NL8302416A - DELAYED MEDICINAL PRODUCT CONTAINING SULOCTIDIL. - Google Patents

Description

1-4 i * t * -1- VO 4937

Delayed acting medicine containing suloctidil.

Suloctidil or 1- [p- (isopropylthio) -phenyl] -2-octylamino-1-propanol is an activating agent for the central and peripheral artery micro-cycle, which is used in a therapy of chronic brain circulation insufficiency.

5 It has been marketed in a number of countries, including Italy, where it is sold under different names such as Loeton.

Later experience has confirmed that this product is effective and well tolerated. However, the medicine has the drawback that it disappears out of the patient's body very quickly.

Thus, if the blood concentration of the drug is plotted against time, after a single administration the drug concentration will rapidly drop below the desired therapeutic concentration. This problem has so far been counteracted by administering the drug several times a day (usually three times a day).

The invention now relates to a sustained-release suloctidil formulation suitable for oral administration. By delayed release is meant that the drug is initially made available to the body in an amount sufficient or slightly excess compared to the amount required for the desired pharmacological effect as soon as possible given the absorption properties. of the drug, while the activity is maintained at the desired level for several hours, which number is greater than usual achieved with a conventional single dose.

The main advantage of this extended acting product is that the medicine is released slowly but constantly to the organism. A further advantage of the product is that the daily administration can be reduced to two times, one in the morning and the other in the evening, so that the number of missed administrations can be limited by forgetting. This benefit is not negligible, since missed administrations, especially in elderly patients, who often need this medicine, are a very practical problem,

The invention therefore relates to a tablet with two separate pieces, one piece that immediately releases the drug and a second piece, which slowly releases the drug. The two pieces of the tablet can be combined in a variety of ways into a dosage form which quickly yields the initially desired Suloctidil level and maintains this level for a long time.

A preferred tablet is in the shape of a cow's eye, i.e.

of a tablet with slow-release product, within which a smaller tablet is located with the fast-dispensing recipe, which is adjacent to one of the outer surfaces (see Figure 1 of the drawing), in which the striped piece represents the quick-release piece. This tablet can be coated with sugar evenly. However, a layered tablet can also be prepared (see Figures 2 and 3), in which two or three separate layers are granulated, which either release the drug slowly or rapidly and are processed into a tablet, or an inner core with a slow releasing material surrounded by an outer component with fast releasing material, the latter optionally in the form of a coating shell (see Figure 4 of the drawing). Preferably, but not necessarily, of course, the fast-release and slow-release granules are colored differently.

The amount of Suloctidil in the two pieces of the tablet as well as the final shape and size of the tablet can vary within wide limits, although a suitable tablet size must of course be maintained for a suitable posology. Tablets with 100-400 mg of Suloctidil are usually preferred, with tablets containing 200-350 mg of active substance being most preferred. Usually, the fast-releasing piece is granulated such that it disintegrates quickly after ingestion, thereby rapidly achieving the desired level, while the slow-releasing piece is formulated to further release the drug slowly and substantially at a constant rate.

The rapid release portion of the tablet comprises about 12-25% of the total tablet weight of Suloctidil. The remainder of the rapid release portion comprises 10-30% of the total tablet weight of inert pharmaceutical excipients. These excipients include, for example, diluents, such as inert substances, which increase the volume of the tablet, such as calcium phosphate, calcium sulfate, calcium carbonate, kaolin, mannitol, corn flour, silicon dioxide, and the like; further binders for increasing the consistency of the powdery material, such as starch, gelatin, sugars, 8302416% by weight of natural and synthetic gums; further lubricants, which must prevent adhesion to the tabletting machine when the tablets are beaten, such as precipitated silica, magnesium stearate, calcium stearate, stearic acid, calcium phosphate, sodium bicarbonate and the like, as well as disintegrants, ie substances which rapidly disintegrate the tablet after administration, such as corn or potato starch, methyl cellosolve, carboxymethyl cellulose, alginic acid, polyvinylpyrrolidone, sodium lauryl sulfate, polyoxyethylene derivatives of sorbitan, esters, lecithins and the like. The specific excipients used in the rapid release piece, as well as their respective amounts are not critical and any suitable formulation with Suloctidil currently on the market can be used. Lubricants or lubricants, however, are usually used in concentrations of 0.5-6% by weight of the fast-release piece, while, in connection with the desired rapid disintegration, disintegrants are often used in concentrations of 10-50% of the quick release piece.

