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Sommaire du brevet 2085873 

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Disponibilité de l'Abrégé et des Revendications

L'apparition de différences dans le texte et l'image des Revendications et de l'Abrégé dépend du moment auquel le document est publié. Les textes des Revendications et de l'Abrégé sont affichés :

  • lorsque la demande peut être examinée par le public;
  • lorsque le brevet est émis (délivrance).
(12) Demande de brevet: (11) CA 2085873
(54) Titre français: TRAITEMENT
(54) Titre anglais: TREATMENT
Statut: Réputée abandonnée et au-delà du délai pour le rétablissement - en attente de la réponse à l’avis de communication rejetée
Données bibliographiques
(51) Classification internationale des brevets (CIB):
  • A61K 33/00 (2006.01)
  • A61K 31/34 (2006.01)
  • A61K 31/415 (2006.01)
  • A61K 31/54 (2006.01)
  • A61K 31/66 (2006.01)
  • A61K 33/08 (2006.01)
  • A61K 33/10 (2006.01)
  • A61K 33/12 (2006.01)
  • A61K 33/42 (2006.01)
(72) Inventeurs :
  • DAVIS, ADRIAN FRANCIS (Royaume-Uni)
(73) Titulaires :
  • BEECHAM GROUP P.L.C.
(71) Demandeurs :
  • BEECHAM GROUP P.L.C. (Royaume-Uni)
(74) Agent: BORDEN LADNER GERVAIS LLP
(74) Co-agent:
(45) Délivré:
(86) Date de dépôt PCT: 1991-06-13
(87) Mise à la disponibilité du public: 1991-12-23
Licence disponible: S.O.
Cédé au domaine public: S.O.
(25) Langue des documents déposés: Anglais

Traité de coopération en matière de brevets (PCT): Oui
(86) Numéro de la demande PCT: PCT/GB1991/000953
(87) Numéro de publication internationale PCT: WO 1992000102
(85) Entrée nationale: 1992-12-18

(30) Données de priorité de la demande:
Numéro de la demande Pays / territoire Date
9013910.6 (Royaume-Uni) 1990-06-22
9018676.8 (Royaume-Uni) 1990-08-24

Abrégés

Abrégé anglais

2085873 9200102 PCTABS00010
Co-administration of a histamine H2-receptor antagonist and
antacid for the treatment of gastric disorders.

Revendications

Note : Les revendications sont présentées dans la langue officielle dans laquelle elles ont été soumises.


WO 92/00102 PCT/GB91/00953
-13-
Claims
1. The use of an orally administrable pharmaceutical
composition comprising a histamine H2-receptor antagonist
and an antacid for the manufacture of a medicament for the
treatment of gastric disorders, characterised in that the
antacid has equilibrium pH, acid neutralising capacity and
gastric residence time values which provide a pH profile
with time conferring a local pH level substantially equal to
that of the pKa of the histamine H2-receptor antagonist.
2. Use as claimed in claim 1 characterised in that local
levels of the histamine H2-receptor antagonist at the
parietal cell receptor are increased, thereby increasing the
acid-secretion reducing capacity of the histamine H2-
receptor antagonist.
3. Use as claimed in claim 1 or 2 for the treatment of
gastric disorders in ulcer patients.
4. Use as claimed in claim 3 for the treatment of
patients who do not respond to conventional histamine H2-
receptor antagonist therapy.
5. Use as claimed in claim 3 for the treatment of acid
hypersecreting patients.
6. Use as claimed in claim 1 or 2 for the single-dose
treatment of acute gastric disorders.
7. Use as claimed in any preceding claim whereby the
histamine H2-receptor antagonist is cimetidine, ranitidine,
or famotidine.

