DE10354862B4 - Ramipril-containing solid pharmaceutical compositions and processes for their preparation - Google Patents

Abstract

Solid pharmaceutical composition comprising the following ingredients
(a) an effective amount of ramipril and / or a pharmaceutically acceptable salt thereof and
(b) one or more pharmaceutically acceptable diluents,
characterized in that the composition is stabilized by a water content of less than 5.5% by weight as measured by Karl Fischer analysis.

Description

The The present invention relates to solid pharmaceutical ramipril Compositions with a suitably low water content and Process for the preparation of the compositions.

The The present invention relates to solid, stable pharmaceutical ramipril containing compositions and methods for making such Compositions. Ramipril (1) is (2S, 3aS, 6aS) -1 - {(S) -N - [(S) -1-carboxy-3-phenylpropyl] alanyl} octahydro-cyclopenta [b] pyrrole. 2-carboxylic acid 1-ethyl ester. Ramipril is used to treat high blood pressure, heart failure, among others and nephropathy.

The production of ramipril was in the EP 0 079 022 A2 described. Stability is an important aspect of a pharmaceutical composition. The degradation of ramipril occurs mainly in two ways: The hydrolysis to ramipriloic acid [(2); the contaminant E] described in the European Pharmacopoeia and the cyclization to the ramiprildiketopiperazide [(3); the impurity D] described in the European Pharmacopoeia.

The in the EP 0 317 878 A1 published information, the data generated in stress stability ^tests of commercial ramipril formulations (eg Delix®) and the data generated internally during the development of proprietary formulations indicate that the major instability stems from the formation of the diketopiperazide. Table 1 shows the amount of ramipril diacid Ramiprildiketopiperazid and after storage of Delix ^® 1,25 mg (batch number C-423, derived from the German market) for 8 weeks at 40 ° C / 75% relative humidity (RH). Table 1

Provided Unless otherwise stated, test values of ramipril (1), ramipril-1-one (2) and Ramiprildiketopiperazid (3) by suitable HPLC methods, for example according to description in the European Pharmacopoeia 2001, Monograph "Ramipril", generated in percent.

The European Pharmacopeia gives a limit of 0.5% for the diketopiperazide and supports this limit. Preferably is the stability a commercial composition so that after a three-month, preferably six months, storage in a controlled environment from 40 ° C / 75% Humidity of the loss of the active ingredient less than 5% and the increase of impurities is preferably lower is twice that specified in the relevant pharmacopoeia Amount, in the case of Ramipril in the European Pharmacopoeia for the relevant Contamination in the amount indicated in the active ingredient. In In the specific case of ramipril should be the amount of ramiprildiketopiperazide preferably after storage at 40 ° C / 75% humidity during 3 Months, preferably 6 months, do not exceed 1.0%.

According to the EP 0 317 878 A1 It is well documented that ramipril formulations prepared by standard techniques show a considerable degree of instability. Hoechst was able to overcome the stability problem by using a commercially expensive and technically complicated technique (coating of ramipril with a polymer before compression). It has surprisingly been found that these prior art stability problems can be overcome by employing standard pharmaceutical techniques with proper control / limitation of water content in the final formulation. It has been found that the stability in the proposed formulations and processes is even better than that of the currently marketed commercial formulations of ramipril. It has surprisingly been found that other prior art approaches to stabilizing ACE inhibitors (formulations with acid donors, formulations with sodium bicarbonate) did not provide a suitable stable formulation unless the water content was concurrently adequately controlled. In addition, it has surprisingly been found that controlled-water test formulations that do not employ the prior art approaches also prove to be sufficiently stable. Although the focus of the tests was on tablet formulations, it could be shown that the principle is also suitable for capsules and is also considered suitable for sachets. The cyclization of ramipril to ramiprildiketopiperazide appears to be directly related to the presence of moisture in the formulation.

