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.

Recent advances in polymeric drug delivery systems

Yong Kiel Sung,Sung Wan Kim 한국생체재료학회 2020 생체재료학회지 Vol.24 No.2

Background: Polymeric drug delivery systems have been achieved great development in the last two decades. Polymeric drug delivery has defined as a formulation or a device that enables the introduction of a therapeutic substance into the body. Biodegradable and bio-reducible polymers make the magic possible choice for lot of new drug delivery systems. The future prospects of the research for practical applications has required for the development in the field. Main body: Natural polymers such as arginine, chitosan, dextrin, polysaccharides, poly (glycolic acid), poly (lactic acid), and hyaluronic acid have been treated for polymeric drug delivery systems. Synthetic polymers such as poly (2-hydroxyethyl methacrylate), poly(N-isopropyl acrylamide)s, poly(ethylenimine)s, dendritic polymers, biodegradable and bio-absorbable polymers have been also discussed for polymeric drug delivery. Targeting polymeric drug delivery, biomimetic and bio-related polymeric systems, and drug-free macromolecular therapeutics have also treated for polymeric drug delivery. In polymeric gene delivery systems, virial vectors and non-virial vectors for gene delivery have briefly analyzed. The systems of non-virial vectors for gene delivery are polyethylenimine derivatives, polyethylenimine copolymers, and polyethylenimine conjugated bio-reducible polymers, and the systems of virial vectors are DNA conjugates and RNA conjugates for gene delivery. Conclusion: The development of polymeric drug delivery systems that have based on natural and synthetic polymers are rapidly emerging to pharmaceutical fields. The fruitful progresses have made in the application of biocompatible and bio-related copolymers and dendrimers to cancer treatment, including their use as delivery systems for potent anticancer drugs. Combining perspectives from the synthetic and biological fields will provide a new paradigm for the design of polymeric drug and gene delivery systems.

Microchannel system for rate-controlled, sequential, and pH-responsive drug delivery

Yang, Dasom,Lee, Jung Seung,Choi, Chang-Kuk,Lee, Hong-Pyo,Cho, Seung-Woo,Ryu, WonHyoung Elsevier 2018 ACTA BIOMATERIALIA Vol.68 No.-

<P><B>Abstract</B></P> <P>Controlled delivery of drug at a constant rate, in a sequential order, or responsive to environment conditions has been pursued for a long time to enhance the efficacy of therapeutic molecules and to minimize side effects of highly potent drugs. However, achieving such delicately-controlled delivery of a drug molecule is non-trivial and still remains a challenge. We propose the use of microchannels to control the rate, sequence, and pH-responsiveness of drug delivery for high precision and predictability. In this study, we introduce elementary drug delivery units consisting of micro-reservoirs and microchannels that have variations in their lengths, widths, numbers, and straightness. The release study demonstrates that the release rates of model drugs can be modulated by the design of microchannels. Finite element modeling of drug release predicts the performance of the drug delivery units with high accuracy. The possibility of sequential drug delivery is also demonstrated using biodegradable polymer plug in microchannels. Finally, pH-responsive delivery of drugs in microfluidic units is also discussed and demonstrated via cell viability tests.</P> <P><B>Statement of Significance</B></P> <P>In this work, we developed microchannel-based drug delivery devices whose release rate could be accurately calculated and controlled by design of microchannel geometry. Although there have been many advances in microfabricated drug delivery systems, in particular, reservoir-based systems, no systematic investigation has been made to utilize the release channels. In our work, an equivalent electrical circuit concept was applied to the microfluidic systems for more detailed design and analysis. A microfluidic channel was regarded as an electrical resistor; their diffusion/electrical flux could be tuned with geometric factors such as length, width, a number of channel/resistor and their connections. Furthermore, from delivery rate control using channel geometry, multifunctional channel-based release systems for sequential and pH-responsive were demonstrated.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

