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WO1993024137A1 - Agent anti-inflammatoire - Google Patents

Agent anti-inflammatoire Download PDF

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Publication number
WO1993024137A1
WO1993024137A1 PCT/GB1993/000990 GB9300990W WO9324137A1 WO 1993024137 A1 WO1993024137 A1 WO 1993024137A1 GB 9300990 W GB9300990 W GB 9300990W WO 9324137 A1 WO9324137 A1 WO 9324137A1
Authority
WO
WIPO (PCT)
Prior art keywords
factor viii
inflammation
group
hours
administration
Prior art date
Application number
PCT/GB1993/000990
Other languages
English (en)
Inventor
David Russell Blake
Christopher John Morris
Richard Bartholomew Williams
Paul Graham Winyard
Original Assignee
British Technology Group Ltd
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 British Technology Group Ltd filed Critical British Technology Group Ltd
Priority to JP6500281A priority Critical patent/JPH07507289A/ja
Priority to EP93910198A priority patent/EP0648125A1/fr
Publication of WO1993024137A1 publication Critical patent/WO1993024137A1/fr

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Classifications

    • 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
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A61K38/37—Factors VIII
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • Inflammation Is associated with a wide range of disorders resulting from both external and internal factors. For example, skin inflammation occurs in many conditions as a result of disease or injury. Other disorders result in internal inflammation, for example in joints affected by arthritis and in intestinal Inflammatory conditions such as colitis. Inflammation is also postulated as participatory in atherosclerosis, diabetes and other endocrine disorders.
  • haemophilia One serious disorder which gives rise to secondary disabilities which are associated with secondary inflammation is haemophilia.
  • haemophilia Two types of haemophilia are recognised, both being X-linked, recessive bleeding disorders with indistinguishable clinical manifestations.
  • haemophilia A is attributable to decreased blood levels of properly functioning clotting factor VIII, whilst in haemophilia B, the defect is a decreased level of functional blood clotting factor IX.
  • Haemophilia patients commonly suffer from progressive arthritis and musculoskeletal disability as a consequence of bleeding into joints and muscles. Much effort is put into management routines for haemophilia by lifestyle adjustments to protect affected joints.
  • management comprises intravenous administration of Factor VIII concentrate, together with rest and simple or sometimes opiate analgesia.
  • Simple analgesics are used in the subacute arthropathy that may persist following an acute bleeding episode.
  • Non-steroidal anti- inflammatory drugs are only seldom used, and then only for pain control in the chronic arthropathy - when advanced joint damage has occurred. They are not generally used in the acute and subacute stages. It is against this background that it has surprisingly been found that factor VIII has an anti-inflammatory utility independent of its recognised blood clotting function.
  • the present invention relates to the use of factor VIII in the preparation of a pharmaceutical composition intended for introduction to the non-haemophiliac human body for the alleviation of inflammation.
  • VIII for example by a topical or intradermal route, is also effective in alleviating inflammation.
  • a pharamaceutical composition for use in local administration for the alleviation of Inflammation, comprising factor VIII and a suitable carrier therefor.
  • the local administration is carried out topically or intradermally at or near the site of inflammation.
  • the dosage employed will of course vary widely with the severity of the condition being treated and also with the method of introduction. For most applications it is envisaged that a unit dose will range from 1 to 4000 international units of factor VIII, preferably from 100 to 1500. Of course the amount actually employed depends on the weight of the patient and is preferably from 1 to 50 per kilogram of body weight.
  • the carrier will depend on the method of introduction of the factor VIII to the patient.
  • the carrier may conveniently be saline.
  • a saline carrier may again prove to be most suitable.
  • a percutaneous penetration enhancer may be included in the carrier. Drug transport through human skin has been reviewed by Barry, Molec. Aspects Med., 12, 1991, 195-241.
