EP1827416A1 - Compositions pharmaceutiques - Google Patents

Compositions pharmaceutiques

Info

Publication number
EP1827416A1
EP1827416A1 EP05853119A EP05853119A EP1827416A1 EP 1827416 A1 EP1827416 A1 EP 1827416A1 EP 05853119 A EP05853119 A EP 05853119A EP 05853119 A EP05853119 A EP 05853119A EP 1827416 A1 EP1827416 A1 EP 1827416A1
Authority
EP
European Patent Office
Prior art keywords
composition
pharmaceutically acceptable
phenoxy
chlorobenzoyl
methyl
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Withdrawn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
EP05853119A
Other languages
German (de)
English (en)
Inventor
Jörg Rosenberg
Marsh Kennan
Matthias Degenhardt
Joerg Breitenbach
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.)
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 EP1827416A1 publication Critical patent/EP1827416A1/fr
Withdrawn legal-status Critical Current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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising primarily amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester and a method of making same, as well as a method of treating dyslipidemia and dyslipoproteinemia by administering a therapeutically effective amount of said pharmaceutical composition to a subject in need thereof.
  • 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester is a prodrug that is absorbed and then hydrolyzed by tissue and plasma esterases to 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid (the active metabolite or active species).
  • 2- [4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester is a benzophenone that contains a para-chlorophenyl and a para- isopropyloxycarbonylisopropoxyphenyl group. Both of these groups are substantially hydrophobic.
  • 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester is marketed and prescribed for the treatment of dyslipidemia and dyslipoproteinemia.
  • 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester has been made available commercially in a pharmaceutical dosage form (known as Lipidil®) which consists of a hard gelatin capsule containing crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl- propanoic acid, 1-methylethyl ester, lactose, pregelatinized starch and magnesium stearate.
  • Lipidil® consists of a hard gelatin capsule containing crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl- propanoic acid, 1-methylethyl ester, lactose, pregelatinized starch and magnesium stearate
  • This formulation has been marketed in the United States as 200 mg and 67 mg capsules. After oral administration, during a meal, about 60% of the dose of this conventional formulation is effectively absorbed and found in the blood as 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid (Weil et al., The metabolism and disposition of 14C-2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester in human volunteers, Drug. Metabol. Dispos. Biol. Fate. Chem., 18:115-120 (1990)).
  • 2- [4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid lowers plasma triglycerides by potentially inhibiting triglyceride synthesis leading to a reduction of low density lipoprotein (LDL) released into the circulation.
  • LDL low density lipoprotein
  • Lipidil Micro® is another pharmaceutical dosage form of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester having improved bioavailability.
  • European Patent Application 330,532 and U.S. Patent No. 4,895,726 disclose a 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1- methylethyl ester composition in which crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2- methyl-propanoic acid, 1-methylethyl ester powder is micronized with a solid wetting agent and a process for making this composition.
  • Sodium lauryl sulfate is described as the wetting agent of choice.
  • the micronized powder is mixed with capsule filling excipients such as lactose, starch, cross-linked polyvinyl pyrrolidone (PVP), and magnesium stearate.
  • excipients such as lactose, starch, cross-linked polyvinyl pyrrolidone (PVP), and magnesium stearate.
  • PVP polyvinyl pyrrolidone
  • a study comparing Lipidil Micro® to Lipidil® showed a statistically significant increase in bioavailability with the Lipidil Micro®.
  • Lipidil Micro® has been marketed in the United States under the name TRICOR® (Micronized) as 160 mg and 54 mg tablets.
  • Lipidil Micro® exhibits improved bioavailability
  • this composition does not lead to complete absorption of the dose of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl- propanoic acid, 1-methylethyl ester and suffers from several disadvantages.
  • bioavailability of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid is improved in Lipidil Micro®, the formulation remains subject to differences in bioavailability when taken with a meal or in the fasted state.
  • compositions that are available that contain primarily amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1- methylethyl ester and have no significant food effect upon oral administration.
  • the pharmaceutical composition of the present invention exhibits enhanced bioavailability when compared to a reference formulation (as defined herein) and provides a formulation that has no significant food effect.
  • the present invention relates to an oral pharmaceutical composition
  • an oral pharmaceutical composition comprising at least one active agent, wherein the active agent comprises primarily amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,l- methylethyl ester.
  • the oral composition of the present invention lacks a significant food effect on oral administration.
  • the 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester is present in the composition in an amount of from about 5 weight percent to about 65 weight percent of the total composition, specifically, from about 10 weight percent to about 50 weight percent of the total composition.
  • the composition of the present invention further comprises at least one pharmaceutically acceptable polymer and, optionally, at least one pharmaceutically acceptable surfactant.
  • the composition of the present invention can also contain at least one solubility-enhancing agent.
  • the composition of the present invention can also contain at least one coating, tableting aids, water-soluble polymers, fillers, binders, pigments, distintegrants, antioxidants, lubricants, flow aids and/or flavorants.
  • the at least one pharmaceutically acceptable polymer can be present in the composition in an amount of from about 20 weight percent to about 95 weight percent, preferably, from about 30 weight percent to about 75 weight percent.
  • the at least one pharmaceutically acceptable polymer that can be used in the composition can be an ionic cellulosic polymer.
  • the ionic cellulosic polymer includes, but is not limited to, carboxymethylcellulose (CMC), carboxymethylcellulose (CMC) salts, such as, but not limited to, carboxymethylcellulose sodium salts, carboxyethylcellulose (CEC), hydroxyethylmethylcellulose acetate phthalate, hydroxyethylrnethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose succinate, hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose acetate trimellitate (HPMCAT), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), hydroxypropylcellulose butyrate phthalate, carboxymethylethylcellulose and salts thereof, such
  • the at least one pharmaceutically acceptable polymer can be a nonionic cellulosic polymer.
