EP1124547A1 - Pharmaceutical combination of mildronate and enalapril - Google Patents

Pharmaceutical combination of mildronate and enalapril

Info

Publication number: EP1124547A1
Authority: EP; European Patent Office
Prior art keywords: enalapril; mildronate; pharmaceutical composition; animals; myocardial infarction
Prior art date: 1998-10-29
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Withdrawn

Application number

EP99949439A

Other languages

German (de)

English (en)

French (fr)

Inventor

Ivars Kalvinsh

Maris Veveris

Juris Bundulis

Ilze Skarda

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Individual

Original Assignee

Individual

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1998-10-29

Filing date

1999-10-27

Publication date

2001-08-22

1999-10-27 Application filed by Individual filed Critical Individual

2001-08-22 Publication of EP1124547A1 publication Critical patent/EP1124547A1/en

Status Withdrawn legal-status Critical Current

Links

108010061435 Enalapril Proteins 0.000 title claims abstract description 29
GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 title claims abstract description 29
229960000873 enalapril Drugs 0.000 title claims abstract description 29
PVBQYTCFVWZSJK-UHFFFAOYSA-N meldonium Chemical compound C[N+](C)(C)NCCC([O-])=O PVBQYTCFVWZSJK-UHFFFAOYSA-N 0.000 title claims abstract description 27
229960002937 meldonium Drugs 0.000 title claims abstract description 26
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
238000011282 treatment Methods 0.000 claims abstract description 10
229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims abstract description 8
208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 7
239000005541 ACE inhibitor Substances 0.000 claims abstract description 6
PPQFUDZMTNGHBJ-UHFFFAOYSA-N propanoic acid;dihydrate Chemical compound O.O.CCC(O)=O PPQFUDZMTNGHBJ-UHFFFAOYSA-N 0.000 claims abstract 3
239000003814 drug Substances 0.000 claims description 11
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
239000013543 active substance Substances 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims 1
208000010125 myocardial infarction Diseases 0.000 description 35
241001465754 Metazoa Species 0.000 description 21
210000005240 left ventricle Anatomy 0.000 description 16
206010019280 Heart failures Diseases 0.000 description 12
206010061216 Infarction Diseases 0.000 description 11
230000007574 infarction Effects 0.000 description 11
230000000747 cardiac effect Effects 0.000 description 8
229940079593 drug Drugs 0.000 description 7
210000004351 coronary vessel Anatomy 0.000 description 6
239000000203 mixture Substances 0.000 description 6
241000700159 Rattus Species 0.000 description 5
230000003205 diastolic effect Effects 0.000 description 5
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
JFWLFLLRLZSBRA-UHFFFAOYSA-N 3-[(trimethylazaniumyl)amino]propanoate;dihydrate Chemical compound O.O.C[N+](C)(C)NCCC([O-])=O JFWLFLLRLZSBRA-UHFFFAOYSA-N 0.000 description 4
239000004480 active ingredient Substances 0.000 description 4
230000036772 blood pressure Effects 0.000 description 4
239000002775 capsule Substances 0.000 description 4
208000035475 disorder Diseases 0.000 description 4
230000006698 induction Effects 0.000 description 4
WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 4
229960002429 proline Drugs 0.000 description 4
230000035488 systolic blood pressure Effects 0.000 description 4
206010007558 Cardiac failure chronic Diseases 0.000 description 3
230000037396 body weight Effects 0.000 description 3
230000035487 diastolic blood pressure Effects 0.000 description 3
230000000694 effects Effects 0.000 description 3
230000000750 progressive effect Effects 0.000 description 3
230000033764 rhythmic process Effects 0.000 description 3
208000024891 symptom Diseases 0.000 description 3
206010020880 Hypertrophy Diseases 0.000 description 2
239000002220 antihypertensive agent Substances 0.000 description 2
229940127088 antihypertensive drug Drugs 0.000 description 2
230000017531 blood circulation Effects 0.000 description 2
239000007894 caplet Substances 0.000 description 2
239000008187 granular material Substances 0.000 description 2
