Methods for preparing solids and lubricants

Abstract

The present invention provides a) preparing a lubricant comprising at least one polyunsaturated fatty acid salt; b) adding the lubricant and solid ingredients to a mixer; c) optionally one or more of granulating, drying, and sizing; d) mixing the contents of the mixer; e) compressing or slugging the mixed contents to form a solid dosage form; The present invention relates to a method for preparing a solid formulation having the formula: The invention further includes the solid dosage form prepared according to this method and the use of polyunsaturated fatty acids (PUFAs) as lubricants in tableting applications for compressing solid ingredients.

Description

[Technical field]

[0001] The present invention relates to a) preparing a lubricant comprising at least one polyunsaturated fatty acid (PUFA) salt; b) adding the lubricant and solids ingredients to a mixer; c) optionally one or more of granulating, drying, and sizing; d) mixing the contents of the mixer; e) compressing or slugging the mixed contents to form a solid dosage form; The present invention relates to a method for preparing a solid formulation having the formula: The invention further includes solid dosage forms prepared according to this method and the use of the PUFA salt as a lubricant in tableting applications for compressing solid ingredients. [Background technology]

[0002] The present invention provides an alternative formulation for nutritional and pharmaceutical tablets that does not contain magnesium stearate and does not require the addition of other known lubricants, thereby avoiding all the problems associated with them.

[0003] Lubricants play a key role in the successful manufacture of pharmaceutical solid dosage forms. They are an essential component of robust formulations to achieve this. Many failures in pharmaceutical manufacturing operations are caused by lubrication issues, yet lubricants generally do not receive enough attention in the development of pharmaceutical formulations.

[0004] In pharmaceutical operations such as blending, roller compaction, tablet making, and capsule filling, lubrication is essential to reduce friction between the surfaces of the manufacturing equipment and the surfaces of organic solids and ensure continuity of operation (Non-Patent Document 1). Pharmaceutical lubricants are agents added in very small amounts (usually 0.25% to 5.0% by weight) to tablet and capsule formulations to improve the powder processability of the formulation. Although in fairly small amounts, lubricants play an important role in manufacturing. They reduce the friction of the contact surface between the tablet surface and the die wall during ejection, thereby reducing the wear of the punch and die. They prevent tablets from sticking to the punch faces and capsules from sticking to the dosator and tamping pins. With regard to powder flow, lubricants can improve the flowability of the mixture and aid in unit operations (Non-Patent Document 2).

[0005] Most of the lubricants used in pharmaceutical processes are metal salts of fatty acids. Magnesium stearate, calcium stearate, zinc stearate, and stearic acid are the most common ones. Magnesium stearate is the most frequently used lubricant. However, the use of stearic acid and its metal salts (e.g. magnesium stearate, calcium stearate) as lubricants has several problems, including undesirable delayed dissolution of active substances, degradation and interactions with certain groups of drugs (e.g. amines, ACE inhibitors).

[0006] In a recent study, the mechanism underlying the delay in drug release caused by magnesium stearate was investigated in model metformin hydrochloride (HCl) tablets containing magnesium stearate using stationary disc method, scanning electron microscope with EDS (energy dispersive X-ray analysis) (SEM-EDS), and Fourier transform infrared spectroscopy (FTIR). The results revealed the process and mechanism of the delay. The exposure of magnesium stearate on the tablet surface increases during the dissolution process, and the dissolution of the tablet is limited by the dispersion of magnesium stearate (Non-Patent Document 3).

[0007] Additionally, some adverse health effects, such as effects on cardiovascular health, eye health, and the immune system, have been associated with the use of stearic acid, palmitic acid, and saturated fats. Most commonly used lubricants (e.g., stearic acid and its derivatives, hydrogenated vegetable oils, glyceryl behanate) contain one or more of the above harmful components or are metabolically converted to stearic acid in vivo, as is the case with sodium stearyl fumarate. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Wang, J. et al., Eur. J. Pharm. Biopharm. 2010, 75, 1-15 [Non-Patent Document 2] Li and Wu, lubricants 2014, 2: 21-43 [Non-Patent Document 3] Aryas et al., Int J Pharm 2016, 511(2):757-764 Summary of the Invention [Problem to be solved by the invention]

[0009] Problem: Magnesium stearate is a common lubricant used in solid pharmaceutical formulations, known for its properties of retarding tablet dissolution and adversely affecting tablet strength at higher concentrations. As described in the prior art section, most of the commonly used lubricants have quality issues or pose health concerns, such as adverse effects on cardiovascular health. The long-term use of these lubricants, for example in dietary supplements, is undesirable, as the health risks may be multiplied.

