WO2022066110A1 - Pharmaceutical compositions comprising mesalamin and relevant excipients - Google Patents

Pharmaceutical compositions comprising mesalamin and relevant excipients Download PDF

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Publication number
WO2022066110A1
WO2022066110A1 PCT/TR2020/050889 TR2020050889W WO2022066110A1 WO 2022066110 A1 WO2022066110 A1 WO 2022066110A1 TR 2020050889 W TR2020050889 W TR 2020050889W WO 2022066110 A1 WO2022066110 A1 WO 2022066110A1
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Prior art keywords
eudragit
enteric
layer
pharmaceutical composition
mesalamin
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PCT/TR2020/050889
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French (fr)
Inventor
Abdulhaluk SANCAK
Ayşe Figen ONUK GÖREN
Trinadh POTUMUDI
Hakan Gürpinar
Yasemin GÖKDENİZ
Asiye SEZGİN
Koray ILMAZ
Original Assignee
Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A.Ş.
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Priority to PCT/TR2020/050889 priority Critical patent/WO2022066110A1/en
Publication of WO2022066110A1 publication Critical patent/WO2022066110A1/en

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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
    • 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
    • A61K9/20—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 the preparation of pharmaceutical compositions comprising mesalamin and also relevant excipients, having an improved formulation design for manufacturing enteric coated tablet composition.
  • Aminosalicylate drugs such as mesalamine, used to treat for mild and moderate disease of inflammatory bowel disease (IBD).
  • Mesalamine also known as 5-aminosalicilic acid (5-ASA)
  • 5-aminosalicilic acid is an anti-inflammatory drug used in the treatment of disturbances on gastrointestinal tract like inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis.
  • Mesalamine has a odorless white to pinkish crystals or purplish-tan powder appearance
  • chemical name is 5-Amino-2-hydroxybenzoic acid, having a molecular weight of 153.135 g/mol, its chemical structure is shown in the Figure I.
  • Mesalamin is used for many years in the treatment of inflammatory bowel disease (IBD), firstly approved in 1984. Dosage forms are available tablets, enema, spposituar, capsule, granule or powder in the market until now.
  • IBD inflammatory bowel disease
  • Inflammatory bowel disease is a cover term for Crohn’s disease and ulcerative colitis that are characterized by chronic inflammation of the gastrointestinal (GI) tract.
  • GI gastrointestinal
  • Crohn's disease is a chronic inflammatory disease of the digestive tract, which symptoms are abdominal pain, fever, fatigue, severe diarrhea, weight loss. Although there's no known cure for Crohn's disease, therapies can greatly reduce its signs and symptoms.
  • Ulcerative colitis is one of inflammatory bowel disease (IBD) that causes long-lasting inflammation and ulcers in digestive tract.
  • IBD inflammatory bowel disease
  • the main symptoms of this disease are abdominal pain, bloody diarrhea, weight loss, fever, and anemia. It causes irritation, inflammation, and ulcers in the lining of large intestine and rectum.
  • Enteric coated tablet also known as gastro-resistant coating tablet type that is coated with active ingredient(s) that prevents the medication from being released until it reaches the small intestine, where it can then be absorbed.
  • enteric coated tablets has a stable surface to highly acidic pH of the stomach but it breaks down rapidly at a less acidic (relatively more basic) pH in intestinal route. Enteric coated tablets can dissolve in the small intestine.
  • enteric coating materials such as resistance to gastric media, permeability to intestinal fluids, high compatibility, nontoxic activity and able to form continuous film are critical for a product of enteric coated tablet. Excipients should be selected according to these parameters and also properties of active ingredient.
  • Enteric coating is used to protect drugs from degradative effects of gastric acidity, to protect the gastric mucosa from irritation and to control the delivery of certain drugs to the intestines to enhance absorption.
  • the main polymers for enteric release film coating are cellulose acetate phthalate, cellulose acetate trimellitate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, polyvinyl acetate phthalate and methacrylic acid copolymers.
  • the present invention relates to the preparation of pharmaceutical compositions comprising mesalamin and also relevant excipients, having an improved formulation design for manufacturing an enteric coated tablet composition.
  • the present invention provides a pharmaceutical enteric tablet composition comprising mesalamin, wherein the enteric coating polymer is Eudragit L100 in the first layer, wherein the enteric coating polymers are Eudragit SI 00 and Eudragit LI 00 in the second layer, wherein the total tablet weight is between 1400mg to 2000mg.
  • the present invention relates to the preparation of pharmaceutical compositions comprising mesalamin and also relevant excipients, having an improved formulation design for manufacturing an enteric coated tablet composition.
  • the present invention provides a pharmaceutical composition comprising mesalamin, wherein the enteric coating polymer is Eudragit L100, wherein the enteric coating polymers are Eudragit S100 and Eudragit L100, wherein the total tablet weight is between 1400mg to 2000mg in enteric coated tablet.
