Lipid-based Excipients Research Articles

Lipid-based particle engineering via spray-drying for targeted delivery of antibiotics to the lung

Pulmonary delivery of antibiotics for the treatment of tuberculosis provides several benefits compared to conventional oral and parenteral administration. API-loaded particles delivered directly to alveolar macrophages, where Mycobacterium tuberculosis resides, can reduce the required dose and decrease the severe side effects of conventional treatment. In this work, lipid-microparticles loaded with rifampicin were engineered via spray-drying to be administered as a carrier-free dry powder for inhalation. Although, it is well-known that spray-drying of lipid-based excipients is strongly limited, a completely lipid-based formulation using diglycerol full ester of behenic acid was produced. The solid state of the lipid, providing high melting temperature, absence of polymorphism and monophasic crystallization, led to high yield of spray-dried particles (83%). Inhalable particles of mass median aerodynamic diameter of 2.36 µm, median geometric size of 2.05 µm, and negative surface (-50.03 mV) were engineered. Such attributes were defined for deep lung deposition and targeted delivery of antibiotics to alveolar macrophages. Superior aerodynamic performance as carrier-free DPI was associated to a high fine particle fraction of 79.5 %. No in vitro cytotoxic effects were found after exposing epithelial cell lines and alveolar macrophages. In vitro uptake of particles into alveolar macrophages indicated the efficiency of their targeted delivery. The use of highly processable and safe lipid-based excipients for particle engineering via spray-drying can extend the availability of materials for functionalized applications for pulmonary delivery.

Regorafenib loaded self-assembled lipid-based nanocarrier for colorectal cancer treatment via lymphatic absorption

Oral chemotherapy can improve the life quality of patients; however, the therapeutic effects are limited by low bioavailability and rapid in vivo elimination of anticancer drugs. Here, we developed a regorafenib (REG)-loaded self-assembled lipid-based nanocarrier (SALN) to improve oral absorption and anti-colorectal cancer efficacy of REG through lymphatic absorption. SALN was prepared with lipid-based excipients to utilize lipid transport in the enterocytes and enhance lymphatic absorption of the drug in the gastrointestinal tract. The particle size of SALN was 106 ± 10 nm. SALNs were internalized by the intestinal epithelium via the clathrin-mediated endocytosis, and then transported across the epithelium via the chylomicron secretion pathway, resulting in a 3.76-fold increase in drug epithelial permeability (Papp) compared to the solid dispersion (SD). After oral administration to rats, SALNs were transported by the endoplasmic reticulum, Golgi apparatus, and secretory vesicles of enterocytes and were found in the lamina propria of intestinal villi, abdominal mesenteric lymph, and plasma. The oral bioavailability of SALN was 65.9-fold and 1.70-fold greater than that of the coarse powder suspension and SD, respectively, and was highly dependent on the lymphatic route of absorption. Notably, SALN prolonged the elimination half-life of the drug (9.34 ± 2.51 h) compared to the solid dispersion (3.51 ± 0.46 h), increased the biodistribution of REG in the tumor and gastrointestinal (GI) tract, decreased biodistribution in the liver, and showed better therapeutic efficacy than the solid dispersion in colorectal tumor-bearing mice. These results demonstrated that SALN is promising for the treatment of colorectal cancer via lymphatic transport and has potential for clinical translation.

Oral Bioactive Self-Nanoemulsifying Drug Delivery Systems of Remdesivir and Baricitinib: A Paradigmatic Case of Drug Repositioning for Cancer Management.

