WO1992014466A1 - Pharmaceutical antitussive compositions - Google Patents
Pharmaceutical antitussive compositions Download PDFInfo
- Publication number
- WO1992014466A1 WO1992014466A1 PCT/GB1992/000257 GB9200257W WO9214466A1 WO 1992014466 A1 WO1992014466 A1 WO 1992014466A1 GB 9200257 W GB9200257 W GB 9200257W WO 9214466 A1 WO9214466 A1 WO 9214466A1
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- WIPO (PCT)
- Prior art keywords
- formulation
- antitussive
- dextromethorphan
- active
- component
- Prior art date
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Classifications
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- 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
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
- A61K31/055—Phenols the aromatic ring being substituted by halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
-
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- 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
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- 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
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
Definitions
- This invention relates to pharmaceutical formulations, in particular pharmaceutical formulations for delivery to the lung and bronchial tract by inhalation via the throat for the treatment of coughs.
- French Patent FR 260/246 and European Patent Application EP-A-0 0 21986 respectively describe the nasal administration of dextromethorphan [ (+) -cis-1, 3,4,9, 10, 10a-hexahydro-6- methoxy-ll-methyl-2H-10, 4a iminoethanophenanthrene] and the principal metabolite of dextromethorpahn i.e. dextrorphan [ (+) -cis-1, 3, 4, 9,10, 10a-hexahydro-ll-methyl-li- methyl-2H-10, 4a iminoethanophenanthrene-6-ol] .
- nasal administration with absorption by the nasal mucosa is used to reduce first pass losses that might occur on oral administratio .
- antitussive formulations administered by throat inhalation via the mouth are effective in the suppression of "trivial coughs" i.e. coughs resulting from minor and/or common diseases of the lung and bronchial tract, such as the common cold, etc.
- the invention therefore provides an antitussive pharmaceutical formulation adapted for delivery to the lung via throat inhalation through the mouth, containing an active antitussive component which is a non-narcotic antitussive or local anaesthetic, the active component being present in the formulation in a form suitable for unit dose delivery.
- a principal advantage of the formulation of the invention is that in many cases it allows delivery of the active antitussive component in a dosage which is substantially lower than would normally be used if the active component were administered orally or nasally. This is believed to be a consequence of a number of effects, for example the direct delivery of the active component to receptor sites in the lung, and in the case of compounds which are metabolised to active components, a reduced degree of metabolic degradation before the active component can have its effect on these receptor sites.
- Non-narcotic antitussive agents such as dextromethorphan and narcotic opioid antitussive agents such as codeine are generally believed to inhibit cough centrally by the action of active metabolites on the cough centre in the CNS.
- a further advantage of the formulation of the invention is the rate of onset of antitussive effect which is more rapid than that observed after oral dosing. This is a further indication of direct delivery of active component to lung receptor sites.
- Preferred active components are dextromethorphan and metabolities thereof such as dextrorphan, 3-methoxymorphinan and morphinan-3-ol, lignocaine, benzocaine, xylocaine, amethocaine, chlorinated phenols and hexylresorcinol, including derivatives thereof, for example pharmaceutically acceptable salts thereof.
- dextromethorphan is preferably present as the hydrobromide salt ("Dex HBr") or as the free base
- lignocaine is preferably present as the hydrochloride salt.
- the formulation may in some cases comprise the active component in a pharmaceutically acceptable degree of purity, the physical form in which it is presented, e.g. a fine powder in an appropriate unit dose quantity, rendering it suitable for unit dose delivery.
- the active component may be present in the formulation together with a pharmaceutically acceptable carrier such as a liquid in which it is dissolved or suspended as fine particles, or a bulking agent.
- the formulation may also contain preservatives, surfactants, buffers and flavouring agents, and other conventional excipients.
- the formulation comprises a solution or suspension of the active component in a carrier which is a volatile propellant such as the known CFC class of propellants, or preferably of a class which is considered to be less environmentally harmful.
- a volatile propellant such as the known CFC class of propellants, or preferably of a class which is considered to be less environmentally harmful.
- This formulation is contained within a small aerosol spray dispenser having a metering outlet valve, e.g. of known type, so that each operation of the valve releases a predetermined volume of spray of liquid propellant and active component, from which the propellant almost immediately vapourises to form a cloud of particles of the active component for inhalation.
- Such a formulation may also include a surfactant material such as for example span 85 (Trade Mark) , to assist in dispersion of the active component.
- a formulation for metered dose inhalation contains 0.05 to 10 weight %, for example 0.1-1 weight % of active antitussive component, and 0.05-0.5 weight % of surfactant, made up to 100% with propellant.
- the formulation comprises a solution or suspension of the active component in a carrier which is water, optionally also containing a surfactant such as a benzalkonium salt, a preservative such as sodium benzoate, a pH buffer, flavouring agents etc.
- a surfactant such as a benzalkonium salt
- a preservative such as sodium benzoate
- a pH buffer e.g. g. a pH buffer
- flavouring agents e.g. of known type
- a formulation for aqueous pump delivery contains 0.05-10 weight %, for example 0.1-10 weight % of active component (the aqueous maximum solubility of Dex HBr is 2.5 wt %) , 0.05-1.0 weight % of an inorganic salt containing chloride ions such as sodium chloride, 0.05-0.5 weight % of preservatives and optionally 0.05-0.5 weight % of surfactant.
