NZ619607B2 - Compositions and methods for improving stability and extending shelf life of sensitive food additives and food products thereof - Google Patents
Compositions and methods for improving stability and extending shelf life of sensitive food additives and food products thereof Download PDFInfo
- Publication number
- NZ619607B2 NZ619607B2 NZ619607A NZ61960712A NZ619607B2 NZ 619607 B2 NZ619607 B2 NZ 619607B2 NZ 619607 A NZ619607 A NZ 619607A NZ 61960712 A NZ61960712 A NZ 61960712A NZ 619607 B2 NZ619607 B2 NZ 619607B2
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- New Zealand
- Prior art keywords
- acid
- composition
- coating layer
- polymer
- fatty
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- 239000000203 mixture Substances 0.000 title claims abstract description 144
- 238000000034 method Methods 0.000 title claims abstract description 65
- 235000013305 food Nutrition 0.000 title claims description 29
- 235000013373 food additive Nutrition 0.000 title description 13
- 239000002778 food additive Substances 0.000 title description 13
- 239000001301 oxygen Substances 0.000 claims abstract description 133
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 133
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 132
- 239000011247 coating layer Substances 0.000 claims abstract description 129
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 103
- 229920000642 polymer Polymers 0.000 claims abstract description 96
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 94
- 229930195729 fatty acid Natural products 0.000 claims abstract description 94
- 239000000194 fatty acid Substances 0.000 claims abstract description 94
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 86
- 239000007787 solid Substances 0.000 claims abstract description 79
- 230000005540 biological transmission Effects 0.000 claims abstract description 54
- 239000010410 layer Substances 0.000 claims abstract description 44
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 38
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 38
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 38
- 238000012360 testing method Methods 0.000 claims abstract description 32
- 230000004888 barrier function Effects 0.000 claims abstract description 31
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 24
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- 235000021355 Stearic acid Nutrition 0.000 claims abstract description 22
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000008117 stearic acid Substances 0.000 claims abstract description 22
- 230000008018 melting Effects 0.000 claims abstract description 15
- 238000002844 melting Methods 0.000 claims abstract description 15
- 239000000155 melt Substances 0.000 claims abstract description 14
- 239000011159 matrix material Substances 0.000 claims abstract description 13
- 230000003111 delayed effect Effects 0.000 claims abstract description 9
- -1 HPMCAS Polymers 0.000 claims description 60
- 239000002245 particle Substances 0.000 claims description 55
- 239000003925 fat Substances 0.000 claims description 54
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- 229920001577 copolymer Polymers 0.000 claims description 49
- 238000000576 coating method Methods 0.000 claims description 34
- 239000001993 wax Substances 0.000 claims description 34
- 239000011248 coating agent Substances 0.000 claims description 32
- 239000002250 absorbent Substances 0.000 claims description 31
- 230000002745 absorbent Effects 0.000 claims description 31
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 30
- 239000000839 emulsion Substances 0.000 claims description 30
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 26
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 26
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 24
- 239000004094 surface-active agent Substances 0.000 claims description 24
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- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 23
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 22
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- 229920002845 Poly(methacrylic acid) Polymers 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 20
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 20
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 17
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 16
- 235000010443 alginic acid Nutrition 0.000 claims description 16
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 16
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 15
- 229920002472 Starch Polymers 0.000 claims description 15
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 13
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 13
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- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 13
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 13
- 229910052708 sodium Inorganic materials 0.000 claims description 13
- 229940083542 sodium Drugs 0.000 claims description 13
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 12
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 12
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 12
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- 239000003381 stabilizer Substances 0.000 claims description 12
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 11
- 239000005639 Lauric acid Substances 0.000 claims description 11
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 235000015424 sodium Nutrition 0.000 claims description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- 229920003134 Eudragit® polymer Polymers 0.000 claims description 10
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 10
- 229920002125 Sokalan® Chemical class 0.000 claims description 10
- 230000035515 penetration Effects 0.000 claims description 10
- 239000004584 polyacrylic acid Chemical class 0.000 claims description 10
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 9
- 108010010803 Gelatin Proteins 0.000 claims description 9
- 229920001800 Shellac Polymers 0.000 claims description 9
- 244000299461 Theobroma cacao Species 0.000 claims description 9
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003240 coconut oil Substances 0.000 claims description 9
- 235000019864 coconut oil Nutrition 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 239000008273 gelatin Substances 0.000 claims description 9
- 229940014259 gelatin Drugs 0.000 claims description 9
- 229920000159 gelatin Polymers 0.000 claims description 9
- 235000019322 gelatine Nutrition 0.000 claims description 9
- 235000011852 gelatine desserts Nutrition 0.000 claims description 9
- 235000019271 petrolatum Nutrition 0.000 claims description 9
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical class OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000004208 shellac Substances 0.000 claims description 9
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 claims description 9
- 229940113147 shellac Drugs 0.000 claims description 9
- 235000013874 shellac Nutrition 0.000 claims description 9
- 239000001856 Ethyl cellulose Substances 0.000 claims description 8
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 8
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 8
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 8
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 8
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- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- WZNRVWBKYDHTKI-UHFFFAOYSA-N cellulose, acetate 1,2,4-benzenetricarboxylate Chemical compound OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.OC(=O)C1=CC(C(=O)O)=CC=C1C(=O)OCC1C(OC2C(C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(COC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)O2)OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)O1 WZNRVWBKYDHTKI-UHFFFAOYSA-N 0.000 claims description 8
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- 150000002632 lipids Chemical class 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 8
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 7
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- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 claims description 6
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- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 claims description 6
- 150000002191 fatty alcohols Chemical class 0.000 claims description 6
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 6
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- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 6
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 6
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 5
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- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 4
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- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 230000009993 protective function Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 235000021067 refined food Nutrition 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 235000015067 sauces Nutrition 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000008470 skin growth Effects 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 235000002316 solid fats Nutrition 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000007655 standard test method Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000025366 tissue development Effects 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 239000000541 tocopherol-rich extract Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007723 transport mechanism Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000007680 β-tocopherol Nutrition 0.000 description 1
- 239000011590 β-tocopherol Substances 0.000 description 1
- 239000002478 γ-tocopherol Substances 0.000 description 1
- QUEDXNHFTDJVIY-DQCZWYHMSA-N γ-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-DQCZWYHMSA-N 0.000 description 1
- 239000002446 δ-tocopherol Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
- A23D7/00—Edible oil or fat compositions containing an aqueous phase, e.g. margarines
- A23D7/005—Edible oil or fat compositions containing an aqueous phase, e.g. margarines characterised by ingredients other than fatty acid triglycerides
- A23D7/0053—Compositions other than spreads
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
- A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
- A23D9/007—Other edible oils or fats, e.g. shortenings, cooking oils characterised by ingredients other than fatty acid triglycerides
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
- A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
- A23D9/02—Other edible oils or fats, e.g. shortenings, cooking oils characterised by the production or working-up
- A23D9/04—Working-up
- A23D9/05—Forming free-flowing pieces
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
- A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
- A23D9/06—Preservation of finished products
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/70—Fixation, conservation, or encapsulation of flavouring agents
- A23L27/72—Encapsulation
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/70—Fixation, conservation, or encapsulation of flavouring agents
- A23L27/74—Fixation, conservation, or encapsulation of flavouring agents with a synthetic polymer matrix or excipient, e.g. vinylic, acrylic polymers
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/70—Fixation, conservation, or encapsulation of flavouring agents
- A23L27/77—Use of inorganic solid carriers, e.g. silica
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
- A23L33/12—Fatty acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P10/00—Shaping or working of foodstuffs characterised by the products
- A23P10/20—Agglomerating; Granulating; Tabletting
- A23P10/25—Agglomeration or granulation by extrusion or by pressing, e.g. through small holes, through sieves or between surfaces
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
- A23P10/00—Shaping or working of foodstuffs characterised by the products
- A23P10/30—Encapsulation of particles, e.g. foodstuff additives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/005—Coating of tablets or the like
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/20—After-treatment of capsule walls, e.g. hardening
- B01J13/22—Coating
Abstract
Disclosed herein is a composition comprising: a core comprising at least one fatty acid; a fatty coating layer comprising at least one hydrophobic solid fat or fatty acid having a melting point lower than 70°C and higher than 25°C; an intermediate coating layer positioned on said fatty coating layer comprising a polymer having an aqueous solution of 0.1% that features a surface tension lower than 60 mN/m when measured at 25°C; at least one barrier coating layer comprising a polymer having oxygen transmission rate of less than 1000 cc/m2/24 hr measured at standard test conditions and a water vapour transmission rate of less than 400 g/m²/day positioned on said intermediate layer; at least one delayed release layer comprising an enteric polymer; and wherein said fatty coating layer is positioned between said core and said intermediate layer. Also disclosed are compositions where the core comprises a fatty acid embedded in a melt matrix of stearic acid or a polyethylene glycol based polymer and methods for the production of the compositions claimed. ayer comprising a polymer having an aqueous solution of 0.1% that features a surface tension lower than 60 mN/m when measured at 25°C; at least one barrier coating layer comprising a polymer having oxygen transmission rate of less than 1000 cc/m2/24 hr measured at standard test conditions and a water vapour transmission rate of less than 400 g/m²/day positioned on said intermediate layer; at least one delayed release layer comprising an enteric polymer; and wherein said fatty coating layer is positioned between said core and said intermediate layer. Also disclosed are compositions where the core comprises a fatty acid embedded in a melt matrix of stearic acid or a polyethylene glycol based polymer and methods for the production of the compositions claimed.
Description
COMPOSITIONS AND METHODS FOR IMPROVING STABILITY AND
EXTENDING SHELF LIFE OF SENSITIVE FOOD ADDITIVES AND FOOD
PRODUCTS THEREOF
INVENTORS: ADEL PENHASI, ISRAEL RUBIN
FIELD OF THE INVENTION
The present invention generally relates to food additives and food products, and
more particularly to novel compositions and methods for improving stability and
extending shelf life of sensitive food additives and food products thereof.
BACKGROUND OF THE INVENTION
Food additives may come in a variety of forms, including solids and liquids.
Although possibly possessing some health benefits, many food additives such as fatty
acids, may be sensitive to environmental conditions, such as temperature, oxidation and
the like.
Omega-3, omega-6 and Allicin are examples of substances which may be
sensitive to oxidation.
Omega-3 and omega-6 are essential fatty acids (EFAs) because they are not
produced by the body and must be obtained through diet or supplementation. These EFAs
are necessary for skin and hair growth, cholesterol metabolism and reproductive
performance. Omega-3 fatty acids are important for proper neural, visual and
reproductive functions while omega-6 fatty acids are critical for proper tissue
development during gestation and infancy.
Omega-3 (n-3) fatty acids are derived from two main dietary sources: marine, and
nut and plant oils. The primary marine-derived omega-3 fatty acids with 20 or more
carbon atoms are eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid
(DHA; C22:6n-3) present in high concentrations in deep water oily fish such as tuna,
salmon, mackerel and herring as well as seal oil, krill and marine algae.
Alliin is a sulfoxide that is a natural constituent of fresh garlic and it is a
derivative of the amino acid cysteine. Allicin is an organosulfur compound obtained from
garlic. Allicin is not present in garlic unless tissue damage occurs and is formed by the
action of the enzyme alliinase on alliin. This compound exhibits antibacterial and anti-
fungal properties.
Most naturally-produced fatty acids (created or transformed in animal or plant
cells with an even number of carbon in chains) are in cis-configuration where they are
more easily transformable. The trans-configuration results in much more stable chains
that are very difficult to further break or transform, forming longer chains that aggregate
in tissues and lack the necessary hydrophilic properties. This trans-configuration can be
the result of the transformation in alkaline solutions, or of the action of some bacteria that
are shortening the carbonic chains. Natural transforms in plant or animal cells more rarely
affect the last n−3 group itself. However, n−3 compounds are still more fragile than n−6
because the last double bond is geometrically and electrically more exposed, notably in
the natural cis-configuration. Like free oxygen radicals, iodine can add to double bonds
of docosahexaenoic acid and arachidonic acid forming iodolipids.
The oxidation process of such oxygen-sensitive agents causes a decline in their
functionality and consequently deficiency in health efficiency and medical benefits. In
some cases, the oxidation process of such oxidizable agents will be accompanied with
unpleasant taste and pungent odor.
The oxidation process is a kinetic process which can be enhanced by increasing
temperature, the stability of such oxygen sensitive liquid agents may be enhanced at
either ambient temperature or higher temperature which will eventually shorten the shelf
life of such oxygen sensitive liquid agents. Additionally, the latter fact may prevent such
oxygen sensitive liquid agents to be added to such functional foods that undergo heating
process during handling and preparation process.
Thus attempts to perform encapsulation of liquid heat sensitive components, for example,
liquid nutraceutical components into matrixes that are edible, have been made in the past
and are generally considered difficult.
Some attempts at encapsulation are described in the following patent documents:
US7344747 (Perlman), US4895725 (Kantor), US20050233002 (Trubiano), US6234464
(Krumbholz), US6500463 (van Lengerich), US20040017017 (van Lengerich),
US6723358 (van Lengerich), US20070098854 (van Lengerich), US7727629 (Yan),
US20060115553 (Gautam), US20050233044 (Rader), US20060134180 (Yan),
US6428461 (Marquez), US4895725, WO92/00130, US5183690 (Carr), US5567730
(Miyashita), WO95/26752, and US5106639 (Lee).
Products implementing such previous efforts require careful handling and excess
heat, moisture, and high shear forces must be avoided, and possess many drawbacks.
First, conventional encapsulation processes expose matrix material and
encapsulants to high temperatures, causing thermal destruction or loss of encapsulant.
Thus, either large overdoses of encapsulant would be required (which would turn out to
be very expensive), or the encapsulant would not sustain the encapsulation process at all.
Second, if the encapsulant can be encapsulated into a matrix under sufficiently
low temperatures and the resulting product may be a soft solid, the softness of the
microencapsules shell, however, disappears under either relatively high temperature of
cooking or even the temperature at which the particles are consumed or the eating
temperature resulting in microencapsules shell either to be removed or be oxygen
permeable. As a result, a sensitive encapsulant may be either exposed to heat and oxygen
or released either in the food or in the mouth when the particles or the food containing
microencapsules are consumed leaving unpleasant odor and taste. Previous products of
this kind exhibit only a partial protection against both oxidation and temperature and are
limited to storage taking place only at low temperature.
