Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/18—Growth factors; Growth regulators
  • A61K38/1858—Platelet-derived growth factor [PDGF]
  • A61K38/1866—Vascular endothelial growth factor [VEGF]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

• the present invention relates to methods and compositions for treating gastrointestinal (GI) ulcers as well as for providing acute gastroprotection.
• GI ulcers include duodenal ulcers, peptic ulcers, drug-induced ulcers, or intestinal ulcers, including but not limited to damage due to non- steroidal (NSAID) and anti-inflammatory drugs, gastro-esphogheal reflux disease or inflammatory bowel disease such as ulcerative colitis and Crohn's disease.
• NSAID non- steroidal
• the present invention relates to treatment of a mammal, including a human, with vascular endothelial cell growth factor (VEGF), which is also a potent vascular permeability factor (VPF), to provide healing of GI ulcers or to provide acute gastroprotection.
• VEGF vascular endothelial cell growth factor
• VPN potent vascular permeability factor
• Vasculogenesis is the de novo formation of blood vessels from differentiating endothelial cell precursors or angioblasts.
• Angiogenesis the sprouting of new capillaries from pre-existing blood vessels, further refines the vascular network and is the principal process by which certain organs, such as the stomach, intestine or brain, become vascularized.
• Vasculogenesis and angiogenesis are complex multistep processes that involve remodelling of the extracellular matrix, migration and proliferation of endothelial cells, lumen formation and functional maturation of blood vessels. Multiple cell-cell or cell-extracellular matrix interactions occur, which require signalling via soluble or cell-bound molecules.
• VEGF vascular endothelial cell growth factor
• vascular endothelial cells While proliferation of the vascular endothelial cells is vital to angiogenesis, uncontrolled proliferation can lead to cancer and metastasis, diabetic retinopathy, atherosclerosis, rheumatoid arthritis, synovitis, psoriasis, dermatitis, endometriosis, encephalitis, and tonsilitis.
• VEGF is a disulfide-linked 46-kDa dimeric glycoprotein first isolated from media conditioned by bovine folliculo stellate cells and its partial amino acid sequence determined (Gospodarowicz et al., PNAS 86(19):7311-7315; Ferrara and Henzel, BBRC 161 (2):851-858 (1989)).
• a candidate regulator of angiogenesis it has several properties expected of a candidate regulator of angiogenesis: it is secreted by normal and tumor cell lines; its is an endothelial-cell-specific mitogen; it is angiogenic in in vivo test systems such as the chorioallantoic membrane and the rabbit cornea; it is chemotactic for endothelial cells and monocytes; and it induces in endothelial cells the production of plasminogen activators, which are involved in the proteolytic degradation of the extra-cellular matrix during capillary sprouting.
• VEGF isoforms are known, which have similar biological activities but differ in their secretion from producer cells and in heparin binding (Georg Breier and Werner Risau, Trends in Cell Biology, 6:454-456( December 1996)). US Pat. Nos.
• vascular endothelial cell growth factor by means of recombinant DNA technology, such as bovine VEGF sub 120, bovine VEGF sub 164, human VEGF sub 121 and human VEGF sub 165, for use as a wound healing agent following vascular graft surgery, balloon angioplasty or to promote collateral circulation in post-myocardial infarction patients or in the treatment of wounds, such as dermal ulcers, including pressure sores, venous ulcers and diabetic ulcers, in the treatment of burns and injuries where angiogenesis is required to prepare the burn or injured site for a skin graft or flap, in cases where plastic surgery reconstruction is required and administration to the site of a bone fracture.
• An additional use relates in keeping wounds clean and non-infected in association with general surgery and following the repair of cuts and lacerations. Parenteral and topical compositions are disclosed.
• US Pat. No. 5,332,671 which is hereby incorporated by reference, discloses the production of a vascular endothelial cell growth factor and/or derivatives thereof by recombinant techniques for use in treating conditions in which a selective action on the vascular endothelial cells, in the absence of excessive tissue growth, is important, e.g., surface ulcers such as diabetic, hemophiliac and varicose ulcers and vascular injuries resulting from trauma such as subcutaneous wounds, incisions and injuries to the blood vessels or heart. Compositions for continuous infusion, sustained release, topical application or injection at empirically determined frequencies are disclosed. PCT Publication No.
