GB1564035A

GB1564035A - Pharmaceutical compositions containing eburnane derivatives

Info

Publication number: GB1564035A
Application number: GB5016376A
Authority: GB
Original assignee: Parcor SARL
Current assignee: Parcor SARL
Priority date: 1975-12-01
Filing date: 1976-12-01
Publication date: 1980-04-02
Also published as: BE848782A; ES453689A1; FR2333507A1; FR2333507B1; IE44187L; IE44187B1; LU76290A1; DK537476A; DE2654119A1; NL7613354A

Description

(54) PHARMACEUTICAL COMPOSITIONS CONTAINING EBURNANE DERIVATIVES (71) We, PARCOR, a French body corporate of 40 Avenue George V, 75008 Paris, France 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 present invention relates to oral pharmaceutical compositions comprising compounds related to eburnane with interesting pharmacological properties, in particular cerebral vasodilatory activity.

Some substances having a structure related to eburnane have hitherto been put to important uses in medicine and have been the subject of numerous studies. Thus, for example, vincamine is used chiefly as a general and more especially a cerebral vasodilator as well as a weak hypotensive.

This substance increases blood flow, and increases the supply and consumption of oxygen in the brain. Similarly, vincanol which is another substance having a structure related to that of eburnane is known for its pharmacological properties, notably with regard to circulatory vascular disorders; in particular it has an effect on the oxygenation and vasoregulation of the brain.

It is necessary for the aforesaid substances to have a very rapid effect to make them valuable as remedies for attacks, particularly headaches, in patients suffering from disorders of cerebral circulation, Therefore, the action of the said substances should preferably be apparent some minutes after administration; thus, Votchal and Tchapidze (Therapia Hung., 1965, 13,91-94) showed that vascular headaches could be overcome within ten to fifteen minutes after the intravenous injection of vincamine. Similar observations were described by Szabor (Therapia Hung 1965, 13, 105-108) in cases of cerebral attacks.

Nevertheless, it must be admitted that the administration of such substances by intravenous route has numerous disadvantages, particularly in elderly people, which may reach the point of causing serious occurrences such as, for example, a sudden fall in blood pressure.

Certainly, these substances can be administered by oral route in the form of tablets, coated tablets or pills, but owing to the fairly long release time of these pharmaceutical forms, it is not possible for the active principle in question to reach the brain rapidly, and this has the drawback that headaches cannot be treated as quickly as necessary.

The present invention therefore aims to eliminate these disadvantages. Thus, by admixing the said active substances with a dispersing agent, our tests have shown that these active principles are rapidly absorbed after oral administration and quickly reach the tissues, particularly of the brain, with the result that the above-mentioned attacks can be overcome soon after administration.

Thus, according to one aspect of the present invention there is provided a pharmaceutical compositions for oral administration comprising, as active ingredient, a compound of the formula

(wherein the symbols ~each represent a bond, only one of which is present in any one compound, R1 is hydrogen or hydroxy, and R2 is -CH2OH, -COOH, -COOCH3 or hydroxy, or R' and R2 together represent oxo) or a pharmaceutically acceptable salt, ester, amide or N-oxide thereof, together with a dispersing agent.

Examples of compounds suitable for use in the compositions according to the invention are, for example, vincamine, vincaminic acid, apovincamine, apovincaminic acid, vincaminol, vincamone and vincanol, which compounds may, if desired, be in the form of the free base or a pharmaceutically acceptable salt, ester, amide or N-oxide thereof.

The compositions may, if desired, contain other active ingredients, such as vitamin C and vitamin P factors, acetylsalicyclic acid, theophylline or papaverine.

It should be understood that the active ingredients may be used in the pharmaceutical compositions of the invention in their different stereoisomeric forms or in the form of their racemic mixtures.

In the new compositions the active compounds are present with a dispersing agent whereby they are brought into a dispersible form. The dispersing agent may for example be cellulose or an insoluble derivative thereof (e.g. carboxymethyl cellulose or hydroxypropyl cellulose), such as methyl cellulose containing 2633% of methoxy groups and consisting of opaque vermiculate grains of a fibrous nature, or purified, phospholipids such as phosphatidylinositol, or pure microcolloidalsilica such as is obtained by pyrolysis of silicon tetrachloride in an oxyhydrogen flame. This is a highly dispersed silica with a well defined particle diameter ranging from about 7-40 nm depending on the type, corresponding to about 1/30 of the wavelength of visible light; this silica is characterised by the size of the particles, the formation of agglomerates, the state of its great adsorption capacity and its chemical inertness. It exists in several particle sizes; it is a light white odourless and flavourless powder. The surface area according to B.E.T. is from 80380 m2.g-1 and preferably 200+ 25m2.gl whilst the average size of the primary particles is 12 nm, the quantity of SiO2 being greater than 99.8%, the pH of the 4% aqueous dispersion being between 3.6 and 4.3.

