RU2848126C2 - Composition of mesalazine with prolonged release and methods for obtaining it - Google Patents

Abstract

FIELD: mesalazine composition with prolonged release and method for its preparation.

SUBSTANCE: a sustained-release mesalazine composition comprises: from about 55 to about 65 wt% mesalazine; from about 26 to about 30 wt% sugar spheres; from about 4 to about 6 wt% binder; from about 0.3 to about 0.75 wt% of a first plasticiser; from about 3 to about 7 wt% of a release-modifying agent; from about 2 to about 5 wt% of a porogen; from about 0.4 to about 1.5 wt% of a second plasticiser; and from about 1 to about 3 wt% of a lubricant. The release-regulating agent acts independently of pH.

EFFECT: the binding agent is a water-miscible aqueous dispersion.

14 cl, 6 dwg, 15 tbl

Description

AREA OF TECHNOLOGY

[0001] The present invention relates to a pharmaceutical composition containing mesalazine with prolonged release. In particular, the present invention relates to a pharmaceutical composition in the form of particles containing the active drug substance mesalazine for oral administration, as well as to a method for producing the same for formulating a sachet dosage form.

LEVEL OF TECHNOLOGY

[0002] Mesalazine, also known as mesalamine, is chemically 5-aminosalicylic acid. The chemical structure of mesalazine is shown below.

[0003] Mesalazine is used to treat ulcerative colitis (a condition in which part or all of the lining of the colon [large intestine] swells or wears away). Delayed-release mesalazine tablets and controlled-release capsules can be used to treat ulcerative colitis affecting any part of the colon. Conventional mesalazine granules have been available for a long time; however, the manufacturing process for conventional granules is not highly reproducible and requires multiple machines to carry out the various manufacturing steps, resulting in a slower process. Furthermore, the layering process to produce conventional mesalamine granules does not produce a high-drug-load suspension.

[0004] Accordingly, there is a need for a sachet dosage form having a composition that has improved prolonged release, requires less manufacturing time, uses a minimal amount of ingredients, has improved bioavailability, as well as a method for producing it for producing a mesalazine composition with prolonged release, which is faster, simpler, easier, more reliable, automated and reproducible.

BRIEF DESCRIPTION OF THE INVENTION

[0005] To achieve and satisfy the above and other

To address the objectives and needs of the present invention, a mesalazine extended-release composition is provided that exhibits improved sustained release, requires less preparation time, uses a minimal amount of ingredients, and exhibits improved bioavailability. Furthermore, the present invention provides a method for producing a mesalazine extended-release composition that is faster, simpler, easier, more reliable, automated, and reproducible, wherein all steps of producing the mesalazine extended-release composition can be performed using minimal equipment.

[0006] In one embodiment, the present invention relates to an extended release mesalazine composition comprising: about 55 to about 65 percent by weight of mesalazine; about 26 to about 30 percent by weight of sugar spheres; about 4 to about 6 percent by weight of a binder; about 0.3 to about 0.75 percent by weight of a first plasticizer; about 3 to about 7 percent by weight of a release controlling agent; about 2 to about 5 percent by weight of a pore-forming agent; about 0.4 to about 1.5 percent by weight of a second plasticizer; and about 1 to about 3 percent by weight of a lubricant. The binder is a water-miscible aqueous dispersion. The release controlling agent acts independently of pH.

[0007] In one or more embodiments, the mesalazine comprises from about 55 to about 65 percent by weight and is a micronized material with a particle size distribution in the D90 range of less than 50 microns.

[0008] In one or more embodiments, the binder is Eudragit L30 D 55.

[0009] In one or more embodiments, the first plasticizer is triethyl citrate.

[0010] In one or more embodiments, the sugar spheres have a size of from about 425 microns to 600 microns.

[0011] In one or more embodiments, the release controlling agent is ethylcellulose No. 20.

[0012] In one or more embodiments, the pore-forming agent is polyvinylpyrrolidone K-30.

[0013] In one or more embodiments, the second plasticizer is dibutyl sebacate.

[0014] In one or more embodiments, the lubricant is purified talc.

[0015] In one or more embodiments, the extended release mesalazine composition comprises in vitro dissolution of: up to 30% dissolution in 1 hour; 20%-60% dissolution in 2 hours; 40%-80% dissolution in 4 hours; and 75%-100% dissolution in 8 hours.

[0016] In one or more embodiments, the composition is in the form of granules packaged in a sachet.

[0017] In another embodiment, the present invention relates to a method for producing a mesalazine composition with an extended release. The proposed method includes: obtaining a binder solution by mixing a binder and a first plasticizer; coating mesalazine on sugar spheres using the binder solution to obtain drug-coated granules; obtaining a prolonged-release coating suspension by mixing a release regulating agent, a pore-forming agent, a second plasticizer, and a lubricant; coating the prolonged-release coating by coating the prolonged-release coating suspension on the drug-coated granules to obtain prolonged-release granules; and lubricating the prolonged-release coated granules.

[0018] In one or more embodiments, the disclosed method includes coating a drug substance layer in a flat-bottomed pan, applying a sustained release coating in a fluid bed coater, and lubrication in a Conta mixer.

[0019] In one or more embodiments, the binder is Eudragit(L30 D 55.

[0020] In one or more embodiments, the first plasticizer is triethyl citrate.

[0021] In one or more embodiments, the sugar spheres have a size of from about 425 microns to 600 microns.

[0022] In one or more embodiments, the release controlling agent is ethylcellulose No. 20.

[0023] In one or more embodiments, the pore-forming agent is polyvinylpyrrolidone K-30 (povidone K 30).

