GB1582207A

GB1582207A - Stable isosorbide dinitrate solutions preparation thereof and use thereof

Info

Publication number: GB1582207A
Application number: GB2042177A
Authority: GB
Original assignee: Sanol Schwarz GmbH
Current assignee: Sanol Schwarz GmbH
Priority date: 1977-05-16
Filing date: 1977-05-16
Publication date: 1981-01-07

Description

(54) STABLE ISOSORBIDE DINITRATE SOLUTIONS, PREPARATION THEREOF AND USE THEROF (71) We, SANOL SCHWARZ-MONHEIM GmbH, of Mittelstrabe 11 - 13, 4019 Monheim, Germany, a corporation organised and existing under the laws of the Federal Republic of Germany, 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: The invention is concerned with stable isosorbide dinitrate solutions, the preparation thereof and the use thereof.

Isosorbide- dinitrate has long been used, with good results, as a medication for angina pectoris, being given orally, like other nitric acid esters, in the form of tablets or capsules.

Recently it has been shown that isosorbide dinitrate can also be used in the treatment of insufficiency of the left ventricle of the heart, myocardial infartion and incipient oedema of the lungs.

Parenteral administration would offer distinct advantages over oral administration where, for example, patients having the aforementioned diseases are in hospital; a correct, controlled dosage by infusion can be given. This method of administration would also overcome the problem of decomposition of the active substance in the liver to mononitrates which occurs with oral administration.

For parenteral administration of isosorbide dinitrate using infusion solutions the dosage should be made up individually according to the acuteness of the respective case. The concentration of isosorbide dinitrate in ampoules from which suitable infusion solutions can be prepared should be substantially 1 mg/ml (i.e. 1 g/l), 2 mg/ml (i.e. 2g/l) or more. From such prepared solutions a low starting concentration as required, for example at the beginning of a treatment, could be given by an infusion solution; also a sufficiently high concentration (as required for the main treatment) could be attained without administering large liquid amounts and the calculation of concentrations would be considerably simplified. In general, the lowest concentration with which therapy can be started is regarded as 5 mg of isosorbide dinitrate per 250 ml of infusion solution. If ampoules containing solutions having a concentration of isosorbide dinitrate of 1 mg/ml were available, 5 ml of these isosorbide dinitrate solutions would have to be diluted to a 250 ml infusion solution. Then the dosage could be increased so that 10 mg of isosorbide dinitrate or even more a day could be administered to the patients.

On the basis of experiments preceding the invention (see Examples 1 and 2) the production of an aqueous isosorbide dinitrate solution having a concentration of substantially 1 mg/ml seemed to be impossible. At room temperature a saturation value of approximately 0.7 g of isosorbide dinitrate/l was found. These experiments were carried out in the usual manner to find out saturation values, i.e. solid isosorbide dinitrate was dissolved in water to saturation point, i.e. when no more crystals would dissolve, at room temperature or crystallised out from an over-saturated solution on cooling to room temperature. The results given roughly correspond to published data (see Table 1 below). These saturation values can be seen to vary within a wide range.

Table I solubility of isosorbide di nitrate in water (g/l) Year Reference 2 1959 Med. Prom. SSSlt 13 (l959) 18 - 20 according to CA 54 (1C)60) 8647 h 1.1 1968 Merck Index (1968) 593 1.089 1968 Merck Index (1968) 593 < 0.5 1975 Anal. Profiles Drug Subst.

4 (1975) 231 0.68 1975 Needleman, Organic Nitrates, Springer (1975)17.

However, we have surprisingly found that it is possible to prepare solutions of isosorbide dinitrate which have isosorbide dinitrate concentrations above our experimentally found saturation values at room temperature (24"C) when preparation is carried out in the absence of solid isosorbide dinitrate. It is both surprising and useful that such oversaturated isosorbide dinitrate solutions can be used for therapeutic purposes as they are stable in that they can be stored without any substantial changes for long periods (usually at least for months). This is especially surprising since it was not possible to charge containers, for example ampoules, with oversaturated solutions without any crystallisation on a large scale unless the solutions, the ampoules and the entire equipment were maintained at an elevated temperature. The oversaturated aqueous isosorbide dinitrate solutions may be diluted for the production of, for example, infusion solutions.

