WO2016019066A1 - Composition et méthode de traitement d'une maladie neurodégénérative - Google Patents

Composition et méthode de traitement d'une maladie neurodégénérative Download PDF

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Publication number
WO2016019066A1
WO2016019066A1 PCT/US2015/042746 US2015042746W WO2016019066A1 WO 2016019066 A1 WO2016019066 A1 WO 2016019066A1 US 2015042746 W US2015042746 W US 2015042746W WO 2016019066 A1 WO2016019066 A1 WO 2016019066A1
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Prior art keywords
composition
weight
concentration
ursodiol
hlb
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PCT/US2015/042746
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English (en)
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Juan C. MENENDEZ
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University Of Tennessee Research Foundation
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    • 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
    • A61K9/08—Solutions
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the presently disclosed subject matter relates to a composition and method of using the composition for treating liver disease. More specifically, the presently disclosed subject matter relates to a pharmaceutical composition comprising Ursodiol, a method of preparing the pharmaceutical composition, and a method of administering this pharmaceutical composition to treat liver disease.
  • the presently disclosed subject matter provides a composition that includes a liquid vehicle having an intermediate hydrophilic-lipophilic balance (HLB) as defined hereinbelow and an effective amount of Ursodiol.
  • the composition further includes a hydrophilic solvent such as water.
  • the composition further includes one or more of a surfactant, preservatives, a sweetener and an alkalinizing agent.
  • the hydrophilic solvent is included in the composition at a concentration from about 65% to about 85% by weight. In specific embodiments, the hydrophilic solvent comprises about 65%, 70%, 75%, 80% or 85% by weight. Water is the preferred hydrophilic solvent.
  • the hydrophilic-lipophilic balance (HLB) of the liquid vehicle of the composition ranges from about 11.0 to about 16.5.
  • this range shall be understood to comprise the range for the "intermediate" HLB value.
  • the HLB ranges from about 12.5 to about 16.5.
  • the hydrophilic-lipophilic balance of the liquid vehicle ranges from about 11.0 to about 15.0.
  • Some specific embodiments include HLB values for the vehicle of about 11.0, 11.5, 12.0, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, or 16.5.
  • the amount of the liquid vehicle having the intermediate HLB in the composition is from about 1.0% to about 10.0% by weight.
  • the liquid vehicle having the intermediate HLB is included in the composition at concentration of about 1.0% to about 6.0% by weight of the composition. In some embodiment, the concentration of the liquid vehicle is from about 1.0% to about 3.0% by weight of the composition.
  • Some specific aspects of the invention include compositions in which the amount of the liquid vehicle is about 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, or 10.0% by weight.
  • the surfactant included in the composition has an HLB range from about 14.0 to about 17.0. In some specific embodiments, the HLB of the surfactant is about 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, or 17.0. In some embodiments, the amount of surfactant included in the composition ranges from about 2.0% to about 9.0% by weight. In some embodiments, the concentration of the surfactant is from about 6.0% to about 9.0% by weight in the composition. In some specific embodiments, the amount of surfactant in the composition is about 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, or 9.0% by weight.
  • the concentration of the Ursodiol in the composition is from about 40.0 to about 60.0 mg/ml.
  • the Ursodiol concentration is about 40.0, 41.0, 42.0, 43.0, 44.0, 45.0, 46.0, 47.0, 48.0, 49.0, 50.0, 51.0, 52.0, 53.0, 54.0, 55.0, 56.0, 57.0, 58.0, 59.0, or 60.0 mg ml.
  • the amount of Ursodiol in the composition is from about 3.5% to about 5.5% by weight.
  • the amount of Ursodiol is about 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, or 5.5% by weight.
  • Such amounts will be understood to be “effective" for purposes of the present invention and allow for one or more doses to be administered with therapeutic effect to a subject.
  • the amount of preservative included in the composition can range from about 0.15% to about 0.30% by weight while in some specific embodiments, the amount of preservative is about 0.15%, 0.20%, 0.25%, or 0.30% by weight.
