Hanoi university

of Pharmacy

CÔNG NGHỆ NANO

ỨNG DỤNG TRONG DƯỢC PHẨM

May 15, 2023

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of Pharmacy

Nội dung

• Lịch sử và đại cương về công nghệ nano và ứng

dụng nano trong ngành Dược

• Tiểu phân thuốc nano và các hệ tiểu phân nano

mang thuốc

• Các phương pháp bào chế tiểu phân nano

• Ví dụ

2 May 15, 2023

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LỊCH SỬ - GIỚI THIỆU

May 15, 2023

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Công nghệ nano

•Thuật ngữ "công nghệ nano" lần đầu tiên được sử
dụng vào năm 1974 (Tiến sĩ Nori Taniguchi)*
•Khoa học nano là ngành nghiên cứu về tính chất và
những đặc tính riêng có của kích cỡ nano (bao gồm :
sinh hóa, từ tính, quang học, điện tử, ...)
•Công nghệ nano trong dược phẩm: ứng dụng những
kiến thức của công nghệ nano vào nghiên cứu phát triển
thuốc.
•Thuốc nano: là loại thuốc dùng để điều trị hoặc chẩn
đoán hình ảnh chứa tiểu phân nano để kiểm soát sự
phân bố của thuốc vào cơ thể, nâng cao hiệu lực, hoặc
giảm độc của thuốc hoặc chế phẩm sinh học (Bobo et al.
2016)
*Tiền tố “nano” bắt nguồn từ chữ Hy lạp “lùn” và một nanomet (nm) bằng
một phần tỷ của mét (= 10-9 m)
•
4 May 15, 2023
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Công nghệ nano trong tự nhiên

Các hiệu ứng nano trong tự nhiên:
tính chất siêu kỵ nước (chống nước) của một số loại lá cây,
khả năng thay đổi màu sắc của động vật

Ref. http://www.sciencebuzz.org/nano

5 May 15, 2023

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Thay đổi các tính chất vốn có

Ví dụ:
Vàng có thể xuất hiện màu đỏ, xanh dương hoặc tím ở kích thước nano.
Các hạt nano sắt phân tán tạo hỗn dịch nano trong chất lỏng, chúng sẽ
trở thành một loại chất lỏng có từ tính

6 May 15, 2023

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Lịch sử phát triển kỹ thuật nano

1959            Richard Feynman có ý tưởng khởi xướng
1974            Thuật ngữ công nghệ nano được Nori Taniguhi sử dụng lần đầu tiên
1975            Khái niệm về PEGylation của các loại thuốc protein
1981            Kính hiển vi quét xuyên hầm được IBM phát minh
1985            “Bucky Balls” * phân tử hình quả bóng tạo thành bằng carbon và có đường kính xấp xỉ một nanomet
1986             Cuốn sách đầu tiên về công nghệ nano “Động cơ sáng tạo” xuất bản bởi K. Eric Drexler,
Kính hiển vi lực nguyên tử (Atomic force microscope)
1989             Logo IBM được tạo ra với các nguyên tử riêng lẻ
1989             Chất mang đưa thuốc từ hệ micell block copolymer đã được giới thiệu bởi Kataoka và Okano
(Kabanov phát triển triblock Pluronic® micelles làm chất mang thuốc)
1991             Sumio Iijima đã khám phá ra carbon nanotube
1995             Sản phẩm chứa liposome-doxorubicin Doxil® đã trở thành hệ đưa thuốc kích thước nano đầu tiên
được cho phép sử dụng trong lâm sàng
1999             Cuốn sách nanomedicine đầu tiên của R. Freitas: “Nano medicine” được xuất bản

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Richard Phillips Feynman

• Nhà vật lý lý thuyết người Mỹ, ông được biết đến với công trình

nghiên cứu về cơ học lượng tử, lý thuyết về điện học lượng tử và

tính chất vật lý siêu lỏng của helium lỏng siêu lạnh

• Giải Nobel Vật lý năm 1965

• Giới thiệu khái niệm về Công nghệ nano Richard P. Feynman (1918-1988)

• Có bài nói chuyện nổi tiếng về công nghệ nano top-down với tên

gọi “There's Plenty of Room at the Bottom“ (1959)

• Hỗ trợ trong việc phát triển bom nguyên tử trong Thế chiến II và là

thành viên của ban điều tra về thảm họa tàu vũ trụ Challenger
10 May 15, 2023
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Nanopharmacy - Nanodrug - Nanopharmaceutical

Pharmaceuticals engineered on the nanoscale, ie,

pharmaceuticals where the nanomaterial plays the pivotal

therapeutic role or adds additional functionality to the previous

compound

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Nanomedicine
• Ứng dụng trong chẩn đoán: Chẩn đoán hình ảnh, chẩn
đoán bằng các thiết bị nano

• Phóng thích thuốc có kiểm soát, phóng thích tại đích tác
dụng (Controlled and targeted drug delivery)

• Regenative medicine: Cấu trúc để tế bào và mô tự phục

hồi, tái sinh

• Theranostic: kết hợp của cả chẩn đoán và điều trị

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Ứng dụng kỹ thuật nano trong ngành Dược

1.Nghiên cứu hệ đưa thuốc có kiểm soát được bắt đầu khoảng 1950

2.Hệ đưa thuốc có kiểm soát đầu tiên (Spansules) xuất hiện vào những năm 1950 (hệ đưa
thuốc chứa dexedrine)

3.Vào giữa những năm 1960, xuất hiện các hệ đưa thuốc mới: dạng nang silicon cấy vào
cơ thể chứa thuốc và dạng liposomes

4.Những năm 1970 và 1980, thuốc cấy dưới da, và miếng dán ngoài da chứa thuốc tránh
thai được sản xuất

5.Sự phát triển của các hệ đưa thuốc có kích thước nano được bắt đầu năm 1970 cùng
lúc với hệ đưa thuốc có kích thước macro

6.Vào giữa những năm 1980, hệ đưa thuốc chứa tiểu phân PLGA tự phân huỷ được sử
dụng cho thuốc cấy dưới da
13 May 15, 2023
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Quá trình phát triển

Bào chế và SDH 1 - D4 - PBT 14 May 15, 2023

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of Pharmacy

Khó khăn trong việc phát triển thuốc dạng nano

Độ ổn định kém: ổn định về mặt vật lý, sinh học, ổn

định trong dạng thuốc, đường dùng….

Khả năng nâng cấp quy mô sản xuất (sai số trong quá
trình sản xuất, kiểm soát quá trình sản xuất, an toàn…)

Khó kiểm soát và dự đoán độc tính của dạng thuốc

nano

Định lượng và đánh giá hoạt tính sinh học, đáp ứng
sinh học của các dạng thuốc nano
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Ứng dụng công nghệ nano trong hệ đưa thuốc

• Phối hợp tác dụng (sử dụng đơn thuần sẽ ko có tác

dụng hoặc độc tính quá cao) (Mepact)

• Hướng đến nhiều cơ chế tác dụng (Nanomag)

• Tối đa hoá tác dụng, giảm liều và độc tính

• Đưa thuốc hướng đích (một cách có kiểm soát, chọn

lọc đích, ưu tiên phân phối, tăng vận chuyển qua các
hàng rào của cơ thể )

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Quá trình phát triển từ liposome -> Doxil

17 May 15, 2023

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of Pharmacy

Quá trình phát triển các dạng thuốc nano

18 May 15, 2023

 been used in the design of potential nanoparticle thera- aspects of both these phenomena. For example, a recent
peutics so far are limited in scope. In one study, lipo- report investigated the effect of particle size and shape
Hanoi university
Timeline | Development of nanoparticle therapeutics
somes that had albumin covalently bound to the surface on the rate of particle internalization
ex vivo, displayed extended circulation times compared non-spherical particles50. A clear correlation between the
Anti-tumour
in HeLaPEG–protein
approved for
cells using
clinical use
conjugate
142

of Pharmacy
1960s first biologically active polymer (divinyl
ether-maleic anhydride copolymer) clinically
to their naked or PEGylated counterparts40. The authors shape and size of the particles onLong-circulating
Ringsdorf first describes
attributed this behaviour to reduced opsonin binding on zation was observed. Furthermore, it was shown that
polymer–drug
the rate of internali-
polymeric
PEGylated
nanoparticles reported165

evaluated but later proved too toxic158,159

exposure to plasma 40
. In a separate
conjugates 137 but related study, the particles with similar volumes but different shapes were
First PEG–protein conjugate
same authors observed improved pharmacokinetic and internalized at vastly entersdifferent rates. It142was
market (Adagen ) also shown
Polymer–drug Bangham pharmacodynamic properties of albumin-coated lipo- recently that the geometry of interaction between a cell
conjugate
reported134
discovers
liposomes135,136
First liposomal–drug
somes containing
formulation reported 160 doxorubicin comparedPLA to nanoparticle
PEGylated
reported 162
Maeda discovers Long-circulating PEGylated
and
EPR
aeffect
particle
61 can induce
liposomes
or inhibit
reported
internalization
163
51
, and
liposomes . Comparing albumin-coated liposomes to that shape has a significant impact on biodistribution48.
39

their PEGylated equivalents, they observed decreased Filamentous engineered nanoparticles that have single
accumulation in the liver, the spleen and the heart, dimensions as long as 18 μm exhibit circulation half-
1955 1964 1965 1972 increased1973 accumulation
1974 in the tumour
1975 1976 and an overall 1983
1981 lives of 1986
~5 days, which 1989 is even longer than
1990 1992the half-life1994 1995
greater than twofold increase in the therapeutic index of of ‘stealth’ liposomes . 55

the drug, which displays dose-limiting cardiotoxicity. Methods for incorporating cargo into engineered
First controlled- Particle size is also
Drug-loaded, known to influence the mechanism
albumin- nanoparticles, with regard to thePolymer-based
First micelle formulation ultimate delivery of
nanoparticle
release polymer of cellular
basedinternalization
nanoparticle
42–44
— that is, phagocytosis, the cargo to the desired location enters
approved (Cremophor, in vivo, cantrials
clinical be classi-
164

device reported 157

macropinocytosis,
reported 161
caveolar-mediated endocytosis or fied into two broad categories. In one category, the
Sandimmune) 142

