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WO1994005294A1 - Formulations gastro-intestinales contenant du dimethylsulfone et l'allopurinol ou l'oxypurinol - Google Patents

Formulations gastro-intestinales contenant du dimethylsulfone et l'allopurinol ou l'oxypurinol Download PDF

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Publication number
WO1994005294A1
WO1994005294A1 PCT/GB1993/001878 GB9301878W WO9405294A1 WO 1994005294 A1 WO1994005294 A1 WO 1994005294A1 GB 9301878 W GB9301878 W GB 9301878W WO 9405294 A1 WO9405294 A1 WO 9405294A1
Authority
WO
WIPO (PCT)
Prior art keywords
allopurinol
oxypurinol
dimethylsulphoxide
dmso
ethanol
Prior art date
Application number
PCT/GB1993/001878
Other languages
English (en)
Inventor
Aws Shakir Mustafa Salim
Original Assignee
Aws Shakir Mustafa Salim
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
Priority claimed from GB929218775A external-priority patent/GB9218775D0/en
Application filed by Aws Shakir Mustafa Salim filed Critical Aws Shakir Mustafa Salim
Priority to AU49749/93A priority Critical patent/AU4974993A/en
Publication of WO1994005294A1 publication Critical patent/WO1994005294A1/fr

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine

Definitions

  • the present invention relates to the treatment of oesophageal and gastrointestinal mucosa and to synergistic compositions for use therein.
  • the invention being presented provides a synergistic composition suitable for use in the treatment of oesophageal and gastrointestinal mucosa which composition comprises at least one of allopurinol and oxypurinol together with dimethylsulphoxide.
  • synergistic pharmaceutical compositions which remove the agents directly involved in injury of the oesophageal and gastrointestinal mucosa while sustaining the integrity of these mucosa and enhancing the repair of any damage it has sustained. Consequently, this invention provides protection against and therapy for a wide variety of digestive disorders be they oesophageal or gastrointestinal.
  • the invention presents synergistic pharmaceutical compositions comprising allopurinol or oxypurinol with dimethylsulphoxide.
  • compositions of this invention has been found in a very surprising and unexpected manner to protect the oesophageal, gastric, duodenal, and intestinal mucosa against injury besides enhancing the healing of its acute and chronic injury, inflammation and ulceration, including the stress-induced variety.
  • the present invention sustains the integrity of the oesophageal and gastrointestinal mucosa and protects against the recurrence of its non-mechanical injuries such as those caused by acid -peptic digestion, drugs, inflammatory processes be they specific or non-specific or ulceration whether stress-induced or otherwise.
  • the active ingredients of this invention interact so as to exhibit a synergistic effect in that the sum total of the actions of the individual ingredients is less than that achieved by their combination together.
  • compositions of the present invention also include a vasodilator, such as for example menthol, in order to further increase the effectiveness of the compositions of the invention in the mucosa.
  • a vasodilator such as for example menthol
  • this invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a composition of the invention in intimate admixture with a physiologically acceptable carrier or vehicle for use in the treatment of the oesophagus and the gastrointestinal mucosa.
  • the carrier or vehicle should be acceptable in terms of exerting no deleterious action on the gastrointestinal mucosa and being compatible with all the other ingredients of the invention. Suitable vehicles are well known in the art being noted for example in such standard works as the British Pharmacopoeia and the British National Formulary.
  • Cytoprotection which refers to sustaining the physio-chemical properties of living tissues, thus increasing their resistance to noxious stimuli.
  • compositions of the present invention optionally with other active ingredients and/or a suitable vehicle can be administered orally, or parenterally, in particular by intravenous injection, or per rectum.
  • the compositions of the invention and any accompanying material may be presented as a draught in water or in a syrup, in capsules, sachets, boluses or tablets, as an aqueous or oleaginous solution or suspension or in suspension in a syrup, such suspensions optionally including suspending agents or as an oil-in-water or water-in-oil emulsion.
  • the compositions of this invention can be taken orally in an alcoholic drink be that a spirit, wine or beer.
  • non-alcoholic forms of these drinks may also serve as vehicles for the oral consumption of compositions of the invention.
  • the compositions of the invention can be added for oral administration to fruit juices, mineral waters be they carbonated or not, and to all forms of soft drinks. Where desirable or necessary flavouring, sweetening, preserving, thickening or emulsifying agents may be included in the formulation.
  • Tablets may contain the active ingredients of the invention and any accompanying materials as a powder or granules optionally mixed with binders, lubricants, inert diluents or surface-active or dispersing agents.
  • compositions of the invention and any accompanying material may be presented in sterile solutions or suspensions in aqueous or oleaginous vehicles, which may also contain preservatives and material for rendering the solution or suspension isotonic with the blood of the intended recipient.
  • aqueous or oleaginous vehicles which may also contain preservatives and material for rendering the solution or suspension isotonic with the blood of the intended recipient.
  • Such formulations may conveniently be presented in unit-dose or multidose sealed containers.
  • Other suitable vehicles are well known in the art and are described in standard publications.
  • the active ingredients of the invention are preferably presented in solution or suspension or emulsion at a concentration of from 0.5 to 15% w/v, more preferably 1 to 10% w/v, e.g. 2% w/v in unit multidose form.
  • each unit dose preferably contains from 50 to 100 mg of allopurinol or oxypurinol with from 200 to 1000 mg of dimethylsulphoxide.
  • compositions of this invention can also be directly delivered to the lung via smoke and in this respect, it can be added as a powder or solution to tobacco leaves or to the tobacco of the cigarettes, cigars or pipes.
  • the compositions of this invention may also be included as a solution or powder in the cigarette's filter or in small delivery compartments included within the cigarette. These compartments may also contain the compositions of this invention in the form of granules which evaporate upon contact with smoke to be then entrained by the smoke for delivery to the lungs.
