FIELD OF INVENTION
[01] The present invention relates generally to taste masking of bitter
pharmaceutical agent ursodeoxycholic acid. More preferably, the present invention
relates to a pharmaceutical composition containing taste masked form of
ursodeoxycholic acid and a method for preparing thereof. More specifically, the
invention relates to a pharmaceutical composition containing taste-masked
ursodeoxycholic acid using ion-exchange resin and method of preparing thereof
BACKGROUND OF THE INVENTION
10 [02] Ursodeoxycholic acid is one of the components comprised in bile which is
produced in the liver. The capacity of the human liver to produce ursodeoxycholic
acid is very small, and thus continual ingestion of ursodeoxycholic acid can be very
helpful for liver health. More specifically, as disclosed in Korean Patent Publication
No. 1997-0000042, ursodeoxycholic acid, silymarin, etc. are known as drugs for
15 promoting regeneration of liver cells or assisting liver function, and a pharmaceutical
composition for recovery from fatigue comprising ursodeoxycholic acid, red ginseng
and vitamins is also disclosed. Korean Patent Publication No. 1997-0005178
discloses a pharmaceutical composition comprising tauro-ursodeoxycholic acid to
show a recovery effect from fatigue.
20 [03] However, because pure ursodeoxycholic acid has an intrinsic bitter taste, it
causes a problem of bitter taste when a drug is not only orally administered but also
refluxed due to reflux oesophagitis caused by oxidative stress from hypersecretion of
acids in gastric ulcer or gastritis. Thus, it has been needed to block the bitter taste of
ursodeoxycholic acid and thus more easily administer the drug for increasing drug-
25 administration compliance.
[04] Several efforts have been made to mask the bitter taste of the ursodeoxycholic
acid e.g. using P-cyclodextrin (US patent 5534505); using micronized form of
ursodeoxycholic acid, preparing its suspension and thereby reducing its dissolved
1
amount in liquid (PCT patent application publication number WO2013057741) and
taste masking of ursodeoxycholic acid by its synthetic hydrotalcite-Eudragit hybrid
(PCT patent application publication number WO2011031099). The bitter taste of
ursodeoxycholic acid make it less palatable and may cause less patient compliance
5 and therefor there is an urgent need to develop an effective technique to mask the
unacceptable taste of highly bitter drug ursodeoxycholic acid, and to develop a taste
masked pharmaceutical composition of ursodeoxycholic acid to make it more
palatable and for increasing patient compliance.
10 SUMMARY OF THE INVENTION
[05] The object of the present invention is taste masking of ursodeoxycholic acid
using ion-exchange resin, a pharmaceutical composition containing taste-masked
form of ursodeoxycholic acid a method for preparing the thereof. The invention
discloses a taste masked form of ursodeoxycholic acid wherein the bitter drug of the
15 ursodeoxycholic acid is masked using crosslink polyacrilic resin.
[06] The present inventors performed intensive studies for developing a
formulation by which ursodeoxycholic acid is administered more easily and drugadministration
compliance is increased. As a result, they developed a resinate of
ursodeoxycholic acid and an ion-exchange resin obtained by physical adsorption of
20 ursodeoxycholic acid on the surface of ion-exchange resin (Doshion P542). The
resinate so obtained resulted in blocking the bitter taste of ursodeoxycholic acid. A
pharmaceutical composition in suspension form is also developed by the inventors of
this invention. Accordingly, this invention discloses a pharmaceutical composition of
ursodeoxycholic acid where the bitter taste of the drug is masked using ion-exchange
25 resin.
[07] In one aspect, the present invention discloses a pharmaceutical composition
containing taste masked form of ursodeoxycholic acid using ion-exchange resin and
pharmaceutical acceptable excipients.
[08] In another aspect, the present invention discloses a pharmaceutical
composition containing taste masked form of ursodeoxycholic acid using crosslinked
polyacrilic resin and pharmaceutical acceptable excipients.
[09] In one another aspect, the present invention discloses a pharmaceutical
5 composition in suspension form where the ursodeoxycholic acid is incorporated in it
in taste-masked form after forming resinate with crosslinked polyacrilic resin.
[10] In one another aspect, the present invention discloses a method of preparing
the pharmaceufical composition in suspension form containing tasked masked form
of ursodeoxycholic acid, where the bitter taste of the ursodeoxycholic acid is masked
10 using crosslinked polyacrilic resin.
