WO1996040090A1 - Procede pour la reduction ou la prevention de la formation d'adherences post-chirurgicales a l'aide d'inhibiteurs de 5-lipoxydase - Google Patents

Procede pour la reduction ou la prevention de la formation d'adherences post-chirurgicales a l'aide d'inhibiteurs de 5-lipoxydase Download PDF

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WO1996040090A1
WO1996040090A1 PCT/US1996/008216 US9608216W WO9640090A1 WO 1996040090 A1 WO1996040090 A1 WO 1996040090A1 US 9608216 W US9608216 W US 9608216W WO 9640090 A1 WO9640090 A1 WO 9640090A1
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composition according
poly
delivery vehicle
lipoxygenase inhibitor
lipoxygenase
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PCT/US1996/008216
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Kathleen Elizabeth Rodgers
Gere Stodder Dizerega
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University Of Southern California
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Priority to JP9500915A priority Critical patent/JPH11507038A/ja
Priority to AU58857/96A priority patent/AU698619B2/en
Priority to EP96920600A priority patent/EP0831796A1/fr
Publication of WO1996040090A1 publication Critical patent/WO1996040090A1/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • 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

Definitions

  • the present invention relates to 5-lipoxygenase (5-LO) inhibitors and their use thereof in a method for reducing or preventing post-operative adhesion formation between tissue, e.g., organ, surfaces in a body cavity.
  • tissue e.g., organ, surfaces in a body cavity.
  • Adhesion formation in particular following peritoneal surgery, is a major source of postoperative morbidity and mortality. Appendectomy and gynecologic surgery are the most frequent surgical procedures implicated in clinically significant adhesion formation. The most serious complication of intraperitoneal adhesions is intestinal obstruction; in addition, adhesions are associated with chronic or recurrent pelvic pain and infertility in females.
  • the pathogenesis of adhesion formation is complex and not entirely understood.
  • the first step is believed to involve excess fibrin deposition to form a scaffold.
  • Barrier agents which have been employed include both mechanical barriers and viscous solutions. Mixed results have been obtained using a barrier comprising a thin sheet of expanded poly-tetrafluoroethylene; in any event, such a membrane is less than ideal, as it must be sutured into place and is nonabsorbable. While an absorbable barrier (for example, a barrier made of oxidized regenerated cellulose) would be preferable, not all studies have demonstrated the efficacy of such barriers in preventing adhesions.
  • Liquid barriers have also been considered for use in preventing adhesions; for example, chondroitin sulfate and carboxymethyl cellulose have both shown some promise in animal models.
  • Anti-inflammatory drugs ha- a been evaluated for their effects on postoperative adhe ⁇ on formation, as they may limit the release of fibrinous exudate in response to inflammation at the surgical site. Two general classes of these drugs were tested: cortico-steroids and nonsteroidal anti-inflammatory drugs.
  • proteolytic enzymes e.g. , pepsin, trypsin and papain
  • pepsin, trypsin and papain should theoretically augment the local fibrinolytic system and limit adhesion formation, these enzymes are rapidly neutralized by peritoneal exudates rendering them virtually useless for adhesion prophylaxis.
  • fibrinolytics for example, fibrinolysin, streptokinase and urokinase
  • fibrinolytics for example, fibrinolysin, streptokinase and urokinase
  • a potential complication to the clinical use of these enzymes in postoperative therapy is excessive bleeding resulting from their administration.
  • rt-PA tissue plasminogen activator
  • the present invention relates to 5-lipoxygenase (5-LO) inhibitors and their use in a method for reducing or preventing adhesion formation between tissue, e.g. , organ, surfaces in body cavities comprising administering to a subject an effective amount of at least one 5-LO inhibitor, e.g., phenidone, nordihydroguaiaretic acid (NDGA), 5,8,11,14-eicosatetraynoic acid (EYTA) and Zileuton.
  • the 5-LO inhibitor is preferably administered in conjunction with a drug delivery system which maintains an effective concentration of the compound at a site of potential adhesion formation during the perioperative interval.
  • adhesion formation is minimized or prevented by administration of at least one 5-LO inhibitor at a site of potential adhesion formation for a period of time sufficient to permit substantial tissue repair (e.g., re-epithelialization or mesothelial repair) at the site.
  • tissue repair e.g., re-epithelialization or mesothelial repair
  • the inventive composition and method are useful in minimizing or preventing formation of adhesions between organ surfaces (not cell-to-cell adhesion) , the most common cause of which is prior surgery.
  • the inventive composition and method have been shown to be especially effective in preventing adhesion formation in the peritoneum following surgery.
  • the present invention finds utility in other contexts, e.g., for cardiovascular, orthopedic, thoracic, ophthalmic, CNS and other uses, where prevention of the formation of adhesions is a significant concern.
  • prevention of adhesion formation or drug loculation during the intraperitoneal administration of chemotherapeutic agent is contemplated as within the scope of the present invention.
  • attention is directed primarily to description of compositions and methods useful in inhibiting peritoneal adhesion formation.
  • the present invention is based on the discovery that compounds which inhibit 5-lipoxygenase (5-LO) activity are useful in reducing or preventing formation of adhesions between tissue surfaces in body cavities following surgical procedures.
