Pharmaceutical composition

Abstract

To provide compositions and devices comprising apomorphine or pharmaceutically acceptable salts.SOLUTION: Compositions may comprise a solution of apomorphine, or a pharmaceutically acceptable salt thereof, and a propellant. The solution may be a non-aqueous solution or an aqueous solution comprising degassed water. Devices may be configured to deliver compositions in form of particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) greater than 10 μm; and / or a fine particle fraction (FRF) less than 30%.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 62 / 895,619, filed September 4, 2019, the entire contents of each of which are incorporated by reference herein and relied upon.

[0002] The present invention relates to pharmaceutical compositions comprising apomorphine and uses thereof, such as compositions for use in treating Parkinson's disease or male erectile dysfunction by buccal or sublingual administration. [Background technology]

[0003] Background of the Invention Parkinson's disease is a chronic, progressive neurological disorder that affects approximately 20 out of 100,000 people. The disease is typically characterized by resting tremor, muscle rigidity, bradykinesia, and impaired postural reflexes. Although the exact pathological course of Parkinson's disease is unknown, dopaminergic neurons in the substantia nigra are progressively destroyed, resulting in a net decrease in the amount of dopamine in the basal ganglia. Dopamine replacement with levodopa is currently the main treatment for Parkinson's disease.

[0004] After a 3-5 year controlled period, 25% of Parkinson's disease sufferers may develop "on-off" fluctuations. These are characterized by alternating periods of minutes to hours during which the patient is easily mobile and able to walk ("on"), with periods of severe immobility ("off"), during which the patient experiences severe immobility. Many patients also experience other unpleasant "off" phenomena (e.g., depression, anxiety, panic, pain, delusions, and dystonia) that parallel the motor stages. These "off" periods can occur several times a day, even when anti-Parkinson's medications are given at optimal doses.

[0005] Dopamine agonists have been shown to reduce dyskinesias and "on-off" fluctuations when combined with levodopa therapy. Apomorphine is a non-ergot dopamine agonist with high affinity for D2, D3, and D4 receptors and low affinity for D1 and D5 receptors. It has the following structural formula: [ka] It has.

[0006] When administered orally and swallowed, apomorphine is rapidly and extensively metabolized during its "first pass" through the liver, with little unmetabolized drug reaching the circulation. High oral doses of apomorphine have been given to attempt to overcome this metabolism. Oral doses of apomorphine in excess of 500 mg have been shown to produce dose-dependent improvements in tremor, rigidity, and akinesia, but are associated with drug-induced nephrotoxicity. This is thought to be the result of nephrotoxic metabolites produced by the liver, likely resulting from extensive first-pass metabolism.

[0007] Subcutaneous injections of apomorphine have been found to be effective in treating "on-off" fluctuations in Parkinson's disease within 5 to 15 minutes, with a duration of 45 to 90 minutes. Clinical trials have shown a concomitant reversal of "off" phase akinesia, a reduction in daily levodopa requirements, and a resulting reduction in the amount of "on" phase dyskinesia. Advantages over other dopamine agonists include a rapid onset of action and a low incidence of psychiatric complications. Regarding "rescue therapy" in patients with "on-off" fluctuations, apomorphine also has advantages over other dopamine agonists, which have a relatively short half-life.

[0008] Because of the large interpatient variability in pharmacokinetics, patients undergo an initial dose titration period when treatment is initiated. Nausea and reactions that may occur as a result of apomorphine's effects can be controlled with domperidone or other antiemetics. Often, patients on long-term apomorphine treatment can discontinue or reduce the dose of antiemetics without a recurrence of these adverse effects.

[0009] The widespread application of apomorphine to control "on-off" fluctuations is limited by the need for subcutaneous administration. As a result, alternative routes of administration are being investigated. Intranasal apomorphine has been shown to be effective in patients with Parkinson's disease, but it caused transient nasal blockage and a burning sensation in two of the five patients tested. Rectal administration of apomorphine has been shown to be effective and to have a longer duration of action than subcutaneously administered drugs; however, due to some first-pass metabolism, higher doses of the drug are required. Furthermore, the delayed onset of action limits its application as rescue therapy.

[0010] Sublingual administration of apomorphine has also been studied. Minimal first-pass metabolism allows for the use of lower doses compared to standard oral administration of apomorphine. In all studies, all patients (those known to respond to subcutaneous apomorphine) were fully "switched on." The mean time to onset of effect was approximately 30 minutes and was comparable between studies. The mean duration of action was longer after sublingual administration compared to subcutaneous administration. Formulation problems were noted due to unpleasant taste and dissolution inconsistencies.

