CA2654529A1 - Compositions with controlled pharmacokinetics - Google Patents

Abstract

The invention encompasses methods for reducing food effect in a drug which exhibits such food effect by preparing a formulation comprising a drug which exhibits food effect and at least one biodegradable binder or lipophilic binder. The invention also encompasses a method for preparing a formulation having a target food effect comprising (a) determining a target food effect; and (b) combining an API which exhibits food effect and a sufficient amount of (i) at least one biodegradable binder, (ii) at least one lipophilic binder, or (iii) combinations thereof, to produce a formulation having the target food effect.

Description

COMPOSITIONS WITH CONTROLLED PHARMACOKINETICS
CROSS REFERENCE TO RELATED APPLICATION
[1] This application claims the benefit of U.S. Provisional Patent Application filed July 6, 2006, entitled "Compositions with Controlled Pharmacokinetics," Serial No.
60/819,041, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[2] The invention encompasses compositions which reduce the effect of food on the bioavailability of the active drug ingredient, methods for making such compositions, and methods for reducing the food effect using such compositions.

BACKGROUND OF THE INVENTION

[3] In general, it is known that the absorption and bioavailability of any particular therapeutic agent can be affected by numerous factors when dosed orally. One such factor is the presence of food in the gastrointestinal (GI) tract. Many pharmaceutical compounds reportedly exhibit a food effect. A food effect can be defined as the difference between absorption rates under fast and fed conditions. The food effect may result from interaction between formulation and gastrointestinal environment, drug metabolism or both.
For some drugs the food effect does not affect the pharmacodynamics of the drug. In such cases the drug can be administered under both fed and fast conditions. For other drugs where food effect is critical in the drug's pharmacodynamics, the effect of a drug is greatly affected by whether it is taken with or without food. Therefore, there is a need in the art for the development of a general method to control or reduce the food effect in a drug composition.

[4] Atorvastatin is a member of the class of drugs called statins and can be used as a drug model to illustrate the general concept of the present invention.

[5] Statins are used alone or in combination (for example, with lipid regulating agents of a different mechanism of action (e.g., fenofibrate, ezetimibe, torcetrapib), with calcium ion antagonists or slow-channel blockers (e.g., amlodipine), with ACE
inhibitors (e.g., benazepril), or with salicilates such as aspirin, clopidogrel, pioglitazone, rosiglitazone, or fosinopril. Statin drugs have been used to reduce low density lipoprotein (LDL) particle concentration in the blood stream of subjects.

[6] Atorvastatin is reportedly disclosed in U.S. Patent No. 4,681,893.
Atorvastatin is sold by Pfizer, Inc. in tablet form under the commercial name Lipitor as an HMG-CoA reductase inhibitor and for the treatment of hypercholesterolemia and hyperlipidemia. It has been reported that a food effect is observed in Lipitor, which indicates that the pharmacokinetics of atorvastatin may be affected by food intake. The influence of food on the administration of a single dose of atorvastatin (10 mg or 80 mg) after breakfast or an evening meal reportedly results in a lower Cm... and longer Tm,,,x with little change in extent of absorption compared to fasted volunteers (Radulovie L.L. et al., J. CLIN.
PHARM., 35: 990-4 (1995); Whitfield, L.R. et al., EUR. J. DRUG METAB. PARMACOKINET., 25: 97-101(2000)). It is further reported that the bioavailability of atorvastatin is significantly reduced when taken with meals (9 % decrease in AUC and 25% decrease in Cmzx ) (Physician's Desk Reference, Jul. 2004). In the development of a bioequivalent formulation to Lipitor, a similar and even higher food effect as expressed by higher CmeX values and ratios (relative to Lipitor) in fast (Cmax ratio f.t = Cmax test(f.t) / Cmax reference f.t ) conditions when compared to fed conditions (Cmax ratio fed = Cmax test fed / Cmax referencefed) has been observed. It has been suggested that the food effect of atorvastatin is controlled in Lipitor by use of a specific ingredient, namely calcium carbonate, although the mechanism by which this might occur is not immediately apparent and thus not controllable by a formulator wishing to develop a similar composition.

[7] Various means of affecting bioavailability, including increasing and decreasing bioavailability, have been disclosed in the literature. However, these methods affect (increase or decrease) bioavailability for both fed and fast conditions. As a result, the food effect remains substantially of the same magnitude.

[8] Therefore, one of the main challenges in the development of formulations containing drugs such as atorvastatin is the effect of food on the bioavailability of the drug.
Accordingly, there is a need for formulations and methods of their preparation that effectively reduce the food effect encountered by the administration of such drugs without the use of calcium carbonate.

SUMMARY OF THE INVENTION

[9] The present invention encompasses methods and compositions which decrease the food effect associated with administration of drugs which exhibit such food effect. In one' embodiment, in addition to having a reduced food effect, the bioavailability of the API in a formulation is equivalent to an. FDA-approved formulation for that API.

[10] The invention also encompasses methods and compositions which effectively control the bioavailability of a drug in fed and fast conditions. In certain embodiments, bioavailability is controlled in fed conditions with minimal effect on fast conditions or the bioavailability is controlled in fast conditions with minimal effect on fed conditions. For example, in one embodiment, the bioavailability is decreased in fasted (or fast) conditions with minimal effect on fed conditions and/or is increased in fed conditions with minimal effect on fast conditions.

[11] In one embodiment, the invention encompasses a method for preparing a formulation having a target food effect comprising (a) determining a target food effect; and (b) combining an API which exhibits food effect and a sufficient amount of (i) at least one biodegradable binder, (ii) at least one lipophilic binder, or (iii) combinations thereof, to produce a formulation having the target food effect.

