METHOD OF PREPARING A SOLID DOSAGE FORM AND A BINDER

Abstract

The present invention is related to a method of preparing a solid dosage form, comprising the steps of: a) preparing a binder consisting of at least one polyunsaturated fatty acid salt; b) adding the binder and ingredients for the solid dosage form to a mixer; c) optionally carrying out one or more of the following steps: granulation, drying and sizing, d) blending the contents of the mixer; and e) compressing or slugging the blended contents to produce a solid dosage form wherein the binding parameter (BP) for the solid dosage form is at least 2 and is determined by: BP=H/C, wherein H is the tablet breaking force in Newton (N) and C is the compression force in kilo Newton (kN). Solid dosage forms prepared according to this method and the use of PUFA salts as binder in tableting applications for compression of solid components are further comprised by the present invention.

Claims

1. A method of preparing a solid dosage form, comprising: preparing a binder consisting of at least one polyunsaturated fatty acid salt; adding the binder and at least one additional ingredient to a mixer to form a mixture; optionally carrying out one or more of the following: granulation, drying and sizing, blending the mixture to form a blend; and compressing or slugging the blended to produce a solid dosage form, wherein a binding parameter (BP) for the solid dosage form is at least 2 and is determined by: $\mathrm{BP}=\frac{H}{C}$ wherein H is the tablet breaking force in Newton (N) and C is the compression force in kilo Newton (kN).

2. The method of claim 1, wherein a friability of the solid dosage form is 5% or less.

3. The method of claim 1, wherein the mean particle size of the binder before mixing is between 2 μm and 600 μm.

4. The method of claim 1, wherein the binder is prepared by: admixing an aqueous, aqueous-alcoholic, or alcoholic solution of a first composition comprising at least one polyunsaturated omega-3 fatty acid or omega-6 fatty acid component and an aqueous, aqueous-alcoholic, or alcoholic solution of a second composition comprising a basic organic acid selected from lysine, arginine, ornithine, choline or at least counter ion selected from magnesium (Mg.sup.2+) and potassium (K.sup.+) and mixtures thereof to form an admixture, and subjecting the resulting admixture to spray drying conditions or an extruder-based process, thereby forming a solid product composition comprising at least one salt of a cation derived from the basic amino acid or magnesium (Mg.sup.2+) or potassium (K.sup.+) with an anion derived from a polyunsaturated omega-3 fatty acid or omega-6 fatty acid.

5. The method of claim 4, wherein the spray drying conditions comprise a pure spray drying, a batch spray granulation process, or continuous spray granulation process.

6. A solid dosage form prepared by the method of claim 1.

7. The solid dosage form of claim 6, wherein the solid dosage form is a tablet or capsule having extended release, immediate release, or delayed release characteristics.

8. The solid dosage form of claim 6, wherein an amount of polyunsaturated fatty acid salt in the solid dosage form is 70 weight-% or less.

9. The solid dosage form of claim 6, wherein an amount of polyunsaturated fatty acid is 65 weight % with respect to a total weight of polyunsaturated fatty acid salt.

10. The solid dosage form of claim 6, wherein the additional ingredient comprises one or more active pharmaceutical or nutraceutical ingredients and one or more excipients, and wherein the excipients are selected from the group 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.

11. The solid dosage form of claim 6, wherein the solid dosage form has a glass transition temperature Tg between 120° C. and 180° C., determined using differential scanning calorimetry (DSC).

12. The solid dosage form of claim 6, wherein the solid dosage form comprises less than 0.5 weight-% magnesium stearate.

13. A tablet binder, comprising at least one polyunsaturated fatty acid salt comprising at least one omega-3 fatty acid salt or omega-6 fatty acid salt selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (ARA), alpha linolenic acid, stearidonic acid, eicosatetraenoic acid, docosapentaenoic acid, linoleic acid, and γ-linolenic acid, wherein the binder provides compression of solid components.

14. The tablet binder of claim 13, wherein the omega-3 fatty acid salt or omega-6 fatty acid salt is an omega-3 fatty acid salt selected from EPA and DHA.

15. The tablet binder of claim 13, wherein the omega-3 fatty acid salt or omega-6 fatty acid salt has an organic counter ion selected from the group consisting of lysine, arginine, ornithine, and choline, or an inorganic counter ion selected from magnesium (Mg.sup.2+), potassium (K.sup.+), and mixtures thereof.

Description

WORKING EXAMPLES:

[0055] Methods

[0056] 1) Tablet friability test: Friability is the tendency for a tablet to chip, crumble or break following compression. This tendency is normally confined to uncoated tablets and surfaces during handling or subsequent storage. Friability test was carried out as per method described in USP chapter <1216>.

