WO2015022559A1

WO2015022559A1 - Pharmaceutical composition containing rosuvastatin and ramipril

Info

Publication number: WO2015022559A1
Application number: PCT/HU2014/000071
Authority: WO
Inventors: Katalin Baranek; György UJFALUSSY; András FEHÉR; Zsolt Zsigmond; Ádám ORBÁN
Original assignee: Egis Pharmaceuticals PLC
Current assignee: Egis Pharmaceuticals PLC
Priority date: 2013-08-16
Filing date: 2014-08-15
Publication date: 2015-02-19
Anticipated expiration: 2016-02-16
Also published as: HUP1300496A2; EA201690395A1; WO2015022560A1; EA033291B1; HU231052B1; HUP1600414A2; WO2015022560A8

Abstract

The present invention relates to a combination composition containing rosuvastatin and ramipril and optionally amlodipin and preparation thereof. The active ingredients are separated from each other in the composition.

Description

Pharmaceutical composition containing rosuvastatin and ramipril Field of the invention

The invention concerns a wide range of pharmaceutical compositions. Briefly, the technical field of the invention is the combination composition containing several active ingredient in one dosage form. Specifically, the invention can be grouped into the combination compositions containing ramipril.

The background of the invention

Ramipril, (2S, 3aS, 6aS) -1 [ (S) -N- [ (S) -l-carboxy-3- phenylpropyl ] -alanyl-octahydrocyclopenta- [b] pyrrole-2-carboxylic acid-ethlyester, is a known drug active ingredient, which is used in the therapy to treat hypertension, heart failure, nephropathy, to promote revascularisation, to decrease the risk of cardiovascular diseases and events, especially stroke and myocardial infarction, and to decrease cardiovascular mortality.

The active ingredient ramipril is sensitive to heat and moisture and decomposes easily. During the decomposition the hydrolysis of the ester groups occurs, which results the impurity corresponding to the active metabolite, that is the ramiprilate (European Pharmacopoeia: Impurity E) . According to the US patent specification No. 5442008, if for example ramipril tablets prepared by dry granulation containing 2.5 mg of active ingredient are stored for six months at a temperature of 40 °C, the concentration of the decomposition product diketopiperazine in the product can reach 22.8%, in case of ramipril capsules filled with powder mixture containing 2.5 mg of active ingredient can reach 6.4%, respectively. According to the published international patent application No. WO200/5041940 apart from the above written the oxidative decomposition of ramipril in the presence of air can result in undesired discoloration.

Rosuvastatin is the selective and competitive inhibitor of

3-hydroxy-3-methyl-glutaryl coenzyme A reductase, which inhibits the rate of the biosynthesis of cholesterol in liver through the inhibition of the enzyme. Rosuvastatin is used for medical purposes in the form of its pharmaceutically acceptable salts, primarily as the calcium salt or as the zinc salt. Rosuvastatin is an active ingredient of Class III of the Biopharmaceutics Classification System (BCS) , which has a high solubility in water and in body fluids.

Amlodipine, 3-ethyl-5-methyl- (+-) -2- [ ( 2-aminoethoxy) methyl ] -

4- (2-chlorophenyl ) -1, 4-dihydro-6-methylpyridine-3, 5-dicarboxylate, is a calcium channel blocker, which was developed to treat hypertension. Amlodipine is hard to tablet and easily decomposes. Amlodipine is used in pharmaceutical compositions in the form of benzenesulfonic acid salt, i.e. amlodipine besylate. It is known from the international publication No. WO2010038091 that in combination compositions amlodipine easily interacts undesirably with the second active ingredient, which leads to decomposition reactions. Due to the hydrolysis of amlodipine besylate in the presence of moisture it is expected that mixing it directly with ramipril the fast decomposition of ramipril will occur in the resulting acidic medium.

Generally it is preferred to combine several active ingredients into one pharmaceutical composition. The costs can be reduced by integrating several active ingredients into one composition. Further, it is advantageous for the patient to take one dosage form in spite of separate dosage forms . The treatment can be simplified by a combination composition, therefore better results can be expected. The large number of patients who are treated with rosuvastatin besides ramipril would justify the marketing of a combination composition for a better patient compliance. However, preparation of such compositions is facing serious difficulties, therefore no solution have been provided until now for the preparation of such a combination composition.

