Pharmaceutical composition of HFA-134A solution containing RPL554 for administration by inhalation

Abstract

The present invention relates to a liquid pharmaceutical composition suitable for administration by inhalation, comprising: (i) a suspension of particles comprising 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one (RPL554); and (ii) a diluent, which is 1,1,1,2-tetrafluoroethane (HFA-134a), wherein the liquid pharmaceutical composition is substantially free of surfactant. The present invention also relates to a pressure metered dose inhaler comprising the liquid pharmaceutical composition.

Description

Field of the Invention

[0001] The present invention relates to a liquid pharmaceutical composition comprising a respiratory medicament and a pressurized metered dose inhaler (pMDI) comprising the liquid pharmaceutical composition. Background of the Invention

[0003] RPL554 (9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one) is a dual PDE3 / PDE4 inhibitor and is described in WO 00 / 58308. As a combined PDE3 / PDE4 inhibitor, RPL554 has anti-inflammatory and bronchodilatory activity and is used to treat respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD). The structure of RPL554 is shown below.

[0004]

[0005] Given its efficacy in treating respiratory disorders, RPL554 is typically administered by inhalation. Administration of RPL554 by nebulizer is known (WO 2016 / 042313). However, it is generally desirable to use a pressurized metered dose inhaler (pMDI) to administer respiratory medications.

[0006] pMDI formulations comprising a salt of RPL554 are contemplated in WO 2015 / 173551. pMDI formulations comprising RPL554 in combination with a second active agent and a surfactant are described in WO 2014 / 140648.

[0007] Known pMDI formulation strategies can involve the use of a wide range of different propellants, excipients, co-solvents and surfactants, and can be in the form of suspensions, solutions or mixtures thereof. For example, pMDI formulations may include one or more propellants, such as alkanes (e.g. propane, n-butane, isobutane, n-pentane, isopentane, neopentane), hydrofluoroalkanes (HFA, such as HFA-227, HFA-134a and HFA 152a), ethers (e.g. dimethyl ether) and hydrofluoro-olefins (HFO, such as HFO-1234ze and HFO-1234yf). Co-solvents such as ethanol and water are generally included in pMDI formulations. Excipients generally included in pMDI formulations include antioxidants, preservatives, wetting agents, chelating agents, emulsifiers, spices, buffers, lubricants, suspending agents and osmotic pressure regulators.

[0008] Drugs with low solubility in diluents are usually formulated into suspensions. In such suspension formulations, an important consideration is the uniform dispersion of the drug particles. Agglomeration, phase separation and flocculation can lead to variability in quantitative doses. Therefore, additional excipients such as surfactants and co-solvents are usually used in suspension formulations to improve suspension characteristics. Other considerations for suspension formulations are particle size distribution. The particle size distribution of the drug is usually maintained in the respirable range (usually less than 5 μm).

[0009] Each component included in a pMDI can have many effects on formulation stability and efficacy, which are highly dependent on the identity of the drug to be formulated. These effects cannot be reliably predicted in advance. The correct formulation of a drug for a pMDI is critical to ensure that the formulation can be successfully used in a clinical setting. SUMMARY OF THE INVENTION

[0011] The present invention surprisingly found that liquid pharmaceutical compositions comprising RPL554 particles and HFA-134a (1,1,1,2-tetrafluoroethane) as a diluent / propellant and substantially free of surfactant are particularly advantageous for delivering RPL554 via a pressure metered dose inhaler. Many benefits have been found to be associated with liquid pharmaceutical compositions. It has been found that a specific combination of RPL554 and HFA-134a results in a suspension pMDI formulation with favorable suspension properties and reduced flocculation. It has also been found that chemically and physically stable formulations can be achieved without the presence of a surfactant.

[0012] The ability to omit surfactants from the compositions of the present invention is highly advantageous. This is because RPL554 may be used in patients with disease states such as COPD, asthma, who are at increased risk of allergic inflammatory reactions to excipients such as surfactants. Furthermore, given the teachings in WO 2014 / 140648 that surfactants are required to achieve adequate pMDI, it is surprising that adequate long-term stability can be achieved without surfactants, without aggregation or flocculation of active ingredient particles.

