WO2014037727A1 - Sels de carcaïnium - Google Patents

Sels de carcaïnium Download PDF

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Publication number
WO2014037727A1
WO2014037727A1 PCT/GB2013/052326 GB2013052326W WO2014037727A1 WO 2014037727 A1 WO2014037727 A1 WO 2014037727A1 GB 2013052326 W GB2013052326 W GB 2013052326W WO 2014037727 A1 WO2014037727 A1 WO 2014037727A1
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WIPO (PCT)
Prior art keywords
carcainium
salt
tussive
cough
salts
Prior art date
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PCT/GB2013/052326
Other languages
English (en)
Inventor
Peter Lionel Spargo
Lewis Siu Leung Choi
Bertrand Michel Claude PLOUVIER
Edward James FRENCH
Julian Scott Northen
Original Assignee
Verona Pharma Plc
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Filing date
Publication date
Priority claimed from PCT/GB2012/052190 external-priority patent/WO2013034909A1/fr
Application filed by Verona Pharma Plc filed Critical Verona Pharma Plc
Publication of WO2014037727A1 publication Critical patent/WO2014037727A1/fr

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Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents

Definitions

  • Cough is the most common respiratory ailment for which patients seek medical help. It is a very common problem in medical practice as it accompanies a great variety of viral or bacterial infections including pneumonia, cold, flu and some underlying diseases, such as asthma, emphysema, lung cancer, etc.
  • Cough is a natural response to mechanical and chemical irritation of trachea and bronchi.
  • the physiological role of cough is to prevent aspiration of foreign objects or excess secretion within the respiratory tract and to remove such objects or secretion or exudates from the trachea and bronchi.
  • carcainium chloride is hygroscopic. It can be difficult to formulate medicaments for inhalation when the active ingredient is hygroscopic. Hygroscopicity can preclude formulation as a dry powder, for example.
  • carcainium salts can in fact provide an effective therapy for cough in humans. That conclusion is based on a new clinical trial in which carcainium chloride is seen to have a statistically significant therapeutic effect in treatment and/or suppression of cough in patients suffering from interstitial lung disease.
  • certain specific salts of carcainium are both crystalline and non-hygroscopic. Crystalline and non-hygroscopic salts are particularly desirable if a drug is to be successfully delivered as a dry powder. Crystalline and non- hygroscopic salts are particularly suitable for processing into dry powders by techniques such as milling and micronization, and generally more stable than non-crystalline or hygroscopic salts.
  • the salt forms of the present invention are also stable to micronisation and can provide a stable formulation having a high fine particle fraction (FPF). A high FPF is highly desirable for administration by inhalation.
  • FPF fine particle fraction
  • the present invention provides a pharmaceutically acceptable addition salt of (i) carcainium, and (ii) oxalic acid, fumaric acid, maleic acid and hydrobromic acid.
  • the invention further provides a pharmaceutical composition comprising a salt of the invention and a pharmaceutically acceptable excipient.
  • the invention further provides a salt of the invention, for use in the treatment of the human or animal body.
  • the invention further provides a salt of the invention, for use in the treatment and/or suppression of cough, tussive attacks or tussive episodes.
  • the invention further provides the use of a carcainium salt of the invention in the manufacture of a medicament for the treatment and/or suppression of cough, tussive attacks or tussive episodes.
  • the invention further provides a method of treatment and/or suppression of cough, tussive attacks or tussive episodes in a patient, which method comprises administering to said patient a therapeutically effective amount of a carcainium salt of the invention.
  • Figures 1 to 3 show the X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns for carcainium maleate prepared in Example 2.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Figures 4 to 6 show the X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns for carcainium oxalate prepared in Example 2.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Figures 7 to 9 show the X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns for carcainium fumarate prepared in Example 2.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Figures 10 to 12 show the X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns for carcainium sulfate prepared in Example 2.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Figures 13 to 15 show the X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) patterns for carcainium bromide prepared in Example 2.
  • Figure 16 shows the inhibition cough by carcainium salts in guinea pigs, as described in Example 8. Each bar represents the mean and the vertical lines represent standard error (SEM) for the guinea pigs tested.
  • Carcainium is the compound N,N-Bis-(phenylcarbamoylmethyl) dimethylammonium and has the following structure.
  • the carcainium salts of the invention are pharmaceutically acceptable addition salts of (i) carcainium, and (ii) oxalic acid, fumaric acid, maleic acid or hydrobromic acid.
  • the salts of the invention are thus carcainium oxalate, carcainium fumarate, carcainium maleate and carcainium bromide.
  • Carcainium oxalate and fumarate are preferred salts, with carcainium oxalate most preferred.
  • the carcainium oxalate salt typically has a stoichiometry of 1 :1 carcainium: oxalate.
  • the carcainium fumarate salt typically has a stoichiometry of 1 :1 carcainium:fumarate.
  • the carcainium maleate salt typically has a stoichiometry of 1 :1 carcainium:maleate.
  • the carcainium bromide salt typically has a stoichiometry of 1 :1 carcainium:bromide.
