KR810000901B1 - Process for preparing compositions of cardiac glycosides - Google Patents

Abstract

New base for medicaments for external application contains mono- or diglycerides of medium-chain (pref. 6-12 C) fatty acids or mixts. of such mono- or diglycerides. Pref. compds. contain structure-imparting fillers e.g. highly dispersed silicic acid, organically modified montmorillonite, cetyl-stearyl alcohol benzylidene-sorbitol or 'Antisettle cvp (RTM). The presence of mono- or diglycerides of medium-chain fatty acids considerably increases the percutaneous penetration or absorption of medicaments.

Description

Preparation method of cardiac glycoside

TECHNICAL FIELD This invention relates to the preparation method of the composition which can absorb cardiac glycoside by the intestinal absorption of cardiac glycoside by itself.

Cardiac glycosides have been used therapeutically for the treatment of cardiac insufficiency due to the effects on the structure of the heart muscle. Cardiac glycosides have been administered to the intestine. In other words, it utilizes the adjustable bioavailability of the active substance. Therefore, many attempts have been made to make cardiac glycosides available for enteral administration.

Chemical modifications of glycosides have had some success, for example in the case of digitoxins or digoxin, which can be absorbed into the intestine completely or in an acceptable range. However, other cardiac glycosides, such as g- and k-stropantin or prosilaridine, should be administered parenterally, i.e., intravenously because they are not sufficiently absorbed when administered intestinal.

Accordingly, the present invention provides a method for preparing the composition by providing a cardiac glycoside in the absorbable intestinal composition of cardiac glycoside alone is difficult to absorb. The term cardiac glycoside ＂, which is difficult to absorb by itself alone, refers to g- and k-stropantin and prosilaridine, as well as other cardiac glycosides which require improvement in intestinal absorption.

One form of the invention provides an absorbable composition in the gut containing at least one kind of cardiac glycosides which cardiac glycosides alone are difficult to absorb, wherein the composition comprises one or more partial glycerides of fatty acids having 6-12 carbon atoms or It consisted of a solution or microcrystalline suspension of cardiac glycosides in a mixture of this partial glycerides.

Another form of the present invention comprises enteric containing cardiac glycosides comprising at least one cardiac glycoside which is difficult to absorb on its own by dissolving cardiac glycosides in one or more partial glycerides of fatty acids having 6-12 carbon atoms or mixtures of these partial glycerides. It provides a method for producing a composition that can be absorbed.

It has already been proposed to dissolve or suspend medicaments in the glycerides of medium chain fatty acids to improve absorption. For example, according to German Patent 1,282,853 chloramphenicol is suspended in triglycerides of medium chain fatty acids. Belgian Kingdom patent 567,598 describes the suspension of antibiotics in triglycerides and British Patent 1,432,784 describes solutions or suspensions of various agents in monoglycerides and German Publication 2,357,389 discloses a mixture of triglycerides and partial glycerides. The solutions or suspensions of the same agents are described.

However, although the improvement of absorption has been described in the above-mentioned known patents, such improvement is so small that dissolution or suspension of cardiac glycosides in partial glycerides of medium-chain fatty acids has not been expected to yield useful results. In the case of cardiac glycosides, a small therapeutic range of the active substance associated with a large personal occupancy in the absorption should be considered. Due to a small therapeutic range, the administration of slightly lower doses may not have any effect on the nature of the active substance, and administration of slightly higher doses may result in a disruption of cardiac function. In other words, dosages that have no effect in one individual result in death in another. For example, there are various problems in which intestinal administration cannot be performed because there is an individual difference of 0.46% to 4.4% of G-stropan, that is, a difference in absorption amount of factor 10. While there is a large individual difference in the absorption of cardiac glycosides, which are difficult to absorb by themselves, attempts to improve the absorption of other drugs by using glycerides have been extremely poor, whereas the results of the absorption of cardiac glycosides that are difficult to absorb from the composition of the present invention. Improvements are unexpected and have not been suggested in the prior art.