230000000004 hemodynamic effect Effects 0.000 description 2
239000004615 ingredient Substances 0.000 description 2
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
229960001412 pentobarbital Drugs 0.000 description 2
239000006187 pill Substances 0.000 description 2
239000000843 powder Substances 0.000 description 2
230000002265 prevention Effects 0.000 description 2
231100000241 scar Toxicity 0.000 description 2
238000009097 single-agent therapy Methods 0.000 description 2
239000000126 substance Substances 0.000 description 2
239000003826 tablet Substances 0.000 description 2
238000002560 therapeutic procedure Methods 0.000 description 2
UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 1
206010002091 Anaesthesia Diseases 0.000 description 1
206010002383 Angina Pectoris Diseases 0.000 description 1
102100030988 Angiotensin-converting enzyme Human genes 0.000 description 1
241001260012 Bursa Species 0.000 description 1
206010015856 Extrasystoles Diseases 0.000 description 1
239000001828 Gelatine Substances 0.000 description 1
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
206010020772 Hypertension Diseases 0.000 description 1
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
208000009525 Myocarditis Diseases 0.000 description 1
108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
206010067268 Post procedural infection Diseases 0.000 description 1
208000000418 Premature Cardiac Complexes Diseases 0.000 description 1
241001088162 Primula auricula Species 0.000 description 1
235000006894 Primula auricula Nutrition 0.000 description 1
DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
230000004075 alteration Effects 0.000 description 1
238000001949 anaesthesia Methods 0.000 description 1
230000037005 anaesthesia Effects 0.000 description 1
210000000709 aorta Anatomy 0.000 description 1
206010003119 arrhythmia Diseases 0.000 description 1
230000006793 arrhythmia Effects 0.000 description 1
BVGLIYRKPOITBQ-ANPZCEIESA-N benzylpenicillin benzathine Chemical compound C=1C=CC=CC=1C[NH2+]CC[NH2+]CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 BVGLIYRKPOITBQ-ANPZCEIESA-N 0.000 description 1
235000013361 beverage Nutrition 0.000 description 1
239000007853 buffer solution Substances 0.000 description 1
210000000038 chest Anatomy 0.000 description 1
150000001875 compounds Chemical class 0.000 description 1
230000003247 decreasing effect Effects 0.000 description 1
201000010099 disease Diseases 0.000 description 1
239000012153 distilled water Substances 0.000 description 1
229920000159 gelatin Polymers 0.000 description 1
235000019322 gelatine Nutrition 0.000 description 1
239000008103 glucose Substances 0.000 description 1
239000003112 inhibitor Substances 0.000 description 1
239000007924 injection Substances 0.000 description 1
238000002347 injection Methods 0.000 description 1
230000000302 ischemic effect Effects 0.000 description 1
239000008101 lactose Substances 0.000 description 1
230000004807 localization Effects 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
230000000877 morphologic effect Effects 0.000 description 1
210000004165 myocardium Anatomy 0.000 description 1
239000003921 oil Substances 0.000 description 1
239000002674 ointment Substances 0.000 description 1
239000011505 plaster Substances 0.000 description 1
201000003144 pneumothorax Diseases 0.000 description 1
238000004321 preservation Methods 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
230000023718 relaxation of cardiac muscle Effects 0.000 description 1
230000029058 respiratory gaseous exchange Effects 0.000 description 1
239000012266 salt solution Substances 0.000 description 1
239000000523 sample Substances 0.000 description 1
239000008279 sol Substances 0.000 description 1
239000000243 solution Substances 0.000 description 1
239000002904 solvent Substances 0.000 description 1
210000002784 stomach Anatomy 0.000 description 1
239000000829 suppository Substances 0.000 description 1
230000002195 synergetic effect Effects 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000006188 syrup Substances 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
208000003663 ventricular fibrillation Diseases 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1

Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

This invention is concerned with pharmaceutical compositions in human medicine, viz. pharmaceutical compositions intended for curing of cardiovascular diseases caused by blood circulation disturbances of different origin and localisation, angina pectoris, myocardial infarction, arrhythmias, hypertension, myocarditis, as well as heart failure.
TUP 3-(2,2,2-trimethylhydrazinium) propionate dihydrate, known also as a medicine Mildronate, Quaterine, THP (GB Patent 2105992) in the treatment of cardiovascular diseases is disclosed.
TUP is administered for the treatment of various blood circulation disturbances and ischemic conditions caused by them.
the influence of THP on, for instance, chronic heart failure is not always sufficient as it eliminates the reduction of the systolic pressure and contractility of the left ventricle only partially, but does not influence the alterations of the diastolic function in case of heart failure appearing as a result of myocardial infarction.
ACE inhibitors e.g. (S)-1- ⁇ N- [l-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl ⁇ -L-proline which is known as an antihypertensive drug Enalapril (U.S. Patent 4.374.829) acting as an inhibitor of angiotensin converting enzyme.
Enalapril has only a positive influence on the systolic function during the period after myocardial infarction, but has no essential influence on the diastolic function.
the aim of this invention was the development of a pharmaceutical composition, applicable for the cure of a progressive heart failure, for example caused by myocardial infarction. This aim was unexpectedly achieved by the combination in the pharmaceutical composition of Mildronate with an ACE inhibitor, for example, Enalapril.
the claimed pharmaceutical composition allows for a much better and more complete cure of cardiovascular diseases, namely, the cure of chronic heart failure during the period after myocardial infarction, as compared to that observed with each of these drugs in monotherapy.
THP has a low or no influence on blood pressure
THP would essentially improve the influence of the known antihypertensive drug - Enalapril on the relaxation of cardiac muscle by reducing the end-diastolic pressure and simultaneously increasing the relaxation rate (-dp/dt), what jointly means an extremely positive influence on the diastolic function of myocardium.
the pharmaceutical composition containing 3-(2,2,2- trimethylhydrazinium) propionate dihydrate (Mildronate) and an ACE inhibitor e.g. (S)- 1 - ⁇ N-[ 1 -(ethoxycarbony l)-3 -pheny lpropy 1] -L-alany 1 ⁇ -L- proline (Enalapril) may be recommended for the cure of cardiovascular diseases, viz.
the Mildronate and Enalapril combination protects not only from the reduction of the cardiac systolic function, but also from that of the diastolic function and the dilatation of the left ventricle and averts the left ventricle hypertrophy more efficiently than Mildronate monotherahy.
Mildronate and Enalapril ratio in the composition may be from 5 : 1 to 15: 1 , preferably from 8: 1 to 12: 1.
the pharmaceutical composition contains 3-(2,2,2-trimethylhydra-zinium) propionate dihydrate and (S)- 1 - ⁇ N- [ 1 -(ethoxycarbony l)-3-pheny lpropy l]-L-alanyl ⁇ -L-proline in the amount of 0.5-40% by total weight of pharmaceutical form and distilled water, physiologic salt solution, glucose solution, or buffer solution as a pharmaceutically acceptable solvent.
pharmaceutical composition contains 0.01-0.5 g of 3-(2,2,2-trimethyl-hydrazinium) propionate dihydrate and (S)-l- ⁇ N-[l-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl ⁇ -L-proline by weight per tablet, caplet, capsule, pill, granule, or powder dosage unit.
Example 1 The experimental treatment of heart failure and myocardial infarction.
the experiments were performed with male rats (310-355 g) of Wistar line. Under pentobarbital anaesthesia (50 mg/kg) in aseptic conditions, the opening of the thorax and that of the cardiac bursa was performed and a loop of twist (sterile Eticon 6/0 thread with an atraumatic needle) was put around the left coronary artery on the level of the left auricula atrii. The quality of manipulation was assessed with a surgical microscope, and the coronary artery of the rat was ligated. Concurrently an ECG was recorded, the wound closure performed and pneumothorax was discontinued. During the operation, in case of need artificial respiration was applied by the use of apparatus V 5kG (Narco Bio-Systems, U.S.A.).
Bicillin-1 (500,000 i.u./kg) was administered i.m. for the prophylaxis of postoperative infection. 48 hours after the operation, the animals were weighed, the occurrence and seriousness of infarction was determined and the animals were randomly distributed into 4 groups (the 5th group, that of "sham control", consisted of rats subject to "sham” operation when no ligation of the coronary artery was performed). The mortality during the operation and 48 hours after it equalled on average 29%. Death was mainly caused by ventricular fibrillations. Each group comprised 10 animals (the infarction control group - 12) who were treated as follows (the substances being administered through a stomach probe):
MI Myocardial infarction control
Enalapril 50+5 mg/kg p.o. once daily for 28 days;
ECG ECG as II standard record
blood pressure from aorta blood pressure in the left ventricle (catheterised through a. carotis)
+dp/dt, -dp/dt with the Polygraphic system RP 6000 Nihon Kohden, Japan
Enalapril administration protects from the reduction of the cardiac systolic function (on grounds of the systolic pressure of the left auricle and +dp/dt), but there is no explicit protection against the reduction of the diastolic pressure (Table 1 ). In case of both drugs combination, also no disorders of cardiac rhythmicity were observed (Table 2).
the macroscopic heart analysis shows that the binding of the coronary artery causes a transmural myocardial infarction in the free anterior wall of the left ventricle. Within a month from the induced infarction, the infarction zone is filled by interstitial tissue and forms a clearly distinguishable scar. The start of the treatment course after 48 hours from the induction of myocardial infarction has no essential influence on the area of the infarction wound (Table 4).
Example 2 The use of composition for the preparing of medicament
the mixture so prepared is filled into the hard gelatine capsules, thus, the final pharmaceutical form - capsules, each containing 0.2 g of the mixture of active substances, is obtained.
MI myocardial infarction
MI myocardial infarction

