Title of Invention

"COMPOSITION FOR USE AS MEDICAMENT COMPRISING AZELAIC ACID"

Abstract "COMPOSITION FOR USE AS MEDICAMENT COMPRISING AZELAIC ACID" Composition for use as a medicament that comprises the following features: (i)    Azelaic acid as a therapeutic active ingredient at a concentration of 5 to 20% by weight, (iii)   triacylglycerides, (iv)   propylene glycol, and (v)    polysorbates (vii)   in an aqueous phase that comprises water and salts, characterized in that the composition comprises (ii)    polyacrylic acid at a concentration of 0.5 to 2% by weight, and (vi)   lecithin as further additives, wherein the lecithin is present in the composition at a concentration of up to 3 % by weight, and that the composition is a hydrogel.
Full Text The present invention relates to composition for use as medicament comprising azelaic acid.
The invention relates to a composition with azelaic acid in a hydrogel. The invention furthermore includes the use of the azelaic acid hydrogel as medicinal product. This application claims the German priorities DE 197 53 044 with the filing date of 19 November 1997 and DE 198 08 086 with the filing date of 20 February 1998.
State of the art
EP 0 336 880 A2. which was filed on 29.3.1998, describes a pharmaceutical composition which consists of (i) azelaic acid in a concentration of 20 percent by weight, of (iii) triacylglycerides and diacyl-glycerides, of (iv) propylene glycol, of (v) polysorbate, for example polyethylene 20 sorbitan monooleate, and of (vii) water and salts. This composition for topical administration is employed to treat various age-related changes in the facial skin. The composition is in the form of a cream. It is furthermore known to employ azelaic acid also as remedy for inflammatory and infectious dermatoses such as, for example, acne and rosacea.
The 1996 Rote Liste (ISBN 3-87193-167-5) describes, under 32 282, a pharmaceutical composition named Skinoren which consists of (i) azelaic acid in a concentration of 20 percent by weight:, of (iii) triacylglycerides and diacylglycerides, of (iv) propylene glycol, of (v) polysorbate, for example macrogol stearate 1000 and of (vii) water and salts. This composition for topical administration is employed for treating acne. The composition is in the form of a cream. This document is regarded as the closest state of the art.
The international application WO 9 6/117 00, which was filed on 29 October 1993, describes a pharmaceutical composition which is employed as adjuvant for a vaccine. This composition is intended to replace Freund's adjuvant. It is injected. Hepatitis B surface proteins are employed, for example, as (i)

pharmaceutical active ingredient. Also used are (ii) polyacrylic acid, (iii) triacylglycerides and/or diacylglycerides such as MIGLYOL, (iv) propylene glycol, and (v) polysorbates in the form of TWEEN, EMULROR and SIMULSOL M-53. There is likewise addition of (vi) soya lecithin. The composition is an (vii) aqueous phase with salts. The composition is not administered topically. The emulsion has particles with a size of from 0.03 to 0.5 pm. preferably 0.5 to 0.2 Mm.
The international application WO 95/05163, which was filed on 5 August 1994, describes a pharmaceutical composition which is in the form of an emulsion for administering bioactive substances to the surface of the skin. This composition contains particles with a size of from 30 to 500 nm, preferably 70 to 200 ran, Antiinflammatory medicines are employed, for example, as (i) pharmaceutical active ingredients. Also used are (ii) polyacrylic acid, (iii) triacylglycerides and/or diacylglycerides, (iv) propylene glycol, and (v) polysorbates in the form of TWEEN. EMULROR, TRITON X and SIMULSOL M-53. There is likewise addition of (vi) soya lecithin. The composition is an (vii) aqueous phase with salts. The composition is administered topically.
European patent application 0 696 452, which was filed on 26 July 1995, describes a nanoemulsion which is employed for a medicine for treating the eyes, the nanoemulsion being administered in the form of eyedrops for topical application. This composition contains particles with an average size of 520 nm. Antiinflammatory medicines are employed, for example, as (i) pharmaceutical active ingredients. Also used are (ii) polyacrylic acid, (iii) triacylglycerides and/or diacylglycerides, (iv) propylene glycol and (v) polysorbates in the form of polyoxyethylene/ polyoxypropy1ene copolymers. The composition is an (vii) aqueous phase with salts. The composition is administered topically.