[12] In a preferred embodiment, the method for preparing a formulation having a target food effect comprises (a) providing a formulation comprising an API
that exhibits an initial food effect and (i) at least one biodegradable binder and/or (ii) at least one lipophilic binder; (b) determining a target food effect; and (c) adjusting the amount of the biodegradable binder or the lipophilic binder in the formulation to a sufficient amount to produce an adjusted formulation having the target food effect.
[131 In another preferred embodiment, the method for preparing a formulation having a target food effect comprises (a) determining an initial food effect of a test formulation comprising an API which exhibits food effect and (i) at least one biodegradable binder and/or (ii) at least one lipophilic binder; (b) determining a reference food effect of a reference formulation comprising an API which exhibits food effect; and (c) adjusting the amount of the biodegradable binder and/or the lipophilic binder in the test formulation to a sufficient amount to produce an adjusted formulation having a relative food effect that is bioequivalent to the reference food effect.
[14] In certain embodiments, the formulation has a relative food effect of about 0.8 to about 1.25, preferably about 0.8 to about 1, and more preferably about 1.
[15] In a preferred embodiment, the formulation includes a biodegradable binder, e.g., a biodegradable binder that includes binders degradable by at least one of a gastrointestinal enzyme, protease, lipase or amylase. Preferably, the biodegradable binder includes a binder degradable by a gastrointestinal enzyme. Preferably, the biodegradable binder includes a binder that is degradable at a pH of about 1 to about 7.5, and more preferably at a pH of about 1.3 to about 6.5 or about 1.2 to about 6.5.
[16) Preferably, the biodegradable binder includes at least one protein, lipid, or polysaccharide. Preferably, the biodegradable binder includes at least one of gelatin, ZEIN, ZEIN derivatives, hydrogenated vegetable oil, hydrogenated castor oil, glycerol palmitostearate, glycerol behenate, PEG ester, or starch.
[17] In a preferred embodiment, the formulation includes a lipophilic binder, e.g., a lipaphilic binder that dissolves in lipophilic media, disintegrates in lipophilic media, or both.
Preferably, the lipophilic binder degrades at a pH of about 2 to about 7, and more preferably at a pH of about 1.3 to about 6.5.
[18] Preferably, the lipophilic binder includes at least one of ethylcellulose or a mixture of ethylcellulose with polyethylene glycol, or poloxamer.
[19] In a preferred embodiment, the formulation comprises a total weight of about 0.5% to about 60% by weight, preferably about 0.5% to about 40%, and more preferably about 1% to about 25% of the biodegradable binder and lipophilic binder. Also preferably, the formulation comprises a total weight of about 5% to about 15% or about 10%
to about 25% by weight of the biodegradable binder and lipophilic binder, depending on the type of binder used. .
[20] In one preferred embodiment, the formulation comprises granules and an extra-granular component. Preferably, the biodegradable binder or lipophilic binder is present in the granules and the extra-granular component. Also preferably, the formulation further comprises at least one non-biodegradable binder or non-lipophilic binder. Preferably, the formulation further comprises at least one disintegrant.
[21] In another preferred embodiment, the formulation further comprises at least one of lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1), magnesium aluminum silicate, or sodium stearyl fumarate.
[22] In another preferred embodiment, the formulation comprises lactose, mannitol, croscanmellose sodium, crospovidone, polacerillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1), magnesium aluminum silicate, and sodium stearyl fumarate.
[23] In one embodiment, the API which exhibits food effect includes at least one 3,5 dihydroxy-acid, e.g., atorvastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, or lovastatin.
[24] Some embodiments also encompass a pharmaceutical composition comprising at least one 3,5 dihydroxy-acid, preferably one that exhibits a food effect, and at least one of a biodegradable binder or lipophilic binder. Preferred 3,5 dihydroxy-acids include atorvastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, or lovastatin.
[25] In one embodiment, the pharmaceutical composition comprises at least one 3,5 dihydroxy-acid and at least one of a biodegradable binder or lipophilic binder, wherein the food effect exhibited by the 3,5 dihydroxy-acid is reduced, e.g., by at least about 10 percent, at least about 20 percent, at least about 50 percent, or at least about 100 peroent compared to an otherwise identical pharmaceutical composition comprising the 3,5 dihydroxy-acid in the absence of a biodegradable binder or a lipophilic binder.
1261 In another embodiment, the pharmaceutical composition comprises at least one 3,5 dihydroxy-acid and about 0.5% to about 60% by weight total of at least one of a biodegradable binder or lipophilic binder.
[27] In one embodiment, the pharmaceutical composition has a relative food effect of about 0.8 to about 1.25, about 0.8 to about 1, or about 1. Preferably, the food effect exhibited by the API is reduced compared to an otherwise identical pharmaceutical composition comprising the API in the absence of a biodegradable binder or a lipophilic binder.
[28] Preferably, the formulation includes a biodegradable binder, e.g., a biodegradable binder including a binder degradable by at least one of a gastrointestinal enzyme, protease, lipase or amylase. More preferably, the biodegradable binder includes a binder degradable by a gastrointestinal enzyme. Preferably, the biodegradable binder includes a binder that is degradable at a pH of about 1 to about 7.5, and more preferably about 1.3 to about 6.5.
[29] In one preferred embodiment, the biodegradable binder includes at least one protein, lipid, or polysaccharide. Preferably, the biodegradable binder includes at least one of gelatin, ZEIN, ZEIN derivatives, hydrogenated vegetable oil, hydrogenated castor oil, glycerol palmitostearate; glycerol behenate, stearoyl macrogolglycerides, or starch.
[30] In another embodiment, the formulation includes a lipophilic binder, e.g., a lipophilic binder that dissolves in lipophilic media, disintegrates in lipophilic media, or both.
Preferably, the lipophilic binder degrades at a pH of about 2 to about 7, and more preferably about 1.3 to about 6.5.
[31] In one preferred embodiment, the lipophilic binder includes at least one of ethylcellulose, a mixture of ethylcellulose and polyethylene glycol, or poloxamer.
[32] In a preferred embodiment, the pharmaceutical composition comprises a total weight of about 0.5% to about 60% by weight, preferably about 0.5% to about 40%, and more preferably about 1% to about 25% of the biodegradable binder and lipophilic binder.
Also preferably, the formulation comprises a total weight of about 5% to about 15% or about 10% to about 25% by weight of the biodegradable binder and lipophilic binder, depending on the type of binder used.
[33] In another preferred embodiment, the pharmaceutical composition comprises granules and an extra-granular component. In another preferred embodiment, the biodegradable binder or lipophilic binder is present in the granules and the extra-granular component.
[34] In one preferred embodiment, the pharmaceutical composition further comprises at least one non-biodegradable binder or non-lipophilic binder. In another preferred embodiment, the pharmaceutical composition further comprises at least one disintegrant.
[35] In one embodiment, the pharmaceutical composition comprises at least one of lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1), magnesium aluminum silicate, or sodium stearyl fumarate.
Preferably, the pharmaceutical composition comprises lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1), magnesium aluminum silicate, and sodium stearyl fumarate.
[36] The invention also encompasses pharmaceutical compositions and formulations of the invention having a relative food effect that is reduced by at least about 10 percent, at least about 20 percent, at least about 50 percent, or at least about 100 percent compared to an otherwise identical pharmaceutical composition comprising the API in the absence of a biodegradable binder or a lipophilic binder.
[37] The present invention encompasses formulations prepared by the methods of the invention, and methods for treating a medical disease by administering these formulations to a manunal in need thereof.
DESCRIPTION OF THE FIGURES
[38] Figure 1. In vitro dissolution rates of Example 1 in simulated fast (Fast Model 1) vs. fed condition (Fed Model 1).

