US3929996A - Pharmaceutical compositions containing a digoxin complex - Google Patents
Pharmaceutical compositions containing a digoxin complex Download PDFInfo
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- US3929996A US3929996A US492827A US49282774A US3929996A US 3929996 A US3929996 A US 3929996A US 492827 A US492827 A US 492827A US 49282774 A US49282774 A US 49282774A US 3929996 A US3929996 A US 3929996A
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- United States
- Prior art keywords
- digoxin
- complex
- composition
- amount
- present
- Prior art date
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- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 title claims abstract description 90
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 title claims description 82
- 229960005156 digoxin Drugs 0.000 title claims description 82
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 title claims description 82
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims abstract description 38
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 claims abstract description 30
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 206010019280 Heart failures Diseases 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 47
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 230000002821 anti-nucleating effect Effects 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- 241001465754 Metazoa Species 0.000 claims description 5
- 230000003177 cardiotonic effect Effects 0.000 claims description 5
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 3
- 229920002307 Dextran Polymers 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 3
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 3
- 235000010445 lecithin Nutrition 0.000 claims description 3
- 239000000787 lecithin Substances 0.000 claims description 3
- 229940067606 lecithin Drugs 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 6
- 150000005205 dihydroxybenzenes Chemical class 0.000 abstract description 4
- 239000000496 cardiotonic agent Substances 0.000 abstract description 3
- 239000012736 aqueous medium Substances 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 229960004337 hydroquinone Drugs 0.000 description 12
- 239000003153 chemical reaction reagent Substances 0.000 description 11
- 230000000536 complexating effect Effects 0.000 description 11
- 239000012535 impurity Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000003963 antioxidant agent Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000036765 blood level Effects 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 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
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- FDWRIIDFYSUTDP-KVTDHHQDSA-N (2r,4r,5s,6r)-6-methyloxane-2,4,5-triol Chemical compound C[C@H]1O[C@@H](O)C[C@@H](O)[C@@H]1O FDWRIIDFYSUTDP-KVTDHHQDSA-N 0.000 description 2
- 241000208011 Digitalis Species 0.000 description 2
- SHIBSTMRCDJXLN-UHFFFAOYSA-N Digoxigenin Chemical group C1CC(C2C(C3(C)CCC(O)CC3CC2)CC2O)(O)C2(C)C1C1=CC(=O)OC1 SHIBSTMRCDJXLN-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 239000008139 complexing agent Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Chemical group CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 2
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical group C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- -1 pyrocateehol Chemical class 0.000 description 2
- 229940001607 sodium bisulfite Drugs 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- 150000005207 1,3-dihydroxybenzenes Chemical class 0.000 description 1
- 150000005208 1,4-dihydroxybenzenes Chemical class 0.000 description 1
- FDWRIIDFYSUTDP-UHFFFAOYSA-N 102850-49-7 Natural products CC1OC(O)CC(O)C1O FDWRIIDFYSUTDP-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- JWFRNGYBHLBCMB-UHFFFAOYSA-N D-Canaytose Natural products CC(O)C(O)C(O)CC=O JWFRNGYBHLBCMB-UHFFFAOYSA-N 0.000 description 1
- 240000001879 Digitalis lutea Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229940123973 Oxygen scavenger Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000000881 depressing effect Effects 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J17/005—Glycosides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Definitions
- ABSTRACT Digoxin forms novel complexes with dihydroxybenzenes such as hydroquinone, resorcinol and pyrocatechol. These complexes exhibit rapid dissolution and high solubility in aqueous media.
- the above-identified digoxin complexes are extremely useful as cardiotonic agents in the treatment of cardiac insufficiency.
- Digoxin is widely used as a cardiotonic agent for the treatment of cardiac insufficiency. It is a naturally oc curring commercially available compound obtained from several species of the foxglove plant, such as Digi talis lanta, Digitalis purpurea (Scrophulariacae). As the compound occurs in nature, it is associated with compounds very similar in structure, and it is difficult to isolate in its pure form. However, the United States Pharmacopeia requires that the compound used as a drug be at least 96% pure as measured by the specific assay in the compendia.
- the maximum (peak) digoxin plasma level of patients receiving ordinary therapeutic doses is 0.1 to 2.1 nanograms per millimeter (Lindenbaum, .I., et al., The New England Journal Medicine, Dec. 9, 1971, page 1344; Huffman, D. H., et al., JAMA, Vol. 222, No. 8, page 957, Nov. 20, 1973; Wagner, J. G., et al., JAMA, Vol. 224, No.2, page 199, Apr. 19, 1973). Within this range, toxic effects may be observed at the high values and no effect at the low values. However, when the drug plasma level is about 3.3 nanograms per millimeter, patients experience toxic effects.