Taxol approved by FDA

Albumin-based clathrin-mediated endocytosis (FIG. 2) —
Polymer-based which in turn cargo is physically entrapped
First controlled-release in or absorbed
(Cremophor onto142
+ paclitaxel)
nanoparticle nanoparticle the nanoparticle
formulation through
approved non-covalent
by interactions. The
first reported138 reported140 second category includes examples in which
FDA (Zoladex) 142
the cargocapable of
Nanoparticles
has been directly attached to the nanoparticle matrix crossing BBBbyreported166
Targeted polymer–drug First targeted delivery degradable or non-degradable covalent bonds. The use
First liposomal
conjugate enters clinical trials169 of siRNA in humans81
General events are marked by a green border, molecular systems by a blue border, self-assembled systemsofbystimuli-responsive a black border and materials, which will formulations be discussed approved by
nanoparticles, as defined below, by a yellow border. Definition ofnanoparticle
First protein-based nanoparticle: nanoparticles for pharmaceutical in more detailare
purposes below,
definedallows FDA (Doxil,
as for the release of the cargo Abelcet)142

solid colloidal particles ranging

Controlled-release polymerin size from 1 nmapprovedto 1,000 bynm. They consist
FDA (Abraxane) 142
of macromolecular materials and can be
once theused therapeutically
engineered nanoparticle reaches its intended
for brain cancer
as drug carriers, in which approved
the active principle (drug or biologically active material) is dissolved, entrapped or
by FDA (Gliadel)142 Shape-specific nanoparticles for location in vivo. The bulkthe
encapsulated, or to which composition of the engineered
active principle is adsorbed or attached. Abraxane, paclitaxel protein-bound particles for injectable suspension (Abraxis/AstraZeneca);
Adagen, PEG–adenosine
drug delivery reported85
deaminase (Enzon); BBB, blood–brain barrier; Copaxone, glatiramer acetate for injection
First biologically active
nanoparticle must be carefully chosen based on its bio-
(Teva Pharmaceuticals);
and retention; FDA, US Foodcompatibility , its immunotoxicity 31 and its ability to
56,57
Cremophor, polymer approved by FDA castor oil (BASF);Preclinical
polyoxyethylated studies of permeability
EPR, enhanced targeted and Drug Administration;
(Copaxone) dendrimer–drug conjugate
solubilize orcyclosporine
sequester the cargo of interest.
142 171
Gliadel, polifeprosan 20 with carmustine implant (Eisai); PEG, polyethylene glycol; PLA, polylactic acid; Sandimmune,
injection (Novartis); Zoladex, goserelin acetate implant (AstraZeneca). Beyond these basic features of nanoparticle design,
a multitude of approaches for targeting specific cellular
1996 1999 2002 2004 2005 2006 2009 populations or for altering the biodistribution of engi-
neered nanoparticles in vivo are being developed58,59.
616 | AUGUST 2010 | VOLUME 9 Targeting has been achieved using three predominant
www.nature.com/reviews/drugdisc
Anti-tumour Preclinical studies of bow-tie
dendrimer–drug doxorubicin-conjugated
strategies that rely on either passive or active modes
© 20 10 Macmillan Publishers Limited. All rights reserved
conjugate reported167 dendrimers172 of action, which can be further characterized as non-
Synthetic polymer First in vivo studies using
selective or selective.
anticancer drug conjugate drug-loaded The first form of targeting is only relevant to oncol-
enters clinical trial168 polymersomes173
ogy applications, and relies on the accumulation of
Cremophor-free, polymeric
engineered nanoparticles in tumours by the enhanced
micelle-formulated paclitaxel permeability and retention effect 60,61(see also BOX 1).
completes Phase I trials143
This accumulation is a passive, non-selective process
First polymer-based micelle 19 that occurs due to leaky, underdeveloped tumour vascu- May 15, 2023
formulation of doxorubicin
lature that allows macromolecules of a certain size range
 macropinocytosis, caveolar-mediated endocytosis or fied into
Hanoi university clathrin-mediated endocytosis (FIG. 2) — which in turn cargo is
the nano
of Pharmacy second c
has been
Targeted polymer–drug First targeted delivery degrada
conjugate enters clinical trials169 of siRNA in humans81
of stimu
First protein-based nanoparticle in more
Controlled-release polymer
for brain cancer approved
approved by FDA (Abraxane)142 once the
by FDA (Gliadel)142 Shape-specific nanoparticles for location
First biologically active
drug delivery reported85 nanopar
polymer approved by FDA Preclinical studies of targeted compati
(Copaxone)142 dendrimer–drug conjugate171
solubiliz
Beyo
a multit
1996 1999 2002 2004 2005 2006 2009 populat
neered
Targetin
Anti-tumour Preclinical studies of bow-tie
dendrimer–drug doxorubicin-conjugated
strategie
conjugate reported167 dendrimers172 of action
Synthetic polymer First in vivo studies using
selective
anticancer drug conjugate drug-loaded The f
enters clinical trial168 polymersomes173
ogy app
Cremophor-free, polymeric
enginee
micelle-formulated paclitaxel permea
completes Phase I trials143
This acc
First polymer-based micelle that occ
formulation of doxorubicin
translated to clinic
20170
lature th
May 15, 2023
to accum
 REVIEWS

Cell membrane-coated
NPs developed to evade Ferumoxytol
immune response100 as an imaging
First controlled- agent to
Liposome release polymer Protein predict EPR
structure system for ionic Discovery Liposomal First targeted siRNA biomarkers and nano-
was molecule and of the EPR doxorubicin (Doxil) polymeric NP (CALAA-01) for predicting therapeutic
published223 macromolecules225 e ect7,8 approved by FDA6 entered clinical trials227 EPR e ect73,74 response63

1964 1976 1980 1986 1994 1995 2005 2007 2008 2010 2011 2014 2015

Sustained First targeted Long PRINT technology Polymeric micelle Iron oxide NP First targeted, controlled-
delivery of liposomes152,153 circulating developed212 paclitaxel (NanoTherm) release polymeric NP (BIND-014)
low molecular PLGA-PEG (Genexol-PM) received entered clinical trials229
weight NPs93 Nab-paclitaxel marketed in Korea226 European
compounds (Abraxane) regulatory
using silicone approved by FDA6 approval for
polymer224 cancer
treatment228

Figure 1 | Historical timeline of major developments in the field of cancer nanomedicine. EPR, enhanced
permeability and retention; FDA, US Food and Drug Administration; nab, nanoparticle albumin‑bound; NatureNP, nanoparticle;
Reviews | Cancer
PLGA-PEG, poly(d,l‑lactic-co-glycolic acid)-b‑poly(ethylene glycol); PRINT, particle replication in non‑wetting template;
siRNA, small interfering RNA.

by antigen-presenting cells, sustained release of antigens has been made to address the effect of EPR on nano-
or adjuvants and NP-mediated phagosome escape of therapeutic efficacy. Several preliminary clinical studies
antigens for cross-presentation4,48–50. have already suggested the value of stratifying subpopu-
 Liposome
Liposome 10% 20%
10%
10%
Polymer (15)
Hanoi universityPolymer
20%
20% Polymer
Nanocrystal
Nanocrystal (15)
of PharmacyNanocrystal
Nanocrystal
Inorganic
Inorganic (5)
30%
30%
30% Inorganic
Inorganic
Micelles
Micelles (1)
Progress in Nanomedicine:
Micelles Approved and Investigational
Micelles 34% Nanodrugs Proteins
Proteins (2)
34%
34%
Proteins
Proteins
preclinical and clinical studies have shown that nanoformu
Figure 1 Types of Nanoparticles in Approved and can passively enhance tumor accumulation, decreasing
Investigational Drugs tissue exposure.2 However, the clinical validation of ac
A. Types of NPs in Approved Drugs Available for Clinical Use targeting
B. Types is more
of NPs limited and Drugs
in Investigational not as(60)
easily
2 achieved.5

