Reduced nitrosamine formation in pharmaceutical compositions comprising methylphenidate

Abstract

To provide a composition for reducing nitrosamine formation in a pharmaceutical composition comprising methylphenidate, a method for producing the composition, and use thereof in the treatment of attention deficit disorder.SOLUTION: Provided is a pharmaceutical composition comprising methylphenidate and at least one ascorbyl fatty acid ester, wherein a molar ratio between the methylphenidate and the at least one ascorbyl fatty acid ester is from 1:0.1 to 1:5.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition containing methylphenidate and having a low nitrosamine concentration. The present invention also relates to a method for preparing the pharmaceutical composition and its use in the treatment of attention deficit disorder. Furthermore, the present invention relates to the use of ascorbyl fatty acid esters to reduce nitrosamine formation in a composition comprising methylphenidate. [Background technology]

[0002] Nitrosamines have been classified as probable human carcinogens. In 2018, nitrosamines were found in several blood pressure medications known as "sartans." Investigations into the origin of this contamination revealed that many active pharmaceutical ingredients (APIs) and drug products are contaminated with nitrosamines. Nitrosamines are typically formed by the reaction of nitrosated drugs, typically derived from nitrites, with secondary or tertiary amines. Because such amines are a common structural motif in APIs and excipients are often contaminated with nitrites, nitrosamines can form in many pharmaceutical compositions. See, for example, R. Boetzel et al., Journal of Pharmaceutical Sciences (2023), 112, 1615-1624.

[0003] Therefore, reducing nitrosamine formation has been the subject of considerable research and development into new formulations of pharmaceutical compositions. For example, Chinese Patent No. CN115721724A proposes reducing nitrosamine formation from secondary amines by adding pharmaceutically acceptable acids. However, nitrosamine formation was only investigated using varenicline, and it remains unclear whether this concept can be applied to other active ingredients and compositions.

[0004] Attention deficit disorder (ADD) is a neurological disorder commonly diagnosed in children and is typically treated with methylphenidate hydrochloride (e.g., commercially available as Ritalin®). Symptoms of ADD include distractibility and impulsivity. A related disorder, called attention deficit hyperactivity disorder (ADHD), is further characterized by symptoms of hyperactivity and is also treated with methylphenidate hydrochloride.

[0005] Because methylphenidate contains a secondary amine structural motif, the formation of nitrosamines in pharmaceutical compositions containing methylphenidate in the presence of nitrite impurities is becoming an increasing challenge for drug manufacturers. Therefore, there is a need to develop methods for reducing nitrosamine formation in pharmaceutical compositions containing methylphenidate. Summary of the Invention [Means for solving the problem]

[0006] In a first aspect, the present invention provides a pharmaceutical composition comprising methylphenidate and at least one ascorbyl fatty acid ester, wherein the molar ratio between methylphenidate and the at least one ascorbyl fatty acid ester is 1:0.1 to 1:5. Surprisingly, the inventors have found that the formation of nitrosamines in a composition with methylphenidate can be significantly reduced by using an ascorbyl fatty acid ester.

[0007] In a further aspect, the present invention relates to a method for preparing a pharmaceutical composition comprising a mixture of methylphenidate and at least one ascorbyl fatty acid ester, wherein the molar ratio between the methylphenidate and the at least one ascorbyl fatty acid ester is from 1:0.1 to 1:5.

[0008] In an even further aspect, the present invention relates to a pharmaceutical composition according to the first aspect for use in the treatment of attention deficit disorder (ADD or ADHD).

[0009] In an even further aspect, the present invention relates to the use of ascorbyl fatty acid esters to reduce nitrosamine formation in compositions comprising methylphenidate.

[0010] Further aspects and embodiments of the present invention are disclosed in the dependent claims and can be taken from the following description, drawings and examples without being limited thereto. DETAILED DESCRIPTION OF THE INVENTION

[0011] definition Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0012] Amounts within the scope of the present invention are given in wt.% unless otherwise stated or clear from the context.

[0013] Unless otherwise indicated, the term "methylphenidate" is used broadly herein to include methylphenidate and its pharmaceutically acceptable salts, including methylphenidate hydrochloride.