DETAILED DESCRIPTION OF THE INVENTION
[11] The following description is full and informative description of the best
method and embodiments presently contemplated for carrying out the present
15 invention which is known to the inventors at the time of filing the patent application.
Of course, many modifications and adaptations will be apparent to those skilled in the
relevant arts in view of the following description and the appended claims. While the
composition and method described herein are provided with a certain degree of
specificity, the present invention may be implemented with either greater or lesser
20 specificity, depending on the needs of the user. Further, some of the features of the
present invention may be used to advantage without the corresponding use of other
features described in the following paragraphs. As such, the present description
should be considered as merely illustrative of the principles of the present invention
and not in limitation thereof, since the present invention is defined solely by the
25 claims.
[12] The foregoing description of the embodiments of the invention has been
presented for the purposes of illustration and description. It is not intended to be
exhaustive or to limit the invenfion to the precise form disclosed. Many
modifications and variations are possible in light of the above teaching. It is intended
that the scope of the invention be limited not by this detailed description, but rather
by the claims appended hereto.
[13] While, the following description is presented to enable a person of ordinary
5 skill in the art to make and use the invention and is provided in the context of the
requirement for a obtaining a patent. The present description is the best presentlycontemplated
method for carrying out the present invention. Various modifications
to the preferred embodiment will be readily apparent to those skilled in the art and the
generic principles of the present invention may be applied to other embodiments, and
10 some features of the present invention may be used without the corresponding use of
other features. Accordingly, the present invention is not intended to be limited to the
embodiment shown but is to be accorded the widest cope consistent with the
principles and features described herein.
[14] The present invention relates to taste masking of ursodeoxycholic acid using
15 ion-exchange resin, a pharmaceutical composition containing taste-masked form of
ursodeoxycholic acid, a method for preparing the thereof The invention discloses a
taste masked form of ursodeoxycholic acid wherein the bitter drug of the
ursodeoxycholic acid is masked using crosslink polyacrilic resin. More specifically
the present invention discloses a pharmaceutical composition in of ursodeoxycholic
20 acid in suspension form wherein the taste of the bitter drug ursodeoxycholic acid is
masked using crosslinked crosslink polyacrilic resin DoshionP542.
[15] In one embodiment, the pharmaceutical composition of present invention
comprises ursodeoxycholic acid, an ion-exchange resin and one or more
pharmaceutical excipients.
25 [16] In one another aspect, the ion-exchange resin is crosslinked polyacrilic resin.
[17] In one another aspect, the crosslinked polyacrilic resin is DoshionP542.
m
[18] The pharmaceutical acceptable excipient may be selected from the group of
preservative, chelating agent, sweetening agent, stabilizer, thickener, co-solvent,
flavoring agent, coloring agent and dispersant.
[19] In one embodiment, the preservative is sodium benzoate, but not limited
5 thereto.
[20] In one embodiment, the chelating agent is disodium EDTA, but not limited
thereto.
[21] In one embodiment, the sweetening agents are sucrose and sucralose, but not
limited thereto.
10 [22] In one embodiment, the stabilizer is colloidal silicon dioxide, but not limited
thereto.
[23] In one embodiment, the thickening agent is xanthan gum, but not limited
thereto.
[24] In one embodiment, the co-solvent is glycerin, but not limited thereto.
15 [25] In one embodiment, the dispersant is purified water, but not limited thereto.
[26] In the illustrated examples of this invention DoshionP542 was used as
crosslined ion-exchange resin to mask the taste of the bitter drug ursodeoxycholic
acid, but the scope of the invention is not limited thereto. Any similar ion-exchange
resin may also be employed to mask the taste of the bitter drug ursodeoxycholic acid.
20 [27] The present invention also discloses a method of preparing pharmaceutical
composition in suspension form of ursodeoxycholic acid in which the taste of the
bitter drug is masked by DoshionP542. Four batches of suspension were prepared by
general method given below. The composition of such four batches are provided in
table-1.
