DESC:[0019] The following is a detailed description of embodiments of the present
5 disclosure. The embodiments are in such detail as to clearly communicate the
disclosure. However, the amount of detail offered is not intended to limit the
anticipated variations of embodiments; on the contrary, the intention is to cover all
modifications, equivalents, and alternatives falling within the spirit and scope of the
present disclosure as defined by the appended claims.
10 [0020] Unless the context requires otherwise, throughout the specification which
follow, the word “comprise” and variations thereof, such as, “comprises” and
“comprising” are to be construed in an open, inclusive sense that is as “including,
but not limited to.”
[0021] Reference throughout this specification to “one embodiment” or “an
15 embodiment” means that a particular feature, structure or characteristic described
in connection with the embodiment is included in at least one embodiment. Thus,
the appearances of the phrases “in one embodiment” or “in an embodiment” in
various places throughout this specification are not necessarily all referring to the
same embodiment. Furthermore, the particular features, structures, or
20 characteristics may be combined in any suitable manner in one or more
embodiments.
[0022] The headings and abstract of the invention provided herein are for
convenience only and do not interpret the scope or meaning of the embodiments.
[0023] The present disclosure relates to enhancement of solubility of curcumin by
25 self-micro emulsifying drug delivery system (SMEDDS).
7
[0024] In the preferred embodiment of the present disclosure, self-micro
emulsifying drug delivery system (SMEDDS) for enhancing curcumin solubility
comprises of camphor oil and menthol oil in equal proportion, saponin as a
surfactant, glycerin as a co-surfactant and distilled water as an aqueous medium.
5 [0025] In an embodiment of the present disclosure, the proportion of camphor oil
and menthol oil is in the ratio 1:1.
[0026] In an embodiment of the present disclosure, the pseudo ternary phase
diagram is constructed by using 1:1, 1:2 and 2:1 ratio of surfactant and co-surfactant
with oil and distilled water. By this pseudo ternary phase diagram 1:1 ratio of
10 surfactant and co-surfactant is more stable and has good emulsification ability.
[0027] In an embodiment of the present disclosure, a process for self-micro
emulsifying drug delivery system (SMEDDS) for enhancing curcumin solubility
comprises of;
15 - dissolving curcumin in menthol and camphor oil kept at 40ºC (mention
temperature) under continuous stirring;
- a surfactant and a co-surfactant mixture are added to curcumin oil mixture
to form a homogenous mixture by continuous stirring;
- the mixture is kept on a vortex mixer for 15 to 25 minutes for complete
20 solubilization of the added ingredients;
- liquid emulsion formed by SMEDDS is further converted into solidSMEDDS by kneading process by using cryoprotectant for improving the
micrometric properties and stability;
- curcumin powder formed after solid- SMEDDS by kneading process is
25 evaluated for parameters like emulsion time, zeta potential, polydispersity
index, % cumulative release and stability.
8
[0028] In another embodiment of the present disclosure, the quantity of curcumin
in SMEDDS is 20 mg, camphor and menthol oil is 1ml, saponin is 2.5 ml, glycerin
is 4.5 ml.
[0029] In another embodiment of the present disclosure, solid-SMEDDS through
5 kneading is prepared by using 2% w/w mannitol as cryoprotectant and the
proportion of curcumin and mannitol is 1:2.
[0030] In another embodiment of the present disclosure, formulation of Curcumin
in the form of solid-SMEDDS enhances the dissolution properties.
10 [0031] In another embodiment of the present disclosure, statistical screening has
been performed by Box Behnken Factorial Design with 3 independent factors, 2
levels prepared by design expert 9 software with 5 centre point and 17 runs; further
all the batches were analyzed using the design expert 9 software. The software itself
suggests Quadratic Model and also gave model equation for dependent variables.
15
The following examples further describe certain specific aspects and embodiments
of the invention and a better understanding of present invention may be obtained
through the following examples and displayed process for manufacturing and it
demonstrates the practice and advantages thereof. It is to be understood that the
20 examples are given by way of illustration only and are not intended to limit the
scope of invention in any manner.