The slow-release portion of the tablet comprises 27-55% of the total tablet weight of Suloctidil and about 8 to 36% of the total tablet weight of inert pharmaceutical excipients. A nonionic or anionic surfactant that promotes bio-erosion of the slow-release piece must be incorporated into the slow-release pharmaceutical excipients. Among the preferred surfactants may be mentioned fatty acids of sorbitol copolymerized with ethylene oxide such as polyoxyethylene sorbitan monooleate (Tween 80), lauryl sulfates and dioctyl sulfosuccinates such as sodium lauryl sulfate and sodium dioctyl sulfosuccinate. These surfactants are used in an amount of about 0.1-2% by weight of the slow release and preferably in amounts of 0.3-0.8%. Furthermore, it is necessary to incorporate into the slow-release portion of the tablet a number of additives which control the release of the active substance. One of these is a water-soluble cellulose derivative such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or hydroxypropylmethyl cellulose. while the other is a slow polymer molecule solubilizer, usually polyethylene glycol having a molecular weight of more than 1000, which promotes bioerosion of the tablet surface. The cellulose derivative is usually used in an amount of about 2-30% of the slow release and preferably between 2 and 10%, while the polyethylene glycol can be used in an amount of about 2-15 % of the slow release, preferably between 2 and 8%. Depending on the specific cellulose derivative used, it may be necessary to add a water-soluble dehydrating agent to counteract a possible swelling effect of the cellulose derivative.

Usually a sugar is used for this in these cases.

It can be used in an amount of about 0% (when the celiac derivative has no swelling effect and therefore no dehydrating agent is required) and 20% of the weight of the slow release. For practical reasons, sugar, usually sucrose, lactose or galactose, is chosen. In addition to these additives, the slow-release portion of the tablet may contain diluents that are insoluble and non-swelling, such as calcium sulfate, calcium phosphate, silicon dioxide, talc, kaolin, and anti-adhesives, such as precipitated silica, calcium phosphates, and the like, as well as optional hydrophobic lubricants, such as magnesium stearate, calcium stearate, stearic acid, castor oil and hydrogenated fatty acid esters.

Finally, if desired, each of the two pieces may contain a dye known per se. If a tablet, as shown in Figure 4, is desired, wherein the fast-release layer, which lines the slow-release inner core, is in the form of a sugar coating, it may be made by a conventional technique by alternating sugar syrup layers with mixtures of the active substance and applying one or more inert excipients, such as silica, talc, calcium carbonate, kaolin, etc. The present tablets are manufactured in a manner known per se. In particular, the quick release and slow release pieces are manufactured and granulated separately.

Although the two pieces can be granulated both wet and dry, wet granulation is highly preferred in either case. In the slow release portion, Suloctidil is preferably first mixed with a tablet binder solution, such as a gelatin solution, glycerogelatine or a starch paste, or a corresponding binder. Then all further desired excipients are added and mixed well. After this, the whole is granulated by working it through an appropriately sized 8302416 3c i -5 sieve. The granules thus obtained are dried to the desired residual moisture content. This granulated material can then be comminuted to a smaller particle size suitable for tabletting, after which appropriate excipients can be added to prevent the granules from adhering to the dies during compression. This step can be performed by dry mixing with adsorbents such as precipitated silica, bi- or tribasic calcium phosphate, talc, etc. Finally, the granulated material is provided with the lubricants and any disintegrants.