Third, liquid nutraceutical components encapsulated as a liquid entrapped in a
solid dense shell may cause problems when the resulting microcapsules are chewed as
they may be broken, releasing liquid nutraceutical components in the mouth during
chewing. Furthermore they cannot also be used as dense pellets for a variety of
processing applications, since such microcapsulating shells mostly are not able to
withstand the shear forces exerted during handling and processing of foodstuff such as
kneading and etc.
Consequently, they may eventually be broken to release the liquid nutraceutical
components in the food. They can therefore be only swallowed as microcapsules or
capsules without chewing.
In the description in this specification reference may be made to subject matter
that is not within the scope of the claims of the current application. That subject matter
should be readily identifiable by a person skilled in the art and may assist in putting into
practice the invention as defined in the claims of this application.
SUMMARY OF THE INVENTION
The present invention provides a composition comprising: a core comprising at
least one fatty acid; a fatty coating layer comprising at least one hydrophobic solid fat
or fatty acid having a melting point lower than 70°C and higher than 25°C; an
intermediate coating layer positioned on said fatty coating layer comprising a polymer
having an aqueous solution of 0.1% that features a surface tension lower than 60 mN/m
when measured at 25°C; at least one barrier coating layer comprising a polymer having
oxygen transmission rate of less than 1000 cc/m /24 hr measured at standard test
conditions and a water vapor transmission rate of less than 400 g/m²/day positioned on
said intermediate layer; at least one delayed release layer comprising an enteric polymer;
and wherein said fatty coating layer is positioned between said core and said intermediate
layer.
The invention also provides a composition comprising: a core comprising at least
one fatty acid embedded into a melt matrix comprising one or more of stearic acid and/or
a PEG based polymer; at least one intermediate coating layer comprising a polymer in an
aqueous solution of 0.1% having a surface tension lower than 60 mN/m measured at
°C; at least one coating layer comprising a polymer having oxygen transmission rate of
less than 1000 cc/m /24 hr measured at standard test conditions and a water vapor
transmission rate of less than 400 g/m²/day positioned on said intermediate layer; and at
least one delayed release layer comprising an enteric polymer positioned on said at least
one coating layer.
The invention also relates to a method of producing a stabilized, multi-layered
particle containing at least one fatty acid, comprising: preparing a core from said at least
one fatty acid and an absorbent; coating the core with a first coating layer to obtain a
water sealed coated particle, the first coating layer comprising a hydrophobic solid fat or
fatty acid, the first coating layer preventing penetration of water into said core; coating
said water sealed coated particle with an intermediate coating layer that adjusts interfacial
tension to obtain a water sealed coated particle having an adjusted surface tension,
wherein said intermediate coating layer comprising a polymer in an aqueous solution of
0.1% having a surface tension lower than 60 mN/m measured at 25°C; and coating said
water sealed coated particle having an adjusted surface tension with a barrier coating
layer comprising a polymer having oxygen transmission rate of less than 1000 cc/m /24
hr measured at standard test conditions that reduces transmission of oxygen and humidity
into the core granule to obtain a multi-layered particle containing fatty acid.
The invention also provides a stabilized, multi-layered particle when produced by
a method of the invention.
BRIEF DESCRIPTION
Described are new compositions and methods for improving stability and
extending shelf life of sensitive food additives and food products thereof.
Described is a composition that may be used as a supplement and/or food
additive, for example, to be added into a food product.
In some demonstrative embodiments, the composition may comprise a core
having at least one oxygen-sensitive liquid natural pharmaceutically or nutritionally
active agent absorbed or adsorbed onto a substrate and at least one coating layer
designed to stabilize the oxygen-sensitive liquid natural pharmaceutically or nutritionally
active agent.
According to some embodiments, the composition may include a core having at
least one oxygen-sensitive liquid natural pharmaceutically or nutritionally active agent,
optionally further comprising at least one excipient, and a plurality of coating layers,
including, for example, a fatty coating layer, an intermediate coating layer, an outer
coating layer and optionally an enteric coating layer.
According to some demonstrative embodiments the composition comprises a core
comprising at least one oxygen-sensitive liquid natural pharmaceutically or nutritionally
active agent absorbed or adsorbed onto an absorbent; an intermediate layer, comprising
an interfacial tension adjusting polymer, wherein said interfacial tension adjusting
polymer is characterized by an aqueous solution of 0.1% having a surface tension lower
than 60 mN/m when measured at 25 C; and at least one barrier coating layer comprising a
polymer having oxygen transmission rate of less than 1000 cc/m /24 hr measured at
standard test conditions and a water vapor transmission rate of less than 400 g/m²/day.
According to some embodiments, the barrier coating layer may comprise one or more of
polyvinyl alcohol (PVA), Povidone (PVP: polyvinyl pyrrolidone), Copovidone
(copolymer of vinyl pyrrolidone and vinyl acetate), Kollicoat Protect (BASF) which is a
mixture of Kollicoat IR (a polyvinyl alcohol (PVA)-polyethylene glycol (PEG) graft
copolymer) and polyvinyl alcohol (PVA), Opadry AMB (Colorcon) which is a mixture
based on PVA, Aquarius MG which is a cellulosic- based polymer containing natural
wax, lecithin, xanthan gum, gelatin, starch and talc, low molecular weight HPC
(hydroxypropyl cellulose), low molecular weight carboxy methyl cellulose such as 7LF,
7L2P, Na-carboxy methyl cellulose.
According to some embodiments, the barrier coating layer may comprise one or more of
Na-carboxy methyl cellulose (CMC), gelatin or starch, or a combination thereof.
According to some embodiments, the core may further comprise a fatty acid.
According to some embodiments, the composition may further comprise an intermediate
coating layer.
According to some embodiments, the composition may further comprise an enteric
coating layer.
According to some embodiments, the absorbent may comprise one or more of MCC
(microcrystalline cellulose), silicon dioxide, lactose, talc, aluminum silicate, dibasic
calcium phosphate anhydrous, starch or a starch derivative, a polysaccharide or a
combination thereof.
According to some embodiments, the starch derivative may comprise one or more of
partially pregelatinized starch, pregelatinized starch, starch phosphate, modified food
starch or a combination thereof.
According to some embodiments, the polysaccharide may comprise one or more of
glucose-based polysaccharides, cellulose, mannose-based polysaccharides (mannan),
galactose-based polysaccharides (galactan), N-acetylglucosamine-based polysaccharides
including chitin, gums such as arabic gum (gum acacia), modified polysaccharides such
as crosslinked pectin, cross linked sodium alginate; cellulose derivatives such as ethyl
cellulose, propyl cellulose, cross-linked cellulose derivatives and a combination thereof.
According to some embodiments, the polysaccharide may comprise one or more of
glucan, glycogen, amylose, amylopectin,
According to some demonstrative embodiments the composition comprises a core
comprising at least one oxygen-sensitive liquid natural pharmaceutically or nutritionally
active agent absorbed or adsorbed onto an absorbent, with the proviso that said liquid is
not in the form of an emulsion; at least one intermediate coating layer comprising
an interfacial tension adjusting polymer; and at least one barrier coating layer comprising
polymer having oxygen transmission rate of less than 1000 cc/m /24 hr measured at
standard test conditions and a water vapor transmission rate of less than 400 g/m²/day.
According to some embodiments, the composition may further comprise a fatty coating
layer comprising at least one hydrophobic solid fat or fatty acid having a melting point
lower than 70 C and higher than 25 C.
According to some embodiments, the fatty coating layer may be positioned directly on
the core.
According to some embodiments, the said fatty coating layer may be positioned between
the core and said intermediate layer.
According to some embodiments, the intermediate layer may comprises an aqueous
solution of 0.1% having a surface tension lower than 60 mN/m measured at 25 C.
According to some embodiments, the surface tension may be lower than 50 mN/m.
According to some embodiments, the surface tension may be lower than 45 mN/m.
According to some demonstrative embodiments the composition comprises
a core comprising at least one oxygen-sensitive liquid natural pharmaceutically or
nutritionally active agent; a fatty coating layer comprising least one hydrophobic solid
fat or fatty acid having a melting point lower than 70 C and higher than 25 C; an
intermediate coating layer positioned on said fatty coating layer; at least one barrier
coating layer comprising a polymer having oxygen transmission rate of less than 1000
cc/m /24 hr measured at standard test conditions and a water vapor transmission rate of
less than 400 g/m²/day positioned on said intermediate layer; and at least one delayed
release layer comprising an enteric polymer.
According to some embodiments, the intermediate layer may comprise a polymer whose
an aqueous solution of 0.1% having a surface tension lower than 60 mN/m measured at
C.
According to some embodiments, the intermediate layer may comprise a water soluble
polymer.
According to some embodiments, the intermediate layer may comprise a polymer
selected from the group including hydroxypropylethylcellulose (HPEC),
hydroxypropylcellulose (HPC), methylcellulose, ethylcellulose, pH-sensitive polymers,
enteric polymers and/or a combination or combinations thereof.
According to some embodiments, the enteric polymer may comprise one or more of
phthalate derivatives such as acid phthalate of carbohydrates, amylose acetate phthalate,
cellulose acetate phthalate (CAP), other cellulose ester phthalates, cellulose ether
phthalates, hydroxypropylcellulose phthalate (HPCP), hydroxypropylethylcellulose
phthalate (HPECP), hydroxyproplymethylcellulose phthalate (HPMCP),
hydroxyproplymethylcellulose acetate succinate (HPMCAS), methylcellulose phthalate
(MCP), polyvinyl acetate phthalate (PVAcP), polyvinyl acetate hydrogen phthalate,
sodium CAP, starch acid phthalate, cellulose acetate trimellitate (CAT), styrene-maleic
acid dibutyl phthalate copolymer, styrene-maleic acid/polyvinylacetate phthalate
copolymer, styrene and maleic acid copolymers, polyacrylic acid derivatives such as
acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof,
polyacrylic and methacrylic acid copolymers, and vinyl acetate and crotonic acid
copolymers. In some embodiments, pH-sensitive polymers include shellac, phthalate
derivatives, CAT, HPMCAS, polyacrylic acid derivatives, particularly copolymers
comprising acrylic acid and at least one acrylic acid ester, EudragitTM S
(poly(methacrylic acid, methyl methacrylate)1:2); Eudragit L100TM (poly(methacrylic
acid, methyl methacrylate)1:1); Eudragit L30DTM, (poly(methacrylic acid, ethyl
acrylate)1:1); and (Eudragit L100-55) (poly(methacrylic acid, ethyl acrylate)1:1)
(EudragitTM L is an anionic polymer synthesized from methacrylic acid and methacrylic
acid methyl ester), polymethyl methacrylate blended with acrylic acid and acrylic ester
copolymers, alginic acid and alginates, ammonia alginate, sodium, potassium,
magnesium or calcium alginate, vinyl acetate copolymers, polyvinyl acetate 30D (30%
dispersion in water), a poly(dimethylaminoethylacrylate) “Eudragit E™, a copolymer of
methylmethacrylate and ethylacrylate with small portion of trimethylammonioethyl
methacrylate chloride (Eudragit RL, Eudragit RS), a copolymer of methylmethacrylate
and ethylacrylate (Eudragit NE 30D), Zein, shellac, gums, poloxamer, polysaccharides.
According to some embodiments, the melting point may be lower than 65˚C and higher
than 30 C.
According to some embodiments, the melting point may be lower than 60 C and higher
than 35 C.
According to some embodiments, the fatty coating layer may comprise one or more of
fats, fatty acids, fatty acid esters, fatty acid triesters, salts of fatty acids, fatty alcohols,
phospholipids, solid lipids, waxes, lauric acid, stearic acid, alkenes, waxes, alcohol esters
of fatty acids, long chain alcohols and glucoles, and combinations thereof.
According to some embodiments, the salt of fatty acids may comprise one or more of
aluminum, sodium, potassium and magnesium salts of fatty acids.
According to some embodiments, the fatty coating layer may comprise one or more of
paraffin wax composed of a chain of alkenes, normal paraffins of type C H ; natural
n 2n+2
waxes, synthetic waxes, hydrogenated vegetable oil, hydrogenated castor oil; fatty acids,
such as lauric acid, myristic acid, palmitic acid, palmitate, palmitoleate,
hydroxypalmitate, stearic acid, arachidic acid, oleic acid, stearic acid, sodium stearat,
calcium stearate, magnesium stearate, hydroxyoctacosanyl hydroxystearate, oleate esters
of long-chain, esters of fatty acids, fatty alcohols, esterified fatty diols, hydroxylated fatty
acid, hydrogenated fatty acid (saturated or partially saturated fatty acids), partially
hydrogenated soybean oil, partially hydrogenated cottonseed oil, aliphatic alcohols,
phospholipids, lecithin, phosphathydil cholin, triesters of fatty acids, coconut oil,
hydrogenated coconut oil, cacao butter; palm oil; fatty acid eutectics; mono and
diglycerides, poloxamers, block-co-polymers of polyethylene glycol and polyesters, and
a combination thereof.
According to some embodiments, the wax may comprise one or more of beeswax,
carnauba wax, japan wax, bone wax, paraffin wax, chinese wax, lanolin (wool wax),
shellac wax, spermaceti, bayberry wax, candelilla wax, castor wax, esparto wax, jojoba
oil, ouricury wax, rice bran wax, soy wax, ceresin waxes, montan wax, ozocerite, peat
waxes, microcrystalline wax, petroleum jelly, polyethylene waxes, Fischer-Tropsch
waxes, chemically modified waxes, substituted amide waxes; polymerized α-olefins, or a
combination thereof.
According to some embodiments, the solid fat or fatty acid may include at least one of
lauric acid, hydrogenated coconut oil, cacao butter, stearic acid, or a combination thereof.
According to some demonstrative embodiments the composition comprises a core
comprising at least one oxygen-sensitive liquid natural pharmaceutically or nutritionally
active agent embedded into a melt matrix comprising one or more of stearic acid and/or a
PEG based polymer; at least one intermediate coating layer comprising a polymer in an
aqueous solution of 0.1% having a surface tension lower than 60 mN/m measured at
C; at least one coating layer comprising a polymer having oxygen transmission rate of
less than 1000 cc/m /24 hr measured at standard test conditions and a water vapor
transmission rate of less than 400 g/m²/day; andat least one delayed release layer
comprising an enteric polymer.
According to some embodiments, the PEG based polymer may comprise a PEG based co-
polymer.
