EXTENDED-RELEASE SOLID ORAL DOSAGE FORM COMPRISING VITAMIN B12 AND A VITAMIN B12 DEPLETING DRUG

Abstract

The present invention relates to a solid oral dosage form comprising an extended-release tablet core that is coated with an immediate-release coating, wherein said extended-release tablet core comprises at least one vitamin B12 depleting drug, and wherein said immediate-release coating comprises vitamin B12 or a spray dried formulation thereof. In a preferred embodiment, the vitamin B12 depleting drug is metformin or a pharmaceutically acceptable salt thereof.

Claims

1. Solid oral dosage form comprising an extended-release tablet core that is coated with an immediate-release coating, wherein said extended-release tablet core comprises at least one vitamin B12 depleting drug, and wherein said immediate-release coating comprises vitamin B12 or a spray dried formulation thereof.

2. Solid oral dosage form according to claim 1, wherein said immediate-release coating comprises a further active pharmaceutical ingredient, and wherein said immediate-release coating comprises preferably empagliflozin or a pharmaceutically acceptable salt thereof.

3. Solid oral dosage form according to claim 1, wherein said at least one vitamin B12 depleting drug is metformin or a pharmaceutically acceptable salt thereof, and wherein said at least one vitamin B12 depleting drug is preferably metformin HCl.

4. Solid oral dosage form according to claim 3, wherein said solid oral dosage form further comprises at least one source of calcium ions, and wherein said source of calcium ions is preferably a calcium salt, and wherein said calcium salt is preferably selected from the group consisting of calcium phosphate, calcium carbonate and calcium citrate, and wherein said calcium salt is more preferably selected from the group consisting of anhydrous calcium citrate, tricalcium dicitrate tetrahydrate, anhydrous monocalcium phosphate, anhydrous dicalcium phosphate, anhydrous tricalcium phosphate and calcium carbonate.

5. Solid oral dosage form according to claim 3, wherein the extended-release tablet core of said solid oral dosage form comprises at least one calcium salt, and wherein said calcium salt is preferably calcium citrate, and wherein said calcium citrate is preferably anhydrous calcium citrate or tricalcium dicitrate tetrahydrate.

6. Solid pharmaceutical dosage form according to claim 1, wherein said immediate-release coating comprises a spray dried formulation of vitamin B12, and wherein said spray dried formulation of vitamin B12 comprises preferably from 0.01 to 1 weight-%, more preferably from 0.05 to 0.5 weight-% and most preferably 0.1 weight-% cyanocobalamin, based on the total weight of the spray dried formulation of vitamin B12.

7. Solid pharmaceutical dosage form according to claim 1, wherein said immediate-release coating is at least partially covered by a protective coating, and wherein said protective coating comprises preferably at least one light-protection agent such as titanium dioxide.

8. Solid oral dosage form according to claim 1, wherein after oral intake of the solid oral dosage form, less than 30 weight-% of the vitamin B12 depleting drug is released in the stomach, based on the total weight of vitamin B12 depleting drug in the solid oral dosage form, and/or wherein after oral intake of the solid oral dosage form, at least 70 weight-% of vitamin B12 is released in the stomach after oral intake of the solid oral dosage form, based on the total weight of vitamin B12 in the solid oral dosage form, and wherein said vitamin B12 is preferably cyanocobalamin.

9. Solid oral dosage form according to claim 1 for use as a medicament.

10. Solid oral dosage form according to claim 3 for use in the treatment or prevention of metformin induced vitamin B12 deficiency.

11. Method of manufacturing a solid oral dosage form which comprises an extended-release tablet core and at least one vitamin B12 depleting drug, wherein said extended-release tablet core is provided with an immediate-release coating that comprises vitamin B12 or spray dried formulation thereof.

12. Method according to claim 10, said method comprising the step of dry granulation of at least one vitamin B12 depleting drug with at least one calcium salt and optionally microcrystalline cellulose, wherein said calcium salt is preferably calcium phosphate, and wherein said calcium salt is most preferably anhydrous dicalcium phosphate.

13. Method according to claim 11, wherein said at least one vitamin B12 depleting drug is metformin or a pharmaceutically acceptable salt thereof, and wherein said at least one vitamin B12 depleting drug is preferably metformin HCl.

14. Method according to claim 11, wherein the solid oral dosage form is manufactured.

15. Use of a spray dried formulation of vitamin B12 for manufacturing an immediate-release coating, wherein said immediate-release coating covers at least partially an extended-release tablet core which comprises at least one vitamin B12 depleting drug.