[0024] In one or more embodiments, the second plasticizer is dibutyl sebacate.

[0025] In one or more embodiments, the lubricant is purified talc.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

[0026] The advantages and features of the present invention will become more apparent with reference to the following detailed description and claims taken in conjunction with the accompanying drawings, in which:

[0027] Fig. 1 depicts a flow chart for producing a sustained release mesalazine composition in accordance with an illustrative embodiment of the present invention;

[0028] Fig. 2 shows in detail the preparation of a binder solution in accordance with the method shown in Fig. 1;

[0029] Fig. 3 shows in detail the production of granules with a layer of a drug substance applied in accordance with the method shown in Fig. 1;

[0030] Fig. 4 shows in detail the preparation of a prolonged release coating suspension in accordance with the method shown in Fig. 1;

[0031] Fig. 5 shows in detail the application of a sustained release coating in the process shown in Fig. 1; and

[0032] Fig. 6 shows in detail the lubrication of the coated granules for extended release in the process shown in Fig. 1.

DETAILED DESCRIPTION OF THE INVENTION

[0033] The illustrative embodiments described in detail herein for illustrative purposes are subject to numerous changes in design and construction. However, it should be emphasized that the present invention is not limited to the shown and described method for producing an extended-release mesalazine composition and the extended-release mesalazine composition thereof. It should be understood that various exclusions and substitutions of equivalents are provided depending on the circumstances indicating them or causing their desirability, but they are intended to be included in the present application or embodiment without departing from the spirit or scope of the claims of the present invention. It should also be understood that the phraseology and terminology used herein are intended for description and should not be construed as limiting.

[0034] The use of the terms "including," "comprising," or "having," and variations thereof, in this context includes the elements listed below and their equivalents, as well as additional elements. Furthermore, the singular form of the terms in this context does not denote a limitation of quantity, but denotes the presence of at least one of the mentioned elements.

[0035] Furthermore, the singular terms in this context do not denote a limitation of quantity, but denote the presence of at least one of the mentioned elements.

[0036] In this context, the term "about" is understood by those skilled in the art and varies to some extent depending on the context in which it is used. In cases where the use of the said term is not understood by those skilled in the art, given the context in which it is used, the term "about" means within plus or minus 10% of the specific value.

[0037] The present invention includes a patient-friendly dosage regimen for mesalazine. The inventors of the present application have found that these properties can be achieved by developing a sachet dosage form containing a mixture of excipients and mesalazine.

[0038] The present invention relates to a mesalazine composition with prolonged release (in the form of granules/sachets) and to a method for producing mesalazine (hereinafter referred to as the method). In particular, the proposed mesalazine composition with prolonged release has an improved prolonged release, requires less time for production, involves the use of a minimum amount of ingredients and has improved bioavailability. In addition, all stages of producing the mesalazine composition with prolonged release can be performed on a minimum number of machines, due to which the production process is carried out using less equipment. Accordingly, the present invention provides a faster, simpler, more reliable, automated and reproducible method for producing a mesalazine composition with prolonged release.

[0039] An extended release mesalazine composition of the present invention comprises: mesalazine; sugar spheres; a binder; a first plasticizer; a release controlling agent; a pore-forming agent; a second plasticizer; and a lubricant. In one embodiment, the extended release mesalazine composition comprises: from about 55 to about 65 percent by weight of mesalazine; from about 26 to about 30 percent by weight of sugar spheres; from about 4 to about 6 percent by weight of a binder; from about 0.3 to about 0.75 percent by weight of a first plasticizer; from about 3 to about 7 percent by weight of a release controlling agent; from about 2 to about 5 percent by weight of a pore-forming agent; from about 0.4 to about 1.5 percent by weight of a second plasticizer; and from about 1 to about 3 percent by weight of the lubricant. The binder is a water-miscible aqueous dispersion. The release agent acts independently of pH.

[0040] In this context, mesalazine, also known as mesalamine or 5-aminosalicylic acid, is an anti-inflammatory drug used to treat inflammatory bowel disease such as ulcerative colitis and mild to moderate Crohn's disease. Mesalazine is a gut-specific aminosalicylate drug that acts locally in the intestine and has a predominant effect there, causing few systemic side effects. Furthermore, in this document, mesalazine granules are fine particles obtained by pressing processed mesalazine obtained by the method described below.

[0041] In this context, the sugar spheres have a size of from about 425 µm to about 600 µm.

[0042] An "inert core" or "core material" is a material onto which a layer of mesalazine is applied to form drug particles. As used herein, the "inert core" or "core material" refers to sugar spheres. The inert core of the present invention is a particle (or a spherical carrier or a granule). The material used for the inert core is chemically inert in that it does not interact with any of the other ingredients of the multilayer particle of the present invention and, in particular, does not interfere with the intended pharmacological mechanism exhibited by the pharmaceutically active ingredient of the multilayer particle. Examples of the material used for the inert core are cellulose, spheres, in particular, of microcrystalline cellulose, starch, lactose, sugar spheres, mannitol spheres or mixtures thereof, or any other granular material such as granulated mannitol, sugar crystals. Commercially available inert core materials can also be used. An advantage was found in using particles with a particle size (diameter) of approximately 425 µm to 600 µm.

[0043] In one embodiment, the mesalazine comprises from about 55 to about 65 percent by weight and is a micronized material with a particle size distribution in the D90 range of less than 50 microns.

[0044] Binders used in accordance with the present invention include, but are not limited to, tragacanth, gum arabic, gelatin, starch, cellulosic materials such as methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polymethacrylates, povidone, sucrose, alginic acids and their salts, polyethyleneglycol, guar gum, polysaccharide acids, sugars, and the like. In the present invention, the binder is a water-miscible aqueous dispersion.