(50)1,13,14 Another way nanopharmaceutical formulations can

cancer treatment
2%
2% is through the incorporation of dru
2% long-circulating NPs that remain active for an extended
3%
3% Lipsome
Liposome(33)
Liposome
4% of time. 5
Consequently, tumor sites experience longe
Lipsome
Liposome(10) sure to the drugs due to the slow rate of Polymer
drug release
Polymer (11) fr
15%
15%
10% 20% NP and the retention of the drug-loaded NPs in the v
Polymer (15) Nanocrystal
Nanocrystal (2)
Nanocrystal
compartment.5
Nanocrystal
Nanocrystal (15) 3%
3%
Inorganic
Inorganic (2)
Inorganic
Potential Safety Benefits
3%
3%
Inorganic
Inorganic (5) The increased drug56% 56%
accumulation in diseased
Micellestissue
Micelles
Micelles (9) p
30%
Micelles
Micelles (1) by nanoformulations may allow the effective dose of a
18%
18% Proteins (1)
Proteins
Proteins
be reduced, diminishing side effects.7 It has been ob
34% Proteins
Proteins (2) that typically less than 0.01% of an injected dose of(2)ang
Dendrimer
Dendrimer
Dendrimer
sized agents accumulates in a target region, compared
5% for NPs.7 Better accumulation, as well as targeted r
can enable dose reduction, which decreases side ef
2
In fact, the earliest nanodrugs were granted approval
B. Types of NPs in Investigational Drugs (60) a Th1-type
FDAresponse
based onagainst intracellular
lower toxicity pathogens.
compared with9,10 Pol
conve
22D,L-lactic acid-co-glycolic acid copolymer May 15, 2023
(PLGA) NPs hav
formulation2% counterparts. 7
Doxil (doxorubicin hydroch
 Abraxane, with annual revenue estimated at $967 million d
(Table 2), is one of the major success stories in the e
a
t
Table 2. Worldwide annual sales of marketed nanoparticle-based drug delivery
systems in $ millions. [
Nano-delivery system License holder/manufacturer Annual sales 2015 t
Oncology a
Abraxane Abraxis, AstraZeneca 967a t
b
Doxil Janssen 181 r
Marqibo Spectrum Pharma 8a
DepoCyt Sigma-Tau/Pacira 4.6a
Infections c
AmBisome Astellas/Gilead 350a i
CNS
Diprivan AstraZeneca 200 b a
Other r
Visudyne Novartis/Valeant 70b i
CNS: central nervous system. m
a
From company website.
b
From evaluategroup.com.
a
 P olyme ric a nd lipid na nopa rticle s :
Hanoi university ~1–100 nm or la rge r
Micros phe re s : > ~1 µm
of Pharmacy
Fig . 45.1 • Approximate size range of various nanomedicines.

Table 45.1 Examples of licensed products that can be considered as nanomedicines

Product Drug Type of system Attributes offered by the nanotechnology

Abraxane® Paclitaxel Nanoparticles These albumin-bound nanoparticles increase the delivery of
paclitaxel by overcoming the low solubility of paclitaxel and
improving tumour cell drug delivery.
Caelyx®/ Doxorubicin Liposomes This formulation contains PEGylated liposomes which can increase
Doxil® systemic circulation times and enhance delivery to tumour sites.
Emend® Aprepitant Nanoparticles These nanoparticles are prepared by a wet milling method and
increase drug solubility and bioavailability.
Mepact® Mifamurtide Liposomes Entrapping the drug within liposomes facilitates drug delivery and
activation of macrophages.
Myocet® Doxorubicin Liposomes Incorporation of doxorubicin into liposomes increases tumour
tissue distribution and reduces cardiac toxicity.
Pegasys® Interferon 2a Polymer-protein Pegylation improves the stability of the protein.
conjugate
Rapamune® sirolimus Nanoparticles The formulation of a nanodispersion stabilized with poloxamer
offers increased stability and bioavailability.
Zevalin® Ibritumomab Antibody-conjugate Conjugation of a radio-isotope to the antibody promotes targeting
tiuxetan and destruction of B-cells.

24 May 15, 2023

Table 1 FDA-Approved Nanodrugs Available for Clinical Use1,2,6,13,14,23
Trade Name (Manufacturer) Generic Name
Liposome NPs
Curosurf (Chiesi USA) Poractant alfa
Doxil (Janssen)
Abelcet (Sigma-Tau)
AmBIsome (Gilead Sciences)
DepoDur (Pacira
Pharmaceuticals)
DepoCyt (Sigma-Tau)
Marqibo (Spectrum
Pharmaceuticals)
Onivyde (Ipsen
Biopharmaceuticals)
Visudyne (Bausch and Lomb)
Vyxeos (Jazz
Pharmaceuticals)
Polymer NPs
Adagen (Leadiant
Biosciences)
Adynovate (Shire)
Cimzia (UCB)
Copaxone (Teva)
Eligard (Tolmar)
Krystexxa (Horizon)
Macugen (Bausch and Lomb) Pegaptinib
Mircera (Vifor)
Neulasta (Amgen)
Oncaspar (Baxalta U.S.)
Pegasys (Genentech)
PegIntron (Merck)
Plegridy (Biogen)
Rebinyn (Novo Nordisk)
(available in 2018)
Renvela (Genzyme); and
Renagel (Genzyme)
Somavert (Pfizer)
Zilretta (Flexion Therapeutics) Triamcinolone acetonide ER
Micelle NPs
Estrasorb (Novavax)
Doxorubicin HCl liposome
injection
Liposomal amphotericin B
lipid complex
Liposomal amphotericin B
Liposomal morphine
sulphate
Liposomal cytarabine
Liposomal vincristine
Liposomal irinotecan
Liposomal verteporfin
Liposomal daunorubicin
and cytarabine
Pegademase bovine
Antihemophilic factor
(recombinant), pegylated
Certolizumab pegol
Glatimer acetate
Leuprolide acetate
and polymer
Pegloticase
Methoxy polyethylene
glycol-epoetin beta
Pegfilgrastim
Pegaspargase
Pegylated IFN alpha-2a
Pegylated IFN alpha-2b
Pegylated IFN beta-1a
Coagulation factor IX
(recombinant), glycopegylated
Sevelamer carbonate; and
Sevelamer HCl
Pegvisomant
injectable suspension
Micellar estradiol
Indication(s)* Benefit of NP**
Respiratory distress syndrome Increased delivery with smaller volume,
decreased toxicity
Danh sách các thuốc
Karposi’s sarcoma, ovarian cancer,
multiple myeloma
Fungal infections
Increased delivery to disease site,
decreased systemic toxicity of free drug
Decreased toxicity
đã được lưu hành sử
Fungal/protozoal infections
Postoperative analgesia
Decreased nephrotoxicity
Extended release
dụng công nghệ
Lymphomatous meningitis
ALL
Increased delivery to tumor site,
decreased systemic toxicity
Increased delivery to tumor site,
nano (50 thuốc)
decreased systemic toxicity
Pancreatic cancer Increased delivery to tumor site,
decreased systemic toxicity
Wet AMD, ocular histoplasmosis, Increased delivery to site of diseased
myopia vessels, photosensitive release
AML, AML with myelodysplasia- Increased efficacy through synergistic
related changes delivery of co-encapsulated agents
SCID Longer circulation time,
decreased immunogenicity
Hemophilia Greater protein stability, longer half-life
Crohn’s disease, rheumatoid Longer circulation time, greater stability
arthritis, psoriatic arthritis, in vivo
ankylosing spondylitis
Multiple sclerosis Controlled clearance
Prostate cancer Longer circulation time,
controlled payload delivery
Chronic gout Greater protein stability
Neovascular AMD Greater aptamer stability
Anemia associated with CKD Greater aptamer stability
Chemotherapy-induced neutropenia Greater protein stability
ALL Greater protein stability
Hepatitis B, hepatitis C Greater protein stability
Hepatitis C Greater protein stability
Multiple sclerosis Greater protein stability
Hemophilia B Longer half-life, greater drug levels
between infusions
CKD Longer circulation time and
therapeutic delivery
Acromegaly Greater protein stability
Osteoarthritis knee pain Extended release
Ventola CL. Progress in Nanomedicine: Approved and
Vasomotor symptoms in menopause Controlled delivery Investigational Nanodrugs. Pharmacy and
table continues Therapeutics. 2017;42(12):742-755.
 Progress in Nanomedicine: Approved and Investigational Nanodrugs

Table 1 FDA-Approved Nanodrugs Available for Clinical Use1,2,6,13,14,23 (continued)