  • the 5-LO enzyme found primarily in polymorphonuclear leukocytes (PMNs) and eosinopils, is a major enzyme involved in second pathway (the "5-LO pathway") of arachidonate metabolism in which arachidonic acid is converted to pro-inflammatory products called •eukotrienes (LTs) .
  • 5-LO catalyses the stereospecific oxidation of arachidonic acid to a 5-hydroperoxyeicosa- tetraenoic acid (5-HPETE) in the initial step towards the biosynthesis of leukotrienes.
  • the enzyme contains non-heme iron in the active site, and the mechanism of the transformation probably involves an organoiron intermediate or a dienyl radical which is trapped by molecular oxygen.
  • 5-LO inhibitors based on structure include substrate or product analogs, catechols, phenols, aminophenols, flavinoids, naphthols, heterocycles such quinones, indazolines, and benzothiophenes, and hydroxamic acid derivatives of common NSAIDs. Examples of these classes of compounds are described in the literature, for instance, in Musser and Kreft (1992) , "5-Lipoxygenase: Properties, pharmacology and the quinolinyl (bridged)aryl class of inhibitors", J. Med. Chem.. Vol. 35, pp. 2501-2524; Salmon et al.
  • 5-LO enzyme is inhibited by substrate and product analogues.
  • Acetylenic, methylated, cyclized, or thia- analogues of arachidonic acid, and cyclopropyl analogues of LTB4 inhibit 5-LO.
  • 5-LO 5,8,11,14-eicosatetraynoic acid
  • EYTA a pleotrophic membrane-active arachidonic acid analogue affects multiple signal transduction pathways in cultured transformed mammalian cells," Clin. Biochem.. Vol. 25, pp. 1-9. See Batt at 6-7.
  • Catechols and aminophenols have also been shown to inhibit 5-LO enzyme.
  • Lipophilic catechols notably nordihydroguaiaretic acid (NDGA) which is used as an example below, were more potent than pyrocatechol.
  • NDGA nordihydroguaiaretic acid
  • the inactivation of 5-LO enzyme is irreversible, and is accompanied by oxidation of phenolic compound.
  • the ortho- dihydroxyphenyl moiety is required for the best potency which correlated with overall lipophilicity of the inhibitor.
  • NDGA and other phenolic compounds have been shown by electron paramagnetic resonance spectroscopy to reduce the active-site iron from Fe-(III) to Fe-(II). Electron-poor, less easily oxidized catechols form stable complexes with the active-site iron atom. See Batt at 8-11 and references cited therein.
  • 5-LO catechol-containing compounds
  • most inhibitors of 5-LO are somewhat less potent against 12-LO, and are often significantly less potent as inhibitors of CO. Potency is often roughly correlated with lipophilicity.
  • Many reports have appeared over the last decade dealing with 5-LO inhibition by flavinoids.
  • vitamin E represents another class of phenolic lipophilic antioxidants, para-substituted by an oxygen atom in a fused saturated ring which inhibits platelet 12-LO and soybean 15-LO.
  • a series of related benzoxanthiols potently inhibit 5-LO; replacement of the propyl group by ethyl, butyl or phenyl maintains this potency.
  • L-651,896 is a compound from a series of dihydrobenzofuranols. Ibid.
  • SAR structure activity relationship
  • L- 651,896 and analogues There is shape specificity for 5-LO inhibition demonstrated by the greater potency of 6-substituted analogues compared to 4- substituted compound.
  • RS-43179 (lonapalene) is a selective 5-LO inhibitor with topical anti-inflammatory activity. SAR studies showed that lipophilicity plays a strong role, but if the compounds are too lipophilic (such as with larger alkoxy groups) activity is reduced.
  • the best substituent on the fused ring is chloro, although other groups capable of ⁇ -electron do-ation (other halogens, methoxy) are also effective.
  • Hyd lysis of at least one of the ester groups appears essential for activity, since compounds with increasing hydrolytic stability (pivalate, benzoate) are less potent.
  • a similar naphthol derivative from UpJohn is U-66,858 (bunaprolast) .
  • Simple 2- substituted 1-naphthols (DuP 654) are both potent 5-LO inhibitors and topical anti-inflammatories. SAR studies showed that various positional isomers are significantly less potent against 5-LO than DuP 654, although the CO inhibition is less sensitive to these changes.
  • Lipophilic phenols lacking the fused ring system, such as 2,6 dibenzylphenol, are also less potent.
  • Lipophilic arylmethyl 2-substituents are favored in vivo although even 2 methyl-1 naphthol is selective (but less potent) for 5- LO. Substitution at the 4-position by electron withdrawing groups reduces potency, as expected for a compound acting by redox mechanism. See Batt at 15-19 and references cited therein. Heterocyclic naphthol isosteres are also potent 5-LO inhibitors. Heterocyclic analogues of bunaprolast are about equipotent with the isocyclic versions. The hydroxyquinoline N-oxide KF 8940 is a potent inhibitor of 5-LO and is quite selective with respect to inhibition of 12-LO and CO. Another heterocyclic inhibitor (L-656,224) is selective for 5-LO.
  • the ⁇ -butyl analogue is less potent, as are analogues with heteroatom- containing chains at the position. Substitution on the benzyl group is relatively unimportant, as long as a carboxyl group is not present. Closely related benzi idazoles shows similar activity. Ibid.