  • the nonionic cellulosic polymer includes, but is not limited to, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylethylcellulose and combinations thereof.
  • the pharmaceutically acceptable polymer can be methyacrylic acid copolymers, aminoalkyl methacrylate copolymers, carboxylic acid functionalized polymethacrylates, amine-functionalized polymethacrylates, poly(vinyl acetal) diethylaminoacetate, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl alcohol/polyvinyl acetate copolymers and combinations thereof.
  • the pharmaceutically acceptable polymer can be polyvinyl pyrrolidone, polyvinyl alcohol/polyvinyl acetate copolymers and combinations thereof.
  • the pharmaceutically acceptable polymer can be polyethylene oxide polyethylene glycol/polypropylene glycol copolymers, polyethylene/polyvinyl alcohol copolymers, dextran, pullulan, acacia, tragacanth, sodium alginate, propylene glycol alginate, agar powder, gelatin, starch, processed starch, glucomman, chitosan and combinations thereof.
  • mixtures of pharmaceutically acceptable polymers can be utilized in the present invention.
  • the polymers may be selected to modulate the hydrophilicity of the pharmaceutical composition.
  • the pharmaceutical composition contains at least one pharmaceutically acceptable surfactant
  • said surfactant can have a hydrophile-lipophile balance (HLB) value from about 1 to about 20.
  • HLB hydrophile-lipophile balance
  • the at least one pharmaceutically acceptable surfactant can be present in the composition in an amount of from about 0.5 weight percent to about 20 weight percent, preferably, from about 1 weight percent to about 8 weight percent.
  • the at least one pharmaceutically acceptable surfactant that can be used in the composition in the present invention includes, but is not limited to, triglycerides of caprylic/capric acid, propylene glycol laurate, glyceryl and polyethylene glycol esters, sorbitan monooleate, sorbitan monolaurate, mono or diglycerides of caprylic/capric acid in glycerol, sorbitan sesquioleate, polyoxyethylene (2) oleyl ether, polyoxypropylene 15 stearyl ether, unsaturated polyglycolyzed glycerides, glyceryl monolinoleate, decaglyceryl decaoleate, triisostearin polyethylene glycol 6 esters, triglyceryl monoleate, glyceryl monooleate, sorbide dioleate, polyoxyethylene castor wax, polyglycolysed glycerides, polyglycolysed glycerides, saturated C 8
  • composition of the present invention contains at least one solubility-enhancing agent
  • said agent is present in the composition in the amount of from about 1 weight percent to about 40 weight percent, preferably, from about 1 weight percent to about 10 weight percent.
  • solubility-enhancing agents include at least one surfactant, at least one pH control agent, glycerides, partial glycerides, glyceride derivatives, polyoxyethylene and polypropylene esters and copolymers, sorbitan esters, polyoxyethylene sorbitan esters, carbonate salts, alkyl sulfonates, cyclodextrins and combinations thereof.
  • the pharmaceutical composition of the present invention can be in the form of a solid dispersion.
  • said solid dispersion When said solid dispersion is placed in contact with an aqueous medium, said solid dispersion forms a suspension comprising particles containing 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.
  • the D 50 of the particles in the suspension are from a D 50 of about l ⁇ m to a D 50 of about 100 ⁇ m.
  • the particles can contain crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1- methylethyl ester, amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1- methylethyl ester or a mixture of crystalline and amorphous 2-[4-(4-chlorobenzoyl)phenoxy]- 2-methyl-propanoic acid, 1-methylethyl ester.
  • the suspension comprising particles containing 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester has improved bioavailability compared to a reference formulation (namely, a 200 mg or 67 mg oral capsule pharmaceutical composition comprising crystalline 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester).
  • the present invention relates to a method of treating dyslipidemia in a subject in need of treatment thereof by administering to said subject a therapeutically effective amount of the hereinbefore described pharmaceutical composition.
  • the present invention relates to a method of treating dyslipoproteinemia in a subject in need of treatment thereof by administering to said subject a therapeutically effective amount of the hereinbefore described pharmaceutical composition.
  • Figure 1 shows six (6) different suspensions containing 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, l-methylethyl ester.
  • Figure 2 is a graph demonstrating the mean plasma concentration of 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid after an approximately 54 mg single orally administered dose of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1- methylethyl ester in fasted dogs.
  • Figure 3 shows the differential scanning calorimetry for solid dispersions 1-0, 1-5, 1- 8, 1-13 and 1-16 as described in Example 6.
  • Figures 4A-4E shows three (3) samples of each of seven (7) different suspensions containing 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, l-methylethyl ester at various time points, specifically, immediately after formation of the suspension ("initial"), at
  • Figures 5A-5E shows the dispersion characterization of each of the suspensions shown in Figure 4 as determined immediately after formation (namely, "initial"), 1 day after initial formation, 3 days after initial formation and 7 days after initial formation.
  • 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.
  • AUC refers to the area under the plasma concentration time curve and is calculated by the trapezoidal rule.
  • AUC 0-t means the area under the plasma concentration curve from time 0 to the last measurable concentration in units of ⁇ g*h/mL as determined using the trapezoidal rule.
  • AUC 0- ⁇ means the area under the plasma concentration curve from time 0 to infinite time.
  • AUC( 0- ⁇ ) is calculated as AUC( 0- t) + LMT/(- ⁇ ), where "LMT” is the last measurable plasma concentration and ⁇ is the terminal phase elimination rate constant.
  • active agent pharmaceutically active agent
  • drug drug
  • 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester The terms also encompass analogs of -[4-(4-chlorobenzoyl)phenoxy]-2- methyl-propanoic acid, 1-methylethyl ester.
