NL1024899C1 - Solid ramipril-containing pharmaceutical compositions. - Google Patents

Description

Solid ramipril-containing pharmaceutical compositions

The present invention relates to solid pharmaceutical compositions comprising ramipril with a suitable low water content, and methods for preparing such compositions.

Description of the invention

The present invention relates to stable pharmaceutical compositions containing ramipril and to methods for preparing such compositions.

Ramipril (1) corresponds to (2S, 3aS, 6aS) -1 - {(S) -N - ([(S) -1-carboxy-3-phenyl-propyl] -alanyl} octahydro-cyclopenta [b] pyrrole -2-carboxylic acid-1-ethyl ester and is used for the treatment of hypertension, heart failure and nephropathia.

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The preparation of ramipril is described in EP 0 079 022 A2.

Stability is an important aspect of a pharmaceutical composition. The degradation of ramipril occurs mainly via two ways: The hydrolysis to ramipril diacid [(2); contamination E described in the European Pharmacopoeia] and ring-forming into ramiprildiketopiperazide [(3): contamination D described in European Pharmacopoeia].

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The information given in EP 0 314 878 A1 based on data generated with voltage stability testing of commercial ramipril formulations (eg Delix®), and data generated internally during the development of proprietary formulations show that the most important Instability is caused by the formation of diketopiperazide. Table 1 shows the level of ramiprildiketopiperazide and ramiprildic acid after storage of Delix® 1.25 mg (batch number C-423; from the German market) for 8 weeks at 40 ° C / 75% relative humidity (RH).

10 Table 1: ramiprildiketopiperazide [%] ramiprildic acid [%] 2 ^ 6 "ÖÏ6

Unless otherwise stated, the measured values in percentages of ramipril (1), ramiprildic acid (2) and ramiprildiketopiperazide (3) are generated by suitable HPLC methods, e.g. such as those described in European Pharmacopoeia 2001, monograph "Ramipril".

The European Pharmacopoeia sets and recommends a limit of 0.5% for diketopiperazide. Preferably, the stability of the commercial composition is such that after storage for 3 months, preferably 6 months, in a controlled environment of 40 ° C / 75% RH, the loss of the active ingredient is less than 20% and the increase to contaminants preferably less than twice the amount mentioned in the relevant Pharmacopoeia, in the case of ramipril the European Pharmacopoeia for the relevant contaminant in the active ingredient. In the particular case of ramipril, the level of ramiprildiketopiperazide should preferably not exceed 1.0% after storage for 3 months, preferably 6 months at 40 ° C / 75% RH.

It is described in detail in EP 0 314 878 A1 that ramipril formulations made with standard technologies show a considerable degree of instability. Hoechst managed to solve the stability problem through a commercially expensive and technically complicated technology (coating ramipril with a polymer prior to compression).

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It was surprisingly found that these stability problems from the prior art can be solved if, when applying standard pharmaceutical technologies, the water content in the final formulation is properly controlled or limited. It was found that the stability with the proposed formulations and methods is even improved compared to the ramipril formulations that are currently available on the market. It was surprisingly found that other known methods for stabilizing ACE inhibitors (formulations with acid donors, formulations with sodium bicarbonate) did not provide a sufficiently stable formulation unless the water content was well controlled at the same time. In addition, it was surprisingly found that test formulations with controlled water content, in which the methods of the prior art were not used, were also found to be sufficiently stable. While the tests were concentrated on tablet formulations, it could be shown that the principle is also suitable for capsules and it is also considered suitable for sachets. The ringing from ramipril to ramiprildiketopiperazide appears to be directly related to the presence of moisture in the formulation.

Therefore, the invention relates to a solid pharmaceutical composition comprising: (a) an effective amount of ramipril and / or of a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable excipients, the composition having a suitably low water content.

Solid pharmaceutical compositions according to the invention include tablets, capsules, capsules, and sachets. Tablet can be suitably coated (coated tablets, pills). Capsule formulations can include both soft and hard capsules.

