SOLID ORAL DOSAGE FORM COMPRISING NAPROXEN AND VITAMIN B6

Abstract

The present invention relates to a solid oral dosage form comprising naproxen and vitamin B6. Preferably, it is a solid oral dosage form for use in the treatment of pain such as low back pain. It is a fixed-dose combination (FDC) which increases patient compliance. The method of preparing such solid oral dosage form comprises the extragranular addition of vitamin B6 to an intragranular composition, wherein said intragranular composition comprises naproxen or a pharmaceutically acceptable salt thereof and at least one binder.

Claims

1. Blend comprising: a) granules, and b) vitamin B6 wherein said granules comprise naproxen or a pharmaceutically acceptable salt thereof and at least one binder.

2. Blend according to claim 1, wherein said blend comprises: a) granules, b) vitamin B6, c) vitamin B12, and wherein said granules comprise naproxen sodium, vitamin B1 and at least one binder, and wherein said vitamin B12 is preferably a spray-dried formulation of vitamin B12.

3. Blend according to claim 1, wherein said blend further comprises at least one pharmaceutically acceptable excipient, and wherein said blend further comprises preferably at least one diluent, at least one disintegrant, at least one lubricant, at least one flowing agent and/or at least one taste masking agent, and wherein more preferably said blend further comprises microcrystalline cellulose, mannitol, croscarmellose sodium and/or magnesium stearate.

4. Blend according to claim 1, wherein at least 80% of the granules pass mesh 16, and/or wherein at least 80% of the granules are retained by mesh 200, based on the total weight of the granules comprised in the blend.

5. Blend according to claim 1, wherein said granules comprise or consist of an alkali salt of naproxen and at least one water-soluble binder, and wherein said granules comprise preferably naproxen sodium and/or polyvinylpyrrolidone.

6. Blend according to claim 1, wherein said granules comprise less than 10 weight-%, preferably less than 5 weight-%, more preferably less than 1 weight-% and most preferably less than 0.1 weight-% vitamin B6, based on the total weight of the granules.

7. Blend according to claim 1, wherein said vitamin B6 is pyridoxine or a pharmaceutically acceptable salt thereof, and wherein said vitamin B6 is preferably pyridoxine hydrochloride.

8. Solid oral dosage form comprising the blend according to claim 1.

9. Solid oral dosage form according to claim 8, wherein said solid oral dosage form is a tablet, and wherein said tablet is preferably obtained by compressing the blend.

10. Solid oral dosage form according to claim 8, wherein said solid oral dosage form is a capsule or a powder, and wherein said powder is preferably a water-soluble or a water-dispersible powder, and wherein said powder is preferably a water-soluble powder comprising at least one taste masking agent.

11. Solid oral dosage form according to claim 8 for use in the treatment of low back pain.

12. Method of preparing a solid oral dosage form, said method comprising the extragranular addition of vitamin B6 to an intragranular composition, wherein said intragranular composition comprises naproxen or a pharmaceutically acceptable salt thereof and at least one binder.

13. Method according to claim 12, said method comprising the steps: a) wet granulating with water as a processing solvent naproxen or a pharmaceutically acceptable salt thereof in the presence of at least one binder to obtain granules b) drying the granules obtained in step a) c) milling the granules obtained in step b) d) mixing the granules obtained in step c) with vitamin B6 and at least one pharmaceutically acceptable excipient.

14. Method according to claim 13, said method comprising the steps: a) wet granulating with water as a processing solvent naproxen or a pharmaceutically acceptable salt thereof in the presence of at least one binder and vitamin B1 to obtain granules b) drying the granules obtained in step a) c) milling the granules obtained in step b) d) mixing the granules obtained in step c) with vitamin B6, at least one pharmaceutically acceptable excipient and optionally at least one spray-dried formulation of vitamin B12.

15. Method according to claim 13, said method further comprising the step: e) compressing the blend obtained in step d) to get tablets, or filling the blend obtained in step d) into capsules or filling the blend obtained in step d) into containers, said containers being preferably bags, sachets or stick-packs.

