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WO1998053800A1 - Compositions et procedes destines a empecher les adherences - Google Patents

Compositions et procedes destines a empecher les adherences Download PDF

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Publication number
WO1998053800A1
WO1998053800A1 PCT/US1998/009903 US9809903W WO9853800A1 WO 1998053800 A1 WO1998053800 A1 WO 1998053800A1 US 9809903 W US9809903 W US 9809903W WO 9853800 A1 WO9853800 A1 WO 9853800A1
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Prior art keywords
composition
phospholipid
gel
group
emulsion
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PCT/US1998/009903
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English (en)
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WO1998053800A8 (fr
Inventor
Michael V. Koroly
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Applied Biotechnologies, Inc.
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Application filed by Applied Biotechnologies, Inc. filed Critical Applied Biotechnologies, Inc.
Priority to AU76857/98A priority Critical patent/AU7685798A/en
Publication of WO1998053800A1 publication Critical patent/WO1998053800A1/fr
Publication of WO1998053800A8 publication Critical patent/WO1998053800A8/fr

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    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers

Definitions

  • the present invention generally relates to compositions and methods for preventing or treating spontaneous or post-operative adhesion formation and fibrosis between biological tissue surfaces.
  • Typical causes of adhesion formation include rough surgical technique or intervention, fulguration, abrasion, localized infection, cautery, excessive bleeding, drying, anti-osmotic lavage, non-specific trauma, endometriosis, peritoneal dialysis, radiation and the like.
  • the biological causes of adhesion formation can be attributed to decreased lubrication, decreased tissue plasminogen activator and increased phospholipase activity.
  • mopping and suctioning of the blood and fluids may wipe away or remove endogenous phospholipids and cause trauma and micro-abrasions that lead to drying out or injury to the parietal and serosal peritoneum (decreased lubrication, decreased tissue plasminogen activator and increased phospholipase activity), thereby leading to adhesion formation.
  • Tissue plasminogen activator is a substance that plays a role in the lysis of thrombi. It is known that t-PN moderates fibrin deposition and formation by breaking down the fibrin deposits before they can become infiltrated with fibroblasts.
  • the pathophysiological stimulus for the ischemia is a disruption of the intrinsic peritoneal fibrinolytic system, which both controls t-PN production and activates alpha-phospholipase N2.
  • fibrin is deposited at the site of an injury and forms thin, filmy adhesions within 3 hours of injury but spontaneously resolve after about 3-5 days.
  • t-PN formation originates in the mesothelium to interact with the fibrin exudate.
  • Deficiencies in normal t-PN activity can allow thin filmy adhesions to become thick, fibrous and vascularized.
  • Activation of the normally present, but inactive, alpha-phospholipase-N2 can cause hydrolysis of the phospholipid lubricant and protective coating.
  • disruptions in the mesothelium often result in fibrosis, adhesion formation and/or pain. It appears that adhesions formed by this disruption or damage are not dependent on either the amount or type of trauma.
  • Lavage infusion treatments using synthetic recombinant t-PA has been shown to be useful in reducing post-operative surgical adhesion formation, but synthetic recombinant t-PA is prohibitively expensive and may cause systemic side effects. It has been shown to interfere with other tissue healing so as to result in poor healing and weakened scars at anastomosis sites, which can result in rupture, spillage and peritonitis.
  • concentration of the agent required to prevent or modify the formation of abdominal adhesions causes a significant reduction in the wound hydroxyproline concentration during the early healing phase, indicating significant reduction of the collagen content of the scar with subsequent loss of wound tensile strength.
  • heparin has been known to actively reduced adhesions in human and animal studies, however, the dosage required to reduce adhesion formation typically results in undesirable hemorrhagic diathesis.
  • dextran has not satisfactorily demonstrated the ability to consistently decrease adhesion formation, and typically causes many side effects, including ascites, pleural effusion, edema of the legs and vulva and even anaphylactic shock.