Trade Name (Manufacturer) Generic Name Indication(s)* Benefit of NP**
Danh sách các
Nanocrystal NPs
Avinza (Pfizer) Morphine sulfate Psychostimulant Greater drug loading and bioavailability, ER
thuốc đã được
EquivaBone (Zimmer Biomet) Hydroxyapatite Bone substitute Mimics bone structure
Emend (Merck)
Focalin (Novartis)
Aprepitant
Dexamethylphenidate HCl
Antiemetic
Psychostimulant
Greater absorption and bioavailability
Greater drug loading and bioavailability
lưu hành sử
Invega Sustenna (Janssen) Paliperidone palmitate Schizophrenia, schizoaffective
disorder
Slow release of injectable
low-solubility drug dụng công nghệ
Megace ES (Par Megestrol acetate Antianorexic Lower dosing
Pharmaceuticals)
NanOss (RTI Surgical) Hydroxyapatite Bone substitute Mimics bone structure
nano (50 thuốc)
Ostim (Heraeus Kulzer) Hydroxyapatite Bone substitute Mimics bone structure
OsSatura (IsoTis Hydroxyapatite Bone substitute Mimics bone structure
Orthobiologics)
Rapamune (Wyeth Sirolimus Immunosuppressant Greater bioavailability
Pharmaceuticals)
Ritalin LA (Novartis) Methylphenidate HCl Psychostimulant Greater drug loading and bioavailability
Ryanodex (Eagle Dantrolene sodium Malignant hypothermia More rapid rate of administration
Pharmaceuticals) at higher doses
Tricor (AbbVie) Fenofibrate Hyperlipidemia Greater bioavailability simplifies administration
Vitoss (Stryker) Calcium phosphate Bone substitute Mimics bone structure
Zanaflex (Acorda) Tizanidine HCl Muscle relaxant Greater drug loading and bioavailability
Inorganic NPs
Dexferrum (American Regent) Iron dextran Iron deficiency in CKD Increased dose
Feraheme (AMAG Ferumoxytol Iron deficiency in CKD Prolonged, steady release
Pharmaceuticals) with less frequent dosing
Ferrlecit (Sanofi-Aventis) Sodium ferric gluconate Iron deficiency in CKD Increased dose
complex in sucrose injection
Infed (Actavis Pharma) Iron dextran Iron deficiency in CKD Increased dose
Venofer (American Regent) Iron sucrose Iron deficiency in CKD Increased dose
Protein NPs
Abraxane (Celgene) Albumin-bound paclitaxel Breast cancer, NSCLC, Greater solubility, increased
pancreatic cancer delivery to tumor
Ontak (Eisai) Denileukin diftitox Cutaneous T-cell lymphoma Targeted T-cell specificity, lysosomal escape
* Refer to complete prescribing information. Ventola CL. Progress in Nanomedicine:
** Compared with conventional formulations. Approved and Investigational Nanodrugs.
ALL = acute lymphoblastic leukemia; AMD = age-related macular degeneration; AML = acute myeloid leukemia; CKD = chronic kidney disease; ER = extended release; Pharmacy and Therapeutics.
HCl = hydrochloride; IFN = interferon; NP = nanoparticle; NSCLC = non–small-cell lung cancer; SCID = severe combined immunodeficiency disease. 2017;42(12):742-755.
Hanoi university
of Pharmacy

ƯU ĐIỂM CỦA
DẠNG THUỐC NANO

May 15, 2023

 Hanoi university
F. Dilnawaz et al. of Pharmacy
International Journal of Pharmaceutics 538 (2018) 263–278

Resistance

28 May 15, 2023

Fig. 1. (i) Hurdles faced by the native drug after systemic administration. (ii) Impediments faced by native drug are surpassed by drug in nanoformulations leading to optimum

 Hanoi university
of Pharmacy

Bào chế và SDH 1 - D4 - PBT 29 May 15, 2023

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of Pharmacy

Mục đích phát triển thuốc dạng nano ?

• Tăng độ tan - Vượt qua giới hạn độ tan (Solubility

barrier )

• Kiểm soát tốc độ giải phóng

• Vượt qua hàng rào sinh học

• Tác dụng tại đích: Chủ động và thụ động

30 May 15, 2023

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of Pharmacy

31 May 15, 2023

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of Pharmacy

Các đặc điểm riêng có của kích thước nano

• Ở mức độ nano, các tính chất hoá lý sinh của các loại vật
liệu rất khác biệt so với ban đầu.

• Các chất mang có kích thước <100nm nhỏ hơn kích

thước của tế bào và tương ứng với các enzymes, hoặc
receptors (hemoglobin 5nm, bề dày của màng lipid 6nm).

• Các tiểu phân nano có kích thước <50nm có thể dễ dàng

xâm nhập vào tế bào, kích thước <20nm có thể vào được
mạch máu, và qua được các hàng rào của cơ thể.

32 May 15, 2023

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of Pharmacy

Ưu điểm của công nghệ nano

Sử dụng công nghệ nano, giúp đạt được:

(1) Cải thiện khả năng đưa các loại thuốc ít tan trong nước;

(2) Đưa thuốc tới đích đến mức độ tế bào hoặc mô

(3) Vận chuyển được các thuốc qua màng biểu mô và thành mạch;;

(4) Đưa được các thuốc phân tử lượng lớn đến các vị trí tác dụng trong tế bào;

(5) Đồng vận chuyển hai hoặc nhiều hoạt chất để phối hợp nhều liệu pháp điều trị

(6) Trực quan hóa các vị trí đưa thuốc bằng cách kết hợp các hoạt chất với các chất dùng
trong chẩn đoán hình ảnh;

(7) Đánh giá trực tiếp về hiệu quả in vivo của các thuốc điều trị.
•

33 May 15, 2023

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of Pharmacy

PHÂN LOẠI CÁC

HỆ NANO MANG THUỐC

May 15, 2023

 other classes of nanostructures, apart from the more common nanospheres,
metals have been used to synthesis a huge range of peculiar structures, such as
Hanoi university
hollow nanospheres, nanorods, nanocubes, nanoprisms, nanocrescents, nanopyr-
of Pharmacy
amids, and many more [13,14]. It is therefore no wonder that a plethora of

Bào chế và SDH 1 - D4 - PBT 35delivery classification. NPs: nanoparticles;

Figure 6.1 Organic nanostructure for drug May 15, 2023
 techniques are time consuming, cannot reduce particle size below a certain limit
(which Hanoi
in most ofuniversity
the cases is about 150–300 nm) and of concern are issues
related to theofsolid-state
Pharmacy changes of the milled product and chemical

Bào chế và SDH 1 - D4 - PBT 36 May 15, 2023

124 6 Nanostructures in Drug Delivery

Figure 6.3 Description and characteristics of organic nanostructures for drug delivery.
 Hanoi university
of Pharmacy

Dạng nano particles

Table 9.5 Marketed products containing API nanoparticles [137,139–142,185,214].

Brand name Drug substance Drug delivery Comminution Company Dosage form Year
platform process

RapamuneTM Sirolimus Elan/Alkermes WBM Wyet/Pfizer Tablet 2000

EmendTM Aprepitant Elan/Alkermes WBM Merck & Co Capsule 2003
TricorTM Fenofibrat Abbott WBM Abbott Tablet 2004
MegaceTM ES Megestrol Elan/Alkermes WBM Par Pharmaceuticals Oral 2005
suspension
TriglideTM Fenofibrat IDD-P® /SkyePharma HPH Sciele Pharma Inc. Tablet 2005
InvegaTM Sustenna (US)/XeplionTM Paliperidone Elan/Alkermes WBM Janssen i.m. 2009
(EU) palmitate suspension
InvegaTM Trinza (US)/TrevictaTM Paliperidone Elan/Alkermes WBM Janssen i.m. 2015
(EU) palmitate suspension
ZorvolexTM Diclofenac iCeuticals Dry milling with Iroko Capsule 2013
matrix Pharmaceuticals
TivorbexTM Indomethacin iCeuticals Dry milling with Iroko Capsule 2014
matrix Pharmaceuticals

Bào chế và SDH 1 - D4 - PBT 38 May 15, 2023

 ence of iron ions (iron oxides as colorants), different precautions were taken: In
Hanoi
early university
products, the active layer was coated with a thin sucrose sugar seal layer
toward theof colorant layer. In later products, α-tocopherol was added to the
Pharmacy
final
active layer as true antioxidant and the sucrose seal layer was spared [215].

Rapamune ®
Table 9.6 Constituents of Rapamune tablets [215].
(Sirolimus, P zer)
Tablet cores Coatings

Lactose monohydrate (diluent) Nanosuspension (API + stabilizer)

Polyethylene glycol 8000 (binder)# Ethylene glycol 20 000
Magnesium stearate (lubricant) Glycerol monooleate
Talc (glidant) Pharmaceutical glace (shellac)
Calcium sulfate anhydrous
Microcrystalline cellulose
Sucrose
Titanium dioxide
Brown and yellow iron oxide
alpha-tocopherol
Povidone
Carnauba wax
Printing ink

Bào chế và SDH 1 - D4 - PBT 39 May 15, 2023

fi
 Hanoi university
of Pharmacy

Emend (Aprepitant, Merck)

9.4 Industrial Status and Framework 215

Table 9.7 Constituents of Emend® capsules [216].

Capsule filling Capsule shell Phương pháp bào chế phù hợp ???

Microcrystalline cellulose (beads) Gelatin

Hydroxypropyl cellulose Titanium dioxide
Sucrose Red and yellow iron oxides
Sodium dodecyl sulfate Printing ink (shellac, potassium hydroxide, iron oxide)

Table 9.8 Main process steps in Emend® production [216].

