GB2235627A - Inhalation medicaments - Google Patents
Inhalation medicaments Download PDFInfo
- Publication number
- GB2235627A GB2235627A GB9019659A GB9019659A GB2235627A GB 2235627 A GB2235627 A GB 2235627A GB 9019659 A GB9019659 A GB 9019659A GB 9019659 A GB9019659 A GB 9019659A GB 2235627 A GB2235627 A GB 2235627A
- Authority
- GB
- United Kingdom
- Prior art keywords
- salmeterol
- fluticasone propionate
- inhalation
- physiologically acceptable
- acceptable salt
- 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.)
- Granted
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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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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)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Pharmaceutical compositions comprising effective amounts of salmeterol (and/or a physiologically acceptable salt thereof) and fluticasone propionate as a combined preparation for simultaneous, sequential or separate administration by inhalation in the treatment of respiratory disorders.
Description
MEDICAMENTS
This invention relates to improvements in the treatment of asthma and other respiratory disorders.
More particularly, it relates to the use of a bronchodilator drug in combination with a steroidal anti-inflammatory drug for the treatment of respiratory disorders such as asthma, and to pharmaceutical compositions containing the two active ingredients.
Asthma is a condition characterised by variable, reversible obstruction of the airways which is caused by a complex inflammatory process within the lungs. In most cases, this process is initiated and maintained by the inhalation of antigens by sensitive atopic individuals (extrinsic asthma). However, in some patients it is caused by other mechanisms which at present are poorly understood but do not involve an allergic process (intrinsic asthma). The disease has therefore two components, spasm of the bronchial (or breathing) tubes and inflammation or swelling of the breathing tubes.
Salbutamol, the first highly selective ss2- adrenoceptor stimulant has been used successfully and effectively by inhalation for the immediate relief of spasm in asthma. However, when given by inhalation, salbutamol has usually a four to six hour duration of action, which is too short either to control nocturnal asthma or for convenient maintenance of the disease in some patients.
Anti-inflammatory corticosteroids such as, for example, beclomethasone dipropionate have also been administered by inhalation in the treatment of asthma, although unlike salbutamol the therapeutic benefits resulting from reduced inflammation may not be immediately apparent.
It has been recognised that asthma may be treated by using both a bronchodilator for immediate relief and a prophylactic anti-inflammatory corticosteroid to treat the underlying inflammation. Such combination therapy directed at the two main underlying events in the lung (i.e. relief of spasm in the breathing tubes and treatment of inflammation in the breathing tubes) using a combination of salbutamol and beclomethasone dipropionate has previously been proposed (Ventide,
Glaxo Group trade mark), but suffers a number of disadvantages in view of the above-mentioned short duration of action exhibited by salbutamol.Thus the need for a 4-hourly dosing regimen may discourage effective patient compliance and also renders the product less than satisfactory in the treatment of nocturnal asthma since the bronchodilator may not remain effective for the duration of the night, leading to impaired sleep for asthmatics troubled by nocturnal cough, breathlessness and wheeze.
The present invention is based on the concept of a novel combination therapy which has markedly greater efficiency and duration of bronchodilator action than previously known combinations and which permits the establishment of a twice daily (bis in diem - b.i.d) dosing regimen with consequent substantial benefits in, for example, the treatment of asthma, particularly nocturnal asthma.
Thus we have found that if the p2-adrenoreceptor stimulant brochodilator salmeterol and/or a physiologically acceptable salt thereof is combined with the anti-inflammatory corticosteroid fluticasone propionate in a form suitable for administration by inhalation, the resulting compositions may be administered on a b.i.d. basis to provide highly effective treatment and/or prophylactic therapy for asthmatics. In particular such administration has been shown to lead to significant improvement in daytime lung function, requirement for additional symptomatic bronchodilator and almost complete abolition of nocturnal asthma while giving rise to minimal systemic side effects.
Salmeterol is one of a range of bronchodilators having extended duration of action which is described in
British Patent Specification No. 2140800, and is systematically named 4-hydroxy-a1-[[[6-(4- phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol.
