Traditional Formulation Research Articles

Biomimetic platelet-like nanoparticles enhance targeted hepatocellular carcinoma therapy

Curcumin (CUR) is a promising natural product for hepatocellular carcinoma (HCC) therapy. However, its clinical application has been limited by some issues such as rapid clearance and inadequate tumor accumulation. To address these drawbacks, we developed platelet membrane-coated CUR-loaded PLGA nanoparticles (PCPNPs). In this work, due to the bioinspired strategy, the PCPNPs exhibited immune evasion, prolonged circulation, and improved accumulation at tumor sites compared to the traditional CUR formulation. The superior tumor targeting of PCPNPs was likely due to the interactions between platelet P-selectin and tumoral CD44. Furthermore, both in vitro and in vivo assays revealed that the PCPNPs showed outstanding anticancer efficacy without obvious toxicity. Therefore, PCPNPs represent a biosafe and promising anti-tumor strategy, overcoming the limitations associated with CUR. These findings not only contribute to the advancement of natural compound nano-formulation but also open new avenues for targeted cancer treatment.

A novel and efficient Hamiltonian dynamic analysis approach for constraint force determination in flexible multibody systems

In the dynamic analysis of flexible multibody systems, Hamiltonian formulations offer advantages in numerical stabilization and systematic handling of systems with varying mass. However, current approaches face challenges. Differential algebraic equations (DAEs) can directly express constraint forces but are computationally inefficient, while ordinary differential equations (ODEs) are more computationally efficient but cannot directly represent constraint forces due to the elimination of the Lagrange multiplier. This paper presents an innovative and efficient dynamic analysis approach based on the Hamiltonian formulation, incorporating velocity transformation and open-constraint coordinate methods. Compared to conventional DAE-based Hamiltonian formulations, our approach conducts analysis efficiently using only independent variables. Compared to conventional ODE-based Hamiltonian formulations, our approach effectively expresses constraint forces through Lagrange multiplier reformulation. Furthermore, when compared to the traditional ODE-based Lagrangian formulation, our approach exhibits superior computational efficiency. Numerical simulations assess our proposed formulation, showing agreement with conventional formulations, shorter calculation time, and alignment with analytical results, confirming the accuracy and usefulness of our approach.

Sildenafil and furosemide nanoparticles as a novel pharmacological treatment for acute renal failure in rats

Hospitalized patients often develop acute renal failure (ARF), which causes severe morbidity and death. This research investigates the potential renoprotective benefits of sildenafil and furosemide in glycerol-induced ARF, and measures kidney function metrics in response to nanoparticle versions of these medications. Inducing ARF is commonly done by injecting 50% glycerol intramuscularly. Rats underwent a 24-h period of dehydration and starvation before slaughter for renal function testing. We investigated urine analysis, markers of oxidative stress, histology of kidney tissue, immunohistochemistry analysis of caspase-3 and interleukin-1 beta (IL-1 β), kidney injury molecule-1 (KIM-1), and neutrophil gelatinase–associated lipocalin (NGAL), which are specific indicators of kidney tissue damage. The results of our study showed that the combination of sildenafil and furosemide, using both traditional and nanoparticle formulations, had a greater protective effect on the kidneys compared to using either drug alone. The recovery of renal tissue indicators, serum markers, and urine markers, which are indicative of organ damage, provides evidence of improvement. This was also indicated by the reduction in KIM-1 and NGAL tubular expression. The immunohistochemistry tests showed that the combination therapy, especially with the nanoforms, greatly improved the damaged cellular changes in the kidneys, as shown by higher levels of caspase-3 and IL-1β. According to the findings, a glycerol-induced rat model demonstrates that sildenafil and furosemide, either alone or in combination, in conventional or nanoparticulate forms, improve ARF dysfunction. The synergistic nanoparticulate compositions show remarkable effectiveness. This observation highlights the possible therapeutic implications for ARF treatment.

Localization of Intramuscular mRNA Delivery Using Deep Eutectic-Lipid Nanocomposites.

