Formulation and evaluation of inhaled Sildenafil-loaded PLGA microparticles for treatment of pulmonary arterial hypertension (PAH): A novel high drug loaded formulation and scalable process via hot melt extrusion technology (Part â ).

In recent years, several techniques were employed to develop a local sustained pulmonary delivery of sildenafil citrate (SC) as an alternative for the intravenous and oral treatment of pulmonary arterial hypertension (PAH). Most of these methods, however, need to be improved due to limitations of scalability, low yield production, low drug loading, and stability issues. In this study, we report the use of hot-melt extrusion (HME) as a scalable process for making Poly (lactic-co-glycolic acid) (PLGA) microparticles with high SC load. The prepared particles were tested in vitro for local drug delivery to the lungs by inhalation. Sodium bicarbonate was included as a porogen in the formulation to make the particles more brittle and to impart favorable aerodynamic properties. Six formulations were prepared with different formulation compositions. Laser diffraction analysis was used to estimate the geometric particle size distribution of the microparticles. In-vitro aerodynamic performance was evaluated by the next-generation cascade impactor (NGI). It was reported in terms of an emitted dose (ED), an emitted fraction (EF%), a respirable fraction (RF%), a fine particle fraction (FPF%), a mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD). The formulations have also been characterized for surface morphology, entrapment efficiency, drug load, and in-vitro drug release. The results demonstrated that PLGA microparticles have a mean geometric particle size between 6 and 14 µm, entrapment efficiency of 77 to 89 %, and SC load between 17 and 33 % w/w. Fifteen percent of entrapped sildenafil was released over 24 h from the PLGA microparticles, and seventy percent over 7 days. The aerodynamic properties included fine particle fraction ranging between 19 and 33 % and an average mass median aerodynamic diameter of 6-13 µm.

Investigation of hot melt extrusion process parameters on solubility and tabletability of atorvastatin calcium in presence of Neusilin® US2.

Reports in the literature indicate that hot-melt extrusion (HME) processing techniques could alter the mechanical properties of the pharmaceutical physical blend, which may alter successful processing during tableting. The aim of this study was to evaluate whether HME processing conditions have an impact on the tabletability of Atorvastatin calcium trihydrate (ATR) in the presence of Neusilin® US2 (NUS2). ATR drug load of 25% was mixed with 75% of NUS2 and extruded using two screw configurations, screw speeds, and feed rates. Solid-state thermal analysis showed that ATR transformed to an amorphous form which led to improved solubility. ATR tabletability was affected positively by screw configuration that had no shearing and mixing force. SEM analysis indicated that a conveying screw configuration preserved the spherical nature of NUS2, thus improving ATR tabletability. This novel study demonstrates the significance of changing and monitoring the HME process parameters, which impact the materials' mechanical properties and may prevent adverse outcomes during tableting.

Development of Subdermal Implants Using Direct Powder Extrusion 3D Printing and Hot-Melt Extrusion Technologies.

Implants are drug delivery platforms that consist of a drug-polymer matrix with the ability of providing a localized and efficient controlled release of the drug with minimal side effects and achievement of the desired therapeutic outcomes with low drug loadings. Direct powder extrusion (DPE) 3D printing technology involves the extrusion of material through a nozzle of the printer in the form of pellets or powder. The present study aimed at investigating the use of the CELLINK BIO X™ bioprinter using DPE 3D printing technique to fabricate and evaluate the impact of different shapes (cuboid, cylinder, and tube) of raloxifene hydrochloride (RFH)-loaded subdermal implants on the release of RFH from the implants. This study further evaluated the impact of different processing techniques, viz., hot-melt extrusion (HME) technology vs. DPE 3D printing technique, on the release of RFH from the implants fabricated by each processing technique. All the fabricated implants were characterized by XRD, DSC, SEM, and FTIR, and evaluated for their water uptake, mass loss, and in vitro RFH release. The current study successfully demonstrated a great opportunity of controlling and/or tuning the release of RFH from the subdermal implants by altering the implant shape, and hence surface area, and could be a great contribution and/or addition to the personalization of medicines and improvement of patient compliance.