Description

FIGURES

[0130] FIG. 1 shows the tablets manufactured in example 9.

[0131] FIG. 2 shows the drink prepared in example 11.

EXAMPLES

Example 1 (Control; Naproxen Sodium Only)

[0132] Example 1 is a control experiment relating to naproxen sodium only (i.e. without any vitamins). First, the physical properties of naproxen sodium (source: Xi'an Wharton Biological Technology Co., Ltd., China) were evaluated. The result of this evaluation is shown in below Table 1.

TABLE-US-00002 TABLE 1 Physical characterizations of Naproxen Sodium BD TD Carr Material (g/ml) (g/ml) Index Description Naproxen Sodium 0.30 0.55 45 very lumpy

[0133] Table 1 shows the bulk density (BD), tapped density (TD), and the Carr Index. The Carr Index is calculated by the formula 100×(1−BD/TD) and is used as an indication of the flowability. A Carr Index greater than 25 is considered to be an indication of poor flowability. As it can be seen in Table 1, naproxen sodium is a lumpy powder with poor flowability. This preliminary evaluation indicates that naproxen sodium is not suitable for direct compression.

[0134] Therefore, naproxen sodium was wet granulated using PVP (polyvinylpyrrolidone) as binder. To do so, dry naproxen sodium was put in a granulator. Then, an aqueous binder solution comprising PVP K30 (available at Ashland) and water was gradually added, and some time was allowed for the kneading of granules. The wet granular mass was then transferred to be spread on a tray. Granules were first dried at 86° C. for 2.5 hours and then dried at 50° C. overnight. Loss on drying (LOD) values of the granules were between 3-4 wt.-%, based on the total weight of the wet granules. Finally, the dried granules were milled using a Fitz Mill equipped with 4 mm screen (milling speed: 20-30 Hz; blade forward). Particles were classified until retains above 20-mesh screen were less than 30%. The composition of the thus obtained naproxen sodium granules is shown in below Table 2, indicated as mg/tablet when targeting a tablet comprising 221.11 mg naproxen sodium (corresponding to a label claim of 220 mg naproxen).

TABLE-US-00003 TABLE 2 Formulation of granulation trial (mg/tablet) Label claim Purity Overage Material mg/tablet (mg) (%) (wt.-%) mg/tablet Naproxen Sodium 221.11 220 99.5 0 221.11 PVP K30 4.42 Total 225.53

[0135] Purity is a nondimensional factor.

[0136] The thus obtained dried granules had a significantly higher density and much smaller Carr Index than the ungranulated naproxen sodium. The result of the applicable test is shown in below Table 3.

TABLE-US-00004 TABLE 3 Physical properties of wet granulation trials and raw material PVP BD TD Carr Description mg/tablet (g/ml) (g/ml) Index Naproxen sodium 0 0.30 0.55 45 Naproxen sodium granules 4.42 0.57 0.66 14

[0137] To produce tablets, the obtained naproxen sodium granules were blended with suitable excipients: microcrystalline cellulose (MCC) as diluent; croscarmellose sodium as disintegrant; and magnesium stearate as lubricant. The tablets were produced on a Piccola B rotary tablet press equipped with ⅜″ standard concave round tooling at 25 rpm press speed. Naproxen tablets (label claim: 200 mg) were compressed with different compression force (1000 Lbs., 2000 Lbs., and 3000 Lbs.). The result of this tableting trial is shown in Table 4.

TABLE-US-00005 TABLE 4 Tableting trial of naproxen sodium granules ingredient mg/tablet Naproxen sodium granules Naproxen Sodium 221.11 PVP K30 4.42 MCC 200 71.47 Croscarmellose Sodium 1.50 Magnesium Stearate 1.50 Total (mg/tablet) 300.00 Compression profile Hardness (kp) 1000 Lbs. (4448.2N) 4.9 2000 Lbs. (8896.4N) 8.5 3000 Lbs. (13344.6N) 9.0

[0138] The hardness of thus obtained naproxen tablets was measured with a Sotax HT10 hardness tester by checking the breaking force and ranged from 4.9 kp to 9.0 kp (1 kp=1 kg force=9.8 N). Example 1 shows that the chosen excipients, equipment and process conditions are suitable for manufacturing a solid oral dosage form that comprises naproxen sodium.

