GB2243779A - Pharmaceutical formulations containing vincamine for the treatment of periphera vascular diseases - Google Patents

Abstract

Vincamine is used for treating peripheral vascular disease for example acrocyanosis or Raynaud's disease by applying vincamine, or a pharmacologically acceptable salt thereof, topically to the skin overlying the site where the vasodilatory effect is required. The use of vincamine, or a pharmacologically acceptable salt thereof, in the manufacture of a pharmaceutical composition for use in such methods is also disclosed.

Description

k PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT OF PERIPHERAL VASCULAR

DISEASES The present invention relates to the treatment of peripheral vascular diseases of functional origin, including acrocyanosis, Raynaud's syndrome and related symptoms of peripheral vascular insufficiency, for example vasospasm in the extremities brought on by cold and trophic skin disturbances. The invention further relates to pharmaceutical compositions for use in such treatments.

Vincamine is an indole alkaloid and was first isolated from Vinea minor L. , a plant belonging to the Apocynaceae family.

The active principle can be obtained in its pure state by extraction from the plant or, alternatively, by partial synthesis (from the indole alkaloid tabersonine) or by total synthesis.

Vincamine has pharmacological properties which have been found to be of therapeutic value in the treatment of cerebrovascular diseases. It is, in fact, capable of improving the cerebral blood flow by exerting a vasodilatory effect on encephalic blood vessels, thereby permitting redistribution of the flow to the benefit of ischaemic regions. Vincamine also intervenes in neuronal metabolism, improving the utilization of glucose and oxygen.

In addition to this cerebral activity, vincamine can exert hypotensive effects resulting from dilatation of the peripheral vascular bed.

The hypotensive action may be clearly demonstrated when the drug is administered parenterally and is dose-related. However, when the drug is administered by mouth, the hypotensive action is negligible.

j Consequently, the use of vincamine as a hypotensive agent has not been proposed as one of the clinical applications of the drug. This is primarily because in order to achieve a significant pharmacological response, it would be necessary to raise the dose to a level that would produce undesirable side effects, particularly on the heart.

EP-A-0 266 968 discloses gelled ointments containing a vasodilating agent which is a member of the group consisting of papaverine, procaine. theophylline, nicotinic acid, verapamil and vincamine and their use in countering human erectile failure. The only ointments specifically described contain papaverine as active ingredient and no pharmacological data is presented in relation to any other vasodilatory agent.

The vasodilatory substances disclosed in EP-A-0 266 968 comprise heterogeneous group of drugs with different mechanisms of action. Up to now they have been used in different therapies as stated in the following table.

Drug Mechanism of action Therapeutical use Procaine Nervous transmission Local anesthetic modulator Theophylline Phosphodiesterase Antiasthma inhibitor Nicotinic acid Smooth muscle relaxant Vasodilator Verapamil Calcium antogonist Antihypertensive, antiangine Papaverine Phosphodiesterase Myorelaxant inhibitor Vincamine Phosphodiesterase Cerebral antiischemic inhibitor i i Thus the data contained in EP-A-0 266 968 relating to the effect of papaverine on the stimulation of erections in human males following application of topical compositions thereof to the penis allows no forecast to be made of the effects of similar use of any of the other vasodilatory agent referred to. Also in view of the peculiar anatomical structure of the vessels of the cavernous body (corpora. cavernosa) it is not possible to extrapolate effects claimed for application of papaverine to the penis to other parts of the body.

In this regard the cavernous spaces, considered by some authors to be venous cavities, are in reality capillaries which are unusually dilated and richly anastomosed. These cavernous spaces are lined with a layer of smooth muscle cells constituting a contractile structure around the vascular cavities. This contractile structure is a feature not found in other body capillaries. Therefore the capillaries of the corpora cavernosa differ significantly from those of other tissues in that they have the capacity to contract (which is fundamental in carrying out its particular functions). Also the arteries that bring blood to the erectile tissues, so-called helicine arteries, are different from those of other tissues and have the function of filling the cavernous spaces at the moment of erection.

