Stable mometasone furoate compositions

Abstract

The present invention relates to a water-soluble film having a mometasone furoate content adjusted to a pH in the range of 3.5 to 5.0. The correspondingly adjusted pH increases the stability of the active ingredient without substantially impairing the mechanical properties of the film. The present invention further relates to methods for producing such films, pharmaceutical dosage forms containing films of the above type in a capsule, and methods for producing such pharmaceutical dosage forms. The pharmaceutical dosage form can especially be used for treating eosinophilic esophagitis.

Description

[0001] Meissner Bolte M / LTSL-086-PC / I

[0002] Stable mometasone furoate-containing formulations

[0003] Description

[0004] The present invention relates to water-soluble polymer films containing mometasone furoate and a buffer for adjusting the pH to a range of 3.5 to 5.0. The present invention further relates to methods for producing such polymer films, pharmaceutical dosage forms containing such polymer films in a capsule, and methods for producing such pharmaceutical dosage forms. The pharmaceutical dosage forms can be used, in particular, for the treatment of eosinophilic esophagitis.

[0005] State of the art

[0006] Eosinophilic esophagitis is a chronic, allergy-like inflammation of the esophagus that causes significant difficulty swallowing solid food. Eosinophilic esophagitis (EE or EoE) was only recognized and described as a distinct disease in the late 1970s. Since then, new indicators have been developed and tested to characterize the inflammation in the esophagus and indicate its severity. It has been diagnosed with increasing frequency since the late 1990s.

[0007] In chronic eosinophilic esophagitis, the esophagus often loses elasticity, and the mucosal changes can also lead to esophageal strictures. Typical symptoms of eosinophilic esophagitis include difficulty swallowing, pain behind the breastbone not associated with swallowing, and food bolus obstruction, meaning a food bolus can become lodged in the esophagus.

[0008] Eosinophilic esophagitis remains incurable. However, medications can help alleviate the inflammation. These include locally acting cortisone preparations, administered as a spray into the throat or as a powder placed on the tongue, or systemically according to Meissner Bolte M / LTSL-086-PC / I.

[0009] These medications are taken orally. However, a problem with these dosage forms is that a large portion of the active ingredient does not reach its target site effectively. For example, a medication taken as a powder passes through the esophagus relatively quickly and enters the stomach, with only a small portion being absorbed in the esophagus. A similar problem arises with administration as a spray, as the active ingredient is mostly inhaled into the trachea rather than the esophagus. Furthermore, cortisone preparations, due to their local weakening of the immune system, are often associated with side effects such as oral thrush.

[0010] Against this background, there is a need for dosage systems and forms for pharmaceutical active ingredients that allow the active ingredient to be released precisely into a specific area of ​​the body where an effect is desired. To ensure the most targeted release possible, the dosage system should also remain in this area of ​​the body for as long as possible and release the active ingredient there.

[0011] In WO 2016 / 102067 Al and WO 2020 / 183005 Al, a concept for administering pharmaceutical agents to mucosal surfaces is described. This concept involves administering a folded formulation of the active ingredient within a capsule, where the folded formulation is modified with a release mechanism. Triggering this mechanism at a predetermined location initiates the unfolding of the folded formulation. As a result of this unfolding, the active ingredient can be released over a larger area, or the unfolded formulation may no longer be able to pass a constriction in the digestive tract (e.g., between the stomach and intestines), thus allowing the active ingredient to be released precisely before this constriction. The capsule serves the purpose of keeping the formulation in its folded form until the release mechanism is activated, which, for example,This can cause the folded formulation to be pulled out of the capsule.

[0012] Based on this technology, a dosage form was developed in which a film containing the active ingredient is administered in rolled-up form inside a capsule. When the capsule is swallowed, the film is pulled out through a slit and adheres to the esophageal mucosa, enabling the release of the active ingredient along the entire length of the esophagus.

