CA1087985A - Readily enterally absorbable pharmaceutical compositions of cardiac glycosides and preparation thereof - Google Patents
Readily enterally absorbable pharmaceutical compositions of cardiac glycosides and preparation thereofInfo
- Publication number
- CA1087985A CA1087985A CA282,536A CA282536A CA1087985A CA 1087985 A CA1087985 A CA 1087985A CA 282536 A CA282536 A CA 282536A CA 1087985 A CA1087985 A CA 1087985A
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- Prior art keywords
- composition
- cardiac glycoside
- mixture
- strophanthin
- chain length
- Prior art date
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- 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
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- 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
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A readily enterally absorbable pharmaceutical composition of cardiac glycosides is disclosed which comprises a therapeutically-effective amount of at least one cardiac glycoside distributed in a vehicle comprising an absorption-enhancing amount of at least one partial glyceride of a fatty acid of medium chain length. The preparation is suited for formulating cardiac glycosides which per se are poorly enterally absorbable,in particular, k-strophanthin, g-strophanthin, and proscillaridin.
A readily enterally absorbable pharmaceutical composition of cardiac glycosides is disclosed which comprises a therapeutically-effective amount of at least one cardiac glycoside distributed in a vehicle comprising an absorption-enhancing amount of at least one partial glyceride of a fatty acid of medium chain length. The preparation is suited for formulating cardiac glycosides which per se are poorly enterally absorbable,in particular, k-strophanthin, g-strophanthin, and proscillaridin.
Description
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-BACKGROUND OF THE INVENTION
The present invention relates to readily absorb-able enteral pharmaceutical formulations of cardiac glycosides, which are poorly absorbable per se, and to a method for pre-paring such formulations.
Because of their favorable effect on the force ofthe myocardial contraction, cardiac glycosides are used therapeutically as cardiotonics for the treatment of myo-i~ cardial insufficiency and congestive heart failure. Yet such a treatment has the disadvantage that upon enteralapplication, most of the cardiac glycosides are absorbed only ! to a low and unpredictable percent and thus, a safe therapy can often be achieved only by intravenous injec~ion. Therefore, various attempts have been made to bring cardiac glycosides ; 15 into a form which is suitable for enteral application.
Chemical derivations of such glycosides have been successful to a certain degree in some cases, e.g., digi-toxin or digoxin, which are absorbable completely or to at least an acceptable degree, respectively. Yet other cardiac glycosides, such as, e.g., g- and k-strophanthin and pro-scillaridin still have to be administered parenterally, that is, intravenously, because of their insufficient enteral absorbability.
For several pharmacologically active agents, it has ~ 25 been proposed to dissolve or suspend them in glycerides of f ' fatty acids having a medium chain length in order to improve ,, ~ -2-`` A~^`;
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their absorption. Thus, for example, according to German Patent No. 1,282,853, chloramphenlcol is suspended in tri-glycerides of fatty acids having a medium chain length.
Belgian Patent No. 567,598 discloses a suspension of anti-biotics in triglycerides. British Patent No. 1,432,784 discloses a solution or suspension of various pharmacologi-cally-active agents in monoglycerides and German Offenlegungsschrift No. 2,357,389 discloses the solution or suspension of the same agents in a mixture of triglycerides and partial glycerides. Yet insofar as any data relative to the achieved absorption are included in the above refer-ences, these data indicate only little improvement of the absorption of the respectiVe pharmacologically-active ingre-dients.
SUM~RY OF THE INVENTION
It is an object of the present invention to provide an enteral pharmaceutical formulation of cardiac glycosides, especially cardiac glycosides, which per se are poorly absorbable, which provide for a high degree of enteral ,l 20 absorption of such glycosides.
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It is a further object of the present invention to ; provide such a formulation wherein the enteral absorption of poorly absorbable cardiac glycosides, especially of g-''I , . . .
,i strophanthin, k-strophanthin and proscillaridin is increased sufficiently to permit an enteral application of these j glycosides.
, It is still a further object of the present inven-,l tion to provide such a formulation wherein the enteral ~ .
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absorption of poorly absorbable cardiac glycosides is sufficiently high to insure a constant degree of absorption of such glycosides after enteral application.
In order to accomplish the foregoing objects and advantages of the present invention, there is provided a readily absorbable pharmaceutical composition which com-prises a therapeutically-effective amount of at least one cardiac glycoside distributed in a vehicle comprising an absorption enhancing amount of at least one partial glyceride of a fatty acid of medium chain length.
The cardiac glycoside may be incorporated in the partial glyceride or a mixture of partial glycerides, respectively, in form of a genuine solution, a solid solu-tion or a microcrystalline suspension.
The preparation according to the present invention is preferably suited for formulating cardiac glycosides , which per se are poorly enterally absorbable, in particular, k-strophanthin, g-strophanthin and proscillaridin.
According to the present invention, there is further provided a process for preparing a readily enterally absorbable pharmaceutical composition of cardiac glycosides which comprises the step of dissolving the cardiac glycosides in at least one partial glyceride of a fatty acid of medium ~` cha.in length.
According to the present invention, there is ~urther provided a method of enteral cardiotonic therapy, whlch comprises enterally, pre~erably orally, administering .;
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,~ . . , . ' 1~7~1!35 the above described pharmaceutical composition to a larger mammal.
DE~AILED DESCRIPTION OF PREFERRED EMBODIMENTS
According to the actual absorption data which are given in some of the above-cited prior art references, the achieved improvement of the absorption of the respective active agents is so little that it could not be expected that dissolving or suspending cardiac glycosides in partial glycerides of fatty acids of medium chain length leads to a useful and satisfactory increase of the enteral absorption of such glycosides. Cardiac glycosides exhibit a low therapeutic ratio, that is, the ratio between the thera-peutically-effective and the toxic amount, combined with a larye range of variations between the individual degrees of enteral absorption in different persons. The low thera~
peutic ratio indicates the fact that such agents have no effect at a dosage only slightly below the effective amount but lead to a perisystole at only a slight overdosage.
ii Thus, due to a difference in the individual enteral absorp-1 20 tion, an enteral dosage which has no effect in onë indivi-dual may already cause the death of another individual.
For example, with g-strophanthin, individual variations in enteral absorption in the range of between about 0.46~ and i~i 4.4%, that is, of a factor of 10, have been observed. Due to this, several authors have published their opinion that an enteral application of these glycosides cannot be effected.
Because of such large individual variations of the degree of _~ enteral absorption of poorly absorbable cardiac glycosides, _5_ , , .
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a very high increase of the absorption has to be achieved in order to sufficiently equalize these individual differ- -ences to insure a safe enteral administration of the glyco-sides. In view of the only very small improvement of the absorption which was achievable by means of glycerides for other pharmacologically-active agents, it is highly sur-prising and unexpected that such a sufficiently large improvement of the enteral absorption of per se poorly absorbable cardlac glycosides is achieved according to the ` 10 present invention.
The term cardiac glycosides, as it is used in the present application, includes cardiotonically-active gly-cosides containing a cardenolid- or bufadienolid ag~ycon, which is substituted in the 3-position by a glycosidic group containing 1 to 4 sugar units,and semi-synthetical deriva-tives thereof. The sugar units may be pentose or hexose units or partial reduction products thereof.
Cardiotonically-active semi-synthetic derivatives ,"
of naturally-occurring cardiac glycosides include the aglycones themselves, glycosides wherein the original number of sugar units is reduced, glycosides wherein the glycosidic group and/or the aglycon are chemically modified by etherifi-cation or esterification of at least part of the hydroxy groups with lower alkyl or lower carboxylic acyl, hydroxyla-tion or dehydrogenation.
