Enteric coated particles containing lactoferrin

Abstract

The present invention generally relates to enteric coated particles comprising lactoferrin. More specifically, the present invention provides enteric coated particles comprising (or essentially consisting of) a) a core comprising (or consisting essentially of) an inert core-forming material selected from cellulose polymers, sugars, sugar alcohols, starches and carnauba wax; b) a first coating layer substantially covering the core, comprising (or consisting essentially of) b-1) lactoferrin, b-2) a pharma-ceutically acceptable binder, and optionally b-3) one or more other suitable excipients, such as plasticizers; and c) a second coating layer substantially covering the first coating layer, comprising (or consisting essentially of) c-1) an enteric coating material, and optionally c-2) one or more suitable excipients, such as plasticizers and / or anti-tack agents. The present invention further provides pharmaceutical compositions and oral dosage forms comprising one or more particles according to the present invention.

Description

[Technical field]

[0001] The present invention generally relates to enteric coated particles comprising lactoferrin. More specifically, the present invention provides enteric coated particles comprising (or essentially consisting of) a) a core comprising (or consisting essentially of) an inert core-forming material selected from cellulose polymers, sugars, sugar alcohols, starches and carnauba wax; b) a first coating layer substantially covering the core, comprising (or consisting essentially of) b-1) lactoferrin, b-2) a pharma-ceutically acceptable binder, and optionally b-3) one or more other suitable excipients, such as plasticizers; and c) a second coating layer substantially covering the first coating layer, comprising (or consisting essentially of) c-1) an enteric coating material, and optionally c-2) one or more suitable excipients, such as plasticizers and / or anti-tack agents. The present invention further provides pharmaceutical compositions and oral dosage forms comprising one or more particles according to the present invention.

[0002] 2. Background of the Invention Food poisoning is most often treated with antibiotics and / or medicinal activated charcoal. The drawback of these approaches is their low selectivity. Antibiotics are also effective against microorganisms important for the proper functioning of the digestive tract. As a result, overuse of antibiotics can cause constipation and at the same time increases the chances of microorganisms mutating into more resistant strains. Therefore, antibiotics are not often prescribed for digestive complications, unless they are absolutely necessary to prevent the patient from becoming dehydrated. Activated charcoal has the effect of binding toxins in the digestive tract and does not usually affect the growth of microorganisms. Therefore, it is difficult to measure its effectiveness in treating food poisoning or water intoxication.

[0003] The solution to the above challenges is the use of selective microbial growth inhibitors for the intestine. In this regard, lactoferrin is recognized as a protein that inhibits bacterial growth and has been found to act selectively only on pathogenic microorganisms. Lactoferrin (LF) or lactotransferrin is an 80 kDa non-heme iron-binding globular glycoprotein belonging to the transferrin family and present in various secretory fluids. It is the major iron-binding protein in milk and has antibacterial, immunomodulatory, antioxidant, anticancer and many other biological functions. There is growing interest in products containing LF due to their potential for the treatment of various diseases, including the so-called traveler's disease.

[0004] On the other hand, lactoferrin generally has low bioavailability after oral administration due to proteolysis in the digestive tract and poor permeability across the intestinal epithelium. The half-life of LF in simulated intestinal fluid is approximately three times that in simulated gastric fluid. Therefore, to increase the stability of LF after oral administration, it is important to protect LF from enzymatic degradation and the strong acidic environment in the stomach. The most common methods for delivering LF intact through the upper digestive tract are increasing the iron saturation of LF (preparation of hololactoferrin), (micro)encapsulation of LF, and PEGylation. However, these methods have the disadvantage of reducing the activity of LF and affecting its effectiveness against microorganisms.

[0005] Thus, there remains a continuing need to provide new formulations of lactoferrin that provide advantageous properties such as high dosage and stability of lactoferrin after oral administration.

[0006] Summary of the Invention The present invention addresses this need by providing an enteric coated particle comprising: a) a core comprising an inert core-forming material; b) a first coating layer substantially covering the core and comprising b-1) lactoferrin; and c) a second coating layer substantially covering the first coating layer and comprising c-1) an enteric coating material.

[0007] Thus, more specifically, the present invention provides enteric coated particles comprising: a) a core comprising an inert core-forming material selected from a cellulose polymer, a sugar, a sugar alcohol, starch and carnauba wax; b) a first coating layer substantially covering the core and comprising b-1) lactoferrin, b-2) a pharma- ceutically acceptable binder, and optionally b-3) one or more other suitable excipients, such as a plasticizer; and c) a second coating layer substantially covering the first coating layer and comprising c-1) an enteric coating material, and optionally c-2) one or more suitable excipients, such as a plasticizer and / or an anti-adherent.

[0008] One advantage of the particles of the present invention is that they can provide a high dose of highly pure lactoferrin per dose.For example, the particles of the present invention can provide a product containing 200mg or more of lactoferrin per dose.In addition, the particles of the present invention provide improved resistance to the conditions found in the digestive tract, thus increasing the overall stability of lactoferrin after oral administration.The use of substantially spherical particles according to the present invention can improve flow properties, thus allowing capsules to be filled more uniformly with less variability, and requiring less enteric coating.

[0009] The invention may further be characterized in that: 1. An enteric coated particle comprising (or consisting essentially of): a) a core comprising (or consisting essentially of) an inert core-forming material selected from cellulose polymers, sugars, sugar alcohols, starches and carnauba wax; b) a first coating layer substantially covering the core and comprising (or consisting essentially of) b-1) lactoferrin, b-2) a pharma-ceutically acceptable binder, and optionally b-3) one or more other suitable excipients, such as a plasticizer; and c) a second coating layer substantially covering the first coating layer and comprising (or consisting essentially of) c-1) an enteric coating material, and optionally c-2) one or more suitable excipients, such as a plasticizer and / or an anti-adherent.

[0010] 2. The particle according to item 1, wherein the inert core-forming material is a cellulose polymer.

[0011] 3. The particles according to item 2, wherein the cellulose polymer is selected from the group consisting of microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and carboxymethyl cellulose.

[0012] 4. The particle according to item 2, wherein the cellulose polymer is microcrystalline cellulose.

[0013] 5. The particle according to item 1, wherein the inert core-forming material is a sugar or sugar alcohol.

[0014] 6. The particle according to item 5, wherein the sugar is selected from the group consisting of glucose, sucrose and lactose.

[0015] 7. The particle according to item 5, wherein the sugar alcohol is selected from the group consisting of isomalt, maltitol, mannitol, xylitol and sorbitol.

[0016] 8. The particle according to any one of the preceding claims, wherein the pharma- ceutically acceptable binder comprised in the first coating layer is selected from the group consisting of cellulose polymers, such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, povidone, such as polyvinylpyrrolidone (PVP), copovidone, agar, gelatin, gum arabic, alginates, such as sodium alginate and polyethylene glycol alginate, polyethylene glycol, polyvinyl alcohol, sugars, sugar alcohols, starches and modified starches, such as potato starch, corn starch, rice starch and pregelatinized starch.

[0017] 9. The particle according to any one of the preceding claims, wherein the pharma- ceutically acceptable binder comprised in the first coating layer is a non-polyvinylpyrrolidone (PVP) binder.

[0018] 10. A particle according to any one of the preceding claims, wherein the pharma- ceutically acceptable binder contained in the first coating layer is hydroxypropylmethylcellulose.

[0019] 11. A particle according to any one of the preceding claims, wherein the first coating layer comprises one or more other suitable excipients, such as a plasticizer.

[0020] 12. The particle according to any one of the preceding claims, wherein the first coating layer comprises a plasticizer.

[0021] 13. Particles according to item 11 or 12, wherein the plasticizer is selected from the group consisting of polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, sorbitol-sorbitan solution, glycerin, deacetylated monoglyceride, tributyl citrate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, castor oil, dibutyl sebacate, diethyl phthalate and triacetin.

[0022] 14. Particles according to item 11 or 12, wherein the plasticizer is polyethylene glycol.

[0023] 15. The particles according to item 14, wherein the polyethylene glycol is selected from polyethylene glycols having an average molecular weight of 1000 g / mol to 20000 g / mol.

[0024] 16. The particles according to item 14, wherein the polyethylene glycol has an average molecular weight of 6000 g / mol.

[0025] 17. A particle according to any one of the preceding claims, wherein the enteric coating material comprised in the second coating layer is selected from polymers or copolymers comprising anionic side groups (preferably carboxylic acid side groups).

[0026] 18. The particle according to any one of the preceding claims, wherein the enteric coating material contained in the second coating layer is selected from the group consisting of anionic (meth)acrylate copolymers and anionic polyvinyl polymers or copolymers.

[0027] 19. The particle according to any one of the preceding claims, wherein the enteric coating material contained in the second coating layer is an anionic (meth)acrylate copolymer.

[0028] 20. The particle according to any one of the preceding claims, wherein the enteric coating material contained in the second coating layer is an anionic (meth)acrylate copolymer composed of methacrylic acid and methyl methacrylate or ethyl acrylate, or an anionic (meth)acrylate copolymer composed of ethyl acrylate and methyl methacrylate.

[0029] 21. Particles according to any one of items 1 to 20, wherein the enteric coating material contained in the second coating layer is an anionic (meth)acrylate copolymer (e.g., EUDRAGIT® L) composed of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate.

