WO2018204040A1 - Compositions orales liquides de valsartan - Google Patents

Compositions orales liquides de valsartan Download PDF

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Publication number
WO2018204040A1
WO2018204040A1 PCT/US2018/027039 US2018027039W WO2018204040A1 WO 2018204040 A1 WO2018204040 A1 WO 2018204040A1 US 2018027039 W US2018027039 W US 2018027039W WO 2018204040 A1 WO2018204040 A1 WO 2018204040A1
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Prior art keywords
valsartan
oral liquid
formulation
compositions
sodium citrate
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PCT/US2018/027039
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English (en)
Inventor
Hugh Greg THOMAS
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Bioramo, Llc
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Publication of WO2018204040A1 publication Critical patent/WO2018204040A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Definitions

  • oral liquid compositions of valsartan with enhanced solubility are also provided herein. Also provided herein, are methods of using oral liquid valsartan compositions for the treatment of hypertension, treatment of heart failure and reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
  • Valsartan is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the ATi receptor subtype and originally disclosed in U.S. Patent No. 5,399,578.
  • Angiotensin II interacts with specific receptors on the surface of a target cell. It has been possible to identify receptor subtypes which are termed, e.g., ATi- and AT2- receptors. Significant efforts have been made to identify substances that bind to the ATi- receptor. Such active ingredients are often termed angiotensin II antagonists. Because of the inhibition of the ATi-receptor, such antagonists can be used, e.g., as antihypertensives or for the treatment of congestive heart failure.
  • Angiotensin II antagonists are therefore understood to be those active ingredients which bind to the ATi-receptor subtype. Prolonged and uncontrolled hypertensive vascular disease ultimately leads to a variety of pathological changes in target organs such as the heart and kidney. Sustained hypertension can lead an increased occurrence of stroke.
  • Valsartan is chemically described as N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5- yl)[l, -biphenyl]-4-yl]methyl]-L-valine.
  • Valsartan is used for treating hypertension, treatment of heart failure and reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
  • Valsartan is typically administered as a solid oral dosage form including, for example, tablets, pills and capsules.
  • Oral ingestion is the most convenient and commonly employed route of drug delivery due to its ease of administration, high patient compliance, cost effectiveness, reduced sterility constraints, and flexibility in the design of dosage form.
  • oral liquid dosage forms including solutions, suspensions and emulsions, can be easier to administer and more suitable for use.
  • solubility is the most important rate limiting parameter to achieve their desired concentration in systemic circulation for pharmacological response. Accordingly, liquid compositions containing active pharmaceutical ingredients that are completely solubilized in a liquid composition are more advantageous over suspension compositions.
  • the extent of solubility of a substance in a specific solvent is measured as the saturation concentration where adding more solute does not increase its concentration in the solution.
  • the extent of solubility ranges widely, from infinitely soluble (fully miscible), for example, ethanol in water, to poorly soluble, for example, silver chloride in water. Solubility is based on the highest-dose strength of an immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250 mL or less of aqueous media over the pH range of 1 to 7.5.
  • oral liquid compositions of valsartan.
  • oral liquid compositions comprising about 4 mg/mL valsartan or a pharmaceutically acceptable salt or solvate thereof, about 2 mg/mL potassium sorbate, about 10 mg/mL sodium citrate; and water.
  • the oral liquid compositions can further comprise about
  • the formulation can further comprise about 0.2 mg/mL sucralose.
  • the mole ratio of sodium citrate to valsartan is about
  • the mole ratio of potassium sorbate to valsartan is about 1.5: 1 in the oral liquid compositions.
  • the mole ratio of paraben to valsartan is about 1.4: 1 in the oral liquid compositions.
  • the formulation is substantially free of solids.
  • the pH of the formulation is about 5.8 to about 6.1.
  • the sodium citrate can be sodium citrate dihydrate. In other words,
  • the pH of the formulation is about 6.0. In other embodiments, the total impurities of the formulation are not more than about 0.4 %. In yet other embodiments, the formulation is stable at about 25 °C ⁇ 2 °C for at least 24 months.
  • a liquid oral formulation comprising about 4 mg/mL valsartan or a pharmaceutically acceptable salt or solvate thereof, about 2 mg/mL potassium sorbate, about 10 mg/mL sodium citrate, and water.
  • a liquid oral formulation comprising about 4 mg/mL valsartan or a pharmaceutically acceptable salt or solvate thereof, about 2 mg/mL potassium sorbate, about 10 mg/mL sodium citrate, and water.
  • a liquid oral formulation comprising about 4 mg/mL valsartan or a pharmaceutically acceptable salt or solvate thereof, about 2 mg/mL potassium sorbate, about 10 mg/mL sodium citrate, and water.
  • valsartan compositions can be useful in the treatment of hypertension, treatment of heart failure and reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
  • the compositions can provide advantages over conventional oral solid dosage administration of valsartan including, for example, ease of administration, improved absorption, increased patient compliance and accurate/precise delivery of valsartan to the patient.
  • valsartan is fully solubilized in the oral liquid compositions, providing oral liquid solutions that have improved bioavailability over liquid compositions that are suspensions, where valsartan is not fully solubilized.
  • valsartan liquid alternative to solid oral dosage forms of valsartan can be prepared by a compounding pharmacist where valsartan solid dosage forms are mixed into a liquid.
