Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods

Definitions

• 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.
• 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.
• 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.
• LDL low density lipoprotein
• 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 C max and longer T max with little change in extent of absorption compared to fasted volunteers (Radulovie L.L.
• the present invention encompasses methods and compositions which decrease the food effect associated with administration of drugs which exhibit such food effect.
• the bioavailability of the API in a formulation is equivalent to an FDA-approved formulation for that API.
• the invention also encompasses methods and compositions which effectively control the bioavailability of a drug in fed and fast conditions.
• 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.
• 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.
• 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.
• 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.
• 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.
• the formulation has a relative food effect of about 0.8 to about 1.25, preferably about 0.S to about 1, and more preferably about 1.
• 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.
• the biodegradable binder includes a binder degradable by a gastrointestinal enzyme.
• 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.
• the biodegradable binder includes at least one protein, lipid, or polysaccharide.
• 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.
• the formulation includes a lipophilic binder, e.g. , a lipophilic binder that dissolves in lipophilic media, disintegrates in lipophilic media, or both.
• a lipophilic binder e.g. , a lipophilic binder that dissolves in lipophilic media, disintegrates in lipophilic media, or both.
• 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.
• the lipophilic binder includes at least one of ethylcellulose or a mixture of ethylcellulose with polyethylene glycol, or poloxamer.
• 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.
• the formulation comprises granules and an extra-granular component.
• the biodegradable binder or lipophilic binder is present in the granules and the extra-granular component.
• the formulation further comprises at least one non-biodegradable binder or non-lipophilic binder.
• the formulation further comprises at least one disintegrant.
• 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.
• the formulation comprises lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, b ⁇ tylmethacrylat-(2-dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1 :2:1), magnesium aluminum silicate, and sodium stearyl fumarate.
• the API which exhibits food effect includes at least one 3,5 dihydroxy-acid, e.g., atorvastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, or lovastatin.
• atorvastatin e.g., fluvastatin, rosuvastatin, pravastatin, simvastatin, or lovastatin.
• 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.
• 3,5 dihydroxy-acids include atorvastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, or lovastatin.
• 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.
• 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.
• 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.
• 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.
• 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.
• the biodegradable binder includes at least one protein, lipid, or polysaccharide.
• 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.
• the formulation includes a lipophilic binder, e.g., a lipophilic binder that dissolves in lipophilic media, disintegrates in lipophilic media, or both.
• a lipophilic binder e.g., a lipophilic binder that dissolves in lipophilic media, disintegrates in lipophilic media, or both.
• the lipophilic binder degrades at a pH of about 2 to about 7, and more preferably about 1.3 to about 6.5.
• the lipophilic binder includes at least one of ethylcellulose, a mixture of ethylcellulose and polyethylene glycol, or poloxamer.
• 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.
• the pharmaceutical composition comprises granules and an extra-granular component.
• the biodegradable binder or lipophilic binder is present in the granules and the extra-granular component.
• 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.
• 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.
• 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.
• 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.
• 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.
• Figure 1 In vitro dissolution rates of Example 1 in simulated fast (Fast Model 1) vs. fed condition (Fed Model 1).
• Figure 2 In vitro dissolution rates of Examples 1 and 2 with and without pepsin in simulated fed condition (Fed Model 2).
• 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.
• 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.
• 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/ Cmaxfast- Thus, a food effect is exhibited where Cmaxf e d/ Cmax ⁇ t is less than or greater than 1.
• Cmax ratio f ed means the Cmaxfe d of the test formulation divided by the Cmaxfed of the reference formulation.
• Cmax ratio fas t means the Cmax fast of the test formulation divided by the Cmaxf ⁇ st of the reference formulation.
• a formulation that is bioequivalent to a reference formulation 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®).
• 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.
• the bioavailability as evidenced by in-vitro dissolution rate, in simulated fasted conditions is affected more than that in fed conditions.
• 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.
• 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.
• 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.
• 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.
• the term "sufficient amount” refers to an amount sufficient to accomplish the desired purpose, e.g., making a formulation having a target food effect.
• 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.
• 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.
• 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.
• preferred binders for use in this invention are those that break down preferentially in the "fed mode" as compared to the "fast mode.”
• 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.
• 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.
• 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.
• 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.
• the biodegradable binder is a polymeric binder.
• 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.
• 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.