[0010] Therefore, there is a need to develop nutritional and pharmaceutical formulations that are free of commonly used lubricants (e.g., stearic acid, magnesium and calcium stearate, hydrogenated vegetable oils, sodium stearyl fumarate, glyceryl behenate, and talc).

[0011] WO 2008 / 130883A highlights the importance and need to find new tablet lubricants and describes the use of an oily liquid embedded in an insoluble matrix as a tablet lubricant. The lubricant-embedded matrix includes an oily liquid finely dispersed in an oil-insoluble material. In an exemplary embodiment, the dietary supplement composition is substantially free of stearate. Oily liquids suitable for dispersion in oil-insoluble materials include vitamin E, preferably in the form of vitamin E acetate, animal oil, synthetic oil, mineral oil, polyethylene glycol, silicone oil, and combinations thereof. Suitable oil-insoluble materials include starch, dextrin, microcrystalline cellulose, ethylcellulose, gelatin, sugar, glucose, maltose, fructose, sorbitol, sucrose, mannitol, sorbitol, lactose, methylcellulose, hydroxypropylmethylcellulose, maltodextrin, silicon dioxide, anhydrous dicalcium phosphate, and combinations thereof. [Means for solving the problem]

[0012] Solution: Surprisingly, it was found that using salts of polyunsaturated fatty acids as lubricants in tablet formulations results in very good tableting behavior for a wide variety of pharmaceutical and nutraceutical ingredients, and that the disintegration / dissolution of these tablets is not significantly delayed even at high concentrations.

[0013] To obtain a superior product, magnesium stearate (Mg) of amino acids or polyunsaturated fatty acids is used as lubricant in the absence of magnesium stearate. 2+ ) salt or potassium (K + It has also been found that the use of .

[0014] The present invention provides a one-step solution to most of the problems associated with the use of existing tabletting lubricants, including quality, processing and health issues.

[0015] The present invention relates to a) at least one polyunsaturated fatty acid salt Consists of preparing a lubricant; b) adding the lubricant and solids ingredients to a mixer; c) optionally one or more of granulating, drying, and sizing; d) mixing the contents of the mixer; e) compressing or slugging the mixed contents to form a solid dosage form; Have The lubricant has a glass transition temperature (Tg) of 120° C. to 180° C. as measured by a differential scanning calorimeter (DSC). The present invention relates to a method for preparing a solid formulation.

[0016] According to this method, due to the surprising lubricating effect of the polyunsaturated fatty acid salt, a solid formulation that is suitable for direct compression and does not require additional known lubricants (e.g., magnesium stearate) can be easily prepared.

[0017] In capsule filling operations, powders are usually filled into capsules after forming slugs in both a dosator and a tamping capsule filling machine. Similarly, to produce denser, more flowable granules, powders are compressed with two rollers or punches to form slugs. The slugs are then broken into smaller particles and further processed into various dosage forms. Both of these methods are referred to as slugging in this invention.

[0018] Extensive evidence collected over the past few decades has correlated many health benefits with supplemental intake of polyunsaturated fatty acids (PUFAs). Prevention of cardiovascular disease and reduction of symptoms of inflammatory conditions are among the most prominent examples, but positive effects in preventing the growth and progression of certain cancers, lowering blood pressure and blood cholesterol, and treating depression and schizophrenia, Alzheimer's disease, developmental dyslexia, and attention deficit or hyperactivity disorder, among others, have been reported as well. Furthermore, infant nutrition is now routinely supplemented with certain PUFAs, as some PUFAs are believed to be essential for the development of the brain, nervous system, and eyes.

[0019] In the context of this specification, the term "PUFA" is used interchangeably with the term "polyunsaturated fatty acid" and is defined as follows: Fatty acids are classified based on the length of the carbon chain and saturation characteristics. Short chain fatty acids have 2 to about 6 carbons and are usually saturated. Medium chain fatty acids have about 6 to about 14 carbons and are usually saturated. Long chain fatty acids have 16 to 24 or more carbons and may or may not be saturated. In long chain fatty acids, one or more points of unsaturation may be present, referred to as "monounsaturated" and "polyunsaturated", respectively. In the context of this specification, long chain polyunsaturated fatty acids having 20 or more carbon atoms are referred to as polyunsaturated fatty acids or PUFAs.

[0020] PUFAs are classified according to the number and position of double bonds in the fatty acid, according to an established nomenclature system. There are two main series or families of LC-PUFAs, depending on the position of the double bond closest to the methyl end of the fatty acid. The ω-3 series has a double bond at the third carbon, whereas the ω-6 series has no double bonds until the sixth carbon. Thus, docosahexaenoic acid (DHA) has a chain length of 22 carbons and six double bonds starting from the third carbon from the methyl end, and is designated "22:6 n-3" (all-cis-4,7,10,13,16,19-docosahexaenoic acid). Another important ω-3 PUFA is eicosapentaenoic acid (EPA), designated "20:5 n-3" (all-cis-5,8,11,14,17-eicosapentaenoic acid). The key omega-6 PUFA is arachidonic acid (ARA), designated "20:4 n-6" (all-cis-5,8,11,14-eicosatetraenoic acid).

