WO2019008101A1

WO2019008101A1 - Enteric coated solid dosage form comprising omega-3 fatty acid amino acid salts

Info

Publication number: WO2019008101A1
Application number: PCT/EP2018/068261
Authority: WO
Inventors: Ashish Guha; Vishal KANERIA; Shraddha Joshi; Suraj BHOSALE; Smitha Shetty; Christine JARECKI
Original assignee: Evonik Technochemie Gmbh
Priority date: 2017-07-06
Filing date: 2018-07-05
Publication date: 2019-01-10
Also published as: EP3648748A1

Abstract

The present invention relates to the field of pharmaceutical and nutraceutical formulations, and, more specifically to enteric coated solid oral dosage forms, food supplements, pharmaceutical products and use of such dosage forms. The enteric coated nutraceutical or pharmaceutical solid oral dosage form comprises a core with a nutraceutical or pharmaceutical active ingredient and an enteric coating wherein the enteric coating comprises shellac and wherein the nutraceutical or pharmaceutical active ingredient comprises one or more omega-3 fatty acid amino acid salts.

Description

Enteric coated solid dosage form comprising omega-3 fatty acid amino acid salts Omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are linked to numerous positive health effects on the cardiovascular system, on inflammatory disorders, on brain development and function, on disruptions of the central nervous system and on other areas (C. H. S. Ruxton, S. C. Reed, M. J. A. Simpson, K. J. Millington, J. Hum. Nutr. Dietet 2004, 17, 449). Therefore, the intake of omega-3 fatty acids is supported by statements of regulatory agencies. For instance, the EFSA (European Food Safety Authority) recommends for adults a daily intake of 250 mg of EPA + DHA (EFSA Panel on Dietetic Products, Nutrition and Allergies, EFSA Journal 2010, 8 (3), 1461 ). The AHA (American Heart Association) advises the intake of at least two meals of fatty fish per week for persons without documented cardiovascular disorders, the intake of about 1 g of EPA + DHA per day from fish or food supplements for persons with documented cardiovascular disorders and the intake of 2-4 g of EPA + DHA per day for the treatment of raised blood lipid values (P. M. Kris-Etherton, W. S. Harris, L. J. Appel, Circulation 2002, 106, 2747). Moreover, the authorities have expressly approved health claims for omega-3 fatty acids determined on the basis of clinical studies (EU Register on Nutrition and Health Claims; see also: EFSA Journal 201 1 , 9 (4), 2078). Therefore, omega-3 fatty acids, especially from fish oil but also from other plant or microbial sources, are increasingly used as food supplements, food additives and medicaments.

According to standard nomenclature, polyunsaturated fatty acids are classified according to the number and position of the double bonds. There are two series or families, depending on the position of the double bond which is closest to the methyl end of the fatty acid. The omega-3 series comprises a double bond at the third carbon atom whereas the omega-6 series has no double bond up to the sixth carbon atom. Thus, docosahexaenoic acid (DHA) has a chain length of 22 carbon atoms with 6 double bonds beginning with the third carbon atom from the methyl end and is referred to as "22:6 n-3" (all-cis-4,7, 10, 13, 16, 19-docosahexaenoic acid). Another important omega- 3 fatty acid is eicosapentaenoic acid (EPA), which is referred to as "20:5 n-3" (all-cis-5,8, 1 1 , 14, 17- eicosapentaenoic acid).

Most of the omega-3 fatty acid products introduced to the market are offered in the form of oils, starting from fish oil with a content of about 30% omega-3 fatty acids up to concentrates with over 90% content of EPA or DHA or mixtures of these two omega-3 fatty acids. The formulations used are predominantly soft gelatine capsules. In addition, numerous further product forms have been described, such as microencapsulations or powder preparations (C. J. Barrow, B. Wang, B.

Adhikari, H. Liu, Spray drying and encapsulation of omega-3 oils, in: Food enrichment with omega- 3 fatty acids (Eds.: C. Jacobsen, N. S. Nielsen, A. Frisenfeldt Horn, A.-D. Moltke Soerensen), pp. 194-225, Woodhead Publishing Ltd., Cambridge 2013, ISBN 978-0-85709-428-5; T.-L. Torgersen, J. Klaveness, A. H. Myrset, US 2012/0156296 A1 ). Chemically, these are usually triglycerides or fatty acid ethyl esters with various concentrations of omega-3 fatty acids, while phospholipids, e.g. as krill oil, free fatty acids (T. J. Maines, B. N. M. Machielse, B. M. Mehta, G. L. Wisler, M. H.

