MX2008015343A - Stable formulation comprising moisture sensitive drug/s and manufacturing procedure thereof. - Google Patents

Abstract

The present invention provides stable pharmaceutical compositions comprising moisture sensitive drugs, in particular an angiotensin converting enzyme (ACE) inhibitor such as Cilazapril, as the active ingredient, and at least one pharmaceutical excipient, wherein the 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 DRUGS SENSITIVE TO HUMIDITY AND MANUFACTURING PROCEDURE OF THE FIELD Field of the Invention The present invention relates to pharmaceutical compositions comprising moisture sensitive drugs, specifically an angiotensin converting enzyme (ACE) inhibitor, such as Cilazapril, as the active ingredient and methods for preparing said pharmaceutical compositions.

Background of the Invention Cilazapril is evidently an inhibitor of 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) -l-ethoxycarbonyl-3-phenylpropylamino] -10-oxoperhydropyridazino [1, 2-a] [1, 2] diazepine-1-carboxylic acid and it is understood that it is disclosed in U.S. Patent No. 4,512,924. Cilazapril has been prescribed in the treatment of patients suffering from hypertension.

One of the requirements for an acceptable pharmaceutical composition is that it must be stable. A stable pharmaceutical composition does not exhibit substantial decomposition of the active pharmaceutical 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 then be characterized as moisture sensitive drugs.

It is known that the tablet mixtures can be wet dry, granular dry or granular before the tablets are made. The choice of processing method, dry mix, dry granulation, wet granulation, or some other granulation process, depends on the properties of the drug and the chosen excipients. In general, it is thought that a dry manufacturing process is preferable for moisture sensitive drugs.

To improve the stability of moisture-sensitive drugs, water scavenging compounds can be incorporated into the matrix of the tablets. One of such water purifying compounds is the Copovidone binder (Plasdone S-6300"), which is specifically recommended for moisture-sensitive drugs, however attempts were made with very little success 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 been considered appropriate for moisture sensitive drugs since the very nature of these processes may include the presence of water / moisture.

Surprisingly, we discovered that the best stability results can be obtained 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.

Extract of the invention The invention provides Cilazapril compositions and methods for their preparation.

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

In another embodiment, the present invention provides a method for preparing a granular composition comprising an active pharmaceutical ingredient sensitive to wet granular moisture comprising the following steps: 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 thus form a granulate.

The present invention also provides 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, preferably Cilazapril, and at least one pharmaceutical excipient, wherein the active pharmaceutical ingredient is wet granulated with a solution of at least one pharmaceutical excipient.

Brief Description of the Figures Figure 1. Shows a comparison of the degradation at 55 ° C during the stability test of different Cilazapril tablets packaged in a blister in cold aluminum form, according to the invention, with a dry granulated tablet and a commercially available tablet . The increase in Cilazapril, the main product of the degradation of Cilazapril, was determined.

Figure 2. Shows the stability behavior of Cilazapril tablets when comparing aqueous and ethanol-based granulation processes.

Figure 3. Shows the stability behavior of Cilazapril tablets when comparing a tablet coating based on Polyvinyl Alcohol (Opadry II (85 Series) and a tablet coating based on Hydroxypropyl Meticellulose.

Detailed description of the invention As used herein, the term "moisture sensitive active pharmaceutical ingredients" refers to an active pharmaceutical ingredient that degrades in the presence of water / moisture.

In one aspect, the present invention provides a stable pharmaceutical composition comprising a moisture sensitive active pharmaceutical ingredient, for example Cilazapril, and at least one pharmaceutically acceptable excipient, wherein at least one pharmaceutically acceptable excipient is a binder. Preferably, the pharmaceutical composition comprises at least two pharmaceutically acceptable excipients.

In one embodiment of the present invention there is provided a stable pharmaceutical composition comprising: a) an active pharmaceutical ingredient sensitive to moisture; and b) at least one pharmaceutical excipient, wherein the active pharmaceutical ingredient is wet granulated with a solution of at least one pharmaceutical excipient. Preferably, the active pharmaceutical ingredient sensitive to moisture is Cilazapril and at least one pharmaceutical excipient is a binder.

Preferably, the amount of the moisture sensitive active pharmaceutical ingredient of the composition is 0.1% 1%, more preferably from 0.5% to 15%, of the total weight of the composition. A more preferred amount of the active pharmaceutical ingredient of the composition is from 0.6% to 2.7% of the total weight of the composition.

In another aspect, the present invention provides a stable pharmaceutical composition comprising a pharmaceutical active ingredient sensitive to moisture and at least one pharmaceutically acceptable excipient, wherein the formulation contains no more than 3% (w / w of the initial amount of the active ingredient) of a degradation product after storage in a package with moisture-sensitive barrier properties that are at least as efficient as cold blisters of aluminum and aluminum. Preferably, the concentration of the degradation product of the stable composition of the present invention after storage as described above is no more than 2%. More preferably, the concentration of the degradation product of the stable pharmaceutical composition of the present invention after storage as 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 degradation product is its main degradation product Cilazapril.

