RU2286156C2 - Method for production of pharmaceutical composition containing 5-aminosalicylic acid useful in treatment of non-specific ulcerative colitis and cron's disease - Google Patents

Abstract

FIELD: medicine, pharmaceuticals.

SUBSTANCE: invention relates to new method for production of granules containing 5-aminosalicylic acid, as well as to new method for production of peroral pharmaceutical composition for treatment of non-specific ulcerative colitis and Cron's disease. Said composition includes 5-aminosalicylic acid as active ingredient, and granulation is carried out by using water as solvent.

EFFECT: granules containing 5-aminosalicylic acid with increased strength, glib surface and narrow granule size distribution.

24 cl, 3 ex, 12 tbl, 9 dwg

Description

The present invention relates to a method for preparing a pharmaceutical composition suitable for the treatment of ulcerative colitis and Crohn's disease, currently referred to as "inflammatory bowel disease" (IBD). More specifically, this invention relates to a new method for the preparation of granules, including 5-aminosalicylic acid (5-ASA), for use in the preparation of solid dosage forms for oral administration.

Nonspecific ulcerative colitis is a chronic inflammatory disease of the colon of unknown etiology. In the acute phases, it resembles an infectious disease, but no microorganisms were finally identified as its cause. The disease causes inflammation of the mucous membrane of the colon with the spread in severe cases to the submucosa. As a rule, not only the colon, but also the rectum is affected, and the ileum is rarely involved. The formation of the ulcer and its spread depend on the stage of development of the disease, but can often be determined macroscopically (sigmoidoscopy and colonoscopy).

A related disease, which is Crohn's disease, also known as regional enteritis or granulomatous colitis, is most often localized in the small intestine, especially in the ileum, but can also affect the jejunum and any part of the colon, including the rectum. In the latter case, the differentiation of Crohn’s disease from ulcerative colitis is a significant diagnostic problem. As a rule, inflammation differs from inflammation in ulcerative colitis by spreading to layers deeper than the mucous membrane, and by less damage to the epithelium.

Both diseases are becoming more frequent, especially in developed countries. In the United States of America, the incidence of ulcerative colitis is 5–15 cases per 100,000 inhabitants, while in the case of Crohn’s disease, the incidence is approximately 5 per 100,000 inhabitants, with rates continuing to increase. Therefore, treatment of IBD is an important problem for modern medicine.

WO 81/02671 discloses a pharmaceutical composition for treating IBD by oral administration. The invention was based on the finding that oral administration of 5-ASA in the form of a free acid or in the form of salts or esters has a beneficial therapeutic effect on ulcerative colitis, especially when administered in the form of sustained release tablets. WO 81/02671 further discloses a method for preparing sustained-release tablets in which the steps of preparing granules from 5-ASA and a solution of polyvinylpyrrolidone in isopropanol are carried out, evaporating the solvent, applying a coating of ethyl cellulose to the granules and preparing the coated tablets from granules.

Further, US 4,632,921 describes a method for preparing readily soluble 5-ASA preparations by mixing 5-ASA with physiologically and toxicologically acceptable basic excipients and / or buffer mixtures, which in a 1% aqueous solution provide pH values in the range of 8 to 12, and the resulting mixture is treated in a known manner with the formation of tablets, film-coated tablets, dragees, capsules or suppositories, that is, a stable and readily soluble pharmaceutical preparation for oral or rectal administration, based on 5-ASA, for use in the treatment of IBD.

US 4,880,794 describes a method for treating IBD, wherein an effective amount of a composition consisting essentially of a pharmaceutically acceptable salt of free 5-ASA is mixed with a pharmaceutically acceptable carrier that can regulate the release of said effective amount of said 5-ASA salt to be administered to the place of current localization of the specified disease.

Further, US Pat. No. 4,960,765 describes a method for treating IBD, in which an effective amount of a composition consisting essentially of free 5-ASA ester in admixture with a pharmaceutically acceptable carrier is orally administered so as to slow down the release of 5-ASA from said composition essentially before as she reaches the patient’s colon. The pH dependent release in the colon is achieved by using a shell leading to the gradual release of 5-ASA. Particles are coated with ethyl cellulose.

US 4,981,073 discloses a method for preparing sustained release tablets suitable for the treatment of IBD by preparing granules containing 5-ASA and polyvinylpyrrolidone (PVP) using an organic solvent. The granulate is coated with a pH sensitive coating (cellulose derivative). A second non-coated granulate is prepared and mixed with the coated granulate and a lubricant.

No. 5,013,727 describes a pharmaceutical composition comprising, as an active ingredient, 5-ASA or a pharmaceutically acceptable salt or ester thereof, which makes it possible to treat IBD by oral administration. A specific preparation in the form of a slow release tablet and its preparation are described.

Further, in US 5541170, a pharmaceutical composition and method for treating IBD by oral administration are described. The pharmaceutical composition may be a solid dosage form, such as a capsule or tablet, containing a pharmacologically active agent coated with an anionic polymer, insoluble in gastric juice and intestinal juice at a pH below 7, but soluble in large intestine juice, so that the drug the oral administration form remains intact until it reaches the colon. A preferred anionic polymer is a methacrylic acid partially methyl esterified polymer wherein the ratio of free carboxyl groups to ester groups is about 1: 2. The disclosed invention has particular use in the dosage forms of prednisolone and its salts, indomethacin, ibuprofen, and in particular 5-aminosalicylic acid.

It turned out that 5-ASA is very useful in the treatment of ulcerative colitis and Crohn's disease. In various countries over the years, various 5-ASA tablets with sustained release of 250 mg and later 500 mg, for example Pentasa ^® , have been registered.

Throughout the prior art relating to 5-ASA tablets, the use of isopropyl alcohol as a main solvent for a binder in the preparation of 5-ASA granules is described. Nowhere has it been described that another solvent, such as water, in the preparation of tablets can replace the organic solvent.

