EP2081563A1 - Pharmaceutical formulations - Google Patents

Pharmaceutical formulations

Info

Publication number
EP2081563A1
EP2081563A1 EP07844238A EP07844238A EP2081563A1 EP 2081563 A1 EP2081563 A1 EP 2081563A1 EP 07844238 A EP07844238 A EP 07844238A EP 07844238 A EP07844238 A EP 07844238A EP 2081563 A1 EP2081563 A1 EP 2081563A1
Authority
EP
European Patent Office
Prior art keywords
active agent
salt
formulation
fenofibric acid
modified release
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07844238A
Other languages
German (de)
English (en)
French (fr)
Inventor
Yi Gao
R. Ju Tzuchi
Dennis Y. Lee
Nicole Nguyen
Hauiliang Wu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fournier Laboratories Ireland Ltd
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP2081563A1 publication Critical patent/EP2081563A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to solid dosage forms comprising salts of 2-[4-(4- chlorobenzoyl)phenoxy] -2-methyl-propanoic acid.
  • fenofibric acid In contrast to fenofibrate, fenofibric acid has higher solubility in the small intestine region. However, this enhanced solubility could cause problems in connection with controlling the delivery of fenofibric acid (such as, the potential for the C max to exceed the accepted (approved) limits of a reference pharmaceutical composition containing fenofibrate). For example, immediate release dosage forms comprising amorphous fenofibric acid are described, for example, in U.S. Patent Application No. 2005/0148594.
  • the formulations comprising amorphous fenofibric acid when administered to a subject, exhibit a bioavailability that is twice as high as a fenof ⁇ brate-containing capsule formulation described in Example 6 of said published application.
  • the active ingredient namely, fenofibrate
  • the active ingredient simply cannot be replaced with fenofibric acid in such dosage forms.
  • solid dosage forms of fenofibric acid that exhibit a lack of a significant food effect when administered to a patient under fed or fasted conditions. Such solid dosage forms would improve patient compliance by giving the patient the flexibility to take said solid dosage form under either fed or fasted conditions.
  • the release rate of a robust drug formulation will be substantially independent of properties of the dissolution media.
  • a robust formulation will have essentially the same release rates in dissolution media of differing ionic strengths.
  • normal fasting levels for the ionic strength in the GI tract is .10-.14 and higher values are induced by the intake of food. It therefore follows that one would expect that the release rate of a robust drug formulation will exhibit minimal variation under fed and fasted conditions in the GI tract.
  • a further feature of a robust drug formulation is that its release rate will not be effected during rigorous steps in scaled-up of manufacturing processes.
  • This object is achieved, according to the present invention, by a hydrophilic gel forming matrix formulation having a prolonged release of fenofibric acid upon exposure to the dissolution media, characterized in that the release rate is substantially ionic-strength independent.
  • Applicants have found several factors contribute in making a modified release fenofibric acid formulations robust.
  • One factor is the salt selection.
  • robust fenofibric acid formulations should comprise a soluble salt.
  • the percentage of the fenofibric acid salt in the formulation also impacts the robustness of the formulation.
  • the presence or absence of a drug enteric coating may have some influence on the robustness of the formulation.
  • the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid wherein the release rate of the formulation in an in vitro dissolution is substantially independent of the ionic strength of the dissolution media.
  • Figure 1 shows the IDR values of seven salts of fenofibric acid and fenofibric acid verses the difference in drug release at 8 hours in an in vitro dissolution at high and low ionic strengths.
  • Figure 2 shows the in vitro dissolution profile of fenofibric acid tablets when done in dissolution media of 0.05M and 0.3M.
  • Figure 3 shows the in vitro dissolution profile of fenofibric acid choline salt tablets when done in dissolution media of 0.05M and 0.3M.
  • Figure 4 shows the in vitro dissolution profile of fenofibric acid metformin salt tablets when done in dissolution media of 0.05M and 0.3M.
  • Figure 5 shows the in vitro dissolution profile of fenofibric acid procaine salt tablets when done in dissolution media of 0.05M and 0.3M.
  • Figure 6 shows the in vitro dissolution profile of fenofibric acid diethanolamine salt tablets when done in dissolution media of 0.05M and 0.3M.
  • Figure 7 shows the in vitro dissolution profile of fenofibric acid ethanolamine salt tablets when done in dissolution media of 0.05M and 0.3M.
  • Figure 8 shows the in vitro dissolution profile of fenofibric acid calcium salt tablets when done in dissolution media of 0.05M and 0.3M.