  • active agent When the terms “active agent,” “pharmacologically active agent” and “drug” are used, it is to be understood that Applicants intend to include 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester per se as well as analogs of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.
  • the term the "bioavailability" when used in connection with a composition or compound is synonymous with the "AUC" of the composition or compound when compared against a reference composition or compound.
  • C max refers to the maximum observed plasma concentration of 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid produced by the ingestion of the compositions of the present invention.
  • dislipidemia and “dyslipoproteinemia” as used herein, include the conditions in the group selected from hypercholesterolemia, abnormal and elevated levels of cholesterol, abnormal and elevated levels of LDL cholesterol, abnormal and elevated levels of total cholesterol, abnormal and elevated levels of plasma cholesterol, abnormal and elevated levels of triglycerides, hypertrigylceridaemia, abnormal levels of lipoproteins, abnormal and elevated levels of low density lipoproteins (LDLs), abnormal and elevated levels of very low density lipoproteins, abnormal and elevated levels of very low intermediate density lipoproteins, abnormal levels of high density lipoproteins, hyperlipidemia, hyperchylomicronemia, abnormal levels of chylomicrons, related disorders, and combinations thereof such as those described in The ILIB Lipid Handbook for Clinical Practice, Blood Lipids and Coronary Heart Disease, Second Edition, A.
  • Elevation of serum cholesterol, triglyercides, or both is characteristic of hyperlipidemias. Differentiation of specific abnormalities usually requires identification of specific lipoprotein fractions in the serum of a patient. Lipoproteins transport serum lipids and can be identified by their density and electrophoretic mobility. Chylomicrons are among the largest and least dense of the lipoproteins.
  • VLDL or pre-beta very low density lipoproteins
  • ILDL or broad-beta intermediate low density lipoproteins
  • LDL or beta low density lipoproteins
  • HDL or alpha high density lipoproteins
  • Triglycerides are transported primarily by chylomicrons and very low density lipoproteins.
  • Cholesterol is transported primarily by low density lipoproteins.
  • Hyperlipidemia types include type I, type Ha, type lib, type III, type IV, and type V. These types can be characterized according to the levels relative to normal of lipids (cholesterol and triglycerides) and lipoproteins described above.
  • 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.
  • T max refers to the time to the maximum observed plasma concentration of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid produced by the ingestion of the formulations of the present invention.
  • 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.
  • fasted patient 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 primarily amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester and analogs of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester 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” refer 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 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.
  • a low fat test meal provides approximately 600 calories to the patient of which approximately 30% of the caloric content is derived from fat content of the meal.
  • suspension refers to particles dispersed in an aqueous medium wherein the particles of such suspension are preferably solid and comprise 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, the particles having a size between about 100 nm and about 500 ⁇ m, preferably between about 1 nm and about lOO ⁇ m.
  • positive food effective refers to when the amount of an active agent or drug taken into the blood from a given oral composition or dosage form by a fasting patient is less than the amount of the active drug taken into the blood from the same oral composition or dosage form by the same patient who has been fed a high fat containing meal proximal to the time of administration of the oral composition or dosage form.
  • pharmaceutically acceptable such as in the recitation of a “pharmaceutically acceptable excipient,” or a “pharmaceutically acceptable additive,” is meant a material that is not biologically or otherwise undesirable, i.e., the material maybe incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects.
  • reference formulation refers to an oral capsule dosage form containing either 200 mg or 67 mg of conventional microcrystalline 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.
  • the reference formulation has been marketed as Lipidil®.
  • solid dispersion refers to an active agent or drug dispersed or dissolved in a vehicle, carrier, diluent or matrix in the solid state.
  • the active agent or drug may be dispersed or dissolved in at least one pharmaceutically acceptable polymer, at least one pharmaceutically acceptable surfactant, a mixture of at least one pharmaceutically acceptable polymer and at least one pharmaceutically acceptable surfactant, etc.
  • subject refers to an animal, preferably a mammal, including a human or non-human.
  • patient and subject may be used interchangeably herein.
  • the present invention relates to oral pharmaceutical compositions that comprise at least one active agent, wherein at least one active agent is primarily amorphous, namely, in a non-crystalline state, 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1- methylethyl ester.
  • the pharmaceutical compositions of the present invention upon contact with an aqueous medium, such as that found in the gastrointestinal tract of a subject, form a suspension that contains particles that comprise 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl- propanoic acid, 1-methylethyl ester.
  • the particles contained within such a suspension typically have a particle size of from about 100 nm (0.1 microns) to about 500 microns, preferably from about 1 micron to about 100 microns.
  • the particles can contain crystalline 2- [4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, amorphous 2- [4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester or a mixture of crystalline and amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1- methylethyl ester.
  • the suspension is stable in water, meaning that the suspension does not coagulate. Particles in the suspensions that are not stable will coagulate and possibly even form an agglomerate.
  • the compositions of the present invention lack a significant food effect.
  • the oral pharmaceutical compositions of the present invention are made by first preparing a solid dispersion comprising primarily amorphous 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, at least one pharmaceutically acceptable polymer and optionally, at least one pharmaceutically acceptable surfactant.
  • the 2-[4-(4-chlorobenzoyl)phenoxy]-2- methyl-propanoic acid, 1-methylethyl ester, in its pure state can be either amorphous or crystalline.
  • the form of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, either amorphous or crystalline, prior to the formation of the solid dispersion is not critical.
  • Solid dispersions comprising amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl- propanoic acid, 1-methylethyl ester can be prepared using techniques known to those skilled in the art, such as, but not limited to, melt extrusion, evaporation, curing, microwaves, milling, ultra sound, spinning disc, etc. Such methods are disclosed in, e.g., U.S. Patent No. 4,880,585, U.S. Patent No. 6,254,889, U.S. Patent No. 6,387,401, U.S. Patent No. 6,706,283, U.S. Patent No. 6,599,528, U.S. Patent No. 5,546,923, U.S. Patent Application No.