  • corticosteroids have been used to prevent adhesion formation, it is believed that peritoneal surgery initiates an inflammatory response that simply overwhelms the therapeutic response to corticosteroids at studied doses.
  • Ar'Rajab A et al., "Phosphatidylcholine Prevents Postoperative Peritoneal Adhesions: An Experimental Study in the Rat," J. Sure. Res., 50:212-215 (1991) discloses the use of Lipostabil TM ( ⁇ atterman, GmbH, Cologne) in rats. Because Ar'Rajab does not disclose the use of sonication treatment or emulsifying/dispersing agents, it appears that they apparently used LipostabilTM in liquid form.
  • LipostabilTM is a non-aqueous extract of naturally occurring lecithin that contains various non- isomer specific phospholipids (i.e., in addition to phosphatidylcholine ), free fatty acids, cholesterol, other chemicals and impurities.
  • the present invention is based on the unexpected discovery that certain phospholipids and synthetic derivatives are useful for preventing adhesion formation. Accordingly, it is a primary object of the present invention to provide a composition and method for inhibiting and preventing the formation and/or reformation of adhesions or fibrosis in mammals.
  • the inventive composition may comprise an admixture of isolated, exogenous, purified and/or synthetic phospholipids, preferably having a positive net charge. Further, by applying a composition of exogenous, synthetic, positively charged, isomer specific, phospholipids (phosphatidylcholine and phosphatidylglycerol) to damaged tissue, natural organ tissue surfaces remain lubricated and tend not to become adherent to adjacent tissue.
  • the isomer- specific (D-isomer) inventive composition possesses both lubricating and properties resistant to alpha-phospholipase-A2.
  • the D-isomer of Phosphatidylcholine may also have inherent t-PA properties without the presence of t-PA.
  • the L-isomer is not resistant to alpha-phospholipase A2 and further more its degradation product can be lethal.
  • the present invention comprises a method for preventing adhesions which comprises replacing or replenishing natural phospholipids normally found in the peritoneal endothelium and underlying mesothelium of damaged tissues via directly or indirectly administering the isomer-specific phospholipid compositions of the present invention via any suitable route, such as lavage, endoscopic administration or topical application.
  • site of surgical trauma shall mean tissue that has been injured in any way including, without limitation, tissue sites that have undergone incision, excision, drying, suturing, fulguration, abrasion, cauterization, contusion, manipulation, laceration, anastomosis, curettage, orthopedic surgery, cardiovascular surgery, neurosurgery, plastic, reconstructive surgery and the like.
  • the term shall also mean tissue that is adjacent to the injured tissue.
  • the term "site of other trauma” shall mean intra-pelvic implants of endometriosis of any type or location, as well as clubbing, occlusion or adherence of the fallopian tubes or other tissues inadvertently manipulated during surgery.
  • solution shall mean aqueous solution, emulsion, micro-emulsion or any other liquid to which a specific phospholipid has been added.
  • gel shall mean a hydrogel that is thermo-reversible or thermo-irreversible, ionic or nonionic, and that serves as a carrier for a solution, emulsion, micro-emulsion or any other liquid to which a specific phospholipid compound has been added. Endogenous phospholipids have been to shown to have numerous purposes.
  • One such purpose is to act as a surfactant that allows internal organs, such as the large and small bowel, omentum, uterus, tubes, ovaries, appendix, gall bladder and sigmoid colon to move freely relative to each other.
  • internal organs such as the large and small bowel, omentum, uterus, tubes, ovaries, appendix, gall bladder and sigmoid colon
  • the monolayer coating of phospholipids acts as a lubricant.
  • certain endogenous phospholipids fill unoccupied spaces between internal organs and coat the outside surface of internal organs with a strongly adherent hydrophobic film.