Davidson, P. R. Wood, US 2013/0209556 A1 ; M. H. Davidson, G. H. Wisler, US 2013/0095179 A1 ; N. J. Duragkar, US 2014/0018558 A1 ; N. J. Duragkar, US 2014/0051877 A1 ) and various salts of fatty acids are also known, e.g. with potassium, sodium, ammonium (H. J. Hsu, S. Trusovs, T. Popova, US 8203013 B2), calcium and magnesium, (J. A. Kralovec, H. S. Ewart, J. H. D. Wright, L. V. Watson, D. Dennis, C. J. Barrow, J. Functional Foods 2009, 1 , 217; G. K. Strohmaier, N. D. Luchini, M. A. Varcho, E. D. Frederiksen, US 7,098,352 B2), where these salts are not water- soluble, aminoalcohols (P. Rongved, J. Klaveness, US 2007/0213298 A1 ), amine compounds such as piperazine (B. L. Mylari, F. C. Sciavolino, US 2014/001 1814 A1 ), and guanidine compounds such as metformin (M. Manku, J. Rowe, US 2012/0093922 A1 ; B. L. Mylari, F. C. Sciavolino, US 2012/0178813 A1 ; B. L. Mylari, F. C. Sciavolino, US 2013/0281535 A1 ; B. L. Mylari, F. C.

Sciavolino, WO 2014/01 1895 A2). The bioavailability of the different omega-3 derivatives for the human body is very diverse. Since omega-3 fatty acids as free fatty acids together with monoacyl glycerides are absorbed in the small intestine, the bioavailability of free omega-3 fatty acids is better than that of triglycerides or ethyl esters since these have firstly to be cleaved to the free fatty acids in the digestive tract (J. P. Schuchhardt, A. Hahn, Prostaglandins Leukotrienes Essent. Fatty Acids 2013, 89, 1 ). The stability to oxidation is also very different in different omega-3 derivatives. Free omega-3 fatty acids are described as very sensitive to oxidation (J. P. Schuchhardt, A. Hahn, Prostaglandins Leukotrienes Essent. Fatty Acids 2013, 89, 1 ). For the use of a solid omega-3 form, an increased stability compared to liquid products is assumed (J. A. Kralovec, H. S. Ewart, J. H. D. Wright, L. V. Watson, D. Dennis, C. J. Barrow, J. Functional Foods 2009, 1 , 217). Furthermore, preparations of omega-3 fatty acids with diverse amino acids, such as lysine and arginine, are known, either as mixtures (P. Literati Nagy, M. Boros, J. Szilbereky, I. Racz, G. Soos, M. Koller, A. Pinter, G. Nemeth, DE 3907649 A1 ) or as salts (B. L. Mylari, F. C. Sciavolino, WO 2014/01 1895 A1 ; T. Bruzzese, EP 0699437 A1 ; T. Bruzzese, EP0734373 B1 ; T. Bruzzese, US 5750572, J. Torras et al., Nephron 1994, 67, 66; J. Torras et al., Nephron 1995, 69, 318; J. Torras et al., Transplantation Proc. 1992, 24 (6), 2583; S. El Boustani et al., Lipids 1987, 22 (10), 71 1 ; H. Shibuya, US 2003/0100610 A1 ). The preparation of omega-3 aminoalcohol salts by spray-drying is also mentioned (P. Rongved, J. Klaveness, US 2007/0213298 A1 ). In general form, the preparation of DHA amino acid salts is described by evaporation to dryness under high vacuum and low temperature or freeze-drying (T. Bruzzese, EP0734373 B1 und US 5750572). The resulting products are described as very thick, transparent oils which transform at low temperature into solids of waxy appearance and consistency.

Despite the extensive prior art, all the known product forms have one or more disadvantages such that further improvement needs exist. For instance, the most common omega-3 triglyceride and ethyl ester oils are inherently less readily bioavailable than the free omega-3 fatty acids. These are in turn particularly sensitive to oxidation. The established formulation as a soft gelatine capsule is more complicated, more expensive and more prone to defects than a simple tabletting of a solid. In addition, many consumers oppose the consumption of gelatine of animal origin on religious or other grounds. Solid omega-3 formulations described to date, either as microencapsulated or bound oil, as mixtures with amino acids or as salts, have other serious disadvantages. For instance, alkali metal salts are strongly alkaline in aqueous solution whereas alkaline earth metal salts are practically water-insoluble which limits the bioavailability.

One major disadvantage of omega-3 fatty acid products is a fishy taste and smell. When the omega-3 fatty acid products are adsorbed in the stomach, further negative effects accrue, such as a fishy reflux and unpleasant fishy regurgitation, which shall be avoided.

Enteric film coatings are applied to oral dosage forms to delay the release of the active ingredients until the dosage form has passed through the acidic environment of the stomach (pH between 1.0 and 3.0) and has reached the less acidic environment of the proximal small intestine. The physical chemical environment of the stomach and gastric physiology are highly variable, due to multiple factors such as disease state, medication, age, and eating. For example in the fasted state stomach, the pH is less than 2.0 in healthy individuals, and gastric emptying occurs approximately every 30 minutes. However, in the fed state (immediately after a meal), gastric emptying is delayed for 2 to 4 hours and gastric pH can be as high as pH 4.0.