[0030] 22. Particles according to any one of items 1 to 20, wherein the enteric coating material contained in the second coating layer is a polymer combination comprising an anionic (meth)acrylate copolymer composed of methacrylic acid and ethyl methacrylate (e.g., EUDRAGIT® L) and an anionic (meth)acrylate copolymer composed of ethyl acrylate and methyl methacrylate (e.g., EUDRAGIT® NM), preferably in a ratio of 25:75.

[0031] 23. A particle according to any one of the preceding claims, wherein the enteric coating material contained in the second coating layer is an anionic polyvinyl polymer or copolymer.

[0032] 24. Particles according to item 23, wherein the anionic polyvinyl polymer or copolymer can contain structural units derived from an unsaturated carboxylic acid other than acrylic acid or methacrylic acid, such as polyvinyl acetate phthalate, a 9:1 copolymer of vinyl acetate and crotonic acid, or polyvinyl acetate succinate.

[0033] 25. The particle according to any one of the preceding claims, wherein the second coating layer further comprises a plasticizer.

[0034] 26. The particles according to item 25, wherein the plasticizer is selected from the group consisting of polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, sorbitol-sorbitan solution, glycerin, deacetylated monoglyceride, tributyl citrate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, castor oil, dibutyl sebacate, diethyl phthalate and triacetin.

[0035] 27. Particles according to item 25 or 26, wherein the plasticizer is triethyl citrate (TEC).

[0036] 28. The particle according to any one of the preceding claims, wherein the second coating layer further comprises an anti-adhesive agent.

[0037] 29. The particles according to item 28, wherein the anti-adhesive agent is talc or glyceryl monostearate.

[0038] 30. The particles according to item 28, wherein the anti-adhesive agent is talc.

[0039] 31. The particles according to item 28, wherein the anti-adhesive agent is glyceryl monostearate.

[0040] 32. The particle according to any one of the preceding claims, wherein the second coating layer further comprises an emulsifier.

[0041] 33. The particles according to item 32, wherein the emulsifier is a non-ionic emulsifier.

[0042] 34. The particles according to item 33, wherein the non-ionic emulsifier is a polysorbate.

[0043] 35. The particles according to item 34, wherein the polysorbate is selected from the group consisting of polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate and polyoxyethylene (20) sorbitan monooleate.

[0044] 36. The particles according to item 34, wherein the polysorbate is polyoxyethylene (20) sorbitan monooleate.

[0045] 37. The particle of item 1, comprising: a) a core comprising microcrystalline cellulose; b) a first coating layer substantially covering the core and comprising b-1) lactoferrin, b-2) hydroxypropyl methylcellulose, and b-3) polyethylene glycol; and c) a second coating layer substantially covering the first coating layer and comprising c-1) anionic (meth)acrylate copolymer, c-2) triethyl citrate (TEC), c-3) glyceryl monostearate, and c-4) polyoxyethylene (20) sorbitan monooleate.

[0046] 38. The particle according to item 1, comprising: a) a core consisting of microcrystalline cellulose; b) a first coating layer substantially covering the core and consisting of a-1) lactoferrin, a-2) hydroxypropylmethylcellulose, a-3) polyethylene glycol, preferably having an average molecular weight of 6000 g / mol, and optionally a-4) contaminants; and c) a second coating layer substantially covering the first coating layer and consisting of c-1) anionic (meth)acrylate copolymer, c-2) triethyl citrate (TEC), c-3) glyceryl monostearate, and c-4) polyoxyethylene (20) sorbitan monooleate.

[0047] 39. The particle of item 1, comprising: a) a core comprising microcrystalline cellulose; b) a first coating layer substantially covering the core and comprising b-1) lactoferrin, b-2) hydroxypropyl methylcellulose, and b-3) polyethylene glycol; and c) a second coating layer substantially covering the first coating layer and comprising c-1) an anionic (meth)acrylate copolymer, c-2) triethyl citrate (TEC), and c-3) talc.

[0048] 40. The particle according to item 1, comprising: a) a core consisting of microcrystalline cellulose; b) a first coating layer substantially covering the core and consisting of b-1) lactoferrin, b-2) hydroxypropylmethylcellulose, b-3) polyethylene glycol, preferably having an average molecular weight of 6000 g / mol, and optionally b-4) contaminants; and c) a second coating layer substantially covering the first coating layer and consisting of c-1) anionic (meth)acrylate copolymer, c-2) triethyl citrate (TEC), and c-3) talc.

[0049] 41. The particle according to any one of items 1 to 40, wherein the core comprises from about 10% to about 50% of the total weight of the particle.

[0050] 42. A particle according to any one of items 1 to 40, wherein the core comprises from about 20% to about 40% of the total weight of the particle.

[0051] 43. A particle according to any one of items 1 to 42, wherein the core comprises about 25% to about 35% of the total weight of the particle.

[0052] 44. A particle according to any one of the preceding claims, wherein the core comprises from about 29% to about 31% of the total weight of the particle.

[0053] 45. The particle according to any one of items 1 to 44, wherein the first coating layer comprises about 40% to about 60% of the total weight of the particle.

[0054] 46. ​​The particle according to any one of items 1 to 45, wherein the first coating layer comprises about 45% to about 55% of the total weight of the particle.

[0055] 47. The particle according to any one of items 1 to 46, wherein the first coating layer comprises about 48% to about 52% of the total weight of the particle.

[0056] 48. The particle according to any one of items 1 to 47, wherein the second coating layer comprises about 10% to about 30% of the total weight of the particle.

[0057] 49. The particle according to any one of items 1 to 48, wherein the second coating layer comprises about 15% to about 25% of the total weight of the particle.

[0058] 50. The particle according to any one of items 1 to 49, wherein the second coating layer comprises about 18% to about 22% of the total weight of the particle.

[0059] 51. A particle according to any one of items 1 to 50, wherein the first coating layer comprises lactoferrin in an amount of about 70% to about 90% of the total weight of the first coating layer.

[0060] 52. A particle according to any one of the preceding claims, wherein the first coating layer comprises lactoferrin in an amount of about 75% to about 85% of the total weight of the first coating layer.

[0061] 53. A particle according to any one of items 1 to 52, wherein the first coating layer comprises lactoferrin in an amount of about 76% to about 80% of the total weight of the first coating layer.

[0062] 54. The particle according to any one of items 1 to 53, wherein the first coating layer comprises a pharma- ceutically acceptable binder in an amount of about 7% to about 30% of the total weight of the first coating layer.

[0063] 55. The particle according to any one of the preceding claims, wherein the first coating layer comprises a pharma- ceutically acceptable binder in an amount of about 10% to about 25% of the total weight of the first coating layer.

[0064] 56. The particle according to any one of items 1 to 55, wherein the first coating layer comprises a pharma- ceutically acceptable binder in an amount of about 10% to about 20% of the total weight of the first coating layer.

[0065] 57. The particle according to any one of the preceding claims, wherein the first coating layer comprises a polymer binder in an amount of about 10% to about 15% of the total weight of the first coating layer.

[0066] 58. The particle according to any one of items 1 to 57, wherein the first coating layer comprises one or more other suitable excipients, such as a plasticizer, in an amount of about 0.1% to about 5% of the total weight of the first coating layer.

[0067] 59. The particle according to any one of the preceding claims, wherein the first coating layer comprises a plasticizer in an amount of about 1% to about 5% of the total weight of the first coating layer.

[0068] 60. The particle according to any one of the preceding claims, wherein the first coating layer comprises a plasticizer in an amount of about 2% to about 4% of the total weight of the first coating layer.

[0069] 61. The particle according to any one of items 1 to 60, wherein the second coating layer comprises an enteric coating material in an amount of about 50% to about 90% of the total weight of the second coating layer.

[0070] 62. The particle according to any one of the preceding claims, wherein the second coating layer comprises an enteric coating material in an amount of about 60% to about 90% of the total weight of the second coating layer.

[0071] 63. The particle according to any one of items 1 to 62, wherein the second coating layer comprises an enteric coating material in an amount of about 60% to about 70% of the total weight of the second coating layer.

[0072] 64. The particle according to any one of items 1 to 62, wherein the second coating layer comprises an enteric coating material in an amount of about 60% to about 65% of the total weight of the second coating layer.

[0073] 65. The particle according to any one of items 1 to 62, wherein the second coating layer comprises an enteric coating material in an amount of about 70% to about 90% of the total weight of the second coating layer.

[0074] 66. The particle according to any one of items 1 to 62, wherein the second coating layer comprises an enteric coating material in an amount of about 80% to about 90% of the total weight of the second coating layer.

[0075] 67. A particle according to any one of items 1 to 66, wherein the second coating layer comprises one or more other suitable excipients, such as a plasticizer, in a total amount of about 5% to about 20% of the total weight of the second coating layer.

[0076] 68. The particle according to any one of items 1 to 67, wherein the second coating layer comprises one or more other suitable excipients, such as a plasticizer, in a total amount of about 10% to about 20% of the total weight of the second coating layer.

[0077] 69. The particle according to any one of items 1 to 68, wherein the second coating layer comprises a plasticizer in an amount of about 5% to about 10% of the total weight of the second coating layer.

[0078] 70. The particle according to any one of the preceding claims, wherein the second coating layer comprises an anti-blocking agent in an amount of about 2% to about 35% of the total weight of the second coating layer.