  • the stoichiometry of the salts can be determined by techniques known to those skilled in the art, such as 3 ⁇ 4 NMR.
  • the carcainium salts of the invention are crystalline. This is advantageous, since crystalline salts are particularly suitable for processing into dry powders by techniques such as milling and micronization.
  • the carcainium salts of the invention are non-hygroscopic. This is advantageous because it avoids processing problems that can arise when hygroscopic salts are transformed into dry powders by techniques such as milling and micronization. Further, pharmaceutical compositions comprising non -hygroscopic salts generally have a significantly longer shelf life than those comprising hygroscopic salts.
  • the salts of the invention are typically in particulate form, and preferably have a fine particle fraction (FPF) of greater than 15%.
  • the FPF is the proportion of particles which are less than 5 ⁇ in size.
  • the FPF is greater than 25%, more preferably greater than 30%, more preferably greater than 35%, most preferably greater than 40%.
  • the FPF can readily be determined by techniques known to those skilled in the art, for example using an impactor.
  • the pharmaceutical composition of the invention comprises a carcainium salt of the invention and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is formulated for administration by inhalation.
  • the pharmaceutical composition is a dry powder which is preferably formulated for administration by inhalation.
  • the fumarate and maleate are particularly preferred for use in dry powders which are formulated for administration by inhalation, since these salts provide dry powders with a high fine particle fraction (FPF).
  • the FPF is the fraction of particles with a size of less than 5 ⁇ .
  • a pharmaceutical composition which is a dry powder is delivered using a dry powder inhaler.
  • the dry powder inhaler is a Clickhaler, Novolizer, Certihaler, Diskus,
  • Multihaler, Gyrohaler (Vectura Group pic), Aerolizer, Handihaler or Tubospin (PH&T S.p.A.), Acu-Breathe unit (Respirics, Inc.), Conix (Cambridge Consultants Limited), Miat Monohaler (Cyclohaler), Eclipse (Sanofi-Aventis), e-flex (Microdrug AG), Flowcaps (Hovione), Prohaler (Valois Pharm), DirectHaler (Trimel BioPharma), Single Dose SDD (Manta technologies), Monodose (Miat SpA), TwinCaps (Hovione), GenX (CCL), SkyeHaler (SkyePharma),
  • a pharmaceutical composition which is a dry powder is prepared by milling, spray drying, fluidized spray drying, spray congealing, micronization, controlled crystallization, co-crystallization, ultrasound assisted crystallization, freeze drying or particle precipitation of the salt.
  • the resulting powder has a particle size with a mass median aerodynamic diameter from about ⁇ ⁇ to about 10 ⁇ , preferably from about 3.5 ⁇ to about 10 ⁇ , more preferably from about 4 ⁇ to about 5.5 ⁇ , or from about 5 ⁇ to about 10 ⁇ , or from about 5.5 ⁇ to about 10 ⁇ or from about 6 ⁇ to about 10 ⁇ .
  • the dry powder composition may additionally comprise an excipient such as lactose, lysine or leucine. Lactose is particularly preferred. It is a finding of the present invention that the salts of the invention are stable when blended with lactose.
  • the pharmaceutical composition may be an aqueous solution which is preferably formulated for administration by inhalation.
  • the oxalate salt is particularly preferred for use in pharmaceutical compositions which are aqueous solution.
  • a pharmaceutical composition which is an aqueous solution is delivered using a nebulizer, preferably an electronic nebulizer.
  • a jet nebulizer may be used.
  • the nebulizer is typically able to aerosolize the carcainium salt solution into an aerosol comprising particles with an MMAD of from about 1 to about 10 ⁇ , preferably from about 3 ⁇ to about 10 ⁇ , more preferably from about 4 ⁇ to about 5.5 ⁇ , or from about 5 ⁇ to about 10 ⁇ , or from about 5.5 ⁇ to about 10 ⁇ or from about 6 ⁇ to about 10 ⁇ .
  • the electronic nebulizer is a PARITM eFlow electronic nebulizer, a DeVilbiss UltraNeb ultrasonic nebulizer, an Omron Micro Air NE-U22V electronic nebulizer or an Aerogen Aerodose electronic nebulizer. More preferably, the electronic nebulizer (such as the PARITM eFlow electronic nebulizer or a DeVilbiss UltraNeb ultrasonic nebulizer) is modified to comprise a vibrating perforate membrane.
  • the carcainium salt solution comprises from about 10 to about 200 mg of carcainium salt dissolved in from about 1 to about 20 ml of a solvent.
  • the solvent generally is normal or diluted saline.
  • Normal saline means water solution containing 0.9% (w/v) NaCl.
  • Diluted saline is normal saline diluted to from 1/20 to 9/10 normal strength.
  • the carcainium salt solution is packaged in a sealed low density polyethylene vial under sterile conditions for storage or in a two component packaging comprising a dry or lyophilized carcainium salt in one component and a normal or diluted saline in a second component.
  • the carcainium salt solution is specifically formulated for inhalation, and thus is preferably preservative free.
  • the osmolality, pH, and viscosity are preferably optimized to be adequate for nebulization, for example via an electronic nebulizer.
