Spraying device comprising aqueous budesonide composition

Abstract

Disclosed is a spray device for nasal or buccal delivery of a buffered aqueous composition comprising solubilized budesonide, the composition having improved long term storage stability and reduced amounts of impurities, the buffering agent being adjusted to pH 4 to 5, where budesonide is dissolved at a concentration of at least 100 / vg / mL, where the composition is free of metal ions, and where the budesonide is dissolved at a concentration of at least 100 / vg / mL. The present invention relates to a composition comprising solubilized budesonide and packaged in a metal-free first container closed with an atomizing pump system, said metal-free first container being packaged in a sealed oxygen-impermeable, oxygen-free second container, and wherein the composition comprises at least 90%, preferably at least 95%, of the nominal initial concentration of the solubilized budesonide after storage at 25 DEG C for a period of 12 months, preferably at least 90%, preferably at least 90%, of the nominal initial concentration of the solubilized budesonide, preferably at least 90%, of the nominal initial concentration of the solubilized budesonide. And total impurities at a concentration of not more than 1% relative to budesonide. The invention further relates to a composition for use as a medicament for the treatment of inflammatory diseases or conditions.

Description

Field of the invention

[0001] The present invention relates to a spray device comprising an aqueous buffered composition of solubilized budesonide with improved storage stability. BACKGROUND

[0002] WO2017009480 discloses a method for significantly increasing the solubility of a poorly water-soluble hydrophobic drug in an aqueous solution. The method comprises dissolving the hydrophobic drug in a suitable organic solvent and mixing the organic solvent with an aqueous buffered solution comprising a saponin component selected from the group of aescin, glycyrrhizin, and quillaja extract, and d-panthenol and optionally additional additives. The solubilization process is based on the formation of saponin micelles in the buffered aqueous environment.

[0003] One such poorly water-soluble drug is budesonide (CAS No. 51333-22-3), a glucocorticoid which is known inter alia as an agonist of the glucocorticoid receptor and for its anti-inflammatory activity. It is therefore frequently used for the treatment of inflammatory conditions of the lungs and the intestinal tract, such as asthma, COPD, Crohn’s disease or ulcerative colitis. The solubility of this drug in water is less than 30 pg / ml. Attempts to solubilize budesonide according to the method disclosed in WO2017009480, i.e. dissolving budesonide in a phosphate buffered aqueous solvent comprising beta-aescin, glycyrrhizin, polypropylene glycol, and d-panthenol as essential ingredients, resulted in an aqueous preparation comprising up to about 850 pg / ml. While this enormous increase of the solubilized drug is indeed surprising, the long-term stability of the preparation was not fully satisfactory and led to partial decomposition and / or reaction products of some of the ingredients.

[0004] Therefore, there is a need to overcome this deficiency and to provide a stable aqueous preparation comprising a rather high concentration of dissolved budesonide, or more precisely solubilized budesonide, without substantial undesirable impurities from decomposition and / or reaction products of some of the ingredients. SUMMARY

[0005] The solubilized budesonide formulation prepared according to the teachings of WO2017009480 Al contains d-panthenol in a typical concentration range of 0.5% to 5% (w / v). d-panthenol is used in these formulations to maximize the solubilization capacity and to stabilize the solubilization of budesonide against precipitation during storage at room temperature, i.e. 20-25 °C. As mentioned above, up to about 850 pg / ml of budesonide can be solubilized and kept dissolved for long-term storage according to the teachings of WO2017009480 Al.

[0006] However, the assessment of the stability of a hydrophilic drug in an aqueous solvent system over a long-term storage does not only encompass the determination of an unimpaired maintenance of the drug concentration over the entire storage time period, but should also include the examination of the chemical stability of the entire solubilized system over the expected storage time period.

[0007] Chemical degradation or decomposition of one or more components of an aqueous buffered pharmaceutical composition, including the active pharmaceutical ingredient (API), and possible reaction products arising from chemical interactions between two or more components and / or decomposition compounds, can limit the stability. Such degradation, decomposition, and / or reaction products are generally considered as undesired impurities and pose an obstacle to obtaining a marketing authorization, potentially limiting the availability of a useful therapy.

[0008] Therefore, it is necessary to remove such impurities from aqueous formulation preparations intended to be used as pharmaceutical compositions as far as possible, and / or to find a way to avoid the generation of such impurities in aqueous solutions comprising solubilized drugs.

[0009] With regard to a solubilized budesonide formulation preparation prepared according to the teachings of WO2017009480A1 and comprising dexpanthenol as part of the solubilizing system, it was found that the long-term storage stability of the preparation was significantly impaired by the gradual generation of an initially unknown and unexpected contaminant (hereinafter referred to as "impurity R"), and additionally a second contaminant (hereinafter referred to as "impurity D").

[0010] "impurity D" is known in the art as 21-dehydro-budesonide, an oxidation product that gradually appears during the storage of aqueous budesonide formulations at ambient temperature. It is not generated by chemical interactions with dexpanthenol or other components of the formulation preparation.