  • Figure 9 shows the in vitro dissolution profile of fenofibric acid tris salt tablets when done in dissolution media of 0.05M and 0.3M.
  • Figure 10 shows the in vitro dissolution profiles of fenofibric acid tablets and fenofibric acid choline salt tablets at 32.5% drug load when done in dissolution media of 0.05M and 0.3M.
  • Figure 11 shows the in vitro dissolution profiles of fenofibric acid tablets and fenofibric acid choline salt tablets at 65.5% drug load when done in dissolution media of 0.05M and 0.3M.
  • Figure 12 shows the in vitro dissolution profiles of coated and uncoated fenofibric acid choline salt tablets when done in dissolution media of 0.05M and 0.3M.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid and wherein the solubility of the active agent is greater than 16.1 mg/ml in water.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid and wherein the solubility of the active agent is at least 19.0 mg/ml in water.
  • the present invention relates to a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid and the salt is selected from the group consisting of choline, ethanolamine, and diethanolamine, and wherein the solubility of the active agent is greater than 16.1 mg/ml in water.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a HPMC matrix wherein the active agent is a salt of fenofibric acid and wherein the solubility of the active agent is greater than 16.1 mg/ml in water.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a HPMC matrix wherein the active agent is a salt of fenof ⁇ bric acid and wherein the solubility of the active agent is at least 19.0 mg/ml in water.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid and the salt is selected from the group consisting of choline, ethanolamine, and diethanolamine, and wherein the IDR of the active agent is greater than 7.09mg/min/cm at a pH of 6.8.
  • the active agent is a salt of fenofibric acid and the salt is selected from the group consisting of choline, ethanolamine, and diethanolamine, and wherein the IDR of the active agent is greater than 7.09mg/min/cm at a pH of 6.8.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a HPMC matrix wherein the active agent is a salt of fenofibric acid and wherein the IDR of the active agent is greater than 7.09mg/min/cm at a pH of 6.8.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a HPMC matrix wherein the active agent is a salt of fenofibric
  • the IDR of the active agent is at least 8.05 mg/min/cm at a pH of 6.8.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid wherein the release rate of the formulation in an in vitro dissolution is substantially independent of the ionic strength of the dissolution media.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a HPMC matrix wherein the active agent is a salt of fenofibric acid wherein the release rate of the formulation in an in vitro dissolution is substantially independent of the ionic strength of the dissolution media.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenof ⁇ bric acid and wherein in an in vitro dissolution the difference in percentage dissolved at time points 0.5, 1, 2, 4, 6, and 8 hours is not greater than 25% when dissolved in dissolution media of 0.05M and 0.3M.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid and the salt is selected from the group consisting of choline, ethanolamine, and diethanolamine, and wherein in an in vitro dissolution the difference in percentage dissolved at time points 0.5, 1, 2, 4, 6, and 8 hours is not greater than 25% when dissolved in dissolution media of 0.05M and 0.3M.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a HPMC matrix wherein the active agent is a salt of fenofibric acid and wherein in an in vitro dissolution the difference in percentage dissolved at time points 0.5, 1, 2, 4, 6, and 8 hours is not greater than 25% when dissolved in dissolution media of O.05M and O.3M.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid and wherein in an in vitro dissolution the difference in percentage dissolved at time points 0.5, 1, 2, 4, 6, and 8 hours is not greater than 21.4% when dissolved in dissolution media of 0.05M and 0.3M.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a HPMC matrix wherein the active agent is a salt of fenofibric acid and wherein in an in vitro dissolution the difference in percentage dissolved at time points 0.5, 1, 2, 4, 6, and 8 hours is not greater than 21.4% when dissolved in dissolution media of 0.05M and 0.3M.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid wherein the percentage of active agent in the formulation is between 33% and 75%.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a HPMC matrix wherein the active agent is a salt of fenofibric acid wherein the percentage of active agent in the formulation is between 33% and 75%.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid wherein the percentage of active agent in the formulation is between 50% and 75%.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid and the salt is selected from the group consisting of choline, ethanolamine, and diethanolamine, wherein the percentage of active agent in the formulation is between 50% and 75%.