Step Operation

1 Production of a slurry of water, hydroxypropyl cellulose, and aprepitant

2 Premilling
3 Addition of an aqueous sodium lauryl sulfate dispersion
4 Media milling to form a colloidal dispersion
5 Addition of an aqueous sucrose dispersion
6 Spray-coating of microcrystalline cellulose beads with the colloidal dispersion
7 Sieving of the coated beads
8 Blending of coated beads with micronized sodium lauryl sulfate
9 Encapsulation of the blended beads

Bào chế và SDH 1 - D4 - PBT 40 May 15, 2023

 Hanoi university
of Pharmacy

Cơ chế kiểm soát tốc độ giải phóng của các thuốc giải
phóng có kiểm soát dựa trên hệ nano mang thuốc

Bào chế và SDH 1 - D4 - PBT 41 May 15, 2023

 2.3 Technical Realization of Nanopharmaceuticals 31

Figure 2.7 Most common nanopharmaceuticals and optional modifications.

Hanoi university
of Pharmacy

Các dạng chất mang nano

International Journal of Pharmaceutics 538 (2018) 263–278

43 May 15, 2023

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of Pharmacy

Các dạng chất mang nano

44 May 15, 2023

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of Pharmacy
Table 24.1 Pure drug nanocrystals for oral administration on the market or under preclinical and clinical trial.

Drug Commercial name/ Pharmacological activity Production method Status Reference

Company

Sirolimus Rapamune® /Wyeth Immunosuppressant Top-down, media milling Commercially [38]

available
Aprepitant Emend® /Merck Antiemetic Top-down, media milling Commercially [39]
available
Fenofibrate Tricor® /Abbott Hypercholesterolemia Top-down, media milling Commercially [39]
available
Fenofibrate TriglideTM/First Horizon Hypercholesterolemia Top-down, high-pressure Commercially [39]
Pharmaceutical homogenization available
Megestrol acetate Megace® ES/Par Appetite stimulant Top-down, media milling Commercially [39]
Pharmaceutical available
Griseofulvin Gris-PEG® /Novartis Antifungal Bottom-up, coprecipitation Commercially [40]
available
Nabilone Cesamet® /Lilly Antiemetic Bottom-up, coprecipitation Commercially [40]
available
Morphine sulfate Avinza/King Psychostimulant Top-down, ball milling Commercially [38]
Pharmaceuticals available
Dexmethylphenidate Focalin® XR/Novartis Psychostimulant in attention-deficit hyper- Top-down, ball milling Commercially [38]
HCl activity disorder (ADHD) and narcolepsy available
Methylphenidate Ritalin® LA/Novartis Psychostimulant in attention-deficit hyper- Top-down, ball milling Commercially [38]
HCl activity disorder and narcolepsy available
Tizanidine HCl Zanaflex CapsulesTM/ Muscle relaxant Top-down, ball milling Commercially [38]
Accorda available

Bào chế và SDH 1 - D4 - PBT 45 May 15, 2023

Hanoi university
of Pharmacy

F. Dilnawaz et al.
Phân loại các hệ tiểu phân nano

46 May 15, 2023

Fig. 2. Schematic depiction of mode of cellular uptake of nanoformulations in cells; A (i) Passive targeting exploits the morphological anomalies of the diseased/tumor ce
 Nanoparticle

a
Physical Structure Targeting
properties (chemical composition) ligand
NP properties

• Size • Surface • Liposomes (natural and synthetic lipids) • Small molecules

• Geometry hydrophobicity, • Polymeric NPs (degradable and non-degradable polymers) • Antibodies and
• Surface charge roughness and • Micelles (amphiphilic biomaterials) fragments
(zeta potential) curvature • Dendrimers (branched biomaterials) • Aptamers and
• Porosity • Electronic, • Protein NPs (natural or synthetic proteins) nucleic acids
• Elasticity magnetic • Viral NPs (engineered viruses and viral proteins) • Proteins and
• Sti ness and optical • Exosomes and natural membrane NPs (biological peptides
membranes) • Sugars
• Metal and metal-derived NPs (gold, silver, platinum, etc.)
• Carbon nanomaterials (various carbon allotropes)
• Hybrid NPs (combination of two or more of above)

b c d e f g Non-responsive
% ID per g tissue

Vascular Tumour cell

concentration

Drug release
Serum
Biological processes

extravasation targeting and

protein into the tumour intracellular
interactions tra cking
Plasma

micro-
environment
and tissue Time
Time penetration
Tumour
Liver
Spleen
Lung
Kidney
Heart

Stimuli-responsive
Stimulus

Drug release
Tumour cell Time
 delivery and targeting

Nanogels **

Nanoparticles **

Nazarov et al. Pharm. Chem. J. Polymer Micelles Nanocapsules **

43(2009)163
SLN
*Nanotechnology-based drug delivery systems (NDDSs)

Dendrimers Liposomes

1 nm 10 nm 100 nm 1 µm
Courtesy of Dr. L. Peltonen, University of Helsinki, Finland; Hamoudeh et al.
 Hanoi university
of Pharmacy Bobo et al.

the development
s. (a) FDA-
edicines stratified
FDA-approved
ratified by
(c) clinical trials
altrials.gov from
th arrow indicating
date of US law
quiring reporting to
d) nanomedicines
investigation
ory overall.

Bobo, D., Robinson, K. J., Islam, J., Thurecht, K. J., & Corrie, S. R. (2016). Nanoparticle-Based Medicines: A Review of FDA-
49 May 15, 2023
Approved Materials and Clinical Trials to Date. Pharmaceutical Research, 33(10), 2373–2387. doi:10.1007/s11095-016-1958-5

 Hanoi university
of Pharmacy

Công nghệ nano sử dụng trong thuốc đường

uống
• API nanoparticles

• Branched nanocarriers: dendrimers

• Polymeric micelles

• Polymeric nanoparticles: PLGA

• Nanoemulsion: self-emulsifying drug delivery systems, Neoral,

Sandimmune (nhược điểm: low control of the droplet size and size
distribution represents a disadvantage to ensure low pharmaco-
kinetic variability)

• Solid lipid nanoparticles: nanostrutured lipid carriers, SNEDDS,

Bào chế và SDH 1 - D4 - PBT 50 May 15, 2023

Table 26.1 Combined selective references for pulmonary, ophthalmic, nasal, and vaccination
routes.
API category/disease
Lung disorders
Anti-inflammatory, antiasthma,
pulmonary hypertension,
antioxidants, anticancer
Lung infections
Tuberculosis, cystic fibrosis
Nasal infections/allergies/systemic
effects
Acute rhinitis, pollen sensitivity,
hypertension, brain targeting of viral
infections, brain tumors, stroke
Ophthalmic infections/allergies/ocular
diseases of the anterior and posterior
segment of the eye
Allergic conjunctivitis, dry eye
syndrome, glaucoma, diabetic
retinopathy, wet age-related
macular degeneration (AMD)
Vaccination
Influenza
Proteins, peptides
Insulin
Surfactant, gene, antibody
Type of particle Reference
Solid lipid nanoparticles, lipid [22–28]
microparticles, liposomes
Solid lipid nanoparticles, lipid [29–31]
microparticles, liposomes
Solid lipid nanoparticles, chitosan [8,32–37]
microparticles, liposomes,
nanoemulsions
Solid lipid nanoparticles (SLN), [9,10,38–49]
lipid microparticles, polymer
nanoparticles, nanoemulsions,
liposomes
Solid lipid nanoparticles, lipid [50–54]
microparticles, virosomes, ISCOM
[55–57]
[58]
 Hanoi university
of Pharmacy

• Macugen: Thuốc tiêm chứa natri pegaptanib điều

trị thoái hoá điểm vàng

• Flumist, In exal: đường xịt mũi chứa vaccine cúm.

• Exubera, Afrezza: Insulin đường hít

52 May 15, 2023

fl

 Hanoi university
of Pharmacy

ĐẶC TÍNH SINH HỌC -VẬT LÝ

CỦA HỆ NANO

May 15, 2023

 Hanoi university
of Pharmacy

Những thông số quan trọng của một hệ nano

• Thông số về thiết kế (designed parameters)

• Thông số về điều trị (therapeutic parameters)

• Thông số về kiểm tra chất lượng (quality control

parameters)

• Thông số về tương thích sinh học (biocompatibility)

54 May 15, 2023

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of Pharmacy

55 May 15, 2023

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5.1 Drug DeliveryofNanosystems
Pharmacy 151

Table 5.1 Basic physicochemical properties of drug delivery nanosystems

Regarding to their use Regarding to their preparation and properties
Surface area Interactions between drug and nanosystems
Shape Interactions between different biomaterials
of the nanosystem
Drug release Hydrophobicity and hydrophilicity of
surfaces of nanosystems surfaces
Diffusion (i.e., tissue and mucus) Size, size distribution, and ζ-potential
Destabilization of nanosystems. Aggregation Adsorption of macromolecules onto surfaces
and/or flocculation (in vitro and in vivo)
Absorption (i.e., into biological and polymeric
membranes)
Deposition (i.e., into surfaces)
Rheology (i.e., into blood)
Flexibility (to help the movement into capillary
networks)

