New formulations of atropine

Abstract

The present invention relates to a novel formulation of atropine in the form of a gel, particularly for use in the treatment of hypersalivation.

Description

[Technical field]

[0001] The present invention relates to a novel formulation of atropine in the form of a gel for use in the treatment of hypersalivation, especially in patients with neurological diseases / disorders secondary to Parkinson's disease or in neurologically impaired children. [Background technology]

[0002] Hypersalivation, also known as sialorrhea, is excessive salivation and is generally associated with neurological disorders, but also with anatomical abnormalities of the oral cavity or swallowing disorders, including cerebral palsy (particularly in children), Parkinson's disease, and amyotrophic lateral sclerosis, or the adverse effects of medications (such as clozapine).

[0003] Sublingual atropine has been proposed to treat hypersalivation in children (Rapoport, J Pain Symptom Manage., 2010;40(5):783-8), following clozapine treatment (Van der Poorten and De Hert, Clin Case Rep. 2019;7(11): 2108-2113), or for patients with Parkinson's disease (Hyson et al, Mov Disord, 2002;17(6):1318-20).

[0004] Atropine is currently used as an eye drop administered via the sublingual route. In clinical practice, atropine is currently used in the form of eye drops administered sublingually in doses of one or two drops based on the patient's symptoms. Therefore, there is a significant risk of toxicity due to under- or overdosing, as the actual packaging does not have precise dropper advice. Moreover, the bitter taste of atropine may reduce patient acceptance of the treatment.

[0005] Thus, there is a need to provide new formulations of atropine that are easier to administer, provide better controlled dosage, and advantageously provide improved onsite delivery (increased time in the patient's mouth). Such formulations should be applied sublingually to allow for the most appropriate means of administering atropine, since sublingual application would transfer the active substance directly from the sublingual mucosa into the blood circulation, thus preventing migration within the gastric environment and improving the therapeutic effect of atropine. Moreover, it is preferable for the formulation to remain in the mouth long enough for atropine to enter the blood circulation without being eluted by saliva.

[0006] This formulation offers several advantages. (a) The formulation is easier to apply than current drop-by-drop formulations of atropine ophthalmic solution. (b) whereas drop-by-drop administration presents the risk of overdose, this formulation offers better control of the dose administered to the patient since the volume can be easily determined prior to sublingual administration, which increases patient safety; (c) this formulation makes it possible to increase the exchange surface in the buccal cavity by placing the gel on the buccal mucosa over a larger surface, where the droplets fall, in particular sublingually; and (d) In some embodiments, the formulation can be used in patients with tracheostomy cannulas. (e) This formulation, by virtue of its gel form, makes it possible to increase the amount of time that the active ingredient is present in the buccal cavity; this formulation makes it possible to obtain better bioavailability. (f) By using suitable buffers, sweeteners, flavorings or fragrances, or masking agents, the formulation may increase patient acceptance and compliance by neutralizing or masking the bitter taste of atropine.

[0007] US 2020297713 (Patent Document 1) describes an eye gel containing atropine, a viscosity enhancing agent, and a buffer.

[0008] US 2004136915 (Patent Document 2) describes a composition for oral administration of atropine. This composition does not solve the problems disclosed above, especially the control of the dose, the possibility of sublingual placement, and the long residence time in the mouth for transfer to the bloodstream. Therefore, there is a need to develop a formulation that addresses these issues and thus provides better properties and ease of use for oral administration of atropine, instead of replacing the formulation of US 2004136915 (Patent Document 2). [Prior art documents] [Patent documents]

[0009] [Patent Document 1] US 2020297713 [Patent Document 2] US 2004136915 [Non-patent literature]

[0010] [Non-Patent Document 1] Rapoport, J Pain Symptom Manage., 2010;40(5):783-8 [Non-Patent Document 2] Van der Poorten and De Hert, Clin Case Rep. 2019;7(11): 2108-2113 [Non-Patent Document 3] Hyson et al, Mov Disord, 2002;17(6):1318-20 Summary of the Invention

[0011] The present invention relates to a composition in the form of a gel, (a) atropine, (b) a thickener, which provides viscosity to the composition; (c) a buffer for stabilizing the pH of the composition at 3.5 to 4.5; The present invention relates to a composition comprising: DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The composition is in a form for oral administration and is intended to be provided under the patient's tongue (sublingual administration) either by direct placement or by spraying, depending on the form of the application system.