Example 2 (Comparative Example; Intragranular Addition of Vitamin B6)

[0139] In Example 2, the tableting trial of example 1 was repeated. However, in example 2, naproxen sodium was granulated together with vitamin B6. As a source of vitamin B6, pyridoxine hydrochloride (available at DSM® Nutritional Products, Switzerland) was used. The composition of the thus obtained granules is shown in below Table 5, indicated as mg/tablet.

TABLE-US-00006 TABLE 5 Formulation of granulation trial (mg/tablet) Label claim Purity Conversion Overage Material mg/tablet (mg) (%) factor (wt.-%) mg/tablet Naproxen 221.11 220 99.5 NA 0 221.11 Sodium Pyridoxine 267.41 200 100 0.8227 10 267.41 Hydrochloride PVP K30 4.42 Total 492.94

[0140] Overage is the amount of dietary ingredient such as vitamins that is more than the target amount. It is indicated as wt.-%, based on the weight of the target amount. In above Table 5, 267.41 mg pyridoxine hydrochloride*0.8227=220 mg pyridoxine hydrochloride has been put into each tablet. This corresponds to an overage of 10 wt.-% (200 mg+10 wt.-%=220 mg).

[0141] Typically, overages are meant to compensate for loss due to degradation during manufacturing or storage.

[0142] The thus obtained dried granules had a significantly higher density and much smaller Carr Index than both, the ungranulated naproxen sodium and the ungranulated pyridoxine hydrochloride. The result is shown in below Table 6.

TABLE-US-00007 TABLE 6 Physical properties of wet granulation trials and raw materials PVP BD TD Carr Description mg/tablet (g/ml) (g/ml) Index Naproxen sodium 0 0.30 0.55 45 Naproxen sodium granules 4.42 0.57 0.66 14 Pyridoxine Hydrochloride 0 0.44 0.62 30 Granules comprising 4.42 0.51 0.65 22 naproxen sodium and Pyridoxine Hydrochloride

[0143] The preliminary evaluation indicates that the obtained granules comprising naproxen sodium and pyridoxine hydrochloride are suitable for direct compression. Tablets were then compressed in the same manner as in Example 1. The result of this tableting trial is shown in below Table 7.

TABLE-US-00008 TABLE 7 Tableting trial of granules comprising naproxen sodium and pyridoxine hydrochloride Material mg/tablet Granules comprising Naproxen Sodium 221.11 naproxen sodium and Pyridoxine Hydrochloride 267.41 pyridoxine hydrochloride PVP K30 4.42 MCC 200 71.47 Croscarmellose Sodium 1.50 Magnesium Stearate 1.50 Total (mg/tablet) 567.41 Compression profile Hardness (kp) 1000 Lbs. Capping 2000 Lbs. Capping 3000 Lbs. Capping

[0144] Although a Carr index of less than 25 had been measured (which indicates that the granules should be suitable for direct compression), it was surprisingly not possible to compress tablets without capping. Due to capping, hardness of the tablets could not be measured.

Example 3 (Extragranular Addition of Vitamin B6)

[0145] Example 2 was repeated. However, in Example 3, pyridoxine hydrochloride was not granulated together with naproxen sodium. Instead, the naproxen sodium granules of Example 1 were used and pyridoxine hydrochloride was added afterwards together with the required excipients. The result of this tableting trial is shown in below Table 8.