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

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. He The binder comprises, for example, one or more of a derivative of cellulose, a polyvinyl pyrrolidone (PVP) and its derivatives, a polyvinyl acetate (PVA) or a polyvinyl alcohol. Examples 5 of cellulose derivatives suitable as a binder of the present ! invention are Hydroxypropylmethyl cellulose (HPMC) or Hydroxypropyl cellulose (HPC). More preferably, the binder is Copovidone, for example Plasdone S-630 (Copovidone), which is a copolymer Synthetic, linear, 60:40, of N-vinyl -2-pyrrolidone and acetate vinyl and having reduced hydrophobicity and a reduced polymer glass transition temperature (Tg) compared to a polyvinyl pyrrolidone homopolymer (PVP). 1 Stable pharmaceutical compositions comprising a 15 active pharmaceutical ingredient sensitive to moisture of the The present invention can also contain excipients such as i-filled tablets and capsules and diluents (such as cellulose i \ microcrystalline, lactose, starch and tribasic calcium phosphate), ! disintegrators (such as starch, croscarmellose sodium, 20 crospovidone and sodium starch glycolate), and glidants j (such as colloidal silicon dioxide and talc), lubricants ! (such as magnesium stearate, sodium lauryl sulfate, acid Stearic and sodium stearyl fumarate).

More specifically, stable diluents and fillers for use in the pharmaceutical composition of the present invention include microcrystalline cellulose (eg Avicel18), lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, calcium phosphate dibasic dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, powdered cellulose, sodium chloride, sorbitol or talc.

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 to the composition. Disintegrants include croscarmellose sodium (eg, Ac Di Sol81, Primellose *), crospovidone (eg, Kollidon8, Polyplasdone *), microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate (eg example, Explotab0, Primoljel *) and starch.

Slides can be added to improve the flowability of a solid composition before compaction and to improve dosing accuracy especially during compaction and filling of the capsule. Excipients that can function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose and talc.

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

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 further comprises Cilazapril, copovidone, lactose monohydrate, sodium starch glycolate, talc sodium fumarate superfine stearyl fumarate.

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 be conveniently presented in a unit dosage form and can be prepared by any of the methods known in the pharmaceutical arts.

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, the non-compacted granulates and powder mixtures that are obtained by the method of the present invention in the precompression steps can be simply provided in a dosage form of a capsule or sachet. Accordingly, the dosage forms of the pharmaceutical compositions of the present invention include solid dosage forms such as tablets, powders, capsules, sachetx, etc. The dosage form of the present invention can also be a capsule containing the composition, preferably a powder or granulated solid composition of the invention, within a hard or soft capsule.

The capsule may be made from gelatin and optionally may contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or dye.

Once a moisture sensitive active pharmaceutical ingredient, specifically Cilazapril, is prepared a solid composition according to the present invention, it is preferably formulated into pharmaceutical formulations such as conventional 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, this cosmetic coating has "moisture barrier" properties. This barrier property for moisture provides protection against environmental humidity for sensitive cores, increases product stability, and improves shelf life. Preferably, the cosmetic coating is a tablet coating 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.

As shown in Figure 3, a comparison is made between the stability of a tablet coated with Opadry®II 85F (a coating with moisture barrier properties) and a tablet coated with a coating based on HP C. series 5 Commercially available powder mixtures to coat the suspension sold as the O series adry81 !! 85F, available from Colorcon, which is based on polyvinyl alcohol, are examples of said cosmetic coating. In addition to polyvinyl alcohol, this series of Opadry products comprises Talc, PEG O 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 granular composition comprising an active pharmaceutical ingredient sensitive to granulated moisture. : moist, preferably Cilazapril, comprising the following steps: a) providing a pharmaceutical active ingredient sensitive to moisture; b) mix the active pharmaceutical ingredient sensitive to the ; moisture with at least one pharmaceutically acceptable excipient, preferably different from a binder and forming a mixture; and c) wet granulating the mixture with a solution of a binder in a processing solvent and forming a granulate.

In preparing a pharmaceutical composition of the present invention a typical granulation process comprises mixing the active ingredient and possibly excipients in a mixer. The binder is dissolved in the solvent used for the granulation although another part of the binder or other binder may be one of the excipients added in the dry mixing state. The granulation solvent, solution or suspension is added to the dry powders in the mixer and mixed until the desired characteristics are obtained. This usually produces a granule that will have suitable characteristics to produce tablets with sufficient hardness, dissolution, uniformity of content and other physical characteristics. After the wet granulation step, the product dries more frequently and then mulled after drying to obtain a major percentage of the product within a desired range of sizes. Preferably, the product after the wet granulation is dried until the loss on drying (LOD) is no more than 1.5%, more preferably not more than 1.1%. Preferably, the product is milled or sized through a 1 mm screen, more preferably through a 0.8 mm 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 p consisting of ethanol, isopropyl alcohol, water and combinations thereof. Preferably, the stable formulation prepared by wet granulation comprises at least 4%, preferably 4% to 20%, more preferably 5% to 10%, of a binder by weight of the formulation. 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.

