Pharmaceutical composition for inhalation containing RPL554 in HFA-134A

Abstract

To provide a liquid pharmaceutical composition suitable for administration by inhalation.SOLUTION: Provided is a liquid pharmaceutical composition for use in the treatment of the human or animal body, which is 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]isoquinoline-4-one (RPL554); and (ii) a diluent which is 1,1,1,2-tetrafluoroethane (HFA-134a), the liquid pharmaceutical composition containing less than 0.05 wt.% of a surfactant to the total weight of the composition.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a liquid pharmaceutical composition containing a respiratory drug and a pressurized metered-dose inhaler (pMDI) containing the liquid pharmaceutical composition.

Background Art

[0002] 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 WO00 / 58308. As a combined PDE3 / PDE4 inhibitor, RPL554 has both anti-inflammatory and bronchodilatory actions and is useful in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). The structure of RPL554 is shown below.

[0003]

Chemical formula

[0004] RPL554 is typically administered by inhalation in view of its effectiveness in the treatment of respiratory diseases. Administration of RPL554 by a nebulizer is known (WO2016 / 042313). However, it is often desirable to administer a respiratory drug using a pressurized metered-dose inhaler (pMDI).

[0005] A pMDI formulation containing a salt of RPL554 is envisioned in WO2015 / 173551. A pMDI formulation containing a combination of RPL554 and a second active agent and a surfactant is described in WO2014 / 140648.

[0006] Known pMDI formulation strategies can involve the use of a wide range of different propellants, excipients, co-solvents and surfactants and may take the form of suspensions, solutions or mixtures thereof. For example The pMDI formulation may contain one or more propellants such as alkanes (e.g., propane, n-butane, isobutane, n-pentane, isopentane, neopentane), hydrofluoroalkanes (HFA, e.g., HFA-227, HFA-134a, and HFA-152a), ethers (e.g., dimethyl ether), and hydrofluoroolefins (HFO, e.g., HFO-1234ze and HFO-1234yf). Cosolvents such as ethanol and water are usually included in the pMDI formulation. Excipients usually included in the pMDI formulation include antioxidants, preservatives, wetting agents, chelating agents, emulsifiers, fragrances, buffers, lubricants, suspending agents, and isotonic agents.

[0007] Drugs with low solubility in diluents are often prescribed as suspensions. In such suspension formulations, a key consideration is the uniform dispersion of drug particles. Aggregation, phase separation, and flocculation can lead to variations in metering dose. Therefore, additional excipients such as surfactants and cosolvents are usually used in suspension formulations to improve the properties of the suspension. A further consideration for suspension formulations is the particle size distribution. The particle size distribution of the drug is usually maintained within a breathable range (typically less than 5 μm).

[0008] Each component in a pMDI can have a significant impact on the stability and efficacy of the formulation, which are highly dependent on the characteristics of the drug being formulated. Such impacts cannot be reliably predicted in advance. Proper formulation of the drug for use in pMDIs is crucial to ensuring that the formulation can be successfully used in clinical practice. [Overview of the project]

[0009] A remarkable discovery of this invention is that a liquid pharmaceutical composition containing RPL554 particles and HFA-134a (1,1,1,2-tetrafluoroethane) as a diluent / propellant, and substantially free of surfactants, is particularly advantageous for the delivery of RPL554 by pressurized metered-dose inhalers. Numerous advantages related to this liquid pharmaceutical composition have been found. It has been found that specific combinations of RPL554 and HFA-134a lead to suspension pMDI formulations with desirable suspension properties and reduced aggregation. It has also been found that chemically and physically stable formulations may be achieved without the need for the presence of surfactants.

[0010] The ability to omit surfactants from the composition of the present invention is highly advantageous. This is because RPL554 is likely to be used in patients suffering from conditions such as COPD and asthma, who are at high risk of allergic inflammatory reactions to excipients such as surfactants. Furthermore, considering the teachings of WO2014 / 140648 which suggest that surfactants are necessary to achieve adequate pMDI, it is remarkable that adequate long-term stability can be achieved without surfactants and without the accumulation or aggregation of active ingredient particles.