Problem and solution
The problem is to provide a pharmaceutical composition with azelaic acid as therapeutic active ingredient, the intention being to increase the bioavailability of the azelaic acid.
In a composition according to the state of the art comprising the following features:
(i) azelaic acid as therapeutic active ingredient,
(iii) triacylglycerides,
(iv) propylene glycol, and
(v) polysorbates
(vii) in an aqueous phase comprising water and salts,
the problem is solved by the composition comprising, as further additions,
(ii) polyacrylic acid, and
(vi) soya lecithin, and the composition moreover being a hydrogel.
Advantages:
The composition according to the invention has the advantage that it allows a larger quantity of pharmaceutical active ingredient to enter the dermis. In this connection, the availability of azelaic acid in the composition according to the invention is factors of three to five times higher than in the azelaic acid cream according to the state of the art. This availability has been demonstrated in a FRANZ continuous flow diffusion cell test which is described in detail in the examples. The dermis is precisely the desired target for azelaic acid. The composition can be employed particularly well with azelaic acid in high concentrations.
Further development of the composition A composition which can be administered topically is advantageous.
A preferred composition according to the invention is one in which the azelaic acid is present

in a concentration of from 5 to 20 percent by weight, more preferably in a concentration of from 10 to 18 percent by weight and most preferably in a concentration of from 14 to 16 percent by weight.
The presence of polyacrylic acid is essential. It is crucial for the production of the hydrogel. The lecithin preferred in the gel is soya lecithin. The lecithin or soya lecithin is advantageous in a concentration of at least 3 percent by weight. A concentration of at least 1.5 percent by weight is more preferred, and a concentration of at least 1 percent by weight is most preferred. The last concentration has the effect that the hydrogel is no longer in the form of a nanoemulsion.
Advantage
It has unexpectedly emerged that the composition according to the invention does not form a classical nanoemulsion according to the state of the art with lecithin concentrations of 1 percent by weight or less. On the contrary, it is in the form of a gel which comprises a homogeneous mass with virtually no vesicles, but with membrane fragments. It was not to be foreseen that azelaic acid and the remainder of the composition do not form a nanoemulsion. It was only with the aid of scanning electron micrographs that clarity was obtainable. It emerged that no nanoemulsion is identifiable on examination under the microscope. The composition according to the invention advantageously shows high penetration into the dermis, which is not observable with creams.
Preferred embodiments
A preferred composition is one where the individual parameters can, independently of one another, have the following concentrations:
(ii) polyacrylic acid in a concentration of from
0.5 to 2 percent by weight,
(iii) triacylglycerides in a concentration of from
0.5 to 5 percent by weight,

(iv) propylene glycol in a concentration of from
5 to 15 percent by weight and
(v) polysorbates in a concentration of from 0.5
to 3 percent by weight.
The ingredients must, of course, be adjusted relative to one another to result in a total of 100%.
A most preferred composition is one where the individual parameters can, independently of one another, have the following concentrations:
(ii) polyacrylic acid in a concentration of 1 ±
0,25 percent by weight,
(iii) triacylglycerides in a concentration of 2 ±
1 percent by weight,
(iv) propylene glycol in a concentration of 10 ±
2 percent by weight and
(v) polysorbates in a concentration of 2 ± 0.5 percent by weight.
The ingredients must, of course, be adjusted relative to one another to result in a total of 100%.
Definitions:
Azelaic acid and its preparation are described in German patent DE 28 17 133.7. Compare also Rompp, Cheitde Lexikon, edited by Jtirgen FALSE and Manfred REGNITZ, 1989, 9th edition, page 323, Thieme Verlag Stuttgart, ISBN 3-13-734609-6.
Pp lyacryj.ic ac i d is an anionic acrylic acid polymer which is only partly soluble in water. A 1 percent strength aqueous suspension has a pH of 3 and approximately the same viscosity as water. Only on neutralization with inorganic or organic bases does gel formation occur, and highly viscous products result. Rudolf VOIGT and Manfred BORNSCHEIN, 1979, Lehrbuch der pharmazeutischen Technologic, page 314, VEB Verlag Volk und Gesundheit Berlin. Compare also Rompp, Chemie Lexilcon, edited by Jvirgen FALSE and Manfred REGNITZ, 1992, 9th edition, page 3508, Thieme Verlag Stuttgart, ISBN 3-13-735009-3.
"TriglyeBride" is a name for esters of glycerol whose three hydroxyl groups are esterified by

