EP1526846A2 - Gelatinkapsel mit verminderter vernetzung - Google Patents
Gelatinkapsel mit verminderter vernetzungInfo
- Publication number
- EP1526846A2 EP1526846A2 EP03772161A EP03772161A EP1526846A2 EP 1526846 A2 EP1526846 A2 EP 1526846A2 EP 03772161 A EP03772161 A EP 03772161A EP 03772161 A EP03772161 A EP 03772161A EP 1526846 A2 EP1526846 A2 EP 1526846A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- dosage form
- drug
- gelatin
- capsule
- 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.)
- Withdrawn
Links
- 238000004132 cross linking Methods 0.000 title claims abstract description 52
- 239000007903 gelatin capsule Substances 0.000 title claims abstract description 39
- 230000002829 reductive effect Effects 0.000 title abstract description 10
- 230000001747 exhibiting effect Effects 0.000 title abstract description 5
- 239000000203 mixture Substances 0.000 claims abstract description 144
- 239000002775 capsule Substances 0.000 claims description 105
- -1 sulfite compound Chemical class 0.000 claims description 90
- 239000003814 drug Substances 0.000 claims description 78
- 229940079593 drug Drugs 0.000 claims description 76
- 108010010803 Gelatin Proteins 0.000 claims description 54
- 229920000159 gelatin Polymers 0.000 claims description 54
- 239000008273 gelatin Substances 0.000 claims description 54
- 235000019322 gelatine Nutrition 0.000 claims description 54
- 235000011852 gelatine desserts Nutrition 0.000 claims description 54
- 239000000463 material Substances 0.000 claims description 53
- 239000002552 dosage form Substances 0.000 claims description 41
- 238000003860 storage Methods 0.000 claims description 35
- 230000015572 biosynthetic process Effects 0.000 claims description 33
- 238000004090 dissolution Methods 0.000 claims description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 239000003795 chemical substances by application Substances 0.000 claims description 24
- 229960000590 celecoxib Drugs 0.000 claims description 18
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 18
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 13
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 13
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 13
- 229920001223 polyethylene glycol Polymers 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 9
- 239000004014 plasticizer Substances 0.000 claims description 9
- 108010037462 Cyclooxygenase 2 Proteins 0.000 claims description 8
- 238000003556 assay Methods 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 238000000338 in vitro Methods 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 235000011187 glycerol Nutrition 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 239000003755 preservative agent Substances 0.000 claims description 7
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 5
- 239000000600 sorbitol Substances 0.000 claims description 5
- 235000010356 sorbitol Nutrition 0.000 claims description 5
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 4
- 125000001769 aryl amino group Chemical group 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 230000002496 gastric effect Effects 0.000 claims description 4
- 150000002334 glycols Chemical class 0.000 claims description 4
- 125000001145 hydrido group Chemical group *[H] 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229940002612 prodrug Drugs 0.000 claims description 4
- 239000000651 prodrug Substances 0.000 claims description 4
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 3
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 3
- 238000000354 decomposition reaction Methods 0.000 claims description 3
- WAZQAZKAZLXFMK-UHFFFAOYSA-N deracoxib Chemical compound C1=C(F)C(OC)=CC=C1C1=CC(C(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 WAZQAZKAZLXFMK-UHFFFAOYSA-N 0.000 claims description 3
- 229960003314 deracoxib Drugs 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229960004945 etoricoxib Drugs 0.000 claims description 3
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- WBHHMMIMDMUBKC-XLNAKTSKSA-N ricinelaidic acid Chemical compound CCCCCC[C@@H](O)C\C=C\CCCCCCCC(O)=O WBHHMMIMDMUBKC-XLNAKTSKSA-N 0.000 claims description 3
- 229960000371 rofecoxib Drugs 0.000 claims description 3
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 229960002004 valdecoxib Drugs 0.000 claims description 3
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 claims description 3
- XNTLXAUHLBBEKP-UHFFFAOYSA-N 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-(4-methylsulfonylphenyl)pyridazin-3-one Chemical compound O=C1C(OCCC(C)(O)C)=C(C=2C=CC(=CC=2)S(C)(=O)=O)C=NN1C1=CC=C(F)C(F)=C1 XNTLXAUHLBBEKP-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 2
- 125000004689 alkyl amino carbonyl alkyl group Chemical group 0.000 claims description 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 125000005164 aryl thioalkyl group Chemical group 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 125000003844 furanonyl group Chemical group 0.000 claims description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 150000007965 phenolic acids Chemical class 0.000 claims description 2
- 229920000151 polyglycol Polymers 0.000 claims description 2
- 239000010695 polyglycol Substances 0.000 claims description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 229960003656 ricinoleic acid Drugs 0.000 claims description 2
- FEUQNCSVHBHROZ-UHFFFAOYSA-N ricinoleic acid Natural products CCCCCCC(O[Si](C)(C)C)CC=CCCCCCCCC(=O)OC FEUQNCSVHBHROZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 239000004408 titanium dioxide Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 5
- 102000010907 Cyclooxygenase 2 Human genes 0.000 claims 4
- 125000001475 halogen functional group Chemical group 0.000 claims 4
- 150000002314 glycerols Chemical class 0.000 claims 2
- 235000013772 propylene glycol Nutrition 0.000 claims 2
- ULFYMTMZNITFSB-UHFFFAOYSA-N 2-(3,5-difluorophenyl)-3-(4-methylsulfonylphenyl)cyclopent-2-en-1-one Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=C(F)C=C(F)C=2)C(=O)CC1 ULFYMTMZNITFSB-UHFFFAOYSA-N 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims 1
- 235000009048 phenolic acids Nutrition 0.000 claims 1
- 230000002335 preservative effect Effects 0.000 claims 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 23
- 238000009472 formulation Methods 0.000 description 52
- 230000008569 process Effects 0.000 description 18
- 239000002904 solvent Substances 0.000 description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 14
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- 150000003141 primary amines Chemical class 0.000 description 10
- 239000003963 antioxidant agent Substances 0.000 description 9
- 235000006708 antioxidants Nutrition 0.000 description 9
- 230000007760 free radical scavenging Effects 0.000 description 9
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 9
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 8
- 239000007983 Tris buffer Substances 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 150000003335 secondary amines Chemical class 0.000 description 8
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 7
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 7
- 230000008859 change Effects 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 6
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- 125000005843 halogen group Chemical group 0.000 description 5
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- 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 description 4
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
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- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 4
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Definitions
- the present invention relates to gelatin capsules which exhibit reduced gelatin cross-linking. Such capsules are useful in, inter alia, the pharmaceutical, nutraceutical, and food industries.