EXAMPLES:
Curcumin Formulation Development and Evaluation
Box Behnken statistical design with 3 Independent factors, 2 levels are prepared by
25 Design expert 9 with 5 centre point and 17 runs is selected for the optimization
study as indicated in Table 1. For optimization of formulation parameters such as
concentration of oil, surfactant and co-surfactant is carried out by evaluating 3
9
response parameters emulsification time, % transmittance and % cumulative release
by Box-Behnken statistical design as indicated in Table 2, 3 and 4.
Table 1: Matrix of Box-Behnken Design for formulation
Std Batch
No
Oil
(ml)
Surfactant
(ml)
Cosurfactant
(ml)
Emulsification
time (Sec)
Transmittance
(%)
% CDR
(%)
8 B1 9 2.5 4.5 46±5.29 80.97±1.76 92.2±0.029
17 B2 5 2.5 2.5 64±4 74.82±1.07 68.51±0.024
16 B3 5 2.5 2.5 65±5.56 75.80±1.26 66.16±0.021
10 B4 5 4.5 0.5 86±3.60 59.15±0.90 52.36±0.022
15 B5 5 2.5 2.5 63±3.60 74.82±1.07 69.74±0.027
1 B6 1 0.5 2.5 50±4.35 88.11±0.76 80.6±0.029
3 B7 1 4.5 2.5 37±3.60 91.27±0.99 86.41±0.031
13 B8 5 2.5 2.5 64±4 75±1.11 69.52±0.026
9 B9 5 0.5 0.5 90±4 43.05±0.79 50.1±0.026
4 B10 9 4.5 2.5 67±2.64 62.9±0.88 63.45±0.018
6 B11 9 2.5 0.5 112±3.60 32.06±0.51 44.08±0.028
7 B12 1 2.5 4.5 18±2.64 99.08±0.23 99.43±0.015
2 B13 9 0.5 2.5 82±2 51.48±0.47 68.82±0.030
14 B14 5 2.5 2.5 63±2.64 76.82±1.07 70.59±0.028
12 B15 5 4.5 4.5 24±2.64 95.35±0.77 96.6±0.011
5 B16 1 2.5 0.5 72±3.60 64.12±0.74 61.11±0.027
10
11 B17 5 0.5 4.5 38±3.60 90.8±1.82 94.35±0.029
Table 2: ANOVA of Emulsification Time
Source
Sum of
Squares
Df
Mean
Square
F
Value
p-value
Prob > F
Model 9350.76 9 1038.97 299.29 <0.0001 Significant
Lack of Fit 21.50 3 7.17 10.24 0.0239 Significant
Pure Error 2.80 4 0.70 - -
Cor Total 9375.06 16 - - -
R-Squared 0.9974
Adj R-Squared 0.9941
Pred R-Squared 0.9628
Table 3: ANOVA of % Transmittance
Source
Sum of
Squares
Df
Mean
Square
F
Value
p-value
Prob > F
Model 5527.29 9 614.14 122.50 < 0.0001 Significant
Lack of Fit 32.10 3 10.70 14.29 0.0133 Significant
Pure Error 3.00 4 0.75 - -
Cor Total 5562.38 16 - - -
11
R-Squared 0.9937
Adj R-Squared 0.9856
Pred R-Squared 0.9068
Table 4: ANOVA of % Cumulative Release
Source
Sum of
Squares
Df
Mean
Square
F
Value
p-value
Prob > F
Model 4432.19 9 492.47 121.33 < 0.0001 Significant
Lack of Fit 16.81 3 5.60 1.93 0.2663 Not
Significant
Pure Error 11.61 4 2.90 - -
Cor Total 4460.60 16 - - -
R-Squared 0.9936
Adj R-Squared 0.9854
Pred R-Squared 0.9357
The pseudo ternary phase diagram is constructed using Menthol: Camphor’s oil
5 phase, Saponin as surfactant phase and Glycerin as co-surfactant phase. For these
the different three ratios 1:1, 1:2 and 2:1 surfactant and co-surfactant is selected.