  • the carcainium salt solution has an osmolality between 150 and 550 mOsm/kg, ion concentration between 31 and 300 mM of the permeant anion, pH between 5.5 and 7.0 and viscosity lower than 1.5 centipoise.
  • the carcainium salt concentration is 5 to 80 mg per ml of saline, for example 10, 40, or 80 mg per ml of saline.
  • Control of the pH of the carcainium salt solution is important for efficacious delivery of the nebulized drug.
  • the drug aerosol is either more acidic or basic than physiological pH, the patient may experience certain side effects, including bronchospasm.
  • any aerosol with a pH below 4.5 or over 8.5 results is more likely to result in lung irritation accompanied by severe bronchospasm, exacerbated cough, and inflammatory reactions.
  • a preferred pH is thus from 5.5 to 7.0.
  • the carcainium salt solution has an osmolality of 275 to 300 mOsm/kg and a pH of from 5.5 to 7.0.
  • the carcainium salt solution has an osmolality of 275 and 300 mOsm/kg and a concentration of between 31 mM and 300 mM.
  • the carcainium salt solution has an osmolality of 275 to 300 mOsm/kg , a pH of from 5.5 to 7.0 and a chloride concentration of between 31 mM and 300 mM.
  • the carcainium salt of the invention is typically delivered as a dry powder aerosol or a nebulized aerosol.
  • the dry powder aerosol or nebulized aerosol typically has particles which have a mass median aerodynamic diameter (MMAD) of from about 1 to about 10 ⁇ , preferably from about 3 ⁇ to about ⁇ , more preferably from about 4 ⁇ to about 5.5 ⁇ , or from about 5 ⁇ to about 10 ⁇ , or from about 5.5 ⁇ to about 10 ⁇ or from about 6 ⁇ to about 10 ⁇ .
  • MMAD mass median aerodynamic diameter
  • the mass median aerodynamic diameter (MMAD) can be measured by any suitable technique known to those skilled in the art, such as laser diffraction. Such particle sizes are preferred for effective delivery of the drug into the conducting and central airways.
  • the carcainium salts of the invention are useful for the treatment and/or suppression of cough, tussive attacks or tussive episodes, preferably in a human patient.
  • Carcainium salts have efficacy as anti-tussives in human patients at dosages at which the salts have no local anaesthetic activity. Accordingly, the present invention also provides a said carcainium salt for use in the treatment and/or suppression of cough, tussive attacks or tussive episodes in a patient, wherein said carcainium salt acts by a mechanism independent of local anaesthesia. The invention also provides a said carcainium salt of the invention for use in the treatment and/or suppression of cough, tussive attacks or tussive episodes in a patient, without causing any substantial local anaesthetic effect. Local anaesthetic activity in inhaled
  • said carcainium salt is for use in the treatment and/or suppression of cough, tussive attacks or tussive episodes in a patient, without causing any substantial oropharyngeal numbing, impairment or loss of gag reflex and/or impairment or loss of the tracheal aspiration reflex.
  • said carcainium salt is for use in the treatment and/or suppression of cough, tussive attacks or tussive episodes in a patient suffering from or susceptible to bronchospasm, oropharyngeal numbing, impairment or loss of gag reflex and/or impairment or loss of the tracheal aspiration reflex, and more typically in a patient suffering from or susceptible to oropharyngeal numbing, impairment or loss of gag reflex and/or impairment or loss of the tracheal aspiration reflex.
  • the carcainium salt is particularly effective in such patients, and also due to the low systemic side effects associated with the invention.
  • said carcainium salt is for use in the treatment and/or suppression of cough, tussive attacks or tussive episodes in a patient, wherein said salt is (a) for use during a surgical or invasive procedure, or (b) for chronic use.
  • a preferred surgical or invasive procedure where said carcainium salt can be used is bronchoscopy.
  • Chronic use typically means administration of said carcainium salt twice a day or more, for example up to five times per day, or administration of said carcainium salt once a day or more over a period of one week or more, for example over a period of two weeks or more.
  • the carcainium salt is administered such that systemic exposure of carcainium salt following delivery to the patient as measured by peak plasma concentration is less than 800 ng/ml, more preferably less than 500 ng/ml, more preferably less than 100 ng/ml, and most preferably less than 70 ng/ml.
  • the plasma concentration of carcainium salt can be measured by any suitable technique known to those skilled in the art, such as a liquid chromatography/tandem mass spectrometry (LC/MS/MS) assay method.
  • the origin of the cough to be treated by the present invention is not particularly limited, and can include virtually any respiratory disorder, such as chronic obstructive pulmonary disease, asthma, tuberculosis, bronchitis, bronchiectasis, suppurative pulmonary disease, respiratory malignancies, allergy, cystic fibrosis, pulmonary fibrosis, respiratory tract inflammation, emphysema, pneumonia, lung cancer, lung neoplasia, sore throat, common cold, influenza, respiratory tract infection, bronchoconstriction, sarcoidosis, smoker's cough, chronic non-productive cough, neoplastic cough; cough due to gastroesophageal reflux, inhalation of irritants, smoke, smog, dust, presence of foreign bodies, air pollution or angiotension converting enzyme (ACE) inhibitor therapy, or acute or chronic cough resulting from or connected with a viral or bacterial infection of the upper airways; or intractable cough resulting from or connected with another underlying disease.