  • phospholipids are synthesized in the mesothelium and secreted by the serosal or parietal peritoneal epithelium. Damage to these cell layers by trauma, infection, surgical intervention, peritonitis, endometriosis, radiation and the like can adversely affect the ability of the mesothelium to secrete phospholipids and t-PN. Alternatively, such damage can activate the alpha-phospholipase-A2 enzyme, thereby leading to additional adhesion formation. Moreover, phospholipids are capable of adhering to the serosal and parietal walls of the mesothelium and/or endothelium in a monolayer densely packed film (depending on the concentration).
  • compositions of the present invention may be used without fear of intra-operative hemorrhaging.
  • replacement or replenishment of positively charged phospholipids during or following surgery or trauma to the peritoneum and mesothelium no matter what origin, promotes normal lubrication and healing without adhesion formation.
  • the mechanism of action for the compositions of the present invention is believed to be replacement of the surfactant/lubricate properties for specific naturally occurring phospholipids, followed by activation of t-PA activity and or inactivation of alpha-phospholipase- A2 enzyme. It is believed that some positively charged phospholipids, especially phosphatidylcholine, have their own t-PA properties and that negatively charged phospholipids can have anti t-PN properties. In addition, that some fragmented phosphatidylcholines are biologically active and can destroy the activity of phospholipase A2, thereby indirectly increasing the level of t-PA through the receptor for platelet activating factor (PAF).
  • PAF platelet activating factor
  • D-isomer of phosphatidylcholine is resistant to alpha-phospholipase-A2.
  • Free zinc ions have been demonstrated to stabilize cell lysosomal membranes, which are restricted to the surface of the peritoneal membrane and decrease the amount of fibrin allowed to leak through cells and gather as exudate.
  • Zinc also has the ability to directly inhibit the ability of phospholipase A2 enzymes to function.
  • a zinc salt may be added.
  • positively charged exogenous phospholipids are formulated as an aqueous adhesion-preventative micro emulsion composition that is capable of providing a long lasting lubricating film and/or protective coating to damaged tissues at the site of surgical or other trauma.
  • the invention restores or replenishes phospholipids and t-PN production/activity to damaged mesothelial cells while being resistant to alpha-phospholipase N2, which can cause hydrolysis of the existing or remaining phospholipid layer. Because o
  • phospholipids are not water soluble, the composition must be manipulated to form an emulsion or micellular solution.
  • compositions of the present invention may be used during or after all types of surgery in which adhesion formation can be a complication.
  • the phospholipids used in the compositions of the present invention may be extracted or obtained from any suitable source, including, without limitation, lecithin, chicken eggs, and soybean materials.
  • the compositions comprise an aqueous solution/emulsion of a derivative or analog, including enantiomers, diastereomers, hydrates, salts or solvents thereof, of a phospholipid selected from the group consisting of phosphatidylglycerol, phosphatidylcholine, phosphatidylinositol, phosphatidylserine and phosphatidylethanolamine.
  • negatively charged phospholipids such as phosphatidylinositol and phosphatidylserine
  • PAL- 1 an inhibitor of t-PA
  • negatively charged phospholipids such as phosphatidylinositol and phosphatidylserine
  • neutral phospholipids such as phosphatidylethanolamine may be used in accordance with the principles of the present invention, they are less preferred. It is noted that if naturally derived lecithin is used, it should be treated/prepared so that the amount or effect of negatively charged phospholipids contained therein is eliminated or substantially reduced and the amount of the D isomer form increased. With the use of lecithin, it is also preferred that other contaminants including, but not limited to, cholesterol and free fatty acids are eliminated.
  • the inventive composition may comprise a racemic isomeric mixture (50/50) of D- and L-forms of suitable phospholipids.
  • a composition substantially containing positively charged D-isomer forms of a phospholipids is preferred over L-isomer forms, which appear to be vulnerable to the alpha phospholipase-A2 enzyme and lethal.