The different trial has shown that the emulsifying effect is good if the ratio of the
surfactant to the co-surfactant is 1:2 and 2:1 but stability properties are inferior at
this ratio, so fixed the 1:1 ratio of surfactant and co-surfactant according to stability.
10 The transparent emulsion is produced at the concentration of 80 mg of
Curcumin/1ml of SMEDDS formulation.
12
According to Box-Behnken statistical design batch B12 has a best emulsification
time 18±2.64 sec, good % transmittance, 99.08±0.23% in vitro% cumulative release
after 45 minutes is found to be 99.43±0.015 %.
All the batches are analyzed using the design expert 9 software. The software itself
5 suggests Quadratic Model and also gave model equation for dependent variables.
The SMEDDS formulations are further evaluated, the batch B1, B12, B15 and B17
has a disperbility grade A expects than other batches. According to the robustness
on dilution study all batches are be stable without any precipitation diluted when
100 times with distilled water and 0.1 N HCL. The highest amount of Curcumin
10 content of batch B12 is found to be 99±0.009 %. The maximum Curcumin release
of batch no B12 is 99.43±0.015 % within the 45 minutes in case of SMEDDS.
The batch B1, B12, B15 and B17 is passed for the thermodynamic stability while other
batches have failed the thermodynamic stability. According to thermodynamic
stability, passed 4 batches is evaluated for the zeta potential, globule size, poly
15 disperbility index and viscosity. These 4 batches are tested in malvernzetasizer
NS90 the batch B12 has best result compare to other 3 batches. The zeta potential
droplet size, globule size and poly disperbility index of batch B12 is found to be -
27.5 mv, 98.28 nm and 0.243respectively.
Liquid emulsion of curcumin is formed by SMEDDS which is further converted
20 into solid-SMEDDS.
Solid-Self micro emulsifying drug delivery system
The solid-SMEDDS formulation prepared by kneading process. Curcumin
complex: Mannitol (1:2) is used as cryoprotectant for the solid-SMEDDS
formulation. The composition of batch Curcumin 20 mg, Oil 1 ml, surfactant 2.5
25 ml, co-surfactant 4.5 ml and Cryoprotectant is used in different ratio for preparation
of solid-SMEDDS. 2% w/v mannitol is used as cryoprotectant that gives the best
result with curcumin complex. The solid-state characteristics of dried powder bulk
density, tapped density, carr’s index, hausner’s ratio and angle of repose is found
to be 0.59±0.012, 0.68±0.03, 14.80±2.76, 1.14±0.03 and 24.91±1.25° respectively
13
as indicated in Table 5. The Curcumin content of kneaded powder is found to be
96.15±0.15%. The emulsification time of curcumin kneaded powder is found to be
20±3.60 sec. The zeta potential, droplet size and poly disperbility index of curcumin
kneaded powder is found to be - 22.5 mv, 98.4 nm and 0.304respectively. The
5 cumulative release within 45 min is found to be 99.28±0.013%, while plain
Curcumin showed only 37.88±0.025 %.
Table 5: Pre-formulation Study of curcumin kneaded powder
Parameters Solid-SMEDDS (after kneading)
Hausner's ratio 1.14 ± 0.03
Carr's index (%) 14.8 ± 2.76
Angle of Repose 24.91 ± 1.250
Solubility Data
Following is the data examined for solubility of Curcumin in different medium as
10 indicated in Table 6. As per different dissolution medium study following are the
dissolution medium is preferable as per dosage design.
