(19)

&  
(11) EP 2 255 783 A2
(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.:

01.12.2010 Bulletin 2010/48 A61K 9/06 (2006.01) A61K 9/127 (2006.01)
A61K 31/20 (2006.01) A61K 8/362 (2006.01)
(21) Application number: 10164060.5 A61Q 19/00 (2006.01)

(22) Date of filing: 27.05.2010

(84) Designated Contracting States: (72) Inventors:

AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • Langner, Marek
GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO 51-314, Wroclaw (PL)
PL PT RO SE SI SK SM TR • Potaczek, Piotr
Designated Extension States: 58-508, Jelenia Gora (PL)
BA ME RS
(74) Representative: Krekora, Magdalena
(30) Priority: 28.05.2009 PL 38813509 ul. Gorna 95
PL-32-091 Michalowice (PL)
(71) Applicant: Przedsiebiorstwo Produkcji
Farmaceutycznej Hasco-Lek S.A.
51-131 Wroclaw (PL)

(54) Azelaic acid gel, and a method of obtaining same

(57) An azelaic acid gel consisting of azelaic acid, soya or egg phosphatidylcholine or from 1,2-dioleoyl-sn-
liposomes, organic solvents, buffer, gelling agents, and glycero-3-phosphatidylcholine. The organic solvents are
preferably additionally consisting of preservatives and propylene glycol, ethanol and triethanolamine. A method
antioxidants. The overall concentration of the azelaic acid of obtaining the said composition is also disclosed.
is 15% by weight. Liposomes are obtained from purified
EP 2 255 783 A2

Printed by Jouve, 75001 PARIS (FR)

 EP 2 255 783 A2

Description

TECHNICAL FIELD

5 [0001] The object of the present invention is a gel comprising azelaic acid as active substance used for medical or
cosmetic purposes, and a method of obtaining an azelaic acid gel.

BACKGROUND ART

10 [0002] European patent EP0336880 describes pharmaceutical composition containing azelaic acid in concentration
of 20% and excipients such as: triacylglycerols, and diacylglycerols, propylene glycol, polysorbate, water, and salt. These
compositions are in the form of ointment, which is used for treatment of skin ageing.
[0003] In Rote Liste from 1996 under the number 32 282 a pharmaceutical composition named Skinoren may be
found. This composition comprising azelaic acid is in the form of ointment, and is used for treatment of simple acne.
15 [0004] Polish patent PL202454 describes pharmaceutical composition in the form of hydrogel, comprising azelaic acid
as active substance, and following excipients: triacylglycerol, propylene glycol, polyacrylic acid, soya lecithin, polisorbate,
water and salt. Content of azelaic acid in pharmaceutical composition described in the patent is between 5-20% by
weight. The most preferable composition of the pharmaceutical formulation described in this patent is a formulation of
14-16% of azelaic acid comprising not less than 1% by weight of soya lecithin. It is used in treatment of acne rosacea,
20 senile skin, melanoderm, or/and skin irritation. This composition, comprising 15% by weight of azelaic acid is sold on
the market under the trademark Skinoren Gel or Finacea.