WO 97/23199 discloses a modified release composition for the treatment of IBD, including spherical granules, including a core of 5-ASA and a spherical adjuvant, prepared in water as a solvent, and coated with a rate-limiting barrier substance . The composition provides a minor release of 5-ASA in the stomach, and the granules can be packaged in a sachet. These granules are not suitable for tablet use.

Due to the ever-increasing demand for pharmaceutical preparations containing 5-ASA, there is a need to improve the preparation of tablets containing 5-ASA.

Summary of the invention

Since each tablet or dose containing 5-ASA contains a relatively large amount of the active ingredient, large quantities of the substance must be processed on the production equipment to maximize the therapeutic effect.

The ever-expanding market for drugs containing 5-ASA has led to the need for improvements in the method used to date for the preparation of tablets containing 5-ASA. In the present invention, these improvements provide a better, faster and less expensive way to prepare tablets containing 5-ASA, without loss of quality and bioavailability of 5-ASA.

The objective of the invention is to provide an improved composition of extruded granules for use in Pentasa ^® or similar tablets. Granules should be strong and smooth, resistant to various stages of processing during preparation, and they should be obtained with a narrow and reproducible distribution of particle sizes.

It has been unexpectedly discovered that improvement can be achieved without changing the basic principle of the existing cooking method.

Tablets comprising 5-ASA prepared in accordance with the present invention are still prepared by initially mixing the active ingredient of 5-aminosalicylic acid with a solution of a pharmaceutically acceptable binder, for example polyvinylpyrrolidone (PVP), in a solvent. This mixture is extruded into granules, which are dried in a fluidized bed. After drying, the granules are ground and sieved before they are ready for coating, for example in a fluidized bed. During the coating process, a polymer is applied to the granules until the desired dissolution rate profile is obtained. The coated granules are then mixed with tablet excipients and compressed into tablets.

In one aspect of the present invention, it was unexpectedly discovered that the organic solvent used in the existing method can be successfully replaced partially or completely with water.

US Pat. No. 3,3239 teaches that 5-ASA has poor stability, being sensitive to moisture and light. The patent discloses a pharmaceutical composition comprising 5-ASA in solution or in suspension together with excipients for stabilizing 5-ASA. In addition, the composition must be packaged in an impermeable to diffusion, opaque packaging under inert gas.

Thus, the use of water as the main solvent contradicts the concept related to the preparation of 5-ASA tablets. In the existing method, problems with stability associated with moisture are avoided by using an organic solvent as the main solvent. Unexpectedly, it has now turned out that water can indeed be used as the main part of the solvent in the preparation of granules containing 5-ASA for use in tablet formulations, essentially without affecting the stability of 5-ASA. It is believed that the use of the continuous drying method, for example, in a fluidized bed, plays an important role in obtaining a stable product, providing a quick and gentle drying method, as well as protecting the product from light.

In WO 97/23199, water was used as a solvent in the preparation of spherical granules, which nevertheless include various binders, and they are treated immediately in a spherical shaping and drying process. Spherical granules are not optimal for tablet use due to segregation.

It has now unexpectedly turned out that replacing all or part of an organic solvent with water leads to a process in which granules with a narrower particle size distribution are obtained and that the resulting granules are more durable with a smoother surface. These improvements lead to an increase in tablet yield with this method. In addition, the smooth surface of the granules results in a more reproducible method of coating and reduces the amount of coating substance used in this method.

In addition to the product improvements described above, a decrease in the use of organic solvents is a result that leads to a reduction in the hazard to the operators of the production equipment and the environment, as well as a decrease in the total organic solvent content in the final product. In addition, the costs of acquiring organic solvents can be significantly reduced.

In a second aspect of the present invention, the preparation of granules from the wet mass of 5-ASA and a binder is part of a continuous production line for the preparation of 5-ASA granules.

In a third aspect of the present invention, a method for preparing granules is part of a method for preparing 5-ASA tablets.

As discussed above, it may be desirable to process large quantities of material on a production line. Therefore, the production line can be favorably designed to be continuous, where 5-ASA is mixed with an aqueous PVP solution in front of or in the extruder and the resulting granules are dried, milled and sieved in one continuous process. The supply of individual ingredients is continuously regulated, for example, by measuring the mass of various starting materials, as part of the production line.

Brief description of graphic materials

On figa shows an enlarged photograph of granules after sieving, prepared in accordance with the existing method (Party No. KGGU 405R).

On figb shows the distribution of particle sizes (particle size analysis) after sieving granules prepared in accordance with the existing method (Party No. KGGU No. 405R).

On figa shows an enlarged photograph of granules after sieving, prepared in accordance with the existing method (Lot No. KGGU 406Q).

On Figb shows the distribution of particle sizes (particle size analysis) after sieving granules prepared in accordance with the existing method (Party No. KGGU No. 406Q).

On figa shows an enlarged photograph of granules after sieving, prepared in accordance with the existing method (Lot No. KGGU 406T).

On figb shows the distribution of particle sizes (particle size analysis) after sieving granules prepared in accordance with the existing method (Party No. KGGU No. 406T).

Figure 4 shows a flowchart of a new method for preparing Pentasa ^® or similar tablets.

On figa shows an enlarged photograph of the granules after grinding and sieving, prepared in accordance with the new method (Lot No. HLGU311).

On figb shows the distribution of particle sizes (particle size analysis) after grinding and sieving granules prepared in accordance with the new method (Lot No. HLGU311).

On figa shows an enlarged photograph of the granules after grinding and sieving, prepared in accordance with the new method (Lot No. HLGU315).

On Figb shows the distribution of particle sizes (particle size analysis) after grinding and sieving granules prepared in accordance with the new method (Lot No. HLGU315).

On figa shows an enlarged photograph of the granules after grinding and sieving, prepared in accordance with the new method (Lot No. HLGU319).

On Figb shows the distribution of particle sizes (particle size analysis) after grinding and sieving granules prepared in accordance with the new method (Lot No. HLGU319).