Also for the slowly disintegrating stretch, the different excipients are gradually added to the active substance. If the formulation is too wet, causing a sticky mass, the excess water for granulation is eliminated by adding a highly adsorptive inert diluent, such as silicon dioxide. It can then be granulated by working the mixture through an appropriate sieve or using a plate with holes of appropriate sizes. In this case too, after drying the granules thus obtained, it is necessary to reduce the particle size in order to obtain a more tablable mixture. One or more anti-adhesives and lubricants are then added and mixed well with the granules. These granules, as well as those for the quick-release piece, are contacted to provide a two-piece tablet shown in the drawing by a method customary in this technique.

The following examples further illustrate the invention.

Example I

Preparation of fast-release granules

The following formulation was used to make these granules, which are the rapid release portion of 25,000 tablets: 30 Grams Ingredient

Suloctidil 2500

Calcium phosphate 50

Aerosil R V 200 125 gelatin 75 35 glycerol 25 mannitol 125 8302416 -6-

Ingredient 1 gram corn starch 1747.5 precipitated silica 100 magnesium s arate 125 5 FDC red 3 (E 127) 2.5 1) A solution of gelatin and glycerol in 450 g distilled water was added to the Suloctidil with stirring.

2) Aerosil V 200, mannitol and 1672.5 g of the corn starch were then added to the resulting mixture and then mixed together to a homogeneous mass.

3) A starch paste was prepared by mixing the rest of the cornmeal with the dye and adding 675 g of distilled water to it. This mixture was heated on a water bath until a red starch paste was obtained.

4) The starch paste was then added to the mixture obtained according to 2) and the whole was stirred until a homogeneous mass was obtained.

5) This mass was sieved through an oscillating granulator equipped with a 3-3.5 mm aperture sieve, after which the granules were dried for several hours at 40 ° C.

6) The granules obtained were passed through a sieve with openings smaller than 1.5 mm.

7) The resulting granules were then mixed with the tribasic calcium phosphate, the magnesium stearate and the precipitated silica.

Example IX

Preparation of slow-release granules

The following composition was used to make granules, which form the slow-release piece for 25,000 tablets. Ingredients grams 30 Suloctidil 5000 tribasic calcium phosphate 250

Tween 80 30 polyethylene glycol 6000 265.75 sucrose 412.5 35 Methocel A 15 300

Aerosil V 200 300 8302416 # »-7-

Ingredients grams of precipitated silica 550 magnesium stearate 166.75 1) The Methocel A 15 was added to a solution of Tween 80, 5 sucrose, polyethylene glycol 6000 and 1675 g of distilled water and heated on a water bath and the resulting mixture was cooled again with stirring .

2) The mixture obtained according to 1) was added to a mixture of Suloctidil and the calcium phosphate, while stirring until an adherent mass was obtained. The Aerosil V 200 was added to this.

3} The mass obtained was sieved through an oscillating granulator, equipped with a sieve with openings of about 6.0-6.5 mm. The resulting granules were then dried at 40 ° C for several hours, then passed through a sieve with openings less than 1.5 mm and dried for a few more hours.

4) The granules obtained according to 3) were mixed with precipitated silica and magnesium stearate.

Example III

Manufacture of a cow-eye tablet 1) The granules of 7) of Example 1 were beaten with a rotary tablet machine Ronchi AM 13/8 with 8.5 mm punches.

The resulting tablets, pink in color, were 4 + 0.1 mm thick and weighed about 195 mg.

2) Each tablet obtained according to 1) was placed * in the center of an 11.5 mm punch of a Kilian Prescoter rotary tabletting machine, which was fed with the granules obtained according to part 4) of example II. The two-part tablets thus obtained had a small pink tablet according to 1) on a surface of the final tablet weighing a total of 486 mg.

