Formulation Strategies Research Articles

Liposomal Phytosterols as LDL-Cholesterol-Lowering Agents in Diet-Induced Hyperlipidemia.

The high blood level of low-density lipoprotein cholesterol (LDL-C) is a primary risk factor for cardiovascular disease. Plant sterols, known as phytosterols (PSs), can reduce LDL-C in a range of 8-14%. The extent of LDL-C reduction depends on its formulation. Encapsulation into liposomes is one formulation strategy to enhance the efficiency of PSs. PSs (campesterol, stigmasterol, and β-sitosterol) have frequently been assessed alone or in combination for their LDL-C-lowering ability. However, one naturally abundant PS, brassicasterol, has not yet been tested for its efficacy. We have previously developed a novel liposomal formulation containing the PS mixture present naturally in canola that is composed of brassicasterol, campesterol, and β-sitosterol. In this work, the efficacy of our novel liposomal PS formulation that includes brassicasterol was assessed in a hamster model. Animals were divided into five groups: (i) liposomal PS in orange juice, (ii) liposomal PS in water, (iii) marketed PS in orange juice, (iv) control orange juice, and (v) control water. The animals were fed a high-fat, cholesterol-supplemented (0.5%) diet to induce hypercholesterolemia. The treatment was administered orally once daily for 4 weeks. Fasting blood samples were collected at baseline, week 2, and week 4. The extent of the reduction of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides was compared among the groups. Liposomal PSs in both orange juice and water significantly reduced LDL-C compared to their controls. Furthermore, the liposomal PS was as effective as a marketed PS-containing product in reducing LDL-C. Liposomal PSs in both orange juice and water showed similar efficacy in LDL-C reduction, highlighting that these vehicles/food matrices do not affect the efficacy of PSs. The liposomal formulation of a natural PS mixture extracted from canola oil, with brassicasterol as a major component, exhibited a significant LDL-C reduction in a hamster model.

Photo-induced site-specific oxidative fragmentation of IgG1 mediated by iron(III)-containing histidine buffer: Mechanistic studies and excipient effects

Fragmentation may compromise the clinical efficacy and safety profile of monoclonal antibodies (mAbs). We recently reported that Fe(III)-containing histidine (His) buffer mediates site-specific mAb fragmentation within the Fc domain when exposed to visible light (Y. Zhang and C. Schöneich, Mol. Pharm. 2023, 20, 650–662). Here, we show that this fragmentation proceeds even more efficiently under near-UV light. Several formulation strategies were applied in an attempt to reduce the photo-induced fragmentation. In solution formulations, the fragmentation can be mitigated by reducing the concentration of His buffer, adding Fe(III)-chelating agents, and replacing His with other amino acids. Fragmentation can be almost completely inhibited by formulating the protein in the lyophilized state. Mechanistically, His plays a critical role in the fragmentation process, likely due to its affinity for Fe(II), driving a photo-redox reaction towards product formation.

Metal-Based Nanoparticles for Cancer Metalloimmunotherapy.

Although the promise of cancer immunotherapy has been partially fulfilled with the unprecedented clinical success of several immunotherapeutic interventions, some issues, such as limited response rate and immunotoxicity, still remain. Metalloimmunotherapy offers a new form of cancer immunotherapy that utilizes the inherent immunomodulatory features of metal ions to enhance anticancer immune responses. Their versatile functionalities for a multitude of direct and indirect anticancer activities together with their inherent biocompatibility suggest that metal ions can help overcome the current issues associated with cancer immunotherapy. However, metal ions exhibit poor drug-like properties due to their intrinsic physicochemical profiles that impede in vivo pharmacological performance, thus necessitating an effective pharmaceutical formulation strategy to improve their in vivo behavior. Metal-based nanoparticles provide a promising platform technology for reshaping metal ions into more drug-like formulations with nano-enabled engineering approaches. This review provides a general overview of cancer immunotherapy, the immune system and how it works against cancer cells, and the role of metal ions in the host response and immune modulation, as well as the impact of metal ions on the process via the regulation of immune cells. The preclinical studies that have demonstrated the potential of metal-based nanoparticles for cancer metalloimmunotherapy are presented for the representative nanoparticles constructed with manganese, zinc, iron, copper, calcium, and sodium ions. Lastly, the perspectives and future directions of metal-based nanoparticles are discussed, particularly with respect to their clinical applications.