- pH buffers may ideally maintain the pH of lung mucous, i.e. around pH 6-8, but in practice the pH will depend on the solubility of the active component, and the optimum value for adequate antimicrobial preservation.
- the formulation may comprise simply the active component, present in a pharmaceutially pure state and in a suitable particle size range.
- the formulation may comprise a mixture of the active antitussive component with a pharmaceutically acceptable carrier, e.g. a bulking agent such as lactose.
- a pharmaceutically acceptable carrier e.g. a bulking agent such as lactose.
- Various methods of dry powder inhalation are known, but in a common one, the formulation is contained within a fragile capsule which is inserted into a dispenser such as an inhaler, ruptured by an operation of the inhaler, and sucked as an aerosol from the capsule down the throat via the mouth.
- the dispensing method generates an aerosol of the active antitussive component having a particle or droplet (i.e. of solution or suspension of active component) size range such that the active component is deposited at suitable positions in the lung and/or tracheal airway so that the active component can act upon suitable receptor sites and have an optimum antitussive effect.
- a particle or droplet i.e. of solution or suspension of active component
- a further example of a particle/droplet size distribution of the active component aerosol is:
- the majority of particles/droplets of active component for example greater than 50% by weight have a size of 5 ⁇ or less. More preferably at least 80% by weight have a size of 5 ⁇ of less.
- the particle size of a bulking agent, e.g. lactose, when present in a formulation of the invention for dry powder inhalation is suitably. in the range 30-120 ⁇ m by weight median diameter.
- the dispenser e.g. metered dose dispenser, aqeuous pump dispenser or dry powder dispenser should preferably be adapted to produce aerosols having these size ranges, for example by suitable nozzles or powder size ranges in capsules or metered dose dispenser formulations.
- the dispenser is adapted to dispense unit doses which are a fraction of the maximum recommended daily dose, preferably with instructions recommending the maximum number of unit doses per day.
- dextromethorphan it is preferred that this is present as the free base or as the hydrobromide salt, for example in a solution or suspension.
- the maximum recommended daily oral dose of dextromethorphan free base is in the region of 75mg/day.
- Dispensers for inhalation of formulations of the invention are preferably adapted to dispense unit doses of 0.05-5, suitably 0.1-2, e.g. cja. 0.1- lmg of dextromethorphan (calculated as the HBr salt) on each operation of the dispenser, e.g. in each dry powder capsule or puff of metered dose or aqueous pump.
- Another aspect of this invention is a dispenser, e.g. of the types described above, adapted to dispense the formulations described above in a form suitable for delivery to the lung for antitussive treatment via throat inhalation; and containing such a formulation.
- Another aspect of this invention is a method of antitussive treatment, comprising delivering to the lung via throat inhalation through the mouth a formulation as desribed above.
- Another aspect of this invention is a method of preparation of a pharmaceutical formulation for delivery to the lung for antitussive treatment via throat inhalation through the mouth which includes the step of mixing an active antitussive component which is a non-narcotic antitussive or local anaesthetic, preferably selected from dextromethorphan and metabolities thereof such as dextrorphan, 3-methoxy ⁇ morphinan and morphinan-3-ol, lignocaine, benzocaine, xylocaine, amethocaine, chlorinated phenols and hexylresorcinol or derivatives thereof with a pharmaceutically acceptable carrier component and/or preparing the components in a particle size range adapted for such delivery.
- an active antitussive component which is a non-narcotic antitussive or local anaesthetic, preferably selected from dextromethorphan and metabolities thereof such as dextrorphan, 3-methoxy ⁇ morphinan and morphinan-3-
- Dex HBr was processed using a 2" pancake microniser to obtain a micronised powder having a particle size distribution:
- This powder was made up into a formulation having the composition below:
- Propellant 11 (known propellant) 24.8 wt %
- Propellant 12 (known propellant) 70.0 wt %
- the formulation was made up by suspending the Dex HBr and Span 85 in the propellant 11, introducing this suspension into a suitable commercially available aerosol container, adding propellant 12, then fitting the container with a commercially available metered dose valve.
- a suitable unit of this formulation was 100 ⁇ l, containing 5mg of Dex HBr per puff.
- Dex HBr was processed as described in Example 1 to obtain a micronised powder having a particle size distribution: ⁇ 3 ⁇ ca. 40%, 3- 5 ⁇ ca. 40%, 5-10 ⁇ ca. 10%, > lO ⁇ ca. 10%. This powder was made up into a formulation having the composition below: Dex HBr 0.5 wt %
- Propellant 11 (known propellant) 25.8 wt %
- Propellant 12 (known propellant) 73.5 wt % Total 100 wt %
- the formulation was made up by suspending the Dex HBr and Span 85 in the propellant 11, introducing this suspension into a suitable commercially available aerosol container, adding propellant 12, then fitting the container with a commercially available metered dose valve.
- a suitable unit of this formulation was 100 ⁇ l, containing 0.5mg of Dex HBr per puff.
