FI116881B - Pharmaceutical compositions enabling delayed release of trimethazidine after oral dosing - Google Patents

Abstract

Compsn. for prolonged liberation of trimetazidine (II) or its salts, uses a polymer insoluble in water and a plasticiser to control liberation.

Description

The present invention relates to a pharmaceutical composition which retards trimethacidine or one of its addition salts with a pharmaceutically acceptable acid.

Trimetazidine or 1- (2,3,4-trimethoxybenzyl) pine of the formula

CH 3 O

11

15 l___NH

cap compound; is a molecule that, by maintaining 20 dun of energy in a cell exposed to swine or ischemia, prevents the collapse of intracellular adenosine triphosphates (ATP). It thus ensures transmembrane virion pumping and sodium-potassium transmembrane flux; "and preserve cell homeostasis.

• * • * »

• M

Among the pharmaceutically acceptable s *: 'trimethidine, among others, dihydrochloride is used in therapy as a coronary vasodilator for the treatment of chest pain, vascular injury and cerebral injury (30 vertigo). Diarrhea in Menieri, ringing in the ears, trimetazidine dihydrochloride is presently Ann ♦ ·: orally in doses of 40-60 mg / day, tab 2

Trimetazidine rochloride is rapidly absorbed and eliminated by the body with a plasma half-life of less than 6 hours. As a result, the active ingredient is compared to two or three daily doses to ensure steady state plasma levels. But due to absorption, these immediate release also lead to high plasma peaks shortly after administration and very low blood levels following dose.

10

The sustained release form has the advantage of providing these peaks in the blood, resulting in smooth, bloody levels. It also allows for one full administration, which is advantageous for treating the patient. It thus allows better care of tar.

In order to accomplish this, it is essential to ensure timely delivery with complete control over time. 20 Release rate should be repeatable and corr. following administration, the main mechanism that can be used to control the diffusion of the active ingredient that can be maintained is diffusion of the active ingredient from the reservoir and through the polymeric membrane when galene • i * V; the form comes into contact with the solubilizing fluid (in vivo or gastric fluid (in vivo)).

Many polymers have been described to help it. diffusion is possible. Major polymers o • · ·

* !!. * ethylcellulose 1a methacrylic meatDDol derivatives. S

In this case, the dosage of the active ingredient jc into a number of small units which are then h either in a gelatin capsule or tablet.

The polymers used to provide the sustained release active ingredient are polymers which are insoluble in the gastrointestinal fluid and may be used in either the organic solution in the form of a dispersion (latex or pseudol). With the aid of a reservoir system which combines 15 active ingredients in tablet form or in milliliter form, each film or tablet is individually coated to form a film of controlled thickness to provide active ingredients that result in well-defined levels of ple. • · · β · β control the release of active ingredients * * * Many of them addressed the following problem: \ The active ingredient is relatively small in size (MP <25 and Because of its high water solubility, active ·· *: the release of the ingredient is relatively complex and not particularly possible to ensure the active ingredient is released for more than 12 hours.

• ♦ • i «• 9« • «* · 30 Previous studies have shown that san. *. trimetatsidiinidihydrokloridia.

• · · ** «· 4 releases over 16 hours. This problem was solved using the reservoir cyst described in the present invention. It appears that the water-insoluble polymer cellulose or polymethacrylate combines a relatively permeable Kali dehydrogenation with the active ingredient, allowing for a uniform release of the ingredient.

The effect of plasticizer on the permeability of polymethacrylate films (Eudragit RS *), as measured by the aid of phenylpropanolamine hydrochloride, is described by K. Lehman, J.W. McGinity, Marcel Dekker, NY (1989), p. 205. compiled into the ti size below.

Softener Permeability Soluble (added 20%) (mg.cm-2.h ”1) in water 1 absorbent temperature: ** I at low (* · 0 • · I Π II ......... Ι · • II | 20 Acetyltriethyl 3.8 0.72 µl citrate // Dibutylphthalate 5.4 0.04

Triethyl Citrate 6.2 6.9!? : Triacetin 6.2 7.1 Tributyl citrate 9.0 <0.00 ·. · · Acetyl tributyl 11.8 <0.00 additional citrate. Diethyl phthalate 14.8 0.15 »i S ______ 4 5, assuming that the best results were obtained with acetyltitrate.

The use of blushes such as acetyltriethyl citrate, ti 5-citrate or triacetin gives a very long delay time, which can be as much as four hours, after which release is faster than acetyl tributyl citrate. These sets are shown in Figure 1 (appendix).

10

For the treatment of the coronary artery disorders to which trimethyl is intended, it was very important that the delivery of the active ingredient can begin upon administration of the galenic form to the patient, so that he or she will receive prompt and effective treatment. The time spent in excess of one hour is therefore a burden that could be countered with this insight. In addition, the gradual release of the active ingredient is essential if relatively constant plasma levels are desired.