Among the cardiac glycosides with cardenolidstructure, there may be cited the digitalis glycosides which ~ occur naturally in digitalis purpurea and digitalis lanata, `; -6-' , , ~
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, and derivatives thereof, e.g., lanatosids A, B or C, purpurea glycosides A or B, digitoxin, digoxin or gitoxin or the aglycons thereof, k-strophanthus glycosides which occur naturally in strophan~us kombe, g-strophanthus glycosides which occur naturally in strophanthus gratus, e.g., k-strophant~ins ~,~ and~ containing the aglycon k-strophanthidin (= 3~, 5,14-trihydroxy-l9-oxo-5~-card-20(22)-enolid) and g-strophanthin containing the aglycon g-strophanthidin (= 1~,3~,5,11~,14,19-hexahydro-5~-card-20(22)-enolid).
Among the cardiac glycosides with bufadienolid structures, there may be cited the squill glycosides which occur naturally in scilla martima, e.g., proscillaridin scillaren A, scillaren s.
; Preparations according to the present invention are especially suited for the enteral application of such cardiac glycosides which per se are particularly poorly enterally absorbable, for example, cardiac glycosides of which only about 5~ or less, e.g., between about 5 and 0.3% are enter-;~ ally absorbed. Examples of per se poorly enterally absorbable cardiac glycosides are g-strophanthin, k-strophanthin and proscillaridin. Preparations according to the present inven-tion are also suited for the enteral application of cardiac glycosides for which it is desirable to improve their enteral ` absorption.
The concentration of the cardiac glycoside in ` the en-teral preparations according to the present invention - may vary considerably depending on the physical and chemical properties, especially the pharmacological activity of the ~ . .. . , :
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respective cardiac glycoside Which is used, on its enteral absorbability per se,and on its sensitivity to metabolic decomposition in the gastrointestinal tract and/or the liver, as well as on the amount of absorption enhancing partial glycerides preSent in the preparation and the contemplated mode of administration, the treated condition and the therapy which is desired. Usually a satisfactory enteral activity is obtained with an amount corresponding to between about 1 and about 3 times, preferably about 1 and about 2 times the parenterally-effective amount of the respective cardiac glycosides. For example, enterally-effective amounts of g-strophanthin, k-strophanthin or proscillaridin within the compositions according to the present invention are between about 0.1 and about 0.3~ preferably about 0.2 and ~ 15 0.25 mg per single dosage unit.
`~ Partial glycosides of fatty acids of medium chain length comprise mono- and diglycerides of fatty acids, pre-ferably saturated monocarboxylic acids, having a chain length o preferably between about 6 to about 12, most preferably between about 8 and about 10 carbon atoms, and mixtures ` thereof. Especially suited are mono- and diglycerides of capric- and caprylic acid and mixtures thereof.
The amount of absorption enhancing partial glycer-` ides of fatty acids of medium chain length in the preparation according to the present invention, which is effective to sufficiently enhance the enteral absorption to permit an enteral administration of a cardiac glycoside, may vary considerably depending on the per se enteral absorbability .. .~
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of the respective cardiac glycoside, as well as on the chemical and physical properties of any other ingredients of the composition. Typically, satisfactory results are obtain-ed with preparations wherein the amount of partial glycerides of fatty acids of medium chain length are between about 20 and about 10~, preferably about 40 and about 100%, of the vehicle. For example, of oral preparations of cardiac glycosides the per se enteral absorbability of which is less than 5~, e.g., between 0.3 and 5%, such as g-strophanthin, k-strophanthin or proscillaridin, the partial glycerides of fatty acids of medium chain length are preferably used in amounts of about 40 to about 100~ of the total vehicle.
The ratio between the amounts of cardlac glycoside and of absorption enhancing partial glycerides of fatty àcids of medium chain length may vary considerably depending on the per se enteral absorbability of the respective cardiac glycoside, as well as on the chemical and physical properties ' of any other ingredients of the composition. For example, - for enteral preparations of cardiac glycosides having a per se enteral absorbability of less than 5%, e.g., of between 0.3 and 5%, a suitable ratio cardiac glycoside/partial glyceride of fatty acids of medium chain length is of be-` tween about 0.5 to 100 and about 0.01 to 100.
The enteral formulations may take the form of solid or liquid formulations for oral or rectal application.Thus, the formulations may be in the form of capsules, tablets, coated tablets, suppositories or emulsions. These formula-- , tions may comprise conventional pharmaceutical carriers and _9..
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additives, especially viscosity-improving and/or structure-or matrix-forming additives which provide for an appropriate viscosity and physical structure. Suitable suah additives are, e.g., inorganic thickening agents, such as, highly dispersed silicic acid (e.g., the commercial products "Aerosil'~ bentonites, collodial clay, modified montmor-illonites, such as alkyl ammonium salts of montmorillonites (e.g., the commercial products "Bentone")~ wherein the alkyl groups may contain 1 to 20 carbon atoms, e.g., dimethyl-dialkyl ammonium salts wherein the alkyl groups contain 16to 18 carbon atoms, organic thickening and structure-forming agents such as, saturated higher fatty acids and alcohols containing, e.g., 12 to 20 carbon atoms, for example, stearic or palmitic acid, stearic or cetylic alcohol, wax~s like beeswax, synthetic esters of higher fatty acids and higher fatty alcohols, or spermaceti, monoglycerides of saturated or unsaturated higher fatty acids, e.g., mono-glycerides of stearic acid, palmitic acid or oleic acid, partial glycerides of fatty polyhydroxy acids (e.g., the - 20 commercial products "Softigen 701 r. Suppositories may further contain any conventional water soluble or fatty suppository bases as additional vehicles. The compositions may further comprise pharmaceutical adjuvants, e.g., binders or lubricants for tabletting, stabilizing-, flavoring-, or emulsifying agents or preservatives.
Since several cardiac glycosides are sensitive to acids, it may be advisable to apply an enteric coating to the oral dosage forms, e.g., gelatin capsules, of such i ` , ~ '~' . ' , . .
glycerides.
The formulations according to the present inven-tion are prepared in any conventional manner, e.g., by dis-solving the cardiac glycosides in the partial glycerides, optionally adding additional adJuvants, and formulating the resulting mixture into the desired dosage form by known pharmaceutical methods, e.g., tabletting, molding into suppositories or filling into capsules.
Depending on the solubility and/or the dis-solution rate of the cardiac glycosides in the partial glycerides and on the melting point of the partial glycerides, the dissolving may be done at room temperature or under heating. In cases where the cardiac glycosides recrystallize and/or the partial glycerides resolidify upon cooling of such ~ 15 solutions which are obtained under heating, microcrystalline - suspensions and/or solid solutions of the glycosides are formed, which exhibit the same absorption behavior as that of actual solutions of the cardiac glycosides.
` In order to facilitate the filling of the mixture into gelatin capsules or the formulating into suppositories or tablets, it may be advisable to further add viscosity-improving or structure- or matrix-forming additives.
Especially, there may be added highly dispersed silicic acid, modified montmorillonites, monoglycerides of oleic i 25 acid or stearic acid, palmitic acid, stearic acid, cetylic or stearic alcohols, beeswax, spermaceti or a mixture of partial glycerides of an unsaturated fatty acid which is sub-stituted by hydroxy groups (e.g., the commercial products . . . ' . : . . : . . -~ . .
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"Softigen 701").
- The high enteral absorption o~ the formulations according to the present invention is demonstrated by toxicity tests, determination of the level of the respective glycosides in the blood or according to a modified Hatcher method as described by Lenke and Schneider (Arzneimittelfor-schung 19 (1969)/ pages 687-693; ibid 20 (1970)-, pages 1199-1206 and 1765-1770).
For testing the toxicity, solutions of g-strophanthin or proscillaridin in a mixture of mono- and diglycerides of ca~ric and caprylic acids (commercial product of "Witafrol 7420'~ manufacturer Dynamit-Nobel AG) and in water are administered orally to female guinea pigs of 250 to 300 g body weight by means of an oral feeding tube.