[0013] It was also unexpectedly found that in the presence of a co-solvent such as ethanol, particles of RPL554 are susceptible to Ostwald ripening (growth of particles during suspension). It is important to avoid Ostwald ripening because increased particle size can reduce the respirable fraction of particles present in the formulation. The liquid pharmaceutical formulations of the present invention were found to avoid Ostwald ripening of RPL554 particles.

[0014] The present invention provides a liquid pharmaceutical composition suitable for administration by inhalation, comprising: (i) a suspension of particles comprising 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one (RPL554); and (ii) a diluent, which is 1,1,1,2-tetrafluoroethane (HFA-134a), wherein the liquid pharmaceutical composition is substantially free of a surfactant.

[0015] The present invention also provides a pressurized metered dose inhaler comprising a liquid pharmaceutical composition of the present invention.

[0016] The present invention also provides a liquid pharmaceutical composition of the present invention for treating a human or animal body. The liquid pharmaceutical composition of the present invention can be used to treat or prevent a disease or disease state selected from the following: asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid-resistant asthma, severe asthma, otologic asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, skin disease, atopic dermatitis, psoriasis, ocular inflammation, cerebral ischemia, inflammatory diseases, and autoimmune diseases.

[0017] The invention also provides a method of treating or preventing a disease or condition as defined herein in a subject, the method comprising administering to the subject an effective amount of a liquid pharmaceutical composition of the invention.

[0018] BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 Schematic diagram showing the visual assessment of suspension performance in pressure-rated glass vials.

[0020] Figure 2 The sedimentation scores for the propellant mixtures are shown for each product dosage.

[0021] Figure 3 A graphic representation of the test tank with the dip tube position in the liquid phase after 24 hours is shown.

[0022] Figure 4 Shown is a solubility graph of RPL554 with increasing ethanol concentrations, with and without oleic acid.

[0023] Figure 5 The mean fine particle dose is shown for the pMDI formulation product dose. DETAILED DESCRIPTION OF THE INVENTION

[0025] The liquid pharmaceutical composition of the present invention comprises a suspension of particles of 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one (RPL554). For the avoidance of doubt, RPL554 is in the form of a free base. Although most particles present in a liquid pharmaceutical composition are typically suspended in a diluent, there are circumstances where some or all of the particles in a liquid pharmaceutical composition of the present invention may have settled to the bottom of a container containing the liquid pharmaceutical composition, for example after a period of storage. The particles may be resuspended in any suitable manner, for example by agitating the liquid pharmaceutical composition (e.g. by shaking a can containing the liquid pharmaceutical composition).

[0026] The diluent in the liquid pharmaceutical composition is 1,1,1,2-tetrafluoroethane, which is called HFA-134a and has the formula CH2FCF3. The diluent also acts as a propellant. Typically, HFA-134a is the only diluent in the liquid pharmaceutical composition. In another embodiment, the liquid pharmaceutical composition comprises a diluent, and the diluent comprises greater than 90% by weight HFA-134a relative to the total weight of the diluent in the liquid pharmaceutical composition. Relative to the total weight of the diluent in the liquid pharmaceutical composition, the diluent may comprise greater than 95% by weight HFA-134a, greater than 98% by weight or greater than 99.5% by weight HFA-134a. The diluent may consist essentially of HFA-134a. A composition consisting essentially of a component typically only comprises the component and any other component that does not substantially affect the basic properties of the component that substantially constitutes the composition. Typically, the diluent consists of HFA-134a. The diluent corresponds to the liquid component of the liquid pharmaceutical composition.

[0027] The liquid pharmaceutical composition is substantially free of surfactants. As used herein, a composition is "substantially free" of a specified component if the composition comprises less than 0.5% by weight, preferably less than 0.1% by weight, more preferably less than 0.01% by weight, e.g., less than 0.001% by weight of the specified component relative to the total weight of the composition. Typically, the liquid pharmaceutical composition does not contain a surfactant.

