FR2529784A1 - DELAYED RELEASE MEDICINE CONTAINING 1- (P- (ISOPROPYLTHIO) -PHENYL) -2-OCTYLAMINO-1-PROPANOL - Google Patents

Abstract

THE INVENTION IN PARTICULAR CONCERNS A DELAYED RELEASE TABLET WHICH HAS A QUICK RELEASE PORTION CONTAINING APPROXIMATELY 12 TO 25 OF 1-P- (ISOPROPYLTHIO) -PHENYL-2-OCTYLAMINO-1-PROPANOL AND APPROXIMATELY 10 TO 30 PHARMACEUTICAL EXCIPIENTS , AND A SLOW RELEASE PORTION CONTAINING APPROXIMATELY 27 TO 55 OF 1-P- (ISOPROPYLTHIO) -PHENYL-2-OCTYLAMINO-1-PROPANOL AND APPROXIMATELY 8 TO 36 OF INERT PHARMACEUTICAL EXCIPIENTS, RESPECTIVELY, RELATIVE TO THE TOTAL WEIGHT OF THE TABLET .

Description

-2529784

  The 'huloctidil "or l-lp- (isopropylthio) -phenylj-2-

  octylamino-l-propanol is an agent that activates arterial microcircuits

  central and peripheral riels used in therapy for insuffi-

  chronic cerebral circulatory fisance.

  It has recently been marketed in a few countries including Italy where it is sold under different names

  brand, in particular by the plaintiff under the name of "Locton".

  Post-market surveillance studies

  confirm that this product is effective and well tolerated.

  However, the drug has the inherent disadvantage

  that it has a fairly high rate of disappearance in the organism.

  Thus, by bringing the blood concentration of the drugs as a function of time, one obtains after a single administration a curve which shows that the concentration of this drug drops after a short time to a value below the desired therapeutic range. now partly resolved by administration of this drug several times a day (the number of administrations generally prescribed by doctors and suggested in the package leaflet is three times per

day).

  The object of the present invention is a delayed release product containing suloctidil, suitable for oral administration The term "delayed release product" means a product in which a medicament is made initially available to the body in an amount which is sufficient or is not too much excess by ratio to the amount required, to elicit the desired pharmacological response as quickly as it is consistent with the properties of the drug determining its intrinsic availability for absorption, and which same

  time maintains activity in the desired therapeutic range during

  for a desired number of hours which is greater than that obtained

with the usual single dose.

  The main advantage of this delayed release product is that it gives a slow and constant distribution of

  drug in the body In addition, another benefit of this pro-

  duit is that the daily doses could be reduced to two, one in the morning and another in the evening, thus limiting the number of doses "missed" as a result of forgetting the patient This advantage should not be overlooked, since the missed doses , especially in elderly patients who usually need this medication, pose a

  real problem In particular the present invention provides a com-

  award winning that contains two separate and distinct portions, a quick release portion and a slow release portion The two portions of the tablet can be combined in several ways

  different to give a dosage form giving ini-

  rapid suloctidil concentrations and continuous suloctidil contents

desired.

  A preferred tablet is in the form of a "roundel" that is to say a tablet of slow release product with insertion of a much smaller tablet of the rapid release composition which appears on one side, see the Figure 1 of the accompanying drawings in which the hatched portions represent the composition to

  quick release This tablet can optionally be dragei-

  However, one can also make a "layered" tablet (see Figures 2 and 3) in which two or three separate layers of granules are incorporated which may be capable of releasing the drug either quickly or slowly, in a tablet or also in the form an internal slow release nucleus surrounded by a component

  rapid release external dosing device, the latter being optional-

  ment in the form of a coating envelope (see FIG. 4) Preferably, but not necessarily, the quick-release and slow-release granules are of different colors The quantity of suloctidil contained in the tablet in two portions as well as the final dimension of the tablet can vary between wide limits, these being however concordant with a suitable dosage and obviously of an acceptable tablet size Generally, tablets containing approximately 100 to 400 mg of suloctidil are preferred but more particularly tablets containing about 200 to