  • the amount of sweetener included in the composition can range from about 0.25% to about 0.50% by weight with amounts of about 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, or 0.50% by weight being used in some other embodiments.
  • the pH of the composition can range from about 7.7 to about 8.6 with values of about 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, or 8.6 being present for specific embodiments.
  • liver disease in a subject in need thereof.
  • the method includes administering to the subject an effective amount of a composition of described herein.
  • Still further embodiments of the present invention include methods of making aqueous pharmaceutical compositions containing Ursodiol.
  • the method includes the steps of preparing a liquid solution at a temperature ranging from about 35°C to about 55°C, wherein the liquid solution includes: a hydrophilic solvent at an initial concentration from about 65% to about 85% by weight, from about 4.0 to about 7.0 % by weight of a liquid vehicle with an intermediate HLB from about 12.5 to about 16.5 such as propylene glycol , and from about 2.5 to about 5.5 % by weight of a surfactant having an HLB ranging from about 14.0 to about 17.0.
  • the method further includes adding and dissolving into the liquid solution the Ursodiol at a concentration from about 40mg/ml to about 60mg/ml and about 3.5% to about 5.5% by weight, a preservative at a concentration from about 0.15 to about 0.30 % by weight, a sweetener in a concentration from about 0.25 to about 0.50 % by weight, and an alkalinizing agent in an amount sufficient to adjust the final pH of the composition to between about 7.7 and about 8.6. All amounts above refer to the final composition. Additionally, the method includes adding a further amount of the hydrophilic solvent, i.e. water, to make up the remaining final volume.
  • the aqueous pharmaceutical composition may be a clear solution while in others the aqueous pharmaceutical composition may be a slightly yellow solution or a clear, slightly yellow solution.
  • compositions for oral delivery include: DESCRIPTION range (mg/ml) weight range
  • Liquid Vehicle e.g. 20.0 - 100.0 2.0-9.0
  • Surfactant e.g. 20.0-120.0 2.0 - 10.0
  • Alkalinizing agent 15.0-30.0 1.5-3.0
  • Preservative(s) e.g. 1.5-3.3 0.15-0.33
  • Sweetener e.g. 2.5-5.0 0.25 - 0.50
  • Figures 1A and IB are photographs showing the physical appearance of re&igerated Ursodiol suspension (20 mgml) (extemporaneous preparation 1).
  • Figure 1A shows a still sample as retrieved from the refrigerator.
  • Figure IB shows a sample after one minute of vortex.
  • Figures 2 A and 2B are photographs showing the physical appearance of refrigerated Ursodiol suspension (50 mg/ml) (extemporaneous preparation 2).
  • Figure 2A shows a still sample as retrieved from the refrigerator.
  • Figure 2B shows a sample after one minute of vortex.
  • Figures 3 A and 3B are photographs showing the physical appearance of refrigerated Ursodiol solution (50 mg/ml) inventive formula 1.
  • Figure 3 A shows a still sample as retrieved from the refrigerator.
  • Figure 3B shows a sample after one minute of vortex.
  • Figures 4A and 4B are photographs showing the physical appearance of refrigerated Ursodiol solution (50 mg/ml) inventive formula 2.
  • Figure 4A shows a still sample as retrieved from the refrigerator.
  • Figure 4B shows a sample after one minute of vortex.
  • Figures 5A and 5B are photographs showing the physical appearance of comparative Ursodiol extemporaneous preparations (1 and 2) poured from HDPE containers stored in an environmental chamber at40°C.
  • Figure 5A shows an Ursodiol suspension (20 mg/ml) prepared with Ora-plus: Ora Sweet (1:1) (v/v).
  • Figure 5B shows an Ursodiol suspension (50 mg/ml) prepared from Sugar syrup NF.
  • Figures 6A and 6B are photographs showing the physical appearance of inventive Ursodiol solutions (50 mg/ml) (formulas 1 and 2) after pouring from HDPE bottles retrieved from an environmental chamber at40°C.
  • Figure 6A shows propylene glycol based Ursodiol solution (50mg/ml) (formula 1).
