EP1189625A1 - Preparation pharmaceutique contenant des modifications de la proteine b du surfactant (sp-b) et de la proteine c du surfactant (sp-c) - Google Patents

Preparation pharmaceutique contenant des modifications de la proteine b du surfactant (sp-b) et de la proteine c du surfactant (sp-c)

Info

Publication number
EP1189625A1
EP1189625A1 EP00938727A EP00938727A EP1189625A1 EP 1189625 A1 EP1189625 A1 EP 1189625A1 EP 00938727 A EP00938727 A EP 00938727A EP 00938727 A EP00938727 A EP 00938727A EP 1189625 A1 EP1189625 A1 EP 1189625A1
Authority
EP
European Patent Office
Prior art keywords
surfactant
seq
pharmaceutical preparation
surfactant protein
modification
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.)
Withdrawn
Application number
EP00938727A
Other languages
German (de)
English (en)
Inventor
Ernst Sturm
Ulrich Kilian
Dietrich Häfner
Paul-Georg Germann
Klaus Eistetter
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.)
Takeda GmbH
Original Assignee
Byk Gulden Lomberg Chemische Fabrik GmbH
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.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik GmbH filed Critical Byk Gulden Lomberg Chemische Fabrik GmbH
Priority to EP00938727A priority Critical patent/EP1189625A1/fr
Publication of EP1189625A1 publication Critical patent/EP1189625A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/785—Alveolar surfactant peptides; Pulmonary surfactant peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0082—Lung surfactant, artificial mucus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the invention relates to a novel pharmaceutical preparation which is suitable for the treatment of disease conditions which are designated as Infant Respiratory Distress Syndrome (IRDS) and ALI (Acute Lung Injury), including ARDS
  • IRDS Infant Respiratory Distress Syndrome
  • ALI acute Lung Injury
  • ARDS acute or Adult Respiratory Distress Syndrome
  • IRDS Infant Respiratory Distress Syndrome
  • IRDS has been treated successfully by introducing pulmonary surfactant preparations into the lungs of the affected children From pilot studies, it is known that pulmonary surfactant preparations are additionally clinically effective in the case of ALI (Acute Lung Injury) including ARDS (reviewed, for example, by B Lachmann, D Gommers and E P Eijking Exogenous surfactant therapy in adults, Atemw -Leptkrkh 1993, 19 581-91 , D Walmrath et al Bronchoscopic surfactant administration in patients with severe adult respiratory distress syndrome and sepsis, Am J Respir C ⁇ t Care Med 1996, 154 57-62, T J Gregory et al Bovine surfactant therapy for patients with acute respiratory distress syndrome, Am J Respir C ⁇ t Care Med 1997, 155 1309-15)
  • ALI acute Lung Injury
  • ARDS Reviewed, for example, by B Lachmann, D Gommers and E P Eijking Exogenous surfactant therapy in adults, Atemw -Lonnek
  • the pulmonary surfactant is either instilled intratracheally as a bolus (IRDS and ARDS) or instilled into individual sections of lung via a bronchoscope (ARDS)
  • IRDS and ARDS a bolus
  • ARDS bronchoscope
  • V Balaraman et al Physiologic response and lung distribution of lavage versus bolus Exosurf® in piglets with acute lung injury, Am J Respir Cnt Care Med 1996, 153 1838-483
  • ARDS bronchoscope
  • compositions which contain only phospholipids can be compositions which contain only phospholipids, but also preparations which, in addition to the phospholipids, also contain surfactant protein, inter alia.
  • surfactant protein commercially available products which may be mentioned are Curosurf® (Serono Pharma GmbH, Un- terschlei ⁇ heim), a highly purified natural surfactant from homogenized pigs lungs, Survanta® (Abbott GmbH, Wiesbaden) and Alveofact® (Dr. Karl Thomae GmbH, Biberach), both extracts of bovine lungs, and also Exosurf® (Deutsche Wellcome GmbH, Burgwedel), a synthetic phospholipid with auxiliaries.
  • Possible pulmonary surfactant proteins are both the proteins obtained from natural sources, such as, for example, pulmonary lavage or extraction from amniotic fluid, and also the genetically engineered or chemically synthesized proteins, and suitable modifications of the surfactant proteins.
  • SP-C surfactant protein C
  • SP-B pulmonary surfactant preparations containing modifications of surfactant protein B
  • the invention accordingly provides pharmaceutical preparations comprising at least one modification of SP-B and at least one modification of SP-C.
  • SP-B in analogy to the nomenclature proposed by Poss- mayer (Possmayer, F.: A Proposed Nomenclature for Pulmonary Surfactant-associated Proteins. Am. Rev. Respir. Dis. 1988, 138, 990-998), is to be understood as meaning the surfactant proteins present in natural lung surfactant or amniotic fluid of mammals referred to as SP-B.
  • modifiedification of SP-B includes those peptides in which, compared to SP-B, one or more amino acids are missing or have been replaced by other amino acids, as long as the peptides, in a mixture with phospholipids, show pulmonary surfactant activity.
  • the pulmonary surfactant activity can be determined in a manner known to the person skilled in the art. Natural pulmonary surfactant has surface-active properties; for example, it reduces the surface tension in the pulmonary alveoli.
  • a simple and fast in vitro test for the determination of the surface activity of pulmonary surfactant preparations is, for example, the so-called Wilhelmy balance [Goerke, J. Biochim. Biophys. Acta, 344: 241-261 (1974), King R.J.
  • Modifications of SP-B is, in particular, also meant to be understood as including those proteins which have an amino acid sequence designed completely independently with a view to its pulmonary surfactant properties, as described, for example, in EP-A-0 593 094, WO 92/22315 and WO 98/49191.
  • polypeptides selected from the group of polypeptides having the amino acid sequence SEQ ID NO:1 KLLLLKLLKLLKLLLLKLLK (KL4; INN: sinapultide), SEQ ID NO:2 KLLLLLLKLLLLLLKLL (KL8), SEQ ID NO:3 KKLLLLLLLKKLLLLLKKL (KL7), SEQ ID NO:4 DLLLLDLLLLDLLLLDLLLLD (DL4), SEQ ID NO:5 RLLLLRLLLLRLLLLRLLLLR (RL4), SEQ ID NO:6 RLLLLLLRLLLLLLLLRLL (RL8), SEQ ID NO:7 RRLLLLLLLRRLLLLLLLRRL (RL7), SEQ ID NO:8 RLLLLCLLLRLLLLCLLLR (RCL1 ), SEQ ID NO:9 RLLLLCLLLRLLLLCLLLRLL (RCL2), SEQ ID NO:10 RLLLLCLLRLLLLCLLLRLLLLCLLLR (RCL3) and
  • amino acid radicals in the amino acid sequences conform with the Standard Polypeptide Nomenclature (J. Biol. Chem., 243: 3557-59, 1969).
  • the amino acid sequences are shown in the customary short notation, with the amino acid which carries the free amino group at the left end (amino terminus) and the amino acid which carries the free carboxyl group at the right end (carboxy terminus).