- Gelatin a mixture of water-soluble proteins derived from collagen by hydrolysis, is widely used in the pharmaceutical and food industries, among others.
- One major application of gelatin is in preparation of both hard and soft gelatin capsules.
- Such capsules are desirable for, inter alia, their versatility (they may contain drug formulations in solid, semi-solid, or liquid form) and for their rapid dissolution characteristics.
- drug dosage forms containing gelatin in an outer layer e.g. liquid or powder filled into a gelatin capsule
- an outer layer e.g. liquid or powder filled into a gelatin capsule
- gelatin capsules could be prepared which are capable of providing a predictable and stable dissolution rate of a drug contained therein, even after storage of such capsules under stressed conditions, a significant advance in the oral delivery of drugs, particularly drugs of low water solubility or drugs whose absorption is dissolution- rate limited, would result.
- composition suitable for preparing a pharmaceutical capsule shell comprising gelatin and a pharmaceutically acceptable sulfite compound.
- the sulfite compound is present in an amount effective to inhibit cross-linking of the gelatin and/or pellicle formation in a capsule shell prepared from the composition.
- capsule shell of the instant composition there is further provided a capsule shell of the instant composition.
- a pharmaceutical dosage form comprising capsule shells of the instant composition, wherein the capsule shells define a fill volume that is at least partially occupied by a fill material.
- the sulfite in the capsule shell of the pharmaceutical dosage form is present in an amount effective to inhibit cross-linking of the gelatin and/or pellicle formation in the capsule shell.
- the dosage form of this invention contains a drug in the fill material, more preferably a drug of low water solubility.
- the drug is a selective cyclooxygenase-2 inhibitory drug.
- the composition and dosage form of the present invention are especially useful for liquid fill materials and for soft gelatin capsules.
- pellicle refers to a relatively water-insoluble membrane formed in a gelatin capsule shell wherein the membrane tends to be thin, tough, and rubbery. It is now understood that one mechanism underlying pellicle formation is gelatin cross-linking. Gelatin cross-linking and pellicle formation result in reduced dissolution rates. Accordingly, quantification of dissolution rate of a first capsule within a reasonably short time after capsule preparation and of a second capsule after storage under stressed conditions (e.g. four weeks at 40°C and 85% relative humidity in a closed container) as described herein provides one means of assessing pellicle formation and/or gelatin cross- linking.
- pellicle resistant herein means that such a gelatin capsule so described has a reduced tendency to form, or exhibits slowed, delayed or reduced formation of a pellicle upon storage under stressed conditions.
- inhibitor of cross-linking or “inhibition of pellicle formation” herein means a slowed, delayed or reduced formation of gelatin cross-links (or pellicle formation) by comparison with an amount a similar capsule lacking only agent as provided herein.
- compositions according to the present invention have been found to exhibit an unexpected and surprisingly substantial reduction in cross-linking of the gelatin in the capsule shell and pellicle formation. As a result, such dosage forms are capable of consistently meeting desired in vitro dissolution criteria, even after storage under stressed conditions. This invention represents a significant improvement over conventional dosage forms and conventional gelatin capsule shells.
- Figure 1 is a graph showing Tier I dissolution rate of Formulation 30 following storage at 25 °C as described in Example 5.
- Figure 2 is a graph showing Tier I dissolution rate of Formulation 30 following storage at 40°C as described in Example 5.
- Figure 3 is a graph showing Tier II dissolution rate of Formulation 30 following storage at 25 °C as described in Example 5.
- Figure 4 is a graph showing Tier ⁇ dissolution rate of Formulation 30 following storage at 40°C as described in Example 5.
- Figure 5 is a graph showing Tier I dissolution rate of Formulation 19 following storage at 25 °C as described in Example 5.
- Figure 6 is a graph showing Tier I dissolution rate of Formulation 19 following storage at 40°C as described in Example 5.
- Figure 7 is a graph showing Tier LT dissolution rate of Formulation 19 following storage at 40°C as described in Example 5.
- composition suitable for preparation of a capsule shell.
