EA015535B1 - Benzimidazole formulation - Google Patents

Abstract

A dry manufacturing process for the production of a pharmaceutical formulation of a benzimidazole and an alkaline substance is described. A tablet is compressed directly from a dry powder or a dry particulate matter avoiding any liquid or excipient conventionally used as a wet binder. The manufacturing process has the advantage of being simple and cost efficient. At the same time an expensive drying step is superfluous. The resulting pharmaceutical formulation has a good stability and a good dissolution profile.

Description

Field of Invention

This invention relates to pharmaceutical formulation. In particular, this invention relates to pharmaceutical formulations including acid-unstable benzimidazoles. The invention provides economical production methods that provide stable formulations.

BACKGROUND OF THE INVENTION

Due to the nature of benzimidazole acid-unstable acids, it is necessary to protect the drug from acid exposure, especially in the presence of moisture. First of all, benzimidazole must be protected from acid during storage of the drug. In the prior art this is achieved by contacting benzimidazole with an alkaline substance in a pharmaceutical formulation. In the next step, benzimidazole should be protected from acid in the stomach. One skilled in the art will understand that this can be achieved using an enteric coating. However, it is recognized in the art that an enteric coating will introduce a stability problem in that the enteric coatings used are acidic in nature. This stability problem is described in European patent EP 0 243 380 (Na881e). The use of neutral peeling to protect the acid-unstable benzimidazole was proposed in European patent EP 244380 to solve the stability problem.

The wet granulation method is commonly used in such formulation approaches. European patent EP 0244380, for example, discloses the use of a conventional granulation method, where a wet granulation binder is used in the same way as a water-based granulating liquid. European patent EP 0589981, for example, discloses the use of polyvinylpyrrolidone as a binder for wet granulation.

International application Χν94 05009410 (Ότ. Kebbu'z) discloses an enteric coated formulation of benzimidazole, where tablets are prepared by various combinations of wet mixing and dry mixing. Example 7, for example, discloses the dry mixing and pressing of esomeprazole and magnesium oxide.

International application XVO 9850019 (8ade) discloses an enteric-coated formulation comprising omeprazole or lansoprazole. In Example 2C, 10 g of omeprazole was mixed with a pharmaceutical adjuvant, anhydrous lactose I8P / 1ME, and then passed through a sieve to obtain granules of uniform size. Example 4 states that a separate granulation of the core was mixed with lactose and talc or magnesium stearate and compressed into tablets by a known pharmaceutical method. No stability studies have been disclosed with tablets according to Example 2C + 4.

International application νθ 04075881 (Kaihahu) discloses an enteric-coated formulation comprising rabeprazole and low viscosity hydroxypropyl cellulose, optionally in combination with antioxidants obtained by a dry granulation process. Thus, several methods are known in the art for providing a stable pharmaceutical formulation of benzimidazoles. The proposed production methods, however, are relatively labor intensive. Thus, in the art there is a need for simple and economical production methods to obtain a benzimidazole formulation with good stability properties and good dissolution profiles. Moreover, in the art there is a need to obtain such tablets of a relatively small size for better passage and delivery of the drug to the intestine.

SUMMARY OF THE INVENTION

The object of the present invention thus provides a stable and economical pharmaceutical formulation that is intended for oral administration and further effective delivery of active benzimidazole to the intestine, where said formulation has good shelf-life and release profile.

In particular, this invention relates to a method for producing a pharmaceutical formulation in the form of a tablet comprising benzimidazole as a biologically active component, wherein said formulation includes an enteric coating to protect the active component from acid in the stomach, said benzimidazole is further stabilized in a tablet using an alkaline substance, said a method comprising the steps of dry granulation and dry pressing of tablets, where the specified formulation, in addition, is characterized by one and or more of the following features:

(ί) the alkaline substance is an alkali metal carbonate with high water solubility and a BET area of at least about 1 m ² / g before any dry granulation and / or dry pressing steps, (i) the alkaline substance is an alkaline earth metal carbonate with low water solubility and a BET area of at least about 1 m ² / g before any dry granulation steps

- 1 015535 and / or dry pressing, (w) benzimidazole and alkaline substance were mixed and dry granulated together before dry pressing, (ίν) the ratio of the weight of benzimidazole and alkaline substance from about 1: 0.2 to about 1: 5, ( ν) the alkaline substance has a pKa value of at least about 10 and the BET area of at least about 1 m ² / g before any stages of dry granulation and / or dry pressing, (νί) if the alkaline substance is polyvalent, the specified alkaline substance has a value pKa1 6 or more and BET area of at least about OLT 1 m ² / g before any steps dry granulation and / or dry pressing, (νίί) the alkaline substance has a surface area BET of at least about 1 m ² / g before any steps dry granulation and / or dry pressing, (νίίί) formulation in the form of a tablet further includes a disintegrating agent in an amount of about 1-30 wt.%.

The invention further relates to a pharmaceutical formulation in the form of a tablet comprising benzimidazole as a biologically active component, wherein said formulation includes an enteric coating to protect the active component from acid exposure in the stomach, said benzimidazole is further stabilized with an alkaline substance in a tablet, wherein said formulation additionally characterized by one or more of the following features:

(ί) the alkaline material starting material is an alkali metal carbonate with high water solubility and a BET area of at least about 1 m ² / g, (ί) the alkaline material starting material is an alkaline earth metal carbonate with a low water solubility and a BET area of at least at least about 1 m ² / g, (w) benzimidazole and the alkaline starting material were mixed and dry granulated together before dry pressing, (ίν) the weight ratio of benzimidazole and alkaline substance was from about 1: 0.2 to about 1: 5, (ν) original the alkaline substance material has a pKa value of at least about 10 and a BET area of at least about 1 m ² / g, (νί) if the alkaline substance is polyvalent, said alkaline substance has a pKa1 value of 6 or more and a BET area of at least at least about 1 m ² / g, (νίί) the alkaline starting material has a BET area of at least about 1 m ² / g, (νίίί) the tablet formulation further comprises a disintegrating agent in an amount of about 1-30 weight .%.

The manufacturing method includes only certain production steps, and the use of any liquid is avoided, making the expensive drying step unnecessary. However, the liquid may be applicable in subsequent coating steps providing an enteric coating and optionally an undercoat.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the invention relates to a pharmaceutical formulation in the form of a tablet comprising benzimidazole as a biologically active component, wherein said formulation includes an enteric coating to protect the active component from acid in the stomach, said benzimidazole is further stabilized in a tablet by an alkaline substance, wherein said formulation additionally characterized by one or more of the following features:

(ί) the alkaline material starting material is an alkali metal carbonate with high water solubility and a BET area of at least about 1 m ² / g, (ί) the alkaline material starting material is an alkaline earth metal carbonate with a low water solubility and a BET area of at least at least about 1 m ² / g, (w) benzimidazole and the alkaline starting material were mixed and dry granulated together before dry pressing, (ίν) the weight ratio of benzimidazole and alkaline substance was from about 1: 0.2 to about 1: 5, (ν) original the alkaline substance material has a pKa value of at least about 10 and a BET area of at least about 1 m ² / g, (νί) if the alkaline substance is polyvalent, said alkaline substance has a pKa1 value of 6 or more and a BET area of at least at least about 1 m ² / g, (νίί) the alkaline starting material has a BET area of at least about 1 m ² / g, (νίίί) the tablet formulation further comprises a disintegrating agent in an amount of about 1-30 weight .%.

In a second aspect, the invention relates to a method for producing a pharmaceutical formulation in the form of a tablet comprising benzimidazole as a biologically active component, wherein

- 20155535 said formulation includes an enteric coating to protect the active component from acid attack in the stomach, said benzimidazole is further stabilized in a tablet with an alkaline substance, said method comprising the steps of dry granulation and dry pressing of tablets, wherein said formulation is further characterized by one or more of following features:

(ί) the alkaline substance is an alkali metal carbonate with high water solubility and a BET area of at least about 1 m ² / g before any dry granulation and / or dry pressing steps, (ίί) the alkaline substance is an alkaline earth metal carbonate with low water solubility and a BET area of at least about 1 m ² / g before any steps dry granulation and / or dry pressing, (ΐϊϊ) benzimidazole and the alkaline substance were mixed together and subjected to dry granulation by dry pressing, (ίν) ratio ve and benzimidazole and the alkaline substance from about 1: 0.2 to about 1: 5, (ν) the alkaline substance has a pKa value at least about 10 and a BET area of at least about 1 m ² / g before any steps dry granulation and / or dry pressing, (νί) if the alkaline substance is polyvalent, the specified alkaline substance has a pKa1 value of 6 or more and the BET area of at least about 1 m ² / g before any stages of dry granulation and / or dry pressing, (νίί) the alkaline substance has a BET area of at least about 1 m ² / g before any steps mi dry granulation and / or dry pressing, (νίίί) tablet formulation further includes an agent that causes disintegration in an amount of about 1-30 wt.%.