• (a) eine wirksame Menge von Ramipril und/oder eines pharmazeutisch akzeptablen Salzes hiervon und
• (b) ein oder mehrere pharmazeutisch akzeptable Streckmittel, wobei die Zusammensetzung dadurch gekennzeichnet ist, dass sie stabilisiert ist durch einen Wassergehalt von weniger als 5,5 Gew.-% gemäß Messung mittels Karl-Fischer-Analyse.

Thus, the present invention relates to a solid pharmaceutical composition comprising the following ingredients

• (a) an effective amount of ramipril and / or a pharmaceutically acceptable salt thereof and
• (b) one or more pharmaceutically acceptable diluents, which composition is characterized by being stabilized by a water content of less than 5.5% by weight as measured by Karl Fischer analysis.

firm pharmaceutical compositions according to the present invention include tablets, capsules, capsulets and sachets. Tablets may be suitable coated (film-coated tablets, pills). capsule formulations can Both soft capsules and hard capsules include.

The Form of ramipril and / or a pharmaceutically acceptable salt this is not particularly limited and includes all pharmaceutical acceptable anhydrates, solvates, hydrates, crystalline and amorphous To shape. The amount of ramipril in the solid pharmaceutical composition is subject no special restrictions and includes any amount that is pharmaceutically effective.

A low water content may be provided by a combination of suitable diluents that exhibit low water content, process parameters that prevent ingestion of moisture during manufacture, and suitable packaging material that absorbs moisture during storage of the final dosage form over the shelf life prevented, be achieved. Suitable diluents with a low water content are most preferably specific grades of microcrystalline cellulose (eg Avicel PH 112), starch (eg starch 1500 LM), silica (eg Syloid AL-1 FP), calcium hydrogen phosphate (eg Dicafos A) the extenders are not intended to be limited to the diluents mentioned herein, but are intended to extend to those which are taught to be low water content extenders, including diluents, binders, lubricants, disintegrants, colorants, etc. low water content. In another embodiment of the present invention, one or more of the diluents may be dried prior to use or during the manufacturing process to achieve the required level of water content. Even when low water content extender agents are used, the mixture and final formulation are susceptible to moisture during manufacture and during storage. Accumulation of humidity during processing may suitably be restricted by carrying out the production under controlled environmental conditions. The preparation is preferably in an environment with an air humidity of 35% at ambient temperature, preferably in an environment of a humidity of 35% at 30 ° C.

A Accumulation of moisture during Storage may suitably be carried out by using packaging materials, the known ones across from are not suitable for ingress of atmospheric moisture become. Preferred packaging materials are containers including lids made of polyethylene and / or polypropylene and / or glass and blister or strips of aluminum or high density polyethylene.

Other embodiments The present invention therefore relates to packages which are compositions Contain with a suitably low water content with packaging materials are packed, which are suitable tight against ingress of humidity are, preferably packaging materials according to the above.

Of the Water content in the composition, for example, by a Loss-on-drying (LOD) and / or Karl Fischer (KF) analysis, as well known to those skilled in the art is to be determined. For the determination of all the given data became the following specified method used. Of these two procedures is the Karl Fischer analysis known better reproducible and more accurate. Thus, the Karl Fischer analysis the preferred method for determining the water content in pharmaceutical Formulations.

LOD: For tablet formulations The tablets are in a mortar Pound to powder with a pestle. For capsule or sachet formulations the content of the capsule or sachet is evacuated. The loss when drying is carried out on a moisture balance, e.g. Mettler LP 16, determined using about 1.0 g of the sample. The mixture gets up evenly the weighing plate distributed the moisture balance. The weighing plate is preheated to 80 ° C and the mixture is subsequently 15 min at 80 ° C dried.

KF: For tablet formulations be tablets in a mortar Pound to powder with a pestle. For capsule or sachet formulations the content of the capsule or sachet is evacuated. The water content is with an automated KF device, such as Metrohm 784 KFP Titrino, using a conventional Karl Fischer reagent determined using 0.1 g of the sample.

