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BR-102024019015-B1 - Solid oral pharmaceutical composition with good compressibility, intended for the treatment or relief of pain.

BR102024019015B1BR 102024019015 B1BR102024019015 B1BR 102024019015B1BR-102024019015-B1

Abstract

SOLID ORAL PHARMACEUTICAL COMPOSITION WITH GOOD COMPRESSIBILITY AND USE THEREOF FOR THE TREATMENT OR RELIEF OF PAIN. The present invention relates to a solid oral pharmaceutical composition comprising dipyrone, or its pharmaceutically acceptable salt, alone and/or in combination with one or more additional active pharmaceutical ingredients (APIs), polyethylene glycol (PEG) as the sole binding agent and additional pharmaceutically acceptable excipients, being substantially free of diluents, exhibiting unexpectedly good compressibility and smaller tablets compared to those commercially available. Furthermore, the invention relates to the therapeutic use of the pharmaceutical composition for the treatment or relief of pain.

Inventors

  • ANDRE LUIZ ROSA
  • CRISTIANE FERNANDA DA COSTA
  • RAPHAELLA CAMBRAIA LASMAR
  • MICHELLE CRISTINA TOLEDO LIMA
  • JULIANE DIAS PIOTTO JUABRE

Assignees

  • HYPERA S.A

Dates

Publication Date
20260317
Application Date
20240916

Claims (6)

  1. 1. Oral solid pharmaceutical composition with good compressibility characterized by comprising: - dipyrone, or its pharmaceutically acceptable salt, alone or in combination with one or more additional active pharmaceutical ingredients (APIs) selected from: - 10% to 12% w/w caffeine as a stimulant and - 7% to 10% w/w orphenadrine as an anticholinergic agent; - 0.5% to 5% w/w polyethylene glycol; - 1% to 5% w/w of at least one disintegrant; - 0.5% to 1% w/w of at least one glide agent; and - 0.5 to 1% w/w of at least one lubricant; - optionally, 1 to 5% w/w of a film former; wherein said composition is substantially free of diluents, in a maximum amount of 5% by weight of the total weight of the pharmaceutical composition; wherein said composition is in the form of a unit dose having an average weight in the range of 400 mg to 900 mg.
  2. 2. Pharmaceutical composition according to claim 1, characterized in that the largest dimension of the unit dosage form is from 9 mm to 15 mm.
  3. 3. Pharmaceutical composition, according to any one of claims 1 to 2, characterized in that: - the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, sodium starch glycolate, hydroxypropylcellulose, pregelatinized starch, modified sodium starch glycolate, alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, sodium carboxymethyl starch, starch, calcium alginate, calcium carboxymethylcellulose, chitosan, guar gum, aluminum and magnesium silicate, methylcellulose, potassium polacrilin and combinations thereof; - the glidant is selected from the group consisting of silicon dioxide, talc, silica, magnesium oxide, magnesium silicate, magnesium trisilicate, aluminum and magnesium silicates, fumed silica or combinations thereof; - the lubricant is selected from the group consisting of magnesium stearate, zinc stearate, calcium stearate, acid Stearic acid, hydrogenated vegetable oil, polyethylene glycol, glyceryl behenate, hydrogenated castor oil, sodium stearyl fumarate, simethicone, glyceryl monostearate, glyceryl palmitostearate, mineral oil, magnesium lauryl sulfate, medium-chain triglycerides, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, potassium benzoate and combinations thereof; - the film former is a coating comprising a polymer selected from hypromellose, polyvinyl alcohol, polymethacrylate, ethylcellulose, polyvinyl acetate, glyceryl behenate, polyethylene glycol or a combination thereof, titanium dioxide, aluminum and potassium silicate, triacetin, medium-chain triglycerides, beeswax, silicon dioxide, talc and dye.
  4. 4. Oral solid pharmaceutical composition with good compressibility characterized by comprising: - 60 to 75% w/w of dipyrone, or its pharmaceutically acceptable salt, alone and/or in combination with one or more additional active pharmaceutical ingredients (APIs); - 0.5 to 5% w/w of polyethylene glycol; - 1 to 5% w/w of croscarmellose sodium; - 0.5 to 1.0% w/w of silicon dioxide; - 0.5 to 1.0% w/w of magnesium stearate; - 1 to 5% w/w of a film former, wherein said composition is substantially free of diluents, in a maximum amount of 5% by weight of the total weight of the pharmaceutical composition; wherein said composition is in the form of a unit dose having an average weight in the range of 400 mg to 900 mg.
  5. 5. Pharmaceutical composition, according to any one of claims 1 to 4, characterized in that the unit dosage form is a tablet.
  6. 6. Use of the oral solid pharmaceutical composition, as defined in any one of claims 1 to 5, characterized in that it is for the preparation of a unit dosage form for the treatment or relief of pain.