  • Suitable enhancers cover a wide diversity of chemical types - solvents (such as water, alcohols, dimethylsulphoxide, dimethyl- formamide and dimethylacetamide, pyrrolidones, propylene glycol), Azone and its derivatives, surfactants (anionic, cationic and non-ion1c), fatty acids and alcohols, terpenes and their derivatives, alkyl sulphoxides, phosphine oxides and sugar esters and miscellaneous materials such as urea and its long chain analogues, N, N-diethyl-m-toluamide, calcium thioglycolate and anticholinergic agents.
  • solvents such as water, alcohols, dimethylsulphoxide, dimethyl- formamide and dimethylacetamide, pyrrolidones, propylene glycol
  • surfactants anionic, cationic and non-ion1c
  • fatty acids and alcohols such as water, alcohols, dimethylsulphoxide
  • factor VIII employed in the composition is preferably human factor VIII and may be that presently available commercially with varying degrees of purity. Different commercial examples of factor VIII have been found to exhibit anti- inflammatory activity as described in the examples which follow. While presently available factor VIII 1s in general derived from blood, it 1s envisaged that factor VIII or a constituent peptide derived from factor VIII manufactured by recombinant DNA technology will be equally suitable.
  • compositions of the invention may be employed to treat a wide variety of inflammatory conditions. Such conditions include early acute inflammation, as often found in skin and mucosal inflammation, or more persistent inflammation as often affects the joint and periodontium, (especially in rheumatoid arthritis and periodontitis) . Life threatening inflammatory conditions both acute and chronic including burns and septic shock would also be included.
  • the compositions may also find use in the treatment of specific mucosal inflammatory disorders, such as colitis, for example by pessary or suppository, or even in the treatment of conditions such as atherosclerosis which are associated with inflammation.
  • factor VIII may be employed for both primary and secondary inflammatory conditions, either external, internal or mucosal .
  • I 1 represents the largest standard deviation observed in the experiment.
  • the symbol 1 in Figs. 5 to 10 represents the standard deviation for each group.
  • Example 1
  • the factor VIII evaluated in this example was freeze-dried factor VIII (heat treated : 8Y 250 - obtained from Bio Products Laboratory, Herts, U.K.).
  • Group A (Control) and Groups B, each of six male rats (Wistar, Albino, weight 180-200g) were employed in the following procedure:
  • Rats were anaesthetised by 1ntraper1toneal (i.p.) injection with 0.1 ml of 6% w/v pentobarbitone sodium (Sagatal - available from May & Baker, Essex, U.K.) using a sterile syringe and dosing needle (size 25G). After achievement of anaesthesia, the rat penile vein was exposed and injected with 0.1ml sterile saline. Immediately after i.v. injection of saline the rats were injected subcutaneously in the subplantar region of the left paw with 0.1 ml (1.5% w/v) carageenan solution in sterile saline.
  • the rats were anaesthetised with Sagatal and then received 0.1 ml of the appropriate factor VIII solution in sterile saline to deliver doses of 15 U/Kg, 7.5U/kg, or 3.75U/kg, where U represents one international unit of anti- hae ophiHc activity which is equivalent to that quantity of anti-haemophilic factor present in 1ml of normal human serum, via the penile vein.
  • U represents one international unit of anti- hae ophiHc activity which is equivalent to that quantity of anti-haemophilic factor present in 1ml of normal human serum, via the penile vein.
  • the rats were injected subcutaneously in the subplantar region of the left paw with 0.1 ml carrageenan solution.
  • Example 1 was repeated employing an alternate source of factor VIII (essentially free of Von Willebrand's Factor), i.e. Factor VIII (Monoclate - P available from Armour Pharmaceuticals Co. Ltd, U.K.
  • Factor VIII Monoclate - P available from Armour Pharmaceuticals Co. Ltd, U.K.
  • the Monoclate-P was employed in heparized sterile saline.
  • As the commercial preparation also contains a mixture of 2% albumin, 0.8% mannltol and 1.2 mM histidine, that mixture was also tested in the model.
  • the procedure outlined Example 1 was employed except that factor VIII was used at a dose of 5.5 U/rat. The results are shown in Fig.2 for factor VIII and in Fig.3 for injection of 0.1 ml. of the albumin/mannitol/histidine mixture.
  • UKg -1 factor VIII showed greater anti-inflammatory (P ⁇ 0.001) activity compared to 100 and lOUKg -1 (P ⁇ 0.01).
  • factor VIII effects were similar to those observed at 3 hours with the exception of lOUkg -1 factor VIII which showed a diminished response.
