Packaged dextromethorphan quinidine orally disintegrating tablets

Abstract

The present invention discloses a stable dextromethorphan-quinidine orally disintegrating tablet, specifically a packaged dextromethorphan-quinidine orally disintegrating tablet. The orally disintegrating tablet comprises dextromethorphan or a pharmaceutically acceptable salt or hydrate thereof, quinidine or a pharmaceutically acceptable salt or hydrate thereof, sucralose, a flavor, a disintegrant, and a blister package. The orally disintegrating tablet can maintain a good appearance after being stored at 40° C. and 75% RH for three months, and can also effectively mask the bitterness and numbing taste of dextromethorphan and quinidine.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, in particular to packaged or stabilized dextromethorphan quinidine orally disintegrating tablets. Background Art

[0002] Dextromethorphan hydrobromide and quinidine sulfate is a combination drug developed by Avanir Pharmaceuticals Inc. for the treatment of pseudobulbar affect (PBA), which was first approved by the FDA in October 2010. This drug is the first and only drug used to treat PBA, also known as emotional incontinence. PBA is primarily secondary to neurological diseases such as Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and stroke, and is characterized by sudden, involuntary crying or laughing.

[0003] Dextromethorphan and quinidine have a very unpleasant taste, being bitter and numbing. They are currently marketed in capsule form. Patients with neurological diseases often experience symptoms such as dysphagia and salivation. Studies have shown that the incidence of dysphagia in Parkinson's disease patients ranges from 11-87%. Over 50% of patients with acute cerebral infarction experience varying degrees of dysphagia. The incidence of dysphagia in stroke patients is approximately 51-73%. Dysphagia is a common problem for patients with periarthritis (PBA), making capsules unsuitable for these patients, as swallowing capsules increases their pain.

[0004] The applicant's prior application CN114469882A disclosed a dextromethorphan-quinidine orally disintegrating tablet, which solved the problems of dysphagia and taste masking. However, during the stability study of the formulation, the applicant discovered that the tablets had spots, resulting in an unqualified appearance.

[0005] In order to solve the problem of spots on dextromethorphan-quinidine tablets, it is urgent to develop a formulation that can simultaneously meet the requirements of no spots in appearance and masking taste. Summary of the Invention

[0006] The object of the present invention is to solve the problem of spots on orally disintegrating tablets in the prior art and to provide dextromethorphan-quinidine orally disintegrating tablets or orally disintegrating tablets with good appearance and stable storage.

[0007] A first aspect of the present invention provides a packaged dextromethorphan-quinidine orally disintegrating tablet, the orally disintegrating tablet comprising dextromethorphan or a pharmaceutically acceptable salt or hydrate thereof, quinidine or a pharmaceutically acceptable salt or hydrate thereof, sucralose, a flavor, and a disintegrant;

[0008] The package is a blister, and the volume ratio of the blister to the orally disintegrating tablet is greater than or equal to 3.3 or the ratio of the cross-sectional diameter of the blister to the diameter of the orally disintegrating tablet is greater than or equal to 2.0.

[0009] In a preferred embodiment, the volume ratio of the blister to the orally disintegrating tablet is greater than 3.3, more preferably greater than 3.6, further preferably greater than 4.0, more preferably greater than 10.0, and most preferably greater than 19.0.

[0010] In another preferred embodiment, the ratio of the blister cross-sectional diameter to the orally disintegrating tablet diameter is 2.0-4.1; preferably, the ratio of the blister cross-sectional diameter to the orally disintegrating tablet diameter is greater than 2.0; preferably, the ratio of the blister cross-sectional diameter to the orally disintegrating tablet diameter is greater than 2.4; preferably, the ratio of the blister cross-sectional diameter to the orally disintegrating tablet diameter is greater than 4.1.

[0011] In another preferred embodiment, the volume ratio of the blister to the orally disintegrating tablet is 3.35 or 3.61 or 19.36, or the ratio of the cross-sectional diameter of the blister to the diameter of the orally disintegrating tablet is 2.0 or 2.4 or 4.1.

[0012] The blister is a double aluminum blister, one side of which is polyamide / aluminum / polyvinyl chloride and the other side is aluminum foil.