DISCLOSURE OF THE INVENTION

25 [0005] The objective of the present invention is to provide a gel for medical or cosmetic purposes comprising azelaic
acid as active substance, which has stability required for such preparations, and at the same time increased accumulation
in skin, what results in decrease of active substance content.
[0006] The invention describes an azelaic acid gel characterised in that it consists of azelaic acid, liposomes, organic
solvents, buffer, gelling agents, and may additionally consist of preservatives and antioxidants. Preferably the overall
30 concentration of the azelaic acid is 15% by weight. Liposomes, being a part of the gel composition, may be obtained
from purified phosphatidylcholine, preferably from soya phosphatidylcholine or egg phosphatidylcholine. Preferably the
overall concentration of purified phosphatidylcholine is from 10 to 15% by weight. Instead of purified phosphatidylcholine,
purified 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine is used as the source of liposomes. Preferably the overall con-
centration of 1,2-dioleoyl-sn-glycero-3- phosphatidylcholine is from 10 to 15% by weight. The azelaic acid gel may
35 comprise monolayer liposomes or multilayer liposomes or a mixture of monolayer liposomes and multilayer liposomes.
The azelaic acid comprised in the gel may be in the form not bound to liposomes or may be in the form bound to liposomes
or in the form both bound and not bound to liposomes. Preferably the organic solvents are propylene glycol, ethanol
and triethanolamine. Preferably the overall concentration of propylene glycol is from 6 to 10% by weight, the overall
concentration of ethanol is from 3 to 5% by weight, the overall concentration of triethanolamine is from 7 to 7.5% by
40 weight. The buffer comprised in the azelaic gel may be citrate buffer, preferably having the pH between 4.5 and 5.5. In
such pH value amiphatic form of azelaic acid is generated resulting in maximum interaction between azelaic acid, and
liposomes, and increase of azelaic acid solubility in the mixture. Preferably the antioxidant is disodium edetate, and its
overall concentration is 0.5% by weight. Preferably the preservative is methyl parahydroxybenzoate, and its overall
concentration is 0.15% by weight. Preferably the gelling agent is polyacrylic acid, and its overall concentration is from
45 1 to 3% by weight. Instead of polyacrylic acid, ammonium acryloyldimethyltaurate/VP copolymer may be used. Preferable
overall concentration of ammonium acryloyldimethyltaurate/VP copolymer is from 1 to 3% by weight.
[0007] A method of obtaining the azelaic acid gel consisting of azelaic acid, liposomes, organic solvents, buffer, gelling
agents, and preservatives and/or antioxidants, described in the invention, is characterised in that purified phosphatidyl-
choline or 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine is dissolved in propylene glycol, and then mixed with aqueous
50 phase comprising buffer, remaining organic solvents, antioxidant, preservative and azelaic acid to obtain a suspension
of liposomes, which is then mixed with remaining part of azelaic acic and gelling substance. Preferably the suspension
of liposomes is obtained by extrusion or by homogenisation.
[0008] Use of liposomes in the topical formulation in accordance with the present invention increases the concentration
of the active substance directing it into the skin, and additionally used liposomes create thin phospholipid layer protecting
55 the ointment against drying too quickly, and prolonging the bioavailability of azelaic acid.
[0009] Use of appropriate mixture of organic solvents for azelaic acid additionally increases bioavailability, what en-
hances efficacy of liposome formulation of azelaic acid.
[0010] Gels obtained in accordance with the examples given below underwent standard test in Franz cells in order to

2
 EP 2 255 783 A2

confirm their efficacy. Tests were carried out on pigs ears, whose impedance has been earlier measured, at the tem-
perature of 32°C for 20 hours, when using phosphate buffer of pH equal to 7.4 in receiving chamber. Each preparation
was tested in nine Franz cells.
[0011] Results from efficacy tests of liposome skin formulations in Franz cells, when pointing out the average con-
5 centration of azelaic acid on the skin, are shown at Diagram 1.

10

15

20

25

30 BEST MODE OF CARRYING OUT THE INVENTION

[0012] The following examples illustrate the invention without setting or delineating its limits.

Example 1.
35
[0013] Monohydrated citric acid, and sodium hydroxide are dissolved at room temperature in purified water receiving
citrate buffer having pH equal to 5.0.
[0014] Ethanol is diluted with citrate buffer to concentration of 50%.
[0015] To the agitator tank equipped with stirrer, and heating jacket are added: azelaic acid (5%), 50% ethanol solution,
40 citrate buffer of pH equal to 5, triethanolamine, disodium edetate, and methyl parahydroxybenzoate. The entirety is
mixed at temperature of about 40°C until complete dissolution of all components.
[0016] Purified soya phosphatidylcholine is dissolved, when mixing, in propylene glycol at the temperature of about
70°C. To the so obtained solution is added by portions with continuous mixing, when deaerating, the solution of azelaic
acid obtained earlier. After thorough deaeration the whole mixture is extruded once through two filters of 100 nm. To
45 the liposome suspension is added remaining part of azelaic acid (10%). The entirety is mixed and deaerated simulta-
neously. Finally to the earlier obtained liposome suspension of azelaic acid is added ammonium acryloyldimethyltau-
rate/VP copolymer, and afterwards the entirety is thoroughly mixed and deaerated.