  • the active agent is a salt of fenofibric acid and the salt is selected from the group consisting of choline, ethanolamine, and diethanolamine, wherein the percentage of active agent in the formulation is between 50% and 75%.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a HPMC matrix wherein the active agent is a salt of fenofibric acid wherein the percentage of active agent in the formulation is between 50% and 75%.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a soluble salt of fenofibric acid wherein the percentage of active agent in the formulation is between 33% and 75%.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a soluble salt of fenofibric acid wherein the percentage of active agent in the formulation is between 50% and 75%.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid wherein the percentage of active agent in the formulation is between 33% and 75% and wherein the release rate of the formulation is substantially independent of the ionic strength of the dissolution media.
  • Another aspect of the present invention provides a modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid wherein the percentage of active agent in the formulation is between 50% and 75% and wherein the release rate of the formulation is substantially independent of the ionic strength of the dissolution media.
  • Another aspect of the present invention provides a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid wherein the difference in disintegration times of the active agent when disintegrated in media of .3M or .05M ionic strength is less than 475 minutes.
  • Another aspect of the present invention provides a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid and the salt is selected from the group consisting of choline, ethanolamine, and diethanolamine, wherein the difference in disintegration times of the active agent when disintegrated in media of .3M or .05M ionic strength is less than 475 minutes.
  • Another aspect of the present invention provides a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid wherein the difference in disintegration times of the active agent when disintegrated in media of .3M or .05M ionic strength is less than 100 minutes.
  • Another aspect of the present invention provides a HPMC matrix wherein the active agent is a salt of fenofibric acid wherein the difference in disintegration times of the active agent when disintegrated in media of .3M or .05M ionic strength is less than 475 minutes.
  • Another aspect of the present invention provides a HPMC matrix wherein the active agent is a salt of fenofibric acid wherein the difference in disintegration times of the active agent when disintegrated in media of .3M or .05M ionic strength is less than 100 minutes.
  • an active agent includes a single active agent as well two or more different active agents in combination
  • an excipient includes mixtures of two or more excipients as well as a single excipient, and the like.
  • active agent As used herein, the terms “active agent,” “pharmacologically active agent,” and “drug” are used interchangeably herein to refer to salts of 2-[4-(4-chlorobenzoyl)phenoxy]-2- methyl-propanoic acid (fenofibric acid). The terms also encompass buffered 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid.
  • Salts of fenofibric acid include, but are not limited to choline, ethanolamine, diethanolamine, dicyclohexylamine, tromethamine, lysine, piperazine, calcium, cyclohexylamine, procaine, metoformin, potassium, lysine, meglumine, diethylamine, sodium and ethylenediamine.
  • counter-ions examples include, but are not limited to, calcium hydroxide, choline hydroxide, diethylethanolamine, diethanolamine, ethylenediamine, guanidine, magnesium hydroxide, meglumine, ethanolamine, piperazine, peperidine, sodium hydroxide, triethylamine, tromethamine, benzathine , benzene-ethanamine, adenine, aluminum hydroxide, ammonium hydroxide, cytosine, diethylamine, glucosamine, guanine, nicotinamide, potassium hydroxide, zinc hydroxide, hydrabamine, tributylamine, deanol, epolamine, lithium hydroxide, procaine, pyridoxine, triethanolamine, ornithine, glycine, lysine, arginine, valine, serine, proline, aspartic acid, a
  • the solid state form of the active agent used in preparing the solid dosage forms of the present invention is not critical.
  • active agent used in preparing the solid dosage form can be amorphous or crystalline.
  • the final dosage form contains at least a detectable amount of crystalline active agent.
  • the crystalline nature of the active agent can be detected using powder X-ray diffraction analysis, by differential scanning calorimetry or any other techniques known in the art.
  • cloud point refers to a phenomenon observed in HPMC gels with increase in their temperature resulting in a precipitation of the polymer molecules, a property which can be measured by light transmission. The temperature at which light transmission reaches 50% is called cloud point.
  • delayed release refers to a type of modified release wherein a drug dosage form exhibits a time delay between oral administration of the drug dosage form and the release of the drug from said dosage form.
  • Pulsed release systems also known as pulsatile drug release
  • enteric coatings which are well known to those skilled in the art, are examples of delayed release mechanisms.
  • dissolution media means aqueous solutions in which release of the drug from the tablet formulations is determined. These solutions could be potassium phosphate (monobasic) solutions with two concentrations (0.05M and 0.3M). 0.05 M and 0.3 M KH 2 PO 4 represent high and low ionic strengths, respectively. pH of these solutions are adjusted to 6.0.
  • an “effective amount” or a “therapeutically effective amount” of an active agent is meant a nontoxic but sufficient amount of the active agent to provide the desired effect.