  • the 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester is dispersed or dissolved in at least one pharmaceutically acceptable polymer for making said solid dispersion
  • the 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester should primarily (e.g., about 80% or greater) be in an amorphous state (in other words, it should be "primarily amorphous"), such that its predominantly non-crystalline nature is identifiable by techniques known in the art, e.g., X-ray diffraction analysis or by differential scanning calorimetry.
  • the solid dispersion can contain a small amount of the 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester (e.g. about 20% or less) in a crystalline state.
  • the solid dispersion may contain from about 5 % to about 65 % by weight of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, preferably from about 10% to about 50% by weight of 2-[4-(4-chlorobenzoyl)phenoxy]-2- methyl-propanoic acid, 1-methylethyl ester, and more preferably from about 10% to about 30% by weight of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.
  • any polymer that can be used with 2-[4-(4-chlorobenzoyl)phenoxy]-2- methyl-propanoic acid, 1-methylethyl ester (amorphous or crystalline) and is a pharmaceutically acceptable polymer can be used to form the dispersion.
  • polymers that can be used can be virtually any natural or synthetic polymer that can be used as a raw material in the manufacture of a pharmaceutical composition.
  • polymers that can be used include pH-sensitive polymers, water-soluble polymers, etc.
  • the amount of the polymer present in the dispersion generally ranges from about 20 wt % to about 95 wt % and preferably from about 50 wt % to about 90 wt%.
  • the choice of polymer to be selected for use in the solid dispersion may depend upon the technique to be used for making said dispersion. Moreover, polymers can be used independently or, if necessary, in combinations of two or more.
  • Polymers that can be used in the dispersion include ionizable and nonionizable cellulosic polymers (including those with ether or ester or a mixture of ester/ether substituents and copolymers thereof, including both so-called “enteric” and “non-enteric” polymers); and vinyl polymers and copolymers having substituents of hydroxyl, alkylacyloxy and cyclicamido.
  • Exemplary ionic cellulosic polymers include, but are not limited to, carboxymethylcellulose (CMC) and salts thereof, such as, but not limited to, sodium salts of carboxymethylcellulose, carboxyethylcellulose (CEC), hydroxyethylmethylcellulose acetate phthalate, hydroxyethylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose succinate, hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose acetate trimellitate (HPMCAT), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), hydroxypropylcellulose butyrate phthalate, carboxymethylethylcellulose and salts thereof, such as, but not limited to, sodium salts
  • Exemplary nonionic cellulosic polymers include, but are not limited to, methylcellulose (MC), ethyl cellulose (EC), hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylethylcellulose and mixtures thereof.
  • MC methylcellulose
  • EC ethyl cellulose
  • HEC hydroxyethyl cellulose
  • HPC hydroxypropylcellulose
  • HPMC hydroxypropylmethylcellulose
  • Exemplary vinyl polymers and copolymers include, but are not limited to, methacrylic acid copolymers, aminoalkyl methacrylate copolymers, carboxylic acid functionalized polymethacrylates, and amine-functionalized polymethacrylates, poly(vinyl acetal) diethylaminoacetate, polyvinyl pyrrolidone (PVP), copovidone, polyvinyl alcohol (PVA), polyvinyl alcohol/polyvinyl acetate (PVA/PVAc) copolymers and mixtures thereof.
  • PVP polyvinyl pyrrolidone
  • PVA/PVAc polyvinyl alcohol/polyvinyl acetate
  • polymers that can be used include, but are not limited to, polyethyleneoxide polyethylene glycol/polypropylene glycol (PEG/PPG) copolymers, polyethylene/polyvinyl alcohol (PE/PVA) copolymers, dextran, pullulan, acacia, tragacanth, sodium alginate, propylene glycol alginate, agar powder, gelatin, starch, processed starch, glucomannan, chitosan and mixtures thereof.
  • PEG/PPG polyethyleneoxide polyethylene glycol/polypropylene glycol
  • PE/PVA polyethylene/polyvinyl alcohol copolymers
  • the solid dispersion can optionally contain at least one pharmaceutically acceptable surfactant.
  • Suitable surfactants will typically be those with hydrophile-lipophile balance (“HLB”) values ranging from about 1 to about 20 and present in an amount of about 0.5 wt % to about 20 wt %, and preferably from about 1 wt % to about 8 wt %.
  • HLB hydrophile-lipophile balance
  • Exemplary surfactants include, but are not limited to, Labrafac® Lipophile WL 1349 (triglyceride of caprylic/capric acid; Gattefosse, Ltd., Great Britain (hereinafter "Gattefosse"), Lauroglycol® FCC (propylene glycol laurate; Gattefosse), Labrafil® M 1944 CS (glyceryl and polyethylene glycol esters; Gattefosse), Span® 80 (sorbitan monooleate; Sigma), Span 20® (sorbitan monolaurate), Capmul® MCM (mono/diglycerides of caprylic/capric acid in glycerol; Abitec), Arlacel® 83 (sorbitan sesquioleate; ICI), Brij® 93 (polyoxyethylene (2) oleyl ether; READ ICI), Acconon® E (polyoxypropylene 15 stearyl ether; Abitec), Labrafil® M 2125 CS (unsaturated polyglyco
  • surfactants examples include Labrafil® M 1944 CS (glyceryl and polyethylene glycol esters; Gattefosse), Span 20® (sorbitan monolaurate), Tween® 85 (polyoxyethylene (20) sorbitan trioleate; Sigma), Cremophor® RH-40 (polyoxyl 35 hydrogenated castor oil; BASF), Miglyol® and combinations of these surfactants, particularly, Miglyol® and Cremophor® RH-40.