WO 92/00102 PCT/GB91/00953
-14-
8. Use as claimed in claim 7 whereby the histamine H2-
receptor antagonist is cimetidine.
9. Use as claimed in claim 8 whereby the dose level of
cimetidine is from 25 to 400mg per dosage form.
10. Use as claimed in claim 9 whereby the dose level of
cimetidine is from 50 to 200mg per dosage form.
11. Use as claimed in any preceding claim whereby the
antacid is aluminium hydroxide, magnesium hydroxide,
aluminium hydroxide-magnesium carbonate co-dried gel,
magnesium carbonate, magnesium oxide, magnesium trisilicate,
sodium bicarbonate, calcium carbonate, bismuth carbonate,
magnesium aluminium silicate, alkali metal salts of citric,
tartaric, benzoic, sorbic or phosphoric acid, or
combinations of any of the aforementioned antacids.
12. A method of treatment of gastric disorders comprising
orally administering to a sufferer an effective amount of a
pharmaceutical composition comprising a histamine H2-
receptor antagonist and an antacid wherein the equilibrium
pH, the acid neutralising capacity and the gastric residence
time values confer a pH level substantially equal to that of
the pKa of the histamine H2-receptor antagonist.
13. A pharmaceutical composition for use in the treatment
of gastric disorders comprising a histamine H2-receptor
antagonist and an antacid wherein the equilibrium pH, the
acid neutralising capacity and the gastric residence time
values confer a pH level substantially equal to that of the
pKa of the histamine H2-receptor antagonist.

Description

Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.


WO92/001~2 PCT/GB91/0~953
-1- 2~ 3
NOVEL TREATMENT
This invention relates to the treatment of gastric ~isorders
and pharmaceutical compositions for use therein. More
s particularly the invention relates to the treatment of
gastric disorders, including acute disorders such as acid
indigestion, heartburn and gastritis, and gastric and peptic
ulcer using an orally administrable pharmaceutical
composition comprising an H2-receptor antagonist and an
10 antacid.
Histamine H2-receptor antagonists, for example cimetidine,
ranitidine, nizatidine and famotidine, reduce acid secretion
by acting directly on the acid-secreting parietal cell
located within the gastric gland of the stomach wall.
Although histamine H2-receptor antagonists are remarkably
effective in the treatment of many gastric disorders, in
particular peptic and gastric ulcers, there exist certain
20 patient groups which do not respond to treatment. In
addition, the time lapse between dosing and onset of action,
limits the potential benefit of hlstamine H2-receptor
antagonists in the treatment of acute, self-limiting gastric
disorders.
A significant proportion of gastric and peptic ulcer
patients, referred to as non-responders, do not respond to
conventional histamine H2-receptor antagonist therapy.
(Walker et al.: Frequent non-response to histamine
30 H2-receptor antagonists in cirrhotics; Gut, 30, 1105-9,
1989; and Brack A. et al.: Clinical failures with
cimetidine; Surgery, 88(3), 417-24.
In addition, the known poor response to histamine
35 H2-receptor antagonist treatment by hypersecreting patients,
for example critically ill, multiple trauma patients (Martin
,
,: : , ,: , ., . :. . . ..

WO92/00102 PCT/GB91/00953
L. et al.: Failure of cimetidine prophylaxis in the
critically ill; Arch. Surg., 114, 492-6, 1979) or those with
Zollinger-Ellison syndrome ~Stabile B.G. et al.: Failure of
histamine H2-receptor antagonist therapy in
s Zollinger-Ellison syndrome; Am. J. Surg., 145, 17-23, 1983)
has led to the development of alternative treatments,
notably the use of proton-pump inhibitors.
Histamine H2-receptor antagonists are of potential benefit
o in the self-medication of acute, self-limiting gastric
disorders such as hyperacidity. However, their slow onset
of action is unlikely to meet the consumer requirement for
rapid relief of symptoms.
15 Moveover, it will be appreciated that use of high dose
levels in an attempt to achieve rapid relief of symptoms is
not appropriate for non-prescription use. Indeed, a
reduction from the standard therapeutic dose would be
desirable for self-medication.
Co-administration of histamine H2-receptor antagonists and
antacids has been investigated. The rationale for
co-administration is that the antacid brings about rapid
relief from the symptoms of excess stomach acidity by
2s neutralisation, whereas the histamine H2-receptor antagonist
independently acts by inhibiting secretion of acid from the
parietal cell.
However, it is well known (Bodemar G. et al., Lancet, 1,
30 444-445, 1979; Mihaly G.W. et al., B.M.J., 285, 998-9, 1982;
Lin. J.H. et al., B.J. Clin. Pharmacol. 24, 551-3, 1987
that when histamine H2-receptor antagonists are
co-administered with antacids, especially antacids with high
acid-neutralising capacity, there is frequently a
3s substantial reduction in the plasma bioavailability of khe
histamine H2-receptor antagonist.
'.