[0014] As is generally known, the term "nitrosamine" refers to a class of chemical compounds characterized by the functional group R2N-N=O, where R is usually an alkyl group and / or hydrogen. Nitrosamines are formed by the chemical reaction between a secondary amine and a nitrosating agent, such as nitrite. In the context of the present invention, the term "nitrosamine" particularly refers to N-nitrosomethylphenidate.

[0015] In the context of the present invention, "tablet" is not particularly limited. As generally understood, a tablet is a solid dosage form that is typically prepared by compressing or molding a homogeneous mixture of one or more pharmaceutically active substances and suitable excipients. Tablets are generally characterized by their solid, compacted structure, formed into a shape and size suitable for oral administration.

[0016] Because the methods described herein may vary, before describing the present invention in illustrative detail, it is to be understood that the present invention is not limited to the specific components of the process steps of such methods. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include singular and / or plural referents unless the context clearly dictates otherwise. For example, the term "a," as used herein, can be understood to mean one single entity or "one or more" entities. It is also to be understood that the plural forms include singular and / or plural referents unless the context clearly dictates otherwise. Furthermore, when a parameter range defined by numerical values ​​is given, it is also to be understood that the range is defined to include those limits.

[0017] In a first aspect, the present invention relates to a pharmaceutical composition comprising methylphenidate and at least one ascorbyl fatty acid ester, wherein the molar ratio between the methylphenidate and the at least one ascorbyl fatty acid ester is from 1:0.1 to 1:5.

[0018] In extensive research, the present inventors have investigated the formation of nitrosamines in methylphenidate-containing compositions to find additives that can reduce or prevent this formation. Common antioxidants and stabilizers have been used. Surprisingly, the present inventors have found that these antioxidants and stabilizers have very different levels of effectiveness in preventing nitrosamine formation. As a result, it is not possible to predict which additive will be effective in reducing the formation of nitrosamines from methylphenidate. In these studies, the present inventors have surprisingly found that ascorbyl fatty acid esters are the most effective in reducing nitrosamine formation. This effect is particularly pronounced at a molar ratio between methylphenidate and ascorbyl fatty acid esters of 1:0.1 to 1:5.

[0019] In some embodiments, the pharmaceutical composition is in an oral dosage form. According to certain embodiments, the pharmaceutical composition is in a solid form. According to some embodiments, the pharmaceutical composition is in a tablet form. In a preferred embodiment, the methylphenidate is methylphenidate hydrochloride.

[0020] According to some embodiments, at least a portion of the methylphenidate and at least a portion of the at least one ascorbyl fatty acid ester are in contact with each other. According to some embodiments, the methylphenidate and the at least one ascorbyl fatty acid ester are co-localized in the same matrix layer of the pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises or consists of a single solid phase, and the methylphenidate and the ascorbyl fatty acid ester are contained in the single solid phase. In this context, "single solid phase" refers to a homogeneous solid state form in which the methylphenidate, the ascorbyl fatty acid ester, and optionally other components of the pharmaceutical composition, such as excipients, are uniformly distributed in a single continuous matrix. In particular, "single solid phase" does not refer to a layered structure. If the pharmaceutical composition has a layered structure, the methylphenidate and the ascorbyl fatty acid ester are in the same layer. In these embodiments, the above-mentioned effects and advantages of the present invention are particularly pronounced.

[0021] According to certain embodiments, the pharmaceutical composition further comprises at least one excipient.In some embodiments, the pharmaceutical composition is prepared by dry mixing methylphenidate, at least one ascorbyl fatty acid ester, and optionally at least one excipient.According to these embodiments, the above-mentioned effects and advantages of the present invention can be further improved.

[0022] In certain embodiments, at least one ascorbyl fatty acid ester is selected from the group consisting of ascorbyl palmitate, ascorbyl stearate, ascorbyl oleate, ascorbyl linoleate, ascorbyl laurate, ascorbyl myristate, ascorbyl behenate, and combinations thereof.According to a preferred embodiment, at least one ascorbyl fatty acid ester is ascorbyl palmitate.In these embodiments, the above-mentioned effects and advantages of the present invention can be further improved.

