CA2672686A1 - Pharmaceutical formulations - Google Patents

Abstract

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.

Description

PHARNIACEUTICAL FORMULATIONS

Related Application Information This application claims priority to U.S. Application No. 60/829,255, filed October 12, 2006, the contents of which are lierein incotporated by reference.
This application is a continuation-in-part of U.S. Application No. 11/548,960, filed on October 12, 2006, which is a continuation-in-part of U.S. Application No.
11/399,964, filed on April 7, 2006, which claims priority to U.S. Application No. 60/669,699, filed on April 8, 2005, the contents of each of which are herein incorporated by reference.
Tllis application is a continuation-in-part of U.S. Application No.
11/548,982, filcd on October 12, 2006, whicti is a continuation-in-part of U.S. Application No.
11/399,983, filed on April 7, 2006, which claims priority to U.S. Application No. 60/669,699, filed on April 8, 2005, the contents of each of which are herein incorporated by reference.
This application is a continuation-in-part of U.S. Application No. 11/549,005, filed on October 12, 2006, which is a continuation-in-part of U.S. Application No.
11/400,113, filed on April 7, 2006, wliich claims priority to U.S. Application I'o. 60/669,699, ftled on April 8, 2005, the contents of each of which are herein incorporated by reference.

Field of the Invention The present invention rclates to solid dosage forms comprising salts of 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid.

Background of the Invention 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl-propanoic acid,l-methylethyl ester, also known as "fenofibrate", from the family of fibrates, is a lipid-regulating agent. Fenofibrate is described in, for example, U.S. Patent Nos. 3,907,792, 4,895,726, 6,074,670 and 6,277,405.
Fenofibrate is commercially available in a variety of different formulations and is used in the treatment of adult endogenous hyperlipidemias, hypercholesterolemias and hypertriglyceridemias. The active metabolite of fcnofibrate is 2-[4-(4-chlorobenzoyl)phcnoxy]-2-methyl-propanoic acid, which is also known as fcnofibric acid.
One of the challenges associated with fibrates, such as fenofibrate, is that these compounds are hydrophobic and poorly soluble in water. Thus, the bioavailability of these compounds (i.e., their absorption in the digestive tract) can be low. Due to the hydrophobic nature and poor solubility of fenofibrate in water, absorption of fenofibrate in the digestive tract of a subject is increased affter ingestion of food by the subject (whcn compared to when the subject ingests the fenofibrate under fasting conditions). This food effect is undesirable when comparing the bioavailability of fenofibrate in fed vei-sus fasting conditions.
Additionally, subject compliance is an issue with drugs having a food effect because the patient must coordinate administration of the drug with the ingestion of food.
Recently, complex technologies have been used to overcome the food effect issues associated witll fenofibrate.
In contrast to fenofibrate, fenofibric acid has higher solubility in the small intestine region. However, tliis enhanced solubility could cause problems in connection with controlling the delivery of fenofibric acid (such as, the potential for ttie C,MIX to exceed the accepted (approved) limits of a reference pharmaceutical composition containing fenofibrate). For example, immediate release dosage fonns comprising amoiphous fenofibric acid are described, for example, in U.S. Patent Application No. 2005!0148594.
As reported therein, the formulations comprising amorphous fenofibric acid when administered to a subject, exhibit a bioavailability that is twice as high as a fenofibrate-containing capsule formulation described in Example 6 of said published application. Thereupon, in view of aforementioned described difference in solubility, the active ingredient, namely, fenofibrate, simply cannot be replaced with fenofibric acid in such dosage forms.
Moreover, there is a need in the art for solid dosage forms of fenofibric acid that exliibit a lack of a significant food effect when administercd 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. For example, a robust formulation will have essentially the same release rates in dissolution media of differing ionic strengths. In humans, 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 rninimal variation under fed and fasted conditions in the Gl 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.
It is the object of the present invention to provide modified release fenofibric acid formulations which are robust. Consequentially the release rate of the formulations of the present invention are substantially independent of thc ion-strength of dissolution medium.
This objcct is achicved, 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.
Applicants have discovered that robust fenofibric acid formulations sliould comprise a soluble salt. Second, the percentage of the fenofibric acid salt in the formulation also impacts the robustness of the formulation. Finally, the presence or absence of a drug enteric coating may have some influence on the robustness of the formulation.

