MỘT SỐ HỆ VI/NANO NHŨ TƯƠNG

TỰ VI/NANO NHŨ HOÁ

Học phần: Công nghệ nano và micro ứng dụng trong

dược phẩm, mỹ phẩm
MỤC TIÊU HỌC TẬP:
- Phân biệt được các khái niệm vi nhũ tương- nano
nhũ tương; hệ tự vi nhũ hoá- nano nhũ hoá.
- Phân tích được nguyên tắc, ưu-nhược điểm của
các kỹ thuật bào chế hệ vi nhũ tương/ nano nhũ
tương; hệ tự vi nhũ hoá/nano nhũ hoá.
- Tổng quan, thuyết trình, thảo luận được các
nguyên tắc đánh giá đặc tính và ứng dụng hệ vi nhũ
tương/ nano nhũ tương; hệ tự vi nhũ hoá/nano nhũ
hoá.
VI NHŨ TƯƠNG
(MICROEMULSION)
 Lịch sử
• Hoar và Shulman năm 1943: nhũ tương trở nên
trong suốt khi thêm một loại alcol.
• Shulman et al. năm 1959: tên gọi
“microemulsion.”
• Lindman năm 1981: định nghĩa VNT
 KHÁI NIỆM VI NHŨ TƯƠNG
• Hệ phân tán cân bằng nhiệt động học của hai chất
lỏng không đồng tan (dầu- nước), được ổn định
bằng một màng mỏng trên bề mặt phân cách pha
của các phân tử chất diện hoạt và đồng diện hoạt.
• Pha phân tán là các tiểu phân hay các giọt có kích
thước từ 5-200 nm, có sức căng bề mặt D/N rất thấp.
• Đường kính giọt nhỏ hơn 25% chiều dài bước sóng
khả kiến, vi nhũ tương trong suốt.
• Vi nhũ tương dễ dàng được tạo thành, tự hình
thành, thường không cần năng lượng tác động.
 PHÂN LOẠI VI NHŨ TƯƠNG

c
a

Cấu trúc chung của vi nhũ tương

(a) D/N
(b) Kép
(c) N/D
PHÂN BIỆT NHŨ TƯƠNG VÀ VI NHŨ TƯƠNG
 Hình ảnh vi nhũ tương (trái) và nhũ tương (phải) với đường
kính giọt
NANOEMULSIONS 35 nm và 1 mm
or MINIEMULSIONS

Gouttes diamètre entre 20 et 200 nm

Le mûrissement d’Ostwald est la source
de déstabilisation principale
PHÂN BIỆT VI NHŨ TƯƠNG VÀ NANO NHŨ TƯƠNG
 showed the specific size range for each emulsion groups. Ea
directly affect their suitability in food application. As for ex
based food such as butter cream while oil in water emulsi
PHÂN BIỆT VI NHŨ TƯƠNG VÀ NANO NHŨ TƯƠNG
beverages.

Figure 1. Types and typical droplet diameter Figur

sizes of macroemulsion, nanoemulsion and oil (lef
microemulsion. Sources: [1]. Source
PHÂN BIỆT VI NHŨ TƯƠNG VÀ NANO NHŨ TƯƠNG
between the two systems is shown sche-
matically in Fig. 3, which compares the
free energy of the colloidal dispersions to
the free energy of the separate phases from
VI NHŨ TƯƠNG D/N
2.1.1. Free energy diagrams. For
a nanoemulsion, the free energy of the
colloidal dispersion (droplets in water) is

Fig. 2 Oil-in-water microemulsions consist of surfactant micelles with oil molecules incorporated
within them. The oil molecules may be incorporated between the surfactant tails and/or within the
core of the micelle.
interphase, where the interfacial tension between oil and water phase is brought
down to zero. However, only on the basis of molecular interactions across the
duplex film, the formation of microemulsion could be ensured rather than other
liquid crystalline phases, in which one bulk phase gets enclosed in the other (in the
form of spheres). Based
CƠ CHẾ on THÀNH
HÌNH the mixed film TƯƠNG
VI NHŨ theory, Robbins [7] devised a theory of
phase behavior of microemulsions, which stated that interactions in a mixed film
direct the direction and extent of curvature, by which the type and size of droplets