[39] Figure 2: In vitro dissolution rates of Examples 1 and 2 with and without pepsin in simulated fed condition (Fed Model 2).
[40] Figure 3. In vitro dissolution rates of Example 3 in simulated fast (Fast Model 1) vs. fed condition (Fed Model 1).

DETAILED DESCRIPTION OF THE INVENTION
1411 The present invention encompasses methods and formulations for effectively reducing the food effect associated with administration of drugs which exhibit such food effect, preferably without need for the use of calcium carbonate as an agent for reducing food effect. Specifically, the present invention is directed to drugs which exhibit a food effect, particularly ones where bioavailability in fed conditions are lower when compared with bioavailability in fast conditions. The present invention also encompasses drug combination products exemplified by the above-mentioned drugs, where the second drug in the combination may or may not exhibit a similar or any food effect.
[42] As used herein, a "food effect" refers to the difference between the absorption rate under fast condition and the absorption rate under fed condition and is defined herein as Cmaxfed / Cmaxr,,,t. Thus, a food effect is exhibited where Cmaxfed / Cmaxfast is less than or greater than 1.
[43] The term "relative food effect" is defined as Cmax ratiored / Cmax ratiof.t.
[44] The term "Cmax ratiored" means the Cmaxfed of the test formulation divided by the Cmaxrea of the reference formulation. Likewise, the term "Cmax ratior"'t"
means the Cmaxrast of the test formulation divided by the Cmaxf.t of the reference formulation.
[45] For example, a formulation that is bioequivalent to a reference formulation (e.g. Lipitor(b) would have a relative food effect that is about 0.8 to about 1.25, preferably about 0.8 to about 1, and more preferably about 1. If the relative food effect is less than 1, the formulation will have a lower food effect than the reference formulation.
A formulation with a relative food effect greater than 1 will exhibit a higher food effect than the reference product (e.g. Lipitor ).
[46] As used herein, the phrase "percent change in food effect" is based on the difference betweeri the initial food effect and 1. For example, a food effect of 1.2 is said to be reduced by 10 percent if the adjusted food effect is 1.18, which is calculated as follows:
1.2-[(1.2- 1) x 10 fo)]= 1.2-0.02= 1.18.

[47] As used herein in connection with a measured quantity, the term "about"
refers to that variation in the measured quantity as would be expected by the skilled artisan performing or interpreting the measurement and exercising a level of care commensurate with the objective of the measurement and the precision of the measuring equipment being used.
[48] The bioavailability of a drug depends on its absorption rate. Absorption rate can be affected, for example, by the type of drug being administered, the contents in the stomach (including the type and amount of food present), and the dissolution rate of the formulation. It has now been discovered that the use of a biodegradable and/or lipophilic binder markedly decreases the in-vitro dissolution rate of the formulation in dissolution media simulating fast conditions, while only exhibiting a minimal effect on the dissolution rate in dissolution media stimulating fed conditions and containing degradation enzymes.
Therefore, the difference between the absorption rates at fast and fed conditions can be reduced by the addition of a biodegradable and/or lipophilic binder.
[49] In preferred formulations encompassed by the present invention, typically the bioavailability, as evidenced by in-vitro dissolution rate, in simulated fasted conditions is affected more than that in fed conditions. With this new finding, one can therefore control substantially independently the bioavailability in fed and fast conditions. As a result, the invention allows for a decrease in food effect for drugs that exhibit such food effect. The invention further allows for the control of the bioavailabilities in fed and fast conditions for bioequivalent formulations of known preparations.
[50] Accordingly, the present invention encompasses methods and formulations for effectively controlling, e.g., reducing, the food effect associated with administration of drugs which exhibit such food effect. In one embodiment, the invention encompasses a method for reducing food effect in a drug which exhibits such food effect by preparing a formulation comprising a drug which exhibits food effect and at least one biodegradable binder or lipophilic binder, wherein the food effect of the API is reduced.
[51] In one embodiment, the invention encompasses a method for preparing a formulation having a target food effect comprising (a) determining a target food effect; and (b) combining an API which exhibits food effect and a sufficient amount of (i) at least one biodegradable binder, (ii) at least one lipophilic binder, or (iii) combinations thereof, to produce a formulation having the target food effect.
[52] As used herein the term "sufficient amount" refers to an amount sufficient to accomplish the desired purpose, e.g., making a formulation having a target food effect.