[0011] The use of apomorphine in treating sexual dysfunction has also been investigated.For example, sublingual administration of apomorphine has been found to have a statistically significant effect on erectile dysfunction when compared with placebo in clinical trials (Dula et al. Urology 2000; 56: 130-135).According to the literature, apomorphine promotes sexual function and performance due to the effect it exerts on the brain, particularly on the neurological mechanisms underlying sexual arousal.Apomorphine can therefore be used to promote or enhance sexual function, treat sexual dysfunction, enhance sexual drive, and / or reduce impotence.

[0012] For optimal oral absorption, the apomorphine used should ideally not be ionized at physiological pH. Because the pKa of apomorphine is 8.9, above a pH of about 9, a significant amount of the drug exists as the free base. Conversely, at acidic pH (e.g., a pH less than 4), the proportion of apomorphine as the free base is negligible: nearly all of the drug exists in the ionic, charged form. Apomorphine in its charged state is poorly absorbed.

[0013] The proportion of non-ionized drug begins to increase significantly as the pH approaches 7; alkaline pH results in an increasing proportion of non-ionized drug. Therefore, for optimal absorption, the drug should be in a non-acidic medium.

[0014] Apomorphine can undergo rapid oxidation when exposed to atmospheric oxygen or dissolved oxygen in a solvent (e.g., water). Traditionally, this is prevented by maintaining an acidic aqueous solution of the drug. Commercially available apomorphine for subcutaneous injection is believed to have a pH of about 3. Because it is intended for injection, the pH does not affect systemic absorption. However, the nasal spray formulations described above are also aqueous solutions and are similarly considered acidic. This means that the formulations are not optimized for nasal absorption, and the reported nasal irritation may be due in large part to the acidic properties of the formulations.

[0015] Administering an acidic apomorphine formulation into the mouth results in stimulation of saliva secretion. The excess saliva produced is rich in bicarbonate, which is intended to neutralize the acid and return the mouth to its normal near-neutral pH. The resulting increase in pH should aid in the absorption of apomorphine, but with the additional volume of saliva, the amount of drug swallowed also increases. As a result, the amount of drug available for oral absorption rapidly decreases.

[0016] There have been previous attempts to produce pharmaceutically stable formulations of apomorphine for buccal administration.

[0017] WO 97 / 06786 discloses a rapid dispensing dosage form of apomorphine comprising an acidified aqueous solution of apomorphine containing gelatin and mannitol, the acidified aqueous solution being freeze-dried to form a solid dosage form which disintegrates when placed in the oral cavity.

[0018] WO 2006 / 120412 discloses a two-compartment system in which an aqueous solution of apomorphine is stabilized by the addition of acid and held in one compartment, and a suitable neutralizing buffer is held in the second compartment. Just prior to administration to the patient, the two liquids are mixed and the acidic apomorphine solution is neutralized and delivered to the mouth.

[0019] WO 2012 / 083269A1 discloses that a zeatin film is made containing acidified apomorphine in one layer and a neutralizing buffer in another layer. When placed in the mouth, the gelatin dissolves and the acidic apomorphine is neutralized, making it suitable for drug absorption. However, there remains a need to optimize the speed, effectiveness, and convenience of apomorphine-based treatments, particularly for the treatment of Parkinson's disease, while overcoming problems related to apomorphine's stability. [Prior art documents] [Patent documents]

[0020] [Patent Document 1] International Publication No. 97 / 06786 [Patent Document 2] International Publication No. 2006 / 120412 [Patent Document 3] International Publication No. 2012 / 083269A1 [Non-patent literature]

[0021] [Non-Patent Document 1] Dula et al. Urology 2000;56:130-135 Summary of the Invention [Means for solving the problem]

[0022] Summary of the Invention According to the present invention, there is provided a composition comprising apomorphine or a pharmaceutically acceptable salt thereof. The composition is preferably a liquid, which may be a solution, dispersion or suspension.

[0023] The apomorphine or a pharmaceutically acceptable salt thereof may be in the form of particles suspended in a liquid medium (e.g., a propellant). The particles may be solid particles. The particles may be insoluble in the liquid medium. However, in one embodiment, the composition is not in the form of a suspension. For example, the composition may not contain solid particles of apomorphine or a pharmaceutically acceptable salt thereof.

[0024] Preferably, the composition is a solution. The advantage of providing a solution rather than a particle suspension is that apomorphine or a salt thereof is rapidly available for absorption, for example, via buccal or sublingual administration. Because solid particles may have to be dissolved in saliva before they can be absorbed, the time to peak concentration in the patient can potentially be delayed.

