USRE39706E1 - Crystalline form of a vitamin D analogue - Google Patents

Crystalline form of a vitamin D analogue Download PDF

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Publication number
USRE39706E1
USRE39706E1 US10/986,575 US98657593A USRE39706E US RE39706 E1 USRE39706 E1 US RE39706E1 US 98657593 A US98657593 A US 98657593A US RE39706 E USRE39706 E US RE39706E
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US
United States
Prior art keywords
calcipotriol
pharmaceutical composition
monohydrate
hydrate
calcipotriol monohydrate
Prior art date
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.)
Expired - Lifetime
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US10/986,575
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English (en)
Inventor
Erik Torngaard Hansen
Niels Smidt Rastrup Andersen
Lene Hoffmeyer Ringborg
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Leo Pharma AS
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Leo Pharma AS
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/02—Apparatus characterised by being constructed of material selected for its chemically-resistant properties
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C5/00—Preparation of hydrocarbons from hydrocarbons containing the same number of carbon atoms
    • C07C5/32—Preparation of hydrocarbons from hydrocarbons containing the same number of carbon atoms by dehydrogenation with formation of free hydrogen
    • C07C5/321—Catalytic processes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C5/00—Preparation of hydrocarbons from hydrocarbons containing the same number of carbon atoms
    • C07C5/32—Preparation of hydrocarbons from hydrocarbons containing the same number of carbon atoms by dehydrogenation with formation of free hydrogen
    • C07C5/327—Formation of non-aromatic carbon-to-carbon double bonds only
    • C07C5/333—Catalytic processes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C5/00—Preparation of hydrocarbons from hydrocarbons containing the same number of carbon atoms
    • C07C5/32—Preparation of hydrocarbons from hydrocarbons containing the same number of carbon atoms by dehydrogenation with formation of free hydrogen
    • C07C5/327—Formation of non-aromatic carbon-to-carbon double bonds only
    • C07C5/333—Catalytic processes
    • C07C5/3335—Catalytic processes with metals
    • C07C5/3337—Catalytic processes with metals of the platinum group
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/02—Apparatus characterised by their chemically-resistant properties
    • B01J2219/0204—Apparatus characterised by their chemically-resistant properties comprising coatings on the surfaces in direct contact with the reactive components
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/02—Apparatus characterised by their chemically-resistant properties
    • B01J2219/0204—Apparatus characterised by their chemically-resistant properties comprising coatings on the surfaces in direct contact with the reactive components
    • B01J2219/0236—Metal based
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/02—Apparatus characterised by their chemically-resistant properties
    • B01J2219/025—Apparatus characterised by their chemically-resistant properties characterised by the construction materials of the reactor vessel proper
    • B01J2219/0277—Metal based
    • B01J2219/0286—Steel
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2523/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group C07C2521/00
    • C07C2523/38—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group C07C2521/00 of noble metals
    • C07C2523/40—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group C07C2521/00 of noble metals of the platinum group metals
    • C07C2523/42—Platinum

