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EP-4734955-A1 - VITAMIN B12 FORMULATION FOR INTRANASAL ADMINISTRATION

EP4734955A1EP 4734955 A1EP4734955 A1EP 4734955A1EP-4734955-A1

Abstract

The invention relates to an aqueous vitamin B12 formulation for intranasal administration, comprising: · 3-100 mg/mL of a vitamin B12 component selected from hydroxocobalamin, cyanocobalamin, adenosylcobalamin, methylcobalamin, pharmaceutically acceptable salts of these cobalamins and combinations thereof · 30-300 mg/mL of sorbitol; wherein the vitamin B12 component and sorbitol are present in a weight ratio of vitamin B12 component : sorbitol of at least 0.2 and wherein the formulation has a pH in the range of 3.0 to 5.5.

Inventors

  • PELLIKAAN, HUBERT CLEMENS

Assignees

  • AAA Investments B.V.

Dates

Publication Date
20260506
Application Date
20240628

Claims (15)

  1. 1 . An aqueous vitamin B12 formulation for intranasal administration comprising: • 3-100 mg/mL of a vitamin B12 component selected from hydroxocobalamin, cyanocobalamin, adenosylcobalamin, methylcobalamin, pharmaceutically acceptable salts of these cobalamins and combinations thereof; • 15-300 mg/mL of sorbitol; wherein the vitamin B12 component and sorbitol are present in a weight ratio of vitamin B12 component : sorbitol of at least 0.2 and wherein the formulation has a pH in the range of 3.0 to 5.5.
  2. 2. Formulation according to claim 1 , wherein the vitamin B12 component is selected from hydroxocobalamin, pharmaceutically acceptable salts of hydroxocobalamin and combinations thereof.
  3. 3. Formulation according to any one of the preceding claims, wherein the formulation comprises 10-90 mg/mL of vitamin B12.
  4. 4. Formulation according to any one of the preceding claims, wherein the formulation comprises 25-250 mg/mL of sorbitol.
  5. 5. Formulation according to any one of the preceding claims, wherein the vitamin B12 component and sorbitol are contained in the formulation in a weight ratio of 0.25 to 1 .0.
  6. 6. Formulation according to any one of the preceding claims, wherein the formulation contains 2-50 mg/mL of thickening agent.
  7. 7. Formulation according to claim 5, wherein the thickening agent is selected from cellulose ethers, xanthan gum, gellan gum, alginate, tragacanth, araya gum, guar gum, starch, dextran, gelatin, pectin, chitosan, polyacrylic acid polymers, poly hydroxyethyl methylacrylate, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl alcohol, carbomer and combinations thereof.
  8. 8. Formulation according to any one of the preceding claims, wherein the formulation contains at least 70 wt.% water.
  9. 9. Formulation according to any one of the preceding claims, wherein the combination of the vitamin B12 component, sorbitol, the thickening agent and water constitutes at least 90 wt.%.
  10. 10. Formulation according to any one of the preceding claims, wherein the formulation has a pH in the range of 3.2 to 5.0.
  11. 11. Formulation according to any one of the preceding claims, wherein the formulation comprises 3-20 pmol/mL of organic acid selected from acetate, citrate and combinations thereof.
  12. 12. Formulation according to any one of the preceding claims, wherein the formulation has a dissolved oxygen content of less than 8 ppm, more preferably of less than 1.5 ppm.
  13. 13. A metered-dose pump spray device comprising • a container holding the aqueous vitamin B12 formulation according to any one of the preceding claims, • a nozzle, and • a manual pump connecting the nozzle and the container, said pump being configured to deliver one spray-unit upon actuation by manual force.
  14. 14. Metered-dose pump spray according to claim 13, wherein the device is adapted to deliver a dose of 10-250 pL.
  15. 15. Formulation for use in the treatment or prevention of vitamin B12 deficiency, Parkinson’s disease, Alzheimer’s disease or multiple sclerosis, said use comprising intranasally administering the formulation according to any one of claims 1-12.

