CA2199155C - Process for stabilizing gelatin products - Google Patents
Process for stabilizing gelatin products Download PDFInfo
- Publication number
- CA2199155C CA2199155C CA002199155A CA2199155A CA2199155C CA 2199155 C CA2199155 C CA 2199155C CA 002199155 A CA002199155 A CA 002199155A CA 2199155 A CA2199155 A CA 2199155A CA 2199155 C CA2199155 C CA 2199155C
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- CA
- Canada
- Prior art keywords
- chloride
- sulfate
- gelatin
- iron
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 229920000159 gelatin Polymers 0.000 title claims abstract description 74
- 235000019322 gelatine Nutrition 0.000 title claims abstract description 73
- 108010010803 Gelatin Proteins 0.000 title claims abstract description 71
- 235000011852 gelatine desserts Nutrition 0.000 title claims abstract description 71
- 239000008273 gelatin Substances 0.000 title claims abstract description 64
- 238000000034 method Methods 0.000 title claims abstract description 14
- 230000008569 process Effects 0.000 title claims abstract description 9
- 230000000087 stabilizing effect Effects 0.000 title description 2
- 239000000654 additive Substances 0.000 claims abstract description 31
- 230000000996 additive effect Effects 0.000 claims abstract description 17
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 238000003860 storage Methods 0.000 claims abstract description 17
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims abstract description 15
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims abstract description 15
- -1 nitrilotrismethylene phosphonic acid Chemical compound 0.000 claims abstract description 13
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims abstract description 12
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 235000013922 glutamic acid Nutrition 0.000 claims abstract description 12
- 239000004220 glutamic acid Substances 0.000 claims abstract description 12
- 150000001299 aldehydes Chemical class 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 239000002775 capsule Substances 0.000 claims description 19
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 14
- 238000004132 cross linking Methods 0.000 claims description 13
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 12
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 12
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 12
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 12
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 12
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 12
- 229960004799 tryptophan Drugs 0.000 claims description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 10
- 235000002639 sodium chloride Nutrition 0.000 claims description 8
- 239000004475 Arginine Substances 0.000 claims description 7
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 7
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 7
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 7
- 239000004472 Lysine Substances 0.000 claims description 7
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 7
- 235000009697 arginine Nutrition 0.000 claims description 7
- 235000003704 aspartic acid Nutrition 0.000 claims description 7
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 7
- 239000001110 calcium chloride Substances 0.000 claims description 7
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 7
- 235000011148 calcium chloride Nutrition 0.000 claims description 7
- 235000018977 lysine Nutrition 0.000 claims description 7
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 7
- 235000011147 magnesium chloride Nutrition 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- 229910021577 Iron(II) chloride Inorganic materials 0.000 claims description 6
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 6
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 6
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 6
- 229910021380 Manganese Chloride Inorganic materials 0.000 claims description 6
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 claims description 6
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 239000006035 Tryptophane Substances 0.000 claims description 6
- 229960005070 ascorbic acid Drugs 0.000 claims description 6
- 235000010323 ascorbic acid Nutrition 0.000 claims description 6
- 239000011668 ascorbic acid Substances 0.000 claims description 6
- 235000009582 asparagine Nutrition 0.000 claims description 6
- 229960001230 asparagine Drugs 0.000 claims description 6
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 6
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 claims description 6
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 claims description 6
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 6
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 claims description 6
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 6
- 229910000360 iron(III) sulfate Inorganic materials 0.000 claims description 6
- INHCSSUBVCNVSK-UHFFFAOYSA-L lithium sulfate Inorganic materials [Li+].[Li+].[O-]S([O-])(=O)=O INHCSSUBVCNVSK-UHFFFAOYSA-L 0.000 claims description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 6
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 6
- 239000011565 manganese chloride Substances 0.000 claims description 6
- 235000002867 manganese chloride Nutrition 0.000 claims description 6
- SQQMAOCOWKFBNP-UHFFFAOYSA-L manganese(II) sulfate Chemical compound [Mn+2].[O-]S([O-])(=O)=O SQQMAOCOWKFBNP-UHFFFAOYSA-L 0.000 claims description 6
- 229910000357 manganese(II) sulfate Inorganic materials 0.000 claims description 6
- 239000001103 potassium chloride Substances 0.000 claims description 6
- 235000011164 potassium chloride Nutrition 0.000 claims description 6
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 6
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 6
- 235000011151 potassium sulphates Nutrition 0.000 claims description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 6
- 235000011152 sodium sulphate Nutrition 0.000 claims description 6
- RBTVSNLYYIMMKS-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)N1CC(N)C1 RBTVSNLYYIMMKS-UHFFFAOYSA-N 0.000 claims description 6
- 235000017103 tryptophane Nutrition 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 5