- Lignocaine was processed as described in Example 1 to obtain a micronised powder having the same size distribution as in Example 1. This powder was made up into a formulation having the composition below in exactly the same way as the formulation of Example 1.
- Propellant 11 (known propellant) 24.8 wt %
- Propellant 12 (known propellant) 70.0 wt %
- the solution was made up simply by dissolving the solids in the water, and the solution was then introduced into a container fitted with a suitable pump, capable of producing an aqueous spray with an MMAD of ca. 5 ⁇ m of this solution.
- the solution was made up as described in Example 4. The solution was introduced into a container fitted with a suitable pump, capable of producing an aqueous spray with an MMAD of ca. 5 ⁇ m of this solution. A suitable volume of this solution for a unit dose was 150 ⁇ l, containing 0.3mg of Dex HBr per puff.
- the solution was made up and introduced into a container fitted with a pump, as described for example 4, lOO ⁇ l being a suitable unit dose, containing 2mg of lignocaine per puff.
- a dry powder mixture was prepared having the following composition:
- Lactose Powder 50 wt % This powder mixture was filled into fragile gelatine capsules each containing lOmg of powder, i.e. a 5mg unit dose of Dex HBr.
- a dry powder mixture was prepared having the following composition:
- This powder mixture was filled into fragile gelatine capsules each containing lOmg of powder, a i.e. 0.5mg unit dose of Dex HBr.
- a dry powder mixture was prepared having the following composition:
- a dry powder mixture was prepared having the following composition:
- the Dex HBr was processed to size range:
- This powder mixture was filled into fragile gelatine capsules each containing lOmg of powder, i.e. a lmg unit dose of Dex HBr.
- a dry powder mixture was prepared having the following composition:
- a dry powder mixture was prepared having the following composition:
- Lignocaine hydrochloride 25 wt %
- This powder mixture was filled into fragile gelatine capsules each containing 20mg of powder, i.e. a 5mg unit dose of Lignocaine hydrochloride.
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Abstract
Pharmaceutical formulations for antitussive treatment adapted for delivery to the lung via the throat inhalation through the mouth.
Description
Pharmaceutical ant*ltussive compositions
This invention relates to pharmaceutical formulations, in particular pharmaceutical formulations for delivery to the lung and bronchial tract by inhalation via the throat for the treatment of coughs.
It is known to deliver drugs and other medications directly to the lung and bronchial tract by inhalation for the treatment of various diseases or the symptoms thereof, for example Thorax (1984) 3_9 1-7 gives a brief review of such treatments.
In the field of antitussive treatment, French Patent FR 260/246 and European Patent Application EP-A-0 0 21986 respectively describe the nasal administration of dextromethorphan [ (+) -cis-1, 3,4,9, 10, 10a-hexahydro-6- methoxy-ll-methyl-2H-10, 4a iminoethanophenanthrene] and the principal metabolite of dextromethorpahn i.e. dextrorphan [ (+) -cis-1, 3, 4, 9,10, 10a-hexahydro-ll-methyl-li- methyl-2H-10, 4a iminoethanophenanthrene-6-ol] . Here nasal administration with absorption by the nasal mucosa is used to reduce first pass losses that might occur on oral administratio .
It is also known, in the field of suppression of lung spasm and/or cough resulting from fairly severe stimulus to the lung, e.g. lung surgery, bronchoscopy, major lung disease or serious lung damage, to administer lignocaine directly to the lung in quite high dosage rates using an aerosol spray. Such work is for example described in Br. J. Dis. Chest (1977) 72, 19 and Er. J. Anaesth. (1976) 4_8 899.
It has now been found that antitussive formulations administered by throat inhalation via the mouth are effective in the suppression of "trivial coughs" i.e. coughs
resulting from minor and/or common diseases of the lung and bronchial tract, such as the common cold, etc.
The invention therefore provides an antitussive pharmaceutical formulation adapted for delivery to the lung via throat inhalation through the mouth, containing an active antitussive component which is a non-narcotic antitussive or local anaesthetic, the active component being present in the formulation in a form suitable for unit dose delivery.
A principal advantage of the formulation of the invention is that in many cases it allows delivery of the active antitussive component in a dosage which is substantially lower than would normally be used if the active component were administered orally or nasally. This is believed to be a consequence of a number of effects, for example the direct delivery of the active component to receptor sites in the lung, and in the case of compounds which are metabolised to active components, a reduced degree of metabolic degradation before the active component can have its effect on these receptor sites. Non-narcotic antitussive agents such as dextromethorphan and narcotic opioid antitussive agents such as codeine are generally believed to inhibit cough centrally by the action of active metabolites on the cough centre in the CNS.
A further advantage of the formulation of the invention is the rate of onset of antitussive effect which is more rapid than that observed after oral dosing. This is a further indication of direct delivery of active component to lung receptor sites.
Preferred active components are dextromethorphan and metabolities thereof such as dextrorphan, 3-methoxymorphinan and morphinan-3-ol, lignocaine, benzocaine, xylocaine,
amethocaine, chlorinated phenols and hexylresorcinol, including derivatives thereof, for example pharmaceutically acceptable salts thereof. When used as the active antitussive component, dextromethorphan is preferably present as the hydrobromide salt ("Dex HBr") or as the free base, and lignocaine is preferably present as the hydrochloride salt.
