Pharmaceutical composition containing salbutamol

Abstract

The present invention relates to a pharmaceutical composition comprising an active ingredient (a) based on salbutamol, 1,1-difluoroethane (b), polyethylene glycol (c), and ethanol (d). The present invention also relates to the use of such a pharmaceutical composition in the treatment of respiratory diseases, a canister containing the same, and a metered-dose inhaler equipped with such a canister. Finally, the present invention relates to the use of this pharmaceutical composition and this canister in a metered-dose inhaler.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition that can be used for the treatment of respiratory diseases and contains an active ingredient based on salbutamol, particularly salbutamol sulfate, and a propellant gas formed by 1,1-difluoroethane.

[0002] The present invention also relates to a canister containing this pharmaceutical composition and a metered-dose inhaler equipped with such a canister.

[0003] Finally, the present invention relates to the use of this pharmaceutical composition and this canister in a metered-dose inhaler.

Background Art

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

[0005] A pharmaceutical composition containing salbutamol or one of its derivatives is usually administered to patients using a metered-dose inhaler (MDI).

[0006] A metered-dose inhaler is an administration device provided with a mouthpiece, comprising a canister containing a pharmaceutical composition, a metering valve capable of dispensing a controlled amount of the pharmaceutical composition containing the active ingredient, and an applicator enabling the application of pressure to the metering valve.

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

[0008] The selection of the propellant gas used in pharmaceutical metered-dose inhalers has been changing year by year.

[0009] In consideration of the harmful effects on the ozone layer, chlorofluorocarbons (CFCs) that have been used for many years have been abandoned, and 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 without adverse effects on the ozone layer and human toxicity, have been selected.

[0010] However, these hydrofluoroalkanes R-134a and R-227ea have a high global warming potential (GWP) and have the characteristic of having a non-negligible impact on the greenhouse effect. Therefore, pharmaceutical compositions containing salbutamol or one of its derivatives and an alternative propellant gas have been proposed.

[0011] For example, Patent Documents 1 to 3, respectively represented as [1] to [3] in the following part of this specification, describe the use of specific hydrofluorocarbons (HFCs), 1,1-difluoroethane (HFC-152a or R-152a), as alternative propellant gases in pharmaceutical compositions containing salbutamol sulfate.

[0012] More specifically, the pharmaceutical compositions described in Documents [1] and [2] contain salbutamol sulfate, R-152a, and one or more surfactants, and the role of these surfactants is to facilitate the dispersion of the particles of the active ingredient in the propellant gas.

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

[0014] Advantageously, the pharmaceutical composition of Document [1] contains only salbutamol sulfate, R-152a, and oleic acid in the absence of ethanol. This Document [1] describes that by selecting R-152a as the propellant gas and oleic acid as the surfactant, a pharmaceutical composition with good therapeutic performance can be obtained when delivered using a drug delivery device such as a metered-dose inhaler even in the absence of ethanol.

[0015] In contrast, in Document [2], at least one of the surfactants is not oleic acid. This surfactant can be selected particularly from ethyl oleate, polyvinylpyrrolidone (PVP), sorbitan monooleate, sorbitan trioleate, isopropyl myristate, polyethylene glycol such as polyethylene glycol 300, polyoxyethylene (20) sorbitan monooleate or monolaurate, propoxylated polyethylene glycol, and lecithin, and it is described that the preferred surfactant is PVP.

[0016] Advantageously, the pharmaceutical composition described in Document [2] contains salbutamol sulfate, R-152a, and one or more surfactants, but does not contain oleic acid. Preferably, these pharmaceutical compositions also do not contain ethanol, but retain good therapeutic performance when delivered using a metered-dose inhaler (MDI) type device.

[0017] Different from the pharmaceutical compositions described in Documents [1] and [2], the pharmaceutical compositions described in Document [3] do not contain a surfactant because the surfactant is not desirable and there is an interest in forming a stable suspension without using those means. Document [3] describes that by using the propellant gas R-152a, it is possible to prepare a pharmaceutical composition that contains neither a surfactant nor a polar excipient and has good therapeutic performance when delivered using a metered-dose inhaler (MDI) type device.

[0018] However, from experience, it is clear that the aerosolization performance of the pharmaceutical compositions described in these Documents [1] to [3], more specifically Documents [1] and [3], is not sufficient.

[0019] In particular, it has been observed that the pharmaceutical composition consisting of salbutamol sulfate, R-152a, and oleic acid according to the teaching of Document [1] is characterized by much lower aerosolization performance than the pharmaceutical composition according to the teaching of Document [3]. However, the pharmaceutical composition according to the teaching of Document [3] does not contain a surfactant, although the surfactant has a role of promoting the dispersion and stabilizing the particles of the active ingredient (salbutamol sulfate) in the propellant gas (R-152a).