Fluticasone propionate is one of a range of topical anti-inflammatory corticosteroids with minimal liability to undesired systemic side effects which is described in
British Patent Specification No. 2088877, and is systematically named S-fluoromethyl 6a,9a-difluoro-llss- hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4- diene-17p-carbothioate. We have found these two compounds to be particularly compatible and complementary in their activity and thus highly effective in the treatment of asthma and other respiratory disorders.
Thus according to one aspect of the invention there are provided pharmaceutical compositions comprising effective amounts of salmeterol (and/or a physiologically acceptable salt thereof) and fluticasone propionate as a combined preparation for simultaneous, sequential or separate administration by inhalation in the treatment of respiratory disorders.
The invention additionally relates to the use of salmeterol (and/or a physiologically acceptable salt thereof) and fluticasone propionate in the manufacture of pharmaceutical compositions as combined preparations for simultaneous, sequential or separate administration of salmeterol and fluticasone propionate by inhalation in the treatment of respiratory disorders.
According to a further feature of the invention there is provided a method of treating respiratory disorders which comprises the simultaneous, sequential or separate administration by inhalation of effective amounts of salmeterol (and/or a physiologically acceptable salt thereof) and fluticasone propionate.
Suitable physiologically acceptable salts of salmeterol include acid addition salts derived from inorganic and organic acids, such as the hydrochloride, hydrobromide, sulphate, phosphate, maleate, tartrate, citrate, benzoate, 4-methoxybenzoate, 2- or 4hydroxybenzoate, 4-chlorobenzoate, p-toluenesulphonate, methanesulphonate, ascorbate, salicylate, acetate, fumarate, succinate, lactate, glutarate, gluconate, tricarballylate, hydroxynaphthalenecarboxylate e.g. 1hydroxy- or 3-hydroxy-2-naphthalenecarboxylate, or oleate. Salmeterol is preferably used in the form of its l-hydroxy-2-naphthalene carboxylate salt (hydroxynaphthoate).
For administration by inhalation, the compositions according to the invention are conveniently delivered by conventional means, e.g. in the form of a metered dose inhaler prepared in a conventional manner or in combination with a spacer device such as the Volumatic (Glaxo Group trade mark) device. In the case of a metered dose inhaler, a metering valve is provided to deliver a metered amount of the composition. Spray compositions may for example be formulated as aqueous solutions or suspensions and may be administered by a nebuliser. Aerosol spray formulations, for example in which the active ingredients are suspended, optionally together with one or more stabilisers, in a propellant, e.g. a halogenated hydrocarbon such as trichlorofluoromethane, dichlorodifluoromethane, 1,2dichlorotetrafluoroethane, trichlorotrifluoroethane, monochloropentafluoroethane, chloroform or methylene chloride, may also be employed. The two drugs may be administered separately in similar ways.
Alternatively, for administration by inhalation or insufflation, the compositions according to the invention may take the form of a dry powder composition, for example a powder mix of the active ingredients and a suitable carrier such as lactose. The powder compositions may be presented in unit dosage form in, for example, capsules, cartridges or blister packs from which the powder may be administered with the aid of an inhaler such as the Rotahaler inhaler (Glaxo Group trade mark) or in the case of blister packs by means of the
Diskhaler inhaler (Glaxo Group trade mark).
The ratio of salmeterol to fluticasone propionate in the compositions according to the invention is preferably within the range 4:1 to 1:20. The two drugs may be administered separately in the same ratio. Each metered dose or actuation of the inhaler will generally contain from 25 ssg to 100 ssg of salmeterol and from 25 ssg to 500 jig of fluticasone propionate. As hereinbefore indicated, it is intended that the pharmaceutical compositions will be administered twice daily.
A suitable daily dose of salmeterol for inhalation is in the range 50 jig to 200 jig.
A suitable daily dose of fluticasone propionate for inhalation is in the range 50 jig to 2000 jig depending on the severity of the disease.
The precise dose employed will of course depend on the method of administration, the age, weight and condition of the patient and will be determined by the clinician depending on the severity and the type of asthma.
In order that the invention may be more fully understood, the following examples are given by way of illustration only.