  • the present invention relates to a mesalamin pharmaceutical composition
  • a mesalamin pharmaceutical composition comprising; a) A first layer comprising Eudragit L100 as an enteric coating polymer and at least one pharmaceutically acceptable excipient, wherein the weight ratio of Eudragit LI 00. b) A second layer comprising Eduragit S100 and Eudragit LI 00 as enteric coating polymers, and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical enteric coated tablet weight is between a specific interval.
  • the present invention relates to a pharmaceutical enteric tablet composition
  • a pharmaceutical enteric tablet composition comprising mesalamin; a) a first layer comprising Eudragit LI 00 as an enteric coating polymer and at least one pharmaceutically acceptable excipient, wherein the weight ratio of Eudragit LI 00 in the first layer to total tablet weight is between 2,5 to 5,0. b) a second layer comprising Eduragit S100 and Eudragit LI 00 as enteric coating polymers, and at least one pharmaceutically acceptable excipient, wherein the weight ratio of Eudragit S100 to Eudragit L100 in the second layer is between 0,5 to 0,8. wherein the pharmaceutical enteric coated tablet weight is between 1400mg to 2000mg.
  • Enteric coating is a oral medication type that is used polymers. These polymers serve as a barrier to prevent the gastric acids in the stomach from dissolving or degrading drugs after swallowing tablets. If enteric protection is not used in pharmaceutical products, most of the drugs would fall apart rapidly with stomach acids.
  • the enteric polymer coating makes a delayed release for tablet dosage forms.
  • drugs are targeted to the small intestine or other stages in digestion it needs to reach.
  • the present invention relates to a pharmaceutical enteric tablet composition, characterized in that it is provided wherein the enteric coating polymer of Eudragit LI 00 is in the first layer and enteric coating polymers of Eudragit S100 and Eudragit LI 00 are in the second layer.
  • the present invention relates to a pharmaceutical composition, the weight ratio of Eudragit L100 in the first layer to total tablet weight is between 2,5 to 5,0.
  • the present invention relates to a pharmaceutical composition
  • the weight ratio of Eudragit L100 in the first layer to total tablet weight is preferably between 2,7 to 3,5, more preferably 2,84.
  • the present invention relates to a pharmaceutical composition, the weight ratio of Eudragit S100 to Eudragit L100 in the second layer is between 0,5 to 0,8.
  • the present invention relates to a pharmaceutical composition, the weight ratio of Eudragit S100 to Eudragit LI 00 in the second layer is preferably between 0,6 to 7,7, more preferably 0,68.
  • the present invention relates to a pharmaceutical composition comprising mesalamine and relevant excipients in an enteric coated tablet dosage form. Releasing active substance from mesalazine tablets begins 3-4 hours later with this dosage form. It reaches peak plasma concentration after about 5 hours. It reaches the region between the ileum and the large intestine within 3-4 hours in the case of fasting, and reaches the upper colon within 4-5 hours. It remains for approximately 17 hours in the colon.
  • the present invention relates to Eudragit and its different types.
  • Eudragit has a structure with methacrylic acid copolymers.
  • Methacrylic acid copolymers are widely used for enteric coating tablets as they contain free carboxylic acid groups. These enteric polymers are marketed most notably by Evonik (formerly known as Rohm GmbH) under the proprietary Eudragit brand name.
  • Evonik formerly known as Rohm GmbH
  • Many types of Eudragit enteric polymers are commercially available in with different physical forms such as aqueous dispersion, organic solution, granules and powders.
  • Eudragits are anionic copolymers based on methacrylic acic and methyl methacrylate.
  • Eudragit L100 is Poly(methacylic acid-co-methyl methacrylate) 1:1.
  • Eudragit S100 is Poly(methacylic acid-co-methyl methacrylate) 1:2.
  • the Eudragit products for enteric coatings are based on anionic polymers of methacrylic acid and methacrylates. It dissolves at ranges from pH 5.5 to pH 7. Some of Eudragit products can be seen in table 1.
  • Eudragit products in enteric coating Some of the outstanding properties of Eudragit products in enteric coating: pH-dependent drug release, protection of actives sensitive to gastric fluid, protection of gastric mucosa from aggressive actives, increase in drug effectiveness, good storage stability, GI and colon targeting.
  • the present invention relates to an enteric coated tablet composition, wherein the product is targeted colon area in human body.
  • the present invention relates to an enteric coated tablet composition, wherein the formulation has two layers comprising mesalamin, enteric coating polymers and relevant excipients.
  • the present invention provides a pharmaceutical composition comprising mesalamine and relevant excipients, wherein pharmaceutical composition has two layers, “first layer” and “second layer”.
