MX2009000358A

MX2009000358A - Stable formulation comprising a combination of a moisture sensitive drug and a second drug and manufacturing procedure thereof.

Info

Publication number: MX2009000358A
Application number: MX2009000358A
Authority: MX
Inventors: Michael Fox
Original assignee: Teva Pharma
Priority date: 2006-07-10
Filing date: 2006-07-10
Publication date: 2009-01-27
Also published as: CA2659814A1; BRPI0621867A2; IL196273A0; WO2008008057A1; JP2009542806A; CN101478983A; NO20090609L

Abstract

The present invention provides stable pharmaceutical compositions comprising a combination of active pharmaceutical ingredients. The pharmaceutical composition of the present invention comprises a moisture sensitive drug, in particular an angiotensin converting enzyme (ACE) inhibitor such as Cilazapril, as an active ingredient, a second pharmaceutically active ingredient such as for example Hydrochlorothiazide, and at least one pharmaceutical excipient, wherein the moisture sensitive active pharmaceutical ingredient is wet granulated with a solution of at least one pharmaceutical excipient, and methods for preparing such stable pharmaceutical compositions.

Description

STABLE FORMULATION COMPRISING A COMBINATION OF A SENSITIVE PHARMACY A. MOISTURE AND A SECOND DRUG AND MANUFACTURING PROCEDURE OF IT Field of the invention The present invention relates to stable pharmaceutical compositions comprising a combination of a pharmaceutical active ingredient sensitive to moisture (drug), in particular an inhibitor of the angiotensin converting enzyme (ACE) such as Cilazapril and a second drug, such as hydrochlorothiazide , as the active ingredients and methods for preparing such stable pharmaceutical compositions.

BACKGROUND OF THE INVENTION Cilazapril is evidently an inhibitor of the angiotensin-converting enzyme ("ACE"), whose enzyme inhibits the formation of angiotensin II from angiotensin I by inhibiting the angiotensin-converting enzyme. It is reported that, chemically, Cilazapril is (1S, 9S) -9- [(S) -1-ethoxycarbonyl-3-phenylpropylamino] -10-oxoperhydropyridazino [1,2-a] [1, 2] diazepine-1-acid. carboxylic acid and is understood to be disclosed in U.S. Patent No. 4,512,924.

? Cilazapril has been prescribed in the treatment of patients suffering from hypertension. Cilazapril has the following general formula: Hydrochlorothiazide is evidently a diuretic and an antihypertensive agent. Chemically, hydrochlorothiazide, a 3,4-dihydro-chlorotyzed derivative, is reported to be 1,1-dioxide-6-chloro-3,4-dihydro-2H-1, 2,4-benzothiazidine-7-sulfonamide and has the following general formula: Hydrochlorothiazide is indicated as an added therapy in the edema associated with congestive heart failure, 15 liver cirrhosis, and corticosteroid therapy and estrogen.

It has been considered useful in edema due to different forms of renal dysfunction such as nephrotic syndrome, acute glomerulonephritis and chronic renal failure. In addition, hydrochlorothiazide is indicated in the management of hypertension as the sole therapeutic agent or to improve the efficacy of other antihypertensive agents in the most severe forms of hypertension.

One of the requirements for an acceptable pharmaceutical composition is that it must be stable. A stable pharmaceutical composition does not 10 exhibits a substantial breakdown of the active ingredient during the time between the manufacture of the composition and its use by a patient. Cilazapril and numerous other drugs have instability problems because the active pharmaceutical ingredient degrades rapidly in the presence of water / moisture.

Said active pharmaceutical ingredients (drugs) can consequently be characterized as moisture sensitive drugs.

It is known that tablet mixtures can be dry-mixed, dry-granulated or wet-granulated prior to the manufacture of tablets. The choice of the above process, the dry mix, the dry granulation, the wet granulation, or some other granulation process, depends on the properties of the drug and the excipients chosen.

Generally, it is thought that a dry manufacturing process is preferable for moisture sensitive drugs.

To improve the stability of moisture-sensitive drugs, water-purifying compounds can be incorporated into a tablet matrix. One such water purifying compound is the Copovidone binder (Plasdone S-630®), whose binder is specifically recommended for moisture-sensitive drugs. However, with very little success, attempts were made to formulate Cilazapril tablets using this material in a dry granulation process. In said Cilazapril tablets the degradation of the active pharmaceutical ingredient was evident.

Wet granulation processes have not been considered appropriate for moisture sensitive drugs since the very nature of these processes may include the presence of water / moisture. However, as described in co-pending US patent application 11 / 446,336, filed on June 2, 2006, the best stability results can be achieved with a composition or formulation comprising the moisture-sensitive drug and a binder such as Copovidona, where the formulation / composition is prepared using a process of wet granulation, which comprises wetting and then drying the composition at an elevated temperature.

The pharmaceutical compositions of said moisture sensitive active pharmaceutical ingredients (active pharmacological substances) may contain one or more additional pharmacological substances in a combination pharmaceutical composition. Said combination pharmaceutical composition can provide improved treatment efficacy or provide a treatment while improving the side effects of one such moisture sensitive active pharmaceutical ingredients. However, the combination of active ingredients in a composition requires that the active pharmaceutical ingredients are compatible in terms of activity, side effects and efficacy for example.

Hydrochlorothraziada (HCTZ) can be used in combination with other antihypertensive drugs. In addition, pharmaceutical compositions for use in the treatment of hypertension may comprise a combination of hydrochlorothiazide and an antihypertensive agent. In addition, HCTZ is compatible with the moisture sensitive active pharmaceutical ingredient Cilazapril for inclusion in a combination pharmaceutical composition.