  • Figure 6B shows ethanol based Ursodiol solution (50 mg/ml) (formula 2).
  • the term "about,” when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments £20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1%, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1% from the specified amount, as such variations are appropriate to achieve the intended result.
  • the presently disclosed subject matter relates to a composition, methods of making and methods of using the composition for treating liver disease. More specifically, the presently disclosed subject matter relates to pharmaceutical compositions comprising one or more doses of Ursodiol or ursodeoxycholic acid, methods of preparing the compositions, and methods of administering the pharmaceutical compositions in order to treat liver disease.
  • Ursodiol refers to ursodeoxycholic acid. Ursodiol is the predominant bile acid in bears, thus the name of "Urso”. Ursodiol was identified in a recent survey conducted in 21 children's hospitals (50 beds or more) as one of the top 10 most commonly prescribed liquid formulations prepared extemporaneously (Lugo et al., 2009). It is FDA-approved for the dissolution of cholesterol-rich gallstones in patients with functioning gallbladders and in the treatment of primary biliary cirrhosis and has been extensively used off- label in children for treatment of some chronic cholestatic liver diseases (Black, 2010). Ursodiol is not water-soluble; the use of a traditional single solvent system is limited because of its potential long term accumulated toxicity in pediatric patients following chronic treatment (Khan, 2012).
  • a liquid dosage form for the selected compound is underscored by the extreme difficulty in young children when swallowing solids because of complex interactions between the developing nervous and physiological systems with the environment that evolves during growth (Bowles etal, 2010).
  • a liquid dosage form is provided in the present disclosure that makes the composition easier to swallow and also leads to a higher flexibility in dosage increments.
  • Ursodiol there is no appropriate dosage form of Ursodiol to be used in pediatric patients.
  • the current standard of treatment is based on the compounding of the so-called extemporaneous preparations from either of two Reference Listed Drugs (RLD's) (Urso250® or Ursoforte® tablets) (US FDA Orange Book) or their generics.
  • RLD's Reference Listed Drugs
  • Ursoforte® tablets Ursoforte® tablets
  • US FDA Orange Book US FDA Orange Book
  • There are, at least, three of these extemporaneous preparations (20 to 60 mg/ml) (Nahata and Pai, 2011).
  • the preparation of a liquid formulation at 50 mg/ml will also represent a benefit for geriatric patients with swallowing problems (Zajicek, 2013).
  • liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can be prepared by conventional techniques with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or f actionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • the preparations can also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
  • Preparations for oral administration can be suitably formulated to give controlled release of the active compound.
  • the present disclosure provides a method of preparing a pharmaceutical composition with a continuous phase which allows reproducibility during dosage administration.
  • a dosage form whose concentration is equivalent to the preparations used as the current standard of treatment is provided.
  • a dosage form physically stable when stored under refrigeration for extended periods of time before and after opening is provided.
  • a dosage form physically stable when stored at temperatures up to 40°C for no less than three months before opening is provided.
  • a dosage form with excipient levels adequate for use in pediatric patients for chronic liver disease treatment is provided.
  • liquid vehicle refers to a liquid compound having an intermediate hydrophilic-lipophilic balance (HLB) as defined in the next paragraph.
  • liquid vehicle or co- solvent useful for inclusion in the compositions of the present invention include propylene glycol (preferred in many embodiments), ethanol, and benzyl alcohol.
  • the term "intermediate hydrophilic-lipophilic balance (HLB)" of the liquid vehicle refers to a HLB value situated between a relatively lipophilic value (11) and highly hydrophilic value (20).
  • the HLB value of the liquid vehicle ranges from about 11.0 to about 16.5.
  • the HLB value of the liquid vehicle ranges from about 12.5 to about 16.5 with the liquid vehicle being present from about 2.0 to about 10.0 % by weight of the composition.
  • the HLB of the liquid vehicle ranges from about 11.0 to about 15.0 and the amount of the liquid vehicle in the composition ranging from about 1.0% to about 6.0 % by weight.