In general, polymers with acidic functional groups are chosen for enteric coatings. In the acidic environment in the stomach, these functional groups are non-ionized, thus rendering the polymer insoluble in water. In the more neutral pH of the intestine, the functional groups then ionize and the polymer film becomes water soluble. Known enteric film coatings include methacrylic acid copolymers, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetylsuccinate.

The use of shellac as enteric coating has also been described in the prior art (WO2009/064429 and WO201 1/002972). Shellac is a natural, food approved, resinous material, which is secreted by the female lac bug Kama lacca and is a complex mixture of materials. The two main components with enteric properties being shelloic and aleuritic acid. While shellac is well known as a material with enteric-like properties, it has a number of drawbacks. Due to insolubility in water, shellac has traditionally been used in the form of organic solvent based solutions. Additionally, in its natural state, shellac is generally not soluble below a pH of 7.5 to 8.0. Rather shellac films simply soften and disintegrate after immersion in water for a number of hours. This is problematic as enteric coatings should generally be soluble or rupturable in the proximal intestinal environment. Lastly, shellac coatings have been reported to undergo esterification during aging, rendering the film completely water insoluble even in alkaline pH. Enteric coating using shellac for liquid omega-3 fatty acid compositions in food products has been described in the international patent application WO2012/168882A1. However, this publication refers to liquid components only.

Due to the disadvantages described, a need exists for solid omega-3 fatty acid preparations, which can be readily and cost-effectively formulated as solid dosage forms, which have better bioavailability and in addition are also more stable than standard liquid formulations. Moreover, these solid dosage forms shall comprise an enteric coating, which allow a release of the omega-3 fatty acids in the small intestine at pH values below pH 7.0. To allow an optimal absorption of omega-3 fatty acids already in the upper intestine, it is desirable that those are released at a slight lower pH-value around pH 5.0.

It has now been found, surprisingly, that enteric coated solid dosage forms according to the present invention can be provided comprising a core with one or more omega-3-fatty acid amino acid salts, and with a coating comprising shellac, which provides a delayed release of the omega-3 -fatty acid amino acid salts in the upper intestine.

The present invention accordingly relates in a first aspect to an enteric coated nutraceutical or pharmaceutical solid oral dosage form comprising a core with a nutraceutical or pharmaceutical active ingredient and an enteric coating wherein the enteric coating comprises shellac and wherein the nutraceutical or pharmaceutical active ingredient comprises one or more omega-3 fatty acid amino acid salts.

According to the present invention, it is preferred to use a food grade or pharma grade shellac. While not excluding other grades of shellac, a preferred type is dewaxed shellac, which is usually refined using a solvent extraction process. For production of light-colored grades, activated carbon is used followed by an additional filtration step to remove the activated carbon. The solvent is removed afterwards by evaporation in a thin film evaporator and recovered. The resin is then drawn to a thin film, which typically breaks into flakes after cooling.

Omega-3 fatty acids, which may be present individually or in any preferred combination in a solid oral dosage form according to the invention, comprise for example a-linolenic acid (ALA) 18:3 (n-3) (cis,cis,cis-9, 12, 15-octadecatrienoic acid), stearidonic acid (SDA) 18:4 (n-3) (all-cis-6,9, 12, 15,- octadecatetraenoic acid), eicosatrienoic acid (ETE) 20:3 (n-3) (all-c;^'s-1 1 , 14, 17-eicosatrienoic acid), eicosatetraenoic acid (ETA) 20:4 (n-3) (all-cis-8, 1 1 ,14, 17-eicosatetraenoic acid),

heneicosapentaenoic acid (HPA) 21 :5 (n-3) (all-cis-6,9,12,15, 18-heneicosapentaenoic acid), docosapentaenoic acid (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), tetracosahexaenoic acid (nisinic acid) 24:6 (n-3) (all-cis- 6,9, 12, 15, 18,21-tetracosahexaenoic acid). Polyunsaturated omega-3 fatty acids may be obtained from any suitable starting material, which may in addition be processed with any suitable method. Typical starting materials include all parts of fish carcasses, vegetables and other plants, and material from microbial fermentation or fermentation of algae. Typical processing methods for such starting materials are, inter alia, steps for crude oil extraction, such as extraction and separation of the starting materials and steps for refining crude oils, such as deposition and degumming, deacidification, bleaching and deodourizing (cf. e.g. "EFSA Scientific Opinion on Fish Oil for Human Consumption"). It is advantageous to use different plant oils as starting material, such as linseed oil, algal oil, hemp seed oil, rapeseed oil, borage seed oil, flaxseed oil, canola oil, soybean oil. Further processing methods include, inter alia, steps for the at least partial conversion of omega-3 fatty acid esters to the corresponding free omega-3 fatty acids or inorganic salts thereof.

In a further preferred embodiment of the present invention, the source for omega-3 fatty acids is chosen from at least one of the following: fish oil, squid oil, krill oil, linseed oil, borage seed oil, algal oil, hemp seed oil, rapeseed oil, flaxseed oil, canola oil, soybean oil.