[0021] Other ω-3 PUFAs include eicosatrienoic acid (ETE) 20:3(n-3) (all-cis-11,14,17-eicosatrienoic acid), eicosatetraenoic acid (ETA) 20:4(n-3) (all-cis-8,11,14,17-eicosatetraenoic acid), heneicosapentaenoic acid (HPA) 21:5(n-3) (all-cis-6,9,12,15,18-heneicosapentaenoic acid), and docosapentaenoic acid (DPA). These include diclofenac (clupanodonic acid) (DPA) 22:5(n-3) (all-cis-7,10,13,16,19-docosapentaenoic acid), tetracosapentaenoic acid 24:5(n-3) (all-cis-9,12,15,18,21-tetracosapentaenoic acid), and tetracosahexaenoic acid (diclofenac) 24:6(n-3) (all-cis-6,9,12,15,18,21-tetracosahexaenoic acid).

[0022] Other omega-6 PUFAs include eicosadienoic acid 20:2(n-6) (all-cis-11,14-eicosadienoic acid), dihomo-gamma-linolenic acid (DGLA) 20:3(n-6) (all-cis-8,11,14-eicosatrienoic acid), docosadienoic acid 22:2(n-6) (all-cis-13,16-docosadienoic acid), and adrenic acid 22:4(n-6) (all-cis-7,10,13,16 -docosatetraenoic acid), docosapentaenoic acid (oxo-bondoic acid) 22:5(n-6) (all-cis-4,7,10,13,16-docosapentaenoic acid), tetracosatetraenoic acid 24:4(n-6) (all-cis-9,12,15,18-tetracosatetraenoic acid), and tetracosapentaenoic acid 24:5(n-6) (all-cis-6,9,12,15,18-tetracosapentaenoic acid).

[0023] Preferred omega-3 PUFAs for use in embodiments of the present invention are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

[0024] In a preferred embodiment of the present invention, the polyunsaturated fatty acid salt contains at least one basic amino acid or magnesium (Mg 2+ ) and potassium (K + In a further preferred embodiment, the omega-3 or omega-6 fatty acid salt has an organic counterion selected from lysine, arginine, ornithine, choline, and mixtures thereof.

[0025] The basic amino acids are preferably selected from lysine, arginine, ornithine and mixtures thereof.

[0026] The present invention is particularly suitable for solid preparations that can be made into tablets and are obtained by compressing the mixed contents using a tablet press.

[0027] Tablet compression leads to compaction of particles into pellets of a particular strength. Tablet compression usually results in particle rearrangement, particle deformation, interparticle bond formation, and elastic recovery during ejection of the compact from the die. The penultimate step in the tablet compression process is ejection. The ejection force is the force required to push the tablet out of the die. When the material and / or die are properly lubricated, a significant reduction in the overall ejection force is observed. The degree of lubrication also becomes important in the final step of tablet compression when the tablet leaves the lower punch. Lubricants are most relevant for the tablet ejection and tablet removal steps, as they reduce friction between the tablet and the metal surface, making the entire tablet compression process smoother.

[0028] It has been observed that powders with acceptable tableting performance in small scale operations may cause problems when run times are extended or scaled up, causing high ejection forces, high tool wear rates and even machine overloads leading to work stoppages. Clearly, reliable prediction of changes in compression and ejection properties from laboratory testing is of substantial importance.

[0029] Therefore, in a preferred embodiment of the present invention, when the solid agent is a tablet, the mixed contents are compressed by a tablet press, and the ejection force of the tablet press is 150N or less, preferably 130N or less, more preferably 120N or less, and most preferably 50N to 120N.

[0030] It is particularly preferable that the average particle size of the lubricant before mixing is 2 μm to 600 μm.

[0031] In an advantageous embodiment of the invention, the lubricant comprises: - a composition comprising at least one polyunsaturated omega-3 or polyunsaturated omega-6 fatty acid component; A basic amino acid selected from lysine, arginine, ornithine, and choline, or magnesium (Mg 2+ ), potassium (K + ), and mixtures thereof; and mixing an aqueous, aqueous alcoholic, or alcoholic solution of The mixture is then spray-dried or extruded to obtain basic amino acids or magnesium (Mg 2+ ) or potassium (K + forming a solid product composition comprising at least one salt of a cation derived from a polyunsaturated omega-3 fatty acid or an anion derived from a polyunsaturated omega-6 fatty acid; It is prepared by:

[0032] Recently, techniques have been described for stabilizing EPA / DHA-free fatty acids with amino acids to produce solid, semi-inert salts of EPA / DHA that can be incorporated into food or supplement preparations. WO 2016 / 102323A1 describes compositions comprising polyunsaturated omega-3 fatty acid salts that can be stabilized against oxidation.