On Fig shows the dissolution rate profiles for tablets Pentasa ^® prepared in accordance with the present invention. Fig. 8 shows the release characteristics that the applicant has set for a product so that it is approved for sale.

Figure 9 shows samples taken from the mixer to document the homogeneity of the mixture.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a new method for the preparation of 5-ASA granules and a new method for the preparation of tablets containing 5-ASA.

The present invention has led to improvements in the general method for the preparation of tablets, as well as the preparation of granules containing 5-ASA, to improvements that were desirable in accordance with the object of the present invention, but which as means for success could neither be expected nor predicted. In the prior art there is no indication that replacing the organic solvent with water could solve the problem of the present invention and, thus, lead to the desired improvements. The method disclosed in the prior art involves the use of a solvent comprising approximately 90% (w / w) of isopropanol and 10% (w / w) of water.

In accordance with the present invention, a solvent suitable for dissolving a binder is based on water. The solvent contains at least 50% (w / w) of water, preferably at least 85% (w / w) of water, more preferably at least 95% (w / w) and most preferably 100% (wt./wt.) water. The remainder of the solvent may be any suitable liquid, such as an organic solvent. The solvent may also include additives important to the process or end product. Such additives are included in the knowledge of a person skilled in the art. Examples are chelating agents, antioxidants, reducing agents, buffers, pH adjusting agents, cosolvents, or any other suitable excipients. Organic solvents may be present in small amounts as a solubilizing agent for additives. Preferably, the solvent is free of organic solvent.

Since each tablet contains a high dose of the active ingredient, which is 5-aminosalicylic acid, it is advisable to process large quantities of the substance in production equipment. Thus, the object of the present invention is to improve the existing method, whereby more tablets can be produced at lower cost, without compromising the quality of the product.

The main focus of this invention was directed to finding a method by which granules that are stronger, have a smoother surface can be obtained, and they are obtained with a narrower particle size distribution compared to granules obtained in accordance with the usual method.

Stronger granules are very important in the subsequent stages of preparation, when it is important that the granules have the ability to withstand pressure, thus minimizing abrasion. Abrasion will lead to the formation of small particles, which are harmful to the method of coating due to the variability of the surface area that they form. In addition, small particles result in a decrease in overall yields.

The smooth surface of the granules is important in order to ensure a reliable measurement of the area of their surface area and, thus, to ensure an accurate calculation of the amount of polymer that must be applied to the granules to ensure a proper dissolution rate profile. In addition, a reduction in the surface area of the granules prepared in accordance with the present invention makes it possible to significantly reduce the amount of coating substance.

A reproducible particle size distribution for the granules is as important as the two above-mentioned parameters in controlling the coating method. The particle size distribution is determined by the method used for conducting particle size analysis. The equipment that can be used in this analysis can be a plurality of sieves with different meshes placed on each other's surface. The mesh of the first mesh is larger than the mesh of the next mesh, which is larger than the mesh of the third mesh and so on. An example of a mesh that can be used together can be 1400 microns, 1250 microns, 1180 microns, 1000 microns, 850 microns, 710 microns, 600 microns and 500 microns. Thus, a fraction of 850-1000 μm is a fraction of granules that are able to pass through a 1000 μm mesh, but not through a 850 μm mesh.

The results of technical development show that it is really possible to obtain granules with the desired properties. It was unexpectedly discovered that the only change compared to the existing method for obtaining the desired properties is that the ratio of isopropyl alcohol and water 9: 1 used in the existing method for dissolving PVP is shifted in the direction of a larger proportion of water. The ratio of the present invention is 1: 1 or less. The main results presented in table 2 demonstrate that the yield is inversely proportional to the content of isopropyl alcohol.

Not wishing to be bound by theory, it is believed that the uneven surface and the variable size of the granules prepared using the existing method arise due to the destruction of the granules at the drying stage, caused by explosive evaporation of isopropyl alcohol, breaking large and small pieces of granules. An uneven surface can also be caused by abrasion of less durable granules during the drying process. It is believed that the use of water granulation in combination with the continuous drying process of the present invention results in softer drying of the granules, resulting in more durable granules with a smoother surface.

In addition, it is believed that the improved strength of the granules leads to the possibility of obtaining predetermined reproducible particle size distributions.

In addition to obtaining the desired properties of the granules in accordance with what was discussed above, the results also demonstrate some advantages with respect to the new method of preparation, namely:

- greater environmental friendliness,

- the environment in the production room is safer for operators,

- lower production costs.

Avoiding or reducing the use of an organic solvent of isopropyl alcohol is a huge advantage both in the processing process, in which operators avoid the risk associated with the use of isopropyl alcohol in the production room, or this risk is minimized, and for the environment with respect to the collection and disposal of isopropyl alcohol in the drying process of the granules and after that. In addition, the cost of purchasing and processing isopropyl alcohol is reduced. However, when appropriate, the organic solvent may be added in such an amount that it is up to 50% (w / w), however, preferably less than 15% (w / w) and more preferably less than 5% (w / w) solvent. Most preferably, an organic solvent is not used at all.

Accordingly, the basic principles of the preparation method of the present invention remain unchanged compared to the existing method. 5-ASA tablets are prepared by initially mixing the active ingredient, which is 5-aminosalicylic acid, with a solution of a binder, for example polyvinylpyrrolidone, in a solvent which according to the present invention contains at least 50% (w / w) water. Preferably, the solvent is free of organic solvent. This wet mass is extruded into granules, which are dried in a continuous fluidized bed. After drying, the granules are ground and sieved before the granules are ready for coating, for example in a fluidized bed. In the process of coating the polymer is applied to the granules to obtain the desired dissolution rate profile. The coated granules are then mixed with tablet excipients and compressed into tablets.

