CA2125156A1 - Pharmaceutical composition - Google Patents
Pharmaceutical compositionInfo
- Publication number
- CA2125156A1 CA2125156A1 CA002125156A CA2125156A CA2125156A1 CA 2125156 A1 CA2125156 A1 CA 2125156A1 CA 002125156 A CA002125156 A CA 002125156A CA 2125156 A CA2125156 A CA 2125156A CA 2125156 A1 CA2125156 A1 CA 2125156A1
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutically acceptable
- compound
- acceptable salt
- benzopyran
- dihydro
- 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.)
- Abandoned
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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Otolaryngology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A pharmaceutical composition comprising trans(3S,4R)-3,4-dihydro-2,2-diméthyle-4-(2-oxopipéridine-1-yl)-6-pentafluoro_ éthyle-2H-1-benzopyran-3-ol('Compound I'), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor, wherein the composition comprises 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Compound I; a method for preparing such a composition and the use of such a composition in medicine.
Description
VO 93/10757 212 S i 5 6 PCr/GB92/022~
PEIAEU~ACEUTICAL COMPOSITION
. . ~, .
This invention relates to a pharmaceutical composition, to processes for the preparation of such a composition and to the use of such a composition . . .
n mealclne.
European Patent Application, Publication Number 0376524 discloses certain benzopyran derivatives which are stated inter alia to be potentially useful as bronchodilators in the treatment of disorders of the --10 respiratory tract, such as reversible airways obstruction and asthma, and also in the treatment of hypertension. ;~ ;
EP 0376524 also discloses trans (3S, 4R)-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin- 1-yl)-6-pentafluoroethyl-2H- 1- benzopyran-3-ol 1~ ('Compound I').
It has now been discovered that a discrete and particular pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is particularly useful for the treatment in humans of disorders of the respiratory tract, such as reversible airways obstruction and asthma: the hypotensive activity of ~uch composition is largely reduced.
Accordingly, in one aspect the present invention provides a 26 pharmaceutical composition comprising Compound I or, a pharmaceutically.acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and optionally a pharmaceutically acceptable carrier therefore, characterised in that the composition comprises 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Compound I.
~ ~
Particular compositions comprise 0.3 to 0.8 mg, 0.4 to 0.7 mg, 0.2 to 0.5 ~ `.
mg,O.5toO.9mg, 1.1to 1.5mg, 1.5to 1.9mg,2.1to2.5mgor2.5to3.0 mg of active compound. -~-Examples of compositions are those comprising 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, ;
0.8, 0.9, 1.1, 1.5, 1.9, 2.1, 2.5 or 3.0 mg of active compound. `: `
~,'"
Suitable pharmaceutically acceptable salts include those described in WO 93J107~7 212 515 ~ PC-r/GB92/022~ ~
PEIAEU~ACEUTICAL COMPOSITION
. . ~, .
This invention relates to a pharmaceutical composition, to processes for the preparation of such a composition and to the use of such a composition . . .
n mealclne.
European Patent Application, Publication Number 0376524 discloses certain benzopyran derivatives which are stated inter alia to be potentially useful as bronchodilators in the treatment of disorders of the --10 respiratory tract, such as reversible airways obstruction and asthma, and also in the treatment of hypertension. ;~ ;
EP 0376524 also discloses trans (3S, 4R)-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin- 1-yl)-6-pentafluoroethyl-2H- 1- benzopyran-3-ol 1~ ('Compound I').
It has now been discovered that a discrete and particular pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, is particularly useful for the treatment in humans of disorders of the respiratory tract, such as reversible airways obstruction and asthma: the hypotensive activity of ~uch composition is largely reduced.
Accordingly, in one aspect the present invention provides a 26 pharmaceutical composition comprising Compound I or, a pharmaceutically.acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and optionally a pharmaceutically acceptable carrier therefore, characterised in that the composition comprises 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Compound I.
