WO1999026652A1 - Systeme d'administration par les muqueuses comprenant un inhibiteur de thrombine lipophile - Google Patents

Systeme d'administration par les muqueuses comprenant un inhibiteur de thrombine lipophile Download PDF

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Publication number
WO1999026652A1
WO1999026652A1 PCT/GB1998/003511 GB9803511W WO9926652A1 WO 1999026652 A1 WO1999026652 A1 WO 1999026652A1 GB 9803511 W GB9803511 W GB 9803511W WO 9926652 A1 WO9926652 A1 WO 9926652A1
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WO
WIPO (PCT)
Prior art keywords
composition
thrombin inhibitor
surfactant
lipophilic
thrombin
Prior art date
Application number
PCT/GB1998/003511
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English (en)
Inventor
Peter Watts
Original Assignee
West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited
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
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Application filed by West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited filed Critical West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited
Priority to JP2000521854A priority Critical patent/JP2001523728A/ja
Priority to CA002310775A priority patent/CA2310775A1/fr
Priority to AU14934/99A priority patent/AU739270B2/en
Priority to EP98958993A priority patent/EP1051188A1/fr
Publication of WO1999026652A1 publication Critical patent/WO1999026652A1/fr
Priority to NO20002647A priority patent/NO20002647L/no

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Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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

