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WO2003000344A1 - Utilisation de phospholipides pour la prevention des adherences chirurgicales - Google Patents

Utilisation de phospholipides pour la prevention des adherences chirurgicales Download PDF

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Publication number
WO2003000344A1
WO2003000344A1 PCT/GB2002/002915 GB0202915W WO03000344A1 WO 2003000344 A1 WO2003000344 A1 WO 2003000344A1 GB 0202915 W GB0202915 W GB 0202915W WO 03000344 A1 WO03000344 A1 WO 03000344A1
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WO
WIPO (PCT)
Prior art keywords
sapl
dppc
adhesions
surgery
paste
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.)
Ceased
Application number
PCT/GB2002/002915
Other languages
English (en)
Inventor
Brian Andrew Hills
Derek Woodcock
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.)
Britannia Pharmaceuticals Ltd
Original Assignee
Britannia Pharmaceuticals 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 Britannia Pharmaceuticals Ltd filed Critical Britannia Pharmaceuticals Ltd
Publication of WO2003000344A1 publication Critical patent/WO2003000344A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Definitions

  • This invention relates to the use of surface active phospholipids (SAPL) to reduce the risk of adhesions after surgery.
  • SAPL surface active phospholipids
  • SAPL respiratory distress syndrome
  • Post-surgical adhesions are the single greatest complication of many surgeries. Post- surgical adhesions are fibrous attachments between tissues that can form inside the body following surgery. Internal tissues that would normally be separate become joined by fibrous scar tissues called adhesions, as a result of the body's normal healing process. Complications from post-surgical adhesions can include chronic back or pelvic pain, intestinal obstruction and infertility. Complications can be severe enough to require re-operation, but adhesions can make subsequent surgeries more difficult to perform.
  • Postsurgical adhesions following back surgery are one of the leading causes of recurrent back pain. It is widely recognised that postsurgical adhesions play a major role in poor patient outcome following surgery, or failed back syndrome. Failed back surgery syndrome is seen in 10-40 percent of patients who undergo back surgery. Postsurgical adhesions are also a significant problem after tendon surgery. Following tendon surgery, adhesions can inhibit the tendons' ability to glide, thereby limiting motion. In peripheral nerve surgery (e.g. carpal tunnel syndrome) adhesions may cause tethering and compression of nerve roots, leading to pain and loss of function.
  • peripheral nerve surgery e.g. carpal tunnel syndrome
  • WO 91/12026 discloses a method of reducing surgical adhesions by means of coating tissue surfaces with a phospholipid, preferably lecithin, in suspension or solution in an inert carrier, such as for example, water, saline, or propylene glycol, or mixtures thereof.
  • a phospholipid preferably lecithin
  • WO 99/51244 (Britannia) describes the use of powdered phosphohpids to prevent surgical adhesions.
  • US Patent 6133249 (McNaught Medical) describes a method of lubricating mammalian joints using a liquid composition comprising of phosphohpids dispersed in propylene glycol.
  • the present invention is based on the surprising discovery that liquid, semi-liquid or pasty compositions of certain phosphohpids dispersed in a physiologically acceptable carrier are equal to or better than the compositions of WO 99/51244 in reducing the risk of surgical adhesions.
  • the powder compositions of WO 99/51244 have the advantage that they are easily administered into body cavities such as the peritoneum by simple "puffers” or other gas stream delivery devices.
  • the advantage of the liquid, and especially the paste, compositions of this invention is that the surgeon can apply the composition as a directed, substantially non-mobile, "slug" to be spread manually using a gloved finger, or apply compositions manually using a gloved finger directly to the desired site, and immediately check visually that the intended area is covered. This is especially advantageous in open surgery, such as on flexor tendons of the hand, or spinal surgery, or peripheral nerve surgery.