[0079] 71. A particle according to any one of items 1 to 70, wherein the second coating layer comprises glyceryl monostearate as an anti-adhesive agent in an amount of about 3% to about 5% of the total weight of the second coating layer, for example, in an amount of about 4% to about 4.5% of the total weight of the second coating layer.

[0080] 72. The particle according to any one of the preceding claims, wherein the second coating layer comprises talc as an anti-adhesive agent in an amount of about 25% to about 35% of the total weight of the second coating layer, for example, in an amount of about 28% to about 32% of the total weight of the second coating layer.

[0081] 73. The particle according to any one of items 1 to 72, wherein the second coating layer comprises an emulsifier in an amount of about 1% to about 3% of the total weight of the second coating layer.

[0082] 74. A particle according to any one of items 1 to 73, wherein the lactoferrin is present in an amount of about 30% to about 50% of the total weight of the particle.

[0083] 75. A particle according to any one of items 1 to 74, wherein the lactoferrin is present in an amount of about 35% to about 45% of the total weight of the particle.

[0084] 76. A particle according to any one of items 1 to 75, wherein the lactoferrin is present in an amount of about 35% to about 40% of the total weight of the particle.

[0085] 77. A particle according to any one of items 1 to 76, wherein the pharma- ceutically acceptable binder in the first coating layer is present in an amount of about 5% to about 10% of the total weight of the particle.

[0086] 78. A particle according to any one of items 1 to 77, wherein the pharma- ceutically acceptable binder in the first coating layer is present in an amount of about 5% to about 8% of the total weight of the particle.

[0087] 79. The particle according to any one of items 1 to 77, wherein the pharma- ceutically acceptable binder in the first coating layer is present in an amount of about 6% to about 7% of the total weight of the particle.

[0088] 80. A particle according to any one of items 1 to 79, wherein the plasticizer, when included in the first coating layer, is present in an amount of about 1% to about 2% of the total weight of the particle.

[0089] 81. A particle according to any one of items 1 to 80, wherein the plasticizer, when included in the first coating layer, is present in an amount of about 1% to about 1.5% of the total weight of the particle.

[0090] 82. The particle according to any one of items 1 to 81, wherein the enteric coating material in the second coating layer is present in an amount of about 15% to about 20% of the total weight of the particle.

[0091] 83. The particle according to any one of items 1 to 82, wherein the enteric coating material in the second coating layer is present in an amount of about 16% to about 18% of the total weight of the particle.

[0092] 84. A particle according to any one of the preceding claims, wherein the plasticizer, when included in the second coating layer, is present in an amount of about 1% to about 2% of the total weight of the particle.

[0093] 85. The particle according to any one of the preceding claims, wherein the anti-adhesive agent, when included in the second coating layer, is present in an amount of about 0.5% to about 10% of the total weight of the particle.

[0094] 86. A particle according to any one of items 1 to 85, wherein when glyceryl monostearate is included in the second coating layer as an anti-adhesive agent, it is present in an amount of about 0.5% to about 1% of the total weight of the particle.

[0095] 87. A particle according to any one of items 1 to 86, wherein the emulsifier, when included in the second coating layer, is present in an amount of about 0.1% to about 1% of the total weight of the particle.

[0096] 88. A particle according to any one of the preceding claims, wherein the emulsifier, when included in the second coating layer, is present in an amount of about 0.1% to about 0.5% of the total weight of the particle.

[0097] 89. The particle according to any one of items 1 to 88, which is in the form of a pellet, spheroid or bead.

[0098] 90. Particles according to any one of items 1 to 88, which are in the form of pellets.

[0099] 91. Particles according to any one of the preceding claims, wherein the particles have an average particle size d50 of about 450 μm to about 650 μm.

[0100] 92. The particle according to any one of items 1 to 91, wherein the particle has a bulk density of about 0.7 g / ml to about 0.8 g / ml, for example, about 0.740 g / mL.

[0101] 93. The particle according to any one of the preceding claims, wherein the particle has a tap density of about 0.75 g / ml to about 0.85 g / ml, for example, about 0.802 g / mL.

[0102] 94. The particle according to any one of the preceding claims, wherein the particle is substantially spherical.

[0103] 95. Particles according to any one of items 1 to 94, in which a maximum of 10% of lactoferrin is released from the particles within 120 minutes, as measured by an in vitro dissolution test according to European Pharmacopoeia 2.9.3.

[0104] 96. A pharmaceutical composition comprising one or more particles according to any one of items 1 to 95, and optionally one or more pharma- ceutically acceptable excipients.

[0105] 97. An oral dosage form comprising one or more particles according to any one of items 1 to 95.

[0106] 98. The oral dosage form according to item 97, which is a solid dosage form such as a capsule or tablet.

[0107] 99. The oral dosage form according to item 97 or 98, which is a capsule.

[0108] 100. The oral dosage form according to any one of items 97 to 99, which is a hard capsule.

[0109] 101. The oral dosage form according to any one of items 97 to 100, comprising 200 mg or more of lactoferrin.

[0110] 102. The oral dosage form of any one of items 97 to 101, comprising about 400 mg to about 600 mg of the particles.

[0111] 103. The oral dosage form according to any one of items 97 to 102, comprising at least 500 mg of said particles.

[0112] 104. A particle according to any one of items 1 to 95, a pharmaceutical composition according to item 96, or an oral dosage form according to any one of items 97 to 103 for use as a medicament.

[0113] 105. A particle according to any one of items 1 to 95, a pharmaceutical composition according to item 96, or an oral dosage form according to any one of items 97 to 103 for use in the prevention and / or treatment of an intestinal disease.

[0114] 106. A particle according to any one of items 1 to 95, a pharmaceutical composition according to item 96, or an oral dosage form according to any one of items 97 to 103 for use in the prevention and / or treatment of traveler's diarrhea.

[0115] 107. A particle according to any one of items 1 to 95, a pharmaceutical composition according to item 96, or an oral dosage form according to any one of items 97 to 103 for use in modulating a healthy balance of the human gut microbiota.

[0116] 108. The particle according to any one of items 1 to 95, the pharmaceutical composition according to item 96, or the oral dosage form according to any one of items 97 to 103, for use in inhibiting the growth of human intestinal microorganisms.

[0117] 109. A food or food supplement comprising one or more particles according to any one of items 1 to 95.

[0118] 110. A food or food supplement according to item 109 for balancing the ratio between pathogens and beneficial microorganisms in the human intestine.

[0119] 111. A method for producing a particle according to any one of items 1 to 95, comprising the steps of applying a first coating layer in the form of an aqueous coating solution, coating aqueous suspension or coating aqueous dispersion to the cores by spraying or fluidized bed spray granulation, and applying a second coating layer in the form of an aqueous coating solution, coating aqueous suspension or coating aqueous dispersion to the first coating layer by spraying or fluidized bed spray granulation.

[0120] 112. The process according to item 111, comprising the step of forming the cores by direct compression, wet or dry granulation, or direct pelletization of the core-forming material.

[0121] 113. A method for producing an oral dosage form according to any one of items 97 to 103, comprising filling a capsule with one or more particles according to any one of claims 1 to 93. [Brief description of the drawings]

[0122] [Figure 1] FIG. 1 shows the dissolution profile (USP II) of the final product. [Diagram 2] FIG. 2 shows particle size distribution of the final product.

[0123] The present invention will now be described in further detail.

[0124] Detailed Description of the Invention As mentioned above, the present invention is based on the finding that by formulating lactoferrin as multi-layered enteric coated particles, it is possible to obtain a high dose of very pure lactoferrin in one administration.For example, the particles of the present invention can provide a product that contains 200mg or more lactoferrin in one administration.In addition, the particles of the present invention provide improved resistance to the conditions found in the digestive tract, thus increasing the overall stability of lactoferrin after oral administration.

[0125] Thus, the present invention provides enteric coated particles comprising (or essentially consisting of): a) a core comprising (or consisting essentially of) a cellulose polymer, a sugar, a sugar alcohol, starch and carnauba wax; b) a first coating layer substantially covering the core and comprising (or consisting essentially of) b-1) lactoferrin, b-2) a pharma- ceutically acceptable binder, and optionally b-3) one or more other suitable excipients, such as a plasticizer; and c) a second coating layer substantially covering the first coating layer and comprising (or consisting essentially of) c-1) an enteric coating material, and optionally c-2) one or more suitable excipients, such as a plasticizer and / or an anti-adherent.

[0126] According to some embodiments, the inert core-forming material is a cellulose polymer, such as a cellulose polymer selected from the group consisting of microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and carboxymethyl cellulose. According to some embodiments, the cellulose polymer is microcrystalline cellulose.

[0127] According to some embodiments, the inert core-forming material is a sugar or sugar alcohol.

[0128] According to some embodiments, the inert core-forming material is a sugar, for example a sugar selected from the group consisting of glucose, sucrose and lactose.

[0129] According to some embodiments, the inert core-forming material is a sugar alcohol, for example a sugar alcohol selected from the group consisting of isomalt, maltitol, mannitol, xylitol and sorbitol.

[0130] According to some embodiments, the inert core-forming material is starch.

[0131] According to some embodiments, the inert core-forming material is carnauba wax.