25
Table-1: Composition for suspension formulation
Ingredients
Ursodeoxycholic
acid USP
Doshion P542
Sodium Benzoate
Disodium EDTA
Sucrose (Pharma
Grade)
Sucralose
Colloidal Silicon
Dioxide
Xanthan Gum
(Transparent)
Glycerin
Flavoring Agent
Purified Water
Quantity (% W/V)
Example-1
2.0
4.0
0.15
0.05
50.0
0.2
0.2
0.25
5.0
0.5
q.s. to 100ml
Example-2
2.5
5.0
0.3
0.05
50.0
0.2
0.2
0.2
4.0
0.5
q.s. to 100ml
Example-3
2.5
5.0
0.15
0.05
50.0
0.2
0.2
0.2
4.0
0.5
q.s. to 100ml
Example-4
5
7.5
0.3
0.05
50.0
0.24
0.16
0.2
4.0
1.35
q.s. to 100ml
General Method-I
Preparation of resinate of ursodeoxycholic acid and ion-exchange resin:
5 The required quantities of ursodeoxycholic acid and ion-exchange resin were
weighed. Approximately five times of their volume, purified water is taken in a vessel
and stirred at moderate speed. To this stirring purified water was added required
amount of ion-exchange resin slowly for 30 minutes. Then, to this resultant mixture
was added ursodeoxycholic acid slowly under continuous stirring in and the mixture
10 was stirred for 1 hr. After one hour, the stirring was stopped and the resinate was
allowed to settle for 5 hr. Then, the supernatant was removed and the resinate was
isolated.
General Method-II:
5 Preparation of pharmaceutical composition (suspension) of ursodeoxycholic
acid:
The required quantities of all the acceptable pharmaceutical excipients were weighed.
Approximately half of the purified water was taken in a vessel and heated at 95° C.
To this heated water, was dissolved preservative sodium benzoate and chelating agent
10 disodium EDTA. The resultant mixture was stirred until a clear solution achieved.
Added sweetening agent sucrose in this solution under continuous stirring and allow
to heat until dissolved completely. The resultant solution was filtered and allowed to
cool at 45° C. Another sweetening agent sucralose were dissolved in minimal quantity
of Purified Water and added to the filtered solution. Anti-cacking agent colloidal
15 silicon dioxide was dispersed in Purified water and added to main mixture with
continuous stirring. Added Resinate Slurry from general method- linto bulk under
stirring and allow stirring for 20 minutes until homogenous mixture is obtained.
Then, to this was added thickening agent xanthan gum dispersed in glycerin for 20
min. To this suspension composition was added suitable flavoring agent and the
20 volume was made up to sufficient quantity adding purified water.
Taste evaluation of oral taste masked ursodeoxycholic acid suspension
Method: Taste evaluation was done by a panel of 9 volunteers using time intensity
method.
25 Procedure: An optimized formulation containing 125 mg Ursodeoxycholic Acid per
5 ml was placed on tongue for 10 seconds. Bitterness was recorded instantly and then
after 1 minute and 2 minutes.
Results: The evaluation was performed by classifying bitter taste using scale from 0
to 4. Results of bitterness threshold for suspension composition example-2 are
summarized in table-2.
Table-2: Result of bitterness threshold for suspension composition of example-2
Volunteer
1
2
3
4
5
6
7
8
9
Bitterness Threshold Level
AfterlO sec
0
0
0
0
1
0
0
1
0
After 1 min
0
1
1
0
1
0
0
1
1
After 2 min
0
2
1
0
2
0
1
1
1
5 Whereas 0= No bitter taste, 1= Acceptable bitterness, Level 2= Slightly bitter, 3=
Moderately bitter, 4= Highly bitter.
Stability studies of oral taste masked ursodeoxycholic acid suspension
Stability studies for the prepared taste masked ursodeoxycholic acid suspension
10 composition of example-2 were also carried out for 6 months on different conditions.
The illustrative examples of such studies were carried out at two different
temperatures.
Procedure: 100 ml of pharmaceutical composition of example-2 was packed in two
amber colored containers and kept at different temperature. The stability study was
15 carried out for two temperature conditions one at 40±2° C, 75±5% RH and second at
30±2° C, 75±5% RH. The stability studies were carried out for 6 months. For the said
8
period 6 months sample were taken from such containers and the formulation were
tested for physical, chemical and microbial stability.
Result: The composition was found physically, chemically and microbial stable in
both the studies. Summary of result is given in table-3.