However, a pharmaceutical composition comprising a pharmacological substance sensitive to moisture and a second drug substance prepared using a single wet granulation process of the combined active ingredients did not appear to be a stable pharmaceutical composition but did exhibit degradation of Cilazapril.

Surprisingly, the best stability results can be achieved if a wet granulation process for preparing the combination pharmaceutical composition is divided into at least two steps, wherein the second drug substance, preferably hydrochlorothiazide (HCTZ) is added to the wet granulate after of which is the wet granulation of the moisture sensitive drug substance, preferably Cilazapril.

Extract of the invention The present invention provides stable pharmaceutical compositions of a combination of Cilazapril and Hydrochlorothiazide (HCTZ), and methods of their preparation.

In one aspect the present invention provides a stable pharmaceutical composition comprising: a) a pharmaceutical active ingredient sensitive to moisture; and b) a second active pharmaceutical ingredient; wherein the moisture sensitive active pharmaceutical ingredient is first wet granulated with a solution of at least one pharmaceutical excipient in at least one processing solvent before granulation with the second active pharmaceutical ingredient. Preferably, at least one excipient is a binder.

In another embodiment, the present invention provides a method for preparing a combined granular composition comprising a moisture sensitive granular moisture sensitive pharmaceutical ingredient and a second active pharmaceutical ingredient comprising the following steps of: a) providing an active pharmaceutical ingredient sensitive to moisture; b) mixing the moisture sensitive active pharmaceutical ingredient with at least one pharmaceutically acceptable excipient which is not a binder, forming a mixture; and c) wet granulating the mixture with a solution of a binder excipient dissolved in one or more processing solvents and forming a wet granulation; d) providing a material comprising a second active pharmaceutical ingredient and optionally one or more pharmaceutical excipients; and e) adding the material of step d) to the wet granulate of step c) and forming a combined granulate, wherein when the material of step d) comprises a second pharmaceutical ingredient and one or more pharmaceutical excipients the material is optionally a mixture obtained by mixing the second pharmaceutical ingredient with one or more pharmaceutical excipients.

In another embodiment of the present invention the method also comprises steps of preparing a pharmaceutical composition in tablets of the present invention wherein the method also comprises the steps of: f) mixing the combined granulate with one or more excipients and forming a final mixture; g) pressing the final mixture into a tablet; and h) optionally coating the tablet with a cosmetic coating.

The present invention also provides a method for treating a patient suffering from a disease, preferably hypertension, comprising administering to a patient in need thereof a therapeutically effective amount of a stable pharmaceutical composition comprising a moisture sensitive pharmaceutical ingredient, preferably Cilazapril , a second active pharmaceutical ingredient, preferably hydrochlorothiazide, and at least one pharmaceutical excipient, wherein the active pharmaceutical ingredients are granulated wet with a solution of at least one pharmaceutical excipient.

Detailed description of the invention As used herein the term "moisture sensitive active pharmaceutical ingredient" refers to an active pharmaceutical ingredient that degrades rapidly in the presence of water / moisture. By understanding the term "moisture-sensitive active pharmaceutical ingredient" it is useful to consider how the exemplified Cilazapril behaves in storage. When commercially available Cilazapril tablets (Vascace®) are stored at 55 ° C and at 75% relative humidity in the commercialized package, the "cold aluminum and aluminum" blister packs, which are considered the "gold standard" at Blister packaging with respect to blister packs with moisture barrier, the degradation evidenced by the formation of Cilazaprilat is on the order of about one percent on the initial content of Cilazaprilat compared to the initial content of Cilazaprilat, over a period of storage of seven days, whereas when the tablets are removed from this package and stored in the same conditions and therefore exposed to moisture, during only 48 hours, the formation of Cilazaprilat is observed more than five times, see Table 1 below. It is this type of characteristic that identifies Cilazapril as an active pharmaceutical ingredient sensitive to moisture. Table 1 Lot No Storage Period Products Storage Conditions, total hours degradation,% No. B2017 Packaging Time "0" 1.1 N ° B2017 Packaging 168 2.1 (1%) No. B2017 Packaging 336 2.8 (1.7%) No. B2017 Not packaged 48 7.5 (6.4%) Wet granulation processes have not been considered appropriate for moisture sensitive drugs since the very nature of these processes may include the presence of water / moisture. However, as described in co-pending US patent application 11 / 446,336, filed on June 2, 2006, the best stability results can be achieved with a composition or formulation comprising the moisture sensitive drug and a binder. such as Copovidone, wherein the formulation / composition is prepared using a wet granulation process, which comprises wetting and then drying the composition at an elevated temperature.

The pharmaceutical compositions of said moisture sensitive active pharmaceutical ingredients (active pharmacological substances) may contain one or more additional active pharmacological substances in a combination pharmaceutical composition. Said combination pharmaceutical composition can provide improved treatment efficacy or provide the treatment while improving the undesirable side effects of said active pharmaceutical ingredient sensitive to moisture. However, the combination of active pharmaceutical ingredients in a composition requires that the pharmacological substances are compatible in terms of activity, side effects, and efficacy for example.

A second compatible drug substance for inclusion in a combination pharmaceutical composition comprising the moisture sensitive drug substance Cilazapril, is for example Hydrochlorothiazide (HCTZ).

However, a pharmaceutical composition comprising a pharmacological substance sensitive to moisture and a second drug substance using wet granulation of the combined pharmacological substances did not appear to be a stable pharmaceutical composition. In particular, said pharmaceutical composition containing only Cilazapril as its active pharmaceutical ingredient was shown to be useful but presented an unacceptable degradation for Cilazaprilat, when Cilazaprilat was combined with a second substance such as HCTZ in a composition where a combined mixture of the drug substance was granulated wet.