In a preferred embodiment, benzimidazole is pantoprazole, for example pantoprazole sodium hydrate or pantoprazole sodium sesquihydrate. In other preferred embodiments, the benzimidazole may be omeprazole or salt and / or its hydrate, lansoprazole or salt and / or its hydrate, esomeprazole or salt and / or its hydrate, aripiprazole or salt and / or its hydrate, rabeprazole or salt and / or its hydrate or thymoprazole or salt and / or its hydrate.

In another preferred embodiment, said formulation further includes other pharmaceutically acceptable excipients, such as fillers, binders for dry granulation, glidants and lubricants. In a particular preferred embodiment, said formulation includes crospovidone as a disintegrating agent in an amount of about 5-20%, preferably 7.5-15%, more preferably 10-13% by weight.

In yet another embodiment, said formulation includes a sublayer. In a particular preferred embodiment, however, said formulation does not include a sublayer. The examples show that it is possible according to this invention to obtain formulations in the form of tablets with good stability properties and good dissolution profiles without the laborious steps of applying the sublayer.

In yet another preferred embodiment, the alkaline substance is a salt of an organic or inorganic acid, where the salt anion is carbonate (Co ₃ ^2- ), hydrogen phosphate (HPO 4 ^2- ) or phosphate (PO 4 ^3- ).

The alkaline substance may also be a salt of an organic or inorganic acid, where the cation is sodium (Να '), calcium (Ca ²⁺ ) or magnesium (Md ² '). Preferably, the salt of the organic and / or inorganic acid is respectively sodium carbonate SchA ₂ CO ₃ ) or calcium carbonate (CaCO ₃ ), trisodium phosphate SchA ₃ PO ₄ ), disodium hydrogen phosphate SchA ₂ NRA ₄ ), hydrazine or its derivatives, lysine or its derivatives, arginine or its derivatives or histidine or its derivatives.

In another preferred embodiment, dry granulation is provided by means of a roller compactor.

In a preferred final embodiment, the mixture was sieved, before compression into a tablet, with a sieve opening (roller seal) of 1.25 mm or less. The examples show that relatively small and relatively homogeneous particles lead to a more accurate dosage of the active compound. Dose accuracy is especially important when preparing relatively small tablets.

In a final aspect, the present invention relates to products obtained or obtained by the methods that are disclosed in this description.

Definitions

Pharmaceutical formulation in tablet form.

The pharmaceutical formulation in the form of a tablet according to this invention is equivalent to a solid dosage form.

- 3 015535

Medicines

According to this invention, the drug substance belongs to the group of benzimidazoles or salts and / or their hydrates. Benzimidazole is preferably pantoprazole, omeprazole, lansoprazole, timoprazole, aripiprazole, rabeprazole or esomeprazole, as well as pharmaceutically acceptable salts, hydrates and mixtures thereof. Preferably, the benzimidazole is pantoprazole sodium sesquihydrate. Any pharmaceutically acceptable salt may be used. Examples of commonly used salts of a drug substance are sodium or potassium salts.

The pharmaceutical formulation according to this invention includes about 1-500 mg of the drug per dose; for example, 1-200 or 1-100 mg. Preferably, the dosage unit comprises 10-120; 15-100; 15-80, 15-70; 15-60; 15-50; 15-45 mg; for example, 20, 30 or 40 mg of benzimidazole, preferably pantoprazole.

A dosage unit is a pharmaceutically formulated unit, including a dosage of a drug substance for administration. The dosage unit may be a tablet.

Alkaline substance.

Due to the nature of the acid-unstable drug substance, the dosage unit includes an alkaline substance or a mixture of two or more different alkaline substances in the core to give stability to the shelf life of the pharmaceutical formulation.

The alkaline substance according to this invention may be soluble in water or even practically insoluble in water. For example, 1 part of a water soluble alkaline substance may be dissolved in about 100, 50, 30, or 10 parts of water or less. 1 part of an alkaline substance with low water solubility can be dissolved in at least 100, 300, 500, 1000, 10,000, or even more than 10,000 parts of water. This is in contrast to conventional manufacturing methods that are used in wet granulation, where water-soluble alkaline substances are preferred. The main reason for using water-soluble alkaline substances in conventional methods is that it is believed that water-soluble alkaline substances form a moist environment with an alkaline pH, protecting the active drug substance during the disintegration of the tablet in the gastric system. In the present invention, it was unexpectedly discovered in Examples 6, 8 or 15 that alkaline substances, such as calcium carbonate, which are practically insoluble in water (1 part in more than 10,000 parts of water, according to the principle of о аг та се се се се 1 1 5 5 ((-(ί. Ι). ), can lead to stable formulations with good dissolution profiles, however, it turns out that alkaline substances with low water solubility should preferably have a large BET area (about 1 m ² / g or more).

Typically, alkaline earth metal salts (such as, for example, calcium carbonate, magnesium oxide, magnesium carbonate) tend to have low water solubility. On the other hand, alkali metal salts (such as, for example, sodium carbonate and potassium carbonate) tend to be more water soluble.

According to the prior art, for example, the international application XVO 05009410 (Ig. K.ebbu'8), the ratios between benzimidazole and alkaline substance are disclosed - about 1: 0.17 (examples 1 and 2). Based on existing information in the art, a specialist would therefore not expect that it would be possible to apply ratios of 1: 0.2 or higher, and definitely not ratios of about 1: 0.5 or 1: 1 or more, while it was expected that increasing amounts of base leads to slow dissolution profiles of the active compound. However, according to this invention, the weight ratio between the drug substance and the alkaline substance ranges between 1: 0.2 and 1:10, preferably between 1: 0.5 and 1: 5 and most preferably 1: 1 and 1: 5, unexpectedly while still providing formulations with a combination of good shelf life stability and good dissolution profiles (examples 6, 8 and 15). The weight ratio between the drug and the alkaline substance, thus, can be about 1: 0.2, or 1: 0.3, or 1: 0.4, or 1: 0.5, or 1: 0.6, or 1: 0.7, or 1: 0.8, or 1: 0.9, or 1: 1, or 1: 1.5, or 1: 2, or 1: 2.5, or 1: 3, or 1: 3,5, or 1: 4, or 1: 4,5, or 1: 5, or 1: 6, or 1: 7, or 1: 8, or 1: 9, or 1:10.

A pKa value of the selected alkaline material of at least 10 is preferred. However, one alone is not enough. If the alkaline material is polyvalent, the pKa1 value (where pKa1 is the most acidic pKa value) should be higher than 6. As shown in Example 6, the use of tricalcium phosphate, in which the pKa1 value is 2.2, leads to insufficient stability than the use of disodium carbonate ( whose pKa1 value is 6.4).

The alkaline substance preferably has a pKa value of 6 or higher. An alkaline substance will typically provide an alkaline pH in the range of 7-12 when it is dissolved and / or dispersed in water at room temperature in an amount of about 10-100 mg / ml.

Accordingly, the term alkaline substance includes the corresponding base of an organic or inorganic acid, for example, provided in the form of a pharmaceutically acceptable salt of an organic or inorganic acid and / or a mixture thereof, and certain amino acids. According to the invention, it is understood that the pharmaceutical formulation may very well contain more than one alkaline substance, if necessary.

It is understood that the starting material of an alkaline substance is an alkaline substance in front of

- 4 015535 by stages of the processing of the formulation.

Examples of alkaline substances are listed in the following table.

Table 1

Examples of alkaline substances

Substance Examples Structure pKa * Carboxylic acid salt (carbonate) and phosphoric acid (phosphate). Soluble salts with pKa values of 9 and higher Disodium carbonate W ₂ CO ₃ 10.3 Sodium bicarbonate 1 CHANSO ₃ 6.4 Tricalcium phosphate Να. _; ΡΟ ₄ 12,4 Disodium hydrogen phosphate SHNRO ₄ 7.2 Sodium dihydrogen phosphate №ιΗ ₂ ΡΟ ₄ 2.2 Salt of carboxylic acid (carbonate). Practically insoluble with a pKa value of 9 or higher Calcium carbonate CaCO ₃ 10.3 Amino acids with pKa values of ₃ 9 or higher Lysine C ₆ H ₁₄ O ₂ P ₂ pKa ₂ : 8.9 pKa ₃ : 10.3 Arginine s ₆ n ₁₄ p ₄ o ₂ pKa ₂ : 9.1 pKa ₃ : 13.2 pH = 11.4 (100 g / l H ₂ O) Histidine C _b 11 <AK _{; 1} pKa _e : 9.0 pH = 7.7 (10 g / lH ₂ O)

* The pKa values in this table are approximate values and refer to the pKa value of the acid. Only relevant pKa values are included,

A suitable disintegration time means that the pharmaceutical formulation must meet the standards set forth in Eigoreap Ryagtasoroe1a. Specialists in this field understand that for compressed tablets, it is desirable to disintegrate within 30 minutes, most preferably within 15 minutes after contact with an aqueous solution, provided that the enteric coating is absent or torn. Preferably, the disintegration was carried out in a dissolution apparatus, for example, by method P11. Eig. Wacke !, as disclosed, for example, in Example 11.