If desired, the cow eye tablets can also be prepared by placing a small fast release tablet on a layer of slow release granulate and then tableting.

Each tablet thus obtained has the following composition (in mg): 35 8302416 -3-

Quick release piece total weight of the quick release piece 195

Suloctidil 100 Inert Pharmaceutical Excipients 95 5 Slow Release Total Weight of Slow Release 291

Suloctidil 200 surfactant 1.2 release controlling agents 22.6 10 inert pharmaceutical excipients 67.2

Total weight of the tablet 486

The tablets thus obtained were monitored for their release of the active substance with a Diffutest device. With this device, which consists of a thermostatic chamber, held at 37 ° C, with a wheel with 15 single projections, rotating at 30 rpm, the tablet undergoes a series of chemical and mechanical conditions, which mimic the physiological conditions and because they are standardized, the results of this test are reproducible (Chiaromonte D. et al-II Farmaco - Ed. Practica - XXV / 4, 257, 1970).

In practice, a carefully weighed tablet (ie equivalent to an appropriate amount of active ingredient) is placed in a special container and a fixed amount of simulated stomach acid is added thereto. The container is then placed in a designated container in the thermostatic space and rotated at 25 rpm for a certain period of time. After this, the suspension is poured into a separate container and the amount of active substance released is measured according to conventional analytical techniques. A fixed amount of simulated intestinal juice is added to the tablet remaining in the container, after which it is rotated again for a fixed period of time. In total, the tablet undergoes the following treatments: 1) 1 hour in simulated gastric acid with pH 1.5 2) 1 hour in simulated intestinal juice with pH 4.5 3) 2 hours in simulated intestinal juice with pH 6.9 35 4) 2 hours in simulated intestinal juice with pH 6.9 5) 2 hours in simulated intestinal juice with pH 7.2 8302416 * fï * -9-

After each rotation period, the amount of active substance delivered to the suspension is measured. The amount of active substance is calculated to one gram and the percentage of release is then calculated by the following equation: ... K x 100 5 percentage release = —-- where K = number of milligrams of active substance released by the tablet at each rotation period Z = number of milligrams of active substance per tablet.

^ Example IV

Determination of the percentage of Suloctidil released after the different rotation periods. Preparation of simulated gastric juice IN HCl (118 cm 2) and 700 cm 2 distilled water were placed in a beaker; 84 ml of 1N NaOH was then added with stirring. The pH was checked because it should be 1.5 + 0.05. It is then made up to 1000 cm 2 with distilled water.

B) Preparation of simulated intestinal juice 3.42 g of potassium monophosphate is poured into a 100 ml volumetric flask and then distilled water is added to the mark. Three 3 portions of 25 cm each of this solution were placed in three * 3 3 individual 1000 cm beakers. In each beaker, 38 cm 1N NaOH and about 700 cm 2 distilled water were added with stirring. The pH was adjusted to 4.5 in the first beaker, to 6.9 in the second and to 7.2 in the third by adding 1 N hydrochloric acid. Each solution 3 was then transferred to a 1000 cm volumetric flask and distilled water added to the mark.

C) Analysis procedure

Appropriate amounts of simulated gastric juice and simulated intestinal juice were prepared and heated to 37 ° C. A slow-release Suloctidil tablet according to Example III was carefully weighed and placed in a 120 cm rotating container. 75 cm of simulated gastric juice was added and the rotating container placed in an appropriate recess of the thermostatic cell previously regulated at 37 ± 0.5 ° C and rotated at 35 rpm. The five-step cycle described above was then performed.