  • Labrafil® M 1944 CS glyceryl and polyethylene glycol esters; Gattefosse
  • Span 20® sorbitan monolaurate
  • Tween® 85 polyoxyethylene (20) sorbitan trioleate
  • Cremophor® RH-40 polyoxyl 35 hydrogenated castor oil
  • Miglyol® and combinations of these surfactants particularly, Miglyol® and Cremophor® RH-40.
  • Suitable oils that can be used as surfactants include, but are not limited to, any pharmaceutically acceptable oil, such as, for example, Labrafac®, Lipophile WL 1349 (triglyceride of caprylic/capric acid; Gattefosse), Myvacet® 9-08 (distillated acetylated monoglycerides), Myvacet® 9-40 (distillated acetylated monoglycerides), Capmul® PG-8 (propylene glycol and mono/di-caprylate; Abitec), Arlamol® E (polyoxypropylene (15) stearyl alcohol; ICI), Captex® 300 (glyceryl tricaprylate/caprate; Abitec), olive oil, Miglyol® 812 (caprylic/capric triglycerides; HULS America), sesame oil (Sigma), Novol® (oleyl alcohol, Croda).
  • any pharmaceutically acceptable oil such as, for example, Labrafac®, Lip
  • Preferred oils include Labrafac®, Lipophile® WL 1349, Myvacet® 9-08, Myvacet® 9-40, Capmul® PG-8 and combinations thereof.
  • the pharmaceutical composition of the present invention can optionally include solubility-enhancing agents that promote the water solubility of the active agent. Such solubility-enhancing agents can be present in an amount ranging from about 1 wt % to about 40 wt %, and preferably from about 1 wt % to about 10 wt % of the total weight of the formulation.
  • solubility-enhancing agents include, but are not limited to, surfactants; pH control agents, such as buffers, organic acids and organic acid salts and organic and inorganic bases; glycerides; partial glycerides; glyceride derivatives; polyoxyethylene and polyoxypropylene ethers and their copolymers; sorbitan esters; polyoxyethylene sorbitan esters; carbonate salts; alkyl sulfonates; and cyclodextrins.
  • surfactants such as buffers, organic acids and organic acid salts and organic and inorganic bases
  • pH control agents such as buffers, organic acids and organic acid salts and organic and inorganic bases
  • glycerides partial glycerides; glyceride derivatives; polyoxyethylene and polyoxypropylene ethers and their copolymers
  • sorbitan esters polyoxyethylene sorbitan esters
  • carbonate salts alkyl sulfonates
  • cyclodextrins
  • the solid dispersion can optionally include a number of additives and excipients that promote its stability, tableting or processing of the dispersion or suspension.
  • additives and excipients include, but are not limited to, at least one coating tableting aids, water-soluble polymers, surfactants, pH modifiers, fillers, binders, pigments, disintegrants, antioxidants, lubricants, flow aids and flavorants.
  • Such components include, but are not limited to, microcrystalline cellulose; metallic salts of acids such as aluminum stearate, calcium stearate, magnesium stearate, sodium stearate, and zinc stearate; fatty acids, hydrocarbons and fatty alcohols such as stearic acid, palmitic acid, liquid paraffin, stearyl alcohol, and palmitol; fatty acid esters such as glyceryl (mono- and di-) stearates, triglycerides, glyceryl (palmitic stearic) ester, sorbitan monostearate, saccharose monostearate, saccharose monopalmitate, and sodium stearyl fumarate; alkyl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; polymers such as polyethylene glycols, polyoxethylene glycols, and polytetrafluoroethylene; and inorganic materials such as talc and dicalcium phosphat
  • compositions of the present invention upon contact with an aqueous medium, form a suspension that comprises particles which contain 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.
  • the inventors of the present invention have developed a method for determining or screening whether solid dispersions which comprise primarily amorphous 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, at least one pharmaceutically acceptable polymer and optionally, at least one pharmaceutically acceptable surfactant, will form a suspension that upon contact with an aqueous medium, comprise particles that contain 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1- methylethyl ester.
  • the first step in manufacturing the compositions of the present invention involves preparing a solid dispersion.
  • methods for making solid dispersions are well known to those skilled in the art and include, but are not limited to, melt extrusion, evaporation, curing, microwaves, milling, ultra sound, spinning disc, etc.
  • the solid dispersion will contain primarily amorphous 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, at least one pharmaceutically acceptable polymer and, optionally, at least one pharmaceutically acceptable surfactant.
  • the solid dispersion is placed in an aqueous medium to form a suspension containing particles of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.
  • aqueous medium is water.
  • the pH of the aqueous medium can be adjusted if necessary by adding salts to the water.
  • any stirring can be stopped and the fully dispersed suspension is left at room temperature for a period of from about fifteen (15) minutes to about seven (7) days, preferably for a period of about thirty (30) minutes to about five (5) days, more preferably from about one (1) hour to about two (2) days.
  • the period of time in which the suspension is left at room temperature is not critical.
  • the suspension still has a cloudy, almost milky appearance, this indicates that when the solid dispersion containing the at least one pharmaceutically acceptable polymer and the primarily amorphous 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, and optionally, the at least one pharmaceutically acceptable surfactant is contacted with an aqueous medium, it forms a suspension comprising particles containing 2-[4-(4-chlorobenzoyl)phenoxy]-2- methyl-propanoic acid, 1-methylethyl ester.
  • the particles contained within such a suspension typically have a particle size of from about 100 nm to about 10,000 nm, preferably from about 200 nm to about 5000 nm.
  • the suspension formed as described herein is stable.
  • the term “stable” refers to the fact that the suspension does not coagulate and does not form an agglomerate.