Summary of the Invention In one aspect, the present invention provides a modified release fonnulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid whercin the rclcase rate of the fonnulation in an in viti-o dissolution is substantially independent of the ionic strength of the dissolution media.

Brief Descrigtion of the FiQures Figure 1 shows the IDR valucs 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 mcdia 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 ethanolaniine 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 fcnofibric 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 1 1 shows the in vitro dissolution profiles of fenofibric acid tablets and fenofibric acid clioline 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.
Detailed Description 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.
Anothcr aspect of the prescnt invention provides a modificd relcase 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/mi in water.
In one aspect, the present invention relates to a modified release for-mulation 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 agcnt in a HPMC 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.
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 - at of fenofibric acid and wherein the IDR of the active agent is greater than 7.09mg/min/cm , a pH of 6.8.
Another aspect of the present invention provides a modified release formulation comprising an active agetlt 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, cthanolaminc, , and diethanolamine, and wherein the IDR of the active agent is greater than 7.09mg/min/cm atapHof6.8.
Another aspect of the present invention provides a modified release formulation comprising an active agent in a HPMC matrix whercin 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 ~
of fenofibric acid and wherein 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 HPMC matrix wherein the active agent is a salt of fenofibric acid and wherein 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 iiivention providcs a modified release formulation comprising an active agent in a HPMC matrix wherein the active agent is a salt of fenofibric acid wherein thc 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 V4'O 2008/046052 PCT/US2007/081267 of fenofibric acid and wherein in an in viti-o dissolution the differcnce in percentage dissolved at timc points 0.5, 1, 2, 4, 6, and 8 houis 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 clloline, ethanolarnine, 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 viti-o 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 wherein in an in viti-o 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 dissolvcd 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 retease 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%.
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 whercin the active agent is a soluble salt of fenofibric acid wherein the percentage of active agent in the formulation is between 50% and 75%.
Anotller 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 rclease 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 for-mulation 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 whercin the active agent is a salt of fenofibric acid and the salt is sclectcd 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 niinutes.
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 whereiii 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 minutcs.
Definitions As used in this specification and the appended claims, the singular forms "a,"
"atl"
and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" includes a single active agent as well two or more different active agents in combination, reference to "an excipicnt" includes mixtures of two or more excipients as well as a single excipient, and the like.
In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.
As used herein, the term "about" is used synonymously with the term "approximately." Illustratively, the use of the term "about" indicates that values slightly outside the cited values, namely, plus or minus 10`%. Such dosages are thus encompassed by the scope of the claims reciting the terms "about" and "approximately."
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, cyclohexylarnine, procaine, metoformin, potassium, lysine, mcgluminc, dicthylaminc, sodium and ctliylcncdiaminc. Exaniplcs of countcr-ions that can be used to provide buffered fenofibric acid, include, but are not limited to, calcium hydroxide, choline hydroxide, diethylethanolamine, diethanolamine, ethylenediaminc, guanidine, magnesium hydroxide, meglumine, ethanolamine, piperazine, peperidine, sodium hydroxide, triethylainine, 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, alanine, isoleucine, leucine, methionine or threnine. The solid state form of the active agent used in preparing the solid dosage forms of the present invention is not critical. For example, 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 othcr techniques known in the art.
As used herein, the term "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.
As used herein, the term "delayed release" refer to a typc of modificd relcase whcrcin 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") and the use of enteric coatings, which are well known to those skilled in the art, are examples of delayed release mechanisms.
As used herein, the term "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 KH2PO4 represent high and low ionic strengths, respectively. pH of these solutions are adjusted to 6Ø
As used herein, the phrase "dissolution at a single pH", "a single pH" or a "single pH
system", as used interchangeably herein, refers to the method described in Table 1 below:

Table 1 Parameter Condition Apparatus USP Apparatus 2 (USP 29 NF 24) Agitation 100 RPM 4%
Medium 1) 0.05 M potassium phosphate buffer 900 mL, pH 6.0 f 0.05 maintained at 37 ~
0.5 C
2) 0.3 M potassium phosphate buffer 900 mL, pH 6.0 0.05 maintained at 37 t 0.5 C
Sampling Time Points 30 minutes to 12 hours UV Spectrophotometry Analysis At 298 nm By 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 effcct. 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 ageiits, 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.
As used hcrcin, the term "extended relcase" or "sustained release" refers to a drug formulation that provides for gradual release of a drug over an extended period of time.
As used herein, 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 cat any food and continues to fast for at least 4 hours after the administration of the formulation. The fonnulation is preferably administered with 240 ml of water during the fasting period, and water can be allowed ad libituin up to I
hour before and 1 hour after ingestion.
As uscd herein, 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 cntire test nlcal 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 libituna up to 1 hour before and 1 hour after ingestion. A high fat test meal provides approximately 1000 calories to the patient of which approxirnately 50% of the caloric content is derived from fat content of the meal. A representative high fat high calorie test meal comprises 2 eggs fi-ied in butter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces of llash brown potatoes and 9 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 fenofibric 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".
As used herein, the terms "forrnulation", "form" or "dosage form" as used interchangeably herein, denotes any form of a pharmaceutical coniposition 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 pai-ticular active agent, including both its pharmacological characteristics and its physical characteristics.
As used herein, the term "hydrophilic polymer" include, but are not limited to, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, hydroxycthyl 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.
As used herein, 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.
As used herein, 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.
As used herein, the term "inert 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.

As used herein, the term "membrane" refers to a film or laycr that is pct-mcable to aqueous solutions or bodily fluids and may also be pcrmcablc to the active agent.
As used herein, the term "modified" refers to a drug containing formulation in which release of the drug is not immediate (See, for example, Guiclance for Industry SUPAC-,t1R:
Il-lodified Release Solid Ora/ Dosage Forms, Scale-Up and Postapproval C17anges:
Cheniistrv, AlanufactUring, and Conti=ols; In Vltl'o DISSOlunon, Testing and In Vivo BIoeq1fZVQlence Documentation, U.S. Department of Health and Human services, Food and Drug Administration, Center for Drug Evaluation and Research ("CDER"), Scptember 1997 CMC 8, page 34, herein incorporated by reference.). In a modified formulation, administration of said formulation does not result in immediate release of the drug or active agent into an absorption pool. The term is used interchangeably with "nonimmediate release"
as defined in Remington: The Science and Pr-actice af Pharniacv, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995). As used herein, the term "modified release" includes extended release, sustained release, delayed release, and controlled release formulations.
As used herein, the phrase "pllatmaceutically acceptable," such as in the recitation of a "pharmaceutically acceptable excipicnt," or a"pharmaccutically acceptable additive," is meant a material that is non-toxic or otherwise physiologically acceptable.
As used herein, the term "soluble salt" means all feno acid salts of which the solubility in water at 25 C is greater than 16.1 mg/ml.
As used herein, the term "subject" refers to an animal, preferably a mammal, including a human or non-human. The tcrnis patient and subject may be used intcrchangcably herein.
As used herein the term "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 iotiic strength of the dissolution media, that is, the difference in %
drug released when dissolutions are conducted in mcdia of low (0.05M) and higli (0.3M) ionic strengths at each time point within 8 hours is less 25%.
As used herein, the terms "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. Thus, for example, "treating" a patient involves prevention of a particular disorder or adverse physiological event in a susceptible individual as well as treatment of a clinicatly symptomatic individual by inhibiting or causing regression of a disorder or discasc.

1. Salt Selection Dissolution Rates and Disintegration Times Applicants have determined that the selcction 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 dctcrmincd according to Examplc 2. Likcwisc, 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 sllows 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 cach fenofibric acid salt formulation verses the difference in dissolution values at 8 hours. As can be seen in Figure 1 and in Table 4 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 strcngths).
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 solublc fcnofibric acid salts are more robust and thus the release rates are less sensitive to the ionic strength of the dissolution media.

