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(別紙)

専攻分野及び研究計画
Field of Study and Research Plan

Name in full,
in your native language

(姓名(自国語)) Sartika , Ayu Try


(Surname) (Given name) (Middle name)

Name in Roman capital letters

(姓名(ローマ字)) Sartika , Ayu Try


(Surname) (Given name) (Middle name)

Nationality

(国 籍) Indonesia

Proposed study program in Japan (Outline your field of study on this side and the specifics of your study
program on the reverse side of this sheet. This section is one of the most important references for
selection. This form must be typewritten or written in block letters. Additional sheets of paper may be
attached if necessary. If plagiarism or fraud is discovered after selection, the selection will be
cancelled retroactively.)
日本での研究計画;この研究計画は、選考及び大学配置の重要な参考となるので、表面に専攻分野の概要を,裏面
に研究計画の詳細を具体に記入すること。記入はタイプ又は楷書によるものとし、必要な場合は別紙を追加しても
よい。なお、採用後に不正、盗用等が判明した場合は遡って採用を取り消す。

If possible, please write in Japanese. (相当の日本語能力を有する者は日本語により記入すること。)

1 Present field of study(現在の専攻分野)

Based on my research interest and experience in the specific field of pharmaceutics, I think that drug
bioavailability and drug disposition to specific targets are essential to provide an effective and
efficient medication to patients. Nanoparticle as one of methods in improving a drug's physicochemical
properties and delivery has been being developed to achieve the goal for approximately two decades since
many drug substances marketed need to turn into an effective therapy. Anti-tubercular drugs (ATDs) for
instance, currently encountering microbial resistance due to patient's low compliance, while
nanoparticle based dosage form is a topic I would like to pursue can enhance ATDs bioavailability to
slowly release the drugs and deliver it to specific target in the lungs to be able to use effectively
and safely. This topic contains physical pharmacy, pharmaceutical formulation as well as drug delivery
along with the knowledge of pharmacokinetics, microbiology, and biomolecular.

2 Your research topic in Japan: Describe articulately the research you wish to carry out
in Japan. (渡日後の研究テーマ:日本においてどういった研究がしたいかを明確に記入すること)

Research title: "Formulation and Evaluation of Inhalable Chitosan Nanoparticles based Drug Powder
Inhalation against Mycobacterium Tuberculosis for an Effective Treatment of Tuberculosis"

This study will elucidate how pulmonary drug delivery works in the specific target of lung and prolongs
the drug effect in the site by formulating ATDs (Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol)
into inhalable chitosan and examining the physicochemical properties, the potency against M. tuberculosis
as well as the drug disposition to alveolar of lung by in vitro method, in order to obtain the the
effective administration of ATDs. Several researches had been conducted to formulate a controlled release
dosage form for ATDs administered by inhalation.

A recent study performed by Debnath et al (2017) formulated chitosan nanoparticles based drug powder
inhalation loaded with the second line ATDs (prothionamide), evaluated the characteristics of the powder
as well as conducted in vivo study towards rats. Based on the results, dry powder of prothinamide
nanoparticles has effective delivery for pulmonary administration, shows sustained release compared to
pure prothionamide, and maintains drug concentration in rat lungs.

The research outcomes reveal that chitosan nanoparticles based dry powder inhalation can be an effective
treatment for tuberculosis. However, the effectiveness of the formulation against Mycobacterium
tuberculosis should be evaluated and its release to specific target in lungs (alveolar) should be
analyzed as well to ensure that the dosage form provides effective anti-microbial activity and
specifically works in targeted tissue. Therefore, the research topic I plan to perform will assess these
aspects. Moreover, first line (Isoniazid, Rifampicin, Pyrazinamide, Ethambutol) ATDs will be formulated
as chitosan nanoparticles since the drugs are widely used for tuberculosis therapy and the chitosan
nanoparticles are considered excellent for inhalation based on the literature review arranged by
Parumasivam et al (2016).

3 Research plan in Japan: (Describe in detail and with specifics — particularly concerning the ultimate
goal(s) of your research in Japan)
(研究計画:詳細かつ具体に記入し、特に研究の最終目標について具体的に記入すること。)

My proposed research will evaluate how the optimal formulation and characterization of chitosan
nanoparticles based dry powder inhalation are that will provide sustained release effect. This study is
also to understand how the effectiveness of chitosan nanoparticle to against M. tuberculosis and the
impact of the formulation to disposition in targeted tissue. By assessing these questions, it is expected
that the results offer a solution for effective medication of tuberculosis which can increase patient
adherence in consuming ATDs so that drug resistance can be prevented and support tuberculosis eradication
in Indonesia particularly, and Japan as well since Japan is categorized as medium-burden country, and
eradication in world generally since World Health Organization (WHO) has established a program to end
tuberculosis by 2030. Furthermore, the novel knowledge of pulmonary drug delivery can be a reference for
pharmaceutical education and research that can be applied further in Indonesia for other related
pulmonary diseases.

To carry out the research and achieve the research goals, methodology I plan to approach is by means of
forming nanoparticles coated with liposome and being formulated as dry powder inhalation. As stated by
Lee et al (2016), nanotechnology-based drug delivery systems offer a promising solution as their
nanostructured systems are highly effective in encapsulating considerable amount of tuberculosis drugs,
highly stable, feasible for various administration routes including inhalation and this approach also
significantly contributes to higher bioavailability as well as minimizing tuberculosis drug resistant
issue. Meanwhile, chitosan nanoparticles have been proved feasible to deliver drugs through inhalation
instead of giving sustained release and protecting drugs form degradation Furthermore, Parumasivam et al
(2016) listed the advantages of inhalation for treatment of tuberculosis compared to conventional
administrations that are allowing a high drug concentration in the lung which can reduce the frequency of
dosing; targeting alveolar macrophages which harbor M. tuberculosis cells; as well as directing
absorption of active agents into systemic circulation bypassing hepatic first-pass metabolism could avoid
the degradation of drug by the acidic environment in the stomach. Hence, by considering the factors
above, chitosan nanoparticles based dry powder inhalation will be my concern methodology along with the
evaluation of its physicochemical properties, delivery to specific tissue in lung, and its microbial
activity.

