SI22339A - Stable formulation of amorphous perindopril erbumine, process for its preparation on industrial scale and its application for treatment of hypertensia - Google Patents

Abstract

A stable formulation of amorphous perindopril erbumine is described, having the formula: , which is obtained by dissolving perindopril erbumine - which may be prepared also in situ from perindopril and tert. butylamine - or perindopril erbumine hydrate in demineralized water or mixture of demineralized water and alcohol, adding a solution of sodium hydrogencarbonate to this solution for stabilization - to wet inert components for tabletting in this manner - drying in vacuum by liophylisation or at normal pressure under the stream of warm air at maximum 40 degrees Celsius, adding hydrophobic additives to facilitate tabletting, homogenizing and tabletting the granulate. Investigations carried out with X-ray powder diffraction technique have shown that perindopril erbumine existed in amorphous form and did not contain any alpha, beta and gamma crystal forms.

Description

A stable formulation of amorphous perindopril erbumine, a process for its industrial scale preparation and its use for the treatment of hypertension.

FIELD OF THE INVENTION

The present invention is in the field of pharmaceutical chemistry and relates to a stable formulation of amorphous perindopril erbumine of formula I:

a process for its industrial-scale preparation and its use for the treatment of hypertension.

A technical problem

Perindopril erbumine is a very effective vasodilator and antihypertensive agent. Due to the high pharmaceutical importance, there was a need for a new, industrially applicable process for the preparation of a stable formulation that would allow the manufacture of pharmaceutical preparations.

The state of the art

In known formulations, the active component is perindopril erbumine in various polymorphic forms of formula I:

The formulation with perindopril erbumine in α-polymorphic form is described in Servier patent WO 01/87835 A1. Β-Polymorphic perindopril erbumine enters the pharmaceutical formulation according to the patent of Adir & Co. WO 01/87836 A1.

Perindopril erbumine in γ-polymorphic form, described in U.S. Patent 2003/0158121 A1 and in the patent of Adir & Co. WO 01 / 83439A1, is less suitable for the pharmaceutical formulation because of the method of preparation of the crystallization compound by chloroform - a solvent which is also traceable in pharmaceutical formulations. None of the above processes lists specific additives to increase the stability of pharmaceutical preparations. However, TEVA patent WO-03/075842 A2 deals with stable formulations containing ACE inhibitors, in particular moexipril with the addition of sodium hydrogen carbonate.

There are several ways to break down ACE inhibitors:

- by hydrolysis of the ester group, especially on the side chain,

- water separation and internal cyclization to form diketopiperazines.

Several patent literature methods are known to address more stable formulations that are intended to prevent these breakdown reactions, for example: U.S. Pat. No. 4,743,450.

U.S. Pat. No. 5,573,780 and nos. No. 5,690,962 lists the stable enalapril formulations and the process for their preparation. Slovenian patent Sl 9111842 A and US patent no. No. 5,350,582 lists stable formulations of enalapril with the addition of a stoichiometric amount of various basic additives, preferably alkali metal carbonates, which are added in solid form. Magnesium carbonate is contemplated as a means of stabilizing quinapril preparations. No. 4,473,450.

German Patent Application DE 10 2004 019 845 A1 deals with the preparation of a preparation with perindopril erbumine containing crystallized α-form of perindopril erbumine mixed with sodium hydrogen carbonate for solid stabilization. In this case, the stabilization effect is not perfect because it is only detectable at the junction of two solid surfaces. In addition, crystalline form a is used, which is protected by other patents, for example WO 01/87835.

Patent WO 03/061691 A1 of Servier lists pharmaceutical preparations, perindopril for oral administration, which are dispersed in the oral cavity and contain additives such as Starlac ®, sodium stearyl fumarate and colloidal silica. The stability data is not given, but here, given the mode of administration and the short absorption, stability is important mainly because of the durability of the preparation.