[0011] Furthermore, it was unexpectedly discovered that RPL554 particles are vulnerable to Ostwald ripening (particle growth in suspension) in the presence of a co-solvent such as ethanol. Since increased particle size can reduce the breathable fraction of particles present in the formulation, it is important to avoid Ostwald ripening. The liquid pharmaceutical formulation of the present invention has been found to avoid Ostwald ripening of RPL554 particles.

[0012] The present invention provides a liquid pharmaceutical composition suitable for administration by inhalation, comprising (i) a suspension of particles containing 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinoline-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 surfactants.

[0013] The present invention further provides a pressurized metered-dose inhaler containing the liquid pharmaceutical composition of the present invention.

[0014] The present invention also provides liquid pharmaceutical compositions for use in the treatment of the human or animal body. The liquid pharmaceutical compositions of the present invention may be used in the treatment or prevention of diseases or conditions 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, childhood asthma, cystic fibrosis, pulmonary fibrosis, interstitial lung disease, skin disorders, atopic dermatitis, psoriasis, ocular inflammation, cerebral ischemia, inflammatory diseases, and autoimmune diseases.

[0015] The present invention also provides a method for treating or preventing a disease or condition as defined herein in a subject, comprising administering an effective amount of the liquid pharmaceutical composition of the present invention to the subject. [Brief explanation of the drawing]

[0016] [Figure 1] Figure 1 shows a schematic diagram of the visual evaluation of the suspension performance in a pressure-rated glass vial. [Figure 2] Figure 2 shows the sedimentation scores for each product strength of the propellant mixture. [Figure 3]Figure 3 shows the test storage container (canister) after 24 hours with the dip tube placed in the liquid phase. [Figure 4] Figure 4 shows the solubility graph of RPL554 as the ethanol concentration increases, with and without oleic acid. [Figure 5] Figure 5 shows the average particle dose relative to the product strength of pMDI formulations. [Modes for carrying out the invention]

[0017] Detailed description of the invention 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]isoquinoline-4-one (RPL554). To avoid misunderstanding, RPL554 is in the form of a free base. While the majority of particles present in the liquid pharmaceutical composition are typically suspended in the diluent, some or all of the particles in the liquid pharmaceutical composition of the present invention may settle to the bottom of the container containing the liquid pharmaceutical composition, for example, after storage for a period of time. These particles may be resuspended by any suitable method, for example, by stirring the liquid pharmaceutical composition (for example, by shaking the storage container containing the liquid pharmaceutical composition).

[0018] The diluent in the liquid pharmaceutical composition is 1,1,1,2-tetrafluoroethane, known as HFA-134a and having the formula CH2FCF3. The diluent also acts as a propellant. Typically, HFA-134a is the sole diluent in the liquid pharmaceutical composition. In another embodiment, the liquid pharmaceutical composition comprises a diluent containing more than 90% by weight of HFA-134a relative to the total weight of the diluent in the liquid pharmaceutical composition. The diluent may contain more than 95% by weight of HFA-134a, more than 98% by weight, or more than 99.5% by weight of HFA-134a relative to the total weight of the diluent in the liquid pharmaceutical composition. The diluent may consist substantially of HFA-134a. A composition consisting substantially of one component typically contains only that component and any other components that do not significantly affect the substantial properties of that component, which the composition substantially comprises. Typically, the diluent consists of HFA-134a. The diluent corresponds to the liquid component of the liquid pharmaceutical composition.

[0019] Liquid pharmaceutical compositions are substantially free of surfactants. When used herein, the composition A substance is "substantially free" of a particular component if it contains less than 0.5% by weight, preferably less than 0.1% by weight, and more preferably less than 0.01% by weight of that particular component, for example, less than 0.001% by weight of that particular component, relative to the total weight of the composition. Typically, liquid pharmaceutical compositions do not contain surfactants.

