EP4106733A2

EP4106733A2 - Stable ramipril composition and fixed dose composition comprising thereof

Info

Publication number: EP4106733A2
Application number: EP21711393.5A
Authority: EP
Inventors: Joanna RZASA; Katarzyna WÓS-LATOSI; Agnieszka CIEPLUCHA.
Original assignee: Adamed Pharma SA
Current assignee: Adamed Pharma SA
Priority date: 2020-02-10
Filing date: 2021-02-10
Publication date: 2022-12-28
Also published as: PL4103158T3; EP4103158A1; EP4103158B1; PT4103158T; WO2021160700A1; ES2992213T3; HRP20241424T1; WO2021162562A2; WO2021162562A3; RS66060B1

Abstract

The invention relates to a stable Ramipril granulate and a fixed dose pharmaceutical composition comprising combination of Ramipril and at least one cardiovascular active substance such as Bisoprolol fumarate, Amlodipine and/or Hydrochlorothiazide, wherein incompatibility of active substances is overcome by using a specific excipient with a dual function.

Description

STABLE RAMIPRIL COMPOSITION AND FIXED DOSE COMPOSITION COMPRISING

THEREOF

Field of the invention The present invention relates to a stable Ramipril granulate and a fixed dose pharmaceutical composition comprising thereof. More specifically, the invention relates to the pharmaceutical composition comprising combination of Ramipril and at least one cardiovascular active substance such as Bisoprolol fumarate, Amlodipine and/or Hydrochlorothiazide, wherein incompatibility of active substances is overcome by using a specific excipient with a dual function. The methods of preparation of fixed dose pharmaceutical compositions comprising stable Ramipril composition are also disclosed.

Background of the invention

Ramipril, an angiotensin converting enzyme (ACE) inhibitor, is approved for the treatment of hypertension. Ramipril can be used as a monotherapy or can be co-administered with other cardiovascular drug substances as the individual products given concurrently in the separate unit dosage forms or at the same dose level as the fixed-dose combination. Such approved combined treatment is the combination of Ramipril and Bisoprolol fumarate, a cardioselective β1 -adrenergic blocking agent used to treat high blood pressure as a comprehensive treatment for additional conditions associated with the disease. The other commercially available fixed dose combined products are Ramipril and a calcium channel blocker Amlodipine (as Amlodipine besilate) or Ramipril and a diuretic Hydrochlorothiazide.

Instability of Ramipril is generally known in the art. It is ascribed to a combination of such factors as heat, moisture, oxidation and, in the case of tablets, the compression processes used in manufacture. The problem is particularly troublesome with tablets containing a low dose of Ramipril, especially 1.25 mg, which are unstable under normal manufacturing and storage conditions.

Efforts made so far to stabilize ACE inhibitors have focused on protective coatings, and the use of selected binders, and/or additives.

Efforts to effect stabilization of active drugs that exhibit decomposition or destabilization when compressed into tablets have been reported in U.S. Patents Nos. 5,151, 433 and 5,442,008. ACE inhibitors coated with polymeric film formers were found to significantly reduce the effect of the compression applied during the tablet forming process. A number of polymers were listed as possibly suitable for protective films, including several cellulose and polymethacrylate based polymers, polyvinyl acetate phthalate, and polyvinylpyrrolidone. As the other remedy to solve this problem, WO 2010/030735 A2 teaches a process for preparing stabilized tablet compositions, wherein a water soluble polyvinyl alcohol is processed with ACE inhibitors and the polymer coated individual particles are compressed into a solid form once excess water is removed. Preparation of a tablet requires further an admixture of a binder and other excipients. Low dose tablets comprising Ramipril coated with polyvinyl alcohol prepared by this process are stable under conditions of high humidity and heat for periods of at least up to six months with less than 8% hydrolysis of the prodrug to the active metabolite diketopiperazine

(DKP).

As described in the above application, however, the conventional methods for coating Ramipril particles involving spray drying fail to provide a protective coating on solid Ramipril when polyvinyl alcohol is used as a polymer coating agent. Instead of that, special methods for processing polyvinyl alcohol and Ramipril to provide stabilized polymer coated API particles are provided. An important aspect of coating Ramipril is to use a method that finely pulverizes or fluidizes polyvinyl alcohol and the drug. Two effective methods of obtaining such an effect are indicated; one by pulverizing Ramipril with a low percent solutions of polyvinyl alcohol, e.g., 3.5-5%, in water or absolute ethanol; and another by spraying a solution of polyvinyl alcohol onto a complex of Ramipril API and PROSOL V using a 15-90% drug load in a high shear granulator or fluid bed granulator/dryer.

However, WO 2010/030735 specifies only the concentration of the used PVA solution, but not the amount of this solution used for coating. Therefore the amount or weight ratio of PVA used for stabilization is unknown. Also amounts of other excipients used are unknown. Therefore, the exact composition, for which the stability results are obtained, is unknown. Besides, in WO 2010/030735 stability tests are performed only on the lowest 1.25 mg Ramipril after compression to a tablet.

Moreover, the granules in WO 2010/030735 are prepared on the base of silicified microcrystalline cellulose (PROSOLV) proved to be ineffective. Our own research has shown that preparations containing Ramipril and silicified microcrystalline cellulose (PROSOLV) are unstable already after 1 month at accelerated storage conditions, with levels of D Ramipril impurity above 8 wt.%, for all registered Ramipril dosages i.e. 1.25, 2.5, 5 and 10 mg. Meaning, that even for the lowest Ramipril dose (1,25 mg ) the level is above the set Pharmacopoeial D-impurity limit 8%), and by far above 5.5 and 5 wt.% D impurity level set respectively for 2.5 and 5-10mg dosages of Ramipril. Moreover, the method of making tablets using polyvinyl alcohol coated Ramipril particles disclosed in the above document is labour- and time-consuming and requires complicated apparatus and equipment.