  • surfactant protein C in analogy to the nomenclature proposed by Possmayer (Possmayer, F.: A Proposed Nomenclature for Pulmonary Surfactant- associated Proteins. Am. Rev. Respir. Dis. 1988, 138, 990-998), is to be understood as meaning the surfactant proteins present in natural lung surfactant or amniotic fluid of mammals referred to as SP-C.
  • modified SP-C includes those peptides in which, compared to SP-C, one or more amino acids are missing or have been replaced by other amino acids, so long as the peptides, in a mixture with phospholipids, show pulmonary surfactant activity.
  • the pulmonary surfactant activity can be determined as described above.
  • Modified derivatives of the pulmonary surfactant proteins designated SP-C which differ from human SP-C in that some amino acids have been replaced are described, for example, in WO 91/18015 and WO 95/32992.
  • the preparations according to the invention comprise, as further components, phospholipids.
  • phospholipids which are contained in natural pulmonary surfactant preparations, such as dipalmitoylphosphatidylcholine (DPPC), palmitoyloleylphosphatidylglycerol (POPG) and/or phosphatidylglycerol (PG).
  • DPPC dipalmitoylphosphatidylcholine
  • POPG palmitoyloleylphosphatidylglycerol
  • PG phosphatidylglycerol
  • Further possible components of the preparations according to the invention are fatty acids, such as, for example, palmitic acid.
  • the preparations may comprise electrolytes, such as calcium, magnesium and/or sodium salts (for example calcium chloride, sodium chloride or sodium bicarbonate).
  • Preparations according to the invention expediently comprise 80 to 95% by weight of phospholipids, 0.2 to 5% by weight of surfactant proteins (total of the modification of SP-B and the modification of SP-C), 2 to 15% by weight of fatty acids and 0 to 5% by weight of electrolytes (based on the dry weight).
  • the phospholipids are preferably mixtures of dipalmitoylphosphatidylcholine (DPPC) and palmitoylo- leylphosphatidylglycerol (POPG), in particular in a ratio (ratio by weight) of from 7 to 3 to 3 to 7.
  • Preferred preparations according to the invention comprise 80 to 95% by weight of phospholipids, 0.5 to 3.0% by weight of surfactant proteins (total of the modification of SP-B and the modification of SP-C), 3 to 15% by weight of fatty acid, preferably palmitic acid, and 0 to 3% by weight of calcium chloride (based on the dry weight).
  • the ratio by weight of the modification of SP-B to the modification of SP-C in the preparations according to the invention is preferably 0.3 to 2.0.
  • Particularly preferred preparations according to the invention comprise 0.2 to 3% by weight of KL4 and 0.2 to 3% by weight of rSP-C (FF/I).
  • the preparations according to the invention are produced in a manner known to the person skilled in the art, for example by incorporating the surfactant proteins into a phospholipid matrix as described in WO 95/32992.
  • the pulmonary surfactant preparations are preferably provided in lyophilized and in particular in spray-dried form. Lyophilized preparations are known, for example, from WO 97/35882, WO 95/32992, WO 91/00871 and DE 3229179.
  • WO 97/26863 describes a process for preparing pulverulent pulmonary surfactant preparations by spray-drying. According to the invention, preference is given to preparations prepared in this manner.
  • ARDS Adult Respiratory Distress Syndrome
  • IRDS Infant Respiratory Distress Syndrome
  • Triggering causes for ALI including ARDS can, for example, be (cited in accordance with Harrison's Principles of Internal Medicine 10th Ed 1983, McGraw-Hill Int Book Comp ) diffuse pulmonary infections (for example due to viruses, bacteria, fungi), aspiration of, for example, gastric juice or in the case of near-drowning, inhalation of toxins or irritants (for
  • the preparations according to the invention are not only suitable for the treatment or prophylaxis of IRDS in prematurely born babies or in the treatment or prophylaxis of ALI including ARDS in adults, but also for the treatment or prophylaxis of pneumonia, bronchitis, meconium aspiration syndrome, COPD (chronic obstructive pulmonary disease), asthma and cystic fibrosis
  • the administration of the preparations according to the invention is carried out in a manner known to the person skilled in the art, preferably by intratracheal installation (infusion or bolus) or in the form an atomization
  • the preparations according to the invention are preferably dissolved or suspended in a suitable solvent or resuspension medium, in particular when the preparations are present in lyophilized or spray-dried form
  • the suitable solvent is preferably physiological saline
  • the preparations according to the invention are preferably administered in such an amount that the amount of phospholipids is between 12 5 and 200 mg per kilogram of body weight
  • Administration is generally carried out once to three times a day over a period of from 1 to 7 days
  • a bronchoalveolar lavage preferably with dilute pulmonary surfactant preparation, can be carried out prior to the administration of the preparations according to the invention
  • a bronchoalveolar lavage preferably with dilute pulmonary surfactant preparation, can be carried out prior to the administration of the preparations according to the invention
  • the invention furthermore provides the use of at least one modification of surfactant protein B (SP-B) and at least one modification of surfactant protein C (SP-C) for preparing pharmaceutical preparations (medicaments) for the treatment or prophylaxis of pneumonia, bronchitis, meconium aspiration syndrome, COPD, asthma, cystic fibrosis, IRDS and/or ALI (including ARDS) in mammals, in particular humans.
  • SP-B surfactant protein B
  • SP-C surfactant protein C
  • the invention furthermore provides a commercial product, consisting of a customary secondary pack, a primary pack containing the pharmaceutical preparation (for example an ampoule) and, if desired, an accompanying leaflet, the pharmaceutical preparation being suitable for the treatment or prophylaxis of pneumonia, bronchitis, meconium aspiration syndrome, COPD, asthma, cystic fibrosis, IRDS and/or ALI (including ARDS), the suitability of the pharmaceutical preparation for the prophylaxis or treatment of the disorders mentioned being indicated on the secondary pack or on the accompanying leaflet of the commercial product, and the pharmaceutical preparation comprising at least one modification of surfactant protein B (SP-B) and at least one modification of surfactant protein C (SP-C), together with suitable pharmaceutical auxiliaries.
  • SP-B surfactant protein B
  • SP-C surfactant protein C