Oral anticancer therapy mostly faces the challenges of low aqueous solubility, poor and irregular absorption from the gastrointestinal tract, food-influenced absorption, high first-pass metabolism, non-targeted delivery, and severe systemic and local adverse effects. Interest has been growing in bioactive self-nanoemulsifying drug delivery systems (bio-SNEDDSs) using lipid-based excipients within nanomedicine. This study aimed to develop novel bio-SNEDDS to deliver antiviral remdesivir and baricitinib for the treatment of breast and lung cancers. Pure natural oils used in bio-SNEDDS were analyzed using GC-MS to examine bioactive constituents. The initial evaluation of bio-SNEDDSs were performed based on self-emulsification assessment, particle size analysis, zeta potential, viscosity measurement, and transmission electron microscopy (TEM). The single and combined anticancer effects of remdesivir and baricitinib in different bio-SNEDDS formulations were investigated in MDA-MB-231 (breast cancer) and A549 (lung cancer) cell lines. The results from the GC-MS analysis of bioactive oils BSO and FSO showed pharmacologically active constituents, such as thymoquinone, isoborneol, paeonol and p-cymenene, and squalene, respectively. The representative F5 bio-SNEDDSs showed relatively uniform, nanosized (247 nm) droplet along with acceptable zeta potential values (+29 mV). The viscosity of the F5 bio-SNEDDS was recorded within 0.69 Cp. The TEM suggested uniform spherical droplets upon aqueous dispersions. Drug-free, remdesivir and baricitinib-loaded bio-SNEDDSs (combined) showed superior anticancer effects with IC50 value that ranged from 1.9-4.2 µg/mL (for breast cancer), 2.4-5.8 µg/mL (for lung cancer), and 3.05-5.44 µg/mL (human fibroblasts cell line). In conclusion, the representative F5 bio-SNEDDS could be a promising candidate for improving the anticancer effect of remdesivir and baricitinib along with their existing antiviral performance in combined dosage form.

Gelucire: A Flexible Formulation Excipients

The utility of lipid-based oral formulations has been familiar for many years. There are an enormous variety of polymeric materials used to modify the delivery platform along with enhancement of therapeutic efficacy. Gelucires are a family of lipid-based excipients comprising of glycerides and esters of polyethylene glycol, these two components conferring hydrophobic and hydrophilic properties to the vehicle. Gelucire is used to enhance the drug’s physicochemical properties, as well as controlled release matrices. This review intends to give a critical overview of the published literature on the properties, chemical nature, advantages over other polymers, methods of characterization of gelucire containing formulations, applications and patents containing various grades of gelucires.

Combined Ramipril and Black Seed Oil Dosage Forms Using Bioactive Self-Nanoemulsifying Drug Delivery Systems (BIO-SNEDDSs).

Purpose: Ramipril (RMP)—an angiotensin-converting enzyme (ACE) inhibitor—and thymoquinone (THQ) suffer from poor oral bioavailability. Developing a combined liquid SNEDDS that comprises RMP and black seed oil (as a natural source of THQ) could lead to several formulations and therapeutic benefits. Methods: The present study involved comprehensive optimization of RMP/THQ liquid SNEDDS using self-emulsification assessment, equilibrium solubility studies, droplet size analysis, and experimentally designed phase diagrams. In addition, the optimized RMP/THQ SNEDDS was evaluated against pure RMP, pure THQ, and the combined pure RMP + RMP-free SNEDDS (capsule-in-capsule) dosage form via in vitro dissolution studies. Results: The phase diagram study revealed that black seed oil (BSO) showed enhanced self-emulsification efficiency with the cosolvent (Transcutol P) and hydrogenated castor oil. The phase diagram studies also revealed that the optimized formulation BSO/TCP/HCO-30 (32.25/27.75/40 % w/w) showed high apparent solubility of RMP (25.5 mg/g), good THQ content (2.7 mg/g), and nanometric (51 nm) droplet size. The in-vitro dissolution studies revealed that the optimized drug-loaded SNEDDS showed good release of RMP and THQ (up to 86% and 89%, respectively). Similarly, the isolation between RMP and SNEDDS (pure RMP + RMP-free SNEDDS) using capsule-in-capsule technology showed >84% RMP release and >82% THQ release. Conclusions: The combined pure RMP + RMP-free SNEDDS (containing black seed oil) could be a potential dosage form combining the solubilization benefits of SNEDDSs, enhancing the release of RMP/THQ along with enhancing RMP stability through its isolation from lipid-based excipients during storage.

Effect of Lipid Vehicles on Solubility, Stability, and Topical Permeation of Delta-9-Tetrahydrocannabinol.