[0023] According to some embodiments, the molar ratio between methylphenidate and at least one ascorbyl fatty acid ester is 1:0.5 to 1:4. In a preferred embodiment, the molar ratio between methylphenidate and at least one ascorbyl fatty acid ester is 1:1 to 1:3. In these embodiments, the above-mentioned effects and advantages of the present invention are particularly pronounced.

[0024] In certain embodiments, the pharmaceutical composition comprises, based on the total weight of the pharmaceutical composition, 1.0 wt.% to 20.0 wt.%, preferably 1.5 wt.% to 15.0 wt.%, and more preferably 2.0 wt.% to 13.0 wt.% of methylphenidate; and 2.5 wt.% to 20.0 wt.%, preferably 5.0 wt.% to 19.5 wt.%, and more preferably 10.0 wt.% to 19.0 wt.% of ascorbyl fatty acid ester. In these embodiments, the above-mentioned effects and advantages of the present invention can be further improved.

[0025] As described above, the pharmaceutical composition may further comprise at least one excipient. The excipient may be selected from the group consisting of a disintegrant, a binder, a filler, a lubricant, a colorant, and a combination thereof. In some embodiments, the pharmaceutical composition comprises a disintegrant and / or a binder, a filler, a lubricant, and optionally a colorant. According to certain embodiments, the pharmaceutical composition consists or essentially of methylphenidate, at least one ascorbyl fatty acid ester, a disintegrant and / or a binder, a filler, a lubricant, and a colorant. The compositions according to these embodiments can further enhance the above-mentioned effects and advantages of the present invention.

[0026] According to certain embodiments, the pharmaceutical composition comprises, based on the total weight of the pharmaceutical composition, 25.0 wt.% to 35.0 wt.%, preferably 26.0 wt.% to 34.0 wt.%, and more preferably 26.5 wt.% to 33.0 wt.% of disintegrants and / or binders; 35.0 wt.% to 60.0 wt.%, preferably 37.0 wt.% to 57.0 wt.%, and more preferably 40.0 wt.% to 59.0 wt.%, and more preferably 40.0 wt.% to 60.0 wt.%, based on the total weight of the pharmaceutical composition. 0.0 wt.% to 55.0 wt.% of a filler; 0.0 wt.% to 3.0 wt.%, preferably 0.5 wt.% to 2.0 wt.%, and more preferably 1.0 wt.% to 1.5 wt.% of a lubricant; and / or 0.0 wt.% to 2.0 wt.%, preferably 0.1 wt.% to 1.0 wt.%, and more preferably 0.3 wt.% to 0.7 wt.% of a colorant. In some embodiments, the pharmaceutical composition comprises, based on the total weight of the pharmaceutical composition, 1.0 wt.% to 20.0 wt.%, preferably 1.5 wt.% to 15.0 wt.%, and more preferably 2.0 wt.% to 13.0 wt.% of methylphenidate; 2.5 wt.% to 20.0 wt.%, preferably 5.0 wt.% to 19.5 wt.%, and more preferably 10.0 wt.% to 19.0 wt.% of ascorbyl fatty acid esters; and 25.0 wt.% to 35.0 wt.%, preferably 26.0 wt.% to 34.0 wt.%, and more preferably 26.5 wt.% to 35.0 wt.%, based on the total weight of the pharmaceutical composition. % to 33.0 wt.% of disintegrant and / or binder; 35.0 wt.% to 60.0 wt.%, preferably 37.0 wt.% to 57.0 wt.%, and more preferably 40.0 wt.% to 55.0 wt.% of filler; 0.0 wt.% to 3.0 wt.%, preferably 0.5 wt.% to 2.0 wt.%, and more preferably 1.0 wt.% to 1.5 wt.% of lubricant; and 0.0 wt.% to 2.0 wt.%, preferably 0.1 wt.% to 1.0 wt.%, and more preferably 0.3 wt.% to 0.7 wt.% of colorant. In these embodiments, the above-mentioned effects and advantages of the present invention are particularly pronounced. If the pharmaceutical composition consists of the above-mentioned components, the weight percentages may add up to a maximum of 100 wt.%, based on the total weight of the pharmaceutical composition.In this context, the phrase "consisting essentially of" means that the pharmaceutical composition may contain, in addition to the ingredients mentioned above, substances that do not materially alter the basic properties of the pharmaceutical composition.