Description

VITAMIN B12 FORMULATION FOR INTRANASAL ADMINISTRATION Technical field of the invention This invention relates to an aqueous vitamin B12 formulation for intranasal administration. The aqueous vitamin B12 formulation of the present invention is concentrated, very stable and has a surprisingly high intranasal bioavailability. The invention also provides a metered-dose pump spray device for intranasal delivery of the vitamin B12 formulation. The aqueous vitamin B12 formulation of the present invention can suitably be used in the treatment or prevention of vitamin B12 deficiency, Parkinson’s disease, Alzheimer’s disease or multiple sclerosis. Background of the invention Vitamin B12, also called cobalamin, is a vitamin that is involved in the metabolism of every cell of the human body: it is a cofactor in DNA synthesis, and in both fatty acid and amino acid metabolism. Vitamin B12 is particularly important in the normal functioning of the nervous system via its role in the synthesis of myelin, and in the maturation of developing red blood cells in the bone marrow. Vitamin B12 is one of eight B vitamins; it is the largest and structurally most complex vitamin. It contains the biochemically rare element cobalt positioned in the centre of a corrin ring. Four of the six coordination sites of vitamin B12 are provided by the corrin ring, and a fifth by the dimethylbenzimidazole group. The sixth coordination site, the reactive centre, is variable, being a cyano group (cyanocobalamin), a hydroxyl group (hydroxocobalamin), a methyl group (methylcobalamin) or a 5'-deoxyadenosyl group (adenosylcobalamin). There are no naturally-occurring vegetable sources of vitamin B12, so vegans and vegetarians are advised to take a vitamin B12 containing supplement or vitamin B12 fortified foods. Most omnivorous people in developed countries obtain enough vitamin B12 from consuming animal products including meat, milk, eggs, and fish. A serum B12 concentration above 300 pg/mL is interpreted as normal. B12 levels between 200 and 300 pg/mL are considered borderline. Subjects with B12 levels below 200 pg/mL are considered deficient. The most common cause of vitamin B12 deficiency in developed countries is impaired absorption due to a loss of gastric intrinsic factor, which must be bound to food-source B12 in order for absorption to occur. Another group affected are those on long term antacid therapy, using proton pump inhibitors, H2 blockers or other antacids. Vitamin B12 supplements are available in single agent or multivitamin tablets; and pharmaceutical preparations may be given by intramuscular injection. The nasal administration route is recognized for its ability to facilitate rapid and efficient absorption of substances. In the US, a nasal spray containing an aqueous solution of cyanocobalamin is marketed by Questcor Pharmaceuticals, Inc. under the brand name Nascobal®. In the Netherlands, a nasal spray containing an aqueous solution of vitamin B12 s marketed by Pronova Laboratories under the brand name Pronofit®. US 2020/0268651 describes a vitamin B12 nasal spray composition that comprises (i) a therapeutic dose of vitamin B12; (ii) synergistic amounts of a polymer, carrageenan and potassium acetate; (iii) optionally a buffer to adjust pH of the formulation between 4.5 and 7.5; (iv) a preservative; (v) a humectant; (vi) purified water; (vii) optionally hydrochloric acid and/or sodium hydroxide to adjust the pH of the formulation between 4.5 and 7.5, and (viii) optionally a drug(s) known to impair absorption of vitamin B12. Used therapeutic dose of vitamin B12 ranges from 0.01 to 10 mg/mL. ES 2074396 concerns a composition for the nasal administration of cyanocobalamin. The composition comprises cyanocobalamin, sorbitol, pantothenol, methylparaben, acetic acid, sodium acetate, methyl cellulose, glycerine, sodium chloride, water and a combination of polyglycerol esters of fatty acids. WO 86/05988 describes a composition for nasal administration comprising vitamin B12 in an isotonic aqueous buffer at a pH of 4 to 6 and having viscosity of 2500 to 6500 cps. WO 2018/142358 describes an intranasal composition comprising methylcobalamin and at least one gelling agent. WO 2022/043526 relates to a liquid aqueous pharmaceutical formulation containing hydroxocobalamin and/or hydroxocobalamin salts dissolved in a concentration above 0.1% (w/v) in water containing at least 3% (w/v) and less than 12% (w/v) mannitol. CA1300014C describes an intranasal formulation containing vitamin B12 in an isotonic aqueous buffer having a pH of 4 to 6 and a viscosity of 2500-6500 cps. CA 2 656 823 describes a pharmaceutical aqueous solution for intranasal administration, comprising cyanocobalamin; citric acid; sodium citrate; a humectant selected from the group consisting of sorbitol, propylene glycol, and glycerin; a preservative and water. Hadinata Lie et al. (Sorbitol enhances the physicochemical stability of B12 vitamers , Int J Vitam Nutr Res (2019), 1