ZA200102961B - Method for preparing a solution for nasal spray containing sex hormones and a cyclodextrin. - Google Patents

Method for preparing a solution for nasal spray containing sex hormones and a cyclodextrin. Download PDF

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Publication number
ZA200102961B
ZA200102961B ZA200102961A ZA200102961A ZA200102961B ZA 200102961 B ZA200102961 B ZA 200102961B ZA 200102961 A ZA200102961 A ZA 200102961A ZA 200102961 A ZA200102961 A ZA 200102961A ZA 200102961 B ZA200102961 B ZA 200102961B
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South Africa
Prior art keywords
solution
cyclodextrin
oestradiol
process according
purified water
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ZA200102961A
Inventor
Gilles Fonknechten
Patrick Wuthrich
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Adir
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Nanotechnology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biophysics (AREA)
  • Reproductive Health (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Otolaryngology (AREA)
  • Diabetes (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

The present invention relates to a process for the preparation of a nasal spray solution comprising one or more sex hormones and a cyclodextrin.
Administration of sex hormones via the nasal route has a number of advantages over other routes of administration conventionally used.
In women, oestrogen deficiency is responsible, in the short term, for climacteric disorders in 70 % of women and, in the longer term, for osteoporosis in 30 % of women and increased cardiovascular risk. Replacement treatment for the menopause is still beset with difficulties associated with compliance, which have been improved only partly by the pharmaceutical forms currently available.
Tablets, which are widely used, have the advantage of being well established and simple, but their dosages lack flexibility for adapting the dose. Moreover, the first-pass effect in the intestine and the liver is responsible for their metabolic disadvantages. Transdermal systems enable that first-pass effect to be avoided but have considerable disadvantages, such as poor local tolerance, the variability of the doses delivered and the difficulty of adapting the doses. The nasal route enables systemic administration of an active ingredient whilst avoiding the first-pass effect in the liver and at the same time enabling ready adaptation of the doses administered by simple modification of the number of sprays.
Patent Specification EP 349 091 describes a formulation for the nasal administration, to women, of sex hormones, such as 17-B-oestradiol or progesterone, that comprises a cyclodextrin.
The development of such a formulation requires that the preparation of a nasal spray solution comply with industrial constraints, such that it should be admissible for product registration and should make it possible to obtain optimum yields, reliability, reproducibility and the safety required of any industrial process.
p 20012961 i ,.
Moreover, the nasal solution as described in Patent Specification EP 349 091, as is often the case, comprises a preservative, such as benzalkonium chloride. In a study of the antimicrobial effectiveness of benzalkonium chloride in a nasal formulation comprising 17-
B-oestradiol and a partially methylated cyclodextrin, the antimicrobial effectiveness of that preservative has been shown to be insufficient.
Moreover, since benzalkonium chloride can cause allergic reactions, it was necessary to prepare sterile solutions whilst respecting the industrial constraints mentioned above.
Finally, solutions for the nasal administration of sex hormones must be prepared using a solvent that is pharmacologically acceptable and that does not cause phenomena of irritation of the nasal mucosa. In that case, an aqueous solution of physiological pH remains the best alternative.
Most sex hormones are insoluble in water. The use of a cyclodextrin as described in Patent
Specification EP 349 091 enables those lipophilic compounds to be solubilised in an aqueous medium by forming an inclusion complex.
The problem to be resolved was therefore a process for the industrial preparation of that aqueous solution, which is the subject matter of the present invention. More specifically, that process relates to the preparation of an aqueous nasal solution comprising one or more sex hormones and a cyclodextrin.
Among the sex hormones that can be used in the pharmaceutical compositions prepared according to the process of the invention, there may be mentioned by way of non-limiting example natural steroidal oestrogens, such as 17-B-OH-progesterone (oestradiol), oestrone and their derivatives, synthetic steroidal oestrogens, such as ethynyloestradiol, progestogens, such as progesterone, pregnanes derived from progesterone or from 17-c-
OH-progesterone, such as dydrogesterone, chlormadinone acetate, medrogesterone, medroxyprogesterone acetate, norpregnanes such as demegestone, promegestone, nomegestrol acetate or derivatives of 19-nortestosterone, such as norethisterone, ethynodiol