[0020] Examples of surfactants include nonionic surfactants, anionic surfactants, cationic surfactants or zwitterionic surfactants. To avoid misunderstanding, the liquid pharmaceutical composition thus substantially does not contain lecithin, oleic acid, polyvinylpyrrolidone K25, polyvinyl alcohol, oligolactic acid, sodium dioctyl sulfosuccinate, polyoxyethylene glycol alkyl ether (e.g., PEG 300, PEG 600, PEG 1000, Brij 30, Brij 35, Brij 56, Brij 76 and Brij 97), polypropylene glycol (e.g., PPG 2000), glucoside alkyl ether, polyoxyethylene glycol octylphenol ether, polyoxyethylene glycol alkylphenol ether, glycerol alkyl ester, polyoxyethylene glycol sorbitan alkyl ester (polysorbate, e.g., polysorbate 20, polysorbate 60 and polysorbate 80), sorbitan alkyl ester (e.g., sorbitan monolaurate (span 20), sorbitan monooleate (span 80) and sorbitan trioleate (span 85)), cocamide MEA, cocamide DEA, dodecyldimethylamine oxide, block copolymer of polyethylene glycol and polypropylene glycol (poloxamer), block copolymer of polyethylene glycol and polypropylene oxide (e.g., Pluronic surfactant) and polyethoxylated tallow amine (POEA).

[0021] In a preferred embodiment, the liquid pharmaceutical composition of the present invention substantially does not contain ethanol.

[0022] More preferably, the liquid pharmaceutical composition substantially does not contain any additional excipients selected from co-solvents and surfactants. The liquid pharmaceutical composition more typically contains no co-solvent and no surfactant.

[0023] Examples of co-solvents include ethanol, pentane, water, isopropanol, glycerol and propylene glycol.

[0024] In a preferred embodiment, the liquid pharmaceutical composition is substantially free of any additional excipients. The additional excipients may be, for example, surfactants or cosolvents as described above, or excipients selected from antioxidants, preservatives, wetting agents, solubilizers, emulsifiers, flavoring agents, chelating agents, humectants, isotonic agents, pH adjusters, dispersants, and suspension aids.

[0025] The liquid pharmaceutical composition may contain less than 0.2% by weight of the surfactant or the additional excipient based on the total weight of the composition. For example, the liquid pharmaceutical composition may contain less than 0.1% by weight of the surfactant or the additional excipient based on the total weight of the composition. The liquid pharmaceutical composition may contain, for example, less than 0.05% by weight, less than 0.01% by weight, or less than 0.001% by weight of the surfactant or the additional excipient based on the total weight of the composition.

[0026] Typically, based on the total weight of all APIs, 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.

[0027] More typically, RPL554 is the sole active ingredient in a liquid pharmaceutical composition. In this embodiment, the liquid pharmaceutical composition of the present invention is substantially free of other activators (e.g., muscarinic receptor antagonists or beta-adrenergic receptor agonists).

[0028] As described above, liquid pharmaceutical compositions containing particles of HFA-134a and RPL554, and substantially free of any additional excipients, have been found to have many advantages. Therefore, typically, a liquid pharmaceutical composition consists substantially of (i)RPL554 and (ii)1,1,1,2-tetrafluoroethane. More typically, a liquid pharmaceutical composition contains at least 99.5% by weight of (i)RPL554 and (ii)1,1,1,2-tetrafluoroethane based on the total weight of the composition. A liquid pharmaceutical composition may consist, for example, of (i)RPL554 and (ii)1,1,1,2-tetrafluoroethane.

[0029] The liquid pharmaceutical composition of the present invention may, for example, contain (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), where the weight percentage is relative to the total weight of the liquid pharmaceutical. Typically, the total amounts of RPL554 and HFA-134a are at least 99% by weight relative to the total weight of the composition.

[0030] RPL554 particles may be of any size suitable for use in liquid pharmaceutical compositions suitable for inhalation. Typically, RPL554 particles are finely powdered. For example, RPL554 particles may have a Dv50 (median particle size by volume) value of 10 μm or less or from about 0.1 μm to about 8 μm.

[0031] Typically, particles have a particle size distribution with Dv50 values ​​ranging from approximately 0.2 μm to approximately 5 μm. More typically, RPL554 particles have a particle size distribution with Dv50 values ​​ranging from approximately 0.7 μm to approximately 3.0 μm. For example, RPL554 particles may have a particle size distribution with Dv50 values ​​ranging from 0.9 μm to 2.7 μm. Often, RPL554 particles have a particle size distribution with Dv50 values ​​ranging from approximately 1.1 μm to approximately 2.1 μm.

[0032] The Dv50 value is the median particle size in the volume distribution. That is, half of the particle volume is contained within particles with a diameter smaller than the Dv50 value, and half of the particle volume is contained within particles with a diameter larger than the Dv50 value. This is a well-known method for describing particle size distribution.