[0033] The composition comprising polyunsaturated fatty acids that can be stabilized against oxidation can be obtained from any suitable raw material, which can be further processed by any suitable method for processing such raw materials. Typical raw materials include materials derived from fish carcasses, vegetables, any part of other plants, and fermentation of microorganisms and / or algae. Typically, such materials also contain significant amounts of other naturally occurring fatty acids. Typical processing methods for such raw materials may include crude oil obtaining steps (e.g., extraction and separation of the raw material), crude oil refining steps (e.g., precipitation and degumming, deacidification, bleaching, and deodorization), and further PUFA concentrate production steps (e.g., deacidification, interesterification, concentration, and deodorization) from the refined oil (see, for example, the European Food Safety Authority's scientific opinion on edible fish oil). Any processing of the raw material may further include a step of at least partially converting the PUFA-esters to the corresponding free PUFAs or their inorganic salts.

[0034] The preferred composition comprising PUFA that can be stabilized against oxidation by the method of the present invention can be obtained from a composition that mainly consists of ester PUFA and other fatty acids that occur naturally by cleavage of ester bond and subsequent removal of the alcohol that was previously bound as ester.Preferably, ester cleavage is carried out under basic conditions.The method of ester cleavage is well known in the art.

[0035] According to the present invention, spray drying includes pure spray drying, or spray granulation processes, or continuous spray granulation.

[0036] The solid forms prepared according to the invention are further subject matter of the present invention. The solid forms may be tablets or capsules and are preferably sustained release, immediate release or delayed release.

[0037] In a preferred embodiment, the amount of the polyunsaturated fatty acid salt in the solid preparation is 50% by weight or less, preferably 40% by weight or less, more preferably 0.5 to 30% by weight.

[0038] The salts of lysine with polyunsaturated fatty acids are themselves known in the art (see EP 0734373B1) and have been described as "a very thick transparent oil that turns into a solid with a waxy appearance and consistency at low temperatures" (see EP 0734373B1, p. 1, lines 47-48). However, salts of PUFAs can be obtained by spray drying conditions as described in WO 2016 / 102323A1 and WO 2016 / 102316A1.

[0039] In a preferred embodiment of the present invention, the amount of the polyunsaturated fatty acid is 65% by weight or less, preferably 60% by weight or less, more preferably 40 to 55% by weight, based on the total weight of the polyunsaturated fatty acid salt.

[0040] The solid dosage form of the present invention comprises one or more active pharmaceutical ingredients or active nutraceutical ingredients and one or more excipients, preferably selected from the group of binders, antioxidants, flow agents, lubricants, pigments, plasticizers, polymers, polishing agents, diluents, flavorings, surfactants, pore formers, stabilizers, or any combination thereof.

[0041] In a preferred embodiment, the composition has a glass transition temperature (Tg) of 120° C. to 180° C. as measured using a differential scanning calorimeter (DSC).

[0042] Since some adverse health effects, such as effects on cardiovascular health, eye health, and immune system, are associated with the use of stearic acid, palmitic acid, and saturated fats, it is desirable to reduce the amount of magnesium stearate in the solid formulation to a minimum. Thus, in a preferred embodiment, the solid formulation contains less than 0.5% by weight, preferably less than 0.2% by weight, more preferably 0-0.1% by weight, or no magnesium stearate at all.

[0043] In a preferred embodiment, the solid formulation is an immediate release tablet, which has a disintegration time in water of 30 minutes or less, preferably 20 minutes or less, more preferably 15 minutes or less, and most preferably 10 minutes or less.

[0044] In the solid preparation, the polyunsaturated fatty acid salt is mixed with at least one basic amino acid or magnesium (Mg 2+ ) and potassium (K + In a more preferred embodiment, the omega-3 fatty acid salt comprises at least one counterion selected from the group consisting of lysine, arginine, ornithine, choline, and mixtures thereof.

[0045] The basic amino acids are preferably selected from lysine, arginine, ornithine and mixtures thereof.

[0046] The present invention also relates to a preparation consisting of at least one polyunsaturated fatty acid salt comprising at least one omega-3 or omega-6 fatty acid selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (ARA), alpha-linolenic acid, stearidonic acid, eicosatetraenoic acid, docosapentaenoic acid, linoleic acid, gamma-linolenic acid, which is used as a lubricant in tabletting applications for the compression of solid ingredients.