Figure 1.
Ternary phase diagram representing three components of the microemulsion.
Giản đồ 3 pha nước-dầu- chất diện hoạt

2
 ƯU ĐIỂM VI NHŨ TƯƠNG

- Tăng tốc độ hấp thu, giảm giao động hấp thu,

tăng SKD
- Tăng độ tan cho các DC thân dầu, tạo ra dạng
bào chế thân nước từ các DC không tan
- Dùng nhiều đường khác nhau: tại chỗ, uống, tiêm
tĩnh mạch
- Che vị
- Tăng độ ổn định cho DC
- Không tốn năng lượng chế tạo
- …
 THÀNH PHẦN VI NHŨ TƯƠNG
- Chất diện hoạt
- Chất cộng diện hoạt (cosolvents / cosurfactants): ethanol,
propanol, butanol....

Các nhóm chất diện hoạt:

(i) Non-ionic: Brij 35 (C12E35 ); sorbitan monooleat (Span 80)
(ii) Zwitterionic : Phospholipids
(iii) Cationic: Muối amoni bậc 4 với hexadecyltrimethyl
ammonium bromide (CTAB), didodcecylammonium bromide
(DDAB)
(iv) Anionic: Natri bis-2-ethylhexylsulphosuccinate (AOT)
- Các tá dược có KLPT TB >1000: gelatin, lecithin, Tweens,
PVP, HPMC, cetomacrogol 1000....
- Các tá dược có KLPT TB <1000: Stearic acid,
benzalkonium chloride, calcium stearate, glycerol
monostearate, cetostearyl alcohol, cetomacrogol
emulsifying wax, sorbitan esters.
 KỸ THUẬT BÀO CHẾ VI NHŨ TƯƠNG
- DC được hòa tan trong pha dầu
- Chất diện hoạt và cộng diện hoạt hòa tan trong nước
- Thêm từ từ pha nước vào pha dầu cho tới khi hệ tạo thành
trong suốt
- Có thể dùng siêu âm để làm giảm kích thước
ỨNG DỤNG
ỨNG DỤNG VỚI THUỐC DÙNG QUA DA

Ví dụ 1: vi nhũ tương acyclovir

- 20 % chất diện hoạt trong IPM
- 4% IL (dimethylimidazolium dimethyl phosphate) trong IPM
- DC: 10–20 % trong IL

Bào chế:
- Trộn Tween, Span và IPM tạo thành dung dịch trong suốt
- Thêm IL vào hỗn hợp, lắc xoáy ở 25oC để tạo thành vi nhũ
tương IL/O
- Muốn điều chế vi nhũ tương W/O, thêm nước thay cho IL
- Dược chất được hòa tan trong IL
Ví dụ 1: vi nhũ tương acyclovir

(a) Schematic representation of ionic liquid-in-oil (IL/o) microemulsions

containing drug molecules. Chemical structure of IL (b) and acyclovir (c)

Source: Int. J. Pharm. 400 (2010) 243–250

Ví dụ 1: vi nhũ tương acyclovir

b : HLBmix = fA HLBA + fB HLBB,where HLBA, HLBB are the HLB values of Tween-80 và
Span-20, fA, fB tỷ lệ khối lượngTween-80 và Span-20.
Thử tính thấm DC qua da của các công thức chứa 5mg/ml
acyclovir trong 24 h:

b: dạng hỗn dịch .