Thus, the present invention relates in a first fundamental aspect to a method for preparing granules comprising 5-aminosalicylic acid (5-ASA) or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable binder, in which the steps are carried out in which:

a) dissolving a pharmaceutically acceptable binder in a solvent,

b) mix the dissolved binder with 5-ASA to form a wet mass,

c) extruding the wet mass into granules and

g) the granules are dried by evaporation of the solvent,

where a new unexpected and favorable feature is that the solvent contains at least 50% (wt./wt.) water.

Then the granules are ground and sieved.

In a preferred embodiment of the invention, the solvent contains more than 85% (w / w) of water. In yet another preferred embodiment, the solvent contains more than 95% (w / w). Most preferably, the solvent is free of organic solvent. The solvent may optionally include one or more than one additive.

In another preferred embodiment, the resulting granules after grinding have a particle size distribution measured by particle size analysis, where the main fraction is from 850 microns to 1000 microns. The holes in the extruder can be varied to obtain the desired particle size. More than 75%, preferably more than 85% and most preferably more than 90% of the granules have a particle size of from 850 microns to 1000 microns.

The ratio of the binder, for example polyvinylpyrrolidone, to the active ingredient, which is 5-ASA, in the resulting granules is preferably up to 8: 100, more preferably up to 6.5: 100 and most preferably up to 5: 100. Other binders, if desired, can replace polyvinylpyrrolidone. Binders that can be considered for use in granules are selected from the group consisting of cellulose derivatives, polyvinylpyrrolidone, pregelatinized corn starch, or any other suitable binder. Such binders can be used in various amounts relative to 5-ASA.

In yet another aspect of the present invention, a first fundamental aspect is used in a method for the preparation of sustained release tablets suitable for the treatment of ulcerative colitis or Crohn's disease, in which the steps are carried out in which:

a) granules are prepared from 5-aminosalicylic acid or a pharmaceutically acceptable salt or ester thereof and a binder taken in an amount up to 8% by weight (solids content based on 5-aminosalicylic acid) in a solvent containing at least 50% ( wt./wt.) water.

b) a polymer composition comprising a solution of a pharmaceutically acceptable polymer substance in an organic solvent is applied to said granules, thereby obtaining coated granules upon evaporation of the solvent,

c) mixing the coated granules with pharmaceutically acceptable tablet excipients and

g) form tablets from the resulting mixture.

The granules are preferably prepared in accordance with the first aspect of the present invention, that is, the granules are extruded, dried, milled and sieved in one continuous process.

In a first embodiment of this method, the granules are dried in a fluidized bed.

In yet another embodiment, the coating material is a cellulose derivative, such as ethyl cellulose.

In yet another embodiment, tablet excipients include a tablet carrier, such as microcrystalline cellulose, a lubricant, such as magnesium stearate, and optionally additional excipients, such as talc.

Industrial applicability

1. General Provisions

Since each tablet or dose contains a relatively large amount of the substance, large quantities of the substance must be processed on the production line. The granules can be prepared in batches or in a continuous manner, that is, the granules can be extruded, dried, milled and sieved in one continuous process.

The production line for the preparation of granules in a continuous process should be able to carry out the following stages of preparation (see also Figure 4).

1. Wet mixing of 5-ASA with a solution of a binder, such as polyvinylpyrrolidone (Povidone), in water (50% (w / w) or more).

2. Extrusion.

3. Drying.

4. Grinding.

5. Screening.

Since the process is continuous, the equipment must be installed so that it is possible to control the flow of various ingredients in the process. By controlling the flow, you can achieve the correct ratio of ingredients throughout the process.

2. Preparation of granules including PVP

Polyvinylpyrrolidone (PVP) is dissolved in a solvent, for example 100% (w / w) water. 5-ASA and an aqueous solution of PVP are mixed and added to the extruder. Alternatively, 5-ASA and an aqueous solution of PVP can be mixed in an extruder. The wet mass, consisting of 5-ASA and PVP, is extruded through a grid and allow it to fall into a device for drying wet granules.

The aqueous solvent is preferably water of suitable quality, but may also contain additives such as chelating agents, antioxidants, reducing agents, buffers and pH adjusting agents.

Advantageously, the extruder includes a mesh that has a plurality of circular holes with a diameter of 0.5 to 1.3 mm, preferably 0.9 mm. The thickness of the mesh is from 0.9 to 2.0 mm, preferably the thickness of the mesh is 1.5 mm. The holes may have the same cross section throughout the entire mesh, or they may taper in any direction. Preferably, the openings are tapered, each opening having a cross section on the inlet side of the mesh greater than a cross section on the outlet side of the grid, with a preferred outlet diameter of 0.9 mm and a preferred inlet diameter of 0.95 mm.

Advantageously, the drying apparatus is preferably a fluidized bed. However, other possible devices known to those skilled in the art may also be used.

If a fluidized bed is used, it can be designed so that the residence time in the fluidized bed is approximately 2.5 hours. However, shorter or longer periods of time are also within the scope of the present invention. Mostly the fluidized bed was divided into two parts, where the granules in the first part are dried on the surface in order to avoid their adhesion. In this part, random mixing of the granules is carried out. In the second part of the fluidized bed, the final drying is carried out and the granules are sent through the fluidized bed by a set of holes into the pallet.

When the granules become dry, they are discharged from the fluidized bed and transferred to a mill to reduce the length of the granules. During grinding, a small amount of fine particles is formed, which is removed by sieving before the granules are ready for coating. At this stage, granulometric analysis can be carried out in accordance with what was previously described.

3. Coating

The resulting granules are coated. The granules can be coated in any coating device suitable for the process. One of ordinary skill in the art will easily determine which devices may be suitable for the present process, such as, for example, a fluidized bed system, such as Kugelcoater. The granules are preferably coated with a polymer dissolved in a suitable polymer solvent, preferably an organic solvent such as acetone.