  • the underlying disease may be chronic obstructive pulmonary disease, asthma, tuberculosis, bronchitis, bronchiectasis, suppurative pulmonary disease, respiratory
  • malignancies allergy, cystic fibrosis, pulmonary fibrosis, respiratory tract inflammation, emphysema, pneumonia, lung cancer, lung neoplasia, soar throat, common cold, influenza, respiratory tract infection, bronchoconstriction, sarcoidosis, gastroesophageal reflux, smoker's cough, chronic non-productive cough, neoplastic cough, or acute or chronic cough resulting from or connected with a viral or bacterial infection of the upper airways.
  • the origin of the cough to be treated by the present invention may be interstitial lung disease.
  • the cough, tussive attacks or tussive episodes result from interstitial lung disease.
  • Interstitial lung diseases affect the interstitium, which is the tissue and space around the air sacs of the lungs, and in particular the alveolar epithelium, pulmonary capillary endothelium, basement membrane, perivascular and perilymphatic tissues.
  • Interstitial lung disease may be irritant-induced (for example by silica dust or asbestos) or drug induced (for example by antibiotics, chemotherapeutic drugs, antiarrhythmic agents, or statins).
  • Interstitial lung disease may also arise from connective tissue diseases (such as systemic sclerosis, polymyositis, dermatomyositis, systemic lupus erythematosus or rheumatoid arthritis), from infection (such as atypical pneumonia, Pneumocystis pneumonia (PCP), tuberculosis, chlamydia trachomatis or respiratory syncytial virus) or from malignancy ( such a lymphangitic carcinomatosis).
  • Interstitial lung disease may also be idiopathic, arising from for example sarcoidosis, idiopathic pulmonary fibrosis, Hamman-Rich syndrome or Antisynthetase
  • the carcainium salt is administered such that substantially whole dose of the drug is delivered to specific target areas, namely the trachea, carina and bronchi, while minimizing the deposition of the drug in other areas where it could cause undesirable local side effects or more easily enter the systemic circulation and cause undesirable side effects.
  • a dry powder aerosol or nebulized aerosol which has particles having a mass median aerodynamic diameter (MMAD) of from about 1 to about 10 ⁇ , typically from about 3 ⁇ to about ⁇ , is preferred for effective delivery of the drug into the conducting and central airways.
  • the carcainium salt is thus typically targeted to the conducting and central airways of the patient.
  • the central airways are the region of the respiratory tract defined by trachea, carina and bronchi.
  • the carina means the ridge separating the opening the right and left main bronchi at their junction with the trachea.
  • the carcainium salt is typically delivered to the patient such that it does not cause bronchospasm, oropharyngeal numbing, impairment or loss of gag reflex, impairment or loss of the tracheal aspiration reflex or systemic exposure that leads to adverse side effects.
  • Efficacy of administration of carcainium salt is measured by the amount of the drug needed for cough abatement, by the frequency of administration needed to suppress tussive attacks or episodes, by the time necessary for delivery of the drug amount and by the percentage of the drug deposited in the specific target areas, namely in trachea, carina and bronchi as well as a lack of deposition in the other areas.
  • the magnitude of the therapeutic or prophylactic dose of carcainium salt required for the treatment and/or suppression of cough, tussive attacks or tussive episodes in a patient will depend upon the severity and nature of the condition being treated and the route of
  • the daily dose and the frequency of the dosing will also vary according to age, body weight and response of the individual patient.
  • the daily dose is determined based on the weight of the patient.
  • the daily dose is 0.5 to 5 mg/kg, for example about 1.0 mg/kg, based on the weight of the patient.
  • the total daily dose of carcainium salt is from about 5 mg to about 300 mg.
  • This may be delivered in a single dose or in repeated doses, for example up to five times a day, but is preferably delivered as a single dose.
  • daily dose it is meant the total quantity of compound of the invention administered to the patient in a day.
  • the daily dose is a single metered nominal dose of from about 5 mg to about 300 mg.
  • a metered nominal dose refers to the quantity of drug substance contained in the metering chamber of the delivery device and is normally expressed as quantity per actuation.
  • the drug substance leaves the device and becomes available to the patient as a "delivered dose".
  • the delivered dose is normally smaller than the metered nominal dose, due to the mechanics of the device.
  • the delivered dose is the amount of the drug which is available at the mouth for inhalation.
  • the delivered dose can be measured using standard techniques known to those skilled in the art.
  • the delivered dose is from about 4.5 mg to about 275 mg.
  • the invention also provides a dry powder inhaler comprising a dry powder of carcainium salt, which inhaler delivers a dry powder aerosol of carcainium salt and wherein the particles present in said aerosol have a mass median aerodynamic diameter (MMAD) of from about 1 ⁇ to about 10 ⁇ , and which inhaler is configured to deliver (a) a metered nominal dose of about 5 mg to about 300 mg carcainium salt , and/or (b) a delivered dose of about 4.5 mg to about 275 mg carcainium salt.