- 238000000576 coating method Methods 0.000 claims description 5
- 239000011248 coating agent Substances 0.000 claims description 3
- 108010025899 gelatin film Proteins 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 229960003121 arginine Drugs 0.000 claims 5
- 229960005261 aspartic acid Drugs 0.000 claims 5
- 229960002989 glutamic acid Drugs 0.000 claims 5
- 229960004198 guanidine Drugs 0.000 claims 5
- 229960003646 lysine Drugs 0.000 claims 5
- 239000007903 gelatin capsule Substances 0.000 claims 3
- 239000000427 antigen Substances 0.000 claims 2
- 102000036639 antigens Human genes 0.000 claims 2
- 108091007433 antigens Proteins 0.000 claims 2
- 229930006000 Sucrose Natural products 0.000 claims 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims 1
- 235000013681 dietary sucrose Nutrition 0.000 claims 1
- 230000007717 exclusion Effects 0.000 claims 1
- 229960004793 sucrose Drugs 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 11
- 239000012467 final product Substances 0.000 abstract description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 43
- 238000004090 dissolution Methods 0.000 description 40
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 8
- 238000005259 measurement Methods 0.000 description 6
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 5
- 229940044197 ammonium sulfate Drugs 0.000 description 5
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 5
- 235000011130 ammonium sulphate Nutrition 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229960005489 paracetamol Drugs 0.000 description 4
- 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 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000001828 Gelatine Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 2
- WWILHZQYNPQALT-UHFFFAOYSA-N 2-methyl-2-morpholin-4-ylpropanal Chemical compound O=CC(C)(C)N1CCOCC1 WWILHZQYNPQALT-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- 241001631455 Opeia Species 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002597 lactoses Chemical class 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 210000004798 organs belonging to the digestive system Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 235000015277 pork Nutrition 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 108010013480 succinylated gelatin Proteins 0.000 description 1
- 229940007079 succinylated gelatin Drugs 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
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- Medicinal Preparation (AREA)
- Jellies, Jams, And Syrups (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cosmetics (AREA)
Abstract
Process for the manufacturing of gelatin products with improved stability against storage under hot and humid conditions and/or aldehydes characterized in that at least one additive, preferred glutamic acid, tryptophan, or nitrilotrismethylene phosphonic acid or a mixture thereof is incorporated into the gelatin before forming the final product as usual as well as the gelatin compositions used and the products obtained by the process.
Description
WO 96114365 219 915 5 p~~S95113950 Process for Stabilizing Gelatin Products FIELD OF THE INVENTION
This invention relats to a process for the enhancement of the stability of gelatin products against higher storage temperatures, humidity and/or chemically influenced crosslinking, as well as suitable gelatin compositions and their use in capsule manufacturing or as coating or binding agents of tablets, casing materials and so on.
DESCRIPTION OF THE PRIOR ART
Gelatin is widely used in the pharmaceutical industry as well as in the health food supplement market to manufacture capsules as containers or as coating agents for the capsules or other dosage forms, or as adjuvants or excipients in pharmaceutical preparations like tablets. A primary objective of these dosage forms is to have a good disintegration after being administrated in order to enable a fast dissolution of the active substances in the appropriate digestive organ. Any delay of the disintegration would consequently retard or even reduce the effect of the drug.
Consequently, this disintegration characteristic has to remain unchanged over time when finished products are stored prior to use. Extensive dissolution stability testing has been conducted to assess this stability.
Unfortunately, as has been widely described in the literature, the risk for the gelatin product to exhibit a delay in disintegration over time is high. A primary cause of the problem, exposure to certain aldehydes contained in the capsules content at the initial stage or originating from the decomposition of the drug or one of the excipients over time, has been reported in many references as a cause. The mechanism of this chemical interaction named "crosslinking"
has been well understood as action of the aldehyde on the free amino groups of the amino acids and especially the lysine and arginine (G. f:~igeni.s et al., ~J. of Pharm. Sci. Vol.
83, No. 7, pp. 915-9:?l; ~~9~~4 ) . It: has a.i.so been used further in the .sense that overcrc:sslirnking oL th<~ gelatin would make it totally insoluble and i_napF>ropriate f<:~r an enteric: dosage form (G. Gutierrez, ~R-8',01.12 i ) .
Various patents have been published which deal with this issue. The resistance to crosslinking by formaldehyde can be obtained by chemically modifying the gelatin (succinylated gelatin: Toyo Jozo Co, JP 61/186315 Nippon Elanco Co, JP-61/186314), by adding ions in it (Sanofi, FR-8708828) or silicones (R.P. Scherer, FR-2346/69) or peptides (NITTA, EP-0 335 982).
Another procedure to protect gelatin from crosslinking is to include in the formulation of the drug a formaldehyde scavenger (Teikoku Hormone Mfg Co, JP-168874/1989 and Lion Corporation EP-0 242 855).
Some literature references have also reported that exgosure or storage to/under hot and humid conditions is another reason for the delay in the disintegration of gelatin products. These conditions were reported in a temperature range of 25 to 55°C and a humidity range of 40% to 90%
relative humidity. This appears to be very important for .most of the pharmaceutical applications of the gelatin where a stability is requested for storage at 40°C with 75% RH over 3 to 6 months without significant delay in drug dissolution.