[0013] The thickening agent provides the viscosity of the formulation, so that the formulation has the form of a gel. It is noted that a gel is a three-dimensional matrix composed of two interpenetrating systems: a thickening agent or gelling agent and a dispersion medium containing the active ingredient (here atropine) in solution.

[0014] The viscosity of the gel should be suitable for oral administration, in particular for sublingual administration. It is therefore preferred if the viscosity is comprised in the range of 200-1000 mPa.s, preferably 200-600 mPa.s, more preferably 250-400 mPa.s at 25°C. Due to the fact that the composition should be stored at room temperature and is used inside the human body, it is preferred if the composition exhibits a viscosity of 200-1000 mPa.s at 20°C-37°C. The viscosity is measured according to methods known in the art. In particular, the rheological analysis can be carried out using an Anton Paar MCR 500 rheometer (Courtaboeuf, France) equipped with a cone-plate combination (diameter = 50 mm; angle = 1°) as a measuring system. This method is preferred, but other modules (8 mm-150 mm, angle 0-5°) can also be used. The apparent viscosity (Pa·s) of the formulation can also be measured with a continuous shear (flow) model.

[0015] The thickening agent is selected so as to be compatible with pharmaceutical use, and is particularly advantageously selected from the group consisting of hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinyl alcohol, gum arabic, guar gum, locust bean gum, gellan gum, carrageenan, xanthan gum, and carob.

[0016] Polymers based on cellulose, especially hydroxyethylcellulose or hydroxypropylmethylcellulose, are preferred. Hydroxyethylcellulose is particularly suitable, and such polymers based on cellulose, especially hydroxyethylcellulose or hydroxypropylmethylcellulose, are generally used at a concentration of 2.0-4.0% (w / w), more preferably 2.5-3.5% (w / w). An amount of about 3.0% (w / w in the composition) is particularly suitable. As intended herein, "about", "around" or "approximately" indicates a possible variation of 5% around the indicated amount.

[0017] To stabilize atropine, the pH of the composition is acidic. This also serves to mask its bitter taste. Of particular interest is the use of a buffer to stabilize the pH of the composition at 3.5 to 4.5. Any buffer suitable for pharmaceutical use can be selected. In particular, the buffer can be selected from the group consisting of citrate buffer, phosphate buffer, citrate-phosphate (McIlvaine) buffer, and acetate buffer. Citrate buffer is of particular note because it also provides a citrus taste. Such a taste is known and contributes to increasing the acceptability by the patient when the composition is administered.

[0018] In some embodiments, the composition also includes at least one agent capable of inducing, enhancing, or improving mucoadhesion or gelation upon buccal administration, particularly sublingual administration, which agent can increase the viscosity of the composition, particularly the agent that is in a liquid state when present in the composition and gels when in contact with the mucosa of the buccal cavity, particularly the sublingual mucosa.

[0019] Agents capable of interacting with divalent cations present in saliva or on the mucosal surfaces of the mouth can be used. In particular, sodium alginate is capable of interacting with the Ca2+ ions present in the mouth. 2+It gels upon contact with cations. The gelling of sodium alginate increases the viscosity of the composition after application in the mouth (preferably under the patient's tongue), which extends the residence time of the composition and therefore improves the transfer of atropine through the mucous membrane into the circulation. When sodium alginate is used, its concentration is preferably 0.15% to 0.35% (w / ), more preferably 0.2% to 0.3% (w / w), in particular approximately 0.25% (w / w).

[0020] Pectins, especially those with low methylation, can also be used, which also react with Ca under acidic conditions. 2+ It is capable of gelling when in contact with cations.