- the dissolution rate is the limiting and determining factor in the rate and extent of absorption of digoxin in the body. Because digoxin is so slowly dissolved and absorbed, it is difficult for physicians to accurately adjust the dosage to achieve the desired digoxin concentration in the blood. Therefore, it is highly desirable to have available for medical use a form of digoxin which would dissolve much more rapidly and provide reproducibility in the gastrointestinal fluids when administered orally in a tablet dosage form so that blood levels of the drug could be accurately related to the dosage and result in reproducible blood levels.
- a number ofdigoxin derivatives have been prepared in an attempt to alter the physical or pharmacological properties of the drug.
- Alterations of the digitoxose portion of the molecule include the formation ofethers (U.S. Pat. No. 3,538,078, German Pat. No. 1,961,034) and formation of acylates (Belg. Pat. No. 750,875, German Pat. No. 2,019,967, U.S. Pat. No. 3,514,441).
- Alterations of the steroid and lactonc portion of the digoxin molecule include digoxin l5',l6'-diacetates (Belgian Pat. No. 749,680) and substitution at the 22 carbon (Belgian Pat. No. 751,768, German Pat. No. 2,052,634).
- the need for a rapidly soluble form of digoxin which does not alter the pharmacological activity of the drug remains.
- the first aspect of this invention relates to the novel complexes formed by digoxin and dihydroxybenzenes such as pyrocateehol, resorcinol and hydroquinone.
- digoxin and dihydroxybenzenes such as pyrocateehol, resorcinol and hydroquinone.
- D represents digoxin
- A represents a dihydroxybenzcne selected from pyrocateehol, hydro quinonc or resorcinol
- n is I, l- /z, or 2.
- this invention relates to administration of digoxin to warm-blooded animals in the form of the novel complexes of this invention, pharmaceutical compositions of the novel complexes and to pharmaceutical compositions of the complexes containing an antinueleating agent or an excess of the dihydroxybenzene.
- the dihydroxybenzene in these compositions may be present from H to 20% by weight of the composition, or more preferably, from 5 4 to 2% by weight of the composition.
- this invention also relates to a novel means for purifying digoxin.
- the novel complexes of this invention when formed from a solution of impure digoxin, precipitate and may be separated from the mother liquor in which the impurities remain. Separation of the crystalline complex and subsequent removal of the dihydroxybenzenc effectively isolates digoxin from closely related impurities which are otherwise difficult to separate.
- the formula for the complexes of this invention set out above encompasses nine separate complexes. They are the pyrocateehol complexes having the ratio of digoxin to pyrocateehol of 1:1, l:l-% and 1:2, the resorcinol complexes having the ratio of digoxin to resorcinol of I l 1:1-% and 1:2 and the hydroquinone complexes having the ratios of digoxin to hydroquinone of 1:1, lzland 1:2. Of these, the hydroquinone com plexes are preferred for rapid solubility, ease of preparation, and safety.
- the complexes of this invention are extremely rapidly soluble in water in comparison with pure crystalline digoxin. However, these complexes do not remain intact in solution but immediately dissociate upon dissolution. Thus, digoxin is available for absorption rapidly. Dosage levels for the complex are comparable to the well-known dosage levels for digoxin.
- the complex could be administered, for example, as a tablet containing the equivalent of 500 or 250 micrograms ofdigoxin.
- the dihydroxybenzenes do not interfere with the digoxin activity, and in these quantities are not significantly toxic. For example, hydroquinone has been ingested by man at 500 mgm per day for five months with no ill effects. (Proc. Soc. Exp. Biol. Med., 84. 684(1953).
- the complexes of this invention are formed by contacting a solution ofdihydroxybenzene with the digoxin and agitating the mixture for an extended period.
- the complexes of this invention are formed by 3 contacting the digoxin in solution with excess complexing reagent. Since the digoxin, the dihydroxybenzene and the complex are in equilibrium, the excess of the complexing agent will favor the formation of the complex and will also tend to depress the solubility of the complex in the mother liquor.
- the actual ratio of com plexing reagent to digoxin is dependent upon solvent, temperature and nature of complexing agent. In general, the complexing reagent should be present in the range of 0.05 to 0.95 of its maximum solubility in the solvent used.
- Oxygen can be excluded from the reaction mixture since oxgycn can interact with the com plexing reagents.
- the complexes of this invention can also be formed in the presence of an antioxidant (oxygen scavenger).
- antioxidants oxygen scavenger
- the use of antioxidants is preferred in an aqueous system but is not essential.
- sodium busulfite is an antioxidant compound which can be used.
- the molar concentration of the antioxidant can range from O to equal to the concentration of the dihydroxybenzene in solution. However, addition of 4 to molar percent of the antioxidant based on the concentration of dihydroxybenzene is adequate.
- the complexing reagent solution and the digoxin should be contacted for long periods of time under conditions of a good agitation.
- the reaction proceeds at ambient pressure.