[0045] In one embodiment, the binder is Eudragit(L30 D55. Eudragit(L30 D55 is an anionic copolymer containing free carboxyl groups in a 1:1 ratio with ester groups.

[0046] A membrane coating of a dosage form with release is an effective means for creating an effective drug delivery system. Polymers applied as a coating in their pure form have a limited ability to form a rate-controlling membrane with good mechanical properties. The addition of a plasticizer is extremely important for the formation of a durable rate-controlling membrane. Plasticizers have the ability to interact with polymer chains and provide the required flexibility, impact resistance, and smoothness of the resulting system. Plasticized polymers are essential in pharmaceutical technology. For example, they can be used as coating materials for dosage forms, free membranes of pharmaceutical films, polymeric membranes of a transdermal system, matrix systems for drug layer formulations or microparticles. In addition to the plasticizing effect, they also play an important role in modulating the release profiles of a drug. The choice of plasticizer is crucial for the stability of the dosage form, processability, and in vivo efficacy.

[0047] In one embodiment, the first plasticizer is triethyl citrate. Triethyl citrate plays an important role as a plasticizer in a variety of pharmaceutical industry processes, improving the processability of polymers used for coatings. Triethyl citrate is an ester of citric acid, which is a colorless, odorless, oily liquid, commonly used as a hydrophilic plasticizer in pharmaceutical compositions.

[0048] When used in the present invention, the release-controlling agent is ethylcellulose with a viscosity of 7 cP to 50 cP. In a preferred embodiment, the release-controlling agent is Ethocel No. 20. Ethocel No. 20 is a polymer that is a high-purity, inert powder with no caloric value and is virtually colorless, odorless, and tasteless. It is a derivative of and has a polymer "backbone" of cellulose, a natural polymer. Ethocel No. 20 is effective as a controlled-release coating, microencapsulation, granulation, and taste-masking agent. When used in the present invention, the release-controlling agent acts independently of pH.

[0049] Water-soluble pore-forming materials include polymeric materials such as povidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, or sugar. When used in the present invention, the water-soluble pore-forming material is povidone.

[0050] In one embodiment, the pore-forming agent is polyvinylpyrrolidone K-30 (povidone K-30). Povidone K-30 is also commonly known as (PVP K-30). Povidone (polyvinylpyrrolidone, PVP) is used in the pharmaceutical industry as a synthetic polymer carrier for dispersing and suspending drugs. It has many applications, including as a binder for tablets and capsules, a film-forming agent for ophthalmic solutions, an additive for flavored liquids and chewable tablets, and an adhesive for transdermal systems. PVP K-30 has a molecular formula of (C ₆ H ₉ NO) _n and is a white to slightly off-white powder in appearance. PVP K-30 compounds are widely used in the pharmaceutical industry due to their ability to dissolve in both water and oil solvents.

[0051] In one embodiment, the second plasticizer is dibutyl sebacate (DBS). Dibutyl sebacate is an organic chemical consisting of esters of n-butyl alcohol and saturated diacids, primarily sebacic acid. Dibutyl sebacate is used in oral pharmaceutical formulations as a plasticizer for film coatings on tablets, grains, and granules. It is also used as a plasticizer in controlled-release tablets and microcapsule formulations. In particular, dibutyl sebacate (DBS) provides excellent compatibility with ethylcellulose and exhibits excellent low-temperature properties, as well as high oil resistance.

[0052] In one embodiment, the lubricant is purified talc. The lubricant prevents the ingredients from sticking together and adhering to the punches of a tablet press or capsule filling machine. In addition, in the formulation of granules, the lubricant reduces the sticking of the granules. The lubricant also allows for the formation and ejection of tablets with low friction between the solid and the die wall. The most commonly used lubricants in tablets or hard gelatin capsules are common minerals such as talc or silicon dioxide, and fats such as vegetable stearin, magnesium stearate, or stearic acid. A lubricant is an agent added in small amounts to tablet and capsule formulations to improve certain processing characteristics.

[0053] In one or more embodiments, the extended release mesalazine composition comprises in vitro dissolution of: up to 30% dissolution at 1 hour; 20%-60% dissolution at 2 hours; 40%-80% dissolution at 4 hours; and 75%-100% dissolution at 8 hours. The dissolution at 8 hours is always greater than 75%, wherein the dissolution parameters for the composition are measured in a paddle system operating at 100 rpm with 900 ml of phosphate buffer at pH 7.5. In a preferred embodiment, the extended release mesalazine composition is always more than 75% dissolved at 8 hours.

[0054] The method according to the present invention includes the steps of: providing a binder; applying a drug layer; providing a suspension of a prolonged-release coating; applying a prolonged-release coating; and lubrication.

[0055] A method for producing a mesalazine composition with an extended release includes: obtaining a binder solution by mixing a binder and a first plasticizer; applying a layer of mesalazine to sugar spheres using the binder solution to obtain granules with the coated drug layer; obtaining a suspension of a coating for an extended release by mixing a release regulating agent, a pore-forming agent, a second plasticizer and a lubricant; applying a coating for an extended release by applying the suspension of the coating for an extended release to the granules with the coated drug layer to obtain granules with an extended release; and lubricating the granules with the coated extended release.