약국서비스 만족에 영향을 미치는 요인 분석 : 환자체감시간과 실 조제시간 비교를 중심으로

박성희,서준규,윤혜설,홍진영,박군제 한국의료QA학회 1998 한국의료질향상학회지 Vol.5 No.2

Purpose : To shorten processing time for variety of medical affairs of the patient at the outpatient clinic of a big hospital is very important to qualify medical care of the patient. Therefore, patient's waiting time for drug delivery after doctor's prescription is often utilized as a strong tool to evaluate patient satisfaction with a medical care provided. We performed this study to investigate factors influencing patient satisfaction related with waiting time for drug delivery. Methods : The data were collected from July 21 to August 12, 1998. A total 535 patients or their families who visited outpatient clinics of Inha University Hospital were subjected to evaluate the drug delivery time and the level of their satisfaction related, which were compared with those objectively evaluated by Quality Improvement Team. The reliability of the scale was tested with Cronbach's alpha, and the data were analyzed using frequency, t-test, ANOVA, correlation analysis and multiple regression. Results : The mean drug delivery time subjectively evaluated by the patient (16.1 13.0 min) was longer than that objectively evaluated (10.9 7.6 min) by 5.2 min. Drug delivery time objectively evaluated was influenced by the prescription contents, total amount or type of drug dispensed, etc, as expected. The time discrepancy between two evaluations was influenced by several causative factors. One of those proved to be a patient's late response to the information from the pharmacy which the drug is ready to deliver. Interestingly, this discrepancy was found to be more prominent especially when waiting place for drug delivery was not less crowded. Other factors, pharmaceutical counseling at the pharmacy, emotional status or behavior of a patient while he waits for the medicine, were also found to influence the time subjectively evaluated. Regarding the degree of patient satisfaction with the drug delivery, majority of patients accepted drug delivery time with less than 10 min. It was also found to be influenced by emotional status of the patient as well as kindness or activity of pharmaceutical counselor. Conclusion : The results show that, besides prescription contents, behavior pattern or emotional status of a patient, environment of the waiting place, and quality of pharmaceutical counseling at the pharmacy, may influence the patient's subjective evaluation of waiting time for drug delivery and his satisfaction related with the service in the big hospital. In order to improve patient satisfaction related with waiting time for drug delivery, it will be cost effective to qualify pharmaceutical counseling and information system at the drug delivery site or waiting place rather than to shorten the real processing time within the pharmacy.

Emerging nanomaterials with advanced drug delivery functions; focused on methotrexate delivery

Choi, Goeun,Kim, Tae-Hyun,Oh, Jae-Min,Choy, Jin-Ho Elsevier 2018 Coordination Chemistry Reviews Vol.359 No.-

<P><B>Abstract</B></P> <P>This review focuses on therapeutic applications of various drug delivery nanovehicles encapsulated with the anti-cancer drug, methotrexate (MTX). Currently, a number of studies have been conducted to explore advanced chemotherapeutic systems with nonviral nanovehicles such as liposomes, polymeric micelles, polymersomes, solid lipids, dendrimers, porous metal and metal oxide particles, carbons with various nanostructures, and layered double hydroxides (LDHs). Out of various anticancer drugs, MTX was hybridized with those drug delivery nanovehicles not only to overcome its adverse effects, but also to induce advanced functions into those hybrid systems, such as enhanced solubility, controlled release, passive and active targeting, aimed to eventually enhance bioavailability of MTX. In particular, two dimensional LDHs are introduced rather in detail as one family of inorganic nanovehicles, since the therapeutic efficacies for MTX-LDHs have been systematically studied with <I>in vivo</I> orthotopic models, those which are clinically better correlated and therefore, more efficient to predict drug efficacy and toxicity than the standard one like xenograft model. Attempts are also made here to provide therapeutic results on chemically well defined MTX-LDH advanced drug delivery systems, such as their <I>in vitro</I> and <I>in vivo</I> targeting functions, biocompatibility and nanotoxicities and ability to overcome drug resistance. In addition, recent advances and challenges in advanced hybrid DDSs are discussed from the viewpoint of state-of-the-art nanomedicine.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Organic and inorganic drug delivery vehicles. </LI> <LI> Enhanced therapeutic efficacy of anti-cancer drug, Methotrexate. </LI> <LI> Two dimensional drug delivery systems based on layered double hydroxides. </LI> <LI> Nano-toxicity of drug delivery vehicles and their nanohybrids with drug. </LI> <LI> Targeting functions of drug delivery systems evidenced by orthotopic and xenograft mice models. </LI> </UL> </P>