[53] In a preferred embodiment, the method for preparing a formulation having a target food effect comprises (a) providing a formulation comprising an API
that exhibits an initial food effect and (i) at least one biodegradable binder and/or (ii) at least one lipophilic binder; (b) determining a target food effect; and (c) adjusting the amount of the biodegradable binder or the lipophilic binder in the formulation to a sufficient amount to produce an adjusted formulation having the target food effect..
[54] In another preferred embodiment, the method for preparing a formulation having a target food effect comprises (a) determining an initial food effect of a test formulation comprising an API which exhibits food effect and (i) at least one biodegradable binder and/or (ii) at least one lipophilic binder; (b) determining a reference food effect of a reference formulation comprising an API which exhibits food effect; and (c) adjusting the amount of the biodegradable binder and/or the lipophilic binder in the test formulation to a sufficient amount to produce an adjusted formulation having a relative food effect that is bioequivalent to the reference food effect.
[55] In one embodiment, the adjusted formulation has a relative food effect of about 0.8 to about 1.25, about 0.8 to about 1, or about 1.
1561 Generally, preferred binders for use in this invention are those that break down preferentially in the "fed mode" as compared to the "fast mode." Thus, it should be possible to analyze a composition comprising a binder candidate by conducting an in vitro disintegration test of a tablet of the composition in the medium used below to simulate the fed mode and a disintegration test of the tablet of the composition in the medium used below to simulate the fasted mode. A significantly faster disintegration time in the fed mode medium as compared with the fast mode medium would indicate that such a binder is a suitable candidate for use in the preferred embodiments of the invention.
[57] Preferably, the biodegradable binder includes binders degradable by at least one of a gastrointestinal enzyme, protease, lipase or amylase. More preferably, the biodegradable binder includes a binder degradable by a gastrointestinal enzyme. Also preferably, the biodegradable binder includes a binder that is degradable at a pH of about 1 to about 7.5, and preferably about 1.3 to about 6.5 or about 1.2 to about 6.5.
[58] Binders are commonly used in pharmaceutical formulations. Their primary role is to provide adhesion and tablet hardness (mechanical strength).
Different binders have different binding properties and are typically characterized by their packing rate, consolidation and compressibility behavior, which lead to differences in a drug's dissolution rate. The binding capacity is determined by the amount of the binder used, the nature of the binder, i.e., by binding per unit weight of the binder and by the binder addition technique, e.g., wet and dry granulation, spray drying, or mixing.
[591 The methods and formulations of the present invention comprise the use of at least one biodegradable binder, particularly binders degraded by gastric enzymes, or lipophilic/hydrophobic binders. Preferably, the biodegradable binder is a polymeric binder.
Also preferably, the biodegradable binder is degradable by enzymes capable of decreasing their molecular weight by cleavage. Examples for such enzymes include pepsin, lipase, trypsin, chymotrypsin, elastase, carboxypeptidase, and amylase. Particularly preferred binders are those degradable by the enzymes pepsin and/or lipase. Particularly preferred binders are those degradable at a pH of about 1 to about 7.5, which can be encountered in the stomach or just distal thereto. Lipophilic binders, on the other hand, have the capability of faster drug release in lipophilic media at a pH of about 2 to about 7, e.g., about 1.3 to about 6.5.
[60] Examples of suitable biodegradable binders include proteins, such as gelatin and ZE1N, ZE1N derivatives (such as COZEEN, VPP), lipids, e.g., hydrogenated vegetable oil, hydrogenated castor oil, glycerol palmitostearate (Precirol ATO5), glycerol behenate (Compritol 888 ATO) and stearoyl macrogolglycerides (e.g., Gelucire 50/13)).
Also preferably, the biodegradable binder includes polysaccharides such as starch and its derivatives (e.g. Contramid) such as chitosan.
[61] Preferably, the lipophilic binder is dissolved in lipophilic media, disintegrated in lipophilic media, or both. Preferably, the lipophilic binder includes at least one of ethylcellulose or a mixture of ethylcellulose with polyethylene glycol, or poloxamer.
Preferably, the lipophilic binder includes at least one of ethylcellulose alone or with polymers such as polyethylene glycol, HPMC, or poloxamer (e.g., 124), proteins such as ZEIN and COZEEN, lipids, e.g., hydrogenated vegetable oil, hydrogenated castor oil, glycerol palmitostearate (Precirol ATO5), glycerol behenate (Compritol 888 ATO), or stearoyl macrogolglycerides (e.g., Gelucire 50/13). More preferably, the lipophilic binder includes ethylcellulose alone or with polymers for example as a mixture with polyethylene glycol, HPMC, or poloxamer (e.g., 124), proteins such as ZEIN and COZEEN, lipids, e.g., hydrogenated vegetable oil, hydrogenated castor oil, glycerol palmitostearate (Precirol ATO5), glycerol behenate (Comprito1888 ATO), and stearoyl macrogolglycerides (e.g., Gelucire 50/13). In addition to their use as binders, the biodegradable and/or lipophilic excipients of the invention can also be used as coating agents, lipophilic matrix formers (AAPS, PharmSciTech, 2003;4(3) and AAPS, PharmSciTech, 2001;2(2)), emulsifying agents, lubricants, disintegrants, diluents, solubilizing agents (U.S. Pat.
No. 6,923,988), or stabilizing agents. The funetionality of these excipients is dependent on their concentrations and the manufacturing process involved. In addition, under certain conditions these excipients can also be used as sustained release binders and matrix formers.
[62] The formulations of the invention preferably comprise about 0.5% to about 60% by weight of the biodegradable binder or lipophilic binder. More preferably, the formulation comprises a total weight about 0.5% to about 40% by weight, and more preferably 1% to about 25% by weight of the biodegradable binder and lipophilic binder.
Preferably, the formulation comprises a total weight about 5% to about 15% or about 10% to about 25% by weight of the biodegradable binder and lipophilic binder, depending on the type of binder used.
[63] In a preferred embodiment, the nature and amount of the binder are such that the degradation of the binder takes place primarily in the stomach at fed conditions. Fed conditions in the stomach are characterized by a highly lipophilic environment with increased pepsin and lipase activity. A suitable binder for use in the invention can be determined by conducting an in vitro disintegration test of a tablet composition containing a particular binder in the medium used herein to simulate the fed mode, and a disintegration test of a tablet composition in the medium used below to simulate the fast mode. A
significantly shorter disintegration time in the fed mode medium compared with the fast mode medium indicates that the binder in question will be suitable for use in this invention.
[64] Preferably, the formulation further comprises at least one non-biodegradable binder or non-lipophilic binder. In order to adjust the bioavailability as desired, additional excipients such as non-biodegradable binders and disintegrants may also be added. Hence, while the food effect is decreased by the use of a biodegradable and/or lipophilic binder, the addition of an appropriate amount a suitable disintegrant can increase the bioavailability in both fast and fed conditions. Similarly, the bioavailability can be reduced for both fed and fast conditions by adding or increasing the content of a non-biodegradable and non-lipophilic binder.
[65] Accordingly, one can control the bioavailability in fed conditions with minimal effect on fast conditions, and/or control the bioavailability in fast'conditions with minimal effect on fed conditions. For example, one can decrease the bioavailability in fast conditions with minimal effect on fed conditions, or increase the bioavailability in fed conditions with minimal effect on fast conditions.