Partial glycerides of the medium chain fatty acids that can be used in the compositions and methods of the present invention are mono- and di-glycerides of fatty acids having chains of 6-12 especially 8-10 carbon atoms as described above.

Depending on the nature of oral or rectal administration, the composition may be in a form suitable for the desired administration. For forms such as tablets, gelatin capsules or suppositories, for example, modified santillonylite sold under the trademark “aerosil” under the trademark “Betone” under the trademark “Betone”. ), Oleic acid monoglyceride, stearic acid monoglyceride, palmitic acid, stearic acid, cetyl and stearyl alcohol, and commercially available trademarks of Softigen 701 containing high levels of lead, spermaceti and hydroxyl. Additives that provide a viscosity change or structure, such as a partial glyceride mixture of saturated fatty acids, such as may be added to the composition. Many Cardiac glycosides are acid sensitive, so forms for oral administration, such as gelatin capsules, are suitably coated with a gastrointestinal resistant coating.

The composition preparation of the present invention can be effectively achieved by dissolving cardiac glycosides in partial glycerides. Dissolution may occur by heating depending on the solubility and dissolution rate of cardiac glycosides in the partial glycerides at the melting point of the partial glycerides. If cardiac glycosides crystallize during cooling of the composition produced by heating or if the partial glycerides solidify, microcrystalline suspensions or solid solutions are formed that act as true solutions when absorbed.

The above-mentioned viscosity-change or structure-imparting additives may be added to the composition to improve the filling in the gelatine capsules of the composition and to make the composition into suppositories or tablets.

The high intestinal absorption of the compositions of the present invention is characterized by toxicity studies, blood level measurements and modified Hatcher processes (Lenke and Shneider, Arzneimittelforschung) (1991), 19 (1968), pages 687-693; 20 (1970), pages 1199-1206; 20 (1970) pages 1765-1770).

In the toxicity studies, g-stropantin and prosilaridine dissolved in water and in mono-glyceride mixtures of capric acid and caprylic acid (available under the witafrol trademark from Dynamit-Nobel) The device of the coronal corpuscle is administered orally in females of 250-300 g body weight.

The following gears were observed:

In the blood-level measurement, g-stropantin, expressed as tritium, dissolved in water and a dose of 50 μg / kg in a monoglyceride mixture of capric acid and caprylic acid (commercially available from Gatefoss as WL2391), the duodenum in cats Administered into. The measured blood-level values were recorded graphically and the ranges were compared under the blood-level curve. From the comparison of the ranges, the following absorption rates were obtained.

19% g-stropantin in water

G-stropantin 61% in WL 2391

Modified Hacher method Filling-up method: 100 µg / kg g-stropantin dissolved in 7420 in witwipe (7420) with chloral-urethane anesthetic (34 non-lethal doses) Two cats died, and the cat was positively administered to the duodenum.

After 4 hours, filling up is promoted by intravenous infusion until cardiac function is inhibited. Depending on survival time, mean statistical absorptions of 60-80% were obtained.

As the amount of absorption of 80% or more that can be achieved as the composition of the present invention, it is possible to obtain oral and rectal effects with high accuracy, which could not be obtained by Cardiac glycoside which is difficult to be absorbed by itself until now.

The following examples are provided to illustrate the present invention. Parts referred to in the examples are parts by weight unless otherwise indicated.

The amount mentioned for a particular cardiac glycoside in the examples may be replaced by one of the same amount of the other two cardiac glycosides mentioned in the examples.

The following items are described in more detail the above-described methods for preparing a glycoside compound (known method), problems of known formulation methods, and special advantages of the present invention compared to known methods.

1) Formulation method (known method) of glycoside compound prior to the present application Cardiac glycoside by itself medium chain of cardiac glycoside for the purpose of improving absorption in order to enable the intestinal absorption of cardiac glycoside which is difficult to enteral absorption The dissolution or suspension of meaium chain fatty acids in glycerides has already been proposed.

For example, according to German patent 1,282,853, chloram phenicol is suspended in triglycerides of medium chain fatty acids. Belgian Kingdom patent 567,598 describes the suspension of antibiotics in triglycerides, while British Patent 1,432,784 describes solutions or suspensions of several agents in monoglycerides and German Publication 2,357,389 describes mixtures of triglycerides and partial glycerides. The solution or suspension of the same agents in the same is described.