[0011] In contrast to impurity D, the structural analysis of impurity R revealed that it is a reaction product of budesonide with 3-amino-1-propanol (3AP). 3AP is a known contaminant of commercially available dexpanthenol, which is acceptable in samples complying with the European Pharmacopoeia (EP) at concentrations of up to 0.5% and in samples complying with the United States Pharmacopeia (USP) at concentrations of up to 1.0%. Furthermore, during the storage of aqueous formulation preparations containing dexpanthenol, 3AP is formed in a time- and temperature-dependent manner according to the reaction scheme shown by formula I due to hydrolysis. This hydrolysis reaction is relatively slow at neutral pH, but is accelerated under acidic or basic conditions.

[0012] Formula I:

[0013]

[0014] In case of dexpanthenol being present together with budesonide in the aqueous solvent system, the following chemical reaction (Formula II) occurs during prolonged storage, leading to the formation of 21-(3-hydroxypropyl)aminobudesonide, i.e. impurity R.

[0015] Formula II

[0016]

[0017] To limit or prevent the formation of impurity R, it was investigated whether a reduction of the dexpanthenol concentration in the buffered aqueous composition, or even the complete removal of dexpanthenol from the aqueous composition, would lead to a significant loss of drug concentration during storage. It is known from WO2017009480A1 that dexpanthenol has both a solubilizing effect as well as a stabilizing effect on budesonide in a buffered aqueous solvent system.

[0018] However, very surprisingly, and contrary to expectations, the reduction, and even the complete elimination of dexpanthenol from the experimental aqueous compositions of the present invention did not induce precipitation of budesonide during several months of storage at room temperature. This surprising behavior can be attributed to the experimental changes of the aqueous solubilizing system of the present invention relative to the aqueous solubilizing system disclosed in WO2017009480A1, i.e. comprising the preferred selection of a-escin instead of b-escin as saponin component, the experimental budesonide concentration used in WO2017009480A1 being less than 850 pg / ml, preferably 100-400 pg / ml, or typically 200 pg / ml, and the adjustment of the aqueous formulation to a pH lower than the pH 5.65 used in WO2017009480A1, preferably to a pH of 4 to 5, and typically to a pH of about 4.3.

[0019] Escin: While the current nomenclature of escins is differentiated based on the differences of the individual molecules contained in the mixture of components, the previously used nomenclature was differentiating the mixture of escin components based on their water solubility. The main fraction of the naturally occurring escin mixture obtainable from horse chestnut extract consists of compounds having an original escin backbone, which is acetylated at the C-22 position and angelicic acid / tiglic acid esterified at the C-21 position (Geisler et al., 2019). This main fraction is referred to as b-escin. In addition to b-escin, two other fractions were identified in the escin mixture, namely a-escin and cryptosin, wherein a-escin is a mixture of cryptosin and b-escin.

[0020] The beta-escin and the aescinate differ in the position of the acetyl group in the backbone. While in beta-escin, also referred to as aescin la and lb in more recent literature, the group is located at C-22, in aescinate it can be found at C-28, the latter also referred to as iso-aescin la and lb in more recent literature, wherein "a" stands for tigloyl and "b" stands for angloyl esterification (Savarino et al., 2023). The two forms can be distinguished by their solubility in water, their melting point, and their hemolytic index. For example, aescinate is soluble in water, while beta-escin is not readily soluble in water or in a buffer solution with a pH of less than pH 5 (Geisler et al., 2019). On the other hand, alpha-escin, which is a 4:6 mixture of beta-escin and aescinate, is better soluble in water than pure beta-escin. Furthermore, alpha-escin remains stable in water or aqueous buffers in the absence of dexpanthenol, while beta-escin precipitates in water or aqueous buffers after some hours in the absence of dexpanthenol, but not after some hours in the presence of dexpanthenol. Thus, the decision was made to select alpha-escin as the preferred saponin component for solubilizing budesonide in aqueous experimental samples. While commercial aescin preparations usually contain both alpha-escin and beta-escin, alpha-escin can be formed by simply heating an aqueous solution of beta-escin, which induces an acyl migration involving the hydroxyl groups at positions C21, C22, and C28.

[0021] An even further improvement of the storage stability is achieved by reducing the generation of impurity D. As disclosed above, the storage stability of the solubilized budesonide aqueous formulation is limited by the oxidation reaction of budesonide, wherein 21-dehydrobudesonide (herein referred to as "impurity D") is formed. By preventing the penetration of molecular oxygen into the liquid formulation, the rate and speed of the formation of this impurity D can be significantly reduced. This can be achieved, for example, by using an oxygen-impermeable protective secondary packaging.

[0022] During the last step of preparing the liquid budesonide formulation, and in the subsequent steps of filling the liquid formulation into the primary container and packaging the liquid formulation into the secondary container under normal atmosphere, small amounts of oxygen can still be dissolved in the formulation and / or become part of the headspace of the primary and secondary containers. Experiments have shown that even these small amounts are sufficient to generate a significant amount of impurity D upon storage.

[0023] One way to avoid such undesirable oxygen ingress into the final formulation is to conduct the filling process under an inert gas atmosphere. Alternatively or additionally, oxidation of budesonide can be limited by including oxygen absorbers within the secondary packaging container which are commercially available for protecting oxygen sensitive products.

[0024] For pharmaceutical development purposes, several external parameters have been tested for their influence on the formation of 21-dehydrobudesonide (Impurity D). It was hypothesized that the formation of Impurity D can be reduced even in the presence of iron and other metal ions in the liquid ready-to-use formulation by reducing the ingress of O2from the surrounding environment during storage.