15 The following lethal doses are observed: -Test solution LD50 mg/kg g-strophanthin in'Witafrol 7420" ~ 5.2 g-strophanthin in water 34.8 Proscillaridin in~Witafrol 7420" ~ 6.8 20 proscillaridm in water 12.3 For determining the blood level values, 50 ~g!kg of tritiated g-strophanthin in form of solutions in a mixture of mono- and diglycerides of~capric and caprylic acids CF~9 ~commercial product"WL 2391",manufacturer Sa. Gattefosse) and in water are administered to cats intraduodenally. The measured blood level values are plotted on a graph and the area beneath the resulting blood level curves are compared.
From the comparison of the areas, the following percentages ~ Ci ,: ` .` `' ~ . ~ ~
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of absorption are calculated:
g~strophanthin in water - 19%
g-strophanthin in"WL 2391' - 61%
According to the modi~ied Hatcher-method ("fill up"-method) 100 ~g/kg g-strophanthin dissolved in Witafrol 7420 is administered intraduodenally to cats of both sex which are under chloralose-ure~hane narcosis (at this dosage which normally is not lethal, two cats out of thirty-four died already). Four hours later, the active agent is I'filled up" by means of intravenous infusion until perisysto~e occurs. The following statistical average absorption rates of between 60 and 80~ are found dependin~ on the predeter-mined perlod of survival.
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Intraduodenal Predetermined Calculated (aver.) Enteral administration period of sur- "fill up" dose of activity vival (min) g-strophanthin %
~g/kg i.v.
g-strophanthin 50 63.9 80.8 "lit ~ufg/okg ~ 100 49.7 60.7 ___________________ ._ _ _________________________ _____________ "Witafrol" 50 144.7 0.1 ml/kg 100 110.4 Due to the high enteral absorption rates of, e.g., ~ up to 80~, which are achieved according to the present inven-.~ tion, a highly secure oral or rectal therapy, e.g., of myocardial insufficiency, with per se poorly ahsorbable cardiac glycosides, which could not be achieved heretofore, is made available.
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~ 7~s ~ The invention will now be further described by the following examples. In these examples, the term "parts"
means "parts by weight" unless stated o~herwise. The amount of a certain cardiac glycoside which is cited in one example can be replacea by the same amount of one of the other two cardiac glycosides which are ci~ed in the examples.
EXA~lPLE 1 Gelatin capsules: ~
Composition of the mixture which is filled into the capsules:
g-strophanthin 0.125 parts mixture of mono- and diglycerides of capric and caprylic acid* 99 875 parts ~ Total 100.000 parts (~
* commercial product'~tL 2391i', manufacturer, Sa. Gattefosse Preparation: g-strophanthin is dissolved in the glyceride mixture at a temperature of 35 to 40C under stirring. The soIu~ion is filled into gelatin capsules in portions of 200 mg per capsule. Each capsule contains 0.25 mg of the active ingredient.
EX~lPLE 2 Gelatin capsules:
Composition of the mixture which is filled into the capsules:
g-strophanthin 0.125 parts mixture of mono- and diglycerides of capric and caprylic acids* 92.375 parts .
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~7g~s highly dispersed silicic acid containing an amount - of C~3 groups equivalent ,- ~o a carbon content of 0.9 - 1.2% ** 7 500 parts Total 100.000 parts * commercial product"WL 239 manufacturer, Sa. Gattfosse ** commercial product"Aerosil R 972", - manufacturer Degussa Preparation: g-strophanthin is dissolved in the glyceride mixture at a temperature of 35 to 40C under ; agitation. Subsequently, the silicic acid is added under , further,agitation. For final homogeniza~ion, the mixture is treated in a colloid mill or a high pressure homogenizer.
'rhe ~lxture is filled into gelatin capsules in portions of 200 mg`per capsule. Each capsule contains 0.25 mg of the ac~ive ingredient.
EXP~PLE 3 ,, Composition of the mixture which is filled into ; 15 the capsules:
k-strophanthin 0.125 parts ; tetraalkyl ammonium salt of magnesium montmorillo-nite** 4.5 parts ; ethanol 2O25 parts mixture of mono- and `~ diglycerides of capric ,~ and caprylic acids*33.125 parts x, 20 Total 100.000 parts .-. ~) `~ * commercial product"WL 2391", manufacturer, Sa. Gattefosse L~
** commercial product of"Bentone 27"'' - manufacturer, Kronos Titan ~`, .
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Preparation: the modified montmorillonite is added to about half the amount of the glyceride mixture and by means of a high speed agitator of the type Rotor/Stator.
It is first dispersed therein and then subsequent to the addition of the ethanol, it is solubilized whereby a viscid gel i~ formed. The k-strophanthin is dissolved in the remaining amount of the glyceride mixture and the resulting' solution is added to the previously prepared gel portion under agitation. Agitation is continued until a uniform consistency of the mixture is achieved. The mixture is filled into gelatin capsules in portion~ of 200 mg each.
Each capsule contains 0.25 mg of active ingredient.
Composition of the mixture which is filled into ., the capsules:
proscillaridin 0~1 parts mixture of partial glycerides of an unsaturated fatty acid rich in hydroxy groups** 50.0 parts mixture of mono-and di-glycerides of capric ' and caprylic acids* 49 9 parts Total 100.0 parts *commercial product"WL 2391' manufacturer, Sa. Gattefosse ., ' ,~
**commercial product"Softigen 701'.
manufacturer, Dynamit-Nobel AG.
Preparation: proscillaridin is dissolved in the mixture o~ mono- and diglycerides of capric and caprylic acids at a temperature of about 35 to 40~C unde'r agitation.
The mixture of partial glycerides of the hydroxylated fatty , . ., . . .,.. ., ,............ ~ ~ .. . .
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~79~35 acid is liquified at a tempexature of 40C and ls added to the above solution. The resulting mixture is cooled to room temperature under agitation. Portions of 200 mg each of the mixture are filled into gelatin capsules. Each capsule contains 0.2 mg of active ingredient.
EXAMP~E S
Composition of the mixture which is filled into the capsules:
g-strophanthin 0.125 parts ~-; 10 oleic acid monoglyceride 40.0 parts mixture of mono- and diglycerides of capric and caprylic acid*59.875 parts Total 100.000 parts ^~ * commercial product"WL 239~',3 manufacturer, Sa. Gat'efosse Preparation: g-strophanthin is dissolved in ~he mixture of mono- and diglycerides of capric and caprylic - acid at a temperature of about 35 to 40C under agitation.
The oleic acid monoglyceride is liquified at a temperature of 50~C and added to the above mixture, which is then allowed to cool at room temperature under agitation. Portions of 200 mg each of the mixture are filled into gelatin capsules. Each capsule contains 0.2 mg of active ingredient.
i' EXAMPLE 6 ,- Composition of the mixture which is filled into the capsules:
g-strophanthin 0.125 parts oleic acid monoglyceride 40.0 parts .
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- I mixture o~ mono-and diglycerides of capric and caprylic acid*59 875 parts ~otal 100.000 parts .~ 1 *commercial produc~"Witafrol 7420"`' manufacturer, Dynamit-Nobel AG
Preparation: g-strophanthin is dissolved in the mixture of mono- and diglycerides of capric and caprylic acid at a temperature of about 35 to 40C under agitation.
The oleic acid monoglyceride is liquified at a temperature of 50C and added to the above mixture, which is then allowed to cool to room temperature under agitationO Portions,of 200 mg each of the mixture are filled into gelatin capsulas which subsequently are coated with an enteric coating. Each , capsule~,contains 0.25 mg of active ingredient.
ExAMæLE 7 Composition of the mixture which is filled into the capsules:
k-strophanthin 0.125 parts capric acid monoglyceride 17.5 parts mixture o~ mono- and diglyceridés of capric and caprylic acid*82.375 parts Total 100.0 parts , 20 *commercial product"Witafrol 7420'~
- manu~acturer, Dynami~-Nobel AG
Preparation: k-strophanthin is dissolved in the mixture of mono- and diglycer,ides of capric and caprylic acid at a temperature of about 35 to 40C under agitation.
