OA16317A - Process for preparing tablets containing in combination rifampicin, isoniazid, pyrazinamide and optionally ethambutol. - Google Patents

Abstract

The present invention relates to a process for the preparation of a pharmaceutical composition in tablet form containing in combination at least the following active principles: rifampicin, isoniazid, and pyrazinamide. Advantageously, said pharmaceutical composition also comprises at least a fourth active principle: ethambutol or one of its salts. In particular, the preparation process according to the present invention is carried out by wet granulation of isoniazid, pyrazinamide and optionally ethambutol. The composition obtained is advantageously a combination composition at a fixed dose of the 3 or 4 active principles mentioned above, with anti-tuberculosis therapeutic activity, suitable for oral administration.

Description

Process for preparing tablets containing in combination rifampicin, isoniazid, pyrazinamide, and optionally ethambutol

The present invention relates to a process for preparing a pharmaceutical composition in tablet form containing in combination at least the following active ingredients: rifampicin, isoniazid and pyrazinamide. Advantageously, said pharmaceutical composition also comprises at least a fourth active principle: ethambutol or one of its salts. In particular, the preparation process according to the present invention is carried out by wet granulation of <10 isoniazid, pyrazinamide and optionally ethambutol. The composition obtained ί is advantageously a combination composition at a fixed dose of the 3 or 4 principles; active agents mentioned above, with anti-tuberculosis therapeutic activity, suitable for * oral administration.

i

Tuberculosis is an infectious disease of bacterial origin (Mycobacterium tuberculosis) which mainly affects the lungs.

Since the discovery of rifampicin in the 1960s, the medication for this disease has continued to evolve resulting in a list of molecules (isoniazid, ethambutol and pyrazinamide in addition to various combinations) with potent anti-tuberculosis activity which is in the pipeline. origin of the very eradication of this scourge from developed countries.

However, although treatable, this disease constitutes a major public health problem because it is widespread in the world (approximately 32% of the world population). Its incidence / prevalence is also significant, affecting eight million people and causing approximately two million deaths each year.

ί Likewise, over the past two decades, we have observed a return of tuberculosis in industrialized countries which believed themselves to be spared from this disease.

Several reasons explain this re-emergence including the north-south mixing of populations resulting from immigration and globalization, but other reasons are no less important, namely:

j * the abolition of compulsory BCG vaccinations;

!

! Ü-L <

rf * the significant growth of the pool of the immunocompromised AIDS population susceptible to tuberculosis;

* increasing poverty and malnutrition, etc.

In recent years, the situation has been further aggravated by the development of resistance, single or multiple ("multi-drug resistance", MDR), to available anti-tuberculosis drugs. The wrong prescription was blamed, but it was above all the lack of patient discipline (partial adherence and treatment interruptions) that proved to be the primary cause of this resistance. This lack of conformity was quickly attributed to the size of the old treatments, given the high number of daily intakes in addition to the long duration of the treatment.

During the 1990s, the World Health Organization (WHO) joined forces with various national and international organizations to issue a series of measures and practices to be followed to address this resistance problem. One of these measures, aimed in particular at the pharmaceutical industry, called for reducing the number of daily intakes that caused patients to not comply with treatment. From this has emerged a new generation of medication commonly called "b'ixed-dose combination" (FDC), consisting of the combination of several known anti-tuberculosis agents (rifampicin, isoniazid, ethambutol and pvrazinamide) in the same galenic form.

Despite its important role in improving patient compliance with their prescription, anti-tuberculosis CDF has also suffered from efficacy problems mainly due to the loss of activity of certain active ingredients, as well as their bioavailability in the patient. So, for example, in addition to its sensitivity to air (oxidation) and light (photosensitivity), rifampicin is not resistant to water (rapid hydrolysis). However, ethambutol is very hygroscopic, which causes the hydrolysis of rifampicin and its inactivation in CDF. Likewise, isoniazid is known to react with rifampicin to form inactive secondary compounds. These physicochemical handicaps have led the scientific community to separate the active principles of FDC to ensure its therapeutic quality.

Several types of formulations have thus been proposed to ensure the separation of the active principles of the FDC combination and to guarantee their activity and better OC bioavailability in the patient. However, many of these formulations are based on expensive techniques and ultimately granulation remains the most commonly used.