According to some embodiments, the composition may be adapted for admixing with a
food product.
According to some embodiments, the composition may further comprise a stabilizer,
selected from the group consisting of dipotassium edetate, disodium edetate, edetate
calcium disodium, edetic acid, fumaric acid, malic acid, maltol, sodium edetate, trisodium
edetate.
According to some embodiments, the composition may further comprise an oxygen
scavenger selected from the group including L-cysteine base or hydrochloride, vitamin E,
tocopherol or polyphenols.
According to some embodiments, the composition may further comprise a surfactant in
any of the coating layers, with the proviso that the surfactant is not present in the core.
According to some embodiments, the composition may further comprise a surfactant in
the core, with the proviso that the surfactant is not part of an emulsion.
According to some embodiments, the surfactant may be selected from the group
including tween 80, docusate sodium, sodium lauryl sulfate, glyceryl monooleate,
polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol and sorbitan esters.
According to some embodiments, the composition may further comprise a glidant.
According to some embodiments, the glidant is silicon dioxide.
According to some embodiments, the composition may further comprise a plasticizer
selected from the group including polyethylene glycol (PEG), e.g., PEG 400, triethyl
citrate and triacetin.
According to some embodiments, the composition may further comprise a filler selected
from the group including microcrystalline cellulose, a sugar, such as lactose, glucose,
galactose, fructose, or sucrose; dicalcium phosphate; sugar alcohols such as sorbitol,
manitol, mantitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch
hydrolysates; corn starch and potato starch.
According to some embodiments, the composition may further comprise a binder selected
from the group including Povidone (PVP: polyvinyl pyrrolidone), Copovidone
(copolymer of vinyl pyrrolidone and vinyl acetate), polyvinyl alcohol, low molecular
weight HPC (hydroxypropyl cellulose), low molecular weight HPMC (hydroxypropyl
methylcellulose), low molecular weight hydroxymethyl cellulose (MC), low molecular
weight sodium carboxy methyl cellulose, low molecular weight hydroxyethylcellulose,
low molecular weight hydroxymethylcellulose, cellulose acetate, gelatin, hydrolyzed
gelatin, polyethylene oxide, acacia, dextrin, starch, and water soluble polyacrylates and
polymethacrylates and low molecular weight ethylcellulose.
According to some demonstrative embodiments described is a method of producing a
stabilized, multi-layered particle containing oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent, comprising preparing a core from an
oxygen-sensitive liquid natural pharmaceutically or nutritionally active agent and an
absorbent; coating the core with a first coating layer to obtain a water sealed coated
particle, the first coating layer comprising a hydrophobic solid fat or fatty acid, the first
coating layer preventing penetration of water into said core; coating said water sealed
coated particle with an intermediate coating layer that adjusts interfacial tension to obtain
a water sealed coated particle having an adjusted surface tension; and coating said water
sealed coated particle having an adjusted surface tension with a barrier coating layer that
reduces transmission of oxygen and humidity into the core granule to obtain a multi-
layered particle containing oxygen-sensitive liquid natural pharmaceutically or
nutritionally active agent.
According to some embodiments, the intermediate coating layer may include an aqueous
solution of 0.1% and having a surface tension less than 60 mN/m as measured at 25 ̊ C
According to some embodiments, the surface tension may be lower than 50 mN/m.
According to some embodiments, the surface tension may be lower than 45 mN/m.
According to some embodiments, the at least one barrier coating layer may comprise a
polymer having oxygen transmission rate of less than 1000 cc/m /24 hr measured at
standard test conditions.
According to some embodiments, the at least one barrier coating layer may comprise a
polymer having oxygen transmission rate of less than 500 cc/m /24 hr measured at
standard test conditions.
According to some embodiments, the at least one barrier coating layer may comprise a
polymer having oxygen transmission rate of less than 100 cc/m2/24 hr measured at
standard test conditions.
According to some embodiments, the at least one barrier coating layer may comprise a
polymer having a water vapor transmission rate of less than 400 g/m²/day.
According to some embodiments, the at least one barrier coating layer may comprise a
polymer having a water vapor transmission rate of less than 350 g/m²/day.
According to some embodiments, the at least one barrier coating layer may comprise a
polymer having a water vapor transmission rate of less than 300 g/m²/day.
BRIEF DESCRIPTION OF THE DRAWINGS
demonstrates an exemplary flow diagram for the compositions described herein in
accordance with some demonstrative embodiments.
demonstrates an exemplary schema of a multiple-layered microencapsulated
oxygen-sensitive liquid natural pharmaceutically or nutritionally active agent in
accordance with some embodiments described herein.
demonstrates an exemplary schema of a multiple-layered microencapsulated
oxygen-sensitive liquid natural pharmaceutically or nutritionally active agent in
accordance with some embodiments described herein.
demonstrates an exemplary schema of a contact angle (θ) formed when a liquid,
according to some demonstrative embodiments described herein, does not completely
spread on a substrate.
demonstrates an exemplary illustration of the effect of capillarity describing the
flow of a penetrant through void or pore on the surface of a solid described herein in
accordance with some demonstrative embodiments.
demonstrates an exemplary oxidation test results in accordance with some
embodiments described herein.
demonstrates an accelerated stability test carried out using ML OXIPRES test
method in accordance with some embodiments described herein.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention, in at least some embodiments, is of new compositions and
methods for improving stability and extending shelf life of sensitive food additives and
food products thereof.
According to some demonstrative embodiments of the present invention there is
provided a composition that may be used as a supplement and/or food additive, for
example, to be added into a food product, including, e.g., engineered foods and functional
foods such as creams, biscuits, biscuit fill-ins, chocolates, sauces, mayonnaise, cereals,
baked goods and the like. Food additives, such as liquid natural pharmaceutically or
nutritionally active agents and/or other nutraceutical agents, may include foods or food
products that provide health and medical benefits, may be sensitive to oxygen (i.e., they
are oxidizable). Such products may range from isolated nutrients, oil products, dietary
supplements, food additives, engineered foods, herbal extracted products, and processed
foods such as functional food, as described above, and the like.
In some demonstrative embodiments, the composition may comprise a core
having at least one oxygen-sensitive liquid natural pharmaceutically or nutritionally
active agent absorbed or adsorbed onto a substrate and at least one coating layer
designed to stabilize the oxygen-sensitive liquid natural pharmaceutically or nutritionally
active agent.
According to some demonstrative embodiments, the at least one oxygen-sensitive
liquid natural pharmaceutically or nutritionally active agent may include, but not limited
to, fatty acids, for example, unsaturated fatty acids, omega 3 fatty acids, omega 6 fatty
acids, and omega 9 fatty acids, α-linolenic acid (18:3, n−3; ALA), eicosapentaenoic acid
(20:5, n−3; EPA), docosahexaenoic acid (22:6, n−3; DHA), oleic acid, fish oil, flax oil,
olive oil, ginseng extract, garlic oil, alliin, allicin, and/or the like.
The term n−3 (also called ω−3 or omega-3) as referred to herein signifies that the
first double bond exists as the third carbon-carbon bond from the terminal methyl end (n)
of the carbon chain n−3 fatty acids which are important in human nutrition such as α-
linolenic acid (18:3, n−3; ALA), eicosapentaenoic acid (20:5, n−3; EPA),
docosahexaenoic acid (22:6, n−3; DHA). These three polyunsaturates have either 3, 5 or
6 double bonds in a carbon chain of 18, 20 or 22 carbon atoms, respectively. All double
bonds are in the cis-configuration; in other words, the two hydrogen atoms are on the
same side of the double bond.
In some demonstrative embodiments of the present invention, the composition
described herein may include one or more coated particles, comprising at least three
layered phases, such as, by way of non- limiting example, a core and at least three coats
(“coating layers”).
In some embodiments, one of the coats may be a hydrophobic solid fat formulated
to contribute to the prevention of water/humidity penetration into the core, e.g., during
the process of coating of other coating layers or during later stages.
In some embodiments, the composition may also include an outer coat which may
be formulated to prevent or diminish transmission of humidity and/or oxygen into the
core, e.g., during the storage and throughout the shelf life of the food product.
In some embodiments, the composition may also include a third coat which is an
intermediate coating layer, which may be formulated to provide and/or promote binding
and/or adhesion of the previous coats to each other. According to some embodiments, the
intermediate coat may further provide oxygen and/or humidity resistance to the core.
According to some demonstrative embodiments, the three coating layers
described hereinabove may include substantially the same chemical polymers with either
same or different viscosities or molecular weights.
Without wishing to be limited to a single hypothesis, in some embodiments, it
may be one of the layers described above that contributes maximally to the resistance of
oxygen/humidity penetration into the core. However, according to some embodiments,
the composition of the present invention may include additional layers that may
contribute to the stability of the oxygen-sensitive liquid natural pharmaceutically or
nutritionally active agents, during the process or method descried below and/or during the
storing said food and/or during digestion and passage through the gastrointestinal (GI)
tract.
The Core
In some demonstrative embodiments, the core may be in the form of one or more
granules, particles or a solid powder and may optionally be coated by a plurality of
coating layers, e.g., as described in detail below.
According to some embodiments, the granules may be prepared using a fluidized
bed technology, such as by way of non-limiting example: Glatt or turbo jet, Glatt or an
Innojet coater/granulator, a Huttlin coater/granulator, a Granulex, and/or the like.
According to some demonstrative embodiments, the core may include a mixture
of the at least one oxygen-sensitive liquid natural pharmaceutically or nutritionally active
agent and at least one excipient, including at least one of an absorbent, a stabilizer, an
antioxidant (“oxygen scavenger”), a filler, a plasticizer, a surfactant (also referred to as a
“surface free energy-lowering agent”), a binder and optionally a hydrophobic solid fat or
fatty acid is in a melt state and/or any other suitable excipient, e.g., as described herein.
According to some embodiments, the mixture may be absorbed or adsorbed onto a
substrate to obtain the core. Although the mixture may optionally comprise an emulsion,
according to preferred embodiments the mixture does not comprise an emulsion and in
fact does not feature an emulsion. Optionally, the mixture consists essentially of the
oxygen-sensitive liquid natural pharmaceutically or nutritionally active agent, without
any added material. Alternatively, the mixture features the oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent in the form of a suspension, whether a
liquid or dry suspension. Also alternatively, the mixture features the oxygen-sensitive
liquid natural pharmaceutically or nutritionally active agent in a solid dispersion, for
example and without limitation a melt. Optionally and more preferably, the melt
comprises stearic acid and/or a PEG based polymer, which may optionally comprise a
PEG based co-polymer, optionally without a substrate for absorbing the melt.
According to some demonstrative embodiments, the total amount of the at least
one oxygen-sensitive liquid natural pharmaceutically or nutritionally active agent in the
mixture is from about 10% to about 90% by weight of the core.
The Absorbent
According to some embodiments, the core may include at least one absorbent
compound which is porous (also referred to herein as a “substrate”).
According to some embodiments, the absorbent may be responsible for absorbing
and/or adsorbing the at least one oxygen-sensitive liquid natural pharmaceutically or
nutritionally active agent by capillary action and/or capillary force.
According to other embodiments, the absorbent is meant to be coated by a
mixture which comprises the at least one oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent and at least one solid fat or solid fatty acid.
According to some embodiments, the solid fat or solid fatty acid may have a melting
point of below 50°C, including, for example, lauric acid and/or cacao butter.
In some embodiments, the higher the capillary force, the more effective the
absorbance and/or adsorbance. As discussed herein, capillarity or capillary action is a
phenomenon in which the surface of a liquid is observed to be elevated or depressed
where it comes into contact with a solid. Capillarity is spontaneous movement of liquids
up or down narrow tubes, or pores existing in the surface of a solid as a part of its surface
texture. As discussed herein, capillary action is a physical effect caused by the
interactions of a liquid with the walls of a thin tube or pores existing in the surface of a
solid, and the capillary effect is a function of the ability of the liquid to wet a particular
material.
According to some embodiments, as discussed with respect to the composition
described herein, an important characteristic of a liquid penetrant material is its ability to
freely wet the surface of a target object. At the liquid-solid surface interface, if the
molecules of the liquid have a stronger attraction to the molecules of the solid surface
than to each other (i.e., the adhesive forces are stronger than the cohesive forces), wetting
of the surface occurs. Alternately, if the liquid molecules are more strongly attracted to
each other than the molecules of the solid surface (i.e., the cohesive forces are stronger
than the adhesive forces), the liquid beads-up and does not wet the surface. One way to
quantify a liquid's surface wetting characteristics is to measure the contact angle of a drop
of liquid placed on the surface of an object. The contact angle is the angle formed by the
solid/liquid interface and the liquid/vapor interface measured from the side of the liquid
(FIGURE 4). Liquids wet surfaces when the contact angle is less than 90 degrees. For a
penetrant material to be effective, the contact angle should be as small as possible.
Wetting ability of a liquid is a function of the surface energies of the solid- gas
interface, the liquid-gas interface, and the solid-liquid interface. The surface energy
across an interface or the surface tension at the interface is a measure of the energy
required to form a unit area of new surface at the interface. The intermolecular bonds or
cohesive forces between the molecules of a liquid cause surface tension. When the liquid
encounters another substance, there is usually an attraction between the two materials.
The adhesive forces between the liquid and the second substance will compete against the
cohesive forces of the liquid. Liquids with weak cohesive bonds and a strong attraction to
another material (or the desire to create adhesive bonds) will tend to spread over the
material. Liquids with strong cohesive bonds and weaker adhesive forces will tend to
bead-up or form a droplet when in contact with another material.
In liquid penetrant testing, there are usually three surface interfaces involved, the
solid-gas interface, the liquid-gas interface, and the solid-liquid interface. For a liquid to
spread over the surface of a part, two conditions must be met. First, the surface energy of
the solid-gas interface must be greater than the combined surface energies of the liquid-
gas and the solid-liquid interfaces. Second, the surface energy of the solid-gas interface
must exceed the surface energy of the solid-liquid interface.
A penetrant's wetting characteristics are also largely responsible for its ability to
fill a void or pore. Penetrant materials are often pulled into surface breaking defects by
capillary action, which may be defined as the movement of liquid within the spaces of a
porous material due to the forces of adhesion, cohesion, and surface tension. Capillarity
can be explained by considering the effects of two opposing forces: adhesion, the
attractive (or repulsive) force between the molecules of the liquid and those of the solid,
and cohesion, the attractive force between the molecules of the liquid. The size of the
capillary action depends on the relative magnitudes cohesive forces within the liquid and
the adhesive forces operating between the liquid and the pore walls (Figure 5).