- the individual complexes within the scope of this invention are precipitated from the reaction mixture by seeding the reaction mixture with seed crystals of the desired prod uct. Following the agitation period, the precipitated digoxin complex is filtered from the mother liquor and as much as the filtrate as possible is removed from the filter cake. Note that it is not possible to purify the complex by recrystallization since the complex dissociates in solution.
- the filtered complex can be dried. Drying this complex under vacuum might be used to remove excess complexing reagents which remained in the filter cake.
- the formation of the complex IS selective in that the impurities usually associated with digoxin, digoxigenin and digoxigenin substituted by one or two digitoxose units, are present in concentrations below that required for impurity-hydroxybenzene complexes to be precipitated.
- the complex may be formed to separate digoxin from the closely related impurities. It is desirable to select as the solvent for complex formation a solvent which has high solvency for impurities present and for complexes formed by such impurities and has low solvency for digoxin complex such that impurities tend to remain in solution and digoxin complex would precipitate.
- the complex precipitated and filtered from the mother liquor will contain few of the impurities, and when the complex is shaken with a solvent, it immediately dissociates leaving purified digoxin and the complexing reagent.
- the solvent is usually one in which the complexing reagent is relatively soluble and digoxin is relatively insoluble.
- the complexing reagent in solution may then be conve niently removed and pure digoxin isolated by methods well known to those skilled in the art, such as filtration of the precipitated digoxin, extraction, etc.
- the preferred solvents are diethyl ether or water, but other solvents might be used without departing from this invention.
- the digoxin complexes of this invention may be formulated and processed to prepare pharmaceutical compositions for oral administration by methods well known to those skilled in this art.
- the digoxin complexes can be formulated in a manner similar to formulations presently used for digoxin. Since the complex dissociates in the presence of most solvents, wet granulation processes should be avoided during the compounding of the dosage form.
- the direct compression technique well known to those in the art, can be used where the complex is dry blended with portions of the pharmaceutical excipients, screened or milled, and then blended with the remainder of the excipients.
- the formulation must contain effective disintegrants in optimum proportions.
- the tablet can contain an excess from 1/100 to 20% of the tablet weight of the dihydroxybenzene complexing reagent. The presence of excess dihydroxybenzene will initially depress the solubility of the digoxin complex, permitting the tablet to disintegrate before digoxin can be precipitated within the tablet. A more preferred range for excess quantities of the complexing reagent is from V4 to 2%.
- Antinucleating agents are well known to those skilled in the art of formulation of pharmaceuticals. Examples of such antinucleating agents are polyvinyl alcohol, lecithin, dextran and various cellulose derivatives such as carboxymethylcellulose and methyl cellulose. Care must be taken to be sure the antinucleating agent chosen is not reactive with either digoxin or the digoxin complex.
- the preferred antinucleating agent is polyvinyl alcohol and the preferred concentration for the antinucleating agent is 0.l to 10 percent by weight.
- EXAMPLE l Preparation of the Complex Digoxin, 46.86 grams (6 X 10 moles), sodium bisulfite, 1.04 grams (l X l0 moles), and hydroquinone, 66.3 grams (6 X 10 moles), were placed in an amber glass vessel and one liter of water was added. The mixture was then thoroughly flushed with a stream of nitrogen and the vessel was sealed with a polyethylene-lined cap. The mixture was rotated in a constant temperature bath at 25C. for 72 hours. At the end of 72 hours, the mixture was filtered and the filter cake pressed and dried at ambient temperature under vacuum. The yield of thel:l complex was about grams.
- EXAMPLE 2 Digoxin, 46.86 (6 X 10" moles), sodiumbisulfite, l.04 grams l X 10 moles), and resorcinol, 55.1 grams (5 X l0 moles), were placed in an amber glass vessel and one liter of water was added. The mixture was then thoroughly flushed with a stream of nitrogen and the vessel was sealed with a polyethylene-lined cap. The mixture was rotated in a constant temperature bath at 25C for 96 hours. At the end of 96 hours, the mixture was filtered and the' filter cake pressed and dried at ambient temperature under vacuum. The yield of the complex was about 60 grams.
- EXAMPLE 3 ingredients Digoxin-Hy- To formulate the tablet, blend the complex and cellulose until the ingredients are uniformly mixed. The lactose is then added in geometric proportions and uniformly blended after'each addition. Finally, the magnesium stearate is uniformly blended into the mixture and the tablets are compressed. Other tablets containing the equivalent of 0.4, 0.3, 0.2, 0.] mgm digoxin as complex, and the like, are prepared in a similar manner. All of the complexes of this invention can be formulated in a similar manner.