[0028] Examples of the surfactant include a nonionic surfactant, an anionic surfactant, a cationic surfactant, or a zwitterionic surfactant. For the avoidance of doubt, the liquid pharmaceutical composition is thus substantially free of lecithin, oleic acid, polyvinyl pyrrolidone K25, polyvinyl alcohol, oligolactic acid, sodium dioctyl sulfosuccinate, polyoxyethylene glycol alkyl ethers (such as PEG 300, PEG 600, PEG 1000, Brij 30, Brij 35, Brij 56, Brij 76 and Brij 97), polypropylene glycol (such as PPG 2000), glucoside alkyl ethers, polyoxyethylene glycol octylphenol ethers, polyoxyethylene glycol alkylphenol ethers, glycerol alkyl esters, polyoxyethylene glycol sorbitan alkyl esters (polysorbates, such as polysorbate 20, polysorbate 60 and polysorbate 80), sorbitan alkyl esters (such as sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80) and sorbitan trioleate (Span 10). 85)), cocamide MEA, cocamide DEA, dodecyl dimethyl amine oxide, block copolymers of polyethylene glycol and polypropylene glycol (poloxamers), block copolymers of polyethylene glycol and polypropylene oxide (e.g., Pluronic surfactants), and polyethoxylated tallow amine (POEA).

[0029] In a preferred embodiment, the liquid pharmaceutical compositions of the present invention are substantially free of ethanol.

[0030] More preferably, the liquid pharmaceutical composition is substantially free of any additional excipients selected from co-solvents and surfactants.The liquid pharmaceutical composition more typically does not comprise any co-solvents and does not comprise any surfactants.

[0031] Examples of co-solvents include ethanol, pentane, water, isopropanol, glycerol, and propylene glycol.

[0032] In a preferred embodiment, the liquid pharmaceutical composition is substantially free of any additional excipients. Additional excipients may be, for example, surfactants or co-solvents as described above or excipients selected from antioxidants, preservatives, wetting agents, solubilizers, emulsifiers, flavoring agents, chelating agents, humectants, tonicity regulators, pH regulators, dispersants and suspending agents.

[0033] Relative to the gross weight of the composition, the liquid pharmaceutical composition may contain less than 0.2% by weight of a surfactant or additional excipient. For example, relative to the gross weight of the composition, the liquid pharmaceutical composition may contain less than 0.1% by weight of a surfactant or additional excipient. Relative to the gross weight of the composition, the liquid pharmaceutical composition may, for example, contain less than 0.05% by weight, less than 0.01% by weight, or less than 0.001% by weight of a surfactant or additional excipient.

[0034] Typically, based on the total weight of all active pharmaceutical ingredients (API), at least 50% by weight, more preferably at least 90% by weight, and more preferably at least 99% by weight of the active pharmaceutical ingredient (API) in the liquid composition of the present invention is RPL554.

[0035] More typically, RPL554 is the only active agent in the liquid pharmaceutical composition. In this embodiment, the liquid pharmaceutical composition of the invention is substantially free of other active agents (eg, muscarinic receptor antagonists or beta-adrenergic receptor agonists).

[0036] As described above, it has been found that liquid pharmaceutical compositions comprising HFA-134a and RPL554 particles and substantially free of any additional excipients have many advantages. Therefore, typically, the liquid pharmaceutical composition is substantially composed of (i) RPL554 and (ii) 1,1,1,2-tetrafluoroethane. More typically, the liquid pharmaceutical composition comprises at least 99.5% by weight of (i) RPL554 and (ii) 1,1,1,2-tetrafluoroethane relative to the total weight of the composition. The liquid pharmaceutical composition can, for example, consist of (i) RPL554 and (ii) 1,1,1,2-tetrafluoroethane.

[0037] The liquid pharmaceutical composition of the present invention may, for example, comprise: (i) 0.005 to 5% by weight of RPL554, and (ii) 95 to 99.995% by weight of 1,1,1,2-tetrafluoroethane (HFA-134a), wherein the % by weight is relative to the total weight of the liquid drug. Typically, the total amount of RPL554 and HFA-134a is at least 99% by weight relative to the total weight of the composition.

[0038] The particles of RPL554 can have any suitable size for a liquid pharmaceutical composition suitable for inhalation. Typically, the particles of RPL554 are micronized particles. For example, the particles of RPL554 can have a Dv50 (volume median diameter) value of less than or equal to 10 μm or about 0.1 μm to about 8 μm.

