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WO1999016436A1 - Compositions pharmaceutiques utilisees dans le traitement de la maladie intestinale inflammatoire et du syndrome du colon irritable - Google Patents

Compositions pharmaceutiques utilisees dans le traitement de la maladie intestinale inflammatoire et du syndrome du colon irritable Download PDF

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Publication number
WO1999016436A1
WO1999016436A1 PCT/GB1998/002933 GB9802933W WO9916436A1 WO 1999016436 A1 WO1999016436 A1 WO 1999016436A1 GB 9802933 W GB9802933 W GB 9802933W WO 9916436 A1 WO9916436 A1 WO 9916436A1
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WO
WIPO (PCT)
Prior art keywords
composition
nitric oxide
oxide donor
disease
glyceryl
Prior art date
Application number
PCT/GB1998/002933
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English (en)
Inventor
John Rhodes
Brian Kenneth Evans
Original Assignee
John Rhodes
Brian Kenneth Evans
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by John Rhodes, Brian Kenneth Evans filed Critical John Rhodes
Priority to CA002304516A priority Critical patent/CA2304516A1/fr
Priority to JP2000513572A priority patent/JP2001517697A/ja
Priority to EP98945401A priority patent/EP1019038A1/fr
Priority to AU92731/98A priority patent/AU9273198A/en
Publication of WO1999016436A1 publication Critical patent/WO1999016436A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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
    • 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

