Pharmaceutical composition containing salbutamol

Description

technical field

[0001] The present invention relates to a pharmaceutical composition which is capable of being used in the treatment of respiratory disorders and which comprises an active ingredient based on salbutamol, in particular salbutamol sulfate, and a propellant gas formed by 1,1-difluoroethane.

[0002] The invention also relates to a cartridge comprising this pharmaceutical composition and to a metered-dose aerosol equipped with such a cartridge.

[0003] The invention also relates to the uses of this pharmaceutical composition and this cartridge in a metered-dose aerosol. Prior art

[0004] Salbutamol and its derivatives are active ingredients known as bronchodilators in the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD).

[0005] Pharmaceutical compositions containing salbutamol or one of its derivatives are classically delivered to patients using a metered dose inhaler (MDI).

[0006] A metered-dose inhaler is a delivery device equipped with a cartridge containing the pharmaceutical composition, a metering valve allowing the distribution of a controlled quantity of pharmaceutical composition containing the active ingredient, and an applicator allowing pressure to be applied to the metering valve and equipped with a mouthpiece.

[0007] The pharmaceutical composition includes a propellant gas in which the active ingredient is dissolved, suspended or dispersed, and possibly one or more other compounds which may be selected from surfactants, polar excipients and preservatives.

[0008] The choice of propellant gas used in pharmaceutical metered-dose inhalers has evolved over the years.

[0009] Given their detrimental effects on the ozone layer, chlorofluorocarbons (CFCs), which were used for a long time, have been abandoned in favor of hydrofluoroalkanes (HFAs) such as 1,1,1,2-tetrafluoroethane (HFA-134a or R-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea or R-227ea) which are compounds that do not have a detrimental effect on the ozone layer or human toxicity.

[0010] However, because these hydrofluoroalkanes R-134a and R-227ea are characterized by a high global warming potential (GWP) with a significant impact on the greenhouse effect, pharmaceutical compositions including salbutamol, or one of its derivatives, and an alternative propellant have been proposed. EP 2749275 describes a metered-dose inhaler containing salbutamol sulfate, HFA-134a, PEG 6000, and ethanol.

[0011] Thus, documents WO 2013 / 054137 A1, WO 2014 / 170689 A1 and WO 2013 / 054135 A1, respectively referenced [1] to [3] in the remainder of this description, describe the implementation of a particular hydrofluorocarbon (HFC) as an alternative propellant gas, 1,1-difluoroethane (HFC-152a or R-152a) in pharmaceutical compositions comprising salbutamol sulfate.

[0012] More specifically, the pharmaceutical compositions described in documents [1] and [2] include salbutamol sulfate, R-152a and one or more surfactants whose role is to help disperse the active ingredient particles in the propellant gas.

[0013] In document [1], at least one of the surfactants is oleic acid.

[0014] Advantageously, the pharmaceutical compositions in document [1] comprise only salbutamol sulfate, R-152a, and oleic acid, without ethanol. This document [1] specifies that the choice of R-152a as the propellant and oleic acid as the surfactant allows for pharmaceutical compositions that, even without ethanol, exhibit good therapeutic performance when delivered from a drug delivery device such as a metered-dose inhaler.

[0015] On the contrary, in document [2], at least one of the surfactants is not oleic acid. This surfactant can notably be chosen from among ethyl oleate, polyvinylpyrrolidone (PVP), sorbitan monooleate, sorbitan trioleate, isopropyl myristate, polyethylene glycols such as polyethylene glycol 300, polyoxyethylene 20 sorbitan monooleate or monolaurate, propoxylated polyethylene glycol and lecithin, it being specified that the preferred surfactant is PVP.

[0016] Advantageously, the pharmaceutical compositions described in document [2] comprise salbutamol sulfate, R-152a, and one or more surfactants, but are free of oleic acid. Preferably, these pharmaceutical compositions are also free of ethanol while maintaining good therapeutic performance when delivered via a metered-dose inhaler (MDI).

[0017] Unlike the pharmaceutical compositions described in documents [1] and [2], the pharmaceutical compositions described in document [3] do not contain any surfactants on the grounds that surfactants would be undesirable and that there would be an advantage in forming a stable suspension without using them. Document [3] specifies that the use of the propellant R-152a makes it possible to prepare pharmaceutical compositions that are not only free of surfactants but also free of polar excipients and that exhibit good therapeutic performance when delivered from a metered-dose inhaler (MDI) device.