The preparation of the product with conventional extenders results in a considerably high reduction of ramipril and increase of ramiprildiketopiperazide upon storage. In the EP 0 317 878 A1 For example, the increase of ramiprildiketopiperazide was attributed to 22.8% after 6 months at 40 ° C / 70% relative humidity and the reduction of ramipril down to 20% after 6 months at 40 ° C mechanical stress, and thus the active ingredient was coated to protect it from mechanical stress.

Tabelle 3 Wassergehalt der ursprünglichen Formulierung gemäß Bestimmung mittels LOD-Analyse

Commercial formulations of ramipril can be taken as a reference to formulations made with conventional extenders and showing normal levels of water content. Results with commercial formulations of ramipril obtained with LOD analysis and KF analysis are given in Tables 2 and 3. Table 2 Water content of the original formulation as determined by KF analysis

Table 3 Water content of the original formulation as determined by LOD analysis

This type of formulation is only stable when ramipril is separated from the hydrous extenders by a polymer barrier. The effect of the barrier was according to EP 0 317 878 A1 However, according to our surprising findings, it can be attributed to a minimization of the contact of ramipril with water during storage over the storage period.

Stability results generated in Examples 3 and 4 show the better stability of the low water content formulations (Table 4). Table 4 Stability of ramipril in tablets as a function of water content

In addition to the choice of low water content extenders, it is essential to carry out the production in an environment of sufficiently low relative humidity as demonstrated in the attached example. A mixture prepared according to Example 1 was well-defined Umweltbedin conditions a relative humidity at ambient temperature up to 6 h exposed. Only maintaining the relative humidity at about 30% was able to maintain the initial moisture loading. At ambient humidity levels (50% to 60%), the mixture picked up significantly already after 2 hours of moisture (Table 5). Considering that normal processing times for pharmaceutical products range from 8 hours to 1 week, control of this parameter becomes essential. Table 5 Water absorption in tablets as a function of relative humidity during production

The third factor for controlling the humidity in the final product is to prevent the absorption of moisture during storage. It is well known that storage of the products in the containers, including polypropylene and / or polyethylene and / or glass or in blisters and / or strips of aluminum or high density polyethylene, prevents them from becoming moisture during storage over the shelf life take up. Table 6 shows the uptake of moisture of tablets prepared according to Example 1 and stored at 40 ° C / 75% relative humidity in various packaging materials. During trilaminate (PVD / PE / PVDC 250 μ / 25 μ / 90 gsm and aluminum foil 20 μm) blister packs reach a saturation level after only 1 month, polypropylene containers with polyethylene lid and aluminum / aluminum plaster show no increase in water content over up to 6 months. Table 6 Water content as a function of the packaging material

A Application of the above principles provides reliable compositions with a suitably low water content, preferably less as 4.0% by weight, the strongest preferably less than 3.0% by weight, as determined by LOD analysis, or of less than 5.5% by weight, in the strongest preferably less than 4.5% by weight as determined using KF analysis. By applying suitable packaging techniques The moisture content in the formulation can be suitably low being held.

It was surprisingly observed that these pharmaceutical compositions are accelerated test conditions only then as sufficiently stable proven when the water content is low. Simultaneously with a Increase in moisture occurred degradation to diketopiperazide.

Working Examples:

Example 1:

During the Manufacturing process were environmental conditions of 30% relative Humidity / 30 ° C held. Ground glycine hydrochloride (0.300 kg) is washed with ramipril (0.125 kg), microcrystalline cellulose (Avicel PH 112, 7.125 kg), Pebble jellies (Syloid AL-1-FP, 0.800 kg) and pregelatinized Strength (strength 1500 LM, 0.450 kg) dry, whereupon the resulting mixture with Glycerin dibehenate (Compritol ATO 888, 0.200 kg) dry mixed and was squeezed. One got 100,000 tablets, each one Contained 1.25 mg ramipril.