[0027] In some embodiments, the disintegrant and / or binder is selected from the group consisting of cellulose, corn starch, and combinations thereof. Alternatively or additionally, the filler may be selected from the group consisting of calcium hydrogen phosphate, lactose, and combinations thereof. Alternatively or additionally, the lubricant may be magnesium stearate. Alternatively or additionally, the colorant may be selected from iron(III) oxide, iron(III) oxyhydroxide, and combinations thereof. In certain embodiments, the cellulose is microcrystalline cellulose. According to some embodiments, the corn starch is pregelatinized corn starch. In some embodiments, the calcium hydrogen phosphate is calcium hydrogen phosphate dihydrate. In certain embodiments, the lactose is lactose monohydrate.

[0028] According to certain embodiments, the pharmaceutical composition contains, based on the total weight of the pharmaceutical composition, 1.0 wt.% to 20.0 wt.%, preferably 1.5 wt.% to 15.0 wt.%, and more preferably 2.0 to 13.0 wt.% of methylphenidate hydrochloride; 2.5 wt.% to 20.0 wt.%, preferably 5.0 wt.% to 19.5 wt.%, and more preferably 10.0 wt.% to 20.0 wt.%, based on the total weight of the pharmaceutical composition; 19.0 wt.% ascorbyl palmitate; 15.0 wt.% to 25.0 wt.%, preferably 17.0 wt.% to 24.0 wt.%, and more preferably 17.5 wt.% to 23.0 wt.% cellulose; 5.0 wt.% to 15.0 wt.%, preferably 7.0 wt.% to 13.0 wt.%, and more preferably 8.0 wt.% to 11.0 wt.% corn starch. 18.0 wt.% to 35.0 wt.%, preferably 20.0 wt.% to 33.0 wt.%, and more preferably 23.0 wt.% to 31.0 wt.% calcium hydrogen phosphate; 13.0 wt.% to 25.0 wt.%, preferably 15.0 wt.% to 23.0 wt.%, and more preferably 16.0 wt.% to 22.5 wt.% lactose; 0.0 wt.% to 3.0 wt. %, preferably 0.5 to 2.0 wt.%, and more preferably 1.0 to 1.5 wt.% magnesium stearate; and 0.0 to 2.0 wt.%, preferably 0.1 to 1.0 wt.%, and more preferably 0.3 to 0.7 wt.% iron(III) oxide and / or iron(III) oxyhydroxide. In these embodiments, the above-mentioned effects and advantages of the present invention are further enhanced. If the pharmaceutical composition consists of the above-mentioned components, the weight percentages may add up to a maximum of 100 wt.% based on the total weight of the pharmaceutical composition.

[0029] In some embodiments, the pharmaceutical composition is a tablet having a methylphenidate dose of 3 mg to 30 mg, preferably 4 mg to 25 mg, and more preferably 5 mg to 20 mg per tablet.

[0030] In a second aspect, the present invention relates to a method for preparing a pharmaceutical composition comprising a mixture of methylphenidate and at least one ascorbyl fatty acid ester, wherein the molar ratio between methylphenidate and at least one ascorbyl fatty acid ester is 1:0.1 to 1:5. The pharmaceutical composition is a pharmaceutical composition according to the first aspect of the present application. In this aspect, reference is made to the above description of the first aspect of the present invention, and such description also applies in its entirety.

[0031] The mixing is not particularly limited. In a preferred embodiment, the mixing is dry mixing. The mixing can be performed in a free-fall mixer, a tumbler mixer, a ribbon blender, a paddle mixer, a planetary mixer, a fluidized bed mixer, a cone screw mixer, and / or a drum mixer. According to a preferred embodiment, the mixing is performed in a free-fall mixer. In some embodiments, the mixing time is 5 to 60 minutes, preferably 10 to 40 minutes, and more preferably 20 to 30 minutes. The effect of reducing nitrosamine formation is particularly pronounced in these embodiments.

[0032] According to certain embodiments, the mixing of methylphenidate and at least one ascorbyl fatty acid ester further comprises mixing a disintegrant and / or binder, a filler, and optionally a colorant.In other words, the method comprises mixing methylphenidate, at least one ascorbyl fatty acid ester, a disintegrant and / or binder, a filler, and optionally a colorant.

