WO2001034123A1 - Hmg-coa reductase inhibitor extended release formulation - Google Patents
Hmg-coa reductase inhibitor extended release formulation Download PDFInfo
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- WO2001034123A1 WO2001034123A1 PCT/US2000/030415 US0030415W WO0134123A1 WO 2001034123 A1 WO2001034123 A1 WO 2001034123A1 US 0030415 W US0030415 W US 0030415W WO 0134123 A1 WO0134123 A1 WO 0134123A1
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- lovastatin
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- drug
- controlled release
- plasma concentration
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
Definitions
- HMG-COA reductase inhibitors for the reduction of serum cholesterol levels.
- These compounds include alkyl esters of hydroxy substituted naphthalenes which are orally effective in the reduction of serum cholesterol levels. Examples of these compounds include mevastatin which is described in U.S. 3,671,523; lovastatin which is described in U.S. 4,231,938; pravastatin which is described in U.S. 4,346,227; and simvastatin which is described in U.S. 4,444,784. All of these patents are incorporated by reference.
- Lovastatin is a metabolite which is produced by the natural fermentation of an fungus of the Aspergillus genus. Lovastatin acts systemically to lower blood serum cholesterol levels by disrupting the biosynthesis of cholesterol in the liver, where 70% to 80% of body cholesterol is produced. Specifically lovastatin interrupts a step in the endogenous production of cholesterol by inhibiting the HMG coenzyme A reductase from combining with bile acids in the digestive tract such that the bile acids are excreted from the body without reabsorption. With synthesis in the liver thusly inhibited, the liver cells must take cholesterol from the bloodstream, and they do so by increasing their production of cell surface receptors for LDL cholesterol. Lovastatin formulations are generally capable of lowering the blood serum cholesterol level by about 30-40%. The other compounds of this class are derived from natural or synthetic sources using well known procedures and have similar mechanisms of activity.
- the present invention provides a novel controlled release formulation of a compound which is an alkyl ester of a hydroxy substituted naphthalene derivative which provides for a gradual release of the compound.
- This formulation has been prepared to provide a slow controlled release of these compounds in order to provide a more constant level of bioavailability in order to provide an enhanced effect that cannot be achieved by conventional immediate release dosing.
- the use of a controlled release form of is believed to be specially useful for those who have meals at irregular times or those who frequently eat snacks between meals.
- U.S. 4,615,698 which have been based on an osmotic dosage form which is designed to collapse and cause the faced surfaces to come into a close contacting arrangement as the drug is delivered through a passageway in the semi-permeable wall of the dosage form.
- U.S. 4,503,030 discloses an osmotic dosage form which has a passageway and a semi-permeable membrane consisting of a particular cellulose polymer and a pH-sensitive material which could be an enteric coating material.
- This patent describes the use of 1 : 1 mixtures of a pH sensitive material and cellulose polymer which are applied at a level of about 70% by weight based on the total weight of the osmotic core tablet and coating material.
- a ratio of 0.75 : 1 , and lower, of pH sensitive material to cellulose polymer may be used to provide a stable membrane around an osmotic core tablet at a coating level of 1-4% by weight based on the total weight of the osmotic core tablet and coating material.
- These osmotic tablets will substantially, completely deliver the compound without the need to provide a passageway in the tablet according to the teachings of the prior art.
- the osmotic tablet of the invention will provide higher bioavailability and lower peak plasma drug concentrations than are provided by the same weight of the alkyl ester of a hydroxy substituted naphthalene derivative in a conventional immediate release dosage form.
- the present invention provides a controlled release dosage formulation of an alkyl ester of a hydroxy substituted naphthalene derivative which substantially completely releases said alkyl ester in about 4 to 30 hours in vitro in a Type 2 USP 23 dissolution apparatus in 2% sodium lauryl sulfate, pH buffer to 7.0 at 37° C and 50rpm.
- the present invention provides a novel controlled release formulation of a compound which is an alkyl ester of a hydroxy substituted naphthalene derivative which provides for a gradual release of the compound. This formulation has been prepared to provide a slow controlled release of these compounds in order to provide a more constant level of bioavailability in order to provide an enhanced effect that cannot be achieved by conventional immediate release dosing.
- the invention is in part directed to a controlled release oral solid dosage form for the reduction of serum cholesterol levels in humans comprising a drug comprising an alkyl ester of hydroxy substituted naphthalenes
- the dosage form providing a mean time to maximum plasma concentration (T max ) of the drug which occurs at about 10 to about 32 hours after oral administration to human patients, the dosage form providing a reduction in serum cholesterol levels when administered to human patients on a once-a-day basis.
- T max mean time to maximum plasma concentration
- the invention is further directed to a controlled release oral solid dosage form for the reduction of serum cholesterol levels in humans, comprising a drug comprising an alkyl ester of hydroxy substituted naphthalenes, and a controlled release carrier for the drug, the dosage form providing a substantially complete release of the drug in about 4 to 30 hours in vitro in a
- T max mean time to maximum plasma concentration
- a controlled release oral solid dosage form for the reduction of serum cholesterol levels in humans comprising a drug comprising an alkyl ester of hydroxy substituted naphthalenes, and a controlled release carrier for the drug, the controlled release dosage form providing a dissolution of from about 0% to about 25% drug released after 2 hours; from about 40% to about 85% drug released after 6 hours; and not less than about 75% drug released after 16 hours, when measured in vitro in a Type 2 USP 23 dissolution apparatus in 2% sodium lauryl sulfate, pH buffer to 7.0 at 37° C and 50rpm, and which preferably provides a time to maximum plasma concentration (T max ) of the drug which occurs at about 10 to about 32 hours after oral administration to human patients, the dosage form achieving a reduction in serum cholesterol levels when administered to human patients on a once-a-day basis.
- T max time to maximum plasma concentration
- the controlled release dosage form provides a dissolution of from about 0% to about 20% drug released after 2 hours; from about 50% to about 80% drug released after 6 hours; and not less than about 80% drug released after 16 hours, when measured in vitro in a Type 2 USP 23 dissolution apparatus in 2% sodium lauryl sulfate, pH buffer to 7.0 at 37 °C and 50rpm.
