Composition for use in pressurized dispensing vessels

Abstract

To provide a composition for use in a pressurized dispensing container.SOLUTION: The present invention provides a composition for use in a pressurized dispensing container, the composition comprising: from 3 to 10 mass% of a monohydric alcohol, based on the total mass of the composition; at least 85 mass% of HFA152a and / or HFO1234ze, based on the total mass of the composition; and albuterol sulfate and / or levalbuterol tartrate.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] The present invention relates to a composition for use in a pressurised dispensing container, particularly a composition for use in a metered aerosol pharmaceutical inhaler device.

Background Art

[0002] Conventional pressurised dispensing containers, such as those used in metered aerosol pharmaceutical inhaler devices, typically contain a propellant such as chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA). The transition from CFCs to HFAs has contributed to the successful recovery of the ozone layer. However, there are still concerns regarding the use of HFAs such as HFA134a and HFA227ea due to their high global warming potential (GWP) and long atmospheric lifetime (AL). Therefore, there is a need in the art and pressure from regulatory agencies to develop compositions for use in pressurised dispensing containers containing alternative propellants, such as those having a lower GWP and a shorter AL. In particular, there is a need and pressure to provide devices, such as metered aerosol pharmaceutical inhaler devices, that can continuously supply such life-saving medications to patients. However, it is unclear whether formulations similar to those containing currently preferred propellants are still suitable for use with the new propellants.

Summary of the Invention

[0003] The present invention aims to address at least some of the problems associated with the prior art or to provide at least a commercially acceptable alternative solution thereto. According to the claims appended hereto, the present invention provides a composition for use in a pressurised dispensing container, a pressurised dispensing container, a pharmaceutical dispensing device, a composition for use in the treatment of bronchospasm and / or asthma, and a method of treating bronchospasm and / or asthma. Specifically, in the first aspect, the present invention relates to a composition for use in a pressurized dispensing vessel, The composition contains 3 to 10% by mass of a monohydric alcohol, relative to the total mass of the composition; The composition contains at least 85% by mass of HFA152a and / or HFO1234ze, relative to the total mass of the composition; Albuterol sulfate and / or revalbuterol tartrate The present invention provides a composition containing [a certain substance]. The inventors have surprisingly discovered that the compositions according to the present invention can be used in a pressurized dispensing vessel and, even after storage, provide performance comparable to conventional devices containing propellants with lower GWP and shorter AL. Compositions containing the balance of components described herein can be used in a pressurized dispensing vessel to provide a good balance of overall performance characteristics and may be equivalent to currently available products containing propellants with higher GWP and longer AL.

[0004] While it is understood that the actuators in which pressurized dispensing vessels are used can be modified to adjust certain performance characteristics, it has been found that the compositions of the present invention can facilitate the provision of devices that can have such equivalent performance characteristics. Without wishing to be bound by theory, this may be due to certain monohydric alcohols, such as ethanol, which are the contents of the compositions in combination with newly investigated propellants. Each aspect or embodiment defined herein may be combined with any other aspect or embodiment unless expressly indicated otherwise. In particular, any feature indicated as preferred or advantageous may be combined with any other feature indicated as preferred or advantageous. HFA152a is also known as 1,1-difluoroethane. HFO1234ze is also known as 1,3,3,3-tetrafluoropropene. Each is a propellant with a lower GWP and shorter AL than those typically used in current compositions for use in pressurized dispensing vessels and especially in metered-dose aerosol medicine inhalation devices. For example, a typical propellant currently in use is HFA-134a, also known as 1,2,2,2-tetrafluoroethane. The composition is typically an inhalable composition.