Delta-9-tetrahydrocannabinol (THC) is one of the most effective antinociceptive agents used in the treatment of peripheral neuropathy. THC is highly lipophilic and susceptible to thermal and oxidative degradation. Identifying appropriate solvents in which THC is stable as well as adequately solubilized is crucial in developing topical dosage forms. Lipid solvent systems are of utmost utility and relevance for formulating highly lipophilic drugs. Hence, the objective of this project was to screen the solubility of THC in lipidic excipients, monitor THC content in the selected vehicles during stability, and study the influence of these excipients on permeation of THC across skin. The solubility of THC in liquid lipid excipients was in the range of 421 to 500mg/g. The solubility of THC in solid lipid excipients was in the range of 250 to 750mg/g. THC in its neat form was poorly stable, but when dissolved in lipid-based excipients, its stability improved significantly. THC in lipid excipients was more stable at 4 ± 3°C compared to samples stored at 25 ± 2°C. The antioxidants (butylated hydroxytoluene and ascorbyl palmitate) used in the excipients further improved the stability of THC. The results demonstrated that the liquid and solid lipid excipients used in the study could solubilize THC freely and mitigate the degradation of THC significantly. The binary combination of lipid excipients enhanced THC skin permeation and retention, demonstrating the potential for topical formulation development of THC.

A Package of Established Analytical Tools to Investigate the Solid-State Alteration of Lipid-Based Excipients.

Lipid-based excipients (LBEs) are low-toxic, biocompatible, and natural-based, and their application supports the sustainability of pharmaceutical manufacturing. However, the major challenge is their unstable solid-state, affecting the stability of the pharmaceutical product. Critical physical properties of lipids for their processing-such as melt temperature and viscosity, rheology, etc.-are related to their molecular structure and their crystallinity. Additives, as well as thermal and mechanical stress involved in the manufacturing process, affect the solid-state of lipids and thus the performance of pharmaceutical products thereof. Therefore, understanding the alteration in the solid-state is crucial. In this work, the combination of powder x-ray diffraction and differential scanning calorimetry (DSC) is introduced as the gold standard for the characterization of lipids' solid state. X-ray diffraction is the most efficient method to screen polymorphism and crystal growth. The polymorphic arrangement and the lamella length are characterized in the wide- and small-angle regions of x-ray diffraction, respectively. The small-angle x-ray scattering (SAXS) region can be further used to investigate crystal growth. Phase transition and separation can be indicated. DSC is used to screen the thermal behavior of lipids, estimate the miscibility of additives and/or active pharmaceutical ingredients (API) in the lipid matrix, and provide phase diagrams. Four case studies are presented in which LBEs are either used as a coating material or as an encapsulation matrix to provide lipid-coated multiparticulate systems and lipid nanosuspensions, respectively. The lipid solid-state and its potential alteration during storage are investigated and correlated to the alteration in the API release. Qualitative microscopical methods such as polarized light microscopy and scanning electron microscopy are complementary tools to investigate micro-level crystallization. Further analytical methods should be added based on the selected manufacturing process. The structure-function-processability relationship should be understood carefully to design robust and stable lipid-based pharmaceutical products.

A Package of Established Analytical Tools to Investigate the Solid-State Alteration of Lipid-Based Excipients

A Package of Established Analytical Tools to Investigate the Solid-State Alteration of Lipid-Based Excipients

Filament-based 3D-printing of placebo dosage forms using brittle lipid-based excipients

In order to expand the limited portfolio of available polymer-based excipients for fabricating three-dimensional (3D) printed pharmaceutical products, Lipid-based excipients (LBEs) have yet to be thoroughly investigated. The technical obstacle of LBEs application is, however their crystalline nature that renders them very brittle and challenging for processing via 3D-printing. In this work, we evaluated the functionality of LBEs for filament-based 3D-printing of oral dosage forms. Polyglycerol partial ester of palmitic acid and polyethylene glycols monostearate were selected as LBEs, based on their chemical structure, possessing polar groups for providing hydrogen-bonding sites. A fundamental understanding of structure–function relationship was built to screen the critical material attributes relevant for both extrusion and 3D-printing processes. The thermal behavior of lipids, including the degree of their supercooling, was the critical attribute for their processing. The extrudability of materials was improved through different feeding approaches, including the common powder feeding and a devised liquid feeding setup. Liquid feeding was found to be more efficient, allowing the production of filaments with high flexibility and improved printability. Filaments with superior performance were produced using polyglycerol ester of palmitic acid. In-house designed modifications of the utilized 3D-printer were essential for a flawless processing of the filaments.

Lipid based Vehicles and Lipid-based Excipients in Drug delivery

In recent years, there has been increasing interest in the use of formulations containing lipid-based excipients that comprise combinations of synthetic or semisynthetic lipids with surfactants, co-surfactants or co-solvents. This review is generally focussed on lipid-based excipients in pharmaceutical formulations which improves the oral bioavailability of poorly water-soluble drugs. Lipid-based formulations can reduce the limitations of slow and incomplete dissolution of poorly water-soluble drugs, and facilitate the formation of solubilised phases from which absorption may occur. The improvement of bio-availability of drugs is one of the greatest challenges in drug formulations. This review discusses novel lipids like Compritol 888 ATO, Dynasan 114, Glyceryl monooleate (GMO), Maisine CC and Precirol ATO 5 focussing on how these can be employed for devising efficient drug delivery systems and also the in vivo effect and fate of lipid excipients.

Fundamental Aspects of Lipid-Based Excipients in Lipid-Based Product Development.

Poor aqueous solubility of drugs is still a foremost challenge in pharmaceutical product development. The use of lipids in designing formulations provides an opportunity to enhance the aqueous solubility and consequently bioavailability of drugs. Pre-dissolution of drugs in lipids, surfactants, or mixtures of lipid excipients and surfactants eliminate the dissolution/dissolving step, which is likely to be the rate-limiting factor for oral absorption of poorly water-soluble drugs. In this review, we exhaustively summarize the lipids excipients in relation to their classification, absorption mechanisms, and lipid-based product development. Methodologies utilized for the preparation of solid and semi-solid lipid formulations, applications, phase behaviour, and regulatory perspective of lipid excipients are discussed.

Promises of Lipid-based Drug Delivery Systems in the Management of Breast Cancer.

Breast cancer is one of the leading types among the common non-cutaneous malignancies in women. All the curative methods available for its treatment are minimal due to their toxicity issues and dose-related side effects. Various evolving nanotechnology techniques displayed the opportunity to target breast cancer. One such delivery system is lipid-based drug delivery systems (LDDS). This concept is constrained only for the laboratory scale should be shifted to the industrial level targeting the nanomedicine with clinical benefits. This work tried to portray the advancements in the LDDS along with the lipid-based excipients, advantages, disadvantages and applications. It even helped in highlighting the recently developed lipid-based nanocarriers for breast cancer management.

Lipid-microparticles for pulmonary delivery of active pharmaceutical ingredients: Impact of lipid crystallization on spray-drying processability

Spray-drying is an extensively used technology for engineering inhalable particles. Important technical hurdles are however experienced when lipid-based excipients (LBEs) are spray-dried. Stickiness, extensive wall deposition, or simply inability to yield a solid product have been associated to the low melting points of LBEs. In this work, solutions containing polyglycerol esters of behenic acid (PGFA-behenates), or other high melting point LBEs, were spray-dried to produce ibuprofen (IBU)-loaded inhalable lipid-microparticles. Prior to spray-drying, rational boundaries for the outlet temperature of the process were defined using LBE-IBU phase diagrams. Despite spray-drying the solutions at outlet temperatures below the boundaries, process performance and yield among LBEs were entirely different. Lipid crystallization into polymorphs or multi-phases negatively impacted the yield (10–47%), associated to liquid fractions unable to recrystallize at the surrounding gas temperature in the spray-dryer. The highest yields (76–82%), ascribed to PGFA-behenates, resulted from monophasic crystallization and absence of polymorphism. Lipid-microparticles, composed of a PGFA-behenate, were characterized by a volume mean diameter of 6.586 µm, tap density of 0.389 g/cm3 and corrugated surface. Application as carrier-free dry powder for inhalation resulted in high emitted fraction (90.9%), median mass aerodynamic diameter of 3.568 µm, fine particle fraction of 45.6% and modified release in simulated lung fluid.

Structural aspects of a self-emulsifying multifunctional amphiphilic excipient: Part II. The case of Cremophor EL

Lipids and lipid-based excipients, such as Cremophor EL used in this study, play an important role in improving the solubility of poorly soluble drugs and drug candidates. The use of such excipients in self-emulsifying formulations has been widely reported in the literature. In the current study, we report the micellar behavior of Cremophor EL at several concentrations (above the critical micelle concentration) and temperatures using small-angle neutron scattering. For all conditions, Cremophor EL formed core–shell spherical micelles with an overall radius of ∼ 50 Å, a hydrophobic core radius of ∼ 25 Å, and a shell thickness of ∼ 23 Å with a polydispersity of ∼ 25%. The thickness of the shell (equivalent to the polymer length in the brush regime), and consequently of the overall micelle, was found to increase with increasing temperature. This study will aid our understanding of how drugs could interact with lipid excipients and how such drug-excipient mixtures behave during manufacture, storage, and after administration.

Structural aspects of a self-emulsifying multifunctional amphiphilic excipient: Part I. The case of Gelucire® 44/14

The use of lipids and lipid-based excipients in self-emulsifying formulations has been widely reported. Such excipients play an important role to improve solubility of poorly soluble drugs and drug candidates. In the current study, we analysed the micellar behavior of a self-emulsifying multifunctional amphiphilic excipient Gelucire® 44/14 at a range of concentrations above the critical micelle concentration (CMC) and at various temperatures using small angle neutron scattering (SANS). At low temperatures, Gelucire® 44/14 was found to form core-shell spherical micelles with an overall radius of ~50 Å, a hydrophobic core radius of ~23 Å and a shell thickness of ~26 Å with a polydispersity of ~20%. The size of the hydrophobic core, and consequently of the overall micelle, was found to increase by less than 10%, with increasing temperature. At concentrations close to its CMC and at the highest temperature studied, the micellar form was transformed to cylindrical or rod-like structures. This study will aid our understanding of how drugs could interact with lipid excipients and how such drug-excipient mixtures behave during manufacturing, storage and after administration.

Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability.

P-glycoprotein (P-gp) is crucial in the active transport of various substrates with diverse structures out of cells, resulting in poor intestinal permeation and limited bioavailability following oral administration. P-gp inhibitors, including small molecule drugs, natural constituents, and pharmaceutically inert excipients, have been exploited to overcome P-gp efflux and enhance the oral absorption and bioavailability of many P-gp substrates. The co-administration of small molecule P-gp inhibitors with P-gp substrates can result in drug–drug interactions and increased side effects due to the pharmacological activity of these molecules. On the other hand, pharmaceutically inert excipients, including polymers, surfactants, and lipid-based excipients, are safe, pharmaceutically acceptable, and are not absorbed from the gut. Notably, they can be incorporated in pharmaceutical formulations to enhance drug solubility, absorption, and bioavailability due to the formulation itself and the P-gp inhibitory effects of the excipients. Different formulations with inherent P-gp inhibitory activity have been developed. These include micelles, emulsions, liposomes, solid lipid nanoparticles, polymeric nanoparticles, microspheres, dendrimers, and solid dispersions. They can bypass P-gp by different mechanisms related to their properties. In this review, we briefly introduce P-gp and P-gp inhibitors, and we extensively summarize the current development of oral drug delivery systems that can bypass and inhibit P-gp to improve the oral absorption and bioavailability of P-gp substrates. Since many drugs are limited by P-gp-mediated efflux, this review is helpful for designing suitable formulations of P-gp substrates to enhance their oral absorption and bioavailability.

Impact of Surface Properties of Core Material on the Stability of Hot Melt-Coated Multiparticulate Systems