Description

FIGURES

[0104] FIG. 1 shows the dissolution profiles in Fasted State Simulated Gastric Fluid (FaSSGF) of uncoated tablet cores which comprise metformin HCl. Two kinds of cores were tested: with and without calcium salt. The composition of the two kinds of cores is given in Tables 2a and 2b.

[0105] FIG. 2 shows the dissolution profiles in Fasted State Simulated Intestinal Fluid (FaSSIF) of uncoated tablet cores which comprise metformin HCl. The same two types of cores were tested as in the experiment shown in FIG. 1.

[0106] FIGS. 3a, 3b and 3c relate to the dissolution profiles of the coated tablet cores. The coating comprises a source of vitamin B12. Two kinds of sources of vitamin B12 were tested: crystalline vitamin B12 and a spray dried formulation of vitamin B12. Thus, two kinds of coated cores were tested. The composition of the two kinds of coating is given in Tables 5a and 5b.

[0107] FIG. 3a shows the dissolution profiles of metformin and empagliflozin in FaSSGF in regard of crystalline vitamin B12. FIG. 3b shows the dissolution profiles of metformin and empagliflozin in FaSSGF in regard of a spray dried formulation of vitamin B12. FIG. 3c shows a comparison of the empagliflozin dissolution from the two kinds of coating in FaSSGF.

[0108] FIGS. 4a, 4b and 4c relate to similar experiments as shown in FIGS. 3a, 3b and 3c. For those experiments, however, the dissolution profiles were measured in FaSSIF instead of FaSSGF.

[0109] FIG. 4a shows the dissolution profiles of metformin and empagliflozin in FaSSIF in regard of crystalline vitamin B12. FIG. 4b shows the dissolution profiles of metformin and empagliflozin in FaSSIF in regard of a spray dried formulation of vitamin B12. FIG. 4c shows a comparison of the metformin dissolution from the two kinds of coating in FaSSIF.

EXAMPLES

Example 1 (Selection of the Preferred Source of Ionic Calcium)

[0110] In Example 1, the solubility of four different calcium salts was analysed in simulated intestinal fluid via determination of the Ca.sup.2+ ions content by ICP-OES (inductively coupled plasma optical emission spectrometry).

[0111] The calcium salts were: [0112] calcium carbonate (95 MD available at Particle Dynamics), [0113] dicalciumphosphat anhydrous (DiCafos A150, available at Budenheim), [0114] tricalcium dicitrate tetrahydrate (available at Merck) [0115] anhydrous calcium citrate (available at Gadot).

[0116] The solubilization medium was: [0117] SIF (simulated intestinal fluid, pH=6.8, prepared according to Ph. Eur.)

[0118] The dissolution medium was heated to 37° C. and the analyses were performed at this temperature. During the analyses, the salts were added in access to the solubilization media and left to mix for 24 h. Afterwards, the solutions were filtered, and the precipitates were investigated using ATR-IR analysis to confirm the presence of the starting material (e.g. respective Ca salt). Attenuated total reflection (ATR) is a sampling technique used in conjunction with infrared spectroscopy which enables samples to be examined directly in the solid or liquid state without further preparation. The filtered solutions were analysed for Ca.sup.2+ ions content. The solubility results that were obtained are shown in the TABLE 1.

TABLE-US-00001 TABLE 1 SIF solubility Ca.sup.2+ solubility mg/ml ions Ca.sup.2+ ions mg/ml average pH mg/ml mg/ml, average Ca carbonate 0.058 0.06 7.5 0.023 0.024 0.060 7.5 0.024 dicalcium 0.093 0.09 6.7 0.027 0.028 phosphate 0.094 6.6 0.028 anhydrous tricalcium dicitrate 2.130 2.11 6.1 0.450 0.445 tetrahydrate 2.090 6.1 0.440 anhydrous calcium 1.920 1.91 6.1 0.460 0.460 citrate 1.890 6.1 0.460

[0119] For in vivo absorption of vitamin B12, a vitamin B12-IF complex needs to be formed which then binds to enterocyte receptors in the ileum. For this process, calcium ions should be present in the patient's ileum.

