Search Results (44)

Background: Fixed-dose combinations have advanced in many therapeutic areas, including otorhinolaryngology, where hearing disorders are increasingly prevalent. Objectives: The present study focuses on developing and evaluating a new capsule combining nicergoline (NIC), piracetam (PIR), and hawthorn extract (HE) for the management of sensorineural hearing loss. Methods: The first phase methodology comprised preformulation studies (DSC, FTIR, and PXRD) to assess compatibility among active substances and excipients. Subsequently, four formulations were prepared and tested for flowability, dissolution behavior in acidic and neutral media, and stability under oxidative, thermal, and photolytic stress. Quantification of the active substances and flavonoids was performed using validated spectrophotometric and HPLC-UV methods. Results: Among the tested variants, the F1 formulation (4.5 mg NIC, 200 mg PIR, 50 mg HE, 2.5 mg magnesium stearate, 2.5 mg sodium starch glycolate, and 240.5 mg monohydrate lactose per capsule) displayed optimal technological properties, superior dissolution in acidic media, and was further selected for evaluation. The antioxidant activity of the formulation was confirmed through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, Trolox Equivalent Antioxidant Capacity (TEAC), and iron chelation tests, and was primarily attributed to the flavonoid content of the HE. Acute toxicity tests in mice and rats indicated a high safety margin (LD₅₀ > 2500 mg/kg), while ototoxicity assessments showed no adverse effects on auditory function. Conclusions: The developed formulation displayed good stability, safety, and therapeutic potential, while the applied workflow could represent a model for the development of future fixed-dose combinations. Full article

In recent years, great attention has been paid to second-generation (from agricultural and industrial wastes) lactic acid (LA) production. In the present study, the possibility of two Lactiplantibacillus plantarum strains, namely 53 and 2HS, to produce LA from waste materials was investigated. Distiller’s dried grains with solubles (DDGS), spent coffee grounds (SCG), wood chips, and cheese whey were used as substrates after pretreatment, and the results were compared with those with lactose as a carbon source. Both strains were capable of assimilating sugars from all waste materials. Nearly 20 g/L LA from 23 g/L reducing sugars (RS) obtained from DDGS, 22 g/L LA from 21 g/L RS from SCG, and 22 g/L LA from 21 g/L whey lactose were produced compared to 22 g/L LA obtained from 22 g/L lactose monohydrate in the fermentation broth. The wood chip hydrolysate (WH) contains only 10 g/L RS, and its fermentation resulted in the production of 5 g/L LA. This amount is twice as low as that produced from 11 g/L lactose monohydrate. A mathematical model was constructed based on the Compertz and Luedeking–Piret equations. Full article

Background/Objectives: Hot-melt extrusion (HME) has gained prominence for the manufacture of sustained-release oral dosage forms, yet the application of wax-based matrices and their resilience to alcohol-induced dose dumping (AIDD) remains underexplored. This study aimed to develop and characterise wax-based sustained-release felodipine formulations, with a particular focus on excipient functionality and robustness against AIDD. Methods: Felodipine sustained-release formulations were prepared via HME using Syncrowax HGLC as a thermally processable wax matrix. Microcrystalline cellulose (MCC) and lactose monohydrate were incorporated as functional fillers and processing aids. The influence of wax content and filler type on mechanical properties, wettability, and drug release behaviour was systematically evaluated. Ethanol susceptibility testing was conducted under simulated co-ingestion conditions (4%, 20%, and 40% v/v ethanol) to assess AIDD risk. Results: MCC-containing tablets demonstrated superior sustained-release characteristics over 24 h, showing better wettability and disintegration. In contrast, tablets formulated with lactose monohydrate remained structurally intact during dissolution, overly restricting drug release. This limitation was effectively addressed through granulation, where reduced particle size significantly improved surface accessibility, with 0.5–1 mm granules achieving a satisfactory release profile. Ethanol susceptibility testing revealed divergent behaviours between the two filler systems. Unexpectedly, MCC-containing tablets showed suppressed drug release in ethanolic media, likely resulting from inhibitory effect of ethanol on filler swelling and disintegration. Conversely, formulations containing lactose monohydrate retained their release performance in up to 20% v/v ethanol, with only high concentrations (40% v/v) compromising matrix drug-retaining functionality and leading to remarkably increased drug release. Conclusions: This study highlights the pivotal role of excipient type and constitutional ratios in engineering wax-based sustained-release formulations. It further contributes to the understanding of AIDD risk through in vitro assessment and offers a rational design strategy for robust, alcohol-resistant oral delivery systems for felodipine. Full article

