EP1019038A1 - Pharmaceutical composition for the treatment of inflammatory bowel disease and irritable bowel syndrome - Google Patents
Pharmaceutical composition for the treatment of inflammatory bowel disease and irritable bowel syndromeInfo
- Publication number
- EP1019038A1 EP1019038A1 EP98945401A EP98945401A EP1019038A1 EP 1019038 A1 EP1019038 A1 EP 1019038A1 EP 98945401 A EP98945401 A EP 98945401A EP 98945401 A EP98945401 A EP 98945401A EP 1019038 A1 EP1019038 A1 EP 1019038A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- nitric oxide
- oxide donor
- disease
- glyceryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 208000022559 Inflammatory bowel disease Diseases 0.000 title claims abstract description 15
- 208000002551 irritable bowel syndrome Diseases 0.000 title claims abstract description 14
- 238000011282 treatment Methods 0.000 title claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000002840 nitric oxide donor Substances 0.000 claims abstract description 39
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960003711 glyceryl trinitrate Drugs 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims description 45
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- 208000011231 Crohn disease Diseases 0.000 claims description 15
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- 201000010099 disease Diseases 0.000 claims description 12
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- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 7
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- 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
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- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
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- GFVHBTOOPNJKLV-UHFFFAOYSA-N 1,2-dinitroglycerol Chemical compound [O-][N+](=O)OC(CO)CO[N+]([O-])=O GFVHBTOOPNJKLV-UHFFFAOYSA-N 0.000 claims description 2
- HXWLJBVVXXBZCM-UHFFFAOYSA-N 2,3-dihydroxypropyl nitrate Chemical compound OCC(O)CO[N+]([O-])=O HXWLJBVVXXBZCM-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- HSNWZBCBUUSSQD-UHFFFAOYSA-N amyl nitrate Chemical compound CCCCCO[N+]([O-])=O HSNWZBCBUUSSQD-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- FFWDIMDPOXTULN-UHFFFAOYSA-N butane-1,2,4-triol;nitric acid Chemical compound O[N+]([O-])=O.OCCC(O)CO FFWDIMDPOXTULN-UHFFFAOYSA-N 0.000 claims description 2
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- BRBAEHHXGZRCBK-UHFFFAOYSA-N pentrinitrol Chemical compound [O-][N+](=O)OCC(CO)(CO[N+]([O-])=O)CO[N+]([O-])=O BRBAEHHXGZRCBK-UHFFFAOYSA-N 0.000 claims description 2
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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.
- 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.
- 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.
- 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 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.
- 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
- 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.
- 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.
- 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)
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- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Emergency Medicine (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
Inflammatory bowel disease and irritable bowel syndrome are treated by oral or rectal administration to a patient of an effective amount of a nitric oxide or a nitric oxide donor or physiologically acceptable derivative thereof. Preferably, the active compound is glyceryl trinitrate.
Description
PHARMACEUTICAL COMPOSITION FOR THE TREATMENT
OF INFLAMMATORY BOWEL DISEASE AND
IRRITABLE BOWEL SYNDROME
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.
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 covers chronic non-specific inflammatory conditions of the gastro-intestinal tract, of which the two major forms are 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.
In 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.
Numerous compounds have been examined in the last twenty years to find effective measures for the treatment of IBD. Such compounds include azathioprine, arsenicals, disodium cromoglycate, metronidazole, lignocaine, 5- aminosalicyclic acid (5-ASA) , fish oils, thalidomide and cyclosporin. The wide diversity of treatments is an indication of the complexity and intransigence of this condition.
There have been a number of different theories of how Crohn's disease is initiated. Surgically resected
specimens from patients with Crohn's disease when perfused with resin, show substantial damage to the normal blood supply - particularly in the areas which are macroscopically abnormal (Lancet 1989, ii : 1057-1062) . This was coined λmultifocal gastrointestinal infarction' . Similar pathological changes are seen in animal models when the blood supply is obstructed (Gastroenterology 1992; 102 (5) :1591-1596) . Granulomas, the pathological hallmark of Crohn's, appear to form mainly within the walls of blood vessels (Gastroenterology 1991;
100 (5) :1279-1287) . Vascular damage with rupture of capillaries occurs early on in the damage process, even before the wall is infiltrated by inflammatory cells (Gut 1993; 34:375-381) .
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) .