ACTIVE SUBSTANCES:
50
Azelaic acid 15,00
EXCIPIENTS:
Purified soya phosphatidylcholine 10,00
55 Propylene glycol 10,00

3
 EP 2 255 783 A2

(continued)

EXCIPIENTS:
Triethanolamine 5,00
5
Ethanol 5,00
Disodium edetate 0,50
Methyl parahydroxybenzoate 0,15
10 Ammonium acryloyldimethyltaurate/VP copolymer 3,00
Sodium hydroxide 0,41
Monohydrated citric acid 1,02
Purified water 49,92
15
TOTAL 100,00

Example 2.

20
[0017] Monohydrated citric acid, and sodium hydroxide are dissolved at room temperature in purified water receiving
citrate buffer having pH equal to 5.0.
[0018] Ethanol is diluted with citrate buffer to concentration of 50%.
[0019] To the agitator tank equipped with stirrer, and heating jacket are added: azelaic acid (7.5%), 50% ethanol
solution, citrate buffer of pH equal to 5, triethanolamine, disodium edetate, and methyl parahydroxybenzoate. The entirety
25
is mixed at temperature of about 40°C until complete dissolution of all components.
[0020] Purified soya phosphatidylcholine is dissolved, when mixing, in propylene glycol at the temperature of about
70°C. To the so obtained solution is added by portions with continuous mixing, when deaerating, the solution of azelaic
acid obtained earlier. After thorough deaeration the whole mixture is extruded once through two filters of 100 nm. To
the liposome suspension is added remaining part of azelaic acid (7.5%). The entirety is mixed and deaerated simulta-
30
neously. Finally to the earlier obtained liposome suspension of azelaic acid is added ammonium acryloyldimethyltau-
rate/VP copolymer, and afterwards the entirety is thoroughly mixed and deaerated.

ACTIVE SUBSTANCES:
35 Azelaic acid 15,00
EXCIPIENTS:
Purified soya phosphatidylcholine 15,00
Propylene glycol 10,00
40
Triethanolamine 7,50
Ethanol 5,00
Disodium edetate 0,50
45 Methyl parahydroxybenzoate 0,15
Ammonium acryloyldimethyltaurate/VP copolymer 1,00
Sodium hydroxide 0,36
Monohydrated citric acid 0,92
50
Purified water 44,57
TOTAL 100,00

55 Example 3.

[0021] Monohydrated citric acid, and sodium hydroxide are dissolved at room temperature in purified water receiving
citrate buffer having pH equal to 5.0.

4
 EP 2 255 783 A2

[0022] Ethanol is diluted with citrate buffer to concentration of 50%.

[0023] To the agitator tank equipped with stirrer, and heating jacket are added: azelaic acid (5%), 50% ethanol solution,
citrate buffer of pH equal to 5, triethanolamine, disodium edetate, and methyl parahydroxybenzoate. The entirety is
mixed at temperature of about 40°C until complete dissolution of all components.
5 [0024] Purified soya phosphatidylcholine is dissolved, when mixing, in propylene glycol at the temperature of about
70°C. To the so obtained solution is added by portions with continuous mixing, when deaerating, the solution of azelaic
acid obtained earlier. After thorough deaeration the whole mixture is extruded once through two filters of 100 nm. To
the liposome suspension is added remaining part of azelaic acid (10%). The entirety is mixed and deaerated simulta-
neously. Carbomer 941 is dispergated in water. Then 30% solution of sodium hydroxide is added in order to gel the
10 polymer. The entirety is mixed and deaerated simultaneously. To such obtained gel is added by portions the liposome
suspension of azelaic acid obtained earlier. The entirety is mixed and deaerated simultaneously.