[0005] Monohydric alcohols are typical excipients of active substances used in such compositions, in which case the active substance is albuterol sulfate and / or revalbuterol tartrate. In alternative embodiments, the composition includes an alternative active substance other than albuterol sulfate and / or revalbuterol tartrate, for example, a pharmaceutically acceptable derivative or salt of albuterol or revalbuterol. As is understood, conventional albuterol is a racemic mixture of (S)-albuterol and (R)-albuterol (revalbuterol). While we do not wish to be bound by theory, revalbuterol is thought to be the therapeutically active component of albuterol, while (S)-albuterol is thought to be inactive and have undesirable effects. Nevertheless, albuterol is commonly used in clinical practice. Next, the present invention will be described in reference to the following non-limiting drawings. [Brief explanation of the drawing]

[0006] [Figure 1] The delivery volume resulting from Example 1A, comparing the prepared formulation with the commercially available product ProAir, is shown. [Figure 2] The aerodynamic particle size distribution obtained by a next-generation impactor, as a result of Example 1B, comparing the prepared formulation with the commercially available product ProAir, is shown. [Figure 3A]The resulting spray patterns from Example 1C, comparing the prepared formulation with the commercially available product ProAir, are shown. Specifically, Figure 3A shows Dmin and Dmax at 30 mm and 60 mm, Figure 3B shows the ellipticity, and Figure 3C shows the area. [Figure 3B] The resulting spray patterns from Example 1C, comparing the prepared formulation with the commercially available product ProAir, are shown. Specifically, Figure 3A shows Dmin and Dmax at 30 mm and 60 mm, Figure 3B shows the ellipticity, and Figure 3C shows the area. [Figure 3C] The resulting spray patterns from Example 1C, comparing the prepared formulation with the commercially available product ProAir, are shown. Specifically, Figure 3A shows Dmin and Dmax at 30 mm and 60 mm, Figure 3B shows the ellipticity, and Figure 3C shows the area. [Figure 4] The delivery volume resulting from Example 2A is shown, comparing the prepared formulation after a longer storage period than in Example 1A. [Modes for carrying out the invention]

[0007] Preferably, the monohydric alcohol is a C1-C3 monohydric alcohol, i.e., a monohydric alcohol containing 1 to 3 carbon atoms, more preferably a monohydric alcohol containing ethanol, and even more preferably the monohydric alcohol is ethanol. It is preferable that the monohydric alcohol is ethanol. Preferably, the hydrofluorocarbon propellant of the composition contains HFA152a, and more preferably HFA152a. In other words, it is preferable that the composition contains at least 85% by mass of HFA152a based on the total mass of the composition. That is, among HFA152a and / or HFO1234ze, HFA152a is preferred. In other words, preferably, the composition contains at least 85% by mass of HFA152a and / or HFO1234ze based on the total mass of the composition, and HFA152a and / or HFO1234ze is only HFA152a. In other words, it is preferable that the hydrofluorocarbon propellant of the composition consists of HFA152a. Preferably, albuterol sulfate and / or revalbuterol tartrate are micronized; that is, preferably, albuterol sulfate and / or revalbuterol tartrate contain micronized albuterol sulfate and / or micronized revalbuterol tartrate, and preferably, albuterol sulfate and / or revalbuterol tartrate are micronized albuterol sulfate and / or micronized revalbuterol tartrate. Preferably, the active substance in the composition contains albuterol sulfate, and more preferably, albuterol sulfate. In other words, it is preferable that the composition contains albuterol sulfate. That is, among albuterol sulfate and / or revalbuterol tartrate, albuterol sulfate is preferred. In other words, it is preferable that the active substance in the composition consists of albuterol sulfate.

[0008] Therefore, a preferred embodiment of the present invention is a composition for use in a pressurized dispensing vessel, The composition contains 3 to 10% by mass of ethanol, relative to the total mass of the composition; The composition contains 85% by mass of HFA152a, relative to the total mass; Albuterol sulfate and It is a composition containing [the specified ingredient]. The composition preferably contains 3 to 9% by mass of monohydric alcohol, more preferably 4 to 8% by mass, based on the total mass of the composition. Surprisingly, it has been found that a monohydric alcohol content of 4 to 8% by mass, in particular, when combined with newly investigated propellants, tends to provide a good balance of overall performance characteristics. In some preferred embodiments, for example, when a consistent delivery rate of the active substance over the entire lifespan of the product is a target performance characteristic for a particular application, the composition preferably contains 5 to 10% by mass, more preferably 6 to 9% by mass, even more preferably 6 to 8% by mass, and even more preferably 7 to 8% by mass, of monohydric alcohol based on the total mass of the composition. In other preferred embodiments, for example, when a consistent average particulate fraction and average aerodynamic median diameter of the sprayed particles after storage are target performance characteristics for a particular application, the composition preferably contains 3 to 7% by mass, more preferably 3 to 6% by mass, even more preferably 4 to 6% by mass, and even more preferably 4 to 5% by mass, of monohydric alcohol based on the total mass of the composition.