Omega-3 fatty acids may also be obtained by cleaving the omega-3 fatty acid esters and subsequent removal of the alcohols previously attached as part of the ester from compositions, which consist principally of omega-3 fatty acid esters. The ester cleavage is preferably carried out under basic conditions. Methods for ester cleavage are well known from the prior art.

The salts of omega-3 fatty acids and amino acids are dissolved in the digestive tract, wherein the free omega-3 fatty acids are released which are suitable for direct absorption by the body, and prior chemical or enzymatic cleavage is no longer required, such as is the case in the omega-3 triglycerides in fish oil or the omega-3 fatty acid ethyl esters prepared therefrom. By coating the solid dosage form with an enteric shellac coating, the omega-3 fatty acids are only released in the small intestine, which demonstrably is the actual location in the body for the absorption of fatty acids from the digestive tract, such that the omega-3 fatty acids are available for immediate absorption in the preferred free form. The effects such as reflux or unpleasant fishy regurgitation often usually linked with the absorption of omega-3 fatty acid oils by the too early release of the omega-3 fatty acid oils in the stomach is thus avoided.

In a preferred configuration of the present invention, the enteric coating further comprises an anionic polymer, preferably pectin or sodium alginate.

According to the present invention, the use of pectin is preferred. It is further preferred that the ratio between shellac and the anionic polymer in the enteric coating is between more than 80:20 (more than 80% of shellac in the mixture of shellac and anionic polymer) and 100:0, preferably between 81 : 19 and 99: 1 , more preferably between 85: 15 and 95:5.. In a more preferred embodiment, the ratio between shellac and the anionic polymer in the enteric coating is between 90:10 and 95:5.

In an alternative embodiment, the enteric coating further comprises one or more plasticizers chosen from glycerol, mineral oil, triacetin, polyethylene glycol, glyceryl monostearate, mono- acetylated triglycerides and polysorbate. Glycerol is the most preferred plasticizer due to its universal status as food plasticizer. Glycerol may be used in an amount ranging from 3% to 30% by weight (relating to the shellac-polymer).

In a further alternative embodiment, the enteric coating further comprises one or more pigments such as titanium dioxide and talc.

In an advantageous configuration the solid oral dosage form further comprises a subcoat, which is selected from the following: cellulose-derived polymers, selected from hydroxyl propyl methyl cellulose (HPMC), methyl hydroxyl ethyl cellulose (MHEC), ethyl cellulose (EC), hydroxyl propyl cellulose (HPC) and sodium carboxy methyl cellulose, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycols (PEG), acrylate polymers, maize starch and mixtures thereof. The subcoat builds an additional coating layer, which has additional taste- and/or odour-masking effects. In an alternative advantageous configuration the solid oral dosage form further comprises an additional layer comprising one or more pigments, natural colours, flavours, sweeteners and/or cyclodextrins.

In a further advantageous configuration of the present invention, the amino acid(s) is/are selected from basic amino acids, preferably from lysine, arginine, ornithine and mixtures of the same.

In an advantageous configuration of the present invention, the omega-3 fatty acid(s) is/are selected from eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and mixtures of the same.

Omega-3 fatty acid amino acid salts are known in principle. As described at the outset, these may be obtained as fine, virtually colourless powders by precipitation from aqueous or aqueous alcoholic media or by spray-drying, which differ advantageously from the waxy consistency of these substances described hitherto. In a preferred configuration, the omega-3 fatty acid amino acid salts are obtained by precipitation from aqueous or alcoholic aqueous solution.

In a further advantageous configuration of the present invention the enteric coated solid oral dosage form is characterized in that the release of the omega-3 fatty acid amino acid salts is less than 10% by weight of the content of omega-3 fatty acid amino acid salt when an in vitro dissolution testing for the solid dosage form is performed in 0.1 N hydrochloric acid for a period of 2 hours.

For analysing the drug release profile of the solid oral dosage forms, in vitro dissolution studies were performed. Dissolution testing is an in vitro method that characterizes how an active pharmaceutical ingredient (API) or an active food ingredient (AFI) is extracted out of a solid dosage form and indicates the efficiency of in vivo dissolution. The specific dissolution technique employed was the industry standard dissolution testing methodology United States Pharmacopoeia (USP) Apparatus 1 basket. The in vitro analysis was performed with 100 rpm and a bath temperature of 37°C (±0.5°C). For the acid stage 900 ml of 0.1 N HCI was used as a media, followed by the buffer stage with 900 ml of phosphate buffer with the respective pH-value (pH 3.5, pH 4.5, pH 5.5 or pH 6.8). The samples were analysed using RP-HPLC at 210nm.

In a further preferred configuration, the enteric coated solid oral dosage form is characterized in that the release of the omega-3 fatty acid amino acid salt is more than 60% by weight of the content of omega-3 fatty acid amino acid salt when an in vitro dissolution testing for the solid dosage form is performed in a solution with a pH between pH 4 and pH 6, preferably in a solution with a pH between pH 4 and pH 5 for a period of 3 hours.