Objectives: This study aimed to evaluate the impact of the different hydration states of magnesium stearate (Mg.st) anhydrate (AH), monohydrate (MH), and dihydrate (DH) on the aerodynamic performance and stability of carrier-based dry powder inhalation (DPI) formulations using arformoterol and budesonide as model drugs. Methods: DPI formulations were prepared using Inhalac 251 lactose and Mg.st in various hydrated forms. The physicochemical properties of Mg.st were characterized using powder X-ray diffraction, differential scanning calorimetry, Fourier-transform infrared spectroscopy, Karl Fischer titration, dynamic vapor absorption, and Raman imaging. The aerodynamic performance was assessed employing a next-generation impactor under initial and accelerated conditions (40 °C, 75% relative humidity). Results: Mg.st-MH exhibited the highest crystallinity and the most stable moisture sorption profile, and showed the smallest particle size within the formulation as observed in the Raman images. Formulations containing Mg.st-MH demonstrated significantly higher fine particle fractions for both arformoterol (51.02 ± 5.16%) and budesonide (61.98 ± 4.09%) compared to formulations with Mg.st-AH or -DH forms. Mg.st-MH also exhibited improved performance retention under accelerated conditions, correlating with its physicochemical stability. Conclusions: The monohydrate form of magnesium stearate was the most effective force control agent, which reduced interparticulate interactions, thereby enhancing the inhalation efficiency and formulation stability. Thus, selecting an appropriate hydration form of Mg.st can improve DPI performance. Full article

Improving the manufacturability of drug formulations via direct compression has been of great interest for the pharmaceutical industry. Selecting excipients plays a vital role in obtaining a high-quality product without the wet granulation processing step. In particular, for diluents which are usually present in a larger amount in a formulation, choosing the correct one is of utmost importance in the production of tablets via any method. In this work, we assessed the possibility of manufacturing a small-molecule drug product, omeprazole, which has been historically manufactured via a multi-step processes such as wet granulation and multiple-unit pellet system (MUPS). For this purpose, four prototypes were developed using several diluents: a co-processed excipient (Microcelac^®), two granulated forms of alpha-lactose monohydrate (Tablettose^® 70 and Tabletose^® 100), and a preparation of microcrystalline cellulose (Avicel^® PH102) and lactose (DuraLac^® H), both of which are common excipients without any enhancement. The tablets were produced using a single punch tablet press and thoroughly characterized physically and chemically in order to assess their functionality and adherence to drug product specifications. The direct compression process was used for the manufacturing of all proposed formulations, and the prototype formulated using Microcelac^® showed the best results and performance during the compression process. In addition, it remained stable over twelve months under 25 °C/60% RH conditions. Full article

Biodegradable polyesters have been researched intensively over the last two decades because of their biodegradability and superb physical properties. However, the use of linear biodegradable polyesters, for the preparation of drug delivery systems (DDS), is hampered by several limitations. In view of this, scientific attention has been shifted to the employment of branched-chain (co-)polymers. In this context, we present herein the development of new melatonin (MLT) tablet formulations, using novel branched polylactide (PLA)-based copolymers of different architectures. Specifically, three PLA-polyol branched polyesters, namely, a three-arm copolymer based on glycerol (PLA-glycerol), a four-arm copolymer based on pentaerythritol (PLA-pentaerythritol), and a six-arm copolymer based on sorbitol (PLA-sorbitol), were utilized. The presence of these polyesters in the formulations was found to be crucial, as the sought MLT release, regarding its use in confronting sleep onset and/or sleep maintenance dysfunctions, was achieved. The copresence of the other excipients in the matrix tablets (lactose monohydrate, hydroxypropylmethylcellulose, microcrystalline cellulose, and sodium alginate) led to a concentration-dependent synergistic effect on the MLT release. To the best of our knowledge, this is the first investigation with these specific polymeric materials, concerning MLT modified release from matrix tablets. Full article