• 9639515 discloses DNA encoding human VEGF-2 used to develop products to promote angiogenesis (e.g., stimulate growth of transplanted tissue following coronary bypass surgery) or endothelialisation in vascular graft surgery.
• PCT Publication No. 9639421 discloses DNA encoding human VEGF-3 used to develop products to promote angiogenesis and wound healing and to promote vascular tissue repair.
• VEGF vascular endothelial growth factor
• administration of a pharmaceutically effective amount of VEGF such as from about 30 ng/kg to about 1000 ⁇ g/kg, preferably about 80 ng/kg to about 800 ⁇ g/kg, more preferably about 400 ng/kg to about 700 ⁇ g/kg per day for about a week to two months, preferably two to three weeks, results in healing of GI ulcers in a mammal, such as a human.
• improved or enhanced mucosal restoration or prominent stimulation of angiogenesis and granulation tissue production at the ulcer edge results from this treatment.
• administering results in acute gastroprotection.
• the administration is targeted to the GI tract, such as by oral administration, for example liquid solutions, immediate release dosage forms, controlled or sustained release dosage forms, or gastro-retentive dosage forms or by rectal administration, for example enemas or suppositories.
• VEGF vascular endothelial cell growth factor
• vascular endothelial cell growth factor refers to the disulfide-linked 46-kDa dimeric glycoprotein (a mammalian growth factor) first isolated from media conditioned by bovine folliculo stellate cells and its partial amino acid sequence determined (Gospodarowicz et al., PNAS 86(19):7311-7315; Ferrara and Henzel, BBRC 161(2):851-858 (1989))(hereinafter native VEGF) together with analogs and variants thereof having the biological activity of the corresponding native VEGF, including human VEGF.
• native VEGF native vascular endothelial cell growth factor
• Analogs or variants are defined as molecules in which the amino acid sequence, glycosylation, or other features of native VEGF have been modified covalently or noncovalently, such as the analogs or variants disclosed above, and including salts thereof .
• An example of VEGF is the human VEGF obtainable from PeproTech, Canton, MA.
• the present invention encompasses administration of a pharmacologically effective amount of VEGF, such as from about 30 ng/kg to about 1000 ⁇ g/kg, preferably about 80 ng/kg to about 800 ⁇ g/kg, more preferably about 400 ng/kg to about 700 ⁇ g/kg per day for about a week to two months, preferably two to four weeks, to treat duodenal ulcers or other GI ulcers in a mammal, such as a human.
• VEGF pharmacologically effective amount of VEGF
• GI ulcers include but are not limited to duodenal ulcers, peptic ulcers, drug-induced ulcers, or intestinal ulcers, including but not limited to damage due to non-steroidal (NSAID) and anti-inflammatory drugs, gastro- esphogheal reflux disease or inflammatory bowel disease such as ulcerative colitis and Crohn's disease.
• the treatment regimen may consist of once daily administration or dividing the daily dose into multiple administrations, such as administration from 2 to 4 times per day.
• the present invention also encompasses administration of from about 3 ⁇ g/kg to about 1000 ⁇ g/kg, preferably about 8 ⁇ g/kg to about 800 ⁇ g/kg, most preferably 400 ⁇ g/kg to about 700 ⁇ g/kg VEGF to provide for acute gastroprotection.
• the administration of VEGF occurs from about 0 minutes to about 60 minutes, preferably from about 0 minutes to about 30 minutes prior to insult to the GI tract, such as ingestion of NSAIDS or ethanol.
• the administration is targeted to the GI tract.
• oral administration is a preferred administration route.
• liquid solutions, immediate release dosage forms, controlled or sustained release dosage forms or gastro-retentive dosage forms are preferred.
• oral buccal dosage forms are useful for the delivery of VEGF.