Generally the weight ratio of dispersing agent to active substance is between 1:1 and 100:1 and preferably between 4:1 and 20:1.

The compositions of the invention may be presented either in dry form or dispersed in a liquid carrier.

The compositions may be in dosage unit form, each dosage unit containing for example 10 to 1200 mg of the active ingredient and from 0.010 to 40 g (e.g. 0.05 to 1 g) of the dispersing agent.

In the preparation of the compositions, one method is to mix the active ingredient and the dispersing agent together by evaporating to dryness a solution or suspension of them in a volatile liquid medium.

For a better understanding of the invention, a composition containing vincamine is taken here as a non-restrictive example, and the method of producing the dispersible preparation is described hereinafter.

The vincamine is put into suspension in 95% ethyl alcohol or in pharmaceutical grade industrial alcohol. The dispersing agent is mixed with this suspension in a mixer of a suitable capacity. The alcohol is removed by evaporation, suitably at a temperature below 50"C. The powder thus obtained is then screened through a mesh.

In order to make it safer to use, this powder is mixed with a water soluble excipient pharmacological, such as, for example, fructose, mannitol or another suitable pharmacologically inert substance, this admixture being intended to provide better distribution of the active principle, which is adsorbed on the surface of the particles of the dispersing agent. Such excipients may generally be used in the compositions of the invention, the weight ratio of the excipient to the active ingredient being for example 100:1 to 250:1.

The final composition thus obtained is then placed in vials, gelating capsules, single dose sachets or cachets. When brought into contact with drinking water, the powder is immediately spread and dispersed uniformly in the liquid; it does not form a sediment which means that there is no need to agitate the liquid before administering it. The liquid remains stable since the dispersing agent also acts as suspending agent in the water.

Experimental studies have shown the advantages presented by a dispersible composition of the substances having an eburnane nucleus. Thus, tests in vitro on the dissolution at a pH between 1.2 and 1.5 (pH substantially identical to that of the human gastric fluids) and on the release of active principle were carried out, in comparison with the conventional galenic form used for these active substances, i.e. tablets, the result being set forth in the Table below.

The administration of a dispersing agent on its own, unaccompanied by vincamine, does not produce any vasodilator effect.

Percentage active ingredient released Duration of test Gain.) Tablet Dispersible powder 2 0 70 5 15 90 10 25 100 20 35 100 30 45 100 60 70 100 90 85 100 120 85 100

Apart from the conventional pharmacological tests (cardio-vascular activity and psychotropic activity) vincamine was also studied, in the form of a dispersible powder, with regard to its absorption and elimination in the rabbit, the rat and the dog.

Similarly, its half-life was studied in rabbits and rats.

In a clinical trial, 131 observations were made on patients aged from 43 to 90 (74 women and 57 men) presenting with the following therapeutic indications: functional manifestation of cerebral circulatory insufficiency and cerebrosclerosis; functional consequences of cerebral vascular damage. A daily dose of vincamine of between 40 mg and 60 mg. in the form of a composition of the invention was used.

These clinical trails demonstrated the characteristics of this dispersible powder, since it means that the active principle can be administered in drinkable form whilst retaining its therapeutic properties.

Moreover, since tablets often involve difficulty in swallowing with the risk of choking in elderly patients or those having neurological syndromes, the drinkable form is an advantageous method of administration.

As is shown by the above Table in the case of all the active principle in the dispersible powder is released and thus available in 5 to 10 minutes, whereas, in the form of tablets, the active principle is never fully released: after 120 minutes, only 85% has been released. Thus, the active principle is released rapidly and therefore is adsorbed and reaches the tissues very quickly. These advantages are not obtained with the conventional tablet form, and hence the superiority of the medicament of the invention.

Pharmacological tests of toxicity were also carried out with the medicament of the invention.

Thus, for a dispersible powder containing 20 mg of vincamine per 2500 mg of finished preparation, no toxic effect was observed when this dosage per kg was adminstered over 24 hours by gastric tubes to mice.

Similarly, the administration of 5000 mg per kg of the same preparation per 24 hours by gastric tube to Wistar rats did not cause any toxic reaction, the animals being kept under observation for 8 days.

Other advantages became apparent during the clinical trails. Thus, in patients resisting treatment (senile persecution syndrome, for example), the dispersible powder can be administered without the patients knowing, by being incorporated in various foods (e.g. jam, yogurt etc.) or in drinks. Similarly, in patients having hypoacidic gastritis syndromes (common after a certain advanced age), gastric disintergration of tablets is often difficult or incomplete, resulting in uncontrollable variations in dosage. The dispersible powder disposed in a liquid carrier, avoids these risks of malabsorption of the medicament.