This phenomenon was described extensively in the literature, but no proposal has been made to explain the mechanism of the chemical reactions involved in responsible for the poorer dissolution performance of the gelatin: H.W.
GOUDA & al., Intl. Jour. Pharmaceutics, 18, 1984, 213-215;
S.A. KFIALIL & al., Pharmazie, 29 H1, 1974, 36-37; T.C. HAHL &
.al., Drug Dvpt Industr. Pharmacy, 17 (7), 1991, 1001-1016; M.
This invention relats to a process for the enhancement of the stability of gelatin products against higher storage temperatures, humidity and/or chemically influenced crosslinking, as well as suitable gelatin compositions and their use in capsule manufacturing or as coating or binding agents of tablets, casing materials and so on.
DESCRIPTION OF THE PRIOR ART
Gelatin is widely used in the pharmaceutical industry as well as in the health food supplement market to manufacture capsules as containers or as coating agents for the capsules or other dosage forms, or as adjuvants or excipients in pharmaceutical preparations like tablets. A primary objective of these dosage forms is to have a good disintegration after being administrated in order to enable a fast dissolution of the active substances in the appropriate digestive organ. Any delay of the disintegration would consequently retard or even reduce the effect of the drug.
Consequently, this disintegration characteristic has to remain unchanged over time when finished products are stored prior to use. Extensive dissolution stability testing has been conducted to assess this stability.
Unfortunately, as has been widely described in the literature, the risk for the gelatin product to exhibit a delay in disintegration over time is high. A primary cause of the problem, exposure to certain aldehydes contained in the capsules content at the initial stage or originating from the decomposition of the drug or one of the excipients over time, has been reported in many references as a cause. The mechanism of this chemical interaction named "crosslinking"
has been well understood as action of the aldehyde on the free amino groups of the amino acids and especially the lysine and arginine (G. f:~igeni.s et al., ~J. of Pharm. Sci. Vol.
83, No. 7, pp. 915-9:?l; ~~9~~4 ) . It: has a.i.so been used further in the .sense that overcrc:sslirnking oL th<~ gelatin would make it totally insoluble and i_napF>ropriate f<:~r an enteric: dosage form (G. Gutierrez, ~R-8',01.12 i ) .
Various patents have been published which deal with this issue. The resistance to crosslinking by formaldehyde can be obtained by chemically modifying the gelatin (succinylated gelatin: Toyo Jozo Co, JP 61/186315 Nippon Elanco Co, JP-61/186314), by adding ions in it (Sanofi, FR-8708828) or silicones (R.P. Scherer, FR-2346/69) or peptides (NITTA, EP-0 335 982).
Another procedure to protect gelatin from crosslinking is to include in the formulation of the drug a formaldehyde scavenger (Teikoku Hormone Mfg Co, JP-168874/1989 and Lion Corporation EP-0 242 855).
Some literature references have also reported that exgosure or storage to/under hot and humid conditions is another reason for the delay in the disintegration of gelatin products. These conditions were reported in a temperature range of 25 to 55°C and a humidity range of 40% to 90%
relative humidity. This appears to be very important for .most of the pharmaceutical applications of the gelatin where a stability is requested for storage at 40°C with 75% RH over 3 to 6 months without significant delay in drug dissolution.
This phenomenon was described extensively in the literature, but no proposal has been made to explain the mechanism of the chemical reactions involved in responsible for the poorer dissolution performance of the gelatin: H.W.
GOUDA & al., Intl. Jour. Pharmaceutics, 18, 1984, 213-215;
S.A. KFIALIL & al., Pharmazie, 29 H1, 1974, 36-37; T.C. HAHL &
.al., Drug Dvpt Industr. Pharmacy, 17 (7), 1991, 1001-1016; M.
WO 96/14365 ' PCT/US95113950 2.99155 DEY & al., Pharmaceutical Res., 10 (9), 1993, 1295-1300; K.S.
MURPHY & al., Pharm. Techno:, March, 1989, 74-82. In the state of the art, no method is known for increasing the i, resistance of the gelatin to storage at hot and humid conditions as described before.
SUMMARY OF THE INVENTION ' The present invention relates to a process for the manufacturing of gelatin products which have improved stability against storage under hot and humid conditions and/or aldehydes in order to improve the dissolution of the gelatin products comprising incorporating additives into the gelatin solution and forming the final product as usual. A
further aspect of the invention is the gelatin compositions used for the gelatin products prepared by the process.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The gelatin to be used with the present invention may be from acid processed pork skin known as A gelatins, from lime processed bones known as B gelatins, from calf skin known as C gelatins, acid processed bones known as AB gelatins or from a combination of two or more of these gelatins.