[0039] Typically, the particles have a particle size distribution with a Dv50 value of about 0.2 μm to about 5 μm. More typically, the particles of RPL554 have a particle size distribution with a Dv50 value of about 0.7 μm to about 3.0 μm. For example, the particles of RPL554 may have a particle size distribution with a Dv50 value of 0.9 μm to 2.7 μm. Typically, the particles of RPL554 have a particle size distribution with a Dv50 value of about 1.1 μm to about 2.1 μm.

[0040] The Dv50 value is the median diameter of the volume distribution. Thus, half of the volume of particles is contained in particles with a diameter smaller than the Dv50 value, and half of the volume of particles is contained in particles with a diameter larger than the Dv50 value. This is a well-known way of describing particle size distribution.

[0041] The particles typically have a particle size distribution with a Dv10 value of about 0.4 μm to about 1.0 μm. The particles typically have a particle size distribution with a Dv90 value of about 2.0 μm to about 4.0 μm. The Dv10 value reflects the particle diameter where 10% of the sample by volume is in particles having a particle size less than the Dv10 value. The Dv90 value reflects the particle diameter where 90% of the sample by volume is in particles having a particle size less than the Dv90 value.

[0042] The technique used to measure the Dv50 value is typically laser diffraction. For example, RPL554 particles typically have a particle size distribution with a Dv50 value of about 0.2 μm to about 5 μm as measured by laser diffraction. Particle size distribution analysis can be performed by laser diffraction using a MalvernSpraytec connected to a wet dispersing element. Typically, the instrument parameters for the Malvern Spraytec are as follows:

[0043] · Grains – standard opaque granules;

[0044] · Refractive index of particles -1.50;

[0045] Refractive index (hypothetical) -0.50;

[0046] Particle density - 1.00;

[0047] The refractive index of the dispersant is -1.33;

[0048] Controller unit - 1000RPM;

[0049] Measurement type – timing;

[0050] Initial sampling time - 30s;

[0051] · Shading - 20% to 30%;

[0052] Dispersant - 1% polysorbate 20 in deionized water.

[0053] Particles of RPL554 can be produced by any pharmaceutically acceptable size reduction method or particle size controlled production method. For example, particles can be produced by spray drying a solution of RPL554, by controlled crystallization, or by size reduction of a solid form of RPL554 such as jet milling, mechanical micronization, or media milling.

[0054] The concentration of particles containing RPL554 in the liquid pharmaceutical composition can vary based on the desired dose of active compound per actuation of the inhaler. For example, the concentration of the particles can be such that the dose of RPL554 delivered per actuation of the inhaler containing the liquid pharmaceutical composition is 5 μg / actuation to 1500 μg / actuation. The concentration of the particles can be such that the dose of RPL554 delivered per actuation is 50 μg / actuation to 1000 μg / actuation.

[0055] The concentration of particles comprising RPL554 in the liquid pharmaceutical composition can be from about 0.01 mg / mL to about 400 mg / mL. The concentration of particles comprising RPL554 in the liquid pharmaceutical composition is typically from about 0.1 mg / mL to about 200 mg / mL. More typically, the concentration of RPL554 particles in the liquid pharmaceutical composition is from about 0.5 mg / mL to about 20 mg / mL.

[0056] For example, the concentration of RPL554 particles in the liquid pharmaceutical composition can be about 0.1 mg / mL to about 3.0 mg / mL or about 0.5 mg / mL to about 2.0 mg / mL. The concentration of RPL554 particles in the liquid pharmaceutical composition can be about 5.0 mg / mL to about 20 mg / mL or about 6.0 mg / mL to about 10 mg / mL.

[0057] The concentration of particles comprising RPL554 in the liquid pharmaceutical composition may be from about 0.01% w / w to about 5.0% w / w. The concentration of particles comprising RPL554 in the liquid pharmaceutical composition is typically from about 0.05% w / w to about 2.0% w / w.

[0058] Liquid pharmaceutical compositions are generally suitable for administration by inhalation. Liquid pharmaceutical compositions are more generally suitable for administration by pressure metered dose inhalers. Pressure metered dose inhalers are inhalers that use pressurized liquefied propellants to deliver atomized doses of liquid pharmaceutical compositions. Pressure metered dose inhalers generally include a tank (or vial) that includes a liquid pharmaceutical composition, a metering valve, an actuator, and an interface.