  • forming valsartan liquid compositions using such techniques can have significant drawbacks, including forming suspensions rather than solutions, large variability in the actual dosage amount of valsartan, incomplete or inconsistent suspension of the valsartan solid dosage form in the liquid, rapid instability, inconsistent formulation methods per compounding pharmacist, and several other potential issues.
  • an oral liquid valsartan composition that includes a citrate salt buffering agent and the preservative sodium benzoate, having a pH of about 5.8 to about 6.1, surprisingly and unexpectedly provides markedly improved solubility of valsartan. Further, such compositions exhibit surprising and unexpected stability of at least 18 months or more. In some embodiments, the oral liquid valsartan compositions exhibit a stability of at least 24 months or more.
  • Embodiments provided herein provide safe and effective administration of valsartan for the treatment of hypertension, treatment of heart failure and reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
  • oral liquid valsartan compositions comprise valsartan and a combination of citrate salt, sorbate salt and a paraben.
  • the citrate salt is a buffering agent and the sorbate salt and paraben are preservatives, present in the oral liquid compositions in ratios and amounts to provide an unexpectedly, highly solubilized composition.
  • Such oral liquid compositions also provide an unexpectedly and highly stable composition.
  • the oral liquid compositions are substantially free of solids, whereby all components are fully solubilized.
  • valsartan is present in about 3.8 mg/mL to about 4.2 mg/mL of the oral liquid composition. In other embodiments, valsartan is present in about 3.8 mg/mL, about 3.9 mg/mL, about 4 mg/mL, about 4.1 mg/mL or about 4.2 mg/mL of the oral liquid composition. In yet other embodiments, valsartan is present in about 4.0 mg/mL of the oral liquid composition.
  • valsartan is present from about 20 % w/w to about 24
  • valsartan is present in about 20.4 % w/w to about 23.6 % w/w of the total solids used to prepare the oral liquid valsartan composition.
  • valsartan is present from about 20.0 % w/w, about 20.1 % w/w, about 20.2 % w/w, about 20.3 % w/w, about 20.4 % w/w, about 20.5 % w/w, about 20.6 % w/w, about 20.7 % w/w, about 20.8 % w/w, about 20.9 % w/w, about 21.0 % w/w, about 21.1 % w/w, about 21.2 % w/w, about 21.3 % w/w, about 21.4 % w/w, about 21.5 % w/w, about 21.6 % w/w, about 21.7 % w/w, about 21.8 % w/w, about 21.9 % w/w, about 22.0 % w/w, about 22.1 % w/w, about 22.2 % w/w, about 22.3 % w/w, about 21.9 %
  • the oral liquid valsartan compositions have a pH of about 5.8 to about 6.2. In other embodiments, the oral liquid valsartan compositions have a pH of about 5.9 to about 6.1. In other embodiments, the oral liquid valsartan compositions have a pH of about 5.8, about 5.9, about 6.0, about 6.1, or about 6.2.
  • the citrate salt is a group IA or group 2A salt.
  • the citrate salt is sodium citrate, potassium citrate, calcium citrate, magnesium citrate, or hydrates, solvates or anhydrous forms thereof.
  • the citrate salt is sodium citrate.
  • the citrate salt is monosodium citrate, disodium citrate, trisodium citrate, trisodium citrate dihydrate, anhydrous trisodium citrate, disodium hydrogen citrate, disodium citrate sesquihydrate, calcium citrate, or magnesium citrate.
  • the citrate salt is sodium citrate dihydrate.
  • the citrate salt is present in the oral liquid compositions in amounts sufficient to provide a pH of about 5.8 to about 6.2. In other embodiments, the citrate salt is present in the oral liquid valsartan compositions in amounts sufficient to provide a pH of about 5.9 to about 6.1. In other embodiments, the citrate salt is present in the oral liquid valsartan compositions in amounts sufficient to provide a pH of about 5.8, about 5.9, about 6.0, about 6.1, or about 6.2.
  • sodium citrate is present from about 9.8 mg/mL to about 10.2 mg/mL of the oral liquid composition. In other embodiments, sodium citrate is present in about 9.8 mg/mL, about 9.9 mg/mL, about 10.0 mg/mL, about 10.1 mg/mL or about 10.2 mg/mL of the oral liquid composition. In yet other embodiments, sodium citrate is present in about 10.0 mg/mL.
  • sodium citrate is present from about 52 % w/w to about
  • sodium citrate is present from about 52.6 % w/w to about 57.4 % w/w of the total solids used to prepare the oral liquid valsartan compositions.
  • sodium citrate is present in about 52.0 % w/w, about 52.1 % w/w, about 52.2 % w/w, about 52.3 % w/w, about 52.4 % w/w, about 52.5 % w/w, about 52.6 % w/w, about 52.7 % w/w, about 52.8 % w/w, about 52.9 % w/w, about 53.0 % w/w, about 53.1 % w/w, about 53.2 % w/w, about 53.3 % w/w, about 53.4 % w/w, about 53.5 % w/w, about 53.6 % w/w, about 53.7 % w/w, about 53.8 % w/w, about 53.9 % w/w, about 54.0 % w/w, about 54.1 % w/w, about 54.2 % w/w, about 54.3 % w/w, about 54.4
  • the sorbate salt is a group IA or a group IIA salt.
  • the sorbate salt is lithium sorbate, potassium sorbate, sodium sorbate, calcium sorbate, or magnesium sorbate.