  • preferred compositions include, without limitation, compositions that comprise about 0.001 % to about 100% of D-alpha or D-L alpha-phosphatidylcholine and about
  • phosphatidylglycerol 0.005% to about 50% of phosphatidylglycerol, more preferably, about 0.01% to about 50.0% of D-alpha-phosphatidylcholine and about 0.05% to about 50.0% of phosphatidylglycerol.
  • the compositions of the present invention may be directly applied to the surgical field.
  • the inventive composition may be intra-operatively administered to a wound to stabilize the peritoneal endothelium, protect the mesothelial cells and to prevent fibrin leaking and early adhesion formation.
  • bowel packs and retractors are used which may inadvertently damage or dry other abdominal tissues not in the direct field of the intended procedure.
  • the inventive composition may be formulated with an irrigation solution, viscous or thixotropic solution, gel, foam ointment, emulsion or aerosol.
  • compositions of the present invention may be introduced into the peritoneal cavity via endoscopic attachments in either a solution or gel form and be applied directly onto or directly adjacent to the diseased tissue, peritoneal, mesothelium etc.
  • inventive compositions may also be applied directly to adjacent tissue via the scope or its accessories. Adequate lavage and irrigation with compositions of the present invention will serve to re-moisten and coat tissues that may be either adjacent or distant, but damaged during this surgical procedure.
  • the compositions of the present invention may be administered by any convenient route or means to prevent the adhesion formation at sites of surgical or other trauma.
  • compositions of the present invention may be administered in any acceptable delivery formulation that is useful for maintaining local effective concentration levels of the phospholipids in the inventive compositions at the site of surgical or other trauma.
  • the inventive compositions may be applied and replenished via an indwelling catheter such as a peritoneal catheter over a suitable amount of time (a few hours to a few days) to insure that an adhesion preventing amount of active ingredient stays within the body cavity.
  • indwelling catheter such as a peritoneal catheter
  • suitable amount of time a few hours to a few days
  • administration routes include, without limitation, oral, intravenous, direct topical, irrigation or lavage.
  • the inventive compositions are topically and non-systemically administered to the surface of damaged tissues via a single dose prior to closing the surgical field.
  • compositions of the present invention are applied not only to the affected tissue, but also to locally adjacent or neighboring tissues, as well. If necessary, compositions of the present invention may also be proximally or distally applied relative to the site or trauma, e.g., intra-peritoneally, to allow natural migration of fluids to occur in response to peristaltic contractions of the intestines.
  • the inventive composition may be administered in an effective amount and for a sufficient period of time to inhibit the formation of surgical adhesions.
  • the compositions are administered before significant healing or adhesion formation has begun.
  • effective treatment of tissue adjacent to, or near, affected tissues may be obtained by topical administration of the phospholipid compositions via an endoscope such as a laparoscope, cystoscope, arthroscope, mediastinoscope, colonoscope, etc., in a solution or gel.
  • the inventive composition may be formulated in any suitable way using any suitable carrier, so long as the phospholipid-based formulation concentration is sufficient to prevent adhesion formation and/or replenish the body's own contribution of phospholipids.
  • Preferred examples include, but are not limited to, a solution, gel, emulsion, micro-emulsion, salve, cream, micellular suspension, film, aerosol or isotonic irrigation or lavage solution, etc. Because neither lecithin nor its component phospholipids are water-soluble, it must be treated, e.g., chemically, prior to being utilized in an aqueous vehicle. For instance, co-surfactants may be required to form a micro-emulsion.
  • dispersing agents may be added to form a true surfactant emulsion that easily froths, bubbles and/or foams. Homogemzation, sonication or the addition of a spreading, wetting or triturating agent may be used to form the emulsion.
  • the addition of such agents to phospholipid compositions for anti adhesion indications is considered to be a necessity that has heretofore been unknown or unrecognized.
  • Sterilization of the formulation may be accomplished using any conventional method including, without limitation, aseptic preservation, filtration, exposure to gamma radiation, autoclaving and the like.