[0025] During production, iron ions can leak from stainless steel tanks or tubing into the ready-to-use formulation. In addition, primary packaging such as amber glass vials or nasal spray pumps contain iron ions. These iron ions can catalyze the oxidation reaction of budesonide via oxygen radicals. In a first series of experiments, it was shown that using HDPE vials instead of amber glass vials as primary packaging containers and running a completely metal-free manufacturing and filling process significantly reduced the formation of Impurity D.

[0026] In a subsequent study, the content and purity of budesonide in a ready-to-use formulation was monitored over time, wherein the formulation was stored in primary packaging (HDPE vials) protected by secondary packaging, i.e. hermetically sealed, oxygen-impermeable bags, which were additionally equipped with one or more oxygen absorbing packets or sachets. For this purpose, different equipment for the manufacturing process was used, i.e. glass equipment only on the one hand and stainless steel equipment on the other hand, to prepare a buffered aqueous formulation containing 200 pg / ml budesonide and adjusted to pH 4.3. The samples were stored in HDPE vials (Becton, Dickinson and Company, Germany) and closed with APF or Classic Line nasal spray pumps (manufacturer Aptar, Germany). The filled vials were stored unsealed or sealed in aluminum-coated bags with or without O2 / H2O absorbing sachets in a constant-temperature room with controlled humidity at 25 °C and 40 °C. The samples were analyzed on day 0 and after 2 weeks, 1 month, and 3 months of storage. The budesonide content as well as the related impurities were quantified using a validated RP-HPLC method. In addition, the pH and the appearance of the samples were recorded at each time point. Germany). The samples were analyzed on day 0 and after 2 weeks, 1 month, and 3 months of storage. The budesonide content as well as the related impurities were quantified using a validated RP-HPLC method. In addition, the pH and the appearance of the samples were recorded at each time point.

[0027] As a result of the foregoing, when using oxygen absorbers within the secondary packaging container, excellent storage stability was achieved with significantly reduced formation of Impurity D. In case such oxygen absorbers release water upon absorption of oxygen, it was proven advantageous to also include a desiccant within the secondary packaging to eliminate the resulting moisture. BRIEF DESCRIPTION OF DRAWINGS

[0028] Figure 1 : Representation of the relative concentration of budesonide in aqueous buffered formulation containing solubilized budesonide, alpha-aescin and 0%, 2% or 5% v / v dexpanthenol, expressed as the percentage of budesonide recovered in the sample with respect to the nominal initial concentration of budesonide (i.e. 100%) after 12 months of storage at 25°C; determined by analysis by HPLC;

[0029] y-axis: Concentration of budesonide recovered in % of nominal initial concentration; x-axis: 0%, 2%, 5% v / v dexpanthenol.

[0030] Figure 2 : Representation of the content of impurity R in aqueous buffered formulation containing solubilized budesonide, alpha-aescin and 0%, 2% or 5% dexpanthenol, determined by HPLC after 12 months of storage at 25°C;

[0031] y-axis: Relative concentration of impurity R expressed as % of the corresponding budesonide recovered concentration; x-axis: 0%, 2%, 5% v / v dexpanthenol.

[0032] Figure 3 : Representation of the content of impurity D in aqueous buffered formulation containing solubilized budesonide, alpha-aescin and 0%, 2% or 5% dexpanthenol, determined by HPLC after 12 months of storage at 25°C;

[0033] y-axis: Relative concentration of impurity D expressed as % of the corresponding budesonide recovered concentration; x-axis: 0%, 2%, 5% v / v dexpanthenol.

[0034] Figure 4 : Representation of the content of total impurities (including impurities "D" and "R") over 0.1% in aqueous buffered formulation containing solubilized budesonide, alpha-aescin and 0%, 2% or 5% dexpanthenol, determined by HPLC after 12 months of storage at 25°C; y-axis: Relative concentration of cumulative impurities, including impurities R, D and possible additional impurities, expressed as % of the corresponding budesonide recovered concentration; x-axis: 0%, 2%, 5% v / v dexpanthenol.

[0035] Figure 5 : Impurity D content (percentage with respect to budesonide content) of samples prepared in glass containers and stored at 25°C for up to 6 months in the indicated primary and secondary packaging. Data presented as mean values (n=2);

[0036] 1 = APF-glass-sealed plus, i.e. glass container equipped with an APF spray pump and packaged in a sealed bag containing O2 / H2O absorber material;

[0037] 2 = Classic - Glass - Sealed Plus, i.e. glass container equipped with a classic spray pump and packed in a sealed bag containing O2 / H2O absorbers;

[0038] 3 = APF - Glass - Unsealed, i.e. glass container equipped with an APF spray pump, without secondary packaging;

[0039] 4 = APF - Glass - Sealed, i.e. same as 1, but without O2 / H2O absorbers;

[0040] 5 = Classic - Glass - Unsealed, i.e. glass container equipped with a classic spray pump, without secondary packaging;

[0041] 6 = Classic - Glass - Sealed, i.e. same as 2, but without O2 / H2O absorbers.