In order to determine the amount of polymer to be applied to the granules, the surface area is measured. Based on the known correlation between the amount of polymer per surface area and the dissolution rate profile, the required amount of polymer can be predicted based on the measured surface area of the granules. The smoother the surface of the granules, the smaller the surface area and the smaller the surface area, the smaller the required amount of polymer. Any agglomerates formed in the coating step are removed by sieving.

The selected polymer for the shell mainly depends on the desired release pattern. It may be selected from rate-limiting barriers, for example, a coating agent that dissolves in the intestine or slows down release, such as polymethacrylate, commercially available in the form of Eudragit ^™ S, Eudragit ^™ RL and Eudragit ^™ RS, respectively. When a semipermeable polymer is used, ethylcellulose is the most preferred polymer.

4. Mixing

The coated granules are mixed with the remaining tablet excipients by the conventional dry mixing method.

Tablet excipients may include any suitable pharmaceutically acceptable carriers that are well known to those skilled in the art, for example lactose, corn starch, potato starch, and lubricants, for example magnesium stearate and talc. A preferred carrier component is microcrystalline cellulose.

Pentasa ^® tablets, which are prepared in accordance with a conventional method, include microcrystalline cellulose, magnesium stearate and talc as excipients for tablets. The tablets of the present invention may advantageously include the same excipients.

5. Pressing and dust removal

The final mixture of coated granules and excipients is compressed into tablets in any suitable tablet machine, such as a rotary tablet machine, and dedusted. The tablets may have any possible size or weight, for example 100 mg to 10 g, more preferably from 500 mg to 3 g.

6. Active ingredient

5-aminosalicylic acid or any salt or ester thereof are the active ingredient in granules. Salts of 5-ASA may be acid addition salts, in particular hydrochloride, but any pharmaceutically acceptable non-toxic organic or inorganic acid may be used.

Salts formed with a carboxylic acid group may also be used. Alkali metal salts (K, Na), alkaline earth metal salts (Ca, Mg) may be mentioned as examples, but any pharmaceutically acceptable non-toxic salt can also be used. Salts of Na and Ca are preferred.

In DE patent application No. 2712394 (application AU No. 7723548), which is referred to here, described many esters of ortho-, meta- and para-salicylic acid. The described meta- (or 5-) aminosalicylic esters and many related esters are also suitable as an active ingredient in a composition prepared in accordance with this invention.

Suitable esters are, for example, straight chain or branched C ₁ -C ₁₈ alkyl ethers, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, and stearyl and so on, C ₂ -C ₁₈ straight or branched chain alkenyl ethers, for example vinyl, allyl, undecenyl, oleyl, linolenyl and so on, C ₃ -C ₈ cycloalkyl ethers, for example cyclopropyl, cyclobutyl, cyclopentyl succinic, cyclohexyl, cycloheptyl and cyclooctyl and so on, aryl ethers, for example phenyl, toluyl, xylyl, naphthyl and so on, alicyclic ethers, for example menthyl and so on, or aralkyl ethers, for example benzyl, phenethyl and so on.

In general, the correct choice of the active ingredient depends on the type of preparation selected, the clinical picture of the disease, in particular the location of the focus and the type of disease, and the desired release of the active ingredient.

The physical state and solubility characteristics of the 5-ASA derivatives should be taken into account when selecting the appropriate carrier composition for the ingredient.

A preferred active ingredient is currently free acid, namely 5-aminosalicylic acid.

The effective dose for oral administration depends on the degree of the disease, and for adults it is usually 0.5-1.0 g four times a day. As a rule, approximately 20 mg of 5-ASA or its salt or ester (calculated as 5-ASA) / kg body weight is recommended for the initial daily dosage, with subsequent adjustment in accordance with the observed treatment results.

Although the preferred coating agent is ethyl cellulose, other coating agents can also be used, provided that they retain the desired release pattern. In particular, it can be assumed that many other cellulose derivatives are applicable. Currently, the preferred release pattern is continuous release after ingestion in the small intestine. This release was originally designed to allow tablets, such as Pentasa ^® , to be effective against both Crohn's disease and ulcerative colitis.

However, in the case where it is desirable to maintain early release in the small intestine (in the case of Crohn's disease) or delayed release until the colon is reached (in the case of ulcerative colitis), the release pattern can be controlled by changing various parameters of the tablet, as discussed in WO 81/02671 referenced here.

EXAMPLE 1

Preparation of Pentasa tablets (existing granulation method. Based on the use of isopropanol)

Pentasa ^® 500 mg slow-release tablets

Component Name Amount per lot (155,000 tablets) Characteristics Active ingredient: 5-aminosalicylic acid 77.5 kg Ferring Other ingredients Povidone 3875 g ± 10% Ph. Eur. Isopropyl alcohol 17.3 kg Ph. Eur. Purified water 1550 g Ph. Eur. Ethyl cellulose a sufficient amount (d. to.) Ph. Eur. Acetone dk Ph. Eur. Magnesium stearate 155 g Ph. Eur. Talc 1395 g Ph. Eur. Microcrystalline cellulose up to 116250 g Ph. Eur.

Cooking equipment:

Equipment Function Mixer NICA M6L Granulation Extruder NICA E 220 Extruding AEROMATIC fluidized bed dryer Drying Vibrator FREWITT MG 8 Vibration Sieve MOGENSEN Tour 0254 Screening HÜTTLIN Kugelcoater HKC 200 or HÜTTLIN Kugelcoater HKC 400 Sheathing Mixer PRODIMA AC-HLR 500 Mixing KILIAN T 300 or KORSCH Pharmapress 250 Tabletting

Cooking stages

Pentasa ^® slow release tablets are prepared in 10 steps.

Stage 0: Starting daily use of equipment and ingredients

All equipment is checked for cleanliness before use.

Stage 1: Weighing

5-aminosalicylic acid is weighed and loaded into a mixer.

Stage 2: Granulation

A granulating liquid (povidone dissolved in a mixture of purified water and 2-propanol) is prepared and added during mixing. Stirring is continued for a certain time after the addition of the granulating liquid.