[0013] In a specific embodiment of the present invention, the content of sucralose in the orally disintegrating tablet is 0.5%-3%, more preferably 0.5-2.33%.

[0014] In a specific embodiment of the present invention, the mass ratio of dextromethorphan or its pharmaceutically acceptable salt or its hydrate to quinidine or its pharmaceutically acceptable salt or its hydrate in the tablet is 2:1;

[0015] Preferably, the weight of dextromethorphan or its pharmaceutically acceptable salt or its hydrate and quinidine or its pharmaceutically acceptable salt or its hydrate as active ingredients in the tablet accounts for 16-20% of the total tablet weight.

[0016] In a specific embodiment of the present invention, the disintegrant is cross-linked polyvinylpyrrolidone or a combination of cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose. The weight of the disintegrant in the tablet accounts for 10-35%, preferably 20-30%, of the total weight of the dextromethorphan-quinidine orally disintegrating tablet.

[0017] In a specific embodiment of the present invention, the flavor is mint flavor.

[0018] In a specific embodiment of the present invention, the orally disintegrating tablet further contains a glidant and a lubricant.

[0019] A second aspect of the present invention provides a packaging method for the above-mentioned dextromethorphan-quinidine orally disintegrating tablets, wherein the sealing temperature of the blister package is less than or equal to 180°C, preferably 150-160°C.

[0020] A third aspect of the present invention provides use of the packaged dextromethorphan-quinidine orally disintegrating tablets described above, or the packaged dextromethorphan-quinidine orally disintegrating tablets obtained by the packaging method described above, in the preparation of a medicament for treating and / or preventing pseudobulbar affect, dysphagia, salivation or speech disorders, and cognitive deficits in patients with neurological diseases.

[0021] Beneficial technical effects

[0022] Compared with the prior art, the present invention provides a dextromethorphan-quinidine orally disintegrating tablet containing a double aluminum package. The orally disintegrating tablet can maintain a good appearance even at 40°C / 75% RH for three months, while effectively masking the bitter and numbing taste of dextromethorphan and quinidine. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 : Effects of high (2.33%) and low (1.01%) sucralose content on tablet properties. DETAILED DESCRIPTION

[0024] Without being bound by any theory, the applicants first speculated that the amount of sucralose used would affect the generation and amount of spots in dextromethorphan-quinidine orally disintegrating tablets. Since dextromethorphan and quinidine are a compound preparation with both extremely strong bitter and numbing tastes, and sucralose is a sweetener, adjusting its dosage presents significant technical challenges. However, contrary to the researchers' expectations, the applicants discovered in experiments that reducing the amount of sucralose still yielded a formulation with satisfactory taste. Further, through extensive research, the applicants found that when the amount of sucralose in dextromethorphan-quinidine orally disintegrating tablets is 0.5%-1.1%, the spots are minimized while achieving a taste-masking effect.

[0025] Therefore, the present invention provides a dextromethorphan-quinidine orally disintegrating tablet, which comprises dextromethorphan or a pharmaceutically acceptable salt or hydrate thereof, quinidine or a pharmaceutically acceptable salt or hydrate thereof, sucralose, a flavor, and a disintegrant; wherein the content of sucralose is 0.5%-1.1%, more preferably 0.5%-1.05%, and even more preferably 0.5%-1.01%.

[0026] In a specific embodiment of the present invention, the mass ratio of dextromethorphan or its pharmaceutically acceptable salt or its hydrate to quinidine or its pharmaceutically acceptable salt or its hydrate in the orally disintegrating tablet is 2:1.

[0027] In a specific embodiment of the present invention, the weight of dextromethorphan or its pharmaceutically acceptable salt or its hydrate and quinidine or its pharmaceutically acceptable salt or its hydrate as active ingredients in the tablet accounts for 16-20% of the total tablet weight.

[0028] In a specific embodiment of the present invention, the weight of the disintegrant in the orally disintegrating tablet accounts for 10-35% of the total tablet weight, preferably 20-30%.

[0029] In a specific embodiment of the present invention, the flavor is mint flavor.

[0030] In a specific embodiment of the present invention, the disintegrant is cross-linked polyvinylpyrrolidone or a combination of cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose.