The present invention accordingly provides a stable preparation suitable for making up into pharmaceutical preparations for parenteral administration, which comprises an oversaturated solution of isosorbide dinitrate in an aqueous and/or pharmaceutically suitable alcoholic solvent, preferably one which has been stabilised by heating to eliminate seed crystal formation. The preparation of the invention is preferably contained in a pharmaceutically suitable container, especially an ampoule.

The term "stable" preparation is used herein to mean a solution which is substantially unchanged after storage at room temperature for at least 10 days, preferably for at least a month.

Preferably the pharmaceutically suitable alcoholic solvent is a polyhydric alcohol, preferably a polyhydric aliphatic alcohol, more preferably a (C3 to C4)diol, especially 1,2-propylene glycol. Where the solution os isosorbide dinitrate is an aqueous one then preferably the solution is one which, at 24"C, contains up to 2.5 g/l, especially in the range of from 1.0 to 2.5 g/l, for example 1.0 or 2.0 g/l. Where the solution is in a pharmaceutically suitable polyhydric alcoholic solvent, then the solution is preferably one which, at 240 C, contains up to 30 grams, especially up to 20 grams, of isosorbide dinitrate solution per litre.

The oversaturated solution of isosorbide dinitrate may additionally contain one or more substances which are suitable for preparing isotonic solutions. For example, the preparation may contain sodium chloride.

A preparation of the invention may be prepared by preparing a solution of isosorbide dinitrate at a raised temperature and cooling it in the absence of isosorbide dinitrate crystals.

Preferably the solution is charged into containers, preferably ampoules, (after filtration if desired) at a raised temperature, the containers closed and then cooled. Preferably the containers have been sterilised, by the methods of the Deutsches Arzneibuch; sterilisation can be carried out after charging when preferably the containers charged with the solution are heated for at least 15 minutes at a temperature of at least 95"C, especially 121"C.

Preferably the solution of isosorbide dinitrate is prepared at a temperature of at least 500C. especially of at least 800 C.

It is possible to prepare a solution having a concentration of isosorbide dinitrate of 1 g/l at at least 80"C and then to charge the containers with the solution at a temperature of at least 50"C. It is also possible to combine solid isosorbide dinitrate with water, for an aqueous solution, in a ratio of 1:1,000 and to then increase the temperature to at least 80"C whilst stirring. When a clear solution has resulted, the said solution is cooled and maintained at a temperature of at least 50 C, filtered, if desired, through a suitable filter arid charged into ampoules. It is then possible to sterilise the ampoules in overheated steam according to the methods of the Deutsches Arzneibuch. When an alcoholic-based solution is prepared the charging of the ampoules may occur, after cooling, at a temperature of at least 30 C, preferably at least 40 C.

The alcoholic-based solution in a preparation of the invention is used where 'it' is hecessa'ry to give the patients large amounts of isosorbide dinitrate by infusion than is possible with a purely aqueous solution. Such a solution may contain 0.5% or more, preferably 5%, 10%, 20%, 50% or more, of a suitable alcoholic solvent. 1,2-Propylene glycol, when used, is preferably used as the sole solvent. The isosorbide dinitrate content may be, as previously indicated, in the range of up to 30 g/l, preferably up to 20 g/l at 240 C. Using 1,2-propylene glycol it is possible to prepare a solution having an isosorbide dinitrate cdncentration of, for example, 20 g/l at about 80 C or more and then charging the containers at, for example, at least 30 C or 40 C or more.

During the preparation of a preparation of the invention special care should be taken to prevent the solution of isosorbide dinitrate from becoming cold. The equipment used for the preparation of the solution and the charging of the containers is th'erefore preferably provided with special tempering means.

The present invention provides a stable oversaturated aqueous solution which at 24 C contains more than 2 grams of isosorbide dinitrate per litre.

The present invention also provides a process for the preparation of a stable preparation of the invention as previously described.

The invention further provides a pharmaceutical preparation for parenteral administration which has been prepared from a preparation of the invention. Preferably an infusion solution is prepared from a preparation of the invention.

The following Examples illustrate the invention. Examples 1 and 2 are for comparison only.

