WO1996026722A1

WO1996026722A1 - Use of isosorbide-5-mononitrate

Info

Publication number: WO1996026722A1
Application number: PCT/SE1995/000206
Authority: WO
Inventors: Gunnar Nyberg
Original assignee: Astra AB
Current assignee: AstraZeneca AB
Priority date: 1995-02-28
Filing date: 1995-02-28
Publication date: 1996-09-06
Anticipated expiration: 1997-08-28
Also published as: AU2269495A; MX9706492A; KR19980702554A; JPH11501026A

Abstract

New use of isosorbide-5-mononitrate for the manufacture of a medicament for the treatment of isolated systolic hypertension in the human or animal body as well as a method for reducing the risk of stroke in a patient having isolated systolic hypertension comprising administering to such a person an effective amount of isosorbide-5-mononitrate.

Description

Use of isosorbide-5-mononi trate

5

This invention relates to improvements in pharmaceutical compounds and is particularly concerned with new formulations and uses for a cardiac drug.

Research work begun in the 1980's and still continuing, has shown that isolated systolic 10 hypertension (ISH) is associated with an increased risk of stroke. For both men and women in the age group 50 to 79, it has been found that the risk for people with ISH was 2 to 4 times greater than that of normotensive people. ISH is commonly defined as a systolic blood pressure (SBP) above 160 mm Hg and diastolic blood pressure (DBP) below 95 mm Hg. 15

One study in 1991 showed that for patients above 60 years of age having an SBP in the range 160 to 219 and a DBP below 90, anti-hypertensive treatment resulted in a reduced risk of a non-fatal stroke of 36% in the treated group compared to an untreated group.

20 In connection with this type of research arterial pressure and flow relationships in subjects of various ages have been studied and some clinical studies have been made on the effect of nitroglycerine as a vasodilator on arteries of various sizes.

One of the objectives in the clinical trials with nitroglycerine has been selectively to be 25 able to reduce systolic blood pressure as it was believed that a reduction in systolic blood pressure would be beneficial in reducing stroke risk.

It is also known that even iii patients suffering from ISH, the systolic blood pressure does decrease during the night when the patient is sleeping. In principle, therefore, this 30 could make therapy simpler as it would not be so important to maintain relevant drug

t>NΪ» levels on a 24 hour basis. However, to date, no satisfactory therapy on ISH based on the use of nitroglycerine has emerged.

We have now found that isosorbide-5-mononitrate can be used to provide satisfactory therapy for the treatment of ISH. Isosorbide-5-mononitrate, hereinafter designated 5- ISMN, is frequently used clinically for the treatment of angina pectoris but we have now found that once daily administration of 5-ISMN can provide selective lowering of the systolic blood pressure, particularly during the day, and so can reduce risk of stroke for those patients at risk.

The present invention provides the use of isosorbide-5-mononitrate for the manufacture of a medicament for the treatment of isolated systolic hypertension in the human or animal body. The present invention also provides a method for reducing the risk of stroke in a patient having isolated systolic hypertension by administering to such a patient an amount of isosorbide-5-mononitrate sufficient to bring about a selective reduction in systolic blood pressure.

We have found that treatment with 5-ISMN from extended relase formulation is a particularly satisfactory form of therapy for the treatment of ISH. One commercially available extended release formulation, containing 60 mg of 5-ISMN per dosage unit, and sold under the registerd trade mark Imdur, has been found to be particularly suitable for once daily treatment of ISH. Imdur is designed for oral administration and normally releases substantially all of the 60 mg 5-ISMN over about a 12-hour period. Our clinical trials have indicated that the Imdur formulation makes 5-ISMN available for absorption into the blood stream over a 12 to 16 hour period so that the therapy is ideal for once daily administration, normally shortly after awaking in the morning.

A further benefit arising from the use of 5-ISMN in an extended release formulation in that the development of tolerance to 5-ISMN is avoided. Clinical studies on 5-ISMN in the treatment of angina have already established that administration of two or three daily doses of 5-ISMN, 20 or 30 mg per dosage, can lead, over a period of time, to the development of drug tolerance, in other words, that ever increasing dosage amounts become necessary to maintain the same therapeutic effect. This tolerance problem is avoided by administration of a once daily 60 mg extended release formulation and of course, results in improved patient compliance as well. These benefits are also observed when 5-ISMN is used to treat ISH.