[0031] In a specific embodiment of the present invention, the orally disintegrating tablet further contains a glidant and a lubricant.

[0032] The "dextromethorphan" in the dextromethorphan quinidine orally disintegrating tablets of the present invention refers to dextromethorphan, its pharmaceutically acceptable salts or hydrates thereof, including but not limited to hydrobromide, hydrochloride, phosphate, hydroiodide, nitrate, formate, sulfate, acetate, propionate, butyrate, trifluoroacetate, p-toluenesulfonate, lysine salt, N,N'-dibenzylethylenediamine salt, procaine salt, chloroprocaine salt, diethylene glycolamine salt, ethylenediamine salt, meglumine salt, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt or hydrates of the above salts, preferably hydrobromide, hydrochloride, phosphate, hydroiodide or hydrates of the above salts, more preferably The term "quinidine" refers to quinidine, a pharmaceutically acceptable salt thereof, or a hydrate thereof, including but not limited to sulfate, polygalacturonate, hydrochloride, hydroiodide, hydrobromide, phosphate, nitrate, oxalate, p-toluenesulfonate, gluconate, lysine salt, N,N'-dibenzylethylenediamine salt, procaine salt, chloroprocaine salt, diethylene glycolamine salt, ethylenediamine salt, meglumine salt, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, or a hydrate of the above salts, preferably sulfate, polygalacturonate, hydrochloride, or a hydrate of the above salts, more preferably sulfate or sulfate hydrate.

[0033] During their research, the inventors unexpectedly discovered that tablets packaged in large blisters are more stable than those packaged in small blisters, maintaining a good appearance for a longer period of time. This provides another solution to the spotting problem. Contrary to the common understanding in the prior art that "larger blisters contain more air, making them less suitable for tablet preservation," this unexpected technical effect is achieved. Without being bound by theory, given that pharmaceutical-standard double aluminum blisters are unlikely to contain volatile impurities, a plausible explanation is that the larger enclosed space provided by the large blisters dilutes the volatile substances generated by the tablets themselves that cause spotting (for example, doubling the blister volume reduces the concentration of volatile substances by half), thereby reducing the rate of spotting.

[0034] Therefore, the present invention also provides packaged dextromethorphan-quinidine orally disintegrating tablets, wherein the package is a blister, the volume ratio of the blister to the orally disintegrating tablet is greater than or equal to 3.3, or the ratio of the cross-sectional diameter of the blister to the diameter of the orally disintegrating tablet is greater than or equal to 2.0.

[0035] In a preferred embodiment, the volume ratio of the blister to the orally disintegrating tablet is greater than 3.6, more preferably greater than 4.0, further preferably greater than 10.0, and most preferably greater than 19.0.

[0036] In another preferred embodiment, the ratio of the blister cross-sectional diameter to the orally disintegrating tablet diameter is 2.0-4.1; preferably, the ratio of the blister cross-sectional diameter of the orally disintegrating tablet to the orally disintegrating tablet diameter is greater than 2.0; preferably, the ratio of the blister cross-sectional diameter to the orally disintegrating tablet diameter is greater than 2.4; preferably, the ratio of the blister cross-sectional diameter to the orally disintegrating tablet diameter is greater than 4.1.

[0037] In another preferred embodiment, the volume ratio of the blister to the orally disintegrating tablet is 3.35, 3.61 or 19.36.

[0038] In another preferred embodiment, the ratio of the cross-sectional diameter of the blister to the diameter of the orally disintegrating tablet is 2.0, 2.4 or 4.1.

[0039] The blister is a double aluminum blister, one side of which is polyamide / aluminum / polyvinyl chloride and the other side is aluminum foil.

[0040] In a preferred embodiment, the orally disintegrating tablet comprises dextromethorphan or a pharmaceutically acceptable salt or hydrate thereof, quinidine or a pharmaceutically acceptable salt or hydrate thereof, sucralose, a flavor, and a disintegrant; wherein the content of sucralose is 0.5%-3%, more preferably 0.5-2.33%; further preferably 0.5%-1.1%, even more preferably 0.5%-1.05%, and most preferably 0.5%-1.01%.