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • Epidemiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Toxicology (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Immunology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une nouvelle préparation pharmaceutique permettant de traiter le syndrome de détresse respiratoire du nouveau-né (IRDS) ou l'atteinte pulmonaire aiguë (ALI), comprenant au moins une modification de la protéine B du surfactant (SP-B) et au moins une modification de la protéine C du surfactant (SP-C).
EP00938727A 1999-06-11 2000-06-02 Preparation pharmaceutique contenant des modifications de la proteine b du surfactant (sp-b) et de la proteine c du surfactant (sp-c) Withdrawn EP1189625A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP00938727A EP1189625A1 (fr) 1999-06-11 2000-06-02 Preparation pharmaceutique contenant des modifications de la proteine b du surfactant (sp-b) et de la proteine c du surfactant (sp-c)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP99111385 1999-06-11
EP99111385 1999-06-11
PCT/EP2000/005032 WO2000076535A1 (fr) 1999-06-11 2000-06-02 Preparation pharmaceutique contenant des modifications de la proteine b du surfactant (sp-b) et de la proteine c du surfactant (sp-c)
EP00938727A EP1189625A1 (fr) 1999-06-11 2000-06-02 Preparation pharmaceutique contenant des modifications de la proteine b du surfactant (sp-b) et de la proteine c du surfactant (sp-c)

