WO2022245307A1 - Composition de formulation de comprimé entérique à base de mésalazine - Google Patents

Composition de formulation de comprimé entérique à base de mésalazine Download PDF

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Publication number
WO2022245307A1
WO2022245307A1 PCT/TR2021/050472 TR2021050472W WO2022245307A1 WO 2022245307 A1 WO2022245307 A1 WO 2022245307A1 TR 2021050472 W TR2021050472 W TR 2021050472W WO 2022245307 A1 WO2022245307 A1 WO 2022245307A1
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WIPO (PCT)
Prior art keywords
enteric
mesalazine
tablet
poly
methyl methacrylate
Prior art date
Application number
PCT/TR2021/050472
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English (en)
Inventor
Hatice ONCEL
Onur Pinarbasli
Feristah BILGIN
Hande GAYRETLI
Nurdan ATILGAN
Asuman AYBEY DOGANAY
Nagehan SARRACOGLU
Original Assignee
Ilko Ilac Sanayi Ve Ticaret A.S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ilko Ilac Sanayi Ve Ticaret A.S. filed Critical Ilko Ilac Sanayi Ve Ticaret A.S.
Priority to PCT/TR2021/050472 priority Critical patent/WO2022245307A1/fr
Priority to EP21940969.5A priority patent/EP4340847A1/fr
Publication of WO2022245307A1 publication Critical patent/WO2022245307A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/005—Coating of tablets or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/606—Salicylic acid; Derivatives thereof having amino groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer

Definitions

  • the present invention relates to formulate a pharmaceutical enteric tablet composition comprising mesalazine, a process for the production of said formulation with a multilayer enteric coating.
  • Mesalazine which is commonly known as 5-ASA and mesalamine, is an aminosalicylate (5-aminosalicylic acid) with anti-inflammatory properties. It is indicated for the induction of remission in patients with active, mild-to-moderate ulcerative colitis and for the maintenance of remission of ulcerative colitis. Its chemical name is 5- amino-2-hydroxybenzoic acid with a molecular formula C 7 H 7 N0 3 .
  • Mesalazine is slightly soluble in water, very slightly soluble in methanol and practically insoluble in chloroform; soluble in diluted HCI and diluted alkali hydroxides.
  • IBD Inflammatory bowel disease
  • Ulcerative colitis is a chronic inflammatory bowel disease affecting only the colon and shows a continuous distribution in the gastrointestinal mucosa. In most patients mainly the distal part of the colon and the rectum are inflamed with often a proximal spread.
  • Enteric coatings have been used for many years to arrest the release of the drug from orally ingestible dosage forms. Depending upon the composition and/or thickness, the enteric coatings are resistant for required periods of time before delivery of the therapeutic agents to the lower part of the gastrointestinal track, especially the large intestine or the colon.
  • Salofalk® Magneticensaftresistente Tabletten, 500 mg & 250 mg; Dr. Falk Pharma GmbH
  • Salofalk® is a known enteric coated tablet, available on the market.
  • Salofalk® was selected as reference product. It is comprised of a core with an enteric coating, where the enteric coating is a polyacrylic ether.
  • Salofalk® is a tablet comprised of mesalazine, butylated methacrylate copolymer, calcium stearate, croscarmellose sodium, iron oxide, glycine, silicon dioxide, hypromellose, macrogol 6000, methacrylic acid: methyl methacrylate copolymer (1:1), microcrystalline cellulose, sodium carbonate, povidone k25, Talc, titanium dioxide.
  • the main site of action of Salofalk® is said to be the terminal ileum and the ascending colon.
  • US4540685 relates to a process for the production of readily soluble pharmaceutical preparations based on 5-aminosalicylic acid.
  • This invention is particularly suitable for the production of tablets, dragee cores or capsules containing from 200 mg to 900 mg of 5 aminosalicylic acid per pharmaceutical formulation unit.
  • These forms of administration have film coatings based on polymeric substances with pH related solubility properties.
  • EP1453487 discloses pharmaceutical mesalazine dosage form with multiple coatings comprising therapeutic agents with improved resistance to coating fractures during processing, manufacturing or packaging.
  • EP2611429 discloses pharmaceutical mesalazine enteric coated tablet having at least an intermediate layer and enteric coating where the tablet core hardness is controlled to be comprised between 80 N and 105 N and the intermediate layer represents less than 2% by weight of the tablet.
  • high dose formulations comprising 500 mg to 10 gram mesalazine as capsule, tablet or sachet forms (EP0977557, W02004/093884, EP2621477,
  • the present invention relates to produce mesalazine enteric coated tablet maintaining specific in-vitro dissolution to provide desired site of delivery of therapeutically effective amount of therapeutic agents in the gastrointestinal track. Delivery directly in the colon requires formulations which are capable of passing over the entire track of the small intestine, including the duodenum, jejenum, and ileum, so that the active ingredients are released directly in the colon.
  • Mesalazine is a locally acting drug and is destroyed by stomach acids as a result of direct oral use, which preventing its performance in the required area.
  • a stable mesalazine enteric coated tablet formulation has been developed to ensure proper in-vitro release initially and during storage conditions especially for whose local release is affected by conditions such as temperature and humidity.
  • a stable pharmaceutical mesalazine enteric tablet formulation the produced enteric tablet releases less than 1% of the labeled amount of mesalazine after 2 hours acid stage when measured using USP dissolution apparatus II (paddle), 100rpm, 500 ml_ of 0.1 N hydrochloric acid medium and less than 1% of the labeled amount of mesalazine after 1 hour buffer stage 1 when measured using USP dissolution apparatus II (paddle), 100 rpm, 900 ml_ of pH 6.0 phosphate buffer, wherein the core tablet contains multilayer enteric coating consisting of;
  • the first enteric coating layer comprises basic butylated methacrylate copolymer with a ratio range of 20:1 to 65:1 active ingredient mesalazine to basic butylated methacrylate copolymer,
  • the second enteric coating layer covering the first enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
  • the second enteric coating layer covering the first enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 in a ratio of 1:2 to 1:4.
  • the second enteric coating layer covering the first enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 in a ratio of 1:4.
  • the core tablets present in the enteric tablet formulation are prepared by wet granulation.
  • the tablet formulation comprises 500 mg mesalazine.
  • the tablet formulation comprises 250 mg mesalazine.