[0021] In another embodiment, the agent capable of inducing or enhancing mucoadhesion or gelation when administered bucally comprises a poloxamer or a mixture of poloxamers. It is reminced that poloxamer refers to a triblock copolymer that comprises or consists of a central polyoxypropylene chain (also called polypropylene glycol, PPO) grafted with polyoxyethylene chains (also known as polyethylene glycol, POE) on both sides. Poloxamers are generally represented by the letter "P" (for poloxamer) followed by three numbers: the first two numbers are multiplied by 100 to obtain the molecular weight of the polyoxypropylene core, and the last number is multiplied by 10 to obtain the percentage of polyoxyethylene content.

[0022] Useful poloxamers are those that are in a liquid state at room temperature, particularly at 2° C. to 25° C., and in a gel state at temperatures above their gelation temperature (Tg), particularly at 30° C. to 40° C., especially under physiological conditions. The gelation temperature (Tg) of a poloxamer can be determined according to conventional methods as described above or is available in reference books such as the Handbook of Pharmaceutical Excipients. These poloxamers are known to be useful for determining the gelation temperature (Tg) of a poloxamer when the temperature is above their gelation temperature (Tg), especially under physiological conditions (around 37° C.). g) or more. Thus, and preferably, the poloxamer gels at temperatures between 30° C. and 37° C., and more preferentially upon contact with the mucous membrane of the mouth. It may be noted that, although sublingual administration is preferred, spraying the composition onto the buccal mucosa is also envisaged when it contains a poloxamer.

[0023] Particularly suitable are poloxamer 407, poloxamer 188, or mixtures thereof.

[0024] The composition may also contain at least one additional component selected from the group consisting of aromas, flavors, dyes, sweeteners, and masking agents, which are used to improve the palatability of the composition (and mask the bitter taste of atropine) and also improve the visual aspects of the composition.

[0025] Low calorie sweeteners such as sucralose and stevia or its extracts (e.g., 97% rebaudioside A) may be included. The taste masking agent may be selected from natural and synthetic flavor liquids. Useful flavors include, but are not limited to, volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins, or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof. A non-limiting list of examples includes citrus oils (such as lemon, orange, grape, lime, and grapefruit), and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, or other fruit flavors. Caramel or cola flavors may also be used. The flavors are preferably associated with an acidic taste to match the pH of the solution. If a citrate buffer is used to stabilize the pH, citrus flavors are preferred, especially lemon or lime flavors.

[0026] Preservatives can also be added to the composition, especially when the formulation is packaged in a multi-dose container. Paraben-based preservatives, such as methyl-paraben, ethyl-paraben, propyl-paraben, or butyl-paraben, are preferably used, but other preservatives, such as benzyl alcohol, cresol, benzoic acid or sodium benzoate, sodium metabisulfite, propylene glycol, ethanol, phenol, or sorbic acid and its salts, can also be envisaged. In some embodiments, the composition does not contain any preservatives. This is particularly true when the composition is presented in a single unit dose (single dose). For this type of presentation, the addition of preservatives is not necessary, but is also undesirable, considering the potential toxicity of the amount of preservatives added depending on the size of the dose.

[0027] If the formulation is presented in a multi-dose format (which can be packaged in suitable packaging, such as airless packaging (to prevent growth or aerobic microorganisms)), it may be advisable to add some preservative, especially an antifungal preservative (since the disclosed compositions already have some bactericidal properties). Those mentioned above are suitable for this purpose.

[0028] The following can also be mentioned: - Benzyl alcohol, which can be used at 1% to 2.5% (w / w), such as around 1.75% (w / w); - Sorbic acid, which can be used at 0.1% to 0.02% (w / w), such as around 0.05% (w / w); - Sodium propionate: 0.02% to 1% (w / w), such as around 0.5% (w / w); - 0.05% to 0.2% (w / w) of benzoic acid, such as around 0.1% (w / w).

[0029] Benzoic acid is of particular interest.

[0030] It is noted that airless packaging or container is such that the formulation is contained in an oxygen-free state and air does not enter the container when used.In the container, an ultraprotective airless bag-in-bottle protects the formulation from contact with air or oxygen.Such designs are known in the art, and an example can be an airless dispensing pump, such as that described in US7891522.

