GB1600639A - Medicament preparation having resorption properties and method of producing the same - Google Patents

Description

(54) MEDICAMENT PREPARATION HAVING IMPROVED RESORPTION PROPERTIES AND METHOD OF PRODUCING THE SAME (71) We, KALI-CHEMIE PHARMA GmbH, a body corporate organised under the laws of the German Federal Republic, of Hans-Böckler-Allee 20 D-3000 Hannover, German Federal Republic, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a pharmaceutical preparation having improved resorption properties, and also to a method of producing such a preparation.

It is known that when are administered orally, rectally, or percutaneously numerous pharmaceuticals require substantially higher doses than when they are injected, thus indicating reduced resorption with these forms of administration.

There is therefore a need to obtain for oral, rectal, or percutaneous administration similar resorption rates to those obtaining in the case of parenteral administration.

Various methods, such as micronisation, solubilisation and formation of complexes, have therefore been used for a long time for the purpose of raising the resorption rate of difficultly resorbable substances. These methods nevertheless have disadvantages. Thus, for example, special apparatus or special process steps are necessary or the nature and amount of additives are greatly restricted for reasons of safety. The number of active substances available for such methods may also be very limited.

Glycerides of fatty acids of medium chain lengths of from 6 to 12 carbon atoms have recently also been recommended as vehicles for pharmaceutically active substances. The range of active substances available is, however, very greatly restricted by solubility criteria when triglycerides are used as the vehicle. In particular, difficulties often arise in the utilisation of glycerides when basic active substances have to be used, since in the form of their bases these have only inadequate stability while in the form of their salts they have insufficient solubility.

According to one aspect of the present invention there is provided a pharmaceutical preparation having improved resorption properties, comprising (a) as its active pharmaceutical substance a cardiac glycoside, a steroid hormone, an antibiotic, a spasmolytic, a coronary therapeutic agent, an anti-phlogistic agent, a sympathomimetic agent, a tranquilliser or a local anaesthetic, the active pharmaceutical substance being in the form of a free base or in the form of a salt of a base with a pharmacologically acceptable acid, and (b) at least one fatty acid of medium chain length containing from 6 to 12 carbon atoms.

It has been found that the aforesaid fatty acids of medium chain length have a surprisingly good solvent power for many medicaments and pharmaceuticals which are in the form of a free base or in the form of a salt of a base with a pharmacologically acceptable acid. Solution in fatty acids of medium chain length of the pharmaceuticals effects their lipophilization so that they are then more readily resorbable by the mucous membranes of the intestines. The consequent improvement of resorption is further intensified because fatty acids of medium chain length pass into the main blood circulation not by way of the lymph tracks like long chain acids, but directly through the portal vein. Thus the active substances can also pass more quickly and with lower losses to the site of their activity.

The fatty acids of medium chain length may naturally be used either singly or in the form of mixtures thereof in any proportions.

In some cases it may also be desirable to add fatty acids of a chain length of from 12 to 18 carbon atoms, in order for example to adjust the preparation to a desired consistency or a desired melting range.

One embodiment of the present preparation includes one or more glycerides in addition to the active substance and fatty acid of medium chain length. In this way the dissolving power of the fatty acid, which is very good, can in some cases be still further increased, particularly when partial glycerides are used. The term "partial glycerides" is to be understood as meaning mono- and/or diglycerides in which the fatty acid radicals have chain lengths of from 6 to 18 carbon atoms and which may be of either a saturated or an unsaturated character. Preferred acid radicals for the glycerides include capric acid, caprylic acid, stearic acid, palmitic acid and oleic acid. There do not appear to be any limiting parameters in respect of the proportions of the glycerides with one another or of the glycerides with fatty acid in the mixtures thereof. The selection of the mixture ratio may therefore be determined in the individual case, for example by the selection and concentration of the active substance, specification of the form of application, or the commercial availability of the fatty acid or fatty acid mixtures or glycerides or glyceride mixtures.

A wide range of active substances may be used in the present preparation.

Thus the active substance is a cardiac glycoside, a steroid hormone, an antibiotic, a spasmolytic, a coronary therapeutic agent, an antiphiogistic agent, a sympathomimetric agent, a tranquiliser, or a local anaesthetic. Examples of such active substances include valethamate bromide, bencyclane base, dipyridamol, indomethacin, synephrine, diazepam, tranquiliser KC 1956 which is 7 - chloro - 1 methyl - 2 - (hydroxymethyl) - 5 - (2' - chlorophenyl) - 1 - H - 2,2 - dihydro 1,4 - benzodiazepine, and procaine. Basic active substances may be used either in the form of the free base or in the form of a salt with a pharmacologically acceptable acid, preferably a fatty acid containing from 6 to 18 or more preferably from 6 to 12 carbon atoms.