In Nature Medicine, Jan. 1997; (3)1: 30-31, it is reported that 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. In Pharmacol. Rev. 1991; 43:109-142
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. In US-A-5574068 , use of S-nitrosothiols (nitric oxide donors) were proposed for disorders which involve non-vascular smooth muscle such as respiratory disorders, gastrointestinal disorders, urological dysfunctions, impotence, uterine dysfunction and premature labour.
The inventors have now discovered that 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. However nitric oxide could also be introduced directly to the intestine, such as in the form of a gas or dissolved gas.
In a first aspect of the invention, there is provided 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.
In a second aspect of the invention, there is provided use of 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-N02] x, where R is an alkyl, cycloalkyl, or alkenyl group having from 1 to 18 carbon atoms or an aromatic group having from 6 to 18 carbon atoms and where x is an integer of from 1 to 5, or a combination of two or more of the foregoing. Other preferred 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.
Although it is thought that 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. In this way 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. Furthermore since 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. Thus high doses of nitric oxide donor can be delivered to treat the disease without the normal concomitant side effects. In this respect glyceryl trinitrate is particularly preferred.
A preferred form of the invention provides a delayed and sustained-release pharmaceutical composition for oral
administration. By delayed release we mean that release is substantially post-gastric, and by 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.
According to one embodiment of the present invention, 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. Useful 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. In the case of a pressurised enema formulation the carrier vehicle may also comprise an effective amount of a 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 Rheomat™ 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 majority of the release will be targeted to the part of the small intestine or colon where the active disease is prevalent and this varies for Crohn's disease and ulcerative colitis. Thus typically for an enteric coated capsule, 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.
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.
Preferably 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.
In one embodiment of the invention, a delayed release oral formulation is provided 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 EUDRAGIT™ 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. 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. For example, for a more lipophilic nitric oxide donor the melting point/HLB could suitably be 42/12, 44/14 or
50/13. On the other hand, for more hydrophilic nitric oxide donor such as various water soluble salts, 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 Gelucire™ (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.
As acidic material for the coating of oral compositions of the invention for delayed-release, 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 EUDRAGIT™ S100 disintegrate in the ascending colon of the patients. EUDRAGIT™ 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 EUDRAGIT™ S and EUDRAGIT L, may be used as coating materials.
In general coating thicknesses of 25 to 200 μm, and especially 75 to 150 μm, are preferred using 3 to 25 mg, preferably 8 to 15 mg, of acidic coating material per cm2 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.
Together with the acidic material, the coating material may contain additives such as colouring agents, plasticisers, opaque film coatings, gloss producers and 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 ) . Preferably, 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. In particular, anionic carboxylic acrylic polymers usually contain 10 to 25% by weight of a plasticiser especially diethyl phthalate, although the presence of such a plasticiser may not be necessary when using an aqueous suspension for coating.
Usually, 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. EUDRAGIT™ L.
In addition to the nitric oxide donor ingredient, the tablet or capsule cores (e.g. in the form of microgranules) 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.
It is preferable to include a suitable disintegrant , such as Explotab™ (a brand of sodium starch glycollate made by K&K Greef) , or Primojel™ (from AVEBE, Netherlands) in the orally administered compositions according to the invention.
In a particularly preferred DRO form of the invention, a capsule containing a nitric oxide donor, such as glyceryl trinitrate, in a polyglycolized excipient such as Gelucire™, is enteric coated, such as by Eudragit™ L (dissolving at pH6.8) or Eudragit™ S for release in the mid to distal small bowel and/or colon.
The invention will now be described by way of example only in which the attached figure is a graph of the release profiles of isosorbide dinitrate from various
capsules containing Gelucire™ of different melting points/HLB.
Example 1
2% w/w isosorbide dinitrate in lactose powder (120 mg =
30 mg isosorbide dinitrate) was incorporated into the melted Gelucire™ and dispersed into size 1 opaque hard gelatin capsules. Initially six formulations were prepared using Gelucire™ (G) 42/12, 44/14, 53/10, 53/13,
46/07 and 48/09 so that each capsule contained 120 mg of the isosorbide powder dispersed in 440 mg of Gelucire™.
Subsequently additional formulations were prepared using mixtures of two Gelucires™. These were G42/12 1 part plus G50/13 2 parts (33%) , G42/12 1 part plus G50/13 6 parts (15%) , and G42/12 1 part plus G50/13 9 parts (10%) .