[0120] Because the tablet core of the invention is an extended-release tablet core, it reaches the patient's intestine partially or fully undissolved. If the core comprises a calcium salt, said calcium salt reaches the patient's intestine also partially or fully undissolved. Calcium salts which remain undissolved in the ileum do not significantly increase absorption of vitamin B12. Thus, any calcium salt comprised in an extended-release core should be well soluble in intestinal fluid.

[0121] Example 1 shows that calcium citrate salts are well soluble in intestinal fluid. Therefore, calcium citrate salts such as tricalcium dicitrate tetrahydrate and anhydrous calcium citrate are particularly suitable to be included in the extended-release tablet core of the invention.

Example 2 (Preparation of Uncoated Extended-Release Metformin Cores, with and without Calcium Salt)

[0122] For the tabletting mixture of the metformin cores, the individual components listed in Tables 2a and 2b, except magnesium stearate and glyceryl behenate (outer phase), were poured into a 2.5 L powder glass bottle and blended for 16 minutes at 32 rpm using a Turbula 3D mixer/blender (WAB plc. Muttenz, Switzerland). Subsequently magnesium stearate and glyceryl behenate were sieved through a 500 micron mesh sized sieve and added to the previous blend. After an additional blending of 4 minutes at 32 rpm this final tabletting mixture was transferred to the XP1 eccentric press from Korsch plc. (Berlin, Germany).

[0123] The only difference of the composition in case of the tablet cores without calcium citrate, the 14.5 wt.-% Ca citrate were compensated (replaced) with the addition of more Prosolv SMCC 90 (to 20.4 wt.-%, cf. TABLE 2b).

[0124] TABLE 2a shows the composition in case of the tablet cores with calcium citrate.

[0125] For all cores, a mean compression force of 31.52±1.16 kN and a tabletting speed of 10 tablets per minute was used.

TABLE-US-00002 TABLE 2a Tablet core composition (with tricalcium dicitrate tetrahydrate) Weight Weight Component name/Supplier (mg) (wt.-%) Metformin granules (92.6 wt.-%)/ 863.9 57.6 Vistin Pharma (Oslo, Norway) Methocel K100M Premium CR/Colorcon 300.0 20.0 inc. (Dartford Kent, United Kingdom) Prosolv SMCC 90/JRS Pharma ltd. & 88.7 5.9 Co. KG (Rosenberg, Germany) Tricalcium dicitrate tetrahydrate/Merck 217.4 14.5 (Darmstadt, Germany) Magnesium stearate/Hanseler plc. 15.0 1.0 (Herisau, Switzerland) Glyceryl behenate (Compritol 888 ATO) 15.0 1.0 Gattefosse plc. (Saint-Priest, France) Sum 1500.0 100.0

TABLE-US-00003 TABLE 2b Tablet core composition (without tricalcium dicitrate tetrahydrate) Weight Weight Component name/Supplier (mg) (wt.-%) Metformin granules (92.6 wt.-%)/Vistin Pharma 863.9 57.6 (Oslo, Norway) Methocel K100M Premium CR/Colorcon inc. 300.0 20.0 (Dartford Kent, United Kingdom) Prosolv SMCC 90/JRS Pharma ltd. & Co. KG 306.1 20.4 (Rosenberg, Germany) Tricalcium dicitrate tetrahydrate/Merck — — (Darmstadt, Germany) Magnesium stearate/Hanseler plc. (Herisau, 15.0 1.0 Switzerland) Glyceryl behenate (Compritol 888 ATO) 15.0 1.0 Gattefosse plc. (Saint-Priest, France) Sum 1500.0 100.0

[0126] The punches that were used had a diameter of 20 mm with two round flat-faced faceted sides. A tablet weight of 1.50 g was targeted, and the resulting core properties are listed in TABLE 3. Tablet weights were recorded on a PB 303-LDR Delta Range balance from Mettler Toledo Itd. (Greifensee, Switzerland). The breaking force and tablet height were measured with the tablet hardness tester TBH 220 TD from Erweka ltd. (Heusentamm, Germany). Friability testing was done according to USP <1216> (10 tablets 100 revolutions at 25 rpm) using the TA 120 friability tester from Erweka Itd. (Heusenstamm, Germany).

TABLE-US-00004 TABLE 3 without tricalcium with tricalcium core formulation dicitrate tetrahydrate dicitrate tetrahydrate Uniformity of mass 1.50 ± 0.002 1.50 ± 0.003 [g] (n = 30) Uniformity of height 4.22 ± 0.01  4.25 ± 0.01  [mm] (n = 30) Mean breaking force 150.20 ± 4.47    147.40 ± 3.50    [N] (n = 10) Friability [weight 0.13 0.18 loss %] (n = 10)

Example 3 (Dissolution Data of Uncoated Extended-Release Metformin Cores, with and without Calcium Salt)

[0127] In Example 3, the effect of calcium salt addition on the release of metformin HCl was tested.