Drug marketing authorities specify serious requirements towards the active ingredient content, stability and purity of pharmaceutical preparations. In order to meet these requirements such pharmaceutical compositions containing ramipril as active ingredient are needed that can be stored for a longer time without quality decrease, without higher decrease of the active ingredient content than the limit, and without higher level of formation of degradation products than the limit. Several solutions were provided to stabilize the active ingredient ramipril as described on pages 3 to 6 of the international patent application No. WO2013/121233, however, difficulties always may occur during the use in a combination composition, on the one hand due to the interaction of active ingredients with each other, on the other hand the release of the active ingredients shall show appropriate rates.

Chinese patent application No. CN101658675 describes several combination compositions, however, does not describe the stability and release features of the compositions. Furthermore, the patent application neither describes the drug formulation containing ramipril and rosuvastatin simultaneously.

Brief description of the invention In case of combination compositions containing several active ingredients one has to take the incompatibility of the certain active ingredients into account. This is particularly true for the combination compositions containing ramipril or rosuvastatin .

International patent application No. O2013/121233 describes a method to produce ramipril granules that are stable in a combination composition. However, we have surprisingly found that stable ramipril granules produced by the method described in the patent application when contacted with the active ingredient rosuvastatin, incompatibility problems will arise. On the one hand also ramipril shows decomposition in the granules, on the other hand also in case of rosuvastatin contacted with the granules decomposition was detected.

The object of our invention is therefore to develop a drug formulation containing ramipril, which applied in a unit dose combination eliminates the incompatibility occurring between ramipril and rosuvastatin described above.

We have surprisingly found that if ramipril granules are produced in such a way where at first ramipril is granulated by a dry method, and the obtained granules are granulated again by a wet method, ramipril granules will be resulted, the use of which in combination compositions can eliminate the incompatibility occurring between active ingredients ramipril and rosuvastatin.

According to a preferred embodiment of the invention, the mixture of 10 - 50 m/m% of ramipril and 50 - 90 m/m% of the diluent calculated to the weight of the coated granules is dry compacted during the dry granulation. During the step of the wet granulation fluidization granulation or vortex granulation can preferably be used. Preferably during the wet granulation 1 - 10 m/m% binder is used calculated to the weight of the coated granules.

More preferably, ramipril granules according to the invention are produced according to the following process:

- ramipril and disintegrant is homogenized,

- the obtained homogeneous mixture is compacted,

- the compact is regranulated and homogenized,

- the obtained homogeneous mixture is granulated by

fluidization and afterwards dried.

In the ramipril granules according to the invention the diluent is preferably crospovidone, the binder is preferably hypromellose .

A further object of the invention is the ramipril granule prepared by any of the above described processes.

The ramipril granule according to the invention preferably contains crosslinked PVP and/or HPMC.

A further object of the invention is a pharmaceutical composition containing ramipril granules according to the invention .

A further object of the invention is a pharmaceutical composition containing ramipril granules according to the invention and rosuvastatin . According to a preferred embodiment the pharmaceutical composition according to the invention contains also amlodipine.

A further object of the present invention is the pharmaceutical use of the pharmaceutical composition of the invention, especially for the treatment of hypertension and to decrease high cholesterol level.

Detailed description of the invention Therefore it seems to be necessary to develop novel combination compositions that are useful in the treatment of patients with hypertension. Our further object was to develop such compositions for this purpose that can reach the desired goal by once daily administration. Therefore our object was to develop a combination pharmaceutical composition containing rosuvastatin, ramipril and optionally amlodipine or salts thereof or complexes thereof in a unit dose, and

a) the active ingredients remain stable during manufacture and storage, i.e. in the composition, or the level of impurities formed during the manufacture does not exceed the level of the approved impurities relating to the given active ingredient of the mono-composition,

b) bioavailability of the combination composition shall be similar or identical to the one, if two or three mono- compositions are administered together, which correspond to the active ingredient content of the combination composition,

c) the release profiles of the certain active ingredients shall not be changed during storage.

The aimed compositions with similar effect and that are preferably bioequivalent are suitable for - in case of already treated patients - switching without risk the simultaneous administration of two or three compositions to the combination composition. This has a particular importance in the treatment of patients with hypertension, because setting the blood pressure by using different active ingredients generally needs longer time, and there is a risk that the effect of the new combination does not reach the required level. In this case the drug search- setting process can last for even months, while the side effects (dizziness, headache, etc.) caused by the hypertension significantly decrease the life quality of the patient, and formation and/or progression of the accompanying diseases are not inhibited. However, if the combination composition is bioequivalent, than the long process of the setting and the risks can be avoided.