Simple pharmaceutical formulation without special stability enhancement additives is cited in WO 2004/046172, (PTC / GB

2003/004981) and GB 2,395.195A by Cipla, wherein perindopril erbumin hydrates enter the formulation.

Description of solution to a technical problem

According to our invention, a stable formulation of perindopril and its salts in amorphous form is prepared by dissolving perindopril or its salt, preferably perindopril erbumine in water or in a water / alcohol mixture, or preparing perindopril erbumine in situ from perindopril and tert. of butylamine which are mixed and allowed to react in a suitable solvent. This solution is filtered and sprayed onto the calculated amount of inert tabletting ingredients (lactose, cellulose and starch), mixed uniformly and then dried in a vacuum or in dry air. This dry mixture is then triturated and the other auxiliaries are mixed together to form a final tablet granulate suitable for tabletting.

We use conventional inert substances as constituents for the preparation of granulate, such as microcrystalline cellulose, anhydrous lactose or its monohydrate and corn starch. More hydrophobic substances such as magnesium stearate and talc, which facilitate tabletting, are best added in the second stage of granulate preparation.

Of particular importance is the addition of trehalose, which has a very beneficial effect on the stability of the preparation. Trehalose is a natural sugar found in yeast (up to 23% on dry matter). It is very stable, non-hygroscopic and very lactose-like, and is a suitable supplement in the manufacture of tablets. As an excipient - a filler - trehalose is as useful as lactose. It is used as a stabilizer for compounds with an amide group, especially peptides and proteins. In the production of enzymes, it is added prior to lyophilization because it greatly increases the stability of the preparations (Colaco C. et al, Extraordinary stability of enzymes dried trehalose, Bio. Technol. 10, 1007 - 1010 (1992); Colaco C. et al, Chemistry of protein stabilization by Trehalose, Formulation and Delivery of Proteins and Peptides, Am Chem. Societry, p. 222-240, (1994) Trehalose has a stabilizing effect on the dehydration reaction (prevents the Maillard reaction), but certainly in re-wetting accelerates rehydration and has a beneficial effect on rehydration. tablet has a surprisingly beneficial effect on the stability of perindopril erbumine.

Trehalose in the amount of 0-100% based on the lactose content can be used in the preparation of the tablet granulate.

In the condition of tablets containing perindopril erbumine, especially at higher temperature and increased air humidity, several degradation products may be produced, two in particular being important: diketopiperazine (approx. DKP or impurity F after pharmacopoeia), which is chemical: ethyl (2S) -2 - [(3S, 5aS, 9aS, 10aS) -3-methyl-1,4-dioxodecahydropyrazino [1,2a] indol-2 (1H) -yl] pentanoate and hydrolysis product (impurity B), which is chemically: (2S , 3aS, 7aS) -1 - [(2S) -2 [[((1S) -1-carboxybutyl] amino] propanoyl] octahydro-1H-indole-2-carboxylic acid).

In the long term, the stability of amorphous perindopril erbumine can be further enhanced by the addition of very weak basic substances such as hydrogen carbonates, basic carbonates and the like. Sodium hydrogen carbonate is a particularly suitable substance because it is a weak enough base to prevent hydrolysis and prevent the formation of diketopiperazide. These stabilizing additives are used in an amount of 0.2 -1 mol per 1 mol of active substance. It has been observed that the effect of these basic additives is significantly greater when added to the solution of perindopril erbumine and then sprayed onto the other ingredients and dried. In this way, significantly better and more uniform contact of components and more effective stabilization of the active substance are achieved.

The active pharmaceutical ingredient - perindopril can be used in the form of free acid and the erbumine can be prepared in situ or in the form of its salts, e.g. erbumine or in the form of perindopril erbumin hydrates produced according to our prior Slovenian patent application Sl P-200400285 and EP 1 647547A1. The amorphous form of the active ingredient is prepared by spraying a solution containing perindopril erbumine and a stabilizer on the other constituents, and by rapid drying with warm air of 25 ° C to a maximum of 40 ° C or freezing the wetted mixture at -30 ° C and lyophilization. Surprisingly, the mass, after drying, as well as after the homogenisation and in the tablets, does not contain perindopril erbumine in any known or known formulation. patented crystalline form.