[0128] Dissolution testing was performed in triplicate on the USP 2 apparatus DT600 HH from Erweka Itd. (Heusenstamm, Germany). A paddle speed of 75 rpm and a temperature of 37° C. was used. The resulting dissolution profiles are shown in FIGS. 1 and 2. As dissolution media for each core 900 ml of Fasted State Simulated Gastric Fluid (FaSSGF) Fasted State Simulated Intestinal Fluid (FaSSIF) were used.

[0129] Preparation of the Bio-Simulating Media FaSSIF and FaSSGF:

[0130] A detailed overview of the compositions is depicted in TABLE 4. For 1 liter of the FaSSIF buffer, 0.420 g of sodium hydroxide pellets (Sigma-Aldrich Chemie plc.; Buchs, Switzerland), 3.954 g of monobasic sodium phosphate anhydrous (Sigma-Aldrich Chemie plc.; Buchs, Switzerland) and 6.186 g sodium chloride (Sigma-Aldrich Chemie plc.; Buchs, Switzerland) were dissolved in 1 liter purified water. The pH value was adjusted with 1M hydrochloric acid (Merck KGaA; Darmstadt, Germany). Finally, 2.240 g of the SIF powder (Biorelevant.com ltd.; London United Kingdom) were dissolved in a total volume of 1 L buffer. After 2 hours of stirring on a magnetic stirring plate, the FaSSIF was ready to use.

[0131] In 1 liter of the buffer for the bio-relevant media FaSSGF, 1.999 g sodium chloride (Sigma-Aldrich Chemie plc.; Buchs, Switzerland) were dissolved in liter purified water. The pH value was adjusted with 1M hydrochloric acid (Merck KGaA; Darmstadt, Germany). Finally, 0.0597 g of the SIF powder (Biorelevant.com Itd.; London, United Kingdom) were dissolved in a total volume of 1 L buffer. The purified water used for the media was treated with an arium Pro from Satorius Lab Instruments GmbH & Co. KG (Göttingen, Germany) and had a conductivity of ≤0.055 μS/cm at 25° C.

TABLE-US-00005 TABLE 4 FaSSIF composition FaSSGF composition Component Concentration (mM) Taurocholate 3 0.08 Phospholipids 0.75 0.02 Sodium 148 34 Chloride 106 59 Phosphate 29 — pH 6.5 1.6

[0132] Samples of 2 ml were taken at different time points (see FIGS. 1 and 2) and the volume in the dissolution vessel was kept constant by immediate replacement with 2 ml of FaSSGF or FaSSIF. The samples were filtered through a Titan PTFE syringe filter (17 mm; 0.45 μm) from infochroma pic. (Goldau Switzerland) and immediately sealed in 2 ml brown HPLC glass vials (Wicom Germany ltd., Heppenheim, Germany).

[0133] HPLC Analysis:

[0134] Drug concentrations were measured in triplicates at room temperature (RT) using a reversed phase method on a HPLC 1200 series instrument from Agilent Technologies ltd. (Waldbronn, Germany) using an UV detector at 277 nm, 1 ml/min flowrate and 20 μL injection volume. The HPLC was equipped with a hydrophobic C18 column (ZORBAX Eclipse Plus, 5 μm, 2.1×150 mm) from Agilent Technologies. As mobile phase, 50% (v/v) methanol and 50% (v/v) phosphate buffer (pH 3.0) was used. For the phosphate buffer 6.8 g potassium phosphate monobasic was dissolved in 1 liter purified water and the pH was adjusted with phosphoric acid (85%) to 3.0. All chemicals used for the mobile phase were supplied from Sigma-Aldrich Chemie plc. (Buchs, Switzerland).

[0135] FIGS. 1 and 2 show the data obtained in Example 3.