- the controlled release dosage form provides a dissolution of from about 10% to about 15% drug released after 2 hours; from about 65% to about 75% drug released after 6 hours; and not less than about 79% drug released after 16 hours, when measured in vitro in a Type 2 USP 23 dissolution apparatus in 2% sodium lauryl sulfate, pH buffer to 7.0 at 37°C and 50rpm.
- the mean time to maximum plasma concentration of the drug preferably occurs at about 14 to about 24 hours after oral administration.
- the mean time to maximum plasma concentration of total HMG-CoA Reductase Inhibitors preferably occurs at about 13 to about 21 hours after oral administration.
- the controlled release formulations of the invention provide a mean time to maximum plasma concentration of active HMG-CoA
- the controlled release formulations in accordance with the invention provide a mean maximum plasma concentration (C max ) of total HMG-CoA Reductase Inhibitors from about 4.7 ng/ml to about 25.4 ng/ml, preferably from about 10.5 ng/ml to about 17.3 ng/ml, and a mean maximum plasma concentration (C max ) of active HMG-CoA Reductase Inhibitors preferably from about 2.1 ng/ml to about 22.5 ng/ml, preferably 6.4 ng/ml to about 13.4 ng/ml (e.g., based on a 40 mg dose of lovastatin).
- C max mean maximum plasma concentration
- active HMG-CoA Reductase Inhibitors preferably from about 2.1 ng/ml to about 22.5 ng/ml, preferably 6.4 ng/ml to about 13.4 ng/ml (e.g., based on a 40 mg dose of lovastatin).
- the drug is selected from the group consisting of lovastatin, a derivative of lovastatin, an active metabolite of lovastatin, mevastatin, pravastatin, simvastatin, and mixtures thereof.
- the controlled release oral solid dosage form includes lovastatin in an amount of from about 10 to about 80 mg (e.g., 10, 20,
- the formulations preferably provide a maximum plasma concentration (C max ) of lovastatin from about 1 ng/ml to about 8 ng/ml, preferably from about 1.5 ng/ml to about 7.1 ng/ml, and more preferably from about 3 ng/ml to about 4 ng/ml, based on a 40 mg dose of lovastatin (the plasma levels of lovastatin preferably being dose proportional, as described herein in the appended Examples).
- C max maximum plasma concentration
- the controlled release formulations of the invention preferably provide a mean AUC 0 ⁇ , 8hr of lovastatin from about 15 to about 90 ng»hr/ml, more preferably from about 34 to about 77 ng»hr/ml.
- the dosage form preferably provides a mean time to maximum plasma concentration of lovastatin acid at about 5.3 to about 28.7 hours after oral administration, and more preferably at about 13.0 to about 20.9 hours, after oral administration.
- the dosage form provides a mean maximum plasma concentration (C max ) of lovastatin acid from about 1.05 ng/ml to about 7.22 ng/ml, preferably from about 2.50 ng/ml to about 4.90 ng/ml, based on a 40 mg dose of lovastatin.
- the dosage from may provide a mean AUC 0 ⁇ , ghr of lovastatin acid from about 9.96 to about 132.54 ng»hr/ml, preferably from about 47.5 to about 91.2 ng «hr/ml.
- the present invention further relates to a method for reducing serum cholesterol levels in humans, comprising orally administering a drug comprising an alkyl ester of hydroxy substituted naphthalenes in a controlled " release oral solid dosage form which provides a mean time to maximum plasma concentration (T max ) of the drug which occurs at about 10 to about 32 hours after oral administration of said dosage form to human patients, and which achieves an effective reduction in serum cholesterol levels when administered to human patients on a once-a-day basis.
- T max mean time to maximum plasma concentration
- the dosage form provides a mean maximum plasma concentration (C max ) of lovastatin from about 1.5 ng/ml to about 7.1 ng/ml, based on a 40 mg dose of lovastatin (e.g., where the plasma levels and C max of lovastatin is dose proportional), after administration of a single dose to human patients.
- C max mean maximum plasma concentration
- orally administering lovastatin in a controlled release oral solid dosage form provides a mean time to maximum plasma concentration (T max ) which occurs at about 14 to about 24 hours after oral administration of said dosage form to human patients, and a maximum plasma concentration (C max ) of the drug of from about 3 ng/ml to about 4 ng/ml (based on a 40 mg dose of lovastatin), such that the dosage form achieves a reduction in serum cholesterol levels when administered to human patients on a once-a-day basis.
- T max mean time to maximum plasma concentration
- C max maximum plasma concentration
- the present invention further relates to a method for reducing serum cholesterol levels in humans, comprising orally administering a drug comprising an alkyl ester of hydroxy substituted naphthalenes in a controlled release oral solid dosage form to human patients in the morning (e.g., after administration of a single dose of lovastatin), which dosage form provides a mean time to maximum plasma concentration (T max ) at about 11 to about 32 hours after oral administration to human patients, the dosage form achieving a reduction in serum cholesterol levels when administered to human patients on a once-a-day basis.
- a drug comprising an alkyl ester of hydroxy substituted naphthalenes in a controlled release oral solid dosage form
- T max mean time to maximum plasma concentration
- the dosage form when the drug is lovastatin, preferably provides a mean maximum plasma concentration (C max ) of said drug from about 1.5 ng/ml to about 6.9 ng/ml, based on a 40 mg dose of lovastatin.
- C max mean maximum plasma concentration
- the dosage form provides a mean time to maximum plasma concentration (T max ) which occurs at about 16 to about 32 hours after oral administration of a single dose, more preferably at about 22 to about 26 hours after oral administration, and that it further preferably provides a mean maximum plasma concentration (C max ) " of the drug from about 1.5 ng/ml to about 4.5 ng/ml, based on a 40 mg dose of lovastatin, after oral administration of a single dose.