Surprisingly, it was determined that the choice of the processing solvent used in the wet granulation impacts the stability of the final product in a different way depending on the dose / amount of Cilazapril in the final product. Therefore, for compositions comprising 1 mg of Cilazapril it was determined that a granulation processing solvent comprising predominantly ethanol, such as ethanol (95%), produces more stable pharmaceutical compositions than the same process wherein the processing solvent predominantly comprises water.

In contrast, with respect to the pharmaceutical compositions comprising 5 mg of Cilazapril, it was determined that a granulation processing solvent comprising predominantly water (aqueous granulation) produces a more stable pharmaceutical composition than the same process wherein the predominantly processing solvent comprises ethanol (95%).

The effect can be characterized in relation to the concentration of the active pharmaceutical ingredient sensitive to moisture in the dried granulate. Accordingly, dried granulates comprising 0.6% of the active pharmaceutical ingredient are preferably prepared by wet granulation with an alcohol granulation processing solvent, while dry granules comprising 2.7% of the active pharmaceutical ingredient preferably they are prepared by wet granulation with an aqueous granulation processing solvent. Granules with intermediate concentrations of the active pharmaceutical ingredient have an intermediate effect.

Accordingly, the final pharmaceutical compositions of the present invention comprising no more than 1.7% of the moisture sensitive active ingredient in the dried granulate are preferably prepared by wet granulation with an alcohol granulation process solvent. Preferably, wet granulation with an alcohol processing solvent is used for such compositions comprising no more than 0.6% of the moisture sensitive active ingredient in the dried granulate. Pharmaceutical compositions comprising more than 1.7% of the moisture sensitive active ingredient in the dried granulate are preferably prepared by wet granulation with water (an aqueous granulation) as the granulation processing solvent. Preferably, wet granulation with an aqueous processing solvent is used for such compositions comprising not less than 2.7% of the moisture sensitive active ingredient in the dried granulate. Cilazapril is the preferred moisture sensitive active pharmaceutical ingredient.

The method of the present invention may also comprise steps in the preparation of a tablet of the pharmaceutical composition of the present invention. In preparing said tablets the method also comprises the steps of: d) mixing the granulate with one or more excipients and forming a final mixture; e) pressing the final mixture into a tablet; and f) optionally coating the tablet with a cosmetic coating. Preferably, the cosmetic coating has barrier properties for moisture. Examples of said 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 tablet in the present invention preferably has "moisture barrier" properties. The commercially available series of powder mixes to coat the suspenson sold as the series O adry0] !! 85F, available in Colorcon, which are based on polyvinyl alcohol, are examples of such a cosmetic coating.

Capsules comprising a hard or soft capsule and containing the composition of the present invention can be prepared. The capsule may be made from gelatin and optionally may contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or dye. A capsule filler of the present invention can 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 they can be subjected to a step of final tablet manufacturing. In addition, said capsules can be prepared by any of the methods known in the pharmaceutical arts.

In addition, in a preferred embodiment, the present invention provides a method for preparing a stable pharmaceutical composition comprising: a) mixing cilazapril, lactose, talc, and sodium starch glycolate; b) adding a solution of copovidone to the mixture obtained from step a) to form a granulate; c) drying and then grinding the granulate; d) combining the milled granulate with another sodium starch glycolate and mixing; and e) adding sodium stearyl glycolate to the mixture obtained from step iv) and mixing to obtain a final mixture.

In a more preferred embodiment, the pharmaceutical composition is a 1 mg tablet and step b) is carried out using a granulation solution comprising ethanol. In an alternative preferred embodiment, the pharmaceutical composition is a 5 mg tablet and step b) is carried out using an aqueous granulation solution.

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

The following examples are presented to further illustrate the invention. In no way should be interpreted that these examples limit the invention.

EXAMPLES Example 1 Tablets of 1 mg, dry granulation, * 5% (w / w) of binder (Comparative Example) (*% of the binder calculated for each tablet core) Into a polyethylene bag were mixed 8.4 g of Cilazapril Monohydrate, 1360 g of Lactose Monohydrate, 64 g of Extra Fine Talc and 80 g of Copovidone. The mixture was sieved through a 0.71 mm sieve, transferred to a dry mixer of two capsules (Y-cone) and mixed for 25 minutes. To this mixture, 16 g of sieved sodium stearyl fumarate were added and all the materials were mixed in a Y-cone mixer for 5 minutes.

The mixture was pressed into pieces on a rotary tablet press and the pieces were ground to a granulate in an oscillating granulator through a 0.8 mm screen.

The obtained granulate was combined with 64 g of sifted Sodium Starch Glicolate (type A) and mixed in a Y-cone mixer for 10 minutes. To the granulated mixture was added 8 g of Sodium Stearyl Fumarate sieved and all the materials were mixed in a Y-cone mixer for 5 minutes.