[0025] In accordance with the present invention, there is provided a composition comprising a solution of apomorphine or a pharmaceutically acceptable salt thereof.

[0026] When the composition contains a solution of apomorphine, the solvent used to dissolve the apomorphine can be degassed to reduce or eliminate any dissolved oxygen. This can be achieved by many conventional methods, such as purging with nitrogen gas. As a result, the solution of the present invention can be substantially free of dissolved oxygen. The solution of the present invention can be formed by using a solvent that is substantially free of dissolved oxygen, such as a solvent containing water.

[0027] The composition may contain water. The solution may be an aqueous solution. The composition may contain at least 5% by weight, at least 10% by weight, at least 20% by weight, or at least 30% by weight of water. The amount of water may be 5 to 50% by weight (e.g., 10 to 40% by weight).

[0028] According to the present invention, there is provided a composition comprising apomorphine or a pharmaceutically acceptable salt thereof and a solvent comprising water, preferably the solvent being degassed to reduce or eliminate dissolved oxygen.

[0029] The composition may include a non-aqueous solvent, which may be an alternative to water or in addition to water.

[0030] The composition may include an excipient. The excipient may include a polymer. For example, the excipient may include polyethylene glycol (PEG) (e.g., PEG 400). The excipient may be present in an amount of at least 0.2% by weight (e.g., at least 0.5% by weight). For example, the excipient may be present in an amount of 0.2-2% by weight (e.g., 0.5-1% by weight). The excipient may aid in dissolution and aerosol formation.

[0031] The composition may contain substantially no water or minimal amounts of water, for example, less than 5%, less than 2%, less than 1%, less than 0.5%, less than 0.2%, or less than 0.1% by weight water.

[0032] The solution may be a non-aqueous solution.

[0033] According to the present invention, there can be provided a composition comprising apomorphine or a pharmaceutically acceptable salt thereof, and a non-aqueous solvent.

[0034] In accordance with the present invention, there is provided a composition comprising a non-aqueous solution of apomorphine or a pharmaceutically acceptable salt thereof.

[0035] The non-aqueous solvent may include an organic solvent. Thus, the non-aqueous solution may be formed by dissolving the apomorphine in the non-aqueous solvent. The non-aqueous solvent preferably includes a propellant. Thus, the composition may include apomorphine dissolved in the propellant. Preferably, the propellant includes a hydrofluorocarbon (HFA). An example of a suitable propellant is HFA134a (1,1,1,2-tetrafluoroethane). Other examples include HFA152a (1,1-difluoroethane) and HFA227ea (1,1,1,2,3,3,3-heptafluoropropane). Thus, the non-aqueous solution may be formed by dissolving apomorphine or a salt thereof in the propellant.

[0036] The propellant may be present in the composition in an amount of at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% by weight. The propellant may be present in an amount up to 99% by weight.

[0037] In accordance with the present invention, there is provided a composition comprising apomorphine or a pharmaceutically acceptable salt thereof, and a propellant.

[0038] In accordance with the present invention, there is provided a composition comprising a non-aqueous solution of apomorphine or a pharmaceutically acceptable salt thereof, said composition including a propellant.

[0039] In one embodiment, the composition consists essentially of apomorphine or a pharmaceutically acceptable salt thereof, and a propellant.

[0040] In addition to the propellant, a non-aqueous co-solvent may be used to aid in the dissolution of apomorphine or its salt. The non-aqueous co-solvent preferably comprises ethanol. The composition may therefore comprise apomorphine dissolved in the propellant and co-solvent. Thus, a non-aqueous solution may be formed by dissolving apomorphine or its salt in the propellant and co-solvent. In one example, the composition may comprise HFA134a and ethanol. The amount of non-aqueous co-solvent (e.g., alcohol (e.g., ethanol)) may be less than 50% by weight, or less than 35% by weight.

[0041] In accordance with the present invention, there is provided a composition comprising apomorphine or a pharmaceutically acceptable salt thereof, a propellant and a cosolvent.

[0042] In accordance with the present invention, there is provided a composition comprising a non-aqueous solution of apomorphine or a pharmaceutically acceptable salt thereof, said composition including a propellant and a co-solvent.

[0043] In one embodiment, the composition consists essentially of apomorphine or a pharmaceutically acceptable salt thereof, a propellant, and a non-aqueous co-solvent.

[0044] In one embodiment, the composition may be free of a co-solvent. For example, the composition may be free of alcohol. For example, the composition may be free of ethanol.

[0045] In one embodiment, the composition may be free of anesthetics, for example, the composition may be free of lidocaine or prilocaine.