[0031] It may also be of interest to add agents that aid in solubilizing the preservative, especially when paraben-based preservatives are used: non-ionic surfactants (such as poloxamer 407 or 188), tocophersolan (tocopherol polyethylene glycol succinate, TPGS, a synthetic water-soluble version of vitamin E), diethylene glycol monoethyl ether, propylene glycol, cyclodextrin, or ionic surfactants such as polysorbates.

[0032] In one embodiment, the composition is packaged as a single unit dose containing 100-2000 μg (0.1-2 mg) of atropine. The design of the single unit dose is adapted for sublingual administration of atropine. Value ranges of the form "x to y" include the ends x and y. In particular, the single unit dose may contain 400-600 μg, in particular about 500 μg, of atropine. The volume of the single unit dose is preferably about 0.2 mL.

[0033] In another embodiment, the composition is packaged in a kit that also includes a syringe-type dose dropper that is compatible with the viscous formulation and that is graduated so that the amount of composition dispensed from the container and administered to the patient can be easily controlled. The syringe can be easily placed under the patient's tongue for administering the composition sublingually.

[0034] In another embodiment, the composition is packaged as a spray, with a dose of 100-2000 μg (0.1-2 mg) of atropine being delivered per spray, more specifically 400-600 μg (in particular about 500 μg). Alternatively, this dose of atromine can be delivered in two or more sprays. Since the composition is already in the form of a gel, in this embodiment the viscosity of the gel can be reduced (within the lower ranges indicated above) compared to the viscosity of the composition placed directly on the sublingual mucosa. The device for spraying the composition can also be adapted to be able to spray the gel composition in a mist. In this embodiment, it is preferred if the composition contains a poloxamer as described above, in order to instantly form a thicker gel on the application area, which is preferentially sublingual.

[0035] The present invention also relates to a method for preparing or making the composition disclosed herein, comprising the steps of: obtaining a composition in the form of a gel containing atropine and having a stabilized pH of 3.5 to 4.5; (a) preparing a solution of atropine in a buffer to obtain a solution having a pH of 3.5 to 4.5; (b) optionally adding aromas, flavors, colors, sweeteners, and masking agents; (c) optionally adding an agent capable of improving mucoadhesion upon buccal administration; (d) optionally adding a preservative; (e) Adding a thickening agent The present invention relates to a method comprising the steps of:

[0036] The addition of the components in (b), (c), (d) and (e) is preferably carried out under stirring to improve and ensure good dissolution of the components. Addition of the thickener under stirring in (e) is particularly recommended.

[0037] When adding a thickening agent, the stirring speed is adapted to the viscosity of the composition. In particular, the agent is added slowly, even if it is a soluble component, to avoid the formation of lumps and poor solubilization. This generally also applies to components in powder form. The composition preferably contains 0.15-0.35% (w / w) atropine, more preferably 0.2-0.3%, more preferably 0.2-0.25%.

[0038] The amount of thickening agent is determined according to the specific characteristics of the agent used in the formulation to obtain the desired rheology of the composition (a gel composition that can be easily placed under the tongue and remain there). The compositions obtained or that can be obtained by this method (and the method of the examples) are also part of the present invention.

[0039] According to one embodiment, the formulation of the invention comprises approximately 0.25% (w / w) atropine, approximately 3% (w / w) hydroxyethylcellulose, approximately 0.25% (w / w) sodium alginate, approximately 0.12% (w / w) sweetener (in particular sucralose), optionally a preservative (in particular propyl-paraben, sodium propionate, or benzoic acid), and qsp 100% citrate buffer. If preservatives are added, they are present in the amounts indicated above. Thus, amounts of approximately 0.12% or 0.01-0.02% w / w can be used.

[0040] The term "approximately" refers to a range of values ​​of ±5% of a particular value.

[0041] The formulation is preferably sterile and may be prepared by sterile filtration, by radiation sterilization, or otherwise under aseptic conditions. More particularly, the solution is prepared and / or stored under sterile conditions in a suitable container (single-dose container, multi-dose container, bottle, optionally equipped with a suitable nebulizer).