Publications (1)

Publication Number Publication Date
EP1189625A1 true EP1189625A1 (fr) 2002-03-27

Family

ID=8238344

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00938727A Withdrawn EP1189625A1 (fr) 1999-06-11 2000-06-02 Preparation pharmaceutique contenant des modifications de la proteine b du surfactant (sp-b) et de la proteine c du surfactant (sp-c)

Country Status (5)

Country Link
EP (1) EP1189625A1 (fr)
JP (1) JP2003501481A (fr)
AU (1) AU5400000A (fr)
CA (1) CA2372558A1 (fr)
WO (1) WO2000076535A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058423A1 (fr) * 2000-02-11 2001-08-16 Altana Pharma Ag Nouvelle utilisation d'un surfactant pulmonaire dans la prophylaxie et le traitement des maladies pulmonaires chroniques
JP2005500349A (ja) * 2001-08-01 2005-01-06 アルタナ　ファルマ　アクチエンゲゼルシャフト 呼吸症候群のための選択的ｃｏｘ−２インヒビターと肺表面活性物質の組合せ物
EP1589980A4 (fr) * 2002-12-09 2007-04-04 Childrens Hosp Medical Center Procedes de diagnostic et de traitement de maladies pulmonaires interstitielles
DE60331601D1 (de) 2003-12-18 2010-04-15 Univ Giessen Justus Liebig Neue chimärische plasminogenaktivatoren und deren pharmazeutische verwendung
US7582312B2 (en) 2004-11-15 2009-09-01 Discovery Laboratories, Inc. Methods to produce lung surfactant formulations via lyophilization and formulations and uses thereof
EP1997502A1 (fr) * 2007-06-01 2008-12-03 CHIESI FARMACEUTICI S.p.A. Agents tensioactifs reconstitués dotés de propriétés améliorées
US8399406B2 (en) 2009-06-05 2013-03-19 Chiesi Farmaceutici S.P.A. Reconstituted surfactant composition containing analogs of surfactant protein B (SP-B) and surfactant protein C (SP-C)
CA3029456A1 (fr) 2016-08-24 2018-03-01 Chiesi Farmaceutici S.P.A. Formulation pharmaceutique stable comprenant une composition de surfactant pulmonaire reconstitue