Moreover, it should be understood that the alkaline substance must be provided in solid form, for example in the form of a powder, granulate or the like.

In connection with this invention (example 16), it was found that different alkaline substances can have different surface areas (BET areas (Brunauer, Emmett, Taylor)) and that the same compounds purchased under different brands (for example, calcium carbonate 8! Igsa1 B and 8), can have different BET areas (see image 8EM (scanning electron spectroscopy) in the drawings). Moreover, it was found that alkaline substances with relatively large BET areas (at least about 0.5, 0.6, 0.7, 0.8, 0.9, preferably at least about 1.0, 1, 1, 1,2, 1,3, 1,4, and most preferably 1.5 m ² / g or more) tend to give tablets with improved stability properties, while maintaining good dissolution properties (Example 15). A possible explanation for the fact that these porous alkaline substances with a relatively large BET area, which was used as the starting material, tends to crush into small particles after mechanical pressure, such as, for example, during dry granulation and / or dry pressing. In contrast, substances with relatively small areas of BET (for example, purchased calcium carbonate of the 8th grade brand) tend to either resist mechanical pressure and / or be fragmented into relatively large particles and / or show a slightly improved particle distribution around the drug substances. Thus, it is preferable to use porous and / or polycrystalline alkaline substances with a relatively large BET area, which tend to crush into very small particles after mechanical pressure. Such alkaline substances in the form of very small particles in the resulting tablet most likely provide the best alkaline protection against acid and moisture, the active compound providing close physical

- 5 015535 contact between the medicinal product and the protective alkaline substance. Example 10 shows that a particular preferred way of providing close physical contact and thus a stable tablet with good dissolution profiles involves the step where the two substances are mixed and subsequently dry granulated together before being compressed into a tablet.

Pharmaceutical excipients.

The examples show that it is possible to compress tablets with good stability and dissolution profiles, where only the pharmaceutical excipient, with the exception of the alkaline substance, is an insignificant amount of MD stearate (Example 5). In the manufacture of tablets according to the invention on a large scale, for example on a production scale, however, it will be advantageous to add at least one of the following ingredients: glidant, a lubricant, a filler, a binder for dry granulation, a colorant and a disintegrating agent in a formulation comprising alkaline substance and benzimidazole. Preferably, only the additional pharmaceutical excipient is a glidant or lubricant, preferably together with at least one disintegrant, thereby providing a simple and economical manufacturing process.

Examples of glidant and lubricants are stearic acid, metal stearates, talc, colloidal silicon oxide, sodium stearyl fumarate and alkyl sulfates.

A binder for dry granulation, such as, for example, sorbitol, isomalt, or mixtures thereof, can be used in the present invention. The binder for dry granulation provides a binding effect for the material and thus provides a powder that can be compressed into a tablet.

An excipient substance is any pharmaceutically acceptable substance that does not interact with a drug substance or other excipients. Commonly used excipient materials are mannitol, dextrins, maltodextrins (e.g., Lobech® 5 and Lobech® 10), inositol, erythritol, isomalt, lactitol, maltitol, mannitol, xylitol, low substituted hydroxypropyl cellulose (for example, Lb, H 21, H 11, H 11, H 11, H 11, H 11, H 11, L LN 22, LN 30, LN 31, LN 32 are available from § Yn-E18 and Sysh1ca1 Co.), Starches or modified starches (e.g., potato starch, corn starch, rice starch, pre-gelatinized starch), polyvinylpyrrolidrolone polyvinyl acetate, polyvinylpyrrolidone, polyvinyl acetate agar (e.g. mer, sodium alginate), carboxyalkyl cellulose, dextrates, gelatin, gum arabic, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyethylene glycol, polyethylene oxide, polysaccharides such as dextran, soy polysaccharide, sodium carbonate and sodium chloride.

A wet granulation binder is an adjuvant that, in combination with water, facilitates the compression of the powder into coherent bodies, such as tablets, or facilitates granulation of the powder into solid particles. The binder for wet granulation should at least be soluble in water. Examples of wet granulation binders are RUR (polyvinyl pyrrolidone), HPMC (hydroxymethyl propyl cellulose) or gelatin. If a wet granulation binder is used according to this invention, the wet granulation binder will simply act as a filler and will not exhibit the binding properties that are typically associated with such wet granulation binders. Thus, it will be understood that excipients, which are generally regarded as binders for wet granulation, can be used as simple excipients in the context of this invention.

A disintegrating agent is a pharmaceutically acceptable substance that improves the disintegration of tablets without interacting with a drug substance or with any other excipients. The disintegrating agent tends to swell after contact with water, causing the tablet to swell / disintegrate and thus release the active component. This effect is shown in the examples (Example 18), where the dissolution profiles are improved after the disintegrating agent is added to the tablet. Typical formulations of benzimidazole after wet granulation usually include large amounts of a disintegrating agent (at least about 30%), since the wet preparation steps cause a significant proportion of the disintegrating agent to swell, and thus irreversibly reduce their swelling ability. However, in connection with this invention, it was unexpectedly discovered that it is possible to obtain a good dissolution profile using relatively small amounts of a disintegrating agent, thereby allowing the production of smaller tablets using more economical methods (disintegrating agents are often relatively expensive ingredients). Small tablets have advantages in ease of swallowing, packaging, storage, transportation, etc. Moreover, small tablets improve movement through the gastric system and are less dependent on gastric emptying. This effect is likely to be achieved because the dry granulation technique does not lead to undesirable preliminary swelling of the disintegrating agent. Moreover, it has been shown that it is possible to use water together with

- 6 015535 peeling and / or enteric coating method without undesirable preliminary swelling and / or disintegration of tablets (example 12, Fig. 8).

Examples of commonly used disintegrating agents are alginic acid — alginates, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, crospovidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose (HPMC), cellulose derivatives such as low-substituted hydroxypropyl, Nbsp; 21, Nbsp; , LN 30, LN 31, LN 32 are available from §Ln-E18 and Sjet1ca1 Co.) And microcrystalline cellulose, potassium or sodium polacryline, polyacrylic acid, polycarbophil, polyethylene glycol, polyvinyl acetate, crosslinked polyvinylpyrrolidone (for example, Rozbop Cb, Po1u1boi® Cb-M, Koshbop® Cb, Po1urlagopope® Xb, Po1ur1acbope® Xb-10); sodium carboxymethyl starch (e.g., RptodeG 'and Exp1o1a®), croscarmellose sodium (e.g., salt of cross-linked sodium carboxymethylcellulose; e.g., Ac-El1-8o1®), sodium starch glycolate, starches (e.g. potato starch, starch, starch) pre-gelatinized starch. The disintegrating agent may be present in the tablet in an amount of about 1-30%, preferably 3-25%, more preferably 5-20% and most preferably 10-15% and even most preferably about 8-14%.

Granulation and pressing.

Powders comprising either the drug in question, an alkaline substance, a pharmaceutical excipient (s), or any combination thereof, are subjected to a dry granulation process. The dry granulation method causes the powder to accumulate in large particles having a size suitable for further processing. Dry granulation, therefore, can be said to improve the flowability of the mixture so that tablets can be produced that fulfill the requirements for changes in mass or uniformity of composition that are described in Eigoreap Ryattasoroya.

The formulations according to the invention can be obtained using one or more mixes and dry granulation steps. The order and number of mixing and granulation steps is not critical. However, it seems important that at least one alkaline substance and the drug was dry granulated before compression into tablets. Dry granulation of the drug and alkaline substance together before compressing the tablet looks surprisingly simple, inexpensive and effective, which provides close physical contact between the alkaline substance and the drug and, thus, the formulation in the form of tablets with good stability properties. The relatively large BET areas of alkaline raw materials also have a beneficial effect on stability properties.

Dry granulation is performed by any mechanical method that transfers energy to the mixture without any use of any liquid substances (neither in the form of aqueous solutions, solutions based on organic solutions, or mixtures thereof), in contrast to conventional wet granulation methods. Mainly, the mechanical method requires a seal, for example provided with a roller seal. An example of an alternative dry granulation process is clumping.