[0132] Inert cores can be commercially available. Non-limiting examples of commercially available beads or pellets used as cores of the particles disclosed herein include sugar spheres (e.g., Paular spheres), Cellets® cores, such as Cellets® 100, Cellets® 200, Cellets® 350, Cellets® 500, Cellets® 700, or Cellets® 1000 (HARKE Group, Mülheim an der Ruhr, Germany), carnauba wax cores, such as C-Wax Pellets®, or mannitol cores, such as M-Cell®. Alternatively, the cores can be freshly prepared using a variety of well-known granulation methods, including high shear wet granulation, spray drying, fluidized bed granulation (including rotary fluidized bed granulation), or direct compression or direct pelletization of the core-forming materials.

[0133] According to some embodiments, the core comprises about 10% to about 50% of the total weight of the particle. According to some embodiments, the core comprises about 20% to about 40% of the total weight of the particle. According to some embodiments, the core comprises about 25% to about 35% of the total weight of the particle. According to some embodiments, the core comprises about 29% to about 31% of the total weight of the particle.

[0134] The first coating layer, which substantially covers the core, generally comprises lactoferrin (as the active ingredient), a pharma- ceutically acceptable binder, and, optionally, one or more other suitable excipients.

[0135] According to some embodiments, the first coating layer comprises about 40% to about 60% of the total weight of the particle. According to some embodiments, the first coating layer comprises about 45% to about 55% of the total weight of the particle. According to some embodiments, the first coating layer comprises about 48% to about 52% of the total weight of the particle. According to some embodiments, the second coating layer comprises about 10% to about 30% of the total weight of the particle. According to some embodiments, the second coating layer comprises about 15% to about 25% of the total weight of the particle. According to some embodiments, the second coating layer comprises about 18% to about 22% of the total weight of the particle.

[0136] Lactoferrin (LF), also known as lactotransferrin (LTF), is used as an active ingredient in the context of the present invention. As mentioned above, it is an 80 kDa non-heme iron-binding globular glycoprotein belonging to the transferrin family and is found in various secretions such as milk, saliva, tears, and nasal secretions. It is the major iron-binding protein in milk and has antibacterial, immunomodulatory, antioxidant, anticancer, and many other biological functions. It is found in the highest concentration in human first milk ("colostrum"), followed by human milk and then cow's milk (150 mg / L). At least 60 lactoferrin gene sequences have been identified in 11 mammalian species. Lactoferrin is commercially available. Alternatively, it can be purified from milk (especially cow's milk) or produced by recombinant technology. Lactoferrin can be used in pure form or as a preparation (e.g., extract) containing at least 90% by weight (such as at least 93% by weight) of lactoferrin. Depending on the preparation method, the resulting lactoferrin-containing preparation may contain some residual contaminants, which may ultimately be present in the first coating layer, but do not significantly affect the basic and novel characteristics of the particles of the present invention.

[0137] According to some embodiments, the first coating layer comprises lactoferrin in an amount of about 70% to about 90% of the total weight of the first coating layer. According to some embodiments, the first coating layer comprises lactoferrin in an amount of about 75% to about 85% of the total weight of the first coating layer. According to some embodiments, the first coating layer comprises lactoferrin in an amount of about 75% to about 82% of the total weight of the first coating layer. According to some embodiments, the first coating layer comprises lactoferrin in an amount of about 76% to about 80% of the total weight of the first coating layer, for example, about 78% of the total weight of the first coating layer.

[0138] According to some embodiments, lactoferrin is present in an amount of about 30% to about 50% of the total weight of the particle. According to some embodiments, lactoferrin is present in an amount of about 35% to about 45% of the total weight of the particle. According to some embodiments, lactoferrin is present in an amount of about 35% to about 40% of the total weight of the particle.

[0139] Pharmaceutically acceptable binders may be, for example, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, povidone, for example, polyvinylpyrrolidone (PVP), copovidone, agar, gelatin, gum arabic, alginates, for example, sodium alginate and polyethylene glycol alginate, polyethylene glycol, polyvinyl alcohol, sugars, sugar alcohols, starch or modified starch, for example, potato starch, corn starch, or rice starch, or pregelatinized starch.

[0140] According to some embodiments, the pharma- ceutically acceptable binder included in the first coating layer is selected from the group consisting of cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, povidone such as polyvinylpyrrolidone (PVP), copovidone, agar, gelatin, gum arabic, alginates such as sodium alginate and polyethylene glycol alginate, polyethylene glycol, polyvinyl alcohol, sugars, sugar alcohols, starches and modified starches such as potato starch, corn starch, rice starch and pregelatinized starch.

[0141] According to some embodiments, the pharma- ceutically acceptable binder in the first coating layer is hydroxypropyl methylcellulose.

[0142] According to some embodiments, the first coating layer comprises a pharma- ceutically acceptable binder in an amount of about 7% to about 30% of the total weight of the first coating layer. According to some embodiments, the first coating layer comprises a pharma- ceutically acceptable binder in an amount of about 10% to about 25% of the total weight of the first coating layer. According to some embodiments, the first coating layer comprises a pharma- ceutically acceptable binder in an amount of about 10% to about 20% of the total weight of the first coating layer. According to some embodiments, the first coating layer comprises a pharma- ceutically acceptable binder in an amount of about 10% to about 15% of the total weight of the first coating layer.

[0143] According to some embodiments, the pharma- ceutically acceptable binder in the first coating layer is present in an amount of about 5% to about 10% of the total weight of the particle. According to some embodiments, the pharma- ceutically acceptable binder in the first coating layer is present in an amount of about 5% to about 8% of the total weight of the particle. According to some embodiments, the pharma- ceutically acceptable binder in the first coating layer is present in an amount of about 6% to about 7% of the total weight of the particle.

[0144] According to some embodiments, the first coating layer includes one or more other suitable excipients, such as a plasticizer.

[0145] According to some embodiments, the first coating layer includes a plasticizer.

[0146] The plasticizer may be, for example, polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, sorbitol-sorbitan solution, glycerin, deacetylated monoglyceride, tributyl citrate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, castor oil, dibutyl sebacate, diethyl phthalate, or triacetin.

[0147] According to some embodiments, the first coating layer comprises a plasticizer selected from the group consisting of polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, sorbitol-sorbitan solution, glycerin, deacetylated monoglycerides, tributyl citrate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, castor oil, dibutyl sebacate, diethyl phthalate, and triacetin.

[0148] According to some embodiments, the plasticizer is a polyethylene glycol, for example a polyethylene glycol selected from polyethylene glycols having an average molecular weight between 1000 g / mol and 20000 g / mol.

[0149] According to some embodiments, the plasticizer is a polyethylene glycol having an average molecular weight between 1000 g / mol and 10000 g / mol.

[0150] According to some embodiments, the plasticizer is a polyethylene glycol having an average molecular weight of 4000 g / mol to 8000 g / mol.

[0151] According to some embodiments, the plasticizer is a polyethylene glycol having an average molecular weight of 6000 g / mol.

[0152] According to some embodiments, the first coating layer includes one or more other suitable excipients, such as a plasticizer, in an amount of about 0.1% to about 5% of the total weight of the first coating layer. According to some embodiments, the first coating layer includes a plasticizer in an amount of about 1% to about 5% of the total weight of the first coating layer. According to some embodiments, the first coating layer includes a plasticizer in an amount of about 2% to about 4% of the total weight of the first coating layer.

[0153] According to some embodiments, the plasticizer, when included in the first coating layer, is present in an amount of about 1% to about 2% of the total weight of the particle. According to some embodiments, the plasticizer, when included in the first coating layer, is present in an amount of about 1% to about 1.5% of the total weight of the particle.

[0154] The second coating layer, which substantially covers the first coating layer, generally functions as an enteric coating, which means that the second coating layer prevents the particles from dissolving or disintegrating in the stomach environment, thereby protecting the lactoferrin from the acidity of the stomach.To this end, the second coating layer comprises an enteric coating material.

[0155] Suitable enteric coating materials are well known to those skilled in the art and include, but are not limited to, polymers or copolymers containing anionic side groups (preferably carboxylic acid side groups), such as methyl methacrylate-methacrylic acid copolymer. Other non-limiting examples of enteric coating materials are cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), shellac, cellulose acetate trimellitate, sodium alginate or zein.

[0156] According to some embodiments, the enteric coating material included in the second coating layer is selected from polymers or copolymers that contain anionic side groups, preferably carboxylic acid side groups.

[0157] According to some embodiments, the enteric coating material included in the second coating layer is selected from the group consisting of anionic (meth)acrylate copolymers and anionic polyvinyl polymers or copolymers.

[0158] According to some embodiments, the enteric coating material included in the second coating layer is an anionic (meth)acrylate copolymer.