W092/00102 PCT/GB91/00953
~3- ~ ~8~7~
Histamine H2-receptor antagonist-antacid combinations are
therefore generally contraindicated. This contraindication
for histamine H2-receptor antagonist-antacid therapy is
5 supported by pharmacokinetic modelling using a standard
two-compartment model which indicates a reduction in the
systemic absorption of the histamine H2-receptor antagonist.
Surprisingly, it has now been found that a combination of
o histamine H2-receptor antagonists with antacids, even those
with high acid-neutralising capacity, leads to an increase
in local stomach wall receptor site bioavailability of the
histamine H2-receptor antagonist and thus further increases
the acid-secretion reducing capacity of the histamine
H2-receptor antagonist compared with that of the histamine
H2-receptor antagonist alone. This synergistic effect is of
benefit in the treatment of gastric disorders, particularly
in the treatment of the so-called ~non responders' and in
the self-medication of acute gastric disorders.
Accordingly, the present invention provides the use of an
orally administrable pharmaceutical composition comprising a
histamine H2-receptor antagonist and an antacid for the
manufacture of a medicament for the treatment of gastric
25 disorders, characterised in that the antacid has equilibrium
pH, acid neutralising capacity and gastric residence time
values which provide a pH profile with time conferring a
local pH level substantially equal to that of the pKa of the
histamine H~-receptor antagonist. Local levels of the
30 histamine H2-receptor antagonist at the parietal cell
receptor are thereby increased, conferring an increase in
the acid-secretion reducing capacity of the histamine
H2 receptor antagonist.
,
,: .

WO92/~0102 PCT/GB91/00~53
7 ~
An increase in acid-secretion reducing capacity is
advantageous in the treatment of ulcer patients, in
particular hypersecreting patients, in the treatment of
those patients diagnosed as non-responders, and also to
5 reduce the onset-phase of single-dose, sel~-medication for
acute gastric disorders, for example gastric disorders due
to hyperacidity.
The invention also provides a method of treatment of gastric
10 disorders comprising orally administering to a sufferer an
effective amount of a pharmaceutical composition comprising
a histamine H2-receptor antagonist and an antacid wherein
the equilibrium pH, the acid neutralising capacity and the
gastric residence time values confer a pH level
substantially equal to that of the pKa of the histamine
H2-receptor antagonist.
In a further aspect, the invention provides a pharmaceutical
composition for use in the treatment of gastric disorders
20 which comprises a histamine H2-receptor antagonist and an
antacid wherein the equilibrium pH, the acid neutralising
capacity and the gastric residence time values con~er a pH
level substantially equal to that of the pKa of the
histamine H2-receptor antagonist.
2s
Histamine H2-receptor antagonists for use in compositions of
the invention include cimetidine, ranitidine and famotidine,
preferably cimetidine and ranitidine, and especially
cimeditine. pKa values for known histamine H2-receptor
30 anta~onists are readily available from pharmacological
publications.
Similarly, the above-mentioned parameters for suitable
antacids are read:ily available to those skilled in the art.
35 Suitable antacids ~or use in compositions of the invention
include aluminium hydroxide, magnesium hydroxida, aluminium
hydroxide-magnesium carbonate co-dried gel, magnesium