  • the present invention relates to an enteric coated tablet composition, wherein Eudragit L100 is used as an enteric polymer in the first layer of composition.
  • the present invention relates to an enteric coated tablet composition, wherein Eudragit L100 and Eudragit S100 are used as enteric polymers in the second layer of composition.
  • the present invention provides a pharmaceutical composition comprising mesalamine and relevant excipients, wherein the total tablet weight is between 1400mg to 2000mg in enteric coated tablet.
  • pharmaceutical composition comprising mesalamine and relevant excipients, wherein the total tablet weight is between 1400mg to 1800mg in enteric coated tablet.
  • enteric coated tablet composition comprising mesalamin, is used for the treatment of inflammatory bowel disease including Crohn’s disease and ulcerative colitis.
  • An object of the present invention is to provide a pharmaceutical composition in oral dosage form as an enteric coated tablet which provides immediate release of drug that exhibits acceptable bioavailability results.
  • the process of preparing the stable pharmaceutical composition comprises steps of preparing a first enteric layer comprising pharmaceutically acceptable excipients and Eudragit LI 00, the second layer comprising pharmaceutically acceptable excipients and Eudragit L100 and Eudragit S 100 followed by compressing of enteric coated tablet and coating by a protective layer.
  • the pharmaceutical composition further comprises at least one excipient selected from a diluent, a binder, a disintegrant, a glidant, a lubricant, a plastizer, an enteric coating polymer and a film coating material.
  • excipient selected from a diluent, a binder, a disintegrant, a glidant, a lubricant, a plastizer, an enteric coating polymer and a film coating material.
  • compositions of the invention are particularly suited for the oral administration.
  • the present invention shows well physical properties depends on its stability characteristics in appropriate excipients. It shows good properties to provide basic physical stability.
  • the present invention provides pharmaceutical composition comprising mesalamin and relevant excipients in enteric coated dosage form, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation Enteric tablet dosage form is convenient to use for intestinal diseases such as ulceratis collitis in gastrointestinal (GI) tract, so it has high patient compliance.
  • enteric coated dosage form characterized by i) A simple and exclusive manufacturing process ii) Stable formulation Enteric tablet dosage form is convenient to use for intestinal diseases such as ulceratis collitis in gastrointestinal (GI) tract, so it has high patient compliance.
  • Layer of enteric coating polymer protects the bioactive agent against degradation in the gastrointestinal tract.
  • the present invention provides pharmaceutical composition comprising mesalamin, wherein the product is targeted colon area in human body.
  • the present invention provides pharmaceutical composition comprising mesalamin and relevant excipients with enteric coated dosage form, characterized by i) to control / program the release of the active ingredients according to well-designed tablet formation, and ii) a smart and well-designed manufacturing process.
  • an enteric tablet product that is convenient to use for intestinal diseases was obtained with enteric polymers such as Eudragit L100 and Eudragit S100 by using minimum excipients in the formulation.
  • the present invention provides pharmaceutical composition comprising mesalamin and relevant excipients, wherein it is convenient to use with total tablet weight between 1400mg to 2000mg for an enteric coated composition. Bigger than 2000mg tablet product is not much comfortable for patients because of swallowing problem.
  • composition is used to indicate a pharmaceutical composition or a medical device composition or a supplement composition or a food composition.
  • treatment means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or 3) relieving the disease or condition that is, causing the regression of clinical symptoms.
  • composition of the present inventions may comprise one or more pharmaceutically acceptable excipient(s).
  • Pharmaceutically acceptable excipients comprise, but are not limited to, diluent, disintegrant, glidant, plastizer, binder, surfactant, lubricant, Enteric coating polymer, solvent and the mixtures thereof, to facilitate the physical formulation of various dosage forms for oral administration like tablets.
  • Diluents can be selected from the group, but are not limited to, calcium hydrogen phosphate calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, maltodextrin, mannitol, microcrystalline cellulose, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, and xylitol or mixture thereof.
  • a preferred diluent is microcrystalline cellulose.
  • Binders can be selected from the group, but are not limited to, methylcellulose, sodium carboxymethycellulose, calcium carboxymethycellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone (Povidon), gelatine, polyvinyl alcohol, compressible sugar, liquid glucose, dextrates, dextrin, dextrose, maltodextrin, magnesium aluminium silicate, polymethacrylates, sorbitol and other materials known to one of ordinary skill in the art.
  • a preferred binder is polyvinylpyrrolidone.
  • a mixture of binders may also be used.
  • Disintegrants can be selected from the group, but are not limited to, alginic acid, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidones, polacrilin potassium, starch, pregelatinised starch, sodium alginate, hydroxypropyl starch and other materials known to one of ordinary skill in the art.
  • the combination of above-mentioned disintegrants can also be used.
  • the preferred disintegrant is croscarmellose sodium.