Surprisingly the best stability results can be achieved, if a wet granulation process for preparing the combination pharmaceutical composition is divided into at least two steps, wherein the second drug substance, preferably Hydrochlorothiazide (HCTZ), is added to the wet granulate after the first granulation of the pharmacological substance sensitive to moisture is finished, preferably Cilazapril. HCTZ can be added to the wet granulate alone or together with other ingredients and / or in a granulation solution.

In one aspect the present invention provides a pharmaceutical composition comprising: a) an active pharmaceutical ingredient sensitive to moisture, preferably Cilazapril, and b) a second pharmaceutical ingredient, preferably hydrochlorothiazide; wherein the pharmaceutical ingredient is first wet granulated with at least one pharmaceutical excipient in at least one processing solvent before granulation with the second active pharmaceutical ingredient. The compositions of this aspect of the invention are stable. In the context of the present invention, the first wet granulation step preferably should not comprise a significant proportion of the second active ingredient, and more preferably does not contain any of the second active pharmaceutical ingredient. Preferably, at least one excipient is a binder and the pharmaceutical composition comprises at least two pharmaceutical excipients.

Preferably, the amount of the moisture sensitive active pharmaceutical ingredient of the composition is from 0.1% to 25%, more preferably from 0.5% to 15% of the total weight of the composition. A more preferred amount of the moisture sensitive pharmaceutical ingredient of the composition is from 0.6% to 2.7% of the total weight of the composition. Preferably, the active ingredient sensitive to moisture is Cilazapril.

Preferably, the amount of the second active ingredient of the composition is from 1% to 25%, more preferably from 3% to 15% of the total weight of the composition. A more preferred amount of the second active pharmaceutical ingredient of the composition is from 5% to 10% of the total weight of the composition. Preferably, when the moisture sensitive active pharmaceutical ingredient is an "ACE inhibitor", the second active pharmaceutical ingredient is preferably a diuretic drug. More preferably, a thiazide derivative. More preferably, hydrochlorothiazide (HCTZ).

The present invention also provides a stable pharmaceutical composition comprising an active pharmaceutical ingredient sensitive to moisture, a second active pharmaceutical ingredient and at least one pharmaceutically acceptable excipient, wherein the composition contains no more than 3% (w / w of the initial amount of the active pharmaceutical ingredient sensitive to moisture) of the main degradation product after storage in a package with moisture barrier properties whose properties are at least as efficient as the cold aluminum and aluminum blisters. Preferably, the concentration of the main product of the degradation of the stable pharmaceutical composition of the present invention after storage described above is no more than 2%. More preferably, the concentration of the main product of the degradation of the stable pharmaceutical composition of the present invention after the storage described above is no more than 1%. Storage may include storage at a temperature of 55 ° C for 14 days and storage at a temperature of 40 ° C and 75% relative humidity for three months. The degradation product can be detected by HPLC analysis. Preferably, the active pharmaceutical ingredient sensitive to moisture is Cilazapril and the main product of the degradation Cilazaprilat. Preferably, the second ingredient is HCTZ.

A stable pharmaceutical composition of the present invention accordingly provides a pharmaceutical composition of an active pharmaceutical ingredient sensitive to moisture and a second pharmaceutical ingredient, preferably Cilazapril and HCTZ respectively, characterized in that it comprises not more than 3%, preferably not more than 2%, more preferably not more than 1%, by weight of the total amount of the moisture sensitive pharmaceutical ingredient, Cilazapril, of its main degradation product of Cilazaprilat when storing it.

It is understood that Cilazaprilat has the following structure: Preferably, the stable pharmaceutical composition of the present invention comprises at least 4% of a binder in the total weight of the composition. Preferably, the pharmaceutical composition comprises from 4% to 20%, more preferably from 5% to 10% of a binder in the total weight of the composition. The binder comprises, for example, one or more of a cellulose derivative, a polyvinyl pyrrolidone (PVP) and its derivatives, a polyvinyl acetate (PVA) or a polyvinyl alcohol. Examples of suitable cellulose derivatives as a binder in the present invention are Hydroxypropylmethyl cellulose (HP C) or Hydroxypropyl cellulose (HPC).

More preferably, the binder is Copovidone, for example Plasdone® S-630 (Copovidone), which is a random, linear, 60:40, synthetic copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, and having a reduced hydroxity and a reduced polymer glass transition temperature (Tg) compared to a polyvinyl pyrrolidone homopolymer (PVP). In the stable pharmaceutical composition of the present invention this binder is wet granulated with the moisture sensitive active pharmaceutical ingredient and one or more pharmaceutical excipients of a processing solvent to form a wet granulate before granulating the wet granulate with a second drug substance .

Stable pharmaceutical compositions comprising a moisture sensitive active pharmaceutical ingredient and a second pharmacological substance of the present invention may also contain excipients such as tablet and capsule fillers and diluents (such as microcrystalline cellulose, lactose, starch and tribasic calcium phosphate) ), disintegrators (such as starch, croscarmellose sodium, crospovidone and sodium starch glycolate), and glidants (such as colloidal silicon dioxide and talc), lubricants (such as stearate) of magnesip, sodium lauryl sulfate, stearic acid and sodium stearyl fumarate).

More preferably, diluents and fillers suitable for use in the pharmaceutical composition of the present invention include microcrystalline cellulose (e.g. Avicel®), lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrose, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, powdered cellulose, sodium chloride, sorbitol and talc.

Preferably, the pharmaceutical composition of the present invention includes lactose monohydrate, more preferably, 55% to 60% by weight of the total composition.

