiple products following a single standard cleaning process regardless of the previously manufactured product. Despite this, residue levels are frequently non-detectable. Regulatory guidelines, such as the EMA Q&A on HBELs, mandate cleaning and visual inspection after each use, with analytical testing required after product changeovers unless otherwise justified. Consequently, cleaning validation (CV) data is typically left-censored, limited in sample size, and subject to multiple upper specification limits (USLs). These realities limit the applicability of traditional parametric capability indices and reduce the robustness of nonparametric methods. Moreover, they hinder the effective use of historical CV data in AI applications, which depend on large, standardized datasets for model training. To address these challenges, we propose a USL-normalization method that standardizes all residue measurements to a unified USL_Pct = 100. This transformation enables the aggregation of USL-heterogeneous datasets and supports robust nonparametric analysis. The cleaning process CQA (critical quality attribute) level upper capability index Ppu is calculated using the KDEDPonUSLND algorithm (kernel density estimation derived percentiles on USL-normalized data), which demonstrates improved robustness compared to traditional approaches. The cleaning process level Ppu is evaluated using either CQAWWC (CQA-wise worst case) or CQAWP (CQA-wise pooling) strategies, both integrated with the KDEDPonUSLND algorithm. The resulting CQAWWC_BAKEDPonUSLND and CQAWP_BAKEDPonUSLND models support an AI-driven CV Stage 3 Continued Cleaning Process Verification/Monitoring system, aligned with regulatory expectations.

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Although FDM is one of the prominent 3D printing technologies, and it has been widely investigated in pharmaceutical sciences, the printability of filaments remains a challenge. Therefore, our primary objective was to evaluate the effect of PEG 400, PEG 4000 and triethyl citrate at different concentrations (10%, 15% and 20% w/w) on the printability behavior of hydrocortisone-loaded Eudragit RS filaments. In this study, physical mixtures and their filaments were produced using a hot melt extruder and the properties of the filaments were examined by DSC, XRD, FESEM, FTIR, MFI and mechanical tests. Release behavior and hardness properties of the 3D-printed tablets were also evaluated. DSC and XRD results showed that the drug converted from crystalline to amorphous during hot melt extrusion and remained so during the 3D printing. FTIR results showed no chemical interactions between the drug and other excipients during hot melt extrusion and 3D printing. FESEM results of filaments showed that triethyl citrate-containing filaments had rougher surfaces, which makes them more suitable for 3D printing, while PEG-contained filaments had smoother surfaces. Mechanical tests showed that filaments containing triethyl citrate were stronger and tougher and had moderate ductility and stiffness. Overall, these filaments showed a good balance between these mechanical characteristics, which makes them a suitable candidate for 3D printing. Release studies showed that regardless of plasticizer type, the concentration of the plasticizer determines the extent of drug release. MFI test showed that formulations containing TEC presented a melt flow closer to 30 g/10 min compared to other formulations. Therefore, it can be deduced that TEC improves printability by enhancing melt flow better than the other two plasticizers (PEG 400 and PEG 4000). Based on the results, it can be concluded that triethyl citrate in 15% concentration is the best plasticizer for the production of hydrocortisone-loaded Eudragit RS tablets.

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High shear wet granulation (HSWG) is a conventional and widely used pharmaceutical drug product manufacturing process. Proper process control of the HSWG is crucial for ensuring the quality of granulation and, consequently, the final drug product. To demonstrate the adequacy of a proposed HSWG commercial process, the control of critical process parameters should be well established based on sufficient development data and scientific rationale. At the U.S. Food and Drug Administration (FDA), during the Chemistry, Manufacturing and Controls (CMC) assessment of original drug applications, deficiencies related to manufacturing process controls have been often found to be one of the causes of extended application review time or cycle numbers. In this paper, we have analyzed deficiencies from the manufacturing assessment of applications from 2017 to 2022 in which HSWG was used to produce oral solid dosage form drug products. The results revealed that the most frequently occurring deficiencies in the control of the HSWG process are related to lack of controls for granulation end point, granulation fluid level, granulation fluid addition rate, wet massing time, and process scale up strategy. This paper discusses the impact of these deficiencies on HSWG and final drug product quality along with recommendations for improvement of process controls.

Psoriasis is a chronic inflammatory skin condition characterized by the hyperproliferation of keratinocytes that results in erythematous and scaly plaques on the epidermal surface. Conventional therapeutic approaches exhibit drawbacks such as inadequate skin penetration, low drug bioavailability, and undesirable side effects. Nanoformulations emerge as a novel strategy to enhance drug delivery for treating psoriatic lesions with modified cyclodextrins (CDs), offering significant potential to improve their efficacy in the field of medicine. Cyclodextrins are well-known as versatile excipients that improve solubility, dissolution rate, chemical stability, and bioavailability through the formation of inclusion complexes. Furthermore, the chemical modifications of cyclodextrins such as sulfation, methylation, and hydroxypropylation have further enhanced their utility in topical formulations. Modified cyclodextrins enhance the delivery of anti-psoriatic agents such as TNF-α or IL-17 inhibitors and target key inflammatory pathways in psoriasis while reducing systemic exposure and minimizing side effects like immunosuppression, infections, and gastrointestinal disturbances. Additionally, modified cyclodextrins help to repair the epidermal barrier by increasing the efficacy of anti-inflammatory and keratinocyte-modulating medications. This article highlights the capabilities of modified cyclodextrins for revolutionizing the transformation of more effective and targeted therapies for psoriasis by identifying the limitations of current therapies and exploring the innovative applications of modified cyclodextrins in nanoformulations.

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The principal of generic product development is to match the critical quality attributes. Most of the time during complex product development, life cycle management; biowaiver, pre- and post-change approvals the significant efforts are made by scientist to match the drug release profile. In order to get the vivo bioequivalence testing waived based on in vitro performance of drug product; the dissolution testing is mostly act as a surrogate or performance indicator. Hence, assessment of similarity or equivalence of release profile is most critical aspect with respect to regulatory decision making. Available guideline defines the methodologies and acceptance criteria for same based on data structure e.g., application of mathematical and statistical model like similarity factor (F2), bootstrapped F2, model independent and model dependent approach etc. However, during regulatory review lot of discrepancies usually raise by regulators with respect to similarity demonstration like selection of proper methodology, define suitable acceptance criteria in case of high variability. Current article emphases on the visions behind regulatory expectations, with respect to dissolution profile comparison and highlights the prerequisites and answer the common question like how to choose the correct methodology, what are the limitations, way forward and regulatory expectations and alternative methodologies in order to evaluate the dissolution data statistically to make wise decision on in vitro equivalence. Overall, various approaches are available for dissolution similarity analysis. However, the intension of statistical comparability should be like; neither force the dissimilar product to pass the criteria, nor fail the product which are similar. This comprehensive review will enhance the overall understanding and help the formulation and biopharmaceutics scientists; how to ensure regulatory compliance during similarity evaluation.

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Bioactive compounds in green coffee beans, such as caffeine (CF) and cafestol (CA), possess potential pharmaceutical benefits, including antioxidant and anti-inflammatory properties, but face challenges in skin penetration. This study developed a novel liposomal system combining CF and CA for the first time, formulated with either Lipoid S 75 or Phospholipon® 90 G and cholesterol (80:20 ratio), aiming to enhance skin penetration of CF and CA by encapsulating them into liposomes dermal application. Formulations with 1% CF and either 0.13% or 0.07% CA were developed and tested for skin permeation utilizing Franz diffusion cells with human cadaver skin. Receptor compartment samples were collected at 2, 4, 8, 12, and 24 h and the amount of CF penetrated (µg/cm²) was quantified using a validated HPLC method. The skin distribution in dermal and epidermal layers of both compounds were also assessed. Results showed that formulation F9 (1% CF, 0.13% CA) significantly improved skin penetration, doubling CF levels in the dermis and increasing CA levels by 5.5-fold in the dermis and 35-fold in the epidermis, despite lower CF permeability compared to the control. F9 also demonstrated high encapsulation efficiency and confirmed safety in cytotoxicity studies. These findings suggest that liposomal formulations of combining CF and CA are promising for topical applications and merit further clinical investigation.

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The work aims to improve the solubility and dissolution rate of the cardiovascular drug carvedilol (CVD) of II class BCS by a co-crystallization approach. The slurry method was used to preparation of CVD cocrystals. The existence of new solid phases was confirmed by PXRD, DSC, TGA, FTIR and UV–vis spectroscopy. The dissolution kinetics of two component systems in a model buffer solution was studied by the classical shake flask method. The process of CVD release from co-crystals tablets were studied in accordance with Pharmacopoeia standard using a dissolution tester. Pharmaceutical cocrystals of CVD with two coformers, 2-hydroxybenzamide (2OHBZA) and 4-hydroxybenzamide (4OHBZA) in molar ratio 1:1, have been obtained for the first time. Thermodynamic characteristics of the cocrystallization reaction of the active pharmaceutical ingredient with the selected coformers have been experimentally determined for the synthesized CVD/2OHBZA and CVD/4OHBZA cocrystals. It has been shown that the process of cocrystal formation is enthalpy-determined, which is typical for most two-component crystals. Kinetic solubility profiles of new solid phases have been determined in a buffer solution pH 7.4, simulating the pH of blood plasma. It was found that the equilibrium solubility of co-crystal forms of carvedilol significantly exceeds the solubility of original drug. In vitro study of the release of CVD from co-crystal tablets showed a improving of the drug release rate into solution to 67% for CVD/2OHBZA and 43% for CVD/4OHBZA, that by 2.6 and 1.7 times higher then the raw drug. Considering the significant enhancement of carvedilol solubility in two-component systems and their stability in aqueous medium, co-crystallization is a promising approach for the development of new dosage forms of this drug with improved bioavailability.

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The current study aims to develop a polymer hybrid scaffold functionalized with Eudragit nanoparticles, having an inherent effect on bone tissue regeneration. Thiolated sodium alginate (TSA) was combined with β-cyclodextrin (β-CD) and polyethylene glycol (PEG) as the interlinking polymer to design the hydrogel scaffold. The freeze–thaw technique was followed to develop the scaffold, and the scaffold was functionalized with Eudragit nanoparticles during freeze-thawing. The Eudragit nanoparticle was characterized by SEM, AFM, and DLS. The prepared nanoparticle-embedded polymeric scaffold was characterized by FTIR, XRD, gel fraction, swelling, water vapor transmission, SEM, and optical profilometry. The polymeric interlinking in the scaffold during the freeze-thawing method was confirmed by FTIR and XRD analysis. The developed scaffold showed swelling degree within a limit of 0.140 ± 0.100 to 0.195 ± 0.100 within 8 h, and gel fraction ranged from 36.67 ± 2.12% and 44.40 ± 2.06%. The surface smoothness and porous structure of the hydrogel scaffold were confirmed by optical profilometry. In vitro, cell line study indicated no toxicity, and molecular docking studies exhibited optimum binding energy with target proteins bone morphogenetic protein-2 and Integrin αvβ3, suggesting potential bone tissue engineering applications of the developed scaffolds.

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Fluconazole (FCZ) is an antifungal drug of the triazole class and is widely used in the treatment of systemic and superficial fungal infections. However, resistance development is high in triazoles. Zinc undecylenate (ZU), on the other hand, has fungistatic properties and inhibits Candida albicans biofilm formation. This study aimed to develop a new compound that would utilize the sequential pharmacodynamic effects of FCZ and ZU to overcome FCZ resistance, eliminate biofilm formation, and reduce infection recurrence. Solid Lipid Nanoparticle-Fluconazole (SLNP-FCZ) suspension was prepared, and the surface of ZU powders was coated using low-pressure radio frequency plasma-chemical vapor deposition (LPRFP-CVD). The resulting SLNP-FCZ-ZU composition was characterized by nuclear magnetic resonance (NMR), optical emission spectroscopy (OES), scanning electron microscopy (SEM), zeta potential, and particle size analyses. Statistical evaluations compared the difference between the ZU and coated form using correlation. A significant difference was observed in the correlation analysis (p < 0.001), and the effect size was found to be high (d = 1.03). The antifungal efficacy of SLNP-FCZ-coated ZU preparations was supported by their sequential mechanism of action. The results obtained demonstrate that the LPRFP technique can combine pharmacotherapeutic agents into a single pharmaceutical preparation. The combination of SLNP-FCZ and ZU can shorten the treatment time and improve patient well-being in persistent Candida infections by reducing resistance and biofilm formation. This approach can be considered an innovative strategy in antifungal therapies.

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