Development and Characterization of Different Dosage Forms of Nifedipine/Indomethacin Fixed-Dose Combinations.

Studies have shown that 40 individuals out of 100,000 are diagnosed with rheumatoid arthritis (RA) yearly, with a total of 1.3 million in the United States. Furthermore, the impact of RA in some cases can extend to cardiovascular diseases (CVD), as the studies showed that 84% of RA patients are at risk of developing hypertension. This study aims to design and develop different dosage forms (capsule-in-capsule and three-dimensional (3D) printed tablet) of nifedipine/indomethacin fixed-dose combination (FDC). The hot-melt extrusion (HME) was utilized alone and with fused deposition modeling (FDM) techniques The developed dosage forms were intended to provide delayed-extended and immediate release profiles for indomethacin and nifedipine, respectively. FDC dosage forms were successfully developed and characterized. Nifedipine formulations showed significant improvement in release profiles, having 94% of the drug release at 30 minutes compared with pure nifedipine, which had a percent release of 2%. Furthermore, the release of indomethacin was successfully delayed at a pH of 1.2 and extended at a pH of 6.8. Differential scanning calorimetry results showed endothermic crystalline peaks at 165 °C and 176 °C for indomethacin and nifedipine, respectively. Moreover, the thermal analysis of all formulations showed the absence of the endothermic peaks indicating complete solubilization of indomethacin and nifedipine in the polymeric carriers. All formulations had post-processing drug content in the range of 95% to 98%. Moreover, results from the stability study showed that all formulations were able to remain chemically and physically stable with no signs of recrystallization or degradation. The designed FDC dosage forms could improve the quality of life by enhancing patient compliance and preventing the need for polypharmacy.

Disulfiram 3D printed film produced via hot-melt extrusion techniques as a potential anticervical cancer candidate.

Cervical cancer is known globally as one of the most common health problems in women. Indeed, one of the most convenient approaches for its treatment is an appropriate bioadhesive vaginal film. This approach provides a local treatment modality, which inevitably decreases dosing frequency and improves patient compliance. Recently, disulfiram (DSF) has been investigated and demonstrated to possess anticervical cancer activity; therefore, it is employed in this work. The current study aimed to produce a novel, personalized three-dimensional (3D) printed DSF extended-release film using the hot-melt extrusion (HME) and 3D printing technologies. The optimization of the formulation composition and the HME and 3D printing processing temperatures was an important factor for overcoming the DSF heat-sensitivity issue. In addition, the 3D printing speed was specifically the most crucial parameter for alleviating heat-sensitivity concerns, which led to the production of films (F1 and F2) with an acceptable DSF content and good mechanical properties. The bioadhesion film study using sheep cervical tissue indicated a reasonable adhesive peak force (N) of 0.24 ± 0.08 for F1 and 0.40 ± 0.09 for F2, while the work of adhesion (N.mm) for F1 and F2 was 0.28 ± 0.14 and 0.54 ± 0.14, respectively. Moreover, the cumulative in vitro release data indicated that the printed films released DSF for up to 24 h. HME-coupled 3D printing successfully produced a patient-centric and personalized DSF extended-release vaginal film with a reduced dose and longer dosing interval.

Hot-Melt extrusion coupled with pressurized carbon dioxide for enhanced processability of pharmaceutical polymers and drug delivery applications - An integrated review.