The dissolution profile of these capsules were tested using a Erweka™ Tablet dissolution tester model DT80.
Peak investigation was determined from which the amount (in mg) of isosorbide dinitrate present in the sample was calculated. The results are shown in the attached figure. A good release pattern over a 4-6 hour time period, (and released 30 mg of isosorbide dinitrate from the Gelucire™) was achieved by the mixture of Gelucire™ 42/12 plus Gelucire™ 50/13, 10% and 15%. These are indicated on the attached figure as G42/50 (10%) and
G42/50 (15%) . The capsule containing Gelucire™ 50/13 also gave a good sustained release of isosorbide dinitrate .
Example 2
Gelatin capsules containing 30 mg isosorbide dinitrite and Gelucire™ 42/12 plus Gelucire™ 50/13 (10% and 15%) were prepared as outlined above and coated using Eudragit™-L.
Example 3
Example 2 was repeated, but using 3 mg glyceryl trinitrite in place of the 30 mg isosorbide dinitrate.
Example 4
A preliminary clinical trial was conducted to assess the effect of oral glycerol trinitrate (GTN) in active Crohn's disease. 14 patients were treated for 6 weeks with 2 capsules of Example 3 (6 mg GTN) twice daily and the CDAI assessed at commencement of the trial and after 3 and 6 weeks. The treatment was withdrawn over the subsequent 4 weeks to enable the patients to assess the effect upon their symptoms. Five of the patients had ileal Crohn's disease, two patients had large bowel Crohn's disease and seven patients had Crohn's disease at both sites. The CDAI was greater than 1 50 in only 7 of the patients at commencement of the trial. Nine of the patients were receiving steroids. There was some change
in the steroid dose in three of them during the course of the trial (one was on a reducing dose before entry; two had an increase in steroids during the trial) . One patient had intra-articular steroids for an arthritis and two patients discontinued their steroids on commencement of the trial. These variations in treatment about the time of and during the trial made it a little difficult to draw firm conclusions.
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 .
Five patients requested to continue with the treatment at the end of the trial. All were women with ileal Crohn's disease; two also had small bowel involvement proximal to the terminal ileum; two had recurrent ileal Crohn's disease after surgical resection; and two had colonic involvement. Four of these 5 patients increased the daily dose to 6 capsules (18 mg GTN) without side effects. All 5 patients reported that their symptoms had improved whilst taking GTN over this period and noticed a reduction in episodes of pain.
Claims
1. A post-gastric delayed release oral (DRO) or a rectally administrable pharmaceutical composition for the treatment or prophylaxis of inflammatory bowel disease or irritable bowel syndrome, said composition comprising nitric oxide or a nitric oxide donor or physiologically acceptable derivative thereof and a pharmaceutically acceptable carrier or vehicle.
2. A composition as claimed in Claim 1, wherein the nitric oxide donor is selected from glyceryl trinitrate, amyl nitrate, octyl nitrate, propatylnitrate, sorbide nitrate, trolnitrate (phosphate) , ethylene glycol dinitrate, glyceryl 1, 2 -dinitrate, glyceryl 1,3- dinitrate, glyceryl 1-mononitrate, butane 1,2,4-triol nitrate, mannitol hexanitrate, pentaerythrityl tetranitrate, pentaerythrityl trinitrate, isosorbide dinitrate, isosorbide mononitrate, erythrityl tetranitrate, or other organic esters of nitric acid of the formula R- [C-0-N02] X, where R is an alkyl, cycloalkyl, or alkenyl group having from 1 to 18 carbon atoms or an aromatic group having from 6 to 18 carbon atoms and where X is an integer of from 1 to 5; and an S- nitrosothiol or a combination of two or more of the foregoing.
3. A composition as claimed in Claim 2, wherein the nitric oxide donor is glyceryl trinitrate.
4. A composition as claimed in any one of the preceding claims, wherein the medicament is a DRO composition.
5. A composition as claimed in Claim 4, wherein the DRO composition is an enteric coated tablet, capsule or granules .
6. A composition as claimed in any one of Claims 1 to 3 , wherein the medicament is a rectally administrable composition.
7. A composition as claimed in Claim 6, wherein the rectally administrable composition is a liquid or foam enema .
8. A composition as claimed in any one of the preceding claims wherein the amount of nitric oxide donor per unit dosage form is from 1 to 50 mg.