[0059] The present invention provides a pressurized metered dose inhaler containing a liquid pharmaceutical composition as defined herein. pMDIs are well known to those of ordinary skill in the art and many such devices are commercially available, representative devices include the AeroBid Inhaler System (Forest Pharmaceuticals), Atrovent Inhalation Aerosol (Boehringer Ingelheim), Flovent RTM (Glax Omith Kline), Maxair inhaler (3M), Proventil RTM Inhaler (Schering) and SereventRTM Inhalation aerosol (Glax Omith Kline).

[0060] The pressurized metered dose inhaler containing the liquid drug composition can be configured to provide an aerosol of the liquid drug composition upon actuation, the aerosol having a mass median aerodynamic diameter (MMAD) of 1.0 μm to 5.0 μm. The aerosol can be prepared in accordance with the pharmacopoeial requirements (European Pharmacopoeia (Ph.Eur.) Method Chapter 2.9.18 and the United States Pharmacopoeia) <601> Chapter ) MMAD measurements using a new generation impactor.

[0061] The present invention provides a liquid pharmaceutical composition as defined herein for use in treating the human or animal body. Typically, the liquid pharmaceutical composition is administered by inhalation.

[0062] Liquid pharmaceutical compositions are typically used to treat or prevent a disease or disease state selected from: asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), steroid-resistant asthma, severe asthma, otologic asthma, cystic fibrosis, lung fibrosis, pulmonary fibrosis, interstitial lung disease, skin disease, atopic dermatitis, psoriasis, ocular inflammation, cerebral ischemia, inflammatory diseases, and autoimmune diseases. The disease or disease state is preferably COPD or asthma. More preferably, the disease or disease state is chronic obstructive pulmonary disease (COPD).

[0063] Typically, the liquid pharmaceutical composition is administered by inhalation from a pMDI containing the liquid pharmaceutical composition at a metered nominal dose of 5 μg to 1000 μg per actuation. For example, the metered nominal dose per actuation may be 10 μg to 500 μg. Typically, two actuations of the pMDI may be inhaled consecutively to provide a single dose.

[0064] Typically, the emitted dose from a pMDI containing a liquid pharmaceutical composition is 80% to 95% of the metered nominal dose.

[0065] Typically, liquid drug compositions are administered to patients by actuating the pMDI 2 to 8 times per day.

[0066] The present invention is described in more detail by the following examples. Example

[0067] Materials and methods

[0068] The materials used are as follows.

[0069] API: micronized RPL554. The properties of micronized RPL554 are shown in Table 1 below.

[0070] Table 1

[0071]

[0072] Propellants: HFA-134a and HFA-227ea.

[0073] • Cosolvent: Ethanol / absolute ethanol (100% USP-NF ethanol) obtained from Hyman Kimia.

[0074] • Surfactant: Oleic acid (Ph. Eur. / Brit. Pharmacopoeia) obtained from Croda International plc.

[0075] Reagents: Analytical grade chemicals were used throughout the study.

[0076] • Borosilicate glass vials with foil-lined polypropylene caps (VWR, Part number 215-3905).

[0077] Glass vial: 15 mL pressure-rated clear glass vial (Neville & Moore, Part No 0771C3 / A3).

[0078] • Valve: Bespak and Aptar 63μL valve.

[0079] Can: Presspart 14mL can.

[0080] Actuator: Presspart actuator.

[0081] All samples were prepared in the laboratory using a Pamasol hand crimper and filler. All samples were mixed by immersion in an ultrasonic bath for 30 seconds.

[0082] The full analytical method was fully developed and tested in vitro using DUSA tubes and by Next Generation Impactor (NGI).

[0083] The analytical test methods used during the analysis were as follows.

[0084] · According to the requirements of pharmacopoeia (European Pharmacopoeia (Ph.Eur.) - Dosage forms for inhalation (0671) and United States Pharmacopoeia <601> 1.3.1.2 Performing Delivered Dose Testing

[0085] ·According to pharmacopoeia requirements (European Pharmacopoeia (Ph.Eur.) Methods Chapter 2.9.18 and United States Pharmacopoeia <601> Aerodynamic Particle Size Distribution (APSD) testing using a new generation impactor

[0086] Example 1 - Evaluation of Suitable Propellants

[0087] An experiment was conducted to compare the suitability of two propellants, HFA-134a and HFA-227ea, for use as diluents for pMDI suspension formulations containing RPL554. Table 2 shows the key physical and chemical properties of the two propellants evaluated.