carboxylic acids. The naturally occurring fats and fatty oils are triglycerides ("neutral fats") which usually contain various fatty acids in the same glycerol molecule. J. Am. Oil. Chem. Soc. Vol. 62, page 730 (1985); and Parfum. Kosmet. Vol. 58, page 353 (1977); and Rompp, Chemie Lexikon, edited by Jtirgen FALSE and Manfred REGNITZ, 1990, 9th edition, pages 1339 - 1342, Thieme Verlag Stuttgart, ISBN 3-13-734709-2.
Propylene glycol is described in H.P. FIEDLER: Lexikon der Hilfsstoffe, 4th edition, 1996, ISBN 3-87193-173 on pages 1278 to 1282.
Polysorbates are described in H.P. FIEDLER: Lexikon der Hilfsstoffe, 4th edition, 1996, ISBN 3-87193-173 on pages 12S1 to 1252.
Lecithins are obtained by extraction from biological material. Thus, a lecithin fraction from soya beans (the most widely used raw material) comprises, for example, palmitic acid, stearic acid, palroitoleic acid, oleic acid, linoleic acid and linolenic acid. Normally, the saturated fatty acid is esterified by the primary, and the unsaturated by the secondary, hydroxyl group of glycerol. Lecithins are constituents of the cell membranes of all life forms. In water/ lecithins initially swell like lyophilic colloids. They subsequently take the form of transparent, colloidal solutions. They form various textures depending on the water content, with the lamellae being formed by lipid bilayers. Liposomes are produced with a relatively high water content. Lit.; Pardun, Die Pflanzenlecithine, Augsburg: Verl. far Chem. Ind. (Ziolkowsky KG) 1988. Other lecithins and their action are described in J. GAREISS et al., 1994, Parfumerie und Kosmetik, Vol. 10/94, pages 652-659. Htithing GmbH, Heidelberg.
A gsl is distinguished by the following properties: it comprises a dimensionally stable, easily deformable disperse system which has a high liquid and, where appropriate, gas content and consists of at least

two components- Rompp, Chemie Lexikon, edited by Jiirgen FALSE and Manfred REGNITZ, 1990, 9th edition, page 1511, Thieme Verlag Stuttgart, ISBN 3-13-734709-2; and Pharro. Unserer Zeit, Vol. 8, pages 179 to 188 (1979); and Parfum. Kosmet., Vol. 58, pages 251 to 253 (1977).
Preservatives may be present in the aqueous phase. Preservatives include, for example, benzoic acid. Because of its antimicrobial property, benzoic acid is particularly suitable as preservative.
Properties on uae as medicine
The composition of the invention shows a pharmacological action. and can be employed as therapeutic active ingredient or as medicine.
A composition according to the invention preferably includes at least one physiologically tolerated pharmacological ancillary substance or excipient. Pharmacological ancillary substances and excipients are described in Remington's Pharmaceutical Science, 15th ed. Mack Publishing Company, Easton Pennsylvania (1980).
The composition of the invention is suitable for treating various indications. A composition of the invention is preferred as therapeutic active ingredient for treating rosacea, age spots, melasma, acne and/or dermal irritation. A composition of the invention is more preferred as therapeutic active ingredient for treating rosacea, age spots, melasma, acne and/or dermal irritation together with at least one physiologically tolerated pharmacological ancillary substance or excipient. The treatment comprises prophylactic and therapeutic measures, (i) The invention furthermore provides
(a) the use of the pharmaceutical composition of the invention for producing a medicine for creating rosacea, age spots, melasma, acne and/or dermal irritation;
(3) a method for treating rosacea. age spots, melasma, acne and/or dermal irritation, which method comprises administering a
pharmaceutical composition according to the
invention, where the amount suppresses the
disorder, and where the pharmaceutical
composition is given to a patient requiring
such a medicine;
() a pharmaceutical composition for treating
rosacea, age spots, melasma, acne and/or
dermal irritation, which treatment comprises
a pharmaceutical composition of the invention
and at least one pharmaceutically acceptable
vehicle, and addition.
The dose suitable for the therapeutic effects
varies and depends, for example, on the concentration
of the individual elements in the pharmaceutical
composition, the host, the nature of the administration
and the nature and severity of the conditions to be
treated.
The pharmaceutical composition of the invention can be administered in every customary way for topical treatment. The gel is preferred.
The pharmaceutical composition of the invention can be processed with the additions and/or excipients customary in pharmaceutical technology by methods known per se to give customary topical administration forms.
The present invention relates to a composition that comprises the following
features:
(i) Azelaic acid as a therapeutic active ingredient,
(iii) triacylglycerides,
(iv) propylene glycol, and
(v) polysorbates
(vii) in an aqueous phase that comprises water and salts,
characterized in that
the composition comprises
(ii) polyacrylic acid, and
(vi) lecithin
as further additives, wherein the lecithin is present in the composition at a
concentration of up to 3 % by weight, and
that the composition is a hydrogel.