Messenger ribonucleic acid (mRNA) has long been touted as a next-generation therapeutic modality for infectious disease, cancer, and genetic disorders. Lipid nanoparticles (LNPs) provide an elegant delivery strategy for mRNA cargo to help realize this potential for vaccination. However, systemic exposure seen with traditional LNP formulations can have significant implications on efficacy and safety. Efforts to mitigate this have largely been focused on laborious lipid or LNP redesign. Here, the use of a deep eutectic-lipid nanocomposite delivery system for the tuning of mRNA expression for intramuscular injections in vivo is reported. One deep eutectic, cholinium malonate, allows for the linear control of percent expression at the muscular injection site based solely on its concentration in the formulation. The same deep eutectic solvent (DES) can increase local muscle expression by 68% and significantly decrease off-target liver expression by 72%. Physico-chemical studies suggest that the DES incorporates into or onto the pre-formed LNPs thus impacting endosomal escape and in situ interactions. These nanocomposites provide new possibilities for previously approved LNP formulations and without the need for lipid redesign to induce localized expression.

In vitro analysis of electrospun nanofibrous polycaprolactone loaded with Rhamnus prinoides leaf extract as potential wound dressing

AbstractRhamnus prinoides, an indigenous Ethiopian traditional medicinal plant, has been used for treating various ailments including skin conditions in traditional formulations. In this study, plant leaf extract has been incorporated into polycaprolactone (PCL) nanofibers through electrospinning at concentrations of 1%, 3%, 5%, 7% wt/vol for the first time. The presence of extract in the nanofiber was analyzed using Fourier transform infrared. The in vitro antibacterial activity, release, contact angle, thermal, and mechanical properties of the nano mats were characterized. The scanning electron microscopy (SEM) analysis revealed that the produced mats are continuous, smooth, bead‐less, and inter connected. The examination of SEM images using ImageJ revealed that the fiber diameter ranged from 219 ± 47 nm to 284 ± 114 nm. The mats showed excellent anti‐bactericidal activity against both Staphylococcus aureus and Escherichia coli. During the 72‐h in vitro release investigation, an initial burst release was observed within the first 12 h, followed by sustained release of the extract over long period of time. The contact angle analysis showed, addition of leaf extract to the PCL nanofiber increased hydrophilicity. Furthermore, the nanofiber membranes had favorable mechanical properties. Overall, these findings suggested that R. prinoides leaf extract‐functionalized PCL nanofibers could be effective wound dressings with broad‐spectrum antimicrobial activity.

A Modern Approach to HEAs: From Structure to Properties and Potential Applications

High-entropy alloys (HEAs) are advanced materials characterized by their unique and complex compositions. Characterized by a mixture of five or more elements in roughly equal atomic ratios, these alloys diverge from traditional alloy formulations that typically focus on one or two principal elements. This innovation has paved the way for subsequent studies that have expanded our understanding of HEAs, highlighting the role of high mixing entropy in stabilizing fewer phases than expected by traditional phase prediction methods like Gibbs’s rule. In this review article, we trace the evolution of HEAs, discussing their synthesis, stability, and the influence of crystallographic structures on their properties. Additionally, we highlight the strength–ductility trade-off in HEAs and explore strategies to overcome this challenge. Moreover, we examine the diverse applications of HEAs in extreme conditions and their promise for future advancements in materials science.

Novel nano-in-micro fabrication technique of diclofenac nanoparticles loaded microneedle patches for localised and systemic drug delivery

Diclofenac, a nonsteroidal anti-inflammatory drug, is commonly prescribed for managing osteoarthritis, rheumatoid arthritis, and post-surgical pain. However, oral administration of diclofenac often leads to adverse effects. This study introduces an innovative nano-in-micro approach to create diclofenac nanoparticle-loaded microneedle patches aimed at localised, sustained pain relief, circumventing the drawbacks of oral delivery. The nanoparticles were produced via wet-milling, achieving an average size of 200 nm, and then incorporated into microneedle patches. These patches showed improved skin penetration in ex vivo tests using Franz-cell setups compared to traditional diclofenac formulations. In vivo tests on rats revealed that the nanoparticle-loaded microneedle patches allowed for quick drug uptake and prolonged release, maintaining drug levels in tissues for up to 72 h. With a systemic bioavailability of 57 %, these patches prove to be an effective means of transdermal drug delivery. This study highlights the potential of this novel microneedle delivery system in enhancing the treatment of chronic pain with reduced systemic side effects.

Efficacy of Shenglin decoction in preventing acute severe lymphocytopenia in patients with non-small cell lung cancer undergoing concurrent chemoradiotherapy: a study protocol for a randomized controlled trial.