[0042] Figure 6 : Impurity D content (percentage relative to budesonide content) of samples prepared in metal containers and stored at 25°C for up to 6 months in the indicated primary and secondary packaging. Data presented as mean values (n=2);

[0043] 1 = APF - Metal - Sealed Plus, i.e. metal container equipped with an APF spray pump and packed in a sealed bag containing O2 / H2O absorber material;

[0044] 2 = Classic - Metal - Sealed Plus, i.e. metal container equipped with a classic spray pump and packed in a sealed bag containing O2 / H2O absorbers;

[0045] 3 = APF - Metal - Unsealed, i.e. metal container equipped with an APF spray pump, without secondary packaging;

[0046] 4 = APF - Metal - Sealed, i.e. same as 1, but without O2 / H2O absorbers;

[0047] 5 = Classic - Metal - Unsealed, i.e. metal container equipped with a classic spray pump, without secondary packaging;

[0048] 6 = Classic - Metal - Sealed, i.e. same as 2, but without O2 / H2O absorbers.

[0049] Figure 7 : Impurity D content (percentage relative to budesonide content) of samples prepared in glass containers and stored at 40°C for up to 6 months in the indicated primary and secondary packaging. Data presented as mean values (n=2);

[0050] 1 = APF - Glass - Sealed Plus;

[0051] 2 = Classic - Glass - Sealed Plus;

[0052] 3 = APF - glass - unsealed

[0053] 4 = APF - glass - sealed

[0054] 5 = classic - glass - unsealed

[0055] 6 = classic - glass - sealed.

[0056] Figure 8 : Impurity D content (percent of budesonide content) of samples prepared in metal containers and stored in the indicated primary and secondary packaging at 40°C for up to 6 months. Data presented as mean (n=2);

[0057] 1 = APF - metal - sealed plus

[0058] 2 = classic - metal - sealed plus

[0059] 3 = APF - metal - unsealed

[0060] 4 = APF - metal - sealed

[0061] 5 = classic - metal - unsealed

[0062] 6 = classic - metal - sealed.

[0063] Figure 9A , Figure 9B : Budesonide drug content during storage of samples without dexpanthenol prepared in glass containers and stored in the indicated primary and secondary packaging at 25°C, 30°C, and 40°C for up to 6 months. Data presented as mean (n=2);

[0064] a = APF, 25°C

[0065] b = classic, 25°C

[0066] c = APF, 30°C

[0067] d = classic, 30°C

[0068] e = APF, 40°C

[0069] f = classic, 40°C

[0070] Figure 9A : Budesonide content in absolute terms (pg / ml)

[0071] Figure 9B : Budesonide content in % of initial value on day 0.

[0072] Figure 10A , Figure 10B: Impurity content during storage of samples without dexpanthenol prepared in glass containers and stored at 25°C, 30°C, and 40°C in the indicated primary and secondary packaging for up to 6 months. Data presented as mean values (n=2);

[0073] a = APF, 25°C;

[0074] b = classic, 25°C;

[0075] c = APF, 30°C;

[0076] d = classic, 30°C;

[0077] e = APF, 40°C;

[0078] f = classic, 40°C;

[0079] Figure 10A : Impurity D content in % relative to the budesonide content;

[0080] Figure 10B : Total impurity content in % relative to the budesonide content. DETAILED DESCRIPTION

[0081] Example 1: In-situ formation of decomposition and / or reaction products during extended storage of aqueous solubilized budesonide compositions

[0082] Table 1 : Experimental compositions

[0083] Ingredients Concentration [mg / ml] Budesonide 0.2 Propylene glycol 104 (10% v / v) Dipotassium hydrogen phosphate 0-50 EDTA 1.0 Alpha-aescin 0.3 Citric acid monohydrate 10.4 Trisodium citrate dihydrate 14.85 Water for injection q.s. Hydrochloric acid for pH adjustment q.s. pH 4.3

[0084] All experimental formulation were stored at 20-25°C in HDPE vials with caps.

[0085] As can be seen from Figure 1 It can be seen that the formulation containing 200 pg / mL budesonide dissolved in a buffered aqueous solution comprising the ingredients listed in Table 1 and adjusted to a pH of 4.3 has a concentration-dependent negative impact on the storage stability of the experimental samples. More specifically, while the formulation without dexpanthenol stably maintained budesonide in solution at 20-25°C for a 12-month observation period, the addition of 2% v / v dexpanthenol resulted in a decrease in recoverable budesonide from about 96% (without dexpanthenol) to about 94% (2% dexpanthenol), and the addition of 5% dexpanthenol resulted in a further decrease in solubilized drug recoverable to about 93% of the nominal starting concentration of budesonide.

[0086] At the same time, the concentration of "Impurity R" increased with increasing dexpanthenol concentration, as Figure 2Elimination of dexpanthenol from the experimental samples, as depicted in Figure 1, or in other words, prevents the in situ formation of impurity R during storage at ambient temperature.

[0087] Furthermore, the reduction or elimination of dexpanthenol in these formulation preparations not only reduces or eliminates the formation of impurity R in the experimental samples, but also reduces the formation of impurity D (see Figure 2). Figure 3 ) It was very surprising to observe a concentration dependent reduction of the formation of impurity D with the experimental samples.