  • the amount of active agent that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like. Thus, it is not always possible to specify an exact “effective amount.” However, an appropriate “effective amount” in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • extended release or “sustained release” refers to a drug formulation that provides for gradual release of a drug over an extended period of time.
  • a “fasted” patient, “fasting conditions” or “fasting” refers to a patient who has not eaten any food, i.e., who has fasted for at least 10 hours before the administration of the oral formulation of the present invention comprising at least one active agent and who does not eat any food and continues to fast for at least 4 hours after the administration of the formulation.
  • the formulation is preferably administered with 240 ml of water during the fasting period, and water can be allowed ad libitum up to 1 hour before and 1 hour after ingestion.
  • a “fed patient”, “fed conditions” or “fed” refers to a patient who has fasted for at least 10 hours overnight and then has consumed an entire test meal beginning 30 minutes before the first ingestion of the test formulations.
  • the formulation of the present invention is administered with 240 ml of water within 5 minutes after completion of the meal. No food is then allowed for at least 4 hours post-dose. Water can be allowed ad libitum up to 1 hour before and 1 hour after ingestion.
  • a high fat test meal provides approximately 1000 calories to the patient of which approximately 50% of the caloric content is derived from fat content of the meal.
  • a representative high fat high calorie test meal comprises 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces of hash brown potatoes and 8 ounces of whole milk to provide 150 protein calories, 250 carbohydrate calories and 500 to 600 fat calories.
  • High fat meals can be used in clinical effect of food studies of fenof ⁇ bric acid.
  • a patient who receives such a high fat test meal is referred to herein as being under "high fat fed conditions”.
  • a low fat test meal provides approximately 500 calories to the patient of which approximately 30% of the caloric content is derived from fat content of the meal.
  • a patient who receives such a low fat test meal is referred to herein as being under "low fat fed conditions”.
  • formulation denotes any form of a pharmaceutical composition that contains an amount of active agent sufficient to achieve the desired therapeutic effect.
  • the frequency of administration that will provide the most effective results in an efficient manner without overdosing will vary with the characteristics of the particular active agent, including both its pharmacological characteristics and its physical characteristics.
  • hydrophilic polymer include, but are not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polyethylene glycols (“PEG”), xanthum gum, alginates, polyvinyl pyrrolidone, starches, cross-linked homopolymers and copolymers of acrylic acid and other pharmaceutically acceptable substances with swelling and/or gel-forming properties and combinations thereof.
  • HPMC hydroxypropyl methylcellulose
  • PEG polyethylene glycols
  • xanthum gum alginates
  • polyvinyl pyrrolidone starches
  • cross-linked homopolymers and copolymers of acrylic acid and other pharmaceutically acceptable substances with swelling and/or gel-forming properties and combinations thereof.
  • the term "ionic strength" of a solution means concentration of ions in a solution or a function of the concentration of ions in a solution. It can be calculated based on the molality of the concentration of ions and the charges of ions.
  • the term "IDR” is abbreviation of intrinsic dissolution rate. The intrinsic dissolution rate is the rate of dissolution of pharmaceutically acceptable ingredients when conditions such as surface area, agitation or stirring speed, pH and ionic strength of the dissolution medium are held constant.
  • insoluble substrate refers to (a) water insoluble substrates or seeds comprising different oxides, celluloses, organic polymers and other materials, alone or in mixtures; or (b) water soluble substrates or seeds comprising different inorganic salts, sugars, non-pareils and other materials, alone or in mixtures.
  • membrane refers to a film or layer that is permeable to aqueous solutions or bodily fluids and may also be permeable to the active agent.
  • the term "modified” refers to a drug containing formulation in which release of the drug is not immediate (See, for example, Guidance for Industry SUPAC-MR: Modified Release Solid Oral Dosage Forms, Scale- Up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution, Testing and In Vivo Bio equivalence Documentation, U.S. Department of Health and Human services, Food and Drug Administration, Center for Drug Evaluation and Research ("CDER”), September 1997 CMC 8, page 34, herein incorporated by reference.).
  • CDER Center for Drug Evaluation and Research
  • modified release includes extended release, sustained release, delayed release, and controlled release formulations.
  • pharmaceutically acceptable such as in the recitation of a “pharmaceutically acceptable excipient,” or a “pharmaceutically acceptable additive,” is meant a material that is non-toxic or otherwise physiologically acceptable.
  • soluble salt means all feno acid salts of which the solubility in water at 25 0 C is greater than 16.1 mg/ml.