X-ray diffractograms show that there are no reflexes at the 2Θ sites, where the reflexes on the crystalline planes for the α, β and γ forms of perindopril erbumine as well as for the hydrated forms are normally visible. Which means that the tablet granules and tablets made from them do not contain the crystalline forms of perindopril erbumine mentioned. However, at prolonged recording times of diffractograms in the narrow region 2Θ, in short at strongly increased sensitivity, traces of wide and insignificant responses are observed in the range of 8-9 ° 2Θ, which in shape, position and configuration do not correspond to the reflexes of crystalline form α, β or γ and, compared to placebo, appear to originate from the other ingredients. The amorphous structure of perindopril erbumine is still unknown in the literature.

X-ray powder diffractograms were recorded on a PANanalytical X'Pert PRO diffractometer with Alfal configuration, CuKa radiation, range 5 ° to 11 ° 2Θ, step 0.034 °, integration time 100 sec / step, 0.02 rad gap, 10 mm. This area was chosen because all known crystalline forms of perindopril erbumine show maximal reflexes here.

In addition, diffractograms were taken at increased sensitivity of the device: in the range 5 to 11 ° 2Θ and with a longer integration time - 10000 sec / degree.

Figure Fig.1. shows an X-ray diffractogram of a granulate or finely ground tablet containing perindopril erbumine in amorphous form made according to Example 4 (curve A) versus placebo (curve B). Figure Fig.2. shows a diffractogram of the same granulate (A) taken at increased sensitivity of the apparatus, even compared to placebo (curve B). The α, β, and γ labels refer to the reflex sites of these polymorphic forms.

The recorded diffractograms show that the image of the granulate with perindopril erbumine is the same as that of placebo - there are no reflexes originating from the known crystalline forms of perindopril erbumine!

The invention is explained in detail by the following embodiments, but is not in any way limited by it:

Example 1.

Composition for 1000 tablets of 4 mg perindopril erbumine:

perindopril erbumin hydrate 4.16 g * lactose anhydrous 39.00 g trehalose anhydrous 20.00 g microcrystalline cellulose 18.00 corn starch 5.00 g magnesium stearate 1.00 g talc_3.00 g total 90.16 g

*) corresponds to 4.0 g of perindopril erbumine

Granulate preparation:

Dissolve 4.16 g of perindopril erbumin hydrate in 28 ml of demineralized water and dilute the clear solution with 20 ml of ethanol.

In particular, 18 g of microcrystalline cellulose, 20 g of trehalose and 39 g of lactose are mixed and the homogeneous mixture is uniformly wetted with the solution prepared above. The mass is then dried under vacuum at a maximum of 30 ° C during occasional stirring. We then detail it and add the other ingredients:

g of corn starch, 1 g of magnesium stearate and 3 g of talc and the mixture is well homogenized. The homogeneous granular material thus prepared is used to prepare tablets or capsules.

Example 2.

Composition for 1000 tablets of 8 mg perindopril erbumine:

perindopril erbumin 8.0 g lactose anhydrous 120.0 g microcrystalline cellulose 34.0 g corn starch 10.0 g magnesium stearate 2.0 g talc_6.0 g total 180.0 g

Granulate preparation:

6.674 g of perindopril are dissolved in 40 ml of ethanol, while 1.92 ml of tertiary butylamine are added while stirring, followed by 48 ml of demineralized water. The clear solution was filtered through a 0.2pm filter. In particular, 120 g of lactose and 34 g of microcrystalline cellulose are mixed and the homogeneous mixture is uniformly moistened with the solution prepared above. The mass was rapidly cooled to -30 ° C to freeze and then dried by freeze-drying in vacuo.