[0088] Without being bound by theory, this unexpected finding can be due to the formation of impurity R in the presence of dexpanthenol, which is 3-amino-1-propanol (3AP), a basic compound with a primary amine function. Despite the use of a buffer system in the solvent, the pH slightly increases with increasing 3AP concentration in the experimental samples. Considering that the formation of the budesonide oxidation product, i.e. impurity D, is more favorable at higher pH, this can explain the observed parallel increase or reduction of impurity R and impurity D.

[0089] From this example it can further be concluded that the aqueous solvent system defined in Table 1, which provides for solubilization of budesonide under the conditions defined in Table 1, allows for the complete release of dexpanthenol as an essential ingredient for the stable maintenance of budesonide in solubilized state during storage at room temperature for at least 12 months. As a beneficial side effect of the elimination of dexpanthenol from aqueous budesonide formulation preparations, the in situ formation of the undesired impurities R and D during storage of the liquid formulation preparations is significantly reduced, as can also be seen from Figure 2. Figure 4 Figure 4 is a graphical representation of the sum of all impurities determined by HPLC in the samples comprising impurities R and D.

[0090] Example 2: Influence of sealed storage on the stability of liquid budesonide formulations

[0091] Impurity D is formed by oxidation of the C21 hydroxyl group of budesonide, which results in the formation of an aldehyde group. This reaction is influenced by molecular oxygen and catalyzed by ions of transition metals such as, for example, iron, manganese, copper, zinc, nickel, etc.

[0092] Abbreviations used hereinafter:

[0093] ACN acetonitrile

[0094] AD distilled water

[0095] EDTA ethylenediaminetetraacetic acid

[0096] HDPE high-density polyethylene

[0097] HPLC high-performance liquid chromatography

[0098] L / N lot number​

[0099] PG propylene glycol

[0100] RP-HPLC reverse phase high performance liquid chromatography

[0101] RRF relative retention factor

[0102] SS stainless steel

[0103] S / N serial number

[0104] UV / Vis ultraviolet / visible

[0105] The experimental budesonide formulations used in this study contained the following ingredients:

[0106]

[0107]

[0108] Additional relevant equipment included:

[0109]

[0110] Two experimental formulations with the same ingredient composition (see above for details) were prepared in different containers, i.e. in glass containers or stainless steel containers. After sterile filtration, each formulation was filled into two different primary packaging systems, HDPE vials closed with 50 μΙ APF nasal spray pumps (Aptar, Germany) (Budesonide Nasal Spray, BNS, 50 μΙ) or HDPE vials closed with 50 μΙ Classic line nasal spray pumps (Aptar, Germany) (Budesonide Nasal Spray, BNS, 50 μΙ). Germany) or HDPE vials closed with 50 μΙ Classic line nasal spray pumps (Aptar, Germany) (Budesonide Nasal Spray, BNS, 50 μΙ). The different primary packaging systems were stored unsealed in aluminium coated pouches, sealed in aluminium coated pouches or sealed in aluminium coated pouches additionally containing small pouches with O2 and H2O absorbers. The formulations were stored at two different temperatures, i.e. at 25°C at 65% relative humidity and at 40°C at 75% relative humidity. Samples were taken at day 0 and after 2 weeks, 1 month, 3 months and 6 months of storage and the most relevant stability indicating parameters were analysed, i.e. budesonide content, impurity D content, impurity R content measured at 240 nm, sum of all impurities present and pH. In addition, as a control, the same formulations without the drug budesonide were prepared and filled into the same different primary packaging systems and stored unsealed or sealed at the same conditions. Samples of each experimental formulation before the final sterile filtration were also taken and subjected to HPLC analysis to check for possible filtration losses.

[0111]

[0112] ​After filling, vials labeled "unsealed" were placed directly in the crates for storage. Vials labeled "sealed" were placed in aluminum-coated bags and sealed using a suitable sealing press, and vials labeled "sealed plus" were placed in aluminum-coated bags additionally equipped with O2and H2O absorber sachets and sealed using a suitable sealing press. For HPLC analysis of day 0 contents, samples of the experimental formulations were filled directly into HPLC sample vials instead of into the experimental containers.

[0113] The experimental formulations were placed in a climate chamber set to 25°C / 60% relative humidity or set to 40°C / 75% relative humidity and stored for 6 months. A temperature logger was used to monitor and record the temperature during storage of the samples.

[0114] Results:

[0115] a) Formulations prepared in glass containers and stored in HDPE vials at 25°C

[0116] The budesonide content decreased by 3-4.5% over 6 months. The best results, i.e. the lowest drug loss, were obtained when an APF nasal spray pump was used for capping and closing the vials and the closed vials (= primary packaging) were placed in airtight, oxygen-impermeable bags (= secondary packaging) additionally equipped with O2 / H2O absorber sachets; after 6 months of storage, the sample still contained 189.4 μg / ml budesonide, corresponding to a recovery of 97% based on the day 0 value.

[0117] Similarly, the use of a classic series nasal spray pump for closing the experimental vials and sealing the closed vials in a secondary packaging bag including O2 / H2O absorber resulted in a comparably low content loss; the sample contained 188.3 μg / ml after 6 months of storage, corresponding to a recovery of 97% based on the day 0 value. Generally, the use of a classic series nasal spray pump resulted in slightly greater drug content loss compared to the corresponding APF nasal spray pump sample.

