SOLUBILITY ENHANCEMENT OF POORLY SOLUBLE ACTIVES

Abstract

The invention provides preparations comprising at least one polyunsaturated fatty acid salt for use in enhancing the solubility in aqueous media for a pharmaceutical or nutraceutical active ingredient in comparison to the pharmaceutical or nutraceutical active ingredient alone by at least 100%, preferably at least 300%. Moreover, a method for preparing a pharmaceutical or nutraceutical dosage form comprising at least one polyunsaturated fatty acid salt and at least one pharmaceutical or nutraceutical active ingredient is disclosed.

Claims

1. A method for enhancing the solubility of a pharmaceutical or nutraceutical active ingredient in an aqueous medium, the method comprising: adding a preparation comprising at least one polyunsaturated fatty acid salt comprising at least one omega-3 fatty acid selected from the group consisting of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to the medium comprising the pharmaceutical or nutraceutical active ingredient, wherein the solubility is enhanced by at least 100% in comparison to the pharmaceutical or nutraceutical active ingredient in the aqueous medium alone.

2. The method of claim 1, wherein the at least one polyunsaturated fatty acid salt comprises at least one counter ion selected from the group consisting of lysine, arginine, ornithine, choline, magnesium, potassium, and mixtures thereof.

3. The method of claim 1, wherein the at least one polyunsaturated fatty acid salt comprises as a counter ion lysine, or a mixture of lysine and one or more selected from the group consisting of arginine, ornithine, magnesium, and potassium, wherein the ratio between the lysine and the arginine, ornithine, magnesium, and potassium is between 10:1 and 1:1.

4. The method of claim 1, wherein the preparation further comprises an ionic polymer.

5. A method of preparing a pharmaceutical or nutraceutical dosage form comprising at least one polyunsaturated fatty acid salt comprising at least one omega-3 fatty acid selected from EPA and DHA, and at least one pharmaceutical or nutraceutical active ingredient, the method comprising: a. co-processing at least one polyunsaturated fatty acid salt comprising at least one omega-3 fatty acid selected from the group consisting of EPA and DHA, at least one pharmaceutical or nutraceutical active ingredient and optionally a pharmaceutically or nutraceutically acceptable excipient; b. optionally mixing the co-processed components from step a. with one or more excipients; and c. formulating the components to produce a dosage form.

6. The method of claim 5, wherein: the dosage form is a tablet, the mixed components from step b. are compressed in a tableting machine to produce a tablet, and the ejection force experienced by the tableting machine is not more than 150 N.

7. The method of claim 5, wherein the ratio of the active ingredient to the polyunsaturated fatty acid salt is between 1:0.5 to 1:50.

8. The method of claim 5, wherein the polyunsaturated fatty acid salt and the pharmaceutical or nutraceutical active ingredient are co-processed with one or more ionic polymers.

9. The method of claim 8, wherein the ratio of the active ingredient to the ionic polymer is between 0.1:1 to 1:0.1.

10. The method of claim 8, wherein the ratio of polyunsaturated fatty acid salt and the ionic polymer is between 0.2:1 to 1:0.2.

11. The method of claim 5, wherein the co-processing in step a. comprises at least one selected from the group consisting of spray drying, pure spray drying, spray-agglomeration, co-milling, freeze drying, physical mixing, co-sifting, vacuum drying, hot-melt extrusion, compaction, slugging, 3D printing, molding, film casting, and coating.

12. The method of claim 5, wherein prior to step a. the pharmaceutical or nutraceutical active ingredient is mixed with one or more lipophilic substances.

13. The method of claim 5, wherein the pharmaceutical active ingredient is at least one selected from the group consisting of BCS classes II, III, and IV.

14. The method of claim 13, wherein the pharmaceutical active ingredient is ionic.

15. A pharmaceutical or nutraceutical dosage form prepared by the method of claim 5, wherein the dosage form is at least one selected from the group consisting of a tablet, a capsule, a soft capsule, a suspension, an emulsions, a granule, a powder, an oral film, a pellet, a suppository, a pessary, and an intra-vascular dosage form.