  • Glidants can be selected from the group, but are not limited to, colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, magnesium trisilicate, amorphous silica, colloidal silicon, silicon hydrogel, powdered cellulose, silicon dioxide, talc, tribasic calcium phosphate and other materials known to one of ordinary skill in the art.
  • the preferred glidants are talc and colloidal silicon dioxide.
  • Lubricants can be selected from the group, but are not limited to, vegetable oils, such as hydrogenated vegetable oil or hydrogenated castor oil, polyethylene glycols; stearic acid; derivatives of stearic acid, such as magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate and sodium stearyl fumarate; mineral salts, such as talc; and polyvinyl alcohols, microcrystalline cellulose, sodium lauryl sulfate, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel and other materials known to one of ordinary skill in the art.
  • the preferred lubricant is calcium stearate.
  • Plasticizer can be selected from the group, but are not limited to, acetylated monoglycerides, triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, trioctyl citrate, acetyl trioctyl citrate, trihexyl citrate, acetyl trihexyl citrate, butyryl trihexyl citrate, trimethyl citrate, PEG, epoxidized vegetable oils, bis(2-ethylhexyl)adipate, dimethyl adipate, monomethyl adipate, dioctyl adipate, dibutyl sebacate, tributyl sebacate, dibutyl maleate, diisobutyl maleate and other materials known to one of ordinary skill in the art.
  • the preferred plastizer is PEG 6000.
  • Enteric coating polymers can be selected from the group, but are not limited to, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, methacrylic acid copolymers (Eudragit L-100, Eudragit S-100) and other materials known to one of ordinary skill in the art.
  • the preferred Enteric coating polymers are Eudragit L-100 and Eudragit S-100.
  • Solvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, distilled water and other materials known to one of ordinary skill in the art and mixtures thereof.
  • the preferred solvent is distilled water.
  • Mesalamine active substance is a molecule in BCS IV class with low solubility and low permeability.
  • the products of the prototype formulations is subjected to dissolution rate tests simulating body fluids in buffers at different pH's.
  • test product was studied at all the gastrointestinal pH ranging from 1,2 - 7,5 and found to be satisfactory.
  • the test product at OGD or QC medium along with FaSSCoF were represented in the above figures showing similar behaviour to that of the selected Reference Salofalk 1g tablets.
  • the product has to be taken one hour before meal, so it clearly predicts the dosage form in-vivo release pattern from the FaSSCoF study.
  • tablet consists of two layers wherein one layer is consisting Eudragit L-100 and relevant excipients, the other layer is consisting Eudragit L-100 and Eudragit S-100 and also relevant excipients in an enteric coated tablet.
  • the components of the pharmaceutical composition according to the present invention are brought together into an enteric coated tablet for oral administration as shown in example 1.
  • the following example is understood to be illustrative only.
  • Example 1 Enteric coated tablet composition of Mesalamine 1g
  • Microcrystalline cellulose, Croscarmellose Sodium and Colloidal Silicon Dioxide was sieved and lubricated with Calcium Stearate.

Abstract

The present invention relates to the preparation of pharmaceutical compositions comprising mesalamin and also relevant excipients, having an improved formulation design for enteric coated tablet manufacturing method.

Description

DESCRIPTION
PHARMACEUTICAL COMPOSITIONS COMPRISING MESALAMIN AND RELEVANT EXCIPIENTS
Field of invention
The present invention relates to the preparation of pharmaceutical compositions comprising mesalamin and also relevant excipients, having an improved formulation design for manufacturing enteric coated tablet composition.
Background of the invention
Aminosalicylate drugs, such as mesalamine, used to treat for mild and moderate disease of inflammatory bowel disease (IBD). Mesalamine, also known as 5-aminosalicilic acid (5-ASA), is an anti-inflammatory drug used in the treatment of disturbances on gastrointestinal tract like inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis.
Mesalamine, has a odorless white to pinkish crystals or purplish-tan powder appearance, chemical name is 5-Amino-2-hydroxybenzoic acid, having a molecular weight of 153.135 g/mol, its chemical structure is shown in the Figure I.
Figure imgf000002_0001
Figure 1: Mesalamine
Mesalamin is used for many years in the treatment of inflammatory bowel disease (IBD), firstly approved in 1984. Dosage forms are available tablets, enema, spposituar, capsule, granule or powder in the market until now.
Inflammatory bowel disease is a cover term for Crohn’s disease and ulcerative colitis that are characterized by chronic inflammation of the gastrointestinal (GI) tract.
Crohn's disease is a chronic inflammatory disease of the digestive tract, which symptoms are abdominal pain, fever, fatigue, severe diarrhea, weight loss. Although there's no known cure for Crohn's disease, therapies can greatly reduce its signs and symptoms.