[0020] Furthermore, the aerosolization performance of these pharmaceutical compositions described in Documents [1] to [3] decreases over time, which has an adverse effect on the therapeutic effectiveness.

Prior Art Documents

Patent Documents

[0021]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0022] Therefore, based on these observations, an object of the present invention is to continuously improve the aerosolization characteristics and, as a result, the therapeutic characteristics brought about by a pharmaceutical composition for treating respiratory diseases.

Means for Solving the Problems

[0023] These objects and the like are first achieved by a pharmaceutical composition of the aforementioned type, that is, a pharmaceutical composition containing an active ingredient (a) based on salbutamol and 1,1-difluoroethane (b).

[0024] According to the present 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.

[0025] The inventors have found that, unexpectedly and surprisingly, a pharmaceutical composition comprising an active ingredient based on salbutamol (a), 1,1-difluoroethane (b), polyethylene glycol (c), and ethanol (d) exhibits much better aerosolization performance than the pharmaceutical compositions of Documents [1] to [3], all of which contain salbutamol and 1,1-difluoroethane and preferably do not contain ethanol, regardless of whether they contain a surfactant such as oleic acid as in Document [1] or not as in Document [3].

Advantages of the Invention

[0026] As shown in the following examples, the pharmaceutical composition according to the present invention is further characterized by having good aerosolization performance that is stable over time and, as a result, having a good therapeutic effect that acts well and persists for a long time.

[0027] The pharmaceutical composition according to the present invention contains an active ingredient (a) based on salbutamol.

[0028] In an advantageous variant of the pharmaceutical composition according to the present invention, this active ingredient (a) is a pharmaceutically acceptable salt of salbutamol.

[0029] In a preferred variant of the present invention, this active ingredient (a) is salbutamol sulfate.

[0030] The active ingredient (a) is preferably in particulate form, and its size is suitable for delivery by inhalation of the pharmaceutical composition containing it. Usually, the median diameter of the particles of the active ingredient (a) is 5 μm or less, preferably 0.5 to 4 μm.

[0031] In a modified example of the composition according to the present invention, the mass ratio of the active ingredient (a) is 0.05 to 0.5% by mass based on the total mass of the pharmaceutical composition. This mass ratio is preferably 0.1 to 0.4% by mass, more preferably 0.2 to 0.35% by mass, based on the total mass of the pharmaceutical composition.

[0032] The pharmaceutical composition according to the present invention also contains 1,1-difluoroethane (b) as a propellant gas.

[0033] In a modified example of the composition according to the present invention, the mass ratio of 1,1-difluoroethane (b) is 87.5 to 99.89% by mass based on the total mass of the pharmaceutical composition.

[0034] In another modified example, the mass ratio of 1,1-difluoroethane (b) is 92.5 to 99.89% by mass based on the total mass of the pharmaceutical composition. This mass ratio is preferably 95.6 to 99.68% by mass, more preferably 97.15 to 99.26% by mass, based on the total mass of the pharmaceutical composition.

[0035] The pharmaceutical composition according to the present invention also contains polyethylene glycol (c) as a surfactant.

[0036] Polyethylene glycol (c) or PEG is a linear polyether synthesized from ethylene oxide monomers and having the formula H-(CH2-CH2-O) n -OH, where n is an integer such that n≧4.

[0037] In a modified example of the composition according to the present invention, the mass average molar mass M w of polyethylene glycol (c) is 20,000 g / mol or less. This mass average molar mass M w of PEG is preferably 100 to 5,000 g / mol, more preferably 200 to 2,000 g / mol.

[0038] In particular, the mass average molar mass M whaving molecular weights of 400 g / mol, 600 g / mol, and 1000 g / mol, and denoted as PEG400, PEG600, and PEG1000 respectively by taking the initials of their molecular weights, are particularly suitable for the pharmaceutical composition according to the present invention.

[0039] In a modified example of the composition according to the present invention, the mass ratio of polyethylene glycol (c) is 0.01 to 2% by mass based on the total mass of the pharmaceutical composition. This total mass ratio is preferably 0.02 to 1% by mass, more preferably 0.04 to 0.5% by mass based on the total mass of the pharmaceutical composition.

[0040] Finally, the pharmaceutical composition according to the present invention contains ethanol (d) as a polar excipient.

[0041] In a modified example of the composition according to the present invention, the mass ratio of ethanol (d) is 0.05 to 10% by mass based on the total mass of the pharmaceutical composition.

[0042] In another modified example, the mass ratio of ethanol (d) is 0.05 to 5% by mass based on the total mass of the pharmaceutical composition.