Table 6: % Concentration of Curcumin after dissolution (0.1N HCL)
Time (min) Plain Curcumin Curcumin within SMEDDS
Curcumin within SolidSMEDDS after kneading
process
0 0 0 0
15 02.01 ± 0.020 % 15.41 ± 0.0017 % 40.01 ± 0.10 %
30 03.81 ± 0.023 % 35.01 ± 0.0016 % 78.14 ± 0.13 %
45 07.88 ± 0.025 % 46 ± 0.0015 % 96.15 ± 0.15 %
According to data available from in-vitro study for solubility in table 6 indicates
that plain Curcumin’s concentration after dissolving in HCL (0.1N) medium
15 increased by around 60% when incorporated in solid-SMEDDS technology.
14
Table 7: % Cumulative release comparison of Curcumin in SMEDDS formulation
with other product
27th December 2023
5
Stability Study:
Table 9: Stability data of optimize batch B12
Sr.
No. Parameters
Conditions
Initial
0 Day 1 Month 2 Months 3 Months
1 % Cumulative release 99.28 ± 0.13 % 99.28 ± 0.13
%
99.28 ± 0.13
%
99.28 ± 0.14
%
2 Dissolution Time 45min 45min
45min ±
0.1sec
45min ±
0.1sec
3 Emulsification time 20 ± 3.60 sec 20 ± 3.60 sec 20 ± 3.61 sec 20 ± 3.61 sec
4 % Transmittance 99.08 ± 0.23 % 99.08 ± 0.23
%
99.08 ± 0.24
%
99.08 ± 0.24
% ,CLAIMS:1) An enhancement of curcumin solubility by Self-micro emulsifying drug
delivery system (SMEDDS) comprising;
- 20 mg of curcumin;
5 - 1 ml of essential oil wherein an essential oil is camphor oil and menthol oil;
- 2.5 ml of surfactant wherein a surfactant is saponin;
- 4.5 ml of co-surfactant wherein a co-surfactant is glycerin;
- q.s of distilled water as an aqueous water.
2) The enhancement of curcumin solubility by Self-micro emulsifying drug
10 delivery system (SMEDDS) as claimed in claim 1, wherein the proportion
of camphor oil and menthol oil is 1:1.
3) The enhancement of curcumin solubility by Self-micro emulsifying drug
delivery system (SMEDDS) as claimed in claim 1, wherein the proportion
of surfactant and co-surfactant is 1:1.
15 4) The enhancement of curcumin solubility by Self-micro emulsifying drug
delivery system (SMEDDS) as claimed in claim 1, wherein essential oil and
natural phytochemical has been used instead of synthetic surfactant in
SMEDDS that assists in enhancing the curcumin solubility when compared
with marketed products.
20 5) A process for self-micro emulsifying drug delivery system (SMEDDS) for
enhancing curcumin solubility comprises of;
a. dissolving curcumin in menthol and camphor oil kept at 40ºC under
continuous stirring;
b. a surfactant and a co-surfactant mixture are added to curcumin oil mixture
25 to form a homogenous mixture by continuous stirring;
c. the mixture is kept on a vortex mixer for 15 to 25 minutes for complete
solubilization of the added ingredients;
16
d. liquid emulsion formed by SMEDDS is further converted into solidSMEDDS by kneading process by using cryoprotectant for improving the
micrometric properties and stability;
e. curcumin powder formed after solid- SMEDDS by kneading process is
5 evaluated for parameters like emulsion time, zeta potential, polydispersity
index, % cumulative release and stability.
6) A process for self-micro emulsifying drug delivery system (SMEDDS) as
claimed in claim 5 wherein, the cryoprotectant in solid- SMEDDS is
mannitol.
10 7) A process for self-micro emulsifying drug delivery system (SMEDDS) as
claimed in claim 5 wherein, the quantity of mannitol is 2% w/v.
8) A process for self-micro emulsifying drug delivery system (SMEDDS) as
claimed in claim 5 wherein, the proportion of curcumin and mannitol is 1:2.
9) A process for self-micro emulsifying drug delivery system (SMEDDS) as
15 claimed in claim 5 wherein, curcumin powder prepared through solid selfmicro emulsifying drug delivery system shows improved micromeritics
properties wherein the % cumulative release of curcumin is 99% within 45
minutes.