16. The pharmaceutical or nutraceutical dosage form of claim 15, further comprising at least one excipient selected from the group of consisting of a binder, an antioxidant, a glidant, a lubricant, a pigment, a plasticizer, a polymer, a brightener, a diluent, a flavor, a surfactant, a pore former, and a stabilizer.

Description

EXAMPLES

[0086] Polyunsaturated Fatty Acid Compositions

[0087] In the examples for the present invention, different polyunsaturated fatty acid compositions were used. Different omega-3 fatty acid salts having an organic counter ion selected from the basic amino acids lysine, arginine and ornithine were prepared. The omega-3 fatty acids Eicosapentaenoic acid (C20:5w3c) (EPA) and Docosahexaenoic acid (C22:6w3c) (DHA) are present in a ratio of around 2:1 (ratio EPA:DHA). The salts were prepared by spray granulation as described in WO2016102323A1.

[0088] The omega-3 lysine salt (omega-3-lys) contains around 32 weight-% of L-lysine and around 65 weight-% of polyunsaturated fatty acids (AvailOm®, Evonik Nutrition and Care GmbH, Darmstadt, Germany). The major polyunsaturated fatty acids in the composition are the omega-3 fatty acids Eicosapentaenoic acid (C20:5w3c) (EPA) and Docosahexaenoic acid (C22:6w3c) (DHA), summing up to around 58 weight-% of the composition. The composition also contains minor amounts of Docosaenoic acid isomer (incl. erucic acid) (C22:1), Docosapentaenoic acid (C22:5w3c) and of the omega-6 fatty acids Arachidonic acid (C20:4w6) and Docosatetraenoic acid (C22:4w6c).

[0089] The omega-3 arginine salt (omega-3-arg) contains around 35 weight-% of L-arginine and around 64 weight-% of polyunsaturated fatty acids. The major polyunsaturated fatty acids in the composition are the omega-3 fatty acids Eicosapentaenoic acid (C20:5w3c) (EPA) and Docosahexaenoic acid (C22:6w3c) (DHA), summing up to around 49 weight-% of the composition. The composition also contains minor amounts of Docosaenoic acid isomer (incl. erucic acid) (C22:1), Docosapentaenoic acid (C22:5w3c) and of the omega-6 fatty acids Arachidonic acid (C20:4w6) and Docosatetraenoic acid (C22:4w6c).

[0090] The omega-3 ornithine salt (omega-3-orn) contains around 29 weight-% of L-ornithine and around 70 weight-% of polyunsaturated fatty acids. The major polyunsaturated fatty acids in the composition are the omega-3 fatty acids Eicosapentaenoic acid (C20:5w3c) (EPA) and Docosahexaenoic acid (C22:6w3c) (DHA), summing up to around 54 weight-% of the composition. The composition also contains minor amounts of Docosaenoic acid isomer (incl. erucic acid) (C22:1), Docosapentaenoic acid (C22:5w3c) and of the omega-6 fatty acids Arachidonic acid (C20:4w6) and Docosatetraenoic acid (C22:4w6c).

[0091] The mixed salts of ornithine and arginine (50:50), ornithine and lysine (50:50) and mixed salts of arginine and lysine (50:50) were prepared by spray granulation as described in WO2016102323A1 using the PUFA composition described above. The Mg.sup.2+ salts and mixed salts of Mg.sup.2+ and arginine (50:50) were prepared by kneading as described in WO2017202935A1 using the PUFA composition described above.

Comparative Examples 1-7

[0092] Acrylic polymers are widely explored and known for its solubility enhancement effect. As comparative examples (table 1), the solubility enhancement effect of such polymers of the EUDRAGIT® type on different advanced food ingredients (AFI) and active pharmaceutical ingredients (API) in water was evaluated.