Table-3: Stability studies of ursodeoxycholic acid
s
No.
1.
2.
3.
4.
5.
Parameter
Description
Weight/ml
pH (3.0-5.0)
Assay (in mg/%)
Microbial limit test
1) Total bacterial
count
2) Total fungal
count
3) Pathogens
a) E. Coli
b) Salmonella
species
6 Months at
40±2'' C, 75±5% RH
White to off-white
homogenous suspension
1.21 g/ml
4.10
109.24%
1) 25cfu/ml
2) <10cfu/ml
3)
a) Absent'ml
b) Absent/ml
6 Months at
30*2" C, 75±5% RH
White to off-white
homogenous suspension
1.22 g/ml
4.00
112.26%
1) 25cfu/ml
2) <10cfu/ml
3)
a) Absent/ml
b) Absent/ml

-.^- -"- ^ mm / j l
MM
WE CLAIM:
1. A pharmaceutical composition of ursodeoxycholic acid, the composition
comprises ursodeoxycholic acid or its salt, Mleast one ion-exchange resin and
optionally one or more pharmaceutically acceptable excipients.
5 2. The pharmaceutical composition of claim 1, wherein the atleast one ion-exchange
resin is a crosslink polyacrilic resin.
3. The pharmaceutical composition of claim 2, wherein the crosslink polyacrilic
resin is DoshionP542.
4. The pharmaceutical composition claims 1 to 3, wherein the ratio of
10 ursodeoxycholic acid and the atleast one ion-exchange resin is 1:1.5 to 1:2.
5. The pharmaceutical composition of any one of the preceding claims, wherein one
or more pharmaceutically acceptable excipients are selected from the group
consisting of preservative, chelating agent, sweetening agent, stabilizer, thickener,
co-solvent, flavoring agent, coloring agent and dispersant.
15 6. A Pharmaceutical composition of ursodeoxycholic acid, the composition
comprises ursodeoxycholic acid from 2-5% w/v, atleast one ion-exchange resin 4-
7.5% w/v, a chelating agent 0.05% w/v, a preservative 0.15-0.3% w/v, atleast one
Sweetening agent 50-55% w/v, an anti-cacking agent 0.16-0.2% w/v, a thickening
agent 0.2-0.25% w/v, a co-solvent 4-5% w/v, a flavoring agent from 0.5-1.35%
20 w/v, a coloring agent 0.001-5%w/v and a dispersant 5-60% w/v.
7. The composition of claim 6, wherein the atleast one sweetening agent is selected
from sucrose and sucralose.
8. The pharmaceutical composition of claims 6 and 7, wherein the composition
comprises ursodeoxycholic acid from 2-5% w/v, ion-exchange resin
25 DoshionP542 4-7.5% w/v, disodium EDTA 0.05% w/v, sodium benzoate 0.15-
0.3% w/v, sucrose 50% w/v, sucralose 0.2-0.24% w/v, colloidal silicon dioxide
20
1 8 W^» ^^^ ^ . -
0.16-0.2% w/v, xanthan Gum 0.2-0.25% w/v, glycerin 4-5% w/v, flavoring agent
from 0.5-1.35% w/v and dispersant 5-60%w/v.
9. The pharmaceutical composition of claim 6 to 8, wherein the composition
comprises ursodeoxycholic acid 2.5% w/v, ion-exchange resin DoshionP542 5%
5 w/v, disodium EDTA 0.05% w/v, sodium benzoate 0.15% w/v, sucrose 50% w/v,
sucralose 0.2% w/v, colloidal silicon dioxide 0.2% w/v, xanthan Gum 0.2% w/v,
glycerin 4% w/v, flavoring agent from 0.5% w/v and dispersant 5-60%w/v.
10. A method of preparing a pharmaceutical composition of ursodeoxycholic acid, the
method comprises:
10 a. preparing a resinate comprising ursodeoxycholic acid and atleast one ionexchange
resin; and
b. preparing the pharmaceutical composition of ursodeoxycholic acid using the
resinate prepared in step (a), the method comprises
i. heating the half of the amount of dispersant;
15 ii. dissolving a one or more pharmaceutical excipients in the dispersant;
iii. adding resinate prepared in step (a) to the mixture prepared in step b(ii);
iv. adding remaining amount of dispersant.