; 4 cUUIZ296]1 diacetate, norgestrel, laevonorgestrel, desogestrel, gestodene or norgestimate, and finally androgens such as testosterone and its derivatives.
More specifically, the nasal pharmaceutical compositions prepared according to the process of the invention are those comprising a partially methylated cyclodextrin.
A preferred composition prepared according to the process of the invention is a composition comprising oestradiol, a mixture of oestradiol/progestogen or an androgen and a randomly partially methylated cyclodextrin.
When the composition comprises a progestogen, the preferred progestogen is norethisterone (acetate).
Given the insolubility of the hormones in an aqueous medium, the inclusion complex of hormone(s)/cyclodextrin can be prepared in conventional manner by dissolving the cyclodextrin and hormones(s) in a pure ethanolic medium, which enables solubilisation of the hormones and thus the formation of the inclusion complex. The ethanol is then removed by evaporation in vacuo at about 40°C and the aqueous solution is obtained by adding purified water to the resulting complex.
This conventional process is neither possible nor recommended on an industrial scale. In fact, it requires the large-scale evaporation of absolute ethanol and its recovery in vacuo requires the use of flameproof industrial equipment, which, in addition to the danger that that represents, considerably increases the industrial cost of manufacturing the solution.
Moreover, the use of a solvent such as ethanol requires determination of residual solvents, which is, of course, a further constraint in manufacturing
Since that type of conventional process is not satisfactory, the Applicant has sought to develop a process for the preparation of that solution for nasal administration that does not use a solvent such as ethanol, which process is the subject matter of the present invention.
More especially, that process is characterised in that the cyclodextrin is dissolved in
= purified water at a concentration of from 100 to 1000 mg/ml. The hormone(s) is/are then added to that solution whilst heating the solution at a temperature of from 40 to 90 °C. The inclusion complex is thus formed. Purified water is then added until the desired final concentration of hormone(s) is obtained, either immediately or after lyophilisation of the preceding solution.
Sodium chloride is then optionally added to that final solution in order to obtain a physiological solution, the pH of which can be adjusted to imitate nasal pH.
In that preparation process, the cyclodextrin is dissolved in purified water at a concentration of preferably from 400 to 500 mg/ml.
The hormone(s) is/are then added to that cyclodextrin solution at a temperature of preferably from 70 to 90 °C.
That process has the essential advantage that an aqueous solution is obtained directly in which the complex is stable and does not redissociate with time. This is obtained as a result of adjusting the concentration of the cyclodextrin in the water and the temperature.
In fact, when that solution is prepared at room temperature, the cyclodextrin dissolves but whatever the concentration of cyclodextrin in the water the addition of the hormone(s) results in a suspension which does not become soluble even after several hours’ stirring : a complex is thus not formed.
When attempting to prepare the solution at a temperature of from 40 to 90 °C, and when the cyclodextrin is dissolved in purified water at a concentration of less than 100 mg/ml, the complex is not formed even after several hours’ stirring.
For concentrations of cyclodextrin of from 100 mg/ml to 1000 mg/ml, the complex is not formed or is formed sparingly if the temperature is less than 40 °C.
The knowledge of the person skilled in the art could not have enabled him in any way to
La WW aS ny ~ - - 4 20012961
N -5- foresee or imagine the preparation process that is the subject matter of the present invention.
The relative concentrations of cyclodextrin and hormone(s) are, of course, a function of the nature of the cyclodextrin itself and of the hormones).
The B-cyclodextrins are the most suitable for the solubilisation of hormones, such as oestradiol. By way of example, 10 mol of hydroxypropyl-B-cyclodextrin are required to complex 1 mol of oestradiol whereas 2 mol of methyl-B-cyclodextrin are sufficient to complex 1 mol of oestradiol.
A particular method of carrying out the invention consists therefore of dissolving a partially methylated cyclodextrin in purified water at a concentration of about 400 mg/ml, and adding the necessary amount of oestradiol at a temperature of about 80 °C.
The complex is thus formed and the final solution is obtained by adding purified water until the desired concentration of oestradiol for the aqueous nasal formulation is obtained.
The following Examples illustrate the invention but do not limit it in any way.
EXAMPLE:
Process for the preparation of a nasal solution comprising oestradiol and a randomly partially methylated cyclodextrin (RAMEB) (RAMEB - cyclodextrin in which the average degree of substitution by methyl groups is about 1.7)
The final concentration of oestradiol must be about 2.14 mg/ml of solution.
Components for 20 litres of final aqueous solution :
Oestradiol hemihydrate eres 42.86 g
RAMEB PP 41892 g
N -6-
Step 4 : Preparation of the oestradiol / RAMEB complex
The RAMEB is added to one litre of purified water and the whole is stirred until complete dissolution.
The oestradiol is then added to that solution and the whole is heated at 80°C and stirred until complete dissolution.
Step B : Preparation of the final solution
To the solution obtained in Step A there are added 18 litres of purified water. The whole is stirred for a few minutes and then 180 g of sodium chloride are added to the preceding solution. After complete dissolution of the sodium chloride, the pH is adjusted to 6 and the total volume of the solution is made up to 20 litres by the addition of purified water.
For sterilisation purposes, the whole is filtered through a cellulose acetate membrane of 0.2 uM porosity.
EXAMPLE 2:
Process for the preparation of a nasal solution comprising oestradiol, norethisterone acetate and a randomly partially methylated cyclodextrin (RAMEB) (RAMEB - cyclodextrin in which the average degree of substitution by methyl groups is about 1.7)
The final concentration of oestradiol must be about 2.14 mg/ml of solution, and the final concentration of norethisterone acetate must be about 6.39 mg/ml of solution.
Components for 20 litres of final aqueous solution :
Oestradiol hemihydrate eeiiieeeen... 42.86 g
Norethisterone acetate eerie... 1278 g
RAMEB fe ereeieereaeieenaeeneee.. 1500 g i
N N
Step 4 : Preparation of the oestradiol, norethisterone acetate / RAMEB complex
The RAMEB is added to three litres of purified water and the whole is stirred until complete dissolution.
The oestradiol and norethisterone acetate are then added to that solution and the whole is heated at 80°C and stirred until complete dissolution.
Step B : Preparation of the final solution
To the solution obtained in Step A there are added 16 litres of purified water. The whole is stirred for a few minutes and then 180 g of sodium chloride are added to the preceding solution. After complete dissolution of the sodium chloride, the pH is adjusted to 6 and the total volume of the solution is made up to 20 litres by the addition of purified water.
For the purposes of sterilisation, the whole is filtered through a cellulose acetate membrane of 0.2 uM porosity.
EXAMPLE 3:
Process for the preparation of a nasal solution comprising progesterone and a randomly partially methylated cyclodextrin (RAMEB) (RAMEB - cyclodextrin in which the average degree of substitution by methyl groups is about 1.7)
The final concentration of progesterone must be about 8.86 mg/ml of solution.
Components for 20 litres of final aqueous solution :
Progesterone ................... 1772 ¢
RAMEB a 1500 g
Step A : Preparation of the oestradiol / RAMEB complex
The RAMEB is added to three litres of purified water and the whole is stirred until
LS -8- complete dissolution.
The progesterone is then added to that solution and the whole is heated at 80°C and stirred until complete dissolution.
Step B : Preparation of the final solution
To the solution obtained in Step A there are added 18 litres of purified water. The whole is stirred for a few minutes and then 180 g of sodium chloride are added to the preceding solution. After complete dissolution of the sodium chloride, the pH is adjusted to 6 and the total volume of the solution is made up to 20 litres by the addition of purified water.
For the purposes of sterilisation, the whole is filtered through a cellulose acetate membrane of 0.2 uM porosity.
EXAMPLE 4:
Process for the preparation of a nasal solution comprising testosterone and a randomly partially methylated cyclodextrin (RAMEB) (RAMEB - cyclodextrin in which the average degree of substitution by methyl groups is about 1.7)
The final concentration of testosterone must be about 2.20 mg/ml of solution.
Components for 20 litres of final aqueous solution:
Testosterone ................. 43.92 g
RAMEB erin. 41892 ¢
Step A : Preparation of the oestradiol / RAMEB complex
The RAMERB is added to one litre of purified water and the whole is stirred until complete dissolution.
The oestradiol is then added to that solution and the whole is heated at 80°C and stirred until complete dissolution.
A -9-
Step B : Preparation of the final solution
To the solution obtained in Step A there are added 18 litres of purified water. The whole is stirred for a few minutes and then 180 g of sodium chloride are added to the preceding solution. After complete dissolution of the sodium chloride, the pH is adjusted to 6 and the total volume of the solution is made up to 20 litres by the addition of purified water.
For the purposes of sterilisation, the whole is filtered through a cellulose acetate membrane of 0.2 pM porosity.