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01501282A (ja) * 1986-12-08 1989-05-11 ホイツトセツト，ジエフリー　エイ． 肺胞疎水性界面活性物質関連タンパク質
US6013619A (en) * 1988-01-06 2000-01-11 The Scripps Research Institute Pulmonary surfactants and therapeutic uses, including pulmonary lavage
DE4418936A1 (de) * 1994-05-31 1996-02-08 Byk Gulden Lomberg Chem Fab Polypeptid
DE4434629C1 (de) * 1994-09-28 1996-06-27 Byk Gulden Lomberg Chem Fab Zusammensetzungen zur Behandlung von IRDS und ARDS
US6315983B1 (en) * 1996-01-24 2001-11-13 Byk Gulden Lomberg Chemische Fabrik Gmbh Process for the production of powdered pulmonary surfactant preparations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0076535A1 *

Also Published As

Publication number Publication date
CA2372558A1 (fr) 2000-12-21
AU5400000A (en) 2001-01-02
JP2003501481A (ja) 2003-01-14
WO2000076535A1 (fr) 2000-12-21

Similar Documents

Publication Publication Date Title
CA2575513C (fr) Composition comprenant un tensioactif pulmonaire et un peptide derive de tnf
AU734122B2 (en) Compositions for the treatment of ARDS or IRDS containing 3-(cyclopropylmethoxy)-n-(3,5-dichloro-4-pyridinyl)-4- (difluoromethoxy)benzamide and lung surfactant
EP1131055B1 (fr) Appareil de traitement contenant des compositions a base de surfactants pulmonaires
WO2001019392A1 (fr) Combinaison de c1-inh et d'un agent tensioactif pulmonaire pour le traitement des troubles respiratoires
US20030091509A1 (en) Novel use of pulmonary surfactant for the prophylaxis and treatment of chronic pulmonary diseases
WO2000076535A1 (fr) Preparation pharmaceutique contenant des modifications de la proteine b du surfactant (sp-b) et de la proteine c du surfactant (sp-c)
US20030007931A1 (en) Compositions comprising phenylaminothiophenacetic acid derivatives for the treatment of acute or adult respiratory distress syndrome (ARDS) and infant respiratory distress syndrome (IRDS)
CA2405811C (fr) Nouvelle utilisation de tensioactif pulmonaire permettant la prevention ou le traitement precoce de troubles pulmonaires aigus
US20040254112A1 (en) Use of pulmonary surfactant for the early treatment of acute pulmonary diseases
EP1098645B1 (fr) Compositions comprenant des derives de l'acide phenylaminothiophenacetique pour le traitement de l'insuffisance respiratoire de l'adulte (ards) et de l'enfant (irds)
JP4762466B2 (ja) サーファクタントタンパク質ｃエステル
DE19926554A1 (de) Neue pharmazeutische Zubereitung

Legal Events

Date Code Title Description
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

17P Request for examination filed

Effective date: 20020111

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

AX Request for extension of the european patent

Free format text: AL PAYMENT 20020111;LT PAYMENT 20020111;LV PAYMENT 20020111;MK PAYMENT 20020111;RO PAYMENT 20020111;SI PAYMENT 20020111

17Q First examination report despatched

Effective date: 20020523

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ALTANA PHARMA AG

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20041012