For the attached stability test, the tablets are immediately packaged in PVC / PE / PVDC 250μ / 25μ / 90gsm and aluminum foil 20μm blister packs and Alu / Alu 40μm strips. The samples are subjected to a stability test at 40 ° C / 75% relative humidity. The LOD analysis of the tablets after preparation gives 3.19 wt%. Table 7 Stability and water content as a function of the packaging material

example Fig. 1 shows that pharmaceutical grade produced with glycine hydrochloride Compounds under accelerated test conditions as prove sufficiently stable when the water content is low, However, they prove to be unstable when the water content on normal levels of moisture in the pharmaceutical formulations increases.

Example 2:

During the manufacturing process, environmental conditions are maintained at 30% relative humidity / 30 ° C. Milled glycine hydrochloride (0.300 kg) is treated with ramipril (0.500 kg), microcrystalline cellulose (Avicel PH 112, 29.36 kg), diatomaceous earth (Syloid RL-1-FP, 3.200 kg), pregelatinized starch (starch 1500 LM, 1.800 kg). and iron oxide red (0.040 kg) are dry blended, and the resulting mixture is dry blended with glycerol-inehenate (Compritol ATO 888, 0.800 kg) and compressed to obtain 100,000 tablets each containing 5 mg of ramipril. These are immediately packaged in PVC / PE / PVDC 250 μ / 25 μ / 90 gsm and aluminum foil 20 μm blister packs, Alu / Alu 40 μm strips and polypropylene containers with polyethylene lid. The LOD analysis of the tablets after preparation gives 3.19 wt%. Table 8 Stability of ramipril (1), generation of ramiprictoetopiperazide (3) and water content as a function of the packaging material

Example 2 supports the results of Example 1. In particular, Example 2 demonstrates that low moisture compositions maintain diketopiperazide levels well below the limit of 0.5% as reported in the European Pharmacopoeia and far below those for a commercial ramipril formulation (Delix ^® 1.25 mg, lot number C-423, comes from the German market, 2.16% diketopiperazide).

Example 3:

Aluminum strips containing tablets having the following composition are prepared analogously to Example 1: Ramipril (1.25 mg), microcrystalline cellulose (Avicel PH 112, 50.32 mg), diatomaceous earth (Syloid AL-1-FP, 4.6 mg), lactose (lactose DCL-21, 37 mg), glycerol dibehenate (Compritol ATO 888, 1.83 mg) on a laboratory scale at ambient environmental conditions. The tablets are packed in Alu / Alu 40 micron strips and subjected to a Stabilityunter search at 40 ° C / 75% relative humidity. The LOD analysis of the tablets after preparation yields 2.71% by weight. Table 9 Stability at low water content

example Figure 3 shows that stabilizers made and stabilized with suitable extenders Prior art non-pharmaceutical agents Compositions no significant degradation over 4 weeks when stored under show accelerated test conditions.

Example 4:

In analogy to example 1, aluminum strips containing tablets of the following composition are prepared: ramipril (1.25 mg), starch (starch 1500, 20.32 mg), silica (Aerosil 200, 1.00 mg), lactose ( Lactose DCL-21, 78.00 mg), Ac-Di-Sol (4.00 mg) and Sterotex (1.80 mg) on a laboratory scale at ambient environmental conditions. The tablets are packed in Alu / Alu 40 μm strips and subjected to a stability test at 40 ° C./75% relative humidity. The LOD analysis of the tablets after preparation yields 6.60% by weight. Table 10 Stability at high water content

example 4 shows that with conventional Extenders prepared and stabilizers of the state non-technology pharmaceutical compositions not when stored under accelerated test conditions stable. Already after 1 week of storage, the content increased Ramipril decreases by more than 5%.