~ ~
Particular compositions comprise 0.3 to 0.8 mg, 0.4 to 0.7 mg, 0.2 to 0.5 ~ `.
mg,O.5toO.9mg, 1.1to 1.5mg, 1.5to 1.9mg,2.1to2.5mgor2.5to3.0 mg of active compound. -~-Examples of compositions are those comprising 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, ;
0.8, 0.9, 1.1, 1.5, 1.9, 2.1, 2.5 or 3.0 mg of active compound. `: `
~,'"
Suitable pharmaceutically acceptable salts include those described in WO 93J107~7 212 515 ~ PC-r/GB92/022~ ~
EP0376524. Generally, Compound I is not in a salted fo~
Suitable pharmaceutically acceptable solvates include those described in EP0376524, in particular hydrates.
Compound I or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be prepared using known methods, for example those disclosed in EP0376524. The ;
disclosures of EP0376524 are incorporated herein by reference.
In one aspect, the invention provides a process for preparing a pharmaceutical composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Co~pound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and optionally a 'I~ pharmaceuticallyi acceptable carrier therefor, which process comprises formulating Compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof and optionally comprises -sdmixing the pharmaceutically acceptable carrier.
20 The composition of the invention is preferably adapted for oral administration. Ho~,vever, it may be adapted for other modes of administration, for example parenteral administration, sublingual or transdermal administration.
`..'''' 25 The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
In order to obtain consistency of administration it is prefelTed that a ~;
30 composition of the in~vention is in the form of a unit dose.
Unit dose presentation forms for oral administration may be tablets and ;~
capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or ~ ~-35 polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starcht calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrvstalline ~ ~
~ ..;.
;~
`~VO 93/10757 212 515 6 PCI/GB92/0~2~
Suitable pharmaceutically acceptable solvates include those described in EP0376524, in particular hydrates.
Compound I or, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, may be prepared using known methods, for example those disclosed in EP0376524. The ;
disclosures of EP0376524 are incorporated herein by reference.
In one aspect, the invention provides a process for preparing a pharmaceutical composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Co~pound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and optionally a 'I~ pharmaceuticallyi acceptable carrier therefor, which process comprises formulating Compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof and optionally comprises -sdmixing the pharmaceutically acceptable carrier.
20 The composition of the invention is preferably adapted for oral administration. Ho~,vever, it may be adapted for other modes of administration, for example parenteral administration, sublingual or transdermal administration.
`..'''' 25 The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
In order to obtain consistency of administration it is prefelTed that a ~;
30 composition of the in~vention is in the form of a unit dose.
Unit dose presentation forms for oral administration may be tablets and ;~
capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or ~ ~-35 polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starcht calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrvstalline ~ ~
~ ..;.
;~
`~VO 93/10757 212 515 6 PCI/GB92/0~2~
cellulose; or pharrnaceutically accep~ble wetting agents such as sodium lauryl sulphate.
The solid oral compositions may be prepared by conventional methods of 5 blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in ~ ~;
normal pharmaceutical practice, in particular with an enteric coating. ~
~''':`
Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution "with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for ` :~`
example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, ~`
carboxymethylcellulose, aluminil~m stearate gel, hydrogenated edible fats; :-emulsifying a~ents, for example lecithin, sorbitan monooleate, or acacia; --non-aqueous vehicles (which may include edible oils), for example almond oil, ~ractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or ;propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents. ``.
For parenteral administration, fluid unit dosage forms are prepared :
utilizing the compound and a stenle vehicle, and, depending on the ~
concentration used, can be either suspended or dissolved in the vehicle. ` ~ -In prepanng solutions the compound can be dissolved in water for ` -injection and filter stenlized before filling into a suitable vial or ampoule - `
and æealing. Advantageously, adjuvants such as a local anaesthetic, a ~;
preservative and buffe~ng agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the l and the water removed under vacuum. Parenteral suspensions are ` `~
prepared in æubst~ntially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accompliæhed by filtration. Ihe compound can be sterilized by exposur~ to ethylene oxide before suspending in the sterîle vehicle. ~ ;-Adv~ntageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
~ '"' .