Ulcerative colitis is one of inflammatory bowel disease (IBD) that causes long-lasting inflammation and ulcers in digestive tract. The main symptoms of this disease are abdominal pain, bloody diarrhea, weight loss, fever, and anemia. It causes irritation, inflammation, and ulcers in the lining of large intestine and rectum. Enteric coated tablet, also known as gastro-resistant coating tablet type that is coated with active ingredient(s) that prevents the medication from being released until it reaches the small intestine, where it can then be absorbed.
Most enteric coated tablets has a stable surface to highly acidic pH of the stomach but it breaks down rapidly at a less acidic (relatively more basic) pH in intestinal route. Enteric coated tablets can dissolve in the small intestine.
Parameters of enteric coating materials such as resistance to gastric media, permeability to intestinal fluids, high compatibility, nontoxic activity and able to form continuous film are critical for a product of enteric coated tablet. Excipients should be selected according to these parameters and also properties of active ingredient.
Enteric coating is used to protect drugs from degradative effects of gastric acidity, to protect the gastric mucosa from irritation and to control the delivery of certain drugs to the intestines to enhance absorption.
The main polymers for enteric release film coating are cellulose acetate phthalate, cellulose acetate trimellitate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, polyvinyl acetate phthalate and methacrylic acid copolymers.
When the combined oral and rectal administration of mesalamine was used, the improvement rate in symptoms was 88%; but this recovery rate is 54% in treatment that used only rectal applications. These results obtained from (Safdi et all. A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis. Am
J Gastroenterol. 1997 Oct;92(10):1867-71)
Summary of the invention
The present invention relates to the preparation of pharmaceutical compositions comprising mesalamin and also relevant excipients, having an improved formulation design for manufacturing an enteric coated tablet composition.
The present invention provides a pharmaceutical enteric tablet composition comprising mesalamin, wherein the enteric coating polymer is Eudragit L100 in the first layer, wherein the enteric coating polymers are Eudragit SI 00 and Eudragit LI 00 in the second layer, wherein the total tablet weight is between 1400mg to 2000mg.
Detailed Description of the invention
The present invention relates to the preparation of pharmaceutical compositions comprising mesalamin and also relevant excipients, having an improved formulation design for manufacturing an enteric coated tablet composition.
The present invention provides a pharmaceutical composition comprising mesalamin, wherein the enteric coating polymer is Eudragit L100, wherein the enteric coating polymers are Eudragit S100 and Eudragit L100, wherein the total tablet weight is between 1400mg to 2000mg in enteric coated tablet.
The present invention relates to a mesalamin pharmaceutical composition comprising; a) A first layer comprising Eudragit L100 as an enteric coating polymer and at least one pharmaceutically acceptable excipient, wherein the weight ratio of Eudragit LI 00. b) A second layer comprising Eduragit S100 and Eudragit LI 00 as enteric coating polymers, and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical enteric coated tablet weight is between a specific interval.
The present invention relates to a pharmaceutical enteric tablet composition comprising mesalamin; a) a first layer comprising Eudragit LI 00 as an enteric coating polymer and at least one pharmaceutically acceptable excipient, wherein the weight ratio of Eudragit LI 00 in the first layer to total tablet weight is between 2,5 to 5,0. b) a second layer comprising Eduragit S100 and Eudragit LI 00 as enteric coating polymers, and at least one pharmaceutically acceptable excipient, wherein the weight ratio of Eudragit S100 to Eudragit L100 in the second layer is between 0,5 to 0,8. wherein the pharmaceutical enteric coated tablet weight is between 1400mg to 2000mg.
Enteric coating is a oral medication type that is used polymers. These polymers serve as a barrier to prevent the gastric acids in the stomach from dissolving or degrading drugs after swallowing tablets. If enteric protection is not used in pharmaceutical products, most of the drugs would fall apart rapidly with stomach acids.
The enteric polymer coating makes a delayed release for tablet dosage forms. As a result of this process, drugs are targeted to the small intestine or other stages in digestion it needs to reach.
The present invention relates to a pharmaceutical enteric tablet composition, characterized in that it is provided wherein the enteric coating polymer of Eudragit LI 00 is in the first layer and enteric coating polymers of Eudragit S100 and Eudragit LI 00 are in the second layer.
The present invention relates to a pharmaceutical composition, the weight ratio of Eudragit L100 in the first layer to total tablet weight is between 2,5 to 5,0.
The present invention relates to a pharmaceutical composition, the weight ratio of Eudragit L100 in the first layer to total tablet weight is preferably between 2,7 to 3,5, more preferably 2,84.
The present invention relates to a pharmaceutical composition, the weight ratio of Eudragit S100 to Eudragit L100 in the second layer is between 0,5 to 0,8.