- the present invention provides a composition suitable for preparation of a capsule shell.
- a composition suitable for preparation of a capsule shell.
- Such a composition comprises gelatin and at least one sulfite compound present in an amount effective to inhibit cross-linking of the gelatin shell and/or pellicle formation upon storage.
- a "composition suitable for preparation of a capsule shell" according to the present invention comprises gelatin, at least one sulfite compound, and optionally one or more excipients.
- a liquid for example water
- a liquid for example water
- such a composition suitable for preparation of a capsule wall comprises gelatin, at least one sulfite compound, and water.
- water will be present in an amount such that the weight ratio of water to gelatin is about 0.8 to about 1.6, and preferably about 1 to about 1.3.
- gelatin is present in a composition of the invention in an amount of about 1% to about 99%, more preferably about 10% to about 80%, and still more preferably about 15% to about 90% of the composition on a dry weight basis. It should be understood that "on a dry weight basis” means total weight excepting water weight.
- any pharmaceutically acceptable sulfite compound can be used in a composition of this embodiment.
- Illustrative pharmaceutically acceptable sulfite compounds include sodium metabisulfite, sodium bisulfite, and sodium thiosulfate (sodium hyposulfite).
- One or more sulfite compounds are preferably present in a composition of the invention in a total amount of not more than about 10%, for example about 0.01% to about 10%, preferably about 0.1% to about 5%, and more preferably about 0.1% to about 2% of the composition on a dry weight basis.
- a composition of the invention can comprise an amine agent comprising at least one pharmaceutically acceptable primary or secondary amine.
- suitable primary amines include tromethamine (Tris), ethanolamine, diethylamine, ethylene N-methyl-D-glucamine, and amino acids such as L-arginine, L- lysine, and guanidine.
- Non-limiting examples of suitable secondary amines include diethanolamine, benethamine (i.e., N-phenymethyl)benezeneethanamine), benzathine (i.e., N,N-dibenzylethylenediamine), piperazine, hydrabamine (i.e., N,N- bis(dehydroabietyl)ethylenediamine), and imidazole.
- the amine compound is present in a composition of the invention in an amount of not more than about 10%, preferably not more than about 5%, and more preferably not more than about 2.5% of the composition on a dry weight basis.
- a composition of the invention in addition to gelatin and a sulfite compound, preferably further comprises one or more pharmaceutically acceptable excipients.
- the composition preferably comprises at least one plasticizer in a total amount of about 2% to about 60%, preferably about 5% to about 45%, and more preferably about 10% to about 40% of the composition on a dry weight basis.
- the weight ratio of plasticizer (non-aqueous portion) to gelatin is about 0.3 to about 1.8 and preferably about 0.4 to about 0.75.
- Non-limiting examples of suitable plasticizers include poly-hydroxy-alcohols such as sorbitol, glycerol, and mannitol; dialkylphthalates; lower alkyl citrates wherein the lower alkyl has 1 - 6 carbon atoms; glycols and polyglycols including polyethylene glycols with a molecular weight range of about 200 to about 40,000, methoxyl-propylene-glycol, and 1,2-propylene glycol; esters of polyhydroxy-alcohols such as mono-, di-, and tri-acetate of glycerol; ricinoleic acid and esters thereof; and mixtures of the above.
- poly-hydroxy-alcohols such as sorbitol, glycerol, and mannitol
- dialkylphthalates lower alkyl citrates wherein the lower alkyl has 1 - 6 carbon atoms
- glycols and polyglycols including polyethylene glycols with a molecular
- a composition of the invention can further comprise one or more preservatives, opacifying agents (e.g. titanium dioxide), decomposition inhibitors (e.g. sulfur dioxide) color, flavor, etc.
- opacifying agents e.g. titanium dioxide
- decomposition inhibitors e.g. sulfur dioxide
- suitable preservatives include mythylparaben, propylparaben, butylparaben, sorbic acid, benzoic acid, editic acid, phenolic acid, potassium sorbate, and sodium propionate.
- a composition suitable for preparation of a capsule wall can be in the form of a solid, a dry powder, a semi-solid, a liquid solution, or a liquid suspension.
- a suitable physical form e.g.
- a composition of the invention can be used to prepare hard gelatin capsules according to any suitable process including but not limited to those processes described in the following patents and/or publications, each of which is hereby incorporated by reference herein.
- One preferred method for preparing hard gelatin capsules of the invention comprises the steps of (a) providing a composition suitable for preparation of a capsule shell (comprising gelatin and a sulfite compound) in dry powder form, (b) preparing a liquid solution or solution/suspension comprising water and the composition, (c) heating the liquid, (d) dipping stainless steel capsule-making pins in the heated liquid, (e) removing the dipped pins from the liquid to form coated pins, and (f) subjecting the coated pins to a drying process to produce a dry capsule half-shell. After drying, capsule half-shells are removed from the pins, trimmed to desired length.
- the capsule half-shells can next be filled with any desired fill material, brought together in a cooperative manner to form a capsule shell, and then capped.
- the cap can be spot welded, fused or banded with molten gelatin to provide a tamper-resistant product.
- the sulfite compound is preferably present in the composition suitable for preparation of a capsule shell, and/or if desired, can also be added during steps (b), (c) and/or (d).