In a preferred configuration, the enteric coated solid dosage form comprises small particulates.

Small particulates, also known as pellets in the pharmaceutical industry can be defined as small, free-flowing, spherical particulates with a relatively narrow size range usually between 0.1 and 2.0 mm and a low porosity (about 10%). The multiparticulate dosage forms offers many important pharmacological and technological advantages over conventional single-unit dosage forms. They can be divided into desired dose strength without formulation or process changes and can be blended to deliver incompatible bioactive agents simultaneously and/or provide different release profiles at different sites in the gastrointestinal tract. When taken orally, pharmaceutical pellets disperse freely in the gastrointestinal tract and maximize drug absorption (due to the higher surface area) and minimize local irritation of the mucosa by certain irritating drugs. Thereby, versatile formulation designs are possible, which can easily be adapted to the different patient requirements.

It is further preferred that the coating of the small particulates is at least 2.0 mg/cm². The weight gain I (mg/cm²), which is achieved by coating of the pellets is calculated according to the following formula:

wherein % Coating weight [w/w] corresponds to the percentage weight gain due to the coating layer (relating to the weight of the pellet core), W [mg] is the weight of the pellet core and A [mm²] is the surface area of the pellet core. In an advantageous embodiment, the enteric coated solid oral dosage form is stable at a temperature of 40 °C and a relative humidity of 75% for at least 3 months. After storage under these conditions for three months, the dissolution profile is similar to the dissolution profile of a freshly prepared solid oral dosage form. In a further aspect, the present invention relates to a food supplement or pharmaceutical product comprising one or more enteric coated small particulates according to the present invention. The dosage form of the food supplement or pharmaceutical product is selected from one of the following: Multiple-Unit Pellet System (MUPS) tablets, capsules, sachets, sprinkles, gummies and straw formulations.

In an advantageous configuration, the dosage form further comprises one or more additional active ingredients selected from anthocyanins, vitamins, minerals, fiber, fatty acids, amino acids and proteins. Further nutraceutically acceptable active ingredients may also be included in the dosage form.

In a further aspect, the present invention relates to the use of a solid dosage form according to the invention as a food supplement or pharmaceutical product. In the context of the present invention, pharmaceutical products may comprise, in addition to the omega-3 fatty acids described here, both pharmaceutically acceptable auxiliaries and

pharmaceutical active ingredients such as statins, anti-hypertensive agents, antidiabetics, antidementia agents, antidepressants, anti-obesity agents, appetite suppressants and agents to improve memory and/or cognitive function.

The present invention is described in detail by means of the following non-limiting experiments. Experiments:

Example 1 : Preparation of omeqa-3 fatty acid lysine salt pellets for coating trials

The Hydroxypropyl Cellulose (HPC) was dissolved in the required quantity of purified water. The omega-3 fatty acid lysine salt was added to the solution under high speed stirring. The solution was then homogenized for 15-20 min until a lump free solution was formed. The final solution was sprayed on sugar spheres to obtain the omega-3 fatty acid lysine pellets.

Example 2 (comparative): Preparation of Metoprolol pellets for coating trials

Metoprolol succinate and the microcrystalline celluloses Avicel PH 101 and CL 61 1 were sifted through a 40# sieve and mixed for 30 min in a rapid mixer granulator (RMG) at slow speed. Water was added under continuous mixing at slow speed and the wet mass was mixed further with chopper. The granulated mass was used for extrusion and the extrudates were obtained. 350-400 g of extrudate was added on a spheronization plate (Cross-Hatched type) for spheronization at 1700 rpm for 4 min to get pellets of optimum size and shape. The pellets were dried at 60°C for 2 hours in a fluid bed dryer granulator. Example 3: Shellac coating on omeqa-3 fatty acid lysine salt pellets

Omega-3 fatty acid lysine salt pellets were prepared as described in Example 1 and used for the coating trials.

The amounts were calculated as % by weight with relation to the polymer shellac (w.r.t. polymer). Ammonium hydrogen carbonate was not considered in the final weight gain, as it evaporates during the process.

Different types of dewaxed decolorized shellac flakes were used for the coating experiments, such as shellac SSB 55 Pharma, shellac SSB 56 Pharma and shellac SSB 55 Astra (all from SSB Stroever GmbH & Co. KG, Germany). The characteristics referring to coating and dissolution of the different types of shellac were similar.

Ammonium hydrogen carbonate was dissolved in the required quantity of water and was heated up to a temperature of 80-90°C. Shellac was added slowly to the solution under stirring, maintaining a constant temperature of 80-90°C to form a lump free solution. Glycerol was added under stirring. Subsequently talc was added to the solution under stirring. The final solution was then sprayed on omega-3 fatty acid lysine salt pellets (50 g of pellet material) until a weight gain of 3.5 mg/cm² was achieved. The solid content of the coating dispersion was 10% (w/w).