  • a stable mesalazine enteric coated tablet maintaining the desired site of delivery of the therapeutically effective amount of active ingredient is provided by the present invention with providing more specific and reliable release of mesalazine than reference product (Salofalk®) to the lower part of the gastrointestinal tract, especially to the colon.
  • reference product Siofalk®
  • the tablets of the invention contain a core tablet, an intermediate layer, and multilayer enteric coatings superimposed on it.
  • the first enteric coating layer comprises basic butylated methacrylate copolymer. It is the protective coating layer for providing durability of the tablet under stability conditions especially humidity condition.
  • the second enteric coating layer comprises mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
  • the present invention provides a method for preparing a mesalazine enteric coated tablet comprising:
  • the mesalazine granulates are produced by granulating active substance with microcrystalline cellulose, povidone, croscarmellose sodium and glycine.
  • the unit dosage form is a compressed spherical or elliptical tablet.
  • the tablet is comprised of a solid form of therapeutically active agent mesalazine and is compressed using conventional equipment and processes.
  • terapéuticaally effective amount refers to an amount, which achieves a desired effect, when administered to a living subject.
  • a dosage form is required which, after oral administration, enables the local availability of the active ingredient mesalazine in a sufficiently high concentration at the site of inflammation.
  • active ingredient or “active pharmaceutical ingredient” means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals.
  • the active ingredient is mesalazine or its pharmaceutically acceptable salts, esters, and solvates thereof.
  • the enteric tablet composition is provided in a unit dose formulation comprising 500 mg and 250 mg mesalazine.
  • 'stable' as used herein means the enteric tablet release the therapeutically effective amounts of active ingredient mesalazine into specific delivery region after production (To, initially) and during the storage conditons throughout the shelf life. Especially the products entail USP performance tests for Mesalamine Delayed Release Tablets.
  • the proposed USP tests for enteric tablets requires that the product withstand agitation (paddle at 100 rpm) in the artificial gastric fluid (0.1 N hydrochloric acid) at 37°C ⁇ 0.5°C, releasing less than 1% of the labeled amount of mesalazine for 2 hours and also the product withstand agitation (paddle at 100 rpm) in the pH 6.0 phosphate buffer at 37°C., releasing less than 1% of the labeled amount of mesalazine for 1 hour, while dissolving not less than 80% (Q) of the labeled amount of mesalazine in 90 minutes at 37°C with a buffer of pH 7.2. This is also considered as dissolution stability as well.
  • the stability of the products can be determined by in-vitro dissolution studies of real time studies or during storage conditions.
  • compositions of this invention also generally comprise pharmaceutically acceptable excipients.
  • excipient means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a subject. Excipients may act to facilitate incorporation of the therapeutically active agent into the dosage form, modify the release of the therapeutically active agent from the dosage form, stabilize the therapeutically active agent, or enhance absorption of the therapeutically active agent.
  • the enteric coating solution used to form the enteric coating layer on the tablets will comprise a water soluble or water dispersible film forming enteric polymer dissolved or dispersed in an aqueous vehicle.
  • a number of such film forming enteric polymers are known in the prior art which will serve the present purposes. These will have conventional solubility characteristics of enteric polymers i.e. they will be insoluble in acid but will be soluble in a neutral-to-nearly alkaline medium.
  • the polymeric coating layer comprises a hydrophilic gelling polymer or copolymer that swells on contact with gastro-intestinal juices to form a film surrounding the core.
  • the swellable polymeric coating layer which surrounds the core protects the integrity of the core and prevents the release of mesalazine during the transit in the small intestine.
  • the swellable polymeric coating layer may be comprised of any suitable hydrophilic gelling polymer known to those skilled in the art.
  • suitable hydrophilic gelling polymers include but are not limited to cellulose polymers such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, hydro xyethylcellulose, hydroxypropylmethylcellulose, and the like, vinyl polymers such as polyvinylpyrrolidone, poly vinyl alcohol, and the like, acrylic polymers and copolymers such as acrylic acid polymer, methyacrylic acid copolymers, ethyl acrylate-methyl methacrylate copolymers, and the like; natural or synthetic rubbers, poloxamers, polysaccharides, and mixtures thereof.
  • multilayer enteric coating comprises basic butylated methacrylate copolymer, poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
  • a first enteric coating layer is applied onto the film coated tablet core with a solution comprising basic butylated methacrylate copolymer (lUPAC name: Poly(butyl methacrylate-co-(2-demethylaminoeethyl) methacrylate-co-methyl methacrylate) 1:2:1).
  • Basic butylated methacrylate copolymer is commonly known as Eudragit® E.