In the case where the active substance is a basic active substance, a particularly preferred embodiment comprises using substantially only sufficient fatty acid to form a fatty acid salt, and dissolving this salt in one or more glycerides, preferably partial glycerides. In this case the fatty acid in the preparation serves to form a fatty acid salt of the basic active substance.

According to another aspect of the present invention there is provided a method of producing a pharmaceutical preparation having improved resorption properties, wherein at least one active pharmaceutical substance is dissolved in a fatty acid of medium chain length containing 6 to 12 carbon atoms, the active pharmaceutical substance being in the form of a free base or in the form of a salt of a base with a pharmacologically acceptable acid and being a cardiac glycoside, a steroid hormone, an antibiotic, a spasmolytic, a coronary therapeutic agent, an anti-phlogistic agent, a sympathomimetic agent, a tranquiliser or a local anaesthetic. As a basic active substance is used, it is not necessary for the fatty acid salt to be produced separately, but in a preferred embodiment the procedure may corhprise dissolving the free base in a mixture of fatty acid and additives such as for example glycerides, preferably partial glycerides.

Preparations produced by this method may be worked up in conventional manner, optionally after the addition of longer-chain fatty acids or glycerides, either directly or after the addition of customary adjuvants, into forms suitable for oral, rectal, or percutaneous administration. Depending upon the type of administration-oral, rectal, or percutaneous-it is advantageous to bring the preparation into a form suitable for the purpose in question. For such forms, such as for example tablets, gelatine capsules, suppositories, or ointments, additives for varying the viscosity or providing structure, such as for example finely-divided silica such as that sold under the registered Trade Mark ("Aerosil"), modified montmorillonites such as that sold under the registered Trade Mark ("Bentone"), cetyl and stearyl alcohols, beeswax, spermaceti, or a partial glyceride mixture of an unsaturated fatty acid rich in hydroxyl groups such as that sold under the registered Trade Mark ("Softigen" 701) may be added to the preparation. In order to protect active substances sensitive to acids it may be advantageous to provide forms for oral administration with a coating capable of temporarily resisting the action of gastric juices.

Confirmation of the high enteral resorption of the present preparations was made by means of blood level measurements and determination of renal secretion.

In the blood level tests, the bio-availability of the tranquilliser KC 1956, that is to say 7 - chloro - 1 - methyl - 2 - (hydroxymethyl) - 5 - (2' - chlorophenyl) - I H - 2,3 - dihydro - 1,4 - benzodiazepine, was tested in human patients. For this purpose fasting patients were given an orally administered dose of 10 mg. of active substance followed by 50 ml. of water. The results in Table 1 show the mean blood level values determined by gas chromatography for 6 patients in nanograms per ml.

of plasma in dependence upon the time when the blood sample was taken, for three different forms of administration.

In comparison with the conventional capsule the use of a capsule composed in accordance with the invention shows a threefold improvement both of sytemic availability and of maximum blood level values.

KC 1956 partial glyceride capsules Prior art KC 1956 capsules according to invention Time x SR X 30 min. 10.9 1.8 24 6.9 lh 10.5 1.7 34 4.0 1.5h 6.4 0.9 24 4.6 2h 4.2 0.3 17 5.1 2.5 h 3.3 0.3 - 3h 2.6 0.2 12 3.1 5h 2.4 1.1 5 0.7 7h 1.9 1.9 4 0.7 Table 1: KC 1956 blood level in human patients in mg./ml. of plasma after oral administration of 10 mg. (N=6) of active substance KC 1956.

The active substance was prepared in micronised form, that is to say in optimum resorbable form according to the prior art, and as a fatty acid salt according to the invention, dissolved in a partial glyceride mixture of the composition shown below: a) Prior art KC 1956 capsules (weight of filling: 200 mg.) ED/mg.

KC 1956 micronised 10 Lactose D 80 121 Maize starch 57 Gelatine 2 "Primojel" (Carboxymethyl starch) 8 Magnesium stearate 2 Total 200 b) KC 1956 partial glyceride capsule according to the invention (weight of filling: 300 mg.) KC 1956 10.0 mg.

Capric Acid 29.0 mg.

"Imvitor" 742* (made by Dynamit Nobel) 261.0 mg.

300.0 mg.

*"Imvitor" is a registered Trade Mark The renal secretion of procaine was determined in three female patients in cross-tests. The total secretion of diazotizable aromatic amino groups in a 72-hour urine yield served as the criterion of the rate of resorption.

