CA1046410A - Cardiotonic composition - Google Patents
Cardiotonic compositionInfo
- Publication number
- CA1046410A CA1046410A CA223,484A CA223484A CA1046410A CA 1046410 A CA1046410 A CA 1046410A CA 223484 A CA223484 A CA 223484A CA 1046410 A CA1046410 A CA 1046410A
- Authority
- CA
- Canada
- Prior art keywords
- composition
- weight
- cardiotonic
- gelatine capsule
- polyethylene glycol
- 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
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Molecular Biology (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A cardiotonic dosage unit form comprises a soft gelatine capsule containing a liquid cardiotonic composition comprising (a) a cardiac glycoside, preferably digitoxin or digoxin; (b) dimethyl formamide or dimethyl acetamide; and (c) a liquid polyethylene glycol and also, optionally, (d) propylene glycol or glycerin. The weight ratio of dimethyl acetamide or dimethyl formamide to cardiac glyceride is from 5:1 to 15:1 and the polyethylene glycol forms at least 75% by weight of the total composition contained in the gelatine capsule.
A cardiotonic dosage unit form comprises a soft gelatine capsule containing a liquid cardiotonic composition comprising (a) a cardiac glycoside, preferably digitoxin or digoxin; (b) dimethyl formamide or dimethyl acetamide; and (c) a liquid polyethylene glycol and also, optionally, (d) propylene glycol or glycerin. The weight ratio of dimethyl acetamide or dimethyl formamide to cardiac glyceride is from 5:1 to 15:1 and the polyethylene glycol forms at least 75% by weight of the total composition contained in the gelatine capsule.
Description
641~
This invention is concerned with improvements in and relating to pharmàceutical composition~ and, more particularly, relates to cardiotonic compositions containing, as active ingredient, a cardiac glycoside derived from Digitalis purpurea or Digitalis lanarta or a derivative thereof. For the sake of convenience such material will hereinafter be ~impl~ referred to as "cardiac glycosides".
Cardiac glycosides are widely used cardiotonic agents and are commonly formulated as tablets for oral administration. Of necessity, each tablet must contain a very small amount of the active ingredient, (e.g. 250 micrograms or less) since these parti ular acti~e agents are administered in such verg small doses, almost always less than 0.5 mg. The fact that each tablet has to contain so little of the active ingredient gives rise to problems in formulation and, in particular, makes it very difficult to ensure perfect compounding of the - tableting mix so that each tablet contains the same amount, with tolerable limits, of the acti~e ingredient, (see, for example, ~homas et al, The ~ancet, December 1, 1973, pp 1267-8; Fraser et al9 5, Pharm. PharmacO, 197~, 25, pp 268-97~; and Shaw et al, Bribish Medical ~ournal, 1973, 4, pp 763-766).
It is an object of the present invention to provide an improved dosage unit suitable for the oral admini-stration of a cardiac glycoside.
Accordingl~, the present invention provides a cardiotonic dosage unit form comprising a soft gelatine . .
. ~ ... . .
, ' ' ' ' . . : ' ', ', ' ' ' ' ~0~64~0 capsule containing a liquid cardiotonic composition comprising (a) a cardiac glycoside; (b) dimethyl formamide or, preferably, dimethyl acetamide; and (c) a liquid polyethylene glycol; and optionally also (d) propylene glycol or glycerine.
The cardiac glycoside used in the compositions of the invention may be, for example, digoxin, digitoxin, digitalin, b lanatoside C, acetyl digitoxin, acetyl digoxin or methyl digoxin.
The most generally preferred cardiac glycosides are digitoxin and digoxin, especially the latter.
The compositions in accordance with the invention will generally be prepared by dissolving the cardiac glycoside in the dimethyl acetamide or dimethyl formamide. The weight ratio of dimethyl acetamide to dimethyl formamide to cardiac glycoside is from 5:1 to 15:1 by weight preferably forming less than 25%
by weight of the total water/ethanol mixture. Suitably the weight ratio of water/ethanol mixture of cardiac glycoside is of the order of about 80:1 or even higher.
