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US-12622875-B2 - Dosage form comprising an alkaline agent and an enteric coating layer

US12622875B2US 12622875 B2US12622875 B2US 12622875B2US-12622875-B2

Abstract

A dosage form contains a) a core, containing a biologically active ingredient, which is stable to a degree of at least 95% at a pH of 3 for 2 hours at 22° C.; b) an intermediate coating layer (ICL) onto or above the core, containing an alkaline agent; and c) an enteric coating layer (ECL) onto or above the intermediate coating layer, containing an enteric polymer. The relation in percent of the alkaline agent in the ICL to the enteric polymer in the ECL is 5 to 95% when calculated by the formula: quantity ⁢ of ⁢ alkaline ⁢ agent ⁢ in ⁢ grams ⁢ in ⁢ the ⁢ ICL × 100 ( quantity ⁢ of ⁢ alkaline ⁢ agent ⁢ in ⁢ grams ⁢ in ⁢ the ⁢ ICL + quantity ⁢ of ⁢ enteric ⁢ polymer ⁢ in ⁢ grams ⁢ in ⁢ the ⁢ ⁢ ECL ) .

Inventors

  • Priyanka HAKSAR
  • Shraddha JOSHI
  • Umesh Kapale
  • Nilam Bharambe
  • Ashish Guha
  • Vinay Jain

Assignees

  • EVONIK OPERATIONS GMBH

Dates

Publication Date
20260512
Application Date
20200917
Priority Date
20191211

Claims (19)