The form of ramipril and / or a pharmaceutically acceptable salt thereof is not particularly limited and includes all pharmaceutically acceptable anhydrates, solvates, hydrates, crystalline and amorphous forms. The amount of ramipril in the solid pharmaceutical composition is not particularly limited and includes any amount that is pharmaceutically effective.

Low water content can be achieved with a combination of suitable excipients that show low water content, process parameters that prevent the absorption of moisture during preparation and good packaging material that prevents the absorption of moisture during storage of the final dosage form during the shelf life. Suitable adjuvants with a low water content are most preferably special grades of microcrystalline cellulose (e.g.

5 Avicel PH 112), starch (e.g. Starch 1500 LM), silicon dioxide (e.g. Syloid AL-1 FP), calcium hydrogen phosphate (e.g. Dicafos A), but are not limited to the aforementioned excipients, but extend over all known auxiliaries with a low water content, including thinners, binders, lubricants, disintegrants, colorants, etc.

In another embodiment of the invention, one or more of the excipients may be dried prior to use or during the preparation process to achieve the required level of water content.

Even if auxiliaries with low water contents are used, the mixture and the final formulation are sensitive to the absorption of moisture during preparation and during storage. Moisture collection during processing can be well limited by carrying out the preparation under controlled environmental conditions. The preparation in an environment equal to or less than 35% RH at ambient temperature is preferred, preferably in an environment equal to or less than 35% RH at 30 ° C or lower.

Collection of moisture during storage can be properly prevented by using packaging materials that are known to close tightly in a manner suitable for moisture penetration. Preferred packaging materials are containers including lids that consist of polyethylene, polypropylene and / or glass, and blister or strip packaging that consist of high density aluminum or polyethylene.

Therefore, other embodiments of the invention are packages that comprise compositions of a suitable low water content that are packaged with packaging materials that close tightly in a moisture-permeable manner, preferably packaging materials as mentioned above.

The water content in the composition can be determined, for example, by loss-during-drying (LOD) and / or Karl-Fischer (KF) analysis known to those skilled in the art. The methods mentioned below are used to determine all the data mentioned. Of these two methods, KF is considered more reproducible and specific. Therefore, KF is the preferred method for determining the water content in pharmaceutical formulations.

LOD: For tablet formulations, tablets are powdered in a mortar with a pestle. For capsule or sachet formulations, the contents of the capsule or sachet are emptied. The loss during drying of about 1.0 g of the sample is determined on a moisture balance, e.g. Mettler LP 16. The mixture is evenly distributed over the moisture balance weighing plate. The weighing plate is preheated to 80 ° C and the mixture is then dried for 15 minutes at 80 ° C.

10 KF: For tablet formulations, tablets are powdered in a mortar with a pestle. For capsule or sachet formulations, the contents of the capsule or sachet are emptied. The water content is determined from 0.1 g of sample with an automatic KF device, e.g. Metrohm 784 KFP Titrino, with conventional Karl-Fischer reagents.

Preparation of the product with previously customary excipients results in a considerably large decrease in ramipril and increase in ramipril dipetopiperazide at - - storage - M-EP-Q-3-1-7-8-78. increase of raimprikikopiperazide-22.8 "% after 6 months at 40 ° C / 70% RH and the decrease of ramipril to 20% after 6 months at 40 ° C attributed to mechanical stress, and therefore the active ingredient was coated to protect this against mechanical stress.

Commercial ramipril formulations can be considered as a reference for formulations prepared with conventional excipients and showing normal levels of water content. The results for ramipril formulations achieved with LOD and KF are shown in Tables 2 and 3.