  • MMAD is from about 3 ⁇ to about 10 ⁇ , more preferably from about 5 ⁇ to about 10 ⁇ , or from about 5.5 ⁇ to about 10 ⁇ or from about 6 ⁇ to about 10 ⁇
  • the invention also provides an electronic nebulizer comprising a solution of carcainium salt , which nebulizer aerosolizes the solution of carcainium salt into an aerosol and wherein the particles present in said aerosol have a mass median aerodynamic diameter (MMAD) of from about 1 ⁇ to about 1 ⁇ , and which nebulizer is configured to deliver (a) a metered nominal dose of about 5 mg to about 300 mg carcainium salt , and/or (b) a delivered dose of about 4.5 mg to about 275 mg carcainium salt.
  • MMAD is from about 3 ⁇ to about ⁇ , more preferably from about 5 ⁇ to about 10 ⁇ , or from about 5.5 ⁇ to about 10 ⁇ or from about 6 ⁇ to about 10 ⁇ .
  • a maintenance dose of carcainium salt may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment should cease. The patient may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • the total daily usage of the carcainium salt will be decided by the attending physician within the scope of sound medical judgment.
  • the specific dose for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • any suitable route of administration may be employed to provide an effective dosage of the compounds of the present invention, although administration by inhalation is preferred, most preferably in aerosol form.
  • Suitable forms of administration include, but are not limited to, inhalation (delivered by, e.g., metered dose inhaler, jet nebulizer, ultrasonic nebulizer, dry powder inhaler, etc.), nasal sprays, nebulization, oral administration such as via tablets, capsules, lozenges, syrups, sprays, suspensions, elixirs, gargles, and other liquid preparations, aerosol foams, parental administration, and sublingual administration. Administration by inhalation is preferred. Topical administration to the lung via inhalation is particularly preferred.
  • compositions of the present invention can include pharmaceutically acceptable carriers and other conventional additives, including aqueous based carriers, co- solvents such as ethyl alcohol, propylene glycol and glycerin, fillers, lubricants, wetting agents, flavoring agents, coloring agents, emulsifying, suspending or dispersing agents, suspending agents, etc.
  • pharmaceutically acceptable diluents, carriers, and/or propellants may be included in the compositions for use in appropriate devices. These are prepared by procedures well known to those skilled in the art (see e.g., Medication Teaching Manual, 5th Ed., Bethesda, Md., American Society of Hospital Pharmacists, 1991).
  • compositions of the present invention may optionally include other known therapeutic agents, including decongestants such as pseudoephedrine HC1, phenylephrine HC1 and ephedrine HC1, non-steroidal anti-inflammatory drugs such as acetaminophen, aspirin, phenacetin, ibuprofen and ketoprofen, expectorants such as glyceryl guaiacolate, terpin hydrate and ammonium chloride, antihistamines such as chlorpheniramine maleate, doxylamine succinate, brompheniramine maleate and diphenhydramine hydrochloride.
  • decongestants such as pseudoephedrine HC1, phenylephrine HC1 and ephedrine HC1
  • non-steroidal anti-inflammatory drugs such as acetaminophen, aspirin, phenacetin, ibuprofen and ketoprofen
  • expectorants such as glyceryl
  • the carcainium salt can be administered in combination with (a) one or more additional anti-tussive agents and/or (b) one or more bronchodilators.
  • Preferred additional anti-tussive agents are menthol or codeine.
  • a preferred bronchodilator is N- ⁇ 2-[(2E)-2-(mesitylimino)-9,10- dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,l -a]-isoquinolin-3(4H)-yl]ethyl ⁇ urea (which is known by the code RPL-554).
  • the present invention also provides a combination comprising a carcainium salt of the invention, and (a) one or more additional anti-tussive agents and/or (b) one or more bronchodilators.
  • the combination is preferably for use in the treatment and/or suppression of cough, tussive attacks or tussive episodes in a patient.
  • the invention further provides a carcainium salt of the invention for use in the treatment and/or suppression of cough, tussive attacks or tussive episodes in a patient, by co-administration with (a) one or more additional anti-tussive agents, and/or (b) one or more bronchodilators.
  • Co- administration can be simultaneous, concurrent, separate or sequential.
  • the invention further provides (a) one or more additional anti-tussive agents and/or (b) one or more bronchodilators, for use in the treatment and/or suppression of cough, tussive attacks or tussive episodes in a patient, by co-administration with a carcainium salt of the invention. Coadministration can be simultaneous, concurrent, separate or sequential.
  • the present invention further provides a product comprising a carcainium salt of the invention and (a) one or more additional anti-tussive agents and/or (b) one or more
  • bronchodilators as a combined preparation for simultaneous, concurrent, separate or sequential use in the treatment and/or suppression of cough, tussive attacks or tussive episodes in a patient.
  • the salts of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • carcainium salts such as carcainium chloride can be synthesized as described in the Examples below.
  • techniques such as those described in US 6,362,197 and Belgian Patent No. 614,154, which follows from Swedish Patent 1779/61, can be used.