The solution of cardiac glycoside is mixed with the polyethylene glycol (optionally containing propylene glycol or glycerine) and the polyethylene glycol forms the major component of the compositions of the invention being present in the amounts of at least 75% by weight, preferably from 80-95% by weight, of the J
: . , total composition contained in the soft gelatine capsule~
~ he gelatine capsulè will be one formed of gelatine containing a plasticiser such as gl~cerine, propylene glycol, diethylene glycol or hexanetriol. ~urther, the plasticiser may comprise one of those mentioned above together with sorbitol in order to improve the proper-ties of the capsules with respect to exposure to moisture containing atmospheres. ~he amount of sorbitol will preferably be about equal to the amount of glycerin or other plasticiser. Accordingly, a preferred capsule comprises gelatineplasticised with from about 8 to 15%
by weight of glycerin preferably about 12.5% by weight9 and f~om 12.5 to 15% by weight of sorbitol preferably about 13.5% of sorbitol, the percentages being based on the total weight ofgelatine glycerine and sorbitol.
~ he total weight of ingredients contained in the gelatine capsule of the compositions of the invention is suitabl~ from about 100 to 300 milligrams, and, clearl~, the weight of cardiac glycoside contained in each capsule will be that generally required ~or a unit dose, for example from 50 to 300 microgram~.
The compositions of the invention are prepared in the liquid phase so that it is possi~le to obtain accurate and consistent dispersion of the acti~e ingredient (cardiac glycoside) throughout the liquid phase of the composition.
Accordingly, it is possible to ensure that each dosage unit (i e. capsule) contains the same amount (within tolerable limits) of the active ingredient.
It has also been found, that the unit dosage forms ... .
' ' ' ' ' ' , ' . ': . ' `' ' ' ' ' ' ~ ' ~. '. . . '. ' . .' ~ ' ' ' ~09~64~.~
of the invention give better or more rapid availability of the active ingredient`(as indicated by release tests carried out in artificial gastric ~uices) than do comparable tablets, Thus, it has been found not only do the capsules of the invention give a more rapid release o~ their contents but also that they gi~e a more complete release of their content than do the tablets which fre-quently release onl~ about 50% or less of their contents.
It will be appreciated, therefore, that the capsules of the invention cons.titute a much more reliable dosage unit than do many tablets since they can be relied upon to release substa~tially all of their active ingredient content within a rel~tively short period of time whereas this is not the case with tablets.
In order that the invention ma~ be.well understood the following examples of formulations for 140 and 280 milligram capsules are given by way o~ illustration onl~.
Ex_mPle~1 140 M~_capsule containing 131 micro~rams of di~ox~n Digoxin 00131 mg Dimethyl acetamide o.75 ~mg PEG 400 140~119 mg amPle 2 1~2_~E_~Qpsule. containin~ 66 micro~rams of di oxin Digoxin 0.066 mg Dimethyl acetamide0.75 mg PEG 400 140.559 mg ., . I
:
-:
6~.gl3 ~ .
140 Mg capsule containin~: 263 micrograms~ of di~;oxin I)igoxin 0. 263 mg Dimethyl acetamide 4. 500 mg PEG 400 139~237 mg
This invention is concerned with improvements in and relating to pharmàceutical composition~ and, more particularly, relates to cardiotonic compositions containing, as active ingredient, a cardiac glycoside derived from Digitalis purpurea or Digitalis lanarta or a derivative thereof. For the sake of convenience such material will hereinafter be ~impl~ referred to as "cardiac glycosides".
Cardiac glycosides are widely used cardiotonic agents and are commonly formulated as tablets for oral administration. Of necessity, each tablet must contain a very small amount of the active ingredient, (e.g. 250 micrograms or less) since these parti ular acti~e agents are administered in such verg small doses, almost always less than 0.5 mg. The fact that each tablet has to contain so little of the active ingredient gives rise to problems in formulation and, in particular, makes it very difficult to ensure perfect compounding of the - tableting mix so that each tablet contains the same amount, with tolerable limits, of the acti~e ingredient, (see, for example, ~homas et al, The ~ancet, December 1, 1973, pp 1267-8; Fraser et al9 5, Pharm. PharmacO, 197~, 25, pp 268-97~; and Shaw et al, Bribish Medical ~ournal, 1973, 4, pp 763-766).
It is an object of the present invention to provide an improved dosage unit suitable for the oral admini-stration of a cardiac glycoside.
Accordingl~, the present invention provides a cardiotonic dosage unit form comprising a soft gelatine . .
. ~ ... . .
, ' ' ' ' . . : ' ', ', ' ' ' ' ~0~64~0 capsule containing a liquid cardiotonic composition comprising (a) a cardiac glycoside; (b) dimethyl formamide or, preferably, dimethyl acetamide; and (c) a liquid polyethylene glycol; and optionally also (d) propylene glycol or glycerine.