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Table 2: Water content of original formulation as determined with KF

Product name Batchnr. Strength Formulation Country Water content _____ [% by weight 1

Delix® 40A428 2.5mg Tablets Germany 8.00_

Delix® 40A475 5mg_Tabletten Germany 7.34_

Delix ^ Protect 1W425__lOmg_Tabletten Germany 7.24_

Tritace® W245__l, 25mg Capsule Austria 11.07_

Tritace® A232_2.5mg Capsule Austria 10.03_

Tritace® A228_5mg_Capsule Austria 9.95_

Tritace® W429__lOmg_Tabletten Austria 7.78_

Table 3: Water content of original formulation as determined by LOD

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Product name Batchnr. Strength Formulation Country Water content _____% by weight 1

Delix® 40A428 2.5mg Tablets Germany 6.37% _

Delix® 40A475 5mg_T abletten Germany 6.11% _

Delix® Protect 1W425 lOmg_Tabletten Germany 5.97% _

Tritace® W245__l, 25mg Capsule Austria 9.52% _

Tritace® A232 2.5mg Capsule Austria 8.68% _

Tritace® A228_5mg_Capsule Austria 8.40% _

Tritace® W429__lOmg__Tablets Austria 6.70% _

This type of formulation is only stable if ramipril is separated from the aqueous auxiliaries by a polymer barrier. The effect of the barrier was attributed in EP 0 317 818 A1 to the reduced mechanical stress during compression, but according to our surprising results, this can also be attributed to minimizing the contact of ramipril with water during storage over the shelf life.

Stability results generated with Examples 3 and 4 show the superior stability of formulations with low water contents (Table 4).

Table 4: Stability of ramipril in tablets as a function of water content

Ramipril assay [%] __ Example 3 (water content with Example 4 (water content with _LOD: 2.71% by weight) _ LOD: 6.60% by weight) _ beginning 101.11_97.85_ 1 week 102.23_ 90.73_ 2 weeks 99.90__ 4 weeks 101.21 __-__

In addition to the choice for auxiliary substances with a low water content, carrying out the preparation in an environment with sufficiently low relative humidity is necessary, as is shown in the attached example. A mixture prepared according to Example 1 was exposed for 6 hours to well-defined ambient conditions of relative humidity at ambient temperature. Only when the relative humidity is kept at about 30% can the original moisture content be maintained. At ambient humidity levels (50 to 60%), the mixture has already absorbed significantly much moisture after 2 hours (Table 5). Taking into consideration that normal processing times for pharmaceutical products are in the range of 8 hours to a week, the control of this parameter becomes necessary.

Table 5: Water intake in tablets as a function of the relative humidity during production

Time of 30% RH 50-60% RH 70% RH

Tod [kf löd | ~ kf löd [kf _ [wt%] [wt%] [wt%] [wt%] [wt%] [wt%] 2__3.21 4.09 5.31 6.60 5.79 6.87 _4.13.19 5.33 5.41 6.62 7.49, 7.70 1 6 1 3.51 4.24 5.91 6.67 7.90 8.46

The third factor to control the humidity in the final product is to prevent the absorption of moisture during storage. It is generally known that storing products in the containers including lid that consist of polyethylene, polypropylene and / or glass or in blister and / or strip packaging consisting of aluminum or high density aluminum prevents these absorbing moisture during storage during the shelf life. Table 6 shows the moisture uptake from tablets prepared according to Example 1 and stored at 40 ° C 7 75% RH in various packaging materials. While blister packs of trilaminate (PVC / PE / PVDC 15 250 μηι / 25 μητ / 90 gsm and aluminum foil 20 μπι) reach their saturation level after 1 month, polypropylene containers with polyethylene and Alu / Alu strip packs allow for up to 6 months not see an increase in water content.

Table 6: Water content as a function of the packaging material [Time LOD [% by weight] [months] ____ blister package of container made of PVC / PE / PVDC Aiu / Alu 40 μηι polypropylene with 250μ / 25μ / 90 gsm and strip packaging lid made of polyethylene __aluminum foil 20 pm___ _0_ 3.29 3.29__3j29_ J__5 / 70__3j51 __: _ 2 __5 / 79__2i61 __: _ J __-__ 2j30__2J *] _ | 6 1 - 1.93 2.79 20

Use of the above components reliably yields compositions with a suitably low water content, preferably less than 4.0% by weight, 8% by weight, most preferably less than 3.0% by weight as measured by LOD, or less than 5.5% by weight, most preferably less than 4.5% by weight as measured by KF. By applying suitable packaging technologies, the moisture content in the formulation can be kept sufficiently low.