[0033] Particles typically have a particle size distribution with Dv10 values ​​ranging from approximately 0.4 μm to approximately 1.0 μm. Particles typically have a particle size distribution with Dv90 values ​​ranging from approximately 2.0 μm to approximately 4.0 μm. The Dv10 value reflects the particle diameter, with 10% of the sample volume consisting of particles with a diameter smaller than the Dv10 value. The Dv90 value reflects the particle diameter, with 90% of the sample volume consisting of particles with a diameter smaller than the Dv90 value.

[0034] The technique typically used to measure the Dv50 value is laser diffraction. For example, RPL554 particles typically have a particle size distribution with Dv50 values ​​ranging from approximately 0.2 μm to approximately 5 μm, as measured by laser diffraction. Particle size distribution analysis can be performed by laser diffraction using a Malvern Spraytec in combination with a wet dispersion cell. Typically, the instrument parameters for the Malvern Spraytec are as follows:

[0035] • Particles - standard opaque particles; • Refractive index particle -1.50; • Refractive index (imaginary number): -0.50; Particle density -1.00; • Refractive index of the dispersant: -1.33; • Controller unit - 1000 RPM; • Measurement type - time specified; Initial sampling time -30 seconds; Ambiguity -20%-30%; • Dispersant - 1% polysorbate 20 in deionized water

[0036] RPL554 particles may be produced by any pharmaceutically acceptable size reduction process or particle size-controlled manufacturing process. For example, particles may be produced by spray-drying a solution of RPL554, by controlled crystallization, or by size reduction of RPL554 in solid form, such as by air jet milling, mechanical pulverization, or media milling.

[0037] The concentration of RPL554-containing particles in the liquid pharmaceutical composition may be modified based on the intended dose of the active compound per inhaler operation. For example, the particle concentration may be such that the dose of RPL554 delivered per inhaler operation containing the liquid pharmaceutical composition ranges from 5 μg / operation to 1500 μg / operation. Alternatively, the particle concentration may be such that the dose of RPL554 delivered per inhaler operation ranges from 50 μg / operation to 1000 μg / operation.

[0038] The concentration of RPL554 particles in the liquid pharmaceutical composition may range from about 0.01 mg / mL to about 400 mg / mL. Typically, the concentration of RPL554 particles in the liquid pharmaceutical composition is about 0.1 mg / mL to about 200 mg / mL. More typically, the concentration of RPL554 particles in the liquid pharmaceutical composition is about 0.5 mg / mL to about 20 mg / mL.

[0039] For example, the concentration of RPL554 particles in the liquid pharmaceutical composition may be approximately 0.1 mg / mL to approximately 3.0 mg / mL or approximately 0.5 mg / mL to approximately 2.0 mg / mL. The concentration of RPL554 particles in the liquid pharmaceutical composition may be approximately 5.0 mg / mL to approximately 20 mg / mL or approximately 6.0 mg / mL to approximately 10 mg / mL.

[0040] The concentration of RPL554-containing particles in the liquid pharmaceutical composition may range from about 0.01% w / w to about 5.0% w / w. Typically, the concentration of RPL554-containing particles in the liquid pharmaceutical composition is about 0.05% w / w to about 2.0% w / w.

[0041] Liquid pharmaceutical compositions are typically suitable for administration by inhalation. More typically, liquid pharmaceutical compositions are suitable for administration by pressurized metered-dose inhalers. A pressurized metered-dose inhaler is an inhaler that delivers an aerosolized dose of a liquid pharmaceutical composition using a pressurized liquefied propellant. A pressurized metered-dose inhaler typically comprises a storage container (or vial) containing the liquid pharmaceutical composition, a metering valve, an actuator, and a mouthpiece.

[0042] The present invention provides a pressurized metered-dose inhaler containing a liquid pharmaceutical composition as defined herein. pMDIs are well known to those skilled in the art, and many such devices are commercially available, typical of which include AeroBid Inhaler System (Forest Pharmaceuticals), Atrovent Inhalation Aerosol (Boehringer Ingelheim), Flovent® (GlaxoSmithKline), Maxair Inhaler (3M), Proventil® Inhaler (Schering), and Serevent® Inhalation Aerosol (GlaxoSmithKline). (Includes line)

[0043] A pressurized metered-dose inhaler containing a liquid pharmaceutical composition may be configured to provide an aerosol of the liquid pharmaceutical composition having a median mass aerodynamic diameter (MMAD) of 1.0 μm to 5.0 μm when in operation. MMAD is defined by official requirements (European Pharmacopoeia (Ph.Eur.) Method Chapter 2.9.18 and the United States Pharmacopoeia). <601> Measurements may be taken using a Next Generation Impactor in accordance with the following chapter.