  • the phospholipid compositions are formulated into a water-soluble gel and packaged in a tube, hypodermic syringe or other suitable device for direct or extruded delivery to damaged tissue.
  • a gel can be constructed to provide sustained release of active ingredient by anyone skilled in the art.
  • the gel may be thermo-reversible or thermo-irreversible and may also be ionic or nonionic.
  • phospholipids may be emulsified, homogenized, micellized or used in liposome form so as to be uniformly distributed in the gel.
  • the viscosity of the gel should be pliant at body temperature and capable of coating traumatized tissues.
  • the mixture may be in the form of a liposome or micellular medicament or may be freeze dried so as to be reconstituted immediately prior to use.
  • the exact mode of administration is not critical so long as the adhesion-preventative composition can be administered in direct or adjacent contact to the injured tissue to achieve the desired effect.
  • an effective dose for topically applying the inventive composition is normally expressed in terms of concentration of the drug in the carrier (% weight/volume) coupled with the number of times per day the drug is applied.
  • the effective dose for any given application will depend upon factors such as the nature of the phospholipid or phospholipid mixture used, nature of the vehicle or carrier, the nature and/or site of the tissue to be treated, the type of trauma or lesion and the mode of delivery, e.g., one-time delivery via a lavage or sustained release vehicle, continuous delivery via indwelling catheter, or direct topical application either manually or via an endoscopic device.
  • an effective dose of a solution containing phosphatidylcholine which replicates the physiologic concentration levels in the peritoneal cavity of the human animal, is at least about 1.0 mg/ml. Minimal concentrations exhibit anti-adhesion activity in most cases. Higher or lower amounts and concentrations of the phospholipids in the compositions of the present invention may be appropriately used as readily determined by one skilled in the art.
  • composition and method of the present invention will be further illustrated in the following, non-limiting Examples.
  • the Examples are illustrative of preferred embodiments only and do not limit the claimed invention regarding the materials, conditions, process parameters and the like recited herein. All amounts are in weight/volume percent unless otherwise noted.
  • An irrigation/lavage solution containing D-Nlpha phosphatidylcholine dipalmitoyl and dispersing agents in an iso-osmotic and/or isotonic saline solution is sterilized and pH buffered with appropiate buffers to a physiologic pH of about 7.4.
  • the solution is applied to the surgical field to keep exposed tissues moist and rinse away blood, pus, fibrin deposits, etc.
  • a final irrigation with the solution is instilled into the surgical field and the surgical wound. It is noted that excess solution may or may not be removed prior to closing of the surgical incision.
  • the solution is allowed to remain in the surgical field thereby providing a protective covering and lubricating agent to the exposed organs.
  • EXAMPLE 2 A gel, ointment or solution containing appropriately dispersed,emulsified, or micellized D-alpha phosphatidylcholine is directly or indirectly applied via an endoscope by extrusion or other methods during endoscopic surgery to areas affected directly or indirectly during the endoscopic surgery so as to provide a protective and lubricating covering to the affected tissues while contributing its anti-adhesion formation properties.
  • EXAMPLE 3 A gel, ointment, solution, foam, aerosol of other suitable method containing appropriately dispersed or emulsified D- Alpha Phosphatidylcholine is directly or indirectly applied by topical route to an open wound such as a of laminectomy surgery, ophthalmologic surgery, burn, incision, excision, etc. so as to provide a protective and lubricating covering to the affected tissues while contributing its anti adhesion formation properties.
  • N surfactant solution of Tyloxapol-saline was first prepared by dissolving 250 mg of Tyloxapol (Sigma Corporation) in 0.1 ⁇ sodium chloride to produce a total volume of 250 ml. Then, 200 mg of D-alpha-phosphatidylcholine dipalmitoyl (DPPC) (Sigma Corporation) and 45 mg of hexadecanol (Sigma) were combined in powder form and placed in a screw cap tube (Composition B). N 30 ml sample of Composition A was added to the powdery Composition B, warmed to 60° C and then vigorously mixed to obtain a uniformly milky suspension solution (adhesion preventative composition).
