GB2047096A

GB2047096A - Naftidrofuryl composition for immediate and delayed release

Info

Publication number: GB2047096A
Application number: GB8011487A
Authority: GB
Original assignee: Sanofi SA
Current assignee: Sanofi SA
Priority date: 1979-04-09
Filing date: 1980-04-08
Publication date: 1980-11-26
Also published as: BE882706A; IT1130110B; ES490877A0; IL59765A0; ES8100881A1; FR2453639B1; IL59765A; GB2047096B; IT8067532A0; FR2453639A1

Abstract

A pharmaceutical composition containing naftidrofuryl comprises: a) microgranules for the immediate release of naftidrofuryl, each of which comprises a carrier particle to which naftidrofuryl is fixed; and b) microgranules for the controlled release of naftidrofuryl, each of which comprises a carrier particle to which naftidrofuryl is fixed and which is covered with a coating of a methacrylic acid polymer or a polymethacrylate. o

Description

SPECIFICATION A pharmaceutical composition containing naftidrofuryl The present invention is concerned with a pharmaceutical composition containing naftidrofuryl.

N-Diethylaminoethyl ss-(1-naphthyl)-ss-tetrahydrofuryl isobutyrate, which is also known as naftidrofuryl, is used for the treatment of arteritis of the limbs, Raynaud's disease and cerebral circulatory insufficiency. It is usually administered parenterally in the form of the base or of a salt with a pharmaceutically acceptable inorganic or organic acid at a daily dose of 40 to 240 mg., by direct injection or slow perfusion, or orally at a daily dose of 300 mg. in the form of dosage units with immediate action containing 50 mg. or 100 mg. of active material.

French Patent Specification No. 77/00810 describes a galenical form of naftidrofuryl with a prolonged therapeutic activity in the form of a coated tablet which is intended to avoid any discontinuity in cerebral irrigation.

It is an object of the present invention to provide novel galenical compositions of naftidrofuryl, in the form of the base or of a salt with a pharmaceutically acceptable inorganic or organic acid, which permits a controlled release of the active material. These compositions are in the form of dosage units with immediate/delayed action, which have the advantage that they immediately release a fairly large loading dose, the subsequent release of naftidrofuryl being sufficiently uniform over 12 hours. Consequently, the use of the medicament is improved and therapeutic protection is thus obtained throughout the nycthemeron, the programmed release ensuring a stable plasma level which is maintained for a long time.

Thus, according to the present invention, there is provided a pharmaceutical composition containing naftidrofuryl, which comprises: a) microgranules for the immediate release of naftidrofuryl, each of which comprises a carrier particle to which naftidrofuryl is fixed; and b) microgranules for the controlled release of naftidrofuryl, each of which comprises a carrier particle to which naftidrofuryl is fixed and which is covered with a coating of a methacrylic acid polymer or a polymethacrylate.

Thus, in the composition according to the present invention, each dosage unit simultaneously contains microgranules of naftidrofuryl, in the form of the base or of a salt with a pharmaceutically acceptable inorganic or organic acid, for immediate release and microgranules of naftidrofuryl, also in the form of the base or of a salt with a pharmaceutically acceptable inorganic or organic acid, for programmed release, the proportions used of the two kinds of microgranules making it possible to obtain dissolution kinetics having characteristics which are such that, under selected experimental conditions, i.e. in artificial media, 30 to 35% by weight of the total amount of the naftidrofuryl present in each dosage unit is released in the course of 10 minutes.The dissolution kinetics then make it possible to obtain the release of 50% of the naftidrofuryl in the course of 1 hour, the amount of active principle released reaching 75% after 4 hours and 100% after 8 hours.

In order to obtain the naftidrofuryl microgranules for immediate release, the active principle can be fixed to carrier particles of about 500 to 600cm diameter. The carrier particles can be obtained by successively coating a grain of sugar with a sugar syrup containing maize starch, talc and an excipient, such as polyvidone, the sugar preferably representing from 50 to 80% of the weight of the carrier particle, the starch preferably representing from 10 to 25% of this weight and the talc preferably representing from 10 to 25% of this weight, especially in the case of microgranules for controlled release. The naftidrofuryl is fixed in the form of an alcoholic solution and preferably of an alkanolic solution, to these microgranules having the desired particle size. The finished microgranules are dried in an oven and then submitted to a control.