The formulation may in some cases comprise the active component in a pharmaceutically acceptable degree of purity, the physical form in which it is presented, e.g. a fine powder in an appropriate unit dose quantity, rendering it suitable for unit dose delivery. Alternatively, the active component may be present in the formulation together with a pharmaceutically acceptable carrier such as a liquid in which it is dissolved or suspended as fine particles, or a bulking agent. The formulation may also contain preservatives, surfactants, buffers and flavouring agents, and other conventional excipients.
Whatever form the formulation takes, it will normally be administered as a fine aerosol of solid particles or liquid droplets drown the throat. There are 3 main known methods of administering the formulation as an aerosol in this way which are convenient for use with formulations primarily intended for "over the counter" treatments for trivial coughs, i.e. which impose minimum cost upon the consumer and minimum manufacturing effort on the producer. These methods are metered dose inhalation, aqueous pump, and dry powder inhalation.
In metered dose inhalation, the formulation comprises a solution or suspension of the active component in a carrier which is a volatile propellant such as the known CFC class of propellants, or preferably of a class which is considered to be less environmentally harmful. This formulation is
contained within a small aerosol spray dispenser having a metering outlet valve, e.g. of known type, so that each operation of the valve releases a predetermined volume of spray of liquid propellant and active component, from which the propellant almost immediately vapourises to form a cloud of particles of the active component for inhalation. Such a formulation may also include a surfactant material such as for example span 85 (Trade Mark) , to assist in dispersion of the active component.
Typically a formulation for metered dose inhalation contains 0.05 to 10 weight %, for example 0.1-1 weight % of active antitussive component, and 0.05-0.5 weight % of surfactant, made up to 100% with propellant.
In aqueous pumps, the formulation comprises a solution or suspension of the active component in a carrier which is water, optionally also containing a surfactant such as a benzalkonium salt, a preservative such as sodium benzoate, a pH buffer, flavouring agents etc. In some cases it may be necessary to include an organic solvent, for example some ethanol in the solution to improve solubility of the active component but the amount should be small in view of the sensitivity of the lung. This formulation is contained within a dispenser in the form of a small container fitted with a spray pump, e.g. of known type, each operation of which ejects a predetermined volume of the formulation as fine droplets for inhalation.
Typically a formulation for aqueous pump delivery contains 0.05-10 weight %, for example 0.1-10 weight % of active component (the aqueous maximum solubility of Dex HBr is 2.5 wt %) , 0.05-1.0 weight % of an inorganic salt containing chloride ions such as sodium chloride, 0.05-0.5 weight % of preservatives and optionally 0.05-0.5 weight % of
surfactant. If pH buffers are used they may ideally maintain the pH of lung mucous, i.e. around pH 6-8, but in practice the pH will depend on the solubility of the active component, and the optimum value for adequate antimicrobial preservation.
In dry powder inhalation the formulation may comprise simply the active component, present in a pharmaceutially pure state and in a suitable particle size range. Alternatively the formulation may comprise a mixture of the active antitussive component with a pharmaceutically acceptable carrier, e.g. a bulking agent such as lactose. Various methods of dry powder inhalation are known, but in a common one, the formulation is contained within a fragile capsule which is inserted into a dispenser such as an inhaler, ruptured by an operation of the inhaler, and sucked as an aerosol from the capsule down the throat via the mouth.
However the aerosol of particles or droplets is produced, for example using the 3 methods suggested above, it is important that the dispensing method generates an aerosol of the active antitussive component having a particle or droplet (i.e. of solution or suspension of active component) size range such that the active component is deposited at suitable positions in the lung and/or tracheal airway so that the active component can act upon suitable receptor sites and have an optimum antitussive effect.
An example of a particle/droplet size distribution of the active component aerosol is:
Size typical range preferred distribution (by weight) (± 5%) (by weight)
< 3μ 30 - 50% 40%
3-5μ 35 - 55% 45% 5-10μ 5 - 20 10% > lOμ 2 - 15% 5%
Preferably the majority of particles/droplets of active component, for example greater than 50% by weight have a size of 5μ or less. More preferably at least 80% by weight have a size of 5μ of less. The particle size of a bulking agent, e.g. lactose, when present in a formulation of the invention for dry powder inhalation is suitably. in the range 30-120μm by weight median diameter.
The dispenser, e.g. metered dose dispenser, aqeuous pump dispenser or dry powder dispenser should preferably be adapted to produce aerosols having these size ranges, for example by suitable nozzles or powder size ranges in capsules or metered dose dispenser formulations.
However the formulation is dispersed, e.g. using the 3 types of dispensing system described above, it is preferred that the dispenser is adapted to dispense unit doses which are a fraction of the maximum recommended daily dose, preferably with instructions recommending the maximum number of unit doses per day.