WO9~/00102 PCT/GB91/00953
_5_ 2~ 3
carbonate, magnesium oxide, magnesium aluminium silicate,
magnesium trisilicate, sodium bicarbonate, calcium
carbonate, bismuth carbonate, alkali metal salts of citric,
tartaric, benzoic, sorbic and phosphoric acid, and
5 combinations thereof.
Further suitable antacids may be selected by pharmacokinetic
analysis of the acid-secretion reducing capacity of a
selected histamine H2-receptor antagonist using a
lo pharmacokinetic model based upon a modified, standard
two-compartment model. With the introduction of further
compartments to separately describe the stomach and the
intestine, and with transport between the tissue
compartment, representing the parietal cell tissue receptor
15 compartment, and the stomach lumen, the model may be used to
describe pharmacokinetics for a selected histamine
H2-receptor antagonist. The model demonstrates the
reduction in local bioavailability of the histamine
H2-receptor antagonist at the parietal cell tissue receptor
20 compartment as a function of gastric excretion and the
increase in local bioavailability in the parietal cell
tissue receptor compartment as a function of local, gastric
absorption, and their dependence on gastric pH. Gastric pH
levels are influenced by antacid. Thus, by inserti~g known
25 ~alues for equilibrium pH, acid neutralising capacity and
gastric residence time, the suitability of any given antacid
may be determined.
The dose level of histamine H2-receptor antagonist may be
30 selected according to the potency of the chosen antagonist
on a weight basis and the severity of the condition. For
example, where the antagonist is cimetidine, it will
generally be present in an amount from about 25 to 400 mg
per dosage form, typically from about 50 to 200 mg of
35 cimetidine per dosage form.
Excretion of histamine H2-receptor antagonist into the
stomach lumen ~rom the parietal cell tissue receptor causes
.
.. . . -. , ....... , . . , .... .,.,.. ., . . ~, . . .. ... . .
-. , . . .: ' -':, '~ . .: .;.. , ,. . , , , . ~. .. . . ,. . . . . . . .. : . ,

WO92/00102 PCr/GB91/00953
-6- ~8~87~
a reduction in local bioavailability of the anta~onist
whilst gastric absorption of histarnine H2-receptor
antagonist into the parietal cell tissue receptor causes an
increase in local bioavailability of the antagonist. An
S advantageous feature of the invention is the potential for
using reduced dose levels of histamine H2-receptor
antagonist brought about by the synergistic effect of
antacid and histamine X2-receptor antagonist, effectively
reducing antagonist excretion into the stomach lumen and
lO increasing absorption from the stomach lumen.
It will be further appreciated that treatment with the
present compositions provides a more rapid onset of action
which renders them particularly suitable for the treatment
of acute gastritis.
A further aspect of the invention is that the amount of
antacid present in any given composition is independent of
the dose of histamine H2-receptor antagonist.
It is a feature of the antacid component that it serves a
dual role. In one aspect, in the accepted mode of action of
antacids, it brings about relief from the symptoms of excess
stomach acidity by neutralisation. In a second aspect, and
2s more importantly, it serves to act as an appropriate
buffered vehicle to histamine H2-receptor antagonist
bioavailability in the parietal cell tissue receptor
compartment.
30 The dose of antacid may be selected to achieve both the
desired acid neutralising effect and to fulfil the role of
the antacid component as a buffered vehicle to con~er a pH
level subs~antially equal to that of the pKa of the
histamine H2-receptor antagonist.
A suitable dose range for magnesium hydroxide is fro~ about
150 mg to 3,000 mg, for example from about 300 mg to l,500

W092/001~2 pcrJG~s1 /00~53
_7_ 2~8~7~
mg, such as from about 300 mg to 600 mg.
A suitable dose range for aluminium hydroxide is from about
180 mg to 3,600 mg, for example from about 360 mg to 1,800
s mg, such as fro~ about 360 mg to 720 mg.
A suitable dose range for sodium bicarbonate is from about
400 mg to 8,000 mg, for example from about 800 mg to 4,000
mg, such as from about 8Q0 mg to 1,600 mg.
Compositions for use in the present invention may also
contain pharmaceutically acceptable carriers. Compositions
may be formulated for oral administration in solid or liquid
form, for example as tablets, capsules, powders, suspensions
or dispersi-ons. Compositions may thus be formulated by
admixture with pharmaceutically acceptable vehicles
additionally containing, as desired, pharmaceutically
acceptable adjuvants including inter alia thickeners,
preservatives, and colouring and flavouring agents.
It will be appreciated that certain pharmaceutical
compositions for use in the present invention are novel and
as such form a further aspect of the invention.
2s The following Examples illustrate the invention.
Powder Formulations
The ingredients are dry blended under conditions of
30 controlled temperature and humidity using conventional
equipment.
~-
,
~,, ., . ' ~ . . '. j, ,