  • a conventional route of synthesis involves three steps and can be described (as in the aforementioned patent; see also T. Takahashi, J. Okada, M. Hori, A. Kato, K. Kanematsu, and Y. Yamamoto, J. Pharm. Soc. Japan 76, 1180-6 (1956)) as follows: i) Chloroacetanilide
  • the aim of the clinical study was to determine the clinical effectiveness and safety of carcainium chloride by the inhaled route in hospital in-patients with intractable, persistent cough due to interstitial lung disease.
  • VAS visual analogue scale
  • Carcainium chloride is a fine white dry powder and was provided in tightly closed vessels and stored in dark at room temperature upon receipt.
  • the vehicle used for the dilution of carcainium chloride and for the placebo was 0.9 % NaCl injection.
  • Carcainium chloride aerosols corresponding to those used in the above clinical study were generated from the same drug product batch and using the same ultrasonic nebulizer (DeVilbiss Ultraneb). The particle size distributions of these carcainium chloride aerosols were measured and analyzed using a Malvern Spraytec with inhalation cell attachment system. Results from two replicate experiments showed an average value of about 5.38 ⁇ for the Spraytec volume median diameter [Dv(50)].
  • LC/MS/MS liquid chromatography/tandem mass spectrometry
  • carcainium chloride was dissolved in deionized water to provide an initial standard or quality control (QC) stock solution at a concentration of 1000 ⁇ g/mL.
  • QC quality control
  • Serial dilutions were carried out with deionized water to provide secondary stock solutions for subsequent preparation of plasma calibration standards or QC samples according to Table 1 below.
  • the internal standard lidocaine was dissolved in deionized water to provide an initial stock solution at a concentration of 1000 ⁇ g/mL.
  • the initial internal standard stock solution was then serially diluted with deionized water to provide a spiking stock solution concentration of 50 ng/mL.
  • a 10 ⁇ _, aliquot of calibration standard stock solution or QC stock solution was transferred into individual 16x100 mm screw cap glass test tubes.
  • 10 ⁇ _, of deionized water was transferred instead.
  • Human blank K 2 EDTA plasma (100 ⁇ .) was then added to each tube.
  • a 50 ⁇ _, aliquot of of lidocaine internal standard spiking stock solution was transferred to each tube except for blank samples.
  • a 50 ⁇ _, aliquot of deionized water was added to blank samples. Samples were then vortex mixed.
  • the supernatant was dried under a gentle stream of nitrogen to complete dryness using a Turbovap or under a gentle stream of air using an air dryer.
  • Each sample was reconstituted with 100 ⁇ of a 1 : 4 (v/v) mixture of 0.1 % FA in MeOH: 0.1 % FA in deionized water. To facilitate reconstitution, the mixture was vortex-mixed for 1 minute followed by sonication for 5 minutes before being transferred to a 250 ⁇ vial and capped. All vials were centrifuged at 5,000 rpm for 5 min and an aliquot of 25 ⁇ was injected for LC/MS/MS analysis.
  • test samples 100- ⁇ of sample was transferred into individual 16x100 mm screw cap glass test tubes. A 10 ⁇ aliquot of deionized water was then transferred to each tube. A 50 ⁇ aliquot of lidocaine internal standard solution was transferred to each tube and vortexed to mix. Test samples were then processed the same as calibration standards and quality control samples mentioned above.
  • a selection of anion exchange resins were generated by modification of a standard hydroxide ion resin with various acids. Treatment of the modified resin with a carcainium chloride solution allowed for exchange of the anions, and formation of new carcainium salts. The carcainium salts were then analyzed, to determine whether they were crystalline (using X- ray powder diffraction) or hygroscopic/non-hygroscopic. The results are set out in Table 2 below.
  • the reaction mixture was cooled to room temperature and DCM (2565 ml) was charged and stirred for 15 minutes. The layers were separated and the aqueous was extracted with DCM (1860 ml). The organic layers were combined and charged to the flask with water (4930 ml). The pH was adjusted to 1 by the addition of concentrated HC1 (280 ml). The layers were separated and the aqueous layer was washed with DCM (1860 ml).
  • the aqueous layer was charged to the flask with DCM (4340 ml) and adjusted to pH8 by the addition of 50 % aq. NaOH (185 ml). The layers were separated and the aqueous layer was extracted with DCM (1860 ml). The organic layers were combined and washed with water (3285 ml), dried over MgS0 4 (660 g), filtered and concentrated to isolate a pale yellow oil.
  • the crude material was purified by silica gel chromatography (30 equivalents) and the product was eluted using ethyl acetate.
  • Anion exchange resin Amberlyst A-26 hydroxide form (28.2 g) was soaked in methanol (100 ml) for 10 minutes with swirling/rotation and filter; it was then rinsed with 2 x 100 ml methanol.
  • the rinsed resin was suspended in methanol (470 ml) and carcainium chloride from step 2 was added as a solution in methanol (4.7 g, 94 ml).
  • the mixture was rotated/gently agitated without grinding for 1.5 hours, with simultaneous testing of the solution above the resin for pH > 8. When this pH was achieved, the solution was tested for residual chloride ions.