c: IL/o ME2 (Tween-80: Span-20 = 3:2 (w/w).
d: vi nhũ tương w/o
e: vi nhũ tương IL/o.
f : ACV herpecia topical cream (5mg ACV)
Drug Dev I
The rheological measurements were performed with the use of
HAAKE! RheoStress!1 (Thermo Scientific, Waltham, MA)
rotational rheometer equipped with PP35Ti plate–plate geometry
(diameter: 35 mm, gap: 1 mm) and Thermo Haake! DC 30
temperature control unit. The measurements were conducted at
25 ± 0.5 ! C. Before the experiments all samples were equilibrated
VD 2: Indomethacin
Figure 2. Indomethacin.
on the plate for 2 minutes to reach the desired temperature.
For each test three replicate measurements with fresh samples
DOI: 10.3109/03639045.2015.1066799
Table 1. Examples of commercial topical products with indomethacin.

Product IND concentration (%) Formulation Table 2. ME composition.

Company Status
Elmetacin! 1 Topical spray STADA Marketed in EU
Indo Top-ratiopharm! Spray 1 Topical spray ME component
Ratiopharm Material % (w/w)
Marketed in EU
Indometacı́nový gél 1% 1 Gel Vulm Marketed in EU
Indobene! 1 Gel Oil phase
Ratiopharm Castor oil Marketed in EU 7.5
Indosin! 2 Gel Sintofarm
Water phase Discontinued brand
Deionized water 11.0
Inteban! 1 Ointment Dainippon Sumitomo Pharma Co., Ltd.! Marketed in Japan
Metindol! 5 Ointment Surfactant
GlaxoSmithKline Tween 80 Marketed in EU26.5
Vi-Gel! 1 Cream Cosurfactant
Cho Dang Pharm Ind Co. Ltd. Ethanol Marketed in South55.0
Korea

DOI: 10.3109/03639045.2015.1066799 Microemulsion-based polymer gels with indomet

Table 2. ME composition. TableMEs
3. Composition of theIngels.
were analyzed. the next step, the final formulat
checked. All measurements were performed in triplicat
ME component Material % (w/w) Component (%, w/w) Gel A Gel B Placebo
Oil phase Castor oil 7.5 Statistical analysis 1.0
Indomethacin 3.0 –
Water phase Deionized water 11.0 !
Surfactant Tween! 80 26.5
Carbopol 960 of the drug
The impact 3.0content 3.0 3.0
on the rheological an
Cosurfactant Ethanol 55.0 Microemulsion 96.0 94.0
parameters was estimated with the use of one-way a97.0
variance (ANOVA). The mean values obtained for a
Karola on 07/23/15

investigated samples were compared with the use of

Table 3. Composition of the gels. Scheffe’s test. For all statistical tests the level of signifi
were performed. Error bars have been omitted for clarity. The
set at 5%.
Component (%, w/w) Gel A Gel B Placebostandard deviation values were below 20% of the mean values.
Indomethacin 1.0 3.0 – Flow behavior
Resultsstudies. Rotational experiments were carried out
and discussion
Carbopol! 960 3.0 3.0 3.0 both in controlled shear rate mode (CR) and controlled stress mode
Composition of the samples !1
 VI NHŨ TƯƠNG CHO THUỐC UỐNG
Ví dụ 3: VNT berberin
- Dầu: oleic acid, isoptopyl myristate and ethyl oleate
- Chất diện hoạt: Polysorbate-80, Triton X-100
- Chất đồng diện hoạt: ethanol, PEG400 and propylene glycol)
ORIGINAL ARTICLES
- CT:15 wt.% oleic acid, 17 wt.% Tween-80, 17 wt.% PEG400, and 51 wt.%
water.