  • Phenolic compounds are readily oxidized to quinones. Likewise, quinones are easily reduced (chemically and metabolically) to 5-LO-inhibiting hydroquinones.
  • AA861 (docebenone) is one such compound which is a standard 5-LO inhibitors used in various physiological and pharmacological studies. The side-chain of docebenone is required for in vitro activity, but partial or full saturation of this group has little effect. Replacement of the methyl groups on the benzoquinone moiety by methoxyls also give similar activity. See Batt at 19-21 and references cited therein.
  • Phenoxazine is a potent inhibitor of 5-LO. Substitution at the 1-position by carboxylic acid, ester or hydroxamic acid decreases potency. Lipophilic substitution at the 2-position is less destructive. A series of substituted dihydrothiazines has also been reported. Substitution on the phenyl group or variation of the benzyl by alkyl or hydroxyalkyi reduces potency about 10-fold. Replacement of the phenyl substituent by benzoyl reduces potency, while reduction of the trisubstituted double bond completely destroys activity. Ibid.
  • Phenidone and BW-755c are inhibitors of 5-LO.
  • A-53612 is a ring-expanded version of phenidone which is selective for 5-LO.
  • A-65620, a perhydro analogue is very similar to A-53612, having equal or slightly reduced potency.
  • the pyridazinones are generally more potent than the triazinones; enhanced lipophilicity (by substitution on the 1-phenyl or the heterocyclic ring) increased potency.
  • Acyclic analogues of phenidone such pyrazolecarboxylic hydrazides, inhibits 15-LO and are inactive against CO.
  • a series of indazolinones, such as ICI 207968, are benzo-fused analogues of phenidone. Some analogues inhibited CO as well, but ICI 207968 itself is highly selective (ca.300-fold) for 5-LO. See Batt at 23-27 and references cited therein.
  • N-Hydroxyarachidonamides are potent reversible inhibitors of 5-LO. Alkylation on nitrogen increased the inhibitory potency significantly. Placement of the hydroxamic acid moiety in 5-position gives analogues of 5- HPETE which also inhibit 5-LO.
  • a series of aralkylhydroxamic acids represented by 9- phenylnonanohydroxamic acid (BMY 30094) , inhibits 5-LO. Small substituents on the phenyl ring (methyl, methoxy, chloro) has little effect on potency, but larger substituents (butyloxy) lead to greatly decreased activity. See Batt at 27-28 and references cited therein.
  • Hydroxamic acid derivatives of common NSAIDs inhibit 5-LO with the following potency: CON(Me)OH>CONHON>CONH(OMe)->COOH.
  • the CO potency ranking is exactly opposite, although the best 5-LO inhibitors still possess significant CO activity.
  • Hydroxamic acids, including many simple ⁇ -aralkylhydroxamic acids have been extensively studied and yielded potent 5-LO inhibitors. The inhibitory activity correlates most strongly with the over-all lipophilicity. However, hydrophobicity in the immediate vicinity of the hydroxamic acid, as well as greater than 12 angstroms away from this moiety, does not greatly influence potency.
  • the hydroxamic acids have a large lipophilic group attached to the carbonyl, and a small alkyl group on nitrogen. SARs are similar to those observed for the arylacetohydroxamic acids: methyl is favored on the carbonyl group, the best group linking the aryl moiety to the nitrogen was CH(Me), and lipophilic substituents on the phenyl ring, preferably in the para position, are optimal. Heterocycles such as benzothiophene, benzofuran, N-methylindole, and dibenzofuran could also serve as the aryl group. See Batt at 27-32 and references cited therein.
  • the benzothiophene analogue A64077 (zileuton) is one of the most interesting 5-LO inhibitors studied to date. Although the original rationale for 5-LO inhibition by hydroxaminacids was iron chelation, this functional group also contains an N-O single bond which is capable of oxidation. N-Alkylhydroxylamines are mixed CO/5-LO inhibitors (approximately equipotent) . O-Methylation increases CO potency and decreases 5-LO potency, while N- methylation has the opposite effect, and larger N- substituents decreases activity. Analogues with 7- substituted 2-naphthyl moieties, exemplified by QA 208-199, give the best 5-LO potency. See Batt at 32-33 and references cited therein.
  • 15-HETE inhibits 5-LO.
  • a series of combined 5-LO inhibitors/LT antagonists were derived from the structure of 15-HETE.
  • REV 5901A is the best of the series with respect to CO and 12-LO inhibition.
  • the quinoline could be replaced by another lipophilic aromatic group, but potency is decreased (naphthalene is 40-fold less potent, and substituted phenyl is 5-to-20-fold less active) .
  • Pyridines are active but also less potent; 2-pyridyl is only 4-fold less active, while 3- and 4-pyridyl are 20-fold weaker. Ortho- and para- substituted phenylene groups are less active. See Batt at 33 and references cited therein.
  • Similar naphthalenemethyloxyphenyl compounds are potent, selective 5-LO inhibitors which display no antioxidant or iron chelation properties. Replacement of the ethyl group by hydrogen or methyl decreases activity, as does conversion of the methoxy to the hydroxy.