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Epidemiology (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Organic Chemistry (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

EP99949439A 1998-10-29 1999-10-27 Pharmaceutical combination of mildronate and enalapril Withdrawn EP1124547A1 (en)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
LV980252		1998-10-29
LVP-98-252A LV12491B (lv)	1998-10-29	1998-10-29	Farmaceitiska kompozīcija
PCT/LV1999/000005 WO2000025773A1 (en)	1998-10-29	1999-10-27	Pharmaceutical combination of mildronate and enalapril

Publications (1)

Publication Number	Publication Date
EP1124547A1 true EP1124547A1 (en)	2001-08-22

Family

ID=19736545

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP99949439A Withdrawn EP1124547A1 (en)	1998-10-29	1999-10-27	Pharmaceutical combination of mildronate and enalapril

Country Status (5)

Country	Link
EP (1)	EP1124547A1 (lv)
EA (1)	EA003470B1 (lv)
LV (1)	LV12491B (lv)
UA (1)	UA71934C2 (lv)
WO (1)	WO2000025773A1 (lv)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
LV13450B (en) *	2004-08-24	2006-11-20	Grindeks As	Novel medicinal use of meldonium and pharmaceutical compositions thereof
EP2420224A1 (en) *	2010-08-11	2012-02-22	Grindeks, a joint stock company	Method for producing a stable 3-(2,2,2-trimethylhydrazinium)propionate dihydrate solid pharmaceutical composition
RU2467748C1 (ru) *	2011-08-08	2012-11-27	Федеральное государственное автономное образовательное учреждение высшего профессионального образования "Белгородский государственный национальный исследовательский университет"	Производное 3-(2,2,2-триметилгидразиний)пропионата - глицинат 3-(2,2,2-триметилгидразиний)пропионат калия, обладающее эндотелиопротекторной активностью
CN105853349A (zh) *	2016-04-29	2016-08-17	济南康和医药科技有限公司	一种米屈肼注射液及其制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IT1254314B (it) *	1992-03-27	1995-09-14	Sigma Tau Ind Farmaceuti	Composizioni farmaceutiche conyenenti l-carnitina e acil- carnitine inassociazione con ace-inibitori per il trattamento di patologie cardiovascolari.
LV11728B (en) *	1995-08-21	1997-08-20	Kalvins Ivars	Pharmaceutical composition

1998
- 1998-10-29 LV LVP-98-252A patent/LV12491B/lv unknown
1999
- 1999-10-27 EP EP99949439A patent/EP1124547A1/en not_active Withdrawn
- 1999-10-27 WO PCT/LV1999/000005 patent/WO2000025773A1/en not_active Application Discontinuation
- 1999-10-27 EA EA200100477A patent/EA003470B1/ru not_active IP Right Cessation
- 1999-10-27 UA UA2001053571A patent/UA71934C2/uk unknown

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0025773A1 *

Also Published As

Publication number	Publication date
LV12491B (lv)	2000-12-20
EA200100477A1 (ru)	2001-10-22
LV12491A (en)	2000-06-20
UA71934C2 (en)	2005-01-17
WO2000025773A1 (en)	2000-05-11
EA003470B1 (ru)	2003-06-26

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WO2000025773A1 (en)	2000-05-11	Pharmaceutical combination of mildronate and enalapril
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US20230143097A1 (en)	2023-05-11	Compositions And Methods To Reduce And/Or Dissolve Calcium Deposits In Arterial Walls
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JPH0526766B2 (lv)	1993-04-19

Legal Events

Date	Code	Title	Description
2001-07-06	PUAI	Public reference made under article 153(3) epc to a published international application that has entered the european phase	Free format text: ORIGINAL CODE: 0009012
2001-08-22	17P	Request for examination filed	Effective date: 20010518
2001-08-22	AK	Designated contracting states	Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE
2001-09-07	GRAG	Despatch of communication of intention to grant	Free format text: ORIGINAL CODE: EPIDOS AGRA
2001-10-10	RIC1	Information provided on ipc code assigned before grant	Free format text: 7A 61K 31/205 A, 7A 61K 38/55 B, 7A 61K 31/40 B, 7A 61P 9/00 B
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