[66] . While the invention is suitable for any formulation where control of bioavailability is desired or needed, it is particularly suitable for drugs exhibiting undesired food effect. The present invention is suitable for drugs showing a food effect, preferably drugs where bioavailability in fed conditions are lower compared with that in fast conditions.
Preferably, the drug which exhibits food effect includes at least one 3,5 dihydroxy-acid.
Preferably, the drug includes at least one of atorvastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, or lovastatin.
[67] In a preferred embodiment, the formulation comprises granules and an extra-granular component. The binder used can be present both intra-granularly and extra-granularly. More preferably, the biodegradable binder or lipophilic binder is present in the granules and/or as an extra-granular component. The formulations of the invention can be prepared, for example, by dry mixing, wet granulation, spray granulation, or a combination thereof.
[68] The formulations of the invention may also include other excipients which are not particularly biodegradable or lipophilic, such as acacia, alginic acid, carbomer (e.g.
carbopol), carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel ) hydroxypropyl methyl cellulose (e.g. Methocel ), liquid glucose, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. Povidone PVP K-30, Kollidon , Plasdone ), pregelatinized starch, and sodium alginate, croscarmellose sodium (e.g. Ac Di Sole, Primellose ), crospovidone (e.g.
Kollidon , Polyplasdone ), microcrystalline cellulose, polacrilin potassium, powdered cellulose, sodium starch glycolate (e.g. Explotabg, Primoljelg) colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, mineral oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
[69] In a preferred embodiment, the formulation further comprises at least one of lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose (e.g. Avicel), hydroxypropyl cellulose (Klucel), povidone (e.g.
PVP K-30), magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-dimethylaminoetliyl)methacrylate-rnethylrriethacrylate copolymer (1':2:1) ( Eudragit E), magnesium aluminum silicate, or sodium stearyl fumarate. In another preferred embodiment, the adjusted formulation comprises lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1), magnesium aluminum silicate, and sodium stearyl fumarate.
[701 Some embodiments also encompass a pharmaceutical composition comprising at least one 3,5 dihydroxy-acid, preferably one that exhibits a food effect, and at least one of a biodegradable binder or lipophilic binder. Preferred 3,5 dihydroxy-acids include atorvastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, or lovastatin.
[71] In one embodiment, the pharmaceutical composition comprises at least one 3,5 dihydroxy-acid and at least one of a biodegradable binder or lipophilic binder, wherein the food effect exhibited by the 3,5 dihydroxy-acid is reduced, e.g., by at least about 10 percent, at least about 20 percent, at least about 50 percent, or at least about 100 percent, compared to an otherwise identical pharmaceutical composition comprising the 3,5 dihydroxy-acid in the absence of a biodegradable binder or a lipophilic binder.
[721 In a preferred embodiment, the pharmaceutical composition has a relative food effect of about 0.8 to about 1.25, about 0.8 to about 1, or preferably about 1. Preferably, the relative food effect exhibited by the API is reduced compared to an otherwise identical pharmaceutical composition comprising the API in the absence of a biodegradable binder or a lipophilic binder. For example, the relative food effect can be reduced by at least about 10 percent, at least about 20 percent, at least about 50 percent, or at least about 100 percent compared to an otherwise identical pharmaceutical composition comprising the API in the absence of a biodegradable binder or a lipophilic binder.
[73] In another embodiment, the pharmaceutical composition comprises at least one 3,5 dihydroxy-acid and about 0.5% to about 60% by weight total of at least one of a biodegradable binder or lipophilic binder.
[74) Preferably, the biodegradable binder includes binders degradable by at least one of a gastrointestinal enzyme, protease, lipase or amylase. More preferably, the biodegradable binder includes a binder degradable by a gastrointestinal enzyme. Preferably, the biodegradable binder includes a binder that is degradable at a pH of about 1 to about 7.5, and more preferably about 1.3 to about 6.5 or about 1.2 to about 6.5.
[75) In one preferred embodiment, the biodegradable binder includes at least one protein, lipid, or polysaccharide. Preferably, the biodegradable* binder includes at least one of gelatin, ZEIN, ZEIN derivatives, hydrogenated vegetable oil, hydrogenated castor oil, glycerol palmitostearate, glycerol behenate, stearoyl macrogoiglycerides, or starch.

[761 In another embodiment, the lipophilic binder dissolves in lipophilic media, disintegrates in lipophilic media, or both. Preferably, the lipophilic binder degrades at a pH
of about 2 to about 7, and more preferably about 1.3 to about 6.5.
[77] In one preferred embodiment, the lipophilic binder includes at least one of ethylcellulose, a mixture of ethylcellulose and polyethylene glycol, or poloxamer.
[78] In a preferred embodiment, the pharmaceutical composition comprises about 0.5% to about 60% by weight, preferably about 0.5% to about 40%, and more preferably about 1% to about 25% of the biodegradable binder or lipophilic binder. Also preferably, the formulation comprises about 5% to about 15% or about 10% to about 25% by weight of the biodegradable binder or lipophilic binder, depending on the type of binder used.
[79] In another preferred embodiment, the pharmaceutical composition comprises granules and an extra-granular component. In another preferred embodiment, the biodegradable binder or lipophilic binder is present in the granules and the extra-granular component.
[801 - In one preferred embodiment, the pharmaceutical composition further comprises at least one non-biodegradable binder or non-lipophilic binder. In another preferred embodiment, the pharmaceutical composition further comprises at least one disintegrant.
[81] In one embodiment, the pharmaceutical composition comprises at least one of lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1), magnesium aluminum silicate, or sodium stearyl fumarate.
Preferably, the pharmaceutical composition comprises lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1), magnesium aluminum silicate, and sodium stearyl fumarate.
[82] The present invention encompasses formulations prepared by the methods of the invention, and methods for treating a medical disease by administering these formulations to a mammal in need thereof.
[83] The formulations of the invention are preferably in solid dosage form, and more preferably in the form of a tablet. Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g.
carbopol), carboxymethylcellulose sodium, dextrin, ethylcellulose, , guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel ), hydroxypropyl methyl cellulose (e.g.
Methocel ), liquid glucose, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g.
Povidone PVP K-30, Kollidon , PlasdoneS), pregelatinized starch, sodium alginate and starch.
[84] A compacted solid pharmaceutical composition may also include the addition of a disintegrant to the composition. Disintegrants include croscarmellose sodium (e.g. Ac-Di-Sol , Primellose ), crospovidone (e.g. Kollidon , Polyplasdone ), microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate (e.g. Explotab , Primoljel ) and starch.
[851 Glidants can be added to improve the flowability of pre-compacted or un-compacted solid compositions and to improve the accuracy of dosing during compaction and capsule filling. Suitable glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, and talc.
[86] A lubricant can also be added to reduce adhesion and/or ease the release of the product from, for example, dyes and punches. Suitable lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
[87] Other excipients which may be incorporated into the formulation include preservatives and/or antioxidants. One of ordinary skill in the art will appreciate that any other excipient commonly used in the pharmaceutical industry may be used.
[88] Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the analysis and processes for making the invention.
It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
[89] The following examples illustrate of concept of the invention using atorvastatin compositions containing gelatin as the biodegradable binder and hydrogenated castor oil as the biodegradable/lipophilic binder. The compositions were tested with in-vitro dissolution models simulating fast and fed conditions at 37 C using USP Paddle Method. The models are distinguished by lipophilicity and by enzyme content as follows:
= Fast Model 1: Hydrophilic medium (buffer phosphate pH 7.5, 700 ml, 80 rpm) with pancreatin. This model is intended as a simulation of intestinal environment under fast condition.
= Fed Model 1: Hydrophobic-lipophilic medium (oil in water emulsion, pH 6.0, 700 ml, 80 rpm) with pancreatin. This model is intended as a simulation of intestinal environment under fed condition.
= Fed Model 2: Hydrophobic medium (milk, eggs, HCI, sesame oil, pH 2.3, 780 ml) with pepsin. This model is intended as a simulation of gastric environment under fed condition.
[90] When a formulation with only 4% gelatin used as a biodegradable binder was tested in dissolution media simulating fast and fed conditions, no effect with gelatin on food effect was observed (Figure 1). However, testing this formulation using the fed model including pepsin (Fed Model 2) showed that gelatin in the formulation could fiuiction as a biodegradable binder (Figure 2). A significant effect on the dissolution rate was observed in the presence of pepsin in fed conditions. Thus, increasing the content of gelatin increases the dissolution rate of fed condition more than the fast condition. As exemplified below, compositions with hydrogenated castor oil resulted in significantly reduced dissolution in fast condition, whereas higher dissolution was observed with lipophilic media simulating fed conditions. It is expected that the behavior observed in in vitro testing will be reflected when tested under in vivo conditions.
Example 1 Prenaration of a Gelatin Formulation Ingredient Amount (mg/dose) %
Part I
Mannitol SD 200 709.5 74.8 Atorvastatin 82.9 8.7 Crospovidone XL-10 20.0 2.1 PVP k-30 32.0 3.4 Magnesium carbonate 12.0 1.3 Granulation solution 1 Alcohol 95%
Vitamin E TPGS 24.0 2.5 Granulation solution 2 Gelatin 38.0 4 water Part II
Crospovidone XL-10 20.0 2.1 Part III
Sodium Stearyl fumarate = 9.6 1.0 Theoretical end weight 948.0 Step 1: The ingredients in Part I were thoroughly blended in a high shear mixer.
Step 2: The blend of Part I was granulated by adding granulation solution 1(alcohol 95% containing melted vitamin E (TPGS)). The resulting granules were dried in a fluidized bed drier (Mini Glatt) and sized through a 0.8 mm aperture screen (Frewitt oscillating granulator).
Step 3: The granules from Step 2 were granulated with granulation solution 2 (33%
gelatin solution in water (w/w) prepared by dissolving gelatin in water at 50-60 C and mixing with a magnetic stirrer). The gelatin solution (50 C) was added to the dry granulates from Step 2 in a high shear mixer with continuous mixing. The resulting granules were dried in a fluidized bed drier and sized through a 1.5-mm aperture screen.
Step 4: The ingredients in Part II were blended with the granules from Step 3.
Step 5: The ingredients in Part III were blended with the blend of Step 4. The final blend was compressed to tablets. The composition was tested under dissolution media simulating the GI conditions in fast and fed states. Although a combination of high shear mixer and fluidized bed drier were used, it is equally possible for all granulation and drying to be in a fluidized bed drier or for that matter a high shear mixer that has an integral drying mechanism.
[91] The results, illustrated in Figure 1, show that the amount of gelatin in Example 1 seems to have no significant effect on the dissolution in fast (Fast Model 1) or fed conditions (Fed Model 1). When tested in dissolution media simulating the gastric condition in fed mode, i.e., including pancreatin (Fed Model. 1, Figure 1), the dissolution of Example I
was as high as in the fast mode. Thus, no significant difference was observed between fast and fed conditions in a formula containing only 4% gelatin.
[92] When tested in dissolution media simulating the gastric condition in fed mode, ' i.e., including pepsin (Fed Model 2, Figure 2), the dissolution of Example 1 exhibits high dissolution similar to the comparative conventional formula without gelatin (control Example 2, having a Cm... of 113% in fed as compared to Lipitor). Therefore, gelatin is "transparent"