- T max mean time to maximum plasma concentration
- C max mean maximum plasma concentration
- the dosage form When the human patients are adminstered the dosage form in the morning in the fasted state, it is preferred that the dosage form provides a mean time to maximum plasma concentration (T max ) which occurs at about 5.3 to about 17 hours after oral administration of a single dose, more preferably at about 9 to about 13 hours after oral administration, and preferably provides a mean maximum plasma concentration (C max ) of the drug from about 2.9 ng/ml to about 6.9 ng/ml, based on a 40 mg dose of lovastatin, after oral administration of a single dose.
- T max mean time to maximum plasma concentration
- C max mean maximum plasma concentration
- the present invention further relates to a method for reducing serum cholesterol levels in humans, comprising orally administering a drug comprising an alkyl ester of hydroxy substituted naphthalenes in a controlled release oral solid dosage form to human patients at dinner time, which dosage form provides a mean time to maximum plasma concentration (T max ) at about 10.4 to about 20.6 hours after oral administration (e.g., after a single dose), the dosage form achieving a reduction in serum cholesterol levels when administered to human patients on a once-a-day basis.
- T max mean time to maximum plasma concentration
- the dosage form provides a mean maximum plasma concentration (C max ) of said drug from about 1.9 ng/ml to about 4.4 ng/ml, based on a 40 mg dose of lovastatin.
- C max mean maximum plasma concentration
- T max mean time to maximum plasma concentration
- the dosage form provides a mean maximum plasma concentration (C max ) of said drug of about 3 ng/ml, based on a 40 mg dose of lovastatin.
- the present invention further relates to a method for reducing serum cholesterol levels in humans, comprising orally administering a drug comprising an alkyl ester of hydroxy substituted naphthalenes in a controlled release oral solid dosage form to human patients at bedtime, which dosage form provides a mean time to maximum plasma concentration (T max ) which occurs at about 10 to about 23.2 hours after oral administration (e.g., of a single dose) to a population of human patients, the dosage form achieving a reduction in serum cholesterol levels when administered to human patients on a once-a-day basis.
- T max mean time to maximum plasma concentration
- the dosage " form provides a mean maximum plasma concentration (C max ) of said drug from about 1 ng/ml to about 8 ng/ml, based on a 40 mg dose of lovastatin.
- C max mean maximum plasma concentration
- the dosage form provides a mean time to maximum plasma concentration (T max ) which occurs at about 14.2 to about 16.9 hours after oral administration of a single dose, and preferably provides a mean maximum plasma concentration (C max ) of the drug of about 4 ng/ml, based on a 40 mg dose of lovastatin, after oral administration of a single dose.
- the dosage forms of the invention When administered at bedtime, the dosage forms of the invention preferably provide a mean time to maximum plasma concentration (T max ) which occurs at about 10 to about 22 hours after oral administration to human patients at steady- state, preferably at about 12 to about 16 hours, and more preferably at about 14 hours after oral administration.
- T max mean time to maximum plasma concentration
- the dosage form provides a mean maximum plasma concentration (C max ) of said drug from about 3 ng/ml to about 8 ng/ml, more preferably about 5.5 ng/ml, based on a 40 mg dose of lovastatin at steady-state.
- the invention also relates to a method for improving the dose-response relationship achieved via the administration of a statin drug orally administered in immediate release form, comprising orally administering the statin in a controlled release dosage form which provides a mean time to maximum plasma concentration (T max ) of the statin drug which occurs at about 10 to about 32 hours after oral administration to human patients.
- T max mean time to maximum plasma concentration
- administration of the controlled release oral solid dosage forms of the invention achieves an accumulation of lovastatin and its latent and active metabolites at steady-state conditions of about 1.4 to about 2 fold the levels attained by immediate release lovastatin administered once daily.
- the dosage forms of the invention provide increased systemic bioavailability of lovastatin, but at the same time do not provide increased bioavailability of lovastatin acid, active or total inhibitors.
- the invention is further related to a controlled release oral solid dosage form, comprising a therapeutically effective amount of lovastatin, and a controlled release carrier providing delivery of said lovastatin when said dosage form is orally administered to human patients, such that a mean maximum plasma concentration (C max ) of lovastatin from about 1 ng/ml to about 5.5 ng/ml and preferably from about 3 ng/ml to about 5.5 ng/ml is attained, after administration of a single dose or at steady-state in a population of human patients in need of such therapy, per 40 mg dose of lovastatin.
- C max mean maximum plasma concentration
- the invention is further related to a method for reducing serum cholesterol levels in humans, comprising orally administering a controlled release oral solid dosage form containing a therapeutically effective amount of lovastatin which provides a mean maximum plasma concentration (C max ) of lovastatin from about 1 ng/ml to about 5.5 ng/ml, preferably from about 3 ng/ml to about 5.5 ng/ml, after administration of a single dose or at steady-state in a population of human patients in need of such therapy, per 40 mg dose of lovastatin.
- C max mean maximum plasma concentration
- the invention is further related to a method for providing increased systemic bioavailability of lovastatin, while at the same time not increasing the bioavailability of lovastatin acid, active or total inhibitors compared to an immediate release reference standard form of lovastatin, comprising preparing a controlled release oral solid dosage form of lovastatin which comprises a therapeutically effective amount of lovastatin and a sufficient amount of a controlled release carrier such that the controlled release dosage form provides a dissolution of from about 0% to about 25% lovastatin released after 2 hours; from about 40% to about 85% lovastatin released after 6 hours; and not less than about 75% lovastatin released after 16 hours, when measured in vitro in a Type 2 USP 23 dissolution apparatus in 2% sodium lauryl sulfate, pH buffer to 7.0 at 37° C and 50rpm, and such that the dosage form provides a mean time to maximum plasma concentration (T max ) of lovastatin from about 10 to about 32 hours after oral administration to human
- statin encompasses alkyl esters of hydroxy substituted naphthalenes which are orally effective in the reduction of serum cholesterol levels, and includes but is not limited to examples of these compounds described in U.S. 3,671,523 (include mevastatin); compounds described in U.S. 4,231,938 (including lovastatin); compounds described in U.S. 4,346,227 (including pravastatin); and compounds is described in U.S. 4,444,784 (including simvastatin).