WO 93/107~7 212 ~15 f~ PCl /GB92/022~
The solid oral compositions may be prepared by conventional methods of 5 blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to methods well known in ~ ~;
normal pharmaceutical practice, in particular with an enteric coating. ~
~''':`
Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution "with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for ` :~`
example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, ~`
carboxymethylcellulose, aluminil~m stearate gel, hydrogenated edible fats; :-emulsifying a~ents, for example lecithin, sorbitan monooleate, or acacia; --non-aqueous vehicles (which may include edible oils), for example almond oil, ~ractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or ;propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents. ``.
For parenteral administration, fluid unit dosage forms are prepared :
utilizing the compound and a stenle vehicle, and, depending on the ~
concentration used, can be either suspended or dissolved in the vehicle. ` ~ -In prepanng solutions the compound can be dissolved in water for ` -injection and filter stenlized before filling into a suitable vial or ampoule - `
and æealing. Advantageously, adjuvants such as a local anaesthetic, a ~;
preservative and buffe~ng agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the l and the water removed under vacuum. Parenteral suspensions are ` `~
prepared in æubst~ntially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accompliæhed by filtration. Ihe compound can be sterilized by exposur~ to ethylene oxide before suspending in the sterîle vehicle. ~ ;-Adv~ntageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
~ '"' .
WO 93/107~7 212 ~15 f~ PCl /GB92/022~
-4- ~
Compositions of this invention, especially for the treatment of reversible airways obstruction and asthma, may also suitably bP presented for administration to the respiratory tract as a snuf~or an aerosol or solution for a nebulizer, or as a microfine powder for insuf~lation, alone or in ;
combination with an inert carrier such as lactose. In such a case the particles of active compound suitably have diameters of less than 50 -~
microns, preferably less than 10 microns ~or example diameters in the range of 1-50 microns, 1-10 microns or 1-5 microns. Where appropriate, small amounts of other anti-asthmatics and bronchodilators, for example `
sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
:
The compositions may contain from 0.1% to 99~ by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration. A preferred range for inhaled administration is 10-99%, especially 60-99~o, for e~ample 90, 95 or 99%. ;~
The present invention further provides a pharmaceutical composition, in p~rticular a composition for inhaled administration, which comprises 0.2 to 3.0 mg of Compound I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the form of a microfine powder and optionally a pharmaceutically acceptable carner. Suitable carriers are those used conventionally in the art, for example lactose.
Preferably the composition for inhaled administration comprises 0.2 to 0.9 mg for example 0.2 to 0.5 mg, or 0.2, 0.3, 0.4 or 0.5 mg, of active compound.
Microfine powder formulations may suitably be admir~istered in an aerosol as a metered dose` or by means of a suitable breath-activated device. ;
Suitable metered dose aerosol fo~nulations comprise conventional ;
propellants, cosolvents, such as ethanol, surfactants such as oleyl alcohol, lub~cants such as oleyl alcohol, desiccants such as calciurn sulphate and density modifiers such as sodium chloride.
~vo 93/10757 212 515 6 PCI/GB92/02234 -5- `
Suitable solutions for a nebulizer are isotonic sterilised solutions, -~
optionally bufFered, at for example between pH 4-7, containing up to 20mg --ml l of compound but more generally 0.1 to 10mg ml 1, for use with standard nebulisation equipment.