Automated High-Throughput Matrix Assisted Laser Desorption Ionization Mass Spectrometry Methodology for Formulation Assessment of Polyethylene-Glycol-Conjugated Cytokine Proteins

Biological therapeutics are major contributors to the pharmaceutical pipeline and continue to grow in sales and scope. Additionally, the field's understanding of cancer biology has advanced such that biopharmaceuticals can harness the power of the immune system for oncology treatments. Several of these novel therapeutics are engineered versions of naturally occurring proteins designed to improve therapeutic properties including potency, target engagement and half-life extension. Cytokines, such as interferons and interleukins, are a broad class of signaling proteins which modulate the body's immune response; engineered cytokines have entered the clinic as promising new immuno-oncology therapies. While these therapies hold great promise, their additional structural complexity introduces analytical challenges, and traditional analytical platforms may be ill-suited to effectively assess product development risks. Further, the pharmaceutical industry relies on streamlining approaches for high-throughput experimentation to achieve speed and efficiency for the discovery and development of new modalities. These demands necessitate the use of state-of-the-art techniques to rapidly characterize these new modalities and guide process development and optimization. Matrix Assisted Laser Desorption Ionization Mass Spectrometry (MALDI-MS) is a rapid, sensitive and automatable technique amenable for high-throughput analysis of proteins. In this work, we have developed an automated MALDI-MS platform to prepare, acquire and analyze molecular degradation in engineered PEGylated cytokines formulation samples. This orthogonal technique integrated seamlessly with current developability risk assessment workflows, ultimately enabling selection of a final formulation strategy for clinical development.

Structural, mechanical, antioxidant and antibacterial properties of soy protein isolate (SPI)-based edible food packaging films as influenced by nanocellulose (NC) and green extracted phenolic compounds from date palm leaves

This study investigated the addition of cellulose nanoparticles (NC) and green extracted phenolic compounds from date palm leaves (DLE) as reinforcing and bioactive agent, respectively, into the soy protein isolate (SPI) edible films. Structural, physiochemical, optical, mechanical, barrier, thermal, and bioactive properties of the films were explored. The incorporation of NC improved the SPI film’s physiochemical, mechanical, and barrier properties but did not show effect on the antioxidant and antibacterial properties. Following the incorporation of DLE in liquid form (DLWE) the film’s antioxidant and antibacterial properties significantly increased but due to the presence of natural deep eutectic solvent (NADES) (plasticizer) all other properties were negatively affected. However, enriching the SPI-NC films with DLE in powder form (DLPE) improved the bioactive properties while maintaining the improved mechanical and barrier properties. These findings indicated that SPI-NC/DLPE films exhibited improvements in the whole performance and provided promising strategy for formulation of biodegradable packaging films. This approach is an effective strategy towards sustainable utilization of unexplored agricultural wastes (date palm leaves derived NC and phenolic compounds) for development of active and environmentally friendly food packaging material.

Nanopesticides: A Review on Current Research and Future Perspective

AbstractThe survival of humans depends critically on crop production, making crop protection absolutely essential. Numerous studies have suggested that nanopesticides could soon fully replace conventional pesticides since they are far more effective than those now in use. Due to an increase in their surface‐to‐volume ratio, nanomaterials exhibit different properties from their bulk counterparts. Nanopesticides are pesticides that have been made with these nanoparticles and have a high application efficiency and significantly fewer hazardous environmental impacts than pesticides that have been made chemically. Various formulation strategies, which include the containment of the active substance by the nanoparticles, have previously been established, exhibiting promising effects on the pests. Target specificity, high stability, and controlled active ingredients (AIs) release are a few of the noteworthy qualities these nanopesticides offer. The development of green nanopesticides derived from nature, which have very low ecotoxicities and nanoscale qualities, can also have a significant positive impact on crop output. However, before being mass‐produced and used, the discovery still has to be thoroughly examined to determine its effects on people and the environment due to the lack of conclusive proof demonstrating its toxicity. This paper aims to represent the use of nanopesticides in crop protection and a detailed overview of the various methods for the formulation of nanopesticides. Also, the possible negative impacts on the non‐target species by the application of nanopesticides have been briefly discussed. The need for the development of green nanopesticides to avoid the negative aspects of nanopesticides has also been highlighted.

Formulation and Processing Strategies to Reduce Acrylamide in Thermally Processed Cereal-Based Foods.