- EXAMPLE 6 The pharmaceutical manufacture of three tablet formulations designed to prevent precipitation of digoxin particles from a solution of the complex is shown below:
- a pharmaceutical composition for treating cardiac insufficiency consisting essentially of a pharmaceutical acceptable inert adjuvant and a digoxin complex of the formula:
- D represents digoxin
- A represents a member selected from the group consisting of resorcinol, hydro quinone and pyrocatcchol, and wherein n represents l, l or 2,
- said digoxin complex being present in a cardiotonic effective amount.
- composition of claim 2 wherein said hydroquinone is present in an amount of from 0.01 to 20.0 percent by weight.
- composition of claim 2 wherein said hydroquinone is present in an amount of from '/4 to 2.0 percent by weight.
- composition of claim 3, wherein said resorcinol is present in an amount of from V4 to 2.0 percent by weight.
- composition of claim 1 wherein an effective antinucleating amount of an antinucleating agent, nonreactive with said digoxin or the digoxin complex is contained therein.
- composition of claim 9 wherein said antinucleating agent is a member selected from the group consisting of lecithin, dextran, polyvinyl alcohol, methylcellulose and carboxymethylcellulose.
- a method of treating cardiac insufficiency in warm-blooded animals which comprises:
- D represents digoxin
- A represents a member selected from the group consisting of resorcinol, hydroquinone and pyrocatechol, and wherein n represents 1. l-% or 2.
- a method for treating cardiac insufficiency in warm-blooded animals which comprises:
- composition of claim 1, wherein said digoxin complex is present in the amount of 250 micrograms.
- composition of claim 1, wherein said digoxin complex is present in the amount of 500 micrograms.
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Abstract
Digoxin forms novel complexes with dihydroxybenzenes such as hydroquinone, resorcinol and pyrocatechol. These complexes exhibit rapid dissolution and high solubility in aqueous media. The above-identified digoxin complexes are extremely useful as cardiotonic agents in the treatment of cardiac insufficiency.
Description
United States Patent 11 1 Higuchi PHARMACEUTICAL COMPOSITIONS CONTAINING A DIGOXIN COMPLEX [75} Inventor:
[73] Assignee: lnterx Research Corporation,
Lawrence, Kans.
[22] Filed: July 29, I974 [21] Appl. No.1 492327 Related US. Application Data [62] Division of Ser. No. 375,052, June 29, I973, Pat. No.
Takeru lliguchi, Lawrence, Kans.
545,267 8/l957 Canada 424/l 82 1451 Dec. 30, 1975 1300.708 7/1962 France 424/ l 82 Primary Examiner-Ethel G. Love Attorney, Agent, or FirmChar1es N. Blitzer [57] ABSTRACT Digoxin forms novel complexes with dihydroxybenzenes such as hydroquinone, resorcinol and pyrocatechol. These complexes exhibit rapid dissolution and high solubility in aqueous media.
The above-identified digoxin complexes are extremely useful as cardiotonic agents in the treatment of cardiac insufficiency.
l7 Claims, No Drawings PHARMACEUTICAL COMPOSITIONS CONTAINING A DIGOXIN COMPLEX CROSS-REFERENCE TO RELATED APPLICATIONS This Application is a divisional application of my earlier eo-pending Application, Ser. No. 375,052, filed Jun. 29, 1973 now U.S. Pat. No. 3,839,3I7.
BACKGROUND OF THE INVENTION Digoxin is widely used as a cardiotonic agent for the treatment of cardiac insufficiency. It is a naturally oc curring commercially available compound obtained from several species of the foxglove plant, such as Digi talis lanta, Digitalis purpurea (Scrophulariacae). As the compound occurs in nature, it is associated with compounds very similar in structure, and it is difficult to isolate in its pure form. However, the United States Pharmacopeia requires that the compound used as a drug be at least 96% pure as measured by the specific assay in the compendia. When digoxin is administered orally as a solid dosage form, the maximum (peak) digoxin plasma level of patients receiving ordinary therapeutic doses is 0.1 to 2.1 nanograms per millimeter (Lindenbaum, .I., et al., The New England Journal Medicine, Dec. 9, 1971, page 1344; Huffman, D. H., et al., JAMA, Vol. 222, No. 8, page 957, Nov. 20, 1973; Wagner, J. G., et al., JAMA, Vol. 224, No.2, page 199, Apr. 19, 1973). Within this range, toxic effects may be observed at the high values and no effect at the low values. However, when the drug plasma level is about 3.3 nanograms per millimeter, patients experience toxic effects. Due to the small difference between the maximum therapeutic and minimum toxic plasma levels, a reliable and reproducible dosage form is essential. It has been shown that blood levels obtained by using the tablet made either by different manufacturers or different lots made by the same manufacturer differ significantly in achieving reproducible blood levels of Digoxin (Lindenbaum, 1., et al., The New England Journal of Medicine, Dec. 9, 1971, page 1344; Wagner, J. G., et al., JAMA, Vol. 224, No. 2, page 199, Apr. 19, 1973; Bertler, A., et al., The Lancet, page 708, Sept. 30, 1972). Digoxin has extremely low water solubility, about 80 to 100 micrograms per milliliter. In addition, the rate of dissolution is extremely slow and is considerably dosage form dependent. Thus, the dissolution rate is the limiting and determining factor in the rate and extent of absorption of digoxin in the body. Because digoxin is so slowly dissolved and absorbed, it is difficult for physicians to accurately adjust the dosage to achieve the desired digoxin concentration in the blood. Therefore, it is highly desirable to have available for medical use a form of digoxin which would dissolve much more rapidly and provide reproducibility in the gastrointestinal fluids when administered orally in a tablet dosage form so that blood levels of the drug could be accurately related to the dosage and result in reproducible blood levels.