Definitive concurrent chemoradiotherapy (CCRT) followed by maintenance therapy with immune checkpoint inhibitors offers the best chance of cure for patients with stage III non-small cell lung cancer (NSCLC). A significant challenge in this regimen is the occurrence of acute severe lymphopenia (ASL), which can compromise treatment efficacy. Currently, there are no effective strategies for preventing and treating ASL. Shenglin decoction (SLD), a traditional Chinese herbal medicine formulation, has demonstrated preliminary efficacy in mitigating ASL. However, robust evidence from clinical trials and a clear understanding of its mechanism of action are still needed. This study aims to comprehensively assess the efficacy, safety, and underlying mechanisms of SLD in the prevention of ASL. This prospective, dual-center, open-label, randomized controlled trial will enroll 140 stage III NSCLC patients. Participants will be randomly allocated in a 1:1 ratio to a control group or an experimental group. Both groups will undergo definitive CCRT. Alongside the commencement of CCRT, the experimental group will receive an additional oral SLD intervention for a duration of three months. The primary outcome is the incidence rate of ASL, defined as the proportion of patients who experience at least one instance of a total lymphocyte count falling below 0.5 × 10^9 cells/L within 3 months of initiating CCRT treatment. Additionally, 16S rRNA gene sequencing analysis of fecal samples to assess gut microbiota, as well as metabolomic analysis of fecal/blood samples, will be conducted to explore potential mechanisms. This study protocol aims to rigorously evaluate the efficacy and safety of SLD, as well as elucidate its mechanism of action in preventing ASL. Successful outcomes could establish SLD as an evidence-based intervention for ASL prevention in NSCLC patients undergoing CCRT. The trial was registered at the Chinese Clinical Trials Registry (ChiCTR2300071788, https://www.chictr.org.cn/).

Harnessing the Power of Traditional Organic Formulations for Crop Growth and Microbial Harmony

Harnessing the Power of Traditional Organic Formulations for Crop Growth and Microbial Harmony

Pharmaceutical Preparation of Amrita Guggulu and its Clinical Efficacy on Vatarakta

This study scrabbles about into the pharmaceutical preparation of Amrita Guggulu, a traditional Ayurvedic formulation known for its therapeutic properties. The focus of the research is on assessing the clinical efficacy of Amrita Guggulu in managing Vatarakta, a condition characterized by vitiated Vata as well as Pitta and associated with inflammatory joint disorders. The pharmaceutical preparation involves meticulous formulation techniques, ensuring the quality and potency of the final product. Standardization parameters include the selection of authentic raw materials, adherence to traditional preparation methods and quality control measures. Clinical Trial Design: The clinical trial was designed as a randomized, double-blind study to assess the efficacy of Amrita Guggulu in patients diagnosed with Vatarakta. Participants were randomly assigned to either the treatment group receiving Amrita Guggulu group A or group B. A comprehensive clinical trial was conducted to evaluate the efficacy of Amrita Guggulu in patients diagnosed with Vatarakta. Key parameters such as joint pain, inflammation in joint, tenderness, burning sensation in affected area, skin rashes and tingling sensation were selected for the study. Overall improvement was assessed using standardized tools and patient-reported outcomes. Result: Preliminary findings indicate promising results, suggesting that Amrita Guggulu may play a significant role in alleviating symptoms associated with Vatarakta. The observed effects include a reduction in joint pain, improved joint function, and decreased inflammatory markers. Conclusion: This research contributes valuable insights into the pharmaceutical preparation of Amrita Guggulu and highlights its potential as an effective intervention for Vatarakta. On the basis of this clinical trial, we can say that S. Uric acid is not the confirmatory parameter for the decision of Vatarakta (gout). Further studies and long-term observations are recommended to solidify these findings and establish Amrita Guggulu as a viable therapeutic option in managing inflammatory joint disorders.

A randomized double-blind active-controlled clinical trial on the efficacy of topical basil (Ocimum basilicum) oil in knee osteoarthritis.