[0057] For tablets with a unit mass equal to or less than 650 mg, a sample of whole tablets corresponding to 6.5 g was taken. For tablets with a unit mass of more than 650 mg, a sample of 10 whole tablets was taken. The tablets were carefully dedusted prior to testing and were then weighted and placed in the drum. The drum was rotated 100 times and the tablets were removed afterwards. Loose dust was removed from the tablets and they were subsequently weighted. Generally, the test is run once. If obviously cracked, cleaved, or broken tablets are present after tumbling, the sample fails the test. If the results are doubtful or if the weight loss is greater than the targeted value, the test was repeated twice and the mean of the three tests was determined.

[0058] A maximum mean weight loss from the samples of not more than 1.0% is considered acceptable for most products. For specialized dosage forms e.g. MUPS tablets, effervescent tablets and chewable tablets may have different specifications as far as friability is concerned.

[0059] 2) Binding parameter (BP): Apart from friability, binding property of a formulation was also determined by calculating binding parameter as a function of the two important factors; tablet breaking force and compression force. A good binder is the one which provides good strength to the tablet at low compression force. For calculation of binding parameter BP following equation was used:

[00002]$\mathrm{BP}=\frac{H}{C}$

[0060] wherein H is the tablet breaking force in Newton (N) and C is the compression force in kilo Newton (kN).

[0061] (a) Tablet breaking force (H): Tablet breaking force was measured by test procedures as described in USP general chapter <1217>using a modern tester employ mechanical drives, strain gauge-based load cells for force measurements, and electronic signal processing. The tablet was placed between the platens and the test was performed. After breaking of the tablet, the results were recorded as tablet breaking force in newton (N).

[0062] (b) Compression force (C): Compression force of tablets was measured from the compression machine equipped with sensors to measure forces applied for compression of tablets during tablet manufacturing. It is recorded in kilo newton (kN).

[0063] Acceptance criteria for binding parameter: For optimal binding property of a binder, the binding parameter (BP) should be more than 2.

[0064] Polyunsaturated Fatty Acid Compositions

[0065] 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 and arginine 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.

[0066] 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, 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).

[0067] 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).

[0068] 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).

[0069] The Mg.sup.2+ salts of omega-3 were prepared by kneading as described in WO2017202935A1 using the PUFA composition described above.

[0070] A) Omega-3 amino acid salt as binder in Metformin tablets

[0071] Metformin tablets were prepared without addition of a binder (comparative examples C-1 and C-2) and with addition of an omega-3 lysine salt as a binder (inventive examples I-1to I-3).

TABLE-US-00001 TABLE 1 Formulations for tableting, the amount of ingredients is given in % w/w Ingredients (% w/w) C-1 C-2 I-1 I-2 I-3 Metformin hydrochloride 100 100 50 70 70 Omega-3 lysine salt 0 0 50 30 0 (spray granulated) Omega-3 lysine salt 0 0 0 0 30 (spray dried) Total 100 100 100 100 100

[0072] Metformin hydrochloride was mixed with omega-3 lysine salt powder as mentioned in table 1. Compression was carried out using 12 mm circular biconvex punch, average weight of the tablet was 555 mg. Friability test and tablets breaking forces were determined as per method describe in United States Pharmacopeia (USP<1216>). A maximum weight loss from the samples of not more than 1.0% is considered acceptable for most products. A weight loss of less than 3% is considered acceptable for specialized dosage forms like MUPS.

TABLE-US-00002 TABLE 2 Results for tableting trials Parameter C-1 C-2 I-1 I-2 I-3 Av. compress. force (kN) 4.50 11.50 4.50 11.50 11.50 Av. tablet break. 5.00 5.00 50.50 50.50 52.50 force (N) Av. ejection force (N) 106.50 106.50 104.50 107.50 105.50 Friability 100 >10 >10 0.7 0.8 0.7 rotations (%) Binding Parameter (BP) 1.11 0.43 11.22 4.39 4.57 Tablet thickness (mm) 5.5-5.6 5.2-5.3 5.5-5.6 5.3-5.4 5.3-5.4 Disintegration time in 1 3 75 30 30 water (min)

[0073] Metformin tablets prepared without omega-3 lysine salt compressed at low compression force (4.5 kN) and compressed at high compression force (11.5 kN) showed capping and breaking after friability test and hence failed the friability test. While tablets prepared with 30% to 50% w/w omega-3 lysine salt showed good strength and passes both the friability test) (<1%) and has high BP-value of more than 2.

[0074] B) Omega-3 amino acid salt as binder in Ashwagandha tablets

[0075] For the comparative examples (C-3 to C-6), Ashwagandha powder was compressed without addition of a binder under different conditions. Compression was carried out using 12 mm circular biconvex punch, average weight of the tablet was 555 mg.