The forces of cohesion act to minimize the surface area of the liquid. When
the cohesive force, acting to reduce the surface area becomes equal to the adhesive force
acting to increase it, equilibrium is reached and the liquid stops rising where it contacts
the solid. Therefore the movement is due to unbalanced molecular attraction at the
boundary between the liquid and the solid pores wall. If liquid molecules near the
boundary are more strongly attracted to molecules in the material of the solid than to
other nearby liquid molecules, the liquid will rise in the tube. If liquid molecules are less
attracted to the material of the solid than to other liquid molecules, the liquid will fall.
The energetic gain from the new intermolecular interactions must be balanced against
gravity, which attempts to pull the liquid back down.
The capillary force driving the penetrant into the crack, voids or pores is a
function of the surface tension of the liquid-gas interface (σ), the contact angle with the
solid surface, and the size of the defect opening (pore diameter (d) or radius (r)). The
driving force for the capillary action can be expressed as the following formula:
Force = 2 πrσ LG cosθ
Where:
r = radius of the pore/ void opening (2 πr is the line of contact between the liquid
and the solid tubular surface.)
σ LG = liquid-gas surface tension
θ= contact angle
Since pressure is the force over a given area, it can be written that the pressure
developed, called the capillary pressure, is
Capillary Pressure = (2 σ LG cosθ)/ r
The above equations are for a cylindrical defect but the relationships of the
variables are the same for a flaw with a noncircular cross section. Capillary pressure
equations only apply when there is simultaneous contact of the penetrant along the entire
length of the crack opening and a liquid front forms that is equidistant from the surface. A
liquid penetrant surface could take-on a complex shape as a consequence of the various
deviations from flat parallel walls that an actual pore could have. In this case, the
expression for pressure is
Capillary Pressure = 2(σ SG - σ SL)/r = 2Σ /r
Where:
σ SG = the surface energy at the solid-gas interface.
σ SL = the surface energy at the solid-liquid interface.
r = the radius of the pore opening.
Σ = the adhesion tension (σ SG - σ SL).
Adhesion tension is the force acting on a unit length of the wetting line from the
direction of the solid. The wetting performance of the penetrant is degraded when
adhesion tension is the primary driving force.
As demonstrated by equations, the surface wetting characteristics (defined by the
surface energies) are important in order for a penetrant to fill a void. A liquid penetrant
will continue to fill the void until an opposing force balances the capillary pressure. This
force is usually the pressure of trapped gas in a void, as most flaws are open only at the
surface of the part. Since the gas originally in a flaw volume cannot escape through the
layer of penetrant, the gas is compressed near the closed end of a void.
Since the contact angle for penetrants is very close to zero, other methods have
been devised to make relative comparisons of the wetting characteristics of these liquids.
One method is to measure the height that a liquid reaches in a capillary tube (Figure 6).
Capillary rise (height) (hc) is a function of the surface tension of the liquid-gas
interface (σ), the contact angle with the solid surface, the size of the defect opening (pore
diameter (d)) and specific weights (γL, γG) of liquid and gas. The capillary rise (height)
as a result of the capillary action can be expressed as the following formula:
hc = 4σ cos(θ) / (γL-γG)d
Since for liquid-vapour interfaces σL>>σG , the equation reduces to:
hc = 4σ cos(θ) / γLd
Therefore, the narrower the tube or the smaller the diameter of pore, the
higher the liquid will climb or be absorbed or adsorbed, because a narrow column of
liquid weighs less than a thick one. Likewise the denser a liquid is, the less likely it is to
demonstrate capillarity. Capillary action is also less common with liquids which have a
very high level of cohesion, because the individual molecules in the fluid are drawn more
tightly to each other than they are to an opposing surface. Eventually, capillary action
will also reach a balance point, in which the forces of adhesion and cohesion are equal,
and the weight of the liquid holds it in place. As a general rule, the smaller the tube, the
higher up it the fluid will be drawn. Cohesion force is due to the relative attraction among
molecules in a fluid. Since this attraction decreases with increases temperature, the
surface tension reduces with increases temperature.
Viscous Flows
Since many of oxygen-sensitive liquid natural pharmaceutically or nutritionally
active agents, such as unsaturated fatty acids, omega 3 fatty acids, omega 6 fatty acids,
and omega 9 fatty acids, α-linolenic acid (18:3, n−3; ALA), eicosapentaenoic acid (20:5,
n−3; EPA), docosahexaenoic acid (22:6, n−3; DHA), oleic acid, fish oil, flax oil, olive
oil, etc., are viscous liquids, the flow rate of such oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agents through pores, void, crack will be also
dependent on their viscosity. Viscosity is like the internal friction of a fluid. Liquids flow
fastest in the center and tend to zero as the wall of the pore is approached. The viscous
force is the force necessary to move the top solid surface confining a fluid, when the
bottom surface does not move. That force is proportional to the surface area, A, and the
velocity, v, and inversely proportional to the distance, d, from the non-moving surface:
F =ƞ A v / d
η= viscosity of penetrant
The constant coefficient is called coefficient of viscosity, measured in N*s/m2,
and it depends on the type of fluid. It is 1.0x10-3 for water at 20 C. In the cgs system the
units of ƞ are dyne*s/cm2 = 1 poise (from Poiseuille). The conversion is 1 poise = 10-1 N
s / m2, so the coefficient of viscosity of water is also 0.01 poise = 1 cp (centipoise).
The flow rate of a penetrant through void, crack, or pore existing on the surface a
solid may be obtained through Poiseuille’s Law, as follows:
v = Δh / Δt = ΔV / Δt
Where
h = capillary height
v = flow rate
V = volume of penetrant flowing on a pore
t = time
and the rate of flow through a pore of A as:
v A = A Δh / Δt = ΔV / Δt
Where
A = cross sectional area of pore or void
It can be seen that the rate of flow is proportional to the volume of fluid flowing on a pore
per unit time.
Poiseuille's law relates this rate of flow to the difference in the pressure, per unit
length in the pore (L), necessary to move the flow into the pore:
Rate of Flow = ΔV / Δt = π r4 (P1 – P2) / (8 ηh)
Where:
P1 and P2 are the pressure on the both sides of the pore with opening radius of r
separated by a distance h
η = viscosity of penetrant
Notice that if the viscosity is larger, a larger force (a large pressure difference) is
needed to push the fluid through the pore or void. More importantly, if there is a
restriction, the flow rate decreases as r. So the flow rate of the penetrant is smaller on the
small diameter voids or pores than on large diameter ones.
The importance of viscosity can be seen based on Reynolds Number. If the flow
velocity is large enough and viscosity low enough, the flow may go from laminar
(smooth) to turbulent (vortices). This happens experimentally when a non-dimensional
parameter, called the Reynolds number, becomes larger than 2,000-3,000. The Reynolds
number is defined as:
Re = ρv r / η
Where:
v is the flow velocity for example through a pore of diameter r,
ρ is the density of the fluid, and
η is the coefficient of viscosity.
It can be seen that the Reynolds number measures the ratio of the momentum of
the fluid per unit volume (ρv instead of mv), and the viscosity per unit length. When the
momentum in the flow is too large compared to the viscosity, the flow is unstable and it
becomes chaotic and forms vortices that cannot be dissipated effectively by viscosity. In
other words, viscosity is what keeps the flow ordered, and without enough of it, the
motion of fluids becomes erratic.
According to some embodiments of the composition described herein, the
absorbent may be a water insoluble material possessing highly porosity and proper
surface tension enabling first the absorption and/or adsorption of an emulsion comprising
the at least one oxygen-sensitive liquid natural pharmaceutically or nutritionally active
agent, water and a surfactant and later the absorption of the oxygen-sensitive liquid
natural pharmaceutically or nutritionally active agent alone when the water is totally
evaporated.
According to other embodiments, the composition described herein, the absorbent
may include a suitable porosity to enable the absorption of a non- emulsion form of the at
least one oxygen-sensitive liquid natural pharmaceutically or nutritionally active agent.
According to these embodiments, when the least one oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent is not in the form of an emulsion there is no
need to use a surfactant in the core of the composition described herein.
Advantageously, if a surfactant is not used and an emulsion is not prepared, then
the oxygen-sensitive liquid pharmaceutically or nutritionally active agent does not need
to be heated when preparing the core, or at least does not need to be heated concomitantly
with exposure to oxygen.
According to some embodiments, examples of a suitable absorbent include, but
are not limited to, microcrystalline cellulose (MCC), silicon dioxide, lactose, talc,
aluminum silicate, dibasic calcium phosphate anhydrous, starch or a starch derivative, a
polysaccharide or a combination thereof. Optionally, the starch derivative comprises one
or more of partially pregelatinized starch, pregelatinized starch, starch phosphate,
modified food starch, or a combination thereof. Optionally the polysaccharide comprises
one or more of glucose-based polysaccharides/glucan including glycogen, starch
(amylose, amylopectin), cellulose, mannose-based polysaccharides (mannan), galactose-
based polysaccharides (galactan), N-acetylglucosamine-based polysaccharides including
chitin, gums such as arabic gum (gum acacia), modified polysaccharides such as
crosslinked pectin, cross linked sodium alginate; cellulose derivatives such as ethyl
cellulose, propyl cellulose, cross-linked cellulose derivatives and a combination thereof.
The Stabilizer
According to some embodiments, the at least one oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent may be mixed in the core with at least one
stabilizer.
In some demonstrative embodiments, the stabilizer may be selected from the
group consisting of dipotassium edetate, disodium edetate, edetate calcium disodium,
edetic acid, fumaric acid, malic acid, maltol, sodium edetate, trisodium edetate.
The Antioxidant (“Oxygen scavenger”).
According to some embodiments, the at least one oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent may be mixed in the core with at least one
antioxidant.
In some demonstrative embodiments, the antioxidant may be selected from the
group consisting of L-cysteine hydrochloride, L-cysteine base, 4,4 (2,3 dimethyl
tetramethylene dipyrocatechol), tocopherol-rich extract (natural vitamin E), α-tocopherol
(synthetic Vitamin E), β-tocopherol, γ-tocopherol, δ-tocopherol, butylhydroxinon, butyl
hydroxyanisole (BHA), butyl hydroxytoluene (BHT), propyl gallate, octyl gallate,
dodecyl gallate, tertiary butylhydroquinone (TBHQ), fumaric acid, malic acid, ascorbic
acid (Vitamin C), sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl
palmitate, and ascorbyl stearate.
According to some demonstrative embodiments described, the core may comprise
both a stabilizer and an antioxidant. Stabilizing agents and antioxidants may optionally be
differentiated. For example, the antioxidant may be L- cysteine hydrochloride or L-
cysteine base or tocopherol or polyphenols and/or a combination thereof whereas the
stabilizer may be dipotassium edetate.
The Surfactant
According to some embodiments, the at least one oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent may be mixed in the core with at least one
surfactant.
In some demonstrative embodiments, the surfactant may be an emulsifier
(emulsifying agent), suspending agent, dispersing agent, and/or any other food grade
surface active agents, such as, by way of non-limiting example, tween 80, docusate
sodium, sodium lauryl sulfate, glyceryl monooleate, polyoxyethylene sorbitan fatty acid
esters, polyvinyl alcohol, sorbitan esters, etc., and/or a combination thereof. Optionally
and more preferably, if a surfactant is used, it is used in the core without forming an
emulsion with the oxygen-sensitive pharmaceutically or nutritionally active agent.
According to at least some embodiments, alternatively a surfactant is present in one or
more of the coating layers but is not present in the core.
The Glidant
According to some embodiments, the at least one oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent may be mixed in the core with at least one
glidant.
In some demonstrative embodiments, the glidant may be silicon dioxide, a metal
stearate or stearic acid, or a combination thereof. The metal stearate may optionally
comprise sodium or magnesium stearate.
The plasticizer
According to some embodiments, the plasticizer described herein may be selected
from the group consisting of polyethylene glycol (PEG), e.g., PEG 400, triethyl citrate,
triacetin and the like.
The Filler
According to some embodiments of the present invention, the filler referred to
herein, may be selected from, but not limited to the group including microcrystalline
cellulose, a sugar, such as lactose, glucose, galactose, fructose, or sucrose; dicalcium
phosphate; sugar alcohols such as sorbitol, manitol, mantitol, lactitol, xylitol, isomalt,
erythritol, and hydrogenated starch hydrolysates; corn starch; and potato starch; and/or a
mixture or mixtures thereof. Preferably, the filler is lactose.
The Binder
According to some embodiments of the present invention, the binder referred to
herein, may be selected from, but not limited to the group including Povidone (PVP:
polyvinyl pyrrolidone), Copovidone (copolymer of vinyl pyrrolidone and vinyl acetate),
polyvinyl alcohol, low molecular weight HPC (hydroxypropyl cellulose), low molecular
weight HPMC (hydroxypropyl methylcellulose), low molecular weight hydroxymethyl
cellulose (MC), low molecular weight sodium carboxy methyl cellulose, low molecular
weight hydroxyethylcellulose, low molecular weight hydroxymethylcellulose, cellulose
acetate, gelatin, hydrolyzed gelatin, polyethylene oxide, acacia, dextrin, starch, and water
soluble polyacrylates and polymethacrylates, low molecular weight ethylcellulose or a
mixture thereof. Preferably, the filler is low molecular weight HPMC.
The hydrophobic solid fat or fatty acid
According to some embodiments, the hydrophobic solid fat or fatty acid as
described herein, may have a melting point lower than 70 C and higher than 25 C,
preferably lower than 65˚C and higher than 30 C, more preferably lower than 60 C and
higher than 35 C.
As used herein the term “fat” or “fats” includes of a wide group of hydrophobic
compounds that are generally soluble in organic solvents and largely insoluble in water.
Chemically, fats are generally triesters of glycerol and fatty acids. Fats may be either
solid or liquid at room temperature, depending on their structure and composition.