WE CLAIM:
1. Composition for use as a medicament that comprises the following
features:
(i) Azelaic acid as a therapeutic active ingredient at a concentration of 5
to 20% by weight,
(iii) triacylglycerides,
(iv) propylene glycol, and
(v) polysorbates
(vii) in an aqueous phase that comprises water and salts,
characterized in that
the composition comprises
(ii) polyacrylic acid at a concentration of 0.5 to 2% by weight, and
(vi) lecithin
as further additives, wherein the lecithin is present in the composition at a
concentration of up to 3 % by weight, and
that the composition is a hydrogel.
2. Composition as claimed in claim 1, wherein the composition can be administered topically.
3. Composition as claimed in any one of the preceding claims, wherein the lecithin is soybean lecithin.

4. Composition as claimed in any one of the preceding claims, wherein the lecithin is present at a concentration of up to 1% by weight.
5. Composition as claimed in claim 1, wherein the polyacrylic acid is present in the composition at a concentration of 1 ± 0.25% by weight.
6. Composition as claimed in any one of claims 1 to 4, wherein the triacylglycerides are present in the composition at a concentration of 0.5 to 5% by weight.
7. Composition as claimed in claim 6, wherein the triacylglycerides are present in the composition at a concentration of 2 ± 1% by weight.
8. Composition as claimed in any one of claims 1 to 4, wherein the propylene glycol is present in the composition at a concentration of 5 to 15% by weight.
9. Composition as claimed in claim 8, wherein the propylene glycol is present in the composition at a concentration of 10 ± 2% by weight.
10. Composition as claimed in any one of claims 1 to 4, wherein the polysorbates are present in the composition at a concentration of 0.5 to 3% by weight.

11. Composition as claimed in claim 10, wherein the polysorbates are present in the composition at a concentration of 2 ± 0.5% by weight.
12. Composition as claimed in any one of the preceding claims, wherein it comprises at least one physiologically acceptable pharmacological adjuvant or carrier.
13. Composition as claimed in claim 12 for use in treating rosacea, presbyderma, melasma, acne, and/or skin irritations.
14. Composition substantially as herein described with reference to foregoing exeimples.

Documents:

3451-DEL-1998-Abstract-(07-01-2009).pdf

3451-DEL-1998-Abstract-(11-12-2008).pdf

3451-del-1998-abstract.pdf

3451-DEL-1998-Claims-(07-01-2009).pdf

3451-DEL-1998-Claims-(11-12-2008).pdf

3451-del-1998-claims.pdf

3451-DEL-1998-Correspondence-Others-(07-01-2009).pdf

3451-DEL-1998-Correspondence-Others-(11-12-2008).pdf

3451-DEL-1998-Correspondence-Others-(23-12-2008).pdf

3451-DEL-1998-Correspondence-Others-(29-12-2008).pdf

3451-del-1998-correspondence-others.pdf

3451-DEL-1998-Description (Complete)-(07-01-2009).pdf

3451-DEL-1998-Description (Complete)-(11-12-2008).pdf

3451-del-1998-description (complete).pdf

3451-DEL-1998-Form-1-(07-01-2009).pdf

3451-DEL-1998-Form-1-(11-12-2008).pdf

3451-del-1998-form-1.pdf

3451-del-1998-form-13-(11-12-2008).pdf

3451-del-1998-form-18.pdf

3451-DEL-1998-Form-2-(07-01-2009).pdf

3451-DEL-1998-Form-2-(11-12-2008).pdf

3451-del-1998-form-2.pdf

3451-DEL-1998-Form-3-(11-12-2008).pdf

3451-DEL-1998-Form-3-(23-12-2008).pdf

3451-del-1998-form-4.pdf

3451-del-1998-form-6-(15-01-2007).pdf

3451-del-1998-form-6.pdf

3451-DEL-1998-GPA-(11-12-2008).pdf

3451-DEL-1998-GPA-(29-12-2008).pdf

3451-del-1998-gpa.pdf

3451-DEL-1998-Petition-137-(11-12-2008).pdf

3451-DEL-1998-Petition-138-(11-12-2008).pdf


Patent Number 236117
Indian Patent Application Number 3451/DEL/1998
PG Journal Number 40/2009
Publication Date 02-Oct-2009
Grant Date 25-Sep-2009
Date of Filing 18-Nov-1998
Name of Patentee INTENDIS GMBH
Applicant Address MAX-DOHRN-STR,10.10589 BERLIN,GERMANY
Inventors:
# Inventor's Name Inventor's Address
1 PATRICK FRANKE RINGBAHNSTR. 7, D-10711 BERLIN GERMANY
2 CLEMENS GUNTHER GOTTSCHEDSTR. 26, D-13357 BERLIN GERMANY
3 JUTTA RIEDL RIEHENER STR. 101A, D-79594 INZLINGEN, GERMANY
PCT International Classification Number A61P 17/10
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 197 53 044 1997-11-19 Germany
2 198 08 086 1998-02-20 Germany