Definitions

  • the present invention relates to calcipotriol, hydrate—a new crystalline form of calcipotriol—with superior technical properties e.g. in the manufacture of crystal suspension formulations, and with superior stability properties.
  • Calcipotriol (INN) (calcipotriene (USAN), (1 ⁇ ,3 ⁇ ,5Z,7E,22E,24S)-24-Cyclopropyl-9,10-secochola-5,7,10(19), 22-tetraene-1,3,24-triol) is described in International patent application No. PCT/DK86/00081, filing date 14th Jul. 1986, publication No. WO 87/00834.
  • Calcipotriol possesses a remarkable profile of biological activity which has proved very useful e.g. in the topical treatment of psoriasis.
  • crystalline bulk drug is usually subjected to micronization or to a wet milling process in order to reduce the crystal size before the final suspension formulation is prepared.
  • This novel product is the monohydrate of calcipotriol which is perfectly crystalline, stable and wet suited for its use in modern therapy.
  • the anhydrous form of calcipotriol shows a considerable degree of decomposition at this temperature and more than 30% degradation is seen after 12 months storage.
  • Calcipotriol monohydrate may be prepared by dissolving crystalline or non-crystalline calcipotriol in an organic solvent, e.g. ethyl acetate or acetone, followed by the addition of water and optionally a non polar solvent, e.g. hexane.
  • organic solvent e.g. ethyl acetate or acetone
  • non polar solvent e.g. hexane.
  • Calcipotriol monohydrate shall form part of pharmaceutical preparations for topical use, such as creams, ointments, solutions, lotions or gels.
  • concentration of the active ingredient will generally be between 1 and 100 ⁇ g/g.
  • the formulations will be applied one or more times daily.
  • the formulations prepared according to the present invention comprise the active compound in association with a pharmaceutically acceptable vehicle and optionally other therapeutic ingredient(s).
  • vehicle(s) must be “acceptable” in the sense of being compatible with the other ingredients of the preparations and not deleterious to the recipient thereof.
  • Preparations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments, pastes or gels; or solutions or suspensions.
  • the preparations of this invention may include one or more additional ingredients such as diluents, buffers, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
  • additional ingredients such as diluents, buffers, surface active agents, thickeners, lubricants, preservatives, e.g. methyl hydroxybenzoate (including anti-oxidants), emulsifying agents and the like.
  • Calcipotriol (2.5 g) was dissolved in ethyl acetate (80 ml) at 50°-80° C. and filtered. The solution was saturated with water, and the product precipitated upon voluntary cooling to room temperature. The resulting slurry was cooled to 0°-10° C. and filtered. The filtered product was dried in vacuo to give calcipotriol, hydrate (2.35 g).
  • Lines characteristic for the hydrate are 1455 (m), 1442 (m), 1330 (w), 1290 (m), 1210 (m), 1085 (m), 907 (m), 895 (m) and 573 (w) cm ⁇ 1 , respectively.
  • Solid state CPMAS 1 CPMAS 13 C NMR The following resonances are characteristic for calcipotriol, hydrate: 147.9, 146.5, 134.8, 130.3, 129.0, 126.5, 116.0, 109.4, 75.5, 68.2, 67.2, 56.9, 55.2, 47.8, 47.5, 42.9, 42.0, 41.3, 30.7, 28.9, 25.6, 23.1, 22.6, 19.5, 14.6, 6.2 and 1.9 ppm, respectively.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US10/986,575 1993-01-15 1993-01-15 Crystalline form of a vitamin D analogue Expired - Lifetime USRE39706E1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939300763A GB9300763D0 (en) 1993-01-15 1993-01-15 Chemical compound
PCT/DK1994/000011 WO1994015912A1 (en) 1993-01-15 1994-01-07 New crystalline form of a vitamin d analogue

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US08/491,892 Reissue US5763426A (en) 1993-01-15 1993-01-15 Crystalline form of a vitamin D analogue

Publications (1)

Publication Number Publication Date
USRE39706E1 true USRE39706E1 (en) 2007-06-26

Family

ID=10728784

Family Applications (2)

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US08/491,892 Ceased US5763426A (en) 1993-01-15 1993-01-15 Crystalline form of a vitamin D analogue
US10/986,575 Expired - Lifetime USRE39706E1 (en) 1993-01-15 1993-01-15 Crystalline form of a vitamin D analogue

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US08/491,892 Ceased US5763426A (en) 1993-01-15 1993-01-15 Crystalline form of a vitamin D analogue

Country Status (17)

Country Link
US (2) US5763426A (es)
EP (1) EP0679154B1 (es)
JP (1) JP3729847B2 (es)
KR (1) KR100309751B1 (es)
CN (1) CN1040746C (es)
AT (1) ATE159717T1 (es)
AU (1) AU663249B2 (es)
CA (1) CA2151730C (es)
DE (1) DE69406529T2 (es)
DK (1) DK0679154T3 (es)
ES (1) ES2111287T3 (es)
FI (1) FI108638B (es)
GB (1) GB9300763D0 (es)
GR (1) GR3025668T3 (es)
NZ (1) NZ259679A (es)
RU (1) RU2128646C1 (es)
WO (1) WO1994015912A1 (es)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080234239A1 (en) * 2007-03-15 2008-09-25 Derek Wheeler Topical composition
US20100056644A1 (en) * 2006-11-29 2010-03-04 Nilendu Sen Pharmaceutical compositions containing anhydrous calcipotriene
US20100093676A1 (en) * 2007-03-15 2010-04-15 Wheeler Derek A Polyaphron topical composition with vitamin d
US20110014135A1 (en) * 2005-06-01 2011-01-20 Stiefel Research Australia Pty Ltd Vitamin formulation
US8263580B2 (en) 1998-09-11 2012-09-11 Stiefel Research Australia Pty Ltd Vitamin formulation
US20130023501A1 (en) * 2009-12-22 2013-01-24 Leo Pharma A/S Pharmaceutical composition comprising solvent mixture and a vitamin d derivative or analogue
US9549896B2 (en) 2007-06-26 2017-01-24 Drug Delivery Solutions Limited Bioerodible patch comprising a polyaphron dispersion
US9610245B2 (en) 2011-03-14 2017-04-04 Drug Delivery Solutions Limited Ophthalmic composition
US11696919B2 (en) 2018-03-19 2023-07-11 MC2 Therapeutics Limited Topical composition