!
in the gastrointestinal tract (Spernath and Aserin 2006; form a homogeneous mixture (Smix) of fixed weight r
Araya et al. 2005; Spernath et al. 2007; Shiokawa et al. surfactant to cosurfactant was regarded as Km. The pse
2005), (3) promoted microemulsion of lymphatic transport diagram of oil, Smix and water was plotted using wate
through transcellular pathway (Gershanik and Benita The phase behavior of system was studied at Km valu
Briefly, mixtures of the oil with Smix were prepared in
SO SÁNH
2000). HẤP THU significant
A statistically BERBERINdifference between the ratios (w/w) of 9 : 1, 8 : 2, 7 : 3, 6 : 4, 5 : 5, 4 : 6, 3 : 7,
tively. A small amount of water with 5% (w/w) increme
the vials. Upon water addition, the mixturesORIGINALin each vi
3–5 min. After equilibration, the mixtures were then e
4.5 observation and polarizing microscope. In the phase dia
sion was the region of monophasic, clear and isotropic so
4 also contain micellar solutions. Gels were claimed for t
Concentration of berberine (mg/L)

3.5 did not show a change in the meniscus when tilted to an

the experiments were performed at 25 ! C (Ghosh et a
3 2006; Subramanian et al. 2004).
The berberine-loaded microemulsion was prepared by
2.5
powder directly into the blank microemulsions. The sam
2 sealed and stored at ambient temperature, and their phy
determined by periodically observing the occurrence of p
1.5
Fig. 3: Transmission electron microscope photographs of berberine micro-
1 3.3. Characterization of berberine-loaded microemulsio
emulsions
0.5 The morphology of berberine-loaded microemulsion was
0 transmission electron microscope (JEM-1230, Jeol, Jap
0 5 10 15 20 25
2.3.
30
Bioavailability
sample wasand pharmacokinetic
deposited studycopper specimen
on a PVA-coated
Time (h) The mean to stand forconcentration
berberine 10 min after which anyblood
in the excessafter
fluidoral
was r
paper. The grid was later stained with one
administration of multi-dose berberine microemulsion and drop of 3%
acid and allowed to dry for 5 min before examination.
Fig. 4: Mean
Mean berberine
berberine blood
blood concentrations
concentrations upon
upon oral suspensions
oral administration
administration of
of of berberine tablets as a reference was illu-
The analysis of particle size was performed by photon c
berberine microemulsion strated in Fig.
scopy4.(which
The concentration-time curve of berber-
berberine ), and
microemulsion(,&and berberine
berberine tabletsuspensions
tablet suspensions (&) analyses the fluctuations in light
ine microemulsion was significantly different from that of
scattering

518 berberine suspensions. The concentration-time dataPharmaz

of the
two preparation were best fitted to a two-compartment
model with a weight of 1/C2, and the relevant pharmacoki-
netic parameters such as Cmax, Tmax, AUC0–24, elimination
constant of the central compartment (K10), the absorption
constant from gastrointestinal (GI) to central compartment
(Ka), mean residence time (MRT) and relative bioavail-
ability (Fr) are given in the Table.
The Cmax of tablet suspension formulation was 0.394 mg/ml
after 8.3 h, whereas it was 4.169 mg/ml for the microemul-
Ví dụ 4: VNT cyclosporin
Viên nang mềm Neoral®:

Alpha-tocopherol
Ethanol anhydrous
Propylene glycol
Corn oil-mono-di-triglycerides
Macrogolglycerol hydroxystearate / polyoxyl 40 hydrogenated
castor oil.
 ỨNG DỤNG VI NHŨ TƯƠNG TRONG BÀO CHẾ MỸ PHẨM