Background/Objectives: Two fibre optic probes were custom designed to perform Raman and near-infrared spectroscopic measurements. Our long-term objective is to develop a non-destructive tool able to collect data in hard-to-access locations for real-time analysis or diagnostic purposes. This study evaluated the quantitative performances of Probe A and Probe B using model pharmaceutical tablets. Methods: Measurements were performed using pharmaceutical tablets containing hydroxyl propylcellulose, titanium dioxide (anatase), lactose monohydrate, and indomethacin (γ form). Material content and thickness of bilayer samples (samples consisting of a top layer and a bottom layer of differing materials) were also assessed using Probe A to evaluate its capabilities to collect sub-surface information. Principal component analysis and partial least squares regression models were using individual and fused data to evaluate the performances of the different probe configurations. Results: Hydroxymethyl cellulose ($R_P^2=0.98$, RMSEP = 2.27% w/w) and lactose monohydrate ($R_P^2=0.97$, RMSEP = 2.96% w/w) content were most effectively estimated by near-infrared spectroscopy data collected using Probe A. Titanium dioxide ($R_P^2=0.99$, RMSEP = 0.21% w/w) content was most effectively estimated using a combination of 785 nm Raman spectroscopy and near-infrared spectroscopy using Probe B. Indomethacin ($R_P^2=0.97$, RMSEP = 1.01% w/w) was best estimated using a low-level fused dataset collected using 0 mm, 2.5 mm, and 5.0 mm lateral offsets of 785 nm spatially offset Raman spectroscopy using Probe A. Conclusions: The different probe configurations were able to reliably collect data and demonstrated robust quantitative performances. These results highlight the advantage of using multiple techniques for analysing different structures. Full article

Background: Olmesartan medoxomil (OLM) is the prodrug of olmesartan, an angiotensin II type 1 receptor blocker that has antihypertensive and antioxidant activities and renal protective properties. It exhibits low water solubility, which leads to poor bioavailability and limits its clinical potential. To improve the solubility of OLM, a host–guest inclusion complex (IC) between heptakis(2,6-di-O-methyl)-β-cyclodextrin (DMβCD) and the drug substance was obtained. Along with active substances, excipients play a crucial role in the quality, safety, and efficacy of pharmaceutical formulations. Therefore, the compatibility of OLM/DMβCD IC with several pharmaceutical excipients was evaluated. Methods: IC was characterized in both solid and liquid states, employing thermoanalytical techniques, universal-attenuated total reflectance Fourier-transform infrared spectroscopy, powder X-ray diffractometry, UV spectroscopy, and saturation solubility studies. Compatibility studies were carried out using thermal and spectroscopic methods to assess potential physical and chemical interactions. Results: The 1:1 OLM:DMβCD stoichiometry ratio and the value of the apparent stability constant were determined by means of the phase solubility method that revealed an A_L-type diagram. The binary system showed different physicochemical characteristics from those of the parent entities, supporting IC formation. The geometry of the IC was thoroughly investigated using molecular modeling. Compatibility studies revealed a lack of interaction between the IC and all studied excipients at ambient conditions and the thermally induced incompatibility of IC with magnesium stearate and α-lactose monohydrate. Conclusions: The results of this study emphasize that OLM/DMβCD IC stands out as a valuable candidate for future research in the development of new pharmaceutical formulations, in which precautions should be considered in choosing magnesium stearate and α-lactose monohydrate as excipients if the manufacture stage requires temperatures above 100 °C. Full article

Background: Spray drying, whilst a popularly employed technique for powder formulations, has limited applications for large-scale proliposome manufacture. Objectives: Thus, the aim of this study was to investigate spray drying parameters, such as inlet temperature (80, 120, 160, and 200 °C), airflow rate (357, 473, and 601 L/h) and pump feed rate (5, 15, and 25%), for individual carbohydrate carriers (trehalose, lactose monohydrate (LMH), and mannitol) for 24 spray-dried (SD) formulations (F1–F24). Methods: Following optimization, the SD parameters were trialed on proliposome formulations based on the same carriers and named as spray-dried proliposome (SDP) formulations. Drug delivery of the formulations was assessed using a dry powder inhaler (DPI) in combination with a next-generation impactor (NGI). Results: Upon analysis, formulations F6 (SD-mannitol), F15 (SD-trehalose), and F20 (SD-LMH) demonstrated high production yields (84.01 ± 3.25, 72.55 ± 5.42, and 70.03 ± 3.39%, respectively), small particle sizes (2.96 ± 1.42, 4.55 ± 0.46, and 5.16 ± 1.32 µm, respectively) and low moisture contents (0.25 ± 0.03, 3.76 ± 0.75, and 1.99 ± 0.77%). These SD optimized parameters were then employed for SDP formulations employing dimyristoly phosphatidylcholine (DMPC) as a phospholipid and beclomethasone dipropionate (BDP) as the model drug. Upon spray drying, SDP-mannitol provided the highest production yield (82.45%) and smallest particle size (2.64 µm), as well as high entrapment efficiency (98%) and a high fine particle dose, fine particle fraction, and respirable fraction (285.81 µg, 56.84%, 86.44%, respectively). Conclusions: The study results are a promising step in the optimization of the large-scale manufacture of proliposome formulations and highlight the versatility of the instrument and variability of formulation properties with respect to the carriers employed for targeting the pulmonary system using dry powder inhalers. Full article