  • the sorbate salt is present in an amount sufficient to provide a stable composition, for example, providing anti-microbial activity that prevents growth and/or spread of bacteria and molds.
  • the sorbate salt is present from about 1 mg/mL to about 3 mg/mL of the oral liquid composition.
  • the sorbate salt is potassium sorbate. In other embodiments, potassium sorbate is present from about 1.8 mg/mL to about 2.2 mg/mL of the oral liquid composition. In yet other embodiments, potassium sorbate is present in about 1.8 mg/mL, about 1.9 mg/mL, about 2.0 mg/mL, about 2.1 mg/mL, or about 2.2 mg/mL of the oral liquid composition. [0033] In some embodiments, the sorbate salt is present from about 5 % w/w to about
  • the sorbate salt is present from about 9 % w/w to about 13 % w/w of the total solids used to prepare the oral liquid valsartan composition. In yet other embodiments, the sorbate salt is present from about 10 % w/w to about 12 % w/w of the total solids used to prepare the oral liquid valsartan composition.
  • potassium sorbate is present from about 9.5 % w/w to about 12.5 % w/w of the total solids used to prepare the oral liquid valsartan composition. In some embodiments, potassium sorbate is present in about 9.5 % w/w, about 9.6 % w/w, about 9.7 % w/w, about 9.8 % w/w, about 9.9 % w/w, about 10.0 % w/w, about 10.1 % w/w, about 10.2 % w/w, about 10.3 % w/w, about 10.4 % w/w, about 10.5 % w/w, about 10.6 % w/w, about 10.7 % w/w, about 10.8 % w/w, about 10.9 % w/w, about 11.0 % w/w, about 11.1 % w/w, about 11.2 % w/w, about 11.3 % w/w,
  • the paraben is methylparaben, ethylparaben, propylparaben or butylparaben.
  • the paraben is present in an amount sufficient to provide a stable liquid composition, for example, providing anti-microbial activity that prevents growth and/or spread of bacteria and molds.
  • the paraben is present from about 1 mg/mL to about 3 mg/mL of the oral liquid composition.
  • the paraben is methylparaben. In other embodiments, methylparaben is present from about 1.8 mg/mL to about 2.2 mg/mL of the oral liquid composition. In yet other embodiments, methylparaben is present in about 1.8 mg/mL, about 1.9 mg/mL, about 2.0 mg/mL, about 2.1 mg/mL, or about 2.2 mg/mL of the oral liquid composition.
  • the paraben is present from about 5 % w/w to about 15
  • the paraben is present from about 9 % w/w to about 13 % w/w of the total solids used to prepare the oral liquid valsartan composition. In yet other embodiments, the paraben is present from about 10 % w/w to about 12 % w/w of the total solids used to prepare the oral liquid valsartan composition.
  • methylparaben is present from about 9.5 % w/w to about 12.5 % w/w of the total solids used to prepare the oral liquid valsartan composition. In some embodiments, methylparaben is present in about 9.5 % w/w, about 9.6 % w/w, about 9.7 % w/w, about 9.8 % w/w, about 9.9 % w/w, about 10.0 % w/w, about 10.1 % w/w, about 10.2 % w/w, about 10.3 % w/w, about 10.4 % w/w, about 10.5 % w/w, about 10.6 % w/w, about 10.7 % w/w, about 10.8 % w/w, about 10.9 % w/w, about 11.0 % w/w, about 11.1 % w/w, about 11.2 % w/w, about 11.3 % w/
  • the mole ratio of citrate salt to valsartan is from about
  • the mole ratio of citrate salt to valsartan is about 3: 1, about 3.1 : 1, about 3.2: 1, about 3.3: 1, about 3.4: 1 about 3.5: 1, about 3.6: 1, about 3.7: 1, about 3.8: 1, about 3.9: 1, or about 4: 1. In other embodiments, the mole ratio of citrate salt to valsartan is about 3.7: 1.
  • the mole ratio of sorbate salt to valsartan is from about
  • the mole ratio of sorbate salt to valsartan is about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9:1 or about 2:1. In some embodiments, the mole ratio of sorbate salt to valsartan is about 1.5:1.
  • the mole ratio of paraben to valsartan is from about 1 : 1 to about 2:1. In other embodiments, the mole ratio of paraben to valsartan is about 1:1, about 1.1:1, about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1, about 1.7:1, about 1.8:1, about 1.9: 1 or about 2:1. In some embodiments, the mole ratio of paraben to valsartan is about 1.4:1.
  • the mole ratio of citrate salt to sorbate salt is from about 2: 1 to about 3:1. In other embodiments, the mole ratio of citrate salt to sorbate salt is about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about 2.6:1, about 2.7: 1, about 2.8: 1, about 2.9: 1, or about 3:1. In yet other embodiments, the mole ratio of citrate salt to sorbate salt is about 2.6:1.
  • the mole ratio of citrate salt to paraben is from about
  • the mole ratio of citrate salt to paraben is about 2:1, about 2.1:1, about 2.2:1, about 2.3:1, about 2.4:1, about 2.5:1, about 2.6:1, about 2.7:1, about 2.8: 1, about 2.9: 1, or about 3:1. In yet other embodiments, the mole ratio of citrate salt to paraben is about 2.6: 1.