In an alternative preferred embodiment, the pharmaceutical composition of the present invention includes talc, more preferably in an amount of 1% to 2% by weight of the composition.

The pharmaceutical composition can also include both lactose monohydrate and talc in the amounts specified above.

The solid pharmaceutical compositions of the present invention that are compacted in a dosage form, such as a tablet, can include the addition of a disintegrator in the composition. Disintegrants include croscarmellose sodium (e.g., Ac Di Sol®, Primellose®), crospovidone (e.g., Kollidon®, Polyplasdone®), microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate. (for example, Explotab®, Primoljel®) and starch.

Preferably, the pharmaceutical composition of the present invention includes starch, more preferably in an amount of 1 20% to 30%, more preferably 25% by weight of the total composition.

Slides can be added to improve the flowability of a solid composition before compaction and to improve the precision of the dosage especially during compaction and filling of the capsules.

Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, and talc.

A lubricant may be added to the composition to reduce adhesion and / or to facilitate the detachment of the product from, for example, the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmito stearate, hydrogenated castor oil, hydrogenated vegetable oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate. .

Preferably, the pharmaceutical composition of the present invention includes sodium stearyl fumarate, more preferably, in an amount of 0.5% to 1.5%, more preferably 1% by weight of the total composition.

Other excipients that may be incorporated into the formulation include preservatives, surfactants, antioxidants, or any other excipient commonly used in the pharmaceutical industry.

In a preferred embodiment of the present invention, the stable formulation comprises Cilazapril, HCTZ, copovidone, lactose monohydrate, sodium starch glycolate, extra fine talc and sodium stearyl fumarate. Preferably, the pharmaceutical composition comprises (in the total weight of the composition), Cilazapril in an amount from 0.5% to 15%, more preferably from 0.6% to 2.7%, HCTZ in an amount of 3% by weight. 15%, more preferably 5% to 10%, lactose monohydrate in an amount of 50% to 65%, more preferably 55% to 60%, talc in an amount of 1% to 2%, starch in an amount of 20%, % to 30%, more preferably 25%, a binder, preferably copovidone, in an amount of 4% to 20%, more preferably 5% to 10%, and sodium stearyl fumarate in an amount of 0.5% at 1.5%, more preferably 1%.

The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal and rectal administration. Although the most appropriate administration in any given case depends on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.

The dosages can conveniently be presented in unit dosage form and prepared by any of the methods known in the pharmaceutical art.

The pharmaceutical composition of the present invention can be prepared in any dosage form such as a compressed granulate in the form of a tablet for example, In addition, uncompressed granules and powder mixtures are obtained which are obtained by the method of the present invention in the precompression steps it can simply be provided in a dosage form of a capsule or sachet. Accordingly, the dosage forms of the pharmaceutical composition of the present invention include solid dosage forms such as tablets, powders, capsules, sachets, etc. The dosage form of the present invention can also be a capsule containing the composition, preferably a granulated powder solid composition of the invention, within a hard or soft capsule. The capsule can be made of gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or dye.

Once a solid composition comprising an active pharmaceutical ingredient sensitive to moisture, preferably Cilazapril, and a second drug substance, preferably HCTZ, is prepared according to the present invention, preferably formulated in pharmaceutical formulations such as dosage forms including tablets and capsules. Tablets are a preferred dosage form. In addition, the tablets can be coated with an optional cosmetic tablet coating. More preferably, the cosmetic coating has "moisture barrier" properties. This moisture barrier property provides protection against ambient humidity for sensitive cores, improves product stability, and improves durability. Preferably, the cosmetic coating is a coating of tablets based on polyvinyl alcohol. More preferably, the cosmetic coating comprises polyvinyl alcohol, talc and polyethylene glycol (PEG). More preferably, the cosmetic coating also comprises an opacifier and / or a colorant, for example titanium dioxide and / or iron oxide.

The commercially available series of powder blends for the coating suspension sold as the Opadry®II 85F series (a coating with moisture barrier properties), available from Colorcon, which are based on polyvinyl alcohol, are examples of such a cosmetic coating. .

In addition to polyvinyl alcohol, this series of Opadry products comprises talc, PeG 3350, Titanium dioxide and pigments. Preferably, the tablets of the present invention comprise a cosmetic coating of 2% to 6% of the weight of the tablet, more preferably 2.5% to 4.5% of the weight of the tablet, more preferably from 3% to 3.5%. % of the weight of the tablet.

In another embodiment the present invention provides a method for preparing a pharmaceutical composition comprising a moisture sensitive active pharmaceutical ingredient and a second active pharmaceutical ingredient comprising the following steps of: a) providing an active pharmaceutical ingredient sensitive to moisture; b) mixing the moisture sensitive active pharmaceutical ingredient with at least one pharmaceutically acceptable excipient, and forming a mixture; and c) wet granulating the mixture with a solution of a binder excipient dissolved in one or more processing solvents and forming a wet granulate; d) providing a material comprising a second active pharmaceutical ingredient and optionally one or more pharmaceutical excipients; Y e) adding the material of step d) to the wet granulate of step c) and forming a combined granulate; wherein when the material of step d) comprises a second pharmaceutical ingredient and one or more pharmaceutical excipients the material is optionally a mixture obtained by mixing the second pharmaceutical ingredient with one or more pharmaceutical excipients.

Preferably, the active pharmaceutical ingredient sensitive to moisture is Cilazapril and the second active pharmaceutical ingredient is hydrochlorothiazide (HCTZ). In a preferred embodiment, the pharmaceutical excipient (s) employed in step b) does not include a binder.