Furthermore, the chemical incompatibility of Ramipril and Bisoprolol fumarate and other active substances such as Amlodipine and Hydrochlorothiazide is broadly described in the prior art. The incompatibility of these active substances can cause formulation difficulties in developing a single fixed dose composition containing both Ramipril and the said active substances. Different technical approaches can be taken under consideration when designing such a fixed dose product. Patent application WO 2015/022560 A1 discloses a solid combined composition comprising Ramipril and Bisoprolol fumarate or a pharmaceutically acceptable salt thereof in form of capsule or mono- or multi-layer tablet. The application teaches that separation of the particles of both active ingredients, Ramipril and Bisoprolol fumarate, is necessaiy to obtain a stable fixed dose product. The particles of both active ingredients are in separate phases whereby they are in contact with each other only at the edge surfaces of the phases.

The separation of the active ingredients is achieved either by limiting phase contact, e.g. two- layer tablet, or by coating of one or both phases before forming a single unit dosage form, e.g. Ramipril coated granulate in combination with coated or uncoated Bisoprolol fumarate compact. The particles of one of both active ingredients or granules, compacts or minitablets containing the same are coated with a polymer soluble or swellable in water, such as HPMC or polyvinylpyrrolidone.

The disclosed approach is described as one that results in a superior stability comparing to compositions wherein phase separation does not take place. However, to support this finding only monthly (1M) results of conducted stability study under accelerated (40°C, 75% RH) and intermediate (30°C, 65% RH) storage conditions for the product comprising Ramipril granules coated with HPMC admixed with particles of Bisoprolol fumarate are presented.

ICH Q1A (R2) guideline “Stability testing: requirements for new dosage forms” recommends conducting the drug product stability testing according to the following regimen: “At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g, 0, 3, and 6 months), from a 6-month study is recommended (...) When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g, 0, 6, 9, 12 months), from a 12-month study is recommended”. Thus, the 1 month stability test results presented in WO 2015/022560 A1 do not meet the guideline standards. Further time points stability, as required by the ICH Q1A (R2) guidelines, cannot be predicted based on the only available 1 -month results.

Furthermore, our own investigations have shown that the 1 -month stability test results presented in WO 2015/022560 A1 are not reproducible. Reproduction of compositions according to examples of WO 2015/022560 A1 do not give promising results from the stability tests.

Thus, there is still a need to develop compositions containing Ramipril as the sole active ingredient or in combination with other active ingredients that would retain a favorable impurity profile and characteristics consistent with the guidelines of drug regulatory authorities over extended storage periods. Disclosure of the invention

It is an object of the present invention to provide a pharmaceutical composition of Ramipril in form of a granulate which may be further compressed to a tablet or a tablet-layer that reduces or overcomes the above-mentioned problems and may readily be used as a single dose form. Another object of the present invention is to provide fixed dose pharmaceutical composition comprising the said Ramipril granulate and another active substance, such as Amlodipine, Bisoprolol fumarate and Hydrochlorothiazide in form of a blend or a tablet, that reduces or overcomes the above-mentioned problems and may readily be used as a single dose alternative in treatments requiring separate Ramipril and one of Amlodipine, Bisoprolol fumarate or Hydrochlorothiazide administration.

As used herein, by the term “fixed dose composition” it is understood that two or more active substances are contained in a single dosage form, such as a capsule or tablet. Here particularly, Ramipril and another active substance, such as Amlodipine, Bisoprolol fumarate and Hydrochlorothiazide are present in a single dosage form. The term blend is understood as a mixture of components.

The term powder, according to Pharmacopoeial definitions (EU Ph 6.0, vol.l, p.738), means dry, solid and loose particles that have the ability to flow freely.

As used herein, the term “granulate” comprises in common granules, pellets, spheres, spheronizates, beads and the other solid forms obtainable by granulation and/or spberonization, acting thus as such for filling capsules or sachets or as a phase for further forming tablets.

The object of the present invention is solved by:

- a granulate comprising Ramipril, and by

- a pharmaceutical fixed dose composition comprising said Ramipril granulate and Amlodipine, Bisoprolol fumarate or Hydrochlorothiazide in form of a powder or granulate or a tablet, according to the appended claims.

In particular, the present invention relates to the following aspects:

(1) According to an aspect of the present invention, provided is a granulate for oral administration comprising Ramipril and polyvinyl alcohol in a wt.% ratio in a range of 1.1 to 6.5 and one or more pharmaceutically acceptable excipients. (2) The granulate according to (1) wherein the Ramipril and polyvinyl alcohol in a wt.% ratio in a range wt.% ratio of Ramipril to polyvinyl alcohol is in a range of 1.15 to 3.9, more preferably 1.7 to 2.8 or 1.75 to 2.85, such as most preferably 2.85.

(3) The granulate according to (1) or (2) wherein pH of water solution of 50 mg Ramipril granulate sample with the concentration of 0.31 mg of Ramipril / 1 mL of water, measured at 20°C, is in a range of 5.0 to 5.8.

(4) The granulate according to (1) to (3), wherein the granulate in not coated with polyvinyl alcohol. (5) The granulate according to (1) to (4), wherein the Ramipril content in the granulate is in a range of 4.0 to 5.5 wt.% to 2.5 wt.%, preferably 4.5 to 5.0 wt.%, more preferably 4.5 to 4.9 wt.%, such as 5 wt.%, based on the total weight of the granulate.

(6) The granulate according to (1) to (5), wherein the Ramipril content in the granulate is in a range of 4.0 to 5.5 wt.% to 2.5 wt.%, preferably 4.5 to 5.0 wt.%, more preferably 4.5 to 4.9 wt.%, such as 5 wt.%, based on the total weight of the granulate.