  • Eudragit® E is a copolymer of 2-(dimethylamino)ethyl methacrylate, butyl methacrylate and methyl methacrylate having a mean relative molecular mass of about 150.000.
  • the ratio of 2-(dimethylamino)ethyl methacrylate groups to butyl methacrylate and methyl methacrylate groups is about 2:1:1.
  • Synonyms of basic butylated methacrylate copolymer are amino methacrylate copolymer; aminoalkyl methacrylate copolymer E; butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate polymer; butyl methacrylate, methyl methacrylate, dimethylaminoethyl methacrylate polymer. It has reliable moisture protection and soluble in gastric juice up to pH 5.0, swellable and permeable above pH 5.0.
  • a second enteric coating layer is applied onto the tablet having one enteric coating layer with a solution comprising mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 in a ratio of 1:2 to 1:4.
  • Poly(methacrylic acid, methyl methacrylate) 1:2 is commonly known as Eudragit® S.
  • Eudragit® S is an anionic copolymer derived from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:2, and a mean molecular weight of approximately 135,000. It has effective and stable enteric coatings with a fast dissolution in the upper Bowel.
  • Eudragit® L Poly(methacrylic acid, methyl methacrylate) 1:1 is commonly known as Eudragit® L.
  • Eudragit® L is an anionic copolymer derived from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:1, and a mean molecular weight of approximately 135,000. It has effective and stable enteric coatings with a fast dissolution in the upper Bowel and site specific drug delivery in intestine by combination with EUDRAGIT S grades.
  • the coating solutions preferably contain a plasticizer.
  • the plasticizer may be a solid plasticizer, a liquid plasticizer, or a combination thereof.
  • the solid plasticizers include polyethylene glycol 3350, polyethylene glycol 4000, polyethylene glycol 8000, or Pluronic F86.
  • the liquid plasticizer include triethyl citrate, glyceryl triacetate, acetyltriethylcitrate, dibutyl sebacate, diethyl phthalate, polyethylene glycol 400, glycerol, castor oil, or mixtures thereof. These plasticizers are present in an amount to facilitate the coating process and to obtain an even coating film with enhanced physical stability. In this present invention, triethyl citrate is preferred.
  • the coating material may also comprise inert solid particulates.
  • preferred inert solid particulates include talc and titanium dioxide.
  • Enteric polymers are generally applied onto the unit dosage forms as solutions in organic or aqueous solvents.
  • the solvents commonly employed as vehicles are water, methylene chloride, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate and combinations thereof.
  • the choice of the solvent is based primarily on the solubility of the polymer, ease of evaporation, and viscosity of the solution. In this present invention, mixture of water and isopropyl alcohol is preferred.
  • excipients like binder, disintegrant, lubricant, surfactants, antifoaming agents, solubilizing agents, coloring agents etc.
  • Lubricant is selected from the one of stearic acid, glycerol, palmitate stearate, magnesium stearate, calcium stearate, talc, micropowder silica gel, hydrogenated vegetable oil, sodium lauryl sulphate.
  • calcium stearate is used.
  • a wet granulation of mesalazine active ingredient and excipients of microcrystalline cellulose, povidone, croscarmellose sodium and glycine, is prepared.
  • the wet granules obtained are passed through a suitable sieve.
  • the drying process is carried out in Fluid Bed Dryer.
  • the required amount of sodium carbonate, colloidal silicon dioxide and calcium stearate are added to the granules obtained as a result of dry grinding and mixed.
  • the blend is compressed into tablets to prepare tablet cores.
  • FT03 6% 200 mg/tablet were observed with the reference product. Appearance, dissolution studies and stability analyzes were considered in the evaluations made in the product development studies of the enteric coating stage.
  • the coatings of the tablets should be uniform; the coating thickness should be evenly distributed over the tablet surface. Because homogeneous coating of qualified coatings such as enteric coating, controlled release coating in oval tablets is important in order to open the tablet at the desired pH. Likewise, attention should be paid to the uniformity of the round tablets in the coating process and to obtain the same thickness of coating all over the tablet.
  • opadry containing coating with hypromellose and polyethylene glycol was coated on the tablet core so that the tablet surface was smooth and the enteric coating could be coated homogeneously on this surface. Coating can be achieved by using fluidized bed equipment and the solid unit dosage forms are coated by continuous spray methods. The film coating layer is applied onto the tablet cores with opadry containing solution.
  • the main purpose of using basic butylated methacrylate copolymer in the formulation is to prevent exposure to moisture during the stability of the core tablet, which is very suitable for moisture absorption.
  • the main scope of using mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1 is to to protect the tablet at pH values below 6 by allowing it to be released at pH values above pH 6.
  • a first enteric coating layer is applied onto the film coated tablet core with a solution comprising basic butylated methacrylate copolymer, talc, triethyl citrate and isopropyl alcohol.