The dry product is detailed, the remaining ingredients are added: 10 g of cornstarch, 2.0 g of magnesium stearate and 6.0 g of talc and well homogenized and sieved through a suitable sieve. The homogeneous substance (granulate) thus prepared is used to make tablets or capsules.

Example 3.

Composition for 1000 tablets of 4 mg perindopril erbumine: perindopril erbumin lactose anhydrous microcrystalline cellulose

4,00 g

59.24 g 18.00 g corn starch 5.00 g magnesium stearate 1.00 g talc_2.00 g total 90.00 g

Granulate preparation:

Dissolve 4.0 g of perindopril erbumine in 25 ml of demineralized water and dilute the clear solution with 20 ml of ethanol. A solution of 0.76 g of sodium hydrogen carbonate dissolved in 15 ml of water was added and mixed well and quickly filtered.

In particular, 60 g of lactose, 18 g of microcrystalline cellulose, 5 g of corn starch, 1 g of magnesium stearate and 2 g of talc are mixed and this mixture is moistened with the solution prepared above. The resulting mass was dried under vacuum while stirring at 30 ° C. The homogeneous mixture (granulate) thus obtained is used to prepare tablets or capsules.

Example 4.

Composition for 22,000 tablets of 4 mg perindopril erbumine:

perindopril erbumine 0,095 kg lactose monohydrate 1,420 kg microcrystalline cellulose 0,426 kg corn starch 0,118 kg magnesium stearate 0,024 kg talc 0.047 kg sodium hydrogen carbonate_0,018 kg total 2,148 kg

Granulation performance:

0.095 kg perindopril erbumine is prepared in situ by dissolving 0.079 kg perindopril in 400 ml ethanol (96%) and 250 ml water and 23 ml tert. of butylamine. A solution of 0.018 kg of sodium hydrogen carbonate in 200 ml of water was added to the solution while stirring and mixed with a pre-prepared solution of perindopril erbumine and filtered.

In a WSG granulation machine, type Glatt GPCG-1, pre-prepare a dry mixture of the following ingredients:

lactose monohydrate ........................................... 1,420 kg corn starch ............................................... .......... 0.059 kg cellulose microcrystalline .................................... 0.426 kg

A pre-prepared solution of perindopril erbumine is sprayed uniformly on this mixture at a rate of ca 15 g / min. Dry with warm, warm air with an inlet temperature of not more than 40 ° C so that the product temperature does not exceed 30 ° C. This intermediate contains 1.8% water.

The resulting granulate in the homogenizer is then mixed with the following ingredients:

corn starch................................................ ........... 0.059 kg talc .................................... ............................... 0,047 kg magnesium stearate ............... ................................... 0,024 kg

This final granulate is used for tablet preparation. We tablet on a Kilian RLA tablet machine at a rate of 30,000 tablets / hour.

Example 5.

Composition for 22,000 tablets with 4 mg perindopril erbumine perindopril erbumine sesquihydrate (5.7% water) ......... 0.100 kg lactose anhydrous ................. .................................. 1,420 kg corn starch ............ ............................................... 0,118 kg cellulose microcrystalline ....................................... 0,426 kg sodium hydrogen carbonate ...... .................................. 0.009 kg talc ............. .................................................. ..... 0 047 kg magnesium stearate ......................................... .......... 0.024 kg total ..................................... ................................. 2,144 kg

The granulate is prepared in the manner described in the preceding example and tableted in the same manner.

Example 6. Determination of tertiary content. of butylamine.

The content of tert. butylamine should not be reduced during the preparation of the granulate, especially after the addition of hydrogen carbonate and drying. The content was determined by potentiometric titration of a previously prepared aqueous suspension of 40 tablets, very finely ground, in 35 ml of water. Titrate with 0.05 molar sulfuric acid (VI).

The results showed that there was no significant decrease in tert.butylamine content (> 98% of the initial amount) and therefore it was found that perindopril was still in the form of erbumine.

Example 7. Stability test

The accelerated stability study was performed with tablets manufactured according to the procedure described in Example 4 above, aged at 40 ° C and 75% air humidity. The tablets were packed in brown bottles with a PE stopper.