In order to obtain the naftidrofuryl microgranules with a controlled release, the carrier particles are produced under the same conditions as above and the naftidrofuryl is fixed in alcoholic solution. These particles are spray coated with an alcoholic solution, preferably an alkanolic solution and more preferably an ethanolic solution of a methacrylic acid polymer or of a poly-(lower alkyl methacrylate), the spray coating operation being interrupted from time to time for powdering with talc and drying in an oven. The polymer coating preferably represents from 3 to 15% of the weight of the microgranules for controlled release.

It is also possible to introduce into a mixer a mixture of 5 parts by volume of acetone and 2 parts by volume of isopropanol, in which cellulose hydroxypropylmethylphthalate is dissolved. An isopropanolic solution of a polymer based on methacrylic acid and methyl methacrylate is then added, followed by the addition of naftidrofuryl, a suspension being formed. The carrier particles are introduced into a drageeing kettle and the above suspension is sprayed on to the carrier particles. After each coating step, the rate of release of the active principle is checked and the various operations are continued until the desired degree of controlled release is obtained. The naftidrofuryl fixed to each carrier particle represents from 200 to 800% of the weight of the particle. The finished microgranules are then again submitted to a control.

The following Example is given for the purpose of illustrating the present invention: Example In order to produce 50,000 dosage units, each containing 150 mg. of naftidrofuryl, 50 mg. of which are for immediate release and 100 mg. for controlled release, naftidrofuryl microgranulesfor immediate release are prepared first. Carrier particles with a diameter of from 500 to 600 jl are produced using about 0.815 kg. of sucrose, 0.195 kg. of maize starch, 0.195 kg. of talc and 0.045 kg. of polyvidone excipient, 2.500 kg. of naftidrofuryl being fixed thereto.The naftidrofuryl microgranules for controlled release are prepared next; 7.5 kg. of naftidrofuryl are fixed to the carrier particles which are composed of 1.45 kg. of sucrose,0.363 of corn starch,3.862 of or talc,0.08 of or polyvidone and 0.450 kg. of methacrylic acid polymer.

The proportions of the microgranules for immediate release and the microgranules for controlled release are defined in accordance with the desired dissolution kinetics, dissolution in aqueous solution releasing the following proportions by weight of naftidrofuryl: at pH 1.5, after 10 minutes, from 30 to 35%, preferably about 33%; after 50 minutes, from 35 to 45%, preferably about 38%; at pH 4.5 and at pH 6.9, after 3 hours, 59%; and at pH 7.2 and at pH 7.5, after 4 hours, 100%.

A toxicological study of the naftidrofuryl dosage units for immediate/delayed release was carried out and compared with naftidrofuryl dosage units without controlled release. After pulverising the contents of the dosage units and suspending the powder obtained in a 5% by weight aqueous solution of gum arabic, the suspension thus obtained was administered, by stomach probe to Swiss mice and to Wistar rats, the animals being equally divided between the two sexes, each dose studied being administered to groups of 5 males and 5 females.The experimental results obtained, expressed as the LD 50/kg., are as follows: LD 50/kg. non-controlled Naftidrofuryl naftidrofuryl with immediate/ delayed action Mice 1,342 mg. on admini- 1.389 mg. on admini stration stration 1,152 mg./24 hours 1,032 mg./24 hours 820 mg./48 hours 810 mg./48 hours 750 mg./72 hours/ 762 mg/72 hours/ 8 days 8 days Rats 3,370 mg./24 hours 3,143 mg./24 hours 2,460 mg./48 hours/ 2,692 mg./48 hours/ 72 hours/8 days 72 hours/8 days It can be seen from this Table that the acute toxicity of the non-controlled naftidrofuryl is essentially identical to that of the naftidrofuryl with immediate/delayed action. Consequently, the galenical form of the active principle in a controlled form does not modify the acute toxicity of the naftidrofuryl.

Experiments were carried out on humans in order to test the immediate/delayed effect of the new compositions in comparison with naftidrofuryl which was also presented in dosage unit form but without any controlled effect. The experiments were carried out on 4 females and 2 males, these subjects being free of cardiovascular, renal, hepatic and gastrointestinal disorders and not having received any medicaments on the preceding days or during the period of study. Each subject received either 300 mg. of non-controlled naftidrofuryl or 300 mg. of naftidrofuryl with immediate/delayed action, according to the present invention.