- steady state means that the blood plasma concentration curve for a given drug has been substantially repeated from dose to dose of the drug formulation.
- single dose means that the human patient has received a single dose of the drug formulation and the drug plasma concentration has not achieved steady state.
- multiple dose means that the human patient has received at least two doses of the drug formulation in accordance with the dosing interval for that formulation (e.g, on a once a day basis). Patients who have received multiple doses of the controlled release formulations of the invention may but not necessarily have attained steady state drug plasma levels, as the term multiple dose is defined herein.
- the term "morning" as it is used herein with respect to the dosing of the controlled release formulations of the invention means that the controlled release formulation is orally administered early in the day after the patient has awakened from overnight sleep, generally between about 6 a.m. and 11 a.m. (regardless of whether breakfast is eaten at that time, unless so specified herein).
- the term “dinnertime” as it is used herein with respect to the dosing of the controlled release formulations of the invention means that the controlled release formulation is orally administered at a time when dinner is normally eaten (regardless of whether a meal is actually eaten at that time, unless so specified herein), generally between about 4 p.m. and 8 p.m.
- bedtime as it is used herein with respect to the dosing of the controlled release formulations of the invention means that the controlled release formulation is orally administered before the patient goes to bed in the evening, generally between about 8 p.m. and 12 p.m.
- therapeutically effective reduction when used herein is meant to signify that serum cholesterol levels are reduced by approximately the same amount as an immediate release reference standard (e.g., Mevacor ® ) or more, when the controlled release dosage form is orally administered to a human patient on a once-a-day basis.
- FIG.l is a graph of in vitro dissolution data which shows the dissolution profile of the formulation of Example 1 in 2% sodium lauryl sulfate at pH 7.0 in NaH 2 PO 4 buffer in a USP XXII Type II dissolution apparatus at 50 rpm at 37 °C.
- FIG. 2 is a graph of in vitro dissolution data which shows the dissolution profiles of the formulations of Examples 2, 3 and 4 in 2% sodium lauryl sulfate at pH 7.0 in NaH 2 PO 4 buffer in a USP XXII Type II dissolution apparatus at 50 rpm at 37 °C.
- FIG. 3 is a graph of the in- vitro dissolution data which shows the dissolution profiles of Examples 2 and 5-7 under similar conditions as set forth above with respect to Fig. 2.
- FIG. 4 is a graph of the in- vitro dissolution data which shows the dissolution profiles of Examples 8 under similar conditions as set forth above with respect to Fig. 3.
- FIG. 5 is a graph of the in- vitro dissolution data which shows the dissolution profiles of Examples 9 under similar conditions as set forth above with respect to Fig. 3.
- FIG. 12 is a graph of a regression line depicting C max plotted against dose for Study No. 5.
- FIG. 13 is a graph of a regression line depicting AUC 0 _ 48hr plotted against dose for Study No. 5.
- the controlled release dosage form is preferably prepared by combining mevastatin, pravastatin, simvastatin or lovastatin with a pharmaceutically acceptable, water swellable polymer and an osmotic agent into a compressed tablet core having an optional first coating for sealing and protection and a second coating comprising a pH sensitive agent water insoluble polymer.
- Mevastatin, pravastatin, simvastatin and lovastatin are well known compounds that are described in the prior art including the particular patents which have been cited herein. It is also within the scope of the invention to use mixtures of different alkyl esters of hydroxy substituted naphthalenes.
- a pharmaceutically acceptable, water swellable polymer and an osmotic agent are combined with the drug which may be micronized or unmicronized or amorphous or crystalline and compressed to form the tablet core.
- the osmotic agent is any nontoxic pharmaceutically acceptable water soluble compound which will dissolve sufficiently in water and increase the osmotic pressure inside the core of the tablet.
- the osmotic agents include the simple sugars and salts such as sodium chloride, potassium chloride, magnesium sulfate, magnesium sulfate, magnesium chloride, sodium sulfate, lithium sulfate, urea, inositol, sucrose, lactose, glucose, sorbitol, fructose, mannitol, dextrose, magnesium succinate, potassium acid phosphate and the like.
- the preferred osmotic agent for the tablet core is a simple sugar such as anhydrous lactose in the range of 0-50% by weight, based on the weight of the compressed, uncoated tablet.
- the pharmaceutically acceptable, water swellable polymer may be any pharmaceutically acceptable polymer which swells and expands in the presence of water to slowly release the lovastatin.
- These polymers include polyethylene oxide, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and the like.
- the water swellable polymer will be polyethylene oxide (obtained from Union Carbide Corporation under the trade name Polyox WSR Coagulant or Polyox WSR N 80) These materials form a viscous gel in water or other solvent system at a sufficient concentration to control the release of the lovastatin. This will generally require a concentration of the pharmaceutically acceptable, water swellable polymer of about 0-50% by weight of the compressed, uncoated tablet.
- Binder may be employed in a sufficient amount so that when it is combined with a suitable solvent, mixed with the water soluble osmotic agent and agitated, granules will be formed which may be compressed into a tablet core.
- the conventional solid pharmaceutical diluents such as microcrystalline cellulose, lactose, dextrose and the like may be added to the granule forming mixture in amounts from about 0 to 51% weight based on the weight of the compressed, uncoated tablet.
- the above mentioned osmotic agent, lactose may function as a binder in the tablet compression step.
- various solvents may be used to prepare the granules.
- various other diluents, excipients, lubricants, dyes, pigments, dispersants, emulsifiers, etc. may be used to optimize the formulations of the invention.
- a surfactant is used in the preferred embodiment.
- the surfactant may be any ionic or non-ionic water soluble surfactant which may be employed in the range of 0-50% by weight or preferably 1-5% by weight.
- the preferred surfactant for the present formulation is sodium lauryl sulfate but other surfactants such as polysorbate 20, 60 or 80; polyoxl stearate and the like.