Thus, the medicament of the invention makes a new important and very valuable contribution to the treatment of cerebral vascular insufficiency.

The following are examples of compositions of the invention. In each case, the active ingredient and the dispersing agent were first mixed together by the method described above in relation to vincamine, and the other ingredients then added. Where appropriate, the mixture was then introduced into sachets or capsules.

1. Single dose sachets vincamine 0.020 g dispersing agent (microcolloidal silica) 0.120g lactose 2.500 g 2. Single dose sachets vincanol 0.015 g dispersing agent (cellulose) 0.150 g mannitol 2.000 g 3. Gelatin capsules deoxyvincamine 0.010 g dispersing agent (microcolloidal silica) 0.050 g starch q.s. to form a gelatin capsule weighing 0.115g 4. Powder vincaminol 1.200 g dispersing agent (cellulose) 40.000 g lactose 100.000 g 5. Single dose sachets vincamine 0.020 g rutine 0.040 g dispersing agent (microcolloidal silica) 0.100 g lactose 3 g 6. Gelatin capsules vincanol 0.015 g theophylline 0.030 g dispersing agent (microcolloidal silica) 0.060 g magnesium stearate 0.010 g WHAT WE CLAIM IS: 1. A pharmaceutical composition for oral administration comprising, as active ingredient, a compound of the formula

(wherein the symbols each represent a bond, only one of which is present in any one compound, R1 is hydrogen or hydroxy, and R2 is -CH2OH, -COOH, -COOCH3 or hydroxy, or R' and R2 together represent oxo) or a pharmaceutically acceptable salt, ester, amide or N-oxide thereof, together with a dispersing agent.

2. A composition as claimed in claim 1 wherein the active ingredient is vincamine.

3. A composition as claimed in claim 1 wherein the active ingredient is vincaminic acid, apovincamine, apovincaminic acid, deoxyvincamine, deoxyvincaminic acid, vincaminol, vincanol or vincamone.

4. A composition as claimed in any of the preceding claims wherein the active ingredient is in the form of a stereoisomer or a racemic mixture thereof.

5. A composition as claimed in any of the preceding claims wherein the weight ratio of dispersing agent to active ingredient is between 1:1 and 100:1.

6. A composition as claimed in claim 5 wherein the weight ratio of dispersing agent to active ingredient is between 4:1 and 20:1.

7. A composition as claimed in any of the preceding claims wherein the dispersing agent is cellulose, a purified phospholipid or colloidal silica.

8. A composition as claimed in claim 7 wherein the cellulose derivative is methyl cellulose containing 2633% of methoxy groups.

9. A composition as claimed in claim 7 wherein the phospholipid is phosphatidyl inositol.

10. A composition as claimed in claim 7 wherein the colloidal silica is microcolloidal silica obtained by pyrolysis of silicon tetrachloride in an oxyhydrogen flame, having a surface area according to B.E.T. of from 80 to 380m2.g-1.

11. A composition as claimed in claim 10 wherein the microlloidal silica has a surface area according to B.E.T. of 200 + 25 m2.gl.

12. A composition as claimed in claim 10 or claim 11 wherein the dispersing agent is in the form of particles having a particle diameter of 7 to 40 nm.

13. A composition as claimed in any of the preceding claims which additionally

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

Claims

**WARNING** start of CLMS field may overlap end of DESC **. agent were first mixed together by the method described above in relation to vincamine, and the other ingredients then added. Where appropriate, the mixture was then introduced into sachets or capsules.

13. A composition as claimed in any of the preceding claims which additionally

comprises a pharmaceutically inactive water-soluble excipient.

14. A composition as claimed in claim 14 wherein water-soluble excipient comprises fructose or mannitol.

15. A composition as claimed in either of claims 14 and 15 wherein the water-soluble excipient is present in a weight ratio of soluble excipient to active ingredient of from 100:1 to 250:1.

16. A composition as claimed in any of the preceding claims in the form of vials, gelatin capsules, single dose sachets or cachets.

17. A composition as claimed in any of the preceding claims in dosage unit form.

18. A composition as claimed in claim 17 wherein each dosage unit comprises 10 to 1200mg of the said active ingredient and from 0.010 to 40g of dispersing agent.

19. A composition as claimed in claim 18 wherein each dosage unit comprises 0.05 to Ig of dispersing agent.

20. A composition as claimed in any of the preceding claims dispersed in a pharmaceutically acceptable liquid carrier.

21. A composition as claimed in any one of claims 1 to 19 in dry form.

22. A pharmaceutical composition substantially as described herein in any one of the Examples.

23. A method of preparing a composition as claimed in any one of claims 1 to 19 which comprises evaporating to dryness a suspension or solution of the active compound and the dispersing agent in a volatile liquid medium.