[0043] The aerosolization performance of the pharmaceutical composition according to the present invention can be achieved with a relatively low mass ratio of ethanol that does not pose a risk to the health of patients, even in young individuals.

[0044] The mass ratio of ethanol (d) can preferably be 0.2 to 3% by mass, more preferably 0.5 to 2% by mass based on the total mass of the pharmaceutical composition.

[0045] Second, the present invention relates to a pharmaceutical composition for use in the treatment of patients suffering from, or prone to suffering from, respiratory disorders.

[0046] According to the present invention, this pharmaceutical composition for use in the treatment of respiratory diseases is as defined above, i.e., 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.

[0047] The features described above in connection with the pharmaceutical composition, in particular, the various compounds (a), (b), (c), and (d) forming this pharmaceutical composition, and the features relating to their respective mass ratios, are of course applicable to this use in the treatment of respiratory diseases.

[0048] Such respiratory diseases can be asthma or chronic obstructive pulmonary disease (COPD).

[0049] In the context of the present invention, a patient can be treated by administering an effective amount, from a therapeutic point of view, of the pharmaceutical composition defined above.

[0050] Thirdly, the present invention relates to a canister containing the pharmaceutical composition and a metered-dose inhaler provided with such a canister.

[0051] According to the present invention, this pharmaceutical composition is as defined above, i.e., 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.

[0052] Similar to the above, the features regarding each of these compounds (a)-(d) can be used alone or in combination.

[0053] Fourthly, the present invention relates to the use of the pharmaceutical composition and / or canister defined above in a metered-dose inhaler (MDI), such a device being commonly used to deliver a pharmaceutical composition containing an active ingredient based on salbutamol or a pharmaceutically acceptable salt thereof.

[0054] Other features and advantages of the present invention will become apparent upon reading the following additional description regarding examples of pharmaceutical compositions and evaluation of their in vitro aerosolization performance. Two of the pharmaceutical compositions are those according to the present invention, denoted as C and C', and the other three are comparative pharmaceutical compositions according to the teachings of references [1] and [3], denoted as C [1] , C [1] ', and C [3] .

Brief Description of the Drawings

[0055]

Figure 1

Figure 2

Figure 3

Figure 4

Modes for Carrying Out the Invention

[0056] Five pharmaceutical compositions C, C', C [1] , C [1] ', and C [3] were prepared from the following compounds. - Salbutamol sulfate (a) as an active ingredient, - R-152a (b) as a propellant gas, - Polyethylene glycol (c) with a molecular weight of 400 g / mol (PEG400) or oleic acid as a surfactant, and / or - Ethanol (d) as a polar excipient.

[0057] The metered-dose inhalers tested were manufactured using the same batch of compound, aluminum canisters, and metering valves according to the same working procedure.

[0058] In the first step, the metering valves were crimped onto each canister using a suitable instrument.

[0059] In the second step, five different series of metered-dose inhalers were filled in two steps by introducing through the metering valves: - A concentrated suspension containing 30.125 mg of salbutamol sulfate, a small amount of R-152a propellant gas, and, if necessary, a surfactant (PEG400 or oleic acid) and ethanol in the mass ratios shown in Table 1 below based on the total mass of the pharmaceutical composition, and then - An amount of R-152a propellant gas sufficient for the total mass of the pharmaceutical composition to reach 9.57 g.

[0060]

Table 1

[0061] Two series of tests regarding the measurement of the aerodynamic particle size distribution (APSD) were conducted.

[0062] These two series of tests to evaluate the aerodynamic particle size of the active ingredient exiting the valve were conducted using a multi-stage pharmaceutical impactor capable of approximating the bronchial tree. The pharmaceutical impactor used this time was the Next Generation Impactor (NGI), which corresponds to Apparatus E of the European Pharmacopoeia.

[0063] More specifically, these two series of tests were carried out by discharging five doses of each pharmaceutical composition into an NGI impactor at a flow rate of 30 L / min.

[0064] A first series of tests regarding the measurement of the aerodynamic particle size distribution was carried out on T0, that is, the pharmaceutical compositions C, C’, C [1] , C [1] ’, and C [3] obtained after the filling step in the above two steps. The results of this first series of tests are shown in Figure 1.

[0065] A second series of tests regarding the measurement of the aerodynamic particle size distribution was carried out on T3M, that is, the same pharmaceutical compositions C, C’, C [1] , C [1] ’, and C [3] after storing the metered-dose inhalers containing them for 3 months. During these 3 months, these metered-dose inhalers were placed upside down (valve facing down). The results of this second series of tests are shown in Figure 2. [1] , C [1] ’, and C [3] Moreover, the results of the first and second series of tests carried out on the pharmaceutical compositions C and C’ according to the present invention are shown in Figure 3 for composition C and Figure 4 for composition C’.