However, granulation has often been used in a complicated way involving multiple granulations. Thus, in some cases, the four ingredients are granulated separately before being compressed or put into sachets (4 granulations) (WO 2005/074937). In other cases, two active ingredients are granulated separately (2 granulations) and two other groups (1 granulation) (WO 2002/087547).

Some simpler methods using a single granulation during the entire FDC preparation process: ("l-step granulation") have also been developed, but most of the methods developed have various disadvantages, such as the addition reducing sugars during granulation while these substances are known to affect the activity of certain active ingredients such as isoniazid, or the exposure of rifampicin to a prior treatment supposed to control the release profile of the latter in the patient. In addition, the preparation methods listed above have generally not been supported by dissolution tests demonstrating the integrity of rifampicin or any other sensitive reagent in the combination therapy in question.

Consequently, there was a need to develop a rapid, simple and effective preparation process which does not have the drawbacks of the prior techniques, and which is capable of reconciling the combination of three or four active ingredients in the same tablet and the preservation of their properties. respective antibiotic activities.

The present invention fulfills this need. The Applicant has thus surprisingly discovered that the preparation of pharmaceutical compositions, in the form of tablets, could be carried out by a rapid, reproducible process, implementing a single granulation, capable of minimizing the handling of sensitive active ingredients and thus limiting their exposure to the external environment, respecting all the conditions necessary for the preservation of the therapeutic activities of the ingredients by avoiding incompatibilities, and not subjecting the active ingredients to any treatment prior to granulation.

Particularly advantageously, the process according to the present invention implements a single granulation, namely the granulation of isoniazid and pyrazinamide, and optionally of ethambutol, without carrying out the granulation of rifampin, and makes it possible to separate the rifampicin from the other active ingredients.

The process according to the present invention thus makes it possible to obtain compositions which are stable over time, exhibiting no modification of the organoleptic characteristics or of the contents of active ingredients, suitable for being administered orally, in the form of tablets, and allowing continuous release. and prolonged active ingredients, without modification compared to tablets containing only one active ingredient.

The subject of the present invention is thus a process for preparing a pharmaceutical composition in tablet form containing in combination rifampicin, isoniazid, and pyrazinamide, and optionally ethambutol or one of its salts, characterized in that it comprises the following successive stages:

wet granulation of isoniazid, pyrazinamide and optionally ethambutol by wetting with at least one binder dissolved in a volatile organic solvent, to obtain grains, drying of the grains, addition of rifampicin, following the addition of rifampicin or during the addition of rifampicin, addition of compression excipients such as lubricants, disintegrants and optionally flavorings, then compression to obtain tablets.

The rifampicin which can be used in the context of the process according to the present invention advantageously has a density of between 0.3 and 1, advantageously between 0.4 and 0.8, typically 0.5.

Ethambutol, when present in the pharmaceutical composition, is advantageously in the form of ethambutol hydrochloride.

Advantageously according to the present invention, the binder is chosen from the group consisting of pregelatinized corn starch, poly vinyl pyrrolidone (PVP), povidone such as povidone K30, and mixtures thereof.

The binder makes it possible to ensure good binding of the following active ingredients: isoniazid, pyrazinamide and, where appropriate, ethambutol, and their sequestration in the grain, thus avoiding any contact with rifampicin when it is then added, so that granulation does not occur. not affect rifampicin.

Furthermore, the Applicant has discovered that granulation in an aqueous medium has the following drawbacks: irregular grains having a high residual percentage of granulation liquid because the total elimination of water is very difficult to achieve. This percentage of residual water facilitates and increases the breakdown of rifampicin.

Thus, particularly advantageously according to the present invention, the granulation is carried out by wetting with an organic solution. Thus, during the wet granulation step, the binder is in solution in a volatile organic solvent and the volatile organic solvent is typically chosen from the group consisting of ethanol (for example 96% ethanol), dichloromethane , and their mixtures.

Generally, the active ingredients, which are in powder form, are premixed before wetting.

According to a particular characteristic of the present invention, the wetting time during which the wetting solution is mixed with isoniazid, pyrazinamide and optionally ethambutol is between 1 and 5 minutes, and is advantageously carried out at room temperature.