The compositions of the invention may be prepared and formulated ~ ` `
according to conventional methods, such a~ tho~e disclosed in standard reference texts, for example the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and ; ~;, Harry's Cosmeticology (Leonard Hill Books). -~
The present invention further provides a method for the treatment of 1~ respiratory tract disorders, such as reversible airways obstruction and, especially asthma, in humans which method comprises administering a total daily dose of 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Compound I, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, to a human in need thereof. -~ ~`
The medicament may be admiI~istered from 1 to 6 times a day, more i ~;
usually from 2 to 4 times a day~ preferably 1 or 2 times per day providing ~;
the total daily dose is 0.2 to 0.9 mg, 1.1 to 1.9 mg or 2.1 to 3.0 mg. ;
It will be appreciated that a unit dose for use in the method of the invention may comprise less than the stated total daily dose (e.g. less than -0.2 to 0.9 mg) of active compound in order to achieve the required total dailydose. ;~
The present invention also provides a pharmaceutical composi~on comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Compound I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier ~j~
therefor, for use as an active therapeutic substance. ;.
-In particular, the present invention provides a pharmaceutical ~ ~`
composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of ~;;
Compound I, or a pharmaceutically acceptable salt thereof, or a ;
.:,, ~,,.
. .
WO93/10757 2125156 -6- PCI/GB92/022~
pha~naceutically acceptable solvate thereof, for use in the treatment of respiratory tract disorders. Also the present invention pro~des the use of a pharmaceutical composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a ;
pharmaceutically acceptable carrier therefor for the manufacture of a ;
medicament for the treatment of respiratory tract disorders. `~
The following Example illustrates the inven~ion but does not limit it in any way. -. .
s ~ ~
~'`
,:
: -~:'";' . .
'`':~.".~
.....
~.
,`"~
~ ~"
.
WO 93/107~7 2 1 2 5 1 5 ~ PCI /GBg2/0223~ .
Example Male Sprague-Dawley rats were anaesthetized using urethane and prepared for determination of airways resistance (RaW)t dynamic lung 5 compliance ~Cdyn) and blood pressure as described by N.E. Bowring et al., 1991, Pulmonary Pharmacolgoy 4, 99-105. ~
.~ ' The rats were challenged with an aerosol of metha~oline for 2 minutes at 15 minute intervals using a concentratian (0.25 to 2.5 mol~ sufficient to raise resistance by about 100% and reduce compliance by about 40%. ~;
When consistent responses had been established Compound 1 was given intravenously 2 minutes before the methacholine challenge, the challenge being repeated at 15 minute intervals until its effect on RaW and C
had returned to near pre-Compound I values, af~er which point a higher 1~- dose of Compound I was given. Blood pressure was measured just prior to each methacholine challenge. When the dose of Compound I was sufficiently high to elicit an e~ect on blood pressure~ this effect was -~
maximal within 2 minutes. Results are means of 5 values :~ S.E. and are ~ ;`
expressed as percentage falls in blood pressure or inhibitions of pre~
20 Compound I responses to the methacholine challenge.
. . .
.~ ! ., WO 93/1075721 2 5 I 5 6 - 8 - PCI`/GB92/022?.4 ~ ~ -~
oo .
~ +~+~*~ . ~, , ,~ ~ ~ . ~':
_~ . ` :;:
* *
~,~
U~ I C
_ ~ ~ _ ~ :~
I
u~ ~ ~ ~ E
~ ! ~ ~ ~ ~ v ~ ~
Compositions of this invention, especially for the treatment of reversible airways obstruction and asthma, may also suitably bP presented for administration to the respiratory tract as a snuf~or an aerosol or solution for a nebulizer, or as a microfine powder for insuf~lation, alone or in ;
combination with an inert carrier such as lactose. In such a case the particles of active compound suitably have diameters of less than 50 -~
microns, preferably less than 10 microns ~or example diameters in the range of 1-50 microns, 1-10 microns or 1-5 microns. Where appropriate, small amounts of other anti-asthmatics and bronchodilators, for example `
sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
:
The compositions may contain from 0.1% to 99~ by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration. A preferred range for inhaled administration is 10-99%, especially 60-99~o, for e~ample 90, 95 or 99%. ;~
The present invention further provides a pharmaceutical composition, in p~rticular a composition for inhaled administration, which comprises 0.2 to 3.0 mg of Compound I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the form of a microfine powder and optionally a pharmaceutically acceptable carner. Suitable carriers are those used conventionally in the art, for example lactose.