Pevonia Botanica Micro-Emulsion Golden Line Microemulsion Eye

Massage Cream Cream Jeunesse
 both types of microemulsion and the groups treated with solution
Water5surfactant-co-surfactant
soluble extract8350(%) in the range 26.00
of 48.39-60.34%,
5.0 6.12
respectively.
93.5 of celery 5extract, solution1350
of A. vera or the mixture5.5 77.6
of both extracts,
Ethanol
6 soluble extract (%)
8500 4.00 5.0 101.18.46 6 that there were 1350significant differences5.0
Apigenin content (% w/w) - 0.036 it was found (p<0.05) in 78.6
hair
Tablein2:
oil,Characteristic of Aloe vera powder and celery growth. The group treated with microemulsion had a longer hair length
MalicW/O:ỨNG DỤNG VI NHŨ TƯƠNG TRONG SẢN PHẨM CHĂM SÓC TÓC
Water
acid (% w/w) O/W: Oil in water 1.44 -
compared to the group treated with solution dosage form. Hair growth
Parameter Aloe vera Celery data from each group was shown in Table 6.
Water content (%) 15.40 Table 6: Data of hair growth
9.00
Table 3: Final
Total ash content (%)
micro emulsion formula
3.25 7.20
Group Length
Water soluble of hair
ash content (%)(mm) at 0.68 2.40
Name of ingredient
Acid insoluble ash contentThe
(%)amount of ingredient (%) in
0.55 the
0.71
Day
Water soluble 7 (%)formula
extract 26.00 Day 14
6.12 Day 21
Ethanol soluble extract (%) 4.00 8.46
Control
Apigenin content (% w/w)O/W Test - T-C W/O Control
0.036 Test T-C Control Test
AVWMalic acid (% w/w)
1.83±0.10 3.15±0.24 1.44 1.32±0.39 - 3.80±0.74 6.40±0.19 2.6±0.61 5.23±0.57 7.98±0.57
Croduret 50 SS 27.5 24.5
CEW
Glycerin 1.88±0.24 27.52.95±0.19 1.07±0.27
5.25 2.40±0.10 6.30±0.23 3.9±0.32 5.18±0.13 8.25±0.25
CEO
Ethanol 1.63±0.10 - 3.10±0.17 1.47±0.13
Table 3: Final micro emulsion formula 5.25 2.47±0.51 6.73±1.05 4.26±0.81 4.15±0.27 8.35±0.24
CeleryAVCEW 2.28±0.10 2.0 3.25±0.19
ethanol extract 0.97±0.29
2.0 3.27±0.21 6.28±0.29 3.01±0.45 4.61±0.20 8.03±0.10
W/O
Aloe vera powder
Name 1.33±0.30 1.0 4.26±0.12
of ingredient 2.93±0.35
1.0 (%) in2.50±0.36
The amount of ingredient the 9.28±0.23 6.78±0.46 4.53±0.49 11.83±0.71
Crodamol
O/WGTCC 1.67±0.30 29.04.07±0.37 formula 12.5
2.40±0.36 3.01±0.36 9.37±0.27 6.36±0.42 5.07±0.49 13.68±0.45
Distilled water 13.0
AVW: Aloe vera in water, CEW: Celery
50.0 Celery extract in oil, Fig. 1: Pseudoternary phase diagram of in
surfactant/co-surfa
O/Wextract in water, CEO:
W/O AVCEW: Mixture of Aloe vera and celery extract water, W/O: Water in
W/O: Water in oil, O/W:
microemulsion Oil in water
containing Crodamol-water
of celery extract and Aloe vera, O/W: Oil in water microemulsion containingfor water
celery in oil
extract andand
Aloeoil in water microemu
vera
Croduret 50 SS 27.5 24.5
Glycerin 27.5 5.25
Ethanol - Table 4:
Table 7: Percentage of hair growth in each group Malic5.25
acid and apigenin contentthe
compared in microemulsions
activity of active ingredient from A. vera and celer
Celery ethanol extract 2.0 2.0
to control simultaneously in promoting hair growth. The last part
Aloe vera powder 1.0 1.0
Marker substance content Aloe vera powder Ethanol extract of celery W/O microemulsion
studies was observation of hair density.O/WThemicroemu
weight o
Crodamol GTCC 29.0 12.5
Malic Group
acid (%w/w)
Distilled water 1.44 Percentage of50.0
13.0 area of each1.37×10
hair -growth at dayFig. 1: Pseudoternary group
phasewas shown
diagram of in Table 8.1.35×10
Hair density in
surfactant/co-surfactant-
Apigenin (% w/w)
W/O: Water in oil, O/W: Oil in water- 3.55×10 that was treated
6.93×10with microemulsions either
6.94×10 W/O or
Crodamol-water for water in oil and oil in water microemulsion
7 14 21
W/O: Water in oil, O/W: Oil in water higher than the other areas.
Aloe vera 1% in water 72.13 68.42 52.58
Table 4: Malic acid and apigenin content in microemulsions
Celery extract 2% in water 57.18 162.50 59.27 Based on data from in vivo studies, it can be concluded t
Celery
Markerextract 2% incontent
substance oil 128.52
Aloe vera powder 176.25 98.80 of A. veraW/O
Ethanol extract of celery and microemulsion
celery extract in the microemulsion dosag
O/W microemulsion
Mixture of Aloe vera 1% and 47.30 92.00 74.29 W/O or O/W type, could improve the penetration of act
Malic acid (%w/w) 1.44 - 1.37×10 1.35×10
celery extract
Apigenin 2% in water
(% w/w) - 3.55×10 into pilosebaceous
6.93×10 gland and induce a maximum cell pr
6.94×10
W/O microemulsion 220.00 271.40 161.25
W/O: Water in oil, O/W: Oil in water hair elongation.
O/W microemulsion 143.70 211.00 169.92
W/O: Water in oil, O/W: Oil in water CONCLUSION
321
The
Pamudji et O/W and W/O microemulsions containing of A. vera
al.
Table 8: Hair density in the tested area of each group extract 2% Asian
wereJ Pharm
prepared
Clin Res,utilizing Crodamol
Vol 8, Issue 4, GTCC a
2015, 319-323
 PHÂN BIỆT VI NHŨ TƯƠNG VÀ KỸ THUẬT
Microemulsions as Nanotemplates: A Soft and Versatile Approach
DOI: http://dx.doi.org/10.5772/intechopen.80758 VI NHŨ HOÁ