Advantageously according to the present invention, the first granulation step of the process is carried out in the absence of reducing sugars, such as sucrose or lactose, which are known to affect the antibiotic activity of isoniazid.

In a particular embodiment, following the first step of wet granulation which leads to the production of grains, the grains are dried by ventilation in a fluidized air bed and the drying time is advantageously between 20 min and 1 hour. , typically between 30 min and 45 min.

In another particular embodiment, the drying of the grains is carried out in an oven, advantageously at a temperature of the order of 40 to 50 ° C, for example 45 ° C.

Typically, the grain drying time is then between 3 hours and 24 hours, for example between 6 and 8 hours. The drying time depends on the quantity of grain to be dried.

Drying the grains advantageously makes it possible to evaporate the solvent and cause the particles to agglomerate with one another.

Following drying, the grain is typically calibrated with conventional screens, for example screens of the order of 0.6 to 1.2 mm.

The rifampicin can then be then added to the dried and advantageously sized grains, without risking any problem of incompatibility or degradation of the various active ingredients. Flavoring agents can optionally also be added.

The composition thus obtained is in the form of grains or granules and contains either 3 active ingredients: isoniazid, pyrazinamide and rifampicin (FDC-3), or 4 active ingredients: isoniazid, pyrazinamide, ethambutol and rifampicin (FDC-4). It is a stable composition which does not degrade over time (preferably at least 2 years of stability).

Advantageously according to the present invention, the composition is formulated to be administered orally.

Typically, the compression excipients are premixed after weighing, for example for 5 to 15 minutes, advantageously for 6 to 9 minutes, before being added to the rifampicin and to the grains obtained beforehand according to the method of the present invention. The mixing of the compression excipients, of the rifampicin and of the grains, for example for 5 to 15 minutes, typically for 6 to 9 minutes, is advantageously carried out under humidity conditions with a humidity level less than or equal to 5%. , for example of the order of 2 to 3%.

Advantageously according to the present invention, the lubricants are chosen from the group consisting of sodium lauryl sulphate, magnesium stearate, and mixtures thereof.

In a particularly advantageous manner, the lubricants are present at a concentration between 0.5 and 3.5% in the finished tablet, ^ L16317

In a particular embodiment according to the present invention, sodium lauryl sulphate is used as lubricant and is present at a concentration of between 0.5 and 2%, typically between 1 and 1.5%, in the finished tablet.

In another particular embodiment according to the present invention, the magnesium stearate is used as a lubricant and is present at a concentration of between 1 and 3.5%, typically between 2 and 3% in the finished tablet.

According to a particular characteristic of the present invention, the disintegrants are chosen from the group consisting of corn starch, crospovidone, and mixtures thereof.

The compression is carried out so as to obtain an appropriate hardness.

The tablets obtained are particularly stable over time (minimum stability of 2 years).

The tablets obtained are then generally coated, typically by spraying with a film-coating solution before being packaged in blisters / packages of particular compositions.

The film coating solution contains a conventional non-aqueous coating / film coating material. This is, for example, a suspension of opadry pink in ethanol (96%). Typically, the Opadry Pink type coating product contains HPMC (Hydroxy propyl methyl cellulose) for example between 60 and 65%, titanium dioxide, for example between 25 and 30%, Macrogol such as Macrogol. 400, for example between 5 and 10% and red iron oxide, for example between 1 and 5%.

Particularly advantageously according to the present invention, the blisters are chosen such that they represent sufficiently sealed packages to prevent the penetration of water vapor into the interior of the tablets. The composition of the blisters typically contains complexes of aluminum polyamide and aluminum PVC.

Typically, isoniazid is present at a concentration of between 9 and 10 30%, for example approximately 9.5%, relative to the total weight of the composition obtained when the composition contains 3 active ingredients.

Typically, isoniazide is present at a concentration of between 6 and 7%, for example approximately 6.5%, relative to the total weight of the composition obtained when the composition contains 4 active ingredients.

Typically, the pyrazinamide is present at a concentration of between 48 and 53%, for example between approximately 50 and 51%, relative to the total weight of the composition obtained when the composition contains 3 active ingredients.