  1. 1 . A dosage form, comprising: a core, comprising a biologically active ingredient which is stable to a degree of at least 95% at a pH of 3 for 2 hours at 22° C., an intermediate coating layer (ICL) onto or above the core, comprising an alkaline agent, and an enteric coating layer (ECL) onto or above the ICL, comprising an enteric polymer, wherein a relation in percent of the alkaline agent in the ICL to the enteric polymer in the ECL is 5 to 95% when calculated by the formula: quantity ⁢ of ⁢ the ⁢ alkaline ⁢ agent ⁢ in ⁢ grams ⁢ in ⁢ the ⁢ ICL × 100 ( quantity ⁢ of ⁢ the ⁢ alkaline ⁢ agent ⁢ in ⁢ grams ⁢ in ⁢ the ⁢ ⁢ ICL + quantity ⁢ of ⁢ the ⁢ enteric ⁢ polymer ⁢ in ⁢ grams ⁢ in ⁢ the ⁢ ⁢ ECL ) , wherein the alkaline agent is selected from the group consisting of calcium oxide, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, and a combination thereof, wherein the enteric polymer in the ECL is selected from the group consisting of an anionic (meth)acrylate copolymer, an anionic cellulose, an anionic polysaccharide, a polyvinyl acetate phthalate, and a mixture thereof, and wherein the biologically active ingredient does not comprise lansoprazole.
  2. 2 . The dosage form according to claim 1 , wherein the core comprises the biologically active ingredient distributed in a matrix structure or bound in a binder in a coating on the core.
  3. 3 . The dosage form according to claim 1 , wherein the biologically active ingredient is selected from the group consisting of acetyl salicylic acid, benazepril, bisascodyl, budesonide, carvediol, etopside, quinidine, ketoconazole, sotalol, an enzyme, a hormone, a liquid natural extract, a solid natural extract, an oligonucleotide, DNA, RNA, mRNA, siRNA, Protacs a peptide hormone, therapeutic bacteria, a prebiotic, a probiotic, a peptide, a protein, an omega-3-fatty acid, a salt of an omega-3-fatty acid, an anthocyanine, a vitamin, and a vaccine.
  4. 4 . The dosage form according to claim 1 , wherein the alkaline agent is magnesium oxide.
  5. 5 . The dosage form according to claim 1 , wherein the alkaline agent is magnesium oxide or magnesium carbonate.
  6. 6 . The dosage form according to claim 1 , wherein the ICL further comprises a plasticizer, a polymeric binder, or both.
  7. 7 . The dosage form according to claim 1 , wherein the enteric polymer in the ECL is an anionic (meth)acrylate copolymer.
  8. 8 . The dosage form according to claim 1 , wherein the enteric polymer is an anionic (meth)acrylate copolymer selected from the group consisting of a copolymer comprising polymerized units of methacrylic acid and ethyl acrylate, a copolymer comprising polymerized units of methacrylic acid and methyl methacrylate, a copolymer comprising polymerized units of methacrylic acid, methyl acrylate, and methyl methacrylate, and a mixture thereof.
  9. 9 . The dosage form according to claim 1 , wherein the enteric polymer is an anionic cellulose selected from the group consisting of carboxymethyl ethyl cellulose, a salt of carboxymethyl ethyl cellulose, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, and a mixture thereof.
  10. 10 . The dosage form according to claim 1 , wherein the biologically active ingredient is released in an amount of 10% or less at a pH of 1.2 for 120 min, and in an amount of 40% or more at a pH from 3 to 5.5 for 45 min.
  11. 11 . The dosage form according to claim 1 , wherein the biologically active ingredient is stable to degradation to a degree of at least 95% for 2 hours at 22° C. at any pH in a pH range from 3.0 to 7.0.
  12. 12 . The dosage form according to claim 1 , wherein the biologically active ingredient which is stable to a degree of at least 95% at a pH of 3 for 2 hours at 22° C., has such stability determined in an assay which is a thin-layer chromatographic identification test, a spectrometric identification test, a nuclear magnetic resonance spectroscopy, a near-infrared spectroscopy, or a Raman spectroscopy.
  13. 13 . The dosage form according to claim 1 , wherein the biologically active ingredient is stable to a degree of at least 95% at a pH of 3.0 for 2 hours at 22° C. in a buffered medium of 0.25 M disodium hydrogen phosphate anhydrous (Na 2 HPO 4 ) aqueous solution adjusted to a pH of 3.0 with ortho-phosphoric acid.
  14. 14 . The dosage form according to claim 1 , wherein the relation in percent of the alkaline agent in the ICL to the enteric polymer in the ECL is 7 to 80%.
  15. 15 . The dosage form according to claim 3 , wherein the biologically active ingredient is bilberries, blueberries, or black currants.
  16. 16 . The dosage form according to claim 1 , wherein the biologically active ingredient comprises benazepril.
  17. 17 . A dosage form, comprising: a core, comprising a biologically active ingredient which is stable to a degree of at least 95% at a pH of 3 for 2 hours at 22° C., an intermediate coating layer (ICL) onto or above the core, comprising an alkaline agent, and an enteric coating layer (ECL) onto or above the ICL, comprising an enteric polymer, wherein a relation in percent of the alkaline agent in the ICL to the enteric polymer in the ECL is 5 to 95% when calculated by the formula: quantity ⁢ of ⁢ the ⁢ alkaline ⁢ agent ⁢ in ⁢ grams ⁢ in ⁢ the ⁢ ICL × 100 ( quantity ⁢ of ⁢ the ⁢ alkaline ⁢ agent ⁢ in ⁢ grams ⁢ in ⁢ the ⁢ ⁢ ICL + quantity ⁢ of ⁢ the ⁢ enteric ⁢ polymer ⁢ in ⁢ grams ⁢ in ⁢ the ⁢ ⁢ ECL ) , wherein the alkaline agent is selected from the group consisting of calcium oxide, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, and a combination thereof, and wherein the enteric polymer in the ECL is selected from the group consisting of an anionic (meth)acrylate copolymer, an anionic cellulose, an anionic polysaccharide, a polyvinyl acetate phthalate, and a mixture thereof, wherein the biologically active ingredients in the core consists only of active ingredients which are stable to a degree of at least 95% at a pH of 3 for 2 hours at 22° C.