~he capric acid monoglyceride is melted at a temperature of 60C and added to the above mixture, which is then allowed ` -18-. I
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to cool to room temperature under agitation. Portions of 200 mg each of the mixture are filled into gelatin capsules, which subsequently are coated with an enteric coating. Each capsule contains 0.25 mg of active ingredient.
Composition of ~he mix~ure which is filled into the capsules:
proscillaridin 0.1 parts stearic acid monoglyceride 5.0 parts mixture of mono and ~diglycerides of capric and caprylic acid* 94.9 parts ___________ Total 100.0 parts ,, 5~
*commercial product"Witafrol 7420', manufacturer, Dynamit-NObel AG
; Preparation: proscillaridin is dissolved in the mixture of mono- and diglycerides of capric and caprylic ` 15 acid at a temperature of about 35 to 40C under agitation.
The stearic acid monoglyceride is melted at a temperature of 70C and added to the above mixture, which is then allowed to cool to room temperature under agitation. Portions of 200 mg each of the mixture are filled into gelatin capsules.
; 20 Each capsule contains 0.2 mg of active ingredient.
Composition of the mixture which is filled into ~he capsules:
Proscillaridin 0.02 parts mixture of partial glycerides of an unsaturated fatty acid rich in hydroxy groups ** 50.0 parts ' -19-~ ~.
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37~5 ' . . ' mixture of mono- and diglycerides of capric and caprylic acids* 49 98 parts Total 100.00 parts * commercial product"Witafrol 7420",'' ; manufacturer, Dynamit-Nobel AG
(i~3 ** commercial product"Softigen 701'~' manufacturer, Dynamit-Nobel AG.
Preparation: proscLllaridin is dissolved in the mixture of mono- and diglycerides of capric and caprylic acid at a temperature of about 35 to 40C under agitation.
The mixture of partial glycerides of the hydroxylated fatty acid is liquified at a temp~rature of 40C and is added to the above so}ution. The resulting mixture is cooled to room temperature under agitation. Portions of l g each of the mixture are filled into gelatin capsules for rectal application. Each capsule contains 0.2 mg of active ingre-dient.
EXAMPLE lO
Gelatin capsules for rectal application.
Composition of the mixture which is filled into ` ~he capsules:
g-strophanthin 0.025 parts 20 mixture of mono- and diglycerides of capric and caprylic acids* 92.475 parts highly dispersed silicic acid containing an amount of CH3 groups equivalent to a carbon content of 0.9 - 1~2~i ** ` 7 500 parts Total 100-000R arts * commercial product"Witafrol 7420", manufacturer, Dynamit-Nobel AG
' -20-.. . .
** commercial product"Aerosil R 972', manufacturer Degussa Preparation: g-strophanthin is dissolved in the glycerides at a temperature of 35 to 40C under agitation.
Subsequently, the silicic acid is added under ~urther agitation. For the final homogenization o$ the mixture is treated in a colloid mill or a high pressure homogenizer.
The mixture is filled into gelatin capsul s for rectal application in portions of lg per capsule. Each capsule contains 0.25 mg of the active ingredient.
Suppositories Composition:
k-strophanthin O.Ol parts ~.
caprylic acid monoglyceride 99,99 parts Total 100.00 parts Pxeparation: the caprylic acid monoglyceride (melting point 35-37C, purity 90~, remainder caprylic acid, diglyceride,and triglyceride and glycerine) is liquified at ; a temperature of 45C and the k-s~rophanthin is dissolved in the molten product under agitation. The molten mixture is filled into suppository molds wherein it solidifies.
Each suppasitory weighs 2.5 g and contains 0.25 mg of k-strophanthin.
EXA~LE 12 : 25 Suppositories Composition:
g-strophanthin 0.01 parts .
~ C~
. .. .
, ' ' 379l~5 caprylic acid monoglyceride ~purity 40~)** 33.0 parts suppository base*** 66.99 parts Total 100.00 parts ** commercial product"Drewmulse GMC-8"3 manufacturex PVO International, Inc.
*** commercial product"Novata C"
manufacturer, Henkel ~G
Preparation: g-strophanthin is dissolved in the caprylic acid monoglyceride at a temperature of 50C under agitation. The suppository base Novata C is also melted ; and added to the above mixture under agitation. ~he mixture is filled into suppository molds wherein it solidifies.
Each suppository weighs 2.5 g and contains 0.25 mg of g-strophanthin.
... ..
; EXAMPLE 13 One capsule which is prepared according to Example 1 is administered orally once a day to an adult person for cardiotonic therapy.
While the invention has now been described in terms of various preferred embodiment, the skilled artisan will readily appreciate that various substitutions, modi-fications, changes, and omissions may be made withoutdeparting ~rom the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by that of the following claims.
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-BACKGROUND OF THE INVENTION
The present invention relates to readily absorb-able enteral pharmaceutical formulations of cardiac glycosides, which are poorly absorbable per se, and to a method for pre-paring such formulations.
Because of their favorable effect on the force ofthe myocardial contraction, cardiac glycosides are used therapeutically as cardiotonics for the treatment of myo-i~ cardial insufficiency and congestive heart failure. Yet such a treatment has the disadvantage that upon enteralapplication, most of the cardiac glycosides are absorbed only ! to a low and unpredictable percent and thus, a safe therapy can often be achieved only by intravenous injec~ion. Therefore, various attempts have been made to bring cardiac glycosides ; 15 into a form which is suitable for enteral application.
Chemical derivations of such glycosides have been successful to a certain degree in some cases, e.g., digi-toxin or digoxin, which are absorbable completely or to at least an acceptable degree, respectively. Yet other cardiac glycosides, such as, e.g., g- and k-strophanthin and pro-scillaridin still have to be administered parenterally, that is, intravenously, because of their insufficient enteral absorbability.
For several pharmacologically active agents, it has ~ 25 been proposed to dissolve or suspend them in glycerides of f ' fatty acids having a medium chain length in order to improve ,, ~ -2-`` A~^`;
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their absorption. Thus, for example, according to German Patent No. 1,282,853, chloramphenlcol is suspended in tri-glycerides of fatty acids having a medium chain length.
Belgian Patent No. 567,598 discloses a suspension of anti-biotics in triglycerides. British Patent No. 1,432,784 discloses a solution or suspension of various pharmacologi-cally-active agents in monoglycerides and German Offenlegungsschrift No. 2,357,389 discloses the solution or suspension of the same agents in a mixture of triglycerides and partial glycerides. Yet insofar as any data relative to the achieved absorption are included in the above refer-ences, these data indicate only little improvement of the absorption of the respectiVe pharmacologically-active ingre-dients.
SUM~RY OF THE INVENTION
It is an object of the present invention to provide an enteral pharmaceutical formulation of cardiac glycosides, especially cardiac glycosides, which per se are poorly absorbable, which provide for a high degree of enteral ,l 20 absorption of such glycosides.
`
It is a further object of the present invention to ; provide such a formulation wherein the enteral absorption of poorly absorbable cardiac glycosides, especially of g-''I , . . .
,i strophanthin, k-strophanthin and proscillaridin is increased sufficiently to permit an enteral application of these j glycosides.
, It is still a further object of the present inven-,l tion to provide such a formulation wherein the enteral ~ .
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~ 91~S
absorption of poorly absorbable cardiac glycosides is sufficiently high to insure a constant degree of absorption of such glycosides after enteral application.
In order to accomplish the foregoing objects and advantages of the present invention, there is provided a readily absorbable pharmaceutical composition which com-prises a therapeutically-effective amount of at least one cardiac glycoside distributed in a vehicle comprising an absorption enhancing amount of at least one partial glyceride of a fatty acid of medium chain length.