Roller compaction is a method that involves very intensive mechanical compaction of one or more substances. The powder is pressed, that is, compressed by rollers, between 2 counter-rotating rollers to create a hard coating, which is subsequently crushed in a sieve to form solid particles. In these solids, close mechanical contact between the substance (s) is achieved. An example of equipment is M1shras1ot® or CePe3 \ Uro1udgap from CePe MaxSpep + Rtosekkptdetet AC.

Compression of the tablets according to the invention takes place without any use of any liquid substances (neither in the form of aqueous solutions, solutions based on organic solutions, or mixtures thereof). In a typical embodiment, the resulting core or tablet should have a crush strength in the range of 10-150 Ν; so, for example, 15-125 N, preferably in the range of 20-100 N.

The core is thus provided by pressing powder or solid particles. Typically, the core has a weight in the range of 75 mg to 2.5 g; so, for example, 80 mg - 1 g; for example, 80-500 mg; for example, 100-300 mg. Preferably, the core is a tablet with a weight in the range of 75 mg to 2.5 g; so, for example, 80 mg - 1 g; for example, 80-500 mg; for example, 100-300 mg. In the present invention, the core is furthermore coated with an enteric coating and optionally an underlayer to obtain the desired tablet formulation.

The tablets of this invention may be smaller than conventional tablets, i.e., having a diameter of about 7, preferably about 6, and most preferably about 5 mm or less. Unlike tablets with a diameter of, for example, 7.5 mm or higher, tablets with a smaller diameter will be able to move freely through the pyloric sphincter of the stomach into the small intestine and thus will be less dependent on gastric emptying.

The layering.

Any commonly used water-soluble film forming an excipient can be used for peeling, for example, sugar, polyethylene glycol, polyvinylpyrrolidone,

- 7 015535 polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetal diethylene amino acetate, COCO! ΙΚ (polyvinyl alcohol is a graft copolymer of polyethylene glycol) and others. Water or any commonly used organic solvent or a mixture thereof is applicable as a peeling solvent.

The main idea within the region is that the sublayer is crucial in the stability of the whole formulation. In 8th (international application XVO 9850019), for example, it is disclosed that the enteric coating and the drug must be separated by an underlayer in order to avoid acid degradation of the drug (p. 8, lines 16-30). Even though the absence of a sublayer can be assumed in various patent documents (for example, as a statement without explanation, in international application νθ 04075881 on page 3, line 21), existing knowledge leads specialists in this field to conclude that tablets obtained without peeling, have insufficient drug resistance. In contrast to the general idea, the inventors of the present invention unexpectedly discovered that it is possible to obtain tablets without delamination having drug resistance compared to tablets with conventional delamination (Table 18 and FIG. 9). Since the peeling method is labor-intensive and time-consuming, the method of obtaining according to the present invention without the labor-intensive peeling steps is thus much more economical, while still obtaining a product with the necessary stability and dissolution properties.

Enteric coating.

Any commonly used enteric coated polymer can be used, for example, cellulose acetate phthalate, such as Ac. | HacoG 'ΟΡΌ (PMC) or C-A-P ΝΕ (Ea81shap Syeshca1), polyvinyl acetate phthalate, such as 8ite1eps® (С1огсоп), carboxymethylethyl cellulose, copolymerized methacrylic acid / methyl esters of methacrylic acid, for example Eibtadi® L 30 Ό or Eibtadi® 12.5 og Eibtadi® L 100 (Eedia - Koish Ryatso Rochelso8, or MAY 30 ΌΡ, or KoShsoa! 100P (BA8E), or Asgu1-Exe (Co1ogsop), or Ea§1asgu1 30 Ό (Yeishap Syesh1sa1), etc.

Preferred plasticizers include cetanol, triacetin, citric acid esters, such as, for example, SytoG1ex® (ΡΓί / eg). phthalic acid esters, dibutyl succinate, acetylated monoglyceride, atsetiltributil citrate atsetiltributila citrate atsetiltrietila, benzyl benzoate, calcium stearate, castor oil, cetanol, chlorobutanol, colloidal silica dioxide, dibutyl phthalate, dibutyl sebacate, diethyl oxalate, dietilmalat, diethyl maleate, diethyl malonate, diethyl fumarate, diethyl phthalate, diethyl sebacate, diethyl succinate, dimethyl phthalate, dioctyl phthalate, glycerin, glycerol tributyrate, glycerol triacetate, glyceryl behenate, glyceryl monostearate, hydrogenated grows linseed oil, lecithin, leucine, magnesium silicate, magnesium stearate, polyethylene glycol, propylene, glycol, polysorbate, silicon, stearic acid, talc, titanium dioxide, triacetin, tributyl citrate, triethyl citrate, zinc stearate, RES (polyethylene glycol) the coatings are well known in the art, such as those described by way of example (81iii C. Royet and Ketschschd1op 2G ' ¹ Eb. 2005, pp. 929), are incorporated herein by reference.

Sustainability.

Preferably, at least 95% (w / w) of the claimed drug content is stored in the tablet formulations of this invention after storage at 25 ° C / 60% KH (relative humidity) for 2, 3, 4 or 5 years . Alternatively, stability can be investigated after storage under other conditions in accordance with the relevant manual 1CH (International Conference on Harmonization (1n1etpa1yupa SopGhepeps op Natshopshabop)). Methods for assessing stability are described in the examples.

Brief Description of the Figures

FIG. 1 is a study of the stability of coated tablets containing sodium carbonate, calcium carbonate (81 gigabytes b) or tricalcium phosphate. The study was carried out in open Petri dishes at 70 ° C and at a relative humidity of not more than 10%, example 6.

FIG. 2 is a study of the stability of coated tablets containing sodium carbonate or calcium carbonate (81itsa1b) in miscible ratios of 1: 0.2 or 1: 0.8. The study was carried out in open Petri dishes at 70 ° C and at a relative humidity of not more than 10%, example 8.

FIG. 3 is a study of the stability of coated tablets containing sodium carbonate (81itsa1b) 1: 0.8, based on different sequential mixing procedures and roller compaction. The study was carried out in open Petri dishes at 70 ° C and at a relative humidity of not more than 10%, example 10.

FIG. 4 shows a particle size distribution using two different sieve orifice sizes (1.25 and 1.0 mm) throughout a roller seal, Example 11.

FIG. 5 - the effect on the change in dose of the size of the openings of the sieve of the roller seal is illustrated by the dissolution of the tablet core, example 11

FIG. 6 - effect on the dissolution of the amount of sublayer, used HPMC E15, example 12.

FIG. 7 - effect on dissolution of the type of sublayer, HPMC E5 and HPMCE 15. Evaluated on coated under

- 8 015535 layer of tablets. example 12.

FIG. 8 - effect on dissolution of the type of sublayer, HPMC E5 and HPMC E15. Estimated for enteric coated tablets, Example 12.

FIG. 9 - stability of batches 13030634 and 31030634 (without the use of a sublayer) at 70 ° C in open Petri dishes, example 14.

FIG. 10 - pantoprazole sodium sesquihydrate (image 8EM).

FIG. 11 - calcium carbonate (81itsa b) (image 8EM).

FIG. 12 - calcium carbonate (8sota1ye) (image 8EM).

FIG. 13 - sodium carbonate (image 8EM).

FIG. 14 - sodium carbonate (image 8EM).

FIG. 15 - Pantoprazole sodium sesquihydrate and calcium carbonate (81iggs1 b). Mixing after clumping (image 8EM).

FIG. 16 — pantoprazole sodium sesquihydrate and calcium carbonate (8). Mixing after clumping (image 8EM).

FIG. 17 - pantoprazole sodium sesquihydrate and sodium carbonate. Mixing after clumping (image 8EM).

FIG. 18 - pantoprazole sodium sesquihydrate and sodium carbonate. Pantoprazole pre-roller compaction, mixing with sodium carbonate and clumping (image 8EM).

FIG. 19 is the effect of a disintegrating agent on the dissolution of a tablet core, Example 18.

It should be noted that according to this invention, embodiments and features that are described in the context of one aspect of this invention are also applicable to other aspects of the invention.

The following non-limiting examples are intended to illustrate the present invention.

Examples

Example 1. Dry production of tablets containing pantoprazole or omeprazole.