[0013] However, a problem with this dosage form has emerged regarding the stability of the active ingredient, which is subject to increased degradation in the film. (Meissner Bolte M / LTSL-086-PC / I)

[0014] Corresponding studies showed, for example, that the active ingredient degraded by approximately 0.5% at 40°C after 8 weeks in the film-coated formulation, which is unacceptable for a pharmaceutical formulation. Against this background, there is a need for film-coated formulations in which the stability of the active ingredient is improved.

[0015] The present invention addresses this need.

[0016] Description of the invention

[0017] The present invention is based on the surprising finding that the stability of mometasone furoate in water-soluble film formulations is impaired by the comparatively high pH value in the film formulations.

[0018] This could be regulated by adjusting the pH value, but it must be ensured that the film properties for use in the concepts presented in WO 2016 / 102067 Al and WO 2020 / 183005 Al are not significantly affected by the pH-adjusting additives.

[0019] Accordingly, the present invention relates in a first aspect to a water-soluble film, in particular a polymer film, containing mometasone furoate or a pharmaceutically acceptable salt thereof, wherein the film is adjusted to a pH value in the range of 3.5 to 5.0. Preferably, the film is adjusted to a pH value in the range of 3.7 to 4.5 and particularly 3.8 to 4.2.

[0020] In principle, any pharmaceutically acceptable acid or buffer (i.e., acid / salt pair) can be used to adjust the pH value, provided it has a pKa value in the range of 3.5 to 5.0. The acid should expediently have a molecular weight of less than 500 g / mol, preferably less than 300 g / mol, and even more preferably less than 200 g / mol. Preferred buffers for use in the water-soluble polymer films according to the invention are buffers based on phosphoric acid or citric acid, since such buffers have only a negligible effect on the other film properties. A particularly preferred buffer is a citric acid buffer, with which the smallest changes in the mechanical properties were observed during prolonged storage of the films.When using buffers for pH adjustment, larger buffer quantities should be avoided, as these not only achieve the desired pH value in the film but also (at least temporarily) alter the physiological pH value in the esophagus, which is usually undesirable. A "smallest Meissner Bolte M / LTSL-086-PC / I."

[0021] The buffer quantity is achieved by adjusting the pH value using only acid, where the neutralization products of the pH adjustment form the base of the buffer.

[0022] Phosphoric acid is a preferred acid for pH adjustment. Citric acid is a further preferred acid for pH adjustment. The amount of acid to be added depends on the pH of the composition without the acid (which determines the minimum amount to be added). If a buffer is used for pH adjustment, the amount of buffer added should not exceed 10% by weight (based on the total amount of non-volatile film components). The use of citric acid as a buffer generally allows for higher additions without significant impairment of the film's mechanical properties, which may be due to citric acid's plasticizing effect in the films.

[0023] The water-soluble film contains, in addition to mometasone furoate as the active ingredient, essentially a water-soluble or water-erosive polymer, wherein a water-soluble polymer within the meaning of the invention is a polymer with a water solubility of at least 33 mg / mL (determined according to the US Pharmacopoeia). Water solubility here refers to equilibrium water solubility, i.e., depending on the formulation, it may take some time for a water-soluble polymer within the meaning of the invention to dissolve completely in water. Such behavior is preferred in the context of the invention.

[0024] The water-soluble polymer is not subject to any relevant restrictions in the context of the present invention, provided that it is a pharmaceutically acceptable polymer that preferably exhibits mucoadhesive properties. Examples of such polymers include, for example, cellulose derivatives, in particular cellulose esters or ethers, such as hydroxypropyl methylcellulose (HMPC) or hydroxypropyl cellulose (HPC), starch and starch derivatives, in particular starch esters and ethers, polyvinyl alcohol, polyethylene oxide, polyacrylic acid and polyacrylate derivatives, polyvinylpyrrolidone, povidone, copovidone, sodium alginate, gelatin, xanthan gum, carrageenan, pectins, dextran, pullulan, and mixtures thereof. Particularly preferred water-soluble or water-erodible polymers include polyvinylpyrrolidone, cellulose derivatives, and polyvinyl alcohol. A most particularly preferred polymer is polyvinyl alcohol.The polymer forms the matrix in the film in which the active ingredient is dissolved or dispersed. Meissner Bolte M / LTSL-086-PC / I.