[0088] Table 2 - HFA propellant properties

[0089]

[0090] The samples were prepared by adding the required amount of RPL554 (see Table 3) to a 15 mL pressure-rated clear glass vial. Propellant HFA-134a, HFA-227ea, or a combination of both (see Table 4) was added through the valve and the samples were mixed in an ultrasonic bath for 30 seconds. The same target fill weight of 11.6 g (± 0.5 g) was used for all samples. The appearance of the API particles in the propellant was evaluated with respect to sedimentation rate and flocculation behavior (see Table 4). Figure 1 The sedimentation rate of the formulations was visually assessed after suspension agitation by recording images of the glass vials using a high-speed camera. The suspension quality was determined by assigning a sedimentation score of 1 to 10 based on the amount of active particles that had settled or floated within 30 seconds, with 1 being the fastest settler / cream (i.e., undesirable) and 10 being the slowest settler / cream (i.e., acceptable).

[0091] Table 3 - Amounts of RPL554 used in the formulations of HFA-134a, HFA-227ea and mixtures thereof

[0092] Product dose (μg / actuation) RPL554 mass (mg / vial) 10 1.5 50 7.5 150 22.5 500 75.0 1000 150.0

[0093] Table 4 - Propellant ratio for each formulation

[0094] HFA-134a(%w / w) HFA-227ea (%w / w) 100 0 75 25 50 50 25 75 0 100

[0095] result

[0096] The RPL554 formulation in HFA-134a was easily suspended when shaken, and rapid flocculation and gradual settling were observed after shaking stopped. The formulations in HFA-227ea and the mixture of HFA-134a / HFA-227ea (50 / 50) were easily suspended when shaken. However, emulsification was observed after shaking stopped for the formulation containing HFA-227ea. The HFA-227ea formulation showed evidence of particles adhering to the container wall after shaking along with more obvious larger floccules.

[0097] exist Figure 2The sedimentation scores for each product dosage using propellant (pure or mixture) are shown in a graphical manner in Table 5. This shows that the best scores (i.e., the slowest sedimentation) are observed in formulations with higher HFA-134a content. Due to the increase in powder loading, the sedimentation score decreases with increasing product dosage. Table 5 shows the individual sedimentation scores.

[0098] Table 5 - Sedimentation scores for formulations prepared with HFA-134a, HFA-227ea and mixtures thereof

[0099]

[0100] As can be seen from Table 5, unexpectedly, formulations containing HFA-134a as a diluent were found to have consistently improved sedimentation scores compared to formulations containing HFA-227ea as a diluent. Formulations containing a higher percentage of HFA-134a were found to result in less flocculation, less emulsification, and less sticking than formulations containing a higher percentage of HFA-227ea.

[0101] Thus, it has been discovered that HFA-134a can be advantageously used as the sole diluent for liquid pharmaceutical compositions comprising a suspension of particles of RPL554.

[0102] Example 2 - Evaluation of Suitable Additional Excipients

[0103] In order to seek to improve the suspension properties, the addition of additional excipients was studied. In particular, formulations that also contained a surfactant (oleic acid, Ph. Eur. / Brit. Pharmacopoeia) and a cosolvent (ethanol, 100% USP-NF) were prepared. Table 6 shows the composition of the formulations tested and the observed sedimentation scores.

[0104] Table 6 - Sedimentation scores for pMDI formulations containing varying amounts of HFA-134a, oleic acid and ethanol

[0105]

[0106]

[0107] It was observed that the suspension scores of formulations containing oil and ethanol were generally similar to or lower than those formulations without such excipients. However, in some samples, it was observed that RPL554 appeared to have dissolved or recrystallized. Solubility analysis was performed to assess the extent to which RPL554 dissolved in additional excipients.