A number ofdigoxin derivatives have been prepared in an attempt to alter the physical or pharmacological properties of the drug. Alterations of the digitoxose portion of the molecule include the formation ofethers (U.S. Pat. No. 3,538,078, German Pat. No. 1,961,034) and formation of acylates (Belg. Pat. No. 750,875, German Pat. No. 2,019,967, U.S. Pat. No. 3,514,441). Alterations of the steroid and lactonc portion of the digoxin molecule include digoxin l5',l6'-diacetates (Belgian Pat. No. 749,680) and substitution at the 22 carbon (Belgian Pat. No. 751,768, German Pat. No. 2,052,634). However, the need for a rapidly soluble form of digoxin which does not alter the pharmacological activity of the drug remains.
SUMMARY OF THE INVENTION The first aspect of this invention relates to the novel complexes formed by digoxin and dihydroxybenzenes such as pyrocateehol, resorcinol and hydroquinone. These complexes are represented by the formula shown below wherein D represents digoxin, A represents a dihydroxybenzcne selected from pyrocateehol, hydro quinonc or resorcinol and n is I, l- /z, or 2.
D.An
In another aspect, this invention relates to administration of digoxin to warm-blooded animals in the form of the novel complexes of this invention, pharmaceutical compositions of the novel complexes and to pharmaceutical compositions of the complexes containing an antinueleating agent or an excess of the dihydroxybenzene. The dihydroxybenzene in these compositions may be present from H to 20% by weight of the composition, or more preferably, from 5 4 to 2% by weight of the composition.
Finally, this invention also relates to a novel means for purifying digoxin. The novel complexes of this invention, when formed from a solution of impure digoxin, precipitate and may be separated from the mother liquor in which the impurities remain. Separation of the crystalline complex and subsequent removal of the dihydroxybenzenc effectively isolates digoxin from closely related impurities which are otherwise difficult to separate.
DESCRIPTION OF THE PREFERRED EMBODIMENTS The formula for the complexes of this invention set out above encompasses nine separate complexes. They are the pyrocateehol complexes having the ratio of digoxin to pyrocateehol of 1:1, l:l-% and 1:2, the resorcinol complexes having the ratio of digoxin to resorcinol of I l 1:1-% and 1:2 and the hydroquinone complexes having the ratios of digoxin to hydroquinone of 1:1, lzland 1:2. Of these, the hydroquinone com plexes are preferred for rapid solubility, ease of preparation, and safety.
The complexes of this invention are extremely rapidly soluble in water in comparison with pure crystalline digoxin. However, these complexes do not remain intact in solution but immediately dissociate upon dissolution. Thus, digoxin is available for absorption rapidly. Dosage levels for the complex are comparable to the well-known dosage levels for digoxin. The complex could be administered, for example, as a tablet containing the equivalent of 500 or 250 micrograms ofdigoxin. The dihydroxybenzenes do not interfere with the digoxin activity, and in these quantities are not significantly toxic. For example, hydroquinone has been ingested by man at 500 mgm per day for five months with no ill effects. (Proc. Soc. Exp. Biol. Med., 84. 684(1953).
The complexes of this invention are formed by contacting a solution ofdihydroxybenzene with the digoxin and agitating the mixture for an extended period. In practice, the complexes of this invention are formed by 3 contacting the digoxin in solution with excess complexing reagent. Since the digoxin, the dihydroxybenzene and the complex are in equilibrium, the excess of the complexing agent will favor the formation of the complex and will also tend to depress the solubility of the complex in the mother liquor. The actual ratio of com plexing reagent to digoxin is dependent upon solvent, temperature and nature of complexing agent. In general, the complexing reagent should be present in the range of 0.05 to 0.95 of its maximum solubility in the solvent used. Oxygen can be excluded from the reaction mixture since oxgycn can interact with the com plexing reagents. The complexes of this invention can also be formed in the presence of an antioxidant (oxygen scavenger). The use of antioxidants is preferred in an aqueous system but is not essential. For example, sodium busulfite is an antioxidant compound which can be used. The molar concentration of the antioxidant can range from O to equal to the concentration of the dihydroxybenzene in solution. However, addition of 4 to molar percent of the antioxidant based on the concentration of dihydroxybenzene is adequate. The complexing reagent solution and the digoxin should be contacted for long periods of time under conditions of a good agitation. Stirring periods of 72 hours or longer give good results, but the exact period is not critical. The reaction proceeds at ambient pressure. The individual complexes within the scope of this invention are precipitated from the reaction mixture by seeding the reaction mixture with seed crystals of the desired prod uct. Following the agitation period, the precipitated digoxin complex is filtered from the mother liquor and as much as the filtrate as possible is removed from the filter cake. Note that it is not possible to purify the complex by recrystallization since the complex dissociates in solution. The filtered complex can be dried. Drying this complex under vacuum might be used to remove excess complexing reagents which remained in the filter cake.