It was surprisingly observed that these pharmaceutical compositions only appear to be sufficiently stable under accelerating test conditions when the water content is low. Simultaneously with the increase in moisture, degradation to diketopiperazide occurs.

10 Examples

Example 1:

During the preparation process, the ambient conditions are kept at 30% RH / 30 ° C. Ground glycine hydrochloride (0.300 kg) is dry mixed with ramipril (0.125 kg), microcrystalline cellulose (Acivel PH112; 7.125 kg), silica precipitate (Sylöid AL-1-FP; 0.800 kg) and pregelatinized starch (Starch 1500 LM 0.450 kg), and the resulting mixture is dry mixed with glycerol dibehenate (Compritol ATO 888; 0.200 kg) and pressed into 100,000 tablets, each containing 1.25 mg of ramipril.

20 For the attached stability test, the tablets are immediately packaged in blister packs of PVC / PE / PVDC 250 μιη / 25 pm / 90 gsm and aluminum foil 20 pm and strip packs of Alu / Alu 40 pm. The samples are subjected to stability tests at 40 ° C / 75% RH. The LOD of the tablets after preparation is 3.19% by weight.

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Table 7: Stability and water content as a function of the packaging material Packaging strip package from Alu / Alu 40 pm blister package from PVC / PE / PVDC

250μιη / 25μηι / 90 gsm and aluminum foil 20 µm

Time LOD Ramipril Diketopi LOD Ramipril Diketopi [months] [% by weight] [%] perazide [%] [% by weight] [%] perazide [%] "Ö 3TI9 9 & M <Ü2 3 ^ 9 9M8 ÖJ2 ~ 2 2 ^ 91 97J87 Öjï 5 ^ 81 65 ^ 63 9 ^ 68 ·· i ·? ·. · 'I 9

Example 1 shows that pharmaceutical compositions prepared with glycine hydrochloride are found to be sufficiently stable under accelerating test conditions when the water content is low, but which appear to be unstable when the water content in the pharmaceutical formulations increases to normal moisture levels.

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Example 2:

During the preparation process, the ambient conditions are kept at 30% RH / 30 ° C. Ground glycine hydrochloride (0.300 kg) is dry mixed with ramipril (0.500 kg), microcrystalline cellulose (Acivel PH112; 29.36 kg), silicon dioxide precipitate (Syloid AL-1-FP; 3,200 kg) and pregelatinized starch (Starch 1500 LM ; 1,800 kg) and Iron Oxide Red (0,040 kg), and the resulting mixture is dry mixed with glycerol dibehenate (Compritol ATO 888; 0,800 kg) and pressed into 100,000 tablets each containing 5 mg of ramipril, which are immediately put in PVC / PE blister packs / PVDC 250 pm / 25 μηι / 90 gsm and aluminum foil 20 15 pm, strip packages of Alu / Alu 40 pm and containers of polypropylene with lids of polyethylene are packed. The LOD of the tablets after preparation is 3.19% by weight.

Table 8: Stability of ramipril (1), production of ramiprildiketopiperazide (3) and the water content as a function of the packaging material Packaging blister packaging of strip packaging of container of PVC / PE / PVDC Alu / Alu 40 pm polypropylene with lid 250pm / 25pm / 90 gsm and of polyethylene aluminum foil 20 pm "Time LÖD Rï) Π3) LÖD Row R3) LÖD Row Γ (3) [months] [wt%] [%] [%] [wt%] [%] [%] [wt .%] [%] [%]

