US3839317A - Digoxin complexes - Google Patents

Digoxin complexes Download PDF

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Publication number
US3839317A
US3839317A US00375052A US37505273A US3839317A US 3839317 A US3839317 A US 3839317A US 00375052 A US00375052 A US 00375052A US 37505273 A US37505273 A US 37505273A US 3839317 A US3839317 A US 3839317A
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US
United States
Prior art keywords
digoxin
complex
complexes
mgm
tablet
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US00375052A
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English (en)
Inventor
T Higuchi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Interx Research Corp
EIDP Inc
Original Assignee
Interx Research Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Interx Research Corp filed Critical Interx Research Corp
Priority to US00375052A priority Critical patent/US3839317A/en
Priority to DE19742430850 priority patent/DE2430850C3/de
Priority to GB2853174A priority patent/GB1462718A/en
Priority to FR7422522A priority patent/FR2234899B1/fr
Priority to SE7408554A priority patent/SE402112B/xx
Priority to CA203,751A priority patent/CA1024980A/en
Priority to JP7489974A priority patent/JPS538768B2/ja
Priority to AU70658/74A priority patent/AU478214B2/en
Priority to US492827A priority patent/US3929996A/en
Application granted granted Critical
Publication of US3839317A publication Critical patent/US3839317A/en
Priority to SE7705958A priority patent/SE7705958L/xx
Assigned to E.I. DU PONT DE NEMOURS AND COMPANY reassignment E.I. DU PONT DE NEMOURS AND COMPANY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ENDO LABORATORIES, INC., A CORP. OF DEL.
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring
    • C07J19/005—Glycosides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/08—Dihydroxy benzenes; Alkylated derivatives thereof
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring

Definitions

  • ABSTRACT g 260/ Digoxin forms novel complexes with dihydroxybem zenes such as hydroquinone, resorcinol and pyrocate
  • Field of Search 260/2105 ch01. These complexes exhibit rapid dissolution
  • References Cited high solubility in aqueous media. These complexes are useful in the treatment of cardiac insufficiency.
  • the United States Pharmacopeia requires that the compound used as a drug be at least 96 percent 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, J 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, .1. G., et al., JAMA, Vol. 224, No. 2, page 199, Apr. 19, 1973).
  • Digoxin has extremely low water solubility, about 80 to 100 micrograms per milliliter.
  • the rate of dissolution is extremely slow and is considerably dosage form dependent.
  • 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.
  • a number of digoxin 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 of ethers (US. 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, US. Pat. No. 3,514,441).
  • Alterations of the steroid and lactone 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 pyrocatechol, resorcinol and hydroquinone.
  • digoxin and dihydroxybenzenes such as pyrocatechol, resorcinol and hydroquinone.
  • D represents digoxin
  • A represents a dihydroxybenzene selected from pyrocatechol, hydroquinone or resorcinol
  • n 1, 1%, 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 antinucleating agent or an excess of the dihydroxybenzene.
  • the dihydroxybenzene in these compositions may be present from H to 20 percent by weight of the composition, or more preferably, from A to 2 percent by weight of the composition.
  • this invention also relates to a novel means forpurifying digoxin.
  • the novel complexes of this invention when formed from a solution of impure digoxin, precipitate and may be separated from themother liquor in which the impurities remain. Separation of the crystalline complex and subsequent removal of the dihydroxybenzene effectively isolates digoxin from closely related impurities which are otherwise difficult to separate.
  • DESCRIPTION OF THE PREFERRED EMBODIMENTS are the pyrocatechol complexes having the ratio of digoxin to pyrocatechol of 1:1, 11% and 1:2, the resorcinol complexes having the ratio of digoxin to resorcinol of 1:1, lzl-l and 1:2 and the hydroquinone complexes having the ratios of digoxin to hydroquinone of 1:1, l:1 /2 and 1:2.
  • the hydroquinone complexes 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 of digoxin.
  • 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 of dihydroxybenzene with the digoxin and agitating the mixture for an extended period.
  • the complexes of this invention are formed by 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 complexing 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 oxygen can interact with the complexing 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. 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 product. 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 conveniently 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 U to 20 percent 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 A to 2 percent.
  • 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 0.1 to 10 percent by weight.
  • Example 1 Preparation of the Complex Digoxin, 46.86 grams (6 X 10' moles), sodium bisulfite, 1.04 grams (1 X 10 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 the 1:1 complex was about 60 grams.
  • Example 2 Digoxin, 46.86 (6 X 10 moles), sodium bisulfite, 1.04 grams (1 X 10 moles), and resorcinol, 55.1 grams (5 X 10 moles), were placed in an amber glass vessel and one liter of water was added.
  • the mixture Ingredients of the complexes of this invention can be formulated in i Y 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 Wt./Tablet Formulation 2 Wt./Tablet Formulation l Wt./Tablet 0.641 mgm 0.64] mgm 0.641 mgm droquinone Complex Polyvinyl Alcohol Hydroquinone, USP Microcry- 0.700 mgm 0.700 mgm 2.800 mgm 2.800 mgm 6.000 mgm 6.000 mgm stalline Cellulose Magnesium 0.150 mgm 0.150 mgm 0.150 mgm Stearate, USP
  • Example 5 The pharmaceutical manufacture of a tablet formulation is shown below:
  • the resulting digoxin was Digoxin-Hydroquinone complex Microcrystalline Cellulose Magnesium Steurate, USP Lactose. Spray Dried, USP
  • H D is digoxin
  • A is a dihydroxybenzene selected from the group consisting of resorcinol, hydroquinone and pyrocatechol
  • n is 1, 1 /2 or 2.
  • A is hydroquinone.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Medicinal Preparation (AREA)
US00375052A 1973-06-29 1973-06-29 Digoxin complexes Expired - Lifetime US3839317A (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US00375052A US3839317A (en) 1973-06-29 1973-06-29 Digoxin complexes
DE19742430850 DE2430850C3 (de) 1973-06-29 1974-06-27 Komplexverbindungen aus Digoxin und Dihydroxybenzolen, diese enthaltende pharmazeutische Zusammensetzungen und Verfahren zur Reinigung von Digoxin über diese Komplexverbindungen
GB2853174A GB1462718A (en) 1973-06-29 1974-06-27 Digoxin complexes
FR7422522A FR2234899B1 (lm) 1973-06-29 1974-06-27
CA203,751A CA1024980A (en) 1973-06-29 1974-06-28 Digoxin complexes
SE7408554A SE402112B (sv) 1973-06-29 1974-06-28 Sett att framstella digoxinkomplex
JP7489974A JPS538768B2 (lm) 1973-06-29 1974-06-29
AU70658/74A AU478214B2 (en) 1973-06-29 1974-07-01 Digoxin complexes
US492827A US3929996A (en) 1973-06-29 1974-07-29 Pharmaceutical compositions containing a digoxin complex
SE7705958A SE7705958L (sv) 1973-06-29 1977-05-20 Sett att dissociera digoxinkomplex