Claims (1)

  1. CLAIMS 1/ Process for the preparation of a nasal spray solution comprising one or more sex hormones and a cyclodextrin, characterised in that : - the cyclodextrin is dissolved in purified water at a concentration of from 100 to
    1000 mg/ml,
    - the hormone(s) is/are added while heating the solution at a temperature of from 40 to 90 °C,
    - purified water is added until the desired final concentration of hormone(s) is obtained, either immediately or after lyophilisation of the preceding solution.
    2/ Process according to claim 1, characterised in that the cyclodextrin is dissolved in purified water at a concentration of from 400 to S00 mg/ml and the hormone(s) is/are added at a temperature of from 70 to 90 °C.
    3/ Preparation process according to either claim 1 or claim 2, characterised in that the cyclodextrin is a partially methylated cyclodextrin.
    4/ Preparation process according to claim 3, characterised in that the cyclodextrin is randomly partially methylated.
    5/ Preparation process according to any one of claims 1, 2, 3 and 4, characterised in that the sex hormone used is oestradiol. 6/ Preparation process according to any one of claims 1, 2, 3 and 4, characterised in that the sex hormones used are oestradiol and/or a progestogen.
    7/ Preparation process according to claim 6, characterised in that the progestogen is a derivative of 19-nortestosterone.
    ¥
    8/ Preparation process according to claim 7, characterised in that the progestogen is norethisterone acetate. 9/ Preparation process according to any one of claims 1, 2, 3 and 4, characterised in that the hormone is testosterone. 10/ Preparation process according to any one of claims 1, 2, 3, 4 and 5, characterised in that : - an aqueous solution of randomly partially methylated B-cyclodextrin of a concentration of from 400 to 500 mg/ml is prepared, - oestradiol is added with stirring and the solution is heated at 80°C, - the volume is made up by the addition of purified water to obtain a final concentration of oestradiol of about 2.14 mg/ml. 11/ Process for the preparation of an aqueous nasal oestradiol solution according to claim 10, characterised in that that solution also comprises sodium chloride and that its pH has been adjusted to 6.
ZA200102961A 1998-10-14 2001-04-10 Method for preparing a solution for nasal spray containing sex hormones and a cyclodextrin. ZA200102961B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
FR9812836A FR2784584B1 (en) 1998-10-14 1998-10-14 PROCESS FOR THE PREPARATION OF A NASAL SPRAY SOLUTION CONTAINING ONE OR MORE SEXUAL HORMONES AND A CYCLODEXTRIN

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ZA200102961B true ZA200102961B (en) 2001-11-20