[0042] The present invention also relates to a pharmaceutical composition comprising or consisting of a gel formulation as defined above, which is provided by the oral route, preferably sublingually or via spray onto the sublingual or buccal mucosa.

[0043] The present invention also relates to the compositions disclosed herein for use in the treatment of hypersalivation, in particular intended for sublingual administration into the buccal cavity. A dose of 500 μg of atropine is perfectly suited for such use.

[0044] As indicated, hypersalivation can be treated in patients suffering from neurological diseases, particularly Parkinson's disease, ALS (amyotrophic lateral sclerosis), multiple sclerosis, or post-stroke sequelae. EXAMPLES

[0045] Example 1. Preparation of atropine gel formulation A stock solution of 2% m / m atropine sulfate in water was prepared, eight times more concentrated than the final product.

[0046] This resulted in a stock solution that was evaluated for chemical stability for at least 21 days and was stored at 4°C.

[0047] Citrate buffer was used as the solvent for the formulation to maintain the pH at 4. The pH was verified before each use.

[0048] For the preparation of the development batch (20 g), the preparation was made by stirring using a magnetic bar of a size suitable for the container. The process consisted in diluting a small volume of the atropine sulfate stock solution with a defined amount of citrate buffer to obtain a solution 2 with a final concentration of atropine sulfate in atropine of 0.25%. The resulting solution was homogenized under stirring.

[0049] Then, in order to sweeten the solution for oral use, sucralose was added to solution 2 since it is an easily solubilized substance. The solubilization of sucralose was rapid without the need to increase the stirring speed. No physically visible incompatibility was observed. Solution 3 was then obtained.

[0050] The next step was the solubilization of sodium alginate. Sodium alginate is a natural polymer that obtains gelation in the presence of calcium ions. In the absence of calcium, the sodium alginate solution remains liquid. Although dissolving sodium alginate was relatively easy in solution 3 since it does not contain calcium ions, dissolution was performed carefully (by the "fine rain" method) due to the possibility of residual solid particles remaining. Addition of the entire amount of polymer, even with stirring, can induce the appearance of lumps that are difficult to dissolve. Therefore, sodium alginate (in powder form) was added in small portions to avoid agglomeration of the powder. Stirring was continued throughout the entire process. No visible incompatibilities were observed after obtaining solution 4.

[0051] Once the sodium alginate was dissolved, hydroxyethylcellulose (HEC) was added to the formulation. Unlike alginate, the addition of HEC induces an increase in the viscosity of the formulation. To solubilize this polymer, it was necessary to adjust the stirring speed to ensure constant vortexing. Solubilization of HEC was performed at room temperature since it is a water-soluble substance. Increasing the heat to initiate or improve solubilization is also preferred. However, care should be taken to avoid potential degradation of the active ingredient. The stirring speed was constantly adjusted according to the viscosity of the solution, while the HEC powder was gradually added in a "drizzle" fashion to prevent the formation of lumps as much as possible.

[0052] To ensure that the polymer chains of HEC were fully hydrated, the preparations were stored overnight at 4° C. Routine testing included pH control, rheological analysis, and mucoadhesive ability analysis.

[0053] Thus, the composition contains about 0.25% (w / w) atropine, about 3.0% hydroxyethylcellulose, and about 0.25% (w / w) sodium alginate prepared in a citrate buffer.

[0054] Example 2. Use of atropine gel formulation An acceptability / preference test of the formulation was carried out on four patients. The results show that: - Two patients found the new formulation to have a "pleasant" taste, one patient found it to have a "neutral" taste, and only one patient found it to have an "unpleasant" taste, especially since they were expecting a savory taste.

[0055] Four patients noted that the taste was different from the eye drop formulation, specifically, much less bitter.

[0056] One patient noted that the taste was better and lasted longer, suggesting that it stayed in the mouth longer.

[0057] On the caregiver side, feedback has also been positive.

[0058] Two nurses felt that the gel formulation was easier to prepare and administer than eye drops because it allowed for better control of the dose and facilitated administration under the tongue.