  • the suspension no longer has a cloudy, almost milky appearance, but has instead coagulated and possibly even formed an agglomerate (See Figures 1 and 4), this indicates that the at least one pharmaceutically acceptable polymer, the at least one pharmaceutically acceptable surfactant (if present) or the at least one pharmaceutically acceptable polymer and at least one pharmaceutically acceptable surfactant is not suitable, and that solid dispersions formed containing said at least one pharmaceutically acceptable polymer, the at least one pharmaceutically acceptable surfactant (if present) or the at least one pharmaceutically acceptable polymer and at least one pharmaceutically acceptable surfactant will not, when contacted with an aqueous medium, form a suspension comprising particles containing 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.
  • the inventors of the present invention have found that a suspension comprising particles containing 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester have improved bioavailability compared to the reference formulation.
  • compositions of the present invention contain as an active agent, primarily amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester, that said compositions lack a significant food effect on oral administration to subjects when compared to the reference formulation.
  • the term "lacks a significant food effect" means that a composition of the present invention containing primarily amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2- methyl-propanoic acid, 1-methylethyl ester, when administered in the fed state to a subject is bioequivalent to the same composition when administered in the fasted state to a subject.
  • Two products or methods are bioequivalent if the 90% confidence intervals (CI) for the individual ratios of fed AUC to fasted AUC and fed C max to fasted C max are between 0.70 to 1.43, preferably between 0.80 to 1.25.
  • compositions of the present invention containing primarily amorphous 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester as the active agent. It was unexpectedly discovered that these compositions lacked significant food effect on oral administration. In contrast, in a separate study, compositions containing 200 mg of conventional microcrystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,l- methylethyl ester exhibited significant food effect on oral administration.
  • the oral compositions of the present invention lack a significant food effect on oral administration a number of benefits are realized. For example, subject convenience is increased which may lead to increasing subject compliance since the subject does not need to ensure that they are taking a dose either with or without food. This is significant, because when there is poor subject compliance, an exacerbation of the medical condition for which the drug is being prescribed may be observed. For example, disease symptoms associated with suboptimal control of blood lipids may occur when there is poor subject compliance with 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.
  • the present invention also provides a method of treating a subject suffering from dyslipidemia and/or dyslipoproteinemia.
  • the method comprises the step of orally administering a therapeutically effective amount of a pharmaceutical composition of the present invention to a subject in need thereof.
  • the subject can be a mammal, such as a human being, that is suffering from dyslipidemia and/or dyslipoproteinemia.
  • the present invention will be understood more clearly from the following non- limiting representative examples.
  • Labrafil® M 1944 CS is glyceryl and polyethylene glycol ester that is available from Gattefosse 2 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.
  • Solid dispersion #1 having the composition shown above in Table 1 was prepared as follows. Specifically, crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester (Helm, Germany) was blended with Copovidon® and Aerosil® 200. This powder mixture was fed by a loss in weight feeder system into a twin-screw extruder having 18 mm screw diameter. Extrusion was performed at a temperature of about 120 0 C resulting in a viscous melt leaving the extruder nozzle. The active agent containing melt was directly formed into tablets by calendaring between two counter-rotating rollers having depressions on the surface of the rollers according to the tablet dimension.
  • the calendared tablets were cooled to room temperature on a conveyor belt. Tablet weight was about 360 mg corresponding to 54 mg of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1- methylethyl ester per tablet.
  • Solid dispersions #2-#6 having the composition shown above in Table 1 were prepared as follows. Each of these solid dispersions (#2-#6) were prepared in the same manner as solid dispersion #1, described above, except that the liquid excipients were granulated with the polymer(s). These polymer/excipient granules were blended with crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester (Helm, Germany) prior to extrusion. Extrusion was performed at a temperature of about 120 °C as with solid dispersion #1.
  • Solid dispersion #7 having the composition shown above in Table 1 was prepared as follows. Solid dispesion #7 was prepared in the same manner as solid dispersion #1, described above, however, extrusion was performed at a temperature of about 165 0 C.
  • Example 1 Melt extruded solid dispersions #l-#6 prepared as described above in Example 1 were dispersed in an aqueous medium, specifically, water, to form a suspension.
  • Figure 1 shows each of the suspensions formed by each of solid dispersions #l-#6 after dispersion in the water.
  • the particle size was measured by laser diffraction techniques, the techniques of which are well known to those skilled in the art.
  • Table 2, below, shows the particle size of each of the nanosuspensiosn. The measurements of the size of the particles in each of the suspensions are reported as D50 ( ⁇ m) and D90 ( ⁇ m).
  • melt extrudate of solid dispersion #2 was manufactured as discussed in Example 1 above, hi addition, the 2-[4-(4-chlorobenzoyi)phenoxy]-2-methyl- propanoic acid, 1-methylethyl ester containing extrudate was milled and the milled extrudate was blended with 1.06 % Aerosil® 200 and 1.3 % sodium stearyl fumarate. This blended mixture was compressed into tablets. The final tablets were film-coated by using a ready-to- use excipient mixture (Opadry®, Colorcon) in a drum coater (film-coating of an aqueous dispersion of Opadry®).
  • a ready-to- use excipient mixture Opadry®, Colorcon
  • the amount of film-coating on the tablet surface was 2.3 % relative to the total weight of the tablet.
  • the resulting firm coated tablets contained 160 mg of amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester.
  • the composition of this tablet is shown in Table 3 below. An aliquot of these tablets were allocated for use as a "Control" formulation as described in more detail below.
  • the remaining tablets were crystallized to different extents by exposing the tablets for 52 days to approximately 75% relative humidity in an open dish for different periods of time. More specifically, the tablets were stored at room temperature in an open dish in a chamber maintained at constant relative humidity of approximately 75% by a saturated salt solution.
  • the amount of crystalline active agent was measured on the dried and ground tablet samples by differential scanning calorimetry. hi 21 days, only a small fraction of the active agent was expected to crystallize whereas in 52 days equilibrium was attained and the active agent had crystallized to the limit of solubility.