[0018] However, experience shows that the aerosolization performance of pharmaceutical compositions described in these documents [1] to [3], and more particularly in documents [1] and [3], is not satisfactory.

[0019] In particular, it is observed that pharmaceutical compositions made up of salbutamol sulfate, R-152a and oleic acid in accordance with the teaching of document [1] are characterized by aerosolization performances which are much lower than those of pharmaceutical compositions in accordance with the teaching of document [3] which are nevertheless free of surfactants, while the role of these surfactants is to help disperse the particles of active ingredient (salbutamol sulfate) and to stabilize it in the propellant gas (R-152a).

[0020] Moreover, the aerosolization performance of these pharmaceutical compositions described in documents [1] to [3] decreases over time, which is detrimental to their therapeutic efficacy.

[0021] It is therefore on the basis of these observations and in a constant concern for improving the aerosolization properties and, consequently, the therapeutic properties conferred by pharmaceutical compositions intended for the treatment of respiratory disorders that the present invention is based. Description of the invention

[0022] These goals and others are achieved, firstly, by a pharmaceutical composition of the aforementioned type, that is to say, which includes an active ingredient based on salbutamol (a) and 1,1-difluoroethane (b).

[0023] According to the invention, the pharmaceutical composition consists of the following compounds: (a) an active ingredient based on salbutamol, (b) 1,1-difluoroethane (R-152a), (c) polyethylene glycol, and (d) ethanol.

[0024] The Inventors have found that, unexpectedly and surprisingly, a pharmaceutical composition consisting of an active ingredient based on salbutamol (a), 1,1-difluoroethane (b), polyethylene glycol (c) and ethanol (d) achieves aerosolization performance far superior to the pharmaceutical compositions in documents [1] to [3], which are all based on salbutamol and 1,1-difluoroethane but preferably free of ethanol, whether these pharmaceutical compositions include a surfactant such as oleic acid as in document [1] or are free of it as in document [3].

[0025] As illustrated in the examples below, the pharmaceutical composition according to the invention is further characterized by high aerosolization performance which is stable over time and, consequently, by effective therapeutic efficacy which is sustained over time.

[0026] The pharmaceutical composition according to the invention comprises an active ingredient (a) based on salbutamol.

[0027] In an advantageous embodiment of the pharmaceutical composition according to the invention, this active ingredient (a) is a pharmaceutically acceptable salbutamol salt.

[0028] In a preferred embodiment of the invention, this active ingredient (a) is salbutamol sulfate.

[0029] The active ingredient (a) is advantageously in the form of particles of a size suitable for delivery by inhalation of the pharmaceutical composition in which it is contained. Typically, the median diameter of the active ingredient particles (a) is less than or equal to 5 µm and, preferably, between 0.5 µm and 4 µm.

[0030] In a variant of the composition according to the invention, the mass proportion of the active ingredient (a) is between 0.05% and 0.5% by mass relative to the total mass of the pharmaceutical composition. This mass proportion is advantageously between 0.1% and 0.4% by mass and, preferably, between 0.2% and 0.35% by mass relative to the total mass of the pharmaceutical composition.

[0031] The pharmaceutical composition according to the invention also includes 1,1-difluoroethane (b) as a propellant gas.

[0032] In one variant of the composition according to the invention, the mass proportion of 1,1-difluoroethane (b) is between 87.5% and 99.89% by mass relative to the total mass of the pharmaceutical composition.

[0033] In another variant, the mass proportion of 1,1-difluoroethane (b) is between 92.5% and 99.89% by mass relative to the total mass of the pharmaceutical composition. This mass proportion is advantageously between 95.6% and 99.68% by mass and, preferably, between 97.15% and 99.26% by mass relative to the total mass of the pharmaceutical composition.

[0034] The pharmaceutical composition according to the invention further comprises polyethylene glycol (c) as a surfactant.

[0035] Polyethylene glycol (c) or PEG is a linear polyether synthesized from ethylene oxide monomers and corresponding to the formula H-(CH2-CH2-O)n-OH, n being an integer such that n ≥ 4.

[0036] In a variant of the composition according to the invention, polyethylene glycol (c) has a mass average molar mass Mw less than or equal to 20,000 g / mol. This mass average molar mass Mw of PEG is advantageously between 100 g / mol and 5,000 g / mol and, preferably, between 200 g / mol and 2,000 g / mol.