Polymeric Tube-Shaped Devices with Controlled Geometry for Programmed Drug Delivery

박민,최영빈,박천권,이승호,이지은,조은빛,Mark R. Prausnitz 한국고분자학회 2012 Macromolecular Research Vol.20 No.9

We developed a modular tube-shaped device as a proof of principle to enable the programmed release of encapsulated molecules for controlled drug delivery. Each drug-delivery tube module was prepared by assembling two separate silicone tubes in a series, one filled with a model compound (sodium fluorescein) and the other with a diffusional barrier material (polyethylene oxide, PEO). We varied the length of the PEO-filled tubes to control the release from the drug-delivery tube devices. The onset times and periods of drug release increased with the length of the PEO tube. To program the drug release, therefore, we prepared devices with combinations of drug-delivery tube modules with different lengths of PEO-filled tubes. Using PEO-filled tubes with very different lengths achieved a pulsatile drug release while a continuous drug release was realized by using PEO-filled tubes with small differences in length. We concluded that the modular combination of drug-delivery tubes, each composed of a diffusionbarrier tube of different length, demonstrates good potential for applications in programmed drug delivery.

일반연구논문 ; 마약수사에서의 통제배달기법 고찰 - 마약류관리에관한법률위반사범 중 밀수범죄와 관련하여 -

예상균 ( Sang Kyun Ye ) 한국법정책학회 2015 법과 정책연구 Vol.15 No.2

우리나라는 마약 청정국으로 분류되고 있다. 그 만큼 국가에서 강력한 의지를 가지고 마약 통제정책을 실시하고 있다는 의미이다. 강력한 마약 통제정책은 국내에서의 마약유통을 근절하는 것뿐만 아니라 국외로부터의 마약반입을 원천적으로 봉쇄하겠다는 의미도 포함한다. 마약의 국내제조가 사실상 사라진 현시점에서 마약통제 정책을 효과적으로 달성하려면 해외로부터의 마약반입 차단이 무엇보다도 중요하다. 결국 공항 및 항만 등에서 엄격한 감시체계를 구축하여 여행객 내지 수화물에 대한 철저한 감시의 필요성이 높아졌다고 할 수 있다. 그러나 현재 출입국 및 통관절차는 서비스적 측면이 부각되어 간편한 출입국 심사, 신속한 통관절차를 지향하고 있는 실정이므로 수화물 등에 대한 철저한 감시는 매우 어려운 일이다. 그렇다면 최첨단 기술을 이용한 간편하고 신속한 검사 및 정보 축적을 통한 마약 혐의자에 국한된 조사만이 현재의 서비스 정신에 충실한 사정이다. 마약밀수 사건에서는 통제배달 수사기법이 종종 사용되고 있다. 사람이 직접 마약을 운반하는 경우보다는 국제우편 및 소포를 통하여 한국으로 마약이 반입되는 것이 더 빈번히 발생하는 일이기 때문이다. 마약이 들어있는 우편물의 이동경로를 따라 실제 반입자를 추적하여야만 이를 수입하고자 했던 범인들을 검거할 수 있다. 최근에는 통제배달의 前단계에서 세관직원이 압수·수색영장 없이 국제우편물을 개봉한 후 시료를 채취한 행위가 적법한지, 수사기관이 압수·수색영장 없이 통제배달 수사기법을 활용한 것이 불법이 아닌지에 대한 유의미한 대법원 판결이 선고되었다. 통제배달 수사기법과 관련된 일련의 과정에 영장주의를 관철하려는 주장들은 세관에서의 해당 우편물의 검사과정 자체를 강제수사인 압수·수색으로 보거나 수사기관이 마약을 확보한 사실 자체를 강제수사인 압수로 보아 이에 대한 영장을 발부받지 아니한 채 배달한 것 자체가 위법하다는 견해를 제시하고 있는 것으로 보인다. 그러나 세관 통관절차에서의 검사는 수사개시 이전단계로서 이에 대하여 형사 소송법적 잣대를 일률적으로 적용하기에는 어려운 점이 있고, 통제배달 수사기 법은 용어 자체적으로도 수사기관의 압수를 전제로 하지 않을 뿐만 아니라 ‘마약류의 분산을 방지하기 위하여 충분한 감시체제가 확보되어 있는 마약류범죄의 수사’기법이기 때문에 배달과정에서의 수사기관의 마약확보를 강제수사인 압수로 보기에는 어렵다. South Korea is classified as a drug-free country. It means that South Korea government carries out the powerful drug control policy with strong will. Powerful drug control policy means it will fundamentally block the importation of drugs from abroad as well as it will eradicate drug trafficking in the country. In order to achieve the drug control policies efficiently, It is most important to block the import of drugs from abroad at the present time domestic production of drug is disappeared. Eventually, it increases the need to establish a strict monitoring system in the airport and port can be a need for thorough monitoring of the traveler and luggage. But, now immigration and customs clearance procedures are highlighted by this easy and speedy service aspect, so it is very difficult to make a perfect surveillance for the traveler and luggage. Then, the speedy surveillance by using high-tech and the limited