  • a second enteric coating layer is applied onto the tablet having one enteric coating layer with a solution comprising mixture of poly(methacrylic acid, methyl methacrylate) 1:2 (A) and poly(methacrylic acid, methyl methacrylate) 1:1 (B), talc, triethyl citrate, yellow iron oxide, titanium dioxide and isopropyl alcohol.
  • the rate of enteric coating polymers (A and B) was changed and the results were evaluated (FT04 - FT09).
  • the final tablets are cured for 1 hour at 40-45°C.
  • Example 2 In-Vitro Dissolution Studies
  • the finished mesalazine enteric coated tablets of present invention were compared with reference product Salofalk® to evaluate their performance in the USP Mesalamine Delayed Release Tablet - Performance tests.
  • Buffer Stage 1** 900 mL of pH 6.0 phosphate buffer 100 rpm, 37°C ⁇ 0.5 °C, 1 hour Specification: Lower than 1% of the labeled amount of mesalazine dissolved
  • Buffer Stage 2 900 mL of pH 7.2 phosphate buffer
  • the content of the percentage of mesalazine (C7H7NO 3 ) released in the test medium was determined by comparing the UV maximum absorbance at 302 nm for acid stage, at 330 nm for buffer stage 1 and at 332 nm for buffer stage 2.
  • the proposed USP tests for enteric tablets requires that the product withstand agitation (paddle at 100 rpm) in the artificial gastric fluid (0.1 N hydrochloric acid) at 37°C ⁇ 0.5°C, releasing less than 1% of the labeled amount of mesalazine for 2 hours and also the product withstand agitation (paddle at 100 rpm) in the pH 6.0 phosphate buffer at 37°C., releasing less than 1% of the labeled amount of mesalazine for 1 hour, while dissolving not less than 80% (Q) of the labeled amount of mesalazine in 90 minutes at 37°C with a buffer of pH 7.2.
  • the artificial gastric fluid 0.1 N hydrochloric acid
  • the first enteric coating was applied with a solution comprising basic butylated methacrylate copolymer into the obtained film coated tablet core.
  • 2%, 3% and 5% enteric coating studies were applied for analyzing the first enteric coating layer.
  • enteric coated tablets containing dose proportional 500 mg and 250 mg mesalazine were prepared with the final formula (FT07) obtained at the end of the above-mentioned formulation determination studies.
  • the finished mesalazine enteric coated tablets of present invention (500mg and 250 mg) were compared with reference product Salofalk® (500mg and 250 mg) to evaluate their in vitro dissolution profiles provided in the USP Mesalamine Delayed Release Tablet performance test. Comparative dissolution tests were conducted based on the general dissolution test method. Dissolution testing measures the portion (%) of mesalazine that have been dissolved in the dissolution medium. Dissolution test was performed with USP Apparatus-ll (paddle) at acid stage and buffer stage.
  • Acid stage is 500 ml_ of 0.1 N hydrochloric acid and 100 rpm for 2 hours.
  • Buffer stage consists of two stages.
  • Buffer stage 1 is 900 ml_ of pH 6.0 phosphate buffer and 100 rpm for 1 hour.
  • Buffer stage 2 is 900 ml_ of pH 7.2 phosphate buffer and 50 rpm for 90 minutes. After 2 hours of acid stage, samples are taken for analysis and the tablets are taken from the medium in order and added to the medium prepared for Buffer stage 1 and proceed immediately to Buffer stage 1.
  • the percentage of labeled amount of mesalazine dissolved in acid stage and buffer stage 1 mediums should not exceed 1% at the end of the two hours.
  • the percentage of labelled amount of mesalazine dissolved should be not less than 80% (Q) (USP, Mesalamine Delayed-Release Tablets, Performance Tests). This also provides release the active substance mesalazine selectively at the inflamed areas in the gastrointestinal tract.
  • Salofalk® 250 mg Enteric Coated Tablet L19010A, Dr.
  • Salofalk® 250 mg Enteric Coated Tablet (L19010A, Dr. Falk Pharma GmbH)
  • enteric coated tablets comprising mesalazine require a defined release profile of mesalazine from the dosage form. Since the criterion for stability of an enteric coated dosage form is that it should not release a significant amount of the active ingredient in the stomach, but should dissolve completely in the higher pH environment of the intestine, in vitro dissolution stability is monitored in 0.1 N hydrochloric acid, pH 6.0 phosphate buffer and pH 7.2 phosphate buffer. The USP standards for enteric coated tablets entails stability testing of the products at elevated temperatures for extended periods of time.
  • enteric tablets coated with multilayer enteric coating polymers prepared as per the Example 1 were packed in PVC/PVDC-ALU blisters and and kept for stability testing together with reference products (Salofalk® 500mg and 250mg Enteric Coated Tablets) under conditions given as 40°C/75% relative humidity for 6 months and 25°C/60% relative humidity for 12 months duration.
  • the products were tested for content, purity and dissolution of mesalazine from enteric- coated tablets at acid and buffer medium conditions in regular intervals. Determination of content and purity was performed with a validated HPLC method at 254 nm. The determination of mesalazine release from enteric coated tablets was performed with a validated UV method at 302 nm for acid stage, at 330 nm for buffer stage 1 and at 332 nm for buffer stage 2.
  • Buffer Stage 1 900 mL of pH 6.0 phosphate buffer 100 rpm, 37°C ⁇ 0.5 °C, 1 hour
  • Buffer Stage 2 900 mL of pH 7.2 phosphate buffer 50 rpm, 37°C ⁇ 0.5 °C, 90 minutes