- the preferred embodiment may comprise a lubricant.
- the lubricant will be in the range of 0.5 to 2.5% by weight of the compressed, uncoated tablet.
- the above described tablet " core is formed, it is coated with: 1) an optional protective first coating on the tablet core and/or an optional pH sensitive coating; 2) an outer coating comprising a pH sensitive agent and a water insoluble polymer.
- a protective first coating may be used at a level in the range of 0-10% by weight which may be applied from a coating system such as opadry Clear sold by Colorcon Corporation.
- the Opadry Clear will be 2.83% by weight and will be combined with an osmotic agent in the range of 0-10% by weight.
- the osmotic agent may be any salt, low molecular weight molecule or water soluble polymers, the preferred agent is sodium chloride.
- the osmotic agent is added to the coating system when the coating system is being dispersed into purified water.
- the coating system which contains the osmotic agent may then be sprayed onto the tablets to form a protective coating layer.
- this protective first coating is optional.
- An optional inner or over coat over the outer coat may also be applied which comprises a pH sensitive polymer which functions as an enteric polymer in that it does not begin to dissolve until pH conditions in excess of the stomach region are encountered. Generally, the pH sensitive materials do not dissolve and begin to release the active drug until a pH above 3.0 and preferably above 5.5.
- Materials such as such as Eudragit L (copolymer of poly(methacrylic acid, methylmethacrylate), 1 : 1 ratio; MW (No. Av. 135,000 USP Type A) or Eudragit S (copolymer of poly(methacrylic acid, methylmethacrylate, 1:2 ratio MW (No. Av.
- hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate and the like may be used in the range of 0-30% by weight and preferably 2 to 4 percent by weight of the combined weight of the compressed, uncoated tablet and the inner coating of the pH sensitive polymer.
- the outer coating comprises a pH sensitive polymer which functions as an enteric polymer in that it does not begin to dissolve until pH conditions in excess of the pH of the stomach region are encountered and a water insoluble polymer which provide controlled release properties to the coating formulation.
- the pH sensitive polymer is the same type of material that is described above as the optional inner coating layer.
- the water insoluble polymer may be a cellulosic polymer such as ethylcellulose, cellulose acylate, cellulose mono-, di- or triacetate.
- the pH sensitive polymer and the insoluble cellulosic polymer are used at a weight ratio of about 0.1 :1 to 0.75:1, preferably 0.25:1 to 0.5:1 of pH sensitive polymer to water insoluble cellulosic polymer.
- a combined coating weight of about 0.5-5% by weight and preferably 1 to 4% by weight and especially preferred is 1 to 3% by weight of the gained weight based on the weight of the coated tablet core.
- Cellulose acetate is the preferred water insoluble polymer and the outer coating is preferably applied as a suspension in acetone.
- a plasticizer or combination of plasticizers may be added to the inner, outer or over coating to provide elasticity and shape to the coating, while the plasticizer or combination of plasticizers may be any water soluble or water insoluble formulation in the range of 0-10% by weight and preferably 0.5 to 5% by weight of the outer coating composition.
- Acetyltributyl citrate is the preferred plasticizer but materials such as acetyl triethyl citrate, dibutyl phthalate, triacetin, diethyl phthalate, polyethylene glycol, propylene glycol and the like may be utilized.
- An antioxidant such as BHA or BHT may be added to the tablet core as a stabilizer at a level of 0.001 to 0.01% by weight of the tablet core.
- a channelling agent is mixed with the aforementioned components of the outer coating.
- a channelling agent may be employed to increase the porosity of the film coating in order- to increase the amount of the fluids that penetrate the tablet core and increase the rate of hydration. This allows the release of the lovastatin after the outer film coat ruptures.
- channelling agents may be any salts, surfactants, or short-chain water soluble polymers in a water channel forming effective amount i.e. 1 to 5% by weight, based on the total weight of the core and all coating components.
- the channeling agents include any pharmaceutically acceptable water soluble salt, surfactant, or short chain water soluble polymer such as sodium chloride, potassium chloride, sucrose, polysorbate-80, hydroxypropyl cellulose, hydroxyethyl cellulose and the like.
- the preferred embodiment of the inner or over coating is supplied with an anti- sticking agent such as talc to overcome any tablet to tablet stickiness during the coating process.
- an anti-sticking agent such as talc to overcome any tablet to tablet stickiness during the coating process.
- the amount of anti-sticking agent is an amount which prevents sticking which may be in the range of 0-6% by weight based on the weight of the tablets and the coating materials on a dry weight basis.
- the tablets of the invention release the lovastatin by osmotic pressure. Water is drawn into the tablet and it expands to the point where the outer coating fails in one particular area to form a constricted opening which releases the internal contents of the tablet which contain the drug. Thereafter, the aqueous medium of the tablet shell will continue to release the drug as it dissolves until the osmotic pressure inside the tablet shell equals that of the surrounding environment. At the late stages of the in vivo release of lovastatin, it is believed that the tablet shell will collapse and/or disintegrate completely to substantially completely release the remaining drug. The water insoluble coating is not absorbed in the gastrointestinal tract and is eliminated in the feces.
- the tablets of the invention may be made in a smooth faced tablet die. Thereafter the tablet is provided with the outer coating which, because of surface tension, will result in a thinner coating layer over the corners of the tablet which will provide an area in the outer coating which will form a channel to is allow intestinal fluid to reach the core of the tablet.
- the tablets of the invention will have the following general formula:
- controlled release formulations of the present invention i.e., formulations which provide a mean Tmax of the drug (i.e., a HMG-CoA reductase inhibitor) at the desired time after oral administration, e.g., in general, at about 10 to about 32 hours after oral administration to a population ⁇ of human patients, and which preferably provide other pharmacokinetic parameters described herein when orally administered to human patients.
- Such formulations can be manufactured as a controlled oral formulation in a suitable tablet or multiparticulate formulation known to those skilled in the art.