• Oral immediate release, sustained release, controlled release, oral buccal and/or gastro-retentive dosage forms can be prepared from nano- or microparticulates including but not limited to biodegradable matrix nano- or microparticles, nanocapsules, microcapsules or spray-dried vehicles. Emulsions, capsules or tablets incorporating these nano- or microparticulate forms can be prepared. Additionally, solid dosage forms can be prepared as tablets, mini- tablets, beads, capsules, etc., including forms with a controlled/sustained release coating. In these forms, the VEGF is typically released by erosion, diffusion, osmotic pressure, or by a combination of these mechanisms. Oral solutions, including elixirs, emulsions and effervescent solutions, can also be employed in this invention.
• Typical controlled, sustained, or gastro-retentive excipients may include, but are not limited to, biodegradable polymers or biopolymers, such as poly- lactide, poly-glycolide, poly(lactide-co-glycolide), other polymers or copolymers of poly( ⁇ -hydroxycarboxylic acids), poly(lactones), poly(acetals), poly(orthoesters), poly(alkylcyanoacrylates) or poly(orthcarbonates).
• biodegradable polymers or biopolymers such as poly- lactide, poly-glycolide, poly(lactide-co-glycolide), other polymers or copolymers of poly( ⁇ -hydroxycarboxylic acids), poly(lactones), poly(acetals), poly(orthoesters), poly(alkylcyanoacrylates) or poly(orthcarbonates).
• Additional excipients useful for oral administration forms include, but are not limited to, polysaccharides, for example cellulose derivatives such as etherified cellulose derivatives, including alkyl celluloses, hydroxyalkyl celluloses, and alkylhydroxyalkyl celluloses, for example, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; starch and fractionated starch; agar; alginic acid and alginates; gum arabic; agarose; carrageenan; dextrans; destins; fructans; chitosans; glycogens; and glucans.
• rectal administration is also a preferred administration route.
• enemas or rectal suppositories are preferred.
• compositions for administering VEGF are preferably those which target the VEGF to the GI tract, such as oral or rectal administration, less preferred but still useful are compositions adapted for other routes of administration, such as vaginal or parenteral administration.
• Chronic duodenal ulcers were induced in Sprague-Dawley female rats (160-200g) by administering cysteamine-HCI (25 mg/100g) 3 times at 4-hour intervals by gavage and cortisone (5 mg/100g) s.c. 4 hours after the last dose of cystemine.
• cysteamine-HCI 25 mg/100g
• cortisone 5 mg/100g
• the animals were anesthetized and laparatomized on the third day following treatment with cysteamine-HCI. After randomization, treatment was started with either vehicle saline (controls) or human VEGF (PeproTech, Canton, MA) at a dose of 1 ⁇ g/100g once daily by gavage for 21 days.
• the size of duodenal ulcers was measured, evaluated by stereomicroscopic planimetry and histologic sections taken. The results revealed that the size of duodenal ulcers in controls was 7.4 ⁇ 1.6 mm 2 . In contrast, the size of the ulcers in the VEGF-treated group were 1.9 ⁇ 0.9 mm 2 (p ⁇ 0.05), histologically accompanied by complete healing or prominent angiogenesis and granulation tissue production. The density of blood vessels per x400 magnification field in the granulation tissue at the ulcer edge was 8.0 ⁇ 0.5 in the controls as opposed to 16.9 ⁇ 1.9 (p ⁇ 0.001) in the VEGF-treated rats. Thus, oral treatment of rats with VEGF (VPF) accelerated the healing of cysteamine-induced chronic duodenal ulcers. In addition, the healing was accompanied by complete mucosal restoration and stimulation of angiogenesis and granulation tissue production.
• Example 2 Example 2
• VEGF vascular endothelial growth factor
• HML hemorrhagic mucosal lesions
• Sprague-Dawley rats (170-200 g) were given 0.1 ml of 6% iodoacetamide (Sigma) in 1% methyl-cellulose intracolonically (i.e.) with Nelston catheter 7 cm from the anus to induce ulcerative colitis-like lesions. From the second day, the rats were treated with vehicle saline or VEGF
• VEGF vascular endothelial growth factor

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• 1998
  • 1998-04-15 EP EP98919780A patent/EP1005355A4/de not_active Withdrawn
  • 1998-04-15 WO PCT/US1998/007686 patent/WO1998046249A1/en not_active Ceased

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