TABLE-US-00001 TABLE 1 Formulation for comparative experiments, Experiment C-1 C-2 C-3 C-4 C-5 C-6 C-7 Method of Coprocessing .. .. SD .. SD .. SD End Dosage Blend Blend Blend Blend Blend Blend Blend form Ingredient % w/w % w/w % w/w % w/w % w/w % w/w % w/w Celecoxib 100 .. .. .. .. .. .. Ritonavir .. 100 25  .. .. .. .. Curcumin .. .. .. 100 25  .. .. Quercetin .. .. .. .. .. 100 14.49 EUDRAGIT ® .. .. 75* .. 75* .. .. EPO EUDRAGIT ® .. .. .. .. .. 43.47* L100-55 MCC PH 102 .. .. .. .. .. .. 33.33** Lactose .. .. .. .. .. .. Total 100 100 100  100 100  100 100 Ethanol: .. .. 100:0 .. 50:50 .. 100:0 Methanol Ratio Solid Content .. ..   13.55 .. 4 .. 10 % w/w **MCC PH 102 was added externally

[0093] For the examples without coprocessing applied for C-1, C-2, C-4 and C-6, the AFI/API was directly used for analysis. For the spray drying process (SD) applied for C-3, C-5 and C-7, the AFI/API was mixed in the solvent and to this solution EUDRAGIT® was added under constant stirring. The solution was spray dried after a clear solution was obtained (parameters shown in table 2). The spray dried powder obtained was then taken for physical mixing with other tableting excipients if any. The blend was then taken directly for analysis.

TABLE-US-00002 TABLE 2 Process parameter for spray drying Parameters C-3 C-5 C-7 Inlet Temperature (° C.) 42-43 43-45 43-45 Aspirator (%) 70-89  87-100 92-93

[0094] Analysis of the blend was done and its solubility in water was analyzed (table 3).

TABLE-US-00003 TABLE 3 Solubility of AFI/API in water Experiment C-1 C-2 C-3 C-4 C-5 C-6 C-7 Solubility of 0.1 μg/ml 0.0 μg/ml 0.0 μg/ml 0.0 μg/ml 0.1 μg/ml 3.6 μg/ml 0.1 μg/ml AFI/API in water

[0095] For the following experiments, acceptance criteria were defined whether there is any enhancement in solubility of the AFI/API of more than 3 times increase water solubility of the AFI/API in relation to observed solubility in the comparative examples as shown above.

Examples 1-7: Solubility Enhancement of Food Ingredients Curcumin and Quercetin (Inventive)

[0096]

TABLE-US-00004 TABLE 4 Formulation for food ingredients Curcumin and Quercetin, Experiment I-1 I-2 I-3 I-4 I-5 I-6 I-7 Method of SD SD SD + PM SD SD SD + PM SD Coprocessing End Dosage Blend Tablet Tablet Tablet Tablet Tablet Tablet form Ingredient % w/w % w/w % w/w % w/w % w/w % w/w % w/w Curcumin  9.1*  9.1* 15.63* 10.21*  6.9* .. .. Quercetin .. .. .. .. .. 12.12*  6.9 MCT Oil .. .. .. .. .. .. .. AvailOm ® 90.9* 90.9* 37.5** 27.27* 31.03* 18.16** 31.03 EUDRAGIT ® .. .. 46.9* 54.55* 62.07* .. 62.1 EPO EUDRAGIT ® .. .. .. .. .. 36.36* L100-55 MCC PH 102 .. .. .. .. .. 33.33 Total 100 100 100 100 100 100 100 Ethanol: 90:10 90:10 .. 80:20 80:20 100:0 80:20 Water Ratio Ethanol: .. .. 50:50 .. .. .. .. Methanol Ratio Solid Content 7.28 7.28 4 9.9 12.66 10 10.39 (% w/w) *ingredients were co-processed together in a single spray drying step, **ingredients were co-processed by only physically mixing with the spray dried powder in the same batch Formulations for the food ingredients Curcumin and Quercetin are shown in table 4.

[0097] For the spray drying process (SD) applied for I-1, I-2, I-4, I-5 and I-7, the food ingredient was added in the non-aqueous media and to this solution EUDRAGIT® if any was added and then AvailOm® (omega-3 lysine salt) was added under constant stirring. After addition of AvailOm®, the remaining amount of water was added and after the solution getting completely clear used for spray drying (parameters shown in table 5). The spray dried powder obtained was then mixed with other tableting excipients if any by passing through a 30# sieve in geometric addition. The blend was then taken for compression (tableting parameters shown in table 6). For I-1, the blend was directly used for analysis.