Because of these particular anatomical characterists the vascular bed of the penis cannot be compared with that of other tissues.

It has now surprisingly been found that vincamine, when applied topically to the skin in the treatment of peripheral vascular diseases, promotes a vasodilatory effect which is essentially limited to the region underlying the area of application, but without producing systemic vasodilatory effects.

Comparable peripheral vasodilatory effects are not obtained when vincamine is administered orally, even with doses as much as 5 times the topical doses and close to the tolerance limit.

Thus according to one aspect of the present invention, there is provided a method of treating peripheral vascular disease in a subject so as to obtain a local vasodilatory effect which comprises applying vincamine, or a pharmacologically acceptable salt thereof, topically to the skin overlying the site where the vasodilatory effect is required.

The invention further provides the use of vincamine, or a pharmacologically acceptable salt thereof, in the manufacture of a pharmaceutical composition for treating peripheral vascular disease in a subject so as to obtain a local vasodilatory effect by applying vincamine, or a pharmacologically acceptable salt thereof, topically to the skin overlying the site where the vasodilatory effect is required.

Topical pharmaceutical compositions for treating peripheral vascular disease in a subject so as to obtain a local vasodilatory effect, said composition comprising vincamine, or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable excipient form a further aspect of the invention.

It is to be understood that the term "peripheral vascular disease" as used herein, refers to diseases involving the peripheral capillaries, as in acrocyanosis and Raynaud's disease and does not encompass conditions associated with male impotence involving the cavernous body of the penis. Thus the term "topically" as used herein specifically excludes application to the penis.

Preferred forms of administration are as creams, ointments, gels and lotions.

The concentration of vincamine is preferably between 0.1 and 10 wt%, preferably between 0.5 and 3 wt%. Pharmaceutically acceptable excipients which may be used include natural and synthetic waxes, petroleum oils, polyoxyethlene polymers, buffering and stabilizing agents, preservatives and perfuming agents. Examples include cetostearyl alcohol, isopropyl myristate, glycols, for example glycerol, polysorbates, vegetable oils, lecithin and other substances belonging to the class of the phytosterols and glucosaminoglycans, particularly ones indicated for topical use.

Examples of pharmacologically acceptable salts of vincamine which may be used according to the invention include salts with inorganic anions e.g. the chloride, sulphate and phospate salts as well as salts with organic anions, e.g. acetates and citrates.

As indicated previously, the methods, compositions and uses according to the invention particularly concerns treatment of peripheral vascular diseases such as acrocyanosis and Raynaud's disease.

The capacity of vincamine to elicit a vasodilatory effect in an animal model is illustrated by the following pharmacological tests.

1. EFFECT ON PERIPHERAL CIRCULATION The topical effect of vincamine on peripheral circulation was assessed by the method of measuring skin temperature in the mouse. It is well known that one of the simplest non-invasive tests for measuring the peripheral circulation is based on the registering of skin temperature (1,2'3). Changes in skin temperature correlate with changes in the blood flow in the subjacent vascular bed: rises in temperature are produced by vasodilatory substances and falls in temperature by vasoconstrictive substances.

The topical activity of vincamine cream was assessed in 75 male Swiss mice with a mean weight of 31.0:tO.3 9. which were housed in rooms at a temperature of 21tlC and relative humidity of 50t5% and fed on standard feed with water ad Libitum.

The skin temperature was measured in the plantar aponeurosis of the hindpaws by leaving a heat-sensitive probe, type TM-16S, connected to a Termist II device (L.S.I., Settala, Milan, Italy) in contact with the skin for 20 seconds.

The mice were divided by randomization into 4 groups of 15 animals, which were treated as follows:

Group 1 Controls: 100 mg of placebo cream were applied to the dorsum of the right forepaw and gently massaged in for 30 seconds.

Group 2 100 mg of cream containing 2% vincamine base were applied to the dorsum of the right paw and massaged in as in group 1.