The blood levels of naftidrofuryl were measured at 0 (before administration) and 0.5, 1, 1.5,2, 3,4,6,8 and 12 hours after administration of the test compositions, samples of venous blood being collected by puncture at the fold of the elbow, through a heparin-treated and fluorinated tube. The naftidrofuryl content of the plasma was determined by spectrophotometry.

The average results obtained, expressed as ,ug/ml, are set out in the following Table: Sampling non-controlled Naftidrofuryl with time naftidrofuryl immediate/delayed (hours) action 0.5 1.32 + 0.05 0.43 + 0.01 1 1.62 + 0.04 0.61 + 0.04 1.5 0.86* 0.04 0.77 + 0.01 2 0.51 + 0.03 0.85 + 0.05 3 0.26 + 0.02 0.77 + 0.05 4 0.17 + 0.02 0.44*0.02 6 0.10 i 0.01 0.27 + 0.01 8 0.03 + 0.01 0.21 + 0.01 12 0.01 0.13 + 0.02 surface areas under the 2.849 + 0.119 4.268 + 0.179 curves This Table shows that, after administration of the immediate/delayed form, the plasma levels are less than those obtained with the comparison non-controlled naftidrofuryl during the first hour, are essentially identical after 1.5 hours and are always greater for the immediate/delayed form up to 12 hours. In other words, the immediate/delayed form makes it possible to obtain a more stable plasma level by lowering the peak obtained with the non-controlled form and by giving a greater area, the level thus being sustained for a longer time; this renders the new composition more suitable for its therapeutic function and demonstrates the clinical value of this new composition, containing the same dose of naftidrofuryl, for the treatment of arteritis of the limbs, Raynaud's disease and cerebral circulatory insufficiency.

Claims

1. A pharmaceutical composition containing naftidrofuryl, which comprises: a) microgranules for the immediate release of naftidrofuryl, each of which comprises a carrier particle to which naftidrofuryl is fixed; and b) microgranules for the controlled release of naftidrofuryl, each of which comprises a carrier particle to which naftidrofuryl is fixed and which is covered with a coating of a methacrylic acid polymer or a polymethacrylate.

2. A composition according to claim 1, wherein the proportion of microgranules for immediate release and of those for controlled release is such that, in aqueous solution at pH 1.5, the composition releases from 30 to 35% and preferably about 33% of the weight of naftidrofuryl present therein, in the course of 10 minutes.

3. A composition according to claim 1 or 2, wherein the proportion of microgranules for immediate release and of those for controlled release is such that, in aqueous solution at pH 1.5, the composition releases from 35 to 45% and preferably about 38% of the weight of naftidrofuryl present therein, in the course of 50 minutes.

4. A composition according to any of the preceding claims wherein the proportion of microgranules for immediate release and of those for controlled release is such that, in aqueous solution at pH 4.5 or 6.9, the composition releases from 50 to 70% and preferably about 50% of the weight of naftidrofuryl present therein, in the course of 3 hours.

5. A composition according to any of the preceding claims, wherein the proportion of microgranules for immediate release and of those for controlled release is such that, in aqueous solution at pH 7.2 or 7.5, the composition releases all the naftidrofuryl present therein, in the course of 4 hours.

6. A composition according to claim 1, wherein the microgranules for immediate release represent from 20 to 35% by weight of the composition.

7. A composition according to any of the preceding claims, wherein each carrier particle has a diameter of 500 to 600 microns.

8. A composition according to any of the preceding claims, wherein each carrier particle comprises a grain of sugar coated with a sugar syrup containing maize starch, talc and an excipient, the sugar preferably representing from 50 to 80% of the weight of the carrier grain, the maize starch representing from 10 to 25% of this weight and the talc representing from 10 to 25% of this weight.

9. A composition according to claim 8, wherein the naftidrofuryl fixed each carrier particle represents from 200 to 800% of the weight of this particle.

10. A composition according to any of the preceding claims, wherein the methacrylic acid polymer or the polymethacrylate represents from 3 to 15% of the weight of the microgranules for controlled release.

11. A pharmaceutical composition according to claim 1 containing naftidrofuryl, substantially as hereinbefore described and exemplified.