The additives are selected from the group consisting of ammonium sulfate, ammonium hydrogen sulfate, ammonium hydrogencarbonate, ammonium phosphate, ammonium hydrogenphosphate, ammonium dihydrogenphosphate, ammonium thiocyanate, sodium sulfate, sodium chloride, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride, calcium sulfate, calcium chloride, magnesium sulfate, magnesium chloride, iron (II) sulfate, iron (II) chloride, iron (III) sulfate, iron (III) chloride, manganese (II) sulfate, manganese (II) chloride, glutamic acid, aspartic acid, asparagine, lysine, tryptophane, arginine, guanidine, urea, citric acid, ascorbic acid, ethylenediamine tetraacetate, nitrilotrismethylene phosphonic acid.
MURPHY & al., Pharm. Techno:, March, 1989, 74-82. In the state of the art, no method is known for increasing the i, resistance of the gelatin to storage at hot and humid conditions as described before.
SUMMARY OF THE INVENTION ' The present invention relates to a process for the manufacturing of gelatin products which have improved stability against storage under hot and humid conditions and/or aldehydes in order to improve the dissolution of the gelatin products comprising incorporating additives into the gelatin solution and forming the final product as usual. A
further aspect of the invention is the gelatin compositions used for the gelatin products prepared by the process.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The gelatin to be used with the present invention may be from acid processed pork skin known as A gelatins, from lime processed bones known as B gelatins, from calf skin known as C gelatins, acid processed bones known as AB gelatins or from a combination of two or more of these gelatins.
The additives are selected from the group consisting of ammonium sulfate, ammonium hydrogen sulfate, ammonium hydrogencarbonate, ammonium phosphate, ammonium hydrogenphosphate, ammonium dihydrogenphosphate, ammonium thiocyanate, sodium sulfate, sodium chloride, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride, calcium sulfate, calcium chloride, magnesium sulfate, magnesium chloride, iron (II) sulfate, iron (II) chloride, iron (III) sulfate, iron (III) chloride, manganese (II) sulfate, manganese (II) chloride, glutamic acid, aspartic acid, asparagine, lysine, tryptophane, arginine, guanidine, urea, citric acid, ascorbic acid, ethylenediamine tetraacetate, nitrilotrismethylene phosphonic acid.
The amount of add~.tiv<,:~ is up t_o 25$, preferab:Ly 0.1 to 10$ by weight of the dry c~k~l.atin. r'ac~h additive can be added alone or in combination wit:.h on.e or more additive.
Two types of storage r_onditions were studied:
1) Hot and humid conditions: temperature varied between 20 and 55°C and humidity between 40~ and 95~ RH.
2) Formaldehyde:
a. Capsules were filled with lactose contaminated by formaldehyde with levels varying between 0-200 ppm, preferably between 1 and 60 ppm. These capsules were either stored in closed battles at 50°C up to 2 months or in the open at hot. and humid conditions up to 6 months.
L5 b. Gelatin films were stored in lactose powder contaminated by formaldehyde with level between 0 and 200 ppm, preferably between 1 and 50 ppm. Films are dipped in the contaminated lactose powder in a closed plastic box and kept at 50°C up to 1 month.
Dissolution measurements:
The dissolution measurements were made with the apparatus described in U.S. Pharmac;opeia XXI:1, 1990 (USP XXII), method II (paddle 50 rpmj. The medium was ciemineralized ;cater at 37°C ~ 0.5°C and two procedures weave used one for the capsules and one for the gelatin f:il.rns. The samples are added in the media iz a special sinkeir which prevents them from .floating.
1. Capsule dissoluti.or::
Two types of storage r_onditions were studied:
1) Hot and humid conditions: temperature varied between 20 and 55°C and humidity between 40~ and 95~ RH.
2) Formaldehyde:
a. Capsules were filled with lactose contaminated by formaldehyde with levels varying between 0-200 ppm, preferably between 1 and 60 ppm. These capsules were either stored in closed battles at 50°C up to 2 months or in the open at hot. and humid conditions up to 6 months.
L5 b. Gelatin films were stored in lactose powder contaminated by formaldehyde with level between 0 and 200 ppm, preferably between 1 and 50 ppm. Films are dipped in the contaminated lactose powder in a closed plastic box and kept at 50°C up to 1 month.
Dissolution measurements:
The dissolution measurements were made with the apparatus described in U.S. Pharmac;opeia XXI:1, 1990 (USP XXII), method II (paddle 50 rpmj. The medium was ciemineralized ;cater at 37°C ~ 0.5°C and two procedures weave used one for the capsules and one for the gelatin f:il.rns. The samples are added in the media iz a special sinkeir which prevents them from .floating.
1. Capsule dissoluti.or::
5 219 915 5 pCT~S95/13950 The capsules are previously stored under one or both of the storage conditions described before. The capsules were filled with Acetaminophen and dissolved in water at 37°C
under agitation (paddle'50 rpm). The percentage of dissolved Acetaminophen is determined by UV spectrophotometry at 300 r nm. The required level of dissolved Acetaminophen is higher than 80~ at 45 min.
2. Gelatin film dissolution Films of gelatin are carted on glass plates. These films are stored at one or both of the conditions described before. The films are then added in demineralized water at 37°C under agitation (paddle 50 rpm) and the percentage of dissolution is determined by UV spectrophotometry at 217 nm.