It has been found that the formation of the complex IS selective in that the impurities usually associated with digoxin, digoxigenin and digoxigenin substituted by one or two digitoxose units, are present in concentrations below that required for impurity-hydroxybenzene complexes to be precipitated. Thus, the complex may be formed to separate digoxin from the closely related impurities. It is desirable to select as the solvent for complex formation a solvent which has high solvency for impurities present and for complexes formed by such impurities and has low solvency for digoxin complex such that impurities tend to remain in solution and digoxin complex would precipitate. The complex precipitated and filtered from the mother liquor will contain few of the impurities, and when the complex is shaken with a solvent, it immediately dissociates leaving purified digoxin and the complexing reagent. The solvent is usually one in which the complexing reagent is relatively soluble and digoxin is relatively insoluble. The complexing reagent in solution may then be conve niently removed and pure digoxin isolated by methods well known to those skilled in the art, such as filtration of the precipitated digoxin, extraction, etc. The preferred solvents are diethyl ether or water, but other solvents might be used without departing from this invention.
The digoxin complexes of this invention may be formulated and processed to prepare pharmaceutical compositions for oral administration by methods well known to those skilled in this art. The digoxin complexes can be formulated in a manner similar to formulations presently used for digoxin. Since the complex dissociates in the presence of most solvents, wet granulation processes should be avoided during the compounding of the dosage form. The direct compression technique, well known to those in the art, can be used where the complex is dry blended with portions of the pharmaceutical excipients, screened or milled, and then blended with the remainder of the excipients.
An additional facet of the formulation of digoxin complexes should be noted. In tablet form, the very rapid solubility of the digoxin complexes, which is the object of this invention, requires special considerations. When a tablet is administered, the tablet first absorbs water or gastric juice and then disintegrates or dissolves. Since the digoxin complex rapidly dissociates and the digoxin goes rapidly into solution in the water that was absorbed by the tablet, the concentration of digoxin could exceed its maximum solubility if the tablet does not disintegrate rapidly, thus precipitating digoxin. In order to avoid this, it is important that the tablets are formulated so they disintegrate before significant amounts of the digoxin complex dissolves and digoxin precipitates. This premature precipitation of pure digoxin can be avoided in several ways. First, the formulation must contain effective disintegrants in optimum proportions. Second, the tablet can contain an excess from 1/100 to 20% of the tablet weight of the dihydroxybenzene complexing reagent. The presence of excess dihydroxybenzene will initially depress the solubility of the digoxin complex, permitting the tablet to disintegrate before digoxin can be precipitated within the tablet. A more preferred range for excess quantities of the complexing reagent is from V4 to 2%.
Another means of initially depressing the precipitation of digoxin within the tablet prior to disintegration is to include antinucleating agents in the formulation. Antinucleating agents are well known to those skilled in the art of formulation of pharmaceuticals. Examples of such antinucleating agents are polyvinyl alcohol, lecithin, dextran and various cellulose derivatives such as carboxymethylcellulose and methyl cellulose. Care must be taken to be sure the antinucleating agent chosen is not reactive with either digoxin or the digoxin complex. The preferred antinucleating agent is polyvinyl alcohol and the preferred concentration for the antinucleating agent is 0.l to 10 percent by weight.
This invention will be further illustrated by the following examples.
EXAMPLE l Preparation of the Complex Digoxin, 46.86 grams (6 X 10 moles), sodium bisulfite, 1.04 grams (l X l0 moles), and hydroquinone, 66.3 grams (6 X 10 moles), were placed in an amber glass vessel and one liter of water was added. The mixture was then thoroughly flushed with a stream of nitrogen and the vessel was sealed with a polyethylene-lined cap. The mixture was rotated in a constant temperature bath at 25C. for 72 hours. At the end of 72 hours, the mixture was filtered and the filter cake pressed and dried at ambient temperature under vacuum. The yield of thel:l complex was about grams.