(7) The granulate according to (1) to (6), wherein the granulate is free of silicified microcrystalline cellulose.

(8) The granulate according to (1) to (7), wherein the granulate comprises 5.00 wt.% of Ramipril, 86.2 wt.% of Lactose monohydrate, 1.75 wt.% of polyvinyl alcohol, 5.00 wt.% of Croscarmellose

Sodium, 2.00 wt.% of Sodium Stearyl Fumarate.

(9) The granulate according to (1) to (8), wherein the granulate is not coated with any coating, including an coat.

(10) The granulate according to (1) to (9), wherein the granulate is further compressed to a tablet or tablet layer.

(11) According to another aspect of the present invention, provided4s fixed dose pharmaceutical composition in form of a capsule for oral administration comprising two separate phases: a) the granulate according to anyone of the above aspects (1) to (9), and b) the powder or granulate or the tablet comprising Bisoprolol fumarate, Amlodipine or Hydrochlorothiazide or salts thereof and one or more pharmaceutically acceptable excipients.

( 12) The composition according to ( 11 ), wherein granulate a) and a powder or granulate or a tablet b) are not coated.

(13) The composition according to (11) or (12), wherein the powder or granulate or a tablet b) comprises 4.5 -5.5%, preferably 4.5 to 5.0 wt.%, more preferably 4.5 to 4.9 wt.%, such as 5 wt.%, of Bisoprolol fumarate, Amlodipine or Hydrochlorothiazide based on the total weight of the powder or granulate or a tablet b).

(14) The composition according to (11) to (13), wherein the powder or granulate or a tablet b) comprises, as the at least one excipient, at least one of a filler, a disintegrant, a lubricant, a glidant and any combination thereof, preferably, the powder or granulate or a tablet b) comprises 80 to 95 wt.% of a filler, 4.0 to 6.0 wt.% of a disintegrant, 1 to 2 wt.% of a lubricant, and 0.1 to 1.0 wt.%, of a glidant, based on the total weight of the powder or granulate or a tablet b).

(15) The composition according to (11) to (14), wherein the powder or granulate or a tablet b) comprises 5.00 wt.% of Bisoprolol Fumarate, 54.50 wt.% of Cellulose Microcrystalline, 33.00 wt.% of Calcium Hydrogen Phosphate, Anhydrous, 5.00 wt.% of Crospovidone type A, 0.50 wt.% of Silica, Colloidal Anhydrous, 2.00 wt.% of Magnesium Stearate, based on the total weight of the powder or granulate or a tablet b). (16) The composition according to (11) to (15), wherein the powder or granulate or a tablet b) comprises Bisoprolol fumarate.

According to a preferred aspect of the present invention, the granulate for oral administration has the features according to the above (1) and (4). Thus, the granulate is provided comprising Ramipril and polyvinyl alcohol in a wt.% ratio in a range of 1.1 to 6.5, which is not coated with polyvinyl alcohol.

According to a preferred aspect of the present invention, the granulate for oral administration has the features according to the above (1) and (3). Thus, the granulate is provided comprising Ramipril and polyvinyl alcohol in a wt.% ratio in a range of 1.1 to 6.5 and having a pH measured at 20°C in a range of 5.0 to 5.8, when the water solution of 50 mg Ramipril granulate sample with the concentration of 0.31 mg of Ramipril / 1 mL of water.

According to a preferred aspect of the present invention, the granulate for oral administration has the features according to the above (1) , (4) and (8). Thus, the granulate is provided comprising Ramipril and polyvinyl alcohol in a wt.% ratio in a range of 1.1 to 6.5, which is not coated with polyvinyl alcohol and comprises 5.00 wt.% of Ramipril, 86.2 wt.% of Lactose monohydrate, 1.75 wt.% of Polyvinyl Alcohol, 5.00 wt.% of Croscarmellose Sodium, 2.00 wt.% of Sodium Stearyl Fumarate.

According to a preferred aspect of the present invention, the fixed dose pharmaceutical composition for oral administration has the features according to the above (11) and (12). Thus, a fixed dose pharmaceutical composition in form of a capsule for oral administration is provided comprising in two separate phases a) the Ramipril granulate according to anyone of the above aspects (1) to (9), and the powder or granulate or a tablet comprising Bisoprolol fumarate, Amlodipine or Hydrochlorothiazide and one or more pharmaceutically acceptable excipients, wherein the granulate a) and the powder or granulate or a tablet b) are not coated. Preferably such fixed dose comprises Ramipril granulate according to aspect (9).

According to a preferred aspect of the present invention, the fixed dose pharmaceutical composition for oral administration has the features according to the above (11).

In one embodiment of the invention, the composition comprises combination of Ramipril and Bisoprolol fumarate.

In another embodiment of the invention, the composition comprises combination of Ramipril and Amlodipine or the salt thereof, preferably Amlodipine besylate.

In the other embodiment of the invention, the composition comprises combination of Ramipril and Hydrochlorothiazide.

According to a preferred aspect of the present invention, the fixed dose pharmaceutical composition for oral administration has the features according to the above (11) and (13). Thus, a fixed dose pharmaceutical composition in form of a capsule for oral administration is provided comprising in two separate phases a) the Ramipril granulate according to anyone of the above aspects (1) to (9), and a granulate b) comprising Bisoprolol fumarate one or more pharmaceutically acceptable excipients, wherein the granulate and the blend are not coated.

According to a another preferred aspect of the present invention, the fixed dose pharmaceutical composition for oral administration has the features according to the above (11) and (13). Thus, a fixed dose pharmaceutical composition in form of a capsule for oral administration is provided comprising in two separate phases a) the Ramipril granulate according to anyone of the above aspects (1) to (9), and a powder blend b) comprising Bisoprolol fumarate one or more pharmaceutically acceptable excipients, wherein the granulate a) and the powder blend b) are not coated.