Uncrosslinked films have a dissolution of more than 90~ at 6 min.
The following examples will demonstrate how the addition of inventive compounds increases the resistance of gelatins to crosslinking by hot and humid storage and/or formaldehyde.
Example 1:
We studied the effect of addition of ammonium sulfate (2~ w/w of gelatin) on the resistance of gelatin to formaldehyde crosslinking. Gelatins type a 240 and type B
200 or two different suppliers with two batches each were studies. The gelatin films were carted from a 30~ gelatin solution containing 2~ w/w of ammonium sulfate ((NH4)2504) and without additives (Reference). Films were dried at room conditions for 24 hours and dissolution samples were prepared and stored in formaldehyde contaminated lactose powder (at 5 ppm formaldehyde at 50°C for 1 week).
- - - ~ _ The dissolution results (%) are summarized in table 1 in comparison to mean values of 4 batches stored for 1 week at room conditions.
Table 1 z-Gelatin Supplier Batch Reference (Nii4)2504 3 ~ min 6 min 3 min 6 min A 1 10% 35% 80% 96%
2 7% 46% 86% 98%
A 240 B 1 11% 60% 76% 98%
2 20% 70% 60% 96%
Mean value for 4 batches 81% 97% 74% 93%
Table 1 demonstrates a very impressive resistance to formaldehyde crosslinking. Gelatin films with ammonium sulfate have practically the same dissolution results at 3 and 6 min as gelatin films stored at room conditions (mean values for 4 batches). A dramatic decrease in dissolution is noted for films without additives (Reference), especially for dissolution measures at 3 min.
Example 2:
The effect of addition of nitrilotrismethylene phosphonic acid (AMP, Masquol*P320) on the dissolution of gelatin films stored in presence of formaldehyde is studied.
The films were prepared by casting a gelatin solution (30%
w/w water) containing MasquoT P320 (1% w/w gelatin on glass plate and drying at room conditions for 24 hours.
The dissolution samples were then prepared and stored dipped in formaldehyde contaminated lactose in a closed plastic box for 1 week at 50°C prior to dissolution measurements.
*trade mark 6 WO 96/14365 PCTlI1S95/13950 The dissolution results are shown in the following table 2.
Table 2 t Gelatin AMP Dissolution 3 min 6 min 9 min 12 min 15 min A 240 0~ 0~ 3% 10%. 16% 21%
1% 3% 15% 26% 41% 52%
B 200 0% 8% 42% 70% 84~ 87%
1% 8% 77% 89% 93% 94%
Here the beneficial effect of the addition of an additive, Masguol P320, on the resistance of gelatin films to formaldehyde crosslinking is clearly demonstrated.
Effectively, a significant increase in the dissolution of gelatin films was observed for both A 240 films (+150% at min) and B 200 films (+85% at 6 min).
Example 3:
Gelatin films with amino acids as additives were 15 prepared and stored at hot and humid conditions prior to dissolution measurements. Gelatin films were casted from 30%
w/w solution containing either 1% Tryptophan or 1% Glutamic acid. Gelatin films of A 240 and of B 200 were prepared.
Films were dried at room conditions for 24 hours prior to sample preparation. The samples were stored at 50°C and 80%
RH for 3 (A240) or 4 months (B 200) prior to dissolution measurements. The results are shown in table 3 in comparison with gelatin without additives stored at room temperature (Ref.).
Table 3 (Storage 50°C/80% RH for 3 (A 240) and 4 months (B 200) , Gelatine Additive Dissolution tes (%) after minu A 240 0% 6% 8% 14% 36% 67%
1% Glu .6% 50% 92% 99% 100%
1% Trp 10% 87% 97% 99% 100%
B 200 0% 3% 76% 92% 98% 98%
1% Glu 54% 92% 97% 99% 100%
1% Trp 59% 97% 100% 100% 100%
A 240 0% Ref. 72% 96% 99% 100% 100%
B 200 0% Ref. 96% 100% 100% 100% 100%
The dissolution results, compared with reference tests, demonstrate that the addition of amino acids, specifically Glutamic acid and Tryptophan at 1% level (in respect of dry gelatin) increases the dissolution of gelatin films especially at 3 min for B 200 and 9 min for A 240 gelatins.
In both cases, we reached the total dissolution of gelatin films (100% dissolution) more rapidly with additives than with reference films stored at the same conditions.
Example.4:
Gelatin films with salts or organic compounds were prepared as in example 3. The following products were added at 1% level compared to dry gelatin weight: urea and Masquol P320 (AMP).
The dissolution measurements were performed as for example 3 and results are summarized in following table 4:
WO 96/14365 . , 2 ) 9 915 5 pCT~s95113950 Table 4 Gelatine Additive Dissolution tes (%) after minu A 240 0% 6% 8% 14% 36% 67%
1% Glu 10% 92% 99$ 100% 100%
1% AMP 94% 97% 100% 100% 100%
B 200 0% 3% 76% 92% 98% 98%
1% Urea 79% 97% 99% 100% 100%
1% AMP 77% 94% 99% 100% 100%
A 240 0% Ref. 72% 96% 99% 100% 100%
B 200 0% Ref. 96% 100% 100% 100% 100%
The addition organic compounds (Urea, Masquol P320) increased significantly the dissolution of gelatin films of both type A
240 and B 200.