Stage 3: Extrusion

The granular mass is extruded into granules in the same way (mesh 1.0 × 1.0 (diameter (mesh thickness)).

Stage 4: Drying

The granules are transferred to a fluidized bed dryer and dried.

Stage 5: Screening

The dried granules are sieved through a Mogensen sieve (inclined sieve). Pellets that pass through a 0.8 mm mesh are discarded or may be collected for reprocessing, stored in sealed, labeled containers. Granules that do not pass through a 1.8 mm mesh are discarded.

Stage 6: Coating

The granules are coated in a Kugelcoater (fluid bed system) with a liquid consisting of ethyl cellulose in acetone. If any lumps are formed, the granules are sieved through a Mongensen sieve (inclined sieve).

Stage 7: Mixing

Coated granules, filler / binder (microcrystalline cellulose) and lubricants (magnesium stearate and talc) are transferred to a mixer and mixed thoroughly.

Stage 8: Pressing

The final mixture of coated granules and lubricants is compressed into tablets on a rotary tablet machine.

Stage 9: Dust removal

Pills dedust.

Stage 10: Packaging

Slow release tablets are placed in a labeled container and stored until approval by the Department of Quality Control is obtained.

1A-3A show enlarged photographs of granules from three different batches prepared using the existing method.

EXAMPLE 2

The effect of changing various method parameters

In the present example, dry and wet material was mixed in an Erweka AR 400E Intensive mixer. Extrusion was carried out in a Niro Fielder E140 extruder. Unless otherwise specified, the mesh used in the extruder has holes with dimensions of 0.9 × 0.9 mm (diameter (mesh thickness). A Retch Vibro sieve is used for particle size analysis.

Firstly, in the 2 ^3- factor analysis, 3 main parameters of the method were investigated: PVP content, water content and mixer speed:

Low level High level Factor a PVP 3% (w / w) 8% (w / w) Factor b Water 0% (w / w) 6% (w / w) Factor in Impeller 33 rpm 66 rpm

The resulting granules were evaluated by the yield after sieving in the range of 0.850-1.0 mm. The test was repeated 5 times, and the results demonstrate that both the water content and the PVP affect the yield in the range of 0.850-1.0 mm. The impeller speed does not affect the output in this range, as shown in table 1:

Table 1
The results of a 2 ^3- factor experiment showing% yield after sieving in the range of 0.850-1.0 mm. Test Average value Standard Deviation (SD) (one) 63.40 3.62 but 60.48 2.22 b 70.22 2.12 ab 80.66 3.74 at 60.68 3,59 av 66.38 4,52 bv 70,44 2.21 a B C 80.22 3.00

To optimize the content of water and PVP in the extruded granules, a new test was carried out in 2 repetitions. The water content along with isopropyl alcohol (IPA) was kept constant at 35% (w / w), and the water content was changed from 6, 12 to 18% (w / w). The PVP content was varied from 5, 6.5 to 8% (w / w).

The results shown in table 2 show that the higher the water content, the higher the yield. If the PVP content was increased to 8% (w / w), the yield decreased due to the formation of agglomerates.

Encouraged by the above results, the inventors conducted another test to investigate what could happen if the water content was further increased and IPA was excluded. The solvent content (water + IPA) was again kept constant at 35% (w / w), while the water content varied from 24, 30 to 35% (w / w). In addition, a solvent free of IPA was used in the test, the content of which was 30 and 33% (w / w). The PVP content ranged from 5 to 6.5% (w / w).

As shown in table 2, if the amount of water increases to 30% (wt./wt.), And IPA is excluded, get a higher yield of granules.

The effect of the mesh on the resulting granules

In order to optimize the holes in the extruder, various grids were tested. The results shown in table 3 indicate that for the selected wet mass, the best choice for obtaining granules having a particle size of 850-1000 μm, is 0.9 × 0.9 mm (diameter (mesh thickness).

Table 3
Particle size distribution as a function of mesh size Hole size mm 1.0 × 1.2 1.0 × 1.0 0.9 × 1.0 0.9 × 0.9 > 1180 2.0% 1.7% 1,0% 0.7% Particle size microns 1000-1180 78.2% 57.0% 4,5% 1.4% 850-1000 17.1% 39.2% 58.6% 92.8% <850 2.7% 2.2% 35.9% 5.2%

In a repeat test, the narrow and reproducible size distribution of the granules prepared in accordance with the preferred method of the present invention was investigated. The results are presented in table 4.

Table 4
Particle size distribution in batches prepared in accordance with the preferred method of the present invention Party number: > 1180 μm 850 μm <x <1180 μm <850 μm humidity% (w / w) 732902 2.2 92.8 4.7 0.56 733101 1,1 94.2 5.7 1.14 733102 0.9 94.2 5.2 0.99 733103 0.8 94.1 5,4 0.53 733104 1,0 94.2 5.3 0.46 733107 2.2 94.5 4.6 0.50 Average 1.4 94.0 5.2 0.51 With 0.65 0.60 0.42 0.04 Rds 48 0.64 8.1 8.3

The moisture content is also at an acceptable level. For practical use of the mesh in manufacturing equipment, a mesh thickness of 1.5 mm is preferred.

The strength of the granules was evaluated by treating the granules for 1 hour in a fluidized bed laboratory apparatus (STREA). Strength was compared with pellets prepared in accordance with existing Pentasa ^® production equipment. As shown in table 5, the strength of the granules prepared in accordance with the present invention increases.