Preferably, the amount of the moisture sensitive active pharmaceutical ingredient of the composition is from 0.1% to 25%, more preferably from 0.5% to 15% of the total weight of the composition. A more preferred amount of the moisture sensitive active pharmaceutical ingredient of the composition is from 0.6% to 2.7% of the total weight of the composition. Preferably, the active pharmaceutical ingredient sensitive to moisture is Cilazapril.

Preferably, the amount of the second active ingredient of the composition is from 1% to 25%, more preferably from 3% to 15% of the total weight of the composition. A more preferred amount of the second active pharmaceutical ingredient of the composition is from 5% to 10% of the total weight of the composition. Preferably, when the moisture sensitive pharmaceutical ingredient is an AGE inhibitor, the second active pharmaceutical ingredient is hydrochlorothiazide (HCTZ).

In preparing a pharmaceutical composition of the present invention, a typical granulation process comprises mixing the moisture sensitive active ingredient and possibly excipients in a mixer. The binder is dissolved in the processing solvent used for the granulation although another portion of the binder or other binder may be one of the excipients added in the initial dry mix state with the moisture sensitive drug substance. The granulation / processing solvent, solution or suspension is added to the dry powders of the mixer and mixed to form a wet granulate. The second drug substance is added to the wet granulate alone or with one or more excipients, optionally in a processing solvent, and mixed until the desired characteristics are achieved.

This usually produces a granule having suitable characteristics to produce tablets with sufficient hardness, dissolution, uniformity of content, and other physical characteristics. After the wet granulation step, the product is most often dried and then ground after drying, to obtain a major percentage of the product within the desired size range. Preferably, the product after the wet granulation is dried until the loss on drying (LOD) is no more than 2.5%, more preferably no more than 1.5%. Preferably, the product is milled or sized through a 1 mm perforated screen, more preferably through a 0.8 mm perforated screen.

Preferably, the stable pharmaceutical composition of the present invention is prepared by wet granulation with a suitable solvent / processing solvent. A suitable solvent / processing solvent can dissolve the selected binder. Preferably, the solvent / processing solvent is capable of dissolving the binder to reach a concentration of at least 10% w / w. More preferably, the solvent / processing solvent is selected from the group consisting of ethanol, isopropyl alcohol, water and combinations thereof. Preferably, the stable formulation prepared by wet granulation comprises 4%, preferably 4% to 20%, more preferably from 5% to 10%, of a binder by weight of the formulation. Suitable binders for use in the method of the present invention include cellulose derivatives, polyvinyl pyrrolidone (PVP) and its derivatives, polyvinyl acetate (PVA), or polyvinyl alcohols. Preferably, the binder comprises at least Copovidone, and more preferably, the binder is applied as a solution in ethanol or water, a preferred solution of the binder in ethanol or water comprises 25% to 55% (w / w) of binder, preferably Copovidone, more preferably 30% to 50% (w / w) of binder, preferably Copovidone.

However, U.S. patent application 11 / 446,336, filed June 2, 2006, incorporated herein by reference, also discloses the preparation of a stable pharmaceutical composition comprising a pharmaceutical active ingredient sensitive to moisture using the wet granulation. Herein described is a process for preparing a wet granulate comprising a moisture sensitive pharmaceutical ingredient and a binder.

The method of the present invention may also comprise steps in the preparation of a tablet or capsule of the pharmaceutical composition of the present invention. In preparing said tablet the method also comprises the steps of: f) mixing the combined granulate of step e) with one or more excipients and forming a final mixture; g) pressing the final mixture into a tablet; and h) optionally coating the tablet with a cosmetic coating. Preferably, the cosmetic coating has barrier properties against moisture. Examples of such cosmetic coatings are tablet coatings based on polyvinyl alcohol. The optional cosmetic coating of the tablet preferably comprises preparing a suspension comprising from 10% to 25%, preferably from 12% to 15%, more preferably from 12% to 13% of a powder mixture for the cosmetic coating, and applying the suspension on the tablet. The cosmetic coating suspension is preferably prepared in such a way that the tablet comprises from 2% to 6%, preferably from 2.5% to 4.5%, of a cosmetic coating. The cosmetic coating of the tablets of the present invention has "moisture barrier" properties. The commercially available series of powder mixes for the coating suspension sold as the Opadry® series! 85F, available in Colorcon, which is based on polyvinyl alcohol, are examples of such a cosmetic coating with barrier properties against moisture.

Capsules comprising a hard or soft capsule and containing the composition of the present invention can be prepared. The capsule can be made of gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or a colorant. A capsule filler of the present invention may comprise the granulates that were described with reference to the manufacture of tablets, a final mixture of a granulation composition of the present invention mixed with one or more excipients, although not subjected to the final step of making tablets. In addition, said capsules can be prepared by any of the methods known in the pharmaceutical art.

In addition, in one embodiment, the present invention provides a method for preparing a stable pharmaceutical composition comprising: a) mixing cilazapril, lactose, talc and starch; b) adding a solution of a binder, preferably copovidone, to the mixture obtained in step a) to form a wet granulate; c) optionally combine the wet granulate with additional starch and mix; d) add HCTZ to the wet granulate and mix; e) drying and then grinding the granulate; and f) adding sodium stearyl fumarate to the granulate obtained in step e) and mixing to obtain a final mixture.

The compositions of the present invention are useful in therapy. In particular, the compositions of the invention are useful in the treatment of hypertension.