TABLE-US-00005 TABLE 5 Process parameter for spray drying Parameters I-1 I-2 I-4 I-5 I-7 Inlet Temperature (° C.) 55-57 55-57 65-69 69-70 69-74 Aspirator (%)  91-100  91-100 70-89  90-100  81-100

TABLE-US-00006 TABLE 6 Tableting parameters Parameter I-2 I-4 I-5 I-7 Punch size (mm) 12.5 10 18*8 18*8 Average Weight (mg) 550 270-280 720-730 720-730 Compression force (KN) 15.23 2.948 5.848 3.672 Ejection force (N) 104.5 96.80 96.80 98 Hardness (N) 70-90 70-90 60-80 —

[0098] For the spray drying physical mixing process (SD+PM) applied for I-3 and I-6, the food ingredient was added in the solvent, EUDRAGIT® was added to this solution under constant stirring and after the solution getting completely clear used for spray drying (table 7). The spray dried powder obtained was then taken for physical mixing with AvailOm® and other tableting excipients if any. The blend was then taken for compression (tableting parameters shown in table 8).

TABLE-US-00007 TABLE 7 Process parameter for spray drying Parameters I-3 I-6 Inlet Temperature (° C.) 42-43 43-45 Aspirator (%)  87-100 89-93

TABLE-US-00008 TABLE 8 Tableting parameters Parameter I-3 I-6 Punch size (mm) 11 12.5 Average Weight (mg) 320 413 Compression force (KN) 3.112 2.529 Ejection force (N) 107.30 107.140 Hardness (N) 60-80 60-80

[0099] All the tablets prepared as shown in table 8 were analyzed in water to check whether there is an enhancement in solubility of the drug when compared to the pure form (table 9).

TABLE-US-00009 TABLE 9 Solubility of AFI, Experiment I-1 I-2 I-3 I-4 I-5 I-6 I-7 Solubility of 11 μg/ml 11 μg/ml 3 μg/ml 60 μg/ml 107 μg/ml 33 μg/ml 17.9 μg/ml AFI in water % Increase in * >300% * >300% * >300% * >300% * >300% 917 497 Solubility Acceptance Yes Yes Yes Yes Yes Yes Yes criteria met * The solubility in water (comparative examples) was zero. Acceptance criteria: >3 times increase water solubility of the AFI/API in relation to its observed solubility

[0100] Additionally, a self-microemulsifying drug delivery system (SMEDDS) was prepared for Curcumin, where MCT oil was added under homogenization. A second dispersion was prepared of AvailOm® and water under homogenization and AvailOm® dispersion was added to MCT and API dispersion, which was kept under homogenization for further for 30-45 mins and spray dried afterwards (inlet temperature 70-73° C., Aspirator 92-100%). The spray dried material was then taken directly for analysis. Solubility of Curcumin in water was 8 μg/ml (>300% increase in solubility).

Examples 8-13: Solubility Enhancement of API Celecoxib (Inventive)

[0101]

TABLE-US-00010 TABLE 10 Formulation for API Celecoxib Experiment I-8 I-9 I-10 I-11 I-12 I-13 Method of PM PM PM SD SD SD Coprocessing End Dosage Tablet Tablet Tablet Tablet Tablet Tablet form Ingredient % w/w % w/w % w/w % w/w % w/w % w/w Celecoxib 50 16.67 9.1 50.00 16.67 9.1 AvailOm ® 50 83.33 90.9 50.00 83.33 90.9 Total 100 100 100 100 100 100 Ethanol: .. .. .. 70:30 70:30 70:30 Water Ratio Solid Content .. .. .. 37.5 40 52.38 (% w/w)

[0102] Formulations for the API Celecoxib are shown in table 10. For the physical mixing process (PM) applied for I-8 to I-10, AvailOm® was mixed in geometric addition by passing through a 30# sieve and the blend was directly taken for compression (parameters in table 11).