TABLE-US-00009 TABLE 8 Tableting trial of granules comprising naproxen sodium only; Pyridoxine Hydrochloride was added afterwards together with the required excipients Material mg/tablet Naproxen sodium granules Naproxen Sodium 221.11 PVP K30 4.42 Pyridoxine Hydrochloride 267.41 MCC 200 71.47 Croscarmellose Sodium 1.50 Magnesium Stearate 1.50 Total (mg/tablet) 567.41 Compression profile Hardness (kp) 1000 Lbs. 6.3 2000 Lbs. 9.7 3000 Lbs. 10.1

[0146] In example 3, no capping was observed although the same amounts of the same ingredients (i.e. as in example 2) were used. In addition to this surprising result, tablet hardness was slightly higher compared to the control (cf. example 1, table 4) at all tested compression forces.

Example 4 (Extragranular Addition of Vitamin B1)

[0147] In example 4, as fixed-dose combination of naproxen sodium and vitamin B1 was prepared. As a source of vitamin B1, thiamine hydrochloride (available at DSM® Nutritional Products, Switzerland) was used. In consideration of the failure in example 2, the approach of example 3 was repeated. Thus, naproxen sodium granules of example 1 were used and thiamine hydrochloride was added afterwards together with the required excipients. The result of this tableting trial is shown in below Table 9.

TABLE-US-00010 TABLE 9 Tableting trial of granules comprising naproxen sodium only; thiamine hydrochloride was added afterwards together with the required excipients Material mg/tablet Naproxen sodium granules Naproxen Sodium 221.11 PVP K30 4.42 Thiamine Hydrochloride 147.18 MCC 200 71.47 Croscarmellose Sodium 1.50 Magnesium Stearate 1.50 Total (mg/tablet) 447.18 Compression profile Hardness (kp) 1000 Lbs. Blend was too fluffy to be compressed into tablet with standard tooling 2000 Lbs. Blend was too fluffy to be compressed into tablet with standard tooling 3000 Lbs. Blend was too fluffy to be compressed into tablet with standard tooling

[0148] Example 4 was not successful because the blend is too fluffy to reach the target tablet weight with ⅜″ standard concave round tooling. Thus, the approach of example 3 failed when replacing vitamin B6 with vitamin B1.

Example 5 (Intragranular Addition of Vitamin B1)

[0149] In Example 5, the tableting trial of example 2 was repeated, wherein vitamin B6 was replaced with vitamin B1. Thus, naproxen sodium was granulated together with vitamin B1. Three different sources of vitamin B1 were tested: thiamine hydrochloride, thiamine mononitrate (both available at DSM® Nutritional Products, Switzerland) and benfotiamine (available at Xi'an Wharton Biological Technology Co., Ltd., China) were used. The composition of the thus obtained granules is shown in below Table 10 indicated as mg/tablet. Label claim of B1 is 100 mg. The corresponding conversion factor is based on molecular weights, potency, and moisture content from historical batches. There is 10 wt.-% overage for all B1 forms.

TABLE-US-00011 TABLE 10 Formulations of granulation trials (mg/tablet) Formulation 1 Formulation 2 Formulation 3 Label claim Purity Conversion Overage Material mg/tablet mg/tablet mg/tablet (mg) (%) factor (wt.-%) mg/tablet Naproxen 221.11 221.11 221.11 220 99.5 NA 0 221.11 Sodium Thiamine 147.18 / / 100 100 0.7474 10 147.18 Hydrochloride Thiamine / 135.70 / 100 100 0.8106 10 135.70 Mononitrate Benfotiamine / / 194.73 100 100 0.5649 10 194.73 PVP K30  4.42  4.42  4.42 Total 372.71 361.23 420.26

[0150] The thus obtained dried granules had a significantly higher density and much smaller Carr Index than both, the ungranulated naproxen sodium and the ungranulated vitamin B1. The result is shown in below Table 11.

TABLE-US-00012 TABLE 11 Physical properties of wet granulation trials and raw materials PVP BD TD Carr Description mg/tablet (g/ml) (g/ml) Index Naproxen sodium 0 0.30 0.55 45 Thiamine hydrochloride 0 0.26 0.46 44 Granules comprising 4.42 0.59 0.69 14.5 naproxen sodium and thiamine hydrochloride Granules comprising 4.42 0.54 0.64 15.6 naproxen sodium and thiamine mononitrate Granules comprising 4.42 0.55 0.69 20.3 naproxen sodium and benfotiamine granulation

[0151] The evaluation indicates that the obtained granules comprising naproxen sodium and vitamin B1 are suitable for direct compression, regardless which source of vitamin B1 is used. Tablets were then compressed in the same manner as in examples 1 and 2. The compositions of the three kinds of tablets is shown in below Tables 12a, 12b and 12c.