The present invention also provides a method for treating a patient suffering from a disease, preferably hypertension, comprising administering to a patient in need thereof a therapeutically effective amount of a stable pharmaceutical composition comprising an active pharmaceutical ingredient sensitive to moisture, preferably Cilazapril, a second active pharmaceutical ingredient, preferably Hydrochlorothiazide, and at least one pharmaceutical excipient, wherein the active pharmaceutical ingredients are granulated wet with a solution of at least one pharmaceutical excipient.

The following examples are presented to further illustrate the invention. It should not be construed in any way that these examples limit the invention.

EXAMPLES Example 1. Wet granulation, Hypromellose (HPMC) as a binder, one-step granulation In a high shear mixer, 7.8 g of Cilazapril Monohydrate, 178.8 g of Lactose Monohydrate, 4.5 g of Extra Fine Talc, 18.8 g of Hydrochlorothiazide and 75.0 g of Starch were mixed for 1 minute. 60 g of 20% (w / w) of aqueous Hypromellose solution was added and the dough was mixed in the high cut mixer for 4 minutes. 6 g of water were added and the mixture was mixed for 1 minute in the high cut mixer. The obtained granulate was dried using a fluid bed dryer and the dried granulate was milled in an oscillating granulator through a 0.8 mm screen. The milled granulate was combined with 2.7 g of Sodium Stearyl Fumarate sieved and mixed in a Y-cone mixer for 5 minutes.

The tablets were pressed from the final mixture in a rotary tablet press. The tablets were packed in a cold formed aluminum blister with aluminum foil.

The packed tablets were shaken at 55 ° C. The main degradation product, Cilazaprilat, was tested using the HPLC method.

Example 2: Wet granulation, Copovidone as a binder, one step granulation In a high-cut mixer, 5.2 g of Cilazapril Monohydrate, 115.3 g of Lactose Monohydrate, 3.0 g of Extra Fine Talc, 12.5 g of Hydrochlorothiazide and 50.0 g of Starch were mixed for 1 minute. 33 g of 36.4% (w / w) of Copovidone aqueous solution were added and the dough was mixed in the high cut mixer for 3 minutes. The obtained granulate was dried using a fluid bed dryer and the dried granulate was milled in an oscillating granulator through a 0.8 mm screen. The milled granulate was combined with 1.6 g of Sodium Stearyl Fumarate sieved and mixed in a Y-cone mixer for 5 minutes.

The tablets were pressed from the final mixture in a rotary tablet press. The tablets were packed in a cold formed aluminum blister covered with an aluminum foil.

The packed tablets were stored at 55 ° C. The main degradation product, Cilazaprilat, was tested using the HPLC method.

Example 3: Wet Granulation, Hypromellose (HPMC) as a binder, two-step granulation In a high-cut mixer, 10.4 g of Cilazapril Monohydrate, 238.4 g Lactose Monohydrate, 6.0 g of Extra Fine Talc, and 100.0 g of Starch were mixed for 1 minute. 80 g of 20% (w / w) of aqueous Hypromellose solution were added and the dough was mixed with a high-cut mixer for 3 minutes. 8.2 g of water were added and the mixture was mixed for 1 minute in a high cut mixer. 25.0 g of Hydrochlorothiazide was added to the wet mixture and the mass was mixed for 2 minutes in the high cut mixer. The obtained granulate was dried using a fluid bed dryer and the dried granulate was milled in an oscillating granulator through a 0.8 mm screen. The milled granulate was combined with 3.8 g of Sodium Stearyl Fumarate sieved and mixed in a Y-cone mixer for 5 minutes.

The tablets were pressed from the final mixture in a rotary tablet press. The tablets were packed in a cold formed aluminum blister covered with an aluminum foil. The packed tablets were stored at 55 ° C. The main degradation product, Cilazaprilat, was tested using an HPLC method.

Example 4: Wet granulation, Copovidone as a binder, two-step granulation In a high shear mixer, 10.4 g of Cilazapril Monohydrate, 234.4 g Lactose Monohydrate, 6.0 g of Extra Fine Talc, and 100.0 g of Starch were mixed for 1 minute. 66 g of 36.4% (w / w) of aqueous Copovidone solution were added and the mass was mixed with a high-cut mixer for 10 minutes. 25.0 g of Hydrochlorothiazide was added to the wet mixture and the mass was mixed for 2 minutes in the high cut mixer. The obtained granulate was dried using a fluid bed dryer and the dried granulate was milled in an oscillating granulator through a 0.8 mm screen. The milled granules were combined with 3.9 g of sieved Sodium Stearyl Fumarate and mixed in a Y-cone mixer for 5 minutes.

The packed tablets were stored at 55 ° C. The main degradation product, Cilazaprilat, was tested using an HPLC method.

Example 5. Wet granulation, Copovidone as a binder, two step granulation, starch and part of the granulation solution added in the second granulation step In a high shear mixer, 5.2 g of Cilazapril Monohydrate, 115.3 g Lactose onhydrate and 3.0 g of Extra Fine Talc were mixed for 1 minute. 27.5 g of 36.4% (w / w) of aqueous Copovidone solution were added and the mass was mixed with a high-cut mixer for 1.7 minutes. 50.0 g of starch was added to the wet mixture and the dough was mixed for 2 minutes in a high cut mixer. 12.5 g of Hydrochlorothiazide were added to the wet mixture and the mass was mixed for 20 minutes in the high cut mixer. 5.5 g of 36.4% (w / w) of aqueous Copovidone solution were added and the mass was mixed in the high-cut mixer for 2 minutes.

The obtained granulate was dried using a fluid bed dryer and the dried granulate was milled in an oscillating granulator through a 0.8 mm screen. The milled granulate was combined with 1.7 g of sieved Sodium Stearyl Fumarate and mixed in a Y-cone mixer for 5 minutes.