EXAMPLE 1 - Metered Dose Inhaler
Active Ingredient Tarqet per Per Inhaler
Actuation % w/w
Salmeterol 25.0 jig (as hydroxynaphthoate) 0.0448
Fluticasone propionate 25.0 jig 0.0309
Stabiliser 5.0 jig 0.0076
Trichlorofluoromethane 23.70 mg 27.8759
Dichlorodifluoromethane 61.25 mg 72.0588
EXAMPLE 2 - Metered Dose Inhaler
Active Ingredient Tarqet Per Per Inhaler
Actuation % w/w
Salmeterol 25.0 jig (as hydroxynaphthoate) 0.0448
Fluticasone propionate 50.0 jig 0.0618
Stabiliser 7.5 jig 0.0106
Trichlorofluoromethane 23.67 mg 27.8240
Dichlorodifluoromethane 61.25 mg 72.0588
EXAMPLE 3 - Metered Dose Inhaler
Active Ingredient Target per Per Inhaler
Actuation % w/w
Salmeterol 25.0 jig (as hydroxynaphthoate) 0.0448
Fluticasone propionate 250.0 jig 0.3088
Stabiliser 25.0 jig 0.0309
Trichlorofluoromethane 23.45 mg 27.5567
Dichlorodifluoromethane 61.25 mg 72.0588
EXAMPLE 4 - Metered Dose Inhaler
Active Inqredient Target per Per Inhaler
Actuation % w/w
Salmeterol 25.0 jig (as hydroxynaphthoate) 0.0448
Fluticasone propionate 125.0 jig 0.1544
Stabiliser 15.0 jig 0.0175
Trichlorofluoromethane 23.56 mg 27.7244
Dichlorodifluoromethane 61.25 mg 72.0588
EXAMPLE 5 - Metered Dose Inhaler
Active Ingredient Target per Per Inhaler
Actuation % w/w
Salmeterol 100.0 jig (as hydroxynaphthoate) 0.1791
Fluticasone propionate 250.0 jig 0.3088
Stabiliser 25.0 jig 0.0309
Trichlorofluoromethane 23.43mg 27.4224
Dichlorodifluoromethane 61.25 mg 72.0588
In Examples 1 to 5 micronised fluticasone propionate and micronised salmeterol (as the hydroxynaphthoate) are added in the proportions given above either dry or after predispersal in a small quantity of stabiliser (disodium dioctylsulphosuccinate, lecithin, oleic acid or sorbitan trioleate)/trichlorofluoromethane solution to a suspension vessel containing the main bulk of the trichlorofluoromethane solution. The resulting suspension is further dispersed by an appropriate mixing system using, for example, a high shear blender, ultrasonics or a microfluidiser until an ultra fine dispersion is created. The suspension is then continuously recirculated to suitable filling equipment designed for cold fill or pressure filling of dichlorodifluoromethane.Alternatively, the suspension may be prepared in a suitable chilled solution of stabiliser, in trichlorofluoromethane/ dichlorodifluoromethane.
EXAMPLE 6 - Metered Dose Dry Powder Formulation
Active Ingredient ag/cartridge or blister
Salmeterol 36.3 (as hydroxynaphthoate)
Fluticasone propionate 50.00
Lactose Ph.Eur. to 12.5 mg or
to 25.Omg
EXAMPLE 7 - Metered Dose Dry Powder Formulation
Active Inqredient ag/cartridge or blister
Salmeterol 72.5 (as hydroxynaphthoate)
Fluticasone propionate 50.00
Lactose Ph.Eur. to 12.5 mg or
to 25.0 mg
EXAMPLE 8 - Metered Dose Dry Powder Formulation
Active Inqredient ss/cartridve or blister
Salmeterol 72.5 (as hydroxynaphthoate)
Fluticasone propionate 100.00
Lactose Ph.Eur. to 12.5 mg or
to 25.0 mg
EXAMPLE 9 - Metered Dose Drv Powder Formulation
Active Ingredient us/cartridse or blister
Salmeterol 72.5 (as hydroxynaphthoate)
Fluticasone propionate 250
Lactose Ph.Eur. to 12.5 mg or
to 25.0 mg
EXAMPLE 10 - Metered Dose Drv Powder Formulation
Active Ingredient uq/cartridge or blister
Salmeterol 72.5 (as hydroxynaphthoate)
Fluticasone propionate 500.0
Lactose Ph. Eur. to 12.5 mg or
to 25.0 mg
EXAMPLE 11 - Metered Dose Drv Powder Formulation
Active Ingredient ssq/cartridqe or blister
Salmeterol 145.0 (as hydroxynaphthoate)
Fluticasone propionate 250.0
Lactose Ph. Eur. to 12.5 mg or
to 25.0 mg
In Examples 6 to 11 the active ingredients are micronised and bulk blended with the lactose in the proportions given above. The blend is filled into hard gelatin capsules or cartridges or in specifically constructed double foil blister packs (Rotadisks blister packs, Glaxo Group trade mark) to be administered by an inhaler such as the Rotahaler inhaler (Glaxo Group trade mark) or in the case of the blister packs with the Diskhaler inhaler (Glaxo Group trade mark).