Description

Field of Invention [001] The present invention relates to the field of solid pharmaceutical compositions with unexpected characteristics of improved compressibility and suitable size for better swallowing when compared to those commercially available. Pharmaceutical compositions are described comprising dipyrone, or its pharmaceutically acceptable salt, alone and/or in combination with one or more additional active pharmaceutical ingredients (APIs), a single binding agent and additional pharmaceutically acceptable excipients, being substantially free of diluents. Fundamentals of the Invention [002] Metamizole (1-phenyl-2,3-dimethyl-5-pyrazolone-4-methylaminomethanesulfonate sodium), also known as dipyrone sodium and popularly called dipyrone, is a therapeutic agent commonly used as an analgesic, antipyretic, and antispasmodic in pharmaceutical compositions. Despite its therapeutic benefits, dipyrone is recognized as an active ingredient with poor compressibility, and its formulation in an oral solid unit dose form requires the incorporation of excipients to ensure adequate dosage distribution, stability, compressibility, and average core weight. [003] Some medications use dipyrone combined with other active pharmaceutical ingredients (APIs) to achieve a greater analgesic effect. One example is the combination of dipyrone, orphenadrine ((RS)-N,N-dimethyl-2-[(2-methylphenyl)-phenylmethoxy]ethanamine dihydrogen 2-hydroxypropane-1,2,3-tricarboxylate) and caffeine (1,3,7-trimethylxanthine) which has a potent analgesic effect, especially in the treatment of muscle and bone pain. This combination is widely marketed, with the lowest dose reference drug being Dorflex® (a tablet containing 35 g of orphenadrine citrate + 300 mg of dipyrone monohydrate + 50 mg of anhydrous caffeine), and the highest dose being Dorflex Max® (a tablet containing 70 g of orphenadrine citrate + 600 mg of dipyrone monohydrate + 100 mg of anhydrous caffeine), both from Sanofi Medley Farmacêutica Ltda. [004] Ideally, formulations with a high concentration of active pharmaceutical ingredient (API) should have a reduced amount of excipients. However, achieving this goal in compositions containing dipyrone is challenging, as this drug has poor compressibility, so excipients, especially diluents, are essential to ensure the efficiency of granulation or direct compression processes. As a result, tablets tend to be larger, which makes swallowing difficult and increases production costs. (Kaur Harparkash, 20121; https://www.drugtopics.com/view/overview-pharmaceutical-excipients-used-tablets-and-capsules; Hummler et al., 2023). [005] The document Melo et al., 2013 analyzed the classification of the components of four different tablet samples containing dipyrone (300 mg), caffeine (50 mg), and orphenadrine (35 mg), a reference drug (R), and three similar drugs (S1, S2, and S3) with different excipients and manufacturing processes. The reference drug R contains corn starch, magnesium stearate, sodium starch glycolate, and talc as excipients. S1 also contains corn starch, ethyl alcohol, microcrystalline cellulose, povidone, and magnesium stearate. The excipients in S2 are corn starch, ethyl alcohol, microcrystalline cellulose, povidone, magnesium stearate, sodium starch glycolate, silicon dioxide, disodium edetate, lactose, and sodium metabisulfite. S3 contains corn starch, ethyl alcohol, povidone, magnesium stearate, and talc as excipients. All of the aforementioned samples contained diluents such as corn starch and microcrystalline cellulose in their composition. [006] WO 2015/089614 discloses an oral pharmaceutical composition comprising dipyrone, codeine, polyethylene glycol (PEG), and pharmaceutically acceptable excipients. This document aims to solve the technical problem of combining dipyrone and codeine, two different active ingredients that require different pH values to maintain stability, in a single dosage form. To achieve this, PEG is used as a binder in solution along with codeine, forming an occasional coating of this active ingredient after drying, providing a certain degree of isolation from dipyrone. According to the document, isolating the active ingredient codeine favors not only its chemical compatibility with the dipyrone granules, since both active ingredient molecules exhibit greater stability under different pH conditions, but also promotes the physical compatibility of the composition, since the active ingredients are difficult to compress. [007] BR 10 2020 02020 3 refers to a stable solid pharmaceutical composition comprising dipyrone, at least one additional active ingredient, polyethylene glycol, and excipients. The document aims to resolve a stability problem in compositions containing dipyrone and at least one additional API by using a binder solution comprising polyethylene glycol, alcohol, and water in a specific ratio. The document exemplifies only dipyrone compositions with at least one additional API, particularly one