  approximately 350 mg of active ingredient Generally, the portion to release

  the quick ration is prepared to disintegrate quickly after ingestion, thereby giving the initial dose of medication, while the slow-release portion is composed so that the drug is available for absorption at a low rate and higher or less constant The portion of the quick-release tablet contains approximately 12 to 25% of suloctidil, based on the total weight of the tablet The remaining portion of the quick-release tablet contains 10 to 30% of inert pharmaceutical excipients relative to the total weight of the tablet These pharmaceutical excipients may include diluents, i.e. inert substances which are added to increase the volume of the tablet, such as calcium phosphate, calcium sulphate, calcium carbonate, kaolin, mannitol, starch. but, silicon dioxide and the like; binders, that is to say agents used to impart cohesion qualities to the powdered material, such as starch, gelatin, sugars, natural gums and

  synthetics and the like; lubricants i.e. ingredients

  dients that are added to the tablet to avoid the defense of the

  tablet material on the surface of the punches during compression

  sion, such as precipitated silica, magnesium stearate, calcium stearate, stearic acid, calcium phosphate, sodium bicarbonate and the like; and disintegrating agents,

  that is to say substances which l Von adds to facilitate the desa-

  tablet gregation after administration, such as corn or potato starch, methylcellosolve, carboxymethylcellulose, alginic acid, polyvinylpyrrolidone, sodium lauryl sulfate, polyoxyethylene derivatives of sorbitan, esters, lecithins etc. The specific excipients used in the rapid release composition comprising suloctidil as well as their respective amounts are not essential and any of the

  compositions containing suloctidil currently on the market.

  However, lubricants are generally used concentra-

  from 0.5 to 6% by weight of the quick-release portion, while taking into account what is desired rapid disintegration, disintegrating agents are used in concentrations of 10 to 50% by weight of the portion to rapid release of the tablet The slow release portion of the tablet comprises approximately 27 to 55% by weight

  suloctidil and approximately 8 to 36% by weight of pharmaceutical excipients

  inert ticks, based on the total weight of the tablet Excipients

  pharmaceuticals contained in the slow release portion of the

  award-winning must include a nonionic surfactant or

  anionic which promotes bioerosion of the slow release tablet.

  Among the preferred surfactants, there will be mentioned fatty acid esters

  sorbitol co-polymerized with ethylene oxide, such as mono-

  polyoxyethylenesorbitan leate manufactured under the name of 'ween 80 ", laurylsulfates and dioctylsulfocuccinates such as sodium laurylsulfate and sodium dioctylsulfosuccinate, and lecithins This surfactant is used in an amount of about 0.1 to 2% by weight of the slow release portion, preferably about 0.3 to 0 8% In addition, it is necessary to introduce into the slow release portion of the tablet a couple of additives which regulate the release of the active ingredient One is a water-soluble cellulose derivative, such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose, while the other is a slow solubilizer for polymer molecules, usually a polyethylene glycol having a molecular weight of more than 1,000 , which promotes bio-erosion of the tablet surface The cellulose derivative is generally used in an amount of about 2 to 30% by weight of the slow-release portion, and preferably pregnant between 2

  and 10%, while polyethylene glycol can be used in quant

  t 2 to 15% 7 by weight of the slow release portion, and pre-

  ference between 2 and 8% 7 Depending on the particular cellulose derivative used

  It may be necessary to add a water-soluble dehydrating agent to avoid a possible swelling effect of the cellulose derivative. Generally, in these cases, a sugar is preferably used. It can be used in an amount varying from 0% (when the cellulose derivative does not give rise to a swelling effect and a dehydrating agent must therefore not be added) to 20% by weight of the slow-release portion For practical reasons, among the sugars which can be used for this purpose, it is preferred

  sucrose, lactose and galactose In addition to the above additives

  above, the slow-release portion of the tablet may contain diluents that are insoluble and do not swell, such as calcium sulfate, calcium phosphate, silicon dioxide, talc, kaolin,

  and non-stick substances such as precipitated silica, phos-

  calcium phate, etc. and certain hydrophobic lubricants, such as magnesium stearate, calcium stearate, stearic acid, oil

  of r 2 cin and esters of hydrogenated fatty acids.

  Finally, if desired, one or other of the formulations

  may contain a coloring agent known in the art.

  If a tablet according to FIG. 4 is desired in which the rapid-release layer which covers the internal slow-release core is in the form of a coated coating, it can be prepared by the usual techniques alternating layers of syrup sugar with dusting with mixtures of the active ingredient and one or more excipients such as silicon dioxide, talc, calcium carbonate, kaolin, etc. The tablets according to the invention are prepared by well-known techniques.

  known in the pharmaceutical field In particular> formulas

  1 st release and quick release lations are prepared

and granulated separately.