[0066] Furthermore, the graphs in Figures 1 to 4 show the percentage of salbutamol (a) deposited in the pharynx and oral cavity (referred to as T&M) on the one hand and in each of the eight stages (referred to as S1 to S8) of the impactor on the other hand.

[0067] To ensure optimal therapeutic efficacy, it is necessary to minimize the percentage deposited in the pharynx and oral cavity T&M, while maximizing the percentage deposited in stages S3 to S5.

[0068] Figure 1 shows that the pharmaceutical compositions C and C’ according to the present invention can effectively optimize this therapeutic effect.

[0069] Figure 1 shows that the pharmaceutical compositions C and C’ according to the present invention can effectively optimize this therapeutic effect.

[0070] On the one hand, it is observed that the proportion of salbutamol deposited at the T&M level using compositions C and C’ is about 25%. This proportion is much lower than the proportions of salbutamol deposited at this same T&M level using comparative pharmaceutical compositions C [1] , C [1] ’, and C [3] , which are about 68%, 60%, and 46% respectively.

[0071] On the other hand, it is observed that the total proportion of salbutamol deposited at stages S3 - S5 using pharmaceutical compositions C and C’ according to the present invention is much higher than the total proportion of salbutamol deposited at these same stages S3 - S5 using comparative pharmaceutical compositions C [1] , C [1] ’, and C [3] . This observation is more prominent for comparative compositions C [1] and C [1] ’, but these compositions use oleic acid, a surfactant which in this case plays a role in promoting and stabilizing the dispersion of the active ingredient particles in the injection gas.

[0072] Furthermore, pharmaceutical compositions C and C’ containing PEG400 at mass ratios of 0.05% and 0.1% respectively are observed to have the characteristic that their performance in terms of therapeutic efficacy is virtually equivalent as long as the respective graphs in Figure 1 are superimposed over the T&M level and the eight stages S1 - S8 of the impactor. Therefore, even a small amount of PEG in the pharmaceutical composition according to the present invention can achieve excellent therapeutic efficacy.

[0073] Figure 2 shows that the pharmaceutical compositions C and C’ according to the present invention maintain this optimized therapeutic efficacy even after 3 months of storage. In contrast, it is observed that the therapeutic efficacy of comparative pharmaceutical compositions C [1] , C [1] ’, and C [3] has significantly decreased.

[0074] From Figures 3 and 4, it can be confirmed that the pharmaceutical compositions C and C' according to the present invention effectively maintain this same excellent therapeutic efficacy substantially even after 3 months of storage. In fact, the graphs of these Figures 3 and 4 can be substantially superimposed, and the proportion of salbutamol deposited at the T&M level using the compositions C and C' is similar or identical at T0 and T3M, reflecting the fact that the total proportion of salbutamol deposited at stages S3 to S5 at T0 and T3M using these same pharmaceutical compositions C and C' is also the same.

[0075] References [1] International Publication No. WO 2013 / 054137 [2] International Publication No. WO 2014 / 170689 [3] International Publication No. WO 2013 / 054135

Claims

1. The following compound: (a) An active ingredient based on salbutamol, (b) 1,1-difluoroethane (R-152a), (c) Polyethylene glycol, and (d) Ethanol A pharmaceutical composition comprising the same.

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

3. The pharmaceutical composition according to claim 2, wherein the active ingredient (a) is salbutamol sulfate.

4. The mass average molar mass M of the polyethylene glycol (c) ｗ is 20,000 g / mol or less, preferably 100 to 5,000 g / mol, and more preferably 200 to 2,000 g / mol, and the pharmaceutical composition according to any one of claims 1 to 3.

5. The mass ratio of the active ingredient (a) is 0.05 to 0.5% by mass, preferably 0.1 to 0.4% by mass, more preferably 0.2 to 0.35% by mass, based on the total mass of the pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 4.

6. The mass ratio of the 1,1-difluoroethane (b) is 87.5 to 99.89% by mass, particularly 92.5 to 99.89% by mass, preferably 95.6 to 99.68% by mass, more preferably 97.15 to 99.26% by mass, based on the total mass of the pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 5.

7. The mass ratio of the polyethylene glycol (c) is 0.01 to 2% by mass, preferably 0.02 to 1% by mass, more preferably 0.04 to 0.5% by mass, based on the total mass of the pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 6.

8. The mass ratio of the ethanol (c) is 0.05 to 10% by mass, particularly 0.05 to 5% by mass, preferably 0.2 to 3% by mass, more preferably 0.5 to 2% by mass, based on the total mass of the pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 7.

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

10. A canister containing the pharmaceutical composition according to any one of claims 1 to 8.

11. A metered-dose inhaler comprising the canister according to claim 10.

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

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