[0056] As shown in Fig. 1, the method 100, at step 102, includes providing a binder solution by mixing a binder and a first plasticizer. At step 104, coating the sugar spheres with mesalazine using the binder solution to form drug-coated granules. At step 106, providing a prolonged release coating suspension by mixing a release regulating agent, a pore-forming agent, a second plasticizer, and a lubricant. At step 108, applying a prolonged release coating by coating the prolonged release coating suspension onto the drug-coated granules to form prolonged release granules. At step 110, lubricating the prolonged release coated granules. Step 102 shown in Fig. 1 is described in detail in Fig. 2. Stage 104 shown in Fig. 1 is described in detail in Fig. 3. Stage 106 shown in Fig. 1 is described in detail in Fig. 4. Stage 108 shown in Fig. 1 is described in detail in Fig. 5. Stage 110 shown in Fig. 1 is described in detail in Fig. 6.

[0057] As shown in Fig. 1, the method 100 in step 102 includes obtaining a binder solution containing Eudragit(L30 D55 and triethyl citrate. In step 102, the preparation of the binder solution begins with dispersing Eudragit(L30 D55 (i.e., the binder) in purified water to obtain a Eudragit suspension. Then, triethyl citrate is added to the Eudragit( suspension to obtain a binder solution. Step 102 shown in Fig. 1 is described in detail in Fig. 2. As shown in Fig. 2, in step 202, Eudragit(L30 D55 is dispersed in purified water in a stainless steel vessel using a pneumatic stirrer to stir the mixture for 15 minutes to obtain a white to off-white suspension. The resulting white or off-white suspension is a Eudragit suspension.

[0058] Then, in step 204, triethyl citrate (i.e., the first plasticizer) is added to the Eudragit suspension obtained in step 202. After the addition is complete, the mixture is stirred for 15 minutes in a stainless steel vessel using a pneumatic stirrer. After this, at the end of step 204, a cloudy suspension ranging from white to off-white in color is obtained. The resulting cloudy suspension is a solution of the binder.

[0059] As shown in Fig. 1, the next step of the method 100, step 104, includes coating the sugar spheres with a mesalazine layer using a binder solution to produce drug-coated granules. As shown in Fig. 3, at step 302, the sugar spheres are coated with a mesalazine layer using a binder solution in a flat-bottomed coating pan to produce drug-coated granules. In particular, the binder solution is continuously sprayed onto the sugar spheres using a Bink Bullow peristaltic pump and a tumble coating pan with a coating pan speed of 12-25 rpm. Mesalazine is periodically added to the coating pan and mixed thoroughly to distribute and adhere it to the sugar spheres. As a result of applying a layer of mesalazine to the sugar spheres at step 302, granules with a layer of the drug substance applied are obtained.

[0060] After all of the mesalazine has adhered to the sugar spheres and drug-coated granules have been obtained, the drug-coated granules are dried in step 304 in a flat-bottomed coating pan at an inlet temperature of 48-52°C and a rotation speed of the coating vessel of 4-6 rpm. After this, the pre-dried drug-coated granules are sieved through 16, 18, and 20 mesh sieves mounted on a vibrating sifter, and agglomerated granules are removed, in step 306. The drug-coated granules are re-sieved through a vibrating sifter equipped with 30 and 40 mesh sieves, and small granules are removed. Collect the sieved granules (with a size of less than 16, 18 and 20 mesh) in a HDPE container with a polyethylene bag inserted into it, and weigh the sieved granules.

[0061] As shown in Fig. 1, the next step of the method 100, step 106, includes preparing a suspension of the extended release coating by mixing a release regulating agent, a pore-forming agent, a second plasticizer and a lubricant. In particular, the suspension of the extended release coating is prepared by mixing ethylcellulose N 20, purified talc, polyvinylpyrrolidone K-30 and dibutyl sebacate. Step 106 shown in Fig. 1 is described in detail in Fig. 4. As shown in Fig. 4, in step 402, Ethocel N 20 is added to isopropyl alcohol in a stainless steel tank equipped with a pneumatic stirrer, and the mixing process is continued for 30 minutes to completely dissolve the mixture. Then, in step 404, povidone K 30 is added to the above solution obtained in step 402 while stirring and dissolved in the process of continuous stirring for 15 minutes to obtain a solution of povidone K 30 and Ethocel N 20. Then, in step 406, purified water is added to the above solution obtained in step 404 while stirring and the stirring process is continued for 10 minutes to obtain a suspension of povidone K 30 and Ethocel N 20. Then, in step 408, dibutyl sebacate and purified talc are added to the above suspension obtained in step 406 while stirring and dissolved in the process of continuous stirring for 30 minutes to obtain a transparent or cloudy suspension. The resulting transparent or cloudy suspension is a suspension of the extended release coating. Then, in step 410, the extended release coating suspension obtained in step 408 is continuously stirred to prevent settling and foaming before coating the drug-coated granules.

[0062] As shown in Fig. 1, the next step of the method 100, step 108, includes applying a sustained release coating by applying a suspension of the sustained release coating to the drug-coated granules to form sustained release coated granules. Step 108 shown in Fig. 1 is described in detail in Fig. 5. As shown in Fig. 4 and Fig. 5, in step 502, the suspension of the sustained release coating obtained in step 410 shown in Fig. 4 is applied to the drug-coated granules in a fluidized bed coater under predetermined parameters. In this context, a non-limiting example of predetermined parameters includes an inlet temperature of from about 30°C to about 50°C, a product temperature of from about 25°C to about 35°C, and an atmospheric pressure of from about 1.0 kg/ ^cm2 to about 3.0 kg/ ^cm2 , to produce granules coated for prolonged release. Although specific predetermined parameters are mentioned above, those skilled in the art will appreciate the possibility of changing the predetermined parameters based on obvious variations.