Also an important goal is that the release profiles do not change during storage time, as a composition with altered release profile can not exert the same effect. Namely, if the release profile of any of the active ingredients changes, the bioavailability can also deviate, and the composition will not be suitable either to replace the corresponding mono-compositions or to use it as a drug.

During our preliminary experiments it turned out that by contacting ramipril and rosuvastatin with each other both ramipril and rosuvastatin undergoes a very high level of decomposition.

According to our experiments in samples where Ramipril and Rosuvastatin Ca active ingredients were put together and stored under conditions of 50 °C for four weeks, we experienced decomposition of both active ingredients. Compared to the starting sample a significant increase of impurities was observed, namely Imp A (lactone) in case of Rosuvastatin and Imp D in case of Ramipril. Impurity Imp B2 of Rosuvastatin is higher than 0.1% also in the starting sample, however, the amount of this impurity did not change significantly during storage. Further, its amount is the same compared to the measured amount of that sample which contained only Rosuvastatin Ca.

In samples where Ramipril granules prepared by Example 1 of the international patent application WO 2013/121233 and active ingredient Rosuvastatin Ca were put together, a significant increase of the impurity Imp A (lactone) of Rosuvastatin and Impurity Imp D of Ramipril was observed after storage. The impurity Imp D of Ramipril was formed in a similar amount during storage, compared to the samples where pure active ingredients were put together, however, impurity Imp A (lactone) of Rosuvastatin was formed in this case in a smaller amount. The amount of impurity Imp B2 of Rosuvastatin was higher also in the starting sample compared to the sample obtained by putting the pure active ingredients together, however, its amount did not change significantly during storage.

We measured also samples containing the only the Ramipril active ingredient during this series of experiments. Impurity Imp D of Ramipril was formed in these samples in a similar rate.

Our measurements are summarized in Table 1 below, it follows from the data that on the one hand ramipril initiates the decomposition of rosuvastatin, but on the other hand also rosuvastatin initiates the decomposition of ramipril.

Table 1

Amount of impurity shown in percentage of the active ingredient

content

< d.l.: below

detection

limit

Our invention is therefore a solid combination pharmaceutical composition containing ramipril and rosuvastatin and optionally amlodipine or pharmaceutically acceptable salts or complexes thereof.

Processes for the manufacture of the compositions according to our invention and apparatus for implementation thereof are generally known in the pharmaceutical industry, these are widely used. Optimization of certain technological steps and determination of the appropriate parameters is part of the general knowledge of the skilled person. Tableting, encapsulation, granulation, compaction, processes and apparatus, for the formation of pellets and minitablets, and technological knowledge relating to these can be found besides several handbooks in the handbook of Encyclopedia of Pharmaceutical Technology (ed: James Swarbrick; Infoma Healthcare USA Inc. 2007) .

For the production of the stable combination composition according to the invention it is preferred to produce the coated ramipril containing granulate by the following method:

mixture of 10-50 m/m%, preferably 10-30 m/m%, most preferably 15-25 m/m% ramipril and 60-93 m/m%, preferably 65-80 m/m%, most preferably 75-80 m/m% disintegrant calculated to the weight of the coated granule, where the disintegrant is preferably crosslinked polyvinylpyrrolidone (e.g. polyplasdone XL 10) is dry-compacted, and compacts are regranulated and coated by 5-10%, preferably 5-8% aqueous solution of 1-15 m/m%, preferably 1-10 m/m%, more preferably 2-6 m/m% HPMC calculated to the weight of the coated granule.

According to one of the most preferred production method of our combination composition coated ramipril granules are produced according to the following method:

ramipril and crosslinked polyvinylpyrrolidone (PVP), preferably polyplasdon XL 10, is homogenized and the resulting mixture is compacted. The obtained compact is subjected to regranulation on a sieve of 0.6 mm, than on 0.5 mm hole size and afterwards homogenized. The obtained homogenized granulate is coated with an aqueous solution of 6 m/m% HPMC in a fluidization granulation apparatus. The resulting coated granules are optionally homogenized with part of the microcrystalline cellulose used for the outer phase, and afterwards the rest of the microcrystalline cellulose and aerosil R972 is added to the obtained mixture. After homogenizing the listed materials compritol 888 (glyceryl behenate) is added and the end-homogenizate is prepared.