TABLE-US-00003 TABLE 3 Results for tableting trials Parameter C-3 C-4 C-5 C-6 Av. compress. force (kN) 3.50 4.50 9.50 15.50 Av. tablet break. force (N) 2.50 2.50 13.00 33.00 Av. ejection force (N) 110.5 110.5 105.5 111 Friability 100 rotations (%) >10 >10 >10 >10 Binding Parameter (BP) 0.71 0.56 1.37 2.13 Tablet thickness (mm) 6.6-6.7 6.5-6.6 5.8-6.0 5.6-5.7 Disintegration time in 0.3 0.3 0.3 0.5 water (min)

[0076] As shown in table 3, at a compression force up to 15.50 kN (up to 21 kN was tested), the tablets had a high friability of >10% when compressed without addition of omega-3 lysine salt. This shows that the Ashwagandha powder is not compressible alone at different compression force tested.

TABLE-US-00004 TABLE 4 Formulations for tableting, the amount of ingredients is given in % w/w Ingredients (% w/w) I-4 I-5 I-6 I-7 I-8 I-9 I-10 I-11 Ashwagandha 50 50 50 70 70 90 90 90 Powder Omega-3 50 50 49.5 30 30 10 0 10 lysine salt Omega-3 0 0 0 0 0 0 10 0 arginine salt Magnesium 0 0 0.5 0 0 0 0 0 stearate Total 100 100 100 100 100 100 100 100

TABLE-US-00005 TABLE 5 Results for tableting trials Parameter I-4 I-5 I-6 I-7 I-8 I-9 I-10 I-11 Av. compress. 3.50 24.00 3.50 4.50 15.50 10.50 10.50 10.50 force (kN) Av. tablet break. 121.5 146.0 93.0 86.00 112.5 51.50 25.00 33.00 force (N) Av. ejection 111.5 104 114.8 113.5 104.5 104.5 108.9 110.5 force (N) Friability 100 0 0.1 0 0 0.1 0.2 0 0 rotations (%) Binding Parameter 34.71 6.08 26.57 19.11 7.26 4.90 2.38 3.14 (BP) Tablet 5.6-5.8 5.5-5.6 5.7-5.8 5.7-5.9 5.5-5.6 5.8-5.9 5.7-5.8 5.8-6.0 thickness (mm) Disintegration 60 60 50 6 10 0.5 0.5 0.5 time in water (min)

[0077] For the inventive examples (I-4 to I-10) Ashwagandha Powder was mixed with omega-3 salt powder as mentioned in table 4. For inventive example I-11 Ashwagandha powder and omega-3-lysine salt were mixed together and wet granulation was carried out using water. Wet granulated mass was dried in tray dryer for 6 hours at 50° C. After drying the prepared granules were sifted through 30190 sieve. Compression was carried out using 12 mm circular biconvex punch, average weight of the tablet was 555 mg. The results are summarized in table 5.

[0078] As shown in table 5, tablets prepared with different concentrations of omega-3 salts prepared by either direct compression or wet granulation had good tablet strength and did not show any sign of breaking or capping during friability test. All inventive examples (I-4 to I-11) had a friability of <1% and a BP value of more than 2.

[0079] C) Omega-3 amino acid salt as binder in lactose tablets

[0080] Lactose tablets were prepared without addition of a binder (comparative example C-7) and with addition of an omega-3 lysine salt as a binder (inventive examples I-12 to I-13).

TABLE-US-00006 TABLE 6 Formulations for tableting, the amount of ingredients is given in % w/w Ingredients (% w/w) C-7 I-12 I-13 Lactose monohydrate 100 90 50 Omega-3 lysine salt 0 10 50 Total 100 100 100

[0081] Lactose monohydrate was mixed with omega-3 lysine salt powder as mentioned in table 6. Compression was carried out using 12 mm circular biconvex punch, average weight of the tablet was 555 mg. Friability test and tablets breaking forces were determined as per method describe in United States Pharmacopeia (USP). The results are summarized in table 7.

TABLE-US-00007 TABLE 7 Results for tableting trials Parameter C-7 I-12 I-13 Av. compress. force (kN) 11.50 11.00 11.00 Av. tablet break. force (N) 9.00 50.00 60.50 Av. ejection force (N) 101 101.5 101.5 Friability 100 rotations (%) >5 0.90 0.60 Binding Parameter (BP) 0.78 4.55 5.50 Tablet thickness (mm) 5.1-5.2 5.1-5.2 5.1-5.2 Disintegration time in 3 9 31 water (min)

[0082] Lactose tablets prepared without omega-3 lysine salt showed capping after friability testing and hence failed the test. While the tablets prepared with omega-3 lysine salt as binder had good strength and friability of <1% and a high BP value of more than 2.