The cardiac glycoside used in the compositions of the invention may be, for example, digoxin, digitoxin, digitalin, b lanatoside C, acetyl digitoxin, acetyl digoxin or methyl digoxin.
The most generally preferred cardiac glycosides are digitoxin and digoxin, especially the latter.
The compositions in accordance with the invention will generally be prepared by dissolving the cardiac glycoside in the dimethyl acetamide or dimethyl formamide. The weight ratio of dimethyl acetamide to dimethyl formamide to cardiac glycoside is from 5:1 to 15:1 by weight preferably forming less than 25%
by weight of the total water/ethanol mixture. Suitably the weight ratio of water/ethanol mixture of cardiac glycoside is of the order of about 80:1 or even higher.
The solution of cardiac glycoside is mixed with the polyethylene glycol (optionally containing propylene glycol or glycerine) and the polyethylene glycol forms the major component of the compositions of the invention being present in the amounts of at least 75% by weight, preferably from 80-95% by weight, of the J
: . , total composition contained in the soft gelatine capsule~
~ he gelatine capsulè will be one formed of gelatine containing a plasticiser such as gl~cerine, propylene glycol, diethylene glycol or hexanetriol. ~urther, the plasticiser may comprise one of those mentioned above together with sorbitol in order to improve the proper-ties of the capsules with respect to exposure to moisture containing atmospheres. ~he amount of sorbitol will preferably be about equal to the amount of glycerin or other plasticiser. Accordingly, a preferred capsule comprises gelatineplasticised with from about 8 to 15%
by weight of glycerin preferably about 12.5% by weight9 and f~om 12.5 to 15% by weight of sorbitol preferably about 13.5% of sorbitol, the percentages being based on the total weight ofgelatine glycerine and sorbitol.
~ he total weight of ingredients contained in the gelatine capsule of the compositions of the invention is suitabl~ from about 100 to 300 milligrams, and, clearl~, the weight of cardiac glycoside contained in each capsule will be that generally required ~or a unit dose, for example from 50 to 300 microgram~.
The compositions of the invention are prepared in the liquid phase so that it is possi~le to obtain accurate and consistent dispersion of the acti~e ingredient (cardiac glycoside) throughout the liquid phase of the composition.
Accordingly, it is possible to ensure that each dosage unit (i e. capsule) contains the same amount (within tolerable limits) of the active ingredient.
It has also been found, that the unit dosage forms ... .
' ' ' ' ' ' , ' . ': . ' `' ' ' ' ' ' ~ ' ~. '. . . '. ' . .' ~ ' ' ' ~09~64~.~
of the invention give better or more rapid availability of the active ingredient`(as indicated by release tests carried out in artificial gastric ~uices) than do comparable tablets, Thus, it has been found not only do the capsules of the invention give a more rapid release o~ their contents but also that they gi~e a more complete release of their content than do the tablets which fre-quently release onl~ about 50% or less of their contents.
It will be appreciated, therefore, that the capsules of the invention cons.titute a much more reliable dosage unit than do many tablets since they can be relied upon to release substa~tially all of their active ingredient content within a rel~tively short period of time whereas this is not the case with tablets.
In order that the invention ma~ be.well understood the following examples of formulations for 140 and 280 milligram capsules are given by way o~ illustration onl~.
Ex_mPle~1 140 M~_capsule containing 131 micro~rams of di~ox~n Digoxin 00131 mg Dimethyl acetamide o.75 ~mg PEG 400 140~119 mg amPle 2 1~2_~E_~Qpsule. containin~ 66 micro~rams of di oxin Digoxin 0.066 mg Dimethyl acetamide0.75 mg PEG 400 140.559 mg ., . I
:
-:
6~.gl3 ~ .
140 Mg capsule containin~: 263 micrograms~ of di~;oxin I)igoxin 0. 263 mg Dimethyl acetamide 4. 500 mg PEG 400 139~237 mg
Claims (6)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A cardiotonic dosage unit form comprising a soft gelatine capsule containing a liquid cardiotonic composition comprising (a) a cardiac glycoside; (b) dimethyl formamide or dimethyl acetamide; and (c) a liquid polyethylene glycol the weight ratio of dimethyl acetamide or dimethyl formamide to cardiac glyceride being from 5:1 to 15:1 and the polyethylene glycol forming at least 75% by weight of the total composition contained in the gelatine capsule.