  • This invention relates to use of a nitric oxide donor for the treatment of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and to post- gastrically delayed release oral (DRO) and rectally administrable compositions containing a nitric oxide or a nitric oxide donor.
  • IBD inflammatory bowel disease
  • IBS irritable bowel syndrome
  • DRO post- gastrically delayed release oral
  • IBS is a functional bowel disorder of abdominal pain and altered bowel habit. Pain is characteristically relieved by defecation and may be associated with increase or decrease in stool frequency, alterations in stool consistency, straining or urgency, a sensation of incomplete evacuation, passage of mucus, or abdominal distension. The pathophysiology is poorly understood despite the fact that about a quarter of the population in the UK may exhibit the symptoms.
  • IBD ulcerative colitis
  • Ulcolitis a chronic non-specific inflammatory condition of the gastro-intestinal tract
  • Crohn's disease and ulcerative colitis including protococolitis, ileocolitis, protitis and pouchitis.
  • the aetiology of these diseases is uncertain.
  • Many inflammatory mediators have been proposed including prostanoids, leu otrienes, platelet activating factor, cytokines, and free oxygen radicals. Although specific inhibitors of most of these have been tried in experimental models, the most effective drugs currently available for these diseases have a broad activity against inflammatory processes.
  • Crohn's disease is characterised by thickened areas of the gastro-intestinal wall, with inflammation extending through all layers, deep ulceration and fissuring of the mucosa, and the presence of granulomas. Affected areas may occur in any part of the gastro- intestinal tract, although the terminal ileum is frequently involved, and they may be interspersed with areas of relatively normal tissue. Symptoms depend on the site of disease but may include abdominal pain, diarrhoea, fever, weight loss and rectal bleeding.
  • ulcerative colitis the disease is limited to the colon and rectum. Inflammation is superficial but continuous over the affected area and granulomas are rare. In mild disease, the rectum alone may be affected (proctitis) . In severe disease ulceration is extensive and much of the mucosa may be lost, with an increased risk of toxic dilatation of the colon, a potentially life-threatening complication.
  • Glyceryl trinitrate and other organic nitrates have been the mainstays of therapy in cardiovascular disease for many years. In recent years, it has been found that these compounds are actually prodrugs for nitric oxide. This in turn has been found to have two main roles: as a vasodilator and as an antiplatelet agent (The American Journal of Cardiology Volume 70, Sept. 24, 1992: A Symposium Nitroglycerin Therapy) . Glyceryl trinitrate and other nitric oxide donors were also found to be useful in the treatment of anal fissures (WO-A-9532715) .
  • nitric oxide levels in the intestines were more than 100 times higher in ulcerative colitis patients and 30 times higher in patients with Crohn's as compared to normal patients.
  • nitric oxide was suggested as an inhibitory nonadrenergic noncholinergic (NANC) neurotransmitter which could play an important role in the autonomic innervation of smooth muscle, in the gastrointestinal tract, the pelvic viscera and the airways.
  • NANC nonadrenergic noncholinergic
  • nitric oxide and physiological derivatives thereof can treat both IBD and IBS.
  • the nitric oxide is delivered in vivo classically by a nitric oxide donor such as is used to treat angina pectoris.
  • nitric oxide could also be introduced directly to the intestine, such as in the form of a gas or dissolved gas.
  • a post-gastric delayed release oral (DRO) or a rectally administrable pharmaceutical composition for the treatment or prophylaxis of IBD or IBS said composition comprising nitric oxide or a nitric oxide donor or pharmacologically acceptable derivative thereof and a pharmaceutically acceptable carrier or vehicle.
  • nitric oxide or a nitric oxide donor or pharmacologically acceptable derivative thereof in the preparation of a medicament for the treatment or prophylaxis of IBD or IBS.
  • a further aspect of the invention is a method for the treatment of IBD or IBS comprising administering to the patient a nitric oxide or a nitric oxide donor or physiologically acceptable derivative thereof.
  • the nitric oxide donor can be selected from the group of compounds known as nitrovasodilators and is preferably an organic nitrate or nitrite such as glyceryl trinitrate, amyl nitrate, octyl nitrate, propatylnitrate, sorbide nitrate, trolnitrate (phosphate), ethylene glycol dinitrate, glyceryl 1, 2-dinitrate, glyceryl 1,3-di- nitrate, glyceryl 1-mononitrate, butane 1,2,4-triol nitrate, mannitol hexanitrate, pentaerythrityl tetra- nitrate, pentaerythrityl trinitrate, isosorbide dinitrate, isosorbide mononitrate, erythrityl tetra- nitrate, or other organic esters of nitric acid of the formula R- [C-0-N0
  • nitric oxide donors are the S-nitrosothiols such as S-nitroso-N- acetylpenicillamine (SNAP) , S-nitrosoglutathione (GSNO) (described in more detail in Analytical Biochemistry 249, 1-9 (1997)), S-nitroso-N-acetylcysteine, S-nitroso- cysteine, S-nitroso-homocysteine, S-nitrosopantathoeine derivatives and S-nitraso-captopril . It is not known how the nitric oxide or its derivatives improve the disease state, but the inflammation is decreased.
  • nitric oxide acts either directly or indirectly to help resolve the disease
  • a derivative of nitric oxide such as the S-nitrosothiols may be involved in the mechanistic pathway. Therefore physiological derivatives of nitric oxide which are metabolised from or as a result of nitric oxide are also within the scope of the invention.
  • the term nitric oxide donor also encompasses pharmaceutically acceptable salts thereof .
  • the nitric oxide donor is preferably delivered to the small or large intestine, rectally or via a post- gastric DRO composition.
  • the active agent can be delivered to the disease site and is believed to exhibit a beneficial topical action against both IBD and irritable bowel system.