[0037] In particular, PEGs having a mass average molar mass Mw of 400 g / mol, 600 g / mol and 1000 g / mol, respectively designated by the acronyms PEG 400, PEG 600 and PEG 1000, are particularly suitable for the pharmaceutical composition according to the invention,

[0038] In a variant of the composition according to the invention, the mass proportion of polyethylene glycol (c) is between 0.01% and 2% by mass relative to the total mass of the pharmaceutical composition. This total mass proportion is advantageously between 0.02% and 1% by mass and, preferably, between 0.04% and 0.5% by mass relative to the total mass of the pharmaceutical composition.

[0039] The pharmaceutical composition according to the invention finally comprises ethanol (d) as a polar excipient.

[0040] In one variant of the composition according to the invention, the mass proportion of ethanol (d) is between 0.05% and 10% by mass relative to the total mass of the pharmaceutical composition.

[0041] In another variant, the mass proportion of ethanol (d) is between 0.05% and 5% by mass relative to the total mass of the pharmaceutical composition.

[0042] The aerosolization performance of the pharmaceutical composition according to the invention can be achieved with a relatively low mass proportion of ethanol, which presents no danger to the health of the patient, even a young one.

[0043] The mass proportion of ethanol (d) may advantageously be between 0.2% and 3% by mass and preferably between 0.5% and 2% by mass relative to the total mass of the pharmaceutical composition.

[0044] The present invention relates, secondly, to a pharmaceutical composition for use in the treatment of patients suffering from or likely to suffer from respiratory disorders,

[0045] According to the invention, this pharmaceutical composition, which is used in the treatment of respiratory disorders, is as defined above, that is to say, it consists of the following compounds: (a) an active ingredient based on salbutamol, (b) 1,1-difluoroethane (R-152a), (c) polyethylene glycol, and (d) ethanol.

[0046] The characteristics described above in connection with the pharmaceutical composition and, in particular, the characteristics relating to the different compounds (a), (b), (c) and (d) constituting this pharmaceutical composition and their respective mass proportions, are of course applicable to the present use in the treatment of respiratory disorders.

[0047] Such respiratory disorders can include asthma or chronic obstructive pulmonary disease (COPD).

[0048] Within the framework of the present invention, patients can be treated by administering a therapeutically effective amount of a pharmaceutical composition as defined above.

[0049] Thirdly, the present invention relates to a cartridge comprising a pharmaceutical composition and to a metered-dose aerosol equipped with such a cartridge.

[0050] According to the invention, this pharmaceutical composition is as defined above, that is to say, it consists of the following compounds: (a) an active ingredient based on salbutamol, (b) 1,1-difluoroethane (R-152a), (c) polyethylene glycol, and (d) ethanol.

[0051] As before, the characteristics relating to each of these compounds (a) to (d) can be taken alone or in combination.

[0052] The present invention relates, fourthly, to the use of a pharmaceutical composition and / or a cartridge as defined above in a metered-dose inhaler (MDI), such a device being classically used to deliver pharmaceutical compositions comprising an active ingredient based on salbutamol or a pharmaceutically acceptable salt thereof.

[0053] Other features and advantages of the invention will become clearer upon reading the following supplementary description, which relates to examples of pharmaceutical compositions and an evaluation of their aerosolization performance. in vitro, two of the pharmaceutical compositions being pharmaceutical compositions in accordance with the invention, denoted C and C', the other three being comparative pharmaceutical compositions in accordance with the teachings of documents [1] and [3], denoted C [1], C [1]' and C [3], Brief description of the drawings

[0054] There figure 1 represents the graphs illustrating the deposited fraction of salbutamol particles (expressed in %) from five doses of pharmaceutical compositions C, C', C[1], C[1]' and C[3] as obtained at T0, as a function of the stages of the NGI pharmaceutical impactor, pharmaceutical compositions C and C' being in accordance with the invention and the other three being comparative pharmaceutical compositions, compositions C[1] and C[1]' being in accordance with the teaching of document [1] and composition C[3] being in accordance with the teaching of document [3]. The figure 2 represents the graphs illustrating the deposited fraction of salbutamol particles (expressed in %) from five doses of the pharmaceutical compositions C, C', C[1], C[1]' and C[3] as obtained at T3M, as a function of the stages of the NGI pharmaceutical impactor. figure 3represents the graphs illustrating the deposited fraction of salbutamol particles (expressed in %) from five doses of the pharmaceutical composition C according to the invention at T0 and T3M, as a function of the stages of the NGI pharmaceutical impactor. figure 4 represents the graphs illustrating the deposited fraction of salbutamol particles (expressed in %) from five doses of the pharmaceutical composition C' according to the invention at T0 and T3M, as a function of the stages of the pharmaceutical impactor NGI. Detailed description of specific implementation methods