Acrylamide, a thermal process contaminant, is generated in carbohydrate-rich foods processed at high temperatures (above 120 °C). Since acrylamide indicates a human health concern, the acrylamide contents of various foods and the dietary exposure of the population to acrylamide are very well investigated. Commonly consumed foods in the daily diet of individuals such as bakery products, potato products and coffee are major dietary sources of acrylamide. In recent years, dietary exposure levels of the population and mitigation measures for reducing acrylamide in different food products have gained importance to decrease the public's exposure to acrylamide. Since the complete elimination of acrylamide in foods is not possible, various mitigation measures to reduce acrylamide to levels as low as reasonably achievable have been developed and applied in the food industry. Mitigation strategies should be applied according to the different product categories during agricultural production, formulation, processing and final consumer preparation stages. The aim of this review is to evaluate formulation and processing strategies to reduce acrylamide in various cereal-based food products and to discuss the applicability of mitigation measures in the food industry by taking into consideration the organoleptic properties, nutritional value, cost and regulations in the light of current knowledge.

Photoactivatable Liposomes for Blue to Deep Red Light-Activated Surface Drug Release: Application to Controlled Delivery of the Antitumoral Drug Melphalan.

Liposome-based nanoparticles able to release, via a photolytic reaction, a payload anchored at the surface of the phospholipid bilayer were prepared. The liposome formulation strategy uses an original drug-conjugated blue light-sensitive photoactivatable coumarinyl linker. This is based on an efficient blue light-sensitive photolabile protecting group modified by a lipid anchor, which enables its incorporation into liposomes, leading to blue to green light-sensitive nanoparticles. In addition, the formulated liposomes were doped with triplet-triplet annihilation upconverting organic chromophores (red to blue light) in order to prepare red light sensitive liposomes able to release a payload, by upconversion-assisted photolysis. Those light-activatable liposomes were used to demonstrate that direct blue or green light photolysis or red light TTA-UC-assisted drug photolysis can effectively photorelease a drug payload (Melphalan) and kill tumor cells in vitro after photoactivation.

The Implications of Drug-Polymer Interactions on the Physical Stability of Amorphous Solid Dispersions.

Amorphous solid dispersions (ASDs) are a formulation and development strategy that can be used to increase the apparent aqueous solubility of poorly water-soluble drugs. Their implementation, however, can be hindered by destabilization of the amorphous form, as the drug recrystallizes from its metastable state. Factors such as the drug-polymer solubility, miscibility, mobility, and nucleation/crystal growth rates are all known to impact the physical stability of an ASD. Non-covalent interactions (NCI) between the drug and polymer have also been widely reported to influence product shelf-life. In this review, the relationship between thermodynamic/kinetic factors and adhesive NCI is assessed. Various types of NCIs reported to stabilize ASDs are described, and their role in affecting physical stability is examined. Finally, NCIs that have not yet been widely explored in ASD formulations, but may potentially impact their physical stability are also briefly described. This review aims to stimulate further theoretical and practical exploration of various NCIs and their applications in ASD formulations in the future.

21st Century Instructional Leadership and Strategic Management of Technical Vocational Education and Training Programs

The present study attempted to examine the relationship between 21stcenturyleadership and strategic management of school principals concerning their strategy formulation, implementation, and evaluation. This is with an end-view of preparing actions and activities to help strengthen their leadership skills in the 21st century era.The study is descriptive-correlational in nature, employing a survey questionnaire responded to by 80 TLE teachers from public secondary schools in Districts II and V of Batangas Province. Quantitative analysis indicated that concerning the 21st century leadership skills of TLE teachers, they generally agree that their school heads manifest strong advocacy and leadership (3.45) while they strongly agree that they display adult professional core (3.52), continuous improvement of teaching expertise (3.50), and results-oriented team (3.51). In terms of the strategic management of TVET programs during this time of the pandemic, they agree that their school heads employ various strategies for strategy formulation (3.36), strategy implementation (3.40), and strategy evaluation (3.41). Pearson’s R correlation revealed a moderate to very high correlation between strong advocacy and leadership, adult professional core, continuous improvement of teaching expertise, and results-oriented teams with their strategic management of the school heads. It was therefore suggested that school heads explore and initiate actions that will help foster their 21st century leadership skills as it was found that it is influential in the strategic management of the TVET programs, particularly during this time of global health emergency.