Dry granulation is accompanied by compression of the obtained solid particles into tablets.

table 2

Source materials Batch number one 2 3 4 5 6 7 8 nine 10 11 a + b 12 a + b one Pantoprazole Ia 1.5 N ₂ O 20,0 20,0 20,0 20,0 20,0 20,0 one Omeprazole No. 20,0 20,0 20,0 20,0 20,0 20,0 2 CaCO ₃ 56.4 56.4 56.4 56.4 2 56.4 56.4 56.4 56.4 2 M; 1 ₂ СО, 56.4 56.4 56.4 56.4 3 Sorbitol 17.6 17.6 17.6 17.6 17.6 17.6 3 Mannitol 17.6 17.6 17.6 17.6 17.6 17.6 4 MCC 5.25 5.25 5.25 5.25 5.25 5.25 5.25 5.25 5.25 5.25 5.25 5.25 5 Mg stearate 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75

*: Amounts in% weight / weight

Table 3

List of ingredients

one Pantoprazole sodium sesquihydrate one Omeprazole sodium 2 CaCO3 81gsa® 2 Sodium iodide triphosphate 2 No. ₂ 0Ο-, sodium carbonate 3 Sorbitol 3 Mannitol 4 MCC; Microcrystalline Cellulose Type 101® 5 Mg stearate; magnesium stearate

Medicinal substance 1) (having an average particle size of about 7 μm) was mixed manually with alkaline substance 2) and 3).

The resulting mixture of ingredients 1) -3) was subjected to roller compaction using the following set of parameters:

- 9 015535 GRS (revolutions per minute): 2.0

Cutter Size 2.5 mm

Sieve opening size 1.25 mm

Strength 10 kN / cm

The obtained solid particles of dry granulation ingredients 1) -3) were added to 4) and 5). After this, the tablets were compressed from a mixture of ingredients 1) -5) using a пресс; · ιΓ TM 20 press and a standard punch with a diameter of 7.5 mm with a concave working surface. Unless otherwise stated, a relatively low compression force was used.

The crushing strength and the disintegration time of the obtained tablets were measured using a BeLeishdeg E2 hardness tester (n = 10) and Bo1ax ΌΤ 2 (n = 6). Both studies were performed according to Eigoreap Ryagteaeoroea

Table 4

Crush strength and disintegration time

Party number Crushing strength, N Disintegration time in water, sec one 39.5 291.0 2 39.5 151.0 3 41.3 520.0 4 39.9 457.8 5 41.1 496.5 6 42.1 523.0 7 32,4 281.8 8 30.9 477.5 nine 36.0 300,0 10 38,0 284.7 11a Low pressing force 45.3 269.7 11b High pressing force 90.6 301.8 12a Low pressing force 40.7 256.8 12b High power pressing 61.7 271.2

The results from the table. 4 show that tablets containing pantoprazole or omeprazole have satisfactory crushing strength and disintegration time, can be made by a dry production method based on solid particles provided by dry granulation obtained by roller compaction.

Moreover, batches 11a + b and 12a + b show that crushing strength can be increased without any significant effect on the disintegration time. This means that the tablets have a quality that allows the use of a standard enteric coating, using standard coating equipment and parameters. Optionally, a sublayer comprising a standard water-soluble film such as HPMC (hydroxypropyl methylcellulose) can be used to protect the enteric coating from the alkaline core.

Example 2. The crushing strength and disintegration time obtained from the compression of solid particles are based on roller pressing.

Table 5

Source materials Batch number thirteen 14 one Pantoprazole sodium sesquihydrate (medium size particles about 7 microns) 21.3 21.3 2 Να-, ΡΟ. | sodium triphosphate 60.0 60.0 3 Sorbitol 18.7 - 3 Mannitol - 18.7

*: Amounts in% weight / weight

1) mixed manually with 2) and 3).

The resulting mixture of ingredients 1) -3) was subjected to roller compaction using the following set of parameters:

- 10 015535 grt (revolutions per minute): 2.0

Cutter Size 2.5 mm

Sieve opening size 1.25 mm

Strength 10 kN / cm

The solid particles obtained by roller compaction of ingredients 1) -3) were pressed into tablets using a ΟίαΓ TM 20 press and a standard punch with a diameter of 7.5 mm with a concave working surface. The crushing strength and the disintegration time of the obtained tablets were measured using a Hardness Tester E2 (n = 10) and Bohax ΌΤ 2 (n = 6).

Table 6

Crush strength and disintegration time

Party number Crushing strength, N Disintegration time, (sec) thirteen 42.6 443.0 14 52.6 486.7

The results from the table. 6 show that tablets containing pantoprazole have a satisfactory crush strength and disintegration time, can be made by pressing solid particles provided by a dry granulation method based on roller compaction granules, without adding additional excipients (excluding a binder for dry granulation). The addition of magnesium stearate may, however, be advantageous on a production scale.

Thus, the tablets have a quality that allows the use of a standard enteric coating, using standard coating equipment and parameters. Optionally, a sublayer comprising a standard water-soluble film, such as HPMC, can be used to protect the enteric coating from the alkaline core.

Example 3. Crush strength and disintegration time of tablets obtained by direct compression of mixtures of pantoprazole and a caustic alkaline excipient.

Table 7

Raw material B (ν; 0.5), pm 10060531 10060532 one Pantoprazole sodium sesquihydrate 7 20.00 20.00 2 Trisodium phosphate, coarse 203 79.26 71.34 2 Trisodium phosphate, fine 40 7.92 3 Magnesium stearate - 0.74 0.74

The drug substance 1) and ingredient 2) were mixed manually, followed by addition to 3). The mixture of ingredients 1) -3) was pressed into tablets using a ΌίαΓ TM 20 press and a standard punch with a diameter of 7.5 mm with a concave working surface.

The crushing strength and the disintegration time of the obtained tablets were measured using a hardness tester BsEeishdeg E2 (n = 10) and Bo1ax ΌΤ 2 (n = 6).

Table 8

Crush strength and disintegration time

Party number Crushing strength, N Disintegration time, sec Change in mass, 8.ge1 (s1 £ that ge1a0 \ e relative standard deviation) -% 10060531 37,4 657.0 0.96 10060532 41.2 631.0

The results shown in the table. 8 show that tablets containing pantoprazole have a satisfactory crush strength and disintegration time obtained by direct compression of the alkaline sealant. The change in mass shows that the flowability of the mixture of ingredients 1) -3) is acceptable. It is assumed that the coarse alkaline substance acts both as a filler and as an alkaline substance in this formulation.

The resulting tablets have a quality that allows the use of a standard enteric coating, using standard coating equipment and parameters. Optional

- 11 015535 a sublayer comprising a standard water-soluble film, such as HPMC, can be used to protect the enteric coating from the alkaline core.

Example 4. The manufacture of tablets having a diameter of 5 mm, based on solid particles obtained by dry granulation in a roller compactor.

Table 9

Source materials * one 2 3 4 5 6 7 8 one Pantoprazole sodium 1.5 N ₂ O 40 40 40 40 one Omeprazole sodium 40 40 40 40 2 Eeyore ₃ RO ₄ 40 40 40 40 2 Ma ^ CO ·; 40 40 40 40 3 Sorbitol 18.25 18.25 18.25 18.25 3 Mannitol 18.25 18.25 18.25 18.25 4 Ms Sgearat 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.75

Amounts in% weight / weight

Table 10

List of ingredients

one Pantoprazole sodium sesquihydrate one Omeprazole sodium 2 14a ₃ PO. |, Sodium triphosphate 2 Iachsoz, sodium carbonate 3 Sorbitol 3 Mannitol 4 Ms stearate; magnesium stearate

The drug substance 1) was mixed manually with 2) and 3).

The resulting mixture of ingredients 1) -3) was subjected to dry granulation with a roller compactor, using the following set of parameters:

grt (revolutions per minute): 2,0

Cutter Size 2.5 mm

Sieve opening size 1.25 mm

Strength 10 kN / cm

The obtained solid particles of dry granulation ingredients 1) -3) were added to 4). The resulting mixture of ingredients 1) -4) was pressed into tablets using a standard punch with a diameter of 5.0 mm with a concave working surface. The resulting tablets have a quality that allows the use of a standard enteric coating, using standard coating equipment and parameters. Optionally, a sublayer comprising a standard water-soluble film, such as HPMC, can be used to protect the enteric coating from the alkaline core.

Example 5. Dry production of tablets containing pantoprazole and alkaline excipients, followed by the use of a sublayer and enteric coating.

- 12 015535

Table 11

The composition of the core tablets,% wt./weight.

Party number 07030631 ЗЗС 10030631 34C 13030634 35C 13030636 36C Seal granulation Pantoprazole, 1 '~ H ₂ O 13.3 11.7 14.1 12.9 Sodium carbonate 13.3 55.2 - Calcium carbonate (81iggs1 b) - 54.9 - - Tricalcium phosphate 60.6 Pantoprazoll-cell excipient 1: 1 1: 4.7 1: 3.9 1: 4.7 Mannitol - 13.5 - 14.9 Crospovidone 0.4 1,1 1,1 1,2 Excipients of the tablet core OYaGov A 62.7 8.5 19,2 - Crospovidone 9.7 9.7 10.0 9.8 MD Stearate 0.5 0.4 0.5 0.5

Table 12

The composition of the sublayer,% wt./weight.