Bào chế và SDH 1 - D4 - PBT 56 May 15, 2023

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of Pharmacy

Đặc tính của hệ nano mang thuốc và các phương

7.1 Regulatory Framework for Nanotechnological 191giá
pháp đánh
Table 7.1 Parameters and characterization methods for the approval of nanoparticles
Parameter Method
Size distribution of and shape of Dynamic light scattering, photon correlation spectroscopy,
nanoparticles electron microscopy
Surface area, porosity Gas absorption
Surface charge, hydrophilicity Electrophoresis, ζ-potential
Surface properties Static secondary ion mass spectroscopy
Analysis of surface elements X-ray photoelectron spectroscopy
Density Pycnometer/densitometer
Molecular weight Size exclusion chromatography
Purity Spectroscopy
Polymorphism, crystalline state X-ray diffraction, thermal analysis
Solvent residues Gas chromatography
Drug release Drug release studies, turbidity

Bào chế và SDH 1 - D4 - PBT 57 May 15, 2023

 Hanoi university
F. Dilnawaz et al. of Pharmacy
International Journal of Pharmaceutics 538 (2018) 263–278

Resistance

58 May 15, 2023

Fig. 1. (i) Hurdles faced by the native drug after systemic administration. (ii) Impediments faced by native drug are surpassed by drug in nanoformulations leading to optimum

 Hanoi university
of Pharmacy

Cải thiện Sinh Khả Dụng

• Sinh khả dụng vào cơ thể

• Cải thiện độ tan của dược chất ít tan

• Tăng khả năng thấm của dược chất thấm kém

• Giúp dược chất không bị phân huỷ trong các môi

trường sinh học

• Khả năng thuốc phân bố đến mô bệnh

• Khả năng thuốc vào được tế bào bệnh (đích tác dụng
cuối cùng)

59 May 15, 2023

Figure 15.3 Molecular and physiological processes defining nanoparticle distribution in the
human body.
teristics of NPs, while critical for their therapeutic effect, have advances in nanotechnology, the in vivo performance of drug
not received adequate attention in the conventional design of delivery systems often does not meet the medical need. One
nanomedicine. For example, the clinically used liposomal for- solution to this inadequacy is to thoroughly understand drug

Figure 1. Illustration of multiple biological barriers to NPs and its delivered drugs before reaching nanoscopic targets of diseased cells. Left panel:
at the macroscopic level (non-cellular), iv administered NPs are sequestered, accumulated and eventually eliminated by mononuclear phagocytic
system (MPS) consisting mainly of the liver and spleen. In addition, the blood-brain barrier (BBB) is highly selective for many foreign substances, thus,
preventing the entry of drug containing NPs into the brain. Middle panel: at the microscopic level (non-cellular), the complex tumor microenvironment
(TME), eg, poor neo-vasculatures, dense extracellular matrix (ECM), limits the tumor permeation and retention of NPs, leading to low drug accumulation
toxicity via higher tumor specificity
Hanoi university
ors present a leaky vasculature, originally allowing nu-
necessary for sustained tumor growth. This anarchical
has been defined by Maeda as enabling Enhanced
of Pharmacy
and Retention (EPR) effect (Maeda, 2001). Liposomal
could passively target the tumor by going through the
aps (i.e., 200 nm (Sawant and Torchilin, 2012)) and be
the tumor because of deficient lymphatic drainage
clinical studies, radiotherapy has been sometimes used to
gaps by depleting the pericytes; further enhancing per-
ayashi et al., 2013) and thus tumor accumulation
l., 2008). Developing stealth agents (e.g., PEG, see above)
ategy to increase the EPR effect since the longer nano-
in the blood, the more they will pass through the
Fig. 2. Schematic representation of the EPR Effect.
2.3.1. Size
As discussed since 1999 (Nagayasu et al., 1999), size is a major
factor that impacts liposomal nanoparticle behavior, once adminis-
tered. The smaller nanoparticles are, the less they will be recognized by
MPS and be eliminated from the body (Liu et al., 1992). However it has
been demonstrated that nanoparticles < 8 nm are mostly eliminated by
the kidneys (Choi et al., 2007), not to mention a loss of stability in
plasma and therefore quicker clearance below a given size. Being too
big (i.e., > 200 nm) is also a major drawback, since it prevents nano-
particles from benefitting from the EPR Effect. Several preclinical stu-
dies have shown how size can affect the distribution phase within
tumor tissue and does indeed matter for tumor accumulation. When
testing three different batches of stealth liposomes of 5-FU of varying
size (i.e., 70–250 nm) in mice bearing resistant breast tumors, data
showed that the smaller the liposomes, the greater the tumor uptake EPR effect
Tiểu phân <8nm dễ bị thải trừ bởi thận
Tiểu phân > 200nm không có hiệu ứng
EPR
Hiệu ứng EPR có thể giúp làm tăng
phân bố thuốc gấp 2 lần
62 May 15, 2023

 Hanoi university
of Pharmacy

EPR effect
Hướng đích tác dụng bằng thụ thể hướng đích
Các thụ thể này có thể là các receptor, peptide,
kháng thể đơn dòng, receptor folate hoặc
transferin, kháng nguyên khối u,…
PT Nhiều chất mang còn được kích thích giải phóng
RI
thuốc nhờ sử dụng các cơ chế chủ động như: sự
SC

thay đổi pH, enzymes, từ trường, nhiệt độ ánh

sáng,…
U

chematic representation of active tumor cells targetingfor

N

osomes.
A
M

63 May 15, 2023

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EPR effect
Enhance Permeability
and Retention effect EPR Effect for A

64 Cancer Nanotechnology May 15, 2023

 Hanoi university
Bernabeu, E., Cagel, M.,of Pharmacy
Lagomarsino, E., Moretton, M., & Chiappetta, D. A. (2017). Paclitaxel: What has been done and the
challenges remain ahead. International Journal of Pharmaceutics, 526(1-2), 474–495. doi:10.1016/j.ijpharm.2017.05.016

Hạn chế của dạng thuốc tự do không có EPR

Figr-2

65 May 15, 2023

other structural moieties that may enhance brain tumor delivery and efficacy.
Preclinical studies of PLD with a glutathione coating (2B3-101) have also shown
promising results in brain cancer models. Glutathione, an endogenous tripeptide,

Figure 19.3 Efficacy studies in an intracranial
model of breast cancer. Median survival
(from times of intracranial cell line injection)
of animals treated with control (PBS, black),
nonliposomal doxorubicin (NonL-doxo, green)
6 mg/kg IV weekly, and PEGylated liposomal
doxorubicin (PLD, blue) 6 mg/kg IV weekly in a
murine model of intracranial breast cancer [39].
(Copyright 2013, Anders et al.).
Figure 19.4 Doc concentration versus time
curve for (a) tumor (0–168 h), (b) tumor
(0–24 h), (c) plasma, (d) lung, (e) spleen, and
(f) liver. Doc concentration values for each
•
mouse are represented by ( ) for Taxotere,
(■) for PRINT-Doc-200 × 200 particles, and (▲)
for PRINT-Doc-80 × 320 particles. The lines are
connected by the mean value for each time
point. (Adapted with permission from Ref. [47].
Copyright 2013, Elsevier Ltd.)
 Hanoi university
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CÁC LOẠI POLYMERS DÙNG

TRONG HỆ NANO

May 15, 2023

 gates (ADCs) [135,136]).
PEGylation reagents have been described using both established and recently
Hanoi university
developed conjugation functional groups [129] to undergo reaction with many
of Pharmacy
different amino acid residues on proteins [99,127,128], including nonnative
amino acid side chains (e.g., aldehyde and alkyne) [130–132]. Of the many
PEGylation reagents that have been described, those designed to undergo reduc-
tive amination with the amine of the N-terminal amino acid (PEG-aldehyde),
acylation of the lysine side chain amine (PEG-N-hydroxysuccinimide (PEG-
NHS), and Michael addition of the cysteine thiol (PEG-maleimide and PEG-bis- PEG hoá
sulfone) tend to dominate (Figure 10.4). Linear PEGylation reagents are

Figure 10.4 Common PEGylation reagents (PEG-maleimide), and the thiols from protein
designed to undergo reactions with the disulfide bonds (PEG-bis-sulfone). Both linear
terminal amine (PEG-aldehyde), other and branched reagents are often used.
protein amines (PEG-NHS), protein thiols

Bào chế và SDH 1 - D4 - PBT 69 May 15, 2023

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244 10 Nanopharmacy: Exploratory Methods for Polymeric Materials

Figure 10.5 Reductive amination used to conjugate PEG to the N-termininus of a protein.

generally
Bào chế và SDH 1 - D4 - PBT in the range of 20–30 kDa because
70 the synthesis of narrow molecular May 15, 2023
 Hanoi university
of Pharmacy

10.5 Conjugation of Polymers to Drugs and Proteins 245

Figure 10.6 PEGylation of a single cysteine thiol with PEG-maleimide.

limitations, PEG-NHS reagents are used in the manufacture of different PEG-

interferon medicines (e.g., Pegasys® and PegIntron® ).
There are many site-specific approaches that have been described
[129,130,132]. Thiol alkylation from a cysteine thiol with an α,β-unsaturated car-
Bào chế và SDH 1 - D4
bonyl - PBT addition reaction) is rapid 71
(Michael in mild conditions that are conducive May 15, 2023
546 22 Nanoparticles for Imaging and Imaging Nanoparticles: State of the Art and Current Prospects