A still further benefit arising from the use of a once daily dose of 5-ISMN from an extended release formulation is that the plasma concentration of 5-ISMN tends to be at its highest during the waking hours immediately following administration and at its lowest during the hours of sleep which is the final part of the 24 hour cycle. This fits in particularly well with the need, in the treatment of ISH, for there to be a high plasma concentration during the waking hours when selective lowering of SBP is required with a reduced concentration during the sleeping hours when SBP tends to be lower anyway, compared to the daytime level.

While commercial availability makes the Imdur extended release formulation a particularly convenient source of 5-ISMN for use in the treatment of ISH, other formulations are also acceptable from the technical point of view. In Imdur, the active 5- ISMN ingredient contained within an inert insoluble porous matrix that is based upon paraffin wax and an alkali metal aluminium silicate. However, extended release formulations are very well-known in the pharmaceutical industry and other types of inert insoluble porous matrices can be used based on different proportions of paraffin wax and sodium aluminium silicate, different types of paraffin wax and sodium aluminium silicate or by the use of other inert insoluble porous matrixforming polymers.

As an alternative to the use of an inert porous matrix system as the basis of the extended release formulation, it is also possible to formulate 5-ISMN for the treatment of ISH in an extended release formulation in which a core of active 5-ISMN is coated with a release rate controlling polymeric membrane. Such coated beads can be filled into gelatin capsules which will dissolve in the stomach to release the coated beads or can be compressed with other conventional excipients into fast disintegrating tablets which will release the coated beads. The coated beads can act as individual delivery units releasing 5-ISMN over a suitable time period. The release rate can be varied by varying the applied amount of the film-forming polymers and/or the ratio between the soluble and insoluble polymers and other ingredients in the film. For example, the beads themselves can comprise 5-ISMN formulated with lactose or mannitol together with cellulose and starch and indeed, such a formulation can be used without coating as a normal release formulation. The normal release formulation can then be coated with a release rate controlling film that can be based upon a mixture of water-soluble and water-insoluble cellulose derivatives. In accordance with procedures well-known in the art, these can be a mixture of the various grades of polymers sold under the name "Eudragit" in proportions that are selected to give the desired release rate of the active ingredient in vivo.

While extended release formulation is normally desirable, so that a once daily dose can be given and so avoid the problems of tolerance development and poor patient compliance as mentioned above, there are situations where immediate release of the 5- ISMN could be of value and such formulations will normally be prepared for example in tablet form, using conventional tabletting excipients. For example 5-ISMN can be formulated with lactose and/or cellulose as filler materials, with starch as a disintegrant and with the customary lubricants and binders. Such immediate release tablets will normally release more than 80% of the formulated drug load within 30 minutes of testing in vitro and their in vivo behaviour will be similar.

So far as amounts of 5-ISMN are concerned, we have found that a daily dose of 60 mg of 5-ISMN, made available on a once daily basis through an extended release formulation that will provide an in vivo release rate of not more than about 40% within the first hour, not more than about 55 % within the first 2 hours, not more than about 85% within the first 6 hours but substantially all of the active ingredient within 12 to 16 hours provides appropriate medication for the treatment of ISH. Formulations containing lower or higher amounts, e.g., 30 mg or 120 mg of 5-ISMN can also be used but here, consideration will need to be given to the achievement of appropriate plasma levels of 5- ISMN.

The following Examples are given to illustrate the invention.

EXA PLE 1

This Example describes an immediate release tablet containing the following ingredients.

5-ISMN 20 mg

Lactose (filler) 270 mg

Microcrystalline cellulose (filler) 60 mg

Maize starch (disintegrant) 10 mg

Magnesium stearate (lubricant) 3.6 mg Polyvinylpyrrolidone (binder) 3 mg

Ethanol q.d.

EXA PLE ?

This Example describes immediate release beads coated with a release rate controlling polymeric membrane.