Claims (6)
1. Pharmaceutical compositions comprising effective amount of salmeterol (and/or a physiologically acceptable salt thereof) and fluticasone propionate as a combined preparation for simultaneous, sequential or separate administration by inhalation in the treatment of respiratory disorders.
2. Compositions as claimed in claim 1 wherein salmeterol is present as its l-hydroxy-2-naphthoate salt.
3. Compositions as claimed in claim 1 or claim 2 presented as a metered spray composition or a dry powder composition.
4. Compositions as claimed in any of claims 1 to 3 in dosage unit form containing 25-100yg of salmeterol (optionally in the form of a physiologically acceptable salt thereof) and 25-500pg of fluticasone propionate per dosage unit.
5. The use of salmeterol (and/or a physiologically acceptable salt thereof) and fluticasone propionate in the manufacture of pharmaceutical compositions as combined preparations for simultaneous, sequential or separate administration of salmeterol and fluticasone propionate by inhalation in the treatment of respiratory disorders.
6. The use of salmeterol (and/or a physiologically acceptable salt thereof) and fluticasone propionate according to claim 5 in the manufacture of pharmaceutical compositions for administration on a twice daily basis.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9019659A GB2235627B (en) | 1989-09-08 | 1990-09-07 | Inhalation medicaments for treating respiratory disorders |
CY181795A CY1817A (en) | 1989-09-08 | 1995-10-20 | Inhalation medicaments for treating respiratory disorders |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB898920392A GB8920392D0 (en) | 1989-09-08 | 1989-09-08 | Medicaments |
GB898923644A GB8923644D0 (en) | 1989-10-20 | 1989-10-20 | Medicaments |
GB9019659A GB2235627B (en) | 1989-09-08 | 1990-09-07 | Inhalation medicaments for treating respiratory disorders |
Publications (3)
Publication Number | Publication Date |
---|---|
GB9019659D0 GB9019659D0 (en) | 1990-10-24 |
GB2235627A true GB2235627A (en) | 1991-03-13 |
GB2235627B GB2235627B (en) | 1993-09-01 |
Family
ID=27264676
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB9019659A Revoked GB2235627B (en) | 1989-09-08 | 1990-09-07 | Inhalation medicaments for treating respiratory disorders |
Country Status (2)
Country | Link |
---|---|
CY (1) | CY1817A (en) |
GB (1) | GB2235627B (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1434587A1 (en) * | 2001-10-12 | 2004-07-07 | Glaxo Group Limited | Pharmaceutical combinations comprising salmeterol and fluticasone proprionate for the treatment of asthma |
US6893628B2 (en) | 1991-12-12 | 2005-05-17 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicament |
WO2005087192A2 (en) * | 2004-03-12 | 2005-09-22 | Cipla Limited | Salmeterol inhalation formulations |
EP1066828B2 (en) † | 1991-12-12 | 2006-12-06 | Glaxo Group Limited | Aerosol compositions |
US7220403B2 (en) | 1999-09-11 | 2007-05-22 | Glaxo Group Limited | Pharmaceutical formulation of fluticasone propionate |
USRE40045E1 (en) | 1989-09-08 | 2008-02-05 | Glaxo Group Limited | Medicaments |
US7994197B2 (en) | 2007-02-11 | 2011-08-09 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