- the controlled release dosage form may optionally include a controlled release carrier which is incorporated into a matrix along with the drug (e.g., HMG-COA reductase inhibitors), or which is applied as a controlled release coating.
- An oral dosage form according to the invention may be provided as, for example, granules, spheroids, beads, pellets (hereinafter collectively refe ⁇ ed to as "multiparticulates") and/or particles.
- An amount of the multiparticulates which is effective to provide the desired dose of opioid over time may be placed in a capsule or may be incorporated in any other suitable oral solid form.
- the controlled release dosage form comprises such particles containing or comprising the active ingredient, wherein the particles have diameter from about 0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about 2 mm.
- suitable multiparticulate formulations are those in which the particles comprise inert beads which are coated with the drug. Thereafter, a coating comprising the controlled release carrier is applied onto the beads.
- a spheronizing agent together with the drug can be spheronized to form spheroids.
- Microcrystalline cellulose is preferred.
- a suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Corporation).
- the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art.
- the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
- the particles comprise normal release matrixes containing the drug. These particles are then coated with the controlled release carrier.
- the controlled release coatings useful in the formulations of the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack- free.
- coatings are provided to permit either pH-dependent or pH-independent release, e.g., when exposed to gastrointestinal fluid.
- a pH-dependent coating serves to release the opioid in desired areas of the gastro-intestinal (GI) tract, e.g., the stomach or small intestine, such that an absorption profile is provided which is capable of providing at least about twelve hour and preferably up to twenty-four hour analgesia to a patient.
- GI gastro-intestinal
- the coating is designed to achieve optimal release regardless of pH- changes in the environmental fluid, e.g., the GI tract. It is also possible to formulate compositions which release a portion of the dose in one desired area of the GI tract, e.g., the stomach, and release the remainder of the dose in another area of the GI tract, e.g., the small intestine.
- Formulations according to the invention that utilize pH-dependent coatings to obtain formulations may also impart a repeat-action effect whereby unprotected drug is coated over the enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract.
- Coatings which are pH- dependent may be used in accordance with the present invention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, and methacrylic acid ester copolymers, and the like.
- the tablet core or multiparticulates containing the drug are coated with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.
- the coating may be applied in the form of an organic or aqueous solution or dispersion.
- the coating may be applied to obtain a weight gain from about 2 to about 25% of the substrate in order to obtain a desired sustained release profile.
- Such formulations are described, e.g., in detail in U.S. Patent Nos. 5,273,760 and 5,286,493, hereby incorporated by reference.
- Other examples of sustained release formulations and coatings which may be used in accordance with the present invention include U.S. Patent Nos.
- the sustained release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like.
- the passageway may be formed by such methods as those disclosed in U.S. Patent Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of which are hereby incorporated by reference).
- the passageway can have any shape such as round, triangular, square, elliptical, i ⁇ egular, etc.
- the desired controlled release of the formulation is achieved via a matrix (either normal or controlled release) having a controlled release coating as set forth above.
- the present invention may also utilize a controlled release matrix that affords in-vitro dissolution rates of the drug within the prefe ⁇ ed ranges and that releases the drug in a pH- dependent or pH-independent manner.
- the materials suitable for inclusion in a controlled release matrix will depend on the method used to form the matrix.
- the controlled release material which may be included in a matrix in addition to the drug includes hydrophilic and/or hydrophobic materials, such as gums, alkylcelluloses, cellulose ethers, acrylic resins, and protein derived materials. This list is not meant to be exclusive, and any pharmaceutically acceptable hydrophobic material or hydrophilic material which is capable of imparting controlled release of the active agent may be used in accordance with the present invention.
- the hydrophobic material is preferably selected from the group consisting of alkylcelluloses, cellulose ethers, acrylic and methacrylic acid polymers and copolymers, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof.
- the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
- acrylic acid and methacrylic acid copolymers methyl
- a spheronizing agent together with the active ingredient can be spheronized to form spheroids.
- Microcrystalline cellulose is prefe ⁇ ed.
- a suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade
- the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxyalkylcelluloses (such as hydroxypropylcellulose) are pre- fe ⁇ ed. Additionally (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
- a water insoluble polymer especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
- a controlled release matrix may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art. The quantities of these additional materials will be sufficient to provide the desired effect to the desired formulation.
- suitable quantities of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms are described in the Handbook of Pharmaceutical Excipients. American Pharmaceutical Association (1986), incorporated by reference herein.
- a portion of the drug may be included in the formulations of the invention in immediate release form.
- the drug may be included in separate normal release matrix particles, or may be co- administered in a different immediate release composition which is either enveloped within a gelatin capsule or is administered separately.
- the particles comprise inert beads which are coated with the drug. Thereafter, a coating comprising the controlled release carrier is applied onto the beads, and then an immediate release drug layer is applied on top of the controlled release coating as an overcoat.
- controlled release tablet formulations in which the controlled release carrier is included in a matrix with the drug or the controlled release carrier is applied in a coating on the surface of the tablet, a portion of the drug may be applied on the surface of the tablet as an immediate release drug layer (as an overcoat if the tablet has a controlled release coating).
- a tablet having the following formula was prepared: lovastatin 11.99wt% 40.0mg
- Eudragit S lOOj 0.34wt% 1.13mg Triacetin 0.08wt% 0.27mg polyethylene glycol 400 0.08wt% 0.27mg sugar, confectioners 6X micronized 0.50wt% 1.66mg 100.0wt%333.66mg
- Hydroxypropyl methylcellulose phthalate 55 1. Dissolve hydroxypropyl methylcellulose phthalate 55 in acetone using a homogenizer.
- FIG. 1 is a graph of in vitro dissolution data which shows the dissolution profile of the formulation of Example 1 in 2% sodium lauryl sulfate at pH 7.0 in NaH 2 PO 4 buffer in a USP
- Lovastatin in these amounts will be particularly effective in inhibiting the biosynthesis of cholesterol in the liver through interruption of HMG coenzyme A reductase.