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Abstract

L'invention concerne une formulation d'une composition pharmaceutique de comprimé entérique comprenant de la mésalazine, un procédé pour la production de ladite formulation avec un enrobage entérique multicouche qui fournit des profils de dissolution in vitro requis montrant l'administration spécifique de la substance active contenue dans la forme posologique au côlon initialement et pendant le stockage dans des conditions de stabilité.
PCT/TR2021/050472 2021-05-21 2021-05-21 Composition de formulation de comprimé entérique à base de mésalazine WO2022245307A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/TR2021/050472 WO2022245307A1 (fr) 2021-05-21 2021-05-21 Composition de formulation de comprimé entérique à base de mésalazine
EP21940969.5A EP4340847A1 (fr) 2021-05-21 2021-05-21 Composition de formulation de comprimé entérique à base de mésalazine

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PCT/TR2021/050472 WO2022245307A1 (fr) 2021-05-21 2021-05-21 Composition de formulation de comprimé entérique à base de mésalazine

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WO2022245307A1 true WO2022245307A1 (fr) 2022-11-24

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102048707A (zh) * 2010-11-29 2011-05-11 黑龙江天宏药业有限公司 美沙拉秦肠溶片及其制备方法
WO2012028698A1 (fr) * 2010-09-01 2012-03-08 Disphar International B.V. Comprimé de mésalazine ayant une dissolution améliorée
WO2014152450A1 (fr) * 2013-03-15 2014-09-25 Warner Chilcott Company, Llc Composition pharmaceutique de mésalamine avec éléments de dose multiples pour variabilité d'administration réduite

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012028698A1 (fr) * 2010-09-01 2012-03-08 Disphar International B.V. Comprimé de mésalazine ayant une dissolution améliorée
CN102048707A (zh) * 2010-11-29 2011-05-11 黑龙江天宏药业有限公司 美沙拉秦肠溶片及其制备方法
WO2014152450A1 (fr) * 2013-03-15 2014-09-25 Warner Chilcott Company, Llc Composition pharmaceutique de mésalamine avec éléments de dose multiples pour variabilité d'administration réduite

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