Figure 22.5 Biodistribution of chromium-
doped persistent luminescence nanoparticles
(PLNPs) following systemic administration in
living mice. The left image corresponds to the
biodistribution of negatively charged PLNPs
that largely accumulate within liver. The right
image shows the biodistribution of the same
nanoparticles after PEG grafting that manage
to evade the global reticuloendothelial reten-
tion. (Adapted with permission from Ref. [23].
Copyright 2011, American Chemical Society.)

to counter opsonization and scavenging by the mononuclear phagocyte system,

thereby preventing the formation of the protein corona [80].
428 17 Nanoparticle Toxicity: General Overview and Insights Into Immunological Compatibility

Figure 17.1 The role of nanoparticle distribution in drug toxicity. Nanoparticles may change bio-
distribution of the drug. Altered distribution results in altered toxicity.
 Hanoi university
of Pharmacy

Polymers tự nhiên dùng trong hệ mang thuốc

nano

Bào chế và SDH 1 - D4 - PBT 74 May 15, 2023

PTMC is generally synthesized by the ROP of trimethylene carbonate (TMC)
Hanoi
which university
is commercially available. TMC is usually prepared from 1,3-propanediol
and ethyl of
chloroformate
Pharmacy or from oxetane and carbon dioxide [203,204]. Nano-
particles [205,206], microparticles [207], and gels [208] have been prepared from
PTMC but more often it has been copolymerized with PLA (poly(lactide)) [209]
Cácto loại
or PCL [210] polymer
improve nhân
its drug delivery tạo có khả năng tự phân
potential.
huỷ sinh học
Figure 10.13 (1) Two-stage synthesis method (a) free CPT and (b) CPT-loaded PPDL-co-PBSu
for copolymerization of ω-pentadecalactone, nanoparticles. Cells and CPT are visualized in
diethyl succinate, and 1,4-butanediol. (2) the red and blue channels, respectively [214].
Confocal microscopic images of Lewis lung (Reproduced with permission from Ref. [214],
carcinoma cells after 2 h incubation with Copyright 2009, Elsevier Ltd.)

Figure 10.11 Structures of commonly used biodegradable polyesters.

Figure 10.14 Structures of lactide and glycolide-derived polymers.

75 May 15, 2023

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10.3 Polymer Structures and Properties 235

Figure 10.1 Examples of block copolymers are shown the arrangement of a linear
homopolymer, a diblock, an A + B + A and A + B + C triblock copolymers, a random or statistical
copolymer, and a dendrimer.

Bào chế và SDH 1 - D4 - PBThydrophilic component to enable dispersion

76 in aqueous media or the blood- May 15, 2023
 Hanoi university
of Pharmacy

• Genexol-PM

3 Schematic presentation of NK911 [49], NK012 [50], NC-6004 [51], and Genexol-
icelles.
Bào chế(Reproduced with
và SDH 1 - D4 permission from Refs [49–51]. 77
- PBT Copyright 2004 [49] and 2005 May 15, 2023
 Hanoi university
of Pharmacy

Các loại polymer tự nhiên tự phân huỷ sinh học

• Chitosan ???

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of Pharmacy

Polymeric micells

Bào chế và SDH 1 - D4 - PBT 79 May 15, 2023

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of Pharmacy

KỸ THUẬT BÀO CHẾ HỆ NANO

May 15, 2023

 Hanoi university
of Pharmacy

Kỹ thuật bào chế nano

• Kỹ thuật bào chế tiểu phân nano dược chất

• Phương pháp nghiền (top-down)

• Phương pháp kết tủa (bottom up)

81 May 15, 2023

 water. In the case of nanopolymeric suspension, the hydrophilic stabilizer and

polymer (biocompatible and biodegradable: polylactides, polyglycolides, and poly
Hanoi university
(lactide-co-glycolides) are dissolved in water. The two solutions are mixed
of Pharmacy
together in order to form a precipitate by organic solvent diffusion in water. The
organic solvent is then removed by extraction or evaporation. This process cate-
gory is illustrated by the flowchart provided in Figure 12.1.
The control of the particle growth/crystal growth using this technique is often
Bottom-up
very challenging. Furthermore, the scaling up of the process is difficult [6].

Phương pháp bào chế bốc hơi dung môi

Figure 12.1 Flowchart of manufacturing of nanocrystalline, nanoamorphous, or nanopolymeric

suspension using solvent diffusion method [5].

Bào chế và SDH 1 - D4 - PBT 82 May 15, 2023

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Ưu điểm của phương pháp bottom-up

• ???

Bào chế và SDH 1 - D4 - PBT 83 May 15, 2023

 The top-down process has several advantages compared to the bottom-up pro-
Hanoi university
cess. In the case where the selected crystalline form of the API is stable in the
milling vehicle (generally water), the top-down process has the following
of Pharmacy
advantages:
i) It is free from organic solvent
ii) APIs that are poorly soluble in organic and aqueous media can be
Nguyên lý chung bào chế top-down
processed.

Figure 12.2 Principle of manufacturing of nanocrystalline suspension [5].

Bào chế và SDH 1 - D4 - PBT 84 May 15, 2023

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Ưu điểm của phương pháp top-down

• ???

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Phương pháp bào chế top-down

“direct-wet milling”
298 12 Scale-Up and cGMP Manufacturing of Nanodrug Delivery Systems for Clinical Investigations

Figure 12.3 Process flowchart of top-down process [5].

Bào chế và SDH 1 - D4 - PBT 86 May 15, 2023

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top-down bằng phương pháp tạo (vi) nhũ tương

12.2 Presentation of Major Manufacturing Processes of Different Nanodrug Delivery Systems 299

Figure 12.4 Flowchart of the manufacturing of nanocrystalline, nanoamorphous, or nanopoly-

meric suspension by emulsification method [5].

Bào chế và SDH 1 - D4 - PBT 87 May 15, 2023

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top-down bằng phương pháp tạo (vi) nhũ tương

D/N
Figure 12.4 Flowchart of the manufacturing of nanocrystalline, nanoamorphous, or nanopoly-
meric suspension by emulsification method [5].

Figure 12.5 Flowchart of the manufacturing of nanoemulsion [14].

together to form a coarse emulsion. The droplet size is then reduced using high-
pressure homogenization. A typical flowchart manufacturing process is illus-
trated in Figure 12.5.

12.2.3
Manufacturing of Liposomes
Bào chế và SDH 1 - D4 - PBT 88 May 15, 2023
 ii) Direct injection: In this manufacturing technique, the organic solution of
lipids and API is injected into an aqueous solution at temperature above
Hanoi university the transition temperature of the lipid. The particle size of the obtained
dispersion is reduced using sonication, colloidal milling, or high-pressure
of Pharmacy homogenization. The organic solvent is removed by in situ evaporation
under vacuum or using agitated thin film evaporator or during freeze-
drying.

Phương pháp Bangham tạo lyposome

A variant of these two options is to prepare liposomes API-free using one of
the techniques described above. The API is then loaded into liposomes simply by
hydrat hoá màng phim lipid
agitation or by pH gradient [15].
Typical manufacturing processes are illustrated in Figures 12.6–12.8.

Nhiệt độ > nhiệt độ chuyển kính của lipid

Figure 12.6 Flowchart of the manufacturing of liposomes using Bangham method [8].

Bào chế và SDH 1 - D4 - PBT 89 May 15, 2023

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of Pharmacy

Phương pháp tiêm trực tiếp tạo lyposome

12.2 Presentation of Major Manufacturing Processes of Different Nanodrug Delivery Systems 301

Figure 12.7 Flowchart of the manufacturing of liposomes using direct injection method [8].

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Hoá rắn và chuyển thành dạng bào chế hoàn chỉnh

302 12 Scale-Up and cGMP Manufacturing of Nanodrug Delivery Systems for Clinical Investigations

Figure 12.9 Downstream processing of nanodrug delivery systems.

nanomedicines, they will not be described in detail here. Figure 12.9 provides
Bào chế và SDH 1 - D4 - PBT 91 May 15, 2023
an overview of the main options.
 Hanoi university
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Lựa chọn phương pháp và phát triển quy trình

bào chế
• Sản phẩm: dạng liposome của dược chất X ít tan trong nước
(độ tan <100mcg/ml), tan tốt trong lecithin tinh khiết.

• X + phospholipid kép ==> liposome

• Dạng bột đông khô pha tiêm, pha với nước tạo hỗn dịch chứa
liposome, sau đó được pha với glucose 5% —> tiêm tĩnh
mạch.

• Quy mô 1l sử dụng phương pháp Bangham,

• Viết lại quy trình bào chế, lựa chọn dung môi, và lựa chọn
phương pháp bào chế ở quy mô 50l, những vấn đề có thể gặp
phải khi sử dụng phương pháp Bangham ở quy mô lớn

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310 12 Scale-Up and cGMP Manufacturing of Nanodrug Delivery Systems for Clinical Investigations

Figure 12.17 Schematic Bangham method used for API As’ liposomes manufacturing.
 Hanoi university
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Sơ đồ quy trình bào chế/sản xuất nano tinh thể

324 bằng phương pháp top-down
12 Scale-Up and cGMP Manufacturing of Nanodrug Delivery Systems for Clinical Investigations

Figure 12.33 Process technology configuration of intravenously injectable nanoparticles using

top-down process.