[0009] The composition preferably contains 0.1 to 1% by mass of albuterol sulfate and / or revalbuterol tartrate, more preferably 0.2 to 0.6% by mass of albuterol sulfate and / or revalbuterol tartrate, based on the total mass of the composition. Such an amount of the active substance is preferable to deliver the desired dose in use. Preferably, the ratio of albuterol sulfate and / or revalbuterol tartrate to monohydric alcohol is 1 to 30% by mass, preferably 2 to 20% by mass, and more preferably 5 to 10% by mass. Such mass ratios of these components in the composition can help achieve the advantageous performance characteristics described herein, such as achieving a desired delivery dose. Preferably, the composition contains at least 89% by mass of HFA152a and / or HFO1234ze, preferably at least 91% by mass of HFA152a and / or HFO1234ze, based on the total mass of the composition. Preferably, the composition contains 85 - 97% by mass of HFA152a and / or HFO1234ze, more preferably 89 - 96% by mass, even more preferably 91 - 96% by mass, even more preferably 91 - 95.9% by mass, even more preferably 91 - 95.5% by mass, based on the total mass of the composition.

[0010] The composition preferably contains, based on the total mass of the composition, 4 - 8% by mass of a monohydric alcohol; 91 - 95.9% by mass of HFA152a and / or HFO1234ze; 0.1 - 1% by mass of albuterol sulfate and / or tartaric acid levalbuterol salt. More preferably, the composition contains, based on the total mass of the composition, 4 - 8% by mass of ethanol; 91 - 95.9% by mass of HFA152a; 0.1 - 1% by mass of albuterol sulfate and. Preferably, the composition can further contain one or more of a surfactant, preferably oleic acid, polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, propoxylated polyethylene glycol, and polyoxyethylene. Most preferably, when the composition further contains a surfactant, the composition further contains oleic acid. That is, the surfactant is preferably oleic acid.

[0011] Preferably, if present, the composition comprises less than 2% by weight of surfactant, more preferably less than 1% by weight of surfactant, even more preferably less than 0.5% by weight of surfactant, based on the total weight of the composition. For example, preferably, if present, the composition comprises from 0.01 to 2% by weight of surfactant, more preferably from 0.05 to 1% by weight of surfactant, even more preferably from 0.1 to 0.5% by weight of surfactant, based on the total weight of the composition. The composition comprises from 3 to 10% by weight of a monohydric alcohol, preferably from 4 to 8% by weight of a monohydric alcohol, based on the total weight of the composition; from 0.1 to 1% by weight of albuterol sulfate and / or levabuterol tartrate, preferably from 0.2 to 0.6% by weight of albuterol sulfate and / or levabuterol tartrate, based on the total weight of the composition; and, together with any inevitable impurities, the balance which is HFA152a and / or HFO1234ze and is preferably essentially composed of, and preferably consists of, these.

[0012] In another preferred embodiment, the composition comprises from 3 to 10% by weight of a monohydric alcohol, preferably from 4 to 8% by weight of a monohydric alcohol, based on the total weight of the composition; from 0.1 to 1% by weight of albuterol sulfate and / or levabuterol tartrate, preferably from 0.2 to 0.6% by weight of albuterol sulfate and / or levabuterol tartrate, based on the total weight of the composition; optionally, from 0.01 to 2% by weight of a surfactant, based on the total weight of the composition; and, together with any inevitable impurities, the balance which is HFA152a and / or HFO1234ze and is preferably essentially composed of, and preferably consists of, these. More preferably, the composition comprises from 3 to 10% by weight of ethanol, preferably from 4 to 8% by weight of ethanol, based on the total weight of the composition; from 0.1 to 1% by weight of albuterol sulfate, preferably from 0.2 to 0.6% by weight of albuterol sulfate, based on the total weight of the composition; Along with all unavoidable impurities, the remainder is HFA152a. Essentially, it consists of them, preferably.