to fed conditions, meaning that the addition of gelatin does not effect the rate of dissolution in the fed mode. In addition, it can be seen that the drug release of Example 1 was enzyme mediated, as lower dissolution was observed in the absence of pepsin from the media (Figure 2). Because gastric conditions in the fast state include a significantly lower pepsin concentration, it is reasonable to assume that a higher percentage content of gelatin in the composition, above 6 percent for example, should have a slower dissolution in the fasted state while remaining constant in the fed state which includes higher pepsin levels.
[93] Therefore, in order to see an in vivo advantage of fed over fast conditions a tune up of the biodegradable binder content (gelatin) should be performed. For example, one can increase the gelatin content in a composition to a concentration threshold over which the dissolution/ in vivo bioavailability in fast conditions will be decreased, without affecting the dissolution/ in vivo bioavailability in fed conditions. This is illustrated by the effect of pepsin on the dissolution rate for gelatin-containing tablets. See Fig. 2.
Example 2 (Control) Preparation of Formulation Without Gelatin Ingredient Amount (mg/dose) %
Part I
Mannitol SD 200 709.5 73.9 Atorvastatin 82.9 8.6 Crospovidone XL-10 20.0 2.1 PVP k-30 32.0 3.3 Dibasic Ca Phosphate 50.0 5.2 Granulation solution 1 Alcoho195%
Vitamin E TPGS 24.0 2.5 Tris in water 12.0 1.3 Part .II
Crospovidone XL-10 20.0 2.1 Part III
Sodium Stearyl fumarate 9.6 1.0 Theoretical end weight 960.0 Step 1: The ingredients in Part I were thoroughly blended.
Step 2: The blend of Part I was granulated by adding granulation solution 1(a mixture of 95% alcohol containing melted vitamin E(TPGS) and Tris in water). The resulting granules were dried in a fluidized bed drier (Mini Glatt) and fitted with a 1.0 mm aperture screen (Frewitt oscillating granulator).
Step 3: The ingredients in Part II were blended with the granules of Step 2.

Step 4: The ingredients in Part III were blended with the blend of Step 3. The final blend was compressed to tablets. The composition was tested under dissolution media simulating the GI conditions in fed states (Fed Model 2) including pepsin (Figure 2).
Example 3 Preparation of a Hydrogenated Castor Oil Formulation [94] This example illustrates how the rate of dissolution in the fast mode can be reduced without influencing the dissolution rate in the fed mode by using an ingredient such as hydrogenated castor oil.
Ingredient Amount m dose %
Part I
Mannitol SD 200 709.5 60_4 Atorvastatin 82.9 7.1 Crospovidone XL-10 20.0 1.7 PVP k-30 16.0 1.4 Dibasic Calcium phosphate 50.0 4.3 Granulation solution #1 Tris-base in water 12.0 1.0 Vitamin E TPGS in alcohol 24.0 2.0 95%
Part II
Hydrogenated castor oil 230 20 Part III
Crospovidone XL-10 20.0 1.7 Part IV
Sodium Stearyl fumarate 9.6 0.8 Theoretical end weight 1174.0 Step 1: The ingredients in Part I were thoroughly blended.
Step 2: The blend of Part I was granulated by adding granulation solution 1(a mixture of 95% alcohol containing melted vitamin E (TPGS) and Tris in water). The resulting granules were dried in a fluidized bed drier (Mini Glatt) and sized through a 1 mm aperture screen (Frewitt oscillating granulator).
Step 3: The ingredients in Part II were blended with the dry granules from Step 2.
Step 4: The ingredients in Part III were blended with the blend from Step 3.
Step 5: The ingredients in Part IV were blended with the blend from Step 4.
The mixture was then compressed into tablets (the mixture alternatively could be filled into capsules).