The pharmaceutical compositions described herein are in particular in the form of container tablets or miniras.

a i a i • 25 Principle of Galenic Form f · · • I 4 • «· β * 1 ·! · 1: Principle of Container Tablets m · lt \ l Tablets are prepared in several steps.

··· 2::: 30 1. First of all, with the help of a premix of the ingredients, it is possible to make 2 nm 1 114 1 ηαο / ί a a-l in Iran 1 nm «114 nan! r -1 4n4 <44 h «> i4i> n1r1 mv 6. The lubrication step then allows the machine to function properly to make tablets vax

After preparation, the tablets are coated with a 5M aqueous solution or suspension selected to ensure diffusion of the viscous component and to control the kinetics of the titration. The plasticizer is used at this point to give the tablet a well coated polymer blade.

10 Principle of preparation of tank granules

The mini-granules can be prepared by two processes, either by a process using extruder 15 and spheronization technology, or by a process of forming an active ingredient around the core of the carcass.

a - Preparation of MinlraJs by Extrusion Formation 20 * In this process, the wet mass containing trlmetazidine dihydrochloride j *** * * · **, with fillers, is pressed through a Reif lattice plate. In oblong cylindrical shape. . The product is then made into a spherical shape using a toothed plate. The resulting mini-granules will be dried! · * * Later, either in a ventilated oven or in a fluidized bed.

• ♦ * 4 · 4 4 4

··· I

: T: 30 b - Preparation of the mini rocket by assembling the active:! \ Neosa around the neutral lumen * · 4 4 «· 4 Λ · β 7 The active ingredient is sprayed on the neutral cores and then dried with hot air, for example.

The mini-granules produced by either process are then weaved in either a coating turbine, a germinated or other type, or a fluidized bed type. The mini-granules are coated with a polymeric solution of 10 selected to ensure fusion of the active ingredient and thereby regulate delivery cams. The plasticizer is used in this step to make the mini granules well coated with a dust film.

15

The following examples illustrate the invention but do not illustrate it in any way.

Tablets 20

Preparation of sustained release tablets: i * λ 9 9 · • 9 9 9 9

Lie A

9 9 99 9 9 9 25 · *! / Mix trlmetazidyl dihydrochloride, dilute * · * 'as a binder polyvidone and moisten with an aqueous or aqueous alcoholic solution * · * The wet mass is then granulated, dried and: T: 30 a granule is obtained whose physical capabilities allow for a fast tablet matr * !! / hp task.

8

Step C

The lubricated mixture obtained in step B is tabletted by a reversible or rotary tabletting machine.

5

Step D

The tablets obtained in Step C are coated with an aqueous or organic polymer solution or suspension 10 which ensures diffusion of the active ingredient. This or the suspension may also contain a plasticizer. The top is carried out in a coating turbine or fluidized bed.

15 Example lr

The sustained release tablet (PR1) is prepared according to the steps outlined in Table 2, in accordance with the steps outlined below.

Table 2 • 1 «: Unit Formulation for PR1 Tablet« M1 • 9 • · • _ _ _ * · ** · Ingredients Amounts (mj * ^ »- ........, 25 Trimetazidine Dihydrochloride 80 V 'Potassium hydrogen phosphate 80

Polyvidone 8 µg:: Silica Colloid 0.4: T: Magnesium Tear a 1.6 µl. 30 • · »#» i · · · 9

The delay time for this long-term release is one hour. Thereafter, in vitro kinetics of solution kinetics for more than ten hours.

Example 2;

The sustained release tablet (PR2) is obtained by following the procedures described above and in Table 2 below. This tablet is coated with an aqueous ethyl cellulose suspension (Aquaooat *) containing dibutyl sebacate in a Manesty-type Accela Cota 10 tear-off tube. The in vitro dissolution profile of this form (PR2) is shown in Figure 3 (appendix).

With this PR2 form, the active ingredient has a dissolution time delay of less than one hour · The Luc rate is higher in this example. Use of an aqueous suspension of ethylcellulose instead of an organic solution $ 20 provides a delivery profile that is slightly different • ► •% ft ft: i'i Mini-granules: ft · · "ft« I • «....: Slow-release mini-granules are prepared; as follows: • · »·« * · * ·.

1 * »• ·

Extrusion and ball forming process ft «

: *! : Step A

ftftft • * «V · 30 ft J Trimethacidine dihydrochloride mixed microki HI · • * V flftl 1 illnncian chicken -tn lrna-hirl-tvf-Aan eon milfoon nnh / l ίο

Step B

The min granules obtained in Formula A are coated with a polymeric organic solution or an aqueous suspension which may also contain a plasticizer, coating coat or fluidized bed apparatus.