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EP (1) EP1121100B1 (en)
JP (1) JP3911125B2 (en)
KR (1) KR100462441B1 (en)
CN (1) CN1323198A (en)
AT (1) ATE237310T1 (en)
AU (1) AU756441B2 (en)
BR (1) BR9914532A (en)
CA (1) CA2346567C (en)
DE (1) DE69907005T2 (en)
DK (1) DK1121100T3 (en)
EA (1) EA003069B1 (en)
ES (1) ES2197672T3 (en)
FR (1) FR2784584B1 (en)
HK (1) HK1040201A1 (en)
HU (1) HUP0103968A3 (en)
NO (1) NO20011673L (en)
NZ (1) NZ510776A (en)
PL (1) PL347322A1 (en)
PT (1) PT1121100E (en)
WO (1) WO2000021503A1 (en)
ZA (1) ZA200102961B (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2827516B1 (en) * 2001-07-19 2003-09-19 Servier Lab PHARMACEUTICAL COMPOSITION FOR NASAL ADMINISTRATION OF ESTRADIOL AND NORETHISTERONE
JPWO2005018607A1 (en) * 2003-08-20 2007-11-01 味の素株式会社 Pharmaceutical formulations with improved solubility
GB2482868A (en) * 2010-08-16 2012-02-22 Franciscus Wilhelmus Henricus Maria Merkus A testosterone liquid spray formulation for oromucosal administration
US20130090315A1 (en) * 2011-10-07 2013-04-11 Florida State University Research Foundation Prophylactic and post-acute use of progesterone to better outcomes associated with concussion
EP2804582B1 (en) 2012-01-20 2016-03-30 Aratana Therapeutics NV Eye drop composition
RU2753511C2 (en) * 2017-05-31 2021-08-17 Аратана Терапьютикс, Инк. Composition of eye drops

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL8801670A (en) * 1988-07-01 1990-02-01 Walter Adrianus Josephus Johan PHARMACEUTICAL PREPARATION.
US5376645A (en) * 1990-01-23 1994-12-27 University Of Kansas Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof
GB9012663D0 (en) * 1990-06-07 1990-08-01 Erba Carlo Spa Galenic formulations containing cyclodextrins
DE4207922A1 (en) * 1992-03-13 1993-09-23 Pharmatech Gmbh New water-soluble inclusion complexes contg randomly substd. methyl-beta-cyclodextrin - for admin. of substances which are only sparingly soluble in water
BE1007402A5 (en) * 1993-03-26 1995-06-06 Adir NASAL PHARMACEUTICAL PREPARATIONS WITH progestagen SUBSTANCE.

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DK1121100T3 (en) 2003-07-21
DE69907005D1 (en) 2003-05-22
CA2346567A1 (en) 2000-04-20
AU756441B2 (en) 2003-01-16
EA200100316A1 (en) 2002-02-28
HUP0103968A2 (en) 2002-04-29
FR2784584B1 (en) 2002-09-20
EP1121100A1 (en) 2001-08-08
HK1040201A1 (en) 2002-05-31
ES2197672T3 (en) 2004-01-01
EP1121100B1 (en) 2003-04-16
CN1323198A (en) 2001-11-21
NO20011673D0 (en) 2001-04-03
HUP0103968A3 (en) 2002-06-28
JP3911125B2 (en) 2007-05-09
PT1121100E (en) 2003-07-31
ATE237310T1 (en) 2003-05-15
KR20010073214A (en) 2001-07-31
NO20011673L (en) 2001-04-03
CA2346567C (en) 2005-06-14
JP2002527374A (en) 2002-08-27
BR9914532A (en) 2001-11-06
KR100462441B1 (en) 2004-12-17
DE69907005T2 (en) 2004-03-18
NZ510776A (en) 2002-10-25
AU6096799A (en) 2000-05-01
WO2000021503A1 (en) 2000-04-20
FR2784584A1 (en) 2000-04-21
PL347322A1 (en) 2002-03-25
EA003069B1 (en) 2002-12-26

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