  • subject refers to an animal, preferably a mammal, including a human or non-human. The terms patient and subject may be used interchangeably herein.
  • substantially independent of ionic strength means release of the drug, fenofibric acid salts, from the tablet formulations in the dissolution media is less affected by the change in ionic strength of the dissolution media, that is, the difference in % drug released when dissolutions are conducted in media of low (0.05M) and high (0.3M) ionic strengths at each time point within 8 hours is less 25%.
  • treating and “treatment” refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage.
  • “treating” a patient involves prevention of a particular disorder or adverse physiological event in a susceptible individual as well as treatment of a clinically symptomatic individual by inhibiting or causing regression of a disorder or disease.
  • Applicants have determined that the selection of the salt in a fenobric acid salt formulation affects the robustness of the formulation.
  • Applicants studied the release rates of fenofibric acid formulations comprising seven different salts of fenofibric acid and fenofibric acid alone. The ingredients for each of the studied formulations are shown in Table 2. The method used to make the tablets is described in Example 1, which follows Table 2.
  • the solubility of each salt was determined according to Example 2.
  • the IDR values for each salt of fenofibric acid were determined according to Example 3.
  • the salts of fenofibric acid and their respective solubility and IDR are shown in Table 4.
  • Applicants determined the dissolution rates of each of the fenofibric acid salt formulations in dissolution media at a high and low ionic strength using the single pH method as defined above.
  • Table 4 shows the % dissolved after 8 hours at 0.05M and 0.3M and the difference for each formulation at these ionic strengths.
  • Applicants have depicted their findings in Figure 1.
  • the graph in Figure 1 plots the IDR for each fenofibric acid salt formulation verses the difference in dissolution values at 8 hours.
  • the fenofibric acid salts with greater salt solubility and higher IDR values are less sensitive to the ionic strength of the dissolution media (that is the difference in the dissolution values at 8 hours and throughout the profile is less when compared at high and low ionic strengths).
  • Figures 2-9 show the dissolution profiles for the fenofibric acid salt and fenofibric acid formulations at 0.05M and .3M ionic strength dissolution media (Table 5 shows dissolution data for formulations tested in media of low ionic strength and Table 6 shows the dissolution data for formulations tested in media of high ionic strength). As can be seen from these figures the formulations with the more soluble fenofibric acid salts are more robust and thus the release rates are less sensitive to the ionic strength of the dissolution media. Table 2
  • Silicon dioxide 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
  • the intra granular ingredients were added into a granulator (or mixer) and dry mixed followed by gradual addition of a suitable amount of water to the granulator and granulating until optimal granulation was achieved.
  • the granulation was then wet massed if necessary for an additional period of time and then dried in an oven or a fluid bed dryer.
  • the dried granules were using the fitzmill or manually screened using a mesh.
  • the Silicon Dioxide and HPC Exf were screened through a 40-mesh screen.
  • the milled granules, and screened silicon dioxide and HPC were charged into a V-blender and blended for 5 minutes at ⁇ 26 rpm.
  • the SSF was screened through a 40-mesh screen.
  • the screened SSF was added into the blender and blended for additional 5 minutes.
  • the granules were weighed and compressed using the rounder tooling into a table with target weight of 275 mg/tablet.
  • Target tablet hardness
  • Solubility values of fenof ⁇ bric acid salts in water were determined at 25 0 C. The salts were weighed into glass vials and water was added. The suspensions were rotated from end to end for about 2 days in a 25 0 C water bath. The pH of the suspensions was measured. The residual solid was then removed via filtration through a 0.45 ⁇ m PTFE membrane filter. The resulting saturated solution was diluted appropriately into the HPLC mobile phase, and analyzed by the HPLC assay described below (Table 3). The powder x-ray diffraction pattern of the collected residual solid was recorded at the end of experiment. HPLC Analysis:
  • Pellets of the salts were prepared by compressing ca. 100 mg of the compound in a stainless steel die under 1300 pounds force with a dwell time of one minute.
  • the die containing the tablet was submerged in 400 mL of the dissolution medium at 37 0 C.
  • the solution was stirred by a paddle at ⁇ 60 rpm.
  • 3 mL of sample was withdrawn and filtered. After discarding the first half of the filtrate, the remainder was collected and assayed by HPLC method above.