[0063] Then, in step 504, the granules with the extended release coating are dried in a fluid bed coater under predetermined parameters. In this context, a non-limiting example of predetermined parameters includes an inlet temperature of from about 30°C to about 50°C, a product temperature of from about 25°C to about 35°C. Although specific predetermined parameters are mentioned above, those skilled in the art will understand the possibility of changing the predetermined parameters based on obvious variations. Then, in step 506, the dried granules of the drug substance are poured and sieved through a vibrating sifter equipped with 16 and 30 mesh screens, and small granules are removed. The sieved granules (with a size of less than 16 mesh) are collected in an HDPE container into which a polyethylene bag is inserted, and the sieved granules are weighed. Finally, after the screening process, granules with a coated extended release coating are obtained.

[0064] As shown in Fig. 1, the next step of the method 100, step 110, includes lubricating the granules with the coating for prolonged release. Step 110, shown in Fig. 1, is described in detail in Fig. 6. Then, in step 602, the granules with the coating for prolonged release are lubricated using purified talc in the hopper of a Conta mixer and by mixing the granules with the coating for prolonged release for about 5 minutes at 8 rpm to obtain lubricated granules of mesalazine. The lubricated granules of mesalazine are then discharged into suitable drums with a label indicating the product name, lot number and weight, and transferred to a granule storage area. Finally, in a sachet filling machine, the sachets are filled with the calculated amount of lubricated granules of mesalazine.

[0065] Conventional tools such as a flat-bottomed coating pan, a Bink Bullows spray gun with a nozzle, a fluid bed coater, a pneumatic stirrer, a Conta mixer, and a sachet filling machine are used to manufacture the mesalazine drug in 1 g and 2 g granules.

[0066] The description of the present invention, which relates to a pharmaceutical composition and a method for preparing the same, is further illustrated by the following non-limiting examples. Those skilled in the art will understand that the specific examples are intended to illustrate, and not limit, the scope of the present invention.

EXAMPLES

Application of a layer of medicinal substance

[0067] The example "Depositing a layer of a drug substance" describes a method for producing a mesalazine composition with an extended release (mesalazine granules).

[0068] In the first batch, the process for producing mesalazine granules began with the preparation of a binder solution. The binder solution contained Eudragit(L30 D55 and triethyl citrate. 505.2 g of Eudragit(L30 D55 was dispersed in a sufficient quantity (Q.S.) of purified water in a stainless steel vessel using a pneumatic stirrer to obtain a white to off-white suspension. The resulting white to off-white suspension constitutes the Eudragit suspension. Then, 15.3 g of triethyl citrate were added to the Eudragit suspension. After the addition was complete, the mixture was stirred in the stainless steel vessel using a pneumatic stirrer. This resulted in a white to off-white turbid suspension. The resulting turbid suspension constitutes the binder solution.

[0069] The next step is to coat the sugar spheres with a binder solution to form drug-coated granules (spherical drug granules) in a flat-bottomed coating pan. Specifically, the binder solution was continuously sprayed onto 880.38 g of sugar spheres (i.e., the inert core) using a Bink Bullow peristaltic pump and a tumble coating pan. 1991.81 g of mesalazine was periodically added to the coating pan and thoroughly mixed to distribute and adhere it to the sugar spheres.

[0070] After all the mesalazine had adhered to the sugar spheres, the sugar spheres were dried in a tumbling pan (with an inlet temperature of 48-52°C) in hot air to obtain dried granules with a coated layer of the drug substance. The granules with the coated layer of the drug substance were then sieved through a sieve mounted on a vibrating sifter, and agglomerated granules were removed. The granules of the drug substance were re-sieved through a sieve mounted on a vibrating sifter, and small granules were removed. The sieved granules were collected in a HDPE container into which a polyethylene bag was inserted, and the sieved granules were weighed. In one embodiment, the layering or coating is carried out in a flat-bottomed pan or in a fluidized bed coater, or using extrusion and spheronization.

[0071] Table 1A below shows the various ingredients for producing drug-coated granules, which includes preparing a binder solution and coating the drug layer. In addition, Table 1B below shows the properties of the drug-coated granules.

[0072] In the second batch, the process for producing mesalazine granules began with the preparation of a binder solution. The binder solution contained Eudragit(L30 D55 and triethyl citrate. 842.0 g of Eudragit(L30 D55 was dispersed in a sufficient quantity (Q.S.) of purified water in a stainless steel vessel using a pneumatic stirrer to obtain a white to off-white suspension. The resulting white to off-white suspension constitutes the Eudragit suspension. Then, 25.5 g of triethyl citrate were added to the Eudragit suspension. After the addition was complete, the mixture was stirred in the stainless steel vessel using a pneumatic stirrer. This resulted in a white to off-white turbid suspension. The resulting turbid suspension constitutes the binder solution.

[0073] The next step is to coat the sugar spheres with a binder solution to form drug-coated granules (spherical drug granules) in a flat-bottomed coating pan. Specifically, the binder solution was continuously sprayed onto 1467.3 g of sugar spheres (i.e., the inert core) using a Bink Bullow peristaltic pump and a tumble coating pan. 3319.69 g of mesalazine was periodically added to the coating pan and thoroughly mixed to distribute and adhere it to the sugar spheres.

[0074] After all of the mesalazine had adhered to the sugar spheres, the sugar spheres were dried in a tumbling pan (with an inlet temperature of 48-52°C) in hot air to obtain dried granules with a coated layer of the drug substance. The granules with the coated layer of the drug substance were then sieved through a sieve mounted on a vibrating sifter, and agglomerated granules were removed. The granules of the drug substance were re-sieved through a sieve mounted on a vibrating sifter, and small granules were removed. The sieved granules were collected in a HDPE container into which a polyethylene bag was inserted, and the sieved granules were weighed. In one embodiment, the layering or coating is carried out in a flat-bottomed pan or in a fluidized bed coater, or using extrusion and spheronization.