Example 1 Finely powdered solid isosorbide dinitrate was added to water in a glass bottle at 24 C and shaken for several hours by means of an automatic shaking apparatus.

The amount of isosorbide dinitrate added was such that after shaking a considerable excess of undissolved isosorbide dinitrate remained. The undissolved isosorbide dinitrate was filtered off and the isosorbide dinitrate content of the clear solution examined by the phenol/disulphonic acid method. The solution tested had an -isosorbide-dinitrate saturation concentration of 0.6858 mg/1.0 ml. The evaluation was given by comparison of 0.5 ml of the test solution with 0.5 ml of a standard solution which containdd pure isosorbide dinitrate (see below).

Experimental Details: Concentration of isosorbide dinitrate - in the standard-.solution r 3;9.94 mg/50 m, I (acetne/water mixture); Extinction of the standard solution by the phenol/disulphonic acid method = 0.396, Extinction of the test solution by the phenol/disulphonic acid method = 0.340.

Example 2 Finely powdered solid isosorbide dinitrate was added to water and stirred with h, a magnetic stirrer for one hour at 50 C. The solution was then left at room temperature for 24 hours and the undissolved isosorbide dinitrate was filtered off. An isosorbide dinitrate saturation concentration of 0.76 mg/ml was found in the filtrate (determination of the c6ncentiation was by the same method as indicated in Example 1 above).

Experimental Details: Concentration of isosorbide dinitrate in the standard solution = 39.65 mg/50 ml (acetone/water mixture); Extinction of the standard solution = 0.416; Extinction of the test solution = 0.396.

Example 3 100 ml of distilled water were added to a mixture of 1 g of solid isosorbide dinitrate and 9 g of solid sodium chloride whilst stirring. The mixture was heated to about 50 C, a clear solution resulted. The solution was then filtered and several ampoules filled with the filtrate.

The ampoules were closed and sterilised in overheated steam at 121 C for about 15 minutes.

The concentration of isosorbide dinitrate in these ampoules was examined, as described below, after exposure to varying conditions. Some of the ampoules were examined after the sterilisation step above. Other of the ampoules were either stored at about 10 C in a refrigerator or stored at -20 C in a deep freezer; both stored for a prolonged period and then analysed. Additionally one of the ampoules was stored at room temperature for a prolonged period and then examined. No crystals formed in any of the ampoules at any time during the experiment.

The analytical results are listed in the following Table 2.

A quantitative thin layer chromatography method was developed to analyse isosorbide dinitrate concentration for this experiment. By this method only undecomposed isosorbide dinitrate was taken into consideration - any decomposition products thereof would be separated from the pure isosorbide by thin layer chromatography. By this analytical method it was possible to find out whether changes had appeared during the production of the storage.

Table 2 Date of Concen Produc- tration of tion Storage* isosorbide Experi- (Month Tempera- Storage dinitrate Analytical ment No. /year) ture Time (mg/ml) method * 132 a 7/73 RT 0 1.045 direct DC 327 b 4/74 RT a few 1.032 polarography days 1.065 1.040 327 b 4/74 RT 15 months 1.007 direct DC 626 4/75 'RT a few 0.970 direct DC days 0.991 0.977 626 4/75 RT & 3 months 0.98 direct DC -200C 1 day C-i 7/75 RT 1-2 days 0.996 direct DC C-2 7/75 RT " 1.026 C-4 7/75 RT " 1.016 726 7/75 RT 2 days 1.099 direct DC 726 7/75 +7"C 2 days 1.057 direct DC * RT = room temperature DC = thin layer chromatography Example 4 Solutions of isosorbide dinitrate having an isosorbide dinitrate concentration of approxi mately 2.5 mg/ml were prepared and stored in ampoules. These solutions showed substantially no changes even after long storage (see Table 3 below).

Table 3 Date of Concen Produc- tration of tion Storage* isosorbide Experi- (Month Tempera- Storage dinitrate Analytical ment No. year) ture Time (mglml) method * C-S 10/75 RT 1 day 2.48 direct DC C-S 10/75 +70C & 1 month 2.53 colorimetry RT 6 months 2.51 direct DC 966 5/76 RT 1 day 2.58 colorimetry 2.65 direct DC * RT = room temperature DC = thin layer chromatography.