  • the present invention provides a method of reducing the risk of surgical adhesions which comprises applying a composition comprising a SAPL to surfaces adjacent an incision during surgery, characterised in that the SAPL is DPPPC, or a mixture of DPPC and PG, or DPPG, dispersed in a physiologically acceptable nonvolatile earner liquid.
  • the present invention provides the use of a SAPL to prepare a medicament for reducing the risk of adhesions following surgery, characterised in that the SAPL is DPPC or a mixture of DPPC and PG or DPPG, dispersed in a physiologically acceptable non- volatile carrier liquid.
  • the carrier liquid is one which is substantially non- volatile or only sparingly volatile at body temperature.
  • Suitable carriers include physiologically acceptable glycols, especially propylene glycol, polyethylene glycols and glycerol.
  • the SAPL may be dispersed in the carrier so as to form liquid, semi-liquid or pasty compositions.
  • Semi-liquid or paste compositions are preferred because they can be applied and spread by a surgeon using a gloved finger, and are particularly suitable for use in open surgery where the surfaces abraded by surgery are well defined and easily accessible.
  • the Figure shows the sites for administration of SAPL compositions of this invention during tendon surgery.
  • Pastes can be prepared by simply dispersing a SAPL powder in the carrier, or when appropriate dissolving the SAPL in heated carrier and allowing the SAPL to precipitate as a powder on cooling, preferably at a loading that will form a paste.
  • a thick paste of the SAPL and carrier is ideal to apply to open wounds to which it adheres well. It enables a much higher concentration of the SAPL to be applied to the incision site.
  • Propylene glycol is especially effective as a carrier because at room temperature SAPL may be dispersed in it as a paste, but at body temperature a mobile solution is formed.
  • a paste of 400 mg/ml of DPPC in propylene glycol has been shown to give 93% protection against adhesions in surgical tests, as described in the experiments below.
  • the pasty compositions of this invention may be applied to surgical sites in conjunction with the powder compositions of WO 99/51244 (Britannia), the latter being used to coat and protect more peripheral areas.
  • compositions based on DPPC alone have out-performed compositions based on DPPC/PG which have been especially effective in the situations covered by the patent applications acknowledged above.
  • pastes prepared by dispersing coarse SAPL particles are more effective than when using fine SAPL particles, such as around 5 ⁇ m in size.
  • the powdered SAPL may have a particle size in the range of 0.5 to 1 OO ⁇ m, more suitably of 0.5 to 20 ⁇ m, preferably 0.5 to lO ⁇ m.
  • compositions may also include preservatives where appropriate, such as fungicides, bactericides and anti-oxidants.
  • the solutions/dispersions/pastes of the present invention are especially suitable for surgical procedures where there is a potential for adhesion in areas that are difficult to access by powder sprays.
  • the Figure of the accompanying drawing shows a situation arising in tendon surgery where both a tendon (1) and its sheath (2) are cut through and require stitching back together.
  • a solution dispersion or paste composition of the invention may be introduced between the tendon and the sheath to prevent adhesions that impair mobility.
  • spinal surgery where the spinal cord is damaged within the spinal cord sheath, and with surgery on other nerves.
  • the viscosity of the solution/dispersion/paste may be varied to suit specific surgical sites or the preferences of individual surgeons. For example, in difficult to access areas (e.g. flexor tendons) a relatively low viscosity fluid may be used, whereas at a site where gravity will effect its distribution a higher viscosity composition may be preferred. Temperature will play a part in the viscosity of the compositions. Typically a range of 0.1 -10 000 cP may be considered. However, formulations outside this range may be required for specific applications at the discretion of the surgeon.