A blank value was then obtained from a 24-hour urine yield from the patients and then 25 mg. of procaine hydrochloride was administered to each of them and the total amount of secretion of diazotizable aromatic amino groups was determined from the 72-hour urine yield. After deducting the blank value, a resorption rate of from 50 to 60% of the amount of procaine hydrochloride administered was obtained.

Basically the same procedure was then applied to the same patients after administration of a medicament of the following composition: 21.7 mg. procaine base (corresponding to 25 mg. of procaine hydrochloride) 40 mg. capric acid 40 mg. lauric acid 100 mg. mono-diglyceride of medium-chain fatty acids (C6-C12) 201.7 mg.

A total resorption rate between 80 and 90% was thus obtained, corresponding to a mean increase of 54%.

The procedure for determining the diazotizable aromatic amino groups was as follows: The total secretion was determined by taking 2 ml. of the total urine yield for a period of 24 hours in each case and heating with 3 ml. of lN-sodium hydroxide for 20 minutes in a water bath. 4 ml. of 1N-hydrochloric acid were then added to the mixture, which was cooled and made up to 10 ml. with water. 4 ml. of this solution were mixed with 1 ml. of a 0.1% by weight solution of sodium nitrite, allowed to stand for 3 minutes, mixed with 1 ml. of a 0.5% by weight solution of amidosulphuric acid, thoroughly shaken up, and allowed to stand again for 3 minutes. After the addition of 2 ml. of a 0.1% by weight solution of N-(naphthyl (1))-ethylene-diammonium dichloride, the mixture was made up to 10 ml with water and after the mixture had been allowed to stand for 10 minutes the extinction was determined at 545 nm. The resulting individual values for each period of 24 hours were added together.

The following Examples will serve to provide a further explanation of the invention. Unless otherwise indicated, the expression "parts" means parts by weight.

Example 1 200 g. of synephrine base are dissolved in 800 g. of a mixture of capric and lauric acids while being heated at 40cC. The mixture, which solidifies at 300C., is filled into gelatine capsules above that temperature, each capsule containing 250 mg. of mixture, corresponding to 50 mg. of synephrine base.

Example 2 165 g. of synephrine base are dissolved, with the addition of 290 g. of caprylic acid, in 500 g. of a mixture of mono- and diclycerides of capric and caprylic acids available under the Trade Mark "Witafrol" 7420 and filled into gelatine capsules, each of which contains 239 mg. of mixture corresponding to 41.25 mg. of synephrine base.

Example 3 217 g. of procaine base are dissolved, with the addition of 400 g. of capric acid and 400 g. of lauric acid, in 1000 g. of a mixture of mono- and diglycerides of capric and caprylic acids ("Witafrol" 7420) and filled into gelatine capsules, each of which contains 202 mg. of mixture, corresponding to 21.7 mg. of procaine base.

Example 4 714 g. of beneyeiane base, with the addition of 650 g. of capric acid and 650 g.

of laurie acid, are dissolved in 1000 g. of a mixture of mono- and diglycerides of capric and caprylic acids ("Witafrol" 7420) and filled into gelatine capsules, each of which contains 211 mg. of mixture corresponding to 50.0 mg. of bencyclane base.

Example 5 714 g. of bencyclane base, with the addition of 650 g. of capric acid and 650 g.

of lauric acid, are dissolved in 4000 g. of a mixture of mono- and diglycerides of capric and caprylic acids.

The solution is worked, with stirring, into a melt of 13.986 kg. of suppository composition in the form of modified triglycerides of saturated fatty acids available under the Trade Mark "Witepsol" H 5 and poured out to form suppositories of 2000 mg. each, corresponding to 71.4 mg of bencyclane base.

Example 6 100 g. of diazepam, with the addition of 290 g. of capric acid, are dissolved in 2.61 kg. of a very pure mixture of mono- and diglycerides of capric and caprylic acids available under the Trade Mark "Imvitor" 742 at 350C. and filled into gelatine capsules, each of which contains 300 mg. of mixture corresponding to 10 mg. of diazepam.

Example 7 100 g. of tranquilliser KC 1956, i.e., 7 - chloro - 1 - methyl - 2 (hydroxymethyl) - 5 - (2' - chlorophenyl) - 1 - H - 2,2 - dihydro - 1,4 benzodiazepine, and 290 g. of capric acid, are dissolved in 2.61 kg. of a very pure mixture of mono- and diglycerides of capric and caprylic acids ("Imvitor" 742) at 35"C. and filled into gelatine capsules, each of which contains 300 mg. of mixture corresponding to an active substance content of 10 mg.