The shellac-coated pellets were tested in dissolution studies in different buffer conditions with various pH-values. The in vitro analysis was performed with 100 rpm and a bath temperature of 37°C (±0.5°C). For the acid stage (120 min) 900 ml of 0.1 N HCI was used as a media, followed by the buffer stage (of further 60 min) with 900 ml of phosphate buffer with the respective pH-value (pH 3.5, pH 4.5, pH 5.5 or pH 6.8). The samples were analysed using RP-HPLC at 210nm. Medium Time [min] % drug release

0.1 N HCI 120 3.6

Phosphate buffer 180 24.5

pH 3.5

Phosphate buffer 180 72.2

pH 4.5

Phosphate buffer 180 79.3

pH 5.5

Phosphate buffer 180 89.9

pH 6.8

The coated pellets showed enteric properties in 0.1 N HCI for 120 minutes (acceptance criteria is <10%) followed by a release in pH 4.5 phosphate buffer and at higher pH-values (acceptance criteria > 60%).

Example 4: Shellac-pectin coating on omeqa-3 fatty acid lysine salt pellets

The amounts were calculated as % by weight with relation to the shellac-pectin (w.r.t. polymer). Ammonium hydrogen carbonate was not considered in the final weight gain, as it evaporates during the process.

Ammonium hydrogen carbonate was dissolved in half of the required quantity of water and was heated up to a temperature of 80-90°C. Shellac was added slowly to the solution under stirring, maintaining a constant temperature of 80-90°C to form a lump free solution. Glycerol followed by pectin was added slowly to the remaining half of water under stirring to form a lump free solution. Subsequently talc was added to the solution under stirring. The final solution was then sprayed on omega-3 fatty acid lysine salt pellets (50 g of pellet material) until a weight gain of 4.3 mg/cm² was achieved. The solid content of the coating dispersion was 10% (w/w).

The pellets coated with shellac-pectin were tested in dissolution studies in different buffer conditions with various pH-values as described in Example 3.

The coated pellets showed enteric properties in 0.1 N HCI for 120 minutes followed by a release pH 4.5 phosphate buffer and at higher pH-values.

Different combinations of Shellac and pectin in the coating composition were analyzed as described above. The results are summarized in the following table:

Acid resistance is achieved with all tested coating compositions. However, when the ratio shellac:pectin is 80:20, no satisfying drug release at pH 4.5 can be achieved and the release at pH 6.8 is not sufficient. For shellac:pectin ratios of 95:5, 90: 10 and 85: 15 there is a resistance in 0.1 N HCI and a sufficient drug release at pH 4.5 and pH 6.8. It can be concluded that mixtures of shellac and pectin can be used with a content of more than 80% shellac in the shellac-pectin mixture. Example 5: Shellac-sodium alginate coating on omeqa-3 fatty acid lysine salt pellets

The coating composition from Example 4 was used for the coating of the omega-3 fatty acid lysine salt pellets in which pectin was replaced by sodium alginate to get shellac-sodium alginate (ratio 95:5) until a weight gain of 4.3 mg/cm² was achieved. The pellets coated with shellac-sodium alginate were tested in dissolution studies in different buffer conditions with various pH-values as described in Example 3.

The coated pellets showed enteric properties in 0.1 N HCI for 120 minutes followed by a release in pH 4.5 phosphate buffer and at higher pH-values.

Example 6 (comparative): Shellac coating on Metoprolol succinate pellets Metoprolol succinate pellets were prepared as described in Example 2 and used for the coating trials. The shellac coating composition from Example 3 was used for the coating of the Metoprolol succinate pellets until a polymeric weight gain of 3.4 mg/cm² and 6.7 mg/cm².

The Metoprolol succinate pellets coated with shellac were tested in dissolution studies in different buffer conditions with various pH-values as described in Example 3.

For both polymeric weight gain samples no drug release could be observed. This shows that plain shellac coating does not work on Metoprolol succinate pellets. Example 7 (comparative): Shellac-pectin coating on Metoprolol succinate pellets

Metoprolol succinate pellets were prepared as described in Example 2 and used for the coating trials. The shellac-pectin coating composition from Example 4 was used for the coating of the Metoprolol succinate pellets until a polymeric weight gain of 2.7 mg/cm² and 1.1 mg/cm².The Metoprolol succinate pellets coated with shellac-pectin were tested in dissolution studies in different buffer conditions with various pH-values as described in Example 3.

For the Metoprolol succinate pellets, only a very slight drug release could be observed at pH 6.8. This shows that the shellac-pectin coating does not work on Metoprolol succinate pellets.

Similar results were obtained with caffeine pellets, where only a slight drug release (<20%) was observed.