[0044] The present invention provides liquid pharmaceutical compositions as defined herein for use in the treatment of the human or animal body. Typically, the liquid pharmaceutical compositions are administered by inhalation.

[0045] Liquid pharmaceutical compositions are typically intended for use in the treatment or prevention of diseases or conditions selected from asthma, allergic asthma, hay fever, allergic rhinitis, bronchitis, emphysema, bronchiectasis, chronic obstructive pulmonary disease (COPD), adult dyspnea syndrome (ARDS), steroid-resistant asthma, severe asthma, childhood asthma, cystic fibrosis, pulmonary fibrosis, interstitial lung disease, skin disorders, atopic dermatitis, psoriasis, ocular inflammation, cerebral ischemia, inflammatory diseases, and autoimmune diseases. Preferably, the disease or condition is COPD or asthma. More preferably, the disease or condition is chronic obstructive pulmonary disease (COPD).

[0046] Typically, liquid pharmaceutical compositions are administered by inhalation from a pMDI containing the liquid pharmaceutical composition at a metered nominal dose of 5 μg to 1000 μg per action. For example, the metered nominal dose per action may be 10 μg to 500 μg. Typically, two actions of the pMDI may be inhaled consecutively to provide a single dose.

[0047] Typically, the dose released from a pMDI containing a liquid pharmaceutical composition is 80% to 95% of the measured nominal dose.

[0048] Typically, liquid pharmaceutical compositions are administered to patients via pMDI (progressive medium-dose injection) activating 2 to 8 times per day.

[0049] The present invention will be described in more detail by the following embodiments. [Examples]

[0050] material and method The materials used are as follows: • API: Micronized RPL554. The characteristics of micronized RPL554 are shown in Table 1 below.

[0051] [Table 1]

[0052] • Propellant: HFA-134a and HFA-227ea • Co-solvent: Ethyl alcohol / dehydrated alcohol (100% USP-NF ethanol) obtained from Hyman Kimia • Surfactant: Oleic acid (Ph.Eur. / BP) obtained from Croda International plc. • Reagents: Analytical-grade chemicals were used throughout the entire test. • Borosilicate glass vial with polypropylene closure lined with metal foil (VWR, part number 215-3905) • Glass vial: 15ml pressure-rated clear glass vial (Neville & Moore, part number 0771C3 / A3) • Valves: Bespak and Aptar 63μl valves • Can: Presspart 14ml can • Actuator: Presspart Actuator

[0053] 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.

[0054] All analytical methods were fully developed, and in vitro studies were performed using DUSA tubes and Next Generation Impaction (NGI).

[0055] The analytical test methods used during the analysis are as follows: • Official requirements (European Pharmacopoeia (Ph.Eur) - Preparation for inhalation (0671) and United States Pharmacopoeia) <601> Dose-delivered trials conducted in accordance with the chapter • Official requirements (European Pharmacopoeia (Ph.Eur.) Method Chapter 2.9.18 and the United States Pharmacopoeia) <601> Chapter) Next Generation Impactor Aerodynamic particle size distribution (APSD) tests performed using Impactor

[0056] Example 1 - Evaluation of suitable propellants The experiment was conducted to compare the suitability of two propellants, HFA-134a and HFA-227ea, for use as diluents in pMDI suspension formulations containing RPL554. Table 2 shows the main physical and chemical properties of the two propellants evaluated.