2. A composition as claimed in claim 1 also containing propylene glycol or-glycerin.
3. A composition as claimed in claim 1 in which the cardiac glycoside is digitoxin or digoxin.
4. A composition as claimed in claim 1, 2 or 3 in which the polyethylene glycol forms from 80 to 95% by weight of the composition contained in the soft gelatine capsule.
5. A composition as claimed in claim 1, 2 or 3 in which the gelatine capsule contains from 100 to 300 milligrams of composition.
6. A composition as claimed in claim 1, 2 or 3 containing from 50 to 300 micrograms of cardiac glycoside.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB14265/74A GB1508770A (en) | 1974-04-01 | 1974-04-01 | Pharmaceutical compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1046410A true CA1046410A (en) | 1979-01-16 |
Family
ID=10038031
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA223,484A Expired CA1046410A (en) | 1974-04-01 | 1975-04-01 | Cardiotonic composition |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS5644045B2 (en) |
| AT (1) | AT342777B (en) |
| AU (1) | AU500001B2 (en) |
| BE (1) | BE827349A (en) |
| CA (1) | CA1046410A (en) |
| DE (1) | DE2513601A1 (en) |
| DK (1) | DK137436B (en) |
| FI (1) | FI63671C (en) |
| FR (1) | FR2265353B1 (en) |
| GB (1) | GB1508770A (en) |
| NL (1) | NL7503881A (en) |
| SE (1) | SE408687B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2380030A1 (en) * | 1977-02-09 | 1978-09-08 | Christiaens Sa A | Liquid and solid solns. of gitoxin - with high bio:availability for treating cardiac disorders |
| JPH0321610Y2 (en) * | 1985-07-12 | 1991-05-10 | ||
| DK1033128T4 (en) | 1993-09-28 | 2012-03-19 | Scherer Gmbh R P | Soft gelatin capsule making |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1481411A (en) * | 1973-07-20 | 1977-07-27 | Scherer Ltd R | Pharmaceutical compositions |
| IL46682A (en) * | 1974-02-22 | 1979-07-25 | Wellcome Found | Pharmaceutical capsules containing difoxin |
-
1974
- 1974-04-01 GB GB14265/74A patent/GB1508770A/en not_active Expired
-
1975
- 1975-03-27 SE SE7503592A patent/SE408687B/en not_active IP Right Cessation
- 1975-03-27 DE DE19752513601 patent/DE2513601A1/en active Granted
- 1975-03-28 BE BE154915A patent/BE827349A/en not_active IP Right Cessation
- 1975-04-01 DK DK138675AA patent/DK137436B/en not_active IP Right Cessation
- 1975-04-01 AU AU79663/75A patent/AU500001B2/en not_active Expired
- 1975-04-01 FR FR7510180A patent/FR2265353B1/fr not_active Expired
- 1975-04-01 CA CA223,484A patent/CA1046410A/en not_active Expired
- 1975-04-01 FI FI750964A patent/FI63671C/en not_active IP Right Cessation
- 1975-04-01 NL NL7503881A patent/NL7503881A/en not_active Application Discontinuation
- 1975-04-01 AT AT244575A patent/AT342777B/en not_active IP Right Cessation
- 1975-04-01 JP JP3968275A patent/JPS5644045B2/ja not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS517117A (en) | 1976-01-21 |
| AU500001B2 (en) | 1979-05-10 |
| DK137436B (en) | 1978-03-06 |
| AT342777B (en) | 1978-04-25 |
| DK137436C (en) | 1978-08-21 |
| DK138675A (en) | 1975-10-02 |
| FI63671B (en) | 1983-04-29 |
| FR2265353A1 (en) | 1975-10-24 |
| DE2513601A1 (en) | 1975-10-02 |
| DE2513601C2 (en) | 1988-05-26 |
| ATA244575A (en) | 1977-08-15 |
| BE827349A (en) | 1975-09-29 |
| FR2265353B1 (en) | 1980-02-15 |
| NL7503881A (en) | 1975-10-03 |
| SE408687B (en) | 1979-07-02 |
| FI750964A (en) | 1975-10-02 |
| JPS5644045B2 (en) | 1981-10-16 |
| FI63671C (en) | 1983-08-10 |
| SE7503592L (en) | 1975-10-02 |
| GB1508770A (en) | 1978-04-26 |
| AU7966375A (en) | 1976-10-07 |
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