Preferably the composition for inhaled administration comprises 0.2 to 0.9 mg for example 0.2 to 0.5 mg, or 0.2, 0.3, 0.4 or 0.5 mg, of active compound.
Microfine powder formulations may suitably be admir~istered in an aerosol as a metered dose` or by means of a suitable breath-activated device. ;
Suitable metered dose aerosol fo~nulations comprise conventional ;
propellants, cosolvents, such as ethanol, surfactants such as oleyl alcohol, lub~cants such as oleyl alcohol, desiccants such as calciurn sulphate and density modifiers such as sodium chloride.
~vo 93/10757 212 515 6 PCI/GB92/02234 -5- `
Suitable solutions for a nebulizer are isotonic sterilised solutions, -~
optionally bufFered, at for example between pH 4-7, containing up to 20mg --ml l of compound but more generally 0.1 to 10mg ml 1, for use with standard nebulisation equipment.
The compositions of the invention may be prepared and formulated ~ ` `
according to conventional methods, such a~ tho~e disclosed in standard reference texts, for example the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and ; ~;, Harry's Cosmeticology (Leonard Hill Books). -~
The present invention further provides a method for the treatment of 1~ respiratory tract disorders, such as reversible airways obstruction and, especially asthma, in humans which method comprises administering a total daily dose of 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Compound I, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, to a human in need thereof. -~ ~`
The medicament may be admiI~istered from 1 to 6 times a day, more i ~;
usually from 2 to 4 times a day~ preferably 1 or 2 times per day providing ~;
the total daily dose is 0.2 to 0.9 mg, 1.1 to 1.9 mg or 2.1 to 3.0 mg. ;
It will be appreciated that a unit dose for use in the method of the invention may comprise less than the stated total daily dose (e.g. less than -0.2 to 0.9 mg) of active compound in order to achieve the required total dailydose. ;~
The present invention also provides a pharmaceutical composi~on comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Compound I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier ~j~
therefor, for use as an active therapeutic substance. ;.
-In particular, the present invention provides a pharmaceutical ~ ~`
composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of ~;;
Compound I, or a pharmaceutically acceptable salt thereof, or a ;
.:,, ~,,.
. .
WO93/10757 2125156 -6- PCI/GB92/022~
pha~naceutically acceptable solvate thereof, for use in the treatment of respiratory tract disorders. Also the present invention pro~des the use of a pharmaceutical composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a ;
pharmaceutically acceptable carrier therefor for the manufacture of a ;
medicament for the treatment of respiratory tract disorders. `~
The following Example illustrates the inven~ion but does not limit it in any way. -. .
s ~ ~
~'`
,:
: -~:'";' . .
'`':~.".~
.....
~.
,`"~
~ ~"
.
WO 93/107~7 2 1 2 5 1 5 ~ PCI /GBg2/0223~ .
Example Male Sprague-Dawley rats were anaesthetized using urethane and prepared for determination of airways resistance (RaW)t dynamic lung 5 compliance ~Cdyn) and blood pressure as described by N.E. Bowring et al., 1991, Pulmonary Pharmacolgoy 4, 99-105. ~
.~ ' The rats were challenged with an aerosol of metha~oline for 2 minutes at 15 minute intervals using a concentratian (0.25 to 2.5 mol~ sufficient to raise resistance by about 100% and reduce compliance by about 40%. ~;
When consistent responses had been established Compound 1 was given intravenously 2 minutes before the methacholine challenge, the challenge being repeated at 15 minute intervals until its effect on RaW and C
had returned to near pre-Compound I values, af~er which point a higher 1~- dose of Compound I was given. Blood pressure was measured just prior to each methacholine challenge. When the dose of Compound I was sufficiently high to elicit an e~ect on blood pressure~ this effect was -~
maximal within 2 minutes. Results are means of 5 values :~ S.E. and are ~ ;`
expressed as percentage falls in blood pressure or inhibitions of pre~
20 Compound I responses to the methacholine challenge.
. . .