[0047] In a preferred embodiment, the omega-3 fatty acid component is selected from EPA or DHA. In a further preferred embodiment, the omega-3 or omega-6 fatty acid salt is selected from lysine, arginine, ornithine, choline, or magnesium (Mg 2+ ), potassium (K + ), and mixtures thereof.

[0048] In a preferred embodiment, the amount of the polyunsaturated fatty acid is 65% by weight or less, preferably 60% by weight or less, more preferably 40 to 55% by weight, based on the total weight of the polyunsaturated fatty acid salt.

[0049] In a preferred embodiment, the amount of the polyunsaturated fatty acid salt in the tableting composition is 50% by weight or less, preferably 40% by weight or less, more preferably 0.5 to 30% by weight. [Brief description of the drawings]

[0050] [Figure 1] FIG. 1 shows C18:0 fatty acid calcium salt particles at 40X magnification. [Diagram 2] FIG. 2 shows omega-3 lysine salt particles at 4X magnification. [Diagram 3] FIG. 3 shows DSC thermograms of omega-3 fatty acid lysine salts and calcium salts of C18:0 fatty acids. EXAMPLES

[0051] Polyunsaturated fatty acid composition In the examples of the present invention, various polyunsaturated fatty acid compositions were used. Various omega-3 fatty acid salts were prepared with organic counterions selected from the basic amino acids lysine, arginine, and ornithine. The omega-3 fatty acids eicosapentaenoic acid (C20:5w3c) (EPA) and docosahexaenoic acid (C22:6w3c) (DHA) are present in a ratio of about 2:1 (ratio=EPA:DHA). The salts were prepared by spray granulation as described in WO 2016 / 102323 A1.

[0052] Omega-3 lysine salt (omega-3-lsy) consists of about 32% by weight L-lysine and about 65% by weight polyunsaturated fatty acids (AvailOm®, Evonik Nutrition and Care GmbH, Germany). The main polyunsaturated fatty acids in the composition are the omega-3 fatty acids eicosapentaenoic acid (C20:5w3c) (EPA) and docosahexaenoic acid (C22:6w3c) (DHA), which together make up about 58% by weight of the composition. The composition also contains small amounts of docosaenoic acid isomers (including erucic acid) (C22:1), docosapentaenoic acid (C22:5w3c), and small amounts of the omega-6 fatty acids arachidonic acid (C20:4w6) and docosatetraenoic acid (C22:4w6c).

[0053] Omega-3 arginine salt (omega-3-arg) is composed of approximately 35% by weight of L-arginine and approximately 64% by 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), which together account for approximately 49% by weight of the composition. The composition also contains small amounts of docosaenoic acid isomers (including erucic acid) (C22:1), docosapentaenoic acid (C22:5w3c), and small amounts of the omega-6 fatty acids arachidonic acid (C20:4w6) and docosatetraenoic acid (C22:4w6c).

[0054] Omega-3 ornithine salt (omega-3-orn) is composed of about 29% by weight of L-ornithine and about 70% by weight of polyunsaturated fatty acids. The main polyunsaturated fatty acids in the composition are the omega-3 fatty acids eicosapentaenoic acid (C20:5w3c) (EPA) and docosahexaenoic acid (C22:6w3c) (DHA), which together account for about 54% by weight of the composition. The composition also contains small amounts of docosaenoic acid isomers (including erucic acid) (C22:1), docosapentaenoic acid (C22:5w3c), and small amounts of the omega-6 fatty acids arachidonic acid (C20:4w6) and docosatetraenoic acid (C22:4w6c).

[0055] K + salt and K + A mixed salt of Mg and lysine (50:50) and a mixed salt of ornithine and lysine (50:50) were prepared by spray granulation as described in WO 2016 / 102323 A1 using the above PUFA composition. 2+ salt and Mg 2+ A mixed salt of lysine and lysine (50:50) was prepared by kneading as described in WO 2017 / 202935 A1 using the PUFA composition described above.