EXAMPLE 2' Digoxin, 46.86 (6 X 10" moles), sodiumbisulfite, l.04 grams l X 10 moles), and resorcinol, 55.1 grams (5 X l0 moles), were placed in an amber glass vessel and one liter of water was added. The mixture was then thoroughly flushed with a stream of nitrogen and the vessel was sealed with a polyethylene-lined cap. The mixture was rotated in a constant temperature bath at 25C for 96 hours. At the end of 96 hours, the mixture was filtered and the' filter cake pressed and dried at ambient temperature under vacuum. The yield of the complex was about 60 grams.
EXAMPLE 3 ingredients Digoxin-Hy- To formulate the tablet, blend the complex and cellulose until the ingredients are uniformly mixed. The lactose is then added in geometric proportions and uniformly blended after'each addition. Finally, the magnesium stearate is uniformly blended into the mixture and the tablets are compressed. Other tablets containing the equivalent of 0.4, 0.3, 0.2, 0.] mgm digoxin as complex, and the like, are prepared in a similar manner. All of the complexes of this invention can be formulated in a similar manner.
EXAMPLE 6 The pharmaceutical manufacture of three tablet formulations designed to prevent precipitation of digoxin particles from a solution of the complex is shown below:
Formulation 3 WtJTablet 0.641 mgm Formulation 2 Wtfl'ablet 0.641 mgm 0.64! mgm droquinone,
Alcohol Hydroquin- 0.700 mgm 0.700 mgm 2.800 mgm 2.800 mgm one, USP
Microcrystalline Cellulose Magnesium Stearate, USP Lactose,
Spray Dried, USP
TOTA L The mixture was rotated in a constant temperature bath at C for 96 hours. At the end of 96 hours, the mixture'was filtered and the filter cake pressed and dried at ambient temperature under vacuum. The yield of the complex was about 60 grams.
EXAMPLE 4 Rate of Dissolution of the Complex EXAMPLE 5 The pharmaceutical manufacture ofa tablet formulation is shown below:
WL/Tablet 0.64! mgm 6.000 mgm 0.150 mgm 28.209 mgrn TOTAL 35.000 mgm Ingredients DigoximHydmquinonc complex Micrucryslzillinc Cellulose Magnesium Stearute, USP Lactose, Spray Dried. USP
0. I50 mgm 0.150 mgm 0150 rngm 24.709 mgm 24.709 mgm 24.709 mgm 35.000 mgm 32.200 mgm 34.300 mgm All of the complexes of this invention can be formulated in a similar manner.
EXAMPLE 7 The purification of digoxin through preparation of the complex is shown below: i
A sample. assayed at 92% digoxin, and shown to contain two impurities was shaken with a solution of hydroquinone as shown in Example 1, and the complex recovered by filtration.
Then, a mixture of the digoxin-hydroquinone complex and diethyl ether (1 ingm complex per milliliter of ether) were shaken at 25C. for 24 hours. The precipitate was recovered by filtration, washed with ether, and shaken with ether again for 24 hours at 25C. The precipitate was again recovered by filtration, washed with ether, and dried in vacuum. The resulting digoxin was virtually l00% pure.
I claim:
I. A pharmaceutical composition for treating cardiac insufficiency consisting essentially of a pharmaceutical acceptable inert adjuvant and a digoxin complex of the formula:
D.An
wherein D represents digoxin, A represents a member selected from the group consisting of resorcinol, hydro quinone and pyrocatcchol, and wherein n represents l, l or 2,
said digoxin complex being present in a cardiotonic effective amount.
2. The composition of claim 1, wherein A is hydro qumone.
3. The composition of claim 1, wherein A is resorcinol.
4. The composition of claim 1, wherein A is pyrocatechol.
5. The composition of claim 2, wherein said hydroquinone is present in an amount of from 0.01 to 20.0 percent by weight.
6. The composition of claim 3, wherein said resorcinol is present in an amount of from 0.01 to 20.0 percent by weight.
7. The composition of claim 2, wherein said hydroquinone is present in an amount of from '/4 to 2.0 percent by weight.
8. The composition of claim 3, wherein said resorcinol is present in an amount of from V4 to 2.0 percent by weight.
9. The composition of claim 1, wherein an effective antinucleating amount of an antinucleating agent, nonreactive with said digoxin or the digoxin complex is contained therein.
10. The composition of claim 9, wherein said antinucleating agent is a member selected from the group consisting of lecithin, dextran, polyvinyl alcohol, methylcellulose and carboxymethylcellulose.
11. The composition of claim 9, wherein said antinuclcating agent is present in an amount of from 0.1 to 10.0 percent by weight.
12. A method of treating cardiac insufficiency in warm-blooded animals which comprises:
orally administering thereto a cardiotonic effective amount of a digoxin complex of the formula:
D.An
wherein D represents digoxin, A represents a member selected from the group consisting of resorcinol, hydroquinone and pyrocatechol, and wherein n represents 1. l-% or 2.