[95] The composition of Example 3 containing 20% hydrogenated castor oil by weight of the total tablet was tested in a dissolution media simulating GI
conditions in fast (Fast Model 1) and fed states (Fed Model 1), as shown in Figure 3.
[96] Figure 3 shows that the presence of hydrogenated castor oil markedly decreases the dissolution in the fast condition. The reduction in the dissolution rate for the fast mode in Example 3 was greater than is probably required to achieve a lack of food effect, but this example shows how the rate of dissolution in the fast mode can be manipulated without a significant affect on the fed mode rate of dissolution. However, when tested in dissolution media simulating the fed condition of lipophilic media containing pancreatin (Fed Model 1), a higher dissolution was observed. Thus, the use of hydrogenated castor oil as a binder has a significant effect on the dissolution rate of the fast condition compared to the fed conditions and therefore reduction in food effect was observed to the extent that the food effect has been reversed.

Example 4 Preparation of a Hydrogenated Castor Oil Formulation of Atorvastatin with Amlodipine Ingredient Amount (mg/dose) %
Part I
Mannitol SD 200 709.5 61.9 Atorvastatin 82.9 7.2 Crospovidone XL-10 20.0 1.7 PVP k-30 16.0 1.4 Magnesium carbonate 12.0 1.0 Granulation solution 1 Vitamin E TPGS in alcohol 24.0 2.0 95%
Part II
Crospovidone XL-10 20.0 1.7 Part III
Amlodipine Besylate 13.9 1.2 Microcrystalline cellulose 60.0 5.2 Croscarmellose sodium 60.0 5.2 Hydrogenated castor oil 116 10.1 Colloidal Si02 1.0 0.087 Part IV
Sodium Stearyl fumarate 10.0 0.8 Theoretical end weight 1144.9 Step 1: The ingredients in Part I are thoroughly blended.
Step 2: The blend of Part I is granulated by adding granulation solution 1(a mixture of 95% alcohol containing melted vitamin E-TPGS). The resulting granules are dried in a Mini Glatt and milled with Frewit (1 mm).
Step 3: The ingredients in Part II are blended with the dry granules from Step 2.
Step 4: The ingredients in Part III are blended with the blend from Step 3.
Step 5: The ingredients in Part IV are blended with the blend from Step 4 to form a final composition, and the mixture is compressed into tablets.

Claims (62)

1. A method for preparing a formulation having a target food effect comprising (a) determining a target food effect; and (b) combining an API which exhibits food effect and a sufficient amount of (i) at least one biodegradable binder, (ii) at least one lipophilic binder, or (iii) combinations thereof, to produce a formulation having the target food effect.

2. The method of claim 1 comprising: (a) providing a formulation comprising an active pharmaceutical ingredient that exhibits an initial food effect and (i) at least one biodegradable binder, (ii) at least one lipophilic binder, or (iii) combinations thereof; (b) determining a target food effect; and (c) adjusting the amount of the biodegradable binder, the lipophilic binder, or both in the formulation to a sufficient amount to produce an adjusted formulation having the target food effect.

3. The method of claim 1 comprising: (a) determining an initial food effect of a test formulation comprising an active pharmaceutical ingredient which exhibits food effect and (i) at least one biodegradable binder, (ii) at least one lipophilic binder, or (iii) combinations thereof; (b) determining a reference food effect of a reference formulation comprising an active pharmaceutical ingredient which exhibits food effect; and (c) adjusting the amount of the biodegradable binder, the lipophilic binder, or both in the test formulation to a sufficient amount to produce an adjusted formulation having a relative food effect that is bioequivalent to the reference food effect.

4. The method of claim 3, wherein the adjusted formulation has a relative food effect of about 0.8 to about 1.25.

5. The method of claim 4, wherein the adjusted formulation has a relative food effect of about 0.8 to about 1.

6. The method of claim 5, wherein the adjusted formulation has a relative food effect of about 1.

7. The method of any one of claims 1-6, wherein the formulation comprises a biodegradable binder including a binder degradable by at least one of a gastrointestinal enzyme, protease, lipase or amylase.

8. The method of any one of claims 1-7, wherein the formulation comprises a biodegradable binder including a binder degradable by a gastrointestinal enzyme.

9. The method of any one of claims 1-8, wherein the formulation comprises a biodegradable binder including a binder that is degradable at a pH of about 1 to about 7.5.

10. The method of any one of claims 1-9, wherein the formulation comprises a biodegradable binder including a binder that is degradable at a pH of about 1.3 to about 6.5.

11. The method of any one of claims 1-10, wherein the formulation comprises a biodegradable binder including at least one protein, lipid, or polysaccharide.

12. The method of any one of claims 1-11, wherein the formulation comprises a biodegradable binder including at least one of gelatin, ZEIN, ZEIN
derivatives, hydrogenated vegetable oil, hydrogenated castor oil, glycerol palmitostearate, glycerol behenate, PEG ester, or starch.

13. The method of any one of claims 1-12, wherein the formulation comprises a lipophilic binder dissolving in lipophilic media, disintegrates in lipophilic media, or both.

14. The method of any one of claims 1-13, wherein the formulation comprises a lipophilic binder degrading at a pH of about 2 to about 7.

15. The method of any one of claims 1-14, wherein the formulation comprises a lipophilic binder including a binder that is degradable at a pH of pH of about 1.3 to about 6.5.

16. The method of any one of claims 1-15, wherein the formulation comprises a lipophilic binder including at least one of ethylcellulose or a mixture of ethylcellulose with polyethylene glycol, or poloxamer.

17. The method of any one of claims 1-16, wherein the formulation comprises about 0.5% to about 60 % by weight total of the biodegradable binder and lipophilic binder.

18. The method of any one of claims 1-17, wherein the formulation comprises about 0.5% to about 40 % by weight total of the biodegradable binder and lipophilic binder.