[0057] [Table 2]

[0058] Samples were prepared by adding the required amount of RPL554 (see Table 3) to a 15 ml pressure-rated clear glass vial. The propellant, HFA-134a, HFA-227ea, or a combination of the two (see Table 4) was added via valve, and the sample was mixed in an ultrasonic bath for 30 seconds. The same target filling weight of 11.6 g (±0.5 g) was used for all samples. The appearance of API particles in the propellant was evaluated with respect to both sedimentation velocity and aggregation behavior (see Figure 1). The sedimentation velocity of the formulation after suspension agitation was visually evaluated by recording images of the glass vial using a high-speed camera. The quality of the suspension was determined by assigning a sedimentation score from 1 to 10, where 1 is the fastest (i.e., undesirable) sedimentation / cream and 10 is the slowest (i.e., acceptable) sedimentation / cream, based on the amount of active particles that settled or floated in 30 seconds.

[0059] [Table 3]

[0060] [Table 4]

[0061] result The RPL554 formulation in HFA-134a readily suspended upon shaking, and rapid aggregation and slow sedimentation were observed after shaking ceased. The formulations in HFA-227ea and the HFA-134a / HFA-227ea blend (50 / 50) also readily suspended upon shaking. However, creaming was observed in both HFA-227ea-containing formulations after shaking ceased. The HFA-227ea formulation showed evidence of particle adhesion to the container wall, along with more distinct and larger flocs, after shaking.

[0062] Figure 2 graphs the sedimentation scores for each product strength using propellant (pure or mixed). This shows that formulations with higher HFA-134a content yielded the best scores (i.e., the slowest sedimentation). As the product strength increased due to the increased powder filling volume, the sedimentation score decreased. Table 5 shows the individual sedimentation scores.

[0063] [Table 5]

[0064] As can be seen from Table 5, formulations containing HFA-134a as a diluent were unexpectedly 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 lead to less aggregation, less creaming, and less adhesion compared to formulations containing a higher percentage of HFA-227ea.

[0065] Therefore, it was found that HFA-134a may be advantageously used as the sole diluent for liquid pharmaceutical compositions containing a suspension of RPL554 particles.

[0066] Example 2 - Evaluation of appropriate additional additives To pursue improvements in the suspension properties, the inclusion of additional excipients was investigated. In particular, formulations containing additional surfactants (oleic acid, Ph.Eur. / BP) and cosolvents (ethanol, 100% USP-NF) were prepared. The composition of the tested formulations and the observed precipitation scores are shown in Table 6.

[0067] [Table 6]

[0068] The suspension scores of formulations containing oleic acid and ethanol were generally observed to be equivalent to or lower than those of formulations without such excipients. However, in some samples, RPL554 appeared to dissolve and recrystallize. Solubility analysis was performed to evaluate the solubility of RPL554 in additional excipients.

[0069] Example 3 - Solubility of RPL554 in ethanol RPL554 was initially considered substantially insoluble in ethanol according to the USP / BP solubility criteria shown in Table 7. However, observations of dissolution and recrystallization at the lowest product strength (10 μg / acting) prompted further investigation into the solubility of RPL554 in ethanol in the presence of oleic acid.

[0070] [Table 7]

[0071] Experimental method Samples were prepared by adding 1.5 mg of RPL554 to a plain 14 mL aluminum storage container containing ethanol, oleic acid, and HFA-134a. Excipients were added to the storage container to maintain an ethanol / oleic acid ratio of 50:1 (see Table 8). Corresponding storage containers containing only RPL554, ethanol, and HFA-134a were also prepared. The storage containers were crimped with a 63 μL pMDI valve with a shortened dip tube (Figure 3) and filled with 11.6 g of HFA-134a via the valve. The length of the dip tube was sufficient to extend only into the liquid propellant / cosolvent phase (i.e., after the API particles had settled). The samples were placed in an ultrasonic bath for 30 seconds.

[0072] [Table 8]

[0073] All storage containers were left at ambient temperature for 24 hours to allow sedimentation and establish dissolution equilibrium. To measure the amount of dissolved API, a 10.0 cm cannula was taken from each storage container in an upright position (through a cannula attached to the valve stem). 3 The solution was sprayed five times into a volumetric flask. The flask was re-voluted with dehydrated ethanol, and the solution was analyzed using UV / Visible spectroscopy (Perkin Elmer, model lambda 35). The concentration of RPL554 was quantitatively calculated against a three-point calibration curve.

[0074] result The amount of dissolved RPL554 increased with increasing ethanol concentration. The presence of oleic acid in the formulation did not appear to affect the solubility of RPL554 (Figure 4).