  • the phospholipid mixture (Pumactant) was supplied by Britannia Pharmaceuticals Ltd, Redhill, U.K.
  • Coarse Pumactant is a dry powder of lO ⁇ m particle size of a mixture of 70% DPPC and 30% egg PG co-precipitated from solution and, therefore, intimately mixed. Fine Pumactant has the same composition but has a particle size of 5 ⁇ m.
  • the DPPC is La - DPPC, which is the optical isomer which occurs naturally and is digested by phospholipases.
  • La - DPPC was supplied by Lipoid GmbH, Ludwigshafen, Germany, who also supplied the dipalmitoyl phosphatidylglycerol (DPPG).
  • the solvent used was clinical grade propylene glycol and all solutions were made to a concentration of 400mg/mL of total phospholipid (i.e. DPPC + DPPG) per mL at 60°C which reverted to pastes at room temperature.
  • the compositions used were DPPC alone, DPPG alone, 7:3 DPPC:DPPG and 1:1 DPPC:DPPG.
  • mice did not have any further intervention except as described above and provided the controls (Group I).
  • a 1mm I.D. polyethylene tube was placed intraperitoneally adjacent to the caecal intraperitoneal defect and exteriorised through a subcutaneous tunnel.
  • Ten of these rabbits (Group IT) received an intraperitoneal puff of Fine ALEC (lOOmg) via a purpose-built device prior to abdominal closure.
  • Another 10 animals (Group III) received Coarse Pumactant powder, i.e. the same material as used in a previous study (21).
  • an adhesion is defined as any connection between bowel and the healed 5 x 1cm parietal peritoneum marked by the silk sutures. Adhesions formed occasionally on the undersurface of the wound, but were not analysed. Treatment was performed by one surgeon who also performed the postmortems.
  • Fine Pumactant was less effective than the Coarse Pumactant, the protection rate of 37% failing to reach 95% significance over controls.
  • Fine Pumactant (5 ⁇ m) were surprising in so far as a larger surface area of DPPC/PG might have been expected to prove more protective than its Coarse (lO ⁇ m) competitor.
  • the lower efficacy could be attributed to the use of a co-powder mixture of DPPC and Egg PG as opposed to Coarse Pumactant in which co- precipitation from an organic solvent ensures mixing at the molecular level.
  • Another factor might be wider dispersion of the same dose of powder, leaving less in the test area. Wide dispersion could prove a benefit in cases of abdominal trauma where bile salts escaping from the gut could have stripped the peritoneal cavity of its protective lining of SAPL, just as they can in the stomach (Hills BA (1989). Oligolamellar lubrication of joints by surface-active phospholipid. J Rheumatol. 16: 82-91).
  • the DPPC paste offers an exciting and possibly more efficient means of preventing surgical adhesions. It is very simple to apply either by a hypodermic syringe without a needle or by simply smearing on the material with a gloved finger or any other mode of application which the individual surgeon may prefer.
  • the DPPC paste is easy to autoclave (20 mins. at 121°C) in its container which can be a vial or hypodermic syringe. It can also be sterilised in its container by ⁇ -irradiation.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition de phospholipides tensioactifs (SAPL) sous la forme d'une solution, d'une dispersion ou, plus particulièrement, d'une pâte comprenant de la DPPC (dipalmitoylphosphatidylcholine). Cette composition permet de réduire le risque d'adhérences après une chirurgie, notamment dans le cas d'une chirurgie ouverte pratiquée sur la colonne vertébrale, les tendons ou les nerfs périphériques.
PCT/GB2002/002915 2001-06-25 2002-06-25 Utilisation de phospholipides pour la prevention des adherences chirurgicales Ceased WO2003000344A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0115505.0 2001-06-25
GBGB0115505.0A GB0115505D0 (en) 2001-06-25 2001-06-25 Prevention of surgical adhesions