  • Diary1 2,3-dihydromidazo [2,l-b]thiazoles in which one of the aryl groups is pyridyl, such as SK&F 86002, are dual CO/5-LO inhibitors.
  • Tepoxaline (RWJ 20485) is a hydroxamic acid derivative which inhibits 5-LO. See Batt at 35 and references cited therein.
  • 5-LO inhibitors As discussed above, a wide variety of agents have been reported as 5-LO inhibitors. The majority of the series appear to be lipophilic reducing agents, including phenols, partially saturated aromatics, and compounds containing heteroatom-heteroatom bonds. However, many of these compounds are not selective 5-LO inhibitors, but often affect CO and other LOs as well. In vivo systemic activity for many of these has been in general, disappointing, probably because of poor bioavailability caused by lipophilicity and metabolic instability (oxidation, and conjugation of phenolic compounds) . However, the method of administration outlined in this application, that is local and slow-release, should overcome some of these difficulties. A few structural types are selective 5-LO inhibitors which have shown systemic activity in vivo and in the clinic.
  • 5-LO inhibitors may inhibit adhesion formation between tissue, e.g. organ, surfaces in body cavities through a variety of mechanisms. For example, 5-LO inhibitors alter arachidonic acid metabolism, which produces mediators, e.g. ,leukotrienes, of an inflammatory response and thus reduces inflammation [Anderson et al.
  • EYTA a pleotrophic membrane-active arachidonic acid analogue affects multiple signal transduction pathways in cultured transformed mammalian cells
  • Clin. Biochem. Vol. 25, pp. 1-9
  • Miyano and Chiou. (1984), "Pharmacological prevention of ocular inflammation induced by lens proteins", Ophthalmic Research. Vol. 16, pp. 256-263.
  • leukotrienes (whose synthesis is blocked by LO inhibitors) are chemotactic for leukocytes [Musser and Kreft (1992), "5-Lipoxygenase: Properties, pharmacology and the quinolinyl (bridged)aryl class of inhibitors", J. Med. Chem.. Vol. 35, pp. 2501-2524; Gulbenkian et al. (1990) , "Anaphylactic challenge causes eosinophil accumulation in bronchoalveolar lavage fluid of guinea pigs.
  • LO inhibitors reduce PMN infiltration [DeMartino et al. (1989) , "The pharmacology of arachidonic acid-induced rat PMN leukocyte infiltration,” Agent Action. Vol. 27, pp. 325-327]. As leukocytes are instrumental in wound repair and lysis of fibrin, these agents may affect adhesion formation through these actions on leukocyte chemotaxis.
  • 5-LO inhibitors As is well recognized in the art, however, no one of these possible mechanisms of action of 5-LO inhibitors would in and of itself be sufficient to enable one to predict whether these compounds would have any utility in reduction of adhesion formation. Indeed, several properties of 5-LO inhibitors would suggest that such compounds would be ineffective at reducing adhesion formation. For example, fibrinolysis is crucial in clearance of fibrin deposited after surgical injury. If the deposition of fibrin is prolonged, then the potential for adhesion formation is increased. NDGA inhibits the production of urokinase (a plasminogen activator) , which catalyzes the cleavage of plasminogen to plasmin, a major fibrinolytic enzyme [Rondeau et al.
  • urokinase a plasminogen activator
  • NSAIDs nonsteroidal anti- inflammatory drugs
  • CO cyclooxygenase
  • Some of the compounds described above and in the Examples below are capable of inhibiting CO.
  • NSAIDs and the compounds that inhibit 5-LO have many distinct biological properties such that a person of ordinary skill in the art would not have any reason to believe that 5-LO inhibitors would reduce adhesion formation.
  • 5-LO inhibitors are distinct from NSAIDs in a number of ways. For instance, NSAIDs reduce early phase of ocular inflammation.
  • NSAIDs increase urokinase production, however, lipoxygenase inhibitors do not affect or reduced urokinase production [Chow et al. (1987) , “Pharmacological modulation of plasminogen activator secretion by P388D1 cell line," Agents and Actions. Vol. 21, pp. 387-389].
  • LO inhibitors decrease granuloma formation, however, NSAIDs have no effect on the formation of granulomas [Kunkel et al. (1984) , "Role of lipoxygenase products of murine pulmonary granuloma formation,” J. Clin. Invest.. Vol. 74, pp. 514-524].
  • LO inhibitors decrease the arachidonic acid-induced increase in myeloperoxidase, whereas NSAIDs have no effect
  • DiMartino et al. (1989) "The pharmacology of arachidonic acid-induced rat PMN leukocyte infiltration," Agents and Action. Vol. 27, pp. 325-327; Griswold et al. (1989) , "Inhibition of inflammatory cell infiltration by bicyclic imidazoles, SK&F 86002 and SK&F 1004493,” Inflammation. Vol. 13, pp. 727-739].
  • LO inhibitors also reduce eosinophil accumulation, while NSAIDs had no effect
  • NSAIDs had no effect
  • betamethasone, phenidone, indomethacin, WEB 2086, and a novel antiallergy agent, SCH 37224 Am. Rev. Respir. Pis.. Vol. 142, pp. 680-685.