[0046] Applicant recognizes the benefit of formulating apomorphine in a manner that is optimized for administration to mucosal membranes (such as in the oral cavity), e.g., by buccal or sublingual administration, and that allows for rapid absorption while being sufficiently stable to prevent autoxidation, which is particularly important since the "on-off" phenomenon in Parkinson's disease can occur very rapidly.

[0047] Surprisingly, it has been found that apomorphine or its pharmaceutically acceptable salt can maintain stability and resistance to oxidation when dissolved in a propellant with or without cosolvent.This avoids the need to provide a more complicated delivery system (such as that described in WO 2006 / 120412, which requires that apomorphine be maintained in an acidic environment before administration).In conclusion, the composition of the present invention may not require the presence of acid.

[0048] The compositions of the present invention may have a pH of at least 4, preferably at least 6 (e.g., a pH of 6 to 8), and more preferably at least 7. If the composition is a non-aqueous solution, when the composition is contacted with water (e.g., when exposed to saliva in the oral cavity), the pH of the resulting solution may be at least 4, preferably at least 6 (e.g., a pH of 6 to 8), and more preferably at least 7.

[0049] A formulation with a propellant means that it can be easily incorporated into a spray device, such as an aerosol spray device, which may allow for effective delivery by buccal administration.

[0050] The apomorphine can be present as a free base or as a pharmaceutically acceptable salt (eg, an acid addition salt, eg, the hydrochloride salt).

[0051] The compositions of the present invention may contain at least 0.1% by weight apomorphine or a pharmaceutically acceptable salt thereof. The compositions of the present invention may contain at least 0.5% by weight apomorphine or a pharmaceutically acceptable salt thereof. For example, the amount of apomorphine in the composition may be 0.1% to 20% by weight (e.g., 0.5% to 15% by weight). The compositions of the present invention may contain at least 20% by weight apomorphine or a pharmaceutically acceptable salt thereof, at least 25% by weight apomorphine or a pharmaceutically acceptable salt thereof, or at least 30% by weight apomorphine or a pharmaceutically acceptable salt thereof. The compositions of the present invention may contain 1% to 50% by weight apomorphine or a pharmaceutically acceptable salt thereof.

[0052] Pharmaceutically acceptable derivatives of apomorphine are known. Examples include esters of apomorphine (e.g., diesters, e.g., diisobutyryl esters). The compositions of the present invention, or compositions for use in the present invention, may contain an apomorphine derivative (e.g., an apomorphine ester, or a salt thereof) instead of, or in addition to, apomorphine (or a salt thereof). However, apomorphine derivatives (e.g., apomorphine esters, or a salt thereof) are less preferred. For example, a diester may be a prodrug that requires enzymatic or chemical biotransformation to produce apomorphine in vivo. Administration of the prodrug may therefore delay the pharmacological effect of apomorphine in the subject.

[0053] The present invention provides a method for forming a composition of the present invention, the method comprising combining or mixing apomorphine or a pharmaceutically acceptable salt thereof with a non-aqueous solvent. The method may comprise forming a non-aqueous solution. The method may comprise combining apomorphine or a pharmaceutically acceptable salt thereof with a propellant. The method may be carried out in the substantial absence of air or oxygen. The method may comprise adding the non-aqueous solution to a container, preferably in the substantial absence of air or oxygen.

[0054] The present invention provides a method for forming a composition of the present invention, the method comprising combining or mixing apomorphine or a pharmaceutically acceptable salt thereof with a solvent comprising water. The solvent is preferably degassed to reduce or eliminate dissolved oxygen. The method may comprise forming an aqueous solution. The method may comprise combining apomorphine or a pharmaceutically acceptable salt thereof with a propellant. The method may be carried out in the substantial absence of air or oxygen. The method may comprise adding the aqueous solution to a container, preferably in the substantial absence of air or oxygen. The method may comprise degassing the solvent to reduce or eliminate the dissolved oxygen.

[0055] Preferably, the propellant is added to the container following no or minimal exposure of the propellant to air.

[0056] The compositions of the present invention may be substantially free of oxygen.

[0057] The compositions of the present invention may include a chelating agent and / or an antioxidant (e.g., sodium metabisulfite). Alternatively, the compositions of the present invention may be substantially free of a chelating agent and / or an antioxidant (e.g., sodium metabisulfite).

[0058] According to the present invention there is provided a container or canister containing the composition of the present invention.

[0059] The container or canister is preferably airtight and therefore substantially impermeable to air and / or oxygen intrusion. The container may be substantially impermeable to water, e.g., moisture. Preferably, the container containing the composition is substantially free of air or oxygen. The container may be substantially free of water, e.g., moisture. The canister may contain an inert gas (e.g., nitrogen).