[0118] On the other hand, the formation of impurity D in samples packaged using an APF nasal spray pump resulted in an impurity D value of 0.3-0.5% relative to the budesonide content. The increase in impurity D was found to be lowest in the sealed samples plus O2 / H2O absorber (see Figure 5 ).

[0119] In contrast, packaging using a classic series nasal spray pump resulted in an impurity D content of about 1.3% of the drug content after 6 months of storage at 25°C; with the exception of the sample stored in the sealed plus O2 / H2O absorber secondary packaging, where the level of impurity D did not exceed 0.38% of the drug content. The values were comparable to those obtained with primary packaging using an APF nasal spray pump.

[0120] The impurity R content in samples stored at 25°C increased to 2% of the initial budesonide content, independent of the choice of primary and secondary packaging.

[0121] Analytical determination of the sum of all impurities formed over a 6 month storage period at 25°C revealed that samples stored in sealed packaging plus O2 / H2O absorber showed the lowest impurity content, i.e. 2.5-2.6% of the drug content, independent of the choice of nasal spray pump.

[0122] b) Formulations prepared in stainless steel containers and stored in HDPE vials at 25°C

[0123] When experimental formulations were obtained from metal containers of stainless steel, the budesonide drug content decreased by 2-4% over 6 months when stored at 25°C / 60% relative humidity. The lowest content loss was found in samples packaged in HDPE vials using APF nasal spray pumps for closure and sealed pouches plus O2 / H2O absorber as secondary packaging system; the samples contained 189.6 μg / ml after 6 months of storage, which corresponds to a drug recovery of 98% based on the value on day 0.

[0124] When using vials capped with classic series nasal spray pumps and sealed in pouches plus O2 / H2O absorber, the experimental samples contained 188.4 μg / ml after 6 months of storage, based on the initial value on day 0, which corresponds to a recovery of 98%. Again, the use of classic series nasal spray pump closure systems resulted in slightly greater drug content loss compared to the corresponding samples using APF nasal spray pump closure systems.

[0125] The formation of impurity D in samples packaged using APF nasal spray pumps resulted in an impurity D content of 0.2-0.8% of the budesonide content. The smallest increase in impurity D was found in samples labeled "sealed plus O2 / H2O absorber".

[0126] In contrast, primary packaging using classic series nasal spray pumps for closure resulted in an impurity D content of about 2% of the drug content after 6 months of storage at 25°C; except for samples in the sealed pouch plus O2 / H2O absorber secondary packaging system, which produced an impurity D content of only up to 0.6% of the drug content. Figure 6 )

[0127] The impurity R content in samples stored at 25°C increased to 2% of the initial budesonide content, independent of the choice of primary and secondary packaging.

[0128] Analytical determination of the sum of all impurities formed over 6 months of storage at 25°C revealed that samples stored in sealed packaging plus O2 / H2O absorber showed the lowest impurity content, i.e. 2.4% and 2.8% of the drug content, independent of the choice of nasal spray pump. The highest total impurity content was determined in samples packaged using classic series pumps (4.3% - unsealed, 4.3% - sealed).

[0129] c) Formulations prepared in glass containers and stored at 40°C in HDPE vials

[0130] The budesonide content decreased by 10-20% over 6 months of storage at 40°C / 75% relative humidity. The best results, i.e. the lowest loss of drug content, were achieved with samples packaged using APF nasal spray pumps for closing the HDPE vials and sealed bags plus O2 / H2O absorber material as secondary packaging systems; after 6 months of storage, the samples still contained 174.4 μg / ml, based on the value on day 0, corresponding to a drug recovery of 90%.

[0131] Surprisingly, the largest drug loss was detected when using classic series nasal spray pumps with vials plus O2 / H2O absorber in airtight sealed bags; after 6 months of storage, the samples contained only 155 μg / ml of budesonide, corresponding to a recovery of 80% relative to the initial value on day 0. In general, classic series nasal spray pump systems caused a greater loss of drug content than APF nasal spray pump systems.

[0132] In samples stored in sealed secondary packaging plus O2 / H2O absorber, the formation of impurity D was lowest, resulting in an impurity D content of 0.42% of the budesonide content. Samples stored unsealed or sealed without absorber contained impurity D in an amount of about 2.6% and 2.5% of the budesonide content, respectively.

[0133] In contrast, after 6 months of storage at 40°C, packaging using classic series nasal spray pumps was accompanied by a budesonide content of 8-12.6% of the impurity D content. The levels of impurity D were much higher compared to the values determined when using APF nasal spray pumps in the primary packaging system (see Figure 7 ).

[0134] Not surprisingly, the content of impurity R varied only slightly among the different types of primary and secondary packaging. Relative to the budesonide content, samples packaged with the APF nasal spray pump contained 9.3-9.8% impurity R, while samples packaged with the classic series nasal spray pump contained 8.7-9% impurity R.

[0135] Analysis of the total sum of all impurities formed over 6 months of storage at 40°C revealed that samples packaged with the APF nasal spray pump showed the lowest impurity content, i.e., a total of 10.3-12.6% impurities relative to the budesonide content, regardless of the choice of secondary packaging. The highest total impurity content was determined in samples packaged with the classic series pump, i.e., 21.2% - unsealed, 21.9% - sealed plus O2 / H2O absorber.