Source materials Coating Liquid Composition Dry film composition Hypromellose 15 5 55.6% Propylene glycol one 11.1% Talc 3 33.3% Purified water 91 % polymer plasticizer 20.0%

Table 13

The composition of the enteric coating,% wt./weight.

Source materials Coating Liquid Composition Dry film composition Methacrylic acid dispersed acrylic copolymer 30% 41.76 62.49 Triethyl citrate 1.25 6.24 Talc 6.27 31.28 Purified water 50.92 % polymer plasticizer 10.00

Table 17 The approximate amount of applied film dry matter,% wt./weight.

Coating 07030631 Zzs 10030631 34C 13030634 35C 13030636 36C Theoretically applied amount of sublayer (mg polymer / cm ² ) 9.7 10.3 10.9 9.0 Theoretically applied amount of enteric coating (mg polymer / cm ² ) 5.5 5,4 5.3 + 2 5.7

Pantoprazole was mixed with an alkaline excipient in a tipping type mixer together with crospovidone and mannitol, followed by roller compaction, as described in Example 1. The remaining excipients were pressed on the tablet cores and tablets using a tablet press ΚοιέοΙι PH106 and punches with a diameter of 6 mm, trying to form concave

- 13 015535 surface with an average weight of 160 mg and a crushing strength of 50 Ν. Then, the tablet cores were coated with a sublayer, then an enteric coating, using laboratory scale honeycombs CoA1a. The resulting coated tablets were used for stability analysis, as described in example 6.

Example 6 (stability analysis).

We performed a stability analysis program with the batches obtained in Example 5. The batches were stored under accelerated conditions for stability studies (open Petri dishes at 70 ° C and relative humidity not more than 10% for three months). Such conditions are likely to be consistent with a shelf life study of at least two years.

The analytical method is as follows: 10 tablets were transferred to a 200 ml volumetric flask. 150 ml of the mobile phase (initial composition) was added and the samples were shaken for 90 minutes. After the pH of the solutions was adjusted to 8.0, the mobile phase was added to the mark. The sample solution was filtered through a 0.45 μm filter and analyzed by reverse phase HPLC to determine the amount of pantoprazole, as well as its cleavage products. The quantity is given in% of the entire area, see table. 19. Moreover, in FIG. 1 amount of pantoprazole is shown as a function of time.

Table 18

HPLC Method Parameters

Mobile phase Ammonium phosphate buffer: methanol: acetonitrile Profile Time % buffer % methanol % acetonitrile gradient 0 min 65 10 25 25 min thirty 10 60 30 min thirty 10 60 31 min 65 10 25 Flow 1.0 ml / min Speaker \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ x an x11 mm particle size Temperature 30 ^and C SPEAKERS Auto dispenser temperature 4 ° C Definition 290 nm UV Input volume 10 μl Long 40 min TH Approximate Pantoprazole 10.7 min retention time Admixture In 6.6 min Admixture A 13.4 min

Table 19

Sustainability Results

The consignment 07030631 10030631 13030634 13030636 Zzs 34C 35C 36C Pantoprazole carbonate sodium 1: 1 1: 3.9 Pantoprazole carbonate calcium 1: 4.7 Pantoprazole: Calcium Phosphate 1: 4.7 Pantoprazole: 01Sa1o5 1: 4.7 1: 0.7 1: 1.4 h n 25/60 C 1 month 99.7 99.7 99.7 99,2 and 70/10 OR 1 month 97.4 96.6 97.3 93.9 s § 5 70/10 OR 2 month 96.4 95.5 96.1 91.9 n c. D 4 "? 70/10 OR 3 month 94.9 94.3 94.6 89.3 TO SY 40/75 3 months 99,4 99,4 99.5 97.2 25/60 C 1 month 0.18 0.15 0.20 0.56 § 5 | 70/10 OR 1 month 2.2 3.2 2,3 6.0 70/10 OR 2 month s, s 4.0 3.6 7.6 2 d '* 5 m ⁴ about V 70/10 OR 3 month 4.3 4.8 4.4 9.3 1st " SC 40/75 3 months 0.5 0.5 0.5 2.6

70/10 OR: 70 ° C / 10% KH in open Petri dishes

25/60: 25 ° C / 60% KH in closed containers

40/75: 40 ° C / 75% KH in closed containers

- 14 015535

According to the table. 19 and FIG. 1 the use of Ca ₅ (PO.- |) ₃ OH as an alkaline substance leads to a relatively greater degree of pantoprazole cleavage compared to the use of Na ₂ CO ₃ , CaCO ₃ and Οίί'αίοδ A as alkaline excipients. Stability data for stressful conditions of stability analysis (70 ° C, open Petri dishes, 70/10 OR (osmotic pressure)) may correspond to a shelf life of at least two years.

Example 7. Dry manufacture of tablets containing pantoprazole and sodium carbonate or calcium carbonate, and an agent that causes disintegration, followed by the use of a sublayer and enteric coating.

Table 20 The composition of the core tablets,% wt./weight.

01050633 ЗР-С 05050632 2P-S 29050636 7P-S 29050640 8P-S Granulation roller sealant Pantoprazole, 1 ^1/2 N ₂ O 14.1 14.1 14.1 14.1 Sodium carbonate 2.82 11.3 Calcium carbonate (81iggs1 b) 2.82 of Pantoprazole 1: 0.2 1: 0.8 1: 0.2 1: 0.8 Tablet core excipients O1Ca1oz A 69.6 61.1 69.6 61.1 Crospovidone 13.0 13.0 13.0 13.0 Mg-Stearate 0.5 0.5 0.5 0.5

Based on the tablet core compositions set forth above, coated tablets were prepared as described in Example 5, with the following exception.

Pantoprazole was preliminarily subjected to roller compaction before mixing with an alkaline excipient, using the following parameters:

rpm (rpm): 2.0

Cutter Size 1.0 mm

Sieve opening size 1.25 mm

Force 4 kN / cm

Preliminary roller compaction led to the formation of pantoprazole granules. The resulting coated tablets were used to study stability in order to study the effect of smaller amounts of alkaline material than used in example 5, and the use of a preliminary roller seal pantoprazole. A stability study is disclosed in Example 8.

Example 8. The study of sustainability.

We performed a stability analysis program with the batches obtained in Example 7. The batches were stored in open Petri dishes at 70 ° C and not more than 10% NN for six weeks.

The analytical method is described in example 6.

Table 21

Result Study

The consignment 01050633 ЗР-С 05050632 2P-S 29050636 7P-S 29050640 8P-S Pantoprazole: sodium carbonate 1: 0.8 1: 0.2 Pantoprazole: Calcium Carboant 1: 0.2 1: 0.8 Pantoprazole: 01SaGoz A 1: 5 1: 4.3 1: 5 1: 4.3 Pantoprazole in% of the area 25/60 from 2 weeks 99.7 99.8 99.8 99.1 70/10 OR 2 weeks 98.3 97.9 98.3 98.1 70/10 OR 6 weeks 97.5 97.2 Fission products in% of the area 25/60 from 2 weeks 0.20 0.15 0.10 0.52 70/10 OR 2 weeks 1,2 1,6 1.4 1,2 70/10 OR 6 weeks 2.0 2,4

From the table. 21 and FIG. Figure 2 shows that the use of sodium carbonate and calcium carbonate as an alkaline auxiliary substance with a component ratio of 1: 0.2 and 1: 0.8 in the mixture leads to almost identical and acceptable splitting ratios when analyzed at 70 ° C and relative humidity

- 15 015535 not more than 10% within six weeks. It came as a surprise that the solubility of the alkaline material obviously does not affect the stability of the benzimidazole composition (calcium carbonate is poorly soluble in water).

Example 9. Dry manufacture of tablets containing pantoprazole and alkaline excipients by mixing and roller compaction followed by an undercoat and enteric coating.

Table 22

The composition of the core tablets,% wt./weight.

Seal granulation Pantoprazole, 1 ^U N ₂ O 14.1 Sodium carbonate 11.3 Pantoprazole: alkaline excipient 1: 0.8 Tablet core excipients B1Ca £ o5 A 61.1 Crospovidone thirteen Magnesium stearate 0.5

The composition shown in the table. 22, mixed and subjected to roller compaction in a different sequential order, as shown in table. 23.

Table 23

Sequential mixing and roller packing

Lot No. (coated tablets) one Mixing with alkaline filler 2 Preliminary roller seal (pantoprazole only) 3 Mixing with alkaline filler 4 Roller seal 01050633 ЗР-С Not used X X X 05050635 X Not used Not used X 05050638 12P-S Not used X X Not used

Mixing and roller compaction were performed as described in example 5.