CONCLUSIONS

[0136] The data of Example 3 relates to uncoated tablet cores whereas the solid oral dosage form of the invention contains a tablet core that is covered with at least one immediate-release coating. Thus, after oral administration of the solid oral dosage form of the invention, the coating of the tablet core will first need to be dissolved. The data shown in FIG. 1 (FaSSGF) relates to a simulation of what will happen once the coating will have been dissolved. As shown in FIG. 1, in the stomach of the patient (i.e. in gastric fluid), only a limited amount of metformin will be released from the tablet core. FIG. 1 also shows that the addition of calcium citrated slightly delays the release of metformin in gastric juice. This is acceptable as the objective is the provision of an extended-release formulation of metformin.

[0137] Approximately 30-60 minutes after oral administration of the solid oral dosage form of the invention, the at least partially undissolved tablet core (without coating; coating has been dissolved in the stomach) will reach the patient's duodenum through the pylorus. The exact amount of time the core needs to pass from the stomach to the intestine depends on the patient's state (fed or fasted). The data shown in FIG. 2 (FaSSIF) relates to a simulation of what happens when the at least partially undissolved tablet core has reached the patient's intestine. The metformin cores with and without calcium show dissolution profiles of an extended release dosage form. After 8 hours in FaSSIF 89±3.5% of the metformin was released for the cores without calcium citrate and 93±1.3% of metformin for the cores with calcium citrate.

[0138] Thus, the addition of calcium citrate does not significantly influence the release of metformin in the intestine. This is an important aspect when seeking for line extension for an existing, approved extended-release formulation of metformin which allows once-daily dosing. It is expected that calcium citrate can be added to an existing, approved formulation without amending the release profile of metformin. In other words, when adding calcium citrate to an existing, approved formulation, a bioequivalent formulation is expected to be obtained.

Example 4 (Coating of Cores Comprising Calcium Salt and Using Two Different Sources of Vitamin B12)

[0139] In Example 4, solid oral dosage forms according to a preferred embodiment of the invention were prepared.

[0140] First, cores identical to the ones of Example 2 were manufactured. The composition of the cores was identical to the composition shown in Table 2, i.e. the cores comprised metformin HCl and tricalcium dicitrate tetrahydrate. The thus obtained extended-release cores were then coated.

[0141] Coating of the extended-release cores was performed using a lab coater GC-1 from Glatt (Pratteln, Switzerland). Two different batches of coated tablets were produced. In the first batch, crystalline vitamin B12 was used as source of vitamin B12. In the second batch, a spray-dried formulation of vitamin B12 (0.1% WS, commercially available at DSM Nutritional Products, Switzerland) was used as source of vitamin B12.

[0142] In both cases, the tablet cores were coated with two coating layers. The first coating layer contained vitamin B12 (either crystalline vitamin B12 or spray dried formulation of vitamin B12) and empagliflozin. A second coating layer was then added on the top of the first coating layer as a protective layer. In the first batch, where crystalline vitamin B12 was used as source of vitamin B12, a rather thick protective layer was added because crystalline vitamin B12 is highly sensitive to light. In the second batch, where a spray dried formulation of vitamin B12 was used as source of vitamin 12, a rather thin protective layer was added because spray dried formulations of vitamin B12 are less light sensitive than crystalline vitamin B12.

[0143] TABLE 5a relates to the use of crystalline vitamin B12 as source of vitamin B12 (i.e. first batch) and shows the composition of both coating layers.

TABLE-US-00006 TABLE 5a Ingredient Amount (g) Amount (wt.-%) Composition of the first coating layer Eudragit E PO Ready-Mix 80.0 10.14 (contains TiO.sub.2) Empagliflozin 13.2 1.67 Vit.B12 (crystalline) 0.01056 0.00134 Ethanol abs. (0.789 g/ml) ad 800 ml 88.19 Composition of the second coating layer Eudragit E PO Ready-Mix 20.0 12.67 (contains TiO.sub.2) Ethanol abs. (0.789 g/ml) ad 200 ml 87.33

[0144] TABLE 5b relates to the use of a spray dried formulation of vitamin B12 as source of vitamin B12 (i.e. second batch) and also shows the composition of both coating layers.