Figure 3.
Structure of nanoparticles (NPs) prepared using microemulsion method.
Các hệ nano được bào chế bằng phương pháp vi nhũ tương
have drawn significant attention because of their emerging applications in the field
of catalysis, clinical diagnostics, and therapy. For the synthesis of metallic NPs using
microemulsion, two schemes have been identified [11]: (a) O/W microemulsion in
which ionic salt (metallic precursor) as the precursor is dissolved in the continuous
 HỆ TỰ VI/NANO NHŨ HOÁ
Self-MICRO/NANO Emulsifying Drug
Delivery Systems- SNEDDS/SMEDDS
Hệ tự vi/nano nhũ hoá là hỗn hợp đẳng hướng, bao gồm dầu, chất
diện hoạt, chất đồng diện hoạt và dược chất/hoạt chất. Hỗn hợp
này sẽ được nhũ hoá khi tiếp xúc với với môi trường nước và
khuấy trộn. Khi được pha loãng, SNEDDS sẽ tạo ra vi/nano nhũ
tương với kích thước giọt 20- 200 nm.
SNEDDS có khả năng:
- Làm lỏng lẻo các màng tế bào ruột
- Ức chế bơm ngược
Tăng SKD qua đường uống:
- DC ít tan, thân dầu
- Thuốc protein
 HỆ TỰ NANO NHŨ HOÁ

Bào chế SNEDDS:

- Bào chế hệ lỏng
- Rắn hoá
- Đưa vào dạng thuốc

Đánh giá SNEDDS:

- Hệ lỏng được nhũ hoá
- Hệ rắn được nhũ hoá?
- Sau khi đưa vào dạng thuốc?
ĐÁNH GIÁ VI NHŨ TƯƠNG VÀ HỆ TỰ NANO NHŨ
HOÁ
1. Hình thái
2. Kích thước giọt
3. Tương tác giữa các thành phần
4. Tỷ lệ dược chất được vi nhũ hoá
5. Giải phóng dược chất
6. …

SO SÁNH VỚI CÁC HỆ NANO?