- the dosage of lovastatin should be individualized depending on the desired and/or degree of serum cholesterol that is desired. Generally 10 to 80mg of lovastatin per day should be administered by mouth depending on the response and the degree of reduction in serum cholesterol level that is indicated.
- Polyox WSR Coagulant NF* 4.54wt% 15.0mg Polyox WSR N 80, NF** 17.71wt% 58.5mg lactose (anhydrous) 51.13wt% 168.9mg sodium lauryl sulfate 3.03t% lO.Omg silicon dioxide Fumed USP/NF 0.45wt% 1.5mg butylated hydroxy anisole 0.03wt% 0.1 Omg Myvaplex 600P*** 1.82wt% 6.0mg
- Eudragit S 100 0.34wt% 1.13mg triacetin 0.08wt% 0.27mg polyethylene glycol 400 0.08wt% 0.27mg sugar, confectioners 6X micronized 0.50wt% 1.66mg
- Coated tablets were prepared using the general procedure of Example 1, except that an indentation was made on the tablet surface.
- Polyox WSR Coagulant NF* 4.57wt% 7.5mg Polyox WSR N 80, NF** 17.84wt% 29.25mg lactose (anhydrous) 51.53wt% 84.5mg sodium lauryl sulfate 3.05wt% 5.0mg silicon dioxide Fumed USP/NF 0.46% 0.75mg butylated hydroxy anisole 0.03wt% 0.05mg Myvaplex 600P*** 1.83wt% 3.0mg * polyethylene oxide Mw No av 5,000,000 ** polyethylene oxide Mw No av 200,000 *** glyceryl monostearate
- Eudragit S 100 1 0.66wt% ' 1.09mg acetyl tributyl citrate 0.32wt% 0.52mg sugar, confectioners 6X micronized 0.98 wt% 1.61 mg
- Coated tablets were prepared using the general procedure of Example 3 except that no inner coating was applied and an outer enteric coating was applied as an overcoat over the outer layer.
- FIG. 2 is a graph of in vitro dissolution data which shows the dissolution profiles of the formulations of Examples 2, 3 and 4 in 2% sodium lauryl sulfate at pH 7.0 in NaH 2 PO 4 buffer in a USP XXII Type II dissolution apparatus at 50 rpm at 37 °C.
- lovastatin should be individualized depending on the desired and/or degree of serum cholesterol that is desired. Generally 10 to 80mg of lovastatin per day should be administered by mouth depending on the response and the degree of reduction in serum cholesterol level that is indicated.
- Examples 5-7 40mg lovastatin tablets were prepared using the general procedure of Example 1. The ingredients of Examples 5-7 are set forth in Table 2 below.
- Example 5 has the same composition as Example 2. However, the tablets of Example 5 do not contain the indentation in the tablet surface that was present in Example 2. Preliminary results of a single-dose study in healthy humans indicated that the indentation in the lovastatin formulation of Example 2 did not improve its pharmacokinetics. Because Example 5 provided the desired safety, efficacy and pharmacokinetic profiles in Studies 1-3 described in detail herein, two more clinical lots were made based on the composition and process of Example 5. Examples 6 and 7 are the two clinical lots made based on the composition of Example 5. A different coater (Glatt coater GPCG3) was used for the manufacturing of these two lots.
- Gaatt coater GPCG3 was used for the manufacturing of these two lots.
- Example 6 Since the new coater had a better coating efficiency, less coating mixtures was required to achieve the same dissolution as that of Example 5. Considering the similarity of the dissolution profiles and the identical coating mixture composition, the "actual composition" of Examples 6 and 7 should be very similar to that of Example 5.
- Example 8 20mg lovastatin tablets were prepared.
- Example 9 lOmg lovastatin tablets were prepared. Both formulations were prepared using the general procedure of Example 1.
- Example 9 The composition of Example 9 is the same as Example 8, except that lOmg of lactose has been used to replace lOmg of drug substance (lovastatin).
- Example 5-9 were evaluated by dissolution testing under the following conditions: USP apparatus 2 (paddles); medium: 2% SLS/sodium phosphate buffer (0.01M), pH 7.0, stir speed 50 ⁇ m, and temperature 37 °C.
- the dissolution profile for Examples 2 and 5-7 are illustrated in Figure 3.
- the dissolution profiles for Examples 3,4 and 8 are illustrated in Figure 4.
- the dissolution profile for Example 9 is illustrated in Figure 5.
- the dissolution profiles of Examples 5-7 and 2 are further provided in Table 4 below.
- the dissolution profiles of Examples 3,4,8 and 9 are further provided in Table 5 below.
- Lovastatin XLTM an immediate release tablet of lovastatin commercially available for more than 10 years (Mevacor ® , Merck & Co., Inc.) was used as a reference standard.
- Study No. 1 was a pharmacokinetics, safety and tolerability open-label, single dose, two-period crossover study of 40 mg Lovastatin XL tablets (Example 5) in comparison to Mevacor. There were 8 healthy male volunteers. The dose of Lovastatin XL and Mevacor was administered at 6:30 p.m., immediately after dinner.
- Study No. 2 was a safety, pharmacokinetics and effect of food open-label, single dose, three-period crossover study comparing Lovastatin XL tablets (Example 5) to Mevacor. There were 9 healthy male volunteers. The dose of Lovastatin XL was administered at 8:00 a.m. (fasting), 8:00 a.m. immediately after breakfast (fed conditions), in comparison to Mevacor administered at 8:00 a.m., immediately after breakfast.
- Study No. 3 examined the safety and pharmacokinetics of Lovastatin XL tablets (Example 5 and Example 2) in an open-label, single-dose, two-period crossover. There were 6 healthy male volunteers. The doses of Lovastatin XL were administered at 8 a.m., immediately after breakfast.