TABLE-US-00007 TABLE 5b Ingredient Amount (g) Amount (wt.-%) Composition of the first coating layer Eudragit E PO Ready-Mix 80.0 10.14 (contains TiO.sub.2) Empagliflozin 13.2 1.67 Vit.B12 (0.1% WS) 10.56 1.34 Ethanol abs. (0.789 g/ml) ad 800 ml 86.85 Composition of the second coating layer Eudragit E PO Ready-Mix 20.0 12.67 (contains TiO.sub.2) Ethanol abs. (0.789 g/ml) ad 200 m 87.33

[0145] The first coating layer contains Eudragit E PO Ready-Mix from Evonik (Darmstadt, Germany). It is a ready to use mixture that comprises basic butylated methacrylate copolymer, talcum and titanium dioxide. Empagliflozin (BOC Sciences, Shirley N.Y., USA) was added in sufficient amount to reach the dosage of 25 mg/tablet. All solid ingredients were weighted and added to a glass beaker. About 10% of solid content in solvent was provided to obtain a well pumpable coating suspension. To the solids in a glass beaker ⅔ of the total amount EtOH abs. was added and stirred continuously for around 45 min with an IKA stirrer blade (Staufen, Germany) at a speed of around 200 rpm. Afterwards the rest of the EtOH abs. was added and mixed for 5 min to obtain a homogenous suspension.

[0146] The same process parameters were used for all coating processes; they are presented at the TABLE 6.

TABLE-US-00008 TABLE 6 Process parameter Inlet temperature (° C.) 35 Volume flow rate air (m.sup.3/h) 30 Rotation speed drum (rpm) 5 Spraying rate (mL/min) 9 Atomizing Air pressure (bar) 1.0 Pattern Air pressure (bar) 1.0 Number of coated tablets 50 per batch

[0147] Weight gain and time of coating for each of the tablet batches is presented in TABLE 7. For the batch where crystalline vitamin B12 was used as source of vitamin B12, coating time for second coating layer was increased to obtain a thicker protective layer. The targeted increase in thickness was confirmed by a higher weight gain.

TABLE-US-00009 TABLE 7 With With Vit.B12 Vit.B12 cryst. 0.1% WS First coating layer Weight gain (wt.-%, based 13.3 13.4 on the weight of the tablet core) Coating time (min) 60 70 Second coating layer Weight gain (wt.-%, based on the weight of 3.3 1.9 the tablet core including the first coating layer) 20 13 Coating time (min)

[0148] The results of the assay analyses are presented in the TABLE 8.

TABLE-US-00010 TABLE 8 Coated tablets with vit. Coated tablets with vit. Vitamin B12 type B12 (0.1% WS) B12 (crystalline) Uniformity of mass 1.740 ± 0.013 g (n = 19) 1.770 ± 0.018 g (n = 24) Mass gain including 0.270 g 0.240 g second coating

Example 5 (Content Analysis of the Two Different Types of Solid Oral Dosage Forms Manufactured in Example 4)

[0149] The contents of vitamin B12, metformin and empagliflozin was measured in the solid oral dosage forms manufactured in Example 4.

[0150] Vitamin B12 Content Analysis:

[0151] The assay of vitamin B12 for the coated tablets was done also using a HPLC method. Vitamin B12 is a collective term for a group of vitamers. All vitamers using this method were determined as cyanocobalamin. Sample preparation was as follows: Four individual tablets were analysed. The individual vitamers are extracted from the sample using sodium acetate buffer and are transformed into the vitamer cyanocobalamin (R═—CN) with the aid of potassium cyanide. For purification, an aliquot of the extract is passed through an immunoaffinity column that contains specific antibodies that bind selectively to cyanocobalamin. The cyanocobalamin is then eluted from the column using methanol. The detection was done at the wave length of 361 nm.

[0152] Mean vit. B12 content for spray dried formulation of vitamin B12 of coated tablets is shown in Table 9.

TABLE-US-00011 TABLE 9 Tablets containing Vitamin B12 0.1% WS Tablet no.: n = 3 (μg/tablet) 1 11.4 2 11.9 3 12.1 Overall mean 11.8 Overall ± std. dev. 0.38

[0153] Metformin and Empagliflozin Content Analysis:

[0154] Five tablets for each batch of the coated tablets (with the crystalline vit. B12 and with the vit. B12 0.1% WS titration) were analyzed regarding their API contents for metformin and empagliflozin. For this purpose, each tablet was dispersed in 250 ml of the HPLC mobile phase (50:50 v/v methanol:phosphate buffer pH 3.0) and stirred at 800 rpm (magnetic stirrer) for 48 hours in aluminum foil covered bottles. From each tablet dispersion, 4 samples were taken and diluted to 1:4 with the HPLC mobile phase to a total concentration of tablet per liter mobile phase. Prior to HPLC analysis, the diluted samples were mixed and filtered with Titan PTFE syringe filters (17 mm; 0.45 μm) from infochroma plc. (Goldau Switzerland). The resulting drug contents are shown in Tables 10a and 10b.