  • Carcainium hydroxide (7 g, 6.56 g active, 0.02 mol) as a solution in methanol (240 ml) was stirred whilst a steady stream of the desired acid solution (1M, 1 equivalent, 20 ml), in methanol for organic acids (oxalic acid, maleic acid, fumaric acid) or 1 : 1 methanol/water for inorganic acids (sulfuric acid, hydrobromic acid), was charged. The mixture was stirred for 5 minutes and the liquors were pH tested. A pH of 4-5 was taken to indicate completion of the reaction. The solution was then evaporated to dryness, yielding a solid and/or a gum.
  • Each salt was then crystallised from water or another defined solvent between room temperature and 40 °C as described below.
  • the carcainium salts were characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The results are summarized in Table 3 below.
  • Example 2 A stability study was performed using carcainium salts prepared in Example 2 within a convection oven equilibrated to 80 °C. Approximately 4 mg of each salt was weighed into a small glass vial. This operation was replicated such that two x 4 mg samples of each were available for isolation and testing by HPLC without sampling, after 1 day and after 7 days.
  • Example 2 were milled.
  • the jet-mill was driven by compressed nitrogen supplied at 7 bar. Venturi and grind pressures were set at 90 psi and 60 psi (50 psi for sulfate), respectively, and each candidate salt was passed through the jet- mill once only.
  • Fumarate Typically less than 5 ⁇ .
  • Bromide Typically 1 -2 ⁇ , very few particles greater than 5 ⁇ .
  • the salts were measured by laser diffraction fitted with a dry powder dispersal unit (Malvern Mastersizer 2000 & Sciroco 2000). The results are provided in Table 6 below.
  • Powder X-ray diffraction was performed using a Bruker D8 Advance instrument in reflection geometry using Cu K al radiation with an incident beam monochromator. The instrument was calibrated against a NIST standard of Corundum (NIST 1976). The samples were analysed as-received on a zerobackground Silicon sample holder, which was spun during analysis. The X-ray diffraction patterns for the unmilled salts were compared to the milled salts. In all cases, peaks were observed in the same places for the unmilled salts as the milled salts, indicating that there is no change in the crystalline phase caused by milling.
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • DSC analysis was performed on a TA Instruments Q2000 equipped with a Tzero cell purged at a constant purge flow rate of 50 ml/minute with dry Nitrogen, and with a RCS 90 cooling system.
  • the instrument was calibrated using Indium as a standard. Between 3 and 5 mg of the samples were weighed into a TAI Tzero Aluminium pan with a pierced lid placed on top prior to being heated from -20 °C to 300 °C at 10 °C per minute, unless otherwise specified in the figure caption.
  • TGA was performed on a TA Instruments Q5000 equipped with an ultrasensitive balance and an infrared furnace purged with dry Nitrogen at a constant flow rate of 10 mL/minute for the reference and 25 mL/minute for the sample.
  • the weight calibration was performed using a certified 100 mg calibration weight.
  • the temperature calibration was performed using Alumel® and Nickel standards. Approximately 7 mg of the samples were weighed into TAI 100 uL Platinum sample pan/holders prior to being heated from ambient temperature to 300 °C at a rate of 10 °C per minute.
  • the instrument was calibrated using a certified 100 mg calibration weight and the calibration against four saturated salt solutions covering the whole relative humidity range was checked against a MgCl 2 saturated salt solution prior analysis.
  • Samples of approximately 13 mg were loaded into the instrument in a mesh sample holder. Samples were exposed to the following relative humidity (RH) cycling sequence: from 0% RH up to 90% RH then down to 0% RH using 20% RH steps (10% RH step between 80 and 90% RH), with a rate of change of mass with time (dm/dt) of 0.002% per minute over ten minutes.
  • RH relative humidity
  • the maximum allowed dwell-time at each RH was two hours - i.e the method was only designed for a qualitative assessment and did not allow for equilibration at each RH step.
  • Example 5 fine particle fraction (FPF) of milled salts blended with lactose
  • the milled salts (1% by weight) from Example 4 were blended with inhalation grade lactose.
  • 20mg (200 ⁇ g of salt) samples were filled into capsules and formulation aerosolised from a Miat monodose capsule device at 90L/min and the average particle size distribution assessed on an impactor.
  • the fine particle fraction (FPF) was determined.
  • the FPF is the fraction of particles in the aerosol with a size of less than 5 ⁇ .
  • Table 8 The table above demonstrates that the carcainium salts have a high fine particle fraction following milling.
  • Example 6 stability of milled salts blended with lactose
  • Example 5 the milled salts (1% by weight) from Example 4 were blended with inhalation grade lactose. Samples of the carcainium salt/lactose blend were then stored under two temperature conditions, i.e. room temperature and 76°C. Samples of lactose alone were also exposed to the two temperature storage conditions.
  • samples (approx. 0.5 g) were transferred to screw cap glass scintillation vials (20 mL) sealed and left on the laboratory bench for 7 days.
  • samples (approx. 0.5g) were transferred to screw cap glass scintillation vials (20 mL) and placed in an oven at 76°C. The vials were not sealed.