[0159] Non-limiting examples of anionic (meth)acrylate copolymers can include ammonio methacrylate copolymer, basic butylated methacrylate copolymer, methacrylic acid-methyl methacrylate copolymer (1:1), methacrylic acid-ethyl acrylate copolymer (1:1), methacrylic acid-ethyl acrylate copolymer (1:1), methacrylic acid-methyl methacrylate copolymer (1:2), polyacrylate dispersion 30%, methacrylic acid copolymer, amino methacrylate copolymer, ammonio methacrylate copolymer, ammonio methacrylate copolymer dispersion, ethyl acrylate and methyl methacrylate copolymer, and combinations thereof. Some anionic (meth)acrylate copolymers are Eudragit® E 12.5, Eudragit® E 100, Eudragit® E PO, Eudragit® L 12.5 P, Eudragit® L 12.5, Eudragit® L 100, Eudragit® L 100-55, Eudragit® L 30 D-55, Eudragit® S 12.5 P, Eudragit® S 12.5, Eudragit® S 100, Eudragit® FS 30 D, Eudragit® RL 12.5, Eudragit® RL 100, Eudragit® RL PO, Eudragit® RL 30 D, Eudragit® RS 12.5, Eudragit® RS 100, Eudragit® RS PO, Eudragit® RS 30 D, Eudragit® NE 30 D, Eudragit® NE 40 D, Eudragit® NM 30 D, Eastacryl™ 30 D, Kollicoat® MAE 30 DP, Kollicoat® MAE 100 P, Acryl-EZE®, Acryl-EZE® 93 A, and Acryl-EZE® MP.

[0160] According to some embodiments, the enteric coating material included in the second coating layer is an anionic (meth)acrylate copolymer composed of methacrylic acid and methyl methacrylate or ethyl acrylate.

[0161] According to some embodiments, the enteric coating material included in the second coating layer is an anionic (meth)acrylate copolymer composed of methacrylic acid and methyl methacrylate.

[0162] According to some embodiments, the enteric coating material included in the second coating layer is an anionic (meth)acrylate copolymer composed of methacrylic acid and ethyl acrylate.

[0163] An example of a (meth)acrylate monomer having an anionic group is acrylic acid, preferably methacrylic acid. Suitable anionic (meth)acrylate copolymers are those composed of 40-60% by weight of methacrylic acid and 60-40% by weight of methyl methacrylate or 60-40% by weight of ethyl acrylate (for example EUDRAGIT® L or EUDRAGIT® L 100-55 type). EUDRAGIT® L is a copolymer of 50% by weight of methyl methacrylate and 50% by weight of methacrylic acid. EUDRAGIT® L 100-55 is a copolymer of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid. EUDRAGIT® L 30 D-55 is a dispersion containing 30% by weight of EUDRAGIT® L 100-55. Likewise suitable are anionic (meth)acrylate copolymers (EUDRAGIT® S type) consisting of 20-40% by weight of methacrylic acid and 80-60% by weight of methyl methacrylate. Suitable (meth)acrylate copolymers are those consisting of 10-30% by weight of methyl methacrylate, 50-70% by weight of methyl acrylate and 5-15% by weight of methacrylic acid (for example EUDRAGIT® FS type). EUDRAGIT® FS is a copolymer of 25% by weight of methyl methacrylate, 65% by weight of methyl acrylate and 10% by weight of methacrylic acid. EUDRAGIT® FS 30 D is a dispersion containing 30% by weight of EUDRAGIT® FS.

[0164] According to some embodiments, the enteric coating material included in the second coating layer is an anionic (meth)acrylate copolymer composed of 40-60% by weight methacrylic acid and 60-40% by weight methyl methacrylate or 60-40% by weight ethyl acrylate.

[0165] According to some embodiments, the enteric coating material included in the second coating layer is an anionic (meth)acrylate copolymer composed of 50% by weight methacrylic acid and 50% by weight methyl methacrylate.

[0166] According to some embodiments, the enteric coating material included in the second coating layer is an anionic (meth)acrylate copolymer composed of ethyl acrylate and methyl methacrylate.

[0167] According to some embodiments, the enteric coating material included in the second coating layer is an anionic (meth)acrylate copolymer composed of 40-60% by weight ethyl acrylate and 60-40% by weight methyl methacrylate (e.g., EUDRAGIT® NM).

[0168] According to some embodiments, the enteric coating material included in the second coating layer is a polymer combination comprising an anionic (meth)acrylate copolymer composed of methacrylic acid and ethyl methacrylate (e.g., EUDRAGIT® L) and an anionic (meth)acrylate copolymer composed of ethyl acrylate and methyl methacrylate (e.g., EUDRAGIT® NM), preferably in a ratio of 25:75.

[0169] According to some embodiments, the enteric coating material included in the second coating layer is a polymer combination comprising an anionic (meth)acrylate copolymer composed of 40-60% by weight methacrylic acid and 60-40% by weight ethyl methacrylate (e.g., EUDRAGIT® L) and an anionic (meth)acrylate copolymer composed of 40-60% by weight ethyl acrylate and 60-40% by weight methyl methacrylate (e.g., EUDRAGIT® NM), preferably in a ratio of 25:75.

[0170] According to some embodiments, the enteric coating material contained in the second coating layer is an anionic polyvinyl polymer or copolymer. Such an anionic polyvinyl polymer or copolymer can include structural units derived from an unsaturated carboxylic acid other than acrylic acid or methacrylic acid, such as polyvinyl acetate phthalate, a 9:1 copolymer of vinyl acetate and crotonic acid, or polyvinyl acetate succinate.

[0171] According to some embodiments, the second coating layer comprises the enteric coating material in an amount of about 50% to about 90% of the total weight of the second coating layer. According to some embodiments, the second coating layer comprises the enteric coating material in an amount of about 60% to about 90% of the total weight of the second coating layer. According to some embodiments, the second coating layer comprises the enteric coating material in an amount of about 60% to about 70% of the total weight of the second coating layer. According to some embodiments, the second coating layer comprises the enteric coating material in an amount of about 60% to about 65% of the total weight of the second coating layer. According to some embodiments, the second coating layer comprises the enteric coating material in an amount of about 70% to about 90% of the total weight of the second coating layer. According to some embodiments, the second coating layer comprises the enteric coating material in an amount of about 80% to about 90% of the total weight of the second coating layer.

[0172] According to some embodiments, the enteric coating material in the second coating layer is present in an amount of about 15% to about 20% of the total weight of the particle. According to some embodiments, the enteric coating material in the second coating layer is present in an amount of about 16% to about 18% of the total weight of the particle.

[0173] The second coating layer may further include one or more suitable excipients, such as a plasticizer and / or an anti-adherent agent.

[0174] According to some embodiments, the second coating layer further comprises a plasticizer, for example, the plasticizer is selected from the group consisting of polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, sorbitol-sorbitan solution, glycerin, deacetylated monoglyceride, tributyl citrate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, castor oil, dibutyl sebacate, diethyl phthalate, and triacetin.

[0175] According to some embodiments, the plasticizer included in the second coating layer is triethyl citrate (TEC).

[0176] According to some embodiments, the plasticizer included in the second coating layer is a polyethylene glycol, for example a polyethylene glycol selected from polyethylene glycols having an average molecular weight between 200 g / mol and 15000 g / mol.

[0177] According to some embodiments, the plasticizer included in the second coating layer is a polyethylene glycol having an average molecular weight of 200 g / mol to 6000 g / mol.

[0178] According to some embodiments, the plasticizer included in the second coating layer is a polyethylene glycol having an average molecular weight of 200 g / mol to 800 g / mol.

[0179] According to some embodiments, the plasticizer included in the second coating layer is polyethylene glycol having an average molecular weight of 400 g / mol.

[0180] According to some embodiments, the second coating layer includes one or more other suitable excipients, such as a plasticizer, in a total amount of about 5% to about 20% of the total weight of the second coating layer. According to some embodiments, the second coating layer includes one or more other suitable excipients, such as a plasticizer, in a total amount of about 10% to about 20% of the total weight of the second coating layer.

[0181] According to some embodiments, the second coating layer includes a plasticizer in an amount of about 5% to about 10% of the total weight of the second coating layer.

[0182] According to some embodiments, the plasticizer, when included in the second coating layer, is present in an amount of about 1% to about 2% of the total weight of the particle.

[0183] According to some embodiments, the second coating layer further comprises an anti-adherent agent, such as talc or glyceryl monostearate.

[0184] According to some embodiments, the anti-adhesive agent is talc.

[0185] According to some embodiments, the anti-adhesive agent is glyceryl monostearate.

[0186] According to some embodiments, the second coating layer comprises an anti-blocking agent in an amount of about 2% to about 35% of the total weight of the second coating layer.

[0187] According to some embodiments, the anti-adhesive agent, when included in the second coating layer, is present in an amount of about 0.5% to about 10% of the total weight of the particle.

[0188] According to some embodiments, the second coating layer comprises glyceryl monostearate as an anti-tack agent in an amount of about 3% to about 5% of the total weight of the second coating layer, e.g., in an amount of about 4% to about 4.5% of the total weight of the second coating layer.

[0189] According to some embodiments, glyceryl monostearate, when included in the second coating layer as an anti-adhesive agent, is present in an amount of about 0.5% to about 1% of the total weight of the particle.

[0190] According to some embodiments, the second coating layer comprises talc as an anti-blocking agent in an amount of about 25% to about 35% of the total weight of the second coating layer, for example, in an amount of about 28% to about 32% of the total weight of the second coating layer.

[0191] According to some embodiments, when talc is included in the second coating layer as an anti-blocking agent, it is present in an amount of about 8% to about 12% of the total weight of the particle.

[0192] According to some embodiments, the second coating layer further comprises an emulsifier.

[0193] According to some embodiments, the emulsifier is a non-ionic emulsifier, such as a polysorbate.