TABLE-US-00013 TABLE 12a Tableting trial of granules comprising naproxen sodium and thiamine hydrochloride Material mg/tablet Granules comprising Naproxen Sodium 221.11 naproxen sodium and Thiamine Hydrochloride 147.18 thiamine hydrochloride PVP K30 4.42 MCC 200 71.47 Croscarmellose Sodium 1.50 Magnesium Stearate 1.50 Total (mg/tablet) 447.18

TABLE-US-00014 TABLE 12b Tableting trial of granules comprising naproxen sodium and thiamine mononitrate Material mg/tablet Granules comprising Naproxen Sodium 221.11 naproxen sodium and Thiamine Mononitrate 135.7 Thiamine Mononitrate PVP K30 4.42 MCC 200 71.47 Croscarmellose Sodium 1.50 Magnesium Stearate 1.50 Total (mg/tablet) 435.70

TABLE-US-00015 TABLE 12c Tableting trial of granules comprising naproxen sodium and benfotiamine Material mg/tablet Granules comprising Naproxen Sodium 221.11 naproxen sodium and Benfotiamine 194.73 benfotiamine PVP K30 4.42 MCC 200 71.47 Croscarmellose Sodium 1.50 Magnesium Stearate 1.50 Total (mg/tablet) 494.73

[0152] The tableting trials were successful, irrespective which source of vitamin B1 was used. Surprisingly, compressibility is significantly improved when vitamin B1 is granulated together with naproxen sodium. This effect occurred for all tested sources of vitamin B1 but was particularly strong when using thiamine hydrochloride or benfotiamine as source of vitamin B1. At 2000 lbs., hardness of the obtained tablet increased from 8.5 kp (control; example 1, table 4) to 16 kp for thiamine hydrochloride and to 17.2 kp for benfotiamine. This is an increase of approx. 100%, compared to the control.

Example 6 (Reducing the Tablet Size; Vitamin B1)

[0153] In Example 6, the tableting trial of example 5 was repeated. However, with the finding of B1's improving naproxen compressibility, the diluent (MCC 200) was completely removed from the tablet formulation. The most promising sources of vitamin B1 (i.e. thiamine hydrochloride and benfotiamine; cf. example 5) were used. The result of this very ambitious tableting trial is shown in below Tables 13a and 13b.

TABLE-US-00016 TABLE 13a Tableting trial of granules comprising naproxen sodium and thiamine hydrochloride, but no MCC 200 Material mg/tablet Granules comprising Naproxen Sodium 221.11 naproxen sodium and Thiamine Hydrochloride 147.18 thiamine hydrochloride PVP K30 4.42 MCC 200 0.00 Croscarmellose Sodium 1.50 Magnesium Stearate 1.50 Total (mg/tablet) 375.71 Compression profile Hardness (kp) 1000 Lbs. 7.1 2000 Lbs. 11.8 3000 Lbs. 12.5

TABLE-US-00017 TABLE 13b Tableting trial of granules comprising naproxen sodium and benfotiamine, but no MCC 200 Material mg/tablet Granules comprising Naproxen Sodium 221.11 naproxen sodium and Benfotiamine 194.73 benfotiamine PVP K30 4.42 MCC 200 0.00 Croscarmellose Sodium 1.50 Magnesium Stearate 1.50 Total (mg/tablet) 423.26 Compression profile Hardness (kp) 1000 Lbs. 8.3 2000 Lbs. 13.3 3000 Lbs. 15.7