In the case of dextromethorphan it is preferred that this is present as the free base or as the hydrobromide salt, for example in a solution or suspension. The maximum
recommended daily oral dose of dextromethorphan free base, is in the region of 75mg/day. Dispensers for inhalation of formulations of the invention are preferably adapted to dispense unit doses of 0.05-5, suitably 0.1-2, e.g. cja. 0.1- lmg of dextromethorphan (calculated as the HBr salt) on each operation of the dispenser, e.g. in each dry powder capsule or puff of metered dose or aqueous pump.
Another aspect of this invention is a dispenser, e.g. of the types described above, adapted to dispense the formulations described above in a form suitable for delivery to the lung for antitussive treatment via throat inhalation; and containing such a formulation.
Another aspect of this invention is a method of antitussive treatment, comprising delivering to the lung via throat inhalation through the mouth a formulation as desribed above.
Another aspect of this invention is a method of preparation of a pharmaceutical formulation for delivery to the lung for antitussive treatment via throat inhalation through the mouth which includes the step of mixing an active antitussive component which is a non-narcotic antitussive or local anaesthetic, preferably selected from dextromethorphan and metabolities thereof such as dextrorphan, 3-methoxy¬ morphinan and morphinan-3-ol, lignocaine, benzocaine, xylocaine, amethocaine, chlorinated phenols and hexylresorcinol or derivatives thereof with a pharmaceutically acceptable carrier component and/or preparing the components in a particle size range adapted for such delivery.
The invention will now be described by way of example only.
Example 1
Formulation for Metered Dose Inhalation of Dextromethorphan
Dex HBr was processed using a 2" pancake microniser to obtain a micronised powder having a particle size distribution:
< 3μ ca. 35%, 3- 5μ ca. 25%, 5-10μ ca. 20%, > lOμ ca. 20%. This powder was made up into a formulation having the composition below:
Dex HBr 5 wt %
Span 85 0.2 wt %
Propellant 11 (known propellant) 24.8 wt % Propellant 12 (known propellant) 70.0 wt %
Total 100 wt %
The formulation was made up by suspending the Dex HBr and Span 85 in the propellant 11, introducing this suspension into a suitable commercially available aerosol container, adding propellant 12, then fitting the container with a commercially available metered dose valve. A suitable unit of this formulation was 100 μl, containing 5mg of Dex HBr per puff.
Example 2
Formulation for Metered Dose Inhalation of Dextromethorphan
Dex HBr was processed as described in Example 1 to obtain a micronised powder having a particle size distribution: < 3μ ca. 40%, 3- 5μ ca. 40%, 5-10μ ca. 10%, > lOμ ca. 10%. This powder was made up into a formulation having the composition below:
Dex HBr 0.5 wt %
Span 85 0.2 wt %
Propellant 11 (known propellant) 25.8 wt %
Propellant 12 (known propellant) 73.5 wt % Total 100 wt %
The formulation was made up by suspending the Dex HBr and Span 85 in the propellant 11, introducing this suspension into a suitable commercially available aerosol container, adding propellant 12, then fitting the container with a commercially available metered dose valve. A suitable unit of this formulation was 100 μl, containing 0.5mg of Dex HBr per puff.
Example 3
Formulation for Metered dose Inhalation of Lignocaine
Lignocaine was processed as described in Example 1 to obtain a micronised powder having the same size distribution as in Example 1. This powder was made up into a formulation having the composition below in exactly the same way as the formulation of Example 1.
Lignocaine Hydrochloride 5 wt %
Span 85 0.2 wt %
Propellant 11 (known propellant) 24.8 wt %
Propellant 12 (known propellant) 70.0 wt %
Total 100 wt %
A suitable unit dose of this formulation was again lOOμl, containing 5mg Lignocaine per puff.
Example 4
Formulation for Agueous Pump Dispenser for Dextromethorphan
Solution was made up having the following composition:
Dex HBr 2 % w/v
Benzalkonium Chloride 0.1 % w/v
Sodium Benzoate 0.1 % w/v Sodium Chloride 0.9 % w/v
Water 96.9 % w/v
Total 100 %
The solution was made up simply by dissolving the solids in the water, and the solution was then introduced into a container fitted with a suitable pump, capable of producing an aqueous spray with an MMAD of ca. 5μm of this solution.
A suitable volume of this solution for a unit dose was
150μl, containing 3mg of Dex HBr per puff.
Example 5
Formulation for Agueous Pump Dispenser for Dextromethorphan
Solution was made up having the following composition:
Dex HBr 0.2 % w/v
Benzalkonium Chloride 0.1 % w/v
Sodium Benzoate 0.1 % w/v Sodium Chloride 0.9 % w/v
Water 98.7 % w/v
Total 100 %
The solution was made up as described in Example 4. The solution was introduced into a container fitted with a suitable pump, capable of producing an aqueous spray with an MMAD of ca. 5μm of this solution. A suitable volume of this solution for a unit dose was 150μl, containing 0.3mg of Dex HBr per puff.
Example 6
Formulation for Agueous Pump Dispenser for Lignocaine
Solution was made up having the following composition:
Lignocaine hydrochloride 2 % w/v Benzalkonium Chloride 0.1 % w/v
Sodium Benzoate 0.1 % w/v
Sodium Chloride 0.9 % w/v
Water 96.9 % w/v
Total 100 %
The solution was made up and introduced into a container fitted with a pump, as described for example 4, lOOμl being a suitable unit dose, containing 2mg of lignocaine per puff.