Example 8: Preparation of Gummies containing omega-3 fatty acid lysine salt pellets coated with shellac-pectin

The shellac-pectin coated omega-3 fatty acid lysine salt pellets were prepared as described in Example 4. Gummies were prepared using the following materials:

Amount Amount

Material [% w/w] [g]

Gelatin 7.00 7.00

High fructose corn syrup 35.90 35.90

Sucrose 50.00 50.00

Citric acid (50% solution) 0.45 0.45

Tri sodium citrate 0.15 0.15

Omega-3 fatty acid lysine salt pellets 5.00 5.00

Lemon flavor 1.50 1.50

HCI g.s. g.s.

Water 20.00 20.00

Sum total 100.00 100.00 The gelatin was dissolved in water under constant heating. The high fructose corn syrup and the sucrose were added and the mixture was stirred until the sucrose was dissolved. Citric acid and tri sodium citrate were added; afterwards the pH was adjusted with 0.1 N HCI below pH 2.5 and the mixture was cooled down to a temperature between 40°C and 45°C. The shellac-pectin coated omega-3 fatty acid lysine salt pellets were added together with the flavour and the mixture was stirred to achieve a uniform composition. The stirred composition was directly poured in the desired moulds for solidifying.

Example 9: Preparation of MUPS tablets containing omeqa-3 fatty acid lysine salt pellets coated with shellac-pectin

The shellac-pectin coated omega-3 fatty acid lysine salt pellets were prepared as described in Example 4. MUPS tablets were prepared using the following materials:

Microcrystalline cellulose (Avicel PH200, 802, 102) crosscarmellose sodium and colloidal silicon dioxide were sifted through a #30 mesh (600 microns). The coated Omega-3 fatty acid lysine salt pellets were mixed with sifted ingredients in double cone blender for 15 minutes. The sodium stearyl fumarate was sifted through #80 mesh (180 microns), added to the mixture and mixed further for 3 minutes. The lubricated blend was finally compressed on a rotary tableting machine.

Example 10: Preparation of capsules containing omeqa-3 fatty acid lysine salt pellets coated with shellac-pectin

The shellac-pectin coated omega-3 fatty acid lysine salt pellets were prepared as described in Example 4 and were filled in size 0 capsules. Example 1 1 : Preparation of straws containing omeqa-3 fatty acid lysine salt pellets coated with shellac-pectin The shellac-pectin coated omega-3 fatty acid lysine salt pellets were prepared as described in Example 4 and filled in straws.

Example 12: Preparation of capsules containing omeqa-3 fatty acid lysine salt pellets coated with shellac-pectin and anthocyanins

The shellac-pectin coated omega-3 fatty acid lysine salt pellets were prepared as described in Example 4. 175 mg of shellac-pectin coated omega-3 fatty acid lysine salt pellets and 150 mg Healthberry® 865 (Evonik Nutrition and Care GmbH, Darmstadt, Germany) containing extracts of bilberries and blackcurrants with high concentrations in anthocyanins were filled in size 0 capsules.

Example 13: Preparation of flavoured omeqa-3 fatty acid lysine salt pellets coated with shellac- pectin

The shellac-pectin coated omega-3 fatty acid lysine salt pellets were prepared as described in Example 4.

The amounts were calculated as % by weight with relation to hydroxypropyl methylcellulose (w.r.t. polymer).

The HPMC 6CPS was dissolved in water under stirring to form a lump free solution. Talc and orange flavour were added to the HPMC-solution under stirring for 15 min. The final dispersion was sprayed on shellac-pectin coated omega-3 fatty acid lysine salt pellets to achieve a polymeric coat of 0.2 mg/cm². Example 14: Preparation of shellac-pectin coated omeqa-3 fatty acid lysine salt pellets coated with β-cyclodextrin The shellac-pectin coated omega-3 fatty acid lysine salt pellets were prepared as described in Example 4. The coating dispersion was prepared with the following materials:

The amounts were calculated as % by weight with relation to β-cyclodextrin (w.r.t. β-cd).

HPMC 6CPS was dissolved in water under stirring to form a lump free solution, β-cyclodextrin was added to the solution under stirring for 15 min. The final dispersion was sprayed on the shellac- pectin coated omega-3 fatty acid lysine salt pellets to achieve a coat of β-cyclodextrin of 0.2 mg/cm².

Example 15: Preparation of barrier coated omeqa-3 fatty acid lysine salt pellets coated with shellac-pectin Omega-3 fatty acid lysine salt pellets were prepared as described in Example 1 and used for the coating trials. The coating dispersion was prepared with the following materials:

The amounts were calculated as % by weight with relation to the EUDRAGUARD® natural polym (w.r.t. polymer). Glycerol was dissolved in the required quantity of purified water. The solution was heated up to 50- 60°C followed by slow addition of the EUDRAGUARD® natural polymer (a maize starch-based functional coating, Evonik Nutrition and Care GmbH, Darmstadt, Germany) under stirring.