According to a another preferred aspect of the present invention, the fixed dose pharmaceutical composition for oral administration has the features according to the above (11) and (13). Thus, a fixed dose pharmaceutical composition in form of a capsule for oral administration is provided comprising in two separate phases a) the Ramipril granulate according to anyone of the above aspects (1) to (9), and a tablet b) comprising Bisoprolol fumarate one or more pharmaceutically acceptable excipients, wherein the granulate a) and the tablet b) are not coated.

In most preferred aspect a pharmaceutical fixed dose composition is provided, which comprises in a capsule: a) granulate comprising 5.00 wt.% of Ramipril, 86.2 wt.% of Lactose monohydrate, 1.75 wt.% of Polyvinyl alcohol, 5.00 wt.% of Croscarmellose Sodium, 2.00 wt.% of Sodium Stearyl Fumarate, and b) a powder or granulate or a tablet comprising 5.00 wt.% of Bisoprolol Fumarate, 54.50 wt.% of Cellulose, Microcrystalline, 33.00 wt.% of Calcium Hydrogen Phosphate, Anhydrous, 5.00 wt.% of Crospovidone type A, 0.50 wt.% of Silica, Colloidal Anhydrous, 2.00 wt.% of Magnesium Stearate.

Further aspect of the invention is a process for the preparation of the solid fixed dose composition comprising preparation of at two distinct phases - Ramipril granulate a), and blend or a tablet b) comprising Bisoprolol fumarate, Amlodipine or Hydrochlorothiazide or salts thereof, and combining them into a single unit dosage form, preferably being a capsule.

Detailed description of the invention

It was established that the granulation of the Ramipril with a polyvinyl alcohol (PVA) in a range of 1.15 to 3.9, more preferably 1.7 to 2.8 or 1.75 to 2.85, such as most preferably 2.85, results in stable Ramipril granules, which may be used as a pharmaceutical dosage form as such or after further compression to form of a tablet or a tablet layer. The said granules or tablets are stable without further coating either with polyvinyl alcohol or with any other coating. It was also established that the Ramipril granulate according to the invention has pH in a range of 5.0 to 5.8, when pH is measured in at 20°C in water solution/suspension of 50 mg Ramipril granulate sample with the concentration of 0.31 mg of Ramipril/ 1 mL of water. (pH of the water used for testing measured at 20°C is equal to 6.98).

In the preferred embodiment of the invention, the composition characterizes in that pH of the water solution/suspension of 50 mg sample of Ramipril granulate composition according to the invention comprising 2.5 mg of Ramipril in form of a free acid in 8 ml of water (i.e. 0.31 mg of Ramipril /I mL of water) measured at 20°C, is in a range of 5.0 to 5.8.

The mentioned sample is a dry granulate composition sample according to the invention having 5wt.% of Ramipril free acid calculated on the diy mass of the sample. Such as 50 mg- sample of granulate comprising 2.5 mg of Ramipril free acid.

More precisely, it is to be understood that 50 mg sample of Ramipril granulate composition according to the invention with concentration of 0.31 mg of Ramipril / 1 mL of water is, e.g., a single 50 mg granulate dosage unit comprising 2.5 mg of granulate with amounts of Ramipril and up to 50 mg of excipients such as presented in details, e.g., in Table 6 below suspended in 8 mL of water. pH value of the Ramipril granulate in a range from 5.0 to 5.8 measured at 20°C results in the stable composition. Compositions of the granulates, standardized solution pH values and accelerated stability results are presented in the experimental section hereinafter. It can be observed that after 6 months in accelerated stability study, D-RAM and E-RAM impurity levels are below Pharmacopoeial limits.

It was established that the Ramipril granulate according to the invention may be further combined with other active substances in a fixed dosage forms. Preferred active substances to be combined with Ramipril are selected form Bisoprolol fumarate, Amlodipine, and Hydrochlorothiazide. Thus, such a fixed dose composition results in a ready to use product wherein two or more active substances, e.g., Ramipril and Bisoprolol fumarate, Ramipril and Amlodipine, or Ramipril and Hydrochlorothiazide, can be present in the single dosage form without affecting the active substances stability.

It has turned out that neither the Ramipril particles nor the Bisoprolol fumarate, Amlodipine or Hydrochlorothiazide particles have to be coated with polyvinyl alcohol to obtain stable fixed dose compositions.

It has also turned out that neither the Ramipril particles nor the Bisoprolol fumarate, Amlodipine or Hydrochlorothiazide particles have to be coated with any coating to obtain stable fixed dose compositions.

Compositions according to the present invention were tested in adequate guideline recommended stability studies and have shown evidence based product stability at accelerated storage conditions. Consequently, based on these results a long term stability of the fixed dose medicinal products comprising Ramipril and additional active substance selected form Bisoprolol fumarate, Amlodipine, and Hydrochlorothiazide could be predicted.

Preferably, the fixed dose pharmaceutical composition according to the invention comprises either:

- combination of Ramipril and Bisoprolol fumarate;

- combination of Ramipril and Amlodipine or the salt thereof, preferably Amlodipine besylate; or

- combination of Ramipril and Hydrochlorothiazide.

A process for the preparation of the solid fixed dose composition according to the invention involves the independent preparation of at least two distinct phases:

- a) a granulate comprising Ramipril, and the

- b) a powder or granulate or a tablet comprising Bisoprolol fumarate, Amlodipine and Hydrochlorothiazide, and combining them into a single unit dosage form, such as capsule.

In one embodiment, the Ramipril phase takes the form of a granulate. Accordingly, Ramipril active substance is comprised in the intragranular part of the Ramipril granulate.

Also, the said Ramipril granulate is further comprised in the fixed dose pharmaceutical composition as granulate a).