[0033] In some embodiments, methylphenidate, at least one ascorbyl fatty acid ester, disintegrant and / or binder, filler, and optionally colorant are mixed to obtain a first mixture, and the method further comprises mixing the first mixture with a lubricant to obtain a second mixture. The mixing of the first mixture with the lubricant is not particularly limited. In a preferred embodiment, the mixing of the first mixture with the lubricant is dry mixing. The mixing of the first mixture with the lubricant can be performed in a free-fall mixer, tumbler mixer, ribbon blender, paddle mixer, planetary mixer, fluidized bed mixer, cone screw mixer, and / or drum mixer. According to a preferred embodiment, the mixing of the first mixture with the lubricant is performed in a free-fall mixer. In some embodiments, the mixing time of the first mixture with the lubricant is 2 to 40 minutes, preferably 5 to 30 minutes, and more preferably 10 to 20 minutes.

[0034] In certain embodiments, methylphenidate, at least one ascorbyl fatty acid ester, disintegrant and / or binder, filler, colorant, and lubricant are used in powder form. In a preferred embodiment, methylphenidate, at least one ascorbyl fatty acid ester, disintegrant and / or binder, filler, colorant, and lubricant are sieved before mixing. Specifically, a sieve with a mesh size of 0.1 mm to 5.0 mm, preferably 0.3 mm to 2.0 mm, and more preferably 0.4 mm to 1.2 mm can be used. In some embodiments, calcium hydrogen phosphate and iron oxide(s) are sieved using a sieve with a mesh size of 0.5 mm, and in this case, methylphenidate, ascorbyl fatty acid ester, cellulose, lactose, corn starch, and magnesium stearate are sieved using a sieve with a mesh size of 1.0 mm. Before sieving and / or mixing, the ingredients may be weighed according to their weight percentage (wt.%) in the pharmaceutical composition of the first aspect of the present invention described above. By "ingredients" is intended methylphenidate, ascorbyl fatty acid esters, and excipients.

[0035] According to some embodiments, the method further comprises compressing the second mixture to obtain tablets. The compression can be carried out using, but is not limited to, a rotary press, a single-shot press, a hydraulic press, and / or a pneumatic press. According to a preferred embodiment, the compression is carried out using a rotary press. In certain embodiments, the compression is carried out using a compression force of 10 to 100 kN, preferably 15 to 50 kN, and more preferably 20 to 30 kN.

[0036] In a third aspect, the present invention relates to a pharmaceutical composition obtainable or obtained by a method according to the second aspect of the invention. Reference is made to the above statements regarding the first and second aspects of the invention, which statements also apply here in their entirety.

[0037] In a fourth aspect, the present invention relates to a pharmaceutical composition according to the first and / or third aspect for use in the treatment of attention deficit disorder (ADD or ADHD). Reference is made to the above statements regarding the first, second and third aspects of the invention, which statements also apply in their entirety here.

[0038] In a fifth aspect, the present invention relates to the use of ascorbyl fatty acid esters to reduce nitrosamine formation in compositions comprising methylphenidate. In a preferred embodiment, "nitrosamine" refers to N-nitrosomethylphenidate. As explained above, the inventors surprisingly found that antioxidants and stabilizers commonly used in pharmaceutical compositions have very different levels of effectiveness in preventing nitrosamine formation from methylphenidate. Therefore, it is not possible to predict which additive will be effective in reducing the formation of nitrosamines from methylphenidate. The inventors further surprisingly found that ascorbyl fatty acid esters are most effective in reducing nitrosamine formation. In a preferred embodiment, the ascorbyl fatty acid ester is ascorbyl palmitate. According to a specific embodiment, the molar ratio between methylphenidate and at least one ascorbyl fatty acid ester is 1:0.1 to 1:5. Reference is made to the above descriptions of the first, second, third and fourth aspects of the present invention, which descriptions also apply here in their entirety.

[0039] The above embodiments can be combined in any suitable manner. Further possible embodiments and implementations of the present invention also comprise combinations of features not explicitly mentioned above or below in view of the examples of the present invention. In particular, those skilled in the art will also add individual aspects as improvements or additions to the respective basic forms of the present invention. [Example]

[0040] The present invention will be described in detail below with reference to several examples, but these examples are merely illustrative and do not limit the scope of the present invention.