- Study No. 4 was a multiple-dose, safety, tolerability, efficacy, pharmacodynamics and pharmacokinetics single-blind, 4-week active treatment, 2-period cross-over study with a 4- week diet/placebo run-in period in which 40 mg Lovastatin XL tablets (Example 5) were compared to Mevacor 40 mg tablets. Patients had a diet/placebo run-in period of 4 weeks prior to randomization to the active treatment. A total of 24 patients were randomized to receive 40 mg/day of Lovastatin XL, or 40 mg/day of Mevacor once daily in active treatment Period I and was switched to the alternate treatment drug in Period II. The Lovastatin XL tablets were administered on a once-daily basis for 4 weeks at about 10:00 p.m. The Mevacor tablets were administered once daily for 4 weeks at about 6 p.m., immediately after dinner.
- Study No. 5 examined the oral pharmacokinetics, pharmacodynamics and safety of 10 mg, 20 mg and 40 mg Lovastatin XL tablets (Examples 9, 8 and 5, respectively).
- the study design was single-dose, 3-period cross-over, with 8 healthy male volunteers. Each of these dosages were administered at bedtime (about 10:00 p.m.).
- Tables 6 and 7 provide mean pharmacokinetic values (for lovastatin and lovastatin acid, respectively) for both Lovastatin XL and Mevacor for Study Nos. 1-5.
- Table 8 provides mean AUC and C max ratios for the 40mg tablets in Study Nos. 1, 2 and 4.
- Table 9 provides pharmacokinetic data (mean AUC and C max ratios) for Lovastatin XL 40mg doses for Study Nos. 1, 2 and 5.
- Study No. 4 was designed to evaluate the safety, efficacy, pharmadynamics, pharmacokinetics, and tolerability of Lovastatin XL relative to MEVACOR after multiple- dose treatment in patients with fasting plasma LDL-cholesterol levels between 130 and 250 mg/dl and triglyceride levels below 350 mg/dl.
- This study had a single-center, single-blind, randomized, two-way crossover design. Patients had a diet/placebo run-in period of 4 weeks prior to randomization to the active treatment. A total of 24 patients were randomized to receive 40 mg/day of lovastatin to the alternate treatment drag in Period II.
- Table 12 provides the Least Squares Means - % change in LDL-Cholesterol, HDL-Cholesterol, Total Cholesterol and Triglycerides of Study No. 4.
- the increased systemic bioavailability of lovastatin when administered as the XL formulation was not accompanied by increased bioavailability of lovastatin acid, active or total inhibitors.
- the mean plasma concentration-time profiles of these compounds following administration of 40 mg/day of Mevacor for four weeks exhibited immediate-release characteristics. No accumulation was observed with Mevacor.
- Lovastatin XL, at 40 mg daily, produced 41 percent lowering in mean LDL-cholesterol. The magnitude of this reduction was 3.9 percentage points greater (p
- Ratio Lovastatin XL after breakfast/Lovastatin XL without breakfast
- Study No. 5 was conducted in healthy volunteers receiving separately single oral doses of 10, 20 and 40 mg of Lovastatin XL. Results of this study indicated that, as the dose of Lovastatin XL increased from 10 to 40 mg, the AUC 0 . 4ghr and C max values of lovastatin appeared to increase linearly (see results for Study No. 5 depicted in Table 6).
- Figure 12 is a graph of a regression line depicting C max plotted against dose for Study No. 5.
- Figure 13 is a graph of a regression line depicting AUC 0 . 48hr plotted against dose for Study No. 5.
- R Geometric mean ratio of C ⁇ or AUC 0 24hr on Day 28 to that on Day 1
- the eluate was then evaporated to dryness and reconstituted in 50 ⁇ l of mobile phase (sodium acetate in acetonitrile/water).
- the sample was injected onto a SCIEX API Ill-Plus LC/MS/MS equipped with a short C18 HPLC column.
- the peak area of the m/z 421.3-319.3 product ion of lovastatin acid was measured against the m z 407.6-305.0 product ion of the internal standard (mevastatin ⁇ -hydroxyacid) using negative ion MRM mode.
- the peak area of the m/z 427.4-325.0 product ion of lovastatin was measured against the m/z 413,2-311.0 product ion of the internal standard (mevastatin) using positive ion MRM mode. Quantitation was performed using a weighted (1 /concentration 2 ) linear least squares regression line generated from plasma calibration standards. The standard lines for lovastatin and lovastatin acid were linear over the concentration range of 0.1-50 ng/ml. The interday precision and accuracy values were 3.7-24.3% relative standard deviation and within 13%, respectively.
- Concentrations of lovastatin and lovastatin acid in plasma samples from Study Nos. 2- 5 were determined by a LC/MS/MS method. The pH of each plasma sample was adjusted with ammonium formate buffer. Lovastatin, lovastatin acid and their corresponding internal standards (d 5 -lovastatin and d 5 -lovastatin acid) were extracted using SPE cartridges and eluted with 75% methanol followed by acetonitrile. The extract was dried under nitrogen, reconstituted and injected onto a LC/MS/MS.
- the peak area of the m z 423.2 ⁇ 303.2 product ion of lovastatin acid was measured against the m z 428.2-303.2 product ion of the internal standard (d 5 -lovastatin acid) using MRM mode.
- the peak area of the m z 405.2-285.2 product ion of lovastatin was measured against the m/z 410.2-285.2 product ion of the internal standard (d 5 -lovastatin) using MRM mode.
- Quantitation was performed using a weighted (1 /concentration) linear least squares regression line generated from plasma calibration standards.
- the standard lines for lovastatin and lovastatin acid were linear over the concentration range of 0.1-20 ng/ml.
- the interday precision and accuracy values were 6.4-9.3% relative standard deviation and within 7%, respectively.
- An enzymatic assay method was used to determine concentrations of active inhibitors (lovastatin acid + active metabolites of lovastatin) and total inhibitors (lovastatin + lovastatin acid + latent and active metabolites of lovastatin) of HMG-CoA reductase inhibitors in plasma samples from the multiple-dose study [Study No. 4]. An aliquot of each sample was subjected to alkaline hydrolysis to determine the concentration of total inhibitors. Concentrations of active inhibitors were determined in unhydrolyzed samples. The inhibitory activity was measured against lovastatin acid as a standard. Lovastatin acid was used in its ammonium salt form