  • DPPC D-alpha-phosphatidylcholine dipalmitoyl
  • hexadecanol Sigma
  • Nliquots of 1.5 ml each (10-mg D-Alpha-DPPC) can be immediately used, for example, as a dosage for intra-peritoneal infusions.
  • the adhesion preventative composition can also be immediately frozen or freeze-dried for long-term storage using routine lyophilizing techniques. If the container is sealed while under vacuum, then the resulting lyophilized product can be stored in vials at room temperature in its powder form. For longer storage periods, the lyophilized product can be stored at 4° C until use, at which time, it must be reconstituted to its aqueous form prior to utilization.
  • a 250 ml aliquot of a first composition is prepared by mixing about 225 mg of NaCl, 250 mg (0.233 ml) of a surfactant (tyloxapol > 99% pure (Sigma)) and 250 cc of sterile water (Baxter).
  • a 60 ml aliquot of a second composition is prepared by mixing about 90 mg of cetyl alcohol (Sigma >90% pure), which has been triturated to a fine dry power, and about 810 mg of D-alpha dipalmitoyl phosphatidylcholine (D- alpha-DPPC) powder (Sigma >98% pure). Then, the first and second compositions are combined to form about 60 ml of a final composition.
  • the final composition is prepared by mixing about 60 ml of the first composition with about 900 mg of the second composition at a temperature of about 70° C for about 20 minutes.
  • the resultant 60 ml aliquot is equivalent to about 13.8 D-alpha-DPPC per ml, of which about 1.48 ml may be used for a 20 mg dose.
  • This Example shows a manner by which a stored, lyophilized, powdery, adhesion-preventative composition surfactant, which is made according to Example 4, can be reconstituted prior to utilization.
  • a dose of distilled or sterile water for injection USP was drawn into a syringe with a standard, sterile, hypodermic needle.
  • the vial cap was penetrated with the needle so that the water was drawn into the hypodermic needle under the vacuum of the vial.
  • the surfactant spontaneously dispersed into solution to form a milky colored adhesion-preventative aqueous composition, which may be used.
  • a dose of 10-mg DPPC was used in rats as an intra peritoneal lavage to achieve desired results according to the principles of the present invention.
  • the surfactant solution was reconstituted prior to administration as a lavage for an affected peritoneal or denuded surgical surface. It must form a stable film that lowers surface tension to very low values (10 milliNewton/meter or less).
  • a relatively simple in vitro test has been devised to test for natural surfactants in amniotic fluid. See Clements, New England Journal of Medicine, Vol. 286, pages 1007-1081 (1972). This test is generally known as the "Shake Test.” While relatively simple to apply, the Shake Test can be used to assay the desired properties required by the inventive surfactant composition. For example, a carefully mixed sample of the composition containing approximately 400 micrograms (about 25 micro liters) is placed in a 20-ml culture tube. Two (2) ml of normal saline is then added and the tube is tightly capped and immersed in a water bath for 5 minutes at 37° C to sufficiently equilibrate the temperature of the sample with the temperature of the bath.
  • the tube is then shaken vigorously by hand for 15 seconds and replaced in the water bath to settle.
  • the presence of copious foam at the meniscus will indicate that the surfactant had been adsorbed into the saline and had created a surface film thereon. If the bubbles are relatively small and remain for 15 minutes or more, then the test confirms that the surface film is stable and will maintain a low surface tension.
  • D-alpha-DPPC greater than 98% pure, Sigma Corporation
  • 1.5 mg/ml of hexadecanol greater than 99% pure, Sigma Corporation
  • the adhesion-preventative composition lowered aqueous surface tension rapidly and produced a surface tension less than 10 milliNewtons per meter.
  • the surface films created by the adhesion-preventative composition were stable after more than eight days after undergoing the Shake Test described above in Example 6.