Typically, pyrazinamide is present at a concentration of between 33 and 37%, for example between approximately 34 and 36%, for example approximately 35%, relative to the total weight of the composition obtained when the composition contains 4 active ingredients.

Typically, rifampicin is present at a concentration of between 18 and 20%, for example approximately 19%, relative to the total weight of the composition obtained when the composition contains 3 active ingredients.

Typically, rifampicin is present at a concentration of between 12-15% and 14%, for example approximately 13%, relative to the total weight of the composition obtained when the composition contains 4 active ingredients.

Typically, where appropriate, ethambutol is present at a concentration of between 22 and 25%, for example between approximately 23 and 24%, relative to the total weight of the composition obtained, said composition containing 4 active ingredients.

The composition obtained according to the process of the present invention is advantageously used as a medicament, in particular for its use in the prevention or treatment of tuberculosis.

The following examples are given without limitation and illustrate the present invention.

Example 1:

In a Lôdige-type mixer tank, Pyrazinamide, of

Micronized Tlsoniazide, Ethambutol Hydrochloride, and Pregelatinized Corn Starch. Mix for 30 seconds.

Ί û

t

Immediately after the 30 s of dry mixing, the fount solution j! (Povidone K30 + Alcohol 96%) is added gradually and the whole is mixed for 2 min,

The mixture is dried at 45 ^Q C until a moisture content of 2.2% at

J 3.0%, | The dried granulate is calibrated (FRFWITT) via a l, 2 mm grid, t

j The Rifampicin and the calibrated granulate are mixed for 10 min and then sieved through the 1.2 mm grid.

The mixture thus obtained and the following excipients for compressing the external phase; corn starch, crospovidone, sodium lauiyl sulfate and magnesium stearate sieved through a 1.2 mm grid are mixed for 5 min,

The compression is done on a rotary machine, 21x9 mm elongated punches with a break bar.

The tablets are film coated with Opadry Pînk (made from alcohol).

Quality control of the manufacturing process

The preparation process that is the subject of the present invention has been subjected to quality analyzes making it possible to determine whether the active principles contained in the FDC-4 composition remain intact (availability in vitro: study of the rate of dissolution of the active principles) and whether their distribution in patients is preserved and is similar to the reference products (bioequivalence),

1- Study of the dissolution rate of the active ingredients of the composition FDC-4 (in vitro study)

The composition resulting from the manufacturing process, object of this invention, as described in Example 1, was subjected to dissolution tests to study the in vitro integrity and the release kinetics of each of its. four active ingredients against that of the reference drugs available on the market.

* 6 ίο

Figure 1 illustrates a comparative study of the availability in vitro (using a dissolution test) of isoniazid in the composition obtained in the context of the present invention in accordance with Example 1 against that of the reference product Rimifon® (Isoniazid 150 mg. Laboratoires LAPHAL INDUSTRŒS / CELGENE).

Figure 2 illustrates a comparative study of the in vitro availability (using a dissolution test) of pyrazinamide in the composition obtained in the context of the present invention in accordance with Example 1 against that of the reference product Pirilene ® (Pyrazinamid 500 mg. SANOFIAVENTIS).

Figure 3 illustrates a comparative study of the in vitro availability (using a dissolution test) of rifampicin in the composition obtained in the context of the present invention in accordance with Example 1 against that of the reference product Rifadine® (Rifampicin 300 mg. SANOFI AVENTIS).

Figure 4 illustrates a comparative study of the in vitro availability (using a dissolution test) of ethambutol in the composition obtained within the scope of the present invention in accordance with Example 1 against that of the product Myambutol® reference (Ethambutol 400 mg. GENOPHARM).

Figures 1, 2, 3 and 4 show an almost perfect superposition of the dissolution curves of the four active ingredients of the FDC-4 composition according to the invention 20 with the dissolution curves of their respective references, thus demonstrating the capacity of this process. manufacturing process to maintain the integrity of the active ingredients of the composition.

2- Bioequivalence (in vivo study)

The bioequivalence study was carried out in the Pharmacology and

Toxicology, Faculty of Medicine and Pharmacy of Rabat.

The composition resulting from the manufacturing process, which is the subject of this invention, was also subjected to a pharmacokinetic study in order to compare the distribution of rifampicin obtained from said composition with that of a reference product, in 24 subjects. healthy volunteers.