[0136] d) Formulations prepared in stainless steel containers and stored in HDPE vials at 40°C

[0137] The budesonide content decreased by 10-20% over 6 months of storage at 40°C / 75% relative humidity in the samples. The lowest loss was found in samples packaged with the APF nasal spray pump and sealed bags plus O2 / H2O absorber; the samples still contained 174.2 μg / ml after 6 months of storage, corresponding to a 90% drug recovery relative to the drug content on day 0.

[0138] When the experimental vials were closed with the classic series nasal spray pump and sealed in bags plus O2 / H2O absorber, the samples contained only 171.2 μg / ml after 6 months of storage (based on the value on day 0, a recovery of 89%). Again, use of the classic series nasal spray pump with the experimental vials resulted in slightly greater drug loss compared to the experimental vials using the APF nasal spray pump closure system.

[0139] Formation of impurity D was lowest in samples packaged with the APF nasal spray pump, sealed in bags plus O2 / H2O absorber. After 6 months at 40°C / 75% relative humidity, the samples showed an impurity D content of only 0.9% relative to the drug content.

[0140] In contrast, primary packaging with the classic series nasal spray pump resulted in an impurity D content of about 1.7-13.7% relative to the budesonide drug content, depending largely on the nature of the secondary packaging. The smallest increase in impurity D was found in samples stored in sealed bags plus O2 / H2O absorber secondary packaging, i.e., 1.7% relative to the drug content. Figure 8 ).

[0141] Again, the impurity R content in the samples stored at 40°C varied only slightly among the different types of primary and secondary packaging equipment. The samples packaged using the APF nasal spray pump contained 9.3-9.7% impurity R relative to the budesonide content, while the samples packaged using the classic series nasal spray pump contained 8.7-9.5% impurity R. The analysis of all impurities formed over the 6 month storage period at 40°C revealed that the samples packaged using the APF nasal spray pump and sealed in the bag plus O2 / H2O absorber showed the lowest total impurity content, i.e., 10.7% of the budesonide content. The samples packaged using the classic series nasal spray pump and sealed in the bag plus O2 / H2O absorber showed the second lowest total impurity content, i.e., 11.4% of the drug content. The highest total impurity content was determined in the samples packaged using the classic series pump, i.e., 22.8% - unsealed and 18.0% - sealed.

[0142] Example 3: Effect of sealed storage on the stability of liquid budesonide formulations without dexpanthenol

[0143] Example 2 was repeated except that the aqueous buffer composition did not contain dexpanthenol. The experimental solutions were prepared in glass containers without metal and filled into HDPE vials, capped with a classic series spray pump system or with a metal-free APF spray pump system as described in Example 2. The closed ready-to-use spray devices containing the experimental budesonide solutions without dexpanthenol were stored for 6 months as described in Example 2 with the following changes:

[0144] a) at 25°C / 60% relative humidity (rh)

[0145] b) at 30°C / 75% relative humidity (rh)

[0146] c) at 40°C / 75% relative humidity (rh)

[0147] As expected, the best stability results, i.e., the smallest drug loss, were determined for the samples using the APF spray pump system and the spray devices sealed in oxygen-impermeable bags. The results depicted in Table 2 and Figure 9A 、 Figure 9B 、 Figure 10A 、and Figure 10B It can also be concluded from the results depicted in Table 2 and

[0148] Table 2

[0149]

[0150] Conclusions

[0151] From the results disclosed above, it can be seen that the primary and secondary packaging has the most significant impact on impurity formation in the experimental samples of liquid budesonide formulation for the observed formation of impurity D, which is not surprising considering that impurity D is an oxidation product of budesonide. Generally, the levels of impurity D were higher in primary containers closed with APTAR Classic series pumps compared to primary containers closed with the same manufacturer's APF nasal spray pumps. This observation can be due to the fact that the Classic series pumps contain two metal components in the fluid path, namely the steel spring and the ball of the check valve, which can come into contact with the liquid budesonide formulation, leading to some leakage of metal ions known to catalyze and thus accelerate the formation of impurity D. Whereas the APF nasal spray pumps do not contain metal elements that can come into contact with the liquid material.

[0152] Samples stored without being sealed in oxygen-impermeable bags generally showed the highest levels of impurity D, followed by vials sealed in these bags without oxygen absorbers. However, no significant positive effect was observed from sealing samples in oxygen-impermeable protective bags without removing oxygen from the atmosphere inside the bags.

[0153] In vials fitted with Classic series pumps, the lowest levels of impurity D were found in vials sealed with oxygen- and water-absorbing sachets in impermeable bags.

[0154] The levels of impurity D observed in vials closed with APTAR APF pumps were significantly lower than those observed in vials fitted with Classic series pumps. For the Classic series pumps, the highest levels of impurity D were observed in vials stored without being sealed in impermeable bags, followed by vials sealed in these bags without oxygen absorbers. The overall lowest levels of impurity D were found in vials sealed with oxygen- and water-absorbing sachets in impermeable bags.

[0155] In fact, in APF-closed vials, the impurity D levels did not further increase after the 3-month time point. The relative concentration of impurity D only rose to 0.18% and 0.42% (relative to budesonide) after 6 months of storage at 25°C and 40°C, respectively. Due to the very low impurity D levels, it seems possible to provide a packaging system that allows the product to be stored at room temperature for up to 12 months or 18 months or even 24 months.