Although the words "oils", "fats", and "lipids" are all used to refer to fats, "oils" is usually
used to refer to fats that are liquids at normal room temperature, while "fats" is usually
used to refer to fats that are solids at normal room temperature. "Lipids" is used to refer
to both liquid and solid fats, along with other related substances. The word "oil" is used
for any substance that does not mix with water and has a greasy feel, such as petroleum
(or crude oil) and heating oil, regardless of its chemical structure. Examples of fats
according to the present invention include but are not limited to fats as described above,
fatty acids, fatty acid esters, fatty acid triesters, salts of fatty acids such as aluminum,
sodium, potassium and magnesium salts, fatty alcohols, phospholipids, solid lipids,
waxes, lauric acid, stearic acid, alkenes, waxes, fatty acids and their salts and alcohol
esters, long chain alcohols and glucoles, and combinations thereof.
Non-limiting examples of such materials include alkenes such as paraffin wax
which is composed of a chain of alkenes, normal paraffins of type CnH2n+2 which are a
family of saturated hydrocarbons which are waxy solids having melting point in the range
of 23-67oC (depending on the number of alkanes in the chain); natural waxes (which are
typically esters of fatty acids and long chain alcohols) and synthetic waxes (which are
long-chain hydrocarbons lacking functional groups) such as beeswax, carnauba wax,
japan wax, bone wax, paraffin wax, chinese wax, lanolin (wool wax), shellac wax,
spermaceti, bayberry wax, candelilla wax, castor wax, esparto wax, jojoba oil, ouricury
wax, rice bran wax, soy wax, ceresin waxes, montan wax, ozocerite, peat waxes,
microcrystalline wax, petroleum jelly, polyethylene waxes, Fischer-Tropsch waxes,
chemically modified waxes, substituted amide waxes; polymerized α-olefins;
hydrogenated vegetable oil, hydrogenated castor oil; fatty acids, such as lauric acid,
myristic acid, palmitic acid, palmitate, palmitoleate, hydroxypalmitate, stearic acid,
arachidic acid, oleic acid, stearic acid, sodium stearat, calcium stearate, magnesium
stearate, hydroxyoctacosanyl hydroxystearate, , oleate esters of long-chain, esters of fatty
acids, fatty alcohols, esterified fatty diols, hydroxylated fatty acid, hydrogenated fatty
acid (saturated or partially saturated fatty acids), partially hydrogenated soybean oil,
partially hydrogenated cottonseed oil, aliphatic alcohols, phospholipids, lecithin,
phosphathydil cholin, triesters of fatty acids for example triglycerides received from fatty
acids and glycerol (1,2,3-trihydroxypropane) including fats and oils such as coconut oil,
hydrogenated coconut oil, cacao butter (also called theobroma oil or theobroma cacao);
palm oil; eutectics such as fatty acid eutectics which are a mixture of two or more
substances which both possess reliable melting and solidification behaviour; mono and
diglycerides, poloxamers which are block-co-polymers of polyethylene oxide and
polypropylene glycol (Lutrol F), block-co-polymers of polyethylene glycol and
polyesters, and a combination thereof.
According to some embodiments, the solid fat or fatty acid is at least one of lauric
acid, hydrogenated coconut oil, cacao butter, stearic acid, and/or a combination thereof.
According to some embodiments, the hydrophobic solid fat or fatty acid may be
capable of forming a stable hydrophobic film, as described in detail herein.
Alternatively, said hydrophobic fat or fatty acid may be capable of forming a
matrix in which an oxygen-sensitive liquid natural pharmaceutically or nutritionally
active agent core granules or particles are embedded.
According to yet another embodiment, the hydrophobic solid fat or fatty acid, e.g.,
in a melt form, may be mixed with an oxygen-sensitive liquid natural pharmaceutically or
nutritionally active agent, and optionally, a stabilizer, to form a uniform mixture.
According to these embodiments, the mixture may be added to an absorbent to form core
particles or granules or an absorbent coated with a film of the mixture. If core particles or
granules are formed, the core particles or granules include the oxygen-sensitive liquid
natural pharmaceutically or nutritionally active agent and said absorbent. If an absorbent
coated with a film of the mixture is formed, the film includes the solid fat or fatty acid
and the oxygen-sensitive liquid natural pharmaceutically or nutritionally active agents
and the stabilizer as a mixture onto or around the absorbent.
The first coating layer
In some demonstrative embodiments, the composition may include a first coating
layer (also referred to herein as “the fatty coating layer”), which may act as the most
inner coating layer coating the core, and which may be formulated to prevent or diminish
humidity and/or oxygen penetration into the core, e.g., during the further coating
processes, as described below.
According to some embodiments, the first coating layer may include at least one
hydrophobic solid fat and/or fatty acid as described hereinabove.
According to some demonstrative embodiments, the at least one hydrophobic
solid fat and/or fatty acid may form a stable hydrophobic film or matrix which may
embed the core containing the at least one oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent.
According to other embodiments of the present invention, the at least one
hydrophobic solid fat and/or fatty acid may form a film directly around the oxygen
sensitive liquid natural pharmaceutically or nutritionally active agent core particles, e.g.,
when being in the form of granules.
The intermediate coating layer
In some demonstrative embodiments, the composition may include an
intermediate coating layer. In some embodiments, as described in detail below, the
intermediate coating layer may be formulated to provide and/or promote binding and/or
adhesion of the previous coats to each other. According to some embodiments, the
intermediate coat may further provide oxygen and/or humidity resistance to the core.
According to some embodiments, the intermediate coating layer may include an
aqueous solution of 0.1% and have a surface tension lower than 60 mN/m, preferably
lower than 50 mN/m and more preferably lower than 45 mN/m (measured at 25 C).
According to some embodiments, the intermediate coating layer may include at
least one interfacial tension adjusting polymer, and accordingly may be used for adjusting
the surface tension for further coating with an outer coating layer, as described in detail
below. The interfacial tension adjusting polymer is preferably characterized by an
aqueous solution of 0.1% having a surface tension lower than 60 mN/m when measured
at 25 C.
As discussed herein, surface tension (ST) is a property of the surface of a liquid
that allows it to resist an external force, that is, surface tension is the measurement of the
cohesive (excess) energy present at a gas/liquid interface. The molecules of a liquid
attract each other. The interactions of a molecule in the bulk of a liquid are balanced by
an equally attractive force in all directions. Molecules on the surface of a liquid
experience an imbalance of forces as indicated below. The net effect of this situation is
the presence of free energy at the surface. The excess energy is called surface free energy
and can be quantified as a measurement of energy/area. It is also possible to describe this
situation as having a line tension or surface tension, which is quantified as a force/length
measurement. The common units for surface tension are dynes/cm or mN/m (these units
are equivalent).
Polar liquids, such as water, have strong intermolecular interactions and thus high
surface tensions. Any factor which decreases the strength of this interaction will lower
surface tension. Thus an increase in the temperature of this system will lower surface
tension. Any contamination, especially by surfactants, will lower surface tension and
lower surface free energy. Some surface tension values of common liquids and solvents
are shown in the following table.
Substance γ (mN/m) γp (mN/m) γd (mN/m)
Water 72.8 51.0 21.8
Glycerol 64 30 34
Ethylene glycol 48 19 29
Dimethyl sulfoxide 44 8 36
Benzyl alcohol 39 11.4 28.6
Toluene 28.4 2.3 26.10
Hexane 18.4 - 18.4
Acetone 23.7 - 23.7
Chloroform 27.15 - 27.15
Diiodomethane 50.8 - 50.8
The adhesion and uniformity of a film are also influenced by the forces which act
between the coating formulation that is in a solution form and the core surface of the film
coated surface. Therefore, coating formulations for certain core surface can be optimized
via determination of wetting behavior, the measure of which is the contact or wetting
angle. This is the angle that forms between a liquid droplet and the surface of the solid
body to which it is applied.
The adhesion and uniformity of a film are also influenced by the forces which act
between the coating formulation which is in a solution form and the core surface of the
film coated surface. Therefore, coating formulations for certain core surface can be
optimized via determination of wetting behavior, the measure of which is the contact or
wetting angle. This is the angle that forms between a liquid droplet and the surface of the
solid body to which it is applied.
When a liquid does not completely spread on a substrate (usually a solid) a
contact angle (θ) is formed which is geometrically defined as the angle on the liquid side
of the tangential line drawn through the three phase boundary where a liquid, gas and
solid intersect, or two immiscible liquids and solid intersect. The contact angle is a direct
measure of interactions taking place between the participating phases. The contact angle
is determined by drawing a tangent at the contact where the liquid and solid intersect.
The contact angle is small when the core surface is evenly wetted by spreading
droplets. If the liquid droplet forms a defined angle, the size of the contact angle may be
described by the Young-Dupre equation:
γγγγSG- γγγγSL= LG cosθ
Where θ = Contact angle
γSG = surface tension of the solid body
γLG= surface tension of the liquid
γSL = interfacial tension between liquid and solid body (cannot typically be
measured directly)
With the aid of this equation it is possible to estimate the surface tension of a solid
body by measuring the relevant contact angles. If one measures them with liquid of
varying surface tension and plots their cosines as a function of the surface tension of the
liquids, the result is a straight line. The abscissa value of the intersection of the straight
line with cosθ = 1 is referred to as the critical surface tension of wetting γC. A liquid with
a surface tension smaller than γC wets the solid in question.
In some embodiments, the wetting or contact angle can be measured by means of
telescopic goniometers (e.g. LuW Wettability Tester by AB Lorentzenu. Wettre, S-10028
Stockholm 49). In some cases, the quantity γC does not suffice to characterize polymer
surfaces since it depends on, amongst other factors, the polar character of the test liquids.
This method can, however, be improved by dividing γ into non-polar part γd (caused by
dispersion forces) and a polar part γp (caused by dipolar interactions and hydrogen
bonds):
γL = γLp + γLd
γS = γSp + γSd
Where
γL= surface tension of the test liquid
γS= surface tension of the solid body
And γSp and γSd can be determined by means of the following equation:
1+ (cosθθ/2)( γL /√γLd) = √γSd + √γSp . √(γL-γLd)/ γLd If 1+ (cosθ/2)( γL
/√γLd) is plotted against √(γL-γLd)/ γLd, straight lines are obtained from the
slopes and ordinate intercepts of which γSp and γSd can be determined and thus
γS calculated. γC and γS are approximately, but not exactly, the same. Since the
measurement is also influenced by irregularities of the polymer surfaces, one
cannot typically obtain the true contact angle θ but rather the quantity θ'. Both
quantities are linked by the relationship:
Roughness factor r = cosθ'/ cosθ
The lower the surface tension of the coating formulation against that of the core
surface, the better the droplets will spread on the surface. If formulations with organic
solvents are used, which may wet the surface very well, the contact angle will be close to
zero, and the surface tensions of such formulations are then about 20 to 30 mN/m.
Aqueous coating dispersion of some polymer like EUDRAGIT L 30 D type shows low
surface tension in the range of 40 to 45 mN/m.
According to some demonstrative embodiments, the contact angle measurements
discussed herein with reference to the composition of the present invention provide the
following information:
• Smaller contact angles give smoother film coatings
• The contact angle becomes smaller with decreasing porosity and film
former concentration.
• Solvents with high boiling point and high dielectric constant reduce the
contact angle.
• The higher the critical surface tension of core, the better the adhesion of
the film to the core.
• The smaller the contact angle, the better the adhesion of the film to the
core.
The critical surface tension of the core or granules coated with a hydrophobic
solid fat is essentially very low. Therefore, for providing better spreading and thus better
adhesion of the outer coating layer film to the core there is a need for reducing the surface
free energy at the interface between the surface of the fat coated core/granules and the
solution of the outer coating layer polymer.
According to some embodiments, the intermediate coating layer may include an
aqueous solution of 0.1% having a surface tension lower than 60 mN/m, preferably,
lower than 50 mN/m more preferably, lower than 45 mN/m (measured at 25 C), for
reducing the surface free energy at the interface between the surface of the fat coated
core/granules and the solution of the outer coating layer polymer.
The following table shows for example the surface tension of the solution
of some water soluble polymers. The Surface tension was measured at 25° C, 0.1%
aqueous solution of the polymers.
Polymer Surface Tension mN/m
Sodium Carboxymethylcellulose (Na-CMC) 71.0
Hydroxyethyl cellulose (HEC) 66.8
Hydroxypropyl cellulose (HPC) 43.6
Hydroxypropyl methyl cellulose (HPMC) 46-51
Hydroxymethyl cellulose (HMC) 50-55
In some demonstrative embodiments, the intermediate coating layer may include,
but not limited to, at least one of the following polymers: hyroxypropylmethylcellulose
(HPMC), hydroxypropylethylcellulose (HPEC), hydroxypropylcellulose (HPC),
methylcellulose, ethylcellulose, pH-sensitive polymers e.g., enteric polymers including
phthalate derivatives such as acid phthalate of carbohydrates, amylose acetate phthalate,
cellulose acetate phthalate (CAP), other cellulose ester phthalates, cellulose ether
phthalates, hydroxypropylcellulose phthalate (HPCP), hydroxypropylethylcellulose
phthalate (HPECP), hydroxyproplymethylcellulose phthalate (HPMCP),
hydroxyproplymethylcellulose acetate succinate (HPMCAS), methylcellulose phthalate
(MCP), polyvinyl acetate phthalate (PVAcP), polyvinyl acetate hydrogen phthalate,
sodium CAP, starch acid phthalate, cellulose acetate trimellitate (CAT), styrene-maleic
acid dibutyl phthalate copolymer, styrene-maleic acid/polyvinylacetate phthalate
copolymer, styrene and maleic acid copolymers, polyacrylic acid derivatives such as
acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof,
polyacrylic and methacrylic acid copolymers, shellac, and vinyl acetate and crotonic acid
copolymers. In some embodiments, pH-sensitive polymers include shellac, phthalate
derivatives, CAT, HPMCAS, polyacrylic acid derivatives, particularly copolymers
comprising acrylic acid and at least one acrylic acid ester, Eudragit S (poly(methacrylic
acid, methyl methacrylate)1:2); Eudragit L100 (poly(methacrylic acid, methyl
methacrylate)1:1); Eudragit L30D , (poly(methacrylic acid, ethyl acrylate)1:1); and
(Eudragit L100-55) (poly(methacrylic acid, ethyl acrylate)1:1) (Eudragit L is an
anionic polymer synthesized from methacrylic acid and methacrylic acid methyl ester),
polymethyl methacrylate blended with acrylic acid and acrylic ester
copolymers, alginic acid and alginates such as ammonia alginate, sodium, potassium,
magnesium or calcium alginate, vinyl acetate copolymers, polyvinyl acetate 30D (30%
dispersion in water), a poly(dimethylaminoethylacrylate) which is a neutral methacrylic
ester available from Rohm Pharma (Degusa) under the name “Eudragit E™, a copolymer
of methylmethacrylate and ethylacrylate with small portion of trimethylammonioethyl
methacrylate chloride (Eudragit RL, Eudragit RS), a copolymer of methylmethacrylate
and ethylacrylate (Eudragit NE 30D), Zein, shellac, gums, poloxamer, polysaccharides
and/or any combination thereof.