Group 3 - 100 mg cream containing 0.5% vincamine base were applied to the dorsum of the right paw and massaged in as in group 1.

Group 4 - Controls: 10 ml/kg of a 0.5% aqueous solution of Methocel were administered orally via a stomach tube.

Group 5 - 300 mg/kg vincamine base, suspended in 10 ml/kg Methocel, as in group 4, were administered orally via a stomach tube.

The quantity of vincamine base administered orally corresponds to 4.5 times that administered topically in the 2% cream.

In all the animals the skin temperature was measured on both the right and the left paw before and 30, 60, go, 120, 150 and 180 minutes after the treatment. The results were subjected to statistical analysis by variance analysis in a split-plot design.

The results obtained are shown in Table 1. It can be seen that in the animals treated with 100 mg placebo cream applied topically and those treated with 10 ml/kg 0.5% Methocel administered orally there were no significant changes in the skin temperature from the initial values in either paw throughout the experimental period. There were no significant differences between the areas under the curves (AUC) for the temperature of the right paws and those for the temperature of the left paws.

In the animals treated with 100 mg 2% vincamine cream, the right paw showed statistically significant increases in temperature from the initial values from one hour after application onwards. By contrast, there was no statistically significant change in the temperature of the contralateral, untreated paw. The AUC for the right paw was significantly greater than both that in the controls and that for the left, untreated paw. There was no difference between the AUC for the left paw and that in the controls.

In the animals treated with 100 mg 0.5% vincamine cream, the right, treated paw showed significant increases in temperature from the initial values from 90 minutes after application. However, these increases were smaller than those produced by an equal quantity of 2% cream, and the area under the curve for the right paw in the animals treated with the 0. 5% cream was about half that in the animals treated with 2% cream. Again in this group, the AUC for the right paw was significantly greater than that for the right paw in the controls, while there was no significant difference between the AUC for the left paw and that in the controls.

TABLE 1 - Skin temperature in the mouse Changes in OC in the right paw (RP) and the left paw (LP) compared with the initial values (Mean + S.E).

Substance Number of Paw Basal Animals Temp. 30' 6o, 901 1201 150' 1801 AUC Placebo RP 23.4to.13 -0.11 0.08 0.17 0.06 0.05tO.O5 0.15 0.04 0.09 0.09 o. lg o.o6 13.6o 5.89 cream 15 10Offig LP 23.3 0.14 -0.04 0.08 0.03 0.08 0.20 0.06 0.23 0.03 0.19 0.07 0. 21 0.05 21.2 6.75 Vincamine RP 23.1 0.15 -0.09 0.10 0.49 0.13 0.68 0.08 0.68 0.08 0.68 0.07 0.60 0.06 82.2 11.05 cream 2% 15 I" L#J 10Offig LP 23.1 0.15 -0.04 0.09 0.19 0.10 0.27 0.06 0.19 0.05 0.24 0.06 0. 27 0.06 31.60t9.66 Vincamine BP 23.3 0.11 0.02 0.13 0.10 0.08 0.30 0.09 0.42 0.09 0.49 0.10 0.35 0.07 43.95 10.50 cream 0.5% 15 10Offig LP 23.2 0.20 0.03 0.11 -0.05 0.12 o.16 o.05 0.15 0.06 0.17 0.08 0. 20 0.04 16.80 8.93 Control RP 23.5 0.12 0.04 0.08 0.03 0.06 0.15 0.08 0.13 0.07 0.20 0.06 0. 16 0.07 18.80 7.70 Methocel 15 0.5% os LP 23.4 o.13 -0.08 0.10 0.00 0.07 o.o4 o.lo 0.11to.08 0.13 0.05 0. 12 0.06 7.8o 9.42 Vincamine RP 23.4 0.10 0.05 0.09 0.07tO.O9 o.o4 o.lo 0.20 0.09 0.20 0.08 0.17 0.06 19.40 9.81 300mg/kg 15 LP 23.3 0.12 -0.09 0.09 0.04 0.11 0.07t0.10 0.09 0.09 0.20 0.06 0.21 0.06 12.1ttlo.45 P < 0.05 vs. all the groups p < 0.01 vs. all the groups Variance analysis in a split-plot design v 1.1 Vincamine base, administered by mouth in a dose of 300 mg/kg, produced no temperature changes in either of the two paws. The AUC values were no different from those in the controls treated orally with 10 ml/kg 0.5% Methocel.