WHAT WE CLAIM IS: 1. A pharmaceutical preparation having improved resorption properties, comprising (a) as its active pharmaceutical substance a cardiac glycoside, a steroid hormone, an antibiotic, spasmolytic, a coronary therapeutic agent, an anti-phlogistic agent, a sympathomimetic agent, a tranquilliser or a local anaesthetic, the active pharmaceutical substance being in the form of a free base or in the form of a salt of a base with a pharmacologically acceptable acid, and (b) at least one fatty acid of medium chain length containing from 6 to 12 carbon atoms.

2. A preparation as claimed in Claim 1, wherein the preparation comprises a mixture of said fatty acids.

3. A preparation as claimed in Claim i or 2, wherein the preparation additionally contains one or more fatty acids having longer chains of from 12 to 18 carbon atoms.

4. A preparation as claimed in any one of Claims 1 to 3, where the preparation additionally contains one or more glycerides of one or more fatty acids.

5. A preparation as claimed in Claim 4, wherein the glycerides are monoand/or di- and/or triglycerides.

6. A preparation as claimed in Claim 4 or 5, wherein the fatty acids forming the glycerides have chain lengths of from 6 to 18 carbon atoms.

7. A preparation as claimed in any one of Claims 4 to 6, wherein the fatty acids of the glycerides are saturated or unsaturated fatty acids.

8. A preparation as claimed in any one of Claims 4 to 7, wherein the fatty acids of the glycerides are selected from capric acid, caprylic acid, stearic acid, palmitic acid, and oleic acid.

9. A preparation as claimed in any one of Claims I to 8, wherein the active pharmaceutical substance is valethamate bromide, bencyclane base, dipyridamol, indomethacin, synephrine, diazepam, 7- chloro - 1 - methyl - 2 (hydroxymethyl)- 5 - (2' - chlorophenyl)- 1 - H - 2,2 - dihydro - 1,4 benzodiazepine, or procaine.

10. A preparation as claimed in any one of Claims 1 to 9, wherein the pharmacologically acceptable acid is a fatty acid containing from 6 to 18 carbon atoms.

11. A preparation as claimed in any one of Claims 1 to 10, wherein the pharmacologically acceptable acid is a fatty acid containing from 6 to 12 carbon atoms.

12. A pharmaceutical preparation in accordance with Claim I substantially as hereinbefore described in any one of the foregoing Examples.

13. A method of producing a pharmaceutical preparation having improved resorption properties, wherein at least one active pharmaceutical substance is dissolved in a fatty acid of medium chain length containing 6 to 12 carbon atoms, the active pharmaceutical substance being in the form of a free base or in the form of a salt of a base with a pharmacologically acceptable acid and being a cardiac glycoside. a steroid hormone, an antibiotic, a spasmolytic, a coronary therapeutic agent. an anti-phlogistic agent, a sympathomimetic agent, a tranquilliser or a local anaesthetic.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (25)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   The solution is worked, with stirring, into a melt of 13.986 kg. of suppository composition in the form of modified triglycerides of saturated fatty acids available under the Trade Mark "Witepsol" H 5 and poured out to form suppositories of 2000 mg. each, corresponding to 71.4 mg of bencyclane base.

   Example 6

   100 g. of diazepam, with the addition of 290 g. of capric acid, are dissolved in 2.61 kg. of a very pure mixture of mono- and diglycerides of capric and caprylic acids available under the Trade Mark "Imvitor" 742 at 350C. and filled into gelatine capsules, each of which contains 300 mg. of mixture corresponding to 10 mg. of diazepam.

   Example 7

   100 g. of tranquilliser KC 1956, i.e., 7 - chloro - 1 - methyl - 2 (hydroxymethyl) - 5 - (2' - chlorophenyl) - 1 - H - 2,2 - dihydro - 1,4 benzodiazepine, and 290 g. of capric acid, are dissolved in 2.61 kg. of a very pure mixture of mono- and diglycerides of capric and caprylic acids ("Imvitor" 742) at 35"C. and filled into gelatine capsules, each of which contains 300 mg. of mixture corresponding to an active substance content of 10 mg.