The cardiac glycoside may be incorporated in the partial glyceride or a mixture of partial glycerides, respectively, in form of a genuine solution, a solid solu-tion or a microcrystalline suspension.
The preparation according to the present invention is preferably suited for formulating cardiac glycosides , which per se are poorly enterally absorbable, in particular, k-strophanthin, g-strophanthin and proscillaridin.
According to the present invention, there is further provided a process for preparing a readily enterally absorbable pharmaceutical composition of cardiac glycosides which comprises the step of dissolving the cardiac glycosides in at least one partial glyceride of a fatty acid of medium ~` cha.in length.
According to the present invention, there is ~urther provided a method of enteral cardiotonic therapy, whlch comprises enterally, pre~erably orally, administering .;
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,~ . . , . ' 1~7~1!35 the above described pharmaceutical composition to a larger mammal.
DE~AILED DESCRIPTION OF PREFERRED EMBODIMENTS
According to the actual absorption data which are given in some of the above-cited prior art references, the achieved improvement of the absorption of the respective active agents is so little that it could not be expected that dissolving or suspending cardiac glycosides in partial glycerides of fatty acids of medium chain length leads to a useful and satisfactory increase of the enteral absorption of such glycosides. Cardiac glycosides exhibit a low therapeutic ratio, that is, the ratio between the thera-peutically-effective and the toxic amount, combined with a larye range of variations between the individual degrees of enteral absorption in different persons. The low thera~
peutic ratio indicates the fact that such agents have no effect at a dosage only slightly below the effective amount but lead to a perisystole at only a slight overdosage.
ii Thus, due to a difference in the individual enteral absorp-1 20 tion, an enteral dosage which has no effect in onë indivi-dual may already cause the death of another individual.
For example, with g-strophanthin, individual variations in enteral absorption in the range of between about 0.46~ and i~i 4.4%, that is, of a factor of 10, have been observed. Due to this, several authors have published their opinion that an enteral application of these glycosides cannot be effected.
Because of such large individual variations of the degree of _~ enteral absorption of poorly absorbable cardiac glycosides, _5_ , , .
`` 1~Y~75~S
a very high increase of the absorption has to be achieved in order to sufficiently equalize these individual differ- -ences to insure a safe enteral administration of the glyco-sides. In view of the only very small improvement of the absorption which was achievable by means of glycerides for other pharmacologically-active agents, it is highly sur-prising and unexpected that such a sufficiently large improvement of the enteral absorption of per se poorly absorbable cardlac glycosides is achieved according to the ` 10 present invention.
The term cardiac glycosides, as it is used in the present application, includes cardiotonically-active gly-cosides containing a cardenolid- or bufadienolid ag~ycon, which is substituted in the 3-position by a glycosidic group containing 1 to 4 sugar units,and semi-synthetical deriva-tives thereof. The sugar units may be pentose or hexose units or partial reduction products thereof.
Cardiotonically-active semi-synthetic derivatives ,"
of naturally-occurring cardiac glycosides include the aglycones themselves, glycosides wherein the original number of sugar units is reduced, glycosides wherein the glycosidic group and/or the aglycon are chemically modified by etherifi-cation or esterification of at least part of the hydroxy groups with lower alkyl or lower carboxylic acyl, hydroxyla-tion or dehydrogenation.
Among the cardiac glycosides with cardenolidstructure, there may be cited the digitalis glycosides which ~ occur naturally in digitalis purpurea and digitalis lanata, `; -6-' , , ~
" ' ' ~ ' ' :
. ~ . . .
, and derivatives thereof, e.g., lanatosids A, B or C, purpurea glycosides A or B, digitoxin, digoxin or gitoxin or the aglycons thereof, k-strophanthus glycosides which occur naturally in strophan~us kombe, g-strophanthus glycosides which occur naturally in strophanthus gratus, e.g., k-strophant~ins ~,~ and~ containing the aglycon k-strophanthidin (= 3~, 5,14-trihydroxy-l9-oxo-5~-card-20(22)-enolid) and g-strophanthin containing the aglycon g-strophanthidin (= 1~,3~,5,11~,14,19-hexahydro-5~-card-20(22)-enolid).
Among the cardiac glycosides with bufadienolid structures, there may be cited the squill glycosides which occur naturally in scilla martima, e.g., proscillaridin scillaren A, scillaren s.
; Preparations according to the present invention are especially suited for the enteral application of such cardiac glycosides which per se are particularly poorly enterally absorbable, for example, cardiac glycosides of which only about 5~ or less, e.g., between about 5 and 0.3% are enter-;~ ally absorbed. Examples of per se poorly enterally absorbable cardiac glycosides are g-strophanthin, k-strophanthin and proscillaridin. Preparations according to the present inven-tion are also suited for the enteral application of cardiac glycosides for which it is desirable to improve their enteral ` absorption.
The concentration of the cardiac glycoside in ` the en-teral preparations according to the present invention - may vary considerably depending on the physical and chemical properties, especially the pharmacological activity of the ~ . .. . , :
` .. : .. . , . : ~ . : .
respective cardiac glycoside Which is used, on its enteral absorbability per se,and on its sensitivity to metabolic decomposition in the gastrointestinal tract and/or the liver, as well as on the amount of absorption enhancing partial glycerides preSent in the preparation and the contemplated mode of administration, the treated condition and the therapy which is desired. Usually a satisfactory enteral activity is obtained with an amount corresponding to between about 1 and about 3 times, preferably about 1 and about 2 times the parenterally-effective amount of the respective cardiac glycosides. For example, enterally-effective amounts of g-strophanthin, k-strophanthin or proscillaridin within the compositions according to the present invention are between about 0.1 and about 0.3~ preferably about 0.2 and ~ 15 0.25 mg per single dosage unit.
`~ Partial glycosides of fatty acids of medium chain length comprise mono- and diglycerides of fatty acids, pre-ferably saturated monocarboxylic acids, having a chain length o preferably between about 6 to about 12, most preferably between about 8 and about 10 carbon atoms, and mixtures ` thereof. Especially suited are mono- and diglycerides of capric- and caprylic acid and mixtures thereof.
The amount of absorption enhancing partial glycer-` ides of fatty acids of medium chain length in the preparation according to the present invention, which is effective to sufficiently enhance the enteral absorption to permit an enteral administration of a cardiac glycoside, may vary considerably depending on the per se enteral absorbability .. .~
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~379~S
of the respective cardiac glycoside, as well as on the chemical and physical properties of any other ingredients of the composition. Typically, satisfactory results are obtain-ed with preparations wherein the amount of partial glycerides of fatty acids of medium chain length are between about 20 and about 10~, preferably about 40 and about 100%, of the vehicle. For example, of oral preparations of cardiac glycosides the per se enteral absorbability of which is less than 5~, e.g., between 0.3 and 5%, such as g-strophanthin, k-strophanthin or proscillaridin, the partial glycerides of fatty acids of medium chain length are preferably used in amounts of about 40 to about 100~ of the total vehicle.
The ratio between the amounts of cardlac glycoside and of absorption enhancing partial glycerides of fatty àcids of medium chain length may vary considerably depending on the per se enteral absorbability of the respective cardiac glycoside, as well as on the chemical and physical properties ' of any other ingredients of the composition. For example, - for enteral preparations of cardiac glycosides having a per se enteral absorbability of less than 5%, e.g., of between 0.3 and 5%, a suitable ratio cardiac glycoside/partial glyceride of fatty acids of medium chain length is of be-` tween about 0.5 to 100 and about 0.01 to 100.
The enteral formulations may take the form of solid or liquid formulations for oral or rectal application.Thus, the formulations may be in the form of capsules, tablets, coated tablets, suppositories or emulsions. These formula-- , tions may comprise conventional pharmaceutical carriers and _9..