  • the Ursodiol or ursodeoxycholic acid is at a concentration between about 40.0 and about 60.0 mg/ml of the composition or about 3.5% to about 5.5% by weight. In some embodiments, the concentration of the Ursodiol is about 50.0 mg/ml.
  • the composition further includes a hydrophilic solvent in amounts of from about 65% to about 85% by weight.
  • a non-limiting example of a suitable hydrophilic solvent is water, including all
  • the composition may further include a surfactant which, in some embodiments, has an HLB value of about 14.0 to about 17.0.
  • the amount of surfactant in the compositions can be from about 2.0% to about 9.0% or from about 6.0% to about 9.0% by weight.
  • Non-limiting examples of the surfactant include Tween 20 and Tween 80.
  • Other suitable surfactants will be well known to those of ordinary skill.
  • the composition includes a preservative which is preferably is effective in alkaline pH (about 8.0) in amounts of from about 0.15% to about 0.30% by weight.
  • a preservative which is preferably is effective in alkaline pH (about 8.0) in amounts of from about 0.15% to about 0.30% by weight.
  • alkaline pH about 8.0
  • a non-limiting example is a combination of methyl paraben used in a ratio to propyl paraben between 8 to 1 and 10 to 1.
  • Other suitable preservatives will be well known to those of ordinary skill.
  • the composition further includes a suitable amount of a sweetener. Amounts of from about 0.25 to about 0.50% by weight can be suitable with other amounts being determined by routine skill.
  • sweeteners include sugar, sodium aspartame, acesulfame potassium (Sucralose), saccharin or any of the sweeteners generally recognized as being safe for human consumption.
  • amount of sweetener in the composition is an amount that provides a sufficient sweetening effect, e.g. equivalent to that obtained with Sucralose.
  • the composition further includes an alkalinizing agent such as, without limitation, sodium bicarbonate, sodium carbonate, sodium hydroxide or potassium hydroxide.
  • the final pH of the composition is from about 7.7 to about 8.6.
  • the composition includes: propylene glycol at about 2.0% to about 9.0% by weight, a surfactant having a HLB of about 14.0 to about 17.0 at about 2.0% to about 10.0% by weight, Ursodiol at about 3.5% to about 5.5% by weight, a preservative at about 0.15% to about 0.33% by weight, a sweetener at about 0.25% to about 0.50% by weight, water at about 70% to about 90.5% by weight, and an alkalinizing agent in an amount sufficient to adjust the final pH to a range from about 7.7 to about 8.6.
  • liver disease in a subject in need thereof.
  • the method includes administering to the subject an effective amount of the pharmaceutical composition disclosed above.
  • the liver disease is chronic.
  • the liver disease is chronic pediatric liver disease.
  • the pharmaceutical composition is administered by oral administration.
  • the subject is a human.
  • treatment refers to the medical management of a subject with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • the associated disease is chronic pediatric liver disease.
  • administering refers to any method of providing a compound and/or pharmaceutical composition thereof to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition (e.g. liver disease).
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • the composition is used to treat liver diseases.
  • the liver disease is chronic.
  • the composition is used to treat chronic pediatric liver disease.
  • Non-limiting liver diseases include Chronic Inflammation of the Liver, Hardening of Liver and Blockage of Bile Ducts, Gallstones, Inflammation with Fibrous Tissue Formation of Bile Ducts, Blockage of Normal Bile Flow, Closure of Some or All of the Major Bile Ducts, Rare
  • a subject will be administered an effective amount of the pharmaceutical composition.
  • the term "effective amount” refers to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition.
  • a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration.
  • compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any
  • Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.
  • Guidance can be found in the above mentioned package insert for the currently FDA approved Ursodiol products. For purposes of illustration, suitable amounts for most indications will range from about 1 to about 40 mg/kg/day in single or divided doses. Alternatively, doses in the range of from about 5 to about 30 mg/kg/day are suitable. Those of ordinary skill will determine suitable dosages based upon clinical experience and without undue experimentation.