19. The method of any one of claims 1-18, wherein the formulation comprises about 1% to about 25 % by weight total of the biodegradable binder and lipophilic binder.

20. The method of any one of claims 1-19, wherein the formulation comprises about 5% to about 15% of total the biodegradable binder and lipophilic binder.

21. The method of any one of claims 1-20, wherein the formulation comprises about 10% to about 25% of total the biodegradable binder and lipophilic binder.

22. The method of any one of claims 1-21, wherein the formulation comprises granules and an extra-granular component.

23. The method of any one of claims 1-22, wherein the biodegradable binder or lipophilic binder is present in the granules and the extra-granular component.

24. The method of any one of claims 1-23, wherein the formulation further comprises at least one non-biodegradable binder or non-lipophilic binder.

25. The method of any one of claims 1-24, wherein the formulation further comprises at least one disintegrant.

26. The method of any one of claims 1-25, wherein the formulation further comprises at least one of lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1), magnesium aluminum silicate, or sodium stearyl fumarate.

27. The method of any one of claims 1-26, wherein the formulation comprises lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1), magnesium aluminum silicate, and sodium stearyl fumarate.

28. The method of any one of claims 1-27, wherein the active pharmaceutical ingredient which exhibits food effect includes at least one 3,5 dihydroxy-acid.

29. The method of any one of claims 1-28, wherein the active pharmaceutical ingredient which exhibits food effect includes at least one atorvastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, or lovastatin.

30. The method of any one of claims 1-29, wherein the active pharmaceutical ingredient which exhibits food effect includes atorvastatin.

31. A formulation prepared by the method of claims 1-30.

32. A pharmaceutical composition comprising at least one 3,5 dihydroxy-acid and at least one of a biodegradable binder or lipophilic binder, wherein the food effect exhibited by the 3,5 dihydroxy-acid is reduced compared to an otherwise identical pharmaceutical composition comprising the 3,5 dihydroxy-acid in the absence of a biodegradable binder or a lipophilic binder.

33. A pharmaceutical composition comprising at least one 3,5 dihydroxy-acid and about 0.5% to about 60% by weight total of at least one of a biodegradable binder or lipophilic binder.

34. The pharmaceutical composition of any one of claims 32 or 33, wherein the 3,5 dihydroxy-acid is at least one atorvastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, or lovastatin.

35. The pharmaceutical composition of any one of claims 32-34, wherein the 3,5 dihydroxy-acid is atorvastatin.

36. The pharmaceutical composition of any one of claims 32-35 having a relative food effect of about 0.8 to about 1.25.

37. The pharmaceutical composition of any one of claims 32-36 having a relative food effect of about 0.8 to about 1.

38. The pharmaceutical composition of any one of claims 32-37 having a relative food effect of about 1.

39. The pharmaceutical composition of any one of claims 32-38, wherein the food effect exhibited by the 3,5 dihydroxy-acid is reduced by at least about 10 %
compared to an otherwise identical pharmaceutical composition comprising the 3,5 dihydroxy-acid in the absence of a biodegradable binder or a lipophilic binder.

40. The pharmaceutical composition of any one of claims 32-39 comprising a biodegradable binder including a binder degradable by at least one of a gastrointestinal enzyme, protease, lipase or amylase.

41. The pharmaceutical composition of any one of claims 32-40 comprising a biodegradable binder including a binder degradable by a gastrointestinal enzyme.

42. The pharmaceutical composition of any one of claims 32-41 comprising a biodegradable binder including a binder that is degradable at a pH of about 1 to about 7.5.

43. The pharmaceutical composition of any one of claims 32-42 comprising a biodegradable binder including a binder that is degradable at a pH of about 1.2 to about 6.5.

44. The pharmaceutical composition of any one of claims 32-43 comprising a biodegradable binder including at least one protein, lipid, or polysaccharide.

45. The pharmaceutical composition of any one of claims 32-44 comprising a biodegradable binder including at least one of gelatin, ZEIN, ZEIN
derivatives, hydrogenated vegetable oil, hydrogenated castor oil, glycerol palmitostearate, glycerol behenate, stearoyl macrogolglycerides, or starch.

46. The pharmaceutical composition of any one of claims 32-45 comprising a lipophilic binder that dissolves in lipophilic media, disintegrates in lipophilic media, or both.

47. The pharmaceutical composition of any one of claims 32-46 comprising a lipophilic binder that degrades at a pH of about 2 to about 7.

48. The method of any one of claims 32-47 comprising a lipophilic binder including a binder that is degradable at a pH of about 1.2 to about 6.5.

49. The pharmaceutical composition of any one of claims 32-48 comprising a lipophilic binder including at least one of ethylcellulose, a mixture of ethylcellulose and polyethylene glycol, or poloxamer.

50. The pharmaceutical composition of any one of claims 32 or 34-49 comprising about 0.5% to about 60% by weight total of the biodegradable binder and lipophilic binder.

51. The pharmaceutical composition of any one of claims 32-50 comprising about 0.5% to about 40% by weight total of the biodegradable binder and lipophilic binder.

52. The pharmaceutical composition of any one of claims 32-51 comprising about 1% to about 25% by weight total of the biodegradable binder and lipophilic binder.

53. The pharmaceutical composition of any one of claims 32-52 comprising about 5% to about 15% by weight total of the biodegradable binder and lipophilic binder.

54. The pharmaceutical composition of any one of claims 32-53 comprising about 10% to about 25% by weight total of the biodegradable binder and lipophilic binder.

55. The pharmaceutical composition of any one of claims 32-54 comprising granules and an extra-granular component.

56. The pharmaceutical composition of any one of claims 32-55, wherein the biodegradable binder or lipophilic binder is present in the granules and the extra-granular component.

57. The pharmaceutical composition of any one of claims 32-56 further comprising at least one non-biodegradable binder or non-lipophilic binder.

58. The pharmaceutical composition of any one of claims 32-57 further comprising at least one disintegrant.

59. The pharmaceutical composition of any one of claims 32-58 comprising at least one of lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1), magnesium aluminum silicate, or sodium stearyl fumarate.

60. The pharmaceutical composition of any one of claims 32-59 comprising lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1:2:1), magnesium aluminum silicate, and sodium stearyl fumarate.

61. The pharmaceutical composition of any one of claims 32-60 having a relative food effect that is reduced by at least about 10 percent compared to compared to an otherwise identical pharmaceutical composition comprising the 3,5 dihydroxy-acid in the absence of a biodegradable binder or a lipophilic binder.

62. A method for treating a medical disease by administering the formulation of any one of claims 31 or 32-61 to a mammal in need thereof.