At the end of each rotation period, the suspension was transferred 8302416 -10-3-3 to a 300 cm volumetric flask, the container was washed with about 10 cm of distilled water, the wash water was then added to the volumetric flask suspension and then ca. 175 ml absolute ethanol were added to the suspension. The mixture was stirred well for 5 minutes to dissolve the Suloctidil granules, absolute ethanol was then added to the mark, the mixture was stirred and filtered in a 300 cc Erlenmeyer flask, discarding the first 50 cc filter solution. The amount of Suloctidil released in these fractions was analyzed spectrophotometrically at 260 nm. Subsequently, simulated intestinal juice with pH 4.5 (75 cm) was added to the remaining tablet material in the rotary container, as shown in the table above and the above operations repeated. The average percentages released at different hours obtained in this procedure are as follows: after the first hour 33%, after the second hour 15 44%, after the fourth hour 67%, after the sixth hour 86% and after the eighth hour 96%. The disintegration time for the small, fast-release tablet piece of Example III, part 1), measured with the equipment of the U.S. Pharmacopoeia XIX, with simulated gastric juice and at a temperature of 37 ° C was 10 minutes.

Example V

Tablets of the same composition as in Example III and obtained in the same manner as described in this example, but slightly modified in the formulation process, were sugar coated with a mixture of sugar syrup: water = 1: 2 and a slight excess of a powder consisting of 20 wt% ground sugar, 60% talc and 20 wt% titanium dioxide. These tablets were also tested for their disintegration rate and release of Suloctidil. The release rate determined as described in Example IV was as follows:

After the first hour 34%, after the second hour 46%, after the fourth hour 70%, 30 after the sixth hour 86% and after the eighth hour 98%.

8302416

Claims (17)

1. Slow release drug suitable for oral administration containing Suloctidil. 2. Slow release tablet containing Suloctidil. Tablet according to claim 2, characterized in that it contains two separate pieces, one of which is the slow-release piece and the other the fast-release piece. The tablet according to claim 3, wherein the rapid release portion contains 12-25% of the total tablet weight of Suloctidil and 10-30% of the total tablet weight of inert pharmaceutical excipients and the slow release portion 27-55%, based on contains the total tablet weight of Suloctidil and 8-36% of the total tablet weight of inert pharmaceutical excipients. Tablet according to claim 4, characterized in that the slow release piece contains at least one anionic or nonionic synthetic or natural surfactant to promote the bio-erosion of the slow release tablet piece and some release agents. anti-toxic agents to control the release of the active substance. Tablet according to claim 5, characterized in that the release-delaying agent for controlling the release of the active substance is a combination of a water-soluble cellulose derivative and a slow solubilizer for polymer molecules. 7. Tablet according to claim 6, characterized in that the water-soluble cellulose derivative is formed by methyl cellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose and the slow solubilizer for the polymeric molecules is a polyethylene glycol with a molecular weight above 1000. 8. Tablet according to claim 5, characterized in that the anionic or non-ionic surfactant is constituted by a polyoxyethylene derivative of sorbitan esters, lauryl sulfates, dioctyl sulfo succinates and lecithins. Tablet according to claim 8, characterized in that the surfactant is a polyoxyethylene sorbitan monooleate. Tablet according to claim 5, characterized in that the surfactant is used in an amount of about 0.1-2% by weight of the slow-release piece. 8302 4 1 6 -12- Tablet according to claim 10, characterized in that the surfactant is used in an amount of about 0.3-0.5%. Tablet according to claim 6, characterized in that a water-soluble dehydrating agent is added to prevent possible swelling. Tablet according to claim 12, characterized in that this dehydrating agent is a sugar. 14. Tablet according to claim 13, characterized in that the sugar 10 consists of sucrose, galactose or lactose. Tablet according to claim 6, characterized in that the water-soluble cellulose derivative is used in an amount of about 2-30% of the slow-release piece and the polyethylene glycol is used in an amount of 2-15% of the slow-release issuing 15 piece. Tablet according to claim 15, characterized in that the water-soluble cellulose derivative and the polyethylene glycol are used in an amount of about 2-10% and about 2-8%, respectively. of the slow release piece. Tablet according to claim 13, characterized in that the sugar is used in an amount of at most 20% of the slow-release piece. 8302416