The tablets were pressed on a rotary tablet press. Subsequently, a part of the tablet cores were coated with: a) Opadry® II 85F22055 (Yellow), comprising polyvinyl alcohol, talc, PEG 3350, titanium dioxide and iron oxide, as a 13% aqueous suspension using a Glatt film coater, to obtain approximately 2.7% w / w coating. The tablets were then packed in aluminum blisters covered with aluminum foil (cold-formed aluminum blisters). Another part of the tablet cores were coated with: b) Opadry * 02G222555 (Yellow), which comprises Hydroxypropyl Methylcellulose (HPMC), talc, PEG, titanium dioxide and iron oxide, as an 11% aqueous suspension, using a Glatt film coater, to obtain approximately 2.2% w / w coating. The tablets were then packaged in aluminum blisters covered with aluminum foil (aluminum blister Cool way). i ! The packed tablets were stored at 55 ° C or 40 ° C and 75% 5 relative humidity (RH). The presence of the main degradation product, Cilazapril, was determined using the HPLC method. Figure 1 shows the presence of this product of the main degradation of Cilazapril after said storage. Furthermore, Figure 3 comprises the degradation of Cilazapril tablets, depending on the presence of this product of the main degradation after storage, of the tablets coated with a cosmetic coating of Opadry® II 85 F22055 with tablets. what; They have a cosmetic coating of Opadry® 02G222555 (based on 1.5 HPMC). i 1 Example 2 Tablets of 1 mg, wet granulation, 5% (w / w) of binder i I 20 2.1 g of Cilazapril Monohydrate, 333.9 g of Lactose ! onohydrate, 16 g of Extra-fine talcum and 16 g of glycolate I Sodium starch (type A) were mixed for 1 minute in a I high cut mixer. 70 g of a 28.6% (w / w) solution of Copovidone (binder) in Alcohol (95%) were added and mixed in the high cut blender for 2.5 minutes. 10 g of Alcohol (95%) were added and mixed for 1 minute. The granulate obtained was dried using a fluid bed dryer until the Loss on Dry (LOD) of the dried granulate (measured with ettler HR73 at 80 ° C, level 5) was no more than (N T) 1.1%. The granulate was milled or "sized" in an oscillating granulator through a 0.8 mm screen.

The milled granulate was combined with 8 g of Sodium Starch Glycolate type A (disintegrator) and mixed in a Y-cone mixer for 10 minutes. 4 g of sieved Sodium Stearyl Fumarate (lubricant) was added to the mixture and mixed for 5 minutes and a final mixture was obtained.

The tablets were pressed from the final mixture into a rotary tablet press. The tablets were coated with a commercially available tablet coating powder blend Opadry®II 85F22055 (Yellow) as a 12% suspension, using a Glatt film coater, to obtain approximately 3% w / w coating.

The tablets were packed in an aluminum blister with aluminum foil. The packed tablets were stored at 55 ° C.

The presence of the main degradation product, Cilazaprilat, was determined using an HPLC method.

EXAMPLE 3 1 mg tablets, wet granulation, 9% (w / w) of lithium 20.1 g of Cilazapril Monohydrate, 3099.1 g of Lactose Monohydrate, 160 g of Extra-fine Talc and 160 g of Sodium Starch Glicolate (type A) were mixed for 2 minutes in a high-cut blender. 790 g of a 45.5% (w / w) solution of Copovidone in Alcohol (95%) were added and mixed in the high cut mixer for 5 minutes. The granulate obtained was dried using a fluid bed dryer until the Loss on Dry (LOD) of the dried granulate was no more than (NMT) 1.1% tested at 80 ° C. The dried granulate was milled in a hammer mill through a 0.84 mm screen.

The milled granulate was combined with 160 g of Sodium Starch Glicolate (type A) and mixed in a Y-cone mixer for 10 minutes. 40 g of sieved Sodium Stearyl Fumarate (lubricant) was added to the mixture and mixed in a Y cone mixer for 5 minutes and a final mixture was obtained.

The tablets were pressed from the final mixture into a rotary tablet press. The tablets were coated with Opadry®II 85F22055 Yellow as a 13% suspension, using a 0 'HARA film coater, to obtain approximately 3.5% w / w coating.

The tablets were packed in an aluminum blister with aluminum foil. The packed tablets were stored at 55 ° C or at 40 ° C and at 75% RH. The presence of the main degradation product, Cilazaprilat, was determined using an HPLC method.

Example 4 Tablets of 1 mg, wet granulation, 10% (w / w) of binder 2.1 g of Cilazapril Monohydrate, 305.9 g of Lactose Monohydrate, 16 g of Extra-fine Talc and 16 g of Sodium Starch Glycolate (type A) were mixed for 1 minute in a high-cut mixer. 105 g of a 38.1% (w / w) solution of Copovidone (binder) in Alcohol (95%) were added and mixed in the high cut blender for 1 minute. The granulate obtained was dried using a fluid bed dryer until the Loss on Dry (LOD) of the dried granulate was no more than (NMT) 1.1% tested at 80 ° C. The granulate was milled in an oscillating granulator through a 0.8 mm screen.