Hot-melt extrusion (HME) technology is one of the primary approaches that has been implemented in recent years to overcome poor drug solubility/dissolution issues through the development of solid dispersion systems. Carbon dioxide (CO2) either in supercritical (SupC) or subcritical (SubC) forms has been introduced to HME as a temporary plasticizer, reducing the operating temperature and eventually processing heat-sensitive molecules more efficiently. In this paper, a comprehensive review of CO2-HME processes focused on pharmaceutical polymers and applications is presented. The steps and requirements for the setup of experimental devices are demonstrated, with a detailed influence of CO2 characteristics on HME processes. The most relevant physical and chemical properties of pharmaceutical grade polymers subjected to the CO2- HME process are described. The basic knowledge and main mechanisms of HME process parameters in conjunction with CO2 concentration with regard to process feasibility and final product formation are discussed. HME coupled with CO2 is extensively reviewed to provide a complete understanding of how to optimize the process parameters and conditions to reach optimized characteristics of final outcomes, as well as the sequential relationship between those outcomes (foaming → porosity → milling → tableting). Pharmaceutical applications of CO2-based HME are presented in detailed case studies, including extrusion feasibility, solubility, dissolution rate enhancement, and gastroretentive or floating drug delivery. Finally, the current status of general CO2-based techniques, as well as future perspectives and opportunities for promising applications through the integration of CO2 with HME is presented.

Fabrication of a shell-core fixed-dose combination tablet using fused deposition modeling 3D printing.

Fixed-dose combinations (FDCs) achieve optimal goals for treatment with minimal side effects, decreased administration of large number of tablets, thus, greater convenience, and improved patient compliance. However, conventional FDCs do not have a guaranteed place in the future of patient-centered drug development because of the difficulty in achieving dose titration of each drug for individualized specific health needs and desired therapeutic outcomes. In the current study, FDCs of two antihypertensive drugs were fabricated with two distinct compartments using fused deposition modeling three-dimensional printing (FDM-3DP). Atorvastatin calcium and Amlodipine besylate loaded filaments were prepared by hot-melt extrusion. Shell-core FDC tablets were designed to have different infills for individualized dosing. Differential scanning calorimetry and powder X-ray diffraction revealed that both drugs were transformed into amorphous forms within the polymeric carriers. The fabricated tablets met the United States Pharmacopeia acceptance criteria for friability, content uniformity, and dissolution testing. The fabricated tablets were stable at room temperature with respect to drug content and thermal behavior over six months. This dynamic dosage form provides flexibility in dose titration and maintains the advantages of FDCs, thus achieving optimal therapeutic outcomes in different healthcare facilities.

Development and evaluation of raloxifene hydrochloride-loaded subdermal implants using hot-melt extrusion technology.

Implantable drug delivery systems are known to provide great patient compliance and allow for controlled delivery of drugs over a prolonged period of time. This study aimed to prepare novel polycaprolactone/polyethylene glycol-based raloxifene hydrochloride subdermal solid cylindrical implants using a single-step hot-melt extrusion (HME) continuous process, for the provision of a sustained and prolonged release of RX-HCl as a cornerstone and alternative treatment and prevention option of osteoporosis, most especially post-menopausal osteoporosis, and invasive breast cancer, while providing better clinical outcomes by circumventing clinical and biopharmaceutical hurdles like first-pass metabolism and patient non-adherence and incompliance associated with the oral dosage forms of raloxifene hydrochloride. The 11-mm co-rotating twin-screw extruder was used to prepare the implants. The prepared cylindrical-shaped solid implants with dimensions of 10 mm (length) by 2 mm (diameter) were characterized by DSC, PXRD, FTIR, SEM, and in vitro dissolution analysis. Based on the physicochemical characterization of the prepared implants, the HME fabrication technology and optimized process parameters were determined to be acceptable and suitable. The prepared implants showed no obvious burst release and no significant amounts of drug on the surface of the implants. F-1, F-2, and F-3 implant batches showed a maximum cumulative percent drug release of 82.9%, 42.2%, and 20.6%, respectively, in a period of 30 days, and 100% drug release would be expected in a period of about 40 days (F-1), 72 days (F-2), and up to 150 days (F-3) by simple extrapolation. Interestingly, implant batches with a low drug load exhibited a relatively faster and higher rate of release of the drug compared to implant batches with high drug loading. In the present study, a single-step HME process was successfully used to fabricate RX-HCl-loaded subdermal implants, that could potentially be used as a cornerstone regimen in the treatment and prevention of osteoporosis, most especially post-menopausal osteoporosis, by providing release of RX-HCl over a long time period, and avoiding the clinical inconveniences and possible patient incompliance caused by daily administration of the drug.