[0083] D) Omega-3 amino acid salt as binder and diluent in Pantoprazole MUPS tablets

[0084] Pentoprazole MUPS tablets were prepared without addition of a binder (comparative example C-8) and with addition of an omega-3 lysine salt as a binder (inventive examples I-14 to I-15).

TABLE-US-00008 TABLE 8 Formulations for tableting, the amount of ingredients is given in % w/w Ingredients (% w/w) C-8 I-14 I-15 Pantoprazole pellets 42.81 42.81 42.81 coated with EUDRAGIT FL 30 D (18/25 mesh size) MCC 101 granules (#20 10.81 — — passed) MCC 102 3 — — MCC 200 29.53 22.19 22.19 Ceolus KG 802 10.31 — — Ac-Di-sol SD-711 2.26 5.0 5.0 Aerosil 200 0.71 — — Sod. Stearyl fumarate 0.57 — — Omega-3 lysine salt — 30 30 Total 100 100 100

[0085] All ingredients as listed in table 8 were mixed and compressed using 17.1×8.6 mm caplet shat punch, average weight of the tablet was 725 mg. Friability test and tablets breaking forces were determined as per method describe in United States Pharmacopeia (USP). The results are summarized in table 9.

[0086] MUPS formulation prepared without omega-3 lysine salt (example C-8) and compressed at compression force of 5.5 kN showed color change of pellets from white to brown in 0.1N HCI after 2 hours, although having a high BP value. When analyzed, there was 16.2% drug release in 0.1 N HCI after 2 hours. This color change and higher release in 0.1 N HCI is not desirable because it leads to degradation of the API due to loss of integrity (breaking/cracking) of coated pellets in the MUPS. While the MUPS formulation prepared with 30 % w/w of omega-3 lysine salt compressed up to compression force of 7.5 kN did not show any color change of pellets after 2 hours exposure to 0.1 N HCI and the drug release was only 3.6% indicating that the integrity of coated pellets maintained due to presence of omega-3 lysine salt. Moreover, those MUPS formulations had a high BP value of more than 2.

TABLE-US-00009 TABLE 9 Results for tableting trials Parameter C-8 I-14 I-15 Av. compress. force (kN) 5.50 2.95 7.50 Av. tablet break. force (N) 85.00 59.60 62.00 Av. ejection force (N) 110.5 110.5 110.5 Friability 100 rotations (%) 0.80 2.90 1.40 Binding Parameter (BP) 15.45 20.20 8.27 Tablet thickness (mm) 6.9-7.0 6.9-7.0 6.5-6.6 Visual observation of Pellets turn No No integrity after 2 hours of brown, indicat. change in change in exposure to 0.1N HCl loss of integrity color color Release of drug after 2 16.2 — 3.6 hours in 0.1N HCl (%, limit: <10%)

[0087] E) Omega-3 fatty acid salts (magnesium and ornithine) as binder in Metformin tablets

[0088] Metformin tablets were prepared without addition of a binder (comparative examples C-1 and C-2) and with addition of an omega-3 magnesium salt and omega-3 ornithine salt as a binder (inventive examples I-16 and I-17).

TABLE-US-00010 TABLE 10 Formulations for tableting, the amount of ingredients is given in % w/w Ingredients (% w/w) I-16 I-17 Metformin hydrochloride 70 70 Omega-3 magnesium salt 30 0 Omega-3 ornithine salt 0 30 Total 100 100

[0089] Metformin hydrochloride was mixed with omega-3 fatty acid salt powder as mentioned in table 10. Compression was carried out using 12 mm circular biconvex punch, average weight of the tablet was 555 mg. Friability test and tablets breaking forces were determined as per method describe in United States Pharmacopeia (USP). A maximum weight loss from the samples of not more than 1.0% is considered acceptable for most products. A weight loss of less than 3% is considered acceptable for specialized dosage forms like MUPS.

[0090] The results for the tableting trials are summarized in table 11. In the comparative example C-1 and C-2, Metformin tablets were prepared without omega-3 fatty acid salts, both compressed at low compression force (4.5 kN) and compressed at high compression force (11.5 kN) showed capping and breaking after friability test and hence failed the friability test (a shown in tables 1 and 2). While the tablets prepared with 30% w/w omega-3 magnesium salt and omega-3 ornithine salt showed good strength and both passed the friability test (<1%). For both formulations, the BP value was more than 2.

TABLE-US-00011 TABLE 11 Results for tableting trials Parameter I-16 I-17 Average Compression force(kN) 11.50 11.50 Average Tablet Breaking Force(N) 34.91 34.18 Average Ejection Force(N) 112.5 113 Friability at 100 rotations (%) 0.9 0.09 Binding Parameter (BP) 3.04 2.97 Tablet thickness(mm) 5.7-5.8 5.4-5.5 Disintegration time water(min) 5 25