[0060] The container or canister may be made from a metal such as aluminum, or may be made from a plastic material such as PET (polyethylene terephthalate).

[0061] The container or canister may be made from a suitable material and coated with a substance known to prevent the ingress of air or oxygen. Examples of such coating materials are polytetrafluoroethylene or PTFE.

[0062] The container or canister may include an outlet for dispensing the composition. For example, the container may include a valve. The valve may allow a predetermined volume of the composition to be dispensed from the container or canister. For example, the valve may be a metering valve.

[0063] The container or canister may be compatible with a dispenser or actuator to dispense the composition from the container or canister. For example, the container or canister may be removably matable with the dispenser or actuator. The dispenser or actuator may provide a means for expanding a valve (e.g., an actuator nozzle) on the container or canister.

[0064] The container or canister and dispenser or actuator may be combined to form a dispensing device (eg, a dispensing device of the present invention).

[0065] According to the present invention, a kit containing the composition of the present invention is provided. The kit may include a) a container or canister of the present invention; and b) a dispenser or actuator for dispensing the composition from the container. The container or canister may preferably be removably mated with the dispenser or actuator. The container / canister and the dispenser / actuator may be separate. Once the contents of the container / canister are depleted, the container / canister may be replaced.

[0066] According to the present invention, there is provided a dispensing device, a device comprising the composition of the present invention. Preferably, the device is a spray device (e.g., an aerosol spray device). The device can be configured to dispense a predetermined dose of the composition.

[0067] The device can be a pressurized dose metered device. For example, the device can include a container or canister containing the composition and a dispenser or actuator for dispensing the composition from the container or canister. The container or canister can be detachably mated with the dispenser or actuator. In one embodiment, the container or canister includes a metering valve, and the actuator includes an actuator nozzle. In use, the valve engages with the actuator, and when the container or canister is depressed against the actuator, the actuator nozzle opens the valve, allowing the composition to be dispensed, preferably as an aerosol.

[0068] In one embodiment, the kit or device can be configured to dispense a dose of 0.05 mg to 100 mg of apomorphine or a pharmaceutically acceptable salt thereof. For example, one application or one spray can dispense 0.05 mg to 100 mg of apomorphine or a pharmaceutically acceptable salt thereof. Alternatively, the kit or device can be configured to dispense a dose of 0.05 mg to 75 mg, 0.1 mg to 50 mg, or 1 mg to 40 mg of apomorphine or a pharmaceutically acceptable salt thereof.

[0069] Preferably, the kit or device is configured to deliver particles or droplets having a size that is not in the respirable range, thereby allowing the buccal or sublingual spray to be delivered without the risk of inhalation.

[0070] The kit or device may be configured to deliver particles or droplets of the composition having an average diameter of greater than 10 μm. For example, the average diameter may be 20 μm or greater. The average diameter may be 50 μm or greater.

[0071] The kit or device may be configured to deliver particles or droplets of the composition, wherein less than 10% of the particles have a diameter of less than 10 μm. Less than 5% of the particles may be less than 10 μm in diameter.

[0072] The kit or device may be configured to deliver particles or droplets of the composition having a mass median aerodynamic diameter (MMAD) greater than 10 μm. MMAD refers to the diameter at which 50% of the particles or droplets, by mass, are larger and 50% are smaller. For particles or droplets to be transported into the lungs, they must be extremely fine (e.g., have an MMAD of less than 10 μm). The MMAD may be at least 20 μm. The MMAD may be at least 50 μm.

[0073] The kit or device may be configured to deliver particles or droplets with a volume median diameter (VMD) greater than 10 μm. Volume median diameter (VMD) refers to the median droplet size (median) where half of the spray volume is in smaller droplets and half of the volume is in droplets larger than the median. The VMD may be at least 20 μm. The VMD may be at least 50 μm.

[0074] The kit or device may be configured to deliver particles or droplets of the composition having a fine respirable fraction or fine particle fraction (FPF) of less than 30%, preferably less than 20%, and more preferably less than 10%, where FPF refers to the percentage of emitted particles or droplets that have a diameter less than 5 μm, or the respirable dose.

[0075] Many methods are available for determining the size distribution of particles or droplets. A cascade impactor (e.g., Anderson Cascade Impactor or Next Generation Impactor (NGI)) can be used to obtain the size distribution of an aerosol. The NGI is a cascade impactor for classifying aerosol particles into size fractions, incorporating seven impact stages and a final micro-orifice collector. It is commercially available, for example, from MSP Corporation (MN, USA). An example of such an impactor is described, for example, in U.S. Pat. No. 6,595,368.