  • the allopurinol or oxypurinol are administered at a dosage in the range of from 1 to 4mg/kg body weight per day, preferably from 1 to 2mg/kg body weight per day while the dimethylsulphoxide is administered at a dosage in the range of from 10 to 400mg/kg body weight per day, preferably from 20 to 60mg/kg body weight per day.
  • the dosage may be administered in one or more doses per day and is preferably given at intervals of from 2 to 8 hours, most preferably every 6 hours.
  • the ingredients of the various compositions of this invention are administered in a slow release or sustained release vehicle, various suitable vehicles of this type being known in the art.
  • papaverine is included, this is generally used at a dosage of 1 mg/kg body weight per day.
  • Addition of procaine is most preferably at a dosage range of from 30 to 50 mg/kg body weight per day.
  • Menthol on the other hand is usually added in a dosage range of from 20 to 40 mg/kg body weight per day.
  • Example 1 Preparation and use of solutions for the treatment of the oesophagus and the gastrointestinal tract
  • the formulation is prepared at a temperature of about 25°C.
  • One gram of allopurinol or oxypurinol powder is dissolved in a few drops of 0.1M NaOH then double distilled water is added to 50 ml and if indicated one gram of finely ground menthol crystals is also added.
  • the mixture is stirred for a few seconds and then the appropriate volume of dimethylsulphoxide stock solution containing 10 grams is added. Finally, the volume is made up to 100 ml with double distilled water and the whole mixture is stirred for a few seconds then placed in airtight dark coloured glass bottles and stored at a temperature not exceeding 26°C.
  • This preparation should not be used for at least 12 hours, should not be left exposed to the air for long periods and should not be directly exposed to the sun.
  • Example 2 Preparation of capsules for treating the Oesophagus and gastrointestinal tract
  • Capsules were prepared at a room temperature of about 26°C. When making capsules which contain menthol, the crystals of this agent were first finely ground. The appropriate weight of powder of each ingredient is added and the whole preparation is thoroughly mixed then filled into gelatinous capsules. These capsules were stored in opaque or dark coloured glass containers away from direct light and at room temperatures not exceeding 26°C.
  • Example 1 When the solutions listed under Example 1 were being used, 5 ml were administered orally every six hours. The capsules listed under Example 2 were taken one every six hours. When the treatment is offered following surgery, administration generally commences on the fifth post-operative day, which is usually the time for the return to solid food intake by mouth. If administration per rectum is indicated, 5 ml of the solutions listed under Example 1 can be given every 6 hours. When this is being carried out post-operatively, treatment can start 2 days after surgery.
  • Treatment is extended for as long as is thought necessary. For therapeutic purposes it is generally recommended that stress-induced acute gastric mucosa1 injury and erosive gastritis should be treated for 5 days, reflux oesophagitis should be treated for between 4 to 8 weeks, peptic ulceration whether oesophageal, gastric, duodenal or that occuring in a Meckle's diverticulum should be treated for 8 to 12 weeks, and ulcerative colitis is treated for about 6 weeks. For symptomatic relief in such cases as non-ulcer dyspepsia, treatment does not usually need to be extended beyond one to two days. Maintenance therapy on the other hand is generally implemented for a year or longer.
  • DMSO dimethylsulphoxide Ethanol is noxious to the gastric mucosa. Application of this agent directly onto the gastric mucosa disrupts its barrier causing hydrogen ion back diffusion and coagulative necrosis. The alcohol-induced acute gastric mucosal injury is mediated by oxygen-derived free radicals. Dose dependent protection against this injury was afforded by each of allopurinol, oxypurinol and DMSO. This protection, however, was enhanced in a synergistic manner when DMSO was combined with allopurinol or oxypurinol. No influences on the gastric acid secretion were associated with the protection thereby indicating cytoprotection.
  • Consecutive patients who were smokers and who had endoscopy proven duodenal ulceration occuring for the first time were randomized into one of 3 groups provided the ulceration was larger than 0.5cm in diameter but not of the giant variety, i.e. >2.5cm in diameter, and treated for 8 weeks then endoscoped again.
  • the study groups were treated as follows: (1) saline, 5ml every 6 hours, and placebo, 400mg b.d., (2) saline, 5ml every 6 hours, and cimetidine, 400mg b.d., and (3) the formulation listed under Example l.B, 5ml every 6 hours, and cimetidine, 400mg b.d.
  • Cimetidine was significantly more effective than placebo in stimulating the healing of peptic ulceration (28(74%) vs 12 (30%)), an action which was significantly (p ⁇ 0.01) heightened by the addition of the formulation of the present invention where complete healing and an intact mucosa was observed in all the patients at the end of the study.
  • Treatment lasted for 5 days. Twenty-five patients were randomized to the control group (19 women and 6 men, age range 26 to 73 years, mean 54) and 27 patients were randomized to the active therapy group (21 women and 6 men, age range 24 to 72 years, mean 56) .
  • Remission or recovery from attacks indicates that the patient has become free of symptoms and has no diarrhoea; flexible sigmoidoscopy shows no contact bleeding or a deeply congested mucosa discharging blood, mucus, or pus; haematological and biochemical data return to normal values; and histological examination shows the disease to be inactive. Patients were given a low residue and milk-free diet, which is high in protein and calories, until their attack subsided.
  • DMSO dimethylsulphoxide
  • dimethylsulphoxide and allopurinol and/or oxypurinol ingredients are used in generally similar amounts, by weight, in the synergistic compositions of the invention, other ratios may also be used. Generally there is used a ratio of from 5:1 to 1:5, preferably from 1:2 to 1:10, most preferably about 1:4, by weight.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à des compositions synergiques comprenant du diméthylsulfoxyde et de l'allopurinol et/ou de l'oxypurinol, ainsi qu'à leur utilisation dans des formulations et des méthodes thérapeutiques et prophylactiques destinées aux lésions des muqueuses gastro-intestinales et ÷sophagiennes.
PCT/GB1993/001878 1992-09-04 1993-09-03 Formulations gastro-intestinales contenant du dimethylsulfone et l'allopurinol ou l'oxypurinol WO1994005294A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU49749/93A AU4974993A (en) 1992-09-04 1993-09-03 Gastrointestinal formulations containing dimethylsulfone and allopurinol or oxypurinol