[0041] Preparation of Exemplary Pharmaceutical Compositions According to the Invention An exemplary preparation of a pharmaceutical composition according to the present invention is described below, with the amounts of each ingredient shown in Table 1. Table 1: Exemplary manufacturing formulations of pharmaceutical compositions according to the present invention

[0042] [Table 1]

[0043] The ingredients were weighed according to the data shown in the table. The iron oxides and calcium hydrogen phosphate dihydrate were sieved using a 0.5 mm mesh sieve. The remaining ingredients were sieved using a 1.0 mm mesh sieve. In the first blending step, methylphenidate hydrochloride, ascorbyl palmitate, microcrystalline cellulose, lactose monohydrate, pregelatinized corn starch, and iron oxides were blended in a free-fall mixer for 20 to 30 minutes. Magnesium stearate was then added to the resulting blend and blended in a free-fall mixer for 10 to 15 minutes in the second blending step. The blend from the second blending step was compressed into tablets in a rotary press using a compression force of 20 to 30 kN.

[0044] The tablets of Example 1 had a methylphenidate content of 5 mg and a molar ratio of methylphenidate:ascorbyl palmitate of 1:3, the tablets of Example 2 had a methylphenidate content of 10 mg and a molar ratio of methylphenidate:ascorbyl palmitate of 1:2, and the tablets of Example 3 had a methylphenidate content of 20 mg and a molar ratio of methylphenidate:ascorbyl palmitate of 1:1.

[0045] Comparison of N-nitrosomethylphenidate formation using different oxidizing / stabilizing agents To determine the effect of various antioxidants or stabilizers on preventing nitrosamine formation in compositions containing methylphenidate, different pharmaceutical compositions were prepared as described in Example 1 above, except that antioxidants / stabilizers other than ascorbyl palmitate were used. However, to allow for better comparison, the molar ratio of methylphenidate to antioxidant / stabilizer was kept constant at 1:3 in all compositions (except for compositions without antioxidant / stabilizer). Thus, the compositions of Example 1 and Comparative Examples 2 to 7 differed only in the type of antioxidant / stabilizer and were otherwise strictly structured as shown in Table 1 above for Example 1. The content of N-nitrosomethylphenidate in the compositions was determined by UHPLC-MS / MS. Therefore, the term "nitrosamine" in this context refers to "N-nitrosomethylphenidate." For sample preparation, the compositions were pulverized, and the resulting powder was extracted with methanol. The following measurement conditions were used for N-nitrosomethylphenidate quantification: LC column: Waters BEH Shield RP18 (100 x 2.1 mm, 1.7 μm) · Flow rate: 0.4mL / min Column temperature: 50℃ Mobile phase: Phase A: Water containing 0.1% by volume of formic acid Phase B: Acetonitrile Gradient conditions: JPEG2025174869000002.jpg42170

[0046] Injection volume: 1 μL Sample temperature: Room temperature (20℃~22℃) MS detector settings: ESI positive in MRM transition mode

[0047] The results of the quantification of the N-nitrosomethylphenidate content in the composition are shown in Table 2. Table 2: N-nitrosomethylphenidate formation in methylphenidate compositions with different antioxidants / stabilizers

[0048] [Table 2]

[0049] As can be seen from Table 2, ascorbyl palmitate is by far the most effective in reducing nitrosamine formation in compositions containing methylphenidate. Surprisingly, the results for individual antioxidants / stabilizers vary widely, with common antioxidants / stabilizers such as BHT or ascorbic acid buffer only able to prevent nitrosamine formation to a small extent. It is clear that even mixtures of several antioxidants / stabilizers, such as those in Comparative Examples 5-7, are not as effective as ascorbyl palmitate in preventing the formation of N-nitrosomethylphenidate. Thus, ascorbyl fatty acid esters, such as ascorbyl palmitate, can be effectively used to reduce nitrosamine formation in compositions containing methylphenidate.

Claims

1. A pharmaceutical composition comprising methylphenidate and at least one ascorbyl fatty acid ester, wherein the molar ratio between said methylphenidate and said at least one ascorbyl fatty acid ester is 1:0.1 to 1:

5.