The said fixed dose pharmaceutical composition besides granulate a), comprises b) a powder or granulate or a tablet comprising Bisoprolol fumarate, Amlodipine and Hydrochlorothiazide.

The granulate a) and the powder or granulate or tablet b) can further comprise the pharmaceutically acceptable carriers and/or excipients, such known to those skilled in the art, for example, from Remington’s Pharmaceutical Science, 14^th ed., Mack Publishing Co.

The granulate comprises, as the at least one excipient, at least one of a filler, a binder, a disintegrant, and a glidant and any combination thereof.

Preferably, the Ramipril granulate (granulate a) comprises 80 to 95 wt.% of the filler, 1.0 to 6.0 wt.% of a disintegrant, 0.5 to 4.5 wt.% of a binder and 1 to 2 wt.%, of a glidant, based on the total weight of the Ramipril granulate.

The powder or granulate or tablet b) comprises at least one excipient, at least one of a filler, a disintegrant, a lubricant, a glidant and any combination thereof.

Preferably, the powder or granulate or tablet b) comprises 80 to 95 wt.% of the filler, 4.0 to 6.0 wt.% of a disintegrant, 1 to 2 wt.% of a lubricant, and 0.1 to 0.5 wt.%, of a glidant, based on the total weight of the powder or granulate or tablet b).

Suitable fillers can be selected from the group consisting of lactose; cellulose and its derivatives, such as microcrystalline cellulose; sugars and other sugar alcohols; inorganic fillers such as calcium hydrogen phosphate, or the combinations thereof, and other inert substances which are approved for use in oral dosage forms. Preferably, in the granulate a) the filler is lactose monohydrate or microcrystalline cellulose or the mixture thereof, in an amount of 80 to 95 wt.%, preferably 40-95% by weight, based on the total weight of the Ramipril granulate (granulate a).

Preferably, in the blend or tablet b) the filler is Cellulose Microcrystalline and/or Calcium Hydrogen Phosphate, Anhydrous or a mixture thereof in total amount of 80 -95 wt.%, preferably 80-90 wt.%, such as mixture of 54.50 wt.% of Cellulose, Microcrystalline, and 33.00 wt.% of Calcium Hydrogen Phosphate, Anhydrous, based on the total weight of the powder or granulate or tablet b)

Suitable disintegrants can be selected from the group consisting of, but not limited to, com starch; pregelatinized starch: calcium or sodium carboxymethylcellulose (sodium croscarmellose, CMC-Ca, CMC-Na); microcrystalline cellulose; cross-linked polyvinylpyrrolidone type A or type B; sodium starch glycolate and others.

Preferably, the granulate a) comprises 1.0 to 6.0 wt.% of a disintegrant. More preferably the disintegrant in the granulate a) is Croscarmellose Sodium in an amount of 1 to 5 wt.%, preferably 5.00 wt.%, based on the total weight of the granulate a).

Preferably, the powder or granulate or tablet b) comprises 4.0 to 6.0 wt.% of a disintegrant. More preferably the disintegrant in the powder or granulate or tablet b) is crospovidone in an amount of 1 to 5 wt.%, preferably 5.00 wt.%, based on the total weight of the powder or granulate or tablet b). Ramipril granulate is preferably manufactured by wet granulation technology.

Wet granulation can be accomplished by various means such as for example high-shear granulation or fluid-bed granulation.

Preferably, in the granulate a) the binder for granulation is used in an amount 0.5 to 5.0 wt.%, most preferably 0.75, 1.75,1.25, 2.25, 2.75, 3.25, 3.75, 4.25, 4.5 and 4.77 wt.%, based on the the total weight of the Ramipril granulate (granulate a).

Preferably, the binder is not present in blend or tablet b).

A binder is at least one independently selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, hydroxycellulose, hydroxyethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, copovidone, pregelatinized starch, gelatine and any combination thereof, preferably the binder is at least one independently selected from the group consisting of hydroxypropyl cellulose, polyvinylpyrrolidone and any combination thereof. Most preferably the binder is polyvinyl alcohol and no other binders are used.

Polyvinyl alcohol can be added both in the form of water or organic solution or as a dry powder altogether with the other excipients of the intragranular phase.

In one embodiment of the process of the invention the solvent used to prepare the granulating solution is water. In another embodiment of the process of the invention the solvent used to prepare the granulating liquid is an organic solvent, e.g., ethyl or isopropyl alcohol.

Techniques and apparatuses for performing wet-granulation are well known in the art.

In the wet granulation process, agglomeration of the active ingredient and excipients occurs to obtain a mass of larger granulate particles. The granulating liquid comprising the binder is fed, especially sprayed, onto the carrier particles as they are agitated in a closed container with blending tools and a chopper, usually in a high-shear mixer or fluidized bed. Dense granules are formed through the liquid and solid bridges that result in the granulate having compact structure and high bulk density. The granulating liquid can be simply poured into the mixture of powders. For improved dose uniformity and to obtain a more even granulate, the granulating liquid can be fed by spraying onto the carrier using a spray nozzle.

The granulation can be performed by high-shear granulation. In high-shear granulation, wherein dry powder of the carrier is placed in a mixing bowl usually containing an impeller, which revolves on a horizontal plane, and a chopper, which rotates either in the vertical or horizontal plane. The dry powders are mixed by the rotating impeller before the granulating liquid binder is sprayed onto the top of the bed of powder. Agitation is maintained by the rotating impeller until a predetermined optimum endpoint is reached. The granules are then usually sieved, transferred to another piece of equipment, such as for example a fluidized-bed dryer, for drying, and finally sieved.

The granulation can be also performed by fluidized bed wet granulation, wherein granulating liquid is fed by spraying onto the carrier particles powder bed that is maintained in a fluidized state such as by a flow of air injected at the base of the granulator. The advantage of the fluidized bed wet granulation is that drying can be performed within the same apparatus.