[0194] According to some embodiments, the non-ionic emulsifier is a polysorbate selected from the group consisting of polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, and polyoxyethylene (20) sorbitan monooleate. According to some embodiments, the non-ionic emulsifier is polyoxyethylene (20) sorbitan monooleate.

[0195] According to some embodiments, the second coating layer comprises an emulsifier in an amount of about 1% to about 3% of the total weight of the second coating layer. According to some embodiments, the second coating layer comprises an emulsifier in an amount of about 1% to about 2% of the total weight of the second coating layer.

[0196] According to some embodiments, the emulsifier, when included in the second coating layer, is present in an amount of about 0.1% to about 1% of the total weight of the particle. According to some embodiments, the emulsifier, when included in the second coating layer, is present in an amount of about 0.1% to about 0.5% of the total weight of the particle.

[0197] Depending on the materials and methods used in the preparation of the particle, the particle of the present invention or any of its layers may contain impurities and / or water, for example in the form of moisture, but these do not significantly affect the basic and novel characteristics of the particle of the present invention. In general, impurities, if present, do not exceed about 5% of the total weight of the particle, and preferably do not exceed about 3% of the total weight of the particle. Specifically, impurities, if present, do not exceed about 10% of the total weight of the first coating layer, and preferably do not exceed about 8.5% of the total weight of the particle. Similarly, water, for example in the form of moisture, if present, does not exceed about 7% of the total weight of the particle, and preferably does not exceed about 5% of the total weight of the particle. Specifically, water, for example in the form of moisture, if present, does not exceed about 7% of the total weight of the first coating layer and / or the second coating layer, and preferably does not exceed about 5% of the total weight of the first coating layer and / or the second coating layer.

[0198] According to certain embodiments, the particles comprise: a) a core comprising microcrystalline cellulose; b) a first coating layer substantially covering the core and comprising b-1) lactoferrin, b-2) hydroxypropyl methylcellulose, and b-3) polyethylene glycol; and c) a second coating layer substantially covering the first coating layer and comprising c-1) anionic (meth)acrylate copolymer, c-2) triethyl citrate (TEC), c-3) glyceryl monostearate, and c-4) polyoxyethylene (20) sorbitan monooleate.

[0199] According to certain embodiments, the particles comprise (or consist essentially of): a) a core consisting essentially of microcrystalline cellulose; b) a first coating layer substantially covering the core and consisting essentially of b-1) lactoferrin, b-2) hydroxypropyl methylcellulose, and b-3) polyethylene glycol; and c) a second coating layer substantially covering the first coating layer and consisting essentially of c-1) anionic (meth)acrylate copolymer, c-2) triethyl citrate (TEC), c-3) glyceryl monostearate, and c-4) polyoxyethylene (20) sorbitan monooleate.

[0200] According to certain embodiments, the particles comprise: a) a core comprising microcrystalline cellulose; b) a first coating layer substantially covering the core and comprising b-1) lactoferrin, b-2) hydroxypropyl methylcellulose, and b-3) polyethylene glycol; and c) a second coating layer substantially covering the first coating layer and comprising c-1) an anionic (meth)acrylate copolymer, c-2) triethyl citrate (TEC), and c-3) talc.

[0201] According to certain embodiments, the particles comprise (or consist essentially of): a) a core consisting essentially of microcrystalline cellulose; b) a first coating layer substantially covering the core and consisting essentially of b-1) lactoferrin, b-2) hydroxypropyl methylcellulose, and b-3) polyethylene glycol; and c) a second coating layer substantially covering the first coating layer and consisting essentially of c-1) anionic (meth)acrylate copolymer, c-2) triethyl citrate (TEC), and c-3) talc.

[0202] According to certain embodiments, the particles comprise: a) a core comprising microcrystalline cellulose, said core comprising about 25% to about 35% of the total weight of the particle; b) a core substantially encasing: b-1) lactoferrin in an amount of about 30% to about 50% of the total weight of the particle, e.g., in an amount of about 35% to about 45% of the total weight of the particle; b-2) hydroxypropyl methylcellulose in an amount of about 5% to about 10% of the total weight of the particle, e.g., in an amount of about 5% to about 8% of the total weight of the particle; and b-3) polyethylene glycol (e.g., polyethylene glycol having an average molecular weight of 6000 g / mol) in an amount of about 1% to about 2% of the total weight of the particle, e.g., in an amount of about 1% to about 1.5% of the total weight of the particle. and c) a second coating layer substantially covering the first coating layer and comprising (or consisting essentially of) c-1) an anionic (meth)acrylate copolymer in an amount of about 15% to about 20% of the total weight of the particle, e.g., about 16% to about 18% of the total weight of the particle, c-2) triethyl citrate (TEC) in an amount of about 1% to about 2% of the total weight of the particle, c-3) glyceryl monostearate in an amount of about 0.5% to about 1% of the total weight of the particle, and c-4) polyoxyethylene (20) sorbitan monooleate in an amount of about 0.1% to about 1% of the total weight of the particle, wherein the sum of all components is 100% of the total weight of the particle.

[0203] According to certain embodiments, the particles comprise: a) a core consisting essentially of microcrystalline cellulose, said core comprising about 25% to about 35% of the total weight of the particle; b) a core substantially encasing: b-1) lactoferrin in an amount of about 30% to about 50% of the total weight of the particle, e.g., in an amount of about 35% to about 45% of the total weight of the particle; b-2) hydroxypropyl methylcellulose in an amount of about 5% to about 10% of the total weight of the particle, e.g., in an amount of about 5% to about 8% of the total weight of the particle; and b-3) polyethylene glycol (e.g., polyethylene glycol having an average molecular weight of 6000 g / mol) in an amount of about 1% to about 2% of the total weight of the particle, e.g., in an amount of about 1% to about 1.5% of the total weight of the particle. and c) a second coating layer substantially covering the first coating layer and comprising (or consisting essentially of) c-1) an anionic (meth)acrylate copolymer in an amount of about 15% to about 20% of the total weight of the particle, e.g., in an amount of about 16% to about 18% of the total weight of the particle, c-2) triethyl citrate (TEC) in an amount of about 1% to about 2% of the total weight of the particle, c-3) glyceryl monostearate in an amount of about 0.5% to about 1% of the total weight of the particle, and c-4) polyoxyethylene (20) sorbitan monooleate in an amount of about 0.1% to about 1% of the total weight of the particle, wherein the sum of all components is 100% of the total weight of the particle.

[0204] According to certain embodiments, the particles comprise: a) a core comprising microcrystalline cellulose, said core comprising about 25% to about 35% of the total weight of the particle; b) a core substantially encasing: b-1) lactoferrin in an amount of about 30% to about 50% of the total weight of the particle, e.g., in an amount of about 35% to about 45% of the total weight of the particle; b-2) hydroxypropyl methylcellulose in an amount of about 5% to about 10% of the total weight of the particle, e.g., in an amount of about 5% to about 8% of the total weight of the particle; and b-3) polyethylene glycol (e.g., PEG-1000) in an amount of about 1% to about 2% of the total weight of the particle, e.g., in an amount of about 1% to about 1.5% of the total weight of the particle. and c) a second coating layer substantially covering the first coating layer and comprising (or consisting essentially of) c-1) an anionic (meth)acrylate copolymer in an amount of about 15% to about 20% of the total weight of the particle, e.g., about 16% to about 18% of the total weight of the particle, c-2) triethyl citrate (TEC) in an amount of about 1% to about 2% of the total weight of the particle, and c-3) talc in an amount of about 3% to about 12% of the total weight of the particle, wherein the sum of all components is 100% of the total weight of the particle.

[0205] According to certain embodiments, the particles comprise: a) a core consisting essentially of microcrystalline cellulose, said core comprising about 25% to about 35% of the total weight of the particle; b) a core substantially encasing: b-1) lactoferrin in an amount of about 30% to about 50% of the total weight of the particle, e.g., in an amount of about 35% to about 45% of the total weight of the particle; b-2) hydroxypropyl methylcellulose in an amount of about 5% to about 10% of the total weight of the particle, e.g., in an amount of about 5% to about 8% of the total weight of the particle; and b-3) polyethylene glycol (e.g., 6-hydroxypropyl methylcellulose) in an amount of about 1% to about 2% of the total weight of the particle, e.g., in an amount of about 1% to about 1.5% of the total weight of the particle. c) a first coating layer consisting essentially of a polyethylene glycol having an average molecular weight of 10,000 g / mol); and c) a second coating layer substantially covering the first coating layer and consisting essentially of c-1) an anionic (meth)acrylate copolymer in an amount of about 15% to about 20% of the total weight of the particle, e.g., in an amount of about 16% to about 18% of the total weight of the particle, c-2) triethyl citrate (TEC) in an amount of about 1% to about 2% of the total weight of the particle, and c-3) talc in an amount of about 3% to about 12% of the total weight of the particle, wherein the sum of all components is 100% of the total weight of the particle.

[0206] The particles of the present invention can have any suitable form. For example, the particles of the present invention can be in the form of pellets, spheroids or beads. According to some embodiments, the particles are in the form of pellets.