The milled granulate was combined with 16 g of Sodium Starch Glicolate (type A) and mixed in a Y-cone mixer for 10 minutes. 4 g of sieved Sodium Stearyl Fumarate was added to the mixture and mixed in a Y cone mixer for 5 minutes and a final mixture was obtained.

The tablets were pressed from the final mixture into a rotary tablet press. The tablets were coated with Opadry®II 85F22055 Yellow as a 12% suspension, using a Glatt film coater, to obtain approximately 3% w / w coating.

The tablets were packed in an aluminum blister with aluminum foil. The packed tablets were stored at 55 ° C. The presence of the product of the main degradation, Cilazaprilat, was determined using an HPLC method.

Example 5 Tablets of 5 mg, wet aqueous granulation, 5% (w / w) of binder The following components were mixed for 1 minute in a high-cut mixer: 10.4 g of Cilazapril Monohydrate, 318 g of Lactose Monohydrate, 16 g of Extra-fine Talc and 16 g of Sodium Starch Glicolate (type A). 50 g of a 40% (w / w) solution of Copovidone in Alcohol (95%) were added and mixed in the high cut mixer for 5 minutes. The granulate obtained was dried using a fluid bed dryer until the Loss on Dry (LOD) of the dried granulate was no > 5 more than (N T) 1.1% tested at 80 ° C. The granulate was milled in an oscillating granulator through a 0.8 mm screen.

The milled granulate was combined with 16 g of Sodium Starch Glicolate (type A) and mixed in a Y-10 cone mixer for 10 minutes. To the resulting mixture was added 4 g of Sodium Stearyl Fumarate sieved and mixed in a Y cone mixer for 5 minutes and a final mixture was obtained.

The tablets were pressed on a rotary tablet press. The tablets were packed in an aluminum blister covered i 'with aluminum foil. The packed tablets were stored At 55 ° C or at 40 ° C and at 75% relative humidity. The presence of I product of the main degradation, Cilazaprilat, was determined Ij 0 using an HPLC method. I Example 6 Comparisons of stability of different pharmaceutical compositions Cilazapril The stability of the pharmaceutical compositions according to the present invention was compared with the stability of an example! comparative dry granulation of a Cilazapril tablet and with, a commercialized product. Samples of the marketed product were 1 mg tablets of Vascace0, produced 0 by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Table 1 shows the formulations of these pharmaceutical compositions with the exception of the marketed product that was obtained as a finished product. 5 0 Table 1. Comparison of formulations and manufacturing methods * Comparative Example The stability was measured by determining the presence of the degradation product of Cilazapril, Cilazaprilat in the pharmaceutical composition after storage. An HPLC method was applied to determine the amount of the degradation products of Cilazapril. The mobile phase was a mixture of triethylamine, tetrahydrofuran and acetonitrile buffer. The detector was an ultraviolet radiation spectrophotometer set at 214 nm.

Figure 1 shows the results of the stability test comparing the degradation after storage at 55 ° C for 14 days of different tablets of Cilazapril, prepared according to the invention by the wet granulation process, with the tablets (control) prepared by dry granulation and commercially available tablets. All the tested tablets were packed in aluminum blisters. The commercially available product is also packaged in an aluminum blister. The presence of increasing levels of Cilazaprilat was determined over time. In addition, the results of the assay for the degradation of some of these formulations under conditions of normal stress are shown in Table 2.

Table 2. Degradation under conditions of "effort" normal (40 ° C 75% relative humidity), of Cilazapril presented in function different formulations and formulation methods * Comparative Example (Example 1) ** Example 3 *** Example 5 Example 7 Tablets of 1 mg, wet granulation, 9% (w / w) of binder (% of the binder calculated per tablet core), (Lot No. : K-33603, as shown in table 3) In a high-cut mixer, the following components were mixed for 2 minutes: 20.9 g of Cilazapril Monohydrate, 3099.1 g of Lactose Monohydrate, 160 g of Extra-fine Talc and 160 g of Sodium Starch Glicolate (type A) . 770 g of a 46.8% (w / w) solution of Copovidone in Alcohol (95%) were added and mixed in the high cut blender for 5 minutes. The obtained granulate was dried using a fluid bed dryer. The Dry Loss (LOD) of the dried granulate was no more than (NT) 1.1% tested with Mettler HR73 at 80 ° C, level 5. The dried granulate was milled in a hammer mill through a 0 sieve. 84 mm The milled granulate was combined with 160 g of Sodium Starch Glicolate (type A) and mixed in a Y-cone mixer for 15 minutes. 40 g of sieved Sodium Stearyl Fumarate were added to the mixture and the materials were mixed in a Y cone mixer for 5 minutes and a final mixture was obtained.