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU710931B2 (en) * 1996-02-28 1999-09-30 Sumitomo Pharmaceuticals Company, Limited Crystalline vitamin D derivative
SK287653B6 (sk) * 1999-04-23 2011-05-06 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Nevodná farmaceutická kompozícia na dermálne použitie
US20090098065A1 (en) * 2000-01-11 2009-04-16 Avikam Harel Composition and methods for the treatment of skin disorders
WO2004046097A1 (en) * 2002-11-18 2004-06-03 Teva Pharmaceutical Industries Ltd. A crystallization method for purification of calcipotriene
US8362287B2 (en) * 2004-03-18 2013-01-29 Leo Pharma A/S Stereoselective synthesis of vitamin D analogues
FR2871696B1 (fr) * 2004-06-17 2006-11-10 Galderma Sa Composition topique pour le traitement du psoriasis
TWI318203B (en) * 2004-09-01 2009-12-11 Leo Pharma As Epimerization of allylic alcohols
EP1987023B1 (en) * 2006-02-10 2010-11-24 Amgen, Inc Hydrate forms of amg706
DE06722936T8 (de) 2006-03-17 2008-06-05 Leo Pharma A/S Isomerisation pharmazeutischer zwischenprodukte
KR20110113664A (ko) * 2006-08-29 2011-10-17 테바 파마슈티컬 인더스트리즈 리미티드 비타민 ｄ 및 코르티코스테로이드를 포함하는 약학 조성물
ES2272198B1 (es) * 2006-12-28 2008-06-01 Laboratorios Viñas S.A. Procedimiento para la obtencion de hidrato de calcipotriol.
US8350079B2 (en) * 2008-05-08 2013-01-08 United Therapeutics Corporation Treprostinil formulation
US20120184514A1 (en) * 2009-07-01 2012-07-19 Vitamin Derivatives Inc. Vitamin d compounds and methods for preparing same
US9254296B2 (en) 2009-12-22 2016-02-09 Leo Pharma A/S Pharmaceutical composition comprising vitamin D analogue and cosolvent-surfactant mixture
RU2500387C1 (ru) * 2009-12-22 2013-12-10 Лео Фарма А/С Фармацевтическая композиция, содержащая аналог витамина d и смесь сорастворитель - поверхностно-активное вещество
AU2010335655B2 (en) * 2009-12-22 2015-03-05 Leo Pharma A/S Calcipotriol monohydrate nanocrystals
JP5873439B2 (ja) 2009-12-22 2016-03-01 レオ ファーマ アクティーゼルスカブ ビタミンｄ類似体および溶媒と界面活性剤の混合物を含む皮膚組成物
US9119781B2 (en) 2010-06-11 2015-09-01 Leo Pharma A/S Pharmaceutical spray composition comprising a vitamin D analogue and a corticosteroid
WO2012127037A2 (en) 2011-03-24 2012-09-27 Leo Pharma A/S A composition comprising lipid nanoparticles and a corticosteroid or vitamin d derivative
JP5652723B2 (ja) * 2012-08-17 2015-01-14 フォーモサ・ラボラトリーズ・インコーポレーテッド マキサカルシトールの新しい結晶形態
CN103724162A (zh) * 2014-01-07 2014-04-16 成都医路康医学技术服务有限公司 一种银屑病治疗药物卡泊三醇溶剂化物的制备方法
MA41818A (fr) 2015-03-27 2018-01-30 Leo Pharma As Timbre à micro-aiguilles pour administration d'un principe actif à la peau

Citations (4)

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US4435325A (en) * 1979-05-23 1984-03-06 Roussel Uclaf 1α,25α-Dihydroxy-cholecalciferol and methods for the production thereof
JPS59104358A (ja) 1982-12-03 1984-06-16 Teijin Ltd １α，２４−ジヒドロキシコレカルシフエロ−ルの一水塩及びその製造法
WO1987000834A1 (en) * 1985-08-02 1987-02-12 Leo Pharmaceutical Products Ltd. A/S Novel vitamin d analogues
US5292727A (en) * 1990-03-01 1994-03-08 Leo Pharmaceutical Products Ltd. Use of the treatment of acne

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4435325A (en) * 1979-05-23 1984-03-06 Roussel Uclaf 1α,25α-Dihydroxy-cholecalciferol and methods for the production thereof
JPS59104358A (ja) 1982-12-03 1984-06-16 Teijin Ltd １α，２４−ジヒドロキシコレカルシフエロ−ルの一水塩及びその製造法
WO1987000834A1 (en) * 1985-08-02 1987-02-12 Leo Pharmaceutical Products Ltd. A/S Novel vitamin d analogues
US4866048A (en) * 1985-08-02 1989-09-12 Leo Pharmaceutical Products Ltd. Novel vitamin D analogues
US5292727A (en) * 1990-03-01 1994-03-08 Leo Pharmaceutical Products Ltd. Use of the treatment of acne