   WHAT WE CLAIM IS: 1. A pharmaceutical preparation having improved resorption properties, comprising (a) as its active pharmaceutical substance a cardiac glycoside, a steroid hormone, an antibiotic, spasmolytic, a coronary therapeutic agent, an anti-phlogistic agent, a sympathomimetic agent, a tranquilliser or a local anaesthetic, the active pharmaceutical substance being in the form of a free base or in the form of a salt of a base with a pharmacologically acceptable acid, and (b) at least one fatty acid of medium chain length containing from 6 to 12 carbon atoms.
2. 2. A preparation as claimed in Claim 1, wherein the preparation comprises a mixture of said fatty acids.
3. 3. A preparation as claimed in Claim i or 2, wherein the preparation additionally contains one or more fatty acids having longer chains of from 12 to 18 carbon atoms.
4. 4. A preparation as claimed in any one of Claims 1 to 3, where the preparation additionally contains one or more glycerides of one or more fatty acids.
5. 5. A preparation as claimed in Claim 4, wherein the glycerides are monoand/or di- and/or triglycerides.
6. 6. A preparation as claimed in Claim 4 or 5, wherein the fatty acids forming the glycerides have chain lengths of from 6 to 18 carbon atoms.
7. 7. A preparation as claimed in any one of Claims 4 to 6, wherein the fatty acids of the glycerides are saturated or unsaturated fatty acids.
8. 8. A preparation as claimed in any one of Claims 4 to 7, wherein the fatty acids of the glycerides are selected from capric acid, caprylic acid, stearic acid, palmitic acid, and oleic acid.
9. 9. A preparation as claimed in any one of Claims I to 8, wherein the active pharmaceutical substance is valethamate bromide, bencyclane base, dipyridamol, indomethacin, synephrine, diazepam, 7- chloro - 1 - methyl - 2 (hydroxymethyl)- 5 - (2' - chlorophenyl)- 1 - H - 2,2 - dihydro - 1,4 benzodiazepine, or procaine.
10. 10. A preparation as claimed in any one of Claims 1 to 9, wherein the pharmacologically acceptable acid is a fatty acid containing from 6 to 18 carbon atoms.
11. 11. A preparation as claimed in any one of Claims 1 to 10, wherein the pharmacologically acceptable acid is a fatty acid containing from 6 to 12 carbon atoms.
12. 12. A pharmaceutical preparation in accordance with Claim I substantially as hereinbefore described in any one of the foregoing Examples.
13. 13. A method of producing a pharmaceutical preparation having improved resorption properties, wherein at least one active pharmaceutical substance is dissolved in a fatty acid of medium chain length containing 6 to 12 carbon atoms, the active pharmaceutical substance being in the form of a free base or in the form of a salt of a base with a pharmacologically acceptable acid and being a cardiac glycoside. a steroid hormone, an antibiotic, a spasmolytic, a coronary therapeutic agent. an anti-phlogistic agent, a sympathomimetic agent, a tranquilliser or a local anaesthetic.
14. 14. A method as claimed in Claim 13, wherein the dissolving is effected with

    heating.
15. 15. A method as claimed in Claim 13 or 14, wherein the active substance is dissolved in a mixture of said fatty acids.
16. 16. A method as claimed in any one of Claims 13 to 15, wherein fatty acids having a longer chain of a length of from 12 to 18 carbon atoms are mixed with the said fatty acid(s) of medium chain length.
17. 17. A method as claimed in any one of Claims 13 to 16, wherein glycerides of one or more fatty acids are additionally present.
18. 18. A method as claimed in Claim 17, wherein the glycerides are mono- and/or di- and/or triglycerides.
19. 19. A method as claimed in Claim 17 or 18, wherein the fatty acids of the glycerides have chain lengths of from 6 to 18 carbon atoms.
20. 20. A method as claimed in any one of Claims 17 to 19, wherein the fatty acids of the glycerides are saturated or unsaturated fatty acids.
21. 21. A method as claimed in any one of Claims 17 to 20 wherein the fatty acid of the glycerides is capric acid. caprylic acid, stearic acid, palmitic acid, or oleic acid.
22. 22. A method as claimed in any one of Claims 13 to 21, wherein the active pharmaceutical substance is valethamate bromide, bencyclane base, dipyridamol, indomethacin, synephrine, diazepam, 7 - chloro - 1 - methyl - 2 (hydroxymethyl)- 5 - (2' - chlorophenyl)- I - H- 2,2- dihydro- 1,4 benzodiazepine or procaine.
23. 23. A method as claimed in any one of Claims 13 to 22, wherein the pharmacologically acceptable acid is a fatty acid containing from 6 to 18 carbon atoms.
24. 24. A method as claimed in any one of Claims 13 to 23, wherein the pharmacologically acceptable acid is a fatty acid containing from 6 to 12 carbon atoms.
25. 25. A method of producing a pharmaceutical preparation having improved resorption properties substantially as hereinbefore described in any one of the foregoing Examples.