The tablets were pressed on a rotary tablet press. The tablets were coated with Opadry * II 85F22055 Yellow as a 13% aqueous suspension, using an O'HARA film coater and a coating of approximately 3.5% w / w was obtained. 5 The tablets were packed in aluminum blisters covered with aluminum foil. The packed tablets were stored at 40 ° C and 75% relative humidity. The presence of the main degradation product, Cilazaprilat, was determined using the HPLC method described above.

Example 8 Tablets of 2.5 mg, wet granulation, * 9% (w / w) of binder 15 * (% of binder calculated per tablet core), (batch No.

K-33604, as shown in table 3).

The following components were mixed for 2 minutes in a high cut I mixer: 52.2 g of Cilazapril Monohydrate, 3068 20 g of Lactose Monohydrate, 160.00 g of Extra-fine Talc and 160.00 g of Sodium Starch Glicolate (type A). 770 g of a 46.8% (w / w) solution of Copovidone in Alcohol (95%) were added and mixed in the high cut blender for 5 minutes. The obtained granulate was dried using a fluid bed dryer.

The Dry Loss (LOD) of the dried granulate was no more than (N T) 1.1% tested with Mettler HR73 at 80 ° C and ground in a hammer mill through a 0.84 mm screen.

The milled granulate was combined with 160.00 g of Sodium Starch Glicolate (type A) and mixed in a Y-cone mixer for 15 minutes. 40.00 g of sieved Sodium Stearyl Fumarate were added to the mixture and the materials were mixed in a Y cone mixer for 5 minutes.

The tablets were pressed on a rotary tablet press. The tablets were coated with Opadry * II 85F22055 Yellow as a 13% aqueous suspension, using an O'HARA film coater and a coating of approximately 3.5% w / w was obtained.

The tablets were packed in aluminum blisters covered with aluminum foil. The packed tablets were stored at 40 ° C and 75% relative humidity. The presence of the main degradation product, Cilazaprilat, was determined using the HPLC method described above.

Example 9 Tablets of 5 mg, wet granulation, 9% (w / w) of binder (% of binder calculated per tablet core), (lot K-33749, as shown in Table 3) The following components were mixed for 2 minutes in a high-cut mixer: 522 g of Cilazapril Monohydrate, 30678 g of Lactose Monohydrate, 1600 g of Extra-fine Talc and 1600 g of Sodium Starch Glicolate (type A). 6600 g of a 54.55% (w / w) solution of Copovidone in Alcohol (95%) were added and mixed in the high cut mixer for 3.5 minutes. The obtained granulate was dried using a fluid bed dryer until the Dry Loss (LOD) of the dried granulate was no more than (NT) 1.1% tested with ettler HR73 at 80 ° C, level 5. The dried granulate ground in a hammer mill through a 0.84 mm screen.

The milled granulate was combined with 1600 g of Sodium Starch Glycolate (type A) and mixed in a Y-cone mixer for 15 minutes. 400 g of Sodium Stearyl Fumarate sieved was added to the mixture and the materials were mixed in a Y cone mixer for 5 minutes and a final mixture was obtained.

The tablets were pressed from the final mixture into a rotary tablet press. The tablets were coated with Opadry® II 85F22055 Yellow as a 13% aqueous suspension, using a 0 'HARA film coater and a coating of approximately 3.5% w / w was obtained.

The tablets were packed in aluminum blisters covered with aluminum foil. The packed tablets were stored at 40 ° C and 75% relative humidity. The presence of the main degradation product, Cilazaprilat, was determined using the HPLC method described above.

Table 3. Composition of Cilazapril tablets, formulated by a wet granulation process. Ethanol (95%) was used as process solvent Example 7 Example 8 Example 9 Tablet Tablets tablets of 1 mg, 2.5 mg, 5 mg, Ingredient K-33603 K-33604 K-33749% Content, total tablet weight Cilazapril 0.50 1.26 1.16 Monohydrate Lactose Monohydrate 74, 86 74, 10 74, 10 Extra-fine talcum 3, 86 3, 86 3, 86 1 1 Starch glycolate, 7, 73 7, 73 7, 73 1 sodium i 5 Copovidone 8, 70 8, 70 8, 70 i Stearyl fumarate 0, 97 0, 97 0, 97 sodium 1 Opadry II 85F22055 3.38 Yellow or Opadry II 85F24033 3, 38 Pink Opadry II 85F25401 3,38 Red * 95% Ethanol (solvent 10.3 10, 3 9.9 1 5 of the process) * Removed during the drying process Example 10 Lot R-02474: 1 mg tablets, wet aqueous granulation, 7.5% (w / w) of binder (as shown in table 4) In a high-cut mixer were mixed for 1 minute: 2.09 g of Cilazapril Monohydrate, 315.91 g of Lactose Monohydrate, 16.00 g of Talc Extra fine and 16.00 g of Sodium Starch Glycolate (type A). 65 g of 46.2% (w / w) of aqueous Copovidone solution were added and mixed in the high cut mixer for 4 minutes. The obtained granulate was dried using a fluid bed dryer. The Loss on Drying (LOD) of the dry granulate was no more than (NMT) 1.1% tested with Mettler HR73 at 80 ° C, level 5 and ground in a hammer mill through a 0.8 mm sieve .