.~ ! ., WO 93/1075721 2 5 I 5 6 - 8 - PCI`/GB92/022?.4 ~ ~ -~
oo .
~ +~+~*~ . ~, , ,~ ~ ~ . ~':
_~ . ` :;:
* *
~,~
U~ I C
_ ~ ~ _ ~ :~
I
u~ ~ ~ ~ E
~ ! ~ ~ ~ ~ v ~ ~
Claims (14)
1. A pharmaceutical composition comprising trans (3S,4R)-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-6-pentafluoroethyl-2H-1-benzopyran-3-ol ('Compound I'), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and optionally a pharmaceutically acceptable carrier therefore, characterised in that, the composition comprises 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of Compound I.
2. A composition according to claim 1, comprising 0.3 to 0.8 mg, 0.4 to 0.7 mg, 0.2 to 0.5 mg, 0.5 to 0.9 mg, 1.1 to 105 mg, 1.5 to 1.9 mg, 2.1 to 2.5 mg or 2.5 to 3.0 mg of active compound.
3. A composition according to claim 1 or claim 2, comprising 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.1, 1.5, 1.9, 2.1, 2.5 or 3.0 mg of active compound.
4. A composition according to any one of claims 1 to 3, adapted for oral administration, parenteral administration, sublingual or transdermal administration.
5. A composition according to any one of claims 1 to 4, adapted for oral administration.
6. A composition according to any one of claims 1 to 5, in the form of a unit dose.
7. A composition according to any one of claims 1 to 6, adapted for administration to the respiratory tract as a snuff, an aerosol, a solution for a nebulizer, or as a microfine powder for insufflation.
8. A pharmaceutical composition for inhaled administration, which comprises 0.2 to 3.0 mg of trans (3S,4R)-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-6-pentafluoroethyl-2H-1- benzopyran-3-ol ('Compound I'), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, in the form of a microfine powder and optionally a pharmaceutically acceptable carrier.
9. A composition according to claim 8, comprising 0.2 to 0.9 mg or 0.2 to 0.5 mg of active compound.
10. A process for preparing a pharmaceutical composition according to any one of claims 1 to 9 and comprising trans (3S,4R)-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-6-pentafluoroethyl-2H-1-benzopyran-3-ol ('Compound I'), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and optionally a pharmaceutically acceptable carrier therefor, which process comprises formulating Compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and optionally comprises admixing the pharmaceutically acceptable carrier.
11. A method for the treatment of respiratory tract disorders, such as reversible airways obstruction in humans, which method comprises administering a total daily dose of 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of trans (3S,4R)-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-6-pentafluoroethyl-2H-1- benzopyran-3-ol ('Compound I'), or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof, to a human in need thereof.
12. A pharmaceutical composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of trans (3S,4R)-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-6-pentafluoroethyl-2H-1-benzopyran-3-ol ('Compound I'), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically r acceptable carrier therefor, for use as an active therapeutic substance.
13. A pharmaceutical composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of trans (3S,4R)-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-6-pentafluoroethyl-2H-1- benzopyran-3-ol ('Compound I'), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for use in the treatment of respiratory tract disorders.