The outer coating layer
In some demonstrative embodiments, the composition may include an outer
coating layer (also referred to herein as the “barrier coating layer”). In some
embodiments, the outer coating layer may be formulated to prevent or diminish
transmission of humidity and/or oxygen into the core, e.g., during the storage and/or
throughout the shelf life of the food product.
According to some embodiments, an outer coating layer may comprise at least
one polymer having oxygen transmission rate of less than 1000 cc/m2/24 hr, preferably
less than 500 cc/m2/24 hr and more preferably, less than 100 cc/m2/24 hr, as measured at
standard test conditions (i.e. 73°F (23°C) and 0% RH). According to some embodiments,
the at least one polymer may have a water vapor transmission rate of less than 400
g/m²/day, preferably, less than 350 g/m²/day, and more preferably, less than 300
g/m²/day.
In some embodiments, the outer coating layer may have an adjusted surface for
reducing or preventing the transmission of oxygen and/or humidity into the core of the
composition described herein in accordance with some embodiments.
Water Vapor Permeability (WVP) of Films
According to some embodiments, the water vapor permeability is an important
property of most outer layer coating films, mainly because of the importance of the role
of water in deteriorative reactions.
Water acts as a solvent or carrier and can cause texture degradation, chemical and
enzymatic reactions and is thus destructive of oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agents. Also the water activity of foods is an
important parameter in relation to the shelf-life of the food and food-containing oxygen-
sensitive liquid natural pharmaceutically or nutritionally active agents. In low-moisture
foods and oxygen-sensitive liquid natural pharmaceutically or nutritionally active agents,
low levels of water activity must be maintained to minimize the deteriorative chemical
and enzymatic reactions and to prevent the texture degradation. The composition of film
forming materials (hydrophilic and hydrophobic character), temperature and relative
humidity of the environment affect the water vapor permeability of the films. When
considering a suitable barrier in foods containing oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agents, the barrier properties of the films may be
important parameters.
Polysaccharide films and coatings may generally be good barriers against oxygen
and carbon dioxide and have good mechanical properties but their barrier property
against water vapor is poor because of the their hydrophilic character.
One way to achieve a better water vapor barrier may be to add an extra
hydrophobic component, e.g. a lipid (waxes, fatty acids), in the film and produce a
composite film. Here the lipid component serves as the barrier against water vapor. By
adding lipid, the hydrophobicity of the film is increased and as a result of this case, water
vapor barrier property of the film increases.
Water Vapor Permeability of a film is a constant that should be independent of the
driving force on the water vapor transmission. When a film is under different water vapor
pressure gradients (at the same temperature), the flow of water vapor through the film
differs, but their calculated permeability should be the same. This behavior does not
happen with hydrophilic films where water molecules interact with polar groups in the
film structure causing plasticization or swelling.
Another assumption inherent to the calculation of permeability is its independence
from film thickness. This assumption may not be true for hydrophilic films and because
of that, experimentally determined water vapor permeability of many films applied only
to the specific water vapor gradients used during testing and for the specific thickness of
the tested specimens, use of the terms "Effective Permeability" or "Apparent
Permeability" may be appropriate.
Moisture transport mechanism through a composite depends upon the material
and environmental conditions. Permeability has two different features in case of
composites. First, in non-porous membranes, permeation can occur by solution and
diffusion, and the other, simultaneous permeation through open pores is possible in
porous membrane.
There are various methods of measuring permeability. Weight loss measurements
are of importance to determine permeability characteristics. Water vapor permeability
may be determined by direct weighing because, despite its inherent problems, mainly
related to water properties such as high solubility and cluster formation within the
polymer and tendency to plasticize the polymer matrix, it can be a straightforward and
relatively reliable method. The major disadvantage of this method resides in its weakness
to provide information for a kinetic profile when such a response is required.
Another measurement method is based on the standard described in ASTM E96–
80 (standard test method procedure for water vapor permeability). According to this
method, water vapor permeability is determined gravimetrically and generally the applied
procedures are nearly the same in many research papers that are related with this purpose.
In this procedure firstly, the test film is sealed to a glass permeation cell which contain
anhydrous calcium chloride (CaCl ), or silica gel (Relative vapor pressure; RVP=0) and
then the cell is placed in the desiccators maintained at specific relative humidity and
temperature (generally 300C, 22% RH) with magnesium nitrate or potassium acetate.
Permeation cells are continuously weighed and recorded, and the water vapor that
transferred through the film and absorbed by the desiccant are determined by measuring
the weight gain. Changes in weight of the cell were plotted as a function of time. When
the relationship between weight gain (∆w) and time (∆t) is linear, the slope of the plot is
used to calculate the water vapor transmission rate (WVTR) and water vapor
permeability (WVP). Slope is calculated by linear regression and correlation coefficient
(r2 >> 0.99).
The WVTR is calculated from the slope (∆w/∆t) of the straight line divided
by the test area (A), (g s-1 m-2):
WVTR = ∆w / (∆t . A) (g.m-2.s-1)
Where
∆w / ∆t = transfer rate, amount of moisture loss per unit of time (g.s-1)
A= area exposed to moisture transfer (m )
The WVP (kg Pa-1 s-1 m-1) is calculated as:
WVP= [WVTR / S (R1-R2)].d
Where S = saturation vapor pressure (Pa) of water at test temperature,
R1 = RVP (relative vapor pressure) in the desiccator,
R2 = RVP in the permeation cell, and
d = film thickness (m).
In some embodiments, at least three replicates of each film should be tested for
WVP and all films should be equilibrated with specific RH before permeability
determination.
The water vapor permeability can also be calculated from the WVTR as follows:
P = WVTR . L / ∆p (g/m^2.s.Pa)
L = film thickness (m)
∆p = water vapor pressure gradient between the two sides of the film (Pa) P =
film permeability (g.m-2.s-1Pa-1)
The rate of permeation is generally expressed by the permeability (P) rather than
by a diffusion coefficient (D) and the solubility (S) of the penetrant in the film. When
there is no interaction between the water vapor and film, these laws can apply for
homogeneous materials. Then, permeability follows a solution-diffusion model as:
P = D.S
Where D is the diffusion coefficient and the S is the slope of the sorption isotherm
and is constant for the linear sorption isotherm.
The diffusion coefficient describes the movement of permeant molecule through a
polymer, and thus represents a kinetic property of the polymer-permeant system.
As a result of the hydrophilic characteristics of polysaccharide films, the water
vapor permeability of films is related to their thickness. The permeability values increase
with the increasing thickness of the films.
Thickness of films and the molecular weight (MW) of the film forming polymers
may also affect both water vapor permeability (WVP) and oxygen permeability (OP) of
the films.
Oxygen Transmission Determination (OTR)
Oxygen transmission rate is the steady-state rate at which oxygen gas permeates
through a film at specified conditions of temperature and relative humidity. Values are
expressed in cc/100 in2/24hr in US standard units and cc/m /24hr in metric (or SI) units.
Gas permeability, especially oxygen permeability, of the polymer may indicate
the protective function of the polymer as a barrier against oxygen transmission. Such
polymers which demonstrate low oxygen permeability may be used in the outer coating
layer. For the purpose of the composition as discussed herein, the relevant gas for
improved stability of the oxygen-sensitive liquid natural pharmaceutically or nutritionally
active agents is oxygen. The viability of oxygen-sensitive liquid natural pharmaceutically
or nutritionally active agents may be significantly reduced upon exposing to oxygen.
Therefore, for providing long term stability and receiving an extended shelf life for
oxygen-sensitive liquid natural pharmaceutically or nutritionally active agents, the outer
coating layer should provide a significant oxygen barrier.
The gas permeability, q, (ml/m /day/atm) (DIN 53380) is defined as the volume
of a gas converted to 0°C and 760 torr which permeates 1 m of the film to be tested
within one day at a specific temperature and pressure gradient. It may therefore be
calculated according to the following formula: q = {To.Pu/[Po .T.A (Pb-Pu)]}.24.
Q.(∆x/∆t).10
Po = normal pressure in atm
To = normal temperature in K
T = experimental temperature in K
A = sample area in m
T = time interval in hrs between two measurements
Pb = atmospheric pressure in atm
Pu = pressure in test chamber between sample and mercury thread
Q = cross section of capillaries in cm
∆x/∆t = sink rate of the mercury thread in cm/hr
The following table shows Oxygen Transmission rate (OTR) and Water vapor
Transmission rate (WVTR) of some example water soluble polymers.
Film Forming Oxygen Transmission rate, Water vapor
Polymer Cm /m /atm O day Transmission rate ,
g/m /day
HPC, Klucel EF Medium Low
776 126
CMC, Aqualon or Low Low
Blanose 7L 18 228
HEC, Natrosol 250L Low Medium
33 360
HPMC 5cps High High
3180 420
Non-limiting examples of outer layer coating polymer include water- soluble,
hydrophilic polymers, such as, for example, polyvinyl alcohol (PVA), Povidone (PVP:
polyvinyl pyrrolidone), Copovidone (copolymer of vinyl pyrrolidone and vinyl acetate),
Kollicoat Protect (BASF) which is a mixture of Kollicoat IR (a polyvinyl alcohol (PVA)-
polyethylene glycol (PEG) graft copolymer) and polyvinyl alcohol (PVA), Opadry AMB
(Colorcon) which is a mixture based on PVA, Aquarius MG which is a cellulosic- based
polymer containing natural wax, lecithin, xanthan gum and talc, low molecular weight
HPC (hydroxypropyl cellulose), starch, gelatin, low molecular weight carboxy methyl
cellulose such as 7LF, 7L2P, Na-carboxy methyl cellulose, or a mixture/mixtures thereof.
In some embodiments, mixture(s) of water soluble polymers with insoluble agents such
as waxes, fats, fatty acids, and/or the like, may be utilized.
In some preferred embodiments, the outer coating polymer(s) are carboxy methyl
cellulose such as 7LF or 7L2P, polyvinyl alcohol, Kollicoat Protect (BASF) which is a
mixture of Kollicoat IR (a polyvinyl alcohol (PVA)-polyethylene glycol (PEG) graft
copolymer) and polyvinyl alcohol (PVA) and silicon dioxide, Opadry AMB (Colorcon)
which is a mixture based on PVA, and Aquarius MG which is a cellulosic-based polymer
containing natural wax. Theses polymers may provide superior barrier properties against
water vapor/ humidity and/or oxygen penetration into the core or granules.
According to some demonstrative embodiments, the outer coating layer may
include one or more other excipients, such as, by way of non-limiting example, at least
one plasticizer.
The enteric coating
According to some demonstrative embodiments, the composition described herein
may optionally include an enteric coating layer. In some embodiments, the enteric
coating layer may provide protection for the composition from destructive parameters
such as low pHs and enzymes, upon digestion and passage through the gastrointestinal
(GI) tract. According to some embodiments, the enteric coating may provide a delayed
release profile for the composition, e.g., upon digestion.
According to some embodiments, the enteric coating layer may include an enteric
polymer selected from, but not limited to, the group including: phthalate derivatives such
as acid phthalate of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate
(CAP), other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose
phthalate (HPCP), hydroxypropylethylcellulose phthalate (HPECP),
hydroxyproplymethylcellulose phthalate (HPMCP), hydroxyproplymethylcellulose
acetate succinate (HPMCAS), methylcellulose phthalate (MCP), polyvinyl acetate
phthalate (PVAcP), polyvinyl acetate hydrogen phthalate, sodium CAP, starch acid
phthalate, cellulose acetate trimellitate (CAT), styrene-maleic acid dibutyl phthalate
copolymer, styrene-maleic acid/polyvinylacetate phthalate copolymer, styrene and maleic
acid copolymers, polyacrylic acid derivatives such as acrylic acid and acrylic ester
copolymers, polymethacrylic acid and esters thereof, polyacrylic and methacrylic acid
copolymers, and vinyl acetate and crotonic acid copolymers. In some embodiments, pH-
sensitive polymers include shellac, phthalate derivatives, CAT, HPMCAS, polyacrylic
acid derivatives, particularly copolymers comprising acrylic acid and at least one acrylic
acid ester, EudragitTM S (poly(methacrylic acid, methyl methacrylate)1:2); Eudragit
L100TM (poly(methacrylic acid, methyl methacrylate)1:1); Eudragit L30DTM,
(poly(methacrylic acid, ethyl acrylate)1:1); and (Eudragit L100-55) (poly(methacrylic
acid, ethyl acrylate)1:1) (EudragitTM L is an anionic polymer synthesized from
methacrylic acid and methacrylic acid methyl ester), polymethyl methacrylate blended
with acrylic acid and acrylic ester copolymers, alginic acid and alginates, ammonia
alginate, sodium, potassium, magnesium or calcium alginate, vinyl acetate copolymers,
polyvinyl acetate 30D (30% dispersion in water), a poly(dimethylaminoethylacrylate)
“Eudragit E™, a copolymer of methylmethacrylate and ethylacrylate with small portion
of trimethylammonioethyl methacrylate chloride (Eudragit RL, Eudragit RS), a
copolymer of methylmethacrylate and ethylacrylate (Eudragit NE 30D), Zein, shellac,
gums, poloxamer, polysaccharides.
In some demonstrative embodiments described is a process and method for
stabilizing at least one oxygen-sensitive liquid natural pharmaceutically or nutritionally
active agents to be used as a supplement, food additive and/or as a supplement which
may be added into a food product.
In some demonstrative embodiments, the process and/or method described herein
may provide for a substantially humidity resistant oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent, and accordingly enable high stability
and/or prolonged shelf life for a food product at ambient temperature, wherein the
composition yielded by the process or method described herein is stable throughout
heating step(s) needed during the preparation of many food products, e.g., as described in
detail above.
According to some demonstrative embodiments, the method may include one or
more ways to prepare a core of a composition, which includes at least one oxygen-
sensitive liquid natural pharmaceutically or nutritionally active agent optionally with one
or more excipients. The method may further include coating the core with one or more
coating layers.