- Soft gelatin capsules of the invention can be prepared according to any suitable process including but not limited to the plate process, vacuum process, or the rotary die process. See, for example, (1) Ansel et al. (1995) in Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed., Williams & Wilkins, Baltimore, MD, pp. 176-182; and (2) Remington: The Science and Practice of Pharmacy, 19th Ed., Mack Publishing Co. Easton. PA, pp. 1646 - 1647, the above-recited pages of which are hereby incorporated by reference herein.
- the rotary die process is a presently preferred process by which to make soft gelatin capsules according to the present invention.
- a composition of the invention comprising gelatin and a sulfite compound is dissolved or suspended in water to form a flowable material and is then placed in an overhead tank.
- the flowable material from the overhead tank is formed into two continuous ribbons by a rotary die machine and the ribbons are then brought together by twin rotating dies.
- metered fill material is injected between ribbons at approximately the same moment that the dies form pockets of the ribbons. These pockets of fill-containing encapsulation material are then sealed by pressure and heat.
- Soft gelatin capsules can be manufactured in different shapes including round, oval, oblong, and tube-shape, among others. Additionally, by using two different ribbon colors, two-tone capsules can be produced.
- capsule shell and “gelatin capsule shell” embraces capsule half-shells (that can cooperate to form a whole capsule shell) and whole capsule shells (that define a fill volume). Such term also embraces soft gelatin capsule shells and hard gelatin capsules, irrespective of the process by which such shells are made.
- the terms "sealed capsule shell”, “sealed in a capsule shell”, “sealing in the capsule shell” and the like are meant to denote a whole capsule shell that defines a fill volume, that such fill volume can contain a fill material, that such fill material is enclosed in the whole capsule shell, and that such enclosure affords the fill material more than a de minimus amount of protection from the atmosphere outside of the whole capsule shell.
- Capsule shells according to the present invention define a fill volume and such fill volume can be occupied at least partially by any fill material.
- the fill material can comprise any active drug.
- the active drug is a drug of low water solubility, also referred to herein as a poorly water soluble drug.
- a "drug of low water solubility” or “poorly water solubility drug” herein refers to any drug or compound having a solubility in water, measured at 37°C, not greater than about 10 mg/ml, and preferably not greater than about 1 mg/ml. Particularly preferred drugs having a solubility in water, measured at 37°C, not greater than about 0.1 mg/ml.
- Solubility in water for many drugs can be readily determined from standard pharmaceutical reference books, for example The Merck Index, 11th ed., 1989 (published by Merck & Co., Inc., Rahway, NJ); the United States Pharmacopoeia, 24th ed. (USP 24), 2000; The Extra Pharmacopoeia, 29th ed., 1989 (published by Pharmaceutical Press, London); and the Physicians Desk Reference (PDR), 2001 ed. (published by Medical Economics Co., Montvale, NJ).
- individual drugs of low solubility as defined herein include those drugs categorized as “slightly soluble”, “very slightly soluble”, “practically insoluble” and “insoluble” in USP 24, pp. 2254-2298; and those drugs categorized as requiring 100 ml or more of water to dissolve 1 g of the drug, as listed in USP 24, pp. 2299-2304.
- suitable drugs of low water solubility include, without limitation, drugs from the following classes: abortifacients, ACE inhibitors, ⁇ - and ⁇ -adrenergic agonists, - and ⁇ -adrenergic blockers, adrenocortical suppressants, adrenocorticotropic hormones, alcohol deterrents, aldose reductase inhibitors, aldosterone antagonists, anabolics, analgesics (including narcotic and non-narcotic analgesics), androgens, angiotensin II receptor antagonists, anorexics, antacids, anthelminthics, antiacne agents, antiallergics, antialopecia agents, antiamebics, antiandrogens, antianginal agents, antiarrhythmics, antiarteriosclerotics, antiarthritic/antirheumatic agents (including selective COX-2 inhibitors), antiasth
- ⁇ on-limiting illustrative examples of suitable drugs of low water solubility include acetohexamide, acetylsalicylic acid, alclofenac, allopurinol, atropine, benzthiazide, ca ⁇ rofen, celecoxib, chlordiazepoxide, chlorpromazine, clonidine, codeine, codeine phosphate, codeine sulfate, deracoxib, diacerein, diclofenac, diltiazem, estradiol, etodolac, etoposide, etoricoxib, fenbufen, fenclofenac, fenprofen, fentiazac, flurbiprofen, griseofulvin, haloperidol, ibuprofen, indomethacin, indoprofen, ketoprofen, lorazepam, medroxyprogesterone
- the amount of drug inco ⁇ orated into fill material to be filled into a capsule of the invention can be selected according to known principles of pharmacy.
- a therapeutically effective amount of drug is specifically contemplated.
- the term "therapeutically and/or prophylactically effective amount” as used herein refers to an amount of drug that is sufficient to elicit the required or desired therapeutic and/or prophylactic response.
- the therapeutic agent is present in an amount of at least about 0.01%, preferably at least about 0.1%, more preferably at least about 1%, and still more preferably at least about 5%, by weight of the fill material.
- the drug is a selective cyclooxygenase-2 inhibitory drug.