Example 7
Formulation for Dry Powder Inhalation of Dextromethorphan
A dry powder mixture was prepared having the following composition:
Dex HBr (processed to size range 50 wt % of Example 1)
Lactose Powder 50 wt %
This powder mixture was filled into fragile gelatine capsules each containing lOmg of powder, i.e. a 5mg unit dose of Dex HBr.
Example 8
Formulation for Dry Powder Inhalation of Dextromethorphan
A dry powder mixture was prepared having the following composition:
Dex HBr (processed to size range 5 wt % of Example 2)
Lactose Powder 95 wt %
This powder mixture was filled into fragile gelatine capsules each containing lOmg of powder, a i.e. 0.5mg unit dose of Dex HBr.
Example 9
Formulation for Dry Powder Inhalation of Dextromethorphan
A dry powder mixture was prepared having the following composition:
Dex HBr (processed to size range 10 wt % of Example 1)
Lactose Powder 90 wt %
This powder mixture was filled into fragile gelatine capsules each containing lOmg of powder, i.e. a l g unit dose of Dex HBr.
Example 10
Formulation for Dry Powder Inhalation of Dextromethorphan
A dry powder mixture was prepared having the following composition:
Dex HBr lOwt %
Lactose Powder 90 wt %
The Dex HBr was processed to size range:
<3μ ca. 40%, 3-5μ ca. 45%, 5-10μ ca. 10%, >10μ ca. 5%.
This powder mixture was filled into fragile gelatine capsules each containing lOmg of powder, i.e. a lmg unit dose of Dex HBr.
Example 11
Formulation for Dry Powder Inhalation of Lignocaine
A dry powder mixture was prepared having the following composition:
Lignocaine hydrochloride 50 wt %
(processed to size range of example 1) Lactose Powder 50 wt %
This powder mixture was filled into fragile gelatine capsules each containing lOmg of powder, i.e. a 5mg unit dose of Lignocaine hydrochloride.
Example 12
Formulation for Dry Powder Inhalation of Lignocaine
A dry powder mixture was prepared having the following composition:
Lignocaine hydrochloride 25 wt %
(processed to size range of example 2)
Lactose Powder 75 wt %
This powder mixture was filled into fragile gelatine capsules each containing 20mg of powder, i.e. a 5mg unit dose of Lignocaine hydrochloride.
Example 13
Antitiussive effect of dextromethorphan hydrobromide in conscious guinea pigs
Male Dunkin Hartley guinea-pigs, (weight range 340-400g) were deprived of food but not water for 18 hours prior to the experiment. Each animal (group size 8) was placed in a plethysmometer and exposed to an aerosolised solution of vehicle (NaCl) or test material for 5 minutes. The aerosol was generated by compressed air at a constant pressure of 1.2kg/crrr- using a Wright nebuliser. The particle size generated was below 8μm.
Five minutes post vehicle/test material exposure, the animals were exposed to 7.5% aqueous citric acid aerosol, similarly generated by a Wright nebuliser, for 10 minutes. The number of coughs elicited within the exposure period was counted.
An inhaled dose of Dex. HBr of 0.13 mg/kg gave a 54% cough reduction. This compares with a reported 44% cough reduction from a 56mg/kg oral dose and a 54% cough reduction from a lOmg/kg iv dose in Sθ2~induced cough in guinea-pigs.
Claims
1. An antitussive pharmaceutical formulation adapted for delivery to the lung via throat inhalation through the 5 mouth, comprising an active antitussive component which is a non-narcotic antitussive or a local anaesthetic and wherein the active component is present in the formulation in a form suitable for unit dose delivery.
102. A formulation as claimed in claim 1 wherein the non- narcotic antitussive is dextromethorphan or a metabolite thereof, and pharmaceutically acceptable derivatives thereof.
153. A formulation as claimed in claim 2 wherein the non- narcotic antitussive is dextromethorphan, dextromethorphan hydrobromide, dextrorphan, 3-methoxymorphinan or morphinan- 3-ol, or a pharmaceutically acceptable derivative thereof.
204. A formulation as claimed in claim 1 wherein the local anaesthetic is lignocaine, benzocaine, xylocaine, amethocaine, a chlorinated phenol or hexylresorcinol, or a pharmaceutically acceptable derivative thereof.
255. A formulation as claimed in any one of claims 1 to 4 further comprising a pharmaceutically acceptable carrier.
6. A formulation as claimed in claim 5 comprising 0.05 to 10 weight % of the active antitussive component.
30
7. A formulation as claimed in any one of claims 1 to 6 adapted for metered dose, aqueous pump or dry powder inhalation in aerosol form.
358. A formulation as claimed in claim 7 wherein at least 80% by weight of the active component aerosol has a particle/droplet size below 10μm.
9. A formulation as claimed in claim 8 wherein at least 80% by weight of the active component aerosol has a particle/droplet size at or below 5μm.
5
10. A formulation as claimed in any one of claims 2 to 9 comprising a unit dose of dextromethorphan in the range 0.05 to 5mg.