Background/Objectives: Improving the production rates of modern tablet presses places ever greater demands on the performance of excipients. Although co-processing has emerged as a promising solution, there is still a lack of directly compressible excipients for modified-release formulations. The aim of the present study was to address this issue by investigating the potential of novel co-processed excipients for the manufacture of modified-release tablets containing ibuprofen. Methods: The excipients were prepared by melt granulation of lactose monohydrate with glyceryl palmitostearate as a binder. The influence of glyceryl palmitostearate particle size, ibuprofen content, compression pressure, and compression speed on the compaction behavior of the tablet blends was analyzed. Results: Novel co-processed excipients ensured good flowability and acceptable mechanical properties of the tablets containing up to 70% ibuprofen. Furthermore, lipid-based co-processed excipients proved to be very promising for directly compressible formulations with high-dose, highly adhesive active pharmaceutical ingredients such as ibuprofen, as they do not require additional lubricants. The influence of compression speed on the tensile strength of the tablets prepared was not pronounced, indicating the robustness of these directly compressible excipients. The investigated lipid-based excipients enabled a prolonged release of ibuprofen over 10 h. Conclusions: The novel lipid-based co-processed excipients have shown great potential for directly compressible formulations with modified release of high-dose, challenging active pharmaceutical ingredients. Full article

Background/Objectives: Increasing drugs’ stability and adequately protecting them against degradation will ensure a decrease in their price and broader availability of pharmaceutical substances. This is of great importance, especially for drugs used to treat the most common diseases in the population, such as hypertension. The study examined two newly synthesized substances from the angiotensin I-converting enzyme inhibitor (ACEI) group as potential drugs. ACEIs are among the leading drugs used in the treatment of hypertension in the world. The chemical modifications of the tested substances applied concerned the places most susceptible to degradation. The presented work analyzed the compatibility of new derivatives with selected excipients used in pharmacy. Methods: Thermogravimetric (TGA) and differential thermal analyses (c-DTA) were used as the main methods. In addition, non-thermal methods such as colorimetry analysis, Fourier-transform infrared (FTIR) and UV spectroscopy were used. Results: Based on the conducted studies, it can be concluded that the incompatibility of IND-1 with glucose anhydrous and lactose monohydrate occurs only when the mixture is stored at higher temperatures. For the remaining IND-1 and IND-2 mixtures with excipients, compatibility was demonstrated. Conclusions: The obtained results confirmed the usefulness of the applied thermal analyses (TGA and c-DTA) for assessing the compatibility of the tested potential drugs with excipients. However, in the case of incompatibility reactions of substances occurring under the influence of elevated temperatures, such as the Maillard reaction, it is necessary to use non-thermal methods to obtain the right result. Full article

The increasing interest in protein- and peptide-based oral pharmaceuticals has culminated in the first protein-based products for oral delivery becoming commercially available. This study investigates the compaction properties of proteins in binary mixtures with common excipients up to 30% (w/w) of particulate protein. Two model proteins, lysozyme and bovine serum albumin, were compacted with either microcrystalline cellulose, spray-dried lactose monohydrate, or calcium hydrogen phosphate dihydrate at two different compaction pressures. Compared to the compacted pure materials, a significant increase in the tensile strength of the compacts was observed for the binary blends containing lysozyme together with the brittle excipients. This could be attributed to the increased bonding forces between the particles in the blend compared to the pure materials. The use of bovine serum albumin with a larger particle size resulted in a decrease in tensile strength for all the compacts. The change in the tensile strength with an increasing protein content was non-linear for both proteins. This work highlights the importance of considering the particulate properties of protein powders and that protein-based compacts can be designed with similar principles as small-molecules in terms of their mechanical tablet properties. Full article