[0013] In other preferred embodiments, the composition The composition contains 3 to 10% by mass of ethanol, preferably 4 to 8% by mass, relative to the total mass of the composition; The composition contains 0.1 to 1% by mass of albuterol sulfate, preferably 0.2 to 0.6% by mass of albuterol sulfate, relative to the total mass of the composition; The composition may optionally contain 0.01 to 2% by mass of oleic acid, relative to its total mass; Along with all unavoidable impurities, the remainder is HFA152a. Essentially, it consists of them, preferably. To be understood, the terms “essentially derived from” or “essentially derived from” as used herein may include the presence of further components other than those listed, provided that they do not substantially affect the essential properties of the composition. Preferably, the composition can provide equivalent delivery performance to a corresponding formulation containing HFA-134a as a propellant, preferably throughout the life of the pressurized dispensing vessel, and preferably the delivery amount remains consistent throughout the life of the pressurized dispensing vessel, for example, within 20%, preferably within 10%, of the initial delivery dose measurement.

[0014] In a further embodiment, the present invention provides a pressurized dispensing vessel containing the composition of any of the above claims. Preferably, the pressurized distribution container is pressurized to a pressure of 300 kPa to 15 MPa, for example, 400 kPa to 5 MPa, and more preferably 500 kPa to 3.5 MPa. Preferably, the pressurized dispensing vessel is coated with fluorinated ethylene propylene, plasma coated, and / or polyester coated, more preferably plasma coated. That is, the inner surface of the pressurized dispensing vessel is preferably at least partially coated with fluorinated ethylene propylene, plasma coated, and / or polyester coated, more preferably plasma coated. Suitable coatings are known in the art. In a further embodiment, the present invention provides a pharmaceutical dispensing device comprising a pressurized dispensing container according to the above embodiment, preferably a metered-dose aerosol pharmaceutical inhalation device. The device of the present invention is not particularly limited, as long as it is suitable for use with the composition of the present invention. Devices such as actuators of the device can be further modified to optimize certain performance characteristics such as spray patterns.

[0015] Preferably, the compositions described herein are for use in the treatment of bronchospasm and / or asthma. Alternatively, in a further embodiment, the present invention provides the use of the compositions described herein for the manufacture of pharmaceuticals for the treatment of bronchospasm and / or asthma. In a further embodiment, the present invention provides a method for treating bronchospasm and / or asthma, comprising administering an effective amount of the composition described herein to a subject, preferably a human. Preferably, administering an effective amount of the composition to a target involves using a pharmaceutical dispensing device according to the above embodiment. [Examples]

[0016] Next, the present invention will be described in relation to the following non-limiting embodiments. ( Example 1 ) Formulation and Test Procedures Formulations having the compositions defined in Table 1 were prepared. Each formulation was prepared by filling a plasma-coated can fitted with a 25 μL valve with a finely atomized albuterol sulfate suspension. All cans were isolated at room temperature for at least 14 days with the valve lowered, and then isolated in a stable state at 40°C / 75% relative humidity (RH) for 1 month. [Table 1]

[0017] In the following examples, the characteristics of formulations 1-3 during use were compared with the commercially available ProAir (hereinafter referred to as PA), a known albuterol sulfate suspension metered-dose inhaler (MDI) containing the propellant HFA-134a. The formulations were tested before and after being stored for one month. In particular, coated cans containing the same valve but different formulations 1-3 were tested against conventional PA products for delivery volume (DD), aerodynamic particle size distribution (APSD) by next-generation impactor (NGI), and spray pattern (SP). In other words, the PA product was used as the baseline for comparison. The same actuator as the PA product was used for all tests with PA and formulations 1-3. Using a United States Pharmacopeia (USP) instrument, DD and NGI samples were collected at 30 L / min and then analyzed by high-performance liquid chromatography (HPLC). SprayVIEW (Proveris Scientific Corporation, USA) was used for SP measurement.