It can therefore be concluded that vincamine, when applied locally to the paw, penetrates into the dermis and causes the blood flow in the underlying vascular bed to increase without inducing a systemic effect. The absence of a systemic effect is demonstrated by the absence of temperature changes in the contralateral, untreated paw.

By contrast, when vincamine is administered by mouth, even in a higher dose than that applied locally, it fails to produce any change in the peripheral blood flow.

This lack of effect can be attributed to the negative inotropic effect of vincamine, which means that the dilatation of the peripheral blood vessels is not accompanied by an increase in the cardiac output and hence in the peripheral blood flow.

2. SYSTEMIC TOXICITY - SINGLE DOSE The acute toxicity of a single dose of vincamine was determined in Swiss mice of both sexes-weighing 30 g by administering vincamine base intravenously, intraperitoneally or via a stomach tube and recording the numbers of deaths during the subsequent 15 days.

The LD 50 values, calculated by the method of Litchfield and Wilcoxon (4), were: 85 (75-95) mg/kg for the intravenous route, 220 (200-242) mg/kg for the intraperitoneal route and 915 (795-1053) mg/kg for the oral route.

3. LOCAL TOLERABILITY The local tolerability on intact and abraded skin was determined by applying 500 mg cream to a depilated area of skin in the mouse measuring 3A cm (roughly equivalent to one third of the total body surface). Swiss mice of both sexes with a mean weight of approximately 30 g were used in this test. In half of the animals the skin was left intact, while in the other half it was scarified.

Local reactions, signs of toxicity and deaths were recorded over the 15day period following application.

The cream was tolerated perfectly, both in the animals with intact skin and in those with abraded skin, and it caused no deaths or signs of local irritation.

4. COMPARISON EXPERIMENTS The peripheral vasodilator activity of vincamine (measured as cutaneous temperature variation in the mouse after topical application) has been compared to the following drugs: nicotinic acid, procaine and Verapamil. The results demonstrate that:

(1) the vasodilator activity of both nicotinic acid (Table 2) and procaine (Table 3) is clearly inferior to that of vincamine (Table 2) which is the only drug that develops a satistically significant effect.

(2) In the used experimental pattern Verapamil develops a statistically significant effect contrary to that of vincamine (Table 4).

-1 1 4 I Table 2

Vincamine and Nicotinic Acid - Activity on Cutaneous Temperature in Nice Dose N. of Preparations Resting Values Area Under Curve Variations in AUC mg/wouse Animals Controls-Natrosol R 2% gel 100 12 23.0 0.1 58.6 t 17.7 Vincamine base 2.5% cream 100 12 22.9 0.1 133.5 19.6 +127.8 Nicotinic acid 2.5% gel 100 12 23.0 0.1 94.0 22.9 + 6o.4 P < 0.05 two-taJled Dunnett t test Table 3

Procaine - Activity on Cutaneous Temperature in Mice Dose N. of Preparations Resting Values Area Under Curve Variations in AUC mg/mouse Animals Controls-Natrosol R 2% gel 100 12 22.7 0.1 91.8 10.5 Procaine.HCl 2.5% gel 100 12 23.0 0.1 107.9 20.4 + 17.5 Procaine.HCl 5% gel 100 12 23.1 0.1 1o6.o 18.1 + 15.5 4 1 0 1 Table 4

Verapamil - Activity on Cutaneous Temperature in Mice Dose N. of Preparations Resting Values Area Under Curve Variations in AUC mg/mouse Animals Controls-Natrosol R 2% gel 100 16 22.8 0.1 89.0 7.5 Verapamil.HCl 0.25% gel 100 16 22.7 0.1 58.2 8.9 - 34.6 P < 0.05 two-tailed Dunnett t test -14The examples below describe embodiments of pharmaceutical compositions according to the invention, without constituting any limitation.