[0075] Table 2A below shows the various ingredients for producing drug-coated granules, which includes preparing a binder solution and coating the drug layer. In addition, Table 2B below shows the properties of the drug-coated granules.

Extended release coating

[0076] The example "Extended Release Coating" describes a method for producing mesalazine granules with an extended release coating.

[0077] In the first batch, a suspension of the extended-release coating was prepared by mixing a release-regulating agent, a pore-forming agent, a second plasticizer, and a lubricant. Specifically, the suspension of the extended-release coating was prepared by mixing ethylcellulose No. 20, polyvinylpyrrolidone K-30, dibutyl sebacate, and purified talc. A stainless steel tank with a pneumatic stirrer was used, into which a sufficient amount of isopropyl alcohol was transferred, and then 29.19 g of ethylcellulose No. 20 (Ethocel No. 20) was added and stirred to thoroughly mix the solution. 19.76 g of povidone K 30 were added to the solution obtained in the above steps to obtain a solution of povidone K 30 and Ethocel N 20. Then, a sufficient amount of purified water was added to the resulting solution with stirring, and stirring was continued to obtain a suspension of povidone K 30 and Ethocel N 20. Then, 5.29 g of dibutyl sebacate and 10.76 g of purified talc were added to the suspension of povidone K 30 and Ethocel N 20 with stirring and dissolved during continuous stirring to obtain a suspension of the extended-release coating. Then, the resulting suspension of the extended-release coating was continuously stirred to prevent settling and foaming before coating the drug granules.

[0078] Then, a prolonged release coating was applied. The prolonged release coating was carried out by applying the resulting prolonged release coating suspension to the drug-coated granules to obtain prolonged release coated granules. In particular, the resulting prolonged release coating suspension was applied to the drug-coated granules in a fluid bed coating device under predetermined parameters. In this context, a non-limiting example of predetermined parameters includes an inlet temperature of from about 30°C to about 50°C, a product temperature of from about 25°C to about 35°C, to obtain prolonged release coated granules. Although specific predetermined parameters are mentioned above, those skilled in the art will understand that the predetermined parameters can be changed based on obvious variations.

[0079] The granules with the coating for the extended release were then dried in a fluid bed coater under predetermined parameters. In this context, a non-limiting example of the predetermined parameters includes an inlet temperature of from about 30°C to about 50°C, a product temperature of from about 25°C to about 35°C. Although specific predetermined parameters are mentioned above, those skilled in the art will understand the possibility of changing the predetermined parameters based on obvious variations. The granules with the coating for the extended release were then poured and sieved through a sieve mounted on a vibrating sifter, and small granules were removed. The sieved granules were collected in an HDPE container into which a polyethylene bag was inserted, and the sieved granules were weighed. Finally, after the sieving process, the granules with the coating for the extended release were obtained.

[0080] Table 3A lists the various ingredients for producing the extended-release coating, which includes preparing the extended-release coating suspension and applying the extended-release coating. In addition, Table 3B below shows the properties of the extended-release coated granules. In addition, Table 3C below presents the dissolution data for the extended-release coated granules.

[0081] In the second batch, a suspension of the extended-release coating was prepared by mixing a release-regulating agent, a pore-forming agent, a second plasticizer, and a lubricant. Specifically, the suspension of the extended-release coating was prepared by mixing ethylcellulose No. 20, polyvinylpyrrolidone K-30, dibutyl sebacate, and purified talc. A stainless steel tank with a pneumatic stirrer was used, into which a sufficient amount of isopropyl alcohol was transferred, and then 53.89 g of ethylcellulose No. 20 (Ethocel No. 20) was added and stirred to thoroughly mix the solution. 36.47 g of povidone K 30 were added to the solution obtained in the above steps to obtain a solution of povidone K 30 and Ethocel N 20. Then, a sufficient amount of purified water was added to the resulting solution with stirring, and stirring was continued to obtain a suspension of povidone K 30 and Ethocel N 20. Then, 9.77 g of dibutyl sebacate and 19.86 g of purified talc were added to the suspension of povidone K 30 and Ethocel N 20 with stirring and dissolved during continuous stirring to obtain a suspension of the extended-release coating. Then, the resulting suspension of the extended-release coating was continuously stirred to prevent settling and foaming before coating the drug granules.

[0082] Then, a prolonged release coating was applied. The prolonged release coating was carried out by applying the resulting prolonged release coating suspension to the drug-coated granules to obtain prolonged release coated granules. In particular, the resulting prolonged release coating suspension was applied to the drug-coated granules in a fluid bed coating device under predetermined parameters. In this context, a non-limiting example of predetermined parameters includes an inlet temperature of from about 30°C to about 50°C, a product temperature of from about 25°C to about 35°C, to obtain prolonged release coated granules. Although specific predetermined parameters are mentioned above, those skilled in the art will understand that the predetermined parameters can be changed based on obvious variations.

[0083] The granules with the coating for the extended release were then dried in a fluid bed coater under predetermined parameters. In this context, a non-limiting example of the predetermined parameters includes an inlet temperature of from about 30°C to about 50°C, a product temperature of from about 25°C to about 35°C. Although specific predetermined parameters are mentioned above, those skilled in the art will understand the possibility of changing the predetermined parameters based on obvious variations. The granules with the coating for the extended release were then poured and sieved through a sieve mounted on a vibrating sifter, and small granules were removed. The sieved granules were collected in an HDPE container into which a polyethylene bag was inserted, and the sieved granules were weighed. Finally, after the sieving process, the granules with the coating for the extended release were obtained.