The present invention relates to a pharmaceutical composition, the weight ratio of Eudragit S100 to Eudragit LI 00 in the second layer is preferably between 0,6 to 7,7, more preferably 0,68. The present invention relates to a pharmaceutical composition comprising mesalamine and relevant excipients in an enteric coated tablet dosage form. Releasing active substance from mesalazine tablets begins 3-4 hours later with this dosage form. It reaches peak plasma concentration after about 5 hours. It reaches the region between the ileum and the large intestine within 3-4 hours in the case of fasting, and reaches the upper colon within 4-5 hours. It remains for approximately 17 hours in the colon.
The present invention relates to Eudragit and its different types. Eudragit has a structure with methacrylic acid copolymers. Methacrylic acid copolymers are widely used for enteric coating tablets as they contain free carboxylic acid groups. These enteric polymers are marketed most notably by Evonik (formerly known as Rohm GmbH) under the proprietary Eudragit brand name. Many types of Eudragit enteric polymers are commercially available in with different physical forms such as aqueous dispersion, organic solution, granules and powders.
Eudragits are anionic copolymers based on methacrylic acic and methyl methacrylate. Eudragit L100 is Poly(methacylic acid-co-methyl methacrylate) 1:1. Eudragit S100 is Poly(methacylic acid-co-methyl methacrylate) 1:2.
Generally, the Eudragit products for enteric coatings are based on anionic polymers of methacrylic acid and methacrylates. It dissolves at ranges from pH 5.5 to pH 7. Some of Eudragit products can be seen in table 1.
Table 1: Properties of Eudragit products
Figure imgf000005_0001
Some of the outstanding properties of Eudragit products in enteric coating: pH-dependent drug release, protection of actives sensitive to gastric fluid, protection of gastric mucosa from aggressive actives, increase in drug effectiveness, good storage stability, GI and colon targeting.
The present invention relates to an enteric coated tablet composition, wherein the product is targeted colon area in human body.
The present invention relates to an enteric coated tablet composition, wherein the formulation has two layers comprising mesalamin, enteric coating polymers and relevant excipients.
The present invention provides a pharmaceutical composition comprising mesalamine and relevant excipients, wherein pharmaceutical composition has two layers, “first layer” and “second layer”.
The present invention relates to an enteric coated tablet composition, wherein Eudragit L100 is used as an enteric polymer in the first layer of composition.
The present invention relates to an enteric coated tablet composition, wherein Eudragit L100 and Eudragit S100 are used as enteric polymers in the second layer of composition. The present invention provides a pharmaceutical composition comprising mesalamine and relevant excipients, wherein the total tablet weight is between 1400mg to 2000mg in enteric coated tablet.
In one embodiment, pharmaceutical composition comprising mesalamine and relevant excipients, wherein the total tablet weight is between 1400mg to 1800mg in enteric coated tablet.
It is found when the weight ratio of Eudragit enteric polymers (Eudragit LI 00 and Eudragit S100) and also total tablet weight is between a specific intervals mentioned above paragraphs, synergestic effect observed and it also provides an optimum formulation design for this enteric coated tablet product.
In one embodiment, enteric coated tablet composition comprising mesalamin, is used for the treatment of inflammatory bowel disease including Crohn’s disease and ulcerative colitis.
An object of the present invention is to provide a pharmaceutical composition in oral dosage form as an enteric coated tablet which provides immediate release of drug that exhibits acceptable bioavailability results.
In an embodiment, the process of preparing the stable pharmaceutical composition comprises steps of preparing a first enteric layer comprising pharmaceutically acceptable excipients and Eudragit LI 00, the second layer comprising pharmaceutically acceptable excipients and Eudragit L100 and Eudragit S 100 followed by compressing of enteric coated tablet and coating by a protective layer.
In another embodiment, the pharmaceutical composition further comprises at least one excipient selected from a diluent, a binder, a disintegrant, a glidant, a lubricant, a plastizer, an enteric coating polymer and a film coating material.
Advantages
It is obtained optimum total tablet weight that is convenient to patient use by using enteric polymers such as Eudragit LI 00 and Eudragit S 100 in an enteric tablet.
The pharmaceutical compositions of the invention are particularly suited for the oral administration.
The present invention shows well physical properties depends on its stability characteristics in appropriate excipients. It shows good properties to provide basic physical stability.
The present invention provides pharmaceutical composition comprising mesalamin and relevant excipients in enteric coated dosage form, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation Enteric tablet dosage form is convenient to use for intestinal diseases such as ulceratis collitis in gastrointestinal (GI) tract, so it has high patient compliance.
Layer of enteric coating polymer protects the bioactive agent against degradation in the gastrointestinal tract.
The present invention provides pharmaceutical composition comprising mesalamin, wherein the product is targeted colon area in human body.