  • a preparation can be administered in a "prophylactically effective amount"; that is, an amount effective for prevention of a disease or condition.
  • the terms "subject” or “subject in need thereof refer to a target of administration, which optionally displays symptoms related to a particular disease, pathological condition, disorder, or the like.
  • the subject of the herein disclosed methods can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human (preferred), non-human primate, dog, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • a patient refers to a subject afflicted with a disease or disorder.
  • the term "subject” includes human and veterinary subjects.
  • Still further embodiments provide methods of producing an aqueous pharmaceutical composition containing Ursodiol or ursodeoxycholic acid.
  • the methods include (1) preparing a liquid solution heated to a temperature from about 35 to about 55 °C that includes: a hydrophilic solvent at an initial concentration designed to achieve between about 65 and about 85 % by weight in the final composition, a vehicle with an intermediate HLB of about 12.5 to about 16.5 and an amount of from about 4.0 to about 7.0 % by weight, and a surfactant with an HLB of between about 14.0 and about 17.0 in amounts of from about 2.5 to about 5.5 % by weight; (2) adding and dissolving into the solution solids, which for the purposes of the present invention include Ursodiol at a concentration between about 40.0 and about 60.0 mg/ml, a preservative in an amount of between about 0.15 and about 0.30 %, by weight, a sweetener agent in an amount of between about 0.25 and about 0.50 % by weight, and an amount of an alkalinizing agent sufficient to adjust the final pH to between about 7.7 and about 8.6; and (3) adding a further amount of the hydrophilic solvent to reach
  • An alternative method of producing the aqueous Ursodiol compositions includes the steps of: (1) preparing a liquid solution heated to a temperature between about 35°C and about 55°C, comprising a hydrophilic solvent at initial concentration designed to achieve between about 65 and about 85 % by weight of the final composition, a liquid vehicle with an intermediate HLB between about 11.0 and about 15.0 in an amount of from between about 1.0 and about 3.0 % by weight, and a surfactant with an HLB between about 14.0 and about 17.0 in an amount of between about 6.0 and about 9.0 % by weight; (2) adding and dissolving into the liquid solution the solids, as described above, including the Ursodiol at a concentration between about 40.0 and about 60.0 mg/ml; a preservative in an amount of between about 0.15 and about 0.30 % by weight; a sweetener in an amount of between about 0.25 and about 0.50 % by weight, and an alkalinizing agent in an amount sufficient to adjust the final pH to
  • the methods of preparing the liquid Ursodiol composition include: (1) preparing a clear liquid mixture solution, heated to a temperature of about 35°C to about 55 °C, including: (i) a hydrophilic solvent, preferably water, at initial concentration designed to achieve between about 60 and 90 % by weight of the final composition; (ii) a liquid vehicle with an intermediate HLB, e.g., between about 12.5 and about 16.5, such as but not limited to, propylene glycol or ethanol, in an amount of between about 2.0 and about 10.0 %, by weight of the final composition; and (iii) a surfactant with an HLB between 14.0 and 17.0, such as but not limited to, Tween 20 or Tween 80, in an amount of between about 2.0 and about 9.0 %, by weight of the final composition; and (2) adding and dissolving the solids including: (i) the Ursodiol, at a concentration of between about 40.0 and about 60.0 mg/ml
  • the final dosage form is a clear and/or slightly yellow solution.
  • the methods of preparing the Ursodiol compositions include: (1) preparing a clear liquid mixture or solution, heated to a temperature between about 35 °C and about 55 °C, that includes: (i) a hydrophilic solvent, preferably water, at an initial concentration between about 60 and about 90 %, by weight, of the final composition; (ii) a liquid vehicle with an intermediate HLB, between about 11.0 and about 15.0, such as but not limited to, propylene glycol, ethanol or benzyl alcohol, in an amount of between about 2.0 and about 6.0 %, by weight of the final composition; (iii) a surfactant with an HLB of about 14.0 to about 17.0, such as but not limited to, Tween 20 or Tween 80 in an amount of between about 2.0 and about 9.0 % by weight of the final composition; (2) adding and dissolving into the clear mixture or solution solids including: (i) Ursodiol at a concentration between about 40.0 about 60.0 mg
  • the composition is stable for up to about 6 months when stored at about 4 °C.