~ Ö 2 ^ 41 99/78 (Ü4 2 ^ 41 99/78 99/78 ÖJT

1 L97 99.56 Öfi9 Ü9Ö 100.88 (Ü2 ~ “I - 1 4 / 7I 92.54 p9 ^ 1 101.61 <Ü8“ “I”

1 - - - Ü5Ö 99 ^ 34 Ö6 "TÏ9 99 ^ 43 OjT

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Example 2 supports the findings of Example 1. In particular, Example 2 shows that low moisture compositions maintain diketopiperazide levels well below the 0.5% limit, as reported in the European Pharmacopoeia and well below the results that are Obtained for QUI 10 commercial ramipril formulations (Delix® 1.25 mg batch number C-423; from the German market; 2.16% diketopiperazide).

Example 3: Analogously to Example 1, aluminum strip packs are prepared containing tablets with the following composition: ramipril (1.25 mg), microcrystalline cellulose (Acivel PH112; 50.32 mg), silicon dioxide precipitate (Syloid AL-1-) FP; 4.6 mg), lactose (Lactose DCL-21; 37 mg) and glycerol dibehenate (Compritol ATO 888; 1.83 mg) on a laboratory scale under ambient conditions. The tablets are packed in 10 strip packages of Alu / Alu 40 µm and tested for stability at 40 ° C / 75% RH. The LOD of the tablets after preparation is 2.71% by weight.

Table 9: Stability at low water ramipril [%] start 101.11 1 week 102.23 2 weeks 99.90 4 weeks 101.21 Example 3 shows that pharmaceutical compositions prepared with suitable excipients and that do not contain stabilizers from the state of the art do not show significant degradation for 4 weeks when stored under accelerated test conditions.

Example 4:

Analogously to Example 1, aluminum strip packages are prepared containing tablets with the following composition: ramipril (1.25 mg), starch (Starch 1500; 20.32 mg), silica precipitate (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 under 25 ambient conditions. The tablets are packaged in Alu / Alu 40 µm strip packages and tested for stability at 40 ° C / 75% RH. The LOD of the tablets after preparation is 6.60% by weight.

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Table 10: Stability at high water content ramipril [%] beginning 97.85 1 week 90.73 2 weeks 4 weeks

Example 4 shows that pharmaceutical compositions prepared with conventional excipients and which do not contain stabilizers from the prior art 5 prove to be unstable when stored under accelerated test conditions. The ramipril content has already decreased by more than 5% after one week of storage.

Example 5: On a laboratory scale at ambient conditions, capsules containing ramipril (1.25 mg) and starch (Starch 1500; 138.75 mg) are prepared by dry blending of StarchT500 rarniprir and the mixture is put into conventional, hard gelatin capsules. The capsules are packed in strip packages of Alu / Alu 40 µm and tested for stability at 40 ° C / 75% RH. The LOD of the capsules is 8.27% by weight.

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Table 11: Stability at high water content

Diketopiperazide [%] beginning 0.15 1 week 0.81 2 weeks 4 weeks 2.14 6 weeks 3.93

Example 5 shows that capsule formulations that have a usual level of water content turn out not to be stable when stored under accelerating test conditions. After storage of 6 weeks under accelerated test conditions, the diketopiperazide content has increased to 4%.

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Example 6:

Analogously to Example 5, aluminum strip packages are prepared containing capsules with the following composition: ramipril (1.25 mg), starch (Starch 1500; 37.00 mg) and perlitol (148.75 mg) are mixed and the mixture is mixed in conventional capsules brought to the laboratory and under environmental conditions. The capsules are packed in strip packages of Alu / Alu 40 µm and tested for stability at 40 ° C / 75% RH. The LOD of the capsules is 5.79% by weight.

Table 12: Stability at high water content _Diketopiperazide [%] _ beginning__0.19_ 1 week__0.81_ 2 weeks__ 4 weeks ___ 1.23_ 6 weeks_3.01_ 10

Example 6 supports the experiences of example 5. An LOD above 5% by weight does not allow a sufficiently stable formulation. A significant trend towards stabilization with reduced moisture content is clear.