- a preferred selective cyclooxygenase-2 inhibitory drug useful herein, or to which a salt or prodrug useful herein is converted in vivo, is a compound of formula (I)
- A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings, preferably a heterocyclyl group selected from pyrazolyl, furanonyl, isoxazolyl, pyridinyl, cyclopentenonyl and pyridazinonyl groups;
- X is O, S or CH 2 ; n is O or 1;
- R 1 is at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, and is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
- R 2 is methyl, amino or aminocarbonylalkyl
- R 3 is one or more radicals selected from hydrido, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkyla
- compositions of the invention are especially useful for selective cyclooxygenase -2 inhibitory drugs having the formula (IT):
- R 5 is a methyl or amino group
- R 6 is hydrogen or a C 1-4 alkyl or alkoxy group
- X 1 is N or CR 7 where R 7 is hydrogen or halogen
- Y and Z are independently carbon or nitrogen atoms defining adjacent atoms of a five- to six-membered ring that is optionally substituted at one or more positions with oxo, halo, methyl or halomethyl groups, or an isomer, tautomer, pharmaceutically-acceptable salt or prodrug thereof.
- Preferred such five- to six-membered rings are cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted at no more than one position.
- capsules of the invention are suitable for delivering celecoxib, deracoxib, valdecoxib, rofecoxib, etoricoxib, 2-(3,5-difluorophenyl)-3-[4-
- Capsules of the invention are also useful for compounds having the formula
- X" is O, S or N-lower alkyl
- R 8 is lower haloalkyl
- R 9 is hydrogen or halogen
- R 10 is hydrogen, halogen, lower alkyl, lower alkoxy or haloalkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, or 5- or 6-membered nitrogen-containing
- a particularly useful compound of formula (IU) is (S)-6,8-dichloro-2-
- the dosage form typically comprises celecoxib in a therapeutically and/or prophylactically effective total amount of about 10 mg to about 1000 mg per dose unit.
- the drug is a selective COX-2 inhibitory drug other than celecoxib
- the amount of the drug per dose unit is therapeutically equivalent to about 10 mg to about 1000 mg of celecoxib.
- a therapeutically and/or prophylactically effective amount of a drug for a subject is dependent inter alia on the body weight of the subject.
- a "subject" herein to which a therapeutic agent or composition thereof can be administered includes a human patient of either sex and of any age, and also includes any nonhuman animal, particularly a domestic or companion animal, illustratively a cat, dog or horse.
- an amount of celecoxib relatively low in the preferred range of about 10 mg to about 1000 mg is likely to be consistent with therapeutic effectiveness.
- an adult human or a large animal e.g., a horse
- therapeutic effectiveness is likely to require dose units containing a relatively greater amount of celecoxib.
- a therapeutically effective amount of celecoxib per dose unit in a dosage form of the present invention is typically about 10 mg to about 400 mg.
- Especially preferred amounts of celecoxib per dose unit are about 100 mg to about 200 mg, for example about 100 mg or about 200 mg.
- an amount of the drug per dose unit can be in a range known to be therapeutically effective for such drugs.
- the amount per dose unit is in a range providing therapeutic equivalence to celecoxib in the dose ranges indicated immediately above.
- a capsule of the invention is filled with a liquid fill material. More preferably, the fill material is self -emulsifying upon contact with simulated gastric fluid.
- Fill material according to this embodiment comprises at least one solvent which is preferably suitable for dissolving the drug and/or any additional ingredients or excipients present therein.
- glycol or glycol ether examples include those conforming to formula (X):
- Glycol ethers used as solvents in fill material typically have a molecular weight of about 75 to about 1000, preferably about 75 to about 500, and more preferably about 100 to about 300.
- the glycol ethers used in fill material of this embodiment must be pharmaceutically acceptable and must meet all other conditions prescribed herein.
- Non-limiting examples of glycol ethers that may be used in fill material of this embodiment include ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethylene glycol monoethyl ether, ethylene glycol diethyl ether, ethylene glycol monobutyl ether, ethylene glycol dibutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, ethylene glycol butylphenyl ether, ethylene glycol te ⁇ inyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol divinyl ether, ethylene glycol monobutyl ether, diethylene glycol dibutyl ether, diethylene glycol monoisobutyl ether, triethylene glycol dimethyl ether, triethylene glycol monoethyl ether, triethylene glycol monobutyl ether,
- glycol ether solvent is diethylene glycol monoethyl ether, sometimes referred to in the art as DGME or ethoxydiglycol. It is available for example under the trademark TranscutolTM of Gattefosse Co ⁇ oration.
- Glycols suitable as solvents in fill material include propylene glycol, 1,3- butanediol and polyethylene glycols.
- a presently preferred solvent is polyethylene glycol (PEG).
- any pharmaceutically acceptable PEG can be used.
- the PEG has an average molecular weight of about 100 to about 10,000, and more preferably about 100 to about 1,000. Still more preferably, the PEG is of liquid grade.
- PEGs that can be used in solvent liquids of this invention include PEG-200, PEG-350, PEG-400, PEG-540 and PEG-600. See for example Flick (1998), op. at, p. 392.
- a presently preferred PEG has an average molecular weight of about 375 to about 450, as exemplified by PEG-400.
- PEGs such as PEG-400 have many desirable properties as solvents for poorly water-soluble drugs.
- the drug can be dissolved or solubilized at a very high concentration in PEG-400, enabling formulation of a therapeutically effective dose in a very small volume of solvent liquid. This is especially important where the resulting solution is to be encapsulated, as capsules of a size convenient for swallowing can be prepared containing a therapeutically effective dose even of a drug such as celecoxib having a relatively high dose requirement for efficacy.