9. A composition as claimed in Claim 8, wherein said amount is from 1 to 15 mg.
10. A composition as claimed in any one of the preceding claims, wherein the nitric oxide donor is in the form of a complex with a polyacrylate.
11. A composition as claimed in any one of Claims 1 to
9. wherein the nitric oxide donor is incorporated in matrix of a polyglycolized glyceride comprising mono-, di- and triglycerides and mono-, di-fatty acid esters of polyethylene glycol .
12. A composition as claimed in Claim 11 which is an enteric coated capsule comprising 1 to 15 mg glyceryl trinitrate in said matrix, the capsule being coated with an anionic copolymer of methacrylic acid and methylmethacrylate .
13. Use of nitric oxide or a nitric oxide donor or physiologically acceptable derivative thereof in the preparation of a medicament for the treatment or prophylaxis of inflammatory bowel disease or irritable bowel syndrome.
14. A use as claimed in Claim 13 , wherein the disease state is Crohn's disease or ulcerative colitis.
15. A use as claimed in Claim 13 or Claim 14, wherein the nitric oxide donor and dosage are as defined in any one of Claims 1 to 12.
16. A method for the treatment of inflammatory bowel disease or irritable bowel syndrome comprising administering to a patient an effective amount of a nitric oxide or a nitric oxide donor or physiologically acceptable derivative thereof.
Applications Claiming Priority (3)
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 | 1997-09-30 | ||
PCT/GB1998/002933 WO1999016436A1 (en) | 1997-09-30 | 1998-09-29 | Pharmaceutical composition for the treatment of inflammatory bowel disease and irritable bowel syndrome |
Publications (1)
Publication Number | Publication Date |
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EP1019038A1 true EP1019038A1 (en) | 2000-07-19 |
Family
ID=10819864
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP98945401A Withdrawn EP1019038A1 (en) | 1997-09-30 | 1998-09-29 | Pharmaceutical composition for the treatment of inflammatory bowel disease and irritable bowel syndrome |
Country Status (7)
Country | Link |
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EP (1) | EP1019038A1 (en) |
JP (1) | JP2001517697A (en) |
AU (1) | AU9273198A (en) |
CA (1) | CA2304516A1 (en) |
GB (1) | GB9720797D0 (en) |
WO (1) | WO1999016436A1 (en) |
ZA (1) | ZA988920B (en) |
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EP1225897B1 (en) * | 1999-11-01 | 2004-09-08 | RHODES, John | Composition for treatment of constipation and irritable bowel syndrome |
US7081475B2 (en) | 2001-09-14 | 2006-07-25 | Prolx Pharmaceuticals Corp. | Wortmannin analogs and methods of using same |
WO2006084913A2 (en) * | 2005-02-11 | 2006-08-17 | Nolabs Ab | Device for treatment of rectal disorders, and manufacturing process for the same, involving nitric oxide |
EP1690557A1 (en) * | 2005-02-11 | 2006-08-16 | NOLabs AB | Device for treatment of rectal disorders, and manufacturing process for the same |
US7507842B2 (en) | 2005-08-12 | 2009-03-24 | Radiorx, Inc. | Cyclic nitro compounds, pharmaceutical compositions thereof and uses thereof |
AU2012203798B2 (en) * | 2005-08-12 | 2013-11-07 | Northrop Grumman Systems Corporation | O-nitro compounds, pharmaceutical compositons thereof and uses thereof |
US20070135380A1 (en) * | 2005-08-12 | 2007-06-14 | Radiorx, Inc. | O-nitro compounds, pharmaceutical compositions thereof and uses thereof |
EP1941876A1 (en) * | 2006-12-28 | 2008-07-09 | Lacer, S.A. | Isosorbide mononitrate derivatives for the treatment of Inflammation and ocular hypertension |
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 |
US8664247B2 (en) | 2011-08-26 | 2014-03-04 | Radiorx, Inc. | Acyclic organonitro compounds for use in treating cancer |
WO2013052803A2 (en) | 2011-10-07 | 2013-04-11 | Radiorx, Inc. | Methods and compositions comprising a nitrite-reductase promoter for treatment of medical disorders and preservation of blood products |