• biodegradable binders include proteins, such as gelatin and ZEIN, ZEIN 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)).
• the biodegradable binder includes polysaccharides such as starch and its derivatives (e.g. Contramid) such as chitosan.
• the lipophilic binder is dissolved in lipophilic media, disintegrated in lipophilic media, or both.
• the lipophilic binder includes at least one of ethylcellulose or a mixture of ethylcellulose with polyethylene glycol, or poloxamer.
• 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) 5 or stearoyl macrogolglycerides (e.g., Gelucire 50/13).
• 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) 5 or stearoyl macrogolglycerides (e.
• 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 (Compritol 888 ATO), and stearoyl macrogolglycerides (e.g., Gelucire 50/13).
• 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 (Compritol 888 ATO), and stearoyl macrogolglycerides (
• 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.
• lipophilic matrix formers AAPS, PharmSciTech, 2003;4(3) and AAPS, PharmSciTech, 2001 ;2(2)
• emulsifying agents emulsifying agents
• lubricants disintegrants
• diluents diluents
• solubilizing agents U.S. Pat. No. 6,923,988
• stabilizing agents U.S. Pat. No. 6,923,988
• 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.
• 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.
• the formulation further comprises at least one non-biodegradable binder or non-lipophilic binder.
• additional excipients such as non-biodegradable binders and disintegrants may also be added.
• a suitable disintegrant can increase the bioavailability in both fast and fed conditions.
• 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.
• 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.
• the drug which exhibits food effect includes at least one 3,5 dihydroxy-acid.
• the drug includes at least one of atorvastatin, fluvastatin, rosuvastatin, pravastatin, simvastatin, or lovastatin.
• 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.
• 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.
• 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
• Explotab®, Primoljel® 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.
• 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- dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1 :2:1) ( Eudragit ® E), magnesium aluminum silicate, or sodium stearyl fumarate.
• lactose lactose
• mannitol mannitol
• crospovidone crospovidone
• polaccrillin potasium e.g. Avicel
• hydroxypropyl cellulose Kerel
• povidone e.g. PVP K-30
• magnesium carbonate e.g. PVP K-30
• the adjusted formulation comprises lactose, mannitol, croscarmeliose sodium, crospovidone, polaccrillin potasium, microcrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacrylat-(2- dimethylaminoethy ⁇ methacrylate-methylmethacrylate copolymer (1:2:1), magnesium aluminum silicate, and sodium stearyl fumarate.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• the biodegradable binder includes at least one protein, lipid, or polysaccharide.
• 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.
• the lipophilic binder dissolves in lipophilic media, disintegrates in lipophilic media, or both.
• the lipophilic binder degrades at a pH of about 2 to about 7, and more preferably about 1.3 to about 6.5.
• the lipophilic binder includes at least one of ethylcellulose, a mixture of ethylcellulose and polyethylene glycol, or poloxamer.
• 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.
• the pharmaceutical composition comprises granules and an extra-granular component.
• the biodegradable binder or lipophilic binder is present in the granules and the extra-granular component.
• 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.
• the pharmaceutical composition comprises at least one of lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, macrocrystalline 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.
• the pharmaceutical composition comprises lactose, mannitol, croscarmellose sodium, crospovidone, polaccrillin potasium, macrocrystalline cellulose, hydroxypropyl cellulose, povidone, magnesium carbonate, vitamin E TPGS, butylmethacryIat-(2- dimethylaminoethyl)methacrylate-methylmethacrylate copolymer (1 :2:1), magnesium aluminum silicate, and sodium stearyl fumarate.
• 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.
• 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®, Plasdone®), pregelatinized starch, sodium alginate and starch.
• povidone e.g. Povidone PVP K-30, Kollidon®, Plasdone®
• pregelatinized starch sodium alginate and starch.
• 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.
• 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.
• 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.
• excipients which may be incorporated into the formulation include preservatives and/or antioxidants.
• preservatives and/or antioxidants include preservatives and/or antioxidants.
• 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).
• granulation solution 1 alcohol 95% containing melted vitamin E (TPGS)
• TPGS melted vitamin E
• 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 0 C and mixing with a magnetic stirrer). The gelatin solution (50 0 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.
• granulation solution 2 33% gelatin solution in water (w/w) prepared by dissolving gelatin in water at 50-60 0 C and mixing with a magnetic stirrer).
• the gelatin solution (50 0 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.
• Example 1 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 C max 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).
• 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.
• 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).
• granulation solution 1 a mixture of 95% alcohol containing melted vitamin E (TPGS) and Tris in water.
• TPGS melted vitamin E
• Tris Tris in water
• 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).
• Step 1 The ingredients in Part I were thoroughly blended.
• Step 2 The blend of Part I was granulated by adding granulation solution l(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).
• granulation solution l a mixture of 95% alcohol containing melted vitamin E (TPGS) and Tris in water.
• TPGS melted vitamin E
• Tris Tris in water
• 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.
• FIG. 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.
• dissolution media simulating the fed condition of lipophilic media containing pancreatin (Fed Model 1)
• a higher dissolution was observed.
• 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
• 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).
• granulation solution 1 a mixture of 95% alcohol containing melted vitamin E -TPGS.
• 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.

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