- ethanol, water, and other excipients identified as co-solvents hereinbelow or elsewhere can, if desired, be used as solvents in a fill material of the invention.
- one or more solvents will be present in a fill material in a total amount of about 5% to about 95%, preferably about 10% to about 90% and more preferably about 15% to about 85%, by weight of the fill material.
- one or more solvents will be present in a fill material in a total amount of about 5% to about 95%, preferably about 10% to about 90% and more preferably about 15% to about 85%, by weight of the fill material.
- a fill material of this embodiment optionally comprises one or more pharmaceutically acceptable co-solvents.
- suitable co-solvents include additional glycols, alcohols, for example ethanol and n-butanol; oleic and linoleic acid triglycerides, for example soybean oil; caprylic/capric triglycerides, for example MiglyolTM 812 of Huls; caprylic/capric mono- and diglycerides, for example CapmulTM MCM of Abitec; polyoxyethylene caprylic/capric glycerides such as polyoxyethylene (8) caprylic/capric mono- and diglycerides, for example LabrasolTM of Gattefosse; propylene glycol fatty acid esters, for example propylene glycol laurate; polyoxyethylene (35) castor oil, for example CremophorTM EL of BASF; polyoxyethylene glyceryl trioleate, for example TagatTM TO of Goldschmidt; lower alkyl
- fill material placed into a capsule of the present invention can further comprise an amine agent comprising at least one primary or secondary amine compound. While any pharmaceutically acceptable primary or seconday amine can be used as described above (for optional amine agents of the composition of this invention).
- a fill material comprises a primary or secondary amine compounds, such amine compounds are not therapeutically or nutritionally active.
- about 50%, preferably at least about 55%, more preferably at least about 60%, and still more preferably at least about 65% of any primary or secondary amine compound present in a dosage form of the invention is present in the fill material.
- Fill material placed into a capsule of the present invention can further comprise a sulfite compound as described herein above.
- a sulfite compound as described herein above.
- at least about 40%, preferably at least about 50%, still more preferably at least about 55%, even more preferably at least about 60%, and yet more preferably at least about 70% of all sulfite compound present in a dosage unit of the invention is present in the capsule shell.
- the capsule shell comprises at least one primary or secondary amine and optionally a sulfite compound.
- the fill material of the dosage form optionally comprises either (1) at least one primary or secondary amine, or (2) a sulfite compound; or (3) at least one primary or secondary amine and a sulfite compound.
- at least one primary or secondary amine contemplates the presence of one or more primary amines, one or more secondary amines, and combinations of primary and secondary amines.
- Fill material of the present invention optionally further comprises at least one pharmaceutically acceptable free radical-scavenging antioxidant.
- a free radical- scavenging antioxidant is to be contrasted with a "non-free radical-scavenging antioxidant", i.e., an antioxidant that does not possess free radical-scavenging properties.
- Non-limiting illustrative examples of suitable free radical-scavenging antioxidants include -tocopherol (vitamin E), ascorbic acid (vitamin C) and salts thereof including sodium ascorbate and ascorbic acid palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), fumaric acid and salts thereof, hypophosphorous acid, malic acid, alkyl gallates, for example propyl gallate, octyl gallate and lauryl gallate, sodium sulfite, sodium bisulfite and sodium metabisulfite.
- Preferred free radical-scavenging antioxidants are alkyl gallates, vitamin E, BHA and BHT.
- the at least one free radical-scavenging antioxidant is propyl gallate.
- One or more free radical-scavenging antioxidants are optionally present in dosage forms of the invention in a total amount effective to substantially reduce formation of an addition compound, typically in a total amount of about 0.01% to about 5%, preferably about 0.01% to about 2.5%, and more preferably about 0.01% to about 1%, by weight of the fill material.
- Fill material according to the invention optionally comprises one or more pharmaceutically acceptable sweeteners.
- suitable sweeteners include mannitol, propylene glycol, sodium saccharin, acesulfame K, neotame and aspartame.
- a viscous sweetener such as sorbitol solution, syrup (sucrose solution) or high-fructose corn syrup can be used and, in addition to sweetening effects, can also be useful to increase viscosity and to retard sedimentation.
- Fill material of the invention optionally comprises one or more pharmaceutically acceptable preservatives other than free radical-scavenging antioxidants.
- Non-limiting examples of suitable preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, thimerosal, etc.
- Fill material of the invention optionally comprises one or more pharmaceutically acceptable wetting agents.
- Surfactants, hydrophilic polymers and certain clays can be useful as wetting agents to aid in dissolution and/or dispersion of a hydrophobic drug such as celecoxib.
- Non-limiting examples of suitable surfactants include benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, dioctyl sodium sulfosuccinate, nonoxynol 9, nonoxynol 10, octoxynol 9, poloxamers, polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., LabrasolTM of Gattefosse), polyoxyethylene (35) castor oil, polyoxyethylene (20) cetostearyl ether, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (10) oleyl ether, polyoxyethylene (40) stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 (e.g., TweenTM 80 of ICI), propylene glycol laurate (e.g., LauroglycolTM of Gattefosse), sodium lauryl sulfate, sorbitan monolaurate, sorbitan monoole
- dosage forms of the invention optionally comprise one or more pharmaceutically acceptable buffering agents, flavoring agents, colorants, stabilizers and/or thickeners.