  • LO inhibitors had no effect on the biphasic response to bradykinin, but NSAIDs altered the response [Calixto and Medeiros. (1991), "Characterization of bradykinin mediating pertussis toxin-insensitive biphasic response in circular muscle of the isolate guinea pig ileum,” J. Pharm. Exper. Ther.. Vol. 259, pp. 659].
  • 5-LO inhibitors would in and of itself have any utility in preventing or reducing post-surgical adhesion formation.
  • NDGA 5,8,11,14-eicosatetraynoic acid
  • ZTA Zileuton
  • 5-LO inhibitors are described in U.S. Patent Nos. 5,246,948, 5,023,255, and 4,708,964; European Patent Application Nos. 0612 729 A2, published August 31, 1994 and 0146 348 A2, published June 26, 1985; and WO 95/04055, published February 9, 1995.
  • the preferred 5-LO inhibitor compounds are those which have little or no toxicity at the local and systemic level and are suitable for topical use in animals, including humans.
  • Methods which may be employed in identifying compounds which inhibit 5-LO activity are disclosed, for example, in Batt (1992) , "5-Lipoxygenase inhibitors and their anti ⁇ inflammatory activities," Prog. Med. Chem.. Vol. 29, pp. 1- 63; Riendeau et al. (1989), "Sensitivity of immunoaffinity- purified porcine 5-lipoxygenase to inhibitors and activating lipid hydroxyperoxides," Biochem. Pharmacol.. Vol. 38, pp. 2313-2321; Miyazawa et al.
  • At least one 5-LO inhibitor is maintained in an effective concentration at the site of potential adhesion formation for a period of time sufficient to permit substantial re- epithelialization.
  • the 5-LO inhibitor is typically administered over the perioperative interval, which for purposes of the present invention may include time shortly prior to surgery through the surgery itself up to some time after completion of surgery.
  • the effective therapeutic concentrations of 5-LO inhibitors is one that minimizes or prevents post-surgical adhesion formation between tissue surfaces in body cavities.
  • concentrations of 5-LO inhibitor which can be administered would be limited by efficacy at the lower end and the solubility of the compound at the upper end.
  • the effective therapeutic concentration of the 5-LO inhibitors is one that inhibits 5-LO activity from between about 1 to about 100%, preferably from between about 10 to about 100%.
  • the 5-LO inhibitor may be administered directly following the surgical procedure in a suitable vehicle, for example, a solution of saline, 5% DMSO in saline or 10% ethanol in saline, to a site at which it is desired to reduce or prevent adhesion formation.
  • a suitable vehicle for example, a solution of saline, 5% DMSO in saline or 10% ethanol in saline
  • at least one 5-LO inhibitor is administered in a single dose delivery (for example, prior to skin closure after surgery) using a drug-delivery system which enables the maintenance of requisite concentrations of the compound for a period of time sufficient for re-epithelialization.
  • a suitable drug-delivery system would itself be essentially non ⁇ inflammatory and non-immunogenic and would permit release of the 5-LO inhibitor so as to maintain effective levels thereof over the desired time period.
  • Suitable delivery vehicles include, but are not limited to, the following: microcapsules or microspheres; liposomes and other lipid-based release systems; crystalloid and viscous instillates; absorbable and/or biodegradable mechanical barriers; and polymeric delivery materials, such as polyethylene oxide/polypropylene oxide block copolymers (e.g. poloxamers) , poly-orthoesters, cross-linkedpolyvinyl alcohol, polyanhydrides, polymethacrylate and polymethacryladmide hydrogels, anionic carbohydrate polymers, etc.
  • Useful delivery systems are well known in the art and are described in, e.g., U.S. Patent No. 4,937,254, the entire disclosure of which is hereby incorporated by reference.
  • One particularly suitable formulation to achieve the desired near pseudo zero-order release of 5-LO inhibitors comprise injectable microcapsules or microspheres prepared from a biodegradable polymer, such as poly(dl-lactide) , poly(dl-lactide-co-glycolide) , poly-caprolactone, polyglycolide, polylactic acid-co-glycolide, poly(hydroxybutyric acid) , a polyortho-ester or a polyacetal.
  • injectable systems comprising microcapsules or microspheres of a diameter on the order of about 50 to about 500 ⁇ m offer advantages over other delivery systems. For example, they generally use less active agent and may be administered by paramedical personnel. Moreover, such systems are inherently flexible in the design of the duration and rate of separate drug release by selection of microcapsule size, drug loading and dosage administered. In addition, such microcapsules can be successfully sterilized with gamma irradiation.
  • Microcapsules are systems comprising a polymeric wall that encloses a liquid or solid core.
  • the capsule wall usually does not react with the core material; however, it is designed to provide sufficient strength to enable normal handling without rupture while being sufficiently thin to allow a high core to wall volume ratio.
  • the capsule contents remain within the wall until released by diffusion or other means that dissolve, melt, break, rupture or remove the capsule material.
  • the capsule wall can be made to degrade and decompose in suitable environments while diffusing the core material through the capsule wall to allow for its slow, prolonged delivery.
  • the mechanism of release in biodegradable microcapsules is a combination of drug diffusion and polymer biodegradation. Therefore, the rate and duration of release are determined by microcapsule size, drug content and quality, and polymer parameters such as crystallinity, molecular weight and composition. In particular, adjustment in the amount of drug released is generally achieved by modification of capsule wall thickness, capsule diameter, or both.