Claims

1. A composition in the form of a gel, comprising: (a) atropine, (b) a thickener to provide viscosity to the composition; (c) Buffer solution to stabilize pH at 3.5 to 4.5 wherein atropine is present in an amount of 0.15 to 0.35% (w / w). The composition.

2. 10. The composition of claim 1, wherein the atropine is present in an amount of 0.2 to 0.3% (w / w).

3. 10. The composition of claim 1, adapted for oral administration.

4. 10. The composition of claim 1, wherein the thickening agent is selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, polyvinyl alcohol, gum arabic, guar gum, locust bean gum, gellan gum, carrageenan, xanthan gum, and carob.

5. 2. The composition of claim 1, wherein the buffer is selected from the group consisting of citrate buffer, phosphate buffer, citrate-phosphate (McIlvaine) buffer, and acetate buffer.

6. 6. The composition of claim 5, wherein the buffer is a citrate buffer.

7. 10. The composition of claim 1, further comprising an agent capable of improving mucoadhesion when administered bucally.

8. 8. The composition according to claim 7, wherein the agent capable of improving mucoadhesion is an agent that gels by complexing with divalent cations present in saliva on the surface of the oral mucosa, in particular sodium alginate.

9. 8. The composition of claim 7, further comprising a poloxamer as an agent that enhances gelation upon contact with the mucosa of the buccal cavity, particularly the buccal or sublingual mucosa.

10. 10. The composition of claim 1, further comprising at least one additional component selected from the group consisting of fragrances, flavors, dyes, sweeteners, and masking agents.

11. 10. The composition of claim 1, further comprising a preservative.

12. 2. The composition of claim 1, wherein the thickening agent is a cellulosic polymer, particularly hydroxyethyl cellulose, and is present at a concentration of 2.0 to 4.0% (w / w), preferably about 3.0% (w / w in the composition).

13. 2. The composition of claim 1, wherein the composition contains about 0.25% (w / w) atropine, about 3.0% hydroxyethylcellulose, about 0.25% (w / w) sodium alginate, and the buffer is a citrate buffer.

14. 10. The composition of claim 1, wherein the preservative is selected from the group consisting of methyl-paraben, ethyl-paraben, propyl-paraben, butyl-paraben, benzyl alcohol, cresol, benzoic acid, sodium benzoate, sodium metabisulfite, sodium propionate, propylene glycol, ethanol, phenol, and sorbic acid.

15. 10. The composition of claim 1, packaged as a single unit dose containing 0.1 to 2 mg of atropine.

16. 10. The composition of claim 1, packaged in a kit further containing a syringe-type dose dropper adapted for viscous formulations.

17. 10. The composition of claim 1, packaged as a spray and delivering atropine in an amount of 0.1 to 2 mg per spray.

18. 10. The composition of claim 1, packaged in a multi-dose format in an airless container.

19. A method for preparing a composition according to any one of claims 1 to 18, comprising the steps of: (a) preparing a solution of atropine in a buffer to obtain a solution having a pH of 3.5 to 4.5; (b) optionally adding aromas, flavors, colors, sweeteners, and masking agents; (c) optionally adding an agent capable of improving mucoadhesion upon buccal administration; (d) optionally adding a preservative; and (e) adding a thickener to provide viscosity to the composition; wherein atropine is present in the composition in an amount of 0.15 to 0.35% (w / w).

20. A composition according to any one of claims 1 to 18 for use in the treatment of hypersalivation, in particular hypersalivation secondary to neurological disorders.

21. Use of atropine for preparing a formulation for the treatment of hypersalivation, comprising: The formulation is in the form of a gel, the formulation further comprises a thickening agent to provide viscosity to the formulation, and a buffer to stabilize the pH at 3.5 to 4.5, and atropine is present in an amount of 0.15 to 0.35% (w / w); The above use.

22. The use described in claim 21, wherein the formulation contains approximately 0.25% (w / w) atropine, approximately 3.0% (w / w) hydroxyethylcellulose as a thickener, approximately 0.25% (w / w) sodium alginate, and the buffer is a citrate buffer.