- Buffers can be used to control pH of a formulation and can thereby modulate drug solubility.
- Flavoring agents can enhance patient compliance by making the dosage form more palatable, and colorants can provide a product with a more aesthetic and/or distinctive appearance.
- suitable colorants include D&C Red No. 33, FD&C Red No. 3, FD&C Red No. 40, D&C Yellow No. 10, and C Yellow No. 6.
- gelatin cross- linking can result from a process by which amino acid residues of gelatin covalently bond to form an insoluble material.
- the process can the result of low levels of aldehydes coming into contact with the gelatin.
- Cross-linking of a gelatin capsule can impact product performance by delaying the release of the formulation (containing the active compound) from the capsule shell. The delay in release can, in turn, affect the rate of abso ⁇ tion of the compound into the blood stream and clinical onset of action.
- 'mild' cross-linking does not necessarily may not have a significant impact on release of the formulation from the dosage form
- 'severe' cross-linking can have a significant impact. When cross-linking is severe, it can lead to a delay of release of formulation from the dosage form in humans, potential bioequivalence problems, and a potential delay in clinical onset of action.
- Capsules according to the present invention are believed to exhibit decreased gelatin cross-linking (and pellicle formation) and, therefore, when filled with a drug- containing composition and placed in an in vitro dissolution assay, are capable of advantageously exhibiting less dissolution rate change during storage under stressed conditions than conventional capsules. Capsules according to the present invention are also believed to exhibit more uniform inter-capsule drug dissolution rate than standard gelatin capsules.
- gelatin cross- linking can result from a process by which amino acid residues of gelatin covalently bond to form an insoluble material.
- the process can be the result of low levels of aldehydes coming into contact with the gelatin.
- Cross-linking of a gelatin capsule can impact product performance by delaying the release of the formulation (containing the active compound) from the capsule shell. The delay in release can, in turn, affect the rate of abso ⁇ tion of the compound into the blood stream and clinical onset of action.
- 'mild' cross-linking does not necessarily have a significant impact on release of the formulation from the dosage form
- 'severe' cross-linking can have a significant impact. When cross-linking is severe, it can lead to a delay of release of formulation from the dosage form in humans, potential bioequivalence problems, and a potential delay in clinical onset of action.
- Capsules according to the present invention are believed to exhibit decreased gelatin cross-linking (and pellicle formation) and, therefore, when filled with a drug- containing composition and placed in an in vitro dissolution assay, are capable of advantageously exhibiting less dissolution rate change during storage under stressed conditions than conventional capsules. Capsules according to the present invention are also believed to exhibit more uniform inter-capsule drug dissolution rate than standard gelatin capsules.
- a liquid fill formulation, F0 is prepared as shown in Table 1.
- compositions suitable for preparation of a capsule wall are prepared as shown in Tables 2 and 3 according to the following procedure.
- Gelatin and one or sulfite compounds are admixed together to form a dry mixture.
- One or more plasticizers glycerol and/or sorbitol
- water are then added to the mixture to form a liquid mixture.
- the liquid mixture is melted at 80°C for up to four hours to form a melt.
- the melt is cooled to 60°C to form a flowable gelatin mix and is fed into the two spreader boxes of a rotary die soft gelatin capsule manufacturing machine, which controls the flow of said mix onto two air-cooled rotating drums, where two white opaque gelatin ribbons are cast and further processed to white opaque, soft gelatin capsules, at a rate of about 15,000 capsules per hour; capsules are filled with 1 ml of fill Formulation F0 of Example 1.
- the capsules are then dried in a tumbler dryer with an air blast at 21 °C and 20% relative humidity, and are then brought to room temperature.
- compositions Cl - C7 for preparing a capsule wall (% wt)
- capsules are stored 40°C and 75% relative humidity for up to 24 weeks. After 24 weeks of storage, each of the capsules are analyzed for pellicle formation. Overall, capsules prepared from compositions Cl - C14 (comprising a sulfite compound) exhibit less pellicle formation than do capsules prepared from comparative compositions CC-1 - CC7 (no sulfite compound).
- capsules containing fill formulation FI (comprising Sodium metabisulfite in an amount of about 3% by weight of the fill material) exhibited no pellicle formation during storage for a period of six months.
- capsules containing fill formulation F2 (no sulfite compound) exhibited pellicle formation by 15 and 30 days of storage, respectively.
- a composition of the invention is prepared by mixing in a vessel (a) 35% B grade, 150 Bloom strength, pharmaceutical grade gelatin; (b) 15% chilled glycerol; (c) 5% sodium thiosulfate; and (d) 45% chilled deionized water.
- the mixture is melted at 80 °C for up to four hours to form a melt.
- the melt is cooled to 60 °C to form a flowable gelatin mix and is fed into the two spreader boxes of a rotary die soft gelatin capsule manufacturing machine, which controls the flow of said mix onto two air-cooled rotating drums, where two white opaque gelatin ribbons are cast and further processed to white opaque, soft gelatin capsules, at a rate of about 15,000 capsules per hour.
- the capsules are then dried in a tumbler dryer with an air blast at 21 C° and 20% relative humidity, and are then brought to room temperature.
- Tier I drug release profile As early as 1 month of storage, there was a marked delay in the Tier I drug release profile at both temperature conditions. This delay increased with storage time.