TABLE-US-00011 TABLE 11 Tableting parameters Parameter I-8 I-9 I-10 Punch size (mm) 9 12.5 17.1*8.6 Average Weight (mg) 200 600 1100 Compression force (KN) 1.1612 5.77 8.269 Ejection force (N) 100.970 95 97.580 Hardness (N) 60-80 70-90 70-90

[0103] For the spray drying process (SD) applied for I-11 to I-13, Celecoxib was added in the non-aqueous media and to this solution AvailOm® was added under constant stirring. After addition of AvailOm®, the remaining amount of water was added and after the solution getting completely clear used for spray drying (table 12). The spray dried powder obtained was then mixed with other tableting excipients if any by passing through 30# sieve in geometric addition. The blend was taken for compression.

TABLE-US-00012 TABLE 12 Process parameter for spray drying Parameters I-11 I-12 I-13 Inlet Temperature (° C.) 55-57 55 69 Aspirator (%)  98-100 90-97 90-100

TABLE-US-00013 TABLE 13 Tableting parameters Parameter I-11 I-12 I-13 Punch size (mm) 9 12.5 17.1*8.6 Average Weight (mg) 200 600 1100 Compression force (KN) 1.1612 5.77 8.269 Ejection force (N) 100.970 95 97.580 Hardness (N) 60-80 70-90 70-90

[0104] The compressed tablets prepared according table 13 were analyzed in water to check whether there is any enhancement in solubility of the drug when compared to the pure form (table 14).

TABLE-US-00014 TABLE 14 Solubility of API in water, Experiment I-8 I-9 I-10 I-11 I-12 I-13 Solubility of AFI in water 2 μg/ml 3 μg/ml 26 μg/ml 70 μg/ml 291 μg/ml 348 μg/ml % Increase in Solubility 2 × 10.sup.3 3 × 10.sup.3 26 × 10.sup.3 70 × 10.sup.3 29.1 × 10.sup.4 34.8 × 10.sup.4 Acceptance criteria met Yes Yes Yes Yes Yes Yes Acceptance criteria: >3 times increase water solubility of the AFI/API in relation to its observed solubility

Examples 14-24: Solubility Enhancement of API Ritonavir (Inventive)

[0105]

TABLE-US-00015 TABLE 15 Formulation for API Ritonavir, Experiment I-14 I-15 I-16 I-17 I-18 I-19 1-20 1-21 1-22 1-23 1-24 Method of SD + PM SD + PM SD SD + PM SD + PM PM HME Co- Wet Wet SD Coprocessing milling granulat. granulat. End Dosage form Blend Tablet Blend Blend Blend Blend Blend Blend Blend Blend Blend Ingredient % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w % w/w Ritonavir 10.21* 10.21* 14.78* 14.20* 11.9** 37.04 18.2 18.2 18.2 25 20* AvailOm ® 24.50** 24.50** 22.17* 8.53** 17.83** 29.63 27.3 27.3 27.3 75 .. EUDRAGIT ® E PO 30.64 30.64 44.35* 42.63* 35.65* .. 54.54 54.54 54.54 .. .. MCC PH 102 32.7 32.7 18.69 32.7 32.7 33.33 .. .. .. .. 60* Ac-di-sol 1.96 1.96 .. 1.96 1.96 .. .. .. .. .. 10  Total 100 100 100 100 100 100 .. .. .. .. 10  Ethanol: Water Ratio 100:0 100:0 90:10 100:0 100:0 .. 100 100 100 100 100   Solid Content (% w/w) 13.55 13.55 9.9 13.55 13.55 .. .. .. .. .. 90:10 *ingredients were co-processed together in a single spray drying step, **ingredients were co-processed by only physically mixing with the spray dried powder in the same batch Formulations for the API Ritonavir are shown in table 15.

[0106] For the spray drying process (SD) applied for I-16, the API was added in the non-aqueous media and EUDRAGIT® E PO was added, then AvailOm® was added under constant stirring to the mixture. After addition of AvailOm®, the remaining amount of water was added and after the solution getting completely clear used for spray drying (Inlet temperature: 55° C., Aspirator: 90-97%). The spray dried powder obtained was then mixed with other tableting excipients if any by passing through a 30# sieve in geometric addition. The blend was directly taken for analysis.