  • the present invention relates to a means of delivering lipophilic thrombin inhibitors across a mucosal surface, for example in the gastrointestinal tract, therein providing enhanced absorption of such drugs with corresponding systemic levels of drug.
  • An essential step in the blood clotting, or coagulation, cascade is the proteolytic cleavage of fibrinogen to release fibrinopeptides A and B. These peptides, in turn, lead to the generation of fibrin which can undergo polymerisation to form a haemostatic plug, or 'blood clot'.
  • a rate limiting step in this process is the cleavage of fibrinogen, which is catalysed by the trypsin-like serine protease thrombin.
  • Pharmacological agents which inhibit thrombin activity and thereby prevent the action of thrombin in the blood coagulation cascade have been studied in detail.
  • Such anticoagulants dings are termed thrombin inhibitors, and can be grouped into three classes of compound; heparins, coumarins and low- molecular weight heparins. Of these, only the coumarins, e.g. warfarin, exhibit significant activity when administered orally.
  • All three classes of anticoagulant therapy act indirectly to inhibit thrombin; heparin and low-molecular weight heparin by activation of endogenous plasma proteins which inhibit thrombin and other proteases of the blood coagulation cascade, and coumarins by inhibition of the hepatic synthesis of vitamin K-dependent proteins (including thrombin). It is as a consequence of these indirect mechanisms that many of the limitations of these agents as therapeutics arise, in particular the need for careful dose titration in order to optimise therapeutic efficacy while minimising any side effects. Such complications include thrombocytopaenia, autoimmune reactions and, in the case of warfarin, skin necrosis. However, arguably the most common problem with current thrombin inhibitor therapies is the occurrence of haemorrhagic complications, which can on occasion prove fatal.
  • Direct-acting thrombin inhibitors have been developed, notably hirudin, hirolog and argatroban, which have shown promise in clinical trials. However, like heparin and low-molecular weight heparin, they are also limited to parenteral administration routes due to their poor oral absorption properties. Recently, modern X-ray crystallographic techniques have facilitated the development of a further type of direct- acting thrombin inhibitor, termed reaction intermediate-based thrombin inhibitors, which interact with the catalytic site of the thrombin molecule.
  • reaction intermediate-based thrombin inhibitors which interact with the catalytic site of the thrombin molecule.
  • One class of such agents is the peptide-like structures containing boron, e.g. peptide-boronic acids and their ester derivatives (Tapparelli et al.
  • the present invention seeks to provide a means of delivering lipophilic thrombin inhibitors across a mucosal surface.
  • One aspect of the invention provides a composition for the delivery across a mucosal surface of a lipophilic thrombin inhibitor.
  • Said composition comprises a lipophilic thrombin inhibitor and a non-ionic surfactant.
  • thrombin inhibitor we mean a compound which is able to substantially inhibit, via direct or indirect means or both, the catalytic action of thrombin.
  • Suitable tests for thrombin inhibitor activity of a compound include the activated partial thromboplastin time (APTT) test (Thomson JL and Poller L The activated partial thromboplastin time. In: Blood coagulation and haemostasis. Ed. Thomson JM, Churchill Livingstone, Edinburgh, 1989, pp301-339).
  • 'lipophilic' we mean a compound having a partition coefficient between 1-n-octanol and water expressed as log P of greater than 1.0 at physiological pH and 25°C.
  • the mucosal surface is in the gastrointestinal tract, nose, mouth, rectum or vagina.
  • the thrombin inhibitor is a direct-acting thrombin inhibitor.
  • direct-acting we mean a thrombin inhibitor which inhibits the blood coagulation cascade by interacting directly with thrombin to inhibit fibrinogen cleavage.
  • the thrombin inhibitor is a peptide boronic acid or ester derivative thereof.
  • peptidomimetic thrombin inhibitors that would be suitable for formulation in the present invention include DUP 714 (acetyl(D)Phe-Pro-boroArg), SDZ 216744 benzyloxy-carboxyl- (D)-Phe-Pro-boromethoxypropylglycine-pinanediol, SDZ 217766 tert-but- oxycarbonyl-(D)-trimemylsUylalanine-Pro-boroArgpinanediol, SDZ 19349 tert-butoxycarbonyl-(D)-trimethyl-silylalanine-Pro-boromethoxy-propyl- glycine-pinanediol (Kettner et al , 1990, J. Biol. Chem. , 265(30), 18289- 97; EP 741747; EP 6883
  • the thrombin inhibitor can be a prodrug.
  • prodrug we mean an inactive compound which, when admimstered, undergoes conversion in vivo to an enzymically-active thrombin inhibitor.
  • Z-D-Phe- pro-borompg-Opinacol (formula weight C 33 H 46 0 7 N 3 B) (molecular weight 607.6) is a lipophilic prodrug of a thrombin inhibitor. Its synthesis has been described in US 5,596,123. It will be referred to subsequently as TRI 50b. The molecule is essentially insoluble in water but has some solubility in oily vehicles.
  • Prototype formulations for parenteral administration have been developed based on alcoholic vehicles with added excipients such as polyethylene glycol.
  • excipients such as polyethylene glycol.
  • systems can have use in early animal and even human studies, they cannot be considered as products for use in patients in the market place due to poor stability and possible toxic reactions to the chosen formulation additives.
  • Non-ionic surfactants are .known in the art and are widely used as pharmaceutical excipients.
  • 'non-ionic' we mean a surfactant which is substantially free of ionic, i.e. electrically-charged, groups in the polar portion of the molecule.
  • Such surfactants are normally non-toxic and non- irritant.
  • Suitable non-ionic surfactants of the present invention include, but are not limited to, alkyl ethers, castor oils, sorbitan fatty acid esters, stearates and glycerides (Wade and Weller, Handbook of Pharmaceutical Excipients 2 nd edition, The Pharmaceutical Press, London).
  • the non-ionic surfactant is ethoxylated.
  • 'ethoxylated' we mean a surfactant containing one or more polyethylene glycol (PEG) groups.
  • PEG polyethylene glycol
  • 'Ethoxylated' and 'polyglycolized' will be used interchangeably throughout this description.
  • the surfactant contains between 4 and 20 ethoxyl (PEG) groups, for example between 10 and 16 ethoxyl groups.
  • the surfactant is a liquid, semi-solid or solid.
  • Ethoxylated surfactants suitable for use in this invention are .known to those skilled in the art and include, but are not limited to, polyglycolized glycerides such as Gelucire ® (produced by Gattefosse, Saint Priest, France). Polyglycolized glycerides are defined as compounds obtained by polyglycolysis of natural hydrogenated oils with polyethylene glycols.
  • the Gelucire ® materials are a range of fatty excipients with different melting points and lipophilicities which are suitable for filling into gelatin capsules for oral administration.
  • Gelucire ® 37/06 a saturated polyglycolized glyceride with an oral LD 50 in the rat of greater than 50 ml/kg (Ash and Ash, 1995), is a preferred material for the present invention.
  • the content of the ethoxylated surfactant in the composition of the present invention can be from 5 to 90%, more preferably from 20 to 80% and, most preferably, from 40 to 70% .
  • the composition may additionally contain a dispersing agent such as polysorbate 80 (Tween 80) in the amount of 1 to 50% most preferable from 5 to 20% and most preferably from 7 to 15% .
  • Suitable dispersing agents are well-l own in the art and include, but are not limited to, surfactants, silica and microcrystalline cellulose.
  • compositions comprising a lipophilic thrombin inhibitor and a non-ionic surfactant contained within a capsule suitable for mucosal administration.
  • capsules are known to persons skilled in the art and include hard and soft capsules made from gelatin, starch or HPMC.
  • the capsule has an enteric coating which enables it to stay intact within the stomach, allowing subsequent release of the thrombin inhibitor in the intestines.
  • a second aspect of the present invention provides a method of making a composition for the delivery across a mucosal surface of a lipophilic thrombin inhibitor, said means comprising admixing a lipophilic thrombin inhibitor with a non-ionic surfactant.
  • the composition may be produced by co-melting and mixing together the drug and excipients at a temperature exceeding the melting point of the drug.
  • the drug is dispersed in the melted surfactant; Gelucire ® 37/06, for example, melts at 37°C.
  • the mixture may then be filled into capsules where it will cool to form a liquid or semi-solid at room temperature.
  • a further aspect of the present invention provides a composition for the delivery across a mucosal surface of a lipophilic thrombin inhibitor for use in medicine.
  • inhibitors of thrombin have utility in the treatment of venous thrombosis, atrial fibrillation, arterial thrombosis, pulmonary embolism, and in the prevention and treatment of cardiovascular disorders including myocardial infarction and stroke.
  • the clinical management of such disorders often necessitates a prolonged period of treatment with a thrombin inhibitor. In these circumstances, it is convenient and preferable to use an oral administration route.
  • thrombin inhibitors have been highlighted.
  • patients with cancer, neurodegenerative disease and certain inflammatory diseases, such as sepsis commonly exhibit enhanced activity of the blood coagulation cascade, providing a rationale for symptomological treatment with thrombin inhibitors.
  • thrombin may be directly involved in the cellular pathophysiology of these diseases, i.e. thrombin activation may be causative rather than consequential.
  • thrombin inhibitors may also have utility in the treatment of such diseases per se and not mere alleviation of their symptoms.
  • thrombin inhibitor TRI 50b a peptide boronic acid derivative (supplied by the Thrombosis Research Institute, London) was formulated into three different oral delivery systems:
  • PEG 400 polyethylene glycol 400, Sigma, Poole, UK
  • PEG 400 polyethylene glycol 400, Sigma, Poole, UK
  • Tween 80 (Polysorbate 80, Sigma, Poole, UK) is a widely used pharmaceutical excipient listed in British, European and US Pharmacopoeias. It is essentially non-toxic and non-irritant (Wade and Weller, 1994). This material is UK approved and FDA approved for the following uses: buccal, intramuscular injectable, intravenous, parenteral, ophthalmic, oral, otic, rectal, topical and vaginal. This material is a surfactant added to increase the dispersion of the drug in the mixture.
  • the TRI 50b content of the hard gelatin capsules was checked by HPLC. The results showed a concentration of 300 mg/ml (theoretical value 333 mg/ml).
  • Cremophor EL ® polyoxyethylene 35 castor oil, BASF, Cheadle, UK
  • Cremophor EL ® is a water soluble material which is widely used as a pharmaceutical excipient in oral, topical and parenteral formulations. It is essentially non-toxic and non-irritant. This material is listed in USPNF XVII (Wade and Weller, 1994).
  • the TRI 50b content of the hard gelatin capsules was checked by HPLC. The results showed a concentration of 292 mg/ml (theoretical value 333 mg/ml). Cremophor EL ® gave rise to interfering peaks and the HPLC conditions used were adjusted to prevent this interference.
  • Gelucire ® 37/06 is a saturated polyglycolized glyceride (Gattefosse, Saint Priest, France).
  • the Gelucire ® materials are a range of fatty excipients with different melting points and lipophilicities which are suitable for filling into gelatin capsules for oral administration.
  • Gelucire ® 37/06 melts at 37 'C and forms a dispersion in water.
  • the oral LD50 in the rat is greater than 50 ml/kg. (Ash and Ash, 1995).
  • the TRI 50b content of the hard gelatin capsules was checked by HPLC. The results showed a concentration of 306 mg/ml (theoretical value 333 mg/ml).
  • the three formulations were evaluated in the mini pig by pharmacokinetic testing.
  • the animals were dosed directly into the duodenum, blood samples were collected at various time-points and the samples analysed for
  • TRI 50b content (using an HPLC method) and thrombin clotting times by the Thrombosis Research Institute, London. TRI 50b plasma levels
  • Figure 1 shows the effect of three different formulation compositions (formulation 1 - O, formulation 2 - ⁇ , formulation 3 - D) on plasma concentration of TRI 50b following admimstration of 20 mg/kg TRI 50b to the mini pig.
  • Figure 2 shows the effect of tliree different formulation compositions (formulation 1 - O, formulation 2 - A, formulation 3 - D) on thrombin clotting time.
  • Bioavailability is the fraction or percentage of a dose that reaches the systemic circulation intact, as compared to an intravenous injection.
  • TRI 50b When administered at a doses of 20 mg/kg, TRI 50b was found to have bioavailabilities of 10.3%, 13.2% and 41.0% from formulations 1, 2 and 3, respectively, calculated as the AUC (area under the curve) for the oral formulation as a percentage of the AUC following direct injection.
  • formulation 3 which contained the saturated polyglycolized glyceride (Gelucire ® ), was found to produce a dramatic and surprising increase in the measured bioavailability of the lipophilic thrombin inhibitor TRI 50b.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