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9218775.6 1992-09-04
GB929218775A GB9218775D0 (en) 1992-09-04 1992-09-04 Synergistic gastrointestinal formulations
GB939300636A GB9300636D0 (en) 1992-09-04 1993-01-14 Synergistic gastrointestinal formulations
GB9300636.9 1993-01-14

Publications (1)

Publication Number Publication Date
WO1994005294A1 true WO1994005294A1 (fr) 1994-03-17

Family

ID=26301552

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/001878 WO1994005294A1 (fr) 1992-09-04 1993-09-03 Formulations gastro-intestinales contenant du dimethylsulfone et l'allopurinol ou l'oxypurinol

Country Status (2)

Country Link
AU (1) AU4974993A (fr)
WO (1) WO1994005294A1 (fr)

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
PARTSCH G. & ALTMANN H.: "Inhibition of Xanthine Oxidase by additives used in pharmaceutical industry", PHARM. IND., vol. 36, no. 4, 1974, pages 263 - 264 *
SALIM A.S.: "Role of Oxygen derived free radicals in the mechanism of chronic gastric ulceration in the rat: Implications for Cytoprotection", DIGESTION, vol. 43, no. 1-2, 1989, pages 113 - 119 *
SALIM A.S.: "The significance of removing oxygen-derived free radicals in the treatment of acute and chronic duodenal ulceration in the rat", J. PHARM. PHARMACOL., vol. 42, no. 1, January 1990 (1990-01-01), pages 64 - 67 *

Also Published As

Publication number Publication date
AU4974993A (en) 1994-03-29

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