2) Problems of Known Formulation Methods

Although specific aspects of absorption improvement have been described in the above-mentioned known patent specification, such improvement is so small that dissolution or suspension of cardiac glycosides in partial glycerides of medium-chain fatty acids could not be expected to yield useful results. In the case of cardiac glycosides, the small therapeutic range of the active substance associated with large individual differences in uptake should be considered. Due to a small therapeutic range, administration of slightly lower doses may not have any effect on the nature of the active substance, and administration of slightly higher doses may result in disruption of cardiac function. In other words, dosages that have no effect in one individual result in death in another. For example, there are various problems in which intestinal administration cannot be performed because there is an individual difference of 0.46% to 4.4% for G-stropantin, that is, a difference in absorption of factor 10.

3) Known methods and features of the present application

The known method shows a large personal difference in the absorption of cardiac glycosides, which is difficult to absorb itself, and attempts to improve the absorption of other drugs by using glycerides, and the result is slight, whereas cardiac glycosides that are difficult to absorb from the composition of the present invention. The improvement of the absorption of N is unexpected and has not been suggested in the prior art.

Partial glycerides of the medium chain fatty acids that can be used in the compositions and methods of the invention are mono and diglycerides of fatty acids having chains of 6-12 especially 8-10 carbon atoms as described above. With 80% or more of the amount of absorption that can be achieved as the composition of the present invention, the oral and rectal effects can be obtained with high accuracy, which could not be obtained by Cardiac glycoside, which has been difficult to absorb by itself until now.

Example 1

The mixture to be filled in a gelatin capsule has the following composition.

The mixture is prepared by dissolving g-stropantin in caprylic acid / capric acid mono- and diglycerides with stirring at a temperature of 35-40 ° C. This solution is filled into a gelatin capsule containing 200 mg of the mixture in each capsule and 0.25 mg of the active ingredient in each capsule.

Example 2

Gelatin capsules

The mixture to be filled in a gelatin capsule has the following composition.

The mixture is prepared by dissolving g-stropantin in carlylic / capric acid mono- and diglycerides under stirring at a temperature of 35-40 ° C. and then adding the aerosils with stirring and then adding the mixture, eg Homogenize well using a colloid mill or high-pressure homogeniser. This mixture is filled into gelatin capsules containing 200 mg of mixture per capsule and 0.25 mg of active substance.

Example 3

Gelatin capsules

The mixture to be filled in the gelatin cap-schule has the following composition.

Using a high speed stirrer in the form of a rotor / stator disperses the benbenton in about half of the above-mentioned amount of the partial glyceride mixture and then adds ethanol to form a viscous gel. K-stropantin is dissolved in the remaining amount of the partial glyceride mixture and the solution is added in small portions with stirring to the gel prepared above and stirring is continued until a homogeneous composition is achieved. In each case 200 mg of the mixture is filled in a gelatin capsule and 0.25 mg of the active ingredient is contained in each capsule.

Example 4

Gelatin capsules

The mixture to be filled in a gelatin capsule has the following composition.

Prosilaridine is dissolved in a mono- and di-glyceride mixture by stirring at a temperature of 35-40 ° C., followed by the addition of the liquidized C. thorifogen® at 40 ° C. and allowed to stand at room temperature with stirring. In each case 200 mg of the mixture is filled in a gelatin capsule and 0.2 mg of active substance is contained in each capsule.

Example 5

Gelatin capsules

The mixture to be filled in a gelatin capsule has the following composition.

While stirring, g-stropantin was dissolved in caprylic acid / capric acid mono- and di-glycoside at a temperature of 35-40 ° C., followed by stirring to bring to room temperature by the addition of ureaic acid monoglyceride liquefied at 50 ° C. It is left to prepare a mixture. In each case 200 mg of the mixture is filled in a gelatin capsule and 0.25 mg of active substance is contained in each capsule.