Example 5:

At laboratory scale at ambient environmental conditions, capsules containing ramipril (1.25 mg) and starch (1500, 138.75 mg) are prepared by dry mixing ramipril and starch 1500 and filling the mixture into conventional hard gelatin capsules. The capsules are packed in Alu / Alu 40 μm strips and subjected to a stability test at 40 ° C / 75% relative humidity. The LOD analysis of the capsules provides 8.27% by weight. Table 11 Stability at high water content

example Figure 5 shows that capsule formulations that are a conventional level of water content do not show up when stored under accelerated test conditions prove stable. After 6 weeks Storage at accelerated test conditions increased the content of diketopiperazide to 4%.

Example 6:

In analogy to example 5, aluminum strips containing capsules of the following composition are prepared: Ramipril (1.25 mg), starch (1500 LM, 37.00 mg) and perlitol (148.75 mg) are mixed and the mixture is filled into conventional capsules on a laboratory scale at ambient environmental conditions. The capsules are packed in Alu / Alu 40 μm strips and subjected to a stability test at 40 ° C / 75% relative humidity. The LOD analysis of the capsules yields 5.79% by weight. Table 12 Stability at high water content

example 6 supported the findings of Example 5. A LOD analysis over 5 wt% does not guarantee sufficiently stable formulation. A significant trend towards Stabilization with reduced moisture loading is obvious.

Example 7:

In analogy to example 5, aluminum strips containing capsules of the following composition are prepared: ramipril (1.25 mg), microcrystalline cellulose (Avicel PH 101, 71.48 mg), starch (starch 1500, 20.47 mg) and arginine (1.80 mg) are mixed and the mixture is filled into conventional capsules on a laboratory scale at ambient environmental conditions. The capsules are packed in Alu / Alu 40 μm strips and subjected to a stability test at 40 ° C / 75% relative humidity. The LOD analysis of the capsules provides 3.24 wt%. Table 13 Stability at low water content

example Figure 7 shows that capsule formulations having a low level of Water content, when stored at accelerated test conditions across from a cyclization of the active ingredient to diketopiperazide as considerable stable. Examples 5, 6 and 7 show that the principle the stabilization of ramipril formulations by exclusion of Moisture in the formulation also applies to capsule formulations. The test for ramipril also remains above 95%.

Claims (9)

A solid pharmaceutical composition comprising the following ingredients: (a) an effective amount of ramipril and / or a pharmaceutically acceptable salt thereof; and (b) one or more pharmaceutically acceptable diluents, characterized in that the composition is stabilized by a less than water content 5.5% by weight as measured by Karl Fischer analysis. A composition according to claim 1, wherein the water content Less than 4.5 wt .-% as measured by means Karl Fischer analysis is. A composition according to any one of the preceding claims, wherein Ramipril and / or a pharmaceutically acceptable salt thereof in Form of a pharmaceutically acceptable anhydrate, solvate and / or hydrate and / or in crystalline and amorphous form. A composition according to any one of the preceding claims, wherein the pharmaceutical composition is a tablet, capsule or a Sachet is. A composition according to claim 4, wherein the tablet is suitably coated to a film-coated tablet and / or deliver a pill. A composition according to claim 5, wherein one of the Extender microcrystalline cellulose, Avicel PH 112, starch, starch 1500 LM, silica, Syloid AL-1 FP, calcium hydrogen phosphate, Dicafos A or A Tab or Anhydrous Emcompress, Lactose, Pharmatose DCL 21, mannitol, perlitol, calcium sulfate, destab or drierite. A composition according to any one of the preceding claims, wherein one or more extenders before use or during the Production process dried to the required level to reach the water content. Process for the preparation of a composition according to one of the preceding claims, the environmental conditions during Manufacture at a relative humidity of ≤ 35% at ambient temperature being held. A process for preparing a composition according to claims 1 to 6, wherein the environmental conditions during manufacture at a relative humidity of ≤ 35% at ≤ 30 ° C.