Table 2 Ingredient Forinulations (%) Intra2ranular A B C D E F G H
Feno acid 65.5 Choline salt 65.5 Diethanolamine salt 65.5 Ethanolamine salt 65.5 Metformin salt 65.5 Procaine salt 65.5 Tris salt 65.5 Calcium salt 65.5 Water gs gs gs gs gs gs gs gs Extragranular Silicon dioxide 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 HPC exf 3 3 3 3 3 3 3 3 Tablet weight: 275 mg Example 1 Tablet Preparation:
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 was -20 SCU.
Example 2 Solubility Determination:Solubility values of fenofibric acid salts in water were determined at 25 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 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 dcscribed below (Tablc 3).
The powder x-ray diffraction pattern of the collected residual solid was recorded at the end of experiment.
HPLC Analysis:

Table 3 HPLC Assay for Fenofibric Acid.
Parameters Conditions Column Waters Symmetry Shield RP18, 5 um, 250x4.6 mm Autosampler Temperature Ambient Column Temperature - 35 C
Flow Rate - 1 ml/min Detection Wavelength 286 nm Injection Volume 25 ul Mobile phase A 25 mM K2 HPO 4 in water, pH adjusted to 2.5 with Mobile phase B Acetonitrile Isocratic clution A/B = 40/60 Retention time minutes Examele 3 Intrinsic Dissolution Rate (IDR): The IDR of salts of fenfibric acid were determined in 50 mM sodium citrate buffer at pH 4.0 or pH 6.8 (u = 0.155 M with NaCI).
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 C. The solution was stirred by a paddle at -60 rpm. At each time point, 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.

Tablc 4 Salt Solubility m/ml IDR* % in 0.05M 8h % in 0.3M@8h Difference@8h Choline >300 14.50 80.0 58.6 21.4 Diethanolamine > 250 12.80 69.2 55.5 13.7 Ethanolamine 19.0 8.05 66.3 50.1 16.2 Metformin 16.1 7.09 55.2 98.8 43.6 Procaine 7.2 1.06 37.0 101.6 64.6 Tris 5.45 0.67 32.0 107.5 75.5 Calcium 0.36 0.10 19,6 95.3 75.7 Free acid 0.265 0.30 21.6 103.5 81.9 *units for IDR mg/min/cm , `; IDR measured at a pH of 6.8 Table 5 Time Dissolution of Formulations in 0.05M Phosphate Buffer, pH 6.0 65.5%
Loadin ) (h) A B C D E F G H
Free acid Choline Diethanolamine Ethanolamine Metformin Procaine Tris Calciurr 0.5 1.6 12.2 9.5 8.0 8.3 4.9 5.2 1.1 1 2.4 19.3 15.1 13.3 12 7.3 7.8 2.2 2 5 31.8 24.3 22.5 19.8 12.4 12.0 4.7 4 10.5 51.8 40.5 38.1 32.8 21.4 19,4 9.4 6 55.6 52.4 44.3 29.5 25.6 14.3 8 21.6 80 69.2 66.3 55.2 37.0 32.0 19.6 81.4 78.9 65 43.9 37.4 24.0 12 32.1 98.7 74.3 50.5 5 Table 6 Time Dissotution of Formulations in 0.3M Phosphate Buffer, pH 6.0 (65.5%
Loading) (h) A B C D E F G H
Free acid Choline Diethanolamine Ethanolamine Metformin Procaine Tris Calcium 0.5 82.9 10.6 10.4 7.8 97 100.2 106.5 -1.7 . .... . . ......_ . . ._. . .... _..._ ..__ ... ...
1 95.6 15.3 15.6 12.3 97.9 101.4 107.0 5.3 .... __ .... .... ......... ................. ........... ............. ....
.........__........_..... .............. ......... . .. .. . ..
............... ....... ... ................ .. . . . .... ................ .
. . .. ..... ... . .....
~._ ....... ..........101....._...........23.8.........
.....__...23.6._..._...... _.........19.9.......... 98.2 101.4 107.0 30.8 _ .. ... ....... ...... ..... ....._.._.. . ._ ...
4 102.9 37.9 36.0 32.0 98.5 101.4 107.2 78.3 _.....: ... .. _ _ .. :_._ _, . ... ,_.: ... .... .._ _. ___._ _ . _ 6 46.3 41.8 98.6 101.4 107.3 89.9 ................. ............................ .................. ......... .
... ............. .... . ............................ .................. . ..
8 103.5 58.6 55.5 50.1 98.7 101.6 107.5 95.3 10 63.8 57.3 98.8 101.8 107.7 98.4 _.__ .. _ ....... _ _ .:__..... __ .. .. __ .. _ ... . _. _,.. ....... _ _ __.. ___ _ _ _.
12 103.8 73.7 98.9 101.7 Applicants also measured the disintegration times of fenofibric acid salt formulations and determined that the more soluble the salt the less disintegration time would be impacted by 10 the ionic strength of the media. The method for measuring disintegration time is presented in Example 4. The disintegration times for the choline fenofibric acid salt, the dicthanolaminc fcnofibric acid salt and fenofibric acid are presented in Table 7.