Table 1. Examples and comparative examples of pharmaceutical compositions comprising Cilazapril, an active pharmaceutical ingredient sensitive to moisture and Hydrochlorothiazide Example Ex. 1 and 3 Ex. 2 Ex. 4 Ex. 5 Binder HP C Copovidone Copovidone Copovidona Ingredient Content,% of the final weight of the tablet Cilazapril 2.61 2, 58 2, 61 2, 61 monohydrate Hydrochlorothiazide 6.25 6, 19 6.25 6, 25 Lactose 59.59 58, 01 57, 64 57, 64 Monohydrate Extra-fine talcum 1.50 1.49 1, 50 1.50 Starch 25.00 24, 75 25, 00 25, 00 Hypromellose 4, 00 Copovidone 5.94 6.00 6, 00 Fumarate of 1, 05 1, 04 1,00 1,00 sodium stearyl Water (only 22,2 / 18,2 10,5 10, 5 10, 5 process solvent) Example 6. Stability test of pharmaceutical compositions of Cilazapril and HCTZ Comparative stability tests were performed comparing the stability of pharmaceutical compositions of Cilazapril and HCTZ prepared in a wet granulation process of a mixture of Cilazapril and HCTZ (a "one-step wet granulation process") with those pharmaceutical compositions prepared in a first wet granulation process of cilazapril which forms a wet granulate to which HCTZ is added (a "two step wet granulation process"). Table 3 shows the storage results of said compositions (Examples 1-5) under 55 ° C stress conditions for 4 weeks. The results of the table indicate that the two step wet granulation process of Cilazapril and HCTZ pharmaceutical compositions of the present invention provides a stable pharmaceutical composition compared to the one step wet granulation process.

Table 3. Degradation under conditions of "effort" (55 ° C, storage period of 4 weeks), of Cilazapril and HCTZ presented according to different formulations and manufacturing methods Description Granulation Granulation Granulation Granulation Granulation of one step. one step Two of two of two HPMC like Copovidona steps, HPMC steps. steps, binder (eg as a binder as a Copovidone Copovidone 1 binder) (eg 2) (eg 3) as a binder as a binder (eg 4) (eg 5) Product 0.3 0.2 0.1 0.1 0.1 principal degradation. Cilazaprilat, "Zero" Time,% of per marked claim of Cilazapril Product 8.8 8.3, 2.4 2.4 1.3 1.4 principal degradation. Cilazaprilat, storage period of 4 weeks. % by marked claim of Cilazapril

Claims

1. A stable pharmaceutical composition comprising: a) an active pharmaceutical ingredient sensitive to moisture, and b) a second active pharmaceutical ingredient, wherein the active pharmaceutical ingredient sensitive to moisture is first wet granulated with a solution of at least one pharmaceutical excipient in at least one processing solvent before granulation with the second active pharmaceutical ingredient.

2. The stable pharmaceutical composition according to claim 1, wherein the amount of the active pharmaceutical ingredient sensitive to moisture is from 0.1% to 25% of the total weight of the composition.

3. The stable pharmaceutical composition according to claim 2, wherein the amount of the active pharmaceutical ingredient sensitive to moisture is from 0.5% to 15% of the total weight of the composition.

4. The stable pharmaceutical composition according to claim 3, wherein the amount of the active pharmaceutical ingredient is from 0.6% to 2.7% of the total weight of the composition.

5. The stable pharmaceutical composition according to claim 1, wherein the active pharmaceutical ingredient sensitive to moisture is Cilazapril.

6. The stable pharmaceutical composition according to claim 1, wherein the amount of the second active pharmaceutical ingredient is from 1% to 25% of the total weight of the composition.

7. The stable pharmaceutical composition according to claim 6, wherein the amount of the second active pharmaceutical ingredient is from 5% to 10% of the total weight of the composition.

8. The stable pharmaceutical composition according to claim 1, wherein the second active ingredient is Hydrochlorothiazide.

9. The stable pharmaceutical composition according to claim 1, wherein at least one pharmaceutical excipient is a binder.

10. The stable pharmaceutical composition according to claim 9, wherein the binder is selected from the group consisting of cellulose derivatives, polyvinyl pyrrolidone and its derivatives, polyvinyl acetates and polyvinyl alcohols.

11. The stable pharmaceutical composition according to claim 10, wherein the binder is selected from the group consisting of Copovidone and Hypromellose.

12. The stable pharmaceutical composition according to claim 9, wherein the amount of the binder is at least 4% of the total weight of the composition.

13. The stable pharmaceutical composition according to claim 12, wherein the amount of the binder is from 4% to 20% of the total weight of the composition.

14. The stable pharmaceutical composition according to claim 13, wherein the amount of the binder is from 5% to 10% of the total weight of the composition.

15. The stable pharmaceutical composition according to claim 1, wherein the active pharmaceutical ingredient sensitive to moisture has a major degradation product and wherein the composition comprises this major product of the degradation in an amount not greater than 3% by weight of the total initial weight of the active pharmaceutical ingredient sensitive to the moisture of the pharmaceutical composition after storage.

16. The stable pharmaceutical composition according to claim 15, wherein in the amount of the main product of the degradation of the active pharmaceutical ingredient sensitive to moisture in the pharmaceutical composition is not more than 2% by weight of the total initial weight of the active pharmaceutical ingredient sensitive to moisture.

17. The stable pharmaceutical composition according to claim 16, wherein in the amount of the main product of the degradation of the active pharmaceutical ingredient sensitive to moisture in the pharmaceutical composition is not more than 1% by weight of the total initial weight of the active pharmaceutical ingredient sensitive to moisture.