  • systemic absorption from the intestine of glyceryl trinitrate and other nitric oxide donors is limited by a high first pass hepatic metabolism, the side effects such as headaches and nausea classically present with nitric oxide is minimised.
  • high doses of nitric oxide donor can be delivered to treat the disease without the normal concomitant side effects.
  • glyceryl trinitrate is particularly preferred.
  • a preferred form of the invention provides a delayed and sustained-release pharmaceutical composition for oral administration.
  • delayed release we mean that release is substantially post-gastric
  • sustained release we mean that the total release of the nitric oxide donor is slow and sustained over a period of time, as opposed to being released as a bolus.
  • the sustained release of the nitric oxide donor will preferably be over a 2 to 12 hour period, preferably a 4 to 8 hour period, such as a 4 to 6 hour period.
  • the pharmaceutical composition takes the form of an enema formulation such as a liquid or foam enema which is rectally administered to the lower colon.
  • enema formulations comprise an effective amount of nitric oxide donor dissolved or dispersed in a suitable flowable carrier vehicle, such as deionised and/or distilled water.
  • the formulation can be thickened with one or more thickeners, such as xanthan gum or carbomer, can contain a buffer, and can also comprise an effective amount of a lubricant such as a natural or synthetic fat or oil, e.g. a tris-fatty acid glycerate or lectithin.
  • Non-toxic non-ionic surfactants can also be included as wetting agents and dispersants.
  • Unit doses of enema formulations can be administered from pre-filled bags or syringes.
  • the carrier vehicle may also comprise an effective amount of a foaming agent such as n-butane, propane or i-butane.
  • foaming agent such as n-butane, propane or i-butane.
  • Such formulations can be delivered from a preloaded syringe or pressurised container, so that the vehicle is delivered to the colon as a foam, which inhibits its escape from the target site.
  • Enema foams may also comprise expanding agents and foam-stabilisers.
  • the viscosity of the enema is preferably 3 to 5 milliNewton metres (mNm) as measured using a RheomatTM 108 rotary viscometer (50 to 85 Pa.s) and the pH is preferably 3.5 to 5.5.
  • the DRO composition of the invention are ideally coated so as to release the unit dosage form in the lower intestinal tract, e.g. in the mid to distal small bowel and/or in the colon of the patient.
  • Enteric coatings such as acrylic or methacrylic acid resins remain intact in the stomach, but dissolve and release the contents of the dosage form once it reaches the region of the intestine where the pH is optimal for dissolution for the coating used.
  • the enteric coating should dissolve in the pH of the jejunum, ileum or colon. Thereafter preferably sustained release, of the nitric oxide donor will take place.
  • nitric oxide donor such as glyceryl trinitrate in a rectally administrable composition typically an enema or foam enema
  • the dosage of nitric oxide donor such as glyceryl trinitrate in a rectally administrable composition typically an enema or foam enema would be 1 to 50 mg, preferably 1 to 15 mg.
  • Aqueous film-coating technology is advantageously employed for the enteric coating of pharmaceutical dosage forms.
  • a useful enteric coating is one that remains intact in the low pH of the stomach, but readily dissolves when the optimum dissolution pH of the particular coating is reached. This can vary between pH 3 to 7.5 depending on the chemical composition of the enteric coating. The thickness of the coating will depend on the solubility characteristics of the coating material and the site to be treated.
  • the unit dosage of nitric oxide donor, such as isosorbide dinitrate or glyceryl trinitrate, in a rectally administrable (e.g. enema) or DRO composition is 1 to 50 mg, more preferably 1 to 30 mg, more preferably still 1 to 15 mg.
  • the inventors are presently using 3 mg glyceryl trinitrate in their trial.
  • the total daily dose for a 70 kg patient for any composition would be from 3 to 100 mg, preferably up to 30 mg.
  • a delayed release oral formulation in which an enteric coated capsule containing a nitric oxide donor of the invention has a coating, thickness of coating and dissolution profile as described in EP-A-0097651 (the contents of which are incorporated herein by reference) .
  • a delayed-release formulation can also be achieved by coating a powder or microgranular formulation of a nitric oxide donor of the invention with, for example, ethylcellulose or an acrylic resin based on acrylic and methacrylic acid esters containing a low content of quaternary ammonium groups at a predetermined molar ratio. Suitable resins include EUDRAGITTM L, S, RL and RS .
  • the coated microgranules or material may then be compressed into tablets or packed into hard gelatin capsules suitable for oral administration. Suitable coatings are thicknesses to achieve this sustained release are disclosed in EP-A-0572486 (incorporated herein by reference) .
  • a sustained release of the nitric oxide donor can also be achieved by incorporating it into a saturated polyglycolized glyceride excipient comprising a mono-, di- and triglycerides and of mono- di-fatty acid esters of polyethylene glycol (PEG) hydrophobic matrix.
  • PEG polyethylene glycol
  • the polyglycolized glyceride can be adapted to have a different melting point and hypophilic-lipophilic balance (HLB) depending on the type and proportion of triglyceride and fatty acid esters of PEG used.
  • the melting point/HLB could suitably be 42/12, 44/14 or
  • the melting point/HLB could suitably be 46/07, 48/09, 53/10 or 50/13.
  • a particularly preferred melting point/HLB, particularly for use with isosorbide dinitrate and glyceryl trinitrate is a mixture of 42/12 and 50/13, or 50/13 alone.
  • An example of a commercially available polyglycolized excipient for use with the invention is GelucireTM (available from Gattefosse, France) .