Beads:

5-ISMN 30% by weight

Lactose or mannitol (filler) 25 % w/w

Microcrystalline cellulose (filler) 30% w/w

Maize starch (disintegrant) 15% w/w Water q.s. The ingredients for the tablet are formulated together with the assistance of the water which is then allowed to evaporate after tabletting of the ingredients.

The resulting tablets are then coated by conventional methods with a film comprising a methylene chloride/isopropyl alcohol solution of 50% w/w ethyl cellulose and 50% w/w Eudragit RL. The film coating is applied at a thickness to provide a release rate of 5- ISMN in vitro of not more than 40% within the first hour, not more than 55% within the first 2 hours, not more than 85% within the first 6 hours but substantially 100% within 12 hours.

EXAMPLE 3

This describes clinical work using the extended release Imdur formulation and shows significant selective reduction in systolic blood pressure (SBP).

This particular study was carried out on a group of 11 patients selected from a group of 70 angina patients. The group of 11 were selected as having a day-time systolic blood pressure in the sitting or standing position at the baseline that was 160 mm Hg or higher. The trial was carried out using 60 mg extended release 5-ISMN in the Imdur formulation. The trial was carried out in a double-blind cross-over study in which the patients took either Imdur or Placebo orally once a day shortly after waking. Each treatment period lasted for 2 weeks preceded by a 2- week placebo run-in period. All of these patients were angina patients who were also been treated by chronic β-andreno- receptor blocking therapy throughout the study. Blood pressure was measured for 3 hours after each administration of Imdur or Placebo. The systolic and diastolic blood pressure was measured in the usual way with a cuff. Systolic blood pressure was measured either standing or sitting.

The following results were obtained for the group of 11 patients. The systolic blood pressure is shown in Table 1, diastolic blood pressure is shown in Table 2. Systolic Blood Pressure - Table 1

Sitting Standing

Baseline Placebo Imdur Baseline Placebo Imdur

Mean 168 160 140 163 155 136

Standard 8 20 23 11 16 22 -Deviation

Diastolic Blood Pressure - Table 2

Sitting Standing

Baseline Placebo Imdur Baseline Placebo Imdur

Mean 92 88 81 86 87 83

Standard 9 10.3 13 12 9 12 Deviation Referring to the systolic blood pressure in Table 1, the reduction for Imdur treatment compared to Placebo is 20 mm for sitting patients, standard deviation 17 mm with p<0.01 while for the standing measurement, the reduction is 19 mm with a standard deviation of 16 mm and p<0.01. These results show a significant lowering of the systolic blood pressure of these hypertensive patients 3 hours after administration of Imdur.

Turning to Table 2, these show a difference in a sitting position of 6 mm with a standard deviation of 10 mm and p <0.05 while for the standing measurement, the reduction is 3 mm with a standard deviation of 10 mm. The diastolic results, included for the purposes of comparison only, show the selective reduction in the systolic blood pressure measured 3 hours after the administration of the extended release Imdur formulation.

The comparison mentioned above is of Imdur treatment compared to Placebo. There is some reduction in systolic blood pressure even amongst the placebo group but if the comparison is made between the Imdur treatment and the baseline measurement for this group of patients, then the selective reduction in systolic blood pressure 3 hours after Imdur administration is even more pronounced.

These results fit in with the theory that the systolic blood pressure decrease causes a sympathetic reaction which maintains the diastolic pressure. In an elderly patient with ISH, as well as in the patient with angina pectoris, this is an advantage since the circulation to the heart is dependent on the diastolic pressure and this may be impaired if the diastolic pressure falls too low. This is perhaps the reason why conventional anti- hypertensive drugs, in particular those that act on the vascular system so that the diastolic pressure as well as the systolic pressure is decreased, may be less effective in the treatment of ISH. EXAMPLE 4

This Example describes a similar study carried out on a different group of angina patients, some of whom were also treated with a β-blocker throughout the study. It was found that there was no significant difference in the systolic blood pressure reduction observed as between those patients receiving β-blocker therapy at the same time and those who did not receive the β-blocker therapy.