10 11. A formulation as claimed in any one of claims 4 to 9 comprising a unit dose of lignocaine in the range 1 to 5mg.
12. A pharmaceutical formulation substantially as hereinbefore described in the accompanying Examples.
15
13. A dispenser adapted to dispense a unit dose of a formulation as defined in any one of claims 1 to 12 and containing such a formulation.
20 14. A method of preparation of a pharmaceutical formulation as defined in any one of claims 1 to 12 comprising mixing the active antitussive component with a pharmaceutically acceptable carrier component and/or preparing the components in a particle size range adapted
25 for such delivery.
15. A method of antitussive treatment comprising delivering to the lung via throat inhalation through the mouth an effective antitussive amount of a formulation as
30 defined in any one of claims 1 to 12.
16. Use of a pharmaceutical formulation as defined in any one of claims 1 to 12 for the manufacture of a medicament for antitussive treatment.
35
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB919103302A GB9103302D0 (en) | 1991-02-16 | 1991-02-16 | Pharmaceutical formulations |
GB9103302.7 | 1991-02-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992014466A1 true WO1992014466A1 (en) | 1992-09-03 |
Family
ID=10690127
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1992/000257 WO1992014466A1 (en) | 1991-02-16 | 1992-02-13 | Pharmaceutical antitussive compositions |
Country Status (5)
Country | Link |
---|---|
AU (1) | AU1227292A (en) |
GB (1) | GB9103302D0 (en) |
IE (1) | IE920484A1 (en) |
WO (1) | WO1992014466A1 (en) |
ZA (1) | ZA921093B (en) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994022422A1 (en) * | 1993-03-29 | 1994-10-13 | Henry Richard A | Lidocaine aerosol anaesthetic |
US5589156A (en) * | 1994-05-02 | 1996-12-31 | Henry; Richard A. | Prilocaine and hydrofluourocarbon aerosol preparations |
US5593661A (en) * | 1993-03-29 | 1997-01-14 | Henry; Richard A. | Lidocaine aerosol anaesthetic |
WO1997039742A1 (en) * | 1996-04-23 | 1997-10-30 | Pharmacia & Upjohn Ab | Transdermally administered dextromethorphan as antitussive agent |
WO1999063985A1 (en) * | 1998-06-09 | 1999-12-16 | Nortran Pharmaceuticals, Inc. | Compositions and methods for treatment of cough |
WO2000035417A1 (en) * | 1998-12-11 | 2000-06-22 | Pharmachemie B.V. | Pharmaceutical preparation for inhalation of an opioid |
WO2002000218A2 (en) * | 2000-06-23 | 2002-01-03 | Mayo Foundation For Medical Education And Research | Methods of treating neutrophil-related diseases with topical anesthetics |
WO2009076236A3 (en) * | 2007-12-06 | 2009-11-26 | Pain Therapeutics, Inc. | Micronized opioid compositions, formulations and dosage forms and methods of making same |
US9233160B2 (en) | 2002-12-13 | 2016-01-12 | Durect Corporation | Oral drug delivery system |
EP2987788A1 (en) * | 2002-05-17 | 2016-02-24 | Taiwanj Pharmaceuticals Co., Ltd. | Opioid and opioid-like compounds and uses thereof |
US9555113B2 (en) | 2013-03-15 | 2017-01-31 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US9592204B2 (en) | 2007-12-06 | 2017-03-14 | Durect Corporation | Oral pharmaceutical dosage forms |
US9884056B2 (en) | 2008-11-03 | 2018-02-06 | Durect Corporation | Oral pharmaceutical dosage forms |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2046093A (en) * | 1979-03-08 | 1980-11-12 | American Home Prod | Benzocaine Aerosol Compositions |
US4241048A (en) * | 1979-05-01 | 1980-12-23 | Bristol-Myers Company | Suspension composition of benzocaine |
US4454140A (en) * | 1982-09-07 | 1984-06-12 | Hoffmann-La Roche Inc. | Nasal administration of dextromethorphan |
EP0219896A1 (en) * | 1985-09-26 | 1987-04-29 | PRODOTTI FORMENTI S.r.l. | Pharmaceutical compositions on the basis of dextrorphan for intranasal application |
EP0323762A1 (en) * | 1988-01-06 | 1989-07-12 | Bouchara S.A. | Antitussive compositions and their preparation |
-
1991
- 1991-02-16 GB GB919103302A patent/GB9103302D0/en active Pending
-
1992
- 1992-02-13 WO PCT/GB1992/000257 patent/WO1992014466A1/en active Application Filing
- 1992-02-13 AU AU12272/92A patent/AU1227292A/en not_active Abandoned
- 1992-02-14 IE IE048492A patent/IE920484A1/en unknown
- 1992-02-14 ZA ZA921093A patent/ZA921093B/en unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2046093A (en) * | 1979-03-08 | 1980-11-12 | American Home Prod | Benzocaine Aerosol Compositions |
US4241048A (en) * | 1979-05-01 | 1980-12-23 | Bristol-Myers Company | Suspension composition of benzocaine |