  • a polyacrylic acid derivative can also be used to achieve sustained release of the nitric oxide donor by, for example, forming a nitric oxide donor - polyacrylate complex.
  • a preferred polyacrylate is a carbomer, such as Carbopol (available from B.F. Goodrich) .
  • Carbomers are synthetic, high molecular weight, non-linear, polymers of acrylic acid, cross-linked with polyalkenyl polyether.
  • a sustained release nicotine-carbomer complex in an enteric coated capsule is described in O-A-9728301 (incorporated herein by reference) and the same technology would be applicable to the present invention.
  • anionic polymers particularly anionic acrylate polymers and especially anionic polymers synthesised from methacrylic acid and methyl methacrylate, may be used.
  • Carboxyl groups in such polymers render the material capable of forming salts in alkaline environments in which they are sparingly soluble while in the acid to neutral pH range the coatings are substantially insoluble and substantially impermeable thus protecting the active ingredient contained within from gastric acids.
  • the coatings may be applied conventionally, typically as a lacquer or solution containing the acidic material from which the solvent or carrier is then evaporated.
  • a particularly suitable acidic material for coating the compositions of the invention for lower bowel treatment is the anionic methacrylate polymer sold under the registered Trade Mark EUDRAGIT S by Rohm Pharma GmbH of Darmstadt, Germany. Capsules coated with EUDRAGITTM S100 disintegrate in the ascending colon of the patients.
  • EUDRAGITTM S is a copolymer of methacrylic acid and methyl methacrylate in which the ratio of free carboxyl groups to ester groups is approximately 1:2 and having a mean molecular weight of 135,000.
  • Coatings of acidic materials such as that sold as EUDRAGIT L (composition as EUDRAGIT S but having a carboxyl/ester ratio of 1:1), may be used in the coating of tablets or capsules to release active agents in the small intestine, although they may be applied in much greater thicknesses than was hitherto conventional thereby delaying release of the active agent until the tablet or capsule reaches the large intestine. It will be apparent to the skilled person that mixtures of substances, such as EUDRAGITTM S and EUDRAGIT L, may be used as coating materials.
  • coating thicknesses of 25 to 200 ⁇ m, and especially 75 to 150 ⁇ m are preferred using 3 to 25 mg, preferably 8 to 15 mg, of acidic coating material per cm 2 of tablet or capsule surface.
  • the precise coating thickness will however depend upon the solubility characteristics of the acidic material used and site to be treated.
  • the coating material may contain additives such as colouring agents, plasticisers, opaque film coatings, gloss producers and auxiliary materials (e.g. talc).
  • auxiliary materials e.g. talc
  • the provision of the coating to the compositions of the invention may be achieved in conventional manner, e.g. by the use of spraying, fluidized bed, immersion tube and immersion blade techniques. (See for example D. Dreher "Film coatings on acrylic resin basis for dosage forms with controlled drug release" Pharma International 1/2 (1975) 3 ) .
  • the coating is applied from aqueous suspension.
  • the coating can, and usually will, contain plasticiser and possibly other coating additives such as colouring agents, gloss producers, talc and/or magnesium stearate as well known in the coating art.
  • plasticiser especially diethyl phthalate, although the presence of such a plasticiser may not be necessary when using an aqueous suspension for coating.
  • the capsule into which the coated material is loaded will be a soft or, preferably, hard gelatin capsule although other capsules which will dissolve in the small intestine can be used.
  • the capsule is coated with an enteric coating which will protect it during passage through the stomach.
  • Any conventional enteric coating material which is soluble in the small intestine can be used, e.g. cellulose acetate phthalate, hydroxy propylmethyl cellulose phthalate or initially ethyl cellulose followed by polyvinyl acetate phthalate, but it is preferred to use an anionic polymer having an appropriate dissolution profile.
  • the presently preferred polymers are anionic carboxylic polymers, e.g. EUDRAGITTM L.
  • the tablet or capsule cores for the compositions of the present invention may also contain additives such as fillers (e.g. lactose or dicalcium phosphate), binders (e.g. starch or polyvinylpyrrolidone) , lubricants (e.g. magnesium stearate, stearic acid or talc) and disintegrants (e.g. alginic acid or sodium starch glycolate) .
  • the tablet or capsule cores may be prepared in a conventional manner.
  • a suitable disintegrant such as ExplotabTM (a brand of sodium starch glycollate made by K&K Greef) , or PrimojelTM (from AVEBE, Netherlands) in the orally administered compositions according to the invention.
  • ExplotabTM a brand of sodium starch glycollate made by K&K Greef
  • PrimojelTM from AVEBE, Netherlands
  • a capsule containing a nitric oxide donor, such as glyceryl trinitrate, in a polyglycolized excipient such as GelucireTM is enteric coated, such as by EudragitTM L (dissolving at pH6.8) or EudragitTM S for release in the mid to distal small bowel and/or colon.
  • each capsule contained 120 mg of the isosorbide powder dispersed in 440 mg of GelucireTM.
  • Gelatin capsules containing 30 mg isosorbide dinitrite and GelucireTM 42/12 plus GelucireTM 50/13 (10% and 15%) were prepared as outlined above and coated using EudragitTM-L.
  • Example 2 was repeated, but using 3 mg glyceryl trinitrite in place of the 30 mg isosorbide dinitrate.
  • GTN oral glycerol trinitrate
  • the GTN was very well tolerated.
  • One patient had vague headaches for a couple of days, and a second patient had a fainting episode but both were able to continue with the treatment.
  • the CDAI was lower at 6 weeks than on commencement in ten patients and the reduction in CDAI appeared clinically significant in 6 of these patients, About half of the patients had a reduction in stool frequency but there was little effect on the pain score .