  • the resultant composition was then used in the following in vivo tests employing 30 Sprague-Dawley rats divided into 2 groups (Groups A and B). .
  • Groups A and B received a laparotomy incision under clean, anesthetized conditions.
  • the cecum of each rat was grasped and vigorously abraded with a dry sponge, then scraped with a scalpel. Five (5) drops of 95% ethyl alcohol were applied to the manipulated cecum to further enhance an inflammatory response.
  • Control Group A received 1.5 ml of normal saline irrigation prior to closure.
  • Group B received a 1.5 ml irrigation of the composition of Example 4 (10 mg D- Alpha-DPPC).
  • the laparotomy incision of both groups was closed with 4-0 chromic suture (Ethicon) and sterile skin staples.
  • the animals in both Groups were maintained under routine conditions, e.g., fed copious food and water. There were no deaths in either group.
  • the test animals were sacrificed and necropsy was performed utilizing the grading criteria described in Table 1 below.
  • Group A Control
  • Group B Inventive Composition

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Abstract

Composition et méthode permettant de prévenir, réduire ou éliminer la fibrose ou la formation ou reformation d'adhérences chez des mammifères à la suite de lésions chirurgicales, traumatiques, organiques ou de radiothérapie subies par des organes internes, la membrane péritonéale et d'autres espaces corporels. Ladite composition contient des phospholipides qui peuvent être sélectionnés dans le groupe constitué par phosphatidylglycérol, phosphatidylinositol ou phosphatidylsérine, phosphatidylcholine et phosphatidyléthanolamine. La présente invention concerne également une composition et des méthodes permettant d'inhiber la fibrose, la cicatrisation et la formation d'adhérences, du fait que ladite composition permet la restauration de la lubrification naturelle, présente des propriétés de l'activateur tissulaire du plasminogène naturel et une résistance à la alpha phospholipase A2. On inhibe la formation d'adhérences en appliquant ladite composition sur les cavités du corps ayant subi des traumatismes ou susceptibles de les subir.
PCT/US1998/009903 1997-05-29 1998-05-22 Compositions et procedes destines a empecher les adherences WO1998053800A1 (fr)

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US4801397P 1997-05-29 1997-05-29
US60/048,013 1997-05-29
US5608697P 1997-08-27 1997-08-27
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Cited By (15)

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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
WO2003000344A1 (fr) * 2001-06-25 2003-01-03 Britannia Pharmaceuticals Limited Utilisation de phospholipides pour la prevention des adherences chirurgicales
WO2003082245A1 (fr) * 2002-04-03 2003-10-09 Lamellar Therapeutics Limited Procedes d'utilisation de corps lamellaires a des fins therapeutiques
WO2004024123A1 (fr) * 2002-09-16 2004-03-25 Vasogen Ireland Limited Acceleration du retablissement suite a des traumas
WO2004082688A1 (fr) * 2003-03-20 2004-09-30 Vasogen Ireland Limited Agonistes et antagonistes de recepteur de phosphatidylglycerol (pg)
WO2006056800A1 (fr) * 2004-11-26 2006-06-01 Britannia Pharmaceuticals Ltd. Utilisation de phospholipides pour la cicatrisation de plaies
US7332179B2 (en) 2003-12-12 2008-02-19 Kimberly-Clark Worldwide, Inc. Tissue products comprising a cleansing composition
WO2009109751A1 (fr) * 2008-03-04 2009-09-11 Britannia Pharmaceuticals Ltd. Phospholipide cristallin, son procédé de production et utilisation dans le traitement de tissu lésé