Hot-melt extruded hydroxypropyl methylcellulose acetate succinate based amorphous solid dispersions: Impact of polymeric combinations on supersaturation kinetics and dissolution performance.

Nucleation inhibition and maintenance of drug supersaturation over a prolonged period are desirable for improving oral absorption of amorphous solid dispersions. The present study investigates the impact of binary and ternary amorphous solid dispersions on the supersaturation kinetics of nifedipine using the polymers hydroxypropylmethylcellulose acetate succinate (HPMCAS) LG, and HG, Eudragit® RSPO, Eudragit® FS100, Kollidon® VA64 and Plasdone™ K-29/32. The amorphous solubility, nucleation induction time, and particle size analysis of nifedipine in a supersaturated solution were performed with and without the presence of polymers, alone or in combination. The HPMCAS-HG and HPMCAS-HG + LG combinations showed the highest nifedipine amorphous solubility of 169.47, 149.151 µg/mL, respectively and delay in nucleation induction time up to 120 min compared to other polymeric combinations. The solid dispersions prepared via hot melt extrusion showed the transformation of crystalline nifedipine to amorphous form. The in-vitro non-sink dissolution study revealed that although the binary nifedipine/HPMCAS-LG system had shown the greater supersaturation concentration of 66.1 µg/mL but could not maintain a supersaturation level up to 360 min. A synergistic effect emerged for ternary nifedipine/HPMCAS-LG/HPMCAS-HG, and nifedipine/HPMCAS-LG/Eudragit®FS100 systems maintained the supersaturation level with enhanced dissolution performance, demonstrating the potential of polymeric combinations for improved amorphous solid dispersion performance.

Effect of pH Modifiers on the Solubility, Dissolution Rate, and Stability of Telmisartan Solid Dispersions Produced by Hot-melt Extrusion Technology.

The aim of the current study was to investigate the dual effect of an amorphous solid dispersion generated by hot melt extrusion and the addition of pH modifiers on the solubility and stability of telmisartan. Hydroxypropyl methylcellulose acetate succinate L grade was used as a polymeric carrier and recrystallization inhibitor, and meglumine, sodium carbonate, or Neusilin S2 were incorporated as pH modifiers to generate a desirable microenvironmental pH in the solid dispersions. Differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared spectroscopy were incorporated to obtain the solid-state characterizations of telmisartan, and the results confirm a partial transformation of telmisartan to an amorphous state. An in vitro release study revealed that the transformation of telmisartan to an amorphous material improved its dissolution rate by 2-fold compared to pure drug and by up to 5-fold with the incorporation of pH modifiers. Results of the stability studies demonstrated that the samples have no significant degradation under accelerated stability conditions at 40 °C/75% RH.

CONTINUOUS PRODUCTION OF RALOXIFENE HYDROCHLORIDE LOADED NANOSTRUCTURED LIPID CARRIERS USING HOT-MELT EXTRUSION TECHNOLOGY.