  • the effects of factor VIII at 50 and lOOUkg -1 ⁇ P 0.05 were reduced at 5 hours whilst 10 UKg -1 dose showed no activity.
  • glucose-oxidase-polyethylene glycol (GO -PEG) model shows an acute inflammatory response (initiated by H 2 0 2 ) caused by the enzyme glucose oxidase and, possibly, 0 2 ⁇ , as shown by the protective effects of the oxygen radical scavengers catalase and superoxide dis utase (SOD).
  • SOD superoxide dis utase
  • the response is exacerbated by i.v. iron dextran at 24 and 48 hours post GO injection.
  • the model consists of a vascular component assessed clinically by measuring oedema and a cellular component consisting of an inflammatory cell infiltrate.
  • the source of factor VIII used in Example 1 was employed.
  • the rats employed (6 per group A,B,C and D) were male Wistar, Albino, weight 200 - 250 g.
  • the procedure was as follows: Group A.
  • the rats anaesthetised by intraperitoneal injection with 0.1ml Sagatal ( 30 mg kg -1 using sterile syringe and dosing needle (size 25G) .
  • the rats were shaved and injected intradermally (i.d.) at two sites with 0.1ml sterile saline containing 64 ⁇ g GO-PEG (The glucose oxidase PE6 was obtained from Sigma Chemical Co., Dorset, U.K.).
  • One site was left constituting the positive control as Group A.
  • Group C This group of 6 rats was anaesthetised with Sagatal and received 64 ⁇ g GO-PEG in 0.1ml. saline at two sites. One site received 4.93U factor VIII topically in 0.1ml oil vehicle to constitute Group C.
  • Group D The other site received topically 4.93U factor VIII in 0.1ml saline vehicle. The time was noted at the beginning of injections. After inflammation induction the inflammatory index (mm) was assessed using calipers measuring the diameter of the oedematous response at time periods of 2,4,6,24 and 48 hours. Standard deviations were calculated as described in Example 1. The results are shown in Fig. 5.
  • Example 4 The procedure described in Example 4 was repeated but employing the following dosed groups of rats.
  • penetration enhancers there were employed dimethyl sulphoxide (DMSO, supplied by Sigma Chemical Co.) and propylene glycol (PG, supplied by DMSO, supplied by Sigma Chemical Co.) and propylene glycol (PG, supplied by DMSO, supplied by Sigma Chemical Co.) and propylene glycol (PG, supplied by DMSO, supplied by Sigma Chemical Co.) and propylene glycol (PG, supplied by DMSO, supplied by Sigma Chemical Co.) and propylene glycol (PG, supplied by
  • Group A Intradermal injection at three shaved sites on the lumbrosacral area with 64 ⁇ g GO-PEG in 0.1ml sterile saline. Each site received either 24.7U (approx lOOUKg -1 ), 12.35U (approx. ⁇ OUKg- 1 ) or 2.47U (approx. lOUKg "1 ) Factor VIII injected intradermal ly with GO-PEG.
  • Group B Intradermal injection at three shaved sites with 64 ⁇ g GO-PEG. These sites received either 36.05U (approx. I ⁇ OUKg- 1 ) or 24.7U (approx. 100 UKg "1 ) Factor VIII topically in 0.1ml 75% DMSO. The remaining site received topical DMSO alone.
  • Group C Intradermal injection at two shaved sites with 64 ⁇ g GO-PEG. These sites received either 12.35U (approx. 50UKG “1 ) or 2.47 U (approx. lOUKg "1 ) Factor VIII topically in 0.1ml 75% DMSO. One other site received topical DMSO alone.
  • Group D Intradermal injection at three shaved sites with 64 ⁇ g GO-PEG. These sites received either 36.05U (approx. lSOUKg “1 ) or 24.7U (approx. lOOUKg “1 ) Factor VIII topically in 0.1ml PG. The remaining site received topical PG alone.
  • Group E Intradermal injection at two shaved sites with 64 ⁇ g GO-PEG. These sites received either 12.35U (approx. 50UKg _1 ) or 2.47U (approx. lOUKg "1 ) Factor VIII topically in 0.1ml PG. One other site received topical PG alone. All Factor VIII solutions were prepared immediately before application.
  • Group B Sterile saline Group C Buffer A ( 50mM tris, 0.64M NaCl , 5mM CaCl 2 , 0.1% Tween 20, pH 7.0)
  • Monoclate P at 25 and 50 Ukg -1 was anti-inflammatory for a 2 to 4 hour period.
  • Low dose highly purified Factor VIII 25 Ukg -1 exerted inhibition at 3 and 4 hours post challenge.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Rheumatology (AREA)
  • Zoology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Le facteur de coagulation VIII est utile dans le traitement de l'inflammation et peut être utilisé dans une composition pharmaceutique destinée à être administrée par voie intradermique ou à être appliquée localement.
PCT/GB1993/000990 1992-06-01 1993-05-14 Agent anti-inflammatoire WO1993024137A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP6500281A JPH07507289A (ja) 1992-06-01 1993-05-14 抗炎症剤
EP93910198A EP0648125A1 (fr) 1992-06-01 1993-05-14 Agent anti-inflammatoire