[0055] Five pharmaceutical compositions C, C', C[1], C[1]' and C[3] were prepared from the following compounds: salbutamol sulfate as the active ingredient (a), R-152a as the propellant gas (b), polyethylene glycol (c) having a molecular mass of 400 g / mol (PEG 400) or oleic acid as the surfactant, and / or ethanol (d) as the polar excipient.

[0056] The metered-dose inhalers that were tested were prepared with the same batches of compounds, aluminum cartridges and metering valves, according to an identical operating protocol.

[0057] In the first step, a metering valve was crimped onto each of the cartridges using appropriate equipment,

[0058] In a second step, five separate sets of metered-dose inhalers were filled in two stages by introducing via the metering valve: - a concentrated suspension comprising 30.125 mg of salbutamol sulfate, a reduced quantity of R-152a propellant gas and, where appropriate, the mass proportion(s) of surfactant (PEG 400 or oleic acid) and ethanol as indicated in Table 1 below, relative to the total mass of pharmaceutical composition, then - a sufficient quantity of R-152a propellant gas to reach a total mass of pharmaceutical composition of 9.57 g. Table 1 Composition C C' C [1] C [1] ' C [3] PEG 400 (% by mass) 0,05 0,1 0 0 0 Oleic acid (% by mass) 0 0 0,03 0,05 0 Ethanol (% by mass) 1,00 1,00 0 0 0

[0059] Two series of aerodynamic particle size distribution (APSD) measurement tests were carried out.

[0060] These two series of tests, which consist of evaluating the aerodynamic size of the active ingredient particles exiting the valve, were performed using a multi-stage pharmaceutical impactor that allows for approximate modeling of the bronchial tree. In this case, the pharmaceutical impactor used was the Next Generation Impactor (NGI), which corresponds to device E of the European Pharmacopoeia.

[0061] More specifically, these two series of tests were carried out at a flow rate of 30 L / min, expelling 5 doses of each of the pharmaceutical compositions into the NGI impactor.

[0062] A first series of aerodynamic particle size distribution measurements was conducted on the pharmaceutical compositions C, C', C[1], C[1]' and C[3] as obtained at T0, i.e., at the end of the two-stage filling step described above. The results of this first series of tests are reported on the figure 1 .

[0063] A second series of aerodynamic particle size distribution measurements was conducted on the same pharmaceutical compositions C, C', C[1], C[1]', and C[3] as obtained at T3M, i.e., after three months of storage of metered-dose inhalers containing said compositions C, C', C[1], C[1]', and C[3], these inhalers being stored in an inverted position (valve downwards) during these three months. The results of this second series of tests are reported on the figure 2 .

[0064] In addition, the results of the first and second series of tests conducted on the pharmaceutical compositions C and C' conforming to the invention are reported on the figure 3 for composition C and on the figure 4 for composition C'.

[0065] The graphs of figures 1 to 4represent the fractions of salbutamol (a) deposited, on the one hand, at the level of the throat and mouth (noted T&M) and, on the other hand, on each of the eight stages of the impactor (noted S1 to S8).

[0066] To ensure optimal therapeutic efficacy, the fraction deposited at the throat and mouth T&M level must be minimized while the fractions deposited on the S3 to S5 levels must on the contrary be maximized.

[0067] There figure 1 shows that the pharmaceutical compositions C and C' according to the invention effectively optimize this therapeutic efficacy.

[0068] On the one hand, we observe that the fraction of salbutamol deposited from compositions C and C' at the T&M level is around 25%. This fraction is significantly lower than the fractions of salbutamol deposited at the same T&M level from the comparative pharmaceutical compositions C [1], C [1]' and C [3], fractions which are respectively around 68%, 60% and 46%.