ACTIVE SUBSTANCES:

15 Azelaic acid 15,00

EXCIPIENTS:
Purified soya phosphatidylcholine 10,00
Propylene glycol 6,67
20
Triethanolamine 5,00
Ethanol 3,33
Disodium edetate 0,50

25 Methyl parahydroxybenzoate 0,15

Carbomer 941 (Polyacrylic acid) 2,00
Sodium hydroxide 1,14
Monohydrated citric acid 0,60
30
Purified water 55,61
TOTAL 100,00

35
Example 4.

[0025] Monohydrated citric acid, and sodium hydroxide are dissolved at room temperature in purified water receiving
citrate buffer having pH equal to 5.0.
[0026] Ethanol is diluted with citrate buffer to concentration of 50%.
40
[0027] To the agitator tank equipped with stirrer, and heating jacket are added: azelaic acid (5%), 50% ethanol solution,
citrate buffer of pH equal to 5, triethanolamine, disodium edetate, and methyl parahydroxybenzoate. The entirety is
mixed at temperature of about 40°C until complete dissolution of all components.
[0028] Purified egg phosphatidylcholine is dissolved, when mixing, in propylene glycol at the temperature of about
70°C. To the so obtained solution is added by portions with continuous mixing, when deaerating, the solution of azelaic
45
acid obtained earlier. After thorough deaeration the whole mixture is extruded once through two filters of 100 nm. To
the liposome suspension is added remaining part of azelaic acid (10%). The entirety is mixed and deaerated simulta-
neously. Finally to the earlier obtained liposome suspension of azelaic acid is added ammonium acryloyldimethyltau-
rate/VP copolymer, and afterwards the entirety is thoroughly mixed and deaerated.

50 ACTIVE SUBSTANCES:
Azelaic acid 15,00
EXCIPIENTS:
Purified egg phosphatidylcholine 10,00
55
Propylene glycol 10,00

5
 EP 2 255 783 A2

(continued)

EXCIPIENTS:
Triethanolamine 5,00
5
Ethanol 5,00
Disodium edetate 0,50
Methyl parahydroxybenzoate 0,15
10 Ammonium acryloyldimethyltaurate/VP copolymer 3,00
Sodium hydroxide 0,41
Monohydrated citric acid 1,02
Purified water 49,92
15
TOTAL 100,00

Example 5.

20
[0029] Monohydrated citric acid, and sodium hydroxide are dissolved at room temperature in purified water receiving
citrate buffer having pH equal to 5.0.
[0030] Ethanol is diluted with citrate buffer to concentration of 50%.
[0031] To the agitator tank equipped with stirrer, and heating jacket are added: azelaic acid (5%), 50% ethanol solution,
citrate buffer of pH equal to 5, triethanolamine, disodium edetate, and methyl parahydroxybenzoate. The entirety is
25
mixed at temperature of about 40°C until complete dissolution of all components.
[0032] 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine is dissolved, when mixing, in propylene glycol at the temperature
of about 70°C. To the so obtained solution is added by portions with continuous mixing, when deaerating, the solution
of azelaic acid obtained earlier. After thorough deaeration the whole mixture is extruded once through two filters of 100
nm. To the liposome suspension is added remaining part of azelaic acid (10%). The entirety is mixed and deaerated
30
simultaneously. Carbomer 941 is dispergated in water. Then 30% solution of sodium hydroxide is added in order to gel
the polymer. The entirety is mixed and deaerated simultaneously. To such obtained gel is added by portions the liposome
suspension of azelaic acid obtained earlier. The entirety is mixed and deaerated simultaneously.

ACTIVE SUBSTANCES:
35
Azelaic acid 15,00
EXCIPIENTS:
1,2-Dioleoilo-sn-glicero-3-fosfatydylocholina 10,00
40 Propylene glycol 6,67
Triethanolamine 5,00
Ethanol 3,33
Disodium edetate 0,50
45
Methyl parahydroxybenzoate 0,15
Carbomer 941 (Polyacrylic acid) 2,00
Sodium hydroxide 1,14
50
Monohydrated citric acid 0,60
Purified water 55,61
TOTAL 100,00

55
Example 6.

[0033] Monohydrated citric acid, and sodium hydroxide are dissolved at room temperature in purified water receiving

6
 EP 2 255 783 A2

citrate buffer having pH equal to 5.0.