Basil is a widely used herb in Persian medicine and is gaining recognition as a functional food worldwide. This trial aimed to assess the effectiveness of a traditional formulation of basil oil in comparison with diclofenac gel in treating knee osteoarthritis, considering its established anti-inflammatory, anti-nociceptive, and anti-oxidative properties. One hundred eligible patients were equally randomized to the traditional basil oil (containing sesame oil) and diclofenac gel groups. They used their respective topical treatments thrice daily for 4weeks. Various measurements were taken at the beginning of the study, 2, and 4 weeks after starting the intervention, including the 8-m walk test, knee pain (based on visual analog scale), flexion angle of the knee joint, analgesic consumption, and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire. No significant differences were observed between the basil oil and diclofenac gel groups in any of the measured outcomes. However, significant improvements were noted within each group for most variables. Topical application of the traditional formulation of basil oil appears to improve clinical symptoms and certain functional indicators of knee osteoarthritis to a similar extent as diclofenac gel. This suggests that basil oil could be considered an effective management option for this condition. Clinical Trial Registration: https://irct.behdasht.gov.ir/, identifier IRCT2017081711341N7.

Functional gradation of material coefficients and size –effects in heat conduction: Numerical simulations

It is well known that the classical theory of heat conduction is scale invariant. On the other hand, it is experimentally evident that size-dependent effects are observable in small samples of micro/nano-scale dimensions. Incorporation of higher-order gradients of primary field variables into constitutive relationships yields a qualitative explanation of size-effects. Form the mathematical point of view, the governing equations are given by the partial differential equations (PDE) with higher-order derivatives in higher-grade continuum theories. As compared with classical theory of continua, the other complication of governing equations occurs in case of continuous media with functional gradation of material coefficients, when the problem is described by the PDE with variable coefficients. The traditional weak formulations are considered in global sense, hence the whole analysed domain/boundary is to be discretized into finite size elements. On the other hand, the strong formulations bring better computational efficiency because of elimination of integrations, but the price which should be paid is the need to approximate higher order derivatives of field variables. One of the most criticized shortcoming of the finite element (FE) approximation is its limited continuity on element intersections. The C0 continuity is insufficient for calculation of gradients of field variables on element intersections as well as for numerical solution of problems with governing equations of higher than 2nd order partial differential equations (PDE). Recently widely spread and elaborated mesh-free approximations utilize the higher order continuous shape functions. Another advantage is elimination of discretization of the analysed domain into finite elements, since only the nodes are scattered on the domain and its boundary. Both the strong and weak formulations are applicable in combination with mesh-free approximations. The Moving Finite Element Approximation (MFEA) and its utilization in mesh-free formulations for heat conduction problems is presented in this paper.

Synergy of botanical drug extracts from Dracaena cochinchinensis stemwood and Ardisia elliptica fruit in multifunctional effects on neuroprotection and anti-inflammation.

Combination therapy is one of the promising approaches in developing therapeutics to cure complex diseases, such as Alzheimer's disease (AD). In Thai traditional medicines, the clinical application often comprises multiple botanical drugs as a formulation. The synergistic interactions between botanical drugs in combination therapies are proposed to have several advantages, including increased therapeutic efficacy, and decreased toxicity and/or adverse effects. This study aimed to explore the therapeutic functions of a botanical hybrid preparation (BHP) of two botanical drugs within a traditional multi-herbal formulation. The synergistic actions of BHP of Dracaena cochinchinensis stemwood (DCS) and Ardisia elliptica fruit (AEF) at a specific ratio of 1:9 w/w were illustrated in neuroprotection and anti-inflammation. In cultured PC12 cells, BHP of DCS and AEF showed synergistic functions in inducing neuronal differentiation, characterized by neurofilament expression and neurite outgrowth. In addition, BHP of DCS and AEF exhibited a synergistic effect in inhibiting the aggregation of Aβ, a hallmark of AD pathology. The activated BV2 microglial cells induced by LPS were synergistically suppressed by the BHP of DCS and AEF, as evaluated by the expression of pro-inflammatory markers, including TNF-α, IL-1β, and iNOS, as well as the morphological change of microglial cells. The findings suggested that the effects of BHP of DCS and AEF were greater than individual botanical drugs in a specific ratio of 1:9 w/w to enhance neuroprotective and anti-inflammatory functions.

Considering traditional Chinese medicine as adjunct therapy in the management of chronic constipation by regulating intestinal flora.