[0084] Table 4A lists various ingredients for producing a sustained-release coating, which includes preparing a suspension of the sustained-release coating and applying the sustained-release coating. In addition, Table 4B below shows the properties of the sustained-release coated granules. In addition, Table 4C below shows the dissolution data of the sustained-release coated granules.

[0085] In the third batch, a suspension of the extended-release coating was prepared by mixing a release-regulating agent, a pore-forming agent, a second plasticizer, and a lubricant. Specifically, the suspension of the extended-release coating was prepared by mixing ethylcellulose No. 20, polyvinylpyrrolidone K-30, dibutyl sebacate, and purified talc. A stainless steel tank with a pneumatic stirrer was used, into which a sufficient amount of isopropyl alcohol was transferred, and then 53.89 g of ethylcellulose No. 20 (Ethocel No. 20) was added and stirred to thoroughly mix the solution. 36.47 g of povidone K 30 were added to the solution obtained in the above steps to obtain a solution of povidone K 30 and Ethocel N 20. Then, a sufficient amount of purified water was added to the resulting solution with stirring, and stirring was continued to obtain a suspension of povidone K 30 and Ethocel N 20. Then, 9.77 g of dibutyl sebacate and 19.86 g of purified talc were added to the suspension of povidone K 30 and Ethocel N 20 with stirring and dissolved during continuous stirring to obtain a suspension of the extended-release coating. Then, the resulting suspension of the extended-release coating was continuously stirred to prevent settling and foaming before coating the drug granules.

[0086] Then, a prolonged release coating was applied. The prolonged release coating was carried out by applying the resulting prolonged release coating suspension to the drug-coated granules to obtain prolonged release coated granules. In particular, the resulting prolonged release coating suspension was applied to the drug-coated granules in a fluid bed coating device under predetermined parameters. In this context, a non-limiting example of predetermined parameters includes an inlet temperature of from about 30°C to about 50°C, a product temperature of from about 25°C to about 35°C, to obtain prolonged release coated granules. Although specific predetermined parameters are mentioned above, those skilled in the art will understand that the predetermined parameters can be changed based on obvious variations.

[0087] The granules with the coating for the extended release were then dried in a fluid bed coater under predetermined parameters. In this context, a non-limiting example of the predetermined parameters includes an inlet temperature of from about 30°C to about 50°C, a product temperature of from about 25°C to about 35°C. Although specific predetermined parameters are mentioned above, those skilled in the art will understand the possibility of changing the predetermined parameters based on obvious variations. The granules with the coating for the extended release were then poured and sieved through a sieve mounted on a vibrating sifter, and small granules were removed. The sieved granules were collected in an HDPE container into which a polyethylene bag was inserted, and the sieved granules were weighed. Finally, after the sieving process, the granules with the coating for the extended release were obtained.

[0088] Table 5A lists the various ingredients for obtaining

The process of producing a prolonged-release coating involves preparing a suspension of the prolonged-release coating and applying the prolonged-release coating. Additionally, Table 5B below shows the properties of the pellets with the prolonged-release coating. Furthermore, Table 5C below presents the dissolution data for the pellets with the prolonged-release coating.

Lubrication

[0089] In the first batch, lubrication of the coated granules for extended release was performed. 565 g of the coated granules for extended release were lubricated with 2.54 g of purified talc in the hopper of a Conta mixer to produce lubricated mesalazine granules.

[0090] Table 6 lists various ingredients for lubricating the granules coated for extended release with purified talc.

[0091] In the second batch, lubrication of the coated extended-release granules was performed. 1620 g of coated extended-release granules were lubricated with 7.29 g of purified talc in the hopper of a Conta mixer to produce lubricated mesalazine granules.

[0092] Table 7 lists various ingredients for lubricating the granules coated for extended release with purified talc.

[0093] In the third batch, lubrication of the coated extended-release granules was performed. 1620 g of the coated extended-release granules were lubricated with 7.29 g of purified talc in the hopper of a Conta mixer to produce lubricated mesalazine granules.

[0094] Table 8 lists various ingredients for lubricating the granules coated for extended release with purified talc.

[0095] The entire process for producing mesalazine granules described in the above examples was carried out in a fluid bed coater, a flat bottom pan and a Conta mixer.

[0096] In one embodiment of the present invention, Table 9 provides the percentage by weight of the quantitative composition of the extended release mesalazine composition based on 1 g and 2 g.

[0097] Table 10 presents the analytical results for 1 g of mesalazine extended-release granules sachet for the first batch. Specification details: description - mesalazine extended-release granules from light beige to dark beige in color, packaged in heat-sealed aluminum sachets, average fill weight - 1666.66 mg + 7.5%, water content - no more than 5.0%, average quantitative content - 1.0 g / sachet (0.95 g / sachet - 1.05 g / sachet), average percentage content - 95.0% - 105.0% of that declared on the label.

[0098] Table 11 presents the analytical results for 1 g of mesalazine extended-release granules sachet for the second batch. Specification details: description - mesalazine extended-release granules from light beige to dark beige in color, packaged in heat-sealed aluminum sachets, average fill weight - 1666.66 mg + 7.5%, water content - no more than 5.0%, average quantitative content - 1.0 g / sachet (0.95 g / sachet - 1.05 g / sachet), average percentage content - 95.0% - 105.0% of the declared on the label.