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additives, especially viscosity-improving and/or structure-or matrix-forming additives which provide for an appropriate viscosity and physical structure. Suitable suah additives are, e.g., inorganic thickening agents, such as, highly dispersed silicic acid (e.g., the commercial products "Aerosil'~ bentonites, collodial clay, modified montmor-illonites, such as alkyl ammonium salts of montmorillonites (e.g., the commercial products "Bentone")~ wherein the alkyl groups may contain 1 to 20 carbon atoms, e.g., dimethyl-dialkyl ammonium salts wherein the alkyl groups contain 16to 18 carbon atoms, organic thickening and structure-forming agents such as, saturated higher fatty acids and alcohols containing, e.g., 12 to 20 carbon atoms, for example, stearic or palmitic acid, stearic or cetylic alcohol, wax~s like beeswax, synthetic esters of higher fatty acids and higher fatty alcohols, or spermaceti, monoglycerides of saturated or unsaturated higher fatty acids, e.g., mono-glycerides of stearic acid, palmitic acid or oleic acid, partial glycerides of fatty polyhydroxy acids (e.g., the - 20 commercial products "Softigen 701 r. Suppositories may further contain any conventional water soluble or fatty suppository bases as additional vehicles. The compositions may further comprise pharmaceutical adjuvants, e.g., binders or lubricants for tabletting, stabilizing-, flavoring-, or emulsifying agents or preservatives.
Since several cardiac glycosides are sensitive to acids, it may be advisable to apply an enteric coating to the oral dosage forms, e.g., gelatin capsules, of such i ` , ~ '~' . ' , . .
glycerides.
The formulations according to the present inven-tion are prepared in any conventional manner, e.g., by dis-solving the cardiac glycosides in the partial glycerides, optionally adding additional adJuvants, and formulating the resulting mixture into the desired dosage form by known pharmaceutical methods, e.g., tabletting, molding into suppositories or filling into capsules.
Depending on the solubility and/or the dis-solution rate of the cardiac glycosides in the partial glycerides and on the melting point of the partial glycerides, the dissolving may be done at room temperature or under heating. In cases where the cardiac glycosides recrystallize and/or the partial glycerides resolidify upon cooling of such ~ 15 solutions which are obtained under heating, microcrystalline - suspensions and/or solid solutions of the glycosides are formed, which exhibit the same absorption behavior as that of actual solutions of the cardiac glycosides.
` In order to facilitate the filling of the mixture into gelatin capsules or the formulating into suppositories or tablets, it may be advisable to further add viscosity-improving or structure- or matrix-forming additives.
Especially, there may be added highly dispersed silicic acid, modified montmorillonites, monoglycerides of oleic i 25 acid or stearic acid, palmitic acid, stearic acid, cetylic or stearic alcohols, beeswax, spermaceti or a mixture of partial glycerides of an unsaturated fatty acid which is sub-stituted by hydroxy groups (e.g., the commercial products . . . ' . : . . : . . -~ . .
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"Softigen 701").
- The high enteral absorption o~ the formulations according to the present invention is demonstrated by toxicity tests, determination of the level of the respective glycosides in the blood or according to a modified Hatcher method as described by Lenke and Schneider (Arzneimittelfor-schung 19 (1969)/ pages 687-693; ibid 20 (1970)-, pages 1199-1206 and 1765-1770).
For testing the toxicity, solutions of g-strophanthin or proscillaridin in a mixture of mono- and diglycerides of ca~ric and caprylic acids (commercial product of "Witafrol 7420'~ manufacturer Dynamit-Nobel AG) and in water are administered orally to female guinea pigs of 250 to 300 g body weight by means of an oral feeding tube.
15 The following lethal doses are observed: -Test solution LD50 mg/kg g-strophanthin in'Witafrol 7420" ~ 5.2 g-strophanthin in water 34.8 Proscillaridin in~Witafrol 7420" ~ 6.8 20 proscillaridm in water 12.3 For determining the blood level values, 50 ~g!kg of tritiated g-strophanthin in form of solutions in a mixture of mono- and diglycerides of~capric and caprylic acids CF~9 ~commercial product"WL 2391",manufacturer Sa. Gattefosse) and in water are administered to cats intraduodenally. The measured blood level values are plotted on a graph and the area beneath the resulting blood level curves are compared.
From the comparison of the areas, the following percentages ~ Ci ,: ` .` `' ~ . ~ ~
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of absorption are calculated:
g~strophanthin in water - 19%
g-strophanthin in"WL 2391' - 61%
According to the modi~ied Hatcher-method ("fill up"-method) 100 ~g/kg g-strophanthin dissolved in Witafrol 7420 is administered intraduodenally to cats of both sex which are under chloralose-ure~hane narcosis (at this dosage which normally is not lethal, two cats out of thirty-four died already). Four hours later, the active agent is I'filled up" by means of intravenous infusion until perisysto~e occurs. The following statistical average absorption rates of between 60 and 80~ are found dependin~ on the predeter-mined perlod of survival.
..... ~ . . .
Intraduodenal Predetermined Calculated (aver.) Enteral administration period of sur- "fill up" dose of activity vival (min) g-strophanthin %
~g/kg i.v.
g-strophanthin 50 63.9 80.8 "lit ~ufg/okg ~ 100 49.7 60.7 ___________________ ._ _ _________________________ _____________ "Witafrol" 50 144.7 0.1 ml/kg 100 110.4 Due to the high enteral absorption rates of, e.g., ~ up to 80~, which are achieved according to the present inven-.~ tion, a highly secure oral or rectal therapy, e.g., of myocardial insufficiency, with per se poorly ahsorbable cardiac glycosides, which could not be achieved heretofore, is made available.
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~ 7~s ~ The invention will now be further described by the following examples. In these examples, the term "parts"
means "parts by weight" unless stated o~herwise. The amount of a certain cardiac glycoside which is cited in one example can be replacea by the same amount of one of the other two cardiac glycosides which are ci~ed in the examples.
EXA~lPLE 1 Gelatin capsules: ~
Composition of the mixture which is filled into the capsules:
g-strophanthin 0.125 parts mixture of mono- and diglycerides of capric and caprylic acid* 99 875 parts ~ Total 100.000 parts (~
* commercial product'~tL 2391i', manufacturer, Sa. Gattefosse Preparation: g-strophanthin is dissolved in the glyceride mixture at a temperature of 35 to 40C under stirring. The soIu~ion is filled into gelatin capsules in portions of 200 mg per capsule. Each capsule contains 0.25 mg of the active ingredient.
EX~lPLE 2 Gelatin capsules:
Composition of the mixture which is filled into the capsules:
g-strophanthin 0.125 parts mixture of mono- and diglycerides of capric and caprylic acids* 92.375 parts .
' l -14-, : . ' ' '~.: ::: . ': ,: ' :: .
~7g~s highly dispersed silicic acid containing an amount - of C~3 groups equivalent ,- ~o a carbon content of 0.9 - 1.2% ** 7 500 parts Total 100.000 parts * commercial product"WL 239 manufacturer, Sa. Gattfosse ** commercial product"Aerosil R 972", - manufacturer Degussa Preparation: g-strophanthin is dissolved in the glyceride mixture at a temperature of 35 to 40C under ; agitation. Subsequently, the silicic acid is added under , further,agitation. For final homogeniza~ion, the mixture is treated in a colloid mill or a high pressure homogenizer.
'rhe ~lxture is filled into gelatin capsules in portions of 200 mg`per capsule. Each capsule contains 0.25 mg of the ac~ive ingredient.
EXP~PLE 3 ,, Composition of the mixture which is filled into ; 15 the capsules:
k-strophanthin 0.125 parts ; tetraalkyl ammonium salt of magnesium montmorillo-nite** 4.5 parts ; ethanol 2O25 parts mixture of mono- and `~ diglycerides of capric ,~ and caprylic acids*33.125 parts x, 20 Total 100.000 parts .-. ~) `~ * commercial product"WL 2391", manufacturer, Sa. Gattefosse L~
** commercial product of"Bentone 27"'' - manufacturer, Kronos Titan ~`, .
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Preparation: the modified montmorillonite is added to about half the amount of the glyceride mixture and by means of a high speed agitator of the type Rotor/Stator.