[0156] At the same time, the data also show that the impact on the budesonide formulation can not be as severe as expected, as long as suitable packaging is used according to the present application, for example adverse storage conditions at elevated temperatures of 40°C, such as can occur for example during the transport of ready-to-use formulations to the final destination in hot and humid regions, or during storage in the shops of retailers without cooling facilities in tropical or subtropical regions.

[0157] Even when oxygen ingress protection measures are applied, the presence of catalytically active metal ions appears to significantly reduce the quality of the buffered, weakly acidic aqueous budesonide formulation during storage. This can be concluded from the observation that formulations which have been in contact with metal parts of the manufacturing and / or filling equipment generally have higher levels of impurity D, even in sealed and oxygen-depleted packaging containers. This observation is also confirmed by the fact that the closure of the small bottles by means of a classic series pump containing metal, although the small bottles are filled into non-metallic glass or HDPE vials, is sufficient to produce increased levels of impurity D, even if the small bottles are sealed into oxygen-impermeable bags as secondary packaging.

[0158] However, the level of impurity R is not affected by the sealing and the depletion of oxygen. It can thus be concluded that the reaction between 3AP and budesonide does not proceed via the initial formation of impurity D and the reaction of the primary amine in 3AP with the C21-aldehyde group of impurity D.

[0159] It can further be concluded from the foregoing disclosure and working examples that the best results, i.e. the lowest total impurity levels in the aqueous buffered budesonide formulation of the present application, are achieved by a formulation which comprises a-escin as the only saponin component and which does not contain dexpanthenol, which is prepared in non-metallic containers and transferred into non-metallic containers, preferably made of glass or HDPE, using metal-free filling equipment, usually after sterile filtration, which are capped and closed with a spray pump for nasal delivery, such as an APTAR APF nasal spray pump, which does not contain metal parts, or in which the sprayable liquid cannot come into contact with any metal parts of the spray pump, and further packaged into a sealed, oxygen-depleted, and preferably moisture-depleted, oxygen-impermeable secondary packaging.

Claims

1. A spray device comprising a container filled with a buffered aqueous composition comprising budesonide dissolved therein, said buffered aqueous composition comprising: - a buffer adjusted to a pH of 4 to 5, preferably to a pH of 4.3; - propylene glycol at a concentration of 5% v / v to 15% v / v, preferably 10% v / v; - aescin, preferably a-escin, as the only saponin component, at a concentration of 0.1-1 mg / ml, preferably 0.3 mg / ml; - EDTA at a concentration of 0.5-2 mg / ml, preferably 1.0 mg / ml; - optionally d-panthenol at a concentration of 5-50 mg / ml; and - solubilized budesonide at a nominal starting concentration of at least 100 pg / mL, preferably at least 200 pg / mL, typically 200 to 400 pg / mL; characterized in that said buffered aqueous composition being a mixture of the ingredients prepared in a metal-free container, said container being made of a metal-free material and capped and closed with a spray pump system suitable for nasal or buccal delivery of the aqueous buffered composition, wherein the capped and closed spray device is hermetically sealed into a secondary packaging container impermeable to oxygen and free of oxygen, the latter preferably containing an oxygen absorber and optionally a moisture absorber.

2. The spray device of claim 1, wherein, Those parts of the primary packaging container comprising the spray pump system which are in physical contact with the buffered aqueous composition during storage and / or handling are made of a metal-free material.

3. The spray device of claim 1 or 2, wherein, The container containing the aqueous buffered composition is made of a metal-free glass or HDPE.

4. The spray device according to any one of claims 1 to 3, characterized in that The aqueous buffered composition is free of ions of transition metals selected from the group consisting of zinc, copper, cobalt, manganese, iron, nickel, cadmium, vanadium, molybdenum, titanium and mercury.

5. The spray device according to any one of claims 1 to 4, characterized in that The aqueous buffered composition contains at least 90%, preferably at least 95%, of the nominal starting concentration of solubilized budesonide and not more than 1% of total impurities, including impurities R and D, relative to the solubilized budesonide concentration, after a period of 12 months of storage at 20-25 °C.

6. The spray device according to any one of claims 1 to 5, wherein, The buffer in the aqueous buffered composition is a citrate buffer, a phosphate buffer or a combination of both.

7. The spray device according to any one of claims 1 to 6, suitable for topical or systemic application, preferably for nasal or buccal spray.

8. The spray device according to any one of claims 1 to 7, filled with a buffered aqueous composition solubilized with budesonide for use as a medicament, preferably as a medicament for the treatment of an inflammatory disease or condition.

9. The spray device for use according to claim 8, wherein the inflammatory disease or condition is selected from inflammation of the respiratory tract, inflammation of the lungs, inflammation of the intestinal tract, inflammation of mucosal tissue, and inflammation of the skin.

10. Use of the spray device according to any one of claims 1 to 7 for the preparation of a medicament, preferably a medicament useful in the treatment of an inflammatory disease or condition, preferably selected from the group consisting of inflammation of the respiratory tract, inflammation of the lungs, inflammation of the intestinal tract, inflammation of mucosal tissue and inflammation of the skin.

Images