[0107] For the spray drying+physical mixing process (SD+PM) applied for I-14, I-15, I-17 and I-18, the API was added in the non-aqueous media and to this solution EUDRAGIT® E PO was added under constant stirring and after the solution getting completely clear used for spray drying (Inlet temperature: 42-43° C., Aspirator: 70-89). The spray dried powder obtained was then taken for physical mixing with AvailOm® and other tableting excipients (table 16). The blend (for I-14, I-17 and I-18) was directly taken for analysis.

TABLE-US-00016 TABLE 16 Tableting parameters Parameter I-15 Punch size (mm) 12.5 Average Weight (mg) 490 Compression force (KN) 1.098 Ejection force (N) 108.650 Hardness (N) 70-90

[0108] For the physical mixing step applied for I-19, the API and AvailOm® were mixed with the other tableting excipients, then mixed in geometric addition by passing through a 30# sieve. The blend was directly taken for analysis.

[0109] For the hot melt extrusion (HME) step applied for I-20, all ingredients were mixed in geometric addition by passing through a 30# sieve. The blend was then directly taken for analysis.

[0110] For the co-milling process applied for I-21, all ingredients were mixed in geometric addition by passing through a 30# sieve. The blend was then co-milled in the mixer grinder by keeping the mixing interval of 3 mins. Then the co-milled blend was passed through a 50# sieve. The above process was repeated for three times. The final blend was directly used for analysis.

[0111] For the wet granulation process applied for I-22 and I-23, all ingredients were mixed in geometric addition by passing through a 30# sieve. The blend was then granulated with water in a planetary mixer, passed through a 12# sieve, then dried in a tray dryer for 30 mins and finally sifted through a 25# sieve. The final blend was directly used for analysis.

[0112] For the spray drying process applied for I-24, API was first added in ethanol under constant stirring, afterwards omega-3-fatty acid arginine salt was added to this solution, water was added and after the solution getting completely clear used for spray drying. The blend obtained was then mixed with the other tableting excipients and was directly used for analysis.

[0113] All the blends and tablets prepared according to table 15 were analyzed in water for any enhancement in solubility of the drug when compared to the pure form. The results are shown in table 17.

TABLE-US-00017 TABLE 17 Solubility of API in water, Experiment I-14* I-15* I-16 I-17 I-18 I-19 I-20 I-21 I-22 I-23 I-24 Solubility of 80 70 140 20 30 40 208 76 40 239 272 API in water μg/ml μg/ml μg/ml μg/ml μg/ml μg/ml μg/ml μg/ml μg/ml μg/ml μg/ml % Increase in *>300% *>300% *>300% *>300% *>300% *>300% *>300% *>300% *>300% *>300% *>300% Solubility Acceptance Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes criteria met *The solubility in water (comparative examples) was zero. Acceptance criteria: >3 times increase water solubility of the AFI/API in relation to its observed solubility

Comparative Examples 8-10

[0114]

TABLE-US-00018 TABLE 18 Formulation for comparative experiments Experiment C-8 C-9 C-10 Method of Processing . . . . . . Capsule filling End Dosage form API Powder API Powder Soft Gelatin Capsules Ingredients % w/w % w/w % w/w Gliclazide 100 . . . . . . Carbamazepine . . . 100 . . . Cholecalciferol . . . . . . 5.1 Arachis Oil . . . . . . 94.9 Total 100 100 100

[0115] For the comparative examples C-8 and C-9, the active ingredient was directly used for solubility analysis. For the example C-10, the active ingredient was diluted with carrier oil and was filled in soft gelatin capsules. The capsules were further analyzed for water solubility of the active ingredient. The results are summarized in table 19.

TABLE-US-00019 TABLE 19 Solubility of the active ingredients in water Experiment C-8 C-9 C-10 Solubility of active ingredient in water 21 μg/ml 240 μg/ml 0 μg/ml

Examples 25-29: Solubility Enhancement of Gliclazide Using Different PUFA Salts (Inventive)

[0116] Formulations for Gliclazide with different salts of omega-3 fatty acids were prepared. For the spray drying process (SD) applied for I-25 to I-29, Gliclazide was added in alcohol and to this, an aqueous solution of omega-3-fatty acid salt was added under constant stirring. After the solution was completely clear, Aerosil® was added under stirring. The dispersion was spray dried using a spray drier (Inlet temperature: 55-60° C., Aspirator: 90-100%).