investigation on the drug suspect by acuumulating information are the only way which agree with the present service mind. Controlled delivery is often used in the case of drug smuggling, because the drug import case by international mail or package more often happens than the direct personal delivery case. The only way to arrest the real importer is to trace the true receiver along the path of movement of the mail containing the drug. Recently, the supreme court ruling was sentenced whether it is legal or not that customs agent open the international package without search and seizure warrant at the previous step of controlled delivery and whether it is illegal or not that investigator do controlled delivery without search and seizure warrant. The arguments which attain its goals of warrant ideology at the controlled delivery procedure consider the screening of the mail by Customs and the possession of drug by investigator as compulsory investigation like search and seizure. So they assert that the controlled delivery without warrant is illegal. But, Criminal procedure yardstick is diffiult to be applied in all cases in point that the inspection at the customs clearence process is prior to the beginning of an investigation. Controlled delivery, the term of itself is not based upon a premise of investigator`s seizure. And because Controlled delivery is drug crime investigation techniques equipped with sufficient monitoring system in order to prevent the spread of drug, it is not seizure as compulsory investigation that the investigator has a possession of drug.

Designing a drug delivery system for improved tumor treatment and targeting by functionalization of a cell-penetrating peptide

Shafq Al‑azzawi,Dhafir Masheta 한국약제학회 2019 Journal of Pharmaceutical Investigation Vol.49 No.6

Antitumor drugs activity is often limited due to the lack of satisfactory tumor specificity and bioavailability. Therefore, it is essential to conjugate the antitumor drug to a specific delivery system that can discriminate between tumors and normal tissue, and potentiate the activity. Purpose: the study was aimed to design a delivery system employing a cell-penetrating peptide, TAT, functionalized with a tumor targeting peptide, CREKA, and loaded with antitumor drug via a biodegradable linkage. Methods: the delivery system was synthesized using solid phase peptide synthesis and characterized by mass spectra and HPLC technique. Confocal microscopy and flow cytometry were used to examine the cellular uptake of the drug conjugate by malignant and normal cells whereas cell viability was tested to assess its cytotoxicity. Inhibition assay on dihydrofolate reductase (DHFR) to study the drug conjugate efficacy, and its stability examination were also performed. Results: characterization results confirmed successful synthesis of the delivery system and its conjugation with the drug. In addition, cellular translocation studies revealed higher cellular uptake of drug conjugate by malignant cell. The results also showed a better efficacy of the drug in conjugation in cytotoxicity and in the inhibition of DHFR and more stability at neutral pH medium. Conclusion: the functionalization with CREKA targeted the delivery of the antitumor drug to the malignant breast cells, decreasing its distribution to the normal cells. Hence this study demonstrated the potential of the designed delivery system to be used in delivering and translocating of therapeutic agents into a specific tumor tissue.