The aim of this study was to utilize a continuous process for the production of orally administered raloxifene hydrochloride (RX-HCl) loaded nanostructured lipid carrier (NLC) formulations for extended drug release using hot-melt extrusion (HME) technology coupled with probe sonication, and also to evaluate the in vitro characteristics of the prepared NLCs. Preparation of the NLCs using HME technology involved two main steps, first formation of a pre-emulsion after extrusion and then size reduction of the pre-emulsion using probe sonication to obtain the NLCs. A screw speed of 100 rpm and a barrel temperature of 85 °C, were used in the extrusion process. NLCs prepared by HME technology showed a lower particle size compared to those prepared by the conventional probe sonication method. The prepared NLCs had high entrapment efficiency values (>90 %). In vitro drug release was evaluated using dialysis bag diffusion technique and USP apparatus I. Overall, the RX-HCl loaded NLCs had a higher rate of drug release than the pure drug. The release profile for the F4-3 NLC formulations and pure drug at the beginning and end of the stability study were comparable. The particle size of the prepared NLCs remained stable over the storage period and all PDI and zeta potential values were ≤ 0.5 and in the range of -15 to -30 mV, respectively, indicating good physical stability of the formulations. In summary, HME technology and probe sonication were successfully used to prepare RX-HCl loaded NLC formulations with shorter processing times as compared to the conventional probe sonication method, which makes this technique a uniquely more industry-friendly method.

Multicomponent crystalline solid forms of aripiprazole produced via hot melt extrusion techniques: An exploratory study.

Multicomponent crystalline solid forms (salts, cocrystals and eutectics) are a promising means of enhancing the dissolution behavior of poorly soluble drugs. The present study demonstrates the development of multicomponent solid forms of aripiprazole (ARP) prepared with succinic acid (SA) and nicotinamide (NA) as coformers using the hot melt extrusion (HME) technique. The HME-processed samples were characterized and analyzed using differential scanning calorimetry (DSC), hot stage microscopy (HSM), Fourier transform infrared (FTIR) spectroscopy, powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). The DSC and HSM analyses revealed a characteristic single melting temperature in the solid forms, which differed from the melting points of the individual components. The discernible changes in the FTIR (amide C=O stretching) and PXRD results for ARP-SA confirm the formation of new crystalline solid forms. In the case of ARP-NA, these changes were less prominent, without the appearance or disappearance of peaks, suggesting no change in the crystal lattice. The SEM images demonstrated morphological differences between the HME-processed samples and the individual parent components. The in vitro dissolution and microenvironment pH measurement studies revealed that ARP-SA showed a higher dissolution rate, which could be due to the acidic microenvironment pH imparted by the coformer. The observations of the present study demonstrate the applicability of the HME technique for the development of ARP multicomponent solid forms.

Formulation development of itraconazole PEGylated nano-lipid carriers for pulmonary aspergillosis using hot-melt extrusion technology.

Pulmonary delivery is a promising alternative for the oral treatment of pulmonary aspergillosis. This study aimed to develop continuous and scalable itraconazole PEGylated nano-lipid carriers (ITZ-PEG-NLC) for inhalation delivery. The feasibility of preparing NLCs utilizing hot-melt extrusion (HME) coupled with probe sonication was investigated. The process parameters for HME and sonication were varied to optimize the formulation. ITZ-PEG-NLC (particle size, 101.20 ± 1.69 nm; polydispersity index, 0.26 ± 0.01) was successfully formulated. The drug entrapment efficiency of ITZ-PEG-NLC was 97.28 ± 0.50%. Transmission electron microscopy was used to characterize the shape of the particles. The developed formulations were evaluated for their aerodynamic properties for pulmonary delivery. The lung deposition of ITZ-PEG-NLC was determined using an Anderson Cascade Impactor and Philips Respironics Sami the Seal Nebulizer Compressor. In vitro cytotoxicity studies were performed using A549 cells. A burst-release pattern was observed in ITZ-PEG-NLC with a drug release of 41.74 ± 1.49% in 60 min. The in vitro aerosolization of the ITZ-PEG-NLC formulation showed a mass median aerodynamic diameter of 3.51 ± 0.28 µm and a geometric standard deviation of 2.44 ± 0.49. These findings indicate that HME technology could be used for the production of continuous scalable ITZ-PEG-NLC.