Example 5 Solid isosorbide dinitrate was dissolved in warm 1,2-propylene glycol to give an isosorbide dinitrate concentration of approximately 20 mg/ml. Several 5 ml ampoules were filled and then closed. Some of the ampoules were sterilised in overheated steam for 20 minutes at 121"C. The remaining ampoules were not sterilised.

After 10 days both groups of ampoules were examined. In each of the non-sterilised ampoules isosorbide dinitrate crystals had formed; these ampoules were found to contain 23.06 mg of isosorbide dinitrate per ml of solution. No crystals were present in any of the sterilised ampoules; these ampoules were found to contain 23.32 mg of isosorbide dinitrate per ml of solution.

Then all of the ampoules were stored at 6"C in a refrigerator; their isosorbide dinitrate content was examined at 6 and 12 days later. Again, in the sterilised ampoules, no crystals formed and no substantial change in isosorbide dinitrate concentration was observed. In the non-sterilised ampoules, however, the proportion of crystals formed had increased and the isosorbide dinitrate concentration had decreased: 13.63 mg/ml after 6 days and 8.70 mg/ml after 12 days.

Claims

WHAT WE CLAIM IS:

1. A stable preparation suitable for making up into pharmaceutical preparations for parenteral administration, which comprises an oversaturated solution of isosorbide dinitrate in an aqueous and/or pharmaceutically suitable alcoholic solvent.

2. A stable preparation as claimed in claim 1, which has been stabilised by heating to eliminate seed crystal formation.

3. A stable preparation as claimed in claim 1 or claim 2, wherein the solution is contained in a pharmaceutically suitable container.

4. A stable preparation as claimed in claim 3, wherein the container is an ampoule.

5. A stable preparation as claimed in claim 3 or claim 4, wherein the container has been sterilised with superheated steam.

6. A stable preparation as claimed in any one of claims 1 to 5, which comprises a solution which at 24"C contains from 1.0 to 2.5 grams of isosorbide dinitrate per litre.

7. A sterilised preparation as claimed in any one of claims I to 6.

8. A stable preparation as claimed in any one of claims 1 to 7, which also contains one or more substances suitable for preparing isotonic solutions.

9. A stable preparation as claimed in any one of claims I to 8, wherein the alcoholic solvent is a pharmaceutically suitable polyhydric alcohol.

10. A stable preparation as claimed in claim 9, wherein the alcohol is 1,2-propylene glycol.

11. A stable preparation as claimed in claim 9 or claim 10, which comprises a solution which at 24"C contains up to 30 grams of isosorbide dinitrate per litre.

12. A stable preparation as claimed in claim 11, which comprises a solution which at 24"C contains up to 20 grams of isosorbide dinitrate per litre.

13. A stable preparation as claimed in any one of claims 1 to 12, which has been obtained by preparing a solution of isosorbide dinitrate at a raised temperature and cooling the solution in the absence of isosorbide dinitrate crystals.

14. A stable preparation as claimed in claim 13, wherein, before cooling, there is prepared a solution of isosorbide dinitrate at a temperature of at least 500C.

15. A stable preparation as claimed in claim 13 or claim 14, wherein, before cooling, there is prepared a solution of isosorbide dinitrate at a temperature of at least 80"C.

16. A stable preparation as claimed in any one of claims 13 to 15, wherein, before cooling, an aqueous solution containing from 1 to 2.5 grams of isosorbide dinitrate per litre is prepared.

17. A stable preparation as claimed in any one of claims'3 to 16, wherein the container with the solution has been heated for at least 15 minutes at a temperature of at least 95 C.

18. A stable preparation as claimed in claim 17, wherein the container with the solution has been heated for at least 15 minutes at a temperature of 121"C.

19. A stable oversaturated aqueous solution which at 240C contains more than 2 grams of isosorbide dinitrate per litre.

20. A stable preparation as claimed in claim 1, substantially as described in any one of Examples 3 to 5 herein.

21. A process for the manufacture of a stable preparation as claimed in claim 1, substantially as described herein.

22. A stable preparation when obtained by the process claimed in claim 21.

23. A pharmaceutical preparation for parenteral administration which has been prepared from a preparation as claimed in any one of claims 1 to 19 and 22.