[0025] The proportion of the water-soluble or water-erosive polymer in the film is generally 50 wt.% or more (based on the total weight of the non-volatile components in the film), in particular more than 60 wt.%, more preferably more than 70 wt.% and even more preferably more than 80 wt.%.

[0026] To impart suitable flexibility that can prevent breakage or tearing of the film, a plasticizer can be incorporated into the film. Suitable plasticizers include pharmaceutically acceptable polyols such as polyethylene glycol, glycerol and other polyhydric alcohols, higher alcohols such as dodecanol, undecanol or octanol, sorbitol, mannitol and other sugar alcohols, or dexpanthenol and triglycerides. Glycerol is a particularly suitable plasticizer in the context of the present invention.

[0027] The amount of plasticizer to be included in the film depends on the mechanical properties of the water-soluble or water-dispersible polymer. Generally, enough plasticizer is added to achieve the desired properties. As a rough guideline, a plasticizer content of 2 to 20 wt%, and particularly 4 to 10 wt%, can be specified.

[0028] Water can also act as a plasticizer in the film, with a water content in the film of less than 10 wt.% being preferred and a content of about 2.0 to 7.5 wt.% being particularly advantageous.

[0029] In addition to the aforementioned components, the film may contain further ingredients, such as lubricants, binders or emulsifiers, additional active ingredients, disintegrants, antioxidants, chelating agents, coating agents, flow agents, preservatives, fillers, penetration enhancers, solubilizers, degradation accelerators, surfactants, or pigments. Suitable emulsifiers include, for example, polyethoxylated sorbitan fatty acid esters, ethoxylated fatty alcohols, or lecithin. Suitable fillers include highly dispersed silicon dioxide, titanium dioxide, zinc oxide, chalk, and starch. Usable permeation enhancers include, for example, fatty acids and fatty acid esters, polyhydric alcohols such as propanediol, tocopherols, or essential oils such as menthol.

[0030] Typically, such additional ingredients are included in the film formulation in small proportions, for example, a maximum of approximately 10% by weight, based on the total weight of the film. Meissner Bolte M / LTSL-086-PC / I

[0031] The dimensions of the film are suitably adapted to the intended application. The film is longer than 5 cm, preferably longer than 10 cm, more preferably longer than 15 cm, and more preferably longer than 20 cm, and preferably shorter than 95 cm, more preferably shorter than 70 cm, and even more preferably shorter than 50 cm. The film thickness can be in a range of 0.01 mm to 2 mm, preferably 0.03 mm to 1 mm, more preferably 0.05 mm to 0.5 mm, more preferably 0.05 mm to 0.2 mm, and even more preferably 0.08 mm to 0.15 mm, or 0.1 mm to 0.12 mm. In this way, a strip-like preparation with a comparatively small thickness is provided.

[0032] The film has an area between 0.5 and 25 cm². 2 on, preferably between 1 and 25 cm 2 , preferably between 5 and 10 cm 2 , preferably larger than 0.5 cm 2 and preferably smaller than 40 cm 2 The ratio between the length and width of the film is between 40:1 and 400:1, or preferably 60:1 and 300:1, or preferably 80:1 and 200:1. Accordingly, the film in most cases has a width in the range of 0.2 to 1 cm, with a width in the range of 0.3 to 0.6 cm being preferred.