[0108] Example 3 - Solubility of RPL554 in ethanol

[0109] RPL554 was initially considered to be virtually insoluble in ethanol based on the USP / BP solubility criteria given in Table 7. However, the observation of dissolution and recrystallization with the lowest product dose (10 μg / actuation) in the presence of oleic acid prompted further investigation of the solubility of RPL554 in ethanol.

[0110] Table 7 - USP and BP Solubility Standards

[0111] Descriptive terms Parts of solvent required per part of solute Very soluble Less than 1 Soluble 1 to 10 Dissolve 10 to 30 Slightly soluble 30 to 100 Slightly soluble 100 to 1000 Very slightly soluble 1000 to 10,000 Almost insoluble More than 10,000

[0112] Experimental methods

[0113] The samples were prepared by adding 1.5 mg of RPL554 to a common 14 mL aluminum can with ethanol, oleic acid, and HFA-134a. Excipients were added to the can to maintain a 50:1 ethanol / oleic acid ratio (see Table 8). Corresponding cans containing RPL554, ethanol, and HFA-134a alone were also produced. A can with a shortened dip tube was crimped with a 63 μL pMDI valve ( Figure 3 ) and fill the canister to 11.6 g with HFA-134a through the valve. The length of the dip tube is sufficient to extend only into the liquid propellant / cosolvent phase (i.e., after the API particles have settled). The sample is placed in an ultrasonic bath for 30 seconds.

[0114] Table 8 - Excipient Concentrations Used to Evaluate the Solubility of RPL554 in Ethanol

[0115]

[0116] All cans were left at ambient temperature for 24 hours to allow sedimentation and establish dissolution equilibrium. To determine the amount of API dissolved, each can was placed in an upright position (via a sleeve fitted to the valve stem) with a 10.0 cm 3 The volumetric flask was filled with anhydrous ethanol and the solution was analyzed using UV / visible spectroscopy (Perkin Elmer, Model Lambda 35). The concentration of RPL554 was quantitatively calculated using a three-point standard curve.

[0117] result

[0118] The amount of dissolved RPL554 increased with increasing ethanol concentration. The presence of oleic acid in the formulation did not appear to have an effect on the solubility of RPL554 ( Figure 4 ).

[0119] A previous assessment of the solubility of RPL554 in ethanol resulted in a classification of "practically insoluble" according to USP / BP standards. The original assessment was performed using analytical reagent grade ethanol. A reassessment of the solubility, this time using anhydrous ethanol (100% USP-NF ethanol, the grade of ethanol commonly used in large-scale pMDI HFA formulation suspension manufacturing) found that the solubility of RPL554 in ethanol was approximately 1 in 2000, which is "very slightly soluble" according to USP / BP standards. Thus, it was unexpectedly found that RPL554 has some solubility in ethanol.

[0120] For suspension formulations, the solubility of the API in the cosolvent / propellant mixture should be minimal to avoid potential problems with chemical and physical instabilities. It was found that any benefits associated with the use of oleic acid and ethanol as excipients were significantly outweighed by the vulnerability of RPL554 dissolution and Ostwald ripening of RPL554 particles. Therefore, it was established that the most promising pMDI formulation for RPL554 is a suspension formulation of RPL554 alone in HFA-134a.

[0121] Example 4 - Validation of HFA-134a-only Formulation

[0122] The HFA-134a-only formulation was further evaluated by preparing samples in pressure-rated glass vials to ensure that RPL554 was sufficiently suspended for delivery via pMDI. Three product doses (50, 150, and 500 μg / actuation) were selected. Visual evaluation of these formulations showed comparable suspension quality and sedimentation rates to the commercially available HFA-134a-only pMDI product.

[0123] The product performance attributes of the formulation based on RPL554 HFA-134a suspension alone were further evaluated by preparing laboratory samples at 3 doses (50, 150 and 500 μg / actuation) in 14 mL plain aluminum cans crimped with Aptar 63 μL valves. The samples were mixed in an ultrasonic bath for 30 seconds before storage, inverted for four days, before being analyzed for delivered dose uniformity (DDU) and aerodynamic particle size distribution (APSD) by next generation impaction (NGI).

[0124] Delivered Dose Uniformity (DDU)

[0125] Three samples of each product dose were run in triplicate for delivered dose uniformity analysis at the beginning, middle and end of can life. Table 9 shows the average delivered dose results.