[0056] Experimental Examples 1-6 (Comparative Examples): Effect of Commonly Used Lubricants on the Disintegration of Benazepril Tablets Benazepril HCl was used as the prototype drug with commonly used lubricants in the recommended range (e.g., magnesium stearate (2-3%), and Lubritab (5-10%)). Benazepril tablets were prepared by direct compression. GalenIQ 721 was passed through a 20# sieve, Benazepril HCl was passed through a 60# sieve, and lubricants (magnesium stearate or Lubritab) were passed through an 80# sieve. Benazepril and galenIQ 721 were mixed for 10 minutes. Then, the required amount of lubricant was added and mixed for 1 minute (*For some batches, the mixing time was 5 minutes after adding the lubricant). Compression of the prepared mixture was performed using 8 mm circular biconvex punches with an average tablet weight of 200 mg (tablet formulation is shown in Table 1). Table 1: Benazepril tablet composition (ingredients are shown in weight %)

[0057] [Table 1]

[0058] The concentration of commonly used lubricants and the mixing time have a negative effect on the disintegration time of tablets, which increased with increasing mixing time and with increasing concentration of the lubricant magnesium stearate (Table 2). Table 2: Tableting test results

[0059] [Table 2]

[0060] Experimental Example 7 (Comparative Example): Quantification of stearic acid and palmitic acid content Metal salts of fatty acids are commonly used as lubricants in the pharmaceutical industry, with magnesium stearate, calcium stearate, and zinc stearate being the three most common metal salts of fatty acids. Magnesium stearate is the most frequently used, but when used in combination with omega-3 fatty acid salts, it increases the concentration of stearic and palmitic acids in the solution. This effect was analyzed in detail.

[0061] To quantify stearic and palmitic acids in water from magnesium stearate alone, 1 mg of magnesium stearate was added to water under high shear homogenization conditions and mixed for 15 minutes under continuous homogenization conditions. After homogenization, the prepared dispersion was centrifuged to remove larger particle sizes. The supernatant solution was then filtered through a 0.2 micron nylon syringe filter and the filtrate was analyzed for stearic and palmitic acid content.

[0062] To quantify stearic and palmitic acids in water from magnesium stearate in combination with omega-3 fatty acid salts, 1 g of magnesium stearate and 10 g of omega-3 fatty acid lysine salt (omega-3-lys) were added to water under high shear homogenization conditions and mixed for 15 minutes under continuous homogenization conditions. After homogenization, the prepared dispersion was centrifuged to remove larger particle sizes. The supernatant was then filtered through a 0.45 μm (B1) or 0.2 μm (B2) nylon syringe filter and the filtrate was analyzed for stearic and palmitic acid content. The results are shown in Table 3. Table 3: Quantification of stearic and palmitic acids in mixtures with omega-3 fatty acid salts (component amounts are given in weight %)

[0063] [Table 3]

[0064] Experimental Examples 1 to 6 (Examples): Effect of omega-3 amino acid salts on the disintegration of benazepril tablets Benazepril HCl was used as the prototype drug using ω-3 lysine salt as lubricant in the range of 2-10%. Benazepril tablets were prepared by direct compression. GalenIQ 721 was passed through a 20# sieve, Benazepril HCl was passed through a 60# sieve, and ω-3 lysine salt was passed through an 80# sieve. After mixing Benazepril and GalenIQ 721, ω-3 lysine salt was added and mixed for 1 minute (*In some batches, the mixing time was 5 minutes or 10 minutes after adding the lubricant). Compression of the prepared mixture was performed using 8 mm circular biconvex punches with an average tablet weight of 200 mg (tablet formulation is shown in Table 4). Table 4: Benazepril tablet composition (ingredients are shown in weight %)

[0065] [Table 4]

[0066] [Table 5]

[0067] As shown in Table 5, the concentration of omega-3 lysine salt and mixing time did not have any adverse effect on the disintegration time of the tablets. The disintegration time did not increase with increasing mixing time and with increasing omega-lysine salt in the tablets. A mixing time of 10 minutes, but not 5 minutes, gave the same value for disintegration time in water (8 minutes).

[0068] Experimental Examples 7-13 (Examples): Effect of omega-3 amino acid salts on the disintegration of diltiazem tablets All tablets were prepared by direct compression. All excipients were passed through a 20# sieve, Diltiazem HCl was passed through a 60# sieve, and the ingredients were mixed for 5 minutes (Table 6). Compression of the prepared mixture was then carried out using a single rotary tablet press. Table 6: Composition of diltiazem tablets (ingredients are shown in weight %)

[0069] [Table 6]

[0070] Tableting tests were carried out with increasing lubricant concentration and the compositions in Table 5. In all tests, the punch size was 11 mm, the average weight was 550 mg, and the compression force was 5.0-7.0 kN. Table 7: Tableting test results

[0071] [Table 7]

[0072] In the comparative example, no tablets were formed. Adhesion to the die wall was observed and the tablets broke into two pieces after compression. Furthermore, the ejection force increased significantly after 1 minute of compression (111 N increase from the beginning) and further tableting was not possible. While using omega-3 lysine salt as lubricant, the increase in ejection force remained below 5 N, the maximum ejection force was only 103 N and the disintegration time was within acceptable limits. The results are summarized in Table 7.