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US00375052A US3839317A (en) 1973-06-29 1973-06-29 Digoxin complexes

Publications (1)

Publication Number Publication Date
US3839317A true US3839317A (en) 1974-10-01

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US00375052A Expired - Lifetime US3839317A (en) 1973-06-29 1973-06-29 Digoxin complexes

Country Status (6)

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US (1) US3839317A (lm)
JP (1) JPS538768B2 (lm)
CA (1) CA1024980A (lm)
FR (1) FR2234899B1 (lm)
GB (1) GB1462718A (lm)
SE (2) SE402112B (lm)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4101652A (en) * 1975-07-01 1978-07-18 Inverni Della Beffa S.P.A. Pharmaceutically active complexes and pharmaceutical compositions containing eascin and sterols
US4568667A (en) * 1982-09-10 1986-02-04 Eisai Company, Ltd. Aqueous preparation containing vitamin E and saponins
US5550028A (en) * 1993-11-04 1996-08-27 Dade International Inc. Tetrahydroxyquinone as an activator component for activated partial thromboplastin time test of blood coagulation
CN114177152A (zh) * 2021-12-16 2022-03-15 北京微智瑞医药科技有限公司 一种地高辛微片及其制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02139531U (lm) * 1989-04-26 1990-11-21

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3223587A (en) * 1962-10-04 1965-12-14 Burroughs Wellcome Co Cardiac active acyl cymarols
US3514441A (en) * 1967-05-19 1970-05-26 Shionogi Seiyaku Kk Process for preparing steroid-acylates of a cardiac glycoside and products thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1441429A (fr) * 1964-10-08 1966-06-10 Searle & Co Procédé pour séparer la gamma-lactone de l'acide 3-(3-oxo-17beta-hydroxy-4, 6-androstadièn-17alpha-yl)-propionique de ses solutions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3223587A (en) * 1962-10-04 1965-12-14 Burroughs Wellcome Co Cardiac active acyl cymarols
US3514441A (en) * 1967-05-19 1970-05-26 Shionogi Seiyaku Kk Process for preparing steroid-acylates of a cardiac glycoside and products thereof
US3531462A (en) * 1967-05-19 1970-09-29 Shionogi Seiyaku Kk Carbonates of cardenolide tridigitoxosides and ester derivatives thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4101652A (en) * 1975-07-01 1978-07-18 Inverni Della Beffa S.P.A. Pharmaceutically active complexes and pharmaceutical compositions containing eascin and sterols
US4568667A (en) * 1982-09-10 1986-02-04 Eisai Company, Ltd. Aqueous preparation containing vitamin E and saponins
US5550028A (en) * 1993-11-04 1996-08-27 Dade International Inc. Tetrahydroxyquinone as an activator component for activated partial thromboplastin time test of blood coagulation
CN114177152A (zh) * 2021-12-16 2022-03-15 北京微智瑞医药科技有限公司 一种地高辛微片及其制备方法

Also Published As

Publication number Publication date
SE7705958L (sv) 1977-05-20
DE2430850A1 (de) 1975-03-06
AU7065874A (en) 1976-01-08
CA1024980A (en) 1978-01-24
GB1462718A (en) 1977-01-26
SE7408554L (lm) 1974-12-30
FR2234899B1 (lm) 1977-05-06
JPS538768B2 (lm) 1978-03-31
JPS5069217A (lm) 1975-06-10
SE402112B (sv) 1978-06-19
FR2234899A1 (lm) 1975-01-24
DE2430850B2 (de) 1977-06-08

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Owner name: E.I. DU PONT DE NEMOURS AND COMPANY, 1007 MARKET S

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:ENDO LABORATORIES, INC., A CORP. OF DEL.;REEL/FRAME:004063/0107

Effective date: 19821110