[0041] In a specific embodiment of the present invention, the mass ratio of dextromethorphan or its pharmaceutically acceptable salt or its hydrate to quinidine or its pharmaceutically acceptable salt or its hydrate in the tablet is 2:1.

[0042] In a specific embodiment of the present invention, the weight of dextromethorphan or its pharmaceutically acceptable salt or its hydrate and quinidine or its pharmaceutically acceptable salt or its hydrate as active ingredients in the tablet accounts for 16-20% of the total tablet weight.

[0043] In a specific embodiment of the present invention, the weight of the disintegrant in the tablet accounts for 10-35% of the total weight of the dextromethorphan-quinidine orally disintegrating tablet, preferably 20-30%.

[0044] In a specific embodiment of the present invention, the flavor is mint flavor.

[0045] In a specific embodiment of the present invention, the disintegrant is cross-linked polyvinylpyrrolidone or a combination of cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose.

[0046] In a specific embodiment of the present invention, the orally disintegrating tablet further contains a glidant and a lubricant.

[0047] The inventors of the present application also found during the research process that the sealing temperature of the blister package of dextromethorphan-quinidine orally disintegrating tablets affects the formation of spots on the preparation, and the higher the temperature, the more likely spots are to form.

[0048] Therefore, another aspect of the present invention provides a packaging method for the above-mentioned dextromethorphan-quinidine orally disintegrating tablets, wherein the sealing temperature of the blister package is less than or equal to 180°C, preferably 150-160°C.

[0049] Another object of the present invention is to provide use of the above-mentioned dextromethorphan-quinidine orally disintegrating tablets, or the above-mentioned packaged dextromethorphan-quinidine orally disintegrating tablets, or the packaged dextromethorphan-quinidine orally disintegrating tablets obtained by the above-mentioned encapsulation method, in the preparation of a medicament for treating and / or preventing pseudobulbar mood, dysphagia, salivation or speech disorders, and cognitive deficits in patients with neurological diseases.

[0050] Compared with the prior art, the present invention provides a dextromethorphan-quinidine orally disintegrating tablet containing a double aluminum package. The orally disintegrating tablet can maintain a good appearance even at 40°C / 75% RH for three months, while effectively masking the bitter and numbing taste of dextromethorphan and quinidine.

[0051] The technical solutions of the present invention will be described in further detail below in conjunction with specific embodiments. It should be understood that the following embodiments are merely illustrative and explain the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope that the present invention is intended to protect.

[0052] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0053] General equipment and methods

[0054] The instruments and equipment used in the present invention mainly include: electronic balance, hopper mixer, orally disintegrating tablet disintegrator, tablet hardness tester, tablet press

[0055] The reagent components and effects used in the present invention are as follows:

[0056]

[0057]

[0058] Determination of spots

[0059] The spots are measured by combining direct observation and UV absorption. The UV method is operated as follows:

[0060] The tablets were dissolved in a fixed volume of methanol and UV absorption was measured at a wavelength of 365 nm. By comparing a large number of UV absorption values ​​with visual inspection of the orally disintegrating tablets for spots, it was found that when spots were present on dextromethorphan-quinidine orally disintegrating tablets, the UV value was always greater than 0.15. Therefore, 0.15 was used as the cutoff. When the UV absorption value was less than or equal to 0.15, the orally disintegrating tablet was considered to have acceptable appearance, and when the UV absorption value was greater than 0.15, the orally disintegrating tablet was considered to have unacceptable appearance.

[0061] Taste masking effect test:

[0062] Before taking the medicine, the volunteer moistened their mouth, placed the tablet on the top of their tongue, moved their tongue until the tablet lumps disappeared, and then spitted out the medicine. The severity of the tongue numbness and bitterness of the tablet tasted were recorded. After rinsing their mouth until no bitterness remained in their mouth, they tasted the next batch of tablets. The evaluation criteria were:

[0063] Grittiness: Acceptable, Unacceptable

[0064] Numb tongue: acceptable, unacceptable

[0065] Comprehensive palatability evaluation: acceptable, unacceptable

[0066] Example 1 Tablets with 0.5% low sucralose content can still meet taste requirements