  • the physical appearance of the composition is still as a clear and/or pale yellow solution after the storage period.
  • the clear and/or pale yellow physical appearance of the solution is retained after storage for up to about 3 months at a temperature of about 40 °C and at no more than 20% relative humidity.
  • Ursodiol suspension (20 mg/ml): prepared from grinding the contents of Ursodiol capsules 300 mg and mixing with equal parts of Ora-plus® and Ora-Sweet® to form a suspension. The powder is initially wetted and then diluted gradually with incremental volumes of the Ora-plus® and Ora-Sweet® mixture until final concentration is achieved. The suspension is vortexed under moderate speed for not less than a minute to obtain a homogeneous dispersion before distributing in specific containers according to the different environment conditions: as a non-limited example: semipermeable sealed plastic containers for storage at 40 °C and semipermeable sealed plastic containers and/ or glass parafilm-sealed containers for storage under refrigeration.
  • Ursodiol suspension 50 mg/ml: prepared from grinding the contents of Ursodiol capsules 300 mg, an initial volume of Glycerin USP (equivalent to 2.5 % of final volume) is added for wetting. Then Sugar syrup NF is added to form a homogeneous paste that becomes a dispersion with incremental volumes of the Glycerin USP. This dispersion becomes a suspension after vortexing at moderate speed for not less than a minute that can be distributed as described above.
  • Ursodiol solution (SO mg/ml) formula 1: in a typical example, but not limited, the active was prepared by direct dissolution at 40 °C with the following excipients (amounts expressed in mg per ml of the final drug product): propylene glycol (72.00); Tween® 80 (51.40); sodium bicarbonate (30.90); methyl paraben (2.50); propyl paraben (0.25); Sucralose (3.85); the final volume adjusted with USP purified water for a final pH of 8.0 ( ⁇ 0.3). After cooling at room temperature the product was distributed as described above.
  • Ursodiol solution 50 mg ml formula 2: as per the previous formulation, the supplied drug powder was placed.in a solution as described below by gently heating up to 40 °C with the following excipients (amounts expressed in mg per ml of the final drug product): ethanol (22.60); Tween® 80 (100.80); sodium bicarbonate (30.90); methyl paraben (2.50 mg); propyl paraben (0.25); Sucralose (3.85); the final volume adjusted with USP purified water for a final pH of 8.0 ( ⁇ 0.3). Final distribution and storage is as described above.
  • ii. Analytical method development the method is modified from one used to determine Ursodiol and metabolites in fecal material. (Cai et al., 2012) This method allows the measurement of the compound of interest in different matrices (formulations and biological fluids).
  • a. Equipment configuration a Shimadzu Prominence UFLC system equipped with LC- 20AD pumps, CTO-20AC column oven, a SIL-30AC autosampler, a DGU-20A 5R degasser, a CBM- 20A communication bus module, and a LCMS-2020 single quadrupole mass spectrometer controlled by LabSolutions software (Tokyo, Japan).
  • Sample preparation the samples were diluted from specified amounts with mobile phase B and then filtered through a 0.45 ⁇ syringe before preparing the vial for the autosampler.
  • Figure 1 illustrates still samples just retrieved from the refrigerator, and (B) after vortexing for a minute.
  • Figure 2(A) shows still samples just retrieved from the refrigerator; and Figure 2(B) shows samples after vortexing for a minute.
  • FIG. 4 which shows the Ursodiol solution (50 mg/ml), ethanol based formulation (formula 2), previously stored in the refrigerator.
  • Figure 4(A) shows still samples just retrieved from the refrigerator and
  • Figure 4(B) shows samples after vortexing for a minute.
  • FIG. 5(A) shows Ursodiol suspension (20 mg/ml) prepared with Ora-plus: Ora Sweet (1:1) (v/v) and Figure 5(B) shows Ursodiol suspension (50 mg/ml) prepared from Sugar syrup NF.