  • Example 7 solubility of carcainium salts in water
  • the equilibrium solubility figures for the different carcainium salts in water at 25°C were determined. The results are set out in Table 10 below.
  • Conscious male guinea pigs 350-600g were placed in individual perspex cylindrical exposure chambers with airflow of 1.5 L/minute and allowed to acclimatize.
  • cough responses were induced by exposing animals to citric acid aerosol (0.3 M) generated by an ultrasonic nebuliser at a nebulisation rate of 0.1 ml/minute for 5 minutes (EMKA, France).
  • Coughs were counted throughout the 5 minute citric acid exposure and for a further 10 minutes. Individual coughs were detected in three ways: 1) via a pressure transducer attached to the exposure chamber amplified and recorded using the IOX (version 1.7.0) data acquisition system, 2) via a microphone placed inside the chamber amplified and recorded using IOX, and 3) via visual observation of the animal.
  • IOX version 1.7.0
  • Coughs were counted by a trained observer and were distinguished from responses by the characteristic changes in pressure in the chamber and by visual observation. Animals were removed from the exposure chamber and allowed to recover before being returned to the animal house. Animals were given at least 96 hours to recover between exposures to citric acid and could be challenged up to 4 times. Drug exposure
  • Animals (263 -342 g) were placed in custom built perspex exposure chamber with 4 arms. After acclimatisation, animals were exposed to nebulised (Devilbiss 99) solutions of vehicle (saline), carcainium salt (10 mg/mL). Animals were then removed and placed in the cough chambers. The time interval between post aerosol exposure and commencement of citric acid (12.6 g in 200 ml; 0.3 M) challenge to induce cough was between +25, +31, +37 and + 43 min post saline or drug challenge.
  • the carcainium salts were dissolved in 0.9 % saline. 26-30ml of each solution was nebulised over the period of 20 min. The pH of each solution is set out in Table 12 below. Carcainium salt pH

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Abstract

L'invention concerne un sel d'addition pharmaceutiquement acceptable de (i) carcaïnium, et de (ii) acide oxalique, acide fumarique, acide maléique ou acide bromhydrique.
PCT/GB2013/052326 2012-09-06 2013-09-05 Sels de carcaïnium WO2014037727A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
PCT/GB2012/052190 WO2013034909A1 (fr) 2011-09-06 2012-09-06 Traitement de la toux et de quintes de toux
PCT/GB2012/052191 WO2013034910A1 (fr) 2011-09-06 2012-09-06 Compositions à inhaler
GBGB1304499.5A GB201304499D0 (en) 2011-09-06 2012-09-06 Carcainium Salts
GBPCT/GB2012/052190 2012-09-06
GBPCT/GB2012/052191 2012-09-06
GB1304499.5 2013-03-13

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2016042313A1 (fr) * 2014-09-15 2016-03-24 Verona Pharma Plc Formulation liquide pour inhalation comprenant du rpl554

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Publication number Priority date Publication date Assignee Title
US6362197B1 (en) * 1998-06-09 2002-03-26 Cardiome Pharma Corp. Compositions and method for treatment of cough

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Publication number Priority date Publication date Assignee Title
US6362197B1 (en) * 1998-06-09 2002-03-26 Cardiome Pharma Corp. Compositions and method for treatment of cough

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Title
J J ADCOCK ET AL: "RSD931, a novel anti-tussive agent acting on airway sensory nerves", BRITISH JOURNAL OF PHARMACOLOGY, vol. 138, no. 3, 1 February 2003 (2003-02-01), pages 407 - 416, XP055042457, ISSN: 0007-1188, DOI: 10.1038/sj.bjp.0705056 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016042313A1 (fr) * 2014-09-15 2016-03-24 Verona Pharma Plc Formulation liquide pour inhalation comprenant du rpl554
KR20170054406A (ko) * 2014-09-15 2017-05-17 베로나 파마 피엘씨 Ｒｐｌ５５４를 포함하는 액상 흡입제
US9956171B2 (en) 2014-09-15 2018-05-01 Verona Pharma Plc Liquid inhalation formulation comprising RPL554
EP3332767A1 (fr) * 2014-09-15 2018-06-13 Verona Pharma PLC Formulation d'inhalation liquide comprenant rpl554
EP3494962A1 (fr) * 2014-09-15 2019-06-12 Verona Pharma PLC Formulation d'inhalation liquide comprenant rpl554
RU2699995C2 (ru) * 2014-09-15 2019-09-12 ВЕРОНА ФАРМА ПиэЛСи Жидкая ингаляционная композиция, содержащая rpl 554
AU2018286571B2 (en) * 2014-09-15 2020-04-02 Verona Pharma Plc Liquid inhalation formulation comprising RPL554
AU2015316592B2 (en) * 2014-09-15 2020-04-02 Verona Pharma Plc Liquid inhalation formulation comprising RPL554
US10945950B2 (en) 2014-09-15 2021-03-16 Verona Pharma Plc Liquid inhalation formulation comprising RPL554
KR102379309B1 (ko) 2014-09-15 2022-03-28 베로나 파마 피엘씨 Ｒｐｌ５５４를 포함하는 액상 흡입제

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