[0034] Ethanol is diluted with citrate buffer to concentration of 50%.
[0035] To the agitator tank equipped with stirrer, and heating jacket are added: azelaic acid (7.5%), 50% ethanol
solution, citrate buffer of pH equal to 5, triethanolamine, disodium edetate, and methyl parahydroxybenzoate. The entirety
5 is mixed at temperature of about 40°C until complete dissolution of all components.
[0036] Purified soya phosphatidylcholine is dissolved, when mixing, in propylene glycol at the temperature of about
70°C. To the so obtained solution is added by portions with continuous mixing, when deaerating, the solution of azelaic
acid obtained earlier. After thorough deaeration the whole mixture is homogenised at room temperature until liposomes
of about 100 nm are obtained. To the liposome suspension is added remaining part of azelaic acid (7.5%). The entirety
10 is mixed and deaerated simultaneously. Finally to the earlier obtained liposome suspension of azelaic acid is added
ammonium acryloyldimethyltaurate/VP copolymer, and afterwards the entirety is thoroughly mixed and deaerated.

ACTIVE SUBSTANCES:

15 Azelaic acid 15,00

EXCIPIENTS:
Purified soya phosphatidylcholine 15,00
Propylene glycol 10,00
20
Triethanolamine 7,50
Ethanol 5,00
Disodium edetate 0,50

25 Methyl parahydroxybenzoate 0,15

Ammonium acryloyldimethyltaurate/VP copolymer 1,00
Sodium hydroxide 0,36
Monohydrated citric acid 0,92
30
Purified water 44,57
TOTAL 100,00

35
Example 7.

[0037] Monohydrated citric acid, and sodium hydroxide are dissolved at room temperature in purified water receiving
citrate buffer having pH equal to 5.0.
[0038] Ethanol is diluted with citrate buffer to concentration of 50%.
40
[0039] To the agitator tank equipped with stirrer, and heating jacket are added: azelaic acid (5%), 50% ethanol solution,
citrate buffer of pH equal to 5, triethanolamine, disodium edetate, and methyl parahydroxybenzoate. The entirety is
mixed at temperature of about 40°C until complete dissolution of all components.
[0040] Purified soya phosphatidylcholine is dissolved, when mixing, in propylene glycol at the temperature of about
70°C. To the so obtained solution is added by portions with continuous mixing, when deaerating, the solution of azelaic
45
acid obtained earlier. After thorough deaeration the whole mixture is homogenised at room temperature until liposomes
of about 100 nm are obtained. To the liposome suspension is added remaining part of azelaic acid (10%). The entirety
is mixed and deaerated simultaneously. Carbomer 941 is dispergated in water. Then 30% solution of sodium hydroxide
is added in order to gel the polymer. The entirety is mixed and deaerated simultaneously. To such obtained gel is added
by portions the liposome suspension of azelaic acid obtained earlier. The entirety is mixed and deaerated simultaneously.
50
ACTIVE SUBSTANCES:
Azelaic acid 15,00
EXCIPIENTS:
55 Purified soya phosphatidylcholine 10,00

7
 EP 2 255 783 A2

(continued)

EXCIPIENTS:
Propylene glycol 6,67
5
Triethanolamine 5,00
Ethanol 3,33
Disodium edetate 0,50
10 Methyl parahydroxybenzoate 0,15
Carbomer 941 (Polyacrylic acid) 2,00
Sodium hydroxide 1,14
Monohydrated citric acid 0,60
15
Purified water 55,61
TOTAL 100,00

20
Claims

1. An azelaic acid gel, characterised in that it consists of azelaic acid, liposomes, organic solvents, buffer, gelling
agents, and may additionally consist of preservatives and antioxidants.

25
2. The azelaic acid gel according to claim 1, characterised in that the overall concentration of the azelaic acid is 15%
by weight.

3. The azelaic acid gel according to claim 1 or 2, characterised in that liposomes are obtained from purified phos-
phatidylcholine, preferably from soya phosphatidylcholine or egg phosphatidylcholine.
30

4. The azelaic acid gel according to claim 3, characterised in that the overall concentration of purified phosphatidyl-
choline is from 10 to 15% by weight.