Research methodology:
a. Preparation of chitosan nanoparticles
Chitosan nanoparticle is prepared by ionotropic gelation method. Amount of chitosan is dissolved in
1% acetic acid pH 5. Different amounts of Isoniazid (INH), Rifampicin (RIF), and Pyrazinamide (PRZ)
are added to the chitosan solution under stirring. Tripolyphosphate (TPP) is added to the mixture of
chitosan, INH, RIF, and PRZ under stirring.(1,2)
b. Preparation of dry powder inhalation
Inhalable nanoparticle is prepared by spray-drying the liposomal anti-tubercular drug with leucine
from 0.5 nozzle. Inlet and outlet temperature are maintained at about 150 degree celcius and 95
degree celcius respectively. Spray dried powder is collected in sample collector.(1,3)
c. Characterization of dry powder inhalation
The characterization includes morphology and size of nanoparticles, zeta potential, as well as
aerodynamic characteristics. Surface morphology of nanoparticles is analyzed by using Scanning
Electron Microscopy (SEM) to observe visualization the nanoparticle shape. Dynamic Light Scattering
(DLS) is used to analyze nanoparticles-size and polydispersity index. Surface charge of the
nanoparticles is observed by Zetasizer. Meanwhile, the aerodynamic characteristics are performed
using multistage liquid impringer (MLI). This characterization is to analyze the dispersion
properties of the drug powder that is delivered by Aerolizer device by determining fine particle
fraction (FPF).(1,3,4)
d. Evaluation of encapsulation efficiency
This evaluation is carried out to determine amount of drug that is trapped in nanoparticles. The
nanoparticles suspensions are separated by centrifugation. The loading capacity (LC) of nanoparticles
are evaluated by measuring the absorption of the supernatant using UV spectrophotometer. The
corresponding calibration curves are made by testing the supernatant of blank nanoparticles (without
drugs). The absorption is measured at maximum wavelength of each drugs encapsulated in
nanoparticles.(5)
e. In vitro evaluation of inhalable chitosan nanoparticles
This evaluation is performed by determining the anti-microbial activity of the formulation,
pharmacokinetics and deposition of the formulation in lung. In vitro cell culture model is used to
examine the anti-microbial activity of inhalable chitosan nanoparticles. This evaluation is carried
out by THP-1 cell line-derived macrophages infected with M. tuberculosis.(4) It provides a
homogeneous population that mimics the behavior of primary human alveolar macrophages. While in vitro
release model using lung epithelial cells is an evaluation to study the pharmacokinetics and
mechanism of trans-epithelial transport of inhaled drugs and small drug molecules. Calu-3 cell line
is chosen as in vitro model to examine those purposes.(6,7)

Research Timeline:
Year 2020
Study month 6 7 8 9 10 11 12
a. Preparation of chitosan nanoparticles
b. Preparation of dry powder inhalation
c. Characterization of dry powder inhalation
- Morphology and size
- Polidispersity index
- Surface charge
- Particle aerodynamic
d. sEvaluation of encapsulation efficiency
e. In vitro evaluation of inhalable chitosan nanoparticles
- In vitro cell culture model
- In vitro release model

References:
1. Garg T., Rath G., Goyal A. K. Inhalable chitosan nanoparticles as antitubercular drug carriers for an
effective treatment of tuberculosis. Artificial Cells, Nanomedicine, and Biotechnology: 1-5 (2015).
2. Bhavya M. V., Gowda D. V., Srivastava A., Aravind Ram A. S., Osmani R. A. M. Development and
Characterization of Ethionamide loaded microparticles as Dry Powder Inhalers for Multi-drug Resistant
Tuberculosis. Der Pharmacia Lettre 8 (8): 273-279 (2016).
3. Podda G. Chitosan and PLGA Microspheres as Drug Delivery System Against Pulmonary Mycobacteria
Infections (Dissertation). University of Cagliari Department Farmaco Chimico Tecnologico.
4. Parumasivam T., Chang R. Y. K., Abdelghany S., Ye T. T., Britton W. J., Chan H. Dry powder inhalable
formulations for anti-tubercular therapy. Advanced Drug Delivery Reviews xxx: xxx–xxx (2016).
5. M. Rajan, V. Raj. Formation and characterization of chitosan-polylacticacid-polyethylene glycol-
gelatin nanoparticles: A novel biosystem for controlled drug delivery. Carbohydrate Polymers 98: 951–
958 (2013).
6. Ong H. X., Traini D., Young P. M. Pharmaceutical applications of the Calu-3 lung epithelia cell line.
Expert Opin. Drug Deliv. 10 (9): 1287-1302 (2013).
7. Paranjpe M., Müller-Goymann C. C. Nanoparticle-Mediated Pulmonary Drug Delivery: A Review. Int. J.
Mol. Sci. 15: 5852-5873 (2014).
8. Debnath S. M., Saisivam S., Debanth M., Omris A. Development and evaluation of Chitosan nanoparticles
based dry powder inhalation formulations of Prothionamide. Plos One. 1-12 (2018).
9. Lee W. H., Loo C. Y., Young P. M., Traini D. The Potential of Nanotechnology for Tuberculosis
Treatment. SM Group (2016).

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