L'invention concerne une composition prévue pour être administrée par les muqueuses d'un inhibiteur de thrombine lipophile, comprenant un inhibiteur de thrombine lipophile, et un tensioactif non ionique. De préférence, les muqueuses sont celles tapissant l'appareil gastro-intestinal, le nez, la bouche, le rectum ou le vagin. De manière avantageuse, l'inhibiteur de thrombine est un acide borique de peptides ou un dérivé d'ester de ce dernier. De manière pratique, le tensioactif non ionique est un glycéride éthoxylé. De manière appropriée, la composition est contenue dans une gélule. En outre, l'invention concerne des procédés de fabrication desdites compositions et l'utilisation de ces compositions en médecine.
PCT/GB1998/003511 1997-11-25 1998-11-25 Systeme d'administration par les muqueuses comprenant un inhibiteur de thrombine lipophile WO1999026652A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP2000521854A JP2001523728A (ja) 1997-11-25 1998-11-25 親油性トロンビン阻害因子を有する粘膜デリバリーシステム
CA002310775A CA2310775A1 (fr) 1997-11-25 1998-11-25 Systeme d'administration par les muqueuses comprenant un inhibiteur de thrombine lipophile
AU14934/99A AU739270B2 (en) 1997-11-25 1998-11-25 Mucosal delivery system comprising lipophilic thrombin inhibitors
EP98958993A EP1051188A1 (fr) 1997-11-25 1998-11-25 Systeme d'administration par les muqueuses comprenant un inhibiteur de thrombine lipophile
NO20002647A NO20002647L (no) 1997-11-25 2000-05-24 Mukosalt administrasjonssystem omfattende lipofile trombin inhibitorer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9724786.0A GB9724786D0 (en) 1997-11-25 1997-11-25 Oral delivery system
GB9724786.0 1997-11-25