The milled granulate (359.34 g) was combined with 15.13 g of Sodium Starch Glicolate (type A) and mixed in a Y-cone mixer for 15 minutes. To the mixture was added 3.78 g of Sodium Stearyl Fumarate sieved to the mixture and the materials were mixed in a Y cone mixer for 5 minutes. The tablets were pressed on a rotary tablet press.

The tablets were packed in aluminum blisters covered with aluminum foil. The packed tablets were stored at 55 ° C or at 40 ° C and at 75% relative humidity. The presence of the main degradation product, Cilazaprilat, was determined using the HPLC method described above.

Table 4. Compositions of Cilazapril tablets, formulated by a wet granulation process. Water was used as a process solvent * Removed during the drying process I Example 11 Comparison of stability of different compositions Pharmaceuticals from Cilazapril The stability of the pharmaceutical compositions of? according to the present invention prepared with ethanol (95%) or water as the processing solvent. In addition, the stability of commercially available products was determined in the same test conditions. Samples of the marketed product were 1 mg Vascace® tablets, produced by F. Hoffmann- La Roche Ltd, Basel, Switzerland. As shown in table 5 the and comparable formulations of Cilazapril formulations and processed predominantly using ethanol, which only ; differ with respect to the content of Cilazapril in mg / tablet 5 have very different degradation profiles, such that i! 1 mg tablets are the most stable and those of 5 mg less Stable Table 5. Monitoring results of Cilazapril tablets, placed under normal stress conditions (40 ° C and 75% relative humidity), compared with a commercially available product. available. Packaging: aluminum blister i I Vascace ™ Test Samples Lot K-33603 K-33604 K-33749 # B2022 # B2141 # B2117 Resistance 1 mg 2, 5 mg 5 mg 1 mg 2, 5 mg 5 mg Principal degradation product, Cilazaprilat Interval% by marked Cilazapril test claim Time "0" 0.2 0.2 0.2 0.9 0, 5 0.4 1 Month 0.3 0.8 1.2 2.0 1.4 0.8 2 Months 0.4 1.1 2.0 2.5 1.7 1.0 3 Months 0.8 2.2 2.7 3.5 2.3 1.3 6 Months 1.6 4.2 4.2 4.8 5.1 3.4 1.8 In contrast, Table 6 shows that comparable formulations of Cilazapril processed predominantly using water as a processing solvent that differ only with respect to the content of Cilazapril in mg / tablet have the opposite degradation characteristics, such that the 5 mg tablets they are the most stable and those of 1 mg the least stable.

Table 6. Monitoring results of Cilazapril tablets, placed under conditions of normal stress (40 ° C and 75% relative humidity). Packaging: blister aluminum Lot R-02474 R-02636 Resistance 1 mg 5 mg Cilazaprilat,% per claim Marked interval of Cilazapril Test Time "0" 1.0 0.2 3 Months 2.9 0.8

Claims (47)

1. A pharmaceutical composition comprising: a) an active pharmaceutical ingredient sensitive to moisture; and b) at least one pharmaceutical excipient, wherein the active pharmaceutical ingredient is wet granulated with a solution of at least one pharmaceutical excipient.

2. The pharmaceutical compositions according to claim 1, wherein the active pharmaceutical ingredient sensitive to moisture is cilazapril.

3. The pharmaceutical composition according to claim 2, wherein the composition comprises from 0.1% to 25.0% of Cilazapril in the total weight of the composition.

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

5. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition comprises at least 4% by weight of the total composition of the binder.

6. The pharmaceutical composition according to the claim 5, wherein the binder comprises 4% to 20% by weight of the pharmaceutical composition.

7. The pharmaceutical composition according to the claim 6, wherein the binder comprises from 5% to 10% by mass of the composition.

8. The pharmaceutical composition according to claim 1, wherein at least one excipient is selected from the group consisting of cellulose derivatives, a polyvinyl pyrrolidone (PVP) and its derivatives, polyvinyl acetates (PVA), polyvinyl alcohols, and mixtures thereof. they.

9. The pharmaceutical composition according to the claim 8, where the excipient is copovidone.

10. The pharmaceutical composition according to the claim 9, where copovidone is Plasdone S-630.

11. The pharmaceutical composition according to claim 4, comprising at least two pharmaceutically acceptable excipients.

12. The pharmaceutical composition according to claim 2, comprising Cilazaprilat, the main product of the degradation of Cilazapril, in an amount of not more than 3% by weight of the initial quantity of Cilazapril, after storage in a package, wherein The package has moisture barrier properties at least as efficient as cold aluminum and aluminum blister packs.