  • Detailed information concerning the design, preparation and use of microspheres and microcapsules is provided by, e.g., Lewis, D.H., "Controlled Release of Bioactive Agents from Lactide/Glycolide Polymers," in "Biodegradable Polymers as Drug Delivery Systems," Jason & Langer, eds., pp.
  • microcapsules As is well known to those skilled in the art, various methods are currently available for preparing microcapsules, any of which could be employed to provide formulations in accordance with the present invention.
  • Biodegradable polymeric materials suitable for preparation of microcapsules for controlled (i.e., near zero-order) release would be readily determined through routine experimentation by those skilled in the art.
  • alternative delivery systems suitable for use in accordance with the present invention for example, fibers or filaments comprising the active agents
  • biodegradable polymers are also contemplated as within the scope of the present invention.
  • An alternative approach for the single-dose delivery of at least one 5-LO inhibitor involves the use of biodegradable polymers, such as the ones described above, in the form of a film.
  • Such films may be produced by spraying or discharging dispersed liquid droplets containing the biopolymer and the 5-LO inhibitor in a suitable carrier from a pressurized container onto the targeted site.
  • Another approach for the single-dose delivery of at least one 5-LO inhibitor involves the use of liposomes and other lipid- based delivery systems.
  • the encapsulation of an active agent in multilamellar vesicles (or liposomes) is a well known technique used to assist in target drug delivery and prolong drug residence.
  • a liposome-forming powdered lipid mixture is added to the desired quantity of active agent in aqueous solution (e.g., phosphate buffered saline) to form a suspension. After a suitable hydration period, the hydrated suspension is then autoclaved to provide the liposome-active agent preparations.
  • aqueous solution e.g., phosphate buffered saline
  • a lipid mixture suitable for formation of liposomes may be prepared from L-alpha-distearoyl phosphatidylcholine and cholesterol dissolved in chloroform, to which alpha-tocopherol is added; other compositions and methods for formation of liposomes would, however, also be useful for this purpose.
  • the intraperitoneal administration of liposomes containing ibuprofen or tolmetin is described in Rodgers, K. et al., "Inhibition of Postsurgical Adhesions by Liposomes Containing Nonsteroidal Anti-inflammatory Drugs," Int. J. Fertil.. Vol. 35, p. 40 (1990) , the entire disclosure of which is hereby incorporated by reference.
  • lipid foams such as DepoFoam extended-release formulations comprising spherical particles bounded by a single bilayer lipid membrane and each containing numerous nonconcentric aqueous chambers which encapsulate the active ingredient (see, e.g, Kim, T.K. et al. (1993) "Extended- release formulation of morphine for subcutaneous administration,” Cancer Chemother. Pharmacol.. Vol. 33, 187; Chatelut, E. et al. (1993) "A slow-release methotrexate formulation for intrathecal chemotherapy," Cancer Chemother. Pharmacol.. Vol.
  • Such lipid particles are made from nontoxic lipids identical to those found in cell membranes.
  • Another suitable lipid-based delivery system for delivering the 5-LO inhibitors according to the invention includes emulsion carrier systems based on egg sphinomyelin and egg phosphatidylcholine. Such emulsion carrier systems have prolonged blood circulation retention times and were developed for delivering highly lipophilic drugs. T. Takino et al. (1994) "Long Circulating Emulsion Carrier Systems for Highly Lipophilic Drugs," Biol. Pharm. Bull.. Vol. 17, pp. 121-125.
  • Crystalloids are known in the art as water soluble crystalline substances, e.g. NaCI, capable of diffusing through a semi-permeable membrane.
  • Solutions of crystalloids, such as saline are known as crystalloids, crystalloid solutions or crystalloid instillates. Crystalloids include, but are not limited to, phosphate buffered saline, saline or lactated Ringer's solution.
  • High-molecular-weight viscous carriers used in admixture with the active agents include, but are not limited to, the following: dextrans and cyclodextrans; hydrogels; cross-linked viscous materials, including viscoelastics and cross-linked viscoelastics; carboxymethylcellulose; hyaluronic acid, crosslinked hyaluronic acid, and hyaluronic acid compounded with orthoesters. While some studies have suggested that the use of viscous barrier solutions per se may have an advantageous effect in reducing the incidence of adhesion formation, it is believed that any such effect is of limited scope when compared to the combination of at least one 5-LO inhibitor and carrier.
  • At least one 5-LO inhibitor is administered in combination with an absorbable mechanical barrier which alone reduces adhesion formation.
  • at least one 5-LO inhibitor may be covalently or non-covalently (e.g., ionically) bound to such a barrier, or it may simply be dispersed therein.
  • a particularly suitable vehicle for use in this particular embodiment of the invention comprises hydroxyethyl starch which is described in U.S. Patent application Ser. No.
  • Another suitable mechanical barrier for use in this invention includes oxidized regenerated cellulose which is available under the designation INTERCEED(TC7) from Johnson and Johnson Medical, Inc., New Brunswick, New Jersey [INTERCEED(TC7) Adhesion Barrier Study Group, "Prevention of postsurgical adhesions by INTERCEED(TC7) , an absorbable adhesion barrier: a prospective, randomized multicenter clinical study," Fertility and Sterility. Vol. 51, p. 933 (1989)].