[0069] On the other hand, it is observed that the sum of the salbutamol fractions deposited on stages S3 to S5 from pharmaceutical compositions C and C' according to the invention is significantly greater than the sum of the salbutamol fractions deposited on these same stages S3 to S5 from the comparative pharmaceutical compositions C [1], C [1]' and C [3]. This observation is even more pronounced with the comparative compositions C [1] and C [1]', which nevertheless employ a surfactant, in this case oleic acid, whose role is to aid in the dispersion of the active ingredient particles and to stabilize them in the propellant gas.

[0070] Furthermore, it is observed that pharmaceutical compositions C and C', which contain respectively a mass proportion of 0.05% and 0.1% of PEG 400, are characterized by performances in terms of therapeutic efficacy that are quite comparable, insofar as their respective graphs on the figure 1overlap at the T&M level and on the eight stages S1 to S8 of the impactor. Thus, even a small amount of PEG in the pharmaceutical composition according to the invention allows for excellent therapeutic efficacy.

[0071] There figure 2 shows that the pharmaceutical compositions C and C' according to the invention retain this optimized therapeutic efficacy after three months of storage. On the contrary, it is observed that this therapeutic efficacy is strongly degraded for all the comparative pharmaceutical compositions C [1], C [1]' and C [3].

[0072] THE figures 3 and 4 confirm that the pharmaceutical compositions C and C' according to the invention do indeed retain this same excellent therapeutic efficacy after three months of storage. Indeed, the graphs of these figures 3 and 4are practically superimposable, reflecting the fact that the fraction of salbutamol deposited from compositions C and C' at level T&M is similar or identical to T0 and T3M, just as is the sum of the fractions of salbutamol deposited on levels S3 to S5 from these same pharmaceutical compositions C and C' at T0 and T3M, Bibliography

[0073] [1] WO 2013 / 054137 A1 [2] WO 2014 / 170689 A1 [3] WO 2013 / 054135 A1

Claims

1. Pharmaceutical composition consisting of the following compounds: (a) an active ingredient based on salbutamol, (b) 1,1-difluoroethane (R-152a), (c) a polyethylene glycol, and (d) ethanol.

2. Pharmaceutical composition according to claim 1, wherein the active ingredient (a) is a pharmaceutically acceptable salt of salbutamol.

3. Pharmaceutical composition according to claim 2, wherein the active ingredient (a) is salbutamol sulphate.

4. Pharmaceutical composition according to any one of claims 1 to 3, wherein the polyethylene glycol (c) has a mass average molar mass Mw less than or equal to 20000g / mol, advantageously between 100g / mol and 5000g / mol and, preferably, between 200g / mol and 2000g / mol.

5. Pharmaceutical composition according to any one of claims 1 to 4, wherein the mass proportion of active ingredient (a) is between 0.05% and 0.5% by mass, advantageously between 0.1% and 0.4% by mass and, preferably, between 0.2% and 0.35% by mass relative to the total mass of the pharmaceutical composition.

6. Pharmaceutical composition according to any one of claims 1 to 5, wherein the mass proportion of 1,1-difluoroethane (b) is between 87.5% and 99.89% by mass, in particular between 92.5% and 99.89% by mass, advantageously between 95.6% and 99.68% by mass and, preferably, between 97.15% and 99.26% by mass relative to the total mass of the pharmaceutical composition.

7. Pharmaceutical composition according to any one of claims 1 to 6, wherein the mass proportion of polyethylene glycol (c) is between 0.01% and 2% by mass, advantageously between 0.02% and 1% by mass and, preferably, between 0.04% and 0.5% by mass relative to the total mass of the pharmaceutical composition.

8. Pharmaceutical composition according to any one of claims 1 to 7, wherein the mass proportion of ethanol (d) is between 0.05% and 10% by mass, in particular between 0.05% and 5% by mass, advantageously between 0.2% and 3% by mass and, preferably, between 0.5% and 2% by mass relative to the total mass of the pharmaceutical composition.

9. Pharmaceutical composition according to any one of claims 1 to 8 for use in the treatment of respiratory disorders, such as asthma and chronic obstructive pulmonary diseases (COPD).

10. Canister comprising a pharmaceutical composition according to any one of claims 1 to 8.

11. Metered-dose inhaler provided with a canister according to claim 10.

12. Use of the pharmaceutical composition according to any one of claims 1 to 8 or of the canister according to claim 10 in a metered-dose inhaler.