An update on Nanoparticle Formulation Design of Piperine to Improve its Oral bioavailability: A Review

Piperine, a crystalline alkaloid compound isolated from Piper nigrum, piper longum, and other types of piper, has had many fabulous pharmacological advantages for preventing and treating some specific diseases, such as analgesic, anti-inflammatory, hepatoprotective, antimetastatic, antithyroid, immunomodulatory, antitumor, rheumatoid arthritis, osteoarthritis, Alzheimer's, and improving the bioavailability of other drugs. However, its potential for clinical use through oral usage is hindered by water solubility and poor bioavailability. The low level of oral bioavailability is caused by low solubility in water and is photosensitive, susceptible to isomerization by UV light, which causes piperine concentration to decrease. Many different formulation approaches have been applied to improve the poor oral bioavailability of piperine. There have been oral formulation strategies that have been successfully implemented in increasing the solubility and bioavailability of piperine within the body, such as the formulation of nanoparticles, nanosuspensions, salt formation, liposomes, complexation using polymers, micro/nano-emulsions, and solid dispersions. This review presents a summary of piperine biopharmaceuticals, new formulation design approaches to improve oral bioavailability of piperine, and several techniques and methods for conducting selective and sensitive analysis of piperine in biological fluids.

Scalable fabrication of uniform nanoparticles for the efficient co-encapsulation of curcumin and procyanidins driven by multiple interactions

The co-delivery of curcumin (CUR) with other polyphenol bioactives often has synergistic benefits. However, conventional co-encapsulation carriers formed by precipitation frequently exhibit limited loading properties, particularly for bioactives with different solubilities. In this study, we designed a highly efficient vehicle for the co-delivery of hydrophobic CUR and hydrophilic procyanidins (PCs), adopting a multiple interactions–based strategy via a two-step flash nanoprecipitation (FNP) process. The optimal nanoparticles (NP), composed of a FeII crosslinked PCs/CUR nanocore (NC) and a soy protein isolates (SPI) shell, showed high individual encapsulation efficiency (∼95%) and a total loading content of ∼38%. Compared with the conventional production process, FNP endowed our NP with a small size (133 nm) and good uniformity (polydispersity index = 0.267). Ultraviolet–visible and Fourier transform infrared spectra revealed multiple interactions (coordination and hydrogen bonding) among the carrier materials and bioactives, which played a central role in achieving excellent loading properties for both PCs and CUR. The core–shell structure of the NP greatly enhanced the thermal–light stability of the encapsulated PCs and CUR. Synergistic antioxidation effect was found between PCs and CUR, and the nano-formulation further increased the antioxidation efficiency. In vitro release experiments showed the favorable pH responsiveness of our NP in the vast gastrointestinal pH gradient effectively preventing the leakage of wrapped bioactives in the stomach pH environment, which benefits the intestinal delivery of the bioactives. Our nanoparticulate co-delivery system fabricated using the FNP process provides new insights into the formulation strategy of multiple bioactives and shows great potential for application in the fields of functional foods and dietary supplements.

Pharmaceutical formulation design for enhancing solubility, stability, and bioavailability of poorly water-soluble drugs: An Analytical Perspective

The development of pharmaceutical formulations for drugs with poor water solubility presents significant challenges in achieving desired therapeutic outcomes. These drugs have limited solubility, which result in suboptimal bioavailability, reduced stability, and compromised efficacy. To overcome challenges, formulation strategies required to enhance drug solubility, stability, and bioavailability. Several approaches explored in pharmaceutical formulation design to address the solubility issues with poorly water-soluble drugs. These approaches particle size reduction, solid dispersion, lipid-based formulations, cyclodextrin complexation, and nanotechnology-based delivery systems. Particle size reduction techniques, such as micronization and nanonization, can significantly increase the surface area and improve dissolution rates, thereby enhancing drug solubility. Techniques such as hot melt extrusion and spray drying help disperse medications with low solubility into water-loving carriers, which boosts their solubility and ability to dissolve. Formulations that are lipid-based, like self-emulsifying drug delivery systems (SEDDS) and lipid nanoparticles, can optimize solubility and absorption of drugs by taking advantage of naturally occurring physiological pathways connected to lipid digestion and absorption. Furthermore, cyclodextrins have the capability to form complexes that aid in the increased solubility and preserving stability of medications that have little water solubility.

Study of Oncolytic Virus Preservation and Formulation.