WO2013052164A1 (en) | 2011-10-07 | 2013-04-11 | Radiorx, Inc. | Organonitro thioether compounds and medical uses thereof |
US10342778B1 (en) | 2015-10-20 | 2019-07-09 | Epicentrx, Inc. | Treatment of brain metastases using organonitro compound combination therapy |
US9987270B1 (en) | 2015-10-29 | 2018-06-05 | Epicentrix, Inc. | Treatment of gliomas using organonitro compound combination therapy |
DK3402480T3 (en) | 2016-01-11 | 2021-06-28 | Epicentrx Inc | COMPOSITIONS AND PROCEDURES FOR INTRAVENOUS ADMINISTRATION OF 2-BROMO-1- (3,3-DINITROAZETIDIN-1-YL) ETHANONE |
WO2017137489A1 (en) * | 2016-02-12 | 2017-08-17 | Dsm Ip Assets B.V. | Anti-methanogenic compositions and uses thereof |
SG11201903312VA (en) | 2016-10-14 | 2019-05-30 | Epicentrix Inc | Sulfoxyalkyl organonitro and related compounds and pharmaceutical compositions for use in medicine |
BR112020000196A2 (en) | 2017-07-07 | 2020-07-07 | Epicentrx, Inc. | compositions for parenteral administration of therapeutic agents |
US11510901B2 (en) | 2018-01-08 | 2022-11-29 | Epicentrx, Inc. | Methods and compositions utilizing RRx-001 combination therapy for radioprotection |
CN110200921B (en) * | 2019-06-19 | 2020-11-17 | 华中科技大学 | Anti-inflammatory liposome with targeting effect and preparation and application thereof |
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US4428925A (en) * | 1981-12-18 | 1984-01-31 | Key Pharmaceuticals, Inc. | Sustained release glycerol trinitrate |
DE3728563A1 (en) * | 1987-08-27 | 1989-03-09 | Pohl Boskamp Gmbh Chem Pharma | MEDICINAL PRODUCT CONTAINING N-ALKYLSCOPOLAMININE SALT AND NITROGLYCERIN, METHOD FOR THE PRODUCTION AND USE THEREOF |
US5004601A (en) * | 1988-10-14 | 1991-04-02 | Zetachron, Inc. | Low-melting moldable pharmaceutical excipient and dosage forms prepared therewith |
WO1993012068A1 (en) * | 1991-12-11 | 1993-06-24 | Brigham And Women's Hospital | S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof |
US5632981A (en) * | 1992-08-24 | 1997-05-27 | The United States Of America As Represented By The Department Of Health And Human Services | Biopolymer-bound nitric oxide-releasing compositions, pharmaceutical compositions incorporating same and methods of treating biological disorders using same |
RU2121830C1 (en) * | 1992-09-18 | 1998-11-20 | Яманоути Фармасьютикал Ко., ЛТД | Hydrogel preparation exhibiting the sustained drug release |
JPH06227969A (en) * | 1993-02-02 | 1994-08-16 | Masayasu Sugihara | Method for improving enteric property of medicine and medicine composition obtained thereby |
US5565466A (en) * | 1993-08-13 | 1996-10-15 | Zonagen, Inc. | Methods for modulating the human sexual response |
DE4420523A1 (en) * | 1994-06-13 | 1995-12-14 | Cassella Ag | Treating and preventing SIRS, e.g. in shock, arthritis or peritonitis |
US5840332A (en) * | 1996-01-18 | 1998-11-24 | Perio Products Ltd. | Gastrointestinal drug delivery system |
-
1997
- 1997-09-30 GB GBGB9720797.1A patent/GB9720797D0/en not_active Ceased
-
1998
- 1998-09-29 JP JP2000513572A patent/JP2001517697A/en active Pending
- 1998-09-29 CA CA002304516A patent/CA2304516A1/en not_active Abandoned
- 1998-09-29 EP EP98945401A patent/EP1019038A1/en not_active Withdrawn
- 1998-09-29 AU AU92731/98A patent/AU9273198A/en not_active Abandoned
- 1998-09-29 WO PCT/GB1998/002933 patent/WO1999016436A1/en not_active Application Discontinuation
- 1998-09-30 ZA ZA988920A patent/ZA988920B/en unknown
Non-Patent Citations (1)
Title |
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See references of WO9916436A1 * |
Also Published As
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JP2001517697A (en) | 2001-10-09 |
AU9273198A (en) | 1999-04-23 |
ZA988920B (en) | 1999-06-09 |
CA2304516A1 (en) | 1999-04-08 |
WO1999016436A1 (en) | 1999-04-08 |
GB9720797D0 (en) | 1997-12-03 |
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