[0076] Particle / droplet size can be measured by laser diffraction techniques. For example, light from a laser can be directed at a number of particles / droplets suspended in a transparent gas such as air. The particles / droplets scatter light; smaller particles / droplets scatter their light at larger angles than larger particles / droplets. The scattered light can be measured by a series of photodetectors positioned at various angles. This is known as the diffraction pattern of the sample. The diffraction pattern can be used to measure the size of the particles / droplets. Particle diameter can be calculated from the measured size of the particles / droplets, assuming a sphere of equal volume.

[0077] According to the present invention, there is provided a dispensing device containing a composition of the present invention (e.g., a composition comprising apomorphine or a pharmaceutically acceptable salt thereof), which is configured to deliver the composition in the form of particles or droplets (e.g., as an aerosol). The particles or droplets may have: i) an average diameter greater than 10 μm (e.g., 20 μm or greater, or 50 μm or greater); ii) Less than 10% of the particles are less than 10 μm in diameter (e.g., less than 5% of the particles are less than 10 μm in diameter). iii) MMAD greater than 10 μm (e.g., 20 μm or greater, or 50 μm or greater); iv) a volume median diameter (VMD) greater than 10 μm (e.g., 20 μm or greater, or 50 μm or greater); and / or v) A fine particle fraction (FPF) of less than 30%, preferably less than 20%, more preferably less than 10%.

[0078] Examples of devices that may be suitable for administering the compositions of the present invention are described in US 2018 / 0344950 A1. Other examples include conventional nasal spray bottles, which allow for the spraying of a solution contained therein by the application of pressure (e.g., by squeezing the bottle or by using a pump).

[0079] According to the present invention, there is provided a composition of the present invention (eg, a composition comprising apomorphine or a pharmaceutically acceptable salt thereof) for use as a pharmaceutical.

[0080] According to the present invention there is provided a composition according to the present invention for use in treating Parkinson's disease in a subject.

[0081] According to the invention there is provided the use of a composition according to the invention in the manufacture of a medicament for use in treating Parkinson's disease in a subject.

[0082] According to the present invention, there is provided a method of treating Parkinson's disease, said method comprising administering a composition of the present invention to a subject, preferably a human, in need of such treatment.

[0083] Alternatively, the compositions of the present invention can be used to promote or enhance sexual function, treat sexual dysfunction, enhance sexual drive, and / or reduce impotence. For example, the compositions of the present invention can be used to treat male erectile dysfunction.

[0084] The compositions may be administered for pre-gastric absorption of the active ingredient, i.e., absorption of the active ingredient from that portion of the digestive tract before the stomach. The term "pre-gastric absorption" therefore includes buccal, sublingual, oropharyngeal,

[0085] and esophageal absorption. Administration can be topical, mucosal administration. In a preferred example, the composition can be administered to the oral cavity, for example, by buccal administration. Alternatively, the composition can be administered to the nasal cavity.

[0086] The apomorphine or salt thereof is preferably formulated in such a way that it is optimized for oral administration, e.g., buccal administration, and therefore for rapid absorption, which is particularly important because the "on-off" phenomenon in Parkinson's disease can occur very rapidly.

[0087] The composition may be administered to a subject to provide 0.05 mg to 100 mg of apomorphine, or alternatively, 0.05 mg to 75 mg, 0.1 mg to 50 mg, or 1 mg to 40 mg of apomorphine or a pharmaceutically acceptable salt thereof.

[0088] The frequency of the dose can depend on the frequency of the subject's condition. For example, it can depend on the frequency of the "on-off" fluctuations of a patient suffering from Parkinson's disease. The dose can be administered each time the patient has an "off" period, for example, at the occurrence of each off period.

[0089] In the context of treating sexual dysfunction (for example, male erectile dysfunction), the frequency of dosage can depend on the subject's desired sexual activity.For example, the dosage can be administered before engaging in sexual activity.For example, it can be administered within 1 hour, 30 minutes, 15 minutes, 10 minutes or 5 minutes before engaging in sexual activity.

[0090] The composition may be administered to the subject as particles or droplets (e.g., an aerosol). The particles or droplets may have: i) an average diameter of greater than 10 μm (e.g., 20 μm or greater, or 50 μm or greater); and / or ii) less than 10% of the particles are less than 10 μm in diameter (e.g., less than 5% of the particles are less than 10 μm in diameter); and / or iii) MMAD greater than 10 μm (e.g., 20 μm or greater, or 50 μm or greater); and / or iv) a volume median diameter (VMD) greater than 10 μm (e.g., 20 μm or greater, or 50 μm or greater); and / or v) A fine particle fraction (FPF) of less than 30%, preferably less than 20%, more preferably less than 10%.