In vivo and in vitro testing of the efficacy of a novel drug delivery fabric

( Ji Yeon Hong ),( Won Jong Oh ),( Tae Rin Kwon ),( I Song Im ),( Sun Young Choi ),( Beom Joon Kim ),( Chang Kwun Hong ) 대한피부과학회 2015 대한피부과학회 학술발표대회집 Vol.67 No.2

Background: Transdermal drug delivery systems provide more reliable and consistent administration than oral routes because they avoid the effects of digestive degradation and first-pass liver metabolism. However, penetration of any compound through the skin is prevented primarily by the epidermis. Objectives: We assess the efficacy of a novel fabric for drug delivery, with the aim of developing an improved method for transdermal drug delivery. Methods: Guinea pigs were divided into a control group and three test groups; treated with slimming cream and no fabric, 100% cotton fabric, or our novel fabric. The amount of fat loss was evaluated by histological staining. The skin penetrance of rhodamine B base was assessed using a fluorescence penetration test and the transdermal penetration of caffeine was also evaluated in vitro using Franz diffusion cells each. Results: Drug delivery with our novel fabric resulted in reduction in adipocyte size after 28 days. The fabric also enhanced the transdermal delivery of rhodamine B base and caffeine penetration compared with the control groups. Conclusion: Our novel drug delivery fabric is an effective way to enhance the transdermal delivery of slimming cream. This fabric can potentially be used to enhance the transdermal delivery of several agents, including drugs.

A drug-delivery strategy for overcoming drug resistance in breast cancer through targeting of oncofetal fibronectin

Saw, Phei Er,Park, Jinho,Jon, Sangyong,Farokhzad, Omid C. Elsevier 2017 NANOMEDICINE Vol.13 No.2

<P><B>Abstract</B></P> <P>A major problem with cancer chemotherapy begins when cells acquire resistance. Drug-resistant cancer cells typically upregulate multi-drug resistance proteins such as P-glycoprotein (P-gp). However, the lack of overexpressed surface biomarkers has limited the targeted therapy of drug-resistant cancers. Here we report a drug-delivery carrier decorated with a targeting ligand for a surface marker protein extra-domain B(EDB) specific to drug-resistant breast cancer cells as a new therapeutic option for the aggressive cancers. We constructed EDB-specific aptide (APT<SUB>EDB</SUB>)-conjugated liposome to simultaneously deliver siRNA(siMDR1) and Dox to drug-resistant breast cancer cells. APT<SUB>EDB</SUB>-LS(Dox,siMDR1) led to enhanced delivery of payloads into MCF7/ADR cells and showed significantly higher accumulation and retention in the tumors. While either APT<SUB>EDB</SUB>-LS(Dox) or APT<SUB>EDB</SUB>-LS(siMDR1) did not lead to appreciable tumor retardation in MCF7/ADR orthotropic model, APT<SUB>EDB</SUB>-LS(Dox,siMDR1) treatment resulted in significant reduction of the drug-resistant breast tumor. Taken together, this study provides a new strategy of drug delivery for drug-resistant cancer therapy.</P> <P><B>Graphical Abstract</B></P> <P>A novel multi-drug resistance cancer therapy – EDB targeting liposome simultaneously encapsulating MDR-1 siRNA and doxorubicin for targeted, co-delivery of drug for the treatment of drug resistant breast cancer.</P> <P>[DISPLAY OMISSION]</P>