Example 1: 2% cream 100 g cream contain:

- vincamine cetostearyl alcohol isopropyl myristate propylene glycol polysorbate 60 citric acid methyl p-hydroxybenzoate purified water Example 2: 1% gel 100 g gel contain: vincamine - propylene glycol hydroxyethylcellulose tartaric acid polysorbate 60 methyl p-hydroxybenzoate - purified water 2.0 g 12.0 6.o 5.0 3.8 0.3 0.2 70.7 g 9 9 9 9 9 1.0 g 5.0 2.0 0.5 0.2 0.2 1.1 9 9 9 9 9 9 k Example_3: 2% lotion Example 4: 0.5% cream Example 5: 2% ml lotion contain: vincamine propylene glycol tartaric acid polysorbate 60 methyl p-hydroxybenzoate 0.1 g purified water q.b. to 100 M1 2.0 g 10.0 0.9 g 0.2 g 9 106 -g cream-contain: vincamine soya lecithin cetostearyl alcohol polysorbate 60 methyl p-hydroxybenzoate purified water cream 100 g cream contain: vincamihe cetostearyl alcohol polysorbate 60 glucosaminoglycans methyl p-hydroxybenzoate purified water 0.5 g 10.0 g 15.0 5.0 0.2 69.3 9 9 9 9 2.0 g 15.0 3.0 5.0 0.2 74.8 9 9 9 9 9 REFERENCES 1) Richter; Acta Pharmacol. et Toxicol., 21(l), 91, 1964 2) Kramer, Lochner, Wetterer; Varied methods and instruments for flow measurements, in Hamilton, W.K.: Handbook of Physiology, Washington D.C.: Am. Physiol. Soc., 1963, Sect. 2, vol. II, p. 1277 3) Green; Blood Flow Measurement, in Potter, V.R.: Methods in Medical Research, Chicago, The Year Book Publishers, 1948, vol. I. P. 66.

4) Litchfield, Wilcoxon; J. Pharm. exp. Ther., 96, 99, 1949

01 1 0 1. A method of treating peripheral vascular disease in a subject so as to obtain a local vasodilatory effect, which comprises applying vincamine, or a pharmacologically acceptable salt thereof, topically to the skin overlying the site where the vasodilatory effect is required.

Claims (1)

1. 2. A method according to Claim 1 wherein said disease is acrocyanosis or

   Raynaud's disease.

   3. The use of vincamine, or a pharmacologically acceptable salt thereof, in the manufacture of a pharmaceutical composition for treating peripheral vascular disease in a subject so as to obtain a local vasodilatory effect in a subject, by a method which comprises applying vincamine, or a pharmacologically acceptable salt thereof, topically to the skin overlying the site where the vasodilatory effect is required.

   4. The use according to Claim 3 wherein said disease is acrocyanosis or Raynaud's disease.

   5. A topical pharmaceutical composition for treating peripheral vascular disease in a subject so as to obtain a local.

   vasodilatory effect in a subject, said composition comprising vincamine, or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable excipient.

   6. A pharmaceutical composition according to Claim 5 in the form of an ointment, cream, lotion or gel.

   7. A pharmaceutical composition according to Claim 5 or Claim 6 3 containing from 0.1 to 10 wt% of said vincamine or pharmacologically acceptable salt.

   8. A pharmaceutical composition according to Claim 7 containing from 0.5 to 3.0 wt% of said vincamine or pharmacologically acceptable salt.

   Published 1991 at The Patent Office. Concept House. Cardiff Road, Newport. Gwent NP9 I RH. Further copies may be obtained frorn Sales Branch, Unit 6. Nine Mile Point, Cwmielinfach, Cross Keys, Newport. NPI 7HZ. Printed by Multiplex techniques lid. St Mary Cray, Kent.