For A 240 the 100% dissolution is obtained at about 6 min compared to only 8% dissolution for gelatin films without additives. This result is comparable to reference films (Ref.) stored at normal conditions. The dissolution is higher than 75% for B 200 gelatin after only 3 min (3% for B
200 films without additives). These results are comparable to reference B 200 films (Ref.) stored at normal conditions.
As demonstrated from these examples, the incorporation of selected additives into the gelatin films increases the resistance<of gelatin films and capsules to crosslinking in presence of aldehydes or when stored in hot and humid conditions.
Example 5:
The dissolution of capsules containing additives and filled with lactose contaminated by formaldehyde (5ppm or 20 WO 96/14365 , PCT/US95/13950 ppm) and stored at 50°C in closed bottles for 1 or 2 months was studied. The results are expressed as the level of , dissolution of acetaminophen filled in the capsules and measured according to the USP XXII Method 2. ' Table 5 Test Additive Dissolution (%) after minutes A p% 12% 40 57% 71% 79%
2% (I) 39% 68% 87% 95% 97%
g p% 24% 50% 66% 78% 88%
2% (I) 40% 72% 90% 98% 100%
1% (II) 39% 79% 95% 100% 100%
C 0% 43% 79% 94% 98% 99%
2 f ldeh de Test A: Storage 4 weeks at 5 C, 0 ppm orma y Test B: Storage 2 months at 50°C, 5 ppm formaldehyde Test C: Reference storage at room conditions Additive (I): Ammoniumsulfate Additive (II): Aspartic acid The dissolution of capsules containing additives is better than the reference one. This dissolution is equal to the dissolution of a standard capsules stored at room conditions.
While there have been described what are presently believed to be the preferred embodiments of the invention, those skilled in the art will realize that various changes and modifications may be made to the invention without departing from the spirit of the invention, and it is intended to claim all such changes and modifications as fall within the scope of the invention.
under agitation (paddle'50 rpm). The percentage of dissolved Acetaminophen is determined by UV spectrophotometry at 300 r nm. The required level of dissolved Acetaminophen is higher than 80~ at 45 min.
2. Gelatin film dissolution Films of gelatin are carted on glass plates. These films are stored at one or both of the conditions described before. The films are then added in demineralized water at 37°C under agitation (paddle 50 rpm) and the percentage of dissolution is determined by UV spectrophotometry at 217 nm.
Uncrosslinked films have a dissolution of more than 90~ at 6 min.
The following examples will demonstrate how the addition of inventive compounds increases the resistance of gelatins to crosslinking by hot and humid storage and/or formaldehyde.
Example 1:
We studied the effect of addition of ammonium sulfate (2~ w/w of gelatin) on the resistance of gelatin to formaldehyde crosslinking. Gelatins type a 240 and type B
200 or two different suppliers with two batches each were studies. The gelatin films were carted from a 30~ gelatin solution containing 2~ w/w of ammonium sulfate ((NH4)2504) and without additives (Reference). Films were dried at room conditions for 24 hours and dissolution samples were prepared and stored in formaldehyde contaminated lactose powder (at 5 ppm formaldehyde at 50°C for 1 week).
- - - ~ _ The dissolution results (%) are summarized in table 1 in comparison to mean values of 4 batches stored for 1 week at room conditions.
Table 1 z-Gelatin Supplier Batch Reference (Nii4)2504 3 ~ min 6 min 3 min 6 min A 1 10% 35% 80% 96%
2 7% 46% 86% 98%
A 240 B 1 11% 60% 76% 98%
2 20% 70% 60% 96%
Mean value for 4 batches 81% 97% 74% 93%
Table 1 demonstrates a very impressive resistance to formaldehyde crosslinking. Gelatin films with ammonium sulfate have practically the same dissolution results at 3 and 6 min as gelatin films stored at room conditions (mean values for 4 batches). A dramatic decrease in dissolution is noted for films without additives (Reference), especially for dissolution measures at 3 min.
Example 2:
The effect of addition of nitrilotrismethylene phosphonic acid (AMP, Masquol*P320) on the dissolution of gelatin films stored in presence of formaldehyde is studied.
The films were prepared by casting a gelatin solution (30%
w/w water) containing MasquoT P320 (1% w/w gelatin on glass plate and drying at room conditions for 24 hours.
The dissolution samples were then prepared and stored dipped in formaldehyde contaminated lactose in a closed plastic box for 1 week at 50°C prior to dissolution measurements.
*trade mark 6 WO 96/14365 PCTlI1S95/13950 The dissolution results are shown in the following table 2.