Afterwards, talc was added to the solution under stirring. During the coating procedure the temperature of the coating dispersion was maintained between 40-50°C. The omega-3 fatty acid lysine salt pellets were coated until a coating of 1.7 mg/cm² was achieved. The barrier coated omega-3 fatty acid lysine salt pellets were further coated with shellac-pectin (95:5) under the same conditions as described in Example 4. The barrier coated omega-3 fatty acid lysine salt pellets coated with shellac-pectin were tested in dissolution studies in different buffer conditions with various pH-values as described in Example 3:

The coated pellets showed enteric properties in 0.1 N HCI for 120 minutes followed by a release in pH 6.8 phosphate buffer and at higher pH-values.

Example 16: Stability studies of omeqa-3 fatty acid lysine salt pellets coated with shellac-pectin The shellac-pectin coated omega-3 fatty acid lysine salt pellets were prepared as described in

Example 4. For analysing the stability of the shellac-pectin coated pellets, the pellets were filled in a HDPE container without silica and were stored at a temperature of 40 °C and a relative humidity (RH) of 75% for a period of 3 months. Dissolution studies were performed after different time points.

After a period of 3 months, the dissolution characteristics of the shellac-pectin coated omega-3 fatty acid lysine salt pellets were found to be similar to the characteristics of the pellets before storage. This shows that the shellac-pectin coated pellets can be stored several months without negative effects on the stability of the pellets.

Claims

1. An enteric coated nutraceutical or pharmaceutical solid oral dosage form comprising a core with a nutraceutical or pharmaceutical active ingredient and an enteric coating

wherein the enteric coating comprises shellac and

wherein the nutraceutical or pharmaceutical active ingredient comprises

one or more omega-3 fatty acid amino acid salts.

2. Enteric coated solid oral dosage form according to Claim 1 , characterized in that the

enteric coating further comprises an anionic polymer, preferably pectin or sodium alginate.

3. Enteric coated solid oral dosage form according to Claim 2, characterized in that the ratio between shellac and the anionic polymer in the enteric coating is between more than 80:20 (more than 80% of shellac in the mixture of shellac and anionic polymer) and 100:0, preferably between 81 : 19 and 99:1 , more preferably between 85: 15 and 95:5.

4. Enteric coated solid oral dosage form according to any of the preceding claims,

characterized in that the solid oral dosage form further comprises a subcoat, which is selected from the following: cellulose-derived polymers, selected from hydroxyl propyl methyl cellulose (HPMC), methyl hydroxyl ethyl cellulose (MHEC), ethyl cellulose (EC), hydroxyl propyl cellulose (HPC) and sodium carboxy methyl cellulose, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyethylene glycols (PEG), acrylate polymers, maize starch and mixtures thereof. 5. Enteric coated solid oral dosage form according to any of the preceding claims,

characterized in that the solid oral dosage form further comprises an additional layer comprising one or more pigments, natural colours, flavours, sweeteners and/or cyclodextrins. 6. Enteric coated solid oral dosage form according to any of the preceding claims,

characterized in that the amino acid(s) is/are selected from lysine, arginine, ornithine and mixtures of the same.

7. Enteric coated solid oral dosage form according to any of the preceding claims,

characterized in that the omega-3 fatty acids comprises at least one of the following: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and mixtures of the same.

8. Enteric coated solid oral dosage form according to any of the preceding claims,

characterized in that the release of the omega-3 fatty acid amino acid salts is less than 10% by weight of the content of omega-3 fatty acid amino acid salt when an in vitro dissolution testing for the solid dosage form is performed in 0.1 N hydrochloric acid for a period of 2 hours.

9. Enteric coated solid oral dosage form according to any of the preceding claims,

characterized in that the release of the omega-3 fatty acid amino acid salt is more than 60% by weight of the content of omega-3 fatty acid amino acid salt when an in vitro dissolution testing for the solid dosage form is performed in a solution with a pH between pH 4 and pH 6, preferably in a solution with a pH between pH 4 and pH 5 for a period of 3 hours.

10. Enteric coated solid oral dosage form according to any of the preceding claims,

characterized in that the solid dosage form comprises small particulates.

1 1. Enteric coated solid oral dosage form according to Claim 10, characterized in that the coating is at least 2.0 mg/cm².

12. Enteric coated solid oral dosage form according to any one of the preceding claims, characterized in that it is stable at a temperature of 40 °C and a relative humidity of 75% for at least 3 months.

13. Food supplement or pharmaceutical product comprising one or more enteric coated solid oral dosage forms according to Claims 10 to 12, characterized in that the dosage form of the food supplement or pharmaceutical product is selected from one of the following:

Multiple-Unit Pellet System (MUPS) tablets, capsules, sachets, sprinkles, gummies and straw formulations.

Food supplement or pharmaceutical product according to Claim 13, characterized in that the dosage form further comprises one or more additional active ingredients selected from anthocyanins, vitamins, minerals, fiber, fatty acids, amino acids and proteins.

15. Use of an enteric coated solid oral dosage form according to any of Claims 1 to 12 as a food supplement or as a pharmaceutical or nutraceutical product.