  • the mole ratio of sorbate salt to paraben is from about
  • the mole ratio of sorbate salt to paraben is about 1:1.
  • the oral liquid valsartan compositions can comprise one or more additional excipients, including but not limited to, sweeteners, flavoring agents, stabilizers, coloring agents, thickeners and the like. Additional excipients can be selected based on function and compatibility with the oral liquid valsartan compositions disclosed herein and may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, PA: Mack Publishing Company, 1995); Hoover, John E.,
  • One or more sweeteners or sweetening agents can be used in the liquid compositions and can include any compounds that provide a sweet taste, including natural and synthetic sugars, natural and artificial sweeteners, natural extracts and any material that initiates a sweet sensation in a subject.
  • the oral liquid valsartan compositions disclosed herein comprise one or more sweeteners.
  • solid, powder sweeteners are used in the liquid compositions disclosed herein.
  • sweeteners in liquid form, also referred to as syrups are used in the oral liquid compositions disclosed herein.
  • Suitable sweeteners include, but are not limited to, glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitoL isonialtulose, IsomaTM (hydrogenated isonialtulose), lactitoi, sorbitol, mannitoL eiythritol, trehalose, maltodextrin, poly dextrose, and the like.
  • sweeteners illustratively include glycerin, inulin, eiythritol, maltoi, acesulfame and salts thereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodium cyclamate, saccharin and salts thereof, e.g., saccharin sodium or saccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin, and the like.
  • glycerin inulin, eiythritol, maltoi
  • acesulfame and salts thereof e.g., acesulfame potassium, alitame, aspartame, neotame, sodium cyclamate
  • saccharin and salts thereof e.g., saccharin sodium or saccharin calcium, neohesperidin dihydrochalcone,
  • Sweeteners can be used in the form of crude or refined products, such as hydrogenated starch hydrolysates, maltitol syrup, high fructose com syrup, etc., and as branded products, e.g., Sweet AmTM liquid (Product Code 918.003 - propylene glycol, ethyl alcohol, and proprietary artificial flavor combination, Flavors of North America) and Sweet AmTM powder (Product Code 918.005 - maltodextnn, sorbitol, and fructose combination and Product Code 918.010 - water, propylene glycol, sorbitol, fructose, and proprietar - natural and artificial flavor combination, Flavors of North America), ProSweetTM (1-10 % proprietary plant/vegetable extract and 90-99 % dextrose combination, Virginia Dare), MaltisweetTM (maltitol solution, ingredion) and SorboTM
  • Sweet AmTM liquid Product Code 918.003 - propylene glyco
  • Sweeteners can be used singly or in combinations of two or more.
  • the sweetener is sucralose. Suitable concentrations of different sweeteners can be selected based on published information, manufacturers' data sheets and by routine testing.
  • the sweetener is present from about 0.1 % w/w to about
  • the sweetener is present from about 0.5 % w/w to about 2,5 % w/w of the total solids used to prepare the liquid composition. In yet other embodiments, the sweetener is present from about 1 % w/w to about 2 % w/w of the total solids used to prepare the liquid composition.
  • the sweetener is sucralose.
  • sucralose is present from about 0.1 mg/mL to about 0.3 mg/mL.
  • sucralose is present from about 0.15 mg/mL to about 0.25 mg/mL.
  • sucralose is present in about 0.15 mg/mL, about 0.16 mg mL, about 0.17 mg/mL, about 0.18 mg/mL, about 0.19 mg/mL, about 0.20 mg/mL, about 0.21 mg/mL, about 0.22 mg/mL, about 0.23 mg/mL, about 0.24 mg/mL, or about 0.25 mg/mL.
  • sucralose is present from about 0.5 % w/w to about 2 % w/w of the total solids used to prepare the oral liquid compositions, in other embodiments, sucralose is present from about 0.9 % w/ to about 1.3% w/w of the total solids used to prepare the oral liquid compositions, in yet other embodiments, sucralose is present in about 0.9 % w/w, about 1.0 % w/w, about 1.1 % w/w, about 1.2 % w/w, or about 1.3 % w/w of the total solids used to prepare the oral liquid compositions.
  • One or more flavoring agents can be used to enhance the taste or aroma of the oral liquid compositions.
  • Suitable natural or synthetic flavoring agents can be selected from standard reference books, for example Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995).
  • Non-limiting examples of suitable natural flavors include almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt, mandarin, molasses, nutmeg, orange, peach, pear, peppermint, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, tutti-frutti, vanilla, wintergreen, and the like.
  • flavoring agents include cherry, grape, and bubblegum.
  • the liquid compositions comprise a grape flavoring agent.
  • the flavoring agent is present from about 1 mg/mL to about 5 mg/mL of the oral liquid composition. In other embodiments, the flavoring agent is present in about 2 mg/mL to about 4 mg/mL. In other embodiments, the flavoring agent is present in about 2.5 mg/mL to about 3.5 mg/mL
  • Coloring agents can be used for identification and/or aesthetic purposes of the resulting liquid compositions. Suitable coloring agents include, but are not limited to, FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide or mixtures thereof.
  • Oral liquid valsartan compositions disclosed herein include, but are not limited to, aqueous solutions, nonaqueous solutions, juices, elixirs, and the like.
  • oral liquid compositions disclosed herein surprisingly are solutions rather than suspensions where there is no active ingredient in particulate matter or solid form in the composition.