The obtained granulate can be used as such, or optionally together with extragranular excipients, for filling capsules or sachets, or for forming tablets or tablets layers.

Accordingly, the composition of the invention further comprises the Ramipril extragranular phase consisting of excipients selected from other fillers, disintegrants, and flowing aids, which improve the flow of the powder mixture and include one or more of the lubricants, glidants and/or anti-adherents.

Lubricants are used in tablet and capsule formulations in order to reduce the friction between particles during compression as well as the friction between the walls of the tablet and the walls of the cavity of tabletting machine. Some common examples of lubricants are stearic acid, calcium or magnesium salts of stearic acid, glyceiyl behenate or talc.

Preferably, lubricant is not present in the Ramipril granulate (granulate a)).

Preferably, the powder or granulate or tablet b) comprises 1.0 to 2.0 wt.% of a lubricant. More preferably the lubricant in the powder or granulate or tablet b) is magnesium stearate in an amount of 2.00 wt.%, based on the total weight of the powder or granulate or tablet b). Glidants are substances used to promote the flow of the granules or the powders. Glidants include, but are not limited to, one or more materials selected from silica, colloidal silica, aluminosilicates, for example colloidal anhydrous silica, sodium stearyl fumarate and talc. Preferably, in the granulate a) the Glidant is sodium stearyl fumarate, in an amount of 1 to 2 wt.%, preferably 2.0 wt.% by weight, based on the total weight of the Ramipril granulate

(granulate a).

Preferably, in the powder or granulate or tablet b) the Glidant is anhydrous colloidal silica in amount of 0.1 to 1 wt.%, preferably 0.5 wt.% based on the total weight of the powder or granulate or tablet b).

Preferably, the powder or granulate or the tablet b) of Bisoprolol fumarate, Amlodipine or Hydrochlorothiazide comprises anhydrous colloidal silica as the glidant to act as an anti-adhesive and flow-promoting agent, especially on a larger scale. It is used in an amount of 0.1% -1.0%, preferably 0.5wt.% by weight based on the total weight of the powder or granulate or a tablet b). Anti-adherents or “non-sticking agents” prevent adhesion of the tablet surface to the die walls and the punches, thus resulting in countering the picking or sticking of tablets.

Suitable anti-adherents include, but are not limited to, one or more materials selected from stearic acid, metal stearates such as magnesium, aluminum or calcium stearate, sodium stearyl fumarate and/ or talc.

The materials known as lubricants, glidants and anti-adherents have more than one function and it is beneficial to use more than one of them to achieve optimal results.

Thus, preferably, the composition contains in the extragranular phase one of the above flowing aids or a combination thereof, such as sodium stearyl fumarate and/or magnesium stearate, in an amount of 0.5% -2.0% by weight, based on the total weight of the Ramipril phase.

Tablets of the desired size and shape can be pressed from the mixture of Ramipril granulate and the components of the extragranular phase with the use of tabletting machine.

The further active substance in the fixed dose composition selected from Bisoprolol fumarate, Amlodipine and Hydrochlorothiazide phase can take the form of a powder or granulate or a tablet.

Granulates understood as i.e. granules, pellets, spheres, spheronizates, beads, etc., or the powders may be further compressed to the tablets made of them with the use of additional excipients known in the art.

In the preferred embodiment of the invention, when in a fixed dose composition Bisoprolol fumarate is used together with Ramipril, the Bisoprolol phase takes the form of a blend of a powder or a blend of granulate or a tablet.

Bisoprolol fumarate tablets can be manufactured by any method known in the art, such as direct compression, wet granulation, dry granulation or slugging. The preferred method comprises admixing Bisoprolol fumarate, with functional excipients such as fillers, disintegrants, flow aids, etc., and subjecting the blend obtained to direct compression, optionally preceded by dry granulation step.

Dry granulation step will incorporate, besides the active ingredient, excipients, e.g. fillers, disintegrants, binders, flow aids into intragranular phase. Additional excipients, e.g. fillers, disintegrants, glidants, lubricants, might be added before the tableting step as an extragranular phase.

In the preferred embodiment of invention, Ramipril granulate takes the form of a granulate and Bisoprolol fumarate phase takes the form of a blend of powders, granulates or tablets.

Ramipril granulate and Bisoprolol fumarate phase are then combined to obtain a finished dosage form.

In one embodiment of the invention, the finished dosage form is a capsule comprising Ramipril granulate combined with Bisoprolol tablet.

In another embodiment of the invention, the finished dosage form is a capsule comprising Ramipril granulate combined with Bisoprolol powder blend.

In most preferred embodiment Ramipril granulate a) and Bisoprolol powder or granulate or a tablet can be filled into a hard gelatine capsule or a sachet to obtain a finished dosage form.

One could also consider the formation of two- or multilayer tablets from the granulates of both active ingredients obtainable by any method known to those skilled in the art.

The fixed dose combination provides stable immediate release finished dosage forms comprising the therapeutically effective amounts of both active ingredients, e.g. fixed dose combination of Ramipril/Bisoprolol fumarate 10/10 mg, 10/5 mg, 5/5 mg, 5/2.5 mg, 2.5/2.5 mg, 2.5/1.5 mg, fixed dose combination ofRamipril/Amlodipine 5/5, 5/10, 10/5, or 10/10 mg, 2.5/12.5 or Ramipril/HCT 5/25 mg and the like.

The invention is further illustrated by the following non-limiting examples.