Chronic constipation is one of the most common gastrointestinal disorders worldwide. Due to changes in diet, lifestyle, and the aging population, the incidence of chronic constipation has increased year by year. It has had an impact on daily life and poses a considerable economic burden. Nowadays, many patients with chronic constipation try to seek help from complementary and alternative therapies, and traditional Chinese medicine (TCM) is often their choice. The intestinal flora play an important role in the pathogenesis of constipation by affecting the body's metabolism, secretion, and immunity. Regulating the intestinal flora and optimizing its composition might become an important prevention and treatment for chronic constipation. TCM has unique advantages in regulating the imbalance of intestinal flora, and its curative effect is precise. Therefore, we reviewed the relationship between intestinal flora and chronic constipation as well as advances in research on TCM as adjunct therapy in the management of chronic constipation by regulating intestinal flora. Some single Chinese herbs and their active ingredients (e.g., Rheum palmatum, Radix Astragalus, and Cistanche deserticola), some traditional herbal formulations (e.g., Jichuan decoction, Zengye decoction, and Zhizhu decoction) and some Chinese patent medicines (e.g., Maren pills and Shouhui Tongbian capsules) that are commonly used to treat chronic constipation by regulating intestinal flora are highlighted and summarized. Moreover, some external forms of TCM, and especially acupuncture, have also been found to improve intestinal movement and alleviate constipation symptoms by regulating intestinal flora. We hope this review can contribute to an understanding of TCM as an adjunct therapy for chronic constipation and that it can provide useful information for the development of more effective constipation therapies.

Influence of non-traditional raw materials on rheological parameters of dough and quality of bakery products

Relevance. At the same time, a prerequisite for a successful product on the market is its high organoleptic properties at a fairly low-price policy. As one of such approaches can be proposed the use of non-traditional plant raw ingredients (whole-milled flour from sprouted grain, β-glucan, pectin, etc.), which will allow to form high-quality food products of functional orientation.Methods. The objects of the study were defined as model mixtures of wheat flour baking flour of the highest grade and non-traditional raw materials, as well as samples of bakery products (sliced loaf) obtained according to the traditional (control) and experimental formulation. The rheological characteristics of the dough were determined by alveograph and farinograph. The quality of the finished bakery products was assessed on a 40-point scale, as well as the control of the specific volume and humidity of the products.Results. The studies showed that the introduction of β-glucan has a minimal effect on the elasticity of the dough, there is a decrease in the values of the quality index of farinograph on average by 17 - 22%. The dough elasticity decreases with the introduction of pectin more than 2 times, the values of quality indicator of farinograph increase, and the best result is characterized by the introduction of pectin in the amount of 2%, the maximum dough stability to kneading and minimum values of dough liquefaction degree are observed. Control and experimental samples of bakery products had high enough total values of organoleptic evaluation. The specific volume of experimental products increased by an average of 12% when beta-glucan was added in an amount of 0.1%, and by 8% when pectin was added in an amount of 4% relative to control samples. The obtained results confirmed the possibility and expediency of using non-traditional raw materials in the formulation of bakery products.

Mechanism of the components compatibility of Scutellariae Radix and Coptidis Rhizoma on mice with hyperlipidemia by regulating the Cyp4a family

Ethnopharmacological relevanceScutellaria baicalensis Georgi (Scutellariae Radix, SR) and Coptis chinensis Franch (Coptidis Rhizoma, CR) is a classic herbal pair used in many Traditional Chinese Medicine formulations in the treatment of hyperlipidemia (HLP). As effective ingredients of the drug pair, the effects and mechanisms of berberine and baicalin in the treatment of HLP in the form of components compatibility are still unclear. Aim of the studyTo explore the mechanism of the components compatibility of SR and CR in the treatment of HLP. Materials and methodsThe HLP model was established by a high-fat diet. Serum biochemical indexes were detected. Transcriptomics and metabolomics were detected. RT-PCR and Western Blot were used to analyze the effect of RA on the expression of the Cyp4a family during the treatment of HLP. ResultsBerberine-baicalin (RA) has a good effect in the treatment of HLP. RA can significantly reduce the body weight and liver weight of HLP, reduce the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL-C), and increase the level of high-density lipoprotein (HDL-C). Through transcriptomic analysis, RA significantly reversed the gene expression of Cyp4a10, Cyp4a12 b, Cyp4a31, and Cyp4a32 in cytochrome P450 family 4 subfamily a (Cyp4a) which related to fatty acid degradation in the liver of HLP mice. The results of fatty acid detection showed that RA could significantly regulate heptanoic acid, EPA, adrenic acid, DH-γ-linolenic acid, and DPA in the cecum of HLP mice. The Cyp4a family genes regulated by RA are closely related to a variety of fatty acids regulated by RA. RT-PCR confirmed that RA could regulate Cyp4a mRNA expression in HLP mice. WB also showed that RA can regulate the protein expression level of Cyp4a. ConclusionThe components compatibility of SR and CR can effectively improve the blood lipid level of HLP mice, its mechanism may be related to regulating Cyp4a gene expression and affecting fatty acid degradation, regulating the level of fatty acid metabolism in the body.