It is first dispersed therein and then subsequent to the addition of the ethanol, it is solubilized whereby a viscid gel i~ formed. The k-strophanthin is dissolved in the remaining amount of the glyceride mixture and the resulting' solution is added to the previously prepared gel portion under agitation. Agitation is continued until a uniform consistency of the mixture is achieved. The mixture is filled into gelatin capsules in portion~ of 200 mg each.
Each capsule contains 0.25 mg of active ingredient.
Composition of the mixture which is filled into ., the capsules:
proscillaridin 0~1 parts mixture of partial glycerides of an unsaturated fatty acid rich in hydroxy groups** 50.0 parts mixture of mono-and di-glycerides of capric ' and caprylic acids* 49 9 parts Total 100.0 parts *commercial product"WL 2391' manufacturer, Sa. Gattefosse ., ' ,~
**commercial product"Softigen 701'.
manufacturer, Dynamit-Nobel AG.
Preparation: proscillaridin is dissolved in the mixture o~ mono- and diglycerides of capric and caprylic acids at a temperature of about 35 to 40~C unde'r agitation.
The mixture of partial glycerides of the hydroxylated fatty , . ., . . .,.. ., ,............ ~ ~ .. . .
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~79~35 acid is liquified at a tempexature of 40C and ls added to the above solution. The resulting mixture is cooled to room temperature under agitation. Portions of 200 mg each of the mixture are filled into gelatin capsules. Each capsule contains 0.2 mg of active ingredient.
EXAMP~E S
Composition of the mixture which is filled into the capsules:
g-strophanthin 0.125 parts ~-; 10 oleic acid monoglyceride 40.0 parts mixture of mono- and diglycerides of capric and caprylic acid*59.875 parts Total 100.000 parts ^~ * commercial product"WL 239~',3 manufacturer, Sa. Gat'efosse Preparation: g-strophanthin is dissolved in ~he mixture of mono- and diglycerides of capric and caprylic - acid at a temperature of about 35 to 40C under agitation.
The oleic acid monoglyceride is liquified at a temperature of 50~C and added to the above mixture, which is then allowed to cool at room temperature under agitation. Portions of 200 mg each of the mixture are filled into gelatin capsules. Each capsule contains 0.2 mg of active ingredient.
i' EXAMPLE 6 ,- Composition of the mixture which is filled into the capsules:
g-strophanthin 0.125 parts oleic acid monoglyceride 40.0 parts .
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- I mixture o~ mono-and diglycerides of capric and caprylic acid*59 875 parts ~otal 100.000 parts .~ 1 *commercial produc~"Witafrol 7420"`' manufacturer, Dynamit-Nobel AG
Preparation: g-strophanthin is dissolved in the mixture of mono- and diglycerides of capric and caprylic acid at a temperature of about 35 to 40C under agitation.
The oleic acid monoglyceride is liquified at a temperature of 50C and added to the above mixture, which is then allowed to cool to room temperature under agitationO Portions,of 200 mg each of the mixture are filled into gelatin capsulas which subsequently are coated with an enteric coating. Each , capsule~,contains 0.25 mg of active ingredient.
ExAMæLE 7 Composition of the mixture which is filled into the capsules:
k-strophanthin 0.125 parts capric acid monoglyceride 17.5 parts mixture o~ mono- and diglyceridés of capric and caprylic acid*82.375 parts Total 100.0 parts , 20 *commercial product"Witafrol 7420'~
- manu~acturer, Dynami~-Nobel AG
Preparation: k-strophanthin is dissolved in the mixture of mono- and diglycer,ides of capric and caprylic acid at a temperature of about 35 to 40C under agitation.
~he capric acid monoglyceride is melted at a temperature of 60C and added to the above mixture, which is then allowed ` -18-. I
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to cool to room temperature under agitation. Portions of 200 mg each of the mixture are filled into gelatin capsules, which subsequently are coated with an enteric coating. Each capsule contains 0.25 mg of active ingredient.
Composition of ~he mix~ure which is filled into the capsules:
proscillaridin 0.1 parts stearic acid monoglyceride 5.0 parts mixture of mono and ~diglycerides of capric and caprylic acid* 94.9 parts ___________ Total 100.0 parts ,, 5~
*commercial product"Witafrol 7420', manufacturer, Dynamit-NObel AG
; Preparation: proscillaridin is dissolved in the mixture of mono- and diglycerides of capric and caprylic ` 15 acid at a temperature of about 35 to 40C under agitation.
The stearic acid monoglyceride is melted at a temperature of 70C and added to the above mixture, which is then allowed to cool to room temperature under agitation. Portions of 200 mg each of the mixture are filled into gelatin capsules.
; 20 Each capsule contains 0.2 mg of active ingredient.
Composition of the mixture which is filled into ~he capsules:
Proscillaridin 0.02 parts mixture of partial glycerides of an unsaturated fatty acid rich in hydroxy groups ** 50.0 parts ' -19-~ ~.
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37~5 ' . . ' mixture of mono- and diglycerides of capric and caprylic acids* 49 98 parts Total 100.00 parts * commercial product"Witafrol 7420",'' ; manufacturer, Dynamit-Nobel AG
(i~3 ** commercial product"Softigen 701'~' manufacturer, Dynamit-Nobel AG.
Preparation: proscLllaridin is dissolved in the mixture of mono- and diglycerides of capric and caprylic acid at a temperature of about 35 to 40C under agitation.
The mixture of partial glycerides of the hydroxylated fatty acid is liquified at a temp~rature of 40C and is added to the above so}ution. The resulting mixture is cooled to room temperature under agitation. Portions of l g each of the mixture are filled into gelatin capsules for rectal application. Each capsule contains 0.2 mg of active ingre-dient.
EXAMPLE lO
Gelatin capsules for rectal application.
Composition of the mixture which is filled into ` ~he capsules:
g-strophanthin 0.025 parts 20 mixture of mono- and diglycerides of capric and caprylic acids* 92.475 parts highly dispersed silicic acid containing an amount of CH3 groups equivalent to a carbon content of 0.9 - 1~2~i ** ` 7 500 parts Total 100-000R arts * commercial product"Witafrol 7420", manufacturer, Dynamit-Nobel AG
' -20-.. . .
** commercial product"Aerosil R 972', manufacturer Degussa Preparation: g-strophanthin is dissolved in the glycerides at a temperature of 35 to 40C under agitation.
Subsequently, the silicic acid is added under ~urther agitation. For the final homogenization o$ the mixture is treated in a colloid mill or a high pressure homogenizer.
The mixture is filled into gelatin capsul s for rectal application in portions of lg per capsule. Each capsule contains 0.25 mg of the active ingredient.
Suppositories Composition:
k-strophanthin O.Ol parts ~.
caprylic acid monoglyceride 99,99 parts Total 100.00 parts Pxeparation: the caprylic acid monoglyceride (melting point 35-37C, purity 90~, remainder caprylic acid, diglyceride,and triglyceride and glycerine) is liquified at ; a temperature of 45C and the k-s~rophanthin is dissolved in the molten product under agitation. The molten mixture is filled into suppository molds wherein it solidifies.
Each suppasitory weighs 2.5 g and contains 0.25 mg of k-strophanthin.
EXA~LE 12 : 25 Suppositories Composition:
g-strophanthin 0.01 parts .
~ C~
. .. .
, ' ' 379l~5 caprylic acid monoglyceride ~purity 40~)** 33.0 parts suppository base*** 66.99 parts Total 100.00 parts ** commercial product"Drewmulse GMC-8"3 manufacturex PVO International, Inc.