This trial was carried out on a group of 44 angina patients, almost all of whom had a baseline systolic blood pressure of at least 160 mm. The trial was carried out in a randomised double-blind, double-dummy cross-over regime using 60 mg of 5-ISMN in the Imdur formulation and Placebo. Medication was administered once a day shortly after awaking. There was a 2-week Placebo run-in period followed by two 4-week periods with active treatment. The age range of the patients was 50 to 83 years old. Systolic blood pressure was measured in the supine position 5 minutes after administration of medication and standing systolic blood pressure was measured 6 minutes after administration of medication. Blood pressure was measured by the usual arm cuff. The results are set out in mm of mercury in Table 3 below.

Table 3 - Systolic Blood Pressure

These results show that for supine systolic blood pressure, the Imdur brought about an 8 mm reduction with a standard deviation of 14 mm, p =0.002, while in the standing measurements, Imdur treatment brought about a reduction of 7 mm with a standard deviation of 20 and p <0.03.

Once again, these results show a stastically significant reduction in the systolic blood pressure of both standing and supine measurements for the Imdur treatment.

Results were also analysed from a similar clinical trial carried out on a group of 109 patients including the 44 patients mentioned above. Blood pressure was again measured in supine position 5 minutes after medication and in the standing position 1 and 6 minutes after medication. The results obtained, in mm of mercury, are set out in Table 4 below.

TaMe 4

____, _

U PCT/SE95/00206

SBP = systolic blood pressure

DPB = diastolic blood pressure

These results show a significant reduction in systolic blood pressure attributable to Imdur in both the supine and standing measurements and also indicate the selective nature of the reduction which is much more pronounced in systolic blood pressure than in the diastolic blood pressure.

Claims

1. The use of isosorbide-5-mononitrate (5-ISMN) for the manufacture of a medicament for the treatment of isolated systolic hypertension.

2. The use of isosorbide-5-mononitτate (5-ISMN) for the manufacture of a medicament for reducing the risk of stroke in a patient having isolated systolic hypertension.

3. A method of treating isolated systolic hypertension in a human or animal patient which comprises administering to a patient in need of treatment an effective amount of isosorbide-5-mononitrate (5-ISMN).

4. A method of reducing the risk of stroke in a human or animal patient having isolated systolic hypertension which comprises administering to a patient in need of treatment an effective amount of isosoιbide-5-mononitrate (5-ISMN).

5. A use or a method according to any one of the preceding claims wherein the 5- ISMN is administered only once in a 24-hour period.

6. A use or a method according to any one of the preceding claims wherein the 5- ISMN is administered orally as an extended release formulation.

7. A use or a method according to claim 6 wherein the extended release formulation contains 60 mg 5-ISMN per unit dose.

8. A use or a method according to claim 6 or 7 wherein the extended release formulation is one that will release at least 60 mg 5-ISMN over about a 12-hour period.

9. A use or a method according to any one of claims 6 to 8 wherein the extended release formulation is one that makes 5-ISMN available for absorption into the bloodstream over a 12 to 16 hour period.

10. A use or a method according to any one of the preceding claims wherein the 5- ISMN is administered orally from an extended release formulation having an inert insoluble porous matrix based upon paraffin wax and an alkali metal aluminium silicate.

11. A use of a method according to any one of claims 1 to 9 wherein the 5-ISMN is administered orally from an extended release formulation having a core of 5-ISMN coated with a release rate controlling polymeric membrane.

12. A use or a method according to claim 11 wherein the polymeric membrane comprises a mixture of water soluble and water insoluble cellulose derivatives.

13. A use or a method according to any one of the preceding claims wherein the 5- ISMN is administered only once in a 24-hour period at a time such that the patient has a maximum plasma concentration of 5-ISMN during waking hours and a minimum plasma concentration of 5-ISMN during sleeping hours.

14. A use or a method according to any one of the preceding claims wherein the 5- ISMN is administered orally in an extended release formulation that will provide an in vivo release rate of 5-ISMN of not more than about 40% within the first hour, not more than about 55% within the first 2 hours, not more than about 85% within the first 6 hours but substantially all of the 5-ISMN within 12 to 16 hours.