Table 5
% of granules having a particle size of 850 μm to 1000 μm before and after processing the granules in a laboratory fluidized bed setup for 1 hour Party number Before Strea After Strea Difference The present invention 733102 94.2 95.2 -1.0 733103 93.9 94.1 -0.2 733104 93.9 94.6 -0.7 733107 94.8 93.9 0.9 Existing method EJGU838C 57.5 54.9 2.6 EJGU838D 63.5 60.9 2.6 EJGU837G 68.5 61.9 6.6 EJGU838H 53.3 44.6 8.7

Example 3

Preparation of tablets comprising 5-ASA (granulation method based on the use of water)

A new method of preparing 5-ASA tablets can be divided into 11 stages (Figure 4):

1. Preparation of granulating liquid

2. Granulation of 5-ASA with water and PVP

3. Extrusion

4. Fluidized bed drying

5. grinding

6. Screening

7. Coating

8. Screening

9. Air purge

10. Dry mixing with excipients

11. Pressing into tablets

Cooking equipment Function Extruder NICA E220 Extruding Rotostat T05 Mixing NIRO Fluid Bed Dryer Drying Quadro Comil U10 Grinding Sieve Mogensen Screening Hürtling Kugelcoater HKC 400 Sheathing Rotary sieve Prodima Screening Purge apparatus Air purge Mixer Prodima AC-HLR 1200 Dry mix Kilian T300-32 Tabletting

Stage 1:

For one batch of granulating liquid, 118.4 kg of water is poured into a Müller drum. The mixer operating parameters are selected and the mixer is started. 32 kg of polyvinylpyrrolidone (PVP) is slowly poured into water and the mixer is left to work for a fixed time until the entire PVP is dissolved.

Stage 2 and 3:

5-ASA is placed in a Prodima vibrating hopper and, through the use of a 5-ASA conveyor, is transported to a weight dispenser dosing 5-ASA into a continuous Niro line. In the first part of the Niro line, 5-ASA and an aqueous PVP solution are mixed until a wet mass is formed before being transported to the extruder. After extruding the wet mass of 5-ASA and the PVP / water mixture through a mesh having a 0.9 mm mesh, the granules fall directly into the fluidized bed dryer.

Stage 4:

The fluid bed dryer is divided into two main compartments. In the first compartment, the granules are dried on the surface to prevent them from sticking together. In this compartment of the fluidized bed, random mixing of the granules occurs. After some residence time, the granules are transferred to the second compartment of the dryer, where the drying itself is carried out. In the second compartment of the dryer, the granules are directed by using a stream of drying air through the dryer (a special pattern of holes in the ribbed plate). When the granules are dry, they are allowed to fall into a drum placed under a fluidized bed dryer. The fluidized bed dryer is designed so that the total residence time in the fluidized bed is approximately 2.5 hours.

Thanks to the continuous process, batch size is determined by how long the equipment operates. Therefore, the equipment is installed in such a way that it is possible to control the flow of various ingredients necessary for the process. In order to document the drying process, table 6 shows the results of loss during drying.

Table 6.
Loss on drying (% moisture in granules after drying) (n.i. = not available). Müller Drum AAA137 AAA138 AAA139 AAA140 one 0.40 0.34 0.37 0.37 2 0.37 0.30 0.40 0.40 3 0.46 0.29 0.37 0.37 four 0.33 0.40 0.40 0.33 5 0.37 0.39 n.i. 0.37 6 n.i. 0.29 n.i. 0.33 7 n.i. 0.34 n.i. 0.33 8 n.i. 0.37 n.i. 0.39 Average 0.37 0.39 0.39 0.36

Stage 5:

Drums containing dry granules are placed upside down on the surface of the mill and the granules are gently milled using a net that only destroys too long granules. After passing through the mill, the granules are allowed to fall into the drum. 5A-7A are enlarged photographs of three different batches of granules prepared in accordance with the present invention. The difference in shape, similarity and uniformity can be clearly detected when compared with granules prepared in accordance with the existing method (Figa-3A).

Stage 6:

Due to the fact that during the grinding process a small number of granules are formed, the size of which is smaller than the specified size, the granules are sieved using a Mogensen vibrating sieve. Pellets that pass through a 0.8 mm net are discarded, or they can be collected for reprocessing, stored in sealed, labeled containers. The results of the particle size analysis of the crushed and sieved granules are shown in Fig.5B-7B.

Stage 7:

200 kg of sieved granules are coated in a Kugel casing apparatus (fluidized bed system) with a casing fluid consisting of ethyl cellulose dissolved in acetone.

In order to be able to correctly determine the amount of polymer required for application to the granules in order to obtain the desired dissolution rate profile, the surface area of the granules is measured before the coating process. A preliminary determination of the amount of polymer that is necessary for application to the granules is based on the fact that there is a correlation between the amount of polymer per surface area and the dissolution rate of the granules. After completion of the coating process, the coated granules are loaded into a drum for further processing.

Stage 8:

After the coating process, the coated granules are sieved through a Prodima rotary sieve. Large lumps are removed.

Stage 9:

After sifting a batch of coated granules, they are distributed in two drums for purging with compressed air or nitrogen. The granules are purged for 6-14 hours. This blowing process is necessary to reduce the amount of residual solvent (acetone) in the coated granules.

The results of the test for the presence of residual solvent in the granules prepared in accordance with the existing method and in accordance with the new method are shown in table 7. As can be seen from table 7, the content of residual solvent is significantly reduced in the granules prepared in accordance with the new method. This can be attributed to the fact that these granules have a smoother surface compared to granules prepared by the existing method, therefore, the required amount of coating substance is reduced.

Table 7.
Residual Solvent in Pentasa ^® Coated Pellets Pentasa ^® granules according to the existing method The amount of acetone to purge air / nitrogen (mn ^-1) Amount of acetone after purging with air / nitrogen Party number (ppm ^-1 ) GIGC 905 5277 2607 GIGC 906 5556 1870 GIGC 907 4310 1798 Pentasa ^® granules according to the new method The amount of acetone to purge air / nitrogen (mn ^-1) Amount of acetone after purging with air / nitrogen Party number (ppm ^-1 ) AAF 333 965 331 AAF322 1125 402 AAF 327 1020 492

Stage 10

178.56 kg of Pentasa coated pellets are weighed and loaded into a Prodima mixer along with 69.34 kg of microcrystalline cellulose. After stirring for 210 seconds, the mixer is stopped. 0.335 kg of magnesium stearate and 3.02 kg of talc are added to the mixture, and the ingredients are mixed for 90 seconds. Mixing produces 335,000 tablets.