  • Fully solubilized active ingredients, such as valsartan, in oral liquid compositions disclosed herein provide advantages over their partially solubilized counterparts (e.g., suspensions, slurries etc.) that include higher drug absorption and drug permeability, lending to improved bioavailability.
  • Suitable liquid vehicles for use in oral liquid valsartan compositions are selected based on imparting desired qualities, including for example, clarity, toxicity, viscosity, compatibility with excipients, chemical inertness, palatability, odor, color and economy.
  • Exemplary liquid vehicles include water, ethyl alcohol, glycerin, propylene glycol, syrup (sugar or other sweetener based, e.g., Ora-Sweet ® SF sugar-free flavored syrup), juices (apple, grape, orange, cranberry, cherry, tomato and the like), other beverages (tea, coffee, soft drinks, milk and the like), oils (olive, soybean, com, mineral, castor and the like), and combinations or mixtures thereof.
  • Certain liquid vehicles e.g., one or more oils and water, can be combined to form emulsions.
  • water is used for as a vehicle for oral liquid valsartan compositions.
  • a syrup is used as a vehicle for oral liquid compositions.
  • a juice is used as a vehicle for oral liquid compositions.
  • oral liquid valsartan compositions disclosed herein are homogenous.
  • "Homogenous liquids,” as used herein refer to those liquids that are uniform in appearance, identity, consistency and drug concentration per volume.
  • Non-homogenous liquids include such liquids that have varied coloring, and/or viscosity, as well as non- uniform drug concentration in each unit volume. Homogeneity in liquids are assessed by qualitative identification or appearance tests and/or quantitative HPLC testing or the like. Such exemplary tests include visual inspection of the resultant liquid for air bubbles and/or undissolved solids which may cause variable dosing.
  • Analytical HPLC testing can also determine drug concentration uniformity by examining aliquots of certain volume sections (e.g., 5 or 10 mL from the top, middle and bottom of a 150 mL bottle).
  • the mixing methods and excipients disclosed herein are selected to impart a homogenous quality to a resultant oral liquid valsartan composition.
  • Mixing methods encompass any type of mixing that result in a homogenous oral liquid valsartan composition.
  • Mixing can include one or more of stirring, shaking, swirling, agitating, inverting, or a combination thereof.
  • individual components of the oral liquid valsartan compositions are added sequentially, concurrently or any combination thereof to a liquid vehicle.
  • individual components are added sequentially, one at a time.
  • the sequential addition of individual components includes mixing for a certain time interval after each or some of the sequential additions.
  • all individual components are added at the same time to a liquid vehicle and then mixed for a certain time interval.
  • mixing occurs for certain time intervals, such as about 10 seconds, about 20 seconds, about 30 seconds, about 40 seconds, about 50 seconds, about 60 seconds, about 90 seconds, about 2 minutes, about 2.5 minutes, about 3 minutes, about 3.5 minutes, about 4 minutes, about 4.5 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes or about 10 minutes or more.
  • time intervals for each mixing can be the same or different.
  • the resulting oral liquid valsartan composition is allowed to stand for a set amount of time, for example, about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 60 minutes, about 90 minutes, about 120 minutes or more to allow any resulting air bubbles arising from mixing to dissipate.
  • Oral liquid valsartan compositions disclosed herein are stable in various storage conditions, including refrigerated and ambient conditions.
  • stable refers to valsartan oral liquid formulations having about 90 % or greater of the initial valsartan amount, having about 95 % or greater of the initial valsartan amount, or having about 98 % or greater of the initial valsartan amount at the end of a given storage period.
  • stable can also refer to valsartan oral liquid formulations having about 1 % w/w or less total impurities or related substances, having 0.5 % w/w or less total impurities or related substances, or having about 0.4 % w/w or less total impurities or related substances at the end of a given storage period.
  • stable can also refer to valsartan oral liquid formulations having about 0.5 % w/w or less individual impurities or related substance, or 0.2 % w/w or less individual impurities or related substance.
  • stable can also refer to valsartan oral liquid formulations having less than about 10 2 total aerobic microbial count at the end of a given storage period.
  • stable can also refer to valsartan oral liquid formulations having less than 10 1 total combined yeast and mold count at the end of a given storage period.
  • stable can also refer to the absence or non-detection of
  • Escherichia coli and/or Burkholderia cepacia are examples of Escherichia coli and/or Burkholderia cepacia.
  • the oral liquid valsartan compositions disclosed herein are stable under refrigerated and ambient conditions for at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 weeks, at least 32 weeks, at least 36 weeks, at least 48 weeks, at least 52 weeks, at least 60 weeks, at least 72 weeks, at least 84 weeks, at least 96 weeks, at least 104 weeks, at least 108 weeks or at least 120 weeks.
  • Ambient conditions also referred to as controlled room temperature (CRT) conditions, include temperature and/or relative humidity (RH) that are at ambient levels (e.g., 25 ⁇ 2 °C; 40 ⁇ 5 % RH).
  • an ambient condition is at about 20 °C, about 21 °C, about 22 °C, about 23 °C, about 24 °C, about 25 °C, about 26 °C, about 27 °C, about 28 °C, about 29 °C, or about 30 °C. In other instances, an ambient condition is about 45 % RH, about 50 % RH, about 55 % RH, about 60 % RH or about 65 % RH. Refrigerated conditions include temperature and/or relative humidity (RH) in typical refrigeration units (e.g., 5 ⁇ 3 °C). In some instances, a refrigerated condition is at about 2 °C, about 3 °C, about 4 °C, about 5 °C, about 6 °C, about 7 °C or about 8 °C.