2. 2. The pharmaceutical composition of claim 1, wherein the at least one ascorbyl fatty acid ester is selected from the group consisting of ascorbyl palmitate, ascorbyl stearate, ascorbyl oleate, ascorbyl linoleate, ascorbyl laurate, ascorbyl myristate, ascorbyl behenate, and combinations thereof, preferably the at least one ascorbyl fatty acid ester is ascorbyl palmitate.

3. 3. The pharmaceutical composition according to claim 1 or 2, wherein the molar ratio between said methylphenidate and said at least one ascorbyl fatty acid ester is from 1:0.5 to 1:4, preferably from 1:1 to 1:

3.

4. 4. The pharmaceutical composition according to any one of claims 1 to 3, comprising, based on the total weight of the pharmaceutical composition: 1.0 wt.% to 20.0 wt.% methylphenidate; 2.5 wt. % to 20.0 wt. % of ascorbyl fatty acid esters; A pharmaceutical composition comprising:

5. 5. The pharmaceutical composition according to claim 1, further comprising at least one selected from the group consisting of a disintegrant, a binder, a filler, a lubricant, a colorant, and combinations thereof, optionally comprising a disintegrant and / or a binder, a filler, a lubricant, and optionally a colorant.

6. 6. The pharmaceutical composition according to any one of claims 1 to 5, comprising, based on the total weight of the pharmaceutical composition: 25.0 wt. % to 35.0 wt. % of a disintegrant and / or binder; 35.0 wt. % to 60.0 wt. % filler; 0.0 wt. % to 3.0 wt. % of a lubricant; and / or 0.0 wt. % to 2.0 wt. % of a colorant; A pharmaceutical composition comprising:

7. 7. The pharmaceutical composition according to any one of claims 1 to 6, comprising, based on the total weight of the pharmaceutical composition: 1.0 wt.% to 20.0 wt.% methylphenidate; 2.5 wt.% to 20.0 wt.% ascorbyl fatty acid esters; 25.0 wt. % to 35.0 wt. % of a disintegrant and / or binder; 35.0 wt. % to 60.0 wt. % filler; 0.0 wt. % to 3.0 wt. % of a lubricant; and 0.0 wt. % to 2.0 wt. % of a colorant; A pharmaceutical composition consisting of or consisting essentially of:

8. 8. The pharmaceutical composition of any one of claims 5 to 7, wherein the disintegrant and / or binder is selected from the group consisting of cellulose, corn starch, and combinations thereof, and / or the filler is selected from the group consisting of calcium hydrogen phosphate, lactose, and combinations thereof, and / or the lubricant is magnesium stearate, and / or the colorant is selected from the group of iron(III) oxide, iron(III) oxyhydroxide, and combinations thereof.

9. A method for producing a pharmaceutical composition comprising a mixture of methylphenidate and at least one ascorbyl fatty acid ester, wherein the molar ratio between the methylphenidate and the at least one ascorbyl fatty acid ester is 1:0.1 to 1:

5.

10. 10. The method according to claim 9, wherein the molar ratio between the methylphenidate and the at least one ascorbyl fatty acid ester is from 1:0.5 to 1:4, preferably from 1:1 to 1:3, and / or the ascorbyl fatty acid ester is ascorbyl palmitate.

11. 11. The method of claim 9, wherein the mixture of methylphenidate and at least one ascorbyl fatty acid ester further comprises a mixture of a disintegrant and / or binder, and a filler, and optionally a colorant.

12. 12. The method of claim 11, wherein the methylphenidate, the at least one ascorbyl fatty acid ester, the disintegrant and / or binder, the filler, and optionally the colorant are mixed to obtain a first mixture, further comprising mixing the first mixture with a lubricant to obtain a second mixture; Optionally, the method further comprises compressing said second mixture to obtain a tablet.

13. 9. A pharmaceutical composition according to any one of claims 1 to 8 for use in the treatment of attention deficit disorder (ADD or ADHD).

14. A method of reducing nitrosamine formation in a composition comprising methylphenidate using an ascorbyl fatty acid ester.

15. 15. The use of claim 14, wherein the ascorbyl fatty acid ester is ascorbyl palmitate, and / or the molar ratio between the methylphenidate and the at least one ascorbyl fatty acid ester is 1:0.1 to 1:5.

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