After mixing, the ready-to-press mixture is spread over the Müller drums.

Stage 11

The final mixture of coated granules and excipients is compressed on a rotary tablet machine. The weight of the tablets is 750 mg. Dust removal of the tablets is carried out in the same way as in the in-line method using a tablet machine. After dedusting the tablets, they are loaded into containers, each of which holds approximately 30,000 tablets.

The method of the present invention leads to an increased overall yield of 5-ASA tablets from the same amount of ingredients as compared to the yield obtained using the existing method. The properties of the tablets of 10 batches prepared in accordance with the present invention are shown in table 8.

As can be seen from these tables, the tablets prepared in accordance with the present invention satisfy the criteria for tablet acceptability, and the overall yield is approximately 85.5% compared to 69.2% for the existing method.

Dissolution rate profiles for Pentasa ^® tablets are shown in Figure 8.

Figure 9 shows the results for samples taken from the mixer to document the homogeneity of the mixture.

Table 8.
Test results for 10 batches of Pentasa ^® tablets Batch of pills Strength, N Weight mg Height mm Disintegration, sec Content uniformity, mg Mass fluctuation, mg Analysis mg / tab. Abrasion,% AAN025 98 749.1 4.10 10 520.0 515.8 507.0 0,03 491.4 498.9 AAN026 one hundred 751.5 4.04 eleven 523.9 509.2 503.8 0.05 497.8 498.4 AAN027 80 750.8 3.97 5 512.3 495.7 492.4 0.20 486.6 487.8 AAN028 99 751,4 4.04 8 514.5 498.4 489.3 0,07 483.7 486.7 AANO30 97 748.1 4.00 8 511.6 495.1 497.1 0,03 486.0 487.2 AAN031 92 750.9 3.98 9 509.9 508.9 502.2 0.04 481.4 496.8 AAN032 96 751.6 3.97 eleven 507.3 499.9 495.9 0.08 485.9 492.6 AANO33 99 753.1 4.02 9 516.6 506.4 504.4 0,03 495.3 499.0 AAN034 103 749.1 4.00 9 513.6 500.9 495.0 0.04 467.3 488.4 AAN035 97 749.8 4.08 7 531.1 493.8 491.8 0.04 487.9 485.2 Eligibility criteria 84-112, the average of 10 735-765, average of 10 3.80-4.20, average of 10 ≤5 min, average of 6 425-575 each tablet 425-575 each tablet 450-550, average of 20 ≤0.8%, average 10 Result Satisfies Satisfies Satisfies Satisfies Satisfies Satisfies Satisfies Satisfies

Claims (24)

1. A method of preparing granules comprising 5-aminosalicylic acid (5-ASA) or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable binder, wherein a) dissolving a pharmaceutically acceptable binder in a solvent, b) mix the dissolved binder with 5-ASA to form a wet mass, c) extruding the wet mass into granules and d) the granules are dried by evaporation of the solvent, characterized in that the solvent contains at least 50% (w / w) of water. 2. The method according to claim 1, where the solvent contains at least 85% (wt./wt.) Water. 3. The method according to claim 1, where the solvent contains at least 95% (wt./wt.) Water. 4. The method according to claim 1, where the solvent is free of organic solvent. 5. The method according to claim 1, where the solvent contains one or more than one additive, such as one or more chelating agents, antioxidants, reducing agents, buffers, pH adjusting agents, cosolvent, or any other suitable excipient. 6. The method according to claim 1, where the wet mass is extruded through a grid having tapering holes, each hole having a cross section on the inlet side of the grid, which is larger than the cross section on the outlet side of the grid. 7. The method according to claim 6, where the outlet diameter is 0.9 mm and the inlet diameter is 0.95 mm. 8. The method according to claim 1, where more than 75% of the granules have a particle size of from 850 microns to 1000 microns. 9. The method according to claim 1, where more than 85% of the granules have a particle size of from 850 microns to 1000 microns. 10. The method according to claim 1, where more than 90% of the granules have a particle size of from 850 microns to 1000 microns. 11. The method according to claim 1, where the dry granules include up to 8% by weight of the specified binder (solids content, based on 5-aminosalicylic acid). 12. The method according to claim 1, where the dry granules include up to 6.5% by weight of a binder (solids content based on 5-aminosalicylic acid). 13. The method according to claim 1, where the dry granules include 5% by weight of a binder (solids content based on 5-aminosalicylic acid). 14. The method according to any one of claims 11 to 13, where the binder is polyvinylpyrrolidone. 15. The method according to claim 1, wherein the drying step is carried out in a fluidized bed. 16. The method according to claim 1, in which additionally carry out the stage of grinding and sieving of granules. 17. The method according to claim 1, where the stages are part of a continuous process. 18. A method of preparing sustained release tablets suitable for the treatment of ulcerative colitis or Crohn’s disease, in which the steps are carried out in which a) granules are prepared in accordance with any one of claims 1-17, b) a coating composition is applied to said granules, comprising a solution of a pharmaceutically acceptable coating substance in an organic solvent, thereby obtaining coated granules by evaporating the solvent, c) mixing the coated granules with one or more than days a pharmaceutically acceptable tablet excipient; and d) form the tablets from the resulting mixture. 19. The method according to p, where the coating substance is selected to obtain on the surface of the granules of the barrier, limiting the speed, preferably a semipermeable barrier. 20. The method according to claim 19, where the coating substance is a cellulose derivative. 21. The method according to claim 20, where the coating substance is ethyl cellulose. 22. The method according to p, where the excipients for tablets include microcrystalline cellulose. 23. The method of claim 18, wherein the tablet excipients include magnesium stearate. 24. The method of claim 18, wherein the tablet excipients include magnesium stearate and talc.

Images