18. The stable pharmaceutical composition according to claim 15, wherein the storage is in a package with moisture barrier properties, which are at least as efficient as aluminum and aluminum cold forming blisters.

19. The stable pharmaceutical composition according to claim 18, wherein the storage is at 55 ° C for four hours.

20. The stable pharmaceutical composition according to claim 1, wherein the composition is in a solid dosage form.

21. The stable pharmaceutical composition according to claim 20, wherein the dosage form selects from the group consisting of a tablet and a capsule.

22. The stable pharmaceutical composition according to claim 21, wherein the dosage form is a tablet.

23. The stable pharmaceutical composition according to claim 22, wherein the tablet comprises a cosmetic tablet coating.

24. The stable pharmaceutical composition according to claim 23, wherein the cosmetic tablet coating has bar properties against moisture.

25. The stable pharmaceutical composition according to claim 24, wherein the cosmetic tablet coating having moisture barrier properties is selected from the group consisting of tablet coatings of the Opadry® 85F series.

26. The stable pharmaceutical composition according to claim 23, wherein the coating for cosmetic tablets is in an amount of 2% to 6% of the weight of the tablet.

27. The stable pharmaceutical composition according to claim 26, wherein the amount of the cosmetic tablet coating is from 3% to 3.5% of the weight of the tablet.

28. A method for preparing a pharmaceutical composition comprising an active pharmaceutical ingredient sensitive to moisture and a second active pharmaceutical ingredient comprising the following steps of: a) providing an active pharmaceutical ingredient sensitive to moisture; b) mixing the moisture sensitive active pharmaceutical ingredient with at least one pharmaceutically acceptable excipient, forming a mixture, and c) wet granulating the mixture with a solution of a binder excipient dissolved in one or more processing solvents and forming a wet granulate; d) providing a material comprising a second active pharmaceutical ingredient and optionally one or more pharmaceutical excipients; and e) adding the material of step d) to the wet granulate of step c) and forming a combined granulate, wherein when the material of step d) comprises a second pharmaceutical ingredient and one or more pharmaceutical excipients the material is optionally a mixture obtained by mixing the second pharmaceutical ingredient with one or more pharmaceutical excipients.

29. The method according to claim 28, wherein the amount of the active pharmaceutical ingredient sensitive to moisture is from 0.1% to 25% and the amount of the second active pharmaceutical ingredient is from 1% to 25% of the total weight of the composition.

30. The method according to claim 29, wherein the amount of the active pharmaceutical ingredient sensitive to moisture is from 0.6% to 2.7% and the amount of the second active pharmaceutical ingredient is from 5% to 10% of the total weight of the composition.

31. The method according to claim 28, wherein the active pharmaceutical ingredient sensitive to moisture is Cilazapril and the second pharmaceutical ingredient is Hydrochlorothiazide.

32. The method according to claim 28, wherein the binder is selected from the group consisting of cellulose derivatives, polyvinyl pyrrolidone and its derivatives, polyvinyl acetate and polyvinyl alcohols.

33. The method according to claim 32, wherein the binder is selected from the group consisting of Copovidone and Hypromellose.

34. The method according to claim 28, wherein the amount of the binder is at least 4% of the total weight of the composition.

35. The method according to claim 34, wherein the amount of the binder is from 5% to 10% of the total weight of the composition.

36. The method according to claim 28, wherein the processing solvent is selected from the group consisting of ethanol, isopropanol, water and combinations thereof.

37. The method according to claim 28, wherein the binder is applied as a solution in water or ethanol.

38. The method according to claim 37, wherein the binder solution in water or ethanol comprises from 25% to 55% (w / w) of the binder. to 50

39. The method according to claim 38, wherein the binder solution in water or ethanol comprises 30% to 50% (w / w) of the binder.

40. The method according to claim 28, wherein the method also comprises the steps of: f) mixing the combined granulate with one or more excipients and forming a final mixture; g) pressing the final mixture into a tablet; and 10) optionally coating the tablet with a cosmetic coating.

41. The method according to claim 40, wherein the step of coating the tablet comprises preparing a suspension that 15 comprises from 10% to 15% of a powder mixture for the cosmetic coating, and apply the suspension on the tablet.

42. The method according to claim 41, wherein the suspension comprises from 12% to 13% of a powder mixture for the cosmetic coating.

43. The method according to claim 41, wherein the cosmetic coating has moisture barrier properties and the powder mixture for the cosmetic coating is selected from the powder mixture of the Opadry® 85F series.

44. The method according to claim 28 in the preparation of a pharmaceutical composition, wherein the method also comprises mixing the granulate with one or more excipients and forming a final mixture and filling a capsule with the final mixture.

45. A method for treating a patient suffering from a disease comprising administering to a patient in need thereof a therapeutically effective amount of a stable pharmaceutical composition comprising an active pharmaceutical ingredient sensitive to moisture, a second active pharmaceutical ingredient and at least one pharmaceutical excipient, wherein the active pharmaceutical ingredients are granulated wet with a solution of at least one pharmaceutical excipient, and wherein the moisture sensitive active pharmaceutical ingredient is first wet granulated with a solution of at least one pharmaceutical excipient in a processing solvent that does not contain the second active pharmaceutical ingredient before granulation with the second active pharmaceutical ingredient.

46. The method according to claim 45, wherein the disease is hypertension.

47. The method according to claim 45, wherein the active pharmaceutical ingredient sensitive to moisture is Cilazapril, the second active pharmaceutical ingredient is Hydrochlorothiazide, and at least one pharmaceutical excipient is a binder.

48. The method according to claim 1, wherein the ligand is selected from the group consisting of Copovidone and Hypromellose.