Publications (1)

Publication Number Publication Date
WO2003000344A1 true WO2003000344A1 (fr) 2003-01-03

Family

ID=9917312

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2002/002915 Ceased WO2003000344A1 (fr) 2001-06-25 2002-06-25 Utilisation de phospholipides pour la prevention des adherences chirurgicales

Country Status (2)

Country Link
GB (1) GB0115505D0 (fr)
WO (1) WO2003000344A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006056800A1 (fr) * 2004-11-26 2006-06-01 Britannia Pharmaceuticals Ltd. Utilisation de phospholipides pour la cicatrisation de plaies
WO2006125970A3 (fr) * 2005-05-23 2007-03-01 Britannia Pharmaceuticals Ltd Phospholipides a utiliser pour traiter un trouble inflammatoire allergique
US8414907B2 (en) 2005-04-28 2013-04-09 Warsaw Orthopedic, Inc. Coatings on medical implants to guide soft tissue healing
US9119901B2 (en) 2005-04-28 2015-09-01 Warsaw Orthopedic, Inc. Surface treatments for promoting selective tissue attachment to medical impants

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989001777A1 (fr) * 1987-08-25 1989-03-09 Macnaught Pty. Limited Composition lubrifiante pour le traitement d'affections rhumatismales
WO1991012026A1 (fr) * 1990-02-14 1991-08-22 Macnaught Pty Limited Procede servant a reduire les phenomenes post-operatoires d'adhesions entre tissus
WO1998053800A1 (fr) * 1997-05-29 1998-12-03 Applied Biotechnologies, Inc. Compositions et procedes destines a empecher les adherences
WO1999051244A1 (fr) * 1998-04-03 1999-10-14 Britannia Pharmaceuticals Limited Utilisation de phospholipides pour la fabrication d'un medicament servant a prevenir les adhesions
WO1999058168A1 (fr) * 1998-05-13 1999-11-18 Ml Laboratories Plc Composition a base de dextrine pour la prevention des adherences chirurgicales
US6133249A (en) * 1995-12-19 2000-10-17 Macnaught Medical Pty Limited Phospholipid and propylene glycol based lubricant
WO2002017878A1 (fr) * 2000-09-01 2002-03-07 Marcus Larsson Compositions tensioactives pulmonaires a dilatation dynamique

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989001777A1 (fr) * 1987-08-25 1989-03-09 Macnaught Pty. Limited Composition lubrifiante pour le traitement d'affections rhumatismales
WO1991012026A1 (fr) * 1990-02-14 1991-08-22 Macnaught Pty Limited Procede servant a reduire les phenomenes post-operatoires d'adhesions entre tissus
US6133249A (en) * 1995-12-19 2000-10-17 Macnaught Medical Pty Limited Phospholipid and propylene glycol based lubricant
WO1998053800A1 (fr) * 1997-05-29 1998-12-03 Applied Biotechnologies, Inc. Compositions et procedes destines a empecher les adherences
WO1999051244A1 (fr) * 1998-04-03 1999-10-14 Britannia Pharmaceuticals Limited Utilisation de phospholipides pour la fabrication d'un medicament servant a prevenir les adhesions
WO1999058168A1 (fr) * 1998-05-13 1999-11-18 Ml Laboratories Plc Composition a base de dextrine pour la prevention des adherences chirurgicales
WO2002017878A1 (fr) * 2000-09-01 2002-03-07 Marcus Larsson Compositions tensioactives pulmonaires a dilatation dynamique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BHANDARKAR D S ET AL: "Spray of phospholipid powder reduces peritoneal adhesions in rabbits.", THE AUSTRALIAN AND NEW ZEALAND JOURNAL OF SURGERY. AUSTRALIA MAY 1999, vol. 69, no. 5, May 1999 (1999-05-01), pages 388 - 390, XP001095870, ISSN: 0004-8682 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006056800A1 (fr) * 2004-11-26 2006-06-01 Britannia Pharmaceuticals Ltd. Utilisation de phospholipides pour la cicatrisation de plaies
US8414907B2 (en) 2005-04-28 2013-04-09 Warsaw Orthopedic, Inc. Coatings on medical implants to guide soft tissue healing
US9119901B2 (en) 2005-04-28 2015-09-01 Warsaw Orthopedic, Inc. Surface treatments for promoting selective tissue attachment to medical impants
WO2006125970A3 (fr) * 2005-05-23 2007-03-01 Britannia Pharmaceuticals Ltd Phospholipides a utiliser pour traiter un trouble inflammatoire allergique

Also Published As

Publication number Publication date
GB0115505D0 (en) 2001-08-15

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