The remaining tablet core excipients (Οίοαίοδ A, Crossspovidone and MDstearate) were added and the tablets were compressed and coated according to Example 5.

Lots 01050633 and 05050638 were used for stability studies in Example 10 and 05050635 were used for comparison with batches of Example 16 to assess the uniformity of the excipient in granules.

Example 10. The study of sustainability.

The sustainability program was completed, including the batches mentioned in Example 9. The batches were stored in open Petri dishes at 70 ° C. for 2 weeks.

The analytical method is described in example 6.

- 16 015535

Table 24

Sustainability Results

Parties 01050633 ЗР-С 05050638 12P-S Pantoprazole: sodium carbonate 1: 0.8 1: 0.8 Pantoprazole: O1Ca1sy A 1: 5 1: 4.3 Preliminary Roller Seal, Mixing, Roller Seal Preliminary roller seal mixing Pantoprazole in% of the area 25/60 from 2 weeks 99.7 99.5 70/10 OR 2 weeks 98.3 97.2 70/10 OR 6 weeks 97.5 Fission products in% of the area 25/60 from 2 weeks 0.20 0.33 70/10 OR 2 weeks 1,2 2.9 70/10 OR 6 weeks 2.0

From the table. 24 and FIG. Figure 3 shows that the cleavage of pantoprazole is relatively small when pantoprazole was pre-roller compacted, mixed with an alkaline adjuvant, and then roller compacted again. Pantoprazole cleavage is relatively high when pantoprazole was pre-compacted and mixed with an alkaline adjuvant without the step of roller compaction of pantoprazole and alkaline together. Impact on resistance has already been observed after two weeks.

Example 11. Dry manufacture of tablets containing pantoprazole and alkaline excipients.

The roller seal was carried out using two different sizes of sieve openings. Tableting was accompanied by the use of a sublayer and enteric coating.

Table 25

The composition of the core tablets,% wt./weight.

Seal granulation Pantoprazole, E'-NPO 14.1 Sodium carbonate 2.82 Pantoprazole: alkaline excipient 1: 0.2 Tablet core excipients □ 1Ca £ o8 A 69.6 Crospovidone 13.0 Magnesium stearate 0.5

Based on the tablet core compositions described above, coated tablets were made as described in Example 5, with the following exception.

Pantoprazole was subjected to preliminary roller compaction before mixing with an alkaline excipient, using the following parameters:

grt (revolutions per minute): 2,0

Cutter Size: 1.0mm

Screen opening size: 1.25 mm (used for batch 29050641) or 1.0 mm (used for batch 29050645)

Strength: 4 kN / cm

Pantoprazole after preliminary roller compaction and sodium carbonate were mixed using a tilting type mixer, and subjected to roller compaction using the following parameters:

grt (revolutions per minute): 2,0

Cutter Size: 2.5mm

Screen opening size: 1.25 mm (used for batch 29050641) or 1.0 mm (used for batch 29050645)

Strength: 10 kN / cm

The remaining tablet core excipients were added and the tablets were compressed and coated according to Example 5.

- 17 015535

The assessment of the effect of the size of the sieve opening was based on particle size analysis and dissolution studies. Dissolution was carried out using the following method.

Table 26

Dissolution method

Dissolution apparatus 1 ϋ8Ρ / Ρ1ι.ΕιΐΓ Spindle Tray Rotation 150 grt Temperature 37 ° C ± 0.5 ° C Filter ^ UbA1tap (3G / P (0.7 μm) Dissolution medium 0-120 minutes 600μπ0.1ΝΗΟΙ After 120 minutes, the dissolution medium was changed to pH = 6.8 200 ml of 0.20 M IazROz added to the vessel (method A, RBI) UV determination 288 nm Sampling time Absorption was measured every 10 min at 288 nm.

From FIG. 4 it can be seen that the use of a sieve with an opening size of 1.0 mm results in a relatively narrow particle size distribution compared with an opening size of 1.25. A narrow particle distribution leads to a better change in the dose of pantoprazole, as can be seen from FIG. 5.

Example 12. Dry manufacture of tablets containing pantoprazole and alkaline excipients, followed by the use of various types and amounts of sublayer.

Table 27

The composition of the core tablets,% wt./weight.

Seal granulation Pantoprazole, 1 H ₂ O 14.1 Sodium carbonate 55.2 Pantoprazole: alkaline excipient 1: 3.9 Crospovidone 1,1 Tablet core excipients О1Са & з А 19,2 Crospovidone 10.0 Mg-Stearate 0.5

The tablet cores according to the aforementioned composition were made as described in Example 5. The sublayer was used as described in Example 5, except for a change in the amount and type of polymer used, as shown in Table 1. 28.

Table 28

The amount (approximate) and type of sublayer used

Party number Type of receiver array Theoretical amount of receiver array, mg / cm ² 13030634 E15 10.9 (1/1 quantity) 31030633 (C) E15 5.3 (1/2 quantity) 21040634 E5 9.9 (1/1 quantity) 31030631 - -

Enteric coating was used as described in example 5.

The assessment of the effect of the quantity and type of sublayer was based on the following dissolution results obtained in Example 11. However, tablets coated with only the sublayer were analyzed exclusively in a dissolution medium with a pH of 6.8.

FIG. 6, 7 and 8 disclose the effect of the type of sublayer on the dissolution rate of both formed tablets with a sublayer and tablets coated with a sublayer + enteric coating. The sub-layer based on HPMC E5 leads to a relatively fast dissolution rate.

Example 13. Dry manufacture of tablets containing pantoprazole and alkaline excipients, followed by the use of enteric coating.

Batch tablet cores 13030634 and 31030634 were prepared as described in Example 12. Batch 13030634 tablet cores were enteric coated as described in Example 5. A batch of 31030634 was prepared with an enteric coating but without using a sublayer. Enteroso Covered

- 18 015535 loving-coated tablets were used for stability studies in example 14.

Example 14. The study of sustainability.

The sustainability program was completed, including the batches mentioned in Example 13. The batches were stored in open Petri dishes at 70 ° C. for 2 and 3 months, respectively.

The analytical method is described in example 6.

Table 29

Sustainability Results

the consignment 13030634 31030634 Pantoprazole in% of the area 25/60 C 1 month 99.7 99.7 70/10 OR 1 month 97.3 97.9 70/10 OR 2 months 96.1 97.4 Fission products in% of the area 25/60 C 1 month 0.20 0.22 70/10 OR 1 month 2,3 1.7 70/10 OR 2 months 3.6 2.2

70/10 OR: 70 ° C / 10% KH in open Petri dishes 25/60: 25 ° C / 60% KH in closed containers

From the table. 29 and FIG. Figure 9 shows that the stability (70 ° C / 10% KH in open Petri dishes and 25 ° C / 60% KH in closed containers) of tablets with a sublayer is fully comparable to tablets that were not coated with a sublayer.

Example 15. The effect of the type and amount of alkaline excipient on the breakdown of pantoprazole in a stress test by adding a slightly acidic component (ibuprofen).

Table 30

The composition of the mixtures, g

Source materials ί Amounts in grams Sodium carbonate 4 sixteen twenty 25 Calcium Carbonate (81 gigabytes b) | 4 sixteen twenty 25 Ibuprofen 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 Pantoprazole, 1 ' ^{! Ί} N ₂ O twenty twenty 10 5 twenty twenty 10 5 Pantoprazole: alkaline excipient 1: 0.2 1: 0.8 1: 2 1: 5 1: 0.2 1: 0.8 1: 2 1: 5

Table 31

The composition of the mixtures, g

Source materials Amounts in grams Calcium Carbonate (81 gigabytes b) 4 sixteen twenty 25 Tricalcium phosphate 4 sixteen twenty 25 Ibuprofen 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 Pantoprazole, 1 ^1/2 N ₂ O twenty twenty 10 5 twenty twenty 10 5 Pantoprazole: alkaline excipient 1: 0.2 1: 0.8 1: 2 1: 5 1: 0.2 1: 0.8 1: 2 1: 5

The mixtures were created by crushing the raw materials in a steel tank and subsequently placed in Petri dishes in sealed aluminum foil bags for two weeks under ambient environmental conditions.

The evaluation of this stability study is shown in Table 32 (pantoprazole cleavage products colored). Bleaching was rated based on a scale of 1-10, where 1 does not indicate bleaching and 10 indicates severe bleaching.

- 19 015535

Table 32

The scale of bleaching powder mixtures table. 30 and 31

Alkaline material Mixing ratio 1: 0.2 Mixing ratio 1: 0.8 Mixing ratio 1: 2 Mixing ratio 1: 5 Sodium carbonate nine 8 4 one Calcium Carbonate (81 gig 1 E) 10 8 4 one Calcium carbonate (8soga1ps) 10 10 7 7 Tricalcium phosphate nine 6 - one

The results of the table. 32 were discussed in Example 16.