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9211538.5 1992-06-01
GB929211538A GB9211538D0 (en) 1992-06-01 1992-06-01 Antiinflammatory agent

Publications (1)

Publication Number Publication Date
WO1993024137A1 true WO1993024137A1 (fr) 1993-12-09

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Application Number Title Priority Date Filing Date
PCT/GB1993/000990 WO1993024137A1 (fr) 1992-06-01 1993-05-14 Agent anti-inflammatoire

Country Status (6)

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EP (1) EP0648125A1 (fr)
JP (1) JPH07507289A (fr)
AU (1) AU4080193A (fr)
CA (1) CA2136646A1 (fr)
GB (1) GB9211538D0 (fr)
WO (1) WO1993024137A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001804A1 (fr) * 1993-07-05 1995-01-19 Pharmacia Ab Formulation du facteur viii de coagulation
WO1995026750A1 (fr) * 1994-03-31 1995-10-12 Pharmacia Ab Formulation pharmaceutique servant a effectuer l'administration sous-cutanee, intramusculaire ou intradermique du facteur viii ou du facteur ix
WO1996015140A1 (fr) * 1994-11-14 1996-05-23 Pharmacia Ab Procede de purification du facteur viii
WO1996015150A1 (fr) * 1994-11-14 1996-05-23 Pharmacia & Upjohn Ab Procede de purification du facteur viii

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4663837B2 (ja) * 1999-12-24 2011-04-06 一般財団法人化学及血清療法研究所 第▲ｖｉｉｉ▼因子を主成分とする血小板減少に伴う出血疾患の予防・治療用医薬組成物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 111, no. 11, 11 September 1989, Columbus, Ohio, US; abstract no. 95246g, D.A. NOE ET AL. 'ACUTE-PHASE BEHAVIOR OF FACTOR VIII PROCOAGULANT AND OTHER ACUTE-PHASE REACTANTS IN RABBITS.' page 567 ; *
JOURNAL OF ORAL SURGERY vol. 36, no. 11, November 1978, CHICAGO, ILL.,US pages 873 - 877 T. NAKAJIMA ET AL. 'TOPICAL APPLICATION OF ANTIHEMOPHILIC FACTOR AFTER DENTAL EXTRACTIONS IN HEMOPHILIC PATIENTS.' *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001804A1 (fr) * 1993-07-05 1995-01-19 Pharmacia Ab Formulation du facteur viii de coagulation
US5972885A (en) * 1993-07-05 1999-10-26 Pharmacia & Upjohn Aktiebolag Method for treatment of hemophilia by extravascular administration of factor VIII deletion derivatives
WO1995026750A1 (fr) * 1994-03-31 1995-10-12 Pharmacia Ab Formulation pharmaceutique servant a effectuer l'administration sous-cutanee, intramusculaire ou intradermique du facteur viii ou du facteur ix
US5925739A (en) * 1994-03-31 1999-07-20 Pharmacia & Upjohn Ab Pharmaceutical formulation for subcutaneous intramuscular or intradermal administration of factor VIII
WO1996015140A1 (fr) * 1994-11-14 1996-05-23 Pharmacia Ab Procede de purification du facteur viii
WO1996015150A1 (fr) * 1994-11-14 1996-05-23 Pharmacia & Upjohn Ab Procede de purification du facteur viii
JPH10509144A (ja) * 1994-11-14 1998-09-08 フアーマシア・アンド・アツプジヨン・アー・ベー ▲ｖｉｉｉ▼因子の精製方法
US5831026A (en) * 1994-11-14 1998-11-03 Pharmacia & Upjohn Ab Process for purifying factor VIII
US6005082A (en) * 1994-11-14 1999-12-21 Genetics Institute, Inc. Process for purification of factor VIII

Also Published As

Publication number Publication date
JPH07507289A (ja) 1995-08-10
CA2136646A1 (fr) 1993-12-09
AU4080193A (en) 1993-12-30
GB9211538D0 (en) 1992-07-15
EP0648125A1 (fr) 1995-04-19

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