TABLE-US-00020 TABLE 20 Formulations for Gliclazide with different salts of omega-3-fatty acid Ingredient (% w/w) I-25 I-26 I-27 I-28 I-29 Gliclazide 25 17.9 23.2 23.3 21.8 Omega-3 lysine salt 75 . . . . . . . . . . . . Omega-3-fatty acid salt of (50%) . . . 53.6 . . . . . . . . . arginine & (50%) ornithine Omega-3-fatty acid salt of (50%) . . . . . . 69.6 . . . . . . ornithine & (50%) lysine Omega-3-fatty acid salt of (50%) . . . . . . . . . 69.76 . . . arginine & (50%) lysine Omega-3-fatty acid salt of (50%) . . . . . . . . . . . . 65.22 arginine & (50%) magnesium Aerosil ® 28.5 7.2 6.97 13.04 Total 100 100 100 100 100 Solvent system (Ethanol:water) 90:10 90:10 90:10 90:10 90:10 Solid Content (% w/w) 10 10 10 4 5

[0117] The spray dried powder was analyzed for solubility in water and was compared with solubility values from the comparative examples from table 18 (comparative example C-8). The data are summarized in table 21 below.

TABLE-US-00021 TABLE 21 Solubility of Gliclazide from its formulations. Acceptance criteria: >3 times increase in solubility of the active ingredient in formulation as compared to its solubility reported in table 18 I-25 I-26 I-27 I-28 I-29 Solubility of Gliclazide in water (μg/ml) 327 326 295 272 263 % Increase in solubility 1557 1552 1404 1295 1252 Acceptance criteria met Yes Yes Yes Yes Yes

Example 30: Solubility Enhancement of Carbamazepine (Inventive)

[0118] For the spray drying process (SD) applied for 1-30; Carbamazepine (9.1% w/w) was added in alcohol (ethanol:water ratio of 90:10) and an aqueous solution of the omega-3-fatty acid lysine salt (90.9 w/w) was added under constant stirring. The solution was spray dried using a spray drier (Inlet temperature: 55-60° C., Aspirator: 90-100%). The spray dried powder was analyzed for solubility in water and was compared with solubility values from the comparative examples from table 18 (comparative example C-9). The solubility of the API in water was 914 μg/ml, which corresponds to an increase in solubility of 381%, so the acceptance criteria (>3 times increase in solubility) was met.

Examples 31-32: Solubility Enhancement of Vitamin D (Inventive)

[0119] For the SMEDDs in soft gel capsule applied for I-31 and I-32, the omega-3-lysine salt was sifted through #80 mesh and triturated with oil to form SMEDDs, size reduced to pass through #80 mesh and dispersed in carrier oil (summarized in table 22). This dispersion was filled in soft gelatin capsules and sealed.

TABLE-US-00022 TABLE 22 Formulations of Vitamin D3 with omega-3-lysine salt Ingredients (% w/w) I-31 I-32 Vitamin D3 4.81 6.25 Omega-3-lysine salt 24.02 31.25 Carrier Oil Peanut Oil Olive Oil Carrier Oil % 71.17 62.5 Total 100 100 Vitamin D:Omega salt 1:05 1:05

[0120] The soft gelatin capsules were analyzed for solubility in water and the values were compared with solubility values from the comparative examples from table 18 (comparative example C-10). The results are summarized in table 23.

TABLE-US-00023 TABLE 23 Solubility of Vitamin D3 in water, *The solubility in water (comparative example C10) was zero. Acceptance criteria: >3 times increase water solubility of the active ingredient in formulation as compared to its solubility reported in table 19 Ingredients (% w/w) I-31 I-32 Solubility of Vitamin D3 in water (μg/ml) 0.42 0.66 % Increase in solubility *More than *More than 300% 300% Acceptance criteria met Yes Yes