  • the stable oral liquid valsartan compositions disclosed herein that are stored under ambient or refrigerated conditions for a specified storage period, provide similar, consistent or equivalent pharmacokinetic parameters as an oral liquid valsartan composition that is formulated immediately prior to administration to a subject (i.e., freshly made).
  • the oral liquid valsartan compositions disclosed herein exhibit high stability after a specified storage period to provide similar, consistent or equivalent pharmacokinetic parameters as a freshly made oral liquid valsartan composition.
  • a 108-week stable oral liquid valsartan composition provides similar, consistent or equivalent pharmacokinetic parameters as an oral liquid valsartan composition made five minutes prior to administration.
  • Pharmacokinetic parameters include Cmax, Tmax, AUClast, AUCinf, Ti/2, Ciast for valsartan.
  • the stable oral liquid valsartan include Cmax, Tmax, AUClast, AUCinf, Ti/2, Ciast for valsartan.
  • compositions disclosed herein provide within 80 % to 125 %, 80 % to 120 %, 85 % to 125 %, 90 % to 110 % pharmacokinetic parameters of a freshly made oral liquid valsartan composition when the stable composition is stored for at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, at least 28 week, at least 32 weeks, at least 36 weeks, at least 48 weeks, at least 52 weeks, at least 60 weeks, at least 72 weeks, at least 84 weeks, at least 96 weeks, at least 104 weeks, at least 108 weeks or at least 120 weeks after preparation. [0062] Methods of Treatment:
  • the oral liquid valsartan compositions disclosed herein can be used to treat hypertension in a subject.
  • Hypertension includes both primary (essential) hypertension or secondary hypertension. Hypertension can be classified in cases when blood pressure values are greater than or equal to 140/90 (systolic/diastolic) mm Hg in an adult subject.
  • the oral liquid valsartan compositions disclosed herein treat primary (essential) hypertension in a subject.
  • the oral liquid valsartan compositions disclosed herein treat secondary hypertension in a subject.
  • the subj ect is a pediatric subject. Pediatric hypertension can be classified in cases where the child's blood pressure is greater than the 95th percentile for the patient's age, sex and height.
  • the subj ect is a geriatric subject. Hypertension in geriatric patients is defined similar to that in adult patients, i.e., blood pressure values greater than or equal to 140/90 (systolic/diastolic) mm Hg.
  • the oral liquid valsartan compositions disclosed herein can be used to treat heart failure. In yet other embodiments, the oral liquid valsartan compositions disclosed herein can be used to reduce cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
  • the valsartan oral liquid compositions are used for the treatment of diseases and conditions disclosed herein.
  • a method for treating any of the diseases or conditions disclosed herein for a subject in need of such treatment involves administration of valsartan oral liquid compositions in therapeutically effective amounts to the subject.
  • Dosages of valsartan oral liquid compositions disclosed herein can be determined by any suitable method.
  • Maximum tolerated dose (MTD) and maximum response dose (MRD) for valsartan can be determined via established animal and human experimental protocols.
  • toxicity and therapeutic efficacy of valsartan can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, for determining the LD50 (the dose lethal to 50 % of the population) and the ED50 (the dose therapeutically effective in 50 % of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50.
  • Valsartan dosages exhibiting high therapeutic indices are desirable.
  • the data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Additional relative dosages, represented as a percent of maximal response or of maximum tolerated dose, are readily obtained via these protocols.
  • the starting dose of valsartan for treating adult hypertension is about 80 mg or about 160 mg once daily. In other embodiments, valsartan can be administered over a dose range of 80 mg to 320 mg daily, administered once a day for treating adult hypertension.
  • the starting dose of valsartan for treating pediatric hypertension is about 1.3 mg/kg once daily, up to about 40 mg total.
  • valsartan can be administered over a dose range of about 1.3 to about 2.7 mg/kg once daily, up to about 40 mg to about 160 mg total for treating pediatric hypertension.
  • the starting dose of valsartan for treating heart failure is about 4 mg twice daily.
  • valsartan can be administered over a dose range of about 40 mg to about 160 mg twice daily for treating heart failure.
  • the starting dose for reducing cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction is about 20 mg twice daily.
  • valsartan can be administered over a dose range of about 20 mg to about 160 mg twice daily for reducing cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
  • the valsartan oral liquid compositions are provided at the maximum tolerated dose (MTD) for valsartan.
  • MTD maximum tolerated dose
  • the amount of the valsartan oral liquid compositions administered is from about 10 % to about 90 % of the MTD, from about 25 % to about 75 % of the MTD, or about 50 % of the MTD.
  • the amount of the valsartan oral liquid compositions administered is from about 5 %, 10 %, 15 %, 20 %, 25 %, 30 %, 35 %, 40 %, 45 %, 50 %, 55 %, 60 %, 65 %, 70 %, 75 %, 80 %, 85 %, 90 %, 95 %, 99 %, or higher, or any range derivable therein, of the MTD for valsartan.
  • the valsartan oral liquid compositions are provided in a dosage that is similar, comparable or equivalent to a dosage of a known valsartan tablet formulation.