Step C

The coated minel granules are placed in a gelatin capsule

Assembly-based process;

Step A 15

For example, neutral granules containing sucrose or sucrose and starch or microcrystalline cellulose are coated with an aqueous solution of the active ingredient which may contain a binder such as polyvidone or hydroxypropyl cellulose. This coating can be carried out in a coating turbine or fluidized bed * * * * # «» * «

V. Step B

»* ·,, 25 Step B is the same as step B of the compression and spherical '11 * process.

f * · * f i m

Step C

♦ ♦ 9 9 * «« · »at · S 30 Coated minl granules are placed in a gelatin capsule« * • * 9 * · · "· *« * Example 3: 11

Table 3 PR3 gelatin capsule formulation I Ingredient Quantities (mg)

Trimethacidine / Hydrochloride 80

Microcrystalline cellulose 80

Ethyl cellulose 40

Acetyl tributyl citrate 4 10

The mini-granules obtained in Step A are coated with an alcoholic solution of ethyl lozenge (read regulatory polymer of the active ingredient) supplemented with acetyltributyl citrate softenable.

The in vitro dissolution profile of this form (PR3) is shown in Figure 4 (Appendix).

Plasma levels of trimetazidine were determined in # * * ·· 20 delta subjects following administration of one: one PR3 gelatin capsule per day or one intermediate ** IR tablet three times daily. The mean concentration curve for P1 <*. *. »Is shown in the figure; (annex).

• · · i: ii 25 'Example 4s f ^ ·

Inside the sustained release mini granules (PR4), the V * Latin capsule is prepared using Table 4; · *; 30 work formulations for assembly-based operation- # 4V **. ** · ManA-l-Al mile 4 oλο * Μ

Table 4 Formulation of 12 PR4 Gelatin Capsules

Ingredients Quantities (mg] 5 Trimetacidine dihydrochloride 80

Neutralrae sucrose-starch 74

Methylhydroxypropylcellulose 6 Ethylcellulose 16

Acetyl tributyl citrate 1.6

The mini-granules obtained in Formula A are coated with an alcoholic solution of ethyl 15 lose supplemented with gun tributyl citrate.

The dissolution profile of PR4 is shown in the figure (appendix).

20 • '·· Example 5; The PR5 * gelatin capsule is prepared using the process described for the PR3-type gelatin capsule (e.g.:... 25 whereby the ethyl alcoholic acid solution is replaced by an aqueous coating of ethyl cellulose

• * I

(Aguacoat *). Its dissolution profile in vitrt. . shown in Figure 7 (appendix).

♦ ♦ «· · M * M * • * * • * · 30 There is no delay. Kinetics of dissolution in vitro • * * · A .t »i -. ju11 .____ 13

Example 6; The PR6 type gelatin capsule is prepared by a process described for a rope gelatin capsule, which is co-coated with an alcoholic solution of ethyl cellulose by means of an aqueous dispersion of polymethacrylates (Eudragit1). Its dissolution profile in vitr <is shown in Figure 8 (Appendix).

10 During Coating with Eudragit1 Aqueous Suspension! so there is no delay. The drop in active ingredient delivery in vitro is virtually linear for 12 hours.

«• 1 i a · • 1 · # · 1 • 9 ·« a • a • · »* · 9 9 9 9 • 9 9 • 1 1 1

• ♦ I

«1 · 9 • 9 • 9 9 • 99 • a a 9 9 9 9 9 9 9 9 9 9 • 9 • 99

Claims (9)

A pharmaceutical composition releasing trimetazidine or a pharmaceutically acceptable salt thereof. 5 retarded, characterized in that the trimetazidine release is controlled by a tank system of a water-insoluble polymer and a plasticizer; the mixture is in the form of a film that covers tablets containing trimetazidine or one of the active ingredients. With a pharmaceutically acceptable acid in the form of: addition salts, and wherein the plasticizer is other than h; oil. Pharmaceutical composition according to claim 1, characterized in that the trimetazidine is in the dihydride form. Pharmaceutical composition according to claim 1, characterized in that the reservoir system comprises 20 chalk tablets. The pharmaceutical composition according to claim 1, characterized in that the container system comprises: : V. pregnancy container capsule containing * · 25 boils. • m * ♦ * * * Pharmaceutical y * * * pharmaceutical composition according to claim 1, characterized in that the polymer used is ethylcellulose in an organic solution or an aqueous dispersion. * 9 * · ft * » Pharmaceutical composition according to claim 1, characterized in that the plasticizer is acetyl tribitrate. Pharmaceutical composition according to claim 1, characterized in that the plasticizer is dibutyl Pharmaceutical composition according to Claim 1, characterized in that it provides a controlled and uniform release of trimetazidine from the beginning and for at least 16 hours. Pharmaceutical composition according to claim 1, characterized in that it is useful in the treatment of: chest pain, vascular; during retinal lesions as well as blood vessels]; during treatment of dizziness. 20 4 * • 4 • 4 * 4 4 4 4 4 4 • 4 * • 44 4 44 4 4 4 4 4 4 4 4 4 • 4 4 4 4 4 4 4 4 4 44 # »4 4 4 4 4 4 4 4 4 4 • 4 4 4 4 4 4 4 444 4 44 4 4 4