Publications (1)

Publication Number Publication Date
WO1999026652A1 true WO1999026652A1 (fr) 1999-06-03

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PCT/GB1998/003511 WO1999026652A1 (fr) 1997-11-25 1998-11-25 Systeme d'administration par les muqueuses comprenant un inhibiteur de thrombine lipophile

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EP (1) EP1051188A1 (fr)
JP (1) JP2001523728A (fr)
AU (1) AU739270B2 (fr)
CA (1) CA2310775A1 (fr)
GB (1) GB9724786D0 (fr)
NO (1) NO20002647L (fr)
WO (1) WO1999026652A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005084686A2 (fr) * 2004-03-09 2005-09-15 Trigen Limited Medicaments a base de boronate a effet anti-trhombotique pour intervention chirurgicale
WO2005084685A2 (fr) * 2004-03-09 2005-09-15 Trigen Limited Medicaments a base de boronate pour a effet anti-coagulant de courte duree
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL376535A1 (pl) * 2002-09-09 2006-01-09 Trigen Limited Sole kwasu boronowego i ich zastosowanie w leczeniu zakrzepicy

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0391369A2 (fr) * 1989-04-05 1990-10-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Emulsions pour médicaments
WO1994020526A1 (fr) * 1993-03-03 1994-09-15 Sandoz Ltd. Derives d'acide bore peptidique a activite d'inhibition des proteases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0391369A2 (fr) * 1989-04-05 1990-10-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Emulsions pour médicaments
WO1994020526A1 (fr) * 1993-03-03 1994-09-15 Sandoz Ltd. Derives d'acide bore peptidique a activite d'inhibition des proteases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KETTNER C ET AL: "THE SELECTIVE INHIBITION OF THROMBIN BY PEPTIDES OF BOROARGININE", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 265, no. 30, 25 October 1990 (1990-10-25), pages 18289 - 18297, XP000160262 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7112572B2 (en) 2002-09-09 2006-09-26 Trigen Limited Multivalent metal salts of boronic acids
US7371729B2 (en) 2002-09-09 2008-05-13 Trigen Limited Boronic acid salts useful in parenteral formulations
WO2005084686A2 (fr) * 2004-03-09 2005-09-15 Trigen Limited Medicaments a base de boronate a effet anti-trhombotique pour intervention chirurgicale
WO2005084685A2 (fr) * 2004-03-09 2005-09-15 Trigen Limited Medicaments a base de boronate pour a effet anti-coagulant de courte duree
WO2005084685A3 (fr) * 2004-03-09 2005-11-24 Trigen Ltd Medicaments a base de boronate pour a effet anti-coagulant de courte duree
WO2005084686A3 (fr) * 2004-03-09 2005-12-01 Trigen Ltd Medicaments a base de boronate a effet anti-trhombotique pour intervention chirurgicale

Also Published As

Publication number Publication date
CA2310775A1 (fr) 1999-06-03
AU739270B2 (en) 2001-10-11
AU1493499A (en) 1999-06-15
EP1051188A1 (fr) 2000-11-15
JP2001523728A (ja) 2001-11-27
GB9724786D0 (en) 1998-01-21
NO20002647D0 (no) 2000-05-24
NO20002647L (no) 2000-05-24

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