  • the valsartan oral liquid compositions are provided in a dosage that provides similar, comparable, or equivalent pharmacokinetic parameters (e.g., AUC, Cmax, Tmax, Cmin, T1/2) as a dosage of a commercially available valsartan tablet formulation.
  • Similar, comparable, or equivalent pharmacokinetic parameters in some instances, refer to within 80 % to 125 %, 80 % to 120 %, 85 % to 125 %, 90 % to 1 10 %, or increments therein, of the given values. It should be recognized that the ranges can, but need not be symmetrical, e.g., 85 % to 105 %.
  • Valsartan oral liquid compositions described herein can be administered at a dosage disclosed herein or at other dose levels contemplated by a medical practitioner.
  • the valsartan oral liquid compositions disclosed herein are administered for prophylactic and/or therapeutic treatments.
  • the valsartan oral liquid compositions are administered to a patient already suffering from an indication, e.g., hypertension, in a therapeutically effective amount sufficient to cure the disease or at least partially arrest or ameliorate the symptoms, e.g., lower blood pressure.
  • Amounts effective for this use depend on the age of the patient, severity of the disease, previous therapy, the patient's health status, weight, and response to the valsartan oral liquid compositions, and are within the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation clinical trial.
  • a valsartan oral liquid composition disclosed herein may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life to ameliorate or otherwise control or limit the symptoms of the patient's disease. In other embodiments, administration of a valsartan oral liquid composition continues until complete or partial response of a disease.
  • a valsartan oral liquid composition is administered to a subject who is in a fasted state.
  • a fasted state refers to the state of a subject who has gone without food or fasted for a specified amount of time.
  • General fasting periods include at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours and at least 16 hours without food.
  • a valsartan oral liquid composition is administered to a subject who has fasted overnight.
  • a valsartan oral liquid composition is administered to a subject who is in a fed state.
  • a fed state refers to the state of a subject who has taken food or has had a meal.
  • a valsartan oral liquid composition is administered to a subject in a fed state 5 minutes post- meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-meal, 1 hour post-meal, or 2 hours post-meal.
  • a valsartan oral liquid is administered to a subject who is in a fed state.
  • a fed state refers to the state of a subject who has taken food or has had a meal.
  • a valsartan oral liquid composition is administered to a subject in a fed state 5 minutes post- meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-me
  • composition is administered to a subject with food.
  • the treatment of certain diseases or conditions in a subject with an oral liquid valsartan composition disclosed herein encompass additional therapies and treatment regimens with other active pharmaceutical ingredients.
  • additional therapies and treatment regimens can include sequential or concurrent administration of a second active ingredient to a subject to treat the same or different disease or condition being treated with an oral liquid valsartan composition.
  • additional therapies and treatment regimens include sequential or concurrent administration of a second active ingredient to a subject to treat adjunct conditions associated with the disease or condition or a side effect from the oral liquid valsartan composition in the therapy.
  • Additional active ingredients for use in combination with an oral liquid valsartan composition disclosed herein include, but are not limited to, diuretics (loop, thiazide, potassium-sparing, and the like), beta blockers (metoprolol, propanolol, pronethalol, and the like), alpha blockers (phentolamine, phenoxybenzamine, tamsulosin, prazosin, and the like), mixed alpha and beta blockers (bucindolol, carvedilol, labetalol), calcium channel blockers (dilitazem, verapamil, dihydropyridines such as nifedipine, amlodipine, etc., and the like), angiotensin II receptor antagonists (saralasin, losartan, eprosartin, irbesartan, and the like), other ACE inhibitors (lisinopril, captopril, quinapril, ramipril), other
  • Example 1 Preparation of oral liquid solutions of valsartan.
  • Valsartan was mixed in propylene glycol with stirring until there were no visible valsartan particles in the (first) mixture. Methylparaben was then added to the first mixture and stirred until there were no visible methylparaben particles in the first mixture.
  • poloxamer 188 was mixed in water and stirred until there were no visible poloxamer 188 particles in this second mixture.
  • Sodium citrate dihydrate was then slowly added to the second mixture and stirred until there were no visible sodium citrate dihydrate particles.
  • the first mixture valsartan, propylene glycol and methylparaben
  • was slowly added to the second mixture polyoxamer 188, water, and sodium citrate dihydrate
  • Potassium sorbate was added to the combined mixture and stirred until there were no visible potassium sorbate particles. Sucralose was then added to the combined mixture and stirred until all particles were dissolved.
  • preparation # 1 water was added quantum satis up to 1000 g for the combined mixture and then flavoring was added.
  • preparations #3-4 flavoring was added to the combined mixture, and then water was added quantum satis up to 1000 g for the combined mixture.
  • Example 2 Preparation of an oral liquid solution of valsartan.
  • Valsartan was mixed in propylene glycol with stirring until there were no visible valsartan particles in the (first) mixture. Methylparaben was then added to the first mixture and stirred until there were no visible methylparaben particles in the first mixture.
  • poloxamer 188 was mixed in water and stirred until there were no visible poloxamer 188 particles in this second mixture.
  • Sodium citrate dihydrate was then slowly added to the second mixture and stirred until there were no visible sodium citrate dihydrate particles.
  • Citric acid anhydrous was then added to the second mixture with stirring until there were no visible citric acid anhydrous particles.