[0207] The particles of the invention can have one or more (e.g., all) of the following characteristics: a) average particle size d50 of about 450 μm to about 650 μm; b) a bulk density of about 0.7 g / ml to about 0.8 g / ml, for example, about 0.740 g / mL; c) a tap density of about 0.75 g / ml to about 0.85 g / ml, for example, about 0.802 g / mL; and d) A dissolution profile such that a maximum of 10% lactoferrin is released from the particles within 120 minutes as measured by an in vitro dissolution test according to European Pharmacopoeia 2.9.3.

[0208] The average particle size d50 can be determined in accordance with the European Pharmacopoeia 10.0, 2.9.31. PARTICLE SIZE ANALYSIS BY LASER LIGHT DIFFRACTION.

[0209] Bulk density can be determined in accordance with European Pharmacopoeia 10.0, 2.9.34. BULK DENSITY AND TAPPED DENSITY OF POWDERS.

[0210] Tapped density can be determined in accordance with European Pharmacopoeia 10.0, 2.9.34. BULK DENSITY AND TAPPED DENSITY OF POWDERS.

[0211] In a related aspect, the invention provides a pharmaceutical composition comprising one or more (eg, a plurality) of particles according to the invention, and optionally one or more pharma- ceutically acceptable excipients.

[0212] Suitable pharma- ceutically acceptable excipients are well known to those skilled in the art and are described in such publications as Remington's Pharmaceutical Sciences, the Handbook of Pharmaceutical Additives, or the Handbook of Pharmaceutical Excipients. Non-limiting examples of suitable pharma-ceutically acceptable excipients include diluents, fillers, binders, disintegrants, lubricants, flow agents, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifying agents, sweeteners, flavoring agents, odor masking agents, colorants, anti-caking agents, chelating agents, plasticizers, thickeners, antioxidants, preservatives, stabilizers, surfactants, and buffers.

[0213] In a related further aspect, the invention provides an oral dosage form comprising one or more (eg, a plurality) of particles according to the invention.

[0214] The oral dosage form may be a solid dosage form, such as a capsule or a tablet. According to some embodiments, the oral dosage form is a capsule, such as a hard capsule.

[0215] The pharmaceutical composition according to the invention or the oral dosage form according to the invention can be used as a medicine, for example for the prevention and / or treatment of intestinal diseases, such as traveller's diarrhea.

[0216] The pharmaceutical composition according to the invention or the oral dosage form according to the invention can be used for regulating a healthy balance of the human intestinal microflora.

[0217] In a related further aspect, the present invention provides a food or food supplement comprising one or more (e.g. a plurality) of particles according to the present invention, which can be used to balance the ratio between pathogens and beneficial microorganisms in the human gut.

[0218] As can be derived from the above, the multilayer particles of the present invention have an "onion-like" structure and are prepared by stepwise or successive coating processes using one or several coating techniques well known to those skilled in the art, in particular layering techniques such as solution layering or suspension layering. Suitable equipment can be used, such as coating pans, coating equipment, granulators or fluidized bed coating equipment using water and / or organic solvents.

[0219] Thus, in a related further aspect, the invention provides a method for producing particles according to the invention, comprising the steps of applying a first coating layer in the form of an aqueous coating solution, coating suspension or coating aqueous dispersion to the cores by spraying or fluid bed spray granulation, and applying a second coating layer in the form of an aqueous coating solution, coating suspension or coating aqueous dispersion to the first coating layer by spraying or fluid bed spray granulation.

[0220] The first coating layer may be applied to the particle cores in the form of an aqueous coating solution, coating suspension or coating dispersion, for example using fluidized bed techniques such as Worcester coating or rotor coating.

[0221] Similarly, the second coating layer may be applied to the first coating layer in the form of an aqueous coating solution, coating suspension or coating dispersion, for example using fluidized bed techniques such as Worcester coating or rotor coating.

[0222] Those skilled in the art will readily understand that coating conditions such as solution spray rate, drying air temperature and flow rate must be adjusted to achieve equilibrium between the application rate of the liquid coating solution and the evaporation rate of the solvent, so that the first and second coatings can be uniformly deposited on the particles to form a continuous film without excessively wetting the particle surface. Details of these methods are well known in the art and are described, for example, in Lieberman et al., "Pharmaceutical Dosage Forms - Tablets: Volume 3", Chapter 3: Particle Coating Methods (1990), which is incorporated herein by reference.

[0223] As a preliminary step, the process may include forming the cores by direct compression, wet or dry granulation, or direct pelletization of the core-forming material.

[0224] The particles obtained according to the present invention can then be formulated as a pharmaceutical composition or used to prepare food or food supplements.For example, the particles obtained according to the present invention can be filled into capsules, such as hard capsules, or compressed into tablets to obtain oral dosage forms according to the present invention.

[0225] As used herein, the term "about" means the numerical value with which it is used plus or minus 10%. When numerical limits or ranges are recited herein, the endpoints are included. Also, all values ​​and subranges within the numerical limits or ranges are expressly included as if explicitly recited.

[0226] As used herein, the indefinite articles "a" and "an" mean "at least one" or "one or more," unless the context clearly dictates otherwise.

[0227] As used herein, the terms "comprising," "including," "having," and grammatical variations thereof are deemed to identify the stated features, steps, or components, but do not exclude the addition of one or more additional features, steps, components, or groups thereof. The use of "comprising" and "comprises" as used herein is understood to disclose "consisting of" and "consists of," in addition to "consisting essentially of" and "consists essentially of," respectively.

[0228] As used herein, the term "consisting essentially of" (and grammatical variations thereof) means that, taken together, additional materials, features, components, elements, or steps may be included that do not materially affect the basic and novel characteristics of the claimed invention. For example, when used in the context of one of the particles and layers of the invention, the term means that the particle or layer may include additional features, components, or elements in addition to those literally disclosed, provided that these additional features, components, or elements do not materially affect the basic and novel characteristics of the claimed particle. For example, the particle or layer may include additional non-essential elements such as water (e.g., in the form of moisture) and / or contaminants.

[0229] As used herein, the term "substantially covers" (and grammatical variations thereof) means that the coating is generally continuous and generally covers the entire surface of the core or underlayer, leaving little or none of the core or underlayer exposed.

[0230] Further, those skilled in the art will understand that the sum of the total amounts of all components making up a particle or any of its layers will typically be 100% of the total weight of the particle or layer, in other words, the sum of all components will not exceed 100% of the total weight of the particle or layer.

[0231] Having generally described the invention, a further understanding can be obtained by reference to specific embodiments, which are provided herein for purposes of illustration only and are not intended to be limiting, unless otherwise specified.

[0232] Working Example 1. Formulation Composition The formulation is a hard capsule of size 0. The volume of the capsule body is 0.67 mL. The capsule is filled with pellets. The pellets consist of a core made of microcrystalline cellulose. Cellets 200, highly spherical starter pellets made of 100% microcrystalline cellulose, were used for the purpose.

[0233] Lactoferrin coating layer The pellet cores were coated with two layers of coating: the first layer contained lactoferrin, HPMC (Pharmacoat 606), and polyethylene glycol (PEG6000).

[0234] Lactoferrin was used in the form of a dry powder containing at least 85% lactoferrin. This powder is dissolved in purified water before the start of the coating process. Alternatively, the chromatography eluate containing lactoferrin can be used directly for coating without the need to dry the eluate to obtain lactoferrin powder. Eluates usable for the coating process contain 4-25% lactoferrin. We used concentrations of 7-16%. The lactoferrin concentration is not constant but varies from batch to batch, with HPMC and PEG 6000 added depending on the total mass of lactoferrin.

[0235] HPMC (Pharmacoat 606) is a well-known polymer used in pharmaceutical coating processes. 606 is a type of polymer, and the degree of polymerization (polymer chain length) determines the viscosity of an HPMC solution.

[0236] PEG 6000 is a polymer that lowers the glass transition temperature of HPMC, making the coating less brittle at room temperature. PEG 6000 is a plasticizer. Alternatively, another type of PEG can be used for the same purpose.

[0237] The main components of the lactoferrin layer include: [Table 1]

[0238] Enteric Coating Layer The enteric layer is prepared according to the polymer manufacturer's recipe. The second coating contains a protective polymer (EUDRAGIT® L), glyceryl monostearate (GMS), triethyl citrate (TEC), and polysorbate (Tween 80). The enteric coating layer comprises 20% of the pellet.

[0239] [Table 2]

[0240] [Table 3]

[0241] Total composition of pellets The composition of the overall formulation is shown in Table 4. The composition is defined for 93% pure lactoferrin. The composition may vary and is dependent on the purity of the lactoferrin. Thus, the amounts of Pharmacoat 606, PEG 6000, contaminants, and Cellets 200 will vary.

[0242] [Table 4]

[0243] 2. Lactoferrin coating with solid lactoferrin in powder form This example is based on lactoferrin with a purity of 93%, which is the average purity used by the inventors. 1. Dissolve 417 g of lactoferrin-containing powder in 3,120 g of purified water to obtain a cloudy, dark red lactoferrin dispersion. 2. Separately, warm 370 g of purified water to 70° C. and add, under high speed stirring, 11.9 g of PEG 6000 and 67.5 g of Pharmacoat 606. Stir until all the agglomerates of Pharmacoat 606 disappear and cool the dispersion to room temperature to 30° C. 3. Add the dissolved binder solution to the lactoferrin solution and stir to obtain a homogenous coating dispersion.