Hot melt coating (HMC) of an active pharmaceutical ingredient (API) powder with lipid-based excipients is an innovative method for manufacturing patient-convenient dosage forms. However, drug release instability is still its main industrial challenge. The correlation between the unstable pharmaceutical product performance with the solid-state alteration of lipids is currently well-investigated. The remaining problem is the inconsistent release alteration of different APIs coated with the same lipid after storage, such as faster release in some cases and slower release in others. The interaction between API surface and lipid-based coating and its alteration during storage were investigated in this work. The surface properties of five different APIs and the coating composition of tripalmitin and polysorbate 65 were screened via Washburn and pendant drop methods, respectively. Metformin hydrochloride and hydrochlorothiazide particles were each coated with the coating composition. The water sorption alteration of coated particles and the crystal growth of tripalmitin in the coating after storage were measured via tensiometry and X-ray diffraction. The cleavage work necessary to overcome the adhesion of coating composition on the core surface was calculated for each API. The accelerated release of the polar core (metformin) after storage was correlated with a low cleavage work and a distinctive phase separation. In contrast, a decelerated release of the hydrophobic core (hydrochlorothiazide) was favored by the crystal growth of the lipid-based coating. The gained knowledge can be used to design the product stability during the formulation development.

Croda, Pfizer sign vaccine excipient deal

Croda International has signed a 5-year contract to supply lipid-based excipients to Pfizer for production of the drugmaker’s messenger RNA–based COVID-19 vaccine candidate The inactive ingredients will be made by Avanti Polar Lipids, a high-purity lipids firm that Croda acquired earlier this year The up-to-$100 million contract specifies that Croda will provide four excipients for the first 3 years of the agreement The drug services firms Lonza and CordenPharma earlier landed lipid supply deals with Moderna, another front-runner in COVID-19 vaccines [ ]

Polyglycerol esters of fatty acids as safe and stable matrix forming tableting excipients: A structure-function analysis

This work describes a novel approach for the development of extended release matrix tablets with stable performance via direct compaction. Selected molecules belong to polyglycerol esters of fatty acids (PGFAs) - a group of lipid-based excipients (LBE) with advanced solid-state stability - were used for developing extended release tablets. Metformin HCl as a freely water soluble API was used as model substance. Three PGFA compounds with a HLB range of 1.8–4.5 were selected as matrix forming agents. The deformation behavior of tableting blends with and without PGFAs and their flow properties studied. Blends composing PGFAs showed reduced yield pressure and decreased internal friction between particles, suggesting the tendency to plastic behavior of PGFAs and improved flow properties of their blends, respectively. The blends of selected lipids with API and filler were directly processable via direct compression without any pretreatment such as granulation. The resulted tablets showed desired tensile strength and friability. Application of PGFAs with different HLB allowed the tailoring of API release profile for different time periods with the same concentration of lipid in the tablet. The stable release profile was related to the stable solid state of lipids as matrix agent. No in vitro cytotoxic effect was observed by assessing the dehydrogenase activity.

Novel approach for overcoming the stability challenges of lipid-based excipients. Part 3: Application of polyglycerol esters of fatty acids for the next generation of solid lipid nanoparticles

Solid lipid nanoparticles (SLN) are an advantageous carrier system for the delivery of lipophilic active pharmaceutical ingredients (APIs). The use of SLN has been limited due to stability issues attributed to the unstable solid state of the lipid matrix. A novel approach for overcoming this problem is the application of polyglycerol esters of fatty acids (PGFAs) as lipid matrices with stable solid state. PG2-C18 full, a PGFA molecule, was used to develop SLN loaded with dexamethasone as a model API. Dexamethasone-loaded SLN were manufactured via melt-emulsification and high pressure homogenization in the dosage form of a lipid nanosuspension. SLN with median particle size of 242.1 ± 12.4 nm, zeta potential of −28.5 ± 7.8 mV, entrapment efficiency of 90.2 ± 0.7% and API released after 24 h of 81.7 ± 0.7%, were produced. Differential Scanning Calorimetry (DSC) and Small and Wide Angle X-Ray Scattering (SWAXS) analysis of the lipid nanosuspension evidenced the crystallization of PG2-C18 full in a monophasic system in α-form and absence of polymorphism and crystallite growth up to 6 months storage at room temperature. This resulted in stable performance of the SLN after storage: absence of particle agglomeration, no API expulsion, and stable release profile. The potential pulmonary administration of SLN was tested by the nebulization capacity of the lipid nanosuspension. Cellular exposures to SLN did not induce cytotoxicity or immune effect on pulmonary cells. The application of PGFAs as safe and stable lipid matrices provide a promising approach for the development of the next generation of SLN.