Example 4 Disintegration Disintegration times were detennined by dropping tablets into a hcatcd (37 C) aqucous media (900 ml 0.05M KH2PO4 pH 6.0 and 900 ml 0.3M KH2PO4 pH 6.0). The tablets were then bobbed up and down at a fixcd rate until they were fully disintegrated, the time for disintegration was recorded in minutes.

Table 7 Disintegration Disintegratioll Tin7e (IT1inUtes) Medium pH 6.0 Choline (B) Diethanolamine (C) Fenofibric acid (A) .3 M phosphate 47 5 39 3.6 11 1 buffer .05 M phosphate 66 1 71t12 486 17 buffer Difference 19 32 475 (minutcs) 11. Salt of Fenofibric Acid Concentration Applicants have discovered that the percentage of the fenofibric acid salt in the formulation also impacts the robustness of the fonnulation. Applicants compared formulations with different pcrccntagcs of fcnofibric 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 dcpict the dissolution curvcs for thc formulations of diffcrcnt concentration active ingredient. Figure 10 shows the release rate of formulations I and K
with 32.5% drug load and Figure 11 shows the release profile of formulations A
and B at 65.5% drug load in dissolution media of high and low ionic strengths.
Applicants discovered that the dissolution profiles of fenofibric acid salt formulations are less affected by the ionic strength at a higher drug load.

Tablc 8 Inaredient Formulations (%0) Intragranular I J K L
Feno acid 49.5 32.75 Feno Choline salt 32.75 Lactose monohydrate 32.75 16 32.75 65.5 Water gs cls cLs qs Extragranular Silicon dioxide 0.5 0.5 0.5 0.5 HPC exf 3 3 3 3 Tablet weight: 275 mg III. Enteric Coatin~

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.
Table 9 Fenofibric acid choline salt (with or without coatin ) Intra-granule Fenofibric Acid Choline Salt 65 Avicci PHIOI 15.75 PVP K30 3.0 Extra- ranules Silicon Dioxide 0.75 Magnesium Stearate 0.5 Coatin o tional Eudragit L30 D55 10.61 Talc 5.31 Trieth l Citrate 1.59 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 fitzrnill 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.
One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The 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 thc scope and spirit of the invention.
All patents and publications mentioned in the specification are indicative of the levels ?0 of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by refercnce to the same extcnt as if each individual publication was specifically and individually indicated to be incorporated by reference.
The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising," "consisting essentially of' and "consisting of' may be replaced with cither of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts hcrein disclosed may bc resorted to by those skillcd in the art, and that such modifications WO 2008/046052 PCTlUS2007/081267 and variations are considered to be within the scope of this invention as defined by the appended claims.

Claims (13)

1. 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.

2. The modified release formulation of claim 1, wherein the solubility of the active agent is at least 19.0 mg/ml in water.

3. 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 intrinsic dissolution rate (IDR) of the active agent is greater than 7.09mg/min/cm2 at a pH of 6.8.

4. The modified release formulation of claims 1 or 3, wherein the hydrophilic polymer matrix is hydroxypropyl methylcellulose.

5. The modified release formulation of claim 3, wherein the IDR is at least 8.05 mg/min/cm2 at a pH of 6.8.

6. A modified release formulation comprising an active agent in a hydrophilic polymer matrix wherein the active agent is a salt of fenofibric acid and further wherein 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.

7. The modified release formulation of claim 1, wherein the percentage of the active agent in the formulation is between 33% and 75%.

8. The modified release formulation according to claim 7, wherein the percentage of active agent in the formulation is between 50% and 75%.

9. The formulation according to claims 7 or 8 wherein the release rate of the formulation is substantially independent of the ionic strength of the dissolution media.

10. 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 difference in disintegration times of the active agent when disintegrated in media of .3M or .05M ionic strength is less than 475 minutes.

11. The modified release formulation of claim 10, 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.

12. 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.

13. The modified release formulation of claim 12, wherein the hydrophilic polymer matrix comprises hydroxypropyl methylcellulose.