[0067] Tablet preparation: 20 mg of dextromethorphan hydrobromide, 10 mg of quinidine sulfate, and 2 mg of colloidal silicon dioxide were weighed, mixed, and sieved. 32 mg of mannitol, 16 mg of xylitol, 40 mg of microcrystalline cellulose, 20 mg of crospovidone, 0.86 mg of sucralose, and 4 mg of mint flavor were added, mixed, and then sieved. 2 mg of sieved sodium stearyl fumarate was added, mixed, and granulated. 20 mg of sieved crospovidone and 2 mg of sieved sodium stearyl fumarate were added, mixed, and tableted to obtain round dextromethorphan quinidine orally disintegrating tablets with a diameter of 8.1 mm.

[0068] After a tasting experiment with 10 volunteers, the masking effect was obtained as shown in Table 1. Although a few subjects reported a tongue numbing effect, the 0.5% sucralose content still had a good effect in masking the bitterness and numbing taste of the compound.

[0069] Table 1 Taste-masking effect of 0.5% sucralose

[0070]

[0071] Example 2: Reduced sucralose content reduces the amount of spots on tablets (small blisters, packaging temperature 180°C)

[0072] Tablets with high and low sucralose contents were prepared, and the spots were observed at different time points under 40°C / 75% RH conditions (see Tables 2 and Figure 1 ):

[0073] Table 2 Comparison of stability of different sucralose contents

[0074] Trait observation period Tablets contain 2.33% sucralose Tablets sucralose content 1.01% January White flakes White flakes February Off-white flakes with obvious large spots White or off-white, some pieces have a few spots March There are many spots on each piece, and some pieces are covered with spots. There are spots on each piece, but the spots are smaller and less in number than those in the 2.33% group.

[0075] Example 3 Optimization of Blister Size (Sucralose Content 1.01%)

[0076] 20 mg of dextromethorphan hydrobromide, 10 mg of quinidine sulfate, and 2 mg of colloidal silicon dioxide were weighed, mixed, and sieved. 32 mg of mannitol, 16 mg of xylitol, 40 mg of microcrystalline cellulose, 20 mg of crospovidone, 1.72 mg of sucralose, and 4 mg of mint flavor were added, mixed, and then filtered. The mixture was mixed again, and 2 mg of sieved sodium stearyl fumarate was added. The mixture was mixed evenly and granulated. 20 mg of sieved crospovidone and 2 mg of sieved sodium stearyl fumarate were added, mixed, and tableted to obtain round dextromethorphan quinidine orally disintegrating tablets with a diameter of 8.1 mm.

[0077] A polyamide / aluminum / polyvinyl chloride solid pharmaceutical composite hard tablet was cold-stamped using a mold of the size shown in Table 3, and the dextromethorphan-quinidine orally disintegrating tablets prepared above were placed therein. The tablets were then sealed with pharmaceutical aluminum foil at the sealing temperature shown in Table 3 to obtain dextromethorphan-quinidine orally disintegrating tablets containing double aluminum packaging.

[0078] The dextromethorphan-quinidine orally disintegrating tablets containing double aluminum packaging obtained above were placed under 40°C / 75% RH conditions for 1 month, 2 months, and 3 months. An appropriate amount of sample was taken at each time point, and the dextromethorphan-quinidine orally disintegrating tablets were taken out after tearing the aluminum foil. After observing the properties, they were dissolved in methanol and the ultraviolet absorption was measured at a wavelength of 365 nm.

[0079] Table 3 Effect of blister size and packaging temperature on spots

[0080]

[0081] *Blister volume and orally disintegrating tablet volume are calculated based on size and shape.

[0082] From the results in Table 3, we can see that at a packaging temperature of 150°C, the properties of the dextromethorphan-quinidine orally disintegrating tablets obtained from large and medium blister packaging remained good after being stored at 40°C / 75% RH for 3 months, indicating that larger blisters are conducive to tablet stability.

[0083] It should be noted that the aforementioned preferred embodiments are further, non-limiting, detailed descriptions of the technical solutions of the present invention and are intended solely to illustrate the technical concepts and features of the present invention. Their purpose is to enable those skilled in the art to understand and implement the present invention, and they are not intended to limit the scope of protection of the present invention. Any equivalent variations or modifications based on the spirit and substance of the present invention are intended to be encompassed within the scope of protection of the present invention.