[0018] 1A-Delivery amount Three cans of each formulation were tested for dose loss (DD) before and after one month of storage, at the beginning, middle, and end of the inhaler's lifespan (BOL, i.e., shot number 1; MOL, i.e., shot number 100; and EOL, i.e., shot number 200). These results were compared to the initial results from PA (i.e., only when not stored for one month). Compared to 88.6 μg from PA, formulation 3 with 8% by mass ethanol delivered a more consistent dose, with averages of 86.5 μg and 86.1 μg before and after storage, and over the overall range of 73.8 μg to 102.1 μg (within a mean of + / - 5%). Formulations containing 2% by mass (formulation 1) and 4% by mass (formulation 2) ethanol showed lower EOL doses, but the DD of formulation 2 was still acceptable. The DD of formulation 2 was also more consistent throughout the entire can's lifespan compared to formulation 1, showing less decrease in MOL dose, particularly after one month of storage. Figure 1 shows the delivery volumes from formulations 1, 2, and 3, containing 2% by mass, 4% by mass, and 8% by mass ethanol, respectively, before (left graph) and after (right graph) storage at 40°C / 75%RH with the valve lowered, compared to those from PA (pre-storage results only). Formulations 2 and 3 (containing 4% by mass and 8% by mass ethanol, respectively) showed little change in delivery volume throughout the inhaler's lifespan before and after storage, demonstrating a more consistent dose.

[0019] 1B - Aerodynamic particle size distribution (APSD) using next-generation impactors (NGI) NGI tested three cans of each formulation for APSD in both BOL and EOL. Figure 2 and Table 2 show the stage deposition rate (%) normalized to DD. Formulations 2 and 3 (containing 4% by mass and 8% by mass ethanol, respectively) showed the most comparable performance to PA. The slightly higher induction port deposition in the low-ethanol formulations is thought to be caused by a higher rate due to higher vapor pressure. Little change in APSD was observed after storage. [Table 2] Figure 2 shows the deposition rates (%) of delivered amounts from formulations 1, 2, and 3 containing 2% by mass, 4% by mass, and 8% by mass ethanol, respectively, before (left graph) and after (right graph) storage at 40°C / 75%RH with the valve lowered, compared to those from PA (pre-storage results only). Almost no change was observed in the deposition rates of all three formulations.

[0020] 1C - Injection Pattern (SP) Figure 3 shows D at 30mm and 60mm after various preservation conditions. min and D max Figure 3A shows the ellipticity (Figure 3B), and the area (Figure 3C). Preparation 3 containing 8% by mass of ethanol at T0, i.e., before storage, is D min , D max The formulations showed good agreement with the PA in terms of ellipticity and area, with percentage differences of 4.1%, 3.3%, 0.7%, and 7.4% at 30 mm, and 0.7%, 0.3%, 1.1%, and 1.9% at 60 mm, respectively. This meets the typical in vitro bioequivalence (IVBE) of generic MDI, which is less than 10%. Formulation 2 is also equivalent, but formulation 1 has a higher percentage difference. Figures 3A, 3B, and 3C also show the data after storage at 40°C / 75%RH for 3 months and after storage at 25°C / 60%RH for 5 months (see Example 2), compared with the data from PA (pre-storage only). For all three formulations, little change was observed before and after storage, and the results were similar to those measured from PA.

[0021] ( Example 2 ) Subsequently, the formulation from Example 1 was stored for a longer period, and several of the same tests were performed. In particular, formulations 1-3 were stored at 40°C / 75%RH for 3 months and at 25°C / 60%RH for 5 months, respectively. The following data were collected. 2A-Delivery amount The same test as in Example 1A was performed here using samples that had been stored for a longer period, and the results are shown in Figure 4.

[0022] Similar to the case of shorter storage periods, formulation 3 containing 8% by mass ethanol showed a consistent dose throughout the life of the inhaler, with an initial (i.e., after no storage time) mean value of 86.5 μg, 86.1 μg and 95.0 μg after 1 month and 3 months of storage at 40°C / 75% RH, respectively, and 95.4 μg after 5 months of storage at 25°C / 60% RH. This is compared to 88.6 μg from PA. Formulations containing 2% by mass (Formulation 1) and 4% by mass (Formulation 2) of ethanol showed lower end-of-life (EOL) doses, although the dead dose (DD) of Formulation 2 was still acceptable. The DD of Formulation 2 was also more consistent throughout the can's lifespan compared to Formulation 1, with less decrease in mouth-of-life (MOL) dose, particularly after storage at 40°C / 75%RH for 1 and 3 months.