[0091] According to the present invention, there is provided a method comprising nebulizing a composition of the present invention (e.g., a composition comprising apomorphine or a pharmaceutically acceptable salt thereof). The method may comprise forming an aerosol. The particles or droplets formed may have the following: i) an average diameter of greater than 10 μm (e.g., 20 μm or greater, or 50 μm or greater); and / or ii) less than 10% of the particles are less than 10 μm in diameter (e.g., less than 5% of the particles are less than 10 μm in diameter); and / or iii) MMAD greater than 10 μm (e.g., 20 μm or greater, or 50 μm or greater); and / or iv) a volume median diameter (VMD) greater than 10 μm (e.g., 20 μm or greater, or 50 μm or greater); and / or v) A fine particle fraction (FPF) of less than 30%, preferably less than 20%, more preferably less than 10%. [Example]

[0092] Example Preparation of formulations Example 1 Formulations of apomorphine were prepared at 1.0 and 10% concentrations in HFA 134a propellant. Details of these preparations are shown in Table 1. [Table 1]

[0093] For the preparation of drug-only formulations with HFA134a, the required drug amount was weighed into an MDI canister, and 50 μL of Butyl elastomer (Bespak, Kings Lynn, UK) was crimped onto the canister. The HFA was filled through the valve, and the formulation was sonicated for 20 minutes. The canister was then placed valve-side down in a circular position for 14 days.

[0094] The chemical stability of different apomorphine formulations prepared in HFA 134a at TO, 24 hours and 72 hours is shown in Table 2. [Table 2]

[0095] Formulations prepared at 1.0% w / w concentration in HFA134a were extremely stable. No signs of impurities had occurred by 72 hours. In the case of the 1.0% w / w formulations, they passed the acceptance criteria as no individual impurity was greater than 0.2% and the sum of all unknown impurities was below 2.0%.

[0096] For the 10% API and HFA134a formulations, the measured impurities increased over time, increasing to 0.55% w / w at 72 hours. No individual impurity was greater than 0.2%. Total impurities were less than 2.0%, so the formulations were within specification.

[0097] Thus, these data suggest that all formulations were chemically stable in HFA 134a.

[0098] Example 2 Formulations of apomorphine were prepared at a 30% concentration in HFA 134a propellant with and without the excipient, polyethylene glycol 400 (PEG 400). Details of these preparations are shown in Table 3. The aqueous solvent was degassed to eliminate dissolved oxygen prior to its use. The formulation was made in the absence of oxygen. [Table 3] *30% concentration equates to a delivered dose of 23.2 mg apomorphine through a 75 μl valve.

[0099] The above composition was added to an MDI canister.

[0100] HFA at T-0, 28 days, 32 days, 36 days, 40 days, and 48 days The chemical stability of different apomorphine formulations prepared in 134a is shown in Table 4. [Table 4]