12.6.2
Bào chế và SDH 1 - D4 - PBT 94Manufacturing of Nanocrystalline Suspension
Process Technology Configuration for May 15, 2023
Using Bottom-Up Process or for Nanoemulsion, Liposomes, or Polymeric
 Hanoi university
of Pharmacy

Sơ đồ quy trình bào chế/sản xuất liposome

12.6 Technological Concept for Manufacture of Drug Product for Human Use (GMP Unit) 325

Figure 12.34 Process technology configuration of intravenously injectable nanoemulsion

liposomes.

 Solvent removal equipment used in case of polymeric nanosuspension or lipo-

Bào chế và SDH 1 - D4 - PBT somes manufacturing. It can be an agitated
95 thin evaporator or an osmotic May 15, 2023
 Hanoi university
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Lựa chọn phương pháp tiệt khuẩn

322 12 Scale-Up and cGMP Manufacturing of Nanodrug Delivery Systems for Clinical Investigations

Figure 12.32 Decision tree of nanodrug delivery systems sterilization.

Bào chế và SDH 1 - D4 - PBT 96 May 15, 2023

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CÁC PHƯƠNG PHÁP ĐO LƯỜNG

TÍNH CHẤT CỦA TIỂU PHÂN NANO

May 15, 2023

 Hanoi university
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7.3 Physicochemical Characterization of Pristine Nanoparticles

Bào chế và SDH 1 - D4 - PBT 98 May 15, 2023

Figure 7.1 Overview of important physicochemical characteristics in nanomedicines.
 example, we can quote the use of quantum dots as a model system to define the
Hanoi university
adequate hydrodynamic diameter and global surface charge that allowed rapid
of Pharmacy
body elimination of nanometer-sized objects by renal filtration. In this study, the
authors suggest a direct link and correspondence between their result, mainly a
size criterion, and the putative clinical utility of the studied nanoparticles [87].

Scheme 22.4 General distribution of nanoparticles as regard to their size and charge. This
schematic view does not take into account nanoparticle density.

Bào chế và SDH 1 - D4 - PBT 99 May 15, 2023

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Các kỹ thuật thường dùng:
Nanometrology
1.Kính hiển vi điện tử truyền qua (TEM)

2.Kính hiển vi điện tử quét (SEM)

3.Kính hiển vi đầu dò quét (ví dụ: Scanning tunneling microscopy, AFM)

4.Nhiễu xạ Laser

5.Quang phổ tương quan photon

6.Tán xạ tia X góc rộng

7.Phân tích nhiệt vi sai (DSC)

8. Cộng hưởng từ hạt nhân

100 May 15, 2023
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8.2 Application Examples 161

Bào chế và SDHFigure

1 - D48.2- PBT
Schematic of a synchrotron light source and
101the three main experiment technique May 15, 2023
Soares et al.
Hanoi university Nanomedicine: Principles, Properties, and Regulatory Issues

of Pharmacy

FIGURE 1 | Schematic representation of the different forms of particles: primary particle, aggregate, and agglomerate (reproduced with permission from Oberdörster,
2010).

102 May 15, 2023

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ĐỘ AN TOÀN CỦA CÁC

TIỂU PHÂN NANO

May 15, 2023

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of Pharmacy

6.4 Summary 187

Toxicity

Size of nanoparticles

Fig. 6.3 Relationship between toxicity and particle size. 1. Sigmoid curve. Progressive increase
of toxicity by reducing the particle size. 2. Below a certain particle size, small variation in particle
size significantly enhances toxicity

Bào chế và SDH 1 - D4diseases

- PBT related to nanotoxicity. Nanotechnology
104 products currently in the market May 15, 2023
are hundreds and relate to everyday life. Mostly they consisted of carbon nanotubes
 the environment and human way of life. The experience is limited, and the small

Hanoi universityfiber behavior resembles the behavior of known chemical fibers, like amianthus
fiber, and of forms called prions and affects human neuron and muscle systems,
causing the known spongiform encephalopathy. The World Health Organization
of Pharmacy reports nanotoxicity as an environmental disease. It is possible that in the next years,
it will be in most medical specialties and all care levels. Figure 6.2 presents the

Diseases associated to nanoparticle exposure

C. Buzea, l. Pacheco, & K.Robbie, Nanomaterials and nanoparticles: Sources and toxicity, Biointerphase 2 (2007) MR17-MR71

Brain Neurological diseases:

Nanoparticles
Parkinson’s disease
internalized
in cells Alzheimer’s disease

Mithocondrion Nanoparticle inhalation

Nucleus
Cytoplasm Asthma
Membrane Lungs Bronchitis
Emphysema
Lipid vesicle
Cancer

Circulatory Artheriosclerosis
system Vasoconstriction
Nanoparticles Thrombus
ingestion High blood pressure

Heart Arrythmia
Heart disease
Gastro-intestinal system Death
Crohn’s disease
Colon cancer Diseases of
Other organs
unknown
etilology in
Orthopedic implant
Lymphatic kidneys, liver
wear debris
Auto-immune diseases system Podoconiosis
Dermatitis Kaposi’s sarcoma
Urticaria Auto-immune diseases
Vasculitis Skin dermatitis

Fig. 6.2 Diseases associated with human exposure to nanoparticles (Adapted from Buzea et al. [1]
with permission from Springer)

Bào chế và SDH 1 - D4 - PBT 105 May 15, 2023

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of Pharmacy

Các bài báo khoa học được công bố về tác động môi trường,
sức khỏe và an toàn của các vật liệu nano

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Độc tính
• Dược động học và phân bố phụ thuộc vào tính chất
lý hoá, hình dạng và kích thước (vd <10nm phân bố
rộng khắp, >10nm chỉ thấy trong máu, gan, lách)

• Phụ thuộc vào đặc tính bề mặt của tiểu phân, bề

mặt có tính tương thích sinh học sẽ không kích thích
hệ miễn dịch

• Sự thải trừ tiểu phân nano phụ thuộc vào kích thước
và đặc tính bề mặt (<20-30nm sẽ dễ bị thải trừ qua
thận, >200nm dễ bị đại thực bào tiêu diệt)

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• Các phương pháp thử, mô hình thử chưa được

công nhận rộng rãi

• Độc tính còn phụ thuộc vào đường dùng

• Các hàng rào phòng vệ của cơ thể bị vô hiệu hoá

bởi kích thước nano.

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Soares et al.
Hệ thống phân loại NCS Nanomedicine: Principles, Properties, and Regulatory Issues

FIGURE 3 | Nanotoxicological classification (reproduced with permission from Keck and Müller, 2013).

to the regular function after elimination. Conversely, non- The traditional manufacturing processes do not create three
biodegradable nanomaterials will stay forever in the body and109dimensional medicines in the nanometer scale. Nanomedicine
May 15, 2023
Hanoi university
of Pharmacy

36 2 Nanoscale Drugs: A Key to Revolutionary Progress in Pharmacy and Healthcare

Figure 2.8 Safety classification system for nanoproducts and materials based on their “non-
nano” forms. (Adapted from Ref. [120].)
110 May 15, 2023
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SEMINAR

May 15, 2023

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of Pharmacy

Nội dung
Lựa chọn một ví dụ thuốc (nghiên cứu) sử dụng cấu trúc
nano, trình bày (30’):

• Vì sao thuốc sử dụng cấu trúc nano (hệ mang thuốc nano).
Lịch sử phát triển thuốc, ưu điểm, của từng biệt dược

• Cấu tạo, kỹ thuật bào chế, kỹ thuật tổng hợp hệ mang

thuốc nano.

• Cơ chế tác dụng, cơ chế hướng đích, cơ chế đào thải

của hệ

112 May 15, 2023

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• Paclitaxel: Taxol, Ambraxol, Genexol

• Insulin: Exubera, Affrezza

• PEG-protein: PEG-Inteferon gamma, PEG-VEGF

Bào chế và SDH 1 - D4 - PBT 113 May 15, 2023

 Các dạng thuốc có cấu trúc nano chứa Paclitaxel

Taxol: polyoxyethylated castor oil (Cremophor EL), ethanol.

Gây ra nhiều tác dụng phụ lên hệ thần kinh, đặc biệt do tá dược
Cremophor EL, trên 25-30%

Bernabeu, E., Cagel, M., Lagomarsino,

Phone/Fax: E., Moretton, M., & Chiappetta, D. A. (2017). Paclitaxel: What has been done and the
+54-11-5287-4637
challenges remain ahead. International Journal of Pharmaceutics, 526(1-2), 474–495. doi:10.1016/j.ijpharm.2017.05.016
Abstract

 Hanoi university
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Abraxane
• Sử dụng công nghệ nano kết hợp Paclitaxel (100mg) với phân tử albumin (900mg)

• Khi pha loãng tạo ra các tiểu phân Paclitaxel-Albumin kích thước 130nm

• Khi vào cơ thể các tiểu phân này vỡ ra thành các mảnh 8nm

• Các tiểu phần Paclitaxel-Albumin mang thế Zeta âm (ổn định) nhờ phân tử albumin

115 May 15, 2023