5. The azelaic acid gel according to claim 1 or 2, characterised in that liposomes are obtained from purified 1,2-
35
dioleoyl-sn-glycero-3-phosphatidylcholine.

6. The azelaic acid gel according to claim 5, characterised in that the overall concentration of 1,2-dioleoyl-sn-glycero-
3-phosphatidylcholine is from 10 to 15% by weight.

40
7. The azelaic acid gel according to any of the preceding claims, characterised in that it comprises monolayer
liposomes.

8. The azelaic acid gel according to any of the claims from 1 to 6, characterised in that it comprises multilayer
liposomes.
45

9. The azelaic acid gel according to any of the claims from 1 to 6, characterised in that it comprises mixture of
monolayer liposomes and multilayer liposomes.

10. The azelaic acid gel according to any of the preceding claims, characterised in that azelaic acid is not bound to
50
liposomes.

11. The azelaic acid gel according to any of the claims from1 to 9, characterised in that azelaic acid is bound to
liposomes.

55
12. The azelaic acid gel according to any of the claims from1 to 9, characterised in that azelaic acid is both bound
and not bound to liposomes.

8
 EP 2 255 783 A2

13. The azelaic acid gel according to any of the preceding claims, characterised in that the organic solvents are
propylene glycol, ethanol and triethanolamine.

14. The azelaic acid gel according to claim 13, characterised in that the overall concentration of propylene glycol is
5 from 6 to 10% by weight.

15. The azelaic acid gel according to claim 13 or 14, characterised in that the overall concentration of ethanol is from
3 to 5% by weight.

10 16. The azelaic acid gel according to claim 13 or 14 or 15, characterised in that the overall concentration of trieth-
anolamine is from 7 to 7.5% by weight.

17. The azelaic acid gel according to any of the preceding claims, characterised in that the buffer is citrate buffer.

15 18. The azelaic acid gel according to claim 17, characterised in that the pH of buffer citrate is between 4.5 and 5.5.

19. The azelaic acid gel according to any of the preceding claims, characterised in that the antioxidant is disodium
edetate.

20 20. The azelaic acid gel according to claim 19, characterised in that the overall concentration of disodium edetate is
0.5% by weight.

21. The azelaic acid gel according to any of the preceding claims, characterised in that the preservative is methyl
parahydroxybenzoate.
25
22. The azelaic acid gel according to claim 21, characterised in that the overall concentration of methyl parahydroxy-
benzoate is 0.15% by weight.

23. The azelaic acid gel according to any of the preceding claims, characterised in that the gelling agent is polyacrylic
30 acid.

24. The azelaic acid gel according to claim 23, characterised in that the overall concentration of polyacrylic acid is
from 1 to 3% by weight.

35 25. The azelaic acid gel according to any of the claims from 1 to 22, characterised in that the gelling agent is ammonium
acryloyldimethyltaurate/VP copolymer.

26. The azelaic acid gel according to claim 25, characterised in that the overall concentration of ammonium acryloyld-
imethyltaurate/VP copolymer is from 1 to 3% by weight.
40
27. A method of obtaining the azelaic acid gel consisting of azelaic acid, liposomes, organic solvents, buffer, gelling
agents, and preservatives and/or antioxidants, characterised in that purified phosphatidylcholine or 1,2-dioleoyl-
sn-glycero-3- phosphatidylcholine is dissolved in propylene glycol, and then mixed with aqueous phase comprising
buffer, remaining organic solvents, antioxidant, preservative and azelaic acid to obtain a suspension of liposomes,
45 which is then mixed with remaining part of azelaic acic and gelling substance.

28. A method of obtaining the azelaic acid gel according to claim 27, characterised in that the suspension of liposomes
is obtained by extrusion.

50 29. A method of obtaining the azelaic acid gel according to claim 27, characterised in that the suspension of liposomes
is obtained by homogenisation.

55

9
 EP 2 255 783 A2

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European
patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be
excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• EP 0336880 A [0002] • PL 202454 [0004]

10