  • INTERCEED(TC7) Adhesion Barrier Study Group, "Prevention of postsurgical adhesions by INTERCEED(TC7) , an absorbable adhesion barrier: a prospective, randomized multicenter clinical study," Fertility and Sterility. Vol. 51, p. 933 (1989)].
  • the use of a mechanical barrier as a carrier to deliver heparin to traumatized surfaces is disclosed in Diamond, M. P.
  • peritoneal sidewall model rabbits were pre- anesthetized with 1.2 mg/kg acetylpromazine and anesthetized with a mixture of 55 mg/kg ketamine hydrochloride and 5 mg/kg xylazine intramuscularly. Following preparation for sterile surgery, a midline laparotomy was performed. A 3 x 5-cm area of peritoneum and transversus abdominis muscle was removed on the right lateral abdominal wall. The cecum was exteriorized, and digital pressure was exerted to create subserosal hemorrhages over all cecal surfaces. The cecum was then returned to its normal anatomic position.
  • the compound to be tested was placed in an Alzet miniosmotic pump (Alza Corporation, Palo Alto, CA, USA) to allow continuous release of the molecule through the postsurgical interval.
  • the Alzet miniosmotic pump was placed in the subcutaneous space and a delivery tube connected the pump with the site of injury at sidewall. Vehicle was placed in the pump of control rabbits. The abdominal wall and skin were closed in a standardized manner.
  • a reduction in the area or the tenacity of the adhesions would be considered beneficial.
  • a rabbit uterine horn model was employed. This model has been previously shown to cause severe adhesions in rabbits after surgery [Nishimura, K. et al., "The Use of Ibuprofen for the Prevention of Postoperative Adhesions in Rabbits," Am. J. Med.. Vol. 77, pp. 102-106 (1984)].
  • the rabbits were anesthetized (130 mg/kg ketamine and 20 mg/kg acetylpromazine im) and prepared for sterile surgery.
  • a midline laparotomy was performed, and surgical trauma was performed on both uterine horns by abrading the serosal surface with gauze until punctate bleeding developed. Ischemia of both uterine horns was induced by removal of the collateral blood supply. After traumatization, the abdominal wall was closed in two layers. The inhibitor to be tested was delivered as described for the peritoneal sidewall model, but the tubing was placed over the injured uterine horns.
  • exemplary 5-lipoxygenase inhibitor compounds phenidone, NDGA, Zileuton, and ETYA were shown to reduce the incidence of peritoneal adhesions.
  • the drug was delivered to the targeted site at a rate of 10 ⁇ l/hour.
  • the concentration ranges employed were 0.0001 to 0.5 mg/ml. For purposes of preventing adhesion formation in accordance with the present invention, it is not believed that high systemic levels of 5-lipoxygenase inhibitors would be necessary.
  • the standard reaction mixture contains 0.55 M Tris-HCl, pH 7.4, 0.2 mM ATP, 0.4 mM CaCl 2 , 20 or 27 mM arachidonic acid (5 ⁇ l of a 100-fold concentrated solution in ethanol) , 24 ⁇ g/ml phosphatidylcholine, and an aliquot of the enzyme preparation (5-75 ⁇ l) in a final volume of 0.5 ml.
  • the volume of enzyme is completed to 100 ⁇ l using a chromatography elution buffer (50 mM sodium carbonate, pH 10, containing 0.2% sodium deoxycholate, 0.5 mM dithiothreitol and 1 mM EDTA into 0.5 M Tris).
  • the buffer solution containing CaCl 2 (0.4 M) and phosphotidylcholine (24 ⁇ g/ml) is filtered through 0.2 ⁇ m Nalgene filters.
  • the assay reactions are performed in semi-micro cuvettes (1.4 ml capacity, 100 mm path length and 4 mm internal width) and initiated by the addition of the enzyme to the assay mixture.
  • the reaction mixture is gently mixed with a Pasteur pipet (15 sec) before recording the variation in A235 as a function of time at room temperature.
  • phenidone Sigma Chemical Co., St. Louis, MO
  • a 5-LO inhibitor discussed above
  • the efficacy of phenidone was evaluated at two doses in a sidewall model.
  • the drug was delivered for 7 days at a rate of 10 ⁇ l/hr and the animals were sacrificed after 7 days.
  • the vehicle used was saline.
  • phenidone was found to be efficacious in 5 of 6 rabbits at the high dose and in 4 of 6 rabbits in the lower dose. No inflammation or precipitation noted at the site of injury.
  • the results are summarized in Table 1. A student t test analysis of the data was performed and the results are also reported in Table 1.
  • NDGA nordihydroguaiaretic acid
  • ETYA 5,8,11,14-eicosatetraynoic acid
  • the efficacy of 5,8,11,14-eicosatetraynoic acid (ETYA) (available from Sigma Chemical, St. Louis, MO) , a 5-LO inhibitor discussed above, in preventing adhesion formation was evaluated at two doses in a sidewall model.
  • the drug was delivered for 7 days at a rate of 10 ⁇ l/hr and the animals were sacrificed after 7 days.
  • the vehicle used was 11.1% ethanol in saline, pH 10.6. Relative to the control, ETYA was efficacious in the prevention of adhesions in this rabbit sidewall model.