[0033] Another aspect of the present invention relates to a method for producing a water-soluble film as described above (i.e., a film whose pH is adjusted in the range of 3.5 to 5.0, preferably 3.7 to 4.5, and particularly 3.8 to 4.2), wherein the method comprises the steps (i) forming a solution or dispersion of mometasone furoate or a pharmaceutically acceptable salt thereof, a water-soluble polymer, and optionally further film components, (ii) casting the solution or dispersion into a film, and (iii) drying the film. The solution in step (i) is prepared by adding a pharmaceutically acceptable solvent, such as water or ethanol, etc., wherein a solution in water (and correspondingly water as the solvent) is preferred. Drying is advantageously carried out at a temperature in the range of 50°C to 100°C, and particularly 65°C to 90°C.

[0034] Finally, another aspect of the present invention relates to the use of an acid for stabilizing mometasone furoate in a water-soluble polymer film, wherein the acid adjusts the pH to a range of 3.5 to 5.0, preferably 3.7 to 4.5, and particularly 3.8 to 4.2. Meissner Bolte M / LTSL-086-PC / I

[0035] The present invention is illustrated in more detail below by means of an example, which, however, is not to be construed in any way as limiting the scope of protection of the application.

[0036] Example 1:

[0037] Various film compositions, with and without phosphate and citric acid, were produced and processed into films. The films each had a basis weight of 100 g / m². 2 The compositions used to manufacture the films under investigation are listed in Table 1 below:

[0038] Table 1

[0039]

[0040] To produce the films, the active ingredient was first finely dispersed in glycerol. Then, polyvinyl alcohol dissolved in water was added and stirred until a homogeneous mixture was obtained. The mixture was degassed, poured onto a support, and dried at 70°C. The pH of the samples was determined by dissolving 2 g of film mass in 50 g of water and subsequently measuring the pH.

[0041] The films were then cut to dimensions of 250 x 4 mm (10 cm). 2 ) punched and exposed to various storage conditions. The films were then tested for their mechanical properties and mometasone furoate content. Meissner Bolte M / LTSL-086-PC / I

[0042] Degradation products were examined. The results are given in Tables 2 and 3 below.

[0043] Table 2

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[0048]

[0049] Table 2 shows that the active ingredient mometasone furoate can be effectively stabilized against degradation, even during prolonged storage, by adjusting the pH to approximately 4. The mechanical properties of the produced films proved suitable for use in the concepts described in WO 2016 / 102067 Al and WO 2020 / 183005 Al.

Claims

Meissner Bolte M / LTSL-086-PC / I Claims 1. Water-soluble film containing mometasone furoate or a pharmaceutically acceptable salt thereof, characterized in that the film is adjusted to a pH value in the range of 3.5 to 5.0, preferably 3.7 to 4.5 and particularly 3.8 to 4.

2.

2. Water-soluble film according to claim 1, characterized in that the water-soluble film is adjusted to the pH value with phosphoric acid or citric acid, preferably with citric acid.

3. Water-soluble film according to at least one of claims 1 or 2, characterized in that the film contains polyvinylpyrrolidone, a cellulose derivative, or polyvinyl alcohol, preferably polyvinyl alcohol, as a matrix polymer for the active ingredient.

4. Water-soluble film according to at least one of the preceding claims, characterized in that the film additionally contains a plasticizer, preferably in the form of a pharmaceutically acceptable polyol, in particular glycerol, and / or water.

5. Water-soluble film according to at least one of the preceding claims, characterized in that the film has a width in the range of 0.2 to 1 cm and preferably 0.3 to 0.6 cm and / or a length in the range of 5 to 95 cm, preferably 10 to 70 cm and further preferably 20 to 50 cm.

6. A method for producing a water-soluble film according to any one of claims 1 to 5, comprising forming a solution or dispersion of mometasone furoate or a pharmaceutically acceptable salt thereof, a water-soluble polymer and optionally further components, casting the solution or dispersion into a film and drying the film.

7. Use of an acid for stabilizing mometasone furoate in a water-soluble film, wherein the acid adjusts the pH to a range of 3.5 to 5.0, preferably 3.7 to 4.5 and particularly 3.8 to 4.2.

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