Example 16. Characterization of alkaline materials.

Alkaline materials:

Calcium carbonate, 8!

Calcium Carbonate, 8%.

Sodium carbonate, anhydrate.

The particle sizes of the alkaline starting material were measured by laser light scattering (Maeger) and the BET area was measured using M1goteggy1C8 betsh 2375 at relative target pressures (P / Po) of 0.1 and 0.2 and 0.3. Samples were dried for at least 12 hours at 40 ° C before measurements.

Table 33 BET Areas

Source materials Area by BET, m ² / g Particle Size Π (ν 0.5), microns Calcium Carbonate, 81 gig 3.0 nine Calcium Carbonate, 8cogN1e 0.2-0.5 29th Sodium Carbonate Anhydrate 2.1 99

The BEM images (FIGS. 10-18) illustrate a significant number of differences in the size and structure of the alkaline starting materials. It should be noted that even though sodium carbonate anhydrate has a larger particle size than calcium carbonate (BsogaShe), sodium carbonate anhydrate has a large BET area. This difference is further illustrated in Example 17 using images from a scanning electron microscope. The effect of BET area and particle size on stability was illustrated in Example 15.

The discoloration shown in the table. 32 shows the effect of BET area (see Example 16, Table 33) and the ratio of components in the mixture on pantoprazole stability. High BET area values contribute to good stability results. From example 16 it is seen that the relative small particle size may not be enough to ensure satisfactory stability. Relatively large particles can be useful, provided that their porosity leads to a sufficiently high BET area.

Moreover, this shows that a high amount of alkaline material is preferred. However, a discoloration study cannot show a lower amount of decay product, as can be seen compared with the addition of tricalcium phosphate in Example 6. This means that tricalcium phosphate is not as effective as, for example, sodium carbonate and calcium carbonate (8! )

Example 17. The effect of the type and amount of alkaline excipients on the homogeneity of the mixture with pantoprazole with alkaline materials.

The composition of the mixtures in the form of pantoprazole powder, 1 ^1/2 H ₂ O: calcium carbonate (8! Itsa 1 b), 1: 0,8 pantoprazole, 1 ^1/2 H ₂ O: calcium carbonate (8 sota1ye), 1: 0,8 pantoprazole, 1 ^1/2 N ₂ O (with preliminary roller compaction): sodium carbonate, 1: 0,8 pantoprazole, 1 ^1/2 Н2О: calcium carbonate (8! itsa 1 b) and pantoprazole, 1 ^1/2 Н2О

The batches of calcium carbonate (BSOGSHE) were mixed on a laboratory scale with a stirrer with high shear forces for 1 min. A batch of pantoprazole, 1 ^1/2 H ₂ O (with preliminary roller compaction) was prepared as described in Example 7 before mixing with sodium carbonate. Mixing was carried out as described above.

All mixtures were slowly mixed on a single-punch tablet machine using flat stamping surfaces with a diameter of 11.3 mm. Slags were evaluated for the homogeneity of the mixture using

- 20 015535 scanning electron microscopy (BEM). For comparison, BEM images of individual starting materials were obtained.

BEM images are shown in FIG. 10-18. FIG. 11 and 12 reveal a significant difference between calcium carbonate (B! IgS1 b) and calcium carbonate (Bogash?). The appearance of the BEM B! Igsa1 b and Bogashe is in full accordance with the BET areas measured in Example 16.

FIG. 13 is an increase in the particles shown in FIG. 14. An increase is illustrated in which the porosity of the particles is shown, fully confirming the detection of a high BET area of sodium carbonate.

FIG. Figures 15 and 16 show that the use of calcium carbonate (B! Igsa1 b) leads to a much more homogeneous mixture than calcium carbonate (BsogShe). The effect on sustainability of this difference was illustrated in Example 15. FIG. 17 shows that the particles of sodium carbonate are fragmented during manufacture. The physical structure of B! Igsa1 b leads to an improved distribution of particles during mechanical pressure.

Acceptable stability is obtained, as illustrated in examples 15 and 6, 8 and 10.

FIG. 18 illustrates the effect of pantoprazole pre-roller compaction prior to mixing with an alkaline substance. Clumping (or roller compaction) of the mixture leads to surface coating of relatively large pantoprazole granules with particles of calcium carbonate (B! Igsa1 b). This coating also leads to acceptable stability, as shown in examples 6 and 8. The need for a roller seal to apply this coating is indicated in example 9, which was based on the use of sodium carbonate.

Example 18. The effect of the agent causing the disintegration on the dissolution rate.

Table 34

The composition of the core tablets,% wt./weight.

Pantoprazole, 1 ΙΕΟ 14D 14.1 Calcium Carbonate (81ygs11) 11.3 11.3 Alkaline excipient 1: 0.8 1: 0.8 [LSaGoz A 74.1 61.1 Crospovidone - thirteen Mg-Stearate 0.5 0.5

Based on the above tablet core compositions, tablets were made as described in Example 7 with the following exception that no coating would be applied.

The cores were investigated relative to the dissolution rate, as described in Example 11, except that the tablet cores were analyzed exclusively in a dissolution medium with a pH of 6.8. The results shown in FIG. 19 illustrate the benefits of combining a disintegrating agent since the presence of a disintegrating agent in the formulation significantly increases the dissolution rate.

Claims (17)

1. A method of obtaining a pharmaceutical formulation in the form of a tablet comprising benzimidazole as a biologically active component, according to which benzimidazole and at least one alkaline substance, taken in a weight ratio of 1: 0.2-1: 5, and, optionally, an agent that causes disintegration in an amount of about 1-30 wt.% were mixed and subjected dry granulation followed by dry compaction, wherein the alkaline substance characterized in that it has a BET area of at least about 1 m ² / g measured before any steps dry grand lyatsii and / or dry pressing, and formulations in the form of tablets coated with an enteric coating to protect the active ingredient against the effects of acid in the stomach. 2. The method according to claim 1, where the alkaline substance is an alkali metal carbonate with high water solubility and BET area of at least about 1 m ² / g, measured before any stages of dry granulation and / or dry pressing. 3. The method according to claim 1, where the alkaline substance is a carbonate of an alkaline earth metal with low water solubility and an area of BET of at least about 1 m ² / g, measured before any stage of dry granulation and / or dry pressing. 4. The method according to claim 1, where the alkaline substance has a pKa of at least about 10 and a BET area of at least about 1 m ² / g, measured before any stages of dry granulation and / or dry pressing. 5. The method according to claims 1 to 4, where the benzimidazole is pantoprazole. 6. The method according to any one of claims 1 to 5, wherein pantoprazole is pantoprazole sodium hydrate or pantoprazole sodium sesquihydrate. - 21 015535 7. The method according to any one of claims 1 to 6, wherein the pharmaceutically acceptable excipients are further included in said formulation. 8. The method according to any one of claims 1 to 7, where crospovidone in an amount of from about 5 to about 15 wt.% Is included in said formulation. 9. The method according to any one of claims 1 to 8, where the sublayer is additionally included in said formulation. 10. The method according to any one of claims 1 to 9, where the alkaline substance is a salt of an organic or inorganic acid and the anion of the salt is carbonate (CO ₃ , ^2- ). hydrogen phosphate (HRO4 ^2- ) or phosphate (PO4 ^3- ). 11. The method according to any one of claims 1 to 10, where the alkaline substance is a salt of an organic or inorganic acid and the cation is sodium (No. 1 '), calcium (Ca ²⁺ ) or magnesium (MD ² '). 12. The method according to claim 10 or 11, where the salt of the organic and / or inorganic acid is, respectively, sodium carbonate (Na ₂ CO ₃ ), trisodium phosphate (Na ₃ PO ₄ ), disodium hydrogen phosphate (Na ₂ NRA ₄ ), hydrazine or its derivatives, lysine or its derivatives, arginine or its derivatives or histidine or its derivatives. 13. The method according to any one of claims 1 and 7-12, where benzimidazole is omeprazole or its salt and / or hydrate, lansoprazole or its salt and / or hydrate, esomeprazole or its salt and / or hydrate, rabeprazole or its salt and / or hydrate, timoprazole or its salt and / or hydrate. 14. The method according to any one of claims 1 to 13, where the tablet has a weight in the range of 75 mg-2.5 g. 15. The method according to any one of claims 1 to 14, where dry granulation is provided by means of a roller seal. 16. The method according to any one of claims 1 to 15, where the mixture is sieved, before compression into a tablet, with a mesh size of 1.25 mm or less. 17. The product obtained by the method according to any one of claims 1 to 16.