Sugar phosphorylation has many applications that can be used to develop dairy and food products. During the phosphorylation process, the color of the solution turns into a dark color. The dark color causes many challenges and limitations in using phosphorylation products. The dark color could cause unpleasant color changes in the products, so it is important to remove that color. Activated carbon has been utilized for decades to remove the dark color and improve the appearance of solutions such as sugar syrup and wastewater. This methodology is cheap and environmentally friendly. The objectives of this study were to develop a method to phosphorylate α-lactose monohydrate and milk permeate and to remove the dark color of solutions. The compositional characteristics of the solution, such as pH, total solids, and color parameters (L*—lightness; a*—redness; and b*—yellowness), were examined at different stages (seven stages) of washing the solutions. α-lactose monohydrate and MPP solutions were diluted with distilled water with a ratio of 1:2.2. Activated carbon was mixed with the solutions and left for 5 min at room temperature. Subsequently, the solutions were filtered. These steps were repeated seven times until there was a transparent (colorless) solutions. The experiment was repeated using three different batches of lactose and milk permeate solutions. Both solutions’ pH and total solids decreased with an increase in the number of washings with activated carbon. The International Commission on Illumination (CIE) L*a*b* scale was studied. The L* of the initial solutions was lower than that of the final solutions. However, the a* and b* of the initial solutions were higher than the final solutions. The total color difference (∆E) was calculated for both solutions. ∆E decreased with an increase in the number of washings with activated carbon in both solutions. We conclude that activated carbon can be used to remove the dark color that results from the phosphorylation process. Full article

We designed a bioequivalent tablet form of solifenacin succinate (SOL) with an improved storage stability using a direct compression (DC) technique. An optimal direct compressed tablet (DCT) containing an active substance (10 mg), lactose monohydrate, and silicified microcrystalline cellulose as diluents, crospovidone as a disintegrant, and hydrophilic fumed silica as an anti-coning agent was constructed by evaluating the drug content uniformity, mechanical properties, and in vitro dissolution. The physicochemical and mechanical properties of the DCT were as follows: drug content 100.1 ± 0.7%, disintegration time of 6.7 min, over 95% release within 30 min in dissolution media (pH 1.2, 4.0, 6.8, and distilled water), hardness > 107.8 N, and friability ~0.11%. The SOL-loaded tablet fabricated via DC showed an improved stability at 40 °C and RH 75%, exhibiting markedly reduced degradation products compared to those fabricated using ethanol or water-based wet granulation or a marketed product (Vesicare^®, Astellas Pharma). Moreover, in a bioequivalence study in healthy subjects (n = 24), the optimized DCT offered a pharmacokinetic profile comparable to that of the marketed product, with no statistical differences in the pharmacokinetic parameters. The 90% CIs for the geometric mean ratios of the test to the reference formulation for the area under the curve and the maximum drug concentration in plasma were 0.98–1.05 and 0.98–1.07, respectively, and satisfied the FDA regulatory criteria for bioequivalence. Thus, we conclude that DCT is a beneficial oral dosage form of SOL with an improved chemical stability. Full article

Pantoprazole is a model substance that requires dosage form adjustments to meet the needs of all patients. Pediatric pantoprazole formulations in Serbia are mostly compounded as capsules (divided powders), while in Western Europe liquid formulations are more common. The aim of this work was to examine and compare the characteristics of compounded liquid and solid dosage forms of pantoprazole. Three syrup bases were used: a sugar-free vehicle for oral solution (according to USP43-NF38), a vehicle with glucose and hydroxypropyl cellulose (according to the DAC/NRF2018) and a commercially available SyrSpend Alka base. Lactose monohydrate, microcrystalline cellulose and a commercially available capsule filler (excipient II, composition: pregelatinized corn starch, magnesium stearate, micronized silicon dioxide, micronized talc) were used as diluents in the capsule formulations. Pantoprazole concentration was determined by the usage of the HPLC method. Pharmaceutical technological procedures and microbiological stability measurements were performed according to the recommendations of the EP10. Although dose appropriate compounding with pantoprazole is suitable using both liquid vehicles as well as solid formulations, chemical stability is enhanced in solid formulation. Nevertheless, according to our results, if liquid formulation is a pH adjusted syrup, it could be safely kept in a refrigerator for up to 4 weeks. Additionally, liquid formulations could be readily applied, while solid formulation should be mixed with appropriate vehicles with higher pH values. Full article