[0075] Previous assessments of the solubility of RPL554 in ethanol led to a classification of "substantially insoluble" according to USP / BP standards. The original assessment was performed using analytical reagent grade ethanol. This time, the solubility was reassessed using dehydrated alcohol (100% USP-NF ethanol, i.e., the grade of ethanol commonly used in the manufacture of bulk pMDI HFA formulation suspensions), and it was found that the solubility of RPL554 in ethanol is approximately 1 part per 2000, which is "very slightly soluble" according to USP / BP standards. Thus, unexpectedly, RPL554 was found to have some solubility in ethanol.

[0076] For suspension formulations, the solubility of the API in the co-solvent / propellant mixture should be minimal to avoid potential problems related to chemical and physical instability. Any advantages associated with the use of oleic acid and ethanol as excipients were found to be significantly outweighed by the solubility of RPL554 and the vulnerability of RPL554 particles to Ostwald maturation. Therefore, the most promising pMDI formulation of RPL554 was established as a suspension formulation of RPL554 with HFA-134a alone.

[0077] Example 4 - Verification of a formulation containing only HFA-134a Further evaluation of formulations containing only HFA-134a confirmed that RPL554 was adequately suspended for delivery via pMDI by preparing samples in pressure-rated glass vials. Three product strengths (50, 150, and 500 μg / acting) were selected. Visual evaluation of these formulations showed comparable suspension quality and sedimentation rate to commercially available HFA-134a-only pMDI products.

[0078] The product performance attributes of the RPL554 HFA-134a-only suspension-based formulation were further evaluated by preparing laboratory samples in 14 mL plain aluminum storage containers of three strengths (50, 150, and 500 μg / acting) crimped with Aptar 63 μL valves. After mixing the samples in an ultrasonic bath for 30 seconds, they were stored and inverted for 4 days, and then analyzed for delivery dose uniformity (DDU) and aerodynamic particle size distribution (APSD) by next-generation impaction (NGI).

[0079] Dose uniformity (DDU) of delivered dose Dose uniformity analysis of delivered doses was performed three times with three samples of each product strength: at the beginning, middle, and end of the storage container's lifespan. The results for the average delivered dose are shown in Table 9.

[0080] Overall, the average dose delivered was close to the expected target label indication for each product strength.

[0081] Shot weight Shot weights were measured at the beginning, middle, and end of the storage container's lifespan to evaluate product performance throughout its lifecycle.

[0082] The shot weight of laboratory-prepared samples was found to be consistent across all samples, with an average value 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.

[0083] Aerodynamic particle size distribution (APSD) To determine the particulate fraction (percentage dose for particles smaller than 5 μm) of the tested formulation, the aerodynamic particle size distribution was measured. The results are shown in Table 9.

[0084] [Table 9]

[0085] Figure 5 shows the correlation between the determined particulate matter dose (FPD) and product strength. A dose-proportional relationship was observed.

[0086] Example 5 - Stability of the formulation Stability testing was performed at all RPL554 formulation strengths. Tables 10 and 11 show the example data for RPL554 HFA-134a pMDI, 500 μg / acting product, for stability tests conducted at 25°C / 60°C and 40°C / 75%RH, respectively. The data demonstrate consistent performance over a 6-month stability period.

[0087] [Table 10]

[0088] [Table 11]

Claims

1. A liquid pharmaceutical composition for use in the treatment or prevention of asthma, suitable for administration by inhalation. (i) A suspension of particles containing 9,10-dimethoxy-2-(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinoline-4-one (RPL554); and (ii) Diluent: 1,1,1,2-tetrafluoroethane (HFA-134a) The liquid pharmaceutical composition comprising the above.

2. The liquid pharmaceutical composition for use according to claim 1, wherein the particles containing RPL554 have a particle size distribution with a Dv50 (median particle size by volume) value of 0.2 μm to 5 μm.

3. The liquid pharmaceutical composition for use according to claim 1, wherein the concentration of particles containing RPL554 in the liquid pharmaceutical composition is from 0.1 mg / mL to 200 mg / mL.

4. A liquid pharmaceutical composition for use according to claim 1, suitable for administration by a pressurized metered-dose inhaler.

5. A liquid pharmaceutical composition for use according to claim 1, wherein the liquid pharmaceutical composition is contained in a pressurized metered-dose inhaler.

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