Table 2 t Gelatin AMP Dissolution 3 min 6 min 9 min 12 min 15 min A 240 0~ 0~ 3% 10%. 16% 21%
1% 3% 15% 26% 41% 52%
B 200 0% 8% 42% 70% 84~ 87%
1% 8% 77% 89% 93% 94%
Here the beneficial effect of the addition of an additive, Masguol P320, on the resistance of gelatin films to formaldehyde crosslinking is clearly demonstrated.
Effectively, a significant increase in the dissolution of gelatin films was observed for both A 240 films (+150% at min) and B 200 films (+85% at 6 min).
Example 3:
Gelatin films with amino acids as additives were 15 prepared and stored at hot and humid conditions prior to dissolution measurements. Gelatin films were casted from 30%
w/w solution containing either 1% Tryptophan or 1% Glutamic acid. Gelatin films of A 240 and of B 200 were prepared.
Films were dried at room conditions for 24 hours prior to sample preparation. The samples were stored at 50°C and 80%
RH for 3 (A240) or 4 months (B 200) prior to dissolution measurements. The results are shown in table 3 in comparison with gelatin without additives stored at room temperature (Ref.).
Table 3 (Storage 50°C/80% RH for 3 (A 240) and 4 months (B 200) , Gelatine Additive Dissolution tes (%) after minu A 240 0% 6% 8% 14% 36% 67%
1% Glu .6% 50% 92% 99% 100%
1% Trp 10% 87% 97% 99% 100%
B 200 0% 3% 76% 92% 98% 98%
1% Glu 54% 92% 97% 99% 100%
1% Trp 59% 97% 100% 100% 100%
A 240 0% Ref. 72% 96% 99% 100% 100%
B 200 0% Ref. 96% 100% 100% 100% 100%
The dissolution results, compared with reference tests, demonstrate that the addition of amino acids, specifically Glutamic acid and Tryptophan at 1% level (in respect of dry gelatin) increases the dissolution of gelatin films especially at 3 min for B 200 and 9 min for A 240 gelatins.
In both cases, we reached the total dissolution of gelatin films (100% dissolution) more rapidly with additives than with reference films stored at the same conditions.
Example.4:
Gelatin films with salts or organic compounds were prepared as in example 3. The following products were added at 1% level compared to dry gelatin weight: urea and Masquol P320 (AMP).
The dissolution measurements were performed as for example 3 and results are summarized in following table 4:
WO 96/14365 . , 2 ) 9 915 5 pCT~s95113950 Table 4 Gelatine Additive Dissolution tes (%) after minu A 240 0% 6% 8% 14% 36% 67%
1% Glu 10% 92% 99$ 100% 100%
1% AMP 94% 97% 100% 100% 100%
B 200 0% 3% 76% 92% 98% 98%
1% Urea 79% 97% 99% 100% 100%
1% AMP 77% 94% 99% 100% 100%
A 240 0% Ref. 72% 96% 99% 100% 100%
B 200 0% Ref. 96% 100% 100% 100% 100%
The addition organic compounds (Urea, Masquol P320) increased significantly the dissolution of gelatin films of both type A
240 and B 200.
For A 240 the 100% dissolution is obtained at about 6 min compared to only 8% dissolution for gelatin films without additives. This result is comparable to reference films (Ref.) stored at normal conditions. The dissolution is higher than 75% for B 200 gelatin after only 3 min (3% for B
200 films without additives). These results are comparable to reference B 200 films (Ref.) stored at normal conditions.
As demonstrated from these examples, the incorporation of selected additives into the gelatin films increases the resistance<of gelatin films and capsules to crosslinking in presence of aldehydes or when stored in hot and humid conditions.
Example 5:
The dissolution of capsules containing additives and filled with lactose contaminated by formaldehyde (5ppm or 20 WO 96/14365 , PCT/US95/13950 ppm) and stored at 50°C in closed bottles for 1 or 2 months was studied. The results are expressed as the level of , dissolution of acetaminophen filled in the capsules and measured according to the USP XXII Method 2. ' Table 5 Test Additive Dissolution (%) after minutes A p% 12% 40 57% 71% 79%
2% (I) 39% 68% 87% 95% 97%
g p% 24% 50% 66% 78% 88%
2% (I) 40% 72% 90% 98% 100%
1% (II) 39% 79% 95% 100% 100%
C 0% 43% 79% 94% 98% 99%
2 f ldeh de Test A: Storage 4 weeks at 5 C, 0 ppm orma y Test B: Storage 2 months at 50°C, 5 ppm formaldehyde Test C: Reference storage at room conditions Additive (I): Ammoniumsulfate Additive (II): Aspartic acid The dissolution of capsules containing additives is better than the reference one. This dissolution is equal to the dissolution of a standard capsules stored at room conditions.
While there have been described what are presently believed to be the preferred embodiments of the invention, those skilled in the art will realize that various changes and modifications may be made to the invention without departing from the spirit of the invention, and it is intended to claim all such changes and modifications as fall within the scope of the invention.