[0154] The tableting trials in example 6 were successful, regardless whether thiamine hydrochloride or benfotiamine was used as source of vitamin B1. Despite of the lack of diluent, the obtained tablets had still a higher hardness than the control (cf. example 1, table 4). Thus, example 6 shows that it is possible to reduce the amount of diluent dramatically when granulating naproxen sodium together with vitamin B1. A reduction of the amount of diluent is very meaningful for a fixed-dose combination that comprises a relatively large amount of various active pharmaceutically ingredients (APIs). In case of thiamine hydrochloride as source of vitamin B1, the tablet weight could be reduced from 447.18 mg to 375.71 mg without changing the label claim. This corresponds to a tablet weight reduction of 16%. In case of benfotiamine as source of vitamin B1, the reduction of tablet weight was smaller but still meaningful (reduction 14.4% from 494.73 mg to 423.26 mg without changing the label claim). Therefore, in the context of the present invention, thiamine hydrochloride is the preferred source of vitamin B1.

Example 7 (Intragranular Addition of Vitamin B12)

[0155] Vitamin B12 crystals are commercially available at DSM® Nutritional Products, Switzerland. DSM® also offers spray-dried forms of vitamin B12. In example 7, a spray-dried formulation of vitamin B12 was used (i) to increase shelf life of the fixed-dose combination and (ii) to improve content uniformity.

[0156] In example 7, the tableting trial of example 2 was repeated. However, in example 7, vitamin B6 was replaced with a spray-dried formulation of vitamin B12. Thus, naproxen sodium was granulated together with the spray-dried formulation of vitamin B12.

[0157] Example 7 failed because the spray-dried formulation of vitamin melted at the drying step, i.e. the granules formed a useless paste at the drying step. Thus, the tested spray-dried formulation of vitamin B12 is not suitable for wet granulation because wet granulation involves a drying step.

Example 8 (Extragranular Addition of Vitamin B12)

[0158] In example 8, as fixed-dose combination of naproxen sodium and vitamin B12 was prepared. As a source of vitamin B12, a spray-dried formulation of vitamin B12 was used (available at DSM® Nutritional Products under the tradename vitamin B12 0.1% WS). In consideration of the failure in example 7, the approach of example 3 was repeated. Thus, naproxen sodium granules of example 1 were used and the spray-dried formulation of vitamin B12 was added afterwards together with the required excipients. The result of this tableting trial is shown in below Table 14.

TABLE-US-00018 TABLE 14 Tableting trial of granules comprising naproxen sodium only; source of vitamin B12 was added afterwards together with the required excipients Material mg/tablet Naproxen sodium granules Naproxen Sodium 221.11 PVP K30 4.42 Spray-dried formulation of vitamin B12 50 MCC 200 71.47 Croscarmellose Sodium 1.50 Magnesium Stearate 1.50 Total (mg/tablet) 350.00 Compression profile Hardness (kp) 1000 Lbs. 4.3 2000 Lbs. 8.0 3000 Lbs. 11.2

[0159] Example 8 was successful. Reasonably hard tablets were obtained, regardless whether a compression force of 1000 lbs., 2000 lbs., or 3000 lbs. was applied.

Example 9 (Tablet with Breaking Notch)

[0160] In example 9, a tablet comprising naproxen and three different B-vitamins was prepared. First, granules comprising naproxen sodium and vitamin B1 were prepared, similar to example 5 (cf. table 10). The thus obtained granules were then blended with vitamin B6, a spray-dried formulation of vitamin B12 and the required excipients. The blend was then compressed into tablets having a target tablet weight of 1100 mg. The composition of the thus obtained tablets is shown in below Table 15.

TABLE-US-00019 TABLE 15 Tablet comprising naproxen (200 mg), vitamin B1 (100 mg), vitamin B6 (200 mg) and vitamin B12 (200 μg) Concentration (wt.-%, based Claim Conversion on total weight Overage Material (mg) factor of compound) (wt.-%) mg/tablet Naproxen & vitamin 372.71 B1 granules Pyridoxine 200 0.8227 10 267.41 Hydrochloride Vitamin B12 0.1% 0.2 0.001 30 260.00 WS MCC 200 186.38 Croscarmellose 5.00 Sodium Silicon Dioxide 3.00 Magnesium Stearate 5.50 Total 1100.00

[0161] The tablets were produced on a Piccola “B” Press equipped with 0.3543×0.7480″ oval shaped tooling with DSM® logo. Compression force was 4000 lbs. Tablet hardness was 12.9 kp and friability was 0.49%.