Preparation of the core
According to some demonstrative embodiments, the method may include
absorbing and/or adsorbing the at least one oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agents onto a core. According to some
embodiments, the at least one oxygen-sensitive liquid natural pharmaceutically or
nutritionally active agent may be absorbed or adsorbed onto the core in the form of a
suspension (wet or dry) or solid dispersion or solution, or may optionally be absorbed or
adsorbed directly.
According to some embodiments, if an emulsion is used, the emulsion may be
prepared by dispersing the oxygen-sensitive liquid natural pharmaceutically or
nutritionally active agent and an oxygen scavenger in purified degassed water, e.g., using
an emulsifier and/or a homogenizer. The resulting emulsion may be sprayed onto an
absorbent, for example, an absorbent which was preheated at 40°C. The spraying may be
done under an inert gas to obtain a core comprising the at least one oxygen-sensitive
liquid natural pharmaceutically or nutritionally active agent which is absorbed by the
absorbent which may be, for example, a solidified oil.
According to other demonstrative embodiments the method described may
include preparing a liquid mixture of an at least one oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent, at least one of a stabilizer, an antioxidant
(“oxygen scavenger”), a filler, a plasticizer, a surfactant (also referred to as a “surface
free energy-lowering agent”), a binder, and optionally a hydrophobic solid fat or fatty
acid is in a melt state. According to these embodiments, the method may include spraying
the liquid mixture onto a substrate to obtain a solid fatty matrix particle. The solid fatty
matrix particle embeds the substrate and oxygen-sensitive liquid natural pharmaceutically
or nutritionally active agent. Additionally or alternatively, spraying the liquid mixture
onto the substrate may form a film around the substrate/core. According to these
demonstrative embodiments, the method may include spraying while using an inert gas
and/or under a non-reactive atmosphere.
Although the mixture may optionally comprise an emulsion, according to
preferred embodiments the mixture does not comprise an emulsion and in fact does not
feature an emulsion. Optionally, the mixture consists essentially of the oxygen-sensitive
liquid natural pharmaceutically or nutritionally active agent, without any added material.
Alternatively, the mixture features the oxygen-sensitive liquid natural pharmaceutically
or nutritionally active agent in the form of a suspension, whether a liquid or dry
suspension. Also alternatively, the mixture features the oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent in a solid dispersion, for example and
without limitation a melt. Optionally and more preferably, the melt comprises stearic acid
and/or a PEG based polymer, which may optionally comprise a PEG based co-polymer,
optionally without a substrate for absorbing the melt.
According to some embodiments, if the core is made in the form of granules, the
granules may be prepared using a fluidized bed technology, such as by way of non-
limiting example: Glatt or turbo jet, Glatt or an Innojet coater/granulator, a Huttlin
coater/granulator, a Granulex, and/or the like.
According to some demonstrative embodiments, the total amount of the at least
one oxygen-sensitive liquid natural pharmaceutically or nutritionally active agent in the
mixture is from about 10% to about 90% by weight of the core.
Coating of the core
In some demonstrative embodiments, the core may be coated by a first coating
layer which may include at least one hydrophobic solid fat and/or fatty acid as described
hereinabove.
According to some embodiments, the method may include using the at least one
hydrophobic solid fat and/or fatty acid to form a stable hydrophobic film or matrix which
may embed to the core or may form a film around the core to obtain hydrophobic solid fat
coated core.
In some demonstrative embodiments, the method may include coating the
hydrophobic solid fat coated core with an intermediate coating layer to obtain
intermediate layer coated core. According to some embodiments, the intermediate coating
layer may include an aqueous solution of 0.1% and have a surface tension lower than 60
mN/m as measured at 25 C. Preferably, the surface tension is lower than 50 mN/m, more
preferably lower than 45 mN/m.
According to some demonstrative embodiments, the method may include coating
the intermediate layer coated core with an outer coating layer to obtain stabilized oxygen-
sensitive liquid natural pharmaceutically or nutritionally active agents (as micro-
particles). According to some embodiments, the outer coating layer may include a
polymer having oxygen transmission rate of less than 1000 cc/m /24 hr, preferably less
than 500 cc/m /24 hr, more preferably less than 100 cc/m /24 hr, as measured at standard
test conditions (i.e. 73°F/23°C and 0% RH). According to some embodiments, the
polymer may have a water vapor transmission rate of less than 400 g/m²/day, preferably,
less than 350 g/m²/day, more preferably, less than 300 g/m²/day.
In some demonstrative embodiments, the method may optionally include coating
the resulting micro-particles with an enteric polymer which may provide protection from
destructive parameters such as low pHs and enzymes upon digestion and passage through
the GI tract.
As illustrated in FIGURE 1, according to some embodiments described, the
process of manufacturing a composition as described herein, i.e., micro encapsulated
oxygen-sensitive liquid natural pharmaceutically or nutritionally active agents, may
comprise:
1. mixing oxygen-sensitive liquid natural pharmaceutically or nutritionally
active agents with at least one absorbent (101) thereby obtaining a core granule or
particle;
2. coating particles of said core granule with an inner coating layer (103)
comprising a hydrophobic solid fat or fatty acid preventing or reducing the
penetration of water or humidity into said core, thereby obtaining water sealed
coated particles;
3. coating said water sealed coated particles with an intermediate coating
layer for adjusting surface tension (105) for further coating with outer coating
layer thereby obtaining water sealed coated particles having an adjusted surface
tension; and
4. coating said water sealed coated particles having an adjusted surface
tension with an outer coating layer (107) for reducing transmission of oxygen and
humidity into the core thereby obtaining a multiple-layered particle containing
oxygen-sensitive liquid natural pharmaceutically or nutritionally active agents
showing superior stability against oxygen and humidity on storage duration and
during the shelf life thus showing higher vitality.
According to other embodiments of the present invention, the process of manufacturing
the composition described may comprise:
• preparing an emulsion of oxygen-sensitive liquid natural pharmaceutically
or nutritionally active agents in water using an appropriate surfactant;
According to some embodiments, the oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agents in water may optionally be
in a non-emulsion form, e.g., in a suspension form, thus obviating the need
to use the surfactant;
• spraying the resulting emulsion/suspension onto at least one absorbent
thereby obtaining a core granule or particle;
• coating particles of said core granule with an inner coating layer
comprising a hydrophobic solid fat or fatty acid for preventing or reducing
the penetration of water or humidity into said core to obtain water sealed
coated particles;
• coating said water sealed coated particles with an intermediate coating
layer for adjusting surface tension for further coating with outer coating
layer thereby obtaining water sealed coated particles having an adjusted
surface tension; and
• coating said water sealed coated particles having an adjusted surface
tension with an outer coating layer for reducing transmission of oxygen
and humidity into the core to obtain a multiple-layered particle containing
oxygen-sensitive liquid natural pharmaceutically or nutritionally active
agents showing superior stability against oxygen and humidity on storage
duration and during the shelf life and thus showing higher vitality.
• Optionally coating the resulting particle with an enteric coating.
In some embodiments, the process of manufacturing the composition described
hereinabove may comprise:
• preparing a mixture of oxygen-sensitive liquid natural pharmaceutically or
nutritionally active agents with melt of at least one solid fat or fatty acid to
obtain a liquid mixture, with or without being in the form of an emulsion;
• spraying the resulting liquid mixture onto at least one absorbent to obtain a
core granule or particle;
• coating particles of said core granule with an inner coating layer
comprising a hydrophobic solid fat or fatty acid preventing or reducing the
penetration of water or humidity into said core to obtain water sealed
coated particles;
• coating said water sealed coated particles are with an intermediate coating
layer for adjusting surface tension for further coating with an outer coating
layer to obtain water sealed coated particles having an adjusted surface
tension; and
• coating said water sealed coated particles having an adjusted surface
tension with an outer coating layer for reducing transmission of oxygen
and humidity into the core to obtain a multiple-layered particle containing
oxygen-sensitive liquid natural pharmaceutically or nutritionally active
agents showing superior stability against oxygen and humidity on storage
duration and during the shelf life thus showing higher vitality.
illustrates a schema of a multiple-layered microencapsulated an oxygen-
sensitive liquid natural pharmaceutically or nutritionally active agent such as fish oil or
omega 3 fatty acids according to one embodiment described. The inner core 201
comprises a porous absorbent saturated by an oxygen-sensitive liquid natural
pharmaceutically or nutritionally active agent. A first fat coating layer 203 which is the
most inner coating layer comprises at least one hydrophobic solid fat or fatty acid having
a melting point lower than 50 C and higher than 25 C, in some embodiments lower than
o o o
45 C and higher than 30 C and in further embodiments lower than 40 C and higher than
C, forming a stable hydrophobic film layer around the inner core 201. The first fat
coating layer 203 is surrounded by the intermediate layer 205, whose aqueous solution of
0.1% has a surface tension lower than 60 mN/m. The outermost layer 207 comprises a
polymer having oxygen transmission rate of less than 1000 cc/m2/24 hr.
illustrates a schema of a multiple-layered microencapsulated oxygen-
sensitive liquid natural pharmaceutically or nutritionally active agent such as fish oil or
omega 3 fatty acids according to one embodiment. An inner core 301 comprises a porous
absorbent saturated and coated by a first coating layer comprising at least one
hydrophobic solid fat or fatty acid having a melting point lower than 50 C and higher
than 25 C and oxygen-sensitive liquid natural pharmaceutically or nutritionally active
agent.
Surrounding the inner core 301 is the intermediate layer 303, whose aqueous
solution of 0.1% has a surface tension lower than 60 mN/m. The outermost layer 305
comprises a polymer having oxygen transmission rate of less than 1000 cc/m /24 hr.
demonstrates an accelerated stability test carried out using ML
OXIPRES test method. The test shows the capability to withstand oxidation at elevated
temperature (90˚C) and under an initial oxygen pressure of 5 bar of a microencapsulated
omega 3 oil prepared according to some embodiments described in Example 1 below, of
omega 3 absorbed by the absorbent and as compared to omega 3 oil.
Example 1
800 g of Vivapur 12 (microcrystalline cellulose-MCC) was used as absorbent. An
emulsion was prepared based on the following composition:
Omega 3 oil = 150 g
Water = 350 g
Tween = 5 g
Tocopherol = 0.15 g
MCC was first loaded into Innojet- IEV2.5 V2, and heated at 40°C for 30 minutes
while fluidizing prior to spraying the emulsion. The emulsion was then sprayed on
microcrystalline cellulose using nitrogen as an inert gas.
After spraying about 100 g of emulsion, 20 g of Aerosil 200 was added and
emulsion was sprayed again. After spraying 228.9 g of emulsion, an additional 10 g
Aerosil 200 was added. The process was stopped and the container of Innojet-IEV2.5 V2
was changed to IPC 3 (IPC 1 was filled up until the upper edge of the container). 838 g of
omega 3 oil-absorbed MCC were re-loaded and spraying of emulsion was renewed. After
338 g of emulsion, an additional 5 g Aerosil 200 was added. The process finished,
yielding 923 g. The inlet temperature was continuously kept at 40°C.
400 g of Omega 3 absorbed-MCC was then loaded into an Innojet coater and
lauric acid (which was previously melted at 60°C) was sprayed using nitrogen as an inert
gas. The process was stop after reaching a weight gain of about 125 g. Then Na-alginate
solution (2% w/w in purified water) was sprayed onto the above resulting particles to
result in Na-alginate coated particles. Finally, the aqueous solution (5% w/w) of Na-
carboxy methyl cellulose and polyethylene glycol (PEG 400, 25% w/w) was sprayed onto
the above resulting Na-alginate coated particles to reach weight gain of 40% of Na-
carboxymethyl cellulose. The final product was dried and kept in a double sealed
polyethylene bag with a proper desiccant in a refrigerator.
Oxidation test
An oxidation test method was used to evaluate the capability of the final product
resulted from Example 1 to withstand oxidation during the shelf life. For this purpose, an
accelerated oxidation test method was used. The method was based on OXIPRES
Method. The ML OXIPRES (MIKROLAB AARHUS A/S Denmark) is a modification
of the bomb method, which is based on oxidation with oxygen under pressure. The test is
accelerated when carried out at elevated pressure and temperature. The consumption of
oxygen, which means that oxidation process occurs, is determined by the pressure drop in
the pressure vessel during the experiment. The time at which the oxygen pressure started
to drop is called Induction Period. A longer Induction Period means that the protection
against oxidation process is higher, indicating that the contents of the microcapsules,
prepared according to some embodiments described hereinabove, are better protected
towards oxidation process.
The capability of microencapsulated omega 3 oil from Example 1 and omega 3
absorbed or adsorbed by the absorbent as compared to omega 3 oil to withstand oxidation
was evaluated using ML OXIPRESTM test method at elevated temperature and under an
initial oxygen pressure of 5 bar. Samples of 5 grams for each pattern were used for the
test. The results, shown by Induction Period, are summarized in Table 1 and Fig.6.
Results
Table 1: Induction Periods of different samples prepared according to an
exemplary embodiment described hereinabove as compared to omega 3 as-is.
Test Induction Estimated
Temperature Period shelf life
Sample (°C) (Hours) (days)
*Microencapsulated 90 >50 266.7
omega 3 oil
Omega 3 absorbed 90 11.2 59.7
by the absorbent
Omega 3 oil 90 5.0 26.7
Omega 3 oil 90 5.0 26.7
Example 2 - Non-emulsion-based microencapsulation process of omega 3 and fish oil
Vivapur 105 (microcrystalline cellulose-MCC) (800 g) was mixed with
concentrated Eicosapentaenoic acid (EPA 88%) of omega 3 oil for about 1 hour at room
temperature.
The resulting mixture was then loaded into Innojet- IEV2.5 V2 and aerosil (25 g)
was added. Poloxamer 188 (a triblock copolymer composed of a central hydrophobic
chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of
polyoxyethylene (poly(ethylene oxide)) (300 g) was melted and sprayed onto the mixture.
The resulting mixture coated by poloxamer was discharged and the container of Innojet-
IEV2.5 V2 10 was changed to IPC 3 (IPC 1 was filled up until the upper edge of the
container). 300 g of the resulting mixture coated by poloxamer were re-loaded and an
aqueous solution (5% w/w) of Na-carboxy methyl cellulose (CMC) and polyethylene
glycol (PEG 400) (CMC:PEG 9:1) was sprayed. The inlet temperature was continuously
kept at 40°C.