[0155] TABLE 10a relates to the use of crystalline vitamin B12 as source of vitamin B12 and shows mean metformin and empagliflozin concentrations.

TABLE-US-00012 TABLE 10a Coated tablets with crystalline vitamin B12 Mean metformin Mean empagliflozin concentration n = 4 concentration n = 4 Tablet no.: (mg/tablet) (mg/tablet) 1 811.02 24.83 2 819.96 26.63 3 833.56 26.31 4 827.60 25.55 5 827.86 26.25 Overall mean 824.00 25.91 Overall ± std. dev. 8.72 0.72

[0156] TABLE 10b relates to the use of a spray-dried formulation of vitamin B12 as source of vitamin B12 and also shows mean metformin and empagliflozin concentrations.

TABLE-US-00013 TABLE 10b Coated tablets with vitamin B12 titration (0.1% WS) Mean metformin Mean empagliflozin concentration n = 4 concentration n = 4 Tablet no.: (mg/tablet) (mg/tablet) 1 854.03 25.48 2 834.08 24.97 3 831.49 26.59 4 820.86 25.30 5 832.01 24.56 Overall mean 834.49 26.38 Overall ± std. dev. 12.07 0.76

Example 6 (Dissolution Test of the Two Different Types of Solid Oral Dosage Forms Provided in Example 4 in Gastric Fluid)

[0157] Upon coating, the dissolution profiles in FaSSGF of metformin, empagliflozin and Vitamin B12 from the coated tablets were analyzed in the same way as uncoated tablet cores described in example 3.

[0158] FIGS. 3a, 3b and 3c show the dissolution profiles of metformin and empagliflozin in FaSSGF.

[0159] FIG. 3a shows the dissolution profiles of metformin and empagliflozin in FaSSGF of the coated tablets with crystalline vitamin B12. FIG. 3b exhibits dissolution profiles of metformin and empagliflozin in FaSSGF of the coated tablets with spray dried formulation of vitamin B12 (0.1% WS). FIG. 3c shows a comparison of the empagliflozin dissolution from the immediate release coating in FaSSGF with vitamin B12 0.1% WS and crystalline vitamin B12.

[0160] There is no significant difference between the two batches in dissolution profiles when crystalline vitamin B12 or the spray dried formulation of vitamin B12 (WS 0.1%) is used in the coating.

[0161] After 30 minutes, the immediate release coating is completely dissolved in FaSSGF for both batches and after 15 minutes, empagliflozin is already dissolved up to 66.4±0.2%.

[0162] For both batches, less than 30% of the metformin is dissolved after 2 hours dissolution (37° C. and 75 rpm) in FaSSGF and after 1 hour only around 17%. It is expected that after this amount of time, the remains of the solid dosage form will have passed from the stomach (gastric fluid) through the pylorus into the duodenum (intestinal fluid).

Example 7 (Dissolution Test of the Two Different Types of Solid Oral Dosage Forms Provided in Example 4 in Intestinal Fluid)

[0163] The dissolution profiles in FaSSIF of metformin, empagliflozin and Vitamin B12 from the coated tablets were analyzed in the same way as uncoated tablet cores described in example 3.

[0164] FIGS. 4a, 4b and 4c show the dissolution profiles of metformin and empagliflozin in FaSSIF.

[0165] FIG. 4a displays the dissolution profiles of metformin and empagliflozin in FaSSIF of the coated tablets with crystalline vitamin B12.

[0166] FIG. 4b depicts the dissolution profiles of metformin and empagliflozin in FaSSIF of the coated tablets with the spray dried formulation of vitamin B12 (0.1% WS).

[0167] FIG. 4c shows a comparison of the metformin dissolution in FaSSIF with vitamin B12 0.1% WS and crystalline vitamin B12.

[0168] In intestinal fluid, after dissolution of the two coating layers, an extended metformin release for both batches is clearly visible. After 8 hours, more than 80% of the metformin is released.

[0169] Even though an effect of the two coating layers can be seen in FIGS. 4a, 4b and 4c (i.e. lag-time), said effect will not be observed in vivo. After oral administration of the dosage form of the invention, the dosage form first arrives in the stomach where it is exposed to gastric juice. While being in the stomach, the two protective layers will be dissolved. At the time when the dosage form will be exposed do intestinal fluid, the two coating layers will be gone.