The efficient oral delivery of therapeutic proteins and peptides poses a tremendous challenge due to their inherent instability, large molecular size, and susceptibility to enzymatic degradation. Several nanocarrier systems, such as liposomes, solid lipid nanoparticles, and polymeric nanoparticles, have been explored to overcome these problems. Liposomes and other lipid-based nanocarriers show excellent biocompatibility and the ability to encapsulate hydrophobic and hydrophilic drugs; however, they often suffer from poor structural stability, premature leakage of the loaded drugs, and poor encapsulation efficiency for macromolecular peptides and proteins. On the other hand, polymeric nanoparticles are more stable and allow better control over drug release; nevertheless, they usually lack the necessary biocompatibility and cellular uptake efficiency. Recently, lipid-polymer hybrid nanoparticles (LPHNs) have emerged as an advanced solution combining the structural stability of polymers and the biocompatibility and surface functionalities of lipids to enhance the controlled release, stability, and bioavailability of protein and peptide drugs. In this review, an attempt was made to set a clear definition of the LPHNs and extend the concept and area, so to our knowledge, this is the first review that highlights six categories of the LPHNs based on their anatomy. Moreover, this review offers a detailed analysis of LPHN preparation methods, including conventional and nonconventional one-step and two-step processes, nanoprecipitation, microfluidic mixing, and emulsification methods. Moreover, the material attributes and critical process parameters affecting the output of the preparation methods were illustrated with supporting examples to enable researchers to select the suitable preparation method, excipients, and parameters to be manipulated to get the LPHNs with the predetermined quality. The number of reviews focusing on the formulation of peptide/protein pharmaceutics usually focus on a specific drug like insulin. To our knowledge, this is the first review that generally discusses LPHN-based delivery of biopharmaceuticals. by discussing representative examples of previous reports comparing them to a variety of nanocarrier systems to show the potentiality of the LPHNs to deliver peptides and proteins. Moreover, some ideas and suggestions were proposed by the authors to tackle some of the shortcomings highlighted in these studies. By presenting this comprehensive overview of LPHN preparation strategies and critically analyzing literature studies on this topic and pointing out their strong and weak points, this review has shown the gaps and enlightened avenues for future research.

For many years, researchers have been making efforts to find a manufacturing technique, as well as a drug delivery system, that will allow for oral delivery of biopharmaceuticals to their target site of action without impairing their biological activity. Due to the positive in vivo outcomes of this formulation strategy, self-emulsifying drug delivery systems (SEDDSs) have been intensively studied in the last few years as a way of overcoming the different challenges associated with the oral delivery of macromolecules. The purpose of the present study was to examine the possibility of developing solid SEDDSs as potential carriers for the oral delivery of lysozyme (LYS) using the Quality by Design (QbD) concept. LYS was successfully ion paired with anionic surfactant, sodium dodecyl sulphate (SDS), and this complex was incorporated into a previously developed and optimized liquid SEDDS formulation comprising medium-chain triglycerides, polysorbate 80, and PEG 400. The final formulation of a liquid SEDDS carrying the LYS:SDS complex showed satisfactory in vitro characteristics as well as self-emulsifying properties (droplet size: 13.02 nm, PDI: 0.245, and zeta potential: −4.85 mV). The obtained nanoemulsions were robust to dilution in the different media and highly stable after 7 days, with a minor increase in droplet size (13.84 nm) and constant negative zeta potential (−0.49 mV). An optimized liquid SEDDS loaded with the LYS:SDS complex was further solidified into powders by adsorption onto a chosen solid carrier, followed by direct compression into self-emulsifying tablets. Solid SEDDS formulations also exhibited acceptable in vitro characteristics, while LYS preserved its therapeutic activity in all phases of the development process. On the basis of the results gathered, loading the hydrophobic ion pairs of therapeutic proteins and peptides to solid SEDDS may serve as a potential method for delivering biopharmaceuticals orally.

Mucoadhesive buccal films have found increased popularity in pharmaceutical drug delivery due to the several advantages that they possess. The present study strives to develop and optimize chitosan-based mucoadhesive buccal films by relying on quality-by-design (QbD) principles. Previous knowledge and experience were employed to firstly identify the critical quality attributes (CQAs), followed by a thorough risk assessment, which led to the selection of seven critical material attributes and process parameters, namely, the polymer grade and concentration, the plasticizer type and concentration, the citric acid (CA) concentration, the amount of the casted solution, and the drying condition. Their effects on the breaking hardness and mucoadhesivity, selected as CQAs, were investigated in three steps by three designs of the experiment (DoE). The medium molecular weight of chitosan (CH) was the preferred choice in the optimized formulation, and its concentration was the most important factor affecting the CQAs, thickness, and moisture content of the films. It was found that 0.364 g/cm² was the suitable amount of the casting solution, and its optimum drying conditions were presented in the form of a design space. Glycerol (Gly) was the best choice as a plasticizer, and a design space representing several combinations of CH and CA concentrations that produce films with the required quality was constructed at a fixed concentration of 35% Gly. A formula from this design space was selected and employed to load with two model drugs to test its drug-carrying properties for drugs with different physicochemical characteristics. Uniform drug distribution with an immediate release profile was achieved in both drugs, although one of the CQAs was outside of the specifications in the case of lidocaine-containing film. To summarize, the obtention of the optimum mucoadhesive buccal film based on CH was efficiently facilitated by the rational application of QbD principles and the DoE approach.

Hydrophobic ion pairing (HIP) complexation was found to be an efficient approach in modulating the release and enhancing the stability and encapsulation of hydrophilic macromolecules such as proteins in hydrophobic nano/microcarriers. The present work strives to develop and optimize the preparation of the HIP complex of the antimicrobial enzyme lysozyme (LYZ) with the ion-pairing agent (IPA) sodium dodecyl sulphate (SDS) relying on the quality-by-design (QbD) approach. The quality target product profile (QTPP) includes the achievement of maximal lipophilicity in a reversible manner to enable the maintenance of biological activity. The related critical quality attributes (CQAs) were defined as complexation efficacy, complex stability, enzyme recovery and activity. Three risk assessment (RA) tools were used to identify and rank the critical process parameters (CPPs) and critical material attributes (CMAs). From this assessment, the pH of the medium, LYZ:SDS molar ratio and drying conditions were determined as high-risk factors that need to be investigated. To the best of our knowledge, for the first time, electrostatic titration was used as a smart approach to determine the optimum molar ratio at different pH values. Based on the predefined CQAs, pH 8 with an LYZ/SDS molar ratio of 1:8 was found to be the optimal condition for complexation efficiency and recovery (%) of a biologically active enzyme. A cost-effective drying process based on a ventilated oven was developed, which resulted in complex qualities comparable to those obtained by the commonly used freeze-drying method. In a nutshell, the optimum conditions for the preparation of the LYZ/SDS HIP complex were efficiently facilitated by the rational application of QbD principles and the utilization of efficient electrostatic titration and ventilated oven-drying methods.

Background: Captopril (CAP), an angiotensin-converting enzyme inhibitor (ACEI), is widely prescribed for managing hypertension, heart failure, and related conditions. When administered orally, CAP undergoes hepatic metabolism, resulting in a bioavailability of 60–75%. However, to bypass the first-pass metabolism and other limitations of the oral route, mucoadhesive buccal films have gained attention as a promising alternative with several advantages. The aim of this work was the formulation and optimization of chitosan-ascorbate mucoadhesive films for buccal delivery of CAP for the management of a hypertension crisis (10 mg and 20 mg) by employing quality by design (QbD) principles and the design of experiment (DoE) approach. Materials and methods: In the present work, chitosan (CHI) was selected as a film-forming agent due to its permeability-enhancing properties, which could be further improved through salification with ascorbic acid (AA). The polymer films were prepared by the solvent casting method. Results: The optimized CAP-loaded formula showed appropriate in vitro mucoadhesion force (>15 N) and breaking hardness (>14 N). The different CAP-containing films had a high drug content (>95%) with homogeneous drug distribution, thus complying with the requirements of Pharmacopeia. FT-IR and RAMAN spectroscopy analyses demonstrated successful incorporation of the drug, and interaction was observed between the excipients of the films, especially in the form of hydrogen bonds. The dissolution test showed immediate release of the API with a similar release pattern from both concentrations of CAP-loaded films. Conclusions: The properties of the prepared films met the predetermined critical quality attribute requirements. The optimized formula of CHI 1.4%, AA 2.5%, and glycerol 0.3% appears to be a promising buccal drug delivery system for CAP.

Background/Objectives: Films in the mouth offer a promising alternative drug delivery system for oral administration, with several advantages over traditional oral formulations. Furthermore, their non-invasive nature and easy administration make them conducive to increasing patient compliance. The use of active agents in these films can further improve their drug delivery properties, making them an even more useful drug delivery system. Methods: In this research, carrageenan was used as a polymer, while glycerine was added as a plasticizer, furthermore, lidocaine hydrochloride and diclofenac sodium were used as the active agents. The prepared films were characterized by analytical techniques. Results: The results showed that glycerine reduced the mucoadhesivity and breaking hardness of the films and increasing the temperature made the films brittle. These results are also confirmed by the statistical analysis. Based on the FTIR results, glycerine can be used in films without structural changes. Conclusions: Based on the findings, films prepared from a solution with a concentration of 1.5% carrageenan and 1.5% glycerine at 70 °C are suitable as a drug delivery system for use on the buccal mucosa when combined with active agents. Carrageenan was successfully used as a carrier for two different types of active agents.