L16317

Figure 5 illustrates the bioequivalence, obtained in 24 healthy volunteers, of rifampicin derived from the FDC-4 combination of the product ERIP-K4® (LOT no.

9333), carried out according to the method of Example 1 described above, with rifampicin from the reference product Rifadine® (AVENTIS Laboratories).

FIG. 5 as well as the statistical analyzes carried out on the various pharmacokinetic parameters (AUC, Cmax and Tmax) * (see Table 1) demonstrate that the composition resulting from the manufacturing process of this invention is bioequivalent to the reference drug tested.

Table 1: Means of the pharmacokinetics of plasma rifampicin in 24 healthy volunteers after administration of ERIP-K4® and the reference

Form A: ERIP-K4®: composition according to the present invention

Form B: Reference RIFADINE Laboratoires AVENTIS

Settings AUC ₀ "(ng.h / ml) AUQm (ng.h / ml) Cmax (ng / ml) Tmax (hour) Average A 29687 ± 13624 21859 ± 8427 4538 ± 1632 2.29 ± 1.20 Average B 32559 ± 14707 23590 ± 7381 5067 ± 1466 2.04 ± 1.00

♦ Pharmacokinetic parameters;

-AUC: area under the plasma concentration curve;

-Cmax: maximum experimental plasma concentration;

-Tmax: time at which the maximum plasma concentration is observed.

Thus, the results of these studies clearly show that the preparation process which is the subject of the present invention guarantees the integrity of the four active ingredients of the composition obtained (FDC) (see Figures 1, 2, 3 and 4), and that the composition pharmaceutical obtained is therapeutically effective since it guarantees the bioavailability of rifampicin in treated patients (see Figure 5). -

CABIN

Pr

B.P 50

Phone. 22 21

E-mail:

TO JAN. 20'5

AZENAVE sari

woun

64 14

Claims (12)

1. Process for preparing a pharmaceutical composition in tablet form containing in combination rifampicin, isoniazid, and pyrazinamide, and optionally ethambutol or one of its salts, characterized in that it comprises the following successive steps : wet granulation of isoniazid, pyrazinamide and optionally ethambutol by wetting with at least one binder dissolved in a volatile organic solvent, to obtain grains, drying of the grains, addition of rifampicin, following the addition of rifampicin or during the addition of rifampicin, addition of compression excipients such as lubricants, disintegrants and possibly flavorings, following the addition of rifampicin or during the addition of rifampicin, then compression to obtain tablets. 2. Method according to claim 1, characterized in that the rifampicin has a density of between 0.3 and 1, advantageously between 0.4 and 0.8. 3. Method according to claim I or 2, characterized in that the binder is selected from the group consisting of pregelatinized corn starch, polyvinylpyrrolidone (PVP), povidone, and mixtures thereof. 4. Method according to one of claims 1 to 3, characterized in that the volatile organic solvent is selected from the group consisting of ethanol, dichloromethane, and mixtures thereof. 5. Method according to any one of the preceding claims, characterized in that the wetting time is between 1 and 5 minutes. 6. Method according to any one of claims 1 to 5, characterized in that the drying of the grains is carried out in a fluidized air bed, the drying time advantageously being between 20 min and 1 hour, typically between 30 min and 45 min. 7. Method according to any one of claims 1 to 5, characterized in that the drying of the grains is carried out in an oven, advantageously at a temperature of the order of 40 to 50 ° C. x 8. Method according to claim 7, characterized in that the grain drying time is between 3 hours and 24 hours. 9. Method according to any one of the preceding claims, characterized in that the first granulation step is carried out in the absence of reducing sugars, 5 such as sucrose or lactose. 10. Method according to any one of the preceding claims, characterized in that the lubricants are chosen from the group consisting of sodium lauryl sulfate, magnesium stearate, and mixtures thereof. 11. Method according to any one of the preceding claims, characterized 10 in that the disintegrants are selected from the group consisting of corn starch, crospovidone, and mixtures thereof. 13 ORIGINAL pages PHARMA 5 LABORATORIES VICARIOUS CAB JAN. 2013 CAZENAVE sari jté Industrial UNDE Ca