The stability of the marketed preparation with perindopril erbumine (tablets containing 4 mg of active substance) was comparatively determined under the same conditions but in the original packaging (blister).

The content of perindopril erbumine and degradation products: diketopiperazine (impurity F) and hydrolysis product (impurity B) were measured by HPLC chromatographic method.

HPLC system:

column: Chromasil 100, RP-18, 150 x4.6 mm mobile phase: 32.5% acetonitrile / 67.5% buffer pH = 2 buffer composition: 0.92 g sodium heptansulfonate and 1 ml triethylamine / 1 L flow rate:

detection:

of water, pH 2 adjusted with perchloric acid. 1 ml / min (isocratic)

UV, 200 nm sample preparation: 22.5 mg of finely divided tablets are suspended in 1 ml of mobile phase, digested for 5 min and filtered fine.

sample application: 20 μΙ_.

Relat. retention times: degradation product B ...... 0.24 degradation product F ...... 2.53 perindopril erbumine 1.00

Test results

Perindopril content in% (HPLC-surface%) and degradation products B and F (surface%) are measured.

Sample: content of components: Go away 15 days 30 days tablets by perindopril erbumin 99.77 99.33 99.24 case 4. product B 0.05 0.09 0.20 product F 0.04 0.06 0.08 pills perindopril erbumin 99.61 99,40 99.21 the other product B 0.03 0.16 0.22 manufacturer product F 0.06 0.22 0.40

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List of image attachments.

Figure Fig.1. shows the X-ray diffractogram of the granulate or. finely detailed tablets containing perindopril erbumine in amorphous form (curve A) versus placebo (curve B).

Fig. 2. shows an X-ray diffractogram of the same granulate (A) taken at increased sensitivity of the apparatus, as well as compared to placebo (B).

The labels α, β, and γ refer to sites where reflexes of polymorphic forms of the active substance may be located.

Claims (10)

A process for the industrial preparation of a stable formulation of the amorphous perindopril erbumine of formula I. characterized in that this compound is dissolved in water or in an alcohol / water mixture in any ratio, this solution is added with a stabilizer solution, mixed and added to a homogeneous mixture of inert constituents for the preparation of granulate, dried in vacuum by lyophilization or air in warm air flow , substances for tableting are added, homogenized and the granulate tableted. 2. A process for the industrial preparation of a stable formulation of an amorphous perindopril erbumine, characterized in that the solution of perindopril erbumine with a stabilizer added is sprayed onto the entire mixture of all inert ingredients, which is dried in vacuo or in air flow, homogenized and tableted. Process according to claims 1 and 2, characterized in that lactose, monohydrate lactose, trehalose, corn starch, microcrystalline cellulose, talc and magnesium stearate are used as inert constituents for the preparation of the granulate. Process according to Claims 1 and 2, characterized in that slightly alkaline substances such as carbonic acid salts, preferably sodium hydrogen carbonate, are used as the stabilizing agent. Method according to claims 1 and 2, characterized in that the drying is carried out in the temperature range from -20 ° C to + 40 ° C. Process according to claims 1 and 2, characterized in that perindopril erbumine is formed in situ in solution by dissolving perindopril in alcohol or an alcohol / water mixture and an equimolecular amount of tert is added. butylamine and an aqueous solution of the stabilizing agent and then, by adding to the other ingredients and drying, prepare a homogeneous mixture, which is subsequently mixed into the granulate. 7. A stable formulation of amorphous perindopril erbumine in admixture with lactose, starch, microcrystalline cellulose, talc and magnesium stearate, showing no reflexes of any known crystalline form of perindopril erbumine in the X-ray powder diffractogram. 8. The formulation according to claims 1 to 6 in the form of a tablet or capsule. Use of a formulation according to claim 7 as a medicament with antihypertensive and vasodilatory action. The amorphous form of perindopril erbumine obtained according to claims 1 to 7.