[0073] Optimal release force is obtained with omega-3 fatty acid salt concentrations in tablets as low as 0.5% by weight, but disintegration times of less than 30 minutes are achieved with concentrations up to about 50% by weight.

[0074] Examples 14-18 (Examples): Salts of omega-3 fatty acids as lubricants with various types of excipients and APIs All tablets were prepared by direct compression. Excipients were passed through a 20# sieve, API through a 60# sieve, and omega-3 fatty acid salts through a 100# sieve. All ingredients except omega-3 lysine or arginine salts were mixed for 10 minutes, followed by addition of the omega-3 salts and mixing for 1 minute. Compression of the blends prepared as shown in Table 8 was then performed using a single rotary tablet press. Table 8: Tablet composition (ingredients are shown in weight percent)

[0075] [Table 8]

[0076] [Table 9]

[0077] In the absence of lubricant during compounding, the ejection force increased (Comparative Example). Within 5 minutes of run time, the ejection force had increased by 90N from the start and no further processing was possible. In the Comparative Example, tablets were formed, but the increased ejection force would cause the press to stop after pressing a few tablets.

[0078] In all tablet formulations, the ejection force did not increase during tablet compression when omega-3 lysine or arginine salts were used as lubricants. Furthermore, disintegration times in water were less than 10 minutes using a wide variety of excipients and APIs with different solubilities. The results are summarized in Table 9.

[0079] Examples 19-24 (Examples): Various salts of omega-3 fatty acids as lubricants for diltiazem tablets Various omega-3 fatty acid salts were used as lubricants, including magnesium salts of EPA and DHA (Mg salts), potassium salts of EPA and DHA (K salts), ornithine salts of EPA and DHA, and mixtures of magnesium and lysine salts of EPA and DHA (50% magnesium salt and 50% lysine salt), potassium and lysine salts of EPA and DHA (50% potassium salt and 50% lysine salt), and ornithine and lysine salts of EPA and DHA (50% ornithine salt and 50% lysine salt).

[0080] All tablets were prepared by direct compression. Excipients were passed through a 20# ASTM sieve, API through a 60# ASTM sieve, and omega-3 fatty acid salts were mixed with GalenIQ 721 in a mixer grinder and then passed through a 40# ASTM sieve. All materials were mixed for 5 minutes. Compression of the mixtures prepared as shown in Table 10 was then carried out using a single rotary tablet compression machine. In all trials, the punch size was 11 mm, the average weight was 550 mg, and the compression force was 5.0-8.0 kN. Table 10: Diltiazem tablet composition (ingredients are shown in weight %)

[0081] [Table 10]

[0082] [Table 11]

[0083] In the comparative example, no tablets were formed. Adhesion to the die wall was observed and the tablet broke into two pieces after compression. Furthermore, after 1 minute of compression, the ejection force increased significantly (111 N increase compared to the start) and further tableting was not possible.

[0084] While using different types of omega-3 salts as lubricants, the increase in ejection force remained below 12 N, the maximum ejection force was only 120 N, and the disintegration time was within acceptable limits. The results are summarized in Table 11.

[0085] Experimental Example 25 (Example): Microscopic analysis of omega-3 fatty acid lysine salts compared to calcium salts of C18:0 fatty acids (calcium stearate) A small amount of C18:0 fatty acid calcium salt or ω-3 fatty acid lysine salt was placed on a glass slide and spread evenly across the slide. The prepared slide was mounted on a digital microscope equipped with a camera (Zeiss) and then focused on the particles at various magnifications such as 4X, 10X, and 40X. Microscopic images were acquired at a magnification where the shape of the particles was clearly visible. Figure 1 shows C18:0 fatty acid calcium salt particles at 40X magnification, and Figure 2 shows ω-3 lysine salt particles at 4X magnification.

[0086] Microscopic examination of the calcium salt of C18:0 fatty acid (calcium stearate) shows very fine particle aggregates and an irregular plate-lamellar layer-like structure (visible at 40x magnification). As reported in the literature (e.g. T. Yamamoto et al., Lubricating and bactericidal properties of calcium salts of fatty acids: influence of the degree of unsaturation, Journal of Oleo Science 64, (10) pp. 1095-1100, 2015), the lubricating effect of calcium salts of C18:0 fatty acids is due to the cleavage of lamellar layers and the disintegration of powder aggregates. This disruption of the structural system allows the absorption of frictional forces between solid surfaces. In addition to this, the hydrophobicity of calcium salts of C18:0 fatty acids reduces the adhesion between particles, resulting in a lubricating effect.