US8080236B2 (en) | 2002-04-17 | 2011-12-20 | Nektar Therapeutics Uk, Ltd | Particulate materials |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU213221B (en) | 1990-03-02 | 1997-03-28 | Glaxo Group Ltd | Inhalation device and medicine packet for device |
US6536427B2 (en) | 1990-03-02 | 2003-03-25 | Glaxo Group Limited | Inhalation device |
US7101534B1 (en) | 1991-12-18 | 2006-09-05 | 3M Innovative Properties Company | Suspension aerosol formulations |
-
1990
- 1990-09-07 GB GB9019659A patent/GB2235627B/en not_active Revoked
-
1995
- 1995-10-20 CY CY181795A patent/CY1817A/en unknown
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE40045E1 (en) | 1989-09-08 | 2008-02-05 | Glaxo Group Limited | Medicaments |
US6893628B2 (en) | 1991-12-12 | 2005-05-17 | Glaxo Group Limited | Aerosol formulations containing P134a and particulate medicament |
US7498020B2 (en) | 1991-12-12 | 2009-03-03 | Glaxo Group Limited | Medicaments |
EP1066828B2 (en) † | 1991-12-12 | 2006-12-06 | Glaxo Group Limited | Aerosol compositions |
US7220403B2 (en) | 1999-09-11 | 2007-05-22 | Glaxo Group Limited | Pharmaceutical formulation of fluticasone propionate |
EP1434587A1 (en) * | 2001-10-12 | 2004-07-07 | Glaxo Group Limited | Pharmaceutical combinations comprising salmeterol and fluticasone proprionate for the treatment of asthma |
US8470301B2 (en) | 2002-04-17 | 2013-06-25 | Nektar Therapeutics | Particulate materials |
US8080236B2 (en) | 2002-04-17 | 2011-12-20 | Nektar Therapeutics Uk, Ltd | Particulate materials |
US8828359B2 (en) | 2002-04-17 | 2014-09-09 | Nektar Therapeutics | Particulate materials |
US9616060B2 (en) | 2002-04-17 | 2017-04-11 | Nektar Therapeutics | Particulate materials |
US10251881B2 (en) | 2002-04-17 | 2019-04-09 | Nektar Therapeutics | Particulate materials |
WO2005087192A3 (en) * | 2004-03-12 | 2006-06-15 | Cipla Ltd | Salmeterol inhalation formulations |
WO2005087192A2 (en) * | 2004-03-12 | 2005-09-22 | Cipla Limited | Salmeterol inhalation formulations |
US7994197B2 (en) | 2007-02-11 | 2011-08-09 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
US8119639B2 (en) | 2007-02-11 | 2012-02-21 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
US8148377B2 (en) | 2007-02-11 | 2012-04-03 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
US9833451B2 (en) | 2007-02-11 | 2017-12-05 | Map Pharmaceuticals, Inc. | Method of therapeutic administration of DHE to enable rapid relief of migraine while minimizing side effect profile |
Also Published As
Publication number | Publication date |
---|---|
CY1817A (en) | 1995-10-20 |
GB2235627B (en) | 1993-09-01 |
GB9019659D0 (en) | 1990-10-24 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
CTFF | Supplementary protection certificate filed |
Free format text: SPC/GB99/016, 19990406 |
|
CTFG | Supplementary protection certificate granted |
Free format text: SPC/GB99/016, 19990902, EXPIRES: 20130906 |
|
7722 | Petition lodged in court (sect. 72/1977) | ||
772R | Patent revoked (sect. 72/1977) | ||
772R | Patent revoked (sect. 72/1977) | ||
775E | Patent revoked (sect. 75/1977) | ||
CTFI | Supplementary protection certificate declared invalid |
Free format text: SPC/GB99/016: 20040405 Spc suppl protection certif: SPC/GB99/016 Filing date: 20040405 |