In recent years, oncolytic viruses (OVs) have emerged as an effective means of treating cancer. OVs have multiple oncotherapeutic functions including specifically infecting and lysing tumor cells, initiating immune cell death, attacking and destroying tumor angiogenesis and triggering a broad bystander effect. Oncolytic viruses have been used in clinical trials and clinical treatment as drugs for cancer therapy, and as a result, oncolytic viruses are required to have long-term storage stability for clinical use. In the clinical application of oncolytic viruses, formulation design plays a decisive role in the stability of the virus. Therefore, this paper reviews the degradation factors and their degradation mechanisms (pH, thermal stress, freeze-thaw damage, surface adsorption, oxidation, etc.) faced by oncolytic viruses during storage, and it discusses how to rationally add excipients for the degradation mechanisms to achieve the purpose of maintaining the long-term stability of oncolytic viral activity. Finally, the formulation strategies for the long-term formulation stability of oncolytic viruses are discussed in terms of buffers, permeation agents, cryoprotectants, surfactants, free radical scavengers, and bulking agent based on virus degradation mechanisms.

Soluplus® as a solubilizing excipient for poorly water-soluble drugs: Recent advances in formulation strategies and pharmaceutical product features

Soluplus® as a solubilizing excipient for poorly water-soluble drugs: Recent advances in formulation strategies and pharmaceutical product features

A dual-cure approach for the ultraviolet-assisted material extrusion of highly loaded opaque suspensions

Ultraviolet-Assisted Material Extrusion (UV-MEX) is an additive manufacturing (AM) technology in which a viscous ink, is selectively extruded and solidified via in-situ UV irradiation (photocuring) in a layer-by-layer fashion to create three-dimensional parts. UV-MEX is an attractive AM technology due to its ability to (i) extrude highly viscous inks that are not processable via other photo-enabled AM technologies, (ii) leverage the broad photopolymer material library and chemistries established for other photo-enabled AM technologies and (iii) process a wide range of loaded inks to enable fabrication of metal, ceramic, polymer, bio-based, and multi-material parts. UV-MEX is well positioned to process highly loaded and highly viscous photocurable inks, a class of materials that cannot be processed by other AM modalities due to their process-induced viscosity constraints. However, opaque particles in the highly loaded systems may absorb and scatter UV irradiation, which will hinder final part properties due to limited cure depth and degree of conversion of the photopolymer matrix. To enable the robust UV-MEX printing of highly loaded inks containing opaque fillers, this work introduces a framework for formulating and characterizing resins that are both photo (UV irradiation) and thermally (heat) curable. This dual-cure strategy is enabled by the facile addition of free radical photo- and thermal initiators into acrylate-based resins. The resin’s responsiveness to UV irradiation enables rapid solidification and stiffening of the resin to reduce the spreading and slumping of the extruded bead. However, due to the absorption of the UV irradiation by the opaque fillers, only a thin cured skin (20-100um) is formed on the surface of the extruded bead. Thus, the secondary thermal cure is used to fully cure the ink and develop the final properties of the printed part. Heating during the printing process is shown to provide in-situ thermal curing of the deposited ink, which further strengthens the deposited material and enables the printing of tall structures. In this work, the dual-cure ink formulation strategy is assessed for its ability to enable the printing of dimensionally stable and high-aspect ratio parts from inks highly loaded with opaque solids. A methodology for characterizing the curing of the highly loaded inks using rheological and differential scanning calorimetry experiments is presented, along with a framework for assessing their printing performance in UV-MEX. The dual-cure ink concept and screening methodology is demonstrated on a dual-cure urethane acrylate ink loaded with 60 vol% aluminum particles.

Chemistry Characterization and Application of Nanocrystals-based Drug Delivery System: Present to Future Perspective.

With the development of new technologies, various drugs with higher efficacy have been found, but their therapeutic use is still limited owing to poor water solubility, which leads to poor systemic bioavailability. Currently, about 40% of newly discovered drugs have a solubility issue. It is a major challenge for formulation scientists to overcome this problem and make a robust and effective formulation. One such unique approach is to formulate the drug as nanocrystals which alter the physical characteristics of the drug, resulting in the development of a novel formulation strategy for poorly soluble drugs. Nanocrystals are produced by various techniques such as top-down, bottom-up, or combination methods. Nanocrystals improve the clinical application of problematic drug molecules by decreasing the particle size, enhancing the dissolution rate and reducing the dose requirement, etc. This approach is not only improving the bioavailability of the drug but also facilitates the drug targeting to specific sites due to its feasibility of surface modification and all administration routes. This article deals with the various aspects of nanocrystals including chemistry, production, stabilization, characterization, and application in the field of pharmacy.