  • a reference composition (TRICOR® 67 mg capsule) was compared to the Control and the stressed tablets prepared as described above.
  • the 160 mg Control and stressed tablets were cut using a knife to provide an approximately 54 mg dose by weight.
  • a single dose of approximately 54 mg (either the Control or one of the stressed tablets) was provided to fasted dogs.
  • the plasma samples were analyzed using HPLC-MS/MS, which is a standard technique known to those skilled in the art.
  • Figure 2 shows the mean plasma concentration of 2-[4-(4-chlorobenzoyl)phenoxy]-2- methyl-propanoic acid after an approximately 54 mg single oral dose of 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester in fasted dogs.
  • the concentration decreases markedly for the samples containing 12% crystalline drug as compared to no crystalline drug in the Control (or clinical batch) tablets.
  • Table 4 shows the pharmacokinetic parameters for the dog studies.
  • the point estimate for AUC decreases as the crystallized drug increases. This indicates that the crystalline drug adversely affects the bioavailability of the formulation.
  • the study shows the importance of maintaining the 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl- propanoic acid, 1-methylethyl ester in a primarily amorphous form.
  • the study shows that bioavailability in dogs is adversely affected by the crystallization of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester in the melt extruded solid dispersion.
  • the bioavailability decreased with an increase in the degree of crystallinity.
  • the study indicates the importance of maintaining the drug in the primarily amorphous form in the 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester melt extruded solid dispersion.
  • This study was to determine the effect of food on the bioavailability of fenofibrate from the 160 mg tablet "Control" formulation described in Example 3, which will also be referred to herein in this Example as the "test formulation” and the 200 mg capsule reference formulation described previously herein (which shall be referred to in this Example as the "reference formulation”).
  • This study was a Phase 1, single-dose, open-label study that was conducted according to a four-period, randomized crossover design.
  • the mean age was 31.8 years (ranging from 20 to 45 years)
  • the mean weight was 73.6 kg (ranging from 56.0 to 89.0 kg)
  • the mean height was 175.4 cm (ranging from 159.0 to 193.0 cm).
  • Blood samples were collected from the subjects by venipuncture into 5 mL evacuated collection tubes containing potassium oxalate plus sodium fluoride prior to dosing (0 hours) and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 48, 72 , 96 and 120 hours after dosing (Study Day 1) in each period.
  • the blood samples were centrifuged to separate the plasma.
  • the plasma samples were stored frozen until analyzed.
  • Plasma concentrations of fenofibric acid were determined using a validated liquid chromatographic method with mass spectrometric detection.
  • Values for the pharmacokinetic parameters of fenofibric acid were estimated using noncompartmental methods.
  • the maximum observed plasma concentration (C ma ⁇ ) and the time to C max (peak time, T max ) were determined directly from the plasma concentration- time data.
  • the value of the terminal phase elimination rate constant ( ⁇ z ) was obtained from the slope of the least squares linear regression of the logarithms of the plasma concentration versus time data from the terminal log-linear phase of the profile. A minimum of three concentration-time data points was used to determine ⁇ 2 .
  • the terminal phase elimination half-life (ti /2 ) was calculated as ln(2)/ ⁇ z .
  • the area under the plasma concentration-time curve (AUC) from time 0 to time of the last measurable concentration (AUC t ) was calculated by the linear trapezoidal rule.
  • the AUC was extrapolated to infinite time by dividing the last measurable plasma concentration (Ct) by ⁇ z to give AUC from time 0 to infinite time (AUC ⁇ ).
  • ANOVA An analysis of variance (ANOVA) was performed for T max and the natural logarithms of C max and AUC.
  • the model included effects for sequence, subject nested within sequence, period and regimen. The effects of sequence, period and regimen were fixed, while the effect of subject was random.
  • the denominator sum of squares for the F statistic was the sum of squares for subject nested within sequence.
  • the denominator sum of squares was the residual sum of squares. The statistical tests were performed at a significance level of 0.05.
  • the bioavailability of the high-fat meal regimen (Regimen C) relative to that of the fasting regimen (Regimen A) was assessed by the two one-sided tests procedure via 90% confidence intervals. Absence of food effect was concluded if the 90% confidence intervals from the analyses of the natural logarithms of AUC and C max were within the 0.80 to 1.25 range.
  • the bioavailability of the low-fat meal test regimen (Regimen B) relative to that of the low-fat meal reference regimen (Regimen D) was assessed by the two one-sided tests procedure via 90% confidence intervals. Bioequivalence was concluded if the 90% confidence intervals from the analyses of the natural logarithms of AUC and C max were within the 0.80 to 1.25 range.
  • Antilogarithm of the difference (test formulation minus reference formulation) of the least squares means for logarithms.
  • Test formulation minus reference formulation Antilogarithm of the difference (test formulation minus reference formulation) of the least squares means for logarithms.
  • the test formulation (Regimen B) was bioequivalent to the reference formulation (Regimen D) because the 90% confidence intervals for evaluating bioequivalence were within the 0.80 to 1.25 range, hi addition, statistical proof of the lack of food effect on the test formulation was provided by the 90% confidence intervals for evaluating food effect (Regimen C versus Regimen A) which were within the 0.80 to 1.25 range.
  • This study was to determine the effect of food on the bioavailability of fenofibrate from a 54 mg tablet formulation made as described in Example 3, which will also be referred to herein in this Example as the "test formulation” and a 67 mg capsule reference formulation described previously herein (which shall be referred to in this Example as the "reference formulation”).
  • This study was a Phase 1, single-dose, open-label study that was conducted according to a four-period, randomized crossover design.