The present invention provides pharmaceutical composition comprising mesalamin and relevant excipients with enteric coated dosage form, characterized by i) to control / program the release of the active ingredients according to well-designed tablet formation, and ii) a smart and well-designed manufacturing process.
In this invention, an enteric tablet product that is convenient to use for intestinal diseases was obtained with enteric polymers such as Eudragit L100 and Eudragit S100 by using minimum excipients in the formulation.
The present invention provides pharmaceutical composition comprising mesalamin and relevant excipients, wherein it is convenient to use with total tablet weight between 1400mg to 2000mg for an enteric coated composition. Bigger than 2000mg tablet product is not much comfortable for patients because of swallowing problem.
In the present invention, the expression "composition” is used to indicate a pharmaceutical composition or a medical device composition or a supplement composition or a food composition.
The term "treatment" or "treating" means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or 3) relieving the disease or condition that is, causing the regression of clinical symptoms.
Pharmaceutical composition of the present inventions may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients comprise, but are not limited to, diluent, disintegrant, glidant, plastizer, binder, surfactant, lubricant, Enteric coating polymer, solvent and the mixtures thereof, to facilitate the physical formulation of various dosage forms for oral administration like tablets.
Diluents can be selected from the group, but are not limited to, calcium hydrogen phosphate calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, maltodextrin, mannitol, microcrystalline cellulose, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, and xylitol or mixture thereof. A preferred diluent is microcrystalline cellulose. Binders can be selected from the group, but are not limited to, methylcellulose, sodium carboxymethycellulose, calcium carboxymethycellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone (Povidon), gelatine, polyvinyl alcohol, compressible sugar, liquid glucose, dextrates, dextrin, dextrose, maltodextrin, magnesium aluminium silicate, polymethacrylates, sorbitol and other materials known to one of ordinary skill in the art. A preferred binder is polyvinylpyrrolidone. A mixture of binders may also be used.
Disintegrants can be selected from the group, but are not limited to, alginic acid, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidones, polacrilin potassium, starch, pregelatinised starch, sodium alginate, hydroxypropyl starch and other materials known to one of ordinary skill in the art. The combination of above-mentioned disintegrants can also be used. The preferred disintegrant is croscarmellose sodium.
Glidants can be selected from the group, but are not limited to, colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, magnesium trisilicate, amorphous silica, colloidal silicon, silicon hydrogel, powdered cellulose, silicon dioxide, talc, tribasic calcium phosphate and other materials known to one of ordinary skill in the art. The preferred glidants are talc and colloidal silicon dioxide.
Lubricants can be selected from the group, but are not limited to, vegetable oils, such as hydrogenated vegetable oil or hydrogenated castor oil, polyethylene glycols; stearic acid; derivatives of stearic acid, such as magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate and sodium stearyl fumarate; mineral salts, such as talc; and polyvinyl alcohols, microcrystalline cellulose, sodium lauryl sulfate, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel and other materials known to one of ordinary skill in the art. The preferred lubricant is calcium stearate.
Plasticizer can be selected from the group, but are not limited to, acetylated monoglycerides, triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, trioctyl citrate, acetyl trioctyl citrate, trihexyl citrate, acetyl trihexyl citrate, butyryl trihexyl citrate, trimethyl citrate, PEG, epoxidized vegetable oils, bis(2-ethylhexyl)adipate, dimethyl adipate, monomethyl adipate, dioctyl adipate, dibutyl sebacate, tributyl sebacate, dibutyl maleate, diisobutyl maleate and other materials known to one of ordinary skill in the art. The preferred plastizer is PEG 6000.
Enteric coating polymers can be selected from the group, but are not limited to, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxyl propyl methyl cellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, methacrylic acid copolymers (Eudragit L-100, Eudragit S-100) and other materials known to one of ordinary skill in the art. The preferred Enteric coating polymers are Eudragit L-100 and Eudragit S-100. Solvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, distilled water and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred solvent is distilled water.
Mesalamine active substance is a molecule in BCS IV class with low solubility and low permeability.
During the development of this product, in vitro studies is designed using buffers prepared with colon-targeted bio-similar chemicals.
After determining the active ingredient and excipients with the appropriate method, the products of the prototype formulations is subjected to dissolution rate tests simulating body fluids in buffers at different pH's.
It is studied buffers at differet pHs; 1.2pH, pH:4.5 acetate buffer, pH:6.0 phosphate buffer, pH: 6.5 phosphate buffer, pH: 6.8 phosphate buffer, pH: 7.2 phosphate buffer, pH: 7.5 phosphate buffer, FaSSCoF and FeSSCoF.
Figure imgf000009_0001
Figure imgf000010_0001
The test product was studied at all the gastrointestinal pH ranging from 1,2 - 7,5 and found to be satisfactory. The test product at OGD or QC medium along with FaSSCoF were represented in the above figures showing similar behaviour to that of the selected Reference Salofalk 1g tablets. The product has to be taken one hour before meal, so it clearly predicts the dosage form in-vivo release pattern from the FaSSCoF study.