[0126] Overall, the average delivered dose was close to the expected target label claim for each product dose.

[0127] Injection weight

[0128] Shot weight is measured at the beginning, middle and end of can life to assess product performance through life.

[0129] The shot weights of the laboratory prepared samples were found to be consistent across all samples, with an average of 80.35 ± 0.54 mg (RSD = 0.67%, n = 9). The theoretical shot weight of 63 μL of HFA-134a is 77.2 mg.

[0130] Aerodynamic Particle Size Distribution (APSD)

[0131] The aerodynamic particle size distribution was measured in order to determine the fine particle fraction (fine particle fraction, % of dose having a particle size less than 5 μm) of the test formulations. Table 9 shows the results.

[0132] Table 9 - Summary of aerodynamic particle size distribution and delivered dose of RPL554 HFA-134apMDI

[0133]

[0134] Figure 5 The correlation between the determined fine particle dose (FPD) and the product dose is shown. Dose proportionality was observed.

[0135] Example 5 - Formulation Stability

[0136] Stability studies were conducted on all RPL554 formulation doses. Tables 10 and 11 present example data for RPL554 HFA-134apMDI, 500 μg / actuation product for stability studies conducted at 25°C / 60 and 40°C / 75% RH, respectively. The data show consistent performance over the 6 month stability period.

[0137] Table 10 - Stability data of RPL554 HFA-134apMDI, 500 μg / actuation - 25°C / 60%RH storage conditions

[0138]

[0139] Table 11 - Stability data of RPL554 HFA-134apMDI, 500 μg / actuation - 40°C / 75%RH storage conditions

[0140]

Claims

1. Use of a liquid pharmaceutical composition in the preparation of a medicament for treating or preventing chronic obstructive pulmonary disease or asthma, The liquid pharmaceutical composition is suitable for administration by inhalation and comprises: (i) a suspension comprising particles of 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one (RPL554); and (ii) a diluent which is 1,1,1,2-tetrafluoroethane (HFA-134a), wherein the liquid pharmaceutical composition contains less than 0.05% by weight of a surfactant relative to the total weight of the composition, and The RPL554 is in the free base form.

2. The use according to claim 1, wherein the liquid pharmaceutical composition contains less than 0.05% by weight of any additional excipient selected from cosolvents and surfactants, relative to the total weight of the composition.

3. The use according to claim 1, wherein the liquid pharmaceutical composition contains less than 0.05% by weight of any additional excipients relative to the total weight of the composition.

4. The use according to claim 1, wherein the liquid pharmaceutical composition contains less than 0.01% by weight of the surfactant or the additional excipient relative to the total weight of the composition.

5. The use according to claim 1, wherein the liquid pharmaceutical composition contains less than 0.001% by weight of the surfactant or the additional excipient relative to the total weight of the composition.

6. The use according to claim 1, wherein the granules comprise at least 50% by weight of RPL554 relative to the total weight of the granules.

7. The use according to claim 1, wherein the granules comprise at least 99% by weight of RPL554 relative to the total weight of the granules.

8. The use according to claim 1, wherein RPL554 is the only active agent in the liquid pharmaceutical composition.

9. The use of claim 1, wherein the liquid pharmaceutical composition consists essentially of (i) RPL554 and (ii) 1,1,1,2-tetrafluoroethane.

10. The use according to claim 1, wherein the liquid pharmaceutical composition comprises at least 99.5% by weight of (i) RPL554 and (ii) 1,1,1,2-tetrafluoroethane relative to the total weight of the composition.

11. The use according to claim 1, wherein the particles comprising RPL554 have a particle size distribution with a Dv50 (volume median diameter) value of 0.2 μm to 5 μm. 12 . The use according to claim 1 , wherein the concentration of the particles comprising RPL554 in the liquid pharmaceutical composition is 0.1 mg / mL to 200 mg / mL.

13. The use according to claim 1, wherein the liquid pharmaceutical composition is suitable for administration by a pressurized metered dose inhaler.

14. The use according to claim 1, wherein the liquid pharmaceutical composition is in a pressurized metered dose inhaler.

15. Use according to claims 1 to 13, wherein the medicament is for the treatment or prevention of chronic obstructive pulmonary disease.

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