Examples

Example 1: preparation of Ramipril (RAM) phase Ramipril granulate with the composition given in a table below was prepared by high-shear granulation using polyvinyl alcohol aqueous solution as a granulating liquid. In the table below presented is 5 mg Ramipril composition. Dosages with 10, and 2.5 mg of Ramipril, respectively are prepared analogously, i.e. using the same wt.%. proportions for all of the constituents, as presented in Table 6 with exemplary fixed dose compositions with Ramipril granulate a) and Bisoprolol fumarate tablets b). Batch RAM42C

The manufacturing process of Ramipril granulate consisted of the following steps:

1. Weighing and sieving of granulate components: weigh specified amounts of intragranular components: lactose monohydrate, croscarmellose sodium, polyvinyl alcohol and Ramipril into separate containers.

2. Preparation of granulation liquid: add a specified amount of a binder into a container with purified water while stirring, and stir until clear solution is obtained.

3. High-shear mixing: load and mix granulate components. 4. Granulation liquid addition: add granulation liquid into granulate components blend.

5. Wet massing: mix wet granulate with high speed for additional period of time.

6. Wet granulate sieving: pass wet granulate through a screen.

7. Fluid bed diying: load wet granules into fluid bed drier to remove water added in the granulation stage. 8. Granulate screening: pass dried granulate through a screen to calibrate the granulate.

9. Admixing granulate with the extragranular phase components: add a specified amount of a glidant onto a granules bed in a mixer bin and mix for a certain time period to obtain homogenous blend.

10. Tabletting: compress the blend into tablets on a rotary tablet press equipped with a set of punches appropriate for a given dose.

Example 2: preparation of Ramipril (RAM) phase

Ramipril granulate with the composition given in a table below was prepared in the same manner as in Example 1. Dosages with 10, and 2.5 mg of Ramipril, respectively are prepared analogously, i.e. using the same wt%. proportions for all of the constituents, as presented in Table 6 with exemplary fixed dose compositions with Ramipril granulate a) and Bisoprolol fumarate tablets b). Experiments 1 and 2 show that the type of glidant doesn’t influence Ramipril granulate stability. Batch RAM43C

Stability tests Stability tests of the Ramipril granulates obtained by the process described in Example 1 were carried out according to an in-house method by the measurement at 20°C of pH values of standardized solutions consisted of 8 ml of deionized water (pH measured 6.98) and a single 50 mg granulate dosage unit comprising 2.5 mg of Ramipril to be tested (concentration 0.31 mg of Ramipril /I mL of water). Granulates of compositions shown in Table 1 were dosed to capsule shells, blisters and stored in stability chambers for a given time period. Afterwards the presence of related substances in capsules was determined by HPLC analytical method. The granulates’ standardized solution pH values and accelerated stability results are presented in Table 2. It is observed that even D-RAM impurity levels close to 2% at the 2 months’ time point can retain stability up to 6 months in accelerated stability study.

Table 1. Compositions of analysed Ramipril granulates

Table 2. Accelerated stability test results - standardized solution pH values for Ramipril granulates

Ramipril granulates having pH value in a range from 5.0 to 5.8 (measured at 20°C, as described above) results in the most stable compositions. Example 3: Fixed dose form comprising Ramipril and Bisoprolol fumarate (RAM-BIS)

A. Preparation of Bisoprolol fumarate (BIS) tablets b) by direct compression

Bisoprolol powder mixture for direct compression with the composition given in a table below 5 was prepared. In the table below presented is 5 mg Bisoprolol fumarate composition. Dosages with 10, 2.5 mg and 1.25 mg of Bisoprolol fumarate, respectively are prepared analogously, i.e. using the same wt.%. proportions for all of the constituents, as presented in Table 6 with exemplary fixed dose compositions with Ramipril granulate a) and Bisoprolol fumarate tablets b). 0 Table 3. Powder mixture for direct compression - BIS1 DC

The manufacturing process of Bisoprolol fumarate phase consisted of the following steps:

1. Weighing and sieving of active substance and excipients: weigh specified amounts of intragranular components cellulose microcrystalline, calcium hydrogen phosphate, anhydrous, Crospovidone, silica colloidal anhydrous, and Bisoprolol fumarate into separate containers.

2. Inserting powders, except of magnesium stearate, into a mixer bin and mixing for a certain time period.

3. Admixing of magnesium stearate.

4. Compressing the blend into tablets.

B. Preparation of Bisoprolol fumarate (BIS) tablets b) by roller compaction

In the Table 4 below presented is 5 mg Bisoprolol fumarate composition. Dosages with 10, 2.5 mg and 1.25 mg of Bisoprolol fumarate, respectively, are prepared analogously, i.e. using the same wt.%. proportions for all of the constituents, as presented in Table 6 with exemplary fixed dose compositions with Ramipril granulate a) and Bisoprolol fumarate tablets b).

Table 4. Powder mixture for direct compression - BIS2 RC.

1. Weighting and sieving of granulate components: weigh specified amounts of intragranular components: cellulose microcrystalline, calcium hydrogen phosphate anhydrous, crospovidone and magnesium stearate and Bisoprolol fumarate into separate containers. 2. Dry granulation of intragranular components by roller compaction.

3. Granulate calibration.

4. Addition and admixing of extragranular components (except Magnesium Stearate).

5. Final Blending: blend all components with Magnesium Stearate to obtain final blend.

6. Compressing final blend into tablets.

C. Finished dosage form

Both phases, Ramipril granulate a) and Bisoprolol fumarate tablets b) were filled into the hard gelatine capsules according to the following procedure.

Encapsulation: adjust the capsulating machine and run the process to obtain capsules with desirable filing - Ramipril granulate and Bisoprolol fumarate tablets.