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La maladie intestinale inflammatoire et le syndrome du côlon irritable sont traités par l'administration orale ou rectale à un patient d'une quantité efficace d'un oxyde nitrique ou d'un donneur d'oxyde nitrique ou d'un dérivé physiologiquement acceptable de ces derniers. De préférence, le composé actif est le glycéryl trinitrate.
PCT/GB1998/002933 1997-09-30 1998-09-29 Compositions pharmaceutiques utilisees dans le traitement de la maladie intestinale inflammatoire et du syndrome du colon irritable WO1999016436A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002304516A CA2304516A1 (fr) 1997-09-30 1998-09-29 Compositions pharmaceutiques utilisees dans le traitement de la maladie intestinale inflammatoire et du syndrome du colon irritable
JP2000513572A JP2001517697A (ja) 1997-09-30 1998-09-29 炎症性腸疾患および過敏性腸症候群を治療するための医薬組成物
EP98945401A EP1019038A1 (fr) 1997-09-30 1998-09-29 Compositions pharmaceutiques utilisees dans le traitement de la maladie intestinale inflammatoire et du syndrome du colon irritable
AU92731/98A AU9273198A (en) 1997-09-30 1998-09-29 Pharmaceutical composition for the treatment of inflammatory bowel disease and irritable bowel syndrome