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Bagot et al., "Immunosuppressive effects of 1,25-dihydroxyvitamin D3 analog (Calcipotriol) on epidermal cells". Chemical Abstracts, vol. 119, No. 5, Aug. 2, 1993, Abstract No. 41719, p. 182, col. 1, see abstract and Proc. Workshop Vitamin D (8th) 1991, pp. 518-519. *
Braeutigam et al., "Effects of calcipotriol (MC903) and calcitriol after topical application on the skin of hairless rats. Much lower effect of calcipotriol on systemic calcium homeostasis". Chemical Abstracts vol. 117, No. 21, Nov. 23, 1992, abstract #205159, p. 93, col. 1, see abstract & Skin Pharmacol. vol. 5, No. 2, 1992, pp. 87-92. *
Kragblle et al., "Vitamin D analogs in the treatment of psoriasis". Chemical Abstracts, vol. 116, No. 25, Jun. 22, 1992, abstract No. 248622, p. 90, col. 1, see abstract & J. Cell. Biochem. vol. 49, No. 1, 1992, pp. 46-52. *
Larsen et al., "Structure and absolute configuration of a monohydrate of calcipotriol (1.alpha.,3,5Z,7E,22E,24S)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-1,3,24-triol", Acta Crystallographica, Section C, Crystal Structure Communications, vol. 49, No. 3, 1993, pp. 618-621, see the whole document. *
Thavarajah et al. "1,25(OH)2D3 and Calcipotriol (MC903) have similar effects on the induction of osteoclast-like cell formation in human bone marrow cultures". Biochemical and Biophysical Research Communications, vol. 171, No. 3, Sep. 28, 1990, pp. 1056-1063. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8263580B2 (en) 1998-09-11 2012-09-11 Stiefel Research Australia Pty Ltd Vitamin formulation
US20110014135A1 (en) * 2005-06-01 2011-01-20 Stiefel Research Australia Pty Ltd Vitamin formulation
US8298515B2 (en) 2005-06-01 2012-10-30 Stiefel Research Australia Pty Ltd. Vitamin formulation
US8629128B2 (en) 2005-06-01 2014-01-14 Stiefel West Coast, Llc Vitamin formulation
US20100056644A1 (en) * 2006-11-29 2010-03-04 Nilendu Sen Pharmaceutical compositions containing anhydrous calcipotriene
US10265265B2 (en) 2007-03-15 2019-04-23 Drug Delivery Solutions Limited Topical composition
US20100093676A1 (en) * 2007-03-15 2010-04-15 Wheeler Derek A Polyaphron topical composition with vitamin d
US20080234239A1 (en) * 2007-03-15 2008-09-25 Derek Wheeler Topical composition
US11065195B2 (en) 2007-03-15 2021-07-20 MC2 Therapeutics Limited Topical composition
US9549896B2 (en) 2007-06-26 2017-01-24 Drug Delivery Solutions Limited Bioerodible patch comprising a polyaphron dispersion
US20130023501A1 (en) * 2009-12-22 2013-01-24 Leo Pharma A/S Pharmaceutical composition comprising solvent mixture and a vitamin d derivative or analogue
US10154959B1 (en) 2011-03-14 2018-12-18 Drug Delivery Solutions Limited Ophthalmic composition containing a polyaphron dispersion
US9610245B2 (en) 2011-03-14 2017-04-04 Drug Delivery Solutions Limited Ophthalmic composition
US11696919B2 (en) 2018-03-19 2023-07-11 MC2 Therapeutics Limited Topical composition

Also Published As

Publication number Publication date
ATE159717T1 (de) 1997-11-15
DE69406529D1 (de) 1997-12-04
CN1040746C (zh) 1998-11-18
JP3729847B2 (ja) 2005-12-21
FI952797A0 (fi) 1995-06-07
DE69406529T2 (de) 1998-05-28
ES2111287T3 (es) 1998-03-01
AU663249B2 (en) 1995-09-28
GB9300763D0 (en) 1993-03-03
CA2151730A1 (en) 1994-07-21
AU5857394A (en) 1994-08-15
KR950704249A (ko) 1995-11-17
JPH08505612A (ja) 1996-06-18
US5763426A (en) 1998-06-09
EP0679154A1 (en) 1995-11-02
FI108638B (fi) 2002-02-28
EP0679154B1 (en) 1997-10-29
GR3025668T3 (en) 1998-03-31
DK0679154T3 (da) 1998-03-30
CN1115979A (zh) 1996-01-31
CA2151730C (en) 2005-01-04
KR100309751B1 (ko) 2002-11-08
RU95116650A (ru) 1997-06-10
RU2128646C1 (ru) 1999-04-10
FI952797A (fi) 1995-06-07
NZ259679A (en) 1996-11-26
WO1994015912A1 (en) 1994-07-21

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