[0023] 2B - Aerodynamic particle size distribution (APSD) using next-generation impactors (NGI) The same test as in Example 1B was performed using samples stored for a long period of time, and the results are shown in Table 3. In particular, Table 3 shows the mean particulate dose (FPD), mean particulate fraction (FPF), mean aerodynamic median mass (MMAD), and mean geometric standard deviation (GSD). Particulate matter refers to particles with a diameter of less than 5 μm. The standard deviation is shown in parentheses. Table 3 shows that FPF, MMAD, and GSD were similar before and after storage for each formulation, although formulations 2 and 3 were closer to PA. However, formulation 3 showed a slightly larger decrease in FPF and an increase in MMAD after storage.

[0024] [Table 3]

[0025] In summary, formulation 3, containing 8% by mass of ethanol, showed consistent DD throughout the inhaler's lifespan, but exhibited a slight decrease in FPF and a greater increase in MMAD after storage. On the other hand, formulation 2, containing 4% by mass of ethanol, showed less change in FPF and MMAD, but a slightly lower end-of-life dose. Therefore, considering both DD and APSD performance, a preferred formulation can contain 4-8% by mass of a monohydric alcohol such as ethanol. Surprisingly, it was found that the monohydric alcohol (i.e., ethanol) content of the formulation is important in controlling delivery performance, and that a content of 3-10% by mass, for example, 4-8% by mass, can provide a good balance of overall performance characteristics in order to be comparable to current formulations containing propellants with higher GWP and longer AL.

[0026] Therefore, using the formulation of the present invention, it is possible to deliver a consistent dose even after storage and provide performance comparable to PA in terms of NGI deposition rate and APSD, as well as spray pattern. The detailed description provided herein is for illustrative purposes only and is not intended to limit the scope of the appended claims. Many variations of the currently preferred embodiments shown herein will be obvious to those skilled in the art and remain within the scope of the appended claims and their equivalents.

Claims

1. A composition for use in a pressurized dispensing container, The composition contains 6 to 9% by mass of a monohydric alcohol, relative to the total mass of the composition; The composition contains at least 85% by mass of HFA152a, relative to the total mass of the composition; Albuterol sulfate and / or revalbuterol tartrate A composition containing the following:

2. The composition according to claim 1, wherein the monohydric alcohol comprises a C1-C3 monohydric alcohol.

3. The composition according to claim 1, comprising albuterol sulfate.

4. The composition according to claim 1, comprising 6 to 8% by mass of the monohydric alcohol based on the total mass of the composition.

5. The composition according to claim 1, comprising 0.1 to 1% by mass of the albuterol sulfate and / or revalbuterol tartrate, based on the total mass of the composition.

6. The composition according to claim 1, wherein the ratio of albuterol sulfate and / or revalbuterol tartrate to monohydric alcohol is 1 to 30% by mass.

7. The composition according to claim 1, comprising at least 89% by mass of HFA152a based on the total mass of the composition.

8. In relation to the total mass of the composition, With 6-8% by mass of monohydric alcohol; With 91-95.9% by mass of HFA152a; 0.1 to 1% by mass of albuterol sulfate and / or revalbuterol tartrate The composition according to claim 1, comprising:

9. The composition according to claim 1, further comprising a surfactant.

10. The composition according to claim 9, wherein the surfactant comprises one or more of oleic acid, polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, propoxylated polyethylene glycol, and polyoxyethylene.

11. The composition contains 6 to 9% by mass of a monohydric alcohol, relative to the total mass of the composition; The composition contains 0.1 to 1% by mass of albuterol sulfate and / or revalbuterol tartrate, based on the total mass of the composition; If present, the surfactant is present in an amount of 0.01 to 2% by mass relative to the total mass of the composition; Along with all unavoidable impurities, the remainder is HFA152a, The composition according to claim 1, which is essentially comprised of the above.

12. A pressurized dispensing vessel containing the composition according to any one of claims 1 to 11.

13. A pharmaceutical dispensing apparatus including a pressurized dispensing container as described in claim 12.

14. A composition according to any one of claims 1 to 11, for use in the treatment of bronchospasm and / or asthma.

15. The composition according to claim 14, administered to a subject using the pharmaceutical distribution device according to claim 13.

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