Table 5. Fixed dose cpsule form comprising Ramipril and Bisoprolol fumarate (RAM-BIS)

Capsule size is selected depending on the strength. The capsules were obtained comprising Ramipril-Bisoprolol fumarate dosages as presented in the table below . Capsule size “0” or “1” are suitable for this strengths. Characteristic of fixed dose compositions according to Table 6, prepared in a form of ramipril granulate a) and Bisoprolol fumarate tablets b)

Example 5: Stability of fixed dose compositions comprising Ramipril and Bisoprolol fumarate (RAM-BIS)

Ramipril encapsulation blends prepared in Examples 1 and 2 were filled into gelatine capsules in combination with Bisoprolol fumarate mixture, Bisoprolol fumarate tablets and Bisoprolol fumarate film-coated tablets. Stability tests of the RAM-BIS combined capsule compositions were carried out in the storage conditions 40°C / 75%RH and analysed by HPLC method.

Quality of the combined product of the invention is more than satisfactory after 6 months storage in accelerated conditions (40°C, 75%RH) (total impurity < 5.0% limit according to ICH Q1A (R2) guideline)

Example 6: Stability of fixed dose compositions comprising Ramipril and Amlodipine (RAM- AML) or Hydrochlorothiazide (RAM-HCT) Ramipril encapsulation blends prepared in Example 1 were filled into gelatin capsules together with the neat active substances: Amlodipine besilate (RAM-AM) and Hydrochlorothiazide (RAM-HCT) to examine robustness of the Ramipril granulate concerning stability profile in case of vast surface contact with another active substance known to be incompatible with. Example 7: Stability of tablets made of Ramipril granulate from Example 1 and Example 2

The final granulates prepared in Example 1 and Example 2 were compressed into a tablet on a rotary tableting machine equipped with the suitable tools to obtain the desired shape of the tablet (e.g., round or oval, with optional engraving). The tablets were not subjected to any coating processes. Stability test of the Ramipril tablets made of the granulate prepared in Example 1 (RAM IT) was carried out at the storage conditions 40°C / 75% RH and analysed by HPLC method.

Table 7. Accelerated stability test results of tablets made of Ramipril granulates of Example 2

Claims

Claims:

1. A granulate for oral administration comprising Ramipril and polyvinyl alcohol in a wt.% ratio in a range of 1.1 to 6.5 and one or more pharmaceutically acceptable excipients.

2. The granulate according to Claim 1, wherein the wt.% ratio of Ramipril to polyvinyl alcohol is in a range of 1.15 to 3.9, more preferably 1.7 to 2.9, such as 2.85.

3. The granulate according to any of the preceding claims, wherein pH of the water solution of 50 mg Ramipril granulate sample with the concentration of 0.31 mg of Ramipril/ 1 mL of water, measured at 20°C, is in a range of 5.0 to 5.8.

4. The granulate according to any of the preceding claims, wherein the granulate in not coated with polyvinyl alcohol.

5. The granulate according to any of the preceding claims wherein the Ramipril content in the granulate is in a range of 4.0 to 5.5 wt.% to 2.5 wt.%, preferably 4.5 to 5.0 wt.%, more preferably 4.5 to 4.9 wt.%, such as 5 wt.%, based on the total weight of the granulate.

6. The granulate according to any of the preceding claims, wherein the granulate comprises, as the at least one excipient, at least one of a filler, a binder, a disintegrant, and a glidant or any combination thereof, preferably, the granulate comprises 80 to 95 wt.% of the filler, 1.0 to 6.0 wt.% of a disintegrant, 0.5 to 5.0 wt.% of a binder and 1 to 2 wt.%, of a glidant, based on the total weight of the granulate.

7. The granulate according to any of the preceding claims, wherein the granulate is free of silicified microcrystalline cellulose.

8. The granulate according to any of the preceding claims, comprising 5.00 wt.% of Ramipril, 86.2 wt.% of Lactose monohydrate, 1.75 wt.% of Polyvinyl alcohol, 5.00 wt.% of Croscarmellose Sodium, 2.00 wt.% of Sodium Stearyl Fumarate.

9. The granulate according to any of the preceding claims, wherein the granulate is not coated.

10. The granulate according to any of the preceding claims further compressed to a tablet or a tablet layer.

11. A fixed dose pharmaceutical composition in form of a capsule for oral administration comprising in two separate phases: a) the granulate according to any one of claims 1 to 9, and b) a powder or granulate or a tablet comprising Bisoprolol fumarate, Amlodipine or Hydrochlorothiazide or salts thereof and one or more pharmaceutically acceptable excipients.

12. The composition according to Claim 11, wherein granulate a) and the powder or granulate or tablet b) are not coated.

13. The composition according to Claims 11 to 12, wherein the tablet b) comprises 4.5 -5.5%, preferably 4.5 to 5.0 wt.%, more preferably 4.5 to 4.9 wt.%, such as 5 wt.%, of Bisoprolol fumarate,

Amlodipine or Hydrochlorothiazide, based on the total weight of the powder or granulate or tablet b).

14. The composition according to Claims 11 to 13, wherein tablet b) comprises Bisoprolol fumarate, Amlodipine or Hydrochlorothiazide, and as the at least one excipient, at least one of a filler, a disintegrant, a lubricant, a glidant and any combination thereof, preferably, the tablet b) comprises 80 to 95 wt.% of the filler, 4.0 to 6.0 wt.% of a disintegrant, 1 to 2 wt.% of a lubricant, and 0.1 to 1.0 wt.%, of a glidant, based on the total weight of the powder or granulate or tablet b).

15. The composition according to Claims 11 to 14, wherein the tablet b) comprises 5.00 wt.% of Bisoprolol, Amlodipine or Hydrochlorothiazide, 54.50 wt.% of Cellulose, Microcrystalline, 33.00 wt.% of Calcium Hydrogen Phosphate, Anhydrous, 5.00 wt.% of Crospovidone type A, 0.50 wt.% of Silica, Colloidal Anhydrous, 2.00 wt.% of Magnesium Stearate, based on the total weight of the powder or granulate or tablet b).

16. The composition according to Claims 11 or 15, wherein the powder or granulate or the tablet b) comprises Bisoprolol fumarate.