WO9~/00102 PCTIGB91/00953
, .
; -8- 2~ 73
Tablet Formulations
The active antacid ingredients are granulated or spray dried
in a conventional manner. The granule and the histamine
5 H2-receptor antagonist are blended along with conventional
tabletting aids, fillers and palatability aids and the blend
is tabletted on a conventional machine.
Liquid SusPensiOns
Aluminium hydroxide and magnesium hydroxide are received as
commercially available suspensions. These active
suspensions are added to a premix of thickeners. The
resulting mixture is then blended with the histamine
15 H2-receptor antagonist, and preservatives and flavours as
appropriate.
... .. .

WO 92/00102 PCr/GB91/00953
-9- ~8~g~3
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WO 92/00102 PCI'/GB91/00953
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WO 92/00102 PCI/GB91/00953
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WO 92/00102 PCr/GB91/00953
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Dessin représentatif

Désolé, le dessin représentatif concernant le document de brevet no 2085873 est introuvable.

États administratifs

2024-08-01 : Dans le cadre de la transition vers les Brevets de nouvelle génération (BNG), la base de données sur les brevets canadiens (BDBC) contient désormais un Historique d'événement plus détaillé, qui reproduit le Journal des événements de notre nouvelle solution interne.

Veuillez noter que les événements débutant par « Inactive : » se réfèrent à des événements qui ne sont plus utilisés dans notre nouvelle solution interne.

Pour une meilleure compréhension de l'état de la demande ou brevet qui figure sur cette page, la rubrique Mise en garde , et les descriptions de Brevet , Historique d'événement , Taxes périodiques et Historique des paiements devraient être consultées.

Historique d'événement

Description Date
Inactive : CIB expirée 2019-01-01
Inactive : CIB de MCD 2006-03-11
Inactive : CIB de MCD 2006-03-11
Inactive : CIB de MCD 2006-03-11
Inactive : CIB de MCD 2006-03-11
Inactive : CIB de MCD 2006-03-11
Le délai pour l'annulation est expiré 1998-06-15
Demande non rétablie avant l'échéance 1998-06-15
Réputée abandonnée - omission de répondre à un avis sur les taxes pour le maintien en état 1997-06-13
Demande publiée (accessible au public) 1991-12-23

Historique d'abandonnement

Date d'abandonnement Raison Date de rétablissement
1997-06-13
Titulaires au dossier

Les titulaires actuels et antérieures au dossier sont affichés en ordre alphabétique.

Titulaires actuels au dossier
BEECHAM GROUP P.L.C.
Titulaires antérieures au dossier
ADRIAN FRANCIS DAVIS
Les propriétaires antérieurs qui ne figurent pas dans la liste des « Propriétaires au dossier » apparaîtront dans d'autres documents au dossier.
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Description du
Document 
Date
(aaaa-mm-jj) 
Nombre de pages   Taille de l'image (Ko) 
Abrégé 1991-12-23 1 43
Page couverture 1991-12-23 1 29
Revendications 1991-12-23 2 91
Abrégé 1991-12-23 1 41
Dessins 1991-12-23 1 11
Description 1991-12-23 12 497
Courtoisie - Lettre d'abandon (taxe de maintien en état) 1997-09-08 1 188
Rappel - requête d'examen 1998-02-16 1 117
Paiement de taxe périodique 1996-03-28 1 67
Paiement de taxe périodique 1995-03-21 1 81
Paiement de taxe périodique 1994-03-23 1 63
Paiement de taxe périodique 1994-05-10 1 46
Rapport d'examen préliminaire international 1992-12-18 15 438