[0101] Formulations prepared at 30% concentration in HFA 134a propellant were extremely stable for up to 48 days despite not being acidified. The present invention provides, for example, the following items. (Item 1) A composition comprising a solution of apomorphine or a pharmaceutically acceptable salt thereof, said composition comprising a propellant, wherein said solution: i) is a non-aqueous solution; or ii) comprises degassed water. (Item 2) Item 1, wherein the propellant comprises a hydrofluorocarbon (HFA). (Item 3) 3. The composition of claim 2, wherein the propellant comprises HFA-134a. (Item 4) The composition of any of the preceding items, including a co-solvent. (Item 5) 5. The composition of claim 4, wherein the co-solvent comprises an organic solvent. (Item 6) 6. The composition according to item 5, wherein the organic solvent comprises an alcohol, preferably ethanol. (Item 7) The composition of any preceding item, wherein the composition comprises an excipient. (Item 8) 8. The composition of claim 7, wherein the excipient is a polymer. (Item 9) 9. The composition of claim 8, wherein the excipient is polyethylene glycol. (Item 10) 10. The composition according to any of items 7 to 9, wherein the excipient is present in an amount of 0.2% to 2% by weight. (Item 11) The composition of any of the preceding items, wherein the apomorphine is present in an amount of 1 to 50% by weight. (Item 12) 12. The composition of claim 11, wherein the apomorphine is present in an amount of at least 5%, 10%, 20% or 30% by weight. (Item 13) The composition according to any of the preceding items, wherein the apomorphine solution contains water, and the amount of water in the composition is 10 to 40% by weight. (Item 14) The composition of any preceding claim, wherein the propellant is present in an amount of at least 30% by weight of the composition, and optionally up to 99% by weight. (Item 15) A kit comprising: a) a canister containing a composition according to any of the preceding items; and b) an actuator for dispensing the composition from the canister. (Item 16) Item 16. The kit of item 15, configured to deliver the composition in the form of particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) greater than 10 μm; and / or a fine particle fraction (FPF) less than 30%. (Item 17) 1. A kit comprising: a) a canister; and b) an actuator for dispensing the composition from the canister, wherein the canister contains a composition, the composition comprising apomorphine or a pharmaceutically acceptable salt thereof, and wherein the kit is configured to deliver the composition in the form of particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) of greater than 10 μm; and / or a fine particle fraction (FPF) of less than 30%. (Item 18) 18. The kit of claim 17, wherein i) the apomorphine or pharmaceutically acceptable salt thereof is in a solution, optionally i) a non-aqueous solution; or ii) a solution comprising degassed water; and / or b) the composition comprises a propellant. (Item 19) 19. The kit according to any one of items 15 to 18, wherein the canister includes a metering valve. (Item 20) 20. The kit according to any of items 15 to 19, wherein the kit is configured to deliver a predetermined dose, preferably wherein the dose is 0.05 mg to 100 mg of apomorphine or a pharmaceutically acceptable salt thereof. (Item 21) 15. A dispensing device comprising the composition according to any one of items 1 to 14. (Item 22) 22. The device of claim 21, wherein the device is configured to deliver the composition in the form of particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) greater than 10 μm; and / or a fine particle fraction (FPF) less than 30%. (Item 23) A dispensing device comprising a composition, the composition comprising apomorphine or a pharmaceutically acceptable salt thereof, the device being configured to deliver the composition in the form of particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) of greater than 10 μm; and / or a fine particle fraction (FPF) of less than 30%. (Item 24) 24. The device of claim 23, wherein i) the apomorphine or a pharmaceutically acceptable salt thereof is in a solution, optionally i) a non-aqueous solution, or ii) a solution comprising degassed water; and / or b) the composition comprises a propellant. (Item 25) 25. The device according to any of items 21 to 24, which is a spray device, preferably a pressurized metered dose dispensing device for dispensing a predetermined dose of the composition. (Item 26) 26. The device according to item 25, comprising: a) a container containing the composition, preferably wherein the container comprises a metering valve; and b) an actuator for dispensing the composition from the container. (Item 27) 27. The device according to any of items 21 to 26, configured to deliver a predetermined dose, preferably wherein said predetermined dose is between 0.05 mg and 100 mg of apomorphine or a pharmaceutically acceptable salt thereof. (Item 28) 15. The composition according to any of items 1 to 14 for use as a medicine. (Item 29) 15. The composition according to any of items 1 to 14 for use in treating Parkinson's disease or male erectile dysfunction. (Item 30) 30. The composition for use according to item 29, wherein the composition is administered to the subject topically, preferably by buccal administration. (Item 31) 31. The composition for use of item 29 or item 30, wherein the composition is administered to the subject in the form of particles or droplets having: i) a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) greater than 10 μm; and / or a fine particle fraction (FPF) of less than 30%. (Item 32) A composition for use in treating Parkinson's disease in a subject, said composition comprising apomorphine or a pharmaceutically acceptable salt thereof, wherein said composition is administered in the form of particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) of greater than 10 μm; and / or a fine particle fraction (FPF) of less than 30%. (Item 33) 33. The composition for use according to item 32, wherein the composition is administered to the subject topically, preferably by buccal administration. (Item 34) 34. The composition for use according to claim 32 or 33, wherein the apomorphine or a pharmaceutically acceptable salt thereof is in solution, optionally i) a non-aqueous solution, or ii) a solution comprising degassed water; and / or the composition comprises a propellant. (Item 35) A method comprising the step of nebulizing a composition comprising apomorphine or a pharmaceutically acceptable salt thereof, wherein the composition forms particles or droplets having a mass median aerodynamic diameter (MMAD) or volume median diameter (VMD) of greater than 10 μm; and / or a fine particle fraction (FPF) of less than 30%. (Item 36) 36. The method of claim 35, wherein the apomorphine or a pharmaceutically acceptable salt thereof is in a solution, optionally i) a non-aqueous solution, or ii) a solution comprising degassed water; and / or the composition comprises a propellant.

Claims

[Claim 1] A composition comprising a solution of apomorphine or a pharmaceutically acceptable salt thereof, said composition comprising a propellant, wherein said solution: i) is a non-aqueous solution; or ii) comprises degassed water.

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