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9720797.1A GB9720797D0 (en) 1997-09-30 1997-09-30 Pharmaceutical composition for the treatment of inflammatory bowel disease and irritable bowel syndrome
GB9720797.1 1997-09-30

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Publication Number Publication Date
WO1999016436A1 true WO1999016436A1 (fr) 1999-04-08

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PCT/GB1998/002933 WO1999016436A1 (fr) 1997-09-30 1998-09-29 Compositions pharmaceutiques utilisees dans le traitement de la maladie intestinale inflammatoire et du syndrome du colon irritable

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EP (1) EP1019038A1 (fr)
JP (1) JP2001517697A (fr)
AU (1) AU9273198A (fr)
CA (1) CA2304516A1 (fr)
GB (1) GB9720797D0 (fr)
WO (1) WO1999016436A1 (fr)
ZA (1) ZA988920B (fr)

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JP2003513045A (ja) * 1999-11-01 2003-04-08 ロデバ・リミテッド 便秘及び過敏性大腸症候群を治療・処置するための組成物
EP1690557A1 (fr) * 2005-02-11 2006-08-16 NOLabs AB Dispositif de traitement de troubles rectals et son procédé de fabrication
WO2006084913A3 (fr) * 2005-02-11 2006-11-16 Nolabs Ab Dispositif pour traiter des troubles rectaux, et procede de fabrication associe comportant de l'oxyde nitrique
EP1924143A2 (fr) * 2005-08-12 2008-05-28 ATK Thiokol Propulsion Inc. Composes o-nitro, compositions pharmaceutiques correspondantes, et leurs utilisations
US7745643B2 (en) 2005-08-12 2010-06-29 Alliant Techsystems Inc. Methods of synthesizing cyclic nitro compounds
US7776908B2 (en) 2001-09-14 2010-08-17 Arizona Board Of Regents Wortmannin analogs and methods of using same
US8471041B2 (en) 2010-02-09 2013-06-25 Alliant Techsystems Inc. Methods of synthesizing and isolating N-(bromoacetyl)-3,3-dinitroazetidine and a composition including the same
AU2012203798B2 (en) * 2005-08-12 2013-11-07 Northrop Grumman Systems Corporation O-nitro compounds, pharmaceutical compositons thereof and uses thereof
US8664247B2 (en) 2011-08-26 2014-03-04 Radiorx, Inc. Acyclic organonitro compounds for use in treating cancer
US9139519B2 (en) 2011-10-07 2015-09-22 Epicentrx, Inc. Organonitro thioether compounds and medical uses thereof
WO2017137489A1 (fr) * 2016-02-12 2017-08-17 Dsm Ip Assets B.V. Compositions antiméthanogéniques et leurs utilisations
US9987270B1 (en) 2015-10-29 2018-06-05 Epicentrix, Inc. Treatment of gliomas using organonitro compound combination therapy
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CN110200921A (zh) * 2019-06-19 2019-09-06 华中科技大学 一种具有靶向作用的抗炎脂质体及其制备与应用
US11008287B2 (en) 2016-10-14 2021-05-18 Epicentrx, Inc. Sulfoxyalkyl organonitro and related compounds and pharmaceutical compounds for use in medicine
US11510901B2 (en) 2018-01-08 2022-11-29 Epicentrx, Inc. Methods and compositions utilizing RRx-001 combination therapy for radioprotection
US11576895B2 (en) 2016-01-11 2023-02-14 Epicentrx, Inc Compositions and methods for intravenous administration of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone
US11660286B2 (en) 2011-10-07 2023-05-30 Epicentrx, Inc. Methods and compositions comprising a nitrite-reductase promoter for treatment of medical disorders and preservation of blood products
US11744859B2 (en) 2017-07-07 2023-09-05 Epicentrx, Inc. Compositions and methods for parenteral administration of therapeutic agents

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EP1941876A1 (fr) * 2006-12-28 2008-07-09 Lacer, S.A. Derivés du mononitrite de l'isosorbide destinées au traitement de l'inflammation et l'hypertension oculaire

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EP1690557A1 (fr) * 2005-02-11 2006-08-16 NOLabs AB Dispositif de traitement de troubles rectals et son procédé de fabrication
WO2006084913A3 (fr) * 2005-02-11 2006-11-16 Nolabs Ab Dispositif pour traiter des troubles rectaux, et procede de fabrication associe comportant de l'oxyde nitrique
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EP1924143A4 (fr) * 2005-08-12 2009-05-13 Atk Thiokol Propulsion Inc Composes o-nitro, compositions pharmaceutiques correspondantes, et leurs utilisations
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US9139519B2 (en) 2011-10-07 2015-09-22 Epicentrx, Inc. Organonitro thioether compounds and medical uses thereof
US11660286B2 (en) 2011-10-07 2023-05-30 Epicentrx, Inc. Methods and compositions comprising a nitrite-reductase promoter for treatment of medical disorders and preservation of blood products
US9468625B2 (en) 2011-10-07 2016-10-18 Epicentrx, Inc. Organonitro thioether compounds and medical uses thereof
US11160784B1 (en) 2015-10-20 2021-11-02 Epicentrx, Inc. Treatment of brain metastases using organonitro compound combination therapy
US10342778B1 (en) 2015-10-20 2019-07-09 Epicentrx, Inc. Treatment of brain metastases using organonitro compound combination therapy
US10543208B2 (en) 2015-10-29 2020-01-28 Epicentrx, Inc. Treatment of gliomas using organonitro compound combination therapy
US9987270B1 (en) 2015-10-29 2018-06-05 Epicentrix, Inc. Treatment of gliomas using organonitro compound combination therapy
US11701351B2 (en) 2015-10-29 2023-07-18 Epicentrx, Inc. Treatment of gliomas using organonitro compound combination therapy
US11576895B2 (en) 2016-01-11 2023-02-14 Epicentrx, Inc Compositions and methods for intravenous administration of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone
WO2017137489A1 (fr) * 2016-02-12 2017-08-17 Dsm Ip Assets B.V. Compositions antiméthanogéniques et leurs utilisations
US11008287B2 (en) 2016-10-14 2021-05-18 Epicentrx, Inc. Sulfoxyalkyl organonitro and related compounds and pharmaceutical compounds for use in medicine
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CA2304516A1 (fr) 1999-04-08

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