  • Table 3 A student t test analysis of the data was performed and the results are also reported in Table 3.
  • phenidone the compound exemplified in Example 2 above
  • the efficacy of phenidone, the compound exemplified in Example 2 above, in preventing adhesion formation was evaluated at two doses in a double uterine horn (DUH) model.
  • the drug was delivered for 7 days at a rate of 10 ⁇ l/hr and the animals were sacrificed after 7 days.
  • the vehicle used was saline.
  • Statistical analysis was performed on the overall score of the nonparametric double uterine horn model data. The data was rank ordered, a rank value was given and an analysis of variance on the ranks was performed. The results are summarized in Tables 4 and 5. Relative to the control, phenidone was efficacious in reducing adhesion formation in this model.
  • NDGA The efficacy of NDGA, the compound exemplified in Example 3 above, in preventing adhesion formation was evaluated at two doses in a double uterine horn model.
  • the drug was delivered for 7 days at a rate of 10 ⁇ l/hr and the animals were sacrificed after 7 days.
  • the vehicle used was 0.1% ethanol in saline, pH 10.3.
  • Statistical analysis was performed on the overall score of the nonparametric double uterine horn model data. The data was rank ordered, a rank value was given and an analysis of variance on the ranks was performed. The results are summarized in Tables 6 and 7. Relative to the control, NDGA was efficacious in reducing adhesion formation in this model.
  • the efficacy of ETYA, the compound exemplified in Example 4 above, in preventing adhesion formation was evaluated at two doses in a double uterine horn model.
  • the drug was delivered for 7 days at a rate of 10 ⁇ l/hr and the animals were sacrificed after 7 days.
  • the vehicle used was 11.1% ethanol in saline, pH 10.6.
  • Statistical analysis was performed on the overall score of the double uterine horn model nonparametric data. The data was rank ordered, a rank value was given and an analysis of variance on the ranks was performed. The results are summarized in Tables 8 and 9. Relative to the control, ETYA was efficacious in the reduction of adhesion formation in this model.
  • Bowel and/or bladder adhered to sidewall at the tube or suture for the tube.
  • Bowel and/or bladder adhered to sidewall at the tube or suture for the tube.
  • the efficacy of Zileuton, a 5-LO inhibitor discussed above, in preventing adhesion formation was evaluated at two doses in a sidewall model.
  • the drug was delivered for 7 days at a rate of 10 ⁇ l/hr and the animals were sacrificed after 7 days.
  • the vehicle used was saline. Relative to the control, Zileuton was found to be efficacious at both concentrations tested. No inflammation or precipitation noted at the site of injury.
  • the results are summarized in Table 14. A student t test analysis of the data was performed and the results are also reported in Table 14.

Abstract

Compositions et procédés permettant de minimiser ou de prévenir la formation d'adhérences post-chirurgicales entre les surfaces de tissus, par exemple d'organes, dans les cavités corporelles. On administre au niveau du site de la lésion cible une quantité à efficacité thérapeutique d'au moins un inhibiteur de 5-lipoxydase tel que la phénidone, le NDGA, l'ETYA et le Zileuton, et ce pendant une période suffisamment longue pour permettre la réparation des tissus. De préférence, on administre l'inhibiteur de 5-lipoxydase en association avec un véhicule d'administration (par exemple des microcapsules, des microsphères, des feuilles polymères biodégradables, des systèmes d'administration à base de lipides tels que des liposomes et des mousses lipidiques, des instillats cristalloïdes ou visqueux et des barrières mécaniques absorbables) permettant de maintenir à des valeurs efficaces les concentrations locales de l'inhibiteur au niveau du site de la lésion, et ce pendant une période prolongée.
PCT/US1996/008216 1995-06-07 1996-05-31 Procede pour la reduction ou la prevention de la formation d'adherences post-chirurgicales a l'aide d'inhibiteurs de 5-lipoxydase WO1996040090A1 (fr)

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AU58857/96A AU698619B2 (en) 1995-06-07 1996-05-31 Method for reducing or preventing post-surgical adhesion formation using 5-lipoxygenase inhibitors
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US6258778B1 (en) 1998-07-13 2001-07-10 University Of Southern California Methods for accelerating bone and cartilage growth and repair
US6475988B1 (en) 1998-05-11 2002-11-05 University Of Southern California Methods to increase white blood cell survival after chemotherapy
US6498138B1 (en) 1998-03-11 2002-12-24 University Of Southern California Method of promoting production of living tissue equivalents
EP1325753A2 (fr) * 2001-12-21 2003-07-09 Ethicon, Inc. Elements biocompatibles pour la liberation controlée de principes actifs aux tissus et méthodes d'utilisation
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US6730775B1 (en) 1999-03-23 2004-05-04 University Of Southern California Methods for limiting scar and adhesion formation
US6762167B1 (en) 1998-05-11 2004-07-13 University Of Southern California Methods for treating a patient undergoing chemotherapy
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US6916783B2 (en) 1998-07-13 2005-07-12 University Of Southern California Methods for accelerating bone and cartilage growth and repair
WO2006131737A3 (fr) * 2005-06-09 2007-03-29 Biolipox Ab Methode et composition de traitement de troubles inflammatoires
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AU5885796A (en) 1996-12-30

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