14. The use of a pharmaceutical composition comprising 0.2 to 0.9 mg or 1.1 to 1.9 mg or 2.1 to 3.0 mg of trans (3S,4R)-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-6-pentafluoroethyl-2H-1- benzopyran-3-ol ('Compound I'), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable carrier therefor for the manufacture of a medicament for the treatment of respiratory tract disorders.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9125862.4 | 1991-12-05 | ||
GB919125862A GB9125862D0 (en) | 1991-12-05 | 1991-12-05 | Pharmaceutical composition |
GB929213042A GB9213042D0 (en) | 1992-06-19 | 1992-06-19 | Pharmaceutical composition |
GB9213042.6 | 1992-06-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2125156A1 true CA2125156A1 (en) | 1993-06-10 |
Family
ID=26299960
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002125156A Abandoned CA2125156A1 (en) | 1991-12-05 | 1992-12-01 | Pharmaceutical composition |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP0615437A1 (en) |
JP (1) | JPH07501538A (en) |
AP (1) | AP382A (en) |
AU (1) | AU2954292A (en) |
BR (1) | BR9206845A (en) |
CA (1) | CA2125156A1 (en) |
CZ (1) | CZ136394A3 (en) |
HU (1) | HUT70745A (en) |
IL (1) | IL103952A0 (en) |
MA (1) | MA22731A1 (en) |
MX (1) | MX9206975A (en) |
RU (1) | RU94030464A (en) |
SI (1) | SI9200365A (en) |
SK (1) | SK65794A3 (en) |
WO (1) | WO1993010757A1 (en) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2107706A (en) * | 1981-09-25 | 1983-05-05 | Beecham Group Plc | Benzopyrans |
EP0093535B1 (en) * | 1982-04-28 | 1986-12-30 | Beecham Group Plc | Novel chromenes and chromans |
IL86798A (en) * | 1987-06-23 | 1992-12-01 | Sanofi Sa | 2,2-dimethylchroman-3-ol derivatives, their preparation and pharmaceutical compositions containing them |
EP0376524B1 (en) * | 1988-12-13 | 1995-03-29 | Beecham Group Plc | Benzopyran and related compounds |
-
1992
- 1992-12-01 CZ CZ941363A patent/CZ136394A3/en unknown
- 1992-12-01 WO PCT/GB1992/002234 patent/WO1993010757A1/en not_active Application Discontinuation
- 1992-12-01 AU AU29542/92A patent/AU2954292A/en not_active Abandoned
- 1992-12-01 JP JP5509963A patent/JPH07501538A/en active Pending
- 1992-12-01 BR BR9206845A patent/BR9206845A/en not_active Application Discontinuation
- 1992-12-01 EP EP92923956A patent/EP0615437A1/en not_active Withdrawn
- 1992-12-01 HU HU9401681A patent/HUT70745A/en unknown
- 1992-12-01 CA CA002125156A patent/CA2125156A1/en not_active Abandoned
- 1992-12-01 SK SK657-94A patent/SK65794A3/en unknown
- 1992-12-01 RU RU94030464/14A patent/RU94030464A/en unknown
- 1992-12-03 MX MX9206975A patent/MX9206975A/en unknown
- 1992-12-03 MA MA23021A patent/MA22731A1/en unknown
- 1992-12-03 IL IL103952A patent/IL103952A0/en unknown
- 1992-12-04 AP APAP/P/1992/000454A patent/AP382A/en active
- 1992-12-04 SI SI19929200365A patent/SI9200365A/en unknown
Also Published As
Publication number | Publication date |
---|---|
AP382A (en) | 1995-05-03 |
WO1993010757A1 (en) | 1993-06-10 |
MA22731A1 (en) | 1993-07-01 |
CZ136394A3 (en) | 1995-02-15 |
BR9206845A (en) | 1996-01-02 |
RU94030464A (en) | 1996-04-27 |
HU9401681D0 (en) | 1994-09-28 |
MX9206975A (en) | 1993-06-01 |
EP0615437A1 (en) | 1994-09-21 |
AU2954292A (en) | 1993-06-28 |
SK65794A3 (en) | 1995-02-08 |
SI9200365A (en) | 1993-06-30 |
JPH07501538A (en) | 1995-02-16 |
HUT70745A (en) | 1995-10-30 |
AP9200454A0 (en) | 1993-01-31 |
IL103952A0 (en) | 1993-05-13 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued |