Pharmaceutical Development and Technology最新文献

Despite a marked decrease in HIV/AIDS-related mortality, HIV remains one of the leading causes of death in specific populations. Despite concerted efforts to find a cure for HIV, to date, none exists. Current antiretroviral therapy inhibits replication of the virus without completely eradicating it. The successful inhibition of viral replication is only achieved using a combination of antiretrovirals, which inhibit viral replication at different stages of the HIV lifecycle. Efavirenz (EFV), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) is one combination used for HIV management. The development of a novel fixed-dose microemulsion formulation of EFV, FTC, and TDF was undertaken. Microemulsions (ME) were manufactured using phase titration and drug loading, particle size, transparency, Zeta potential, and pH were determined. Transmission Electron Microscopy was used to visualize the microemulsion. In vitro release testing was used to evaluate active pharmaceutical ingredient release behavior. The optimized ME had an average Zeta potential of 33.8 mV and droplet size of 117 nm, determined using Dynamic Light Scattering and confirmed using Transmission Electron Microscopy. Powder X-ray diffraction and Differential Scanning Calorimetry analysis revealed the presence of a molecular dispersion of drugs. These findings demonstrate the potential value of using ME as a fixed-dose combination technology for the delivery of EFV, FTC, and TDF.

Combination therapy with chemotherapy and phytochemical drugs is a promising cancer treatment method. In this study, noisome with Tween 20, span 40 and cholesterol in 80:20 ration was prepared for co-delivery of piperine (PIP) and doxorubicin (DOX) (Nio-DOX/PIP) using thin-layer hydration method. Niosomes indicated spherical structure, average size 653 ± 3.25 nm and a zeta potential of ∼-15.88 mV with an encapsulation efficiency of 84.15% and 67.50% for DOX and PIP, respectively. Release of DOX (69.25%) and PIP (35.10%) after 24 h from niosomal dispersion is less than free solution that indicate release of drug in a sustained way from niosomes. Combination index and isobologram analysis using CompuSyn software indicated that combination of DOX and PIP at IC₅₀ concentration generated synergism anticancer effect (CI value <0.9). Nio-DOX/PIP (IC₅₀: 0.14/14 µM) exhibited greater inhibitory effect on viability of MCF-7 cells in comparison with free drugs (IC₅₀: 0.67/67 µM). Expression analysis using Real time PCR showed that Nio-DOX/PIP reduces expression of CD133 and ABCB (33-fold), CD44 (10-fold), ALDH1: (5.8-fold) and NANOG and SOX2 (more than 90%) significantly more than free DOX. In conclusion, results showed that PIP can potentiate cytotoxicity of DOX and niosomes are suitable carriers for encapsulation of PIP and DOX.

Chronic inflammatory conditions, such as psoriasis, require effective therapeutic strategies to manage both local and systemic inflammation. This study aimed to develop a thermosensitive hydrogel (Gel) based on Pluronic F127 and F68, incorporating NLC (Gel-NLC) loaded with anti-inflammatory phytochemicals, such as curcuminoids, resveratrol, and/or piperine, for the topical treatment of psoriasis. Phytochemicals-loaded NLC presented encapsulation efficiency > 90%, particle size values between 39-49 nm, and polydispersity indices <0.211. Compared to curcuminoids and resveratrol from NLC and Gel-NLC, piperine alone or in combination with other phytochemicals showed superior release and transdermal flux both in vitro and ex vivo. Simultaneous encapsulation of resveratrol and piperine significantly decreased the permeation of the former, while an increase in the permeation of piperine was observed when combined with curcuminoids or resveratrol. Confocal microscopy analysis revealed that curcuminoids displayed the highest retention in the skin when encapsulated in NLC as a single agent, followed by resveratrol and piperine. These variations can be attributed to their physicochemical properties. The developed formulations are presented as effective delivery systems that can enhance the availability of these phytochemicals, thereby increasing their anti-inflammatory potential in the treatment of psoriasis.

This work looked to determine if a rationally designed amorphous nanoparticle formulation of Grazoprevir (GZP) could provide a benefit over its amorphous dispersion formulation by either enabling superior bioperformance or accessing higher drug loadings. GZP-ethylcellulose nanoparticles were created at two different drug loadings (33 and 66%) by high-pressure homogenization. The GZP-ethylcellulose nanoparticles could rapidly release the drug, but neither system could match the extent of release of the amorphous dispersion. This limited extent of release led to the GZP-ethylcellulose nanoparticle formulations failing to present equivalent performance as the amorphous solid dispersion formulation in dog PK studies. Two GZP- HPMCAS-L nanoparticle formulations (50/50 GZP/HPMCAS-L and 45/45/10 GZP/HPMCAS-L/SLS) were made by a coprecipitation process followed by spray drying. These materials were analyzed and found to be composed of nanoparticles of pure amorphous drug which is stabilized by the excipients. This was confirmed by characterization techniques such as ultracentrifugation and FIB-SEM. Bio-relevant dissolution experiments demonstrated that both formulations could match the extent of drug release of the GZP amorphous dispersion formulation, but only the 45/45/10 GZP/HPMCAS-L/SLS could match the rate of release of the amorphous dispersion. The 45/45/10 GZP/HPMCAS-L/SLS nanoparticle formulation and the amorphous dispersion formulation were evaluated in a dog PK study, with the 45/45/10 GZP/HPMCAS-L/SLS formulation provided equivalent PK. These results highlight the potential benefit of directly designed nanoparticle formulations to maximize formulation bioperformance at higher drug loadings or to enable smaller dosage forms.

Fluvoxamine maleate is efficient in treatment of depression and obsessive-compulsive disorder. However, it has several side effects which are believed to be minimized by administration of slow-release formulation. This work introduces geriatric friendly rapidly disintegrating sustained release (RDSR) tablets for fluvoxamine intraoral administration. Fluvoxamine was subjected to wet co-processing with increasing weight ratios of Eudragit S100 in presence and absence of avicel. Fluvoxamine release was monitored using continuous pH variation strategy using USP II dissolution apparatus. Formulations exhibiting acceptable sustained release pattern were subjected to different investigations. Optimized systems were fabricated as RDSR tablets. Optimized systems were also assessed in vivo using forced swimming test using albino rats. Incorporation of avicel in the co-processed formulations showed faster release with avicel-free systems sustaining fluvoxamine release. Optimum formulations contained fluvoxamine and Eudragit at weight ratios of 4:12 (F2), 4:15 (F4) and 4:16 (F6) liberated the drug with release efficiency of 61.65, 41.76 and 34.5%, respectively. Thermal analysis and XRD reflected dispersion of fluvoxamine in amorphous form in Eudragit with no significant chemical interaction being reflected from FTIR. The developed RDSR tablets showed acceptable sustained release. In vivo studies reflected the superiority of sustained release systems compared to unprocessed fluvoxamine. The study developed RDSR tablets for sustained delivery of fluvoxamine.

This study aimed to develop in situ gel formulations containing vanillic acid to enhance patient compliance and accelerate wound healing. Vanillic acid-loaded in situ gels were prepared, and their physicochemical properties were evaluated through in vitro release and ex vivo permeation studies. Additionally, antioxidant capacity, cytotoxicity, wound healing, prostaglandin E2 levels, IL-6 inhibition, and skin irritation tests were conducted. The optimized IN3-VA formulation exhibited a gelling temperature of 32.394 ± 0.842, a pH value of 4.780 ± 0.010 and a viscosity of 2473.33 ± 11.54 cP. It demonstrated specific mechanical properties, including hardness of 27.94 ± 1.30 g and adhesiveness of -97.00 ± 14.60 g.mm. The IN15-VA formulation showed improved parameters, with a hardness of 38.84 ± 3.33 g, adhesiveness of -126.35 ± 22.78 g.mm, pH value of 4.870 ± 0.010, viscosity of 3853.33 ± 30.55 cP, and a gelling temperature of 31.854 ± 0.345. Both formulations demonstrated sustained release behavior, releasing 60% of the medication in vitro over 6 h with no cytotoxic effects. They also decreased copper ion reduction and the release of nitric oxide, with cellular proliferation rates of 63% for IN3-VA and 73% for IN15-VA. Moreover, IN15-VA significantly reduced prostaglandin E2 levels, controlled IL-6 increase, and exhibited non-irritating properties. The results suggest that these vanillic acid-loaded in situ gels hold promising potential in wound treatment due to their sustained release over 48 h.

This study presents the development of salicylate polyacrylic copolymer gel systems incorporating mumio particulates as a bioactive agent for the topical treatment of rheumatoid arthritis. Using an experimental design, formulations were optimized based on mumio, salicylic acid, and polyacrylate copolymer ratios. Rheological behavior was assessed through frequency, temperature, and time sweep tests to evaluate shear response, stability, and application suitability. Spectral and morphological analyses confirmed the uniformity and surface characteristics of the gels. Antimicrobial activity was tested against Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger. Cytotoxicity was evaluated using NIH-3T3 mouse fibroblast cells. Results showed over 60% microbial inhibition after 24 hours and maintained cell viability above 70% at both 24 and 48 hours, indicating good biocompatibility. The gels also exhibited smooth texture, consistent bioactive dispersion, and non-irritating properties. Overall, these findings support the potential of mumio-loaded salicylate-polyacrylic gels as stable, biocompatible, and effective topical therapeutics for rheumatoid arthritis.

The dual solubility enhancement effect of nanofiber technology and pH-sensitive Eudragit L100-55 and S100 on class IV Cefditoren pivoxil (CEF) was studied. Nanofibers of different drug-polymer ratios were prepared. In-vitro characterization of CEF-loaded nanofibrous systems was performed through scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and in-vitro drug release. SEM showed that the nanofiber prepared using S100 is thicker than that prepared using L100-55 without entrapping any drug crystals in the polymer matrix. DSC scan proved the drug was entrapped in its molecular state due to the disappearance of the drug's crystallinity. The drug release profile indicated that all nanofiber formulations exhibited a considerably higher dissolution rate than free drug in the following order ED L100-55 > ED S100 > pure drug. Drug permeability enhancement was studied by using the modified non-everted sac technique. The drug permeability agrees in the same order as the drug release profile. Histology of the intestinal segment after 90 min showed the appearance of nanoparticles in the cytoplasm of the enterocytes, indicating that the drug absorption mechanism is mainly transcellular. Histology of the intestinal segment at the end of the experiment showed a highly significant increase in the mean length of the intercellular space of EL100-55 (p < 0.001), indicating drug enhancement via the paracellular pathway.

This study aimed to prepare paclitaxel nanocrystals (PTX-NCs) for developing a delivery platform for this poorly water-soluble drug. Using biocompatible polymers as stabilizers, paclitaxel (PTX) was formulated as a nanosuspension using two techniques: (I) ultrasonication followed by freeze-drying and (II) melt-based precipitation (MBP) approach. The effectiveness of stabilizers in inhibiting crystal growth and agglomeration of PTX-NCs was discussed. Nanosuspensions developed using the MBP method by employing polyethylene glycol (PEG) derivatives offered superior results compared to the ultrasonication method. Among the various stabilizers, Pluronic F-68 and myrj 52 were more efficient against particle size enlargement. The optimized formulation containing PTX/PEG/Pluronic F-68/myrj 52 produced re-dispersible particles of about 74 nm with a smooth spherical morphology, which were stable for ∼8 h in water, indicating good physical stability following reconstitution. The particles obtained after redispersion of MBP-PTX-NCs enhanced the dissolution of PTX compared to plain crystals and had superior chemical stability. A 6-month stability test showed no significant changes in drug content or X-ray powder diffraction (XRPD) pattern. These findings highlighted the potential of forming fine particles from MBP method using biocompatible polymers as a promising method for producing drug nanocrystals (NCs) for poorly soluble drugs without expensive, time-consuming freeze-drying steps.

The treatment of hypertrophic scars is constrained by inefficient transdermal delivery and challenges in co-delivery of multiple drugs. Although tanshinone IIA and salvianolic acid B exhibit multi-target antifibrotic potential, their divergent physicochemical properties limit combined application. This study proposes a novel transdermal system integrating co-loaded liposomes with dissolving microneedles (DMNs). TSA-SAB liposomes were prepared via thin-film dispersion with pH gradient method, optimized using Box-Behnken design to overcome traditional single-factor limitations. High-efficiency co-loading was achieved for lipophilic TSA (encapsulation efficiency: 86.10%) and hydrophilic SAB (98.43%). Integration with centrifugally cast microneedles yielded loadings of 216.01 μg/patch (TSA) and 371.65 μg/patch (SAB). Leveraging microneedle-mediated penetration and liposomal sustained release, the system showed 3-fold higher transdermal efficiency than free drugs, establishing a dermal reservoir. In vitro release followed Higuchi model (24 h: 68.33% TSA, 76.33% SAB) without burst release. Integrating nanocarriers with microneedles, this study provides a strategy to address multi-drug incompatibility and transdermal barriers, laying groundwork for HS therapy translation.