Claims

1. A packaged dextromethorphan / quinidine orally disintegrating tablet, comprising dextromethorphan or a pharmaceutically acceptable salt or hydrate thereof, quinidine or a pharmaceutically acceptable salt or hydrate thereof, sucralose, a flavor, and a disintegrant, wherein the package is a blister. The volume ratio of the blister to the orally disintegrating tablet is greater than 3.6 or the ratio of the diameter of the blister cross section to the orally disintegrating tablet diameter is greater than 2.0; The content of sucralose in the orally disintegrating tablet is 0.5%-1.1%; The mass ratio of dextromethorphan or its pharmaceutically acceptable salt or its hydrate to quinidine or its pharmaceutically acceptable salt or its hydrate in the tablet is 2:1; The weight of dextromethorphan or its pharmaceutically acceptable salt or its hydrate and quinidine or its pharmaceutically acceptable salt or its hydrate as active ingredients in the tablet accounts for 16-20% of the total tablet weight; The disintegrant is cross-linked polyvinylpyrrolidone or a combination of cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose, and the weight of the disintegrant in the tablet accounts for 10-35% of the total weight of the dextromethorphan-quinidine orally disintegrating tablet; The flavor is mint flavor; The sealing temperature of blister packaging is 150-160℃.

2. The packaged dextromethorphan-quinidine orally disintegrating tablets according to claim 1, wherein the volume ratio of the blister to the orally disintegrating tablet is greater than 4.0; or the ratio of the cross-sectional diameter of the blister to the diameter of the orally disintegrating tablet is greater than 2.

4.

3. The packaged dextromethorphan-quinidine orally disintegrating tablets according to claim 2, wherein the volume ratio of the blister to the orally disintegrating tablet is greater than 10.0; or the ratio of the cross-sectional diameter of the blister to the diameter of the orally disintegrating tablet is greater than 4.

1.

4. The packaged dextromethorphan-quinidine orally disintegrating tablets according to claim 3, wherein the volume ratio of the blister to the orally disintegrating tablet is greater than 19.

0.

5. The packaged dextromethorphan-quinidine orally disintegrating tablets according to claim 1, wherein the volume ratio of the blister to the orally disintegrating tablet is 3.6-19.36; or the ratio of the cross-sectional diameter of the blister to the diameter of the orally disintegrating tablet is 2.4-4.

1.

6. The packaged dextromethorphan-quinidine orally disintegrating tablets according to claim 1, wherein the volume ratio of the blister to the orally disintegrating tablet is 3.61 or 19.36, or the ratio of the cross-sectional diameter of the blister to the diameter of the orally disintegrating tablet is 2.4 or 4.

1.

7. The packaged dextromethorphan-quinidine orally disintegrating tablet according to any one of claims 1 to 3, wherein the content of sucralose in the orally disintegrating tablet is 0.5% to 1.05%.

8. The packaged dextromethorphan-quinidine orally disintegrating tablet according to claim 7, wherein the content of sucralose in the orally disintegrating tablet is 0.5%-1.01%.

9. The packaged dextromethorphan-quinidine orally disintegrating tablet according to any one of claims 1 to 3, wherein the weight of the disintegrant in the tablet accounts for 20-30% of the total weight of the dextromethorphan-quinidine orally disintegrating tablet.

10. The packaged dextromethorphan-quinidine orally disintegrating tablet according to any one of claims 1 to 3, further comprising a glidant and a lubricant.

11. The packaging method of the dextromethorphan-quinidine orally disintegrating tablets according to any one of claims 1 to 10, characterized in that: The sealing temperature of blister packaging is 150-160℃.

12. Use of the packaged dextromethorphan-quinidine orally disintegrating tablets according to any one of claims 1 to 10, or the packaged dextromethorphan-quinidine orally disintegrating tablets obtained by the encapsulation method according to claim 11, in the preparation of a medicament for treating and / or preventing pseudobulbar mood, dysphagia, salivation or speech disorders, and cognitive deficits in patients with neurological diseases.

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