  Although both compositions can be treated using wet granulation and dry granulation techniques, wet granulation is highly preferred in both cases. For the slow release formulation, suloctidil is preferably mixed first with a binder solution for tablets such as a gelatin solution, a glycerogelatin paste or

  starch and / or similar binders.

  Then all the other desired excipients are

  added and mixed thoroughly When the formu-

  lation is finished, the composition is granulated by passing through a sieve of suitable size. The granules thus obtained are dried to the desired residual moisture content.

  granulated can then be further ground to a part size

  smaller cules suitable for pelletizing and suitable excipients can be added to it to prevent sticking of the granules on the punches or dies during the pelletizing This step can be carried out either by dusting or by dry mixing with adsorbents such as precipitated silica , bi or tri-basic calcium phosphate, talc, etc. Finally, the granulated material is suitably

  lubricated and optionally supplemented with disintegrating agents.

  For the slow-release formulation, also, the various excipients are gradually added to the active principle. If the formulation is too wet and gives a sagging mass, the excess water is removed before the granulation step by adding a diluent. inert strongly adsorbent, such as silicon dioxide Granulation can then be carried out by passing the mixture either through a suitable sieve, or

  through a plate with holes of a suitable size

  In this case also, after drying of the granules thus obtained, it may be necessary to reduce their particle size to improve the tableting. One or more non-stick agents and lubricants are then added and mixed well to give the granules of final size. These granules, like those of the quick-release formulation, are used to feed a tablet press and give the tablets in two portions represented in the accompanying drawings, according to the techniques.

  well known to those skilled in the art.

  The following examples illustrate the invention without

however limit its scope.

Example 1

  Preparation of the rapid-release granules The following composition is used to prepare granules which form the rapid-release portion of 000 tablets: Ingredient Grams Suloctidil 2,500 Calcium phosphate 50 "Aerosil V 200" 125 Gelatin 75 Glycerin 25 Mannitol 125 Corn starch 1,747.5 Precipitated silica 100 Magnesium stearate 125 "FDC Red 3" (E 127) 2.5 1) A solution is added to Suloctidil

  gelatin and glycerin in 450 g of distilled water.

  2) The mannitol and part (1,672.5 g) of the corn starch are then added to the mixture obtained with "AEROSIL V 200", and the whole is mixed until a homogeneous mass is obtained. 3) A starch paste is prepared by mixing the rest of the corn starch with the coloring agent and 675 g of distilled water. The mixture is heated in a water bath until a

red starch paste.

  4) Then add the starch paste to the mixture prepared according to 2) above and stir everything until a

homogeneous mass.

  ) This mass is sieved through a granulator

  oscillating fitted with a sieve having openings of about 3-3.5 mm.

  The granules are then dried at 40 ° C. for a few hours.

  6) The granules thus o b are then forced to pass through a sieve having openings of less than

1.5 mm.

  7) The granules o obtained are mixed with the phosphate

  of tribasic calcium, magnesium stearate and the above silica

pitied.

Example 2

  Preparation of slow-release granules The following composition is used to prepare

  the granules that form the slow release portion of 25,000

  award-winning. Ingredients Grams Suloctidil 5,000 Tribasic calcium phosphate 250 "Tween 80" 30 Polyethylene glycol, P M 6000 265.75 Sucrose 412.5 "Mathocel A 15" 300 "Aerosil V 200 '" 300 Precipitated silica 550

Magnesium stearate 166.75 -

  1) Add "lethocel A 15" to a solution of "t Lween 80", sucrose, polyethylene glycol 6000 in 1 675 g of distilled water c auffé bain-marie and the mixture is cooled

obtained by shaking.

  2) The mixture prepared according to 1) is added to a mixture of Suloctidil and calcium phosphate, with stirring, until a slump is obtained. Then added to it.

1 '"' erosil V 200".

  3) The mass obtained is sieved through a granule

  oscillating lator provided with a sieve having openings of approximately 6.0-6.5 mm The granules obtained are dried at 40 ° C. for a few hours, then they are forced through a sieve having openings of 1.5 min and we know again for a few more hours. 4) The granules are mixed under 3) above

  with precipitated silica and magnesium stearate.

Example 3

  Preparation of a Rosette Tablet -1) The granules prepared according to paragraph 7) of Example 1 are pressed into tablets on a Ronchi AM 13/8 rotary tableting machine having punches of 8.5 mm. The pink tablets obtained have a thickness of 4 + 0.1 mm and a weight

about 195 mg.

  2) Each tablet prepared according to 1) is placed

  top in the middle of an 11.5 mm punch of a Kilian Prescoter rotary pelletizing machine supplied with the granules obtained according to

  paragraph 4 of example 2 Tablets are obtained in two

  tions, in which the small pink tablet prepared according to 1) above

  above appears on one side of the final tablet These tablets weigh

about 486 mg.

  You can also prepare the roundel by placing the small quick-release tablet on a layer of the

  slow release granulation and then pressing into tablets.

  Each tablet thus obtained has the following composition (the weights are in mg): Quick-release portion Total weight of the quick-release portion 195 Suloctidil 100 Inert pharmaceutical excipients 95 Slow-release portion Total weight of the slow-release portion 291 Suloctidil 200 Surfactant 1.2 Agents regulating the release of the active ingredient 22.6 Inert pharmaceutical excipients 67.2 Total weight of the tablet 486 The speed of dissolution of the active ingredient on the tablets thus obtained is determined by means of the "Diffutest" device By means of this device, which consists of a thermostatic chamber set at 370 C with a wheel carrying clamps set, to rotate at 30 rpm, the tablet undergoes a series of chemical and mechanical conditions which simulate physiological conditions and like them are established beforehand, the results of the test

  are reproducible (Chiaromonte D and Coll Il Farmaco Ed.

Pratica XXV / 4, p 257 (1970)).

  In practice, a carefully weighed tablet (therefore equivalent to an appropriate amount of active ingredient) is placed in a special bottle and a fixed amount of artificial gastric juice is added to it. The bottle is placed in the appropriate bottle holder in the thermostatic chamber. and it is rotated at 30 rpm for a determined period of time after which the suspension is poured into a separate container and the quantity of active principle released is measured by conventional analytical techniques. An amount is added to the tablet remaining in the bottle. of artificial intestinal juice fixed and rotated again for a fixed period The tablet undergoes in total the following treatment cycle: I) 1 h in artificial gastric juice pl 1.5 II) 1 h in artificial gastric juice p H 4.5 III) 2 h in artificial gastric juice p 1 6.9 IV) 2 h in artificial intestinal juice pa 6.9 V) 2 h in artificial intestinal juice p H 7.2

  After each rotation period, the quantity

  amount of active ingredient released into the suspension The amount of

  active ingredient released is related to one gram and the percentage of release is then calculated using the following equation: i O io K x 100 release,% = K x 100 in which K is the quantity in mg of active ingredient released by the tablet in each rotation period,

  Z is the quantity in mg of active ingredient per tablet.

Example 4

  Determination of the percentage of Suloctidil released after the periods

of different rotation.

  A) Preparation of artificial gastric juice In a 1000 ml beaker, 118 ml of 1 N HC and 700 ml of distilled water are placed; 84 ml of 1 N Na OR are then added

  by shaking We determine the p H since it must be 1.5 + 0.05.

  Distilled water is then added to make up to 1000 ml.

  B) Preparation of artificial intestinal juice 3.42 g of potassium monophosphate are poured into a 100 ml volumetric flask and distilled water is added.

  up to volume We transfer three 25 ml portions of this solution

  tion in three separate 1000 ml beakers Add with stirring

  in each beaker 38 ml of Na O Hl 1 E and approximately 700 ml of distilled water.

  The p Hi is adjusted to 4.5 in the first beaker, to 6.9 in the second and to 7.2 in the third by adding HC 1 IN. Each solution is poured into a volumetric flask of 1000 ml and added some water

distilled to volume.

  C) Assay Method Suitable quantities of artificial gastric juice and artificial intestinal juice are prepared and heated to 37 C. A tablet of delayed release Suloctidil from Example 3 is carefully weighed and placed in a rotary ml bottle 75 mil of artificial gastric juice are added and the bottle is placed in the appropriate clamp of the thermostatic cell,

  -5 previously adjusted to 37 + 0.5 C and rotated at 30 rpm.

  The five-stage cycle described above is implemented.

  At the end of each rotation period, the suspension is transferred to a volumetric flask of 300 ml. The bottle is washed with approximately 10 ml of distilled water, which is then added to the suspension in the flask. It is then added to the suspension. about 175 ml of absolute ethyl alcohol and shake vigorously

  the mixture for 5 minutes to dissolve the granules of Suloc-

  tidil Then absolute ethanol is added to the volume, the mixture is stirred and filtered into a 300 ml Erlenmeyer flask,

  throwing away the first 50 ml of filtrate We dose spectrally

  photometric at 260 ml the amount of Suloctidil released in these fractions Then added to the remaining tablet in the rotating bottle 75 ml of artificial intestinal juice at p H 4.5 as indicated in the table above and the operations above are repeated The average percentages of release of the active ingredient obtained at

  different times in the above procedure are the following

  before hour 33% 2nd hour 44% 4th hour 67% 6th hour 86% 8th hour 96%

  The disintegration time of the small release tablet

  rapid ration of example 3 paragraph 1, measured by means of the apparatus proposed for this purpose by US Pharmacopea XIX, with the artificial gastric juice and maintaining the temperature at 37 ° C., is

10 minutes.

Example 5

  Tablets with the same composition are coated

  tion as in Example 3 and prepared substantially as described in the

  m Same example, but with a slight modification of the formulation process

  lation, by means of a syrup mixture of s: crenel 1: 2 and a slight excess of a powder composed of 20% ground sugar, 60 i talc and% titanium dioxide The tablets were determined on dissolution rate of Suloctidil The release rates determined as described in Example 4 are as follows: the hour 34% 2 nd hour A 6 '4 th hour 70 6 th hour 86%

8 th hour 98%.

Claims (11)

  1 Drug containing 1-lp- (isopropylthio) -phenyll-   2-octylamino-l-propanol, suitable for oral administration,   characterized in that it is in a delayed release form.   2 medicament according to claim 1, characterized in that it is in the form of a delayed release tablet. 3 tablet according to claim 2, characterized in that it contains two separate and distinct portions, one portion   quick release and a slow release portion.   4 Tablet according to claim 3, characterized in that the rapid-release portion comprises approximately 12 to 25% of 1-lp- (isopropylthio) phenyll-2-octylamino-l-propanol and approximately 30% of inert pharmaceutical excipients, based on the total weight of the tablet, and the slow-release portion includes   about 27 to 55% of 1-lp- (isopropylthio) -phenyll-2-octylamino-1-   propanol and approximately 8 to 36% of inert pharmaceutical excipients,   based on the total weight of the tablet.   Tablet according to claim 4, characterized in that the pharmaceutical excipients of the slow-release portion comprise at least one synthetic or natural, anionic or non-ionic surfactant to facilitate bioerosion of the   slow-release tablet and certain slow-release agents   ration to regulate the release of the active ingredient.   6 tablet according to claim 5, characterized in that one uses as agent delaying the release, to regulate   release of the active ingredient, a combination of a hydro-   soluble in cellulose and a slow solubilizer of poly-   mothers. 7 tablet according to claim 6, characterized in that the water-soluble cellulose derivative is chbisi among   methylcellulose, hydroxymethylcellulose, hydroxypropyl-   cellulose and hydroxypropyl methylcellulose and the slow solubilizer   polymer molecules is a polyethylene glycol of a molecular weight ring greater than 1000.   8 tablet according to claim 5, characterized in that the anionic or nonionic surfactant is chosen from   polyoxy, -thylene derivatives of sorbitan esters, laurvlsul-   fates, dioctylsulfosuccinates and lecithins.   9 tablet according to claim 8, characterized in   what the surfactant is polyoxyethylene monooleate-   sorbitan. Tablet according to claim 5, characterized in that the surfactant is used in an amount of approximately   0.1 to 2% by weight of the slow release portion.   11 Tablet according to claim 10, characterized in that the surfactant is used in an amount of about 0.3 at 0.5%.   12 Tablet according to claim 6, characterized in that a water-soluble dehydrating agent is added to avoid a possible swelling effect.   13 Tablet according to claim 12, characterized in   that said dehydrating agent is a sugar.   14 Tablet according to claim 13, characterized in that the sugar is chosen from sucrose, lactose and galactose. Tablet according to claim 6, characterized in that the water-soluble cellulose derivative is used in an amount of about 2 to 30% by weight of the slow-release portion and the polyethylene glycol is used in an amount of about 2 to 15% by weight.   weight of the slow-release portion.   16 Tablet according to claim 15, characterized in that the water-soluble cellulose derivative and the polyethylene glycol are used in amounts of approximately 2 to 10% and approximately 2 to 8% respectively, relative to the weight of the slow-release portion. 17 Tablet according to claim 13, characterized in that the sugar is used in an amount of not more than 20%, for   relative to the weight of the slow-release portion.