Example 6

Gelatin capsules

The mixture to be filled in a gelatin capsule has the following composition.

The mixture is prepared by dissolving g-stropantin in Muwitaprolol 7420 with stirring at a temperature of 30-40 ° C. and then adding liquefied oleic acid monoglyceride at 50 ° C. and leaving it to room temperature with stirring. In each case, 200 mg of the mixture was filled into a gelatin capsule to make it resistant to gastric juice so that 0.25 mg of active material was contained in each capsule.

Example 7

Gelatin capsules

The mixture to be filled in a gelatin capsule has the following composition.

K-stropantinol was dissolved with stirring in Uwitaprolol 7420 at a temperature of 35-40 ° C., followed by addition of capric acid monoglyceride, melting at 60 ° C., and allowed to stand at room temperature with stirring to prepare a mixture. In each case, 200 mg of the mixture is filled into a gelatin capsule to be resistant to gastric juice and each capsule contains 0.25 mg of active substance.

Example 8

Gelatin capsules

The mixture to be filled in a gelatin capsule has the following composition.

Prosilaridine is dissolved under stirring at M-witaprolol 7420 at a temperature of 35-40 ° C., followed by the addition of molten glycerol monostearate at 70 ° C. and left to cool to room temperature with stirring to prepare a mixture. In each case 200 mg of the mixture was filled in a gelatin capsule and 0.2 mg of active substance was contained in each capsule.

Example 9

Rectal capsule

The mixture to be filled into a gelatin capsule for rectal administration has the following composition.

Prosilaridine was dissolved under 35-40 ° C. in stirring with Wittaprolol 7420, followed by the addition of the liquidized C. Sofkingen 701 at 40 ° C. and left to stir to room temperature with stirring to prepare a mixture. In each case 1 g of the mixture was filled into a gelatin capsule for rectal administration so that 0.2 mg of active substance was contained in each rectal capsule.

Example 10

Rectal capsule

The mixture to be filled in a gelatin capsule for rectal administration has the following composition.

The g-stropantin is dissolved in caprylic / capric acid mono- and diglycerides under a temperature of 35-40 ° C. with stirring, followed by the addition of “aerosil” with stirring and then the mixture, e.g. The mixture is prepared by homogenizing well in the cabin. In each case 1 g of the mixture is filled in a gelatin capsule for rectal tours and 0.25 mg of active substance is contained in each rectal capsule.

Example 11

Suppository

The mixture to be made suppositories has the following composition.

Caprylic acid monoglycerides (melting point 35-37 ° C., purity 90%, rest caprylic acid multi- and tri-glycerides and glycerol) are liquefied at 45 ° C. and then K-stropantin is dissolved in the melt with stirring. It is then solidified by pouring into the suppository mold. Each suppository is 2.5 g in weight and contains 0.25 mg of K-stropantin.

Example 12

Suppository

The suppository preparation mixture has the following composition.

G-stropantin was dissolved in caprylic acid monoglyceride (manufactured by PVO International Co., Ltd.) with stirring at 50 ° C, and then the suppository composition Junnovata C (manufactured by Henkel) was similarly dissolved and stirred in the mixture. Add.

The composition is poured into suppository molds and then solidified. Each suppository is 2.5 g in weight and contains 0.25 mg of g-stropantin.

Claims (1)

Cardiac glycosides by dissolving cardiac glycoside compounds selected from g-stropantin, K-stropantin, prosilaridine groups in at least one mono- or diglyceride of fatty carbonic acid having 6-12 carbon atoms or mixtures thereof Solution or microcrystalline suspension of microsilica, modified montmorillonite, oleic acid monoglyceride, stearic acid monoglyceride, palmitic acid, stearic acid, cetyl alcohol, stearyl alcohol, beeswax, spermatozoon, hydroxyl group By selectively adding water or mixtures thereof in the glycerides of the portion of the saturated fatty acid, including the saturated fatty acid, to formulate the resulting solution or suspension into a form suitable for administration, such as tablets, suppositories or capsules, which are resistant to gastric juice. Cardiac Glyceride with Intestinal Absorption How formulation.