  • Ursodiol solution 50 mg/ml ethanol based formulation (formula 2).
  • Table 1 shows assayed Ursodiol concentrations for extemporaneous preparations made with 20 mg/ml and 50 mg/ml Ursodiol.
  • the assayed values were determined using HPLC on samples retrieved from the environmental chamber. The values represent the "Area under the curve" or "AUC".
  • the assayed concentration values were obtained from the ratio of At/Ar where At is the AUC for the extemporaneous preparations and Ar is the AUC for the propylene glycol based formulation. The ratio is expressed as a percentage. For the 20 mg/ml extemporaneous preparations, the injection volume was doubled (so the theoretical value would have been equivalent to 40 mg/ml).
  • Table 1 Assayed values estimated for formulations retrieved from the environmental chamber.
  • HDPE containers showed a slightly higher assay value (expressed as percentage of the theoretical claim) for the extemporaneous preparations as compared to those tested from PET bottles.
  • the assay range for a product to be approved is 85 to 115 %. None of the prior art extemporaneous preparations were within this limit, mainly because of the physical instability of the formulation; a significant amount of solids were found at the bottom of the container that could not be effectively resuspended leading to a sub therapeutic dose.
  • the inventive Ursodiol composition showed physical stability for up to about 6 months at 4°C and up to about 3 months at 40 °C and relative humidity of no more than 20 %.
  • HLB Hydrophilic-Lipophilic Balance
  • Labrafil® M 2125 4 B Insoluble, it led to a dark colored suspension.
  • Zajicek A Chief of the Obstetric and Pediatric Pharmacology and Therapeutics Branch at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Personal communication (January 3, 2013). Moroi Y., Kitagawa M., and Itoh H., Aqueous solubility and acidity constants of cholic, deoxycholic, chenodeoxycholic, and ursodeoxycholic acids, J. LipidRes., 33 (1): 49-53 (1992)

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Abstract

La présente invention concerne une composition et une méthode d'utilisation de ladite composition dans le traitement d'une maladie du foie. Plus spécifiquement, la présente invention concerne une composition pharmaceutique comprenant de l'ursodiol, un procédé de préparation de ladite composition pharmaceutique et un méthode d'administration de cette composition pharmaceutique pour traiter une maladie du foie.
PCT/US2015/042746 2014-07-29 2015-07-29 Composition et méthode de traitement d'une maladie neurodégénérative WO2016019066A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210340504A1 (en) * 2018-10-09 2021-11-04 Intrexon Corporation Cells and Methods for the Production of Ursodeoxycholic Acid and Precursors Thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5534505A (en) * 1993-08-30 1996-07-09 Medichemie Ag Ursodeoxycholic acid-containing medicament in a liquid adminstration form
US20020031558A1 (en) * 1998-07-24 2002-03-14 Yoo Seo Hong Preparation of aqueous clear solution dosage forms with bile acids
US20120156263A1 (en) * 2009-09-11 2012-06-21 Daewoong Pharmaceutical Co., Ltd. Ursodeoxycholic Acid-Synthetic Hydrotalcite-Eudragit Hybrid, Pharmaceutical Composition Containing the Same and Method for Preparing the Same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5534505A (en) * 1993-08-30 1996-07-09 Medichemie Ag Ursodeoxycholic acid-containing medicament in a liquid adminstration form
US20020031558A1 (en) * 1998-07-24 2002-03-14 Yoo Seo Hong Preparation of aqueous clear solution dosage forms with bile acids
US20120156263A1 (en) * 2009-09-11 2012-06-21 Daewoong Pharmaceutical Co., Ltd. Ursodeoxycholic Acid-Synthetic Hydrotalcite-Eudragit Hybrid, Pharmaceutical Composition Containing the Same and Method for Preparing the Same

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210340504A1 (en) * 2018-10-09 2021-11-04 Intrexon Corporation Cells and Methods for the Production of Ursodeoxycholic Acid and Precursors Thereof

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