Further details of the invention will be known from the following example, however, this example shall not be deemed to be a limiting one, it serves only for better understanding of the invention .

EXAMPLE

Example 1

Capsule containing rosuvastatin/ramipril/amlodipine quantitative composition

(Quantity /

Name Function

capsule

Capsule filling

Rosuvastatin Calcium active 20.840 mg

ingredient (20.000) mg

active

Ramipril 10.000 mg

ingredient

Amlodipine besylate (AMD 12 VT) 13.900 mg

active

Amlodipim besylate

ingredient

(Amlodipine) (10.000) mg

Prosolv HD 90*** diluent 127.185 mg

Vivapur 200

diluent 80.740 mg

Cellulose, microcrystalline

Poliplasdone XL- 10 GAF quality

diluent 40.000 mg

Crospovidone

Hypromellose 2910. 6 cP

binder 2.360 mg

Hypromellose

Magnesium stearate of vegetable origin

lubricant 1.750 mg

Magnesium stearate

Aerosil R 972

glidant 1.500 mg

Silica, hydrophobic colloidal

Compritol 888

lubricant 1.500 mg

Glycerol dibehenate

Aerosil 200

glidant 0.225 mg

Silica. Colloidal Anhydrous

Weight of the filling 300.00 mg

Shell

Capsule capsule 96.00 mg

Weight of the filled capsule 396.00 mg Preparation of rami ril granulate

Preparation of the granulate is made by a two-step granulation, first dry granulation (compaction) , than wet granulation occurs. During the manufacture process the necessary amount of active ingredient and additive is mixed, sieved, homogenized followed by compaction by a dry granulation apparatus, than regranulation and homogenization occurs, and the further granulation follows in a fluidization granulation apparatus by spraying the granulation solution. The material with an appropriate drying loss is preferably homogenized after regranulation .

Preparation of Rosuvastatin Ca tablet

As known by the person skilled in the art, the active ingredient rosuvastatin is sensitive to light, therefore the strong lighting during the whole manufacturing process shall be avoided. The preferably sieved magnesium stearate of vegetable origin is added during the manufacturing process to materials of the prehomogenized internal phase (Rosuvastatin Ca compact and Prosolv HD 90) , than the press-ready end-homogenizate is prepared by end-homogenization, which can preferably be tableted in a rotary tablet press.

The flow diagram of the preparation of the combination composition is the following:

Preparation of the amlodipine compact occurs preferably by multiple steps of mixing, sieving, regranulation and homogenization of amlodipine besylate (AMD 12 VT) and Vivapur 200

If also amlodipine is used in the combination composition, than preferably the prepared amlodipine granulate is mixed with the Ramipril granulate and further agents (Aerosil R 972, Vivapur 200), homogenized, and after the addition of Compritol 888 the end-homogenizate is prepared by homogenization.

In the first step of encapsulation preferably the end- homogenizate containing the Ramipril and optionally Amlodipine is filled into the capsule shells, and as the second step Rosuvastatin Ca tbl 20 mg (0.02 M) is filled onto the homogenizate .

Surprisingly we have found that in capsule prepared by this way the active ingredients remain particularly stable during six months of storage at conditions of 30 °C / 65% relative humidity, and also even during storage at 40 °C / 75% relative humidity. Comparing data of Table 2 below with that of Table 1 it can be seen that the combination composition according to the invention showed to be particularly stable.

Table 2: purity (HPLC) (%)