[0244] 3. Lactoferrin coating with lactoferrin chromatography eluent In this example, it is assumed that the lactoferrin-containing eluate contains 10% total solids, dissolved or undissolved, of which 93% is lactoferrin and 7% is contaminants. 1. Weigh out 4170 g of the eluate containing lactoferrin. 2. Separately, warm 370 g of purified water to 70° C. and add, under high speed stirring, 11.9 g of PEG 6000 and 67.5 g of Pharmacoat 606. Stir until all the agglomerates of Pharmacoat 606 disappear and cool the dispersion to room temperature to 30° C. 3. Add the dissolved binder solution to the lactoferrin solution and stir to obtain a homogenous coating dispersion.

[0245] 4. Coating process parameters The pellets are coated in a bottom spray fluid bed coater (Glatt GPCG1) using a Worcester chamber. 303 g of Cellets 200 are placed in the treatment chamber. The fluidization process is started, the inlet temperature is set to 70° C. and the pellets are heated to 38° C. Once this temperature is reached, the spray process is started and the coating is controlled under the following conditions: [Table 5]

[0246] The diameter of the spray nozzle is 1.2 mm and the Worcester cylinder is positioned 15 mm above the distribution plate. The coating dispersion is prepared according to sections 2 and 3 above.

[0247] 5. Enteric Coating The enteric coating is applied after the first layer coating is completed. A Worcester chamber with the same configuration as in Example 3 is prepared. 800 g of lactoferrin coated pellets are weighed out and the fluidization process is started. The pellets are warmed to 35° C. and the spraying process is started. The coating is controlled under the following conditions: [Table 6]

[0248] 200 g of the coating dispersion is applied. The coating dispersion is prepared according to the manufacturer's instructions (https: / / corporate.evonik.com / en).

[0249] 6. Capsule filling Prior to capsule filling, the finished product is sieved through a 710 μm mesh size sieve to remove any agglomerates. Size 0 hard capsules with a hydroxypropyl methylcellulose shell are then filled with the resulting particles. However, gelatin capsules and other types of shells can also be used.

[0250] 7. Testing 7.1 Dissolution Profile The dissolution profile of the pellets was tested using the "USP II Apparatus", a standard dissolution method commonly used in the pharmaceutical field. The dissolution test was performed according to the pharmacopoeia guidelines for enteric coated formulations. Two dissolution media were used. First, 0.1 M HCl solution was used to simulate the conditions in the stomach for 2 hours, then Na3PO4 solution was added to increase the pH of the medium to pH 6.8. The volume of the acidic medium was 750 mL and the volume of 0.2 M Na3PO4 x 12H2O was 250 mL. 10 g of pellets were tested in each test. The temperature of the medium was set at 37°C and the paddle rotation at 100 rpm. Dissolution samples were taken at 5, 30, 60, 120, 125, 150, 180, 240, and 300 min. The sampling volume (2.3 mL) was replaced with fresh phosphate buffer at pH 6.8. All samples were filtered through a PVDF 0.2 μm membrane filter and analyzed by HPLC. The dissolution profile (Figure 1) complies with the regulatory criteria stipulating that less than 10% of the active ingredient was dissolved after 2 hours in acidic medium. Moreover, when the pH was increased to 6.8, more than 80% of the total dose was released within 30 minutes.

[0251] 7.2 Particle size distribution Particle size distribution was measured using a Malvern Mastersizer 3000 laser diffraction analyzer. An Aero S dry sample dispersion unit was used. The pellets were transferred to the cone of the dispersion unit with the gap position set to a value of 3.0. The air pressure was 1.2 bar and the feed rate was 25%. The measurement time was 4 seconds, with a background measurement also set to 4 seconds. Five repeated measurements were performed and the average values ​​are shown in Figure 2.

[0252] 7.3 Bulk Density The pellets were carefully transferred into a graduated cylinder. The mass was weighed and the pellet volume was read from the graduated cylinder. The bulk density was calculated based on the results obtained. This operation was repeated three times and the density was expressed as the average result.

[0253] [Table 7]

[0254] 7.4 Conclusion These results indicate that the layers of the various coating dispersions are compatible. Moreover, the method is highly efficient, achieving efficiencies of over 90% on a relatively small scale. A product with a moisture content of less than 7% is produced with just one processing unit. The protective layer proved to be essential for extending the shelf life of the formulation. It also promotes safe intestinal delivery of LF by preventing contact of LF with the harsh gastric environment. The formulation presented herein contains a high dose of LF, which has a beneficial effect on the human intestinal microflora through selective bacteriostatic action against pathogenic microorganisms. The formulation is in the form of a pellet-filled capsule, allowing patients to take the capsule regardless of the time of day and with or without food. The protective layer effectively protects the LF and does not significantly affect the release rate even when the pH of the environment increases. As shown in Figure 1, the release after 120 minutes is consistent with an immediate release formulation. As a result, the formulation of the present invention is a sustained release formulation containing a dose of LF suitable for the treatment or prevention of various intestinal diseases such as traveler's diarrhea.

Claims

1. 1. An enteric-coated particle comprising: a) a core comprising an inert core-forming material selected from a cellulose polymer, a sugar, a sugar alcohol, a starch, and a carnauba wax; b) a first coating layer substantially enclosing the core and comprising b-1) lactoferrin, b-2) a pharmaceutically acceptable binder, which is a non-polyvinylpyrrolidone (PVP) binder, and optionally b-3) one or more other suitable excipients; and c) a second coating layer substantially enclosing the first coating layer and comprising c-1) an enteric coating material, and optionally c-2) one or more other suitable excipients.

2. 10. The particle of claim 1, wherein the inert core-forming material is a cellulose polymer.

3. 3. The particle of claim 2, wherein the cellulose polymer is selected from the group consisting of microcrystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose.

4. 2. The particle of claim 1, wherein the pharmaceutically acceptable binder contained in the first coating layer is selected from the group consisting of cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and carboxymethylcellulose, agar, gelatin, gum arabic, alginates such as sodium alginate and polyethylene glycol alginate, polyethylene glycol, polyvinyl alcohol, sugars, sugar alcohols, starches and modified starches such as potato starch, corn starch, rice starch and pregelatinized starch.

5. The particle of claim 1 , wherein the first coating layer comprises a plasticizer.

6. 10. The particle of claim 1, wherein the enteric coating material included in the second coating layer is selected from a polymer or copolymer containing anionic side groups.

7. 10. The particle of claim 1, wherein the enteric coating material included in the second coating layer is selected from the group consisting of anionic (meth)acrylate copolymers and anionic polyvinyl polymers or copolymers.

8. 2. The particle of claim 1, wherein the enteric coating material contained in the second coating layer is an anionic (meth)acrylate copolymer composed of methacrylic acid and methyl methacrylate or ethyl acrylate, or an anionic (meth)acrylate copolymer composed of ethyl acrylate and methyl methacrylate.

9. 2. The particle of claim 1, wherein the enteric coating material contained in the second coating layer is a polymer combination comprising an anionic (meth)acrylate copolymer composed of methacrylic acid and ethyl methacrylate (e.g., EUDRAGIT® L) and an anionic (meth)acrylate copolymer composed of ethyl acrylate and methyl methacrylate (e.g., EUDRAGIT® NM).

10. The particle of claim 1 , wherein the second coating layer further comprises a plasticizer.

11. 11. The particles of claim 10, wherein the plasticizer is selected from the group consisting of polyethylene glycol, polyethylene glycol monomethyl ether, propylene glycol, sorbitol-sorbitan solution, glycerin, deacetylated monoglyceride, tributyl citrate, acetyl tributyl citrate, triethyl citrate, acetyl triethyl citrate, castor oil, dibutyl sebacate, diethyl phthalate, and triacetin.

12. The particle of claim 1 , wherein the second coating layer further comprises an anti-blocking agent.

13. The particle of claim 1 , wherein the second coating layer further comprises an emulsifier.

14. 10. The particle of claim 1, comprising: a) a core comprising microcrystalline cellulose; b) a first coating layer substantially enclosing the core and comprising b-1) lactoferrin, b-2) hydroxypropyl methylcellulose, and b-3) polyethylene glycol; and c) a second coating layer substantially enclosing the first coating layer and comprising c-1) anionic (meth)acrylate copolymer, c-2) triethyl citrate (TEC), c-3) glyceryl monostearate, and c-4) polyoxyethylene (20) sorbitan monooleate.

15. 10. The particle of claim 1, comprising: a) a core comprising microcrystalline cellulose; b) a first coating layer substantially surrounding the core and comprising b-1) lactoferrin, b-2) hydroxypropyl methylcellulose, and b-3) polyethylene glycol; and c) a second coating layer substantially surrounding the first coating layer and comprising c-1) an anionic (meth)acrylate copolymer, c-2) triethyl citrate (TEC), and c-3) talc.

16. 10. The particle of claim 1, wherein the lactoferrin is present in an amount of about 30% to about 50% of the total weight of the particle.

17. An oral dosage form comprising one or more particles according to any one of claims 1 to 16 and 200 mg or more of lactoferrin.

18. The oral dosage form of claim 17, which is a hard capsule.

19. The oral dosage form of claim 17, comprising about 400 mg to about 600 mg of the particles.

20. 17. A pharmaceutical composition comprising one or more particles according to any one of claims 1 to 16, 200 mg or more lactoferrin, and optionally one or more pharmaceutically acceptable excipients.

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