- the Tier H drug release profile at 25° C / 60% RH and at 40° C / 75% RH shows a significant but markedly reduced delay in release profile.
- Tier I and Tier JJ results are very similar for this 6 month sample indicating that the change in drug release profile is not attributable to cross-linking.
- the change in the Tier JJ drug release profile i.e. reduced delay
- Tier I delayed release is the result of cross-linking for this formulation and further indicates that a significant delay in the drug release profile in humans would be likely.
- the Formulation 19, containing sodium metabisulfite exhibits no measurable cross-linking through 6 months at stringent (40° C / 75% RH) storage conditions.
- sodium metabisulfite is believed to inhibit cross-linking by a process in which sodium metabisulfite reacts with aldehydes forming a bisulfite addition product.
- sodium metabisulfite can effectively scavenges aldehydes making them ' unavailable to promote cross-linking in the gelatin.
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Applications Claiming Priority (9)
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US399808P | 2002-07-31 | ||
PCT/US2003/024045 WO2004010974A2 (en) | 2002-07-31 | 2003-07-31 | Gelatin capsule exhibiting reduced cross-linking |
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EP1526846A2 true EP1526846A2 (de) | 2005-05-04 |
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EP03772160A Withdrawn EP1526845A2 (de) | 2002-07-31 | 2003-07-31 | Pharmazeutische dosierungsform geeignet zum aufrechterhalten lagerstabiler auflösungsgeschwindigkeit |
EP03772159A Withdrawn EP1526844A2 (de) | 2002-07-31 | 2003-07-31 | Gelatinkapsel mit verminderter bildung einer membranabdeckung |
EP03772161A Withdrawn EP1526846A2 (de) | 2002-07-31 | 2003-07-31 | Gelatinkapsel mit verminderter vernetzung |
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EP1549299B1 (de) | 2002-06-05 | 2014-08-20 | IVAX Pharmaceuticals s.r.o. | Verringerung der gelatine-vernetzung |
AU2006214164B2 (en) | 2005-02-17 | 2010-12-09 | Synta Pharmaceuticals Corp. | Isoxazole combretastin derivatives for the treatment of disorders |
US7485323B2 (en) | 2005-05-31 | 2009-02-03 | Gelita Ag | Process for making a low molecular weight gelatine hydrolysate and gelatine hydrolysate compositions |
PL1906938T3 (pl) | 2005-07-26 | 2011-05-31 | Nicox Science Ireland | Formulacja farmaceutyczna nitrooksypochodnych NSAID |
JP5503939B2 (ja) * | 2009-10-16 | 2014-05-28 | 東洋カプセル株式会社 | アゼラスチン塩酸塩含有カプセル剤 |
JP6887456B2 (ja) | 2018-07-04 | 2021-06-16 | キャプシュゲル・ベルジウム・エヌ・ヴィ | 白色化剤として界面活性剤又は界面活性剤と塩を含有する皮膜形成性組成物 |
US11364478B2 (en) * | 2019-05-22 | 2022-06-21 | Mezzimatic, LLC | Method of manufacturing throwable paintballs and paintballs made therefrom |
WO2022119269A1 (ko) * | 2020-12-01 | 2022-06-09 | 주식회사 엘지화학 | 1-(3-시아노-1-아이소프로필-인돌-5-일)피라졸-4-카르복실산을 포함하는 안정한 경구용 제제 |
CN113230241A (zh) * | 2021-06-11 | 2021-08-10 | 北京畅盛医药科技有限公司 | 三羟甲基氨基甲烷盐在治疗心脑血管病的药物中的应用 |
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JPS5115094B2 (de) * | 1972-11-01 | 1976-05-14 | ||
US4349529A (en) * | 1980-04-14 | 1982-09-14 | E. R. Squibb & Sons, Inc. | Diagnostic and therapeutic capsules and method of producing |
US4590183A (en) * | 1985-04-22 | 1986-05-20 | Sterling Drug Inc. | Gastric cytoprotection with sodium thiosulfate in oral administration of aspirin |
FR2617047B1 (fr) * | 1987-06-23 | 1991-05-10 | Sanofi Sa | Composition de gelatine resistant au tannage, capsules a base de cette composition et leur application pharmaceutique, notamment au fenofibrate |
JP2790659B2 (ja) * | 1989-06-30 | 1998-08-27 | 帝国臓器製薬株式会社 | ゼラチンカプセル剤 |
EP0672414B1 (de) * | 1994-03-15 | 2005-06-08 | Senju Pharmaceutical Co., Ltd. | Verfahren zur Stabilisierung von Pranoprofen und stabile flüssige Zubereitung von Pranoprofen |
IT1269583B (it) * | 1994-04-26 | 1997-04-08 | Bayer Italia Spa | Preparazioni farmaceutiche a base di una soluzione di ketoprofene in capsule di gelatina molle e metodo per la loro produzione |
DE69519340T2 (de) * | 1994-08-05 | 2001-06-21 | Shionogi & Co., Ltd. | Gegen Denaturierung beständige Hartgelatine-Kapseln und Verfahren zu ihrer Herstellung |
US5620704A (en) * | 1994-11-07 | 1997-04-15 | Warner-Lambert Company | Process for stabilizing gelatin products |
US7115565B2 (en) * | 2001-01-18 | 2006-10-03 | Pharmacia & Upjohn Company | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability |
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