US4454140A (en) * | 1982-09-07 | 1984-06-12 | Hoffmann-La Roche Inc. | Nasal administration of dextromethorphan |
EP0219896A1 (en) * | 1985-09-26 | 1987-04-29 | PRODOTTI FORMENTI S.r.l. | Pharmaceutical compositions on the basis of dextrorphan for intranasal application |
EP0323762A1 (en) * | 1988-01-06 | 1989-07-12 | Bouchara S.A. | Antitussive compositions and their preparation |
Non-Patent Citations (1)
Title |
---|
STN International Information Services Data Base; Chemical Abstracts, vol. 89, no. 13, 1977, (Columbus, Ohio, US), D.B. SCOTT et al.: "Plasma lignocaine concentrations following endotracheal spraying with an aerosol", see abstract no. 100266x, & PROC. EUR. SOC. TOXICOL., 18(CLIN. TOXICOL.), 255-7, see the abstract * |
Cited By (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5593661A (en) * | 1993-03-29 | 1997-01-14 | Henry; Richard A. | Lidocaine aerosol anaesthetic |
WO1994022422A1 (en) * | 1993-03-29 | 1994-10-13 | Henry Richard A | Lidocaine aerosol anaesthetic |
US5589156A (en) * | 1994-05-02 | 1996-12-31 | Henry; Richard A. | Prilocaine and hydrofluourocarbon aerosol preparations |
WO1997039742A1 (en) * | 1996-04-23 | 1997-10-30 | Pharmacia & Upjohn Ab | Transdermally administered dextromethorphan as antitussive agent |
US6335030B1 (en) | 1996-04-23 | 2002-01-01 | Pharmacia & Upjohn Ab | Transdermally administered dextromethorphan as antitussive agent |
WO1999063985A1 (en) * | 1998-06-09 | 1999-12-16 | Nortran Pharmaceuticals, Inc. | Compositions and methods for treatment of cough |
WO2000035417A1 (en) * | 1998-12-11 | 2000-06-22 | Pharmachemie B.V. | Pharmaceutical preparation for inhalation of an opioid |
US7816374B2 (en) | 2000-06-23 | 2010-10-19 | Mayo Foundation For Medical Education And Research | Method of treating neutrophil-related diseases with topical anesthetics |
WO2002000218A2 (en) * | 2000-06-23 | 2002-01-03 | Mayo Foundation For Medical Education And Research | Methods of treating neutrophil-related diseases with topical anesthetics |
WO2002000218A3 (en) * | 2000-06-23 | 2002-05-16 | Mayo Foundation | Methods of treating neutrophil-related diseases with topical anesthetics |
US6861449B2 (en) | 2000-06-23 | 2005-03-01 | Mayo Foundation For Medical Education And Research | Method of treating neutrophil-related diseases with topical anesthetics |
EP2987788A1 (en) * | 2002-05-17 | 2016-02-24 | Taiwanj Pharmaceuticals Co., Ltd. | Opioid and opioid-like compounds and uses thereof |
US9918982B2 (en) | 2002-12-13 | 2018-03-20 | Durect Corporation | Oral drug delivery system |
US9233160B2 (en) | 2002-12-13 | 2016-01-12 | Durect Corporation | Oral drug delivery system |
US9517271B2 (en) | 2002-12-13 | 2016-12-13 | Durect Corporation | Oral drug delivery system |
US9592204B2 (en) | 2007-12-06 | 2017-03-14 | Durect Corporation | Oral pharmaceutical dosage forms |
WO2009076236A3 (en) * | 2007-12-06 | 2009-11-26 | Pain Therapeutics, Inc. | Micronized opioid compositions, formulations and dosage forms and methods of making same |
US9339463B2 (en) | 2007-12-06 | 2016-05-17 | Michael Zamloot | Micronized opioid compositions having a specific particle size distribution |
US9655861B2 (en) | 2007-12-06 | 2017-05-23 | Durect Corporation | Oral pharmaceutical dosage forms |
US10206883B2 (en) | 2007-12-06 | 2019-02-19 | Durect Corporation | Oral pharamaceutical dosage forms |
EP2559428A1 (en) * | 2007-12-06 | 2013-02-20 | Pain Therapeutics, Inc. | Micronized opioid compositions and dosage forms and methods of making same |
US9884056B2 (en) | 2008-11-03 | 2018-02-06 | Durect Corporation | Oral pharmaceutical dosage forms |
US10328068B2 (en) | 2008-11-03 | 2019-06-25 | Durect Corporation | Oral pharmaceutical dosage forms |
US9855333B2 (en) | 2013-03-15 | 2018-01-02 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US9907851B2 (en) | 2013-03-15 | 2018-03-06 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US9572885B2 (en) | 2013-03-15 | 2017-02-21 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US9555113B2 (en) | 2013-03-15 | 2017-01-31 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
US10300142B2 (en) | 2013-03-15 | 2019-05-28 | Durect Corporation | Compositions with a rheological modifier to reduce dissolution variability |
Also Published As
Publication number | Publication date |
---|---|
GB9103302D0 (en) | 1991-04-03 |
ZA921093B (en) | 1993-01-27 |
IE920484A1 (en) | 1992-08-26 |
AU1227292A (en) | 1992-09-15 |
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