  • the first mixture (valsartan, propylene glycol and methylparaben) was slowly added to the second mixture (poloxamer 188, water, sodium citrate dihydrate and citric acid anhydrous) until the combined mixture was clear.
  • Potassium sorbate was added to the combined mixture and stirred until there were no visible potassium sorbate particles. Sucralose was then added to the combined mixture and stirred until all particles were dissolved. Flavoring was added to the combined mixture, and then water was added quantum satis up to 1000 g for the combined mixture.
  • Example 3 Preparation of an oral solution of valsartan.
  • valsartan oral liquid solutions of Example 3 were packaged in 4 ounce (120 mL), Boston white, round HDPE bottles with 28 mm ribbed side, smooth top resin closures and stored upright under the following storage conditions: refrigerated condition (REF) (5 °C ⁇ 3 °C), controlled room temperature condition (CRT) (25 °C ⁇ 2 °C / 40 % ⁇ 5 % relative humidity (RH)), intermediate condition (INT) (35 °C ⁇ 2 °C / 65 % ⁇ 5 % RH) and accelerated condition (ACC) (40 °C ⁇ 2 °C / not more than (NMT) 25 % RH). Samples were taken at set time intervals to assay for valsartan, pH, individual unspecified impurities, total impurities, total aerobic microbial count and total yeast/mold count.
  • REF refrigerated condition
  • CRT controlled room temperature condition
  • RH relative humidity
  • INT intermediate condition
  • ACC accelerated
  • Example 3 The 4 oz valsartan oral liquid solution of Example 3 was stable for up to 24 months storage under refrigerated (REF) conditions. [00101] Table 5. Assay for Valsartan Oral Liquid Solution Under CRT (25 °C ⁇ 2 °C /
  • Example 3 The 4 oz valsartan oral liquid solution of Example 3 was stable for up to 24 months storage under controlled room temperature (CRT) conditions.
  • Example 3 The 4 oz valsartan oral liquid solution of Example 3 was stable for up to 24 months storage under intermediate (INT) conditions.
  • Example 3 The 4 oz valsartan oral liquid solution of Example 3 was stable for up to 24 months storage under accelerated (ACC) conditions.
  • Example 5 Stability of 0.4 % Valsartan Oral Liquid Composition Stored in
  • HDPE High Density Polyethylene
  • valsartan oral liquid solutions of Example 3 were packaged in 16 ounce, Boston white, round HDPE bottles with 28 mm ribbed side, smooth top resin closures and stored upright under the following storage conditions: refrigerated condition (REF) (5 °C ⁇ 3 °C), controlled room temperature condition (CRT) (25 °C ⁇ 2 °C / 40 % ⁇ 5 % relative humidity (RH)), intermediate condition (INT) (35 °C ⁇ 2 °C / 65 % ⁇ 5 % RH) and accelerated condition (ACC) (40 °C ⁇ 2 °C / not more than (NMT) 25 % RH). Samples were taken at set time intervals to assay for valsartan, pH, individual unspecified impurities, total impurities, total aerobic microbial count and total yeast/mold count.
  • REF refrigerated condition
  • CRT controlled room temperature condition
  • RH relative humidity
  • INT intermediate condition
  • ACC accelerated condition
  • Samples
  • Example 3 The 16 oz valsartan oral liquid solution of Example 3 was stable for up to 24 months storage under refrigerated conditions.
  • Example 6 Stability of 0.4 % Valsartan Oral Liquid Composition Stored in
  • Example 3 The 25 mL Unit Dose valsartan oral liquid solution of Example 3 was stable for up to 24 months storage under refrigerated conditions.
  • Example 3 The 25 mL Unit Dose valsartan oral liquid solution of Example 3 was stable for up to 24 months storage under controlled room temperature conditions.
  • Example 3 The 25 mL Unit Dose valsartan oral liquid solution of Example 3 was stable for up to 24 months storage under intermediate conditions.
  • Example 3 The 25 mL Unit Dose valsartan oral liquid solution of Example 3 was stable for up to 24 months storage under accelerated conditions.

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Abstract

La présente invention concerne des compositions liquides orales de valsartan présentant une solubilité améliorée. L'invention concerne également des procédés d'utilisation de compositions de valsartan liquides orales pour le traitement de l'hypertension, le traitement de l'insuffisance cardiaque et la réduction de la mortalité cardiovasculaire chez des patients cliniquement stables avec une insuffisance ventriculaire gauche ou un dysfonctionnement ventriculaire gauche à la suite d'un infarctus du myocarde.
PCT/US2018/027039 2017-05-01 2018-04-11 Compositions orales liquides de valsartan WO2018204040A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100222334A1 (en) * 2007-10-09 2010-09-02 Wayne Talamonti Pharmaceutical Formulation of Valsartan
US20100267787A1 (en) * 2007-11-12 2010-10-21 Gregory Harasymiw Pharmaceutical Compositions
US9463183B1 (en) * 2015-10-30 2016-10-11 Silvergate Pharmaceuticals, Inc. Lisinopril formulations

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100222334A1 (en) * 2007-10-09 2010-09-02 Wayne Talamonti Pharmaceutical Formulation of Valsartan
US20100267787A1 (en) * 2007-11-12 2010-10-21 Gregory Harasymiw Pharmaceutical Compositions
US9463183B1 (en) * 2015-10-30 2016-10-11 Silvergate Pharmaceuticals, Inc. Lisinopril formulations

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