  • the total volume of the dissolution medium was kept at a constant by replenishing the lost volume at each data point with fresh buffer at 37 C. Table 4
  • Example 4 Disintegration times for the choline fenofibric acid salt, the diethanolamine fenofibric acid salt and fenofibric acid are presented in Table 7.
  • Example 4 Disintegration times for the choline fenofibric acid salt, the diethanolamine fenofibric acid salt and fenofibric acid are presented in Table 7.
  • Disintegration times were determined by dropping tablets into a heated (37 0 C) aqueous media (900 ml 0.05M KH 2 PO 4 pH 6.0 and 900 ml 0.3M KH 2 PO 4 pH 6.0). The tablets were then bobbed up and down at a fixed rate until they were fully disintegrated, the time for disintegration was recorded in minutes.
  • a heated (37 0 C) aqueous media 900 ml 0.05M KH 2 PO 4 pH 6.0 and 900 ml 0.3M KH 2 PO 4 pH 6.0
  • Applicants have discovered that the percentage of the fenofibric acid salt in the formulation also impacts the robustness of the formulation.
  • Applicants compared formulations with different percentages of fenofibric acid salt or fenofibric acid and found that when the percentage of the fenofibric acid salt or fenofibric acid is between 33 and 75 the formulation is most robust.
  • Applicants compared the robustness of formulations I and K (presented in Table 8) to formulations A and B (presented in Table 2) by evaluating the impact of the ionic strength of the dissolution media on the dissolution rate of the formulation.
  • Figures 10 and 11 depict the dissolution curves for the formulations of different concentration active ingredient.
  • Figure 10 shows the release rate of formulations I and K with 32.5% drug load
  • Figure 11 shows the release profile of formulations A and B at
  • Applicants have determined that the presence or absence of an enteric coating may have some influence on the robustness of the formulation.
  • Applicants compared the dissolutions profiles of fenofibric acid choline salt made with and without a coating.
  • the composition of the formulations tested, with and without the coating, is shown in Table 9. These tablets were manufactured according to the manufacturing process of Example 6.
  • Figure 12 shows the dissolution profiles of the coated and uncoated tablets when dissolved in the .05 M and .3 M dissolution media. As shown in Figure 12, the coated tablets' dissolution is less impacted by the ionic strength of the dissolution media.
  • Example 5 Manufacturing process for coated and uncoated tablets:
  • Granulations were prepared by dry blending the powders, followed by the gradual addition of water until optimal granulation was achieved. The granulation was then wet massed if necessary for an additional period of time and then dried in an oven or a fluid bed dryer. The dried granulation was milled using the f ⁇ tzmill or manually screened using a mesh and then blended with the extra-granular excipients such as magnesium stearate. The final blend was weighed out and punched into tablets using a compression machine. Tablets were optionally coated using a pan coater.
  • compositions, formulations, methods, procedures, treatments, molecules, specific compounds described herein are presently representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention. It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention.

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EP07844238A 2006-10-12 2007-10-12 Pharmaceutical formulations Withdrawn EP2081563A1 (en)

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CN102046153B (zh) * 2008-05-30 2015-06-17 Ucb医药有限公司 包含布立西坦的药物组合物
CN102304103A (zh) * 2011-06-03 2012-01-04 郑州泰基鸿诺药物科技有限公司 一种非诺贝特酸盐、制备方法、药物组合物及应用
CN102659570B (zh) * 2012-05-17 2014-05-28 安润医药科技（苏州）有限公司 二氟非诺贝特酸及其在药学上可接受的盐，以及它们的制备方法和应用
FR3050112B1 (fr) * 2016-04-15 2020-09-04 Soc Civ Immobiliere Gecinq Utilisation de l'acide fenofibrique dans le traitement des maladies hepatiques
CN107496397A (zh) * 2016-06-14 2017-12-22 重庆安格龙翔医药科技有限公司 一种二甲双胍与非诺贝酸的复合物及其制剂

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US7259186B2 (en) * 2002-12-17 2007-08-21 Abbott Laboratories Salts of fenofibric acid and pharmaceutical formulations thereof
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CN101480384A (zh) * 2002-12-17 2009-07-15 阿伯特有限及两合公司 包含非诺贝酸、其生理可接受的盐或衍生物的制剂
EP1559419A1 (en) * 2004-01-23 2005-08-03 Fournier Laboratories Ireland Limited Pharmaceutical formulations comprising metformin and a fibrate, and processes for their obtention
US20060280790A1 (en) * 2005-04-08 2006-12-14 Ju Tzuchi R Pharmaceutical formulations

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