*** commercial product"Novata C"
manufacturer, Henkel ~G
Preparation: g-strophanthin is dissolved in the caprylic acid monoglyceride at a temperature of 50C under agitation. The suppository base Novata C is also melted ; and added to the above mixture under agitation. ~he mixture is filled into suppository molds wherein it solidifies.
Each suppository weighs 2.5 g and contains 0.25 mg of g-strophanthin.
... ..
; EXAMPLE 13 One capsule which is prepared according to Example 1 is administered orally once a day to an adult person for cardiotonic therapy.
While the invention has now been described in terms of various preferred embodiment, the skilled artisan will readily appreciate that various substitutions, modi-fications, changes, and omissions may be made withoutdeparting ~rom the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by that of the following claims.
: ~ .:
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Claims (30)
1. A readily enterally absorbable pharmaceutical composition which comprises a therapeutically-effective amount of at least one poorly enterally absorbable cardiac glycoside distributed in a vehicle comprising an enteral absorption-enhancing amount of at least one partial glyceride of a fatty acid of medium chain length containing from 6 to 12 carbon atoms.
2. The composition as defined in Claim 1, which comprises a solution of the cardiac glycoside in the partial glyceride.
3. The composition as defined in Claim 2, wherein the solution is a genuine solution.
4. The composition as defined in Claim 2, wherein the solution is a solid solution.
5. The composition as defined in Claim 1, which comprises a microcrystalline suspension of the cardiac glycoside in the partial glyceride.
6. The composition as defined in Claim 1, wherein the cardiac glycoside is a cardiac glycoside having a per se enteral absorbability of between about 0.3 and about 5%.
7. The composition as defined in Claim 1, wherein the cardiac glycoside is selected from the group consisting of g-strophanthin,k-strophanthin and proscillaridin.
8. The composition as defined in Claim 1, wherein the amount of the cardiac glycoside per single dosage unit is about 1 to about 2 times the parenterally-effective amount of the respective cardiac glycoside.
9. The composition as defined in Claim 8, wherein the amount of the cardiac glycoside per single dosage unit is between about 0.1 and 0.3 mg.
10. The composition as defined in Claim 1, wherein the fatty acids contain 8 to 10 carbon atoms.
11. The composition as defined in Claim 1, which comprises partial glycerides of fatty acids of medium chain length selected from the group consisting of monoglycerides, diglycerides and mixtures thereof.
12. The composition as defined in Claim 11, which comprises a mixture of mono- and diglycerides of capric and caprylic acids.
13. The composition as defined in Claim 1, wherein the amount of partial glycerides of fatty acids of medium chain length is between about 20 and about 100%
by weight of the vehicle.
by weight of the vehicle.
14. The composition as defined in Claim 13, wherein the amount of the partial glycerides of fatty acids of medium chain length is from about 40 to about 100% by weight of the vehicle.
15. The composition as defined in Claim 1, wherein the per weight ratio cardiac glycoside/partial glyceride of fatty acids of medium chain length is of between about 0.5 to 100 and 0.01 to 100.
16. The composition as defined in Claim 1, which further comprises pharmaceutical additives having viscosity-improving or structurizing properties.
17. The composition as defined in Claim 16, wherein the additives are selected from the group consisting of highly dispersed silicic acid, modified montmorillonites, oleic acid monoglyceride, stearic acid monoglyceride, palmitic acid, stearic acid, cetylic alcohol, stearylic alcohol, beeswax, spermaceti, and a mixture of partial glycerides of an unsaturated hydroxy substituted fatty acid.
18. The composition as defined in Claim 1, which is contained in a gelatin capsule.
19. The composition as defined in Claim 18, wherein the gelatin capsule is provided with an enteric coating.
20. The composition as defined in Claim 1, which is formed into suppositories.
21. A process for preparing the readily enterally absorbable pharmaceutical composition as defined in Claim 1, which comprises the step of dissolving at least one poorly enterally absorbable cardiac glycoside in at least one partial glyceride of a fatty acid of medium chain length containing from 6 to 12 carbon atoms.
22. The process as defined in Claim 21, wherein the dissolving step is effected under heating.
23. The process as defined in Claim 21, wherein the fatty acids contain 8 to l0 carbon atoms.
24. The process as defined in Claim 21, wherein the partial glycerides of fatty acids of medium chain length are selected from the group consisting of monoglycerides, diglycerides and mixtures thereof.
25. The process as defined in Claim 21, which further comprises the step of adding pharmaceutical additives which exhibilt viscosity-improving or structur-izing properties.
26. The process as defined in Claim 25, wherein the additives are selected from the group consisting of highly dispersed silicic acid, modified montmorillonites, oleic acid monoglyceride, stearic acid monoglyceride, palmitic acid, stearic acid, cetylic alcohol, stearylic alcohol, beeswax, spermaceti, and a mixture of partial glycerides of an unsaturated hydroxy substituted fatty acid.
27. The process as defined in Claim 21, which further comprises the step of filling the composition into gelatin capsules.
28. The process as defined in Claim 27, which further comprises the step of applying an enteric coating to the gelatin capsule.
29. The process as defined in Claim 21, which further comprises formulating the composition into supposi-tories.
30. The process as defined in Claim 23, wherein the cardiac glycoside is a cardiac glycoside having a per se enteral absorbability of between about 0.3 and about 5%.
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762631281 DE2631281A1 (en) | 1976-07-12 | 1976-07-12 | Increasing solubility of pharmaceuticals for use in gelatin capsules - by dissolving in fatty acid mono:glyceride and opt. di:glyceride cpds. |
| DEP2631281.2 | 1976-07-12 | ||
| DEP2652508.6 | 1976-11-18 | ||
| DE19762652508 DE2652508A1 (en) | 1976-11-18 | 1976-11-18 | Cardiac glycoside compsns. with good enteric resorption - with the glycoside dissolved or suspended in (mixed) fatty acid partial glycerides |
| DEP2654386.2 | 1976-12-01 | ||
| DE19762654386 DE2654386A1 (en) | 1976-12-01 | 1976-12-01 | Cardiac glycoside compsns. with good enteric resorption - with the glycoside dissolved or suspended in (mixed) fatty acid partial glycerides |
| DEP2654844.7 | 1976-12-03 | ||
| DE19762654844 DE2654844A1 (en) | 1976-12-03 | 1976-12-03 | Cardiac glycoside compsns. with good enteric resorption - with the glycoside dissolved or suspended in (mixed) fatty acid partial glycerides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1087985A true CA1087985A (en) | 1980-10-21 |
Family
ID=27432128
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA282,536A Expired CA1087985A (en) | 1976-07-12 | 1977-07-12 | Readily enterally absorbable pharmaceutical compositions of cardiac glycosides and preparation thereof |
Country Status (5)
| Country | Link |
|---|---|
| CA (1) | CA1087985A (en) |
| GB (1) | GB1544576A (en) |
| IE (1) | IE45448B1 (en) |
| IL (1) | IL52472A (en) |
| NZ (1) | NZ184612A (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR880012221A (en) * | 1987-04-13 | 1988-11-26 | 사노 가즈오 | Pharmaceutical compositions containing esters or amides as active ingredients |
| ITMI20070084A1 (en) * | 2007-01-22 | 2008-07-23 | Carlo Ghisalberti | LIPID BASED VAGINAL ANTISEPTIC DEVICES |
-
1977
- 1977-07-04 IE IE137977A patent/IE45448B1/en unknown
- 1977-07-04 GB GB2798577A patent/GB1544576A/en not_active Expired
- 1977-07-06 IL IL5247277A patent/IL52472A/en unknown
- 1977-07-11 NZ NZ18461277A patent/NZ184612A/en unknown
- 1977-07-12 CA CA282,536A patent/CA1087985A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| NZ184612A (en) | 1978-12-18 |
| IE45448B1 (en) | 1982-08-25 |
| IE45448L (en) | 1978-01-12 |
| GB1544576A (en) | 1979-04-19 |
| IL52472A (en) | 1980-11-30 |
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