[0087] In contrast, microscopic examination of omega-3 fatty acid lysine salts shows large spherical particles (visible at 4X magnification). Contrary to calcium salts of C18:0 fatty acids, omega-3 fatty acid lysine salts are water-soluble and hydrophilic, with different particle morphology. The results suggest that the lubricating effect of the omega-3 salts according to the present invention is new, and that the lubricating effect is independent of particle size morphology and hydrophobicity as reported in the literature for calcium salts of C18:0 fatty acids.

[0088] Example 26 (Example): Differential Scanning Calorimetry (DSC) Analysis of Omega-3 Fatty Acid Lysine Salts Compared to Calcium Salts of C18:0 Fatty Acids (Calcium Stearate) Samples (5–10 mg) of ω-3 fatty acid lysine salts and calcium salts of C18:0 fatty acids were placed in aluminum pans with crimped airtight lids and heated from 0 to 180 °C at a rate of 10 °C per minute using a DSC (TA Instruments, USA, Q20 model). Nitrogen was used as the purge gas with a flow rate of 50 mL per minute. Temperature and heat flow calibrations were performed using standard indium samples. Figure 3 shows the DSC thermograms of ω-3 fatty acid lysine salts and calcium salts of C18:0 fatty acids.

[0089] DSC analysis of calcium salts of C18:0 fatty acids (calcium stearate) shows a sharp melting peak at 130 °C. Such a sharp melting peak indicates the crystalline nature of the material. The crystalline structure of calcium salts of C18:0 fatty acids is involved in the lubricating properties as reported in the literature (e.g. T. Yamamoto et al., Lubricating and bactericidal properties of calcium salts of fatty acids: influence of degree of unsaturation, Journal of Oleo Science 64, (10) pp. 1095-1100, 2015). On the other hand, no sharp peak was observed in the case of ω-3 fatty acid lysine salts. This indicates the amorphous nature of the material, which is emphasized in the literature as not suitable for providing a lubricating effect.

Claims

1. a) preparing a lubricant comprising at least one polyunsaturated fatty acid salt; b) adding the lubricant and solids ingredients to a mixer; c) optionally one or more of granulating, drying, and sizing; d) mixing the contents of the mixer; e) compressing or slugging the mixed contents to form a solid dosage form; wherein the lubricant has a glass transition temperature (Tg) of 120° C. to 180° C. as measured using a differential scanning calorimeter (DSC).

2. 2. The method according to claim 1, wherein when the solid formulation is a tablet, the mixed contents are compressed by a tablet press, and the ejection force of the tablet press is 150N or less.

3. The method according to claim 1 or 2, wherein the polyunsaturated fatty acid salt comprises ω-3 fatty acids EPA and / or DHA.

4. The polyunsaturated fatty acid salt contains at least one basic amino acid or magnesium (Mg ２＋ ) and potassium (K ＋ The method of any one of claims 1 to 3, further comprising at least a counter ion selected from the group consisting of:

5. The method according to any one of claims 1 to 4, wherein the average particle size of the lubricant before mixing is from 2 µm to 600 µm.

6. The lubricant is - a composition comprising at least one polyunsaturated omega-3 fatty acid component or a polyunsaturated omega-6 fatty acid component, and a basic amino acid selected from lysine, arginine, ornithine, choline or magnesium (Mg ２＋ ), potassium (K ＋ ), and mixtures thereof, with an aqueous, aqueous-alcoholic, or alcoholic solution of The mixture is then spray-dried or extruded to obtain the basic amino acid or magnesium (Mg ２＋ ) or potassium (K ＋ forming a solid product composition comprising at least one salt of a cation derived from the fatty acid salt of the present invention and an anion derived from a polyunsaturated omega-3 fatty acid or a polyunsaturated omega-6 fatty acid; The method according to any one of claims 1 to 5, wherein the composition is prepared by the steps of:

7. The method of claim 6, wherein the spray drying comprises pure spray drying, or a spray granulation process, or continuous spray granulation.

8. 2. A preparation comprising at least one polyunsaturated fatty acid salt comprising at least one ω-3 or ω-6 fatty acid selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (ARA), alpha-linolenic acid, stearidonic acid, eicosatetraenoic acid, docosapentaenoic acid, linoleic acid, and gamma-linolenic acid, for use as a lubricant in tableting applications for the compression of solid ingredients.

9. The use according to claim 8, wherein the omega-3 fatty acid component is selected from EPA or DHA.

10. The at least one polyunsaturated fatty acid salt containing an ω-3 fatty acid or an ω-6 fatty acid is selected from the group consisting of lysine, arginine, ornithine, choline, magnesium (Mg ２＋ ), potassium (K ＋ 9. The method of claim 8, having a counterion selected from the group consisting of aryl, aryloxy ...

Images