  • the mean age was 33.5 years (ranging from 24 to 44 years)
  • the mean weight was 75.4 kg (ranging from 56.0 to 104.0 kg)
  • the mean height was 174.3 cm (ranging from 155.0 to 189.0 cm).
  • AU of the twenty (20) subjects that entered the study completed the study.
  • Subjects were confined to the study site and supervised for approximately 6 days in each study period. Confinement in each period began in the afternoon on Study Day 1 (1 day prior to the dosing day) and ended after the collection of the 120-hour blood samples and scheduled study procedures were completed on the morning of Study Day 6. Strenuous activity during the confinement was not permitted.
  • Blood samples of the subjects were collected from the subjects by venipuncture into 5 mL evacuated collection tubes containing potassium oxalate plus sodium fluoride prior to dosing (0 hours) and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 48, 72 , 96 and 120 hours after dosing (Study Day 1) in each period.
  • the blood samples were centrifuged to separate the plasma.
  • the plasma samples were stored frozen until analyzed.
  • Plasma concentrations of fenofibric acid were determined using a validated liquid chromatographic method with mass spectrometric detection. Values for the pharmacokinetic parameters of fenofibric acid were estimated using noncompartmental methods. First, the maximum observed plasma concentration (C max ) and the time to C max (peak time, T max ) were determined directly from the plasma concentration- time data. Second, the value of the terminal phase elimination rate constant ( ⁇ z ) was obtained from the slope of the least squares linear regression of the logarithms of the plasma concentration versus time data from the terminal log-linear phase of the profile. A minimum of three concentration-time data points was used to determine ⁇ z . The terminal phase elimination half-life (h /2 ) was calculated as ln(2)/ ⁇ z.
  • the area under the plasma concentration-time curve (AUC) from time 0 to time of the last measurable concentration (AUC t ) was calculated by the linear trapezoidal rule.
  • the AUC was extrapolated to infinite time by dividing the last measurable plasma concentration (C t ) by ⁇ z to give AUC from time 0 to infinite time (AUC ⁇ ).
  • ANOVA An analysis of variance (ANOVA) was performed for T max and the natural logarithms of C max and AUC.
  • the model included effects for sequence, subject nested within sequence, period and regimen. The effects of sequence, period and regimen were fixed, while the effect of subject was random.
  • the denominator sum of squares for the F statistic was the sum of squares for subject nested within sequence.
  • the denominator sum of squares was the residual sum of squares. The statistical tests were performed at a significance level of 0.05.
  • the bioavailability of the high-fat meal regimen (Regimen C) relative to that of the fasting regimen (Regimen A) was assessed by the two one-sided tests procedure via 90% confidence intervals. Absence of food effect was concluded if the 90% confidence intervals from the analyses of the natural logarithms of AUC and C max were within the 0.80 to 1.25 range.
  • the bioavailability of the low-fat meal test regimen (Regimen B) relative to that of the low-fat meal reference regimen (Regimen D) was assessed by the two one-sided tests procedure via 90% confidence intervals. Bioequivalence was concluded if the 90% confidence intervals from the analyses of the natural logarithms of AUC and C max were within the 0.80 to 1.25 range.
  • Mean ⁇ standard deviation (SD) pharmacokinetic parameters of fenofibric acid after administration of the four regimens are listed in below in Table 8.
  • Antilogarithm of the difference (test formulation minus reference formulation) of the least squares means for logarithms.
  • the test formulation (Regimen B) was bioequivalent to the reference formulation (Regimen D) because the 90% confidence intervals for evaluating bioequivalence were within the 0.80 to 1.25 range.
  • statistical proof of the lack of food effect on the test formulation was provided by the 90% confidence intervals for evaluating food effect (Regimen C versus Regimen A) which were within the 0.80 to 1.25 range.
  • Lauroglycol® FCC is propylene glycol laurate that is available from Gattefosse.
  • Solid dispersion #1-0 having the composition shown above in Table 11 was prepared as follows. Specifically, crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester (Helm, Germany) was blended with Copovidon®. The powder mixture was added manually to the 5 cc micro extruder (DSM Research) and maintained at a temperature of from about 110°C. The powder mixture was mixed in the micro extruder at the elevated temperature for about 2 to about 3 minutes. The melted mass was discharged from the equipment and collected.
  • Solid dispersions #1-5, 1-8, 1-13, 1-16, 1-17 and 1-21 having the composition shown above in Table 11 were prepared as follows. Each of these solid dispersions (#2-#6) were prepared in the same manner as solid dispersion #1, described above, except that the liquid excipients and polymer were blended with crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2- methyl-propanoic acid, 1-methylethyl ester (Helm, Germany) prior to extrusion. Extrusion was performed at a temperature of about 110 °C as with solid dispersion #1.
  • each of the three samples was measured by laser diffraction techniques, the techniques of which are well known to those skilled in the art.
  • Table 12 shows the particle size of each of suspensions measured immediately after formation of the suspension (namely, "initial"), 1 day after initial formation, 3 days after initial formation and 7 days after initial formation.
  • the D50 ( ⁇ m) values are shown below in Table 12.
  • Figure 5 shows the polarized light microscopy characterization of each of the suspensions as determined immediately after formation (namely, "initial"), 1 day after initial formation, 3 days after initial formation and 7 days after initial formation.
  • the results indicate that the resulting particles contain crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2- methyl-propanoic acid, 1-methylethyl ester.
  • the amorphous 2-[4-(4- chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester was converted to crystalline 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester or a mixture of crystalline and amorphous 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester particles one hour after dispersion in an aqueous medium.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant prioritairement un acide amorphe 2-[4-(4-chlorobenzoyl)phénoxy]-2-méthyl-propanoïque, et 1-méthyléthyl ester.
EP05853119A 2004-12-03 2005-12-02 Compositions pharmaceutiques Withdrawn EP1827416A1 (fr)

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