Ramipril Amlodipin Rosuvastatin * Total

impurities

Ram A <0.02 D <0.02 ROS-01 0.45

Ram B <0.02 F 0.03 ROS-02 <0.02

starting Ram C 0.08 ROS-03 0.04 <0.02 0.67

Ram D 0.07 Sun 1 <0.02

Ram E <0.02 Sun 2 <0.02

Ram A <0.02 D <0.02 ROS-01 0.51

1 month Ram B <0.02 F 0.03 ROS-02 <0.02

40°C/75 % Ram C 0.06 ROS-03 0.05 <0.02 1.14

Ram D 0.49 Sun 1 <0.02

Ram E <0.02 Sun 2 <0.02

Ram A <0.02 D <0.02 ROS-01 0.47

Ram B <0.02 F 0.03 ROS-02 <0.02 Ramipril Amlodipin Rosuvastatin * Total

impurities

1 month Ram C 0.07 ROS-03 0.05 <0.02 0.82 30°C/65 % Ram D 0.20 Sun 1 <0.02

Ram E <0.02 Sun 2 <0.02

Ram A <0.02 D <0.02 ROS-01 0.54

Ram B <0.02 F 0.02 ROS-02 <0.02

2 months Ram C 0.07 ROS-03 0.05 <0.02 1.49 40°C/75 % Ram D 0.81 Sun 1 <0.02

Ram E <0.02 Sun 2 <0.02

Ram A <0.02 D <0.02 ROS-01 0.47

Ram B <0.02 F 0.02 ROS-02 <0.02

2 months Ram C 0.08 ROS-03 0.05 <0.02 0.92 30°C/65 % Ram D 0.30 Sun 1 <0.02

Ram E <0.02 Sun 2 <0.02

Ram A <0.02 D <0.02 ROS-01 0.58

Ram B <0.02 F 0.03 ROS-02 <0.02

3 months Ram C 0.07 ROS-03 0.06 <0.02 1.86 40°C/75 % Ram D 1.12 Sun 1 <0.02

Ram E <0.02 Sun 2 <0.02

Ram A <0.02 D <0.02 ROS-01 0.54

Ram B <0.02 F 0.03 ROS-02 <0.02

3 months Ram C 0.07 ROS-03 0.05 <0.02 1.07 30°C/65 % Ram D 0.38 Sun 1 <0.02

Ram E <0.02 Sun 2 <0.02

Ram A <0.02 D <0.02 ROS-01 0.63

Ram B <0.02 F 0.03 ROS-02 <0.02 1

6 months Ram C 0.08 ROS-03 0.08 piece 2.66 40°C/75 % Ram D 1.93 Sun 1 <0.02 <0.1 %

Ram E <0.02 Sun 2 <0.02 (0.02)

Ram A <0.02 D <0.02 ROS-01 0.53

Ram B <0.02 F 0.03 ROS-02 <0.02

6 months Ram C 0.07 ROS-03 0.06 <0.02 1.19 30°C/65 % Ram D 0.60 Sun 1 <0.02

Ram E <0.02 Sun 2 <0.02

*Impurities not identified one by

We have also analyzed the release of the three active ingredients compared to mono-component products. We found during our experiments that putting two (rosuvastatin and ramipril) or three (rosuvastatin, ramipril and amlodipine) active ingredients into one drug formulation we succeeded to prepare a stable preparation with a similar release rate than the corresponding mono-component preparation.

Claims

Process for the preparation of ramipril granule, characterized by that ramipril is dry granulated first, and the resulting granulate is granulated by a wet method.

Process according to claim 1, wherein during the dry granulation the mixture of 10-50 m/m% of ramipril and 50-90 m/m% of diluent calculated to the weight of the coated granules, is dry compacted.

Process according to claim 1 or claim 2, wherein the wet granulation is fluidization granulation or vortex granulation.

Process according to any of claims 1 to 3, wherein during the wet granulation 1-10 m/m % binder calculated to the weight of the coated granules, is used.

Process according to claim 4, wherein

- ramipril and disintegrant is homogenized,

- the obtained homogeneous mixture is compacted,

- the compact is regranulated and homogenized,

the obtained homogeneous mixture is granulated by fluidization and afterwards dried.

Process according to claim 5, wherein the diluent is crospovidone, the binder is hypromellose .

Ramipril granulate obtainable by the process of any of claims 1 to 6.

8. Ramipril granulate according to claim 7, which contains crosslinked PVP and/or HPMC.

9. Ramipril granulate according to claim 7, wherein the crosslinked PVP is poliplasdone XL-10 and the HPMC is Hypromellose 2910.

10. Pharmaceutical composition, which contains the ramipril granulate according to any of claims 7 to 9.

11. Pharmaceutical composition, which contains ramipril and rosuvastatin as active ingredients.

12. Pharmaceutical composition according to claim 11, containing amlodipine as active ingredient.

13. Pharmaceutical composition according to claim 11 or claim 12, containing ramipril granulate according to any of claims 7 to 9.

14. Pharmaceutical composition according to any of claims 10 to 13 for pharmaceutical use.

15. Pharmaceutical composition according to any of claims 10 to 13 for lowering hypertension and high cholesterol level at the same time.