13. A method for treating cardiac insufficiency in warm-blooded animals which comprises:
orally administering thereto, a cardiotonic effective amount of the complex of claim 1.
14. The composition of claim 1, wherein said digoxin complex is present in the amount of 250 micrograms.
15. The composition of claim 1, wherein said digoxin complex is present in the amount of 500 micrograms.
16. The method of claim 12, wherein said digoxin complex is present in the amount of 250 micrograms.
17. The method of claim 12, wherein said digoxin complex is present in the amount of 500 micrograms. 2k =0 i UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Inventor s Jakorn I-h gnr-h-l It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
IN THE CLAIMS:
Claim 13, line 4, delete "complex" and insert --composition.
Signed and Scaled this Tenth Day of August 1976 [SEAL] Arrest:
RUTH C. MASON C. MARSHALL DANN Arresting Officer (ummiuinner oj'l'alenl: and Trademarks
Claims (17)
1. A PHARMACEUTICAL COMPOSITION FOR TREATING CARDIAC INSUFFICIENCY CONSISTING ESSENTIALLY OF A PHARMACEUTICAL ACCEPTABLE INERT ADJUVANT AND A DIGOXIN COMPLEX OF THE FORMULA:
2. The composition of claim 1, wherein A is hydroquinone.
3. The composition of claim 1, wherein A is resorcinol.
4. The composition of claim 1, wherein A is pyrocatechol.
5. The composition of claim 2, wherein said hydroquinone is present in an amount of from 0.01 to 20.0 percent by weight.
6. The composition of claim 3, wherein said resorcinol is present in an amount of from 0.01 to 20.0 percent by weight.
7. The composition of claim 2, wherein said hydroquinone is present in an amount of from 1/4 to 2.0 percent by weight.
8. The composition of claim 3, wherein said resorcinol is present in an amount of from 1/4 to 2.0 percent by weight.
9. The composition of claim 1, wherein an effective antinucleating amount of an antinucleating agent, nonreactive with said digoxin or the digoxin complex is contained therein.
10. The composition of claim 9, wherein said antinucleating agent is a member selected from the group consisting of lecithin, dextran, polyvinyl alcohol, methylcellulose and carboxymethylcellulose.
11. The composition of claim 9, wherein said antinucleating agent is present in an amount of from 0.1 to 10.0 percent by weight.
12. A method of treating cardiac insufficiency in warm-blooded animals which comprises: orally administering thereto a cardiotonic effective amount of a digoxin complex of the formula: D . An wherein D represents digoxin, A represents a member selected from the group consisting of resorcinol, hydroquinone and pyrocatechol, and wherein n represents 1, 1- 1/2 or 2.
13. A METHOD FOR TREATING CARDIAC INSUFFICIENCY IN WARMBLOODED ANIMALS WHICH COMPRISES: ORALLY ADMINISTERING THERETO, A CARDIOTONIC EFFECTIVE AMOUNT OF THE COMPLEX OF CLAIM 1.
14. The composition of claim 1, wherein said digoxin complex is present in the amount of 250 micrograms.
15. The composition of claim 1, wherein said digoxin complex is present in the amount of 500 micrograms.
16. The method of claim 12, wherein said digoxin complex is present in the amount of 250 micrograms.
17. The method of claim 12, wherein said digoxin complex is present in the amount of 500 micrograms.
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US00375052A US3839317A (en) | 1973-06-29 | 1973-06-29 | Digoxin complexes |
US492827A US3929996A (en) | 1973-06-29 | 1974-07-29 | Pharmaceutical compositions containing a digoxin complex |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4254099A (en) * | 1978-10-18 | 1981-03-03 | Beiersdorf Aktiengesellschaft | Pharmaceutical tablet composition |
US4755504A (en) * | 1985-10-03 | 1988-07-05 | Yaguang Liu | Pharmaceutical composition from Tienchi |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA545267A (en) * | 1957-08-20 | S. Trupp Malcolm | Stabilized digoxin solutions | |
FR1300708A (en) * | 1958-08-07 | 1962-08-10 | Chemiewerk Homburg Ag | Digoxin solubilization process |
-
1974
- 1974-07-29 US US492827A patent/US3929996A/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA545267A (en) * | 1957-08-20 | S. Trupp Malcolm | Stabilized digoxin solutions | |
FR1300708A (en) * | 1958-08-07 | 1962-08-10 | Chemiewerk Homburg Ag | Digoxin solubilization process |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4254099A (en) * | 1978-10-18 | 1981-03-03 | Beiersdorf Aktiengesellschaft | Pharmaceutical tablet composition |
US4755504A (en) * | 1985-10-03 | 1988-07-05 | Yaguang Liu | Pharmaceutical composition from Tienchi |
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