Example 7:

Analogously to Example 5, aluminum strip packages are prepared containing capsules with the following composition: ramipril (1.25 mg), microcrystalline cellulose (Acivel PH112; 71.48 mg), starch (Starch 1500; 20.47 mg) and arginine (1 (80 mg) are mixed and placed in conventional capsules on a laboratory scale under 20 ambient conditions. The capsules are packed in strip packages of Alu / Alu 40 µm and tested for stability at 40 ° C / 75% RH. The LOD of the capsules is 3.24% by weight.

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Table 13: Stability at low water content

Diketopiperazide [%] beginning 0.71 1 week 0.23 2 weeks 4 weeks 0.32

Example 7 shows that capsule formulations that exhibit low water content appear to be considerably stable for ringing the active ingredient to diketopiperazide when stored under accelerating test conditions. Examples 5, 6 and 7 show that the principle of stabilizing ramipril formulations by excluding moisture in the formulation also applies to capsule formulations. The determined ramipril content also remains above 95%.

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Claims (26)

A solid, pharmaceutical composition comprising: (a) an effective amount of ramipril and / or of a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable excipients, wherein the composition has a suitable low water content. The composition of claim 1, wherein the water content is less than about 5.5% by weight as measured by a Karl-Fischer analysis. The composition of claim 1, wherein the water content is less than about 4.5% by weight as measured by a Karl-Fischer analysis. A composition according to any one of the preceding claims, wherein ramipril and / or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutically acceptable anhydrate, solvate, hydrate and / or in crystalline and amorphous form. 5. A composition according to any one of the preceding claims, wherein the pharmaceutical composition is a tablet. The composition of claim 5, wherein the tablet is suitably coated into a coated tablet and / or a pill. The composition of any one of claims 1-4, wherein the pharmaceutical composition is a capsule. The composition of any one of claims 1-4, wherein the pharmaceutical composition is a sachet. 30 The composition of any one of the preceding claims, wherein the excipients have a suitably low water content. fc The composition of claim 9, wherein one of the excipients is microcrystalline cellulose. The composition of claim 9, wherein one of the excipients is starch. 5 The composition of claim 9, wherein one of the excipients is silica. The composition of claim 9, wherein one of the excipients is calcium hydrogen phosphate. The composition of claim 9, wherein one of the excipients is lactose. The composition of claim 9, wherein one of the excipients is mannitol. The composition of claim 9, wherein one of the excipients is calcium sulfate 17. A composition according to any one of the preceding claims, wherein one or more auxiliaries are dried prior to use or during the preparation process to achieve the required level of water content. 18. A method for preparing a solid, pharmaceutical composition comprising: (a) an effective amount of ramipril and / or of a pharmaceutically acceptable salt thereof and (b) one or more pharmaceutically acceptable excipients, wherein the environmental conditions during the preparation on a relative humidity of equal or less than 35% is kept at ambient temperature or lower. 30 The method of claim 18, wherein the ambient conditions during the preparation are maintained at a relative humidity of equal or less than 35% at 30 ° C or lower. A method according to claim 18 or 19, wherein the pharmaceutical composition is packaged in a packaging material that closes tightly in a manner suitable to prevent moisture penetration. 5 A method according to claim 20, wherein the packaging material is a container including lid that consists of polyethylene, polypropylene and / or glass. 22. Method as claimed in claim 20, wherein the packaging material is a strip or blister package which consists of aluminum that can be suitably coated or of high density polyethylene. 23. Packaging comprising a composition according to any one of claims 1-17, wherein the composition is packaged with packaging material that closes tightly in a manner suitable for moisture penetration. A package according to claim 23, wherein the package material is a container including lid that consists of polyethylene, polypropylene and / or glass. The package of claim 23, wherein the package material is a strip or blister package that consists of aluminum that may be suitably coated or high density polyethylene. 1 U: ·. v.