Claims (8)
1. A process for the manufacturing of gelatin films, capsules, casings or coatings with improved stability for storage under hot and humid conditions or improved resistance to crosslinking when stored in the presence of aldehydes wherein said gelatin films, capsules, casings or coatings are prepared from a dry gelatin, characterized in that at least one additive selected from the group consisting essentially of sodium sulfate, sodium chloride, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride, calcium sulfate, calcium chloride, magnesium sulfate, magnesium chloride, iron (II) sulfate, iron (II) chloride, iron (III) sulfate, iron (III) chloride, manganese (II) sulfate, manganese (II) chloride, glutamic acid, aspartic acid, asparagine, lysine, tryptophane, arginine, guanidine, ascorbic acid, ethylenediamine tetraacetate, nitrilotrismethylene phosphonic acid or a mixture thereof in an amount of up to 25% by weight of the dry gelatin is incorporated into the gelatin before forming a final gelatin product.
2. A process according to claim 1, wherein the additive or the mixture of additives is incorporated in the gelatin in an amount of from about 0.1 to about 10% by weight of the dry gelatin.
3. A gelatin composition containing additives with improved stability for storage under hot and humid conditions or improved resistance to crosslinking when stored in the presence of aldehydes, comprising at least one additive selected from the group consisting essentially of sodium sulfate, sodium chloride, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride, calcium sulfate, calcium chloride, magnesium sulfate, magnesium chloride, iron (II) sulfate, iron (II) chloride, iron (III) sulfate, iron (III) chloride, manganese (II) sulfate, manganese (II) chloride, glutamic acid, aspartic acid, asparagine, lysine, tryptophane, arginine, guanidine, ascorbic acid, ethylenediamine tetraacetate, nitrilotrismethylene phosphonic acid or a mixture thereof with the exclusion of lyophilised antigen preparations consisting of sodium chloride, magnesium chloride, calcium chloride, gelatin, saccharose and an antigen.
4. Gelatin films, capsules, casings or coatings prepared from compositions with improved stability for storage under hot and humid conditions or improved resistance to crosslinking when stored in the presence of aldehydes comprising at least one additive selected from the group consisting essentially of sodium sulfate, sodium chloride, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride, calcium sulfate, calcium chloride, magnesium sulfate, magnesium chloride, iron (II) sulfate, iron (II) chloride, iron (III) sulfate, iron (III) chloride, manganese (II) sulfate, manganese (II) chloride, glutamic acid, aspartic acid, asparagine, lysine, tryptophane, arginine, guanidine, ascorbic acid, ethylenediamine tetraacetate, nitrilotrismethylene phosphonic acid or a mixture thereof.
5. A gelatin product according to claim 4, wherein said gelatin film, capsule, casing or coating comprises 0.1 to 10% by weight of at least one additive of the group consisting of tryptophan, glutamic acid or nitrilotrismethylene phosphonic acid or mixtures thereof.
6. A pharmaceutical gelatin capsule shell prepared from compositions with improved stability for storage under hot and humid conditions or improved resistance to crosslinking when stored in the presence of aldehydes comprising at least one additive selected from the group consisting essentially of sodium sulfate, sodium chloride, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride, calcium sulfate, calcium chloride, magnesium sulfate, magnesium chloride, iron (II) sulfate, iron (II) chloride, iron (III) sulfate, iron (III) chloride, manganese (II) sulfate, manganese (II) chloride, glutamic acid, aspartic acid, asparagine, lysine, tryptophane, arginine, guanidine, ascorbic acid, ethylenediamine tetraacetate, nitrilotrismethylene phosphonic acid or a mixture thereof.
7. A pharmaceutical gelatin capsule shell containing 0.1 to 10% by weight of at least one additive of the group consisting essentially of sodium sulfate, sodium chloride, potassium sulfate, potassium chloride, lithium sulfate, lithium chloride, calcium sulfate, calcium chloride, magnesium sulfate, magnesium chloride, iron (II) sulfate, iron (II) chloride, iron (III) sulfate, iron (III) chloride, manganese (II) sulfate, manganese (II) chloride, glutamic acid, aspartic acid, asparagine, lysine, tryptophane, arginine, guanidine, ascorbic acid, ethylenediamine tetraacetate, nitrilotrismethylene phosphonic acid or a mixture thereof, urea, tryptophan, glutamic acid or nitrilotrismethylene phosphonic acid or mixtures thereof.
8. A pharmaceutical gelatin capsule shell according to claim 7 containing 0.1 to 10% by weight of at least one additive of the group consisting essentially of tryptophan, glutamic acid or nitrilotrismethylene phosphonic acid or mixtures thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US334,974 | 1994-11-07 | ||
| US08/334,974 US5620704A (en) | 1994-11-07 | 1994-11-07 | Process for stabilizing gelatin products |
| PCT/US1995/013950 WO1996014365A2 (en) | 1994-11-07 | 1995-10-31 | Process for stabilizing gelatin products |
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| CA2199155C true CA2199155C (en) | 2006-02-07 |
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| US20140069296A1 (en) * | 2007-05-02 | 2014-03-13 | University Of South Florida | Anti-fouling bio-hydrogel composition |
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