Theophylline-nicotinamide pharmaceutical co-crystals generated using hot melt extrusion technology: Impact of polymeric carriers on processability.

The objective of the current study was to develop theophylline (TPH) nicotinamide (NAM) pharmaceutical co-crystals using the hot melt extrusion (HME) technology and evaluate the processability of the co-crystals using different polymeric carriers. A physical mixture of 1:1 M ratio of TPH and NAM was employed to prepare the co-crystals. Hydroxypropylmethylcellulose acetate succinate, polyethylene oxide, and Kollidon® VA-64 (5% w/w) were investigated as polymeric carriers for the HME process. Solid-state characterization using differential scanning calorimetry showed two endothermal peaks, one at 126.4 °C indicating eutectic formation and another at 174 °C indicating the melting point of the co-crystal for all formulations, except the Kollidon® VA-64 extrudates, which showed a single peak at 174 °C. Fourier-transform infrared spectroscopy and powder X-ray diffraction studies revealed the formation of co-crystals. The feasibility to formulate the extrudates into solid dosage forms was assessed by formulating a tablet blend. The three-month stability studies showed no degradation at the accelerated stability conditions of 40 (±2) ° C and 75 (±5) % RH. Finally, the results demonstrated that the presence of mixing zones in screw configuration and extrusion temperature are critical processing parameters that influence co-crystal formation.

Processability of AquaSolve™ LG polymer by hot-melt extrusion: Effects of pressurized CO2 on physicomechanical properties and API stability.

The objective of this study was to investigate the processability of AquaSolve™ hydroxypropyl methylcellulose acetate succinate L grade (HPMCAS LG) via hot-melt extrusion and to examine the effect of pressurized carbon dioxide (P-CO2) on the physicomechanical properties of efavirenz (EFA)-loaded extrudates. To optimize the process parameters and formulations, various physical mixtures of EFA (30%, 40%, and 50%, w/w) and HPMCAS LG (70%, 60%, and 50%, w/w), respectively, were extruded using a co-rotating twin-screw extruder with a standard screw configuration, with P-CO2 injected into zone 8 of the extruder. Thermal characterization of the extrudates was performed using differential scanning calorimetry and thermogravimetric analysis. Scanning electron microscopy was employed to study the morphology and porosity of the formulations. Notably, the macroscopic morphology changed to a foam-like structure by P-CO2 injection resulting in an increased specific surface area, porosity, and dissolution rate. Thus, HPMCAS LG extrusion, coupled with P-CO2 injection, yielded faster dissolving extrudates. Stability studies indicated that HPMCAS LG was able to physically and chemically stabilize the amorphous state of high-dose EFA. Furthermore, the milling efficiency of the extrudates produced with P-CO2 injection improved because of their increased porosity.

Stability of Organoleptic Agents in Pharmaceuticals and Cosmetics.

Organoleptic agents constitute an important niche in the field of pharmaceutical excipients. These agents encompass a range of additives responsible for coloring, flavoring, sweetening, and texturing formulations. All these agents have come to play a significant role in pharmaceuticals and cosmetics due to their ability to increase patient compliance by elevating a formulation's elegance and esthetics. However, it is essential to review their physical and chemical attributes before use, as organoleptic agents, similar to active pharmaceutical ingredients (APIs), are susceptible to physical and chemical instability leading to degradation. These instabilities can be triggered by API-organoleptic agent interaction, exposure to light, air and oxygen, and changes in pH and temperature. These organoleptic agent instabilities are of serious concern as they affect API and formulation stability, leading to API degradation or the potential for manifestation of toxicity. Hence, it is extremely critical to evaluate and review the physicochemical properties of organoleptic agents before their use in pharmaceuticals and cosmetics. This literature review discusses commonly used organoleptic agents in pharmaceutical and cosmeceutical formulations, their associated instabilities, and probable approaches to overcoming them.