13. The pharmaceutical composition according to claim 12, wherein the storage is at a temperature of 55 ° C for 14 days.

14. The pharmaceutical composition according to claim 12, wherein the storage is at a temperature of 40 ° C and a relative humidity of 75% for 3 months.

15. The pharmaceutical composition according to claim 14, which comprises not more than 2% by weight of a major degradation product of Cilazapril.

16. The pharmaceutical composition according to claim 14, which comprises not more than 1% by weight of a major degradation product of Cilazapril.

17. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is in a solid dosage form selected from the group consisting of tablets, powders, capsules, sachets, chips and pills.

18. The pharmaceutical composition according to claim 17, wherein the solid dosage form is a tablet.

19. The pharmaceutical composition according to claim 18, wherein the tablet undertakes from 2% to 6% by weight of a cosmetic tablet coating.

20. The pharmaceutical composition according to claim 19, wherein the tablet comprises from 2.5% to 4.5% by weight of a cosmetic tablet coating.

21. The pharmaceutical composition according to claim 19, wherein the cosmetic tablet coating has barrier properties for moisture.

22. The pharmaceutical composition according to claim 21, wherein the cosmetic tablet coating is prepared using powder mixtures for coating suspensions of the Opadry * II 85F series.

23. A method for preparing a pharmaceutical composition that comprises an active pharmaceutical ingredient sensitive to granulated moisture comprising the following steps: j) a) providing an active pharmaceutical ingredient sensitive to 5 humidity; b) mix the active pharmaceutical ingredient sensitive to the i moisture with at least one excipient pharmaceutically acceptable and form a mixture; c) wet granulate the mixture with a solution of a binder in a 10 process solvent and form a pharmaceutical composition.

24. The method according to claim 23, wherein active pharmaceutical ingredient sensitive to moisture i Cilazapril. fifteen

25. The method according to claim 24, wherein the

The composition comprises from 0.1% to 25.0% of Cilazapril in the weight total of the composition. i j 20 26. The method according to claim 23, wherein the Binder comprises at least 4% of the total weight of the composition.

27. The method according to claim 23, wherein the binder is selected from the group consisting of cellulose derivatives, a polyvinyl pyrrolidone (PVP) and its derivatives, polyvinyl acetates (PVA), polyvinyl alcohols and mixtures thereof.

28. The method according to claim 27, wherein the binder is copovidone.

29. The method according to claim 28, wherein the copovidone is Plasdone S-630.

30. The method according to claim 23, wherein the process solvent is selected from the group consisting of solvents capable of dissolving the binder to reach a concentration of at least 10% w / w.

31. The method according to claim 23, wherein the process solvent is selected from the group consisting of water, ethanol, isopropyl alcohol, and combinations thereof.

32. The method according to claim 31, wherein the process solvent is a concentrated ethanol solution and wherein the concentration of the moisture sensitive active pharmaceutical ingredient in the pharmaceutical composition is no more than 1.7%.

33. The method according to claim 32, wherein the concentration of the active pharmaceutical ingredient sensitive to moisture is not more than 0.6% in the pharmaceutical composition.

34. The method according to claim 31, wherein the process solvent is water and wherein the concentration of the active pharmaceutical ingredient sensitive to moisture is more than 1.7% in the pharmaceutical composition.

35. The method according to claim 34, wherein the concentration of the active pharmaceutical ingredient sensitive to moisture is no more than 2.7% in the pharmaceutical composition.

36. The method according to claim 23, which also comprises the steps of: d) mixing the granulate with one or more excipients and forming a final mixture; and e) pressing the final mixture into a tablet.

37. The method according to claim 36, which also comprises the steps of: f) coating the tablet with a cosmetic tablet coating.

38. The method according to claim 37, wherein the cosmetic tablet coating has barrier properties for moisture.

39. The method according to claim 38, wherein the cosmetic tablet coating comprises a powder mixture for coating suspensions of the Opadry'8 II 85F series.

40. The method according to claim 39, which also comprises a step of providing the powder mixture for coating suspensions of the Opadry8 II 85F series in a solution or suspension comprising from 10% to 25% of the powder coating powder mixture. cosmetic tablet.

41. The method according to claim 40, wherein the powder mixture for coating suspensions of the Opadry * II series 85F is provided in a solution or suspension comprising from 12% to 13% of the cosmetic tablet coating powder mixture.

42. The method according to claim 37, wherein the cosmetic tablet coating comprises 2% to 6% of the pharmaceutical composition.

43. The method according to claim 37, wherein the cosmetic tablet coating comprises from 2.5% to 4.5% of the pharmaceutical composition.

44. A method for treating a patient suffering from a disease comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an active pharmaceutical ingredient sensitive to moisture and at least one pharmaceutically acceptable excipient, wherein the Active pharmaceutical ingredient is wet granulated with at least one pharmaceutical excipient.

45. A method according to claim 44, wherein the active pharmaceutical ingredient sensitive to moisture is Cilazapril.

46. The method according to claim 45, wherein at least one pharmaceutically acceptable excipient is a binder.

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