US7642395B2 (en) 2004-12-28 2010-01-05 Kimberly-Clark Worldwide, Inc. Composition and wipe for reducing viscosity of viscoelastic bodily fluids
EP2355803A1 (fr) * 2008-11-14 2011-08-17 Archer-Daniels-Midland Company Compositions et procédés de production d organogel
US8846126B2 (en) 2008-11-14 2014-09-30 Archer Daniels Midland Company Food compositions comprising organogels
US9119901B2 (en) 2005-04-28 2015-09-01 Warsaw Orthopedic, Inc. Surface treatments for promoting selective tissue attachment to medical impants
US9173901B2 (en) 2003-09-25 2015-11-03 Lamellar Therapeutics Limited Compositions and methods of using lamellar bodies for modifying linear biological macromolecules
CN107920994A (zh) * 2015-06-23 2018-04-17 板层小体生物医学有限公司 用于治疗目的的板层小体的组合物和方法
CN114788899A (zh) * 2022-05-07 2022-07-26 西安德诺海思医疗科技有限公司 光固化防粘连凝胶及其制备方法

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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
WO2003000344A1 (fr) * 2001-06-25 2003-01-03 Britannia Pharmaceuticals Limited Utilisation de phospholipides pour la prevention des adherences chirurgicales
US7906139B2 (en) 2002-04-03 2011-03-15 Lamellar Therapeutics Limited Compositions and methods of using lamellar bodies for therapeutic purposes
JP2005526101A (ja) * 2002-04-03 2005-09-02 ラメラー セラピューティクス リミテッド 治療に適したラメラ体の使用方法
EP2177212A1 (fr) * 2002-04-03 2010-04-21 Lamellar Biomedical Limited Méthodes d'utilisation de corps lamellaires à des fins thérapeutiques
WO2003082245A1 (fr) * 2002-04-03 2003-10-09 Lamellar Therapeutics Limited Procedes d'utilisation de corps lamellaires a des fins therapeutiques
JP4657608B2 (ja) * 2002-04-03 2011-03-23 ラメラー バイオメディカル リミテッド 医薬品組成物および薬剤調合へのラメラ体の使用
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WO2004082688A1 (fr) * 2003-03-20 2004-09-30 Vasogen Ireland Limited Agonistes et antagonistes de recepteur de phosphatidylglycerol (pg)
US9750766B2 (en) 2003-09-25 2017-09-05 Lamellar Biomedical Limited Compositions and methods of using lamellar bodies for modifying linear biological macromolecules
US9173901B2 (en) 2003-09-25 2015-11-03 Lamellar Therapeutics Limited Compositions and methods of using lamellar bodies for modifying linear biological macromolecules
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US7642395B2 (en) 2004-12-28 2010-01-05 Kimberly-Clark Worldwide, Inc. Composition and wipe for reducing viscosity of viscoelastic bodily fluids
US9119901B2 (en) 2005-04-28 2015-09-01 Warsaw Orthopedic, Inc. Surface treatments for promoting selective tissue attachment to medical impants
WO2009109751A1 (fr) * 2008-03-04 2009-09-11 Britannia Pharmaceuticals Ltd. Phospholipide cristallin, son procédé de production et utilisation dans le traitement de tissu lésé
US8846126B2 (en) 2008-11-14 2014-09-30 Archer Daniels Midland Company Food compositions comprising organogels
AU2009313928B2 (en) * 2008-11-14 2015-07-09 Archer Daniels Midland Company Organogel compositions and processes for producing
EP2711001A3 (fr) * 2008-11-14 2014-07-02 Archer-Daniels-Midland Company Compositions et procédés de production d'organogel
EP2355803A4 (fr) * 2008-11-14 2012-04-25 Archer Daniels Midland Co Compositions et procédés de production d organogel
EP2355803A1 (fr) * 2008-11-14 2011-08-17 Archer-Daniels-Midland Company Compositions et procédés de production d organogel
CN107920994A (zh) * 2015-06-23 2018-04-17 板层小体生物医学有限公司 用于治疗目的的板层小体的组合物和方法
CN114788899A (zh) * 2022-05-07 2022-07-26 西安德诺海思医疗科技有限公司 光固化防粘连凝胶及其制备方法

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