Machine learning-based fatigue life prediction of lamellar titanium alloys: A microstructural perspective

Fatigue life prediction based on the traditional empirical formulation in large fatigue regimes is limited and prone to over-fitting. In this regard, we propose an integrated approach for fatigue life prediction of lamellar titanium alloys incorporating crystal plasticity simulations and a variety of machine learning methods from a microstructural perspective. Firstly, various defect shapes and distinct lamellar distributions are employed to characterize fatigue performance under different microstructural features. By utilizing fatigue indicator parameters (FIPs) to get an expanded dataset, this work employs algorithms including artificial neural networks (ANN), random forests regression (RFR), support vector regression (SVR), and particularly convolutional neural networks (CNN) to predict fatigue life. The results indicate that CNN outperforms the previously mentioned algorithms in prediction accuracy, due to its ability to directly extract microstructural features from images. Our proposed approach provides a microstructural perspective for fatigue life prediction of lamellar titanium alloys, broadening the way for life assessment of materials with diverse microstructures.

Liposome-Hydrogel Composites for Controlled Drug Delivery Applications.

Various controlled delivery systems (CDSs) have been developed to overcome the shortcomings of traditional drug formulations (tablets, capsules, syrups, ointments, etc.). Among innovative CDSs, hydrogels and liposomes have shown great promise for clinical applications thanks to their cost-effectiveness, well-known chemistry and synthetic feasibility, biodegradability, biocompatibility and responsiveness to external stimuli. To date, several liposomal- and hydrogel-based products have been approved to treat cancer, as well as fungal and viral infections, hence the integration of liposomes into hydrogels has attracted increasing attention because of the benefit from both of them into a single platform, resulting in a multifunctional drug formulation, which is essential to develop efficient CDSs. This short review aims to present an updated report on the advancements of liposome-hydrogel systems for drug delivery purposes.

The Study of Various Approaches for the Transdermal Patches Possess Therapeutic Potential

A non-invasive method of administering drugs through the skin's surface, transdermal delivery allows for the drug to be delivered across the dermis at a predefined rate, either locally or systemically. It might be used in place of hypodermic injections and the oral medication delivery system. Despite being more expensive than traditional formulations, transdermal dosage forms are gaining traction due to their distinct benefits. Transdermal systems have been used to formulate many medications, and more are being tested to see if this is a feasible way to administer them such as beta-blockers, calcium channel blockers, non-steroidal anti-inflammatory drugs, contraceptives, anti-arrhythmic drugs, insulin, antivirals, hormones, alpha-interferon, and cancer chemotherapeutic agents. Additionally, studies on several chemical penetration enhancers that can facilitate the delivery of medicinal compounds are still ongoing. This review article discusses personalized patch designs, transdermal patches' range of therapeutic uses in addition in-vitro and in-vivo studies.

A mathematical model for the integrated problem of production network design and inventory positioning

In this paper, an integrated approach is addressed to tackle the production network design and inventory positioning problem in a single-sourcing, multi-product, and multi-period context. The objective of our model is to simultaneously determine the optimal network structure, safety stock amounts, and their respective locations, considering normal demand conditions. The main goal is to minimize the overall production network cost. The proposed model merges the traditional network design formulation with that for inventory positioning using the concept of guaranteed service. The developed model is implemented and tested on a case study of office furniture manufacturing, where the bill of materials is considered. The effectiveness of the proposed model is demonstrated by comparing it to a sequential approach where the network structure and safety stock decisions are made sequentially. The results reveal that the integrated approach surpasses the sequential approach, with cost savings ranging from 1.7% to 3.7%. In addition, a higher optimal cycle service level is obtained by the integrated approach compared to that of the sequential approach. To further evaluate the model's performance, a sensitivity analysis is conducted to examine the influence of the model's parameters, i.e., committed service time and coefficient of variation of demand, on its solutions. The analysis shows that when the coefficient of the demand variation remains unchanged, longer committed service times lead to lower safety stock costs and higher optimal service levels. Moreover, it is observed that more safety stocks of components are kept in the upstream layer of the network than those of finished goods.