[0099] Table 12 presents the analytical results for 1 g of mesalazine extended-release granules sachet for the third batch. Specification details: description - mesalazine extended-release granules from light beige to dark beige in color, packaged in heat-sealed aluminum sachets, average fill weight 1666.66 mg + 7.5%, water content - no more than 5.0%, average quantitative content - 1.0 g / sachet (0.95 g / sachet - 1.05 g / sachet), average percentage content - 95.0% - 105.0% of that declared on the label.

[00100] Table 13 presents the analytical results for 2 g sachets of mesalazine extended-release granules for the first batch. Specification details: description - mesalazine extended-release granules from light beige to dark beige in color, packaged in heat-sealed aluminum sachets, average fill weight 3333.33 mg + 7.5%, water content - no more than 5.0%, average quantitative content - 2.0 g / sachet (1.90 g / sachet - 2.10 g / sachet), average percentage content - 95.0% - 105.0% of that declared on the label.

[00101] Table 14 presents the analytical results for 2 g sachets of mesalazine extended-release granules for the second batch. Specification details: description: mesalazine extended-release granules from light beige to dark beige in color, packaged in heat-sealed aluminum sachets, average fill weight - 3333.33 mg + 7.5%, water content - no more than 5.0%, average quantitative content - 2.0 g / sachet (1.90 g / sachet - 2.10 g / sachet), average percentage content - 95.0% - 105.0% of that declared on the label.

[00102] Table 15 presents the analytical results for 2 g sachets of mesalazine extended-release granules for the third batch. Specification details: description - mesalazine extended-release granules from light beige to dark beige in color, packaged in heat-sealed aluminum sachets, average fill weight 3333.33 mg + 7.5%, water content - no more than 5.0%, average quantitative content - 2.0 g / sachet (1.90 g / sachet - 2.10 g / sachet), average percentage content - 95.0% - 105.0% of that declared on the label.

[00103] The present invention provides a mesalazine composition with extended release, which contains granules with improved extended release, requires less manufacturing time, and which uses a minimum amount of ingredients. In addition, the present invention provides a method for producing a mesalazine composition with extended release, which is faster, simpler, easier, more reliable, automated and reproducible, wherein all steps of producing the mesalazine composition with extended release can be performed using minimal equipment, which allows the production process to be carried out with less equipment/machines.

[00104] The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and it is obvious that numerous modifications and variations are possible in view of the above teaching. The embodiments shown have been chosen and described to best explain the principles of the present invention and its practical application, so that others skilled in the art can best utilize the present invention and the various embodiments with various modifications consistent with the particular intended application. (It should be understood that various exceptions and substitutions of equivalents are provided as circumstances indicate or dictate their appropriateness, but they are intended to be included in the present application or embodiment without departing from the spirit or scope of the claims of the present invention.)

Claims (34)

1. A mesalazine composition with prolonged release, containing, wt.%: from 55 to 65 mesalazine; from 26 to 30 sugar spheres; from 4 to 6 binder, wherein the binder is a water-miscible aqueous dispersion; from 0.3 to 0.75 of the first plasticizer; from 3 to 7 release regulating agents, wherein the release regulating agent acts independently of pH; from 2 to 5 pore-forming agent; from 0.4 to 1.5 of the second plasticizer; and from 1 to 3 lubricants, wherein the composition is presented in the form of granules, the binder is Eudragit® L30 D 55, the first plasticizer is triethyl citrate, the second plasticizer is dibutyl sebacate. 2. A mesalazine composition with prolonged release according to claim 1, characterized in that the mesalazine constitutes from 55 to 65% by weight and is a micronized material with a particle size distribution in the range of D90 less than 50 μm. 3. The extended release mesalazine composition of claim 1, wherein the sugar spheres have a size of 425 to 600 µm. 4. The extended release mesalazine composition of claim 1, wherein the release regulating agent is ethylcellulose No. 20. 5. The extended release mesalazine composition of claim 1, wherein the pore-forming agent is polyvinylpyrrolidone K-30. 6. The extended release mesalazine composition of claim 1, wherein the lubricant is purified talc. 7. The extended release mesalazine composition of claim 1, having the following in vitro mesalazine dissolution profile: a) up to 30% dissolution in 1 hour; b) 20%-60% dissolution in 2 hours; c) 40%-80% dissolution in 4 hours; and d) 75%-100% dissolution in 8 hours. 8. A prolonged release mesalazine composition according to claim 1, packaged in a sachet. 9. A method for producing a mesalazine composition with prolonged release, comprising: obtaining a solution of a binder by mixing a binder and a first plasticizer; applying a layer of mesalazine to sugar spheres using a binder solution to obtain granules with a layer of the drug applied; obtaining a suspension of a prolonged release coating by mixing a release regulating agent, a pore-forming agent, a second plasticizer and a lubricant; applying a sustained release coating by applying a suspension of the sustained release coating to the drug-coated granules to obtain sustained release coated granules; and lubrication of coated granules for prolonged release, wherein the binder is a water-miscible aqueous dispersion of Eudragit® L30 D 55, the first plasticizer is triethyl citrate, the second plasticizer is dibutyl sebacate, and The release regulating agent acts independently of pH. 10. The method according to claim 9, characterized in that the application of a layer of the medicinal substance is carried out in a flat-bottomed coating pan, the application of a coating for prolonged release is carried out in a device for applying a coating in a fluidized bed, and lubrication is carried out in a Conta mixer. 11. The method according to claim 9, characterized in that the sugar spheres have a size from 425 to 600 µm. 12. The method according to claim 9, characterized in that the release regulating agent is ethyl cellulose No. 20. 13. The method according to claim 9, characterized in that the pore-forming agent is polyvinylpyrrolidone K-30. 14. The method according to claim 9, characterized in that the lubricant is purified talc.