In the present invention, tablet consists of two layers wherein one layer is consisting Eudragit L-100 and relevant excipients, the other layer is consisting Eudragit L-100 and Eudragit S-100 and also relevant excipients in an enteric coated tablet. The components of the pharmaceutical composition according to the present invention are brought together into an enteric coated tablet for oral administration as shown in example 1. The following example is understood to be illustrative only.
Example 1: Enteric coated tablet composition of Mesalamine 1g
Figure imgf000011_0001
Procedure for composition comprising Mesalamin 1g enteric film coated tablet;
1. Stage 1 Mixing and Granulation
Mixing and Granulation: Mesalamin, microcrystalline cellulose and Povidon.
2. Stage 2 Sieving, Lubrication and Tablet compression
Microcrystalline cellulose, Croscarmellose Sodium and Colloidal Silicon Dioxide was sieved and lubricated with Calcium Stearate.
3. Stage 3 Enteric Coating - 1
Eudragit L-100, ethanol, PEG 6000 and talc.
4. Stage 4 Enteric Coating - 2
Eudragit L-100, Eudragit S-100, ethanol, PEG 6000 and talc
5. Film Coating
Film coating material

Claims

1. A pharmaceutical enteric coated tablet composition comprising mesalamin, wherein the composition comprising: a) a first layer comprising Eudragit LI 00 as an enteric coating polymer and at least one pharmaceutically acceptable excipient, wherein the weight ratio of Eudragit LI 00 in the first layer to total tablet weight is between 2,5 to 5,0, b) a second layer comprising Eduragit S100 and Eudragit LI 00 as enteric coating polymers, and at least one pharmaceutically acceptable excipient, wherein the weight ratio of Eudragit S100 to Eudragit L100 in the second layer is between 0,5 to 0,8, wherein the pharmaceutical enteric coated tablet weight is between 1400mg to 2000mg.
2. The pharmaceutical composition according to claim 1, the weight ratio of Eudragit L100 in the first layer to total tablet weight is between 2,7 to 3,5, preferably 2,84.
3. The pharmaceutical composition according to any one of the proceeding claims, wherein the weight ratio of Eudragit S100 to Eudragit L100 in the second layer is between 0,6 to 0,7, preferably 0,68.
4. The pharmaceutical composition according to any one of the proceeding claims, wherein the pharmaceutical enteric coated tablet weight is between 1400mg to 1800mg.
5. The pharmaceutical composition according to any one of the proceeding claims, wherein the composition further comprises at least one excipient selected from a diluent, a binder, a disintegrant, a glidant, a lubricant, a plastizer, an enteric coating polymer and a film coating material.
6. The pharmaceutical composition according to any one of the proceeding claims for use in the the treatment of inflammatory bowel disease including Crohn’s disease and ulcerative colitis.
PCT/TR2020/050889 2020-09-25 2020-09-25 Pharmaceutical compositions comprising mesalamin and relevant excipients WO2022066110A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998026767A2 (en) * 1996-12-17 1998-06-25 Poli Industria Chimica S.P.A. Site-specific controlled release dosage formulation for mesalamine
US20090169622A1 (en) * 2007-12-27 2009-07-02 Roxane Laboratories, Inc. Delayed-release oral pharmaceutical composition for treatment of colonic disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998026767A2 (en) * 1996-12-17 1998-06-25 Poli Industria Chimica S.P.A. Site-specific controlled release dosage formulation for mesalamine
US20090169622A1 (en) * 2007-12-27 2009-07-02 Roxane Laboratories, Inc. Delayed-release oral pharmaceutical composition for treatment of colonic disorders

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "EUDRAGIT® Acrylic Polymers for Solid Oral Dosage Forms", EVONIK, 1 January 2021 (2021-01-01), XP055931656, Retrieved from the Internet <URL:https://healthcare.evonik.com/sites/lists/NC/DocumentsHC/Evonik-Eudragit_brochure.pdf> [retrieved on 20220615] *
KHAN M Z I, STEDUL H P, KURJAKOVIC N: "A PH-DEPENDENT COLON-TARGETED ORAL DRUG DELIVERY SYSTEM USING METHACRYLIC ACID COPOLYMERS II. MANIPULATION OF DRUG RELEASE USING EUDRAGIT L100 AND EUDRAGIT S100 COMBINATIONS", JOURNAL DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, NEW YORK, NY, US, vol. 26, no. 05, 1 January 2000 (2000-01-01), US , pages 549 - 554, XP000981442, ISSN: 0363-9045, DOI: 10.1081/DDC-100101266 *

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