Neutralisation of SARS-CoV-2 by monoclonal antibody through dual targeting powder formulation.

Neutralising monoclonal antibody (mAb) is an important weapon in our arsenal for combating respiratory viral infections. However, the effectiveness of neutralising mAb has been impeded by the rapid emergence of mutant variants. Early administration of broad-spectrum mAb with improved delivery efficiency can potentially enhance efficacy and patient outcomes. WKS13 is a humanised mAb which was previously demonstrated to exhibit broad-spectrum activity against SARS-CoV-2 variants. In this study, a dual targeting formulation strategy was designed to deliver WKS13 to both the nasal cavity and lower airways, the two critical sites of infection caused by SARS-CoV-2. Dry powders of WKS13 were first prepared by spray drying, with cyclodextrin used as stabiliser excipient. Two-fluid nozzle (TFN) was used to produce particles below 5μm for lung deposition (C-TFN formulation) and ultrasonic nozzle (USN) was used to produce particles above 10μm for nasal deposition (C-USN formulation). Gel electrophoresis and size exclusion chromatography studies showed that the structural integrity of mAb was successfully preserved with no sign of aggregation after spray drying. To achieve dual targeting property, C-TFN and C-USN were mixed at various ratios. The aerosolisation property of the mixed formulations dispersed from a nasal powder device was examined using a Next Generation Impactor (NGI) coupled with a glass expansion chamber. When the ratio of C-TFN in the mixed formulation increased, the fraction of particles deposited in the lung increased proportionally while the fraction of particles deposited in the nasal cavity decreased correspondingly. A customisable aerosol deposition profile could therefore be achieved by manipulating the mixing ratio between C-TFN and C-USN. Dual administration of C-TFN and C-USN powders to the lung and nasal cavity of hamsters, respectively, was effective in offering prophylactic protection against SARS-CoV-2 Delta variant. Viral loads in both the lung tissues and nasal wash were significantly reduced, and the efficacy was comparable to systemic administration of unformulated WKS13. Overall, dual targeting powder formulation of neutralising mAb is a promising approach for prophylaxis of respiratory viral infections. The ease and non-invasive administration of dual targeting nasal powder may facilitate the widespread distribution of neutralising mAb during the early stage of unpredictable outbreaks.

Nanocarriers for ocular drug delivery: Recent advances and future opportunities.

Topical route of administration is very important and the most commonly used method of drug delivery for treatment of ocular diseases. However, due to unique anatomical and physiological barriers of eye, it is difficult to achieve the therapeutic concentration in the targeted tissue within the eye. To overcome the effect of these barriers in absorption and to provide targeted and sustained drug delivery, various advances have been made in developing safe and efficient drug delivery systems. Various formulation strategies for ocular drug delivery are used, like basic formulation techniques for improving availability of drugs, viscosity enhancers, and use of mucoadhesives for drug retention and penetration enhancers to promote drug transport to the eye. In this review, we present a summary of the current literature to understand the anatomical and physiological limitations in achieving adequate ocular bioavailability and targeted drug delivery of topically applied drugs and use of new techniques in formulating dosage forms in overcoming these limitations. The recent and future advances in nanocarrier-mediated drug delivery may have the potential to provide patient-friendly and noninvasive techniques for the treatment of diseases related to the anterior and posterior segments of the eye.

Local Delivery Strategies for Peptides and Proteins into the CNS: Status Quo, Challenges, and Future Perspectives.

Over the past decades, peptides and proteins have been increasingly important in the treatment of various human diseases and conditions owing to their specificity, potency, and minimized off-target toxicity. However, the existence of the practically impermeable blood brain barrier (BBB) limits the entry of macromolecular therapeutics into the central nervous systems (CNS). Consequently, clinical translation of peptide/protein therapeutics for the treatment of CNS diseases has been limited. Over the past decades, developing effective delivery strategies for peptides and proteins has gained extensive attention, in particular with localized delivery strategies, due to the fact that they are capable of circumventing the physiological barrier to directly introduce macromolecular therapeutics into the CNS to improve therapeutic effects and reduce systemic side effects. Here, we discuss various local administration and formulation strategies that have shown successes in the treatment of CNS diseases using peptide/protein therapeutics. Lastly, we discuss challenges and future perspectives of these approaches.