The process was stopped after reaching a weight gain of about 10% of Na-
carboxymethyl cellulose/PEG.
Then Na-alginate solution (2% w/w in purified water) was sprayed onto 290 g of
the above resulting particles to result in Na-alginate coated particles having 11% (w/w)
Na-alginate. Then finally an additional 7.7% (w/w) of Na-carboxy methyl cellulose
(CMC) and polyethylene glycol (PEG 400) (CMC:PEG 9:1) was added to 301 g of the
above particles to obtain the following composition:
Amount
[g] Substance Amount [abs %]
70.97 MCC Vivapur 106 21.77
57.13 EPA oil 17.52
8.87 Aerosil 2.72
106.45 Poloxamer 189 32.65
CMC/PEG 400
24.34 (90:10) 7.47
33.24 Na-Alginat 10.20
CMC/PEG 400
.00 (90:10) 7.67
326.00
The final product was dried and kept in a double sealed polyethylene bag with a proper
desiccant in a refrigerator.
Example 3
200 g of Vivapur 12 (microcrystalline cellulose-MCC) was first loaded into
Innojet- IEV2.5 V2, and aerosil (4 g) was added. Then a mixture of fish oil (96.9 g) in
fused stearic acid (115.1 g), which was previously melted at 70°C, was sprayed on
microcrystalline cellulose to obtain coated particles. Then Poloxamer 188 (a triblock
copolymer composed of a central hydrophobic chain of polyoxypropylene
(poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene
(poly(ethylene oxide)) (74 g) was melted and sprayed onto 367 g of the above coated
mixture. Then an aqueous solution (5% w/w) of Na-carboxy methyl cellulose (CMC) and
polyethylene glycol (PEG 400) (CMC:PEG 9:1), was sprayed onto 300 g of the resulting
mixture coated by poloxamer. The inlet temperature was continuously kept at 40°C.
The process was stopped after reaching a weight gain of about 20% of Na-
carboxymethyl cellulose/PEG to have the following composition:
Amount Amount [abs
[g] Substance %]
120.03 MCC Vivapur 12 33.34
2.40 Aerosil 0.67
58.15 Fish oil 16.15
69.08 Stearic acid 19.19
50.34 Poloxamer 188 13.98
CMC/PEG 400
60.00 (90:10) 16.67
360.00
The final product was dried and kept in a double sealed polyethylene bag with a proper
desiccant in a refrigerator.
It is appreciated that certain features of the invention, which are, for clarity,
described in the context of separate embodiments, may also be provided in combination
in a single embodiment. Conversely, various features of the invention, which are, for
brevity, described in the context of a single embodiment, may also be provided separately
or in any suitable subcombination.
Although the invention has been described in conjunction with specific
embodiments thereof, it is evident that many alternatives, modifications and variations
will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such
alternatives, modifications and variations that fall within the spirit and broad scope of the
appended claims. All publications, patents and patent applications mentioned in this
specification are herein incorporated in their entirety by reference into the specification, to
the same extent as if each individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein by reference. In addition,
citation or identification of any reference in this application shall not be construed as an
admission that such reference is available as prior art to the present invention.
The term “comprising” as used in this specification means “consisting at least in
part of”. When interpreting each statement in this specification that includes the term
“comprising”, features other than that or those prefaced by the term may also be present.
Related terms such as “comprise” and “comprises” are to be interpreted in the same
manner.
Claims (38)
1. A composition comprising: a core comprising at least one fatty acid; a fatty coating layer comprising at least one hydrophobic solid fat or fatty acid having a melting point lower than 70 C and higher than 25 C; an intermediate coating layer positioned on said fatty coating layer comprising a polymer having an aqueous solution of 0.1% that features a surface tension lower than 60 mN/m when measured at 25 C; at least one barrier coating layer comprising a polymer having oxygen transmission rate of less than 1000 cc/m /24 hr measured at standard test conditions and a water vapor transmission rate of less than 400 g/m²/day positioned on said intermediate layer; at least one delayed release layer comprising an enteric polymer; wherein said fatty coating layer is positioned between said core and said intermediate layer.
2. The composition of claim 1, wherein said intermediate layer comprises a water soluble polymer.
3. The composition of claim 1, wherein said intermediate layer comprises a polymer selected from the group of hydroxypropylethylcellulose (HPEC), hydroxypropylcellulose (HPC), methylcellulose, ethylcellulose, pH-sensitive polymers, enteric polymers, alginic acid, alginates and/or a combination or combinations thereof.
4. The composition of claim 3, wherein the alginates are selected from ammonia alginate, sodium, potassium, magnesium or calcium alginate.
5. The composition of claim 3, wherein said enteric polymer comprises one or more of phthalate derivatives, polyacrylic acid derivatives or pH- sensitive polymers.
6. The composition of claim 5, wherein the one or more phthalate derivatives are selected from acid phthalate of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate (CAP), other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose phthalate (HPCP), hydroxypropylethylcellulose phthalate (HPECP), hydroxyproplymethylcellulose phthalate (HPMCP), hydroxyproplymethylcellulose acetate succinate (HPMCAS), methylcellulose phthalate (MCP), polyvinyl acetate phthalate (PVAcP), polyvinyl acetate hydrogen phthalate, sodium CAP, starch acid phthalate, cellulose acetate trimellitate (CAT), styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid/polyvinylacetate phthalate copolymer, styrene and maleic acid copolymers.
7. The composition of claim 5, wherein the polyacrylic acid derivatives are selected from acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof, polyacrylic and methacrylic acid copolymers, and vinyl acetate and crotonic acid copolymers.
8. The composition of claim 5, wherein the pH sensitive polymers are selected from shellac, phthalate derivatives, CAT, HPMCAS, polyacrylic acid derivatives, alginic acid and alginates, ammonia alginate, sodium, potassium, magnesium or calcium alginate, vinyl acetate copolymers, polyvinyl acetate 30D (30% dispersion in water), a poly(dimethylaminoethylacrylate) “Eudragit E™, a copolymer of methylmethacrylate and ethylacrylate with small portion of trimethylammonioethyl methacrylate chloride (Eudragit RL, Eudragit RS), a copolymer of methylmethacrylate and ethylacrylate (Eudragit NE 30D), Zein, shellac, gums, poloxamer, polysaccharides.
9. The composition of claim 8, wherein the polyacrylic acid derivatives are selected from copolymers comprising acrylic acid and at least one acrylic acid ester, EudragitTM S (poly(methacrylic acid, methyl methacrylate)1:2); Eudragit L100TM (poly(methacrylic acid, methyl methacrylate)1:1); Eudragit L30DTM, (poly(methacrylic acid, ethyl acrylate)1:1); and (Eudragit L100-55) (poly(methacrylic acid, ethyl acrylate)1:1) (EudragitTM L is an anionic polymer synthesized from methacrylic acid and methacrylic acid methyl ester), polymethyl methacrylate blended with acrylic acid and acrylic ester copolymers.
10. The composition of any one of claims 1-9, wherein said melting point is lower than 65˚C and higher than 30 C.
11. The composition of claim 10, wherein said melting point is lower than 60 C and higher than 35 C.
12. The composition of any one of claims 1-11, wherein said fatty coating layer comprises one or more of fats, fatty acids, fatty acid esters, fatty acid triesters, salts of fatty acids, fatty alcohols, phospholipids, solid lipids, waxes, lauric acid, stearic acid, alkenes, waxes, alcohol esters of fatty acids, long chain alcohols and glucoles, and combinations thereof.
13. The composition of claim 12, wherein said salt of fatty acids comprises one or more of aluminum, sodium, potassium and magnesium salts of fatty acids.
14. The composition of claim 13, wherein said fatty coating layer comprises one or more of paraffin wax composed of a chain of alkenes, normal paraffins of type C H ; natural waxes, synthetic waxes, hydrogenated n 2n+2 vegetable oil, hydrogenated castor oil; fatty acids, palm oil; fatty acid eutectics; mono and diglycerides, poloxamers, block-co-polymers of polyethylene glycol and polyesters, and a combination thereof.
15. The composition of claim 14, wherein the fatty acids are selected from lauric acid, myristic acid, palmitic acid, palmitate, palmitoleate, hydroxypalmitate, stearic acid, arachidic acid, oleic acid, stearic acid, sodium stearat, calcium stearate, magnesium stearate, hydroxyoctacosanyl hydroxystearate, oleate esters of long-chain, esters of fatty acids, fatty alcohols, esterified fatty diols, hydroxylated fatty acid, hydrogenated fatty acid (saturated or partially saturated fatty acids), partially hydrogenated soybean oil, partially hydrogenated cottonseed oil, aliphatic alcohols, phospholipids, lecithin, phosphathydil cholin, triesters of fatty acids, coconut oil, hydrogenated coconut oil and cacao butter.
16. The composition of claim 14, wherein said wax comprises one or more of beeswax, carnauba wax, japan wax, bone wax, paraffin wax, chinese wax, lanolin (wool wax), shellac wax, spermaceti, bayberry wax, candelilla wax, castor wax, esparto wax, jojoba oil, ouricury wax, rice bran wax, soy wax, ceresin waxes, montan wax, ozocerite, peat waxes, microcrystalline wax, petroleum jelly, polyethylene waxes, Fischer- Tropsch waxes, chemically modified waxes, substituted amide waxes; polymerized α-olefins, or a combination thereof.
17. The composition of any one of claims 11-16, wherein said solid fat or fatty acid is at least one of lauric acid, hydrogenated coconut oil, cacao butter, stearic acid, or a combination thereof.
18. A composition comprising: a core comprising at least one fatty acid embedded into a melt matrix comprising one or more of stearic acid and/or a PEG based polymer; at least one intermediate coating layer comprising a polymer in an aqueous solution of 0.1% having a surface tension lower than 60 mN/m measured at 25 C; at least one coating layer comprising a polymer having oxygen transmission rate of less than 1000 cc/m /24 hr measured at standard test conditions and a water vapor transmission rate of less than 400 g/m²/day positioned on said intermediate layer; and at least one delayed release layer comprising an enteric polymer positioned on said at least one coating layer.
19. The composition of claim 18, wherein said PEG based polymer comprises a PEG based co-polymer.
20. The composition of any one of the preceding claims, wherein said composition is adapted for admixing with a food product.
21. The composition of any one of the preceding claims, further comprising a stabilizer, selected from the group consisting of dipotassium edetate, disodium edetate, edetate calcium disodium, edetic acid, fumaric acid, malic acid, maltol, sodium edetate, and trisodium edetate.
22. The composition of any one of the preceding claims, further comprising an oxygen scavenger selected from the group of L-cysteine base or hydrochloride, vitamin E, tocopherol and polyphenols.
23. The composition of any one of the preceding claims, further comprising a surfactant in any of the coating layers, with the proviso that the surfactant is not present in the core.
24. The composition of any one of the preceding claims, further comprising a surfactant in the core, with the proviso that the surfactant is not part of an emulsion.
25. The composition of claims 23 or 24, wherein said surfactant is selected from the group of tween 80, docusate sodium, sodium lauryl sulfate, glyceryl monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol and sorbitan esters.
26. The composition of any one of the preceding claims, further comprising a glidant.
27. The composition of claim 26, wherein said glidant is silicon dioxide.
28. The composition of any one of the preceding claims, further comprising a plasticizer selected from the group including polyethylene glycol (PEG), triethyl citrate and triacetin.
29. The composition of claim 28 wherein the PEG is selected from PEG 400.
30. The composition of any one of the preceding claims, further comprising a filler selected from the group of microcrystalline cellulose, a sugar, dicalcium phosphate; sugar alcohols corn starch and potato starch.
31. The composition of claim 30, wherein the sugar is selected from the group of lactose, glucose, galactose, fructose, and sucrose.
32. The composition of claim 30, wherein the sugar alcohol is selected from the group of sorbitol, manitol, mantitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated starch hydrolysates.
33. The composition of any one of the preceding claims, further comprising a binder selected from the group of Povidone (PVP: polyvinyl pyrrolidone), Copovidone (copolymer of vinyl pyrrolidone and vinyl acetate), polyvinyl alcohol, low molecular weight HPC (hydroxypropyl cellulose), low molecular weight HPMC (hydroxypropyl methylcellulose), low molecular weight hydroxymethyl cellulose (MC), low molecular weight sodium carboxy methyl cellulose, low molecular weight hydroxyethylcellulose, low molecular weight hydroxymethylcellulose, cellulose acetate, gelatin, hydrolyzed gelatin, polyethylene oxide, acacia, dextrin, starch, and water soluble polyacrylates and polymethacrylates and low molecular weight ethylcellulose.
34. A method of producing a stabilized, multi-layered particle containing at least one fatty acid, comprising: preparing a core from said at least one fatty acid and an absorbent; coating the core with a first coating layer to obtain a water sealed coated particle, the first coating layer comprising a hydrophobic solid fat or fatty acid, the first coating layer preventing penetration of water into said core ; coating said water sealed coated particle with an intermediate coating layer that adjusts interfacial tension to obtain a water sealed coated particle having an adjusted surface tension, wherein said intermediate coating layer comprising a polymer in an aqueous solution of 0.1% having a surface tension lower than 60 mN/m measured at 25 C; and coating said water sealed coated particle having an adjusted surface tension with a barrier coating layer comprising a polymer having oxygen transmission rate of less than 1000 cc/m /24 hr measured at standard test conditions that reduces transmission of oxygen and humidity into the core granule to obtain a multi-layered particle containing fatty acid.
35. The method of claim 34, wherein the surface tension is lower than 50 mN/m.
36. The method of claim 35, wherein the surface tension is lower than 45 mN/m.
37. The method of claim 34, wherein the at least one barrier coating layer comprises a polymer having oxygen transmission rate of less than 500 cc/m /24 hr measured at standard test conditions.
38. The method of claim 34, wherein the at least one barrier coating layer comprises a polymer having oxygen transmission rate of less than 100 cc/m
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161494218P | 2011-06-07 | 2011-06-07 | |
US61/494,218 | 2011-06-07 | ||
PCT/IB2012/052857 WO2012168882A1 (en) | 2011-06-07 | 2012-06-06 | Compositions and methods for improving stability and extending shelf life of sensitive food additives and food products thereof |
Publications (2)
Publication Number | Publication Date |
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NZ619607A NZ619607A (en) | 2015-12-24 |
NZ619607B2 true NZ619607B2 (en) | 2016-03-30 |
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