  18. 18 . The dosage form according to claim 1 , wherein the biologically active ingredients in the core do not contain ingredients which are not stable to a degree of at least 95% at a pH of 3 for 2 hours at 22° C.
  19. 19 . The dosage form according to claim 1 , wherein the biologically active ingredient excludes acid labile drugs.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is the National Stage entry under § 371 of International Application No. PCT/EP2020/075960, filed on Sep. 17, 2020, and which claims the benefit of priority to Indian Application No. 201941051238, filed on Dec. 11, 2019. The content of each of these applications is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION Field of the Invention The invention is in the field of pharmaceuticals and nutraceuticals, especially in the field of dosage forms comprising an alkaline agent in an intermediate coating layer and an enteric coating layer. Background Description of Related Art U.S. Pat. No. 4,786,505 describes an oral pharmaceutical preparation comprising (a) a core region comprising an effective amount of a material selected from the group of omeprazole plus an alkaline reacting compound, an alkaline omeprazole salt plus an alkaline compound and an alkaline omeprazole salt alone, (b) an inert subcoating which is soluble or rapidly disintegrating in water disposed on said core, said subcoating comprising one or more layers of materials selected from among tablet excipients and polymeric film-forming compounds; and (c) an outer layer disposed on said subcoating comprising an enteric coating. The subcoating layer also serves as a pH-buffering zone. The pH buffering properties of subcoating layer may be further strengthened by introducing substances chosen from a group of compounds usually used in antacid formulations such as, for instance, magnesium oxide, hydroxide or carbonate, aluminium or calcium hydroxide, carbonate or silicate; composite aluminium/magnesium compounds such as, for instance [Al2O3·6MgO·CO2·12H2O or MgO·AlO3·2SiO2·n-H2O], wherein n is not an integer and less than 2. The object of U.S. Pat. No. 4,786,505 is to provide an enteric coated dosage form of omeprazole, which is resistant to dissolution in acid media and which dissolves rapidly in neutral to alkaline media and which has a good stability during long term storage. In examples 1 and 6 of U.S. Pat. No. 4,786,505 the percentage of alkaline substance (magnesium oxide or aluminium hydroxide/magnesium carbonate) in the subcoating layer, calculated on the weight of alkaline agent and the enteric polymer (hydroxypropyl methylcellulose phthalate) in the enteric coating layer is about 4.1 or 6.6% by weight respectively. US2005/0214371A1 describes a stable composition of an acid labile drug, comprising a) an inner core with the acid labile drug; b) a first intermediate coating devoid of an alkaline stabilizing agent and the acid labile drug; c) a second intermediate coating comprising an alkaline stabilizing agent; and d) an outer enteric layer, wherein the acid labile drug can degrade at pH 3. The term “acid labile drug” refers to any drug or medicament or active pharmaceutical ingredient (API) that will degrade at a pH of 3. Examples of “acid labile drug” include pharmaceutically active substituted benzimidazole compounds, statins (e.g. pravastatin, fluvastatin and atorvastatin), antibiotics (e.g. penicillin G, ampicillin, streptomycin, clarithromycin and azithromycin), dideoxy cytosine (ddC), digoxin, pancreatin, bupropion and pharmaceutically acceptable salts thereof, such as buprion HCl. The term “pharmaceutically active substituted benzimidazole compound” refers to any pharmaceutically active substituted 2-(2-pyridylmethyl)-sulfinyl-1H-benzimidazole compound (e.g. lansoprazole, omeprazole, hydroxy omeprazole, pantoprazole, rabeprazole, esomeprazole, preprazole, pariprazole, rabeprazole and tenatoprazole) and pharmaceutically active substituted 2-(phenylmethy)-sulfinyl-1H-benzimidazole compound (e.g. leminoprazole). US2005/0214371A1 does not mention or suggest an unexpected release of the acid labile drugs at low pH values. US2005/0214371A1 also provides a method of treating a disease selected from gastric or duodenal ulcer, severe erosive esophagitis, Zolinger-Elison syndrome, gastroesophageal reflux and H. pylori infection, comprising an effective amount of a stable pharmaceutical composition of the invention to a subject inflicted with the disease, preferably a subject in need of the treatment, wherein the acid labile drug in the stable pharmaceutical composition is selected from lansoprazole, omeprazole, pantoprazole, rabeprazole, hydroxy omeprazole, esomeprazole, pariprazole, preprazole, tenatoprazole, leminoprazole, and acceptable salts thereof. IPCOM000009757D (IP.com Prior Art Database Technical Disclosure IP.com Number IPCOM000009757D, IP.com electronic publication date Sep. 17, 2002, Authors et al.: Disclosed Anonymously) describes “Stabilized Pharmaceutical Formulation of an Acid labile Benzimidazole Compound and its Preparation”. The general disclosure IPCOM000009757D is very similar to that of US2005/0214371A1 with the exception that no “b) a first intermediate coating devoid of an alkaline stabilizing agent and the acid labile drug” is mentioned. U