[0162] Friability was measured by putting minimum 10 tablets and minimum 6.5 g of tablets into a Sotax F1 friabilator and then tumbling the tablets for 100 revolutions. The weight loss/the initial weight×100% is friability. This is in accordance with USP chapter 1216, Year 2017.

[0163] Disintegration was measured on a Sotax DT2 disintegration apparatus (purified water, in accordance with USP chapter 701, Year 2017). Disintegration time is as short as 1 min 50 sec. Individual tablet weight variation (RSD) is 1.57% (calculated based on 10 tablets). Image of the tablets of example 9 is shown in FIG. 1.

Example 10 (Capsule)

[0164] In example 10, hard-shell capsules comprising naproxen and three different B-vitamins were prepared. First, granules comprising naproxen sodium and vitamin B1 were prepared, similar to example 5. The thus obtained granules were then blended with vitamin B6, a spray-dried formulation of vitamin B12 and the required excipients. The blend was then filled into capsules. The composition of the thus obtained capsules is shown in below Table 16.

TABLE-US-00020 TABLE 16 Capsule comprising naproxen (200 mg), vitamin B1 (100 mg), vitamin B6 (200 mg) and vitamin B12 (200 μg) Concentration (wt.-%, based Claim Conversion on total weight Overage Material (mg) factor of compound) (wt.-%) mg/capsule Naproxen & vit 372.71 B1 granules Pyridoxine 200 0.8227 10 267.41 Hydrochloride Vitamin B12 0.2 0.001 30 260.00 0.1% WS MCC 200 6.88 Silicon Dioxide 3.00 Total 910.00

[0165] In contrast to the tablet formulation of example 9, the amount of MCC 200 is significantly reduced because it is a hard-shell capsule formulation instead of a tablet. Croscarmellose sodium and magnesium stearate were completely omitted. The serving size is 910 mg powder in one or more capsules. The fill weight range of the blend in size “0” capsule shells is 335.3 mg to 456.8 mg. The fill weight range of the blend in size “00” capsule shells is 445.6 mg to 615.3 mg. Therefore, the serving size of capsules are 2 capsules in either “0” or “00” capsule shells.

Example 11 (RTM Stick-Pack)

[0166] In example 11, RTM (ready-to-mix) stick-packs comprising naproxen and three different B-vitamins were prepared. First, granules comprising naproxen sodium and vitamin B1 were prepared, similar to example 5. The thus obtained granules were then blended with vitamin B6, a spray-dried formulation of vitamin B12 and other suitable excipients. The blend was then filled into stick packs. The composition of the blend in the thus obtained stick-packs is shown in below Table 17.

TABLE-US-00021 TABLE 17 RTM comprising naproxen (200 mg), vitamin B1 (100 mg), vitamin B6 (200 mg) and vitamin B12 (200 μg) Concentration (wt.-%, based Claim Conversion on total weight Overage Material (mg) factor of compound) (wt.-%) mg/RTM Naproxen & 372.71 vit B1 granules Pyridoxine 200 0.8227 10 267.41 Hydrochloride Vitamin B12 0.2 0.001 30 260.00 0.1% WS Nat Lemon 44.81 Flavor Nat 56.02 Raspberry Flavor Citric Acid 44.81 Malic Acid 33.61 Sucralose 22.41 Mannitol 898.22 Total 2000.00

[0167] Besides the actives, flavors and acids have been added to improve taste; mannitol is used as a diluent. The serving size is 2 g/stick-pack to be dispersed in 8 oz of water. An image of the drink can be seen in FIG. 2. The pink color of the drink matches the flavor.