Drug delivery to the brain via the nasal route of administration: exploration of key targets and major consideration factors

정승현,장지훈,이용복 한국약제학회 2023 Journal of Pharmaceutical Investigation Vol.53 No.1

Background Cranial nerve-related diseases such as brain tumors, Alzheimer’s disease, and epilepsy are serious diseases that continue to threaten human. Brain-related diseases are increasing worldwide, including in the United States and Korea, and these increases are closely related to the exposure to harmful substances and excessive stress caused by rapid industrialization and environmental pollution. Drug delivery to the brain is very important for the effective prevention and treatment of brainrelated diseases. However, due to the presence of the blood–brain barrier and the extensive first-pass metabolism effect, the general routes of administration such as oral and intravenous routes have limitations in drug delivery to the brain. Therefore, as an alternative, the nasal-brain drug delivery route is attracting attention as a route for effective drug delivery to the brain. Areas covered This review includes physiological factors, advantages, limitations, current application status, especially in clinical applications, and the necessary factors for consideration in formulation development related to nasal-brain drug delivery. Expert opinion The nasal-brain drug delivery route has the advantage of enhancing drug delivery to the brain locally, mainly through the olfactory route rather than the systemic circulation. The nasal-brain lymphatic system has recently attracted attention, and it has been implied that the delivery of anticancer drugs to the brain nervous system is possible effectively. However, there are limitations such as low drug permeability, as well as nasal mucosa and the mucociliary system, as obstacles in nasal-brain drug delivery. Therefore, to overcome the limitations of nasal-brain drug delivery, the use of nanocarriers and mucoadhesive agents is being attempted. However, very few drugs have been officially approved for clinical application via the nasal-brain drug delivery route. This is probably because the understanding of and related studies on nasal-brain drug delivery are limited. In this review, we tried to explore the major considerations and target factors in drug delivery through the nasal-brain route based on physiological knowledge and formulation research information. This will help to provide a mechanistic understanding of drug delivery through the nasal-brain route and bring us one step closer to developing effective formulations and drugs in consideration of the key factors for nasal-brain drug delivery.

Strategies for non-invasive delivery of biologics

Chung, Seung Woo,Hil-lal, Taslim A.,Byun, Youngro Informa Healthcare 2012 JOURNAL OF DRUG TARGETING Vol.20 No.6

<P>Macromolecular therapeutics, in particular, many biologics, is the most advancing category of drugs over conventional chemical drugs. The potency and specificity of the biologics for curing certain disease made them to be a leading compound in the pharmaceutical industry. However, due to their intrinsic nature, including high molecular weight, hydrophilicity and instability, they are difficult to be administered via non-invasive route. This is a major quest especially in biologics, as they are frequently used clinically for chronic disorders, which requires long-term administration. Therefore, many efforts have been made to develop formulation for non-invasive administration, in attempt to improve patient compliance and convenience. In this review, strategies for non-invasive delivery, in particular, oral, pulmonary and nasal delivery, that are recently adopted for delivery of biologics are discussed. Insulin, calcitonin and heparin were mainly focused for the discussion as they could represent protein, polypeptide and polysaccharide drugs, respectively. Many recent attempts for non-invasive delivery of biologics are compared to provide an insight of developing successful delivery system.</P>

In vitro Nasal Cell Culture Systems for Drug Transport Studies

Cho, Hyun-Jong,Termsarasab, Ubonvan,Kim, Jung-Sun,Kim, Dae-Duk The Korean Society of Pharmaceutical Sciences and 2010 Journal of Pharmaceutical Investigation Vol.40 No.6

Growing interest in the nasal route as a drug delivery system calls for a reliable in vitro model which is crucial for efficiently evaluating drug transport through the nasal cells. Various in vitro cell culture systems has thus been developed to displace the ex vivo excised nasal tissue and in vivo animal models. Due to species difference, results from animal studies are not sufficient for estimating the drug absorption kinetics in humans. However, the difficulty in obtaining reliable human tissue source limits the use of primary culture of human nasal epithelial cells. This shortage of human nasal tissue has therefore prompted studies on the "passage" culture of nasal epithelial cells. A serially passaged primary human nasal epithelial cell monolayer system developed by the air-liquid interface (ALI) culture is known to promote the differentiation of cilia and mucin gene and maintain high TEER values. Recent studies on the in vitro nasal cell culture systems for drug transport studies are reviewed in this article.

In vitro Nasal Cell Culture Systems for Drug Transport Studies

조현종,Ubonvan Termsarasab,김정선,김대덕 한국약제학회 2010 Journal of Pharmaceutical Investigation Vol.40 No.6

Growing interest in the nasal route as a drug delivery system calls for a reliable in vitro model which is crucial for efficiently evaluating drug transport through the nasal cells. Various in vitro cell culture systems has thus been developed to displace the ex vivo excised nasal tissue and in vivo animal models. Due to species difference, results from animal studies are not sufficient for estimating the drug absorption kinetics in humans. However, the difficulty in obtaining reliable human tissue source limits the use of primary culture of human nasal epithelial cells. This shortage of human nasal tissue has therefore prompted studies on the “passage” culture of nasal epithelial cells. A serially passaged primary human nasal epithelial cell monolayer system developed by the air-liquid interface (ALI) culture is known to promote the differentiation of cilia and mucin gene and maintain high TEER values. Recent studies on the in vitro nasal cell culture systems for drug transport studies are reviewed in this article.

In vitro Nasal cell Culture Systems for Drug Transport Studies

( Hyun Jong Cho ),( Ubonvan Termsarsab ),( Jung Sun Kim ),( Dae Duk Kim ) 한국약제학회 2010 Journal of Pharmaceutical Investigation Vol.40 No.6

Growing interest in the nasal route as a drug delivery system calls for a reliable in vitro model which is crucial for efficiently evaluating drug transport through the nasal cells. Various in vitro cell culture systems has thus been developed to displace the ex vivo excised nasal tissue and in vivo animal models. Due to species difference, results from animal studies are not sufficient for estimating the drug absorption kinetics in humans. However, the difficulty in obtaining reliable human tissue source limits the use of primary culture of human nasal epithelial cells. This shortage of human nasal tissue has therefore prompted studies on the “passage” culture of nasal epithelial cells. A serially passaged primary human nasal epithelial cell monolayer system developed by the air-liquid interface (ALI) culture is known to promote the differentiation of cilia and mucin gene and maintain high TEER values. Recent studies on the in vitro nasal cell culture systems for drug transport studies are reviewed in this article.

Nanoemulsions loaded Carbopol® 934 based gel for intranasal delivery of neuroprotective Centella asiatica extract: in–vitro and ex–vivo permeation study

Maneesh Jaiswal,Arun Kumar,Shivani Sharma 한국약제학회 2016 Journal of Pharmaceutical Investigation Vol.46 No.1

The objective of the present study was to develop a formulation for sustained release of phytotherapeutics through nasal membrane for brain targeting (anti- Alzheimer) in order to overcome their low residence time and poor nasal permeability issues. A dual approach containing nanoemulsions within gel (NE-gels) was used to achieve the objectives utilizing biocompatible biomaterials. Nanoemulsions were characterized for particle size and zeta potential. NE-gels loaded with Centella asiatica (CA) extract were developed using Carbopol® 934 and were characterized for rheological properties (spreadability, viscosity), drug release and prolong anti-oxidant profile. In vitro nasal permeation and free radical scavenging activity were performed to investigate their expected sustained pharmacological responses. With increasing Carbopol ® content, viscosity of NE-gels was found to increase up to 6237.3 ± 1.1 cp which adversely influenced the spreadability (3.06 ± 0.98) of the NE-gels. Enhancement in sustained release of the CA extract across the nasal membrane (four fold; up to 48 h) as well as retention time in nasal cavity (four fold; i.e. 48 h) were observed with NEgels in comparison to CA solution (i.e. 12 h). In vitro nasal permeation study showed 10 folds enhancement of percentage drug permeation across the nasal mucosa in comparison to extract solution while three folds increase in free radical scavenging activity was observed by NE-gel (i.e.48 h) in comparison to nanoemulsion (i.e. 24 h), respectively. Extensive in vitro investigation established these nanocarriers as suitable nanoformulations for brain targeting of water insoluble phytochemicals.

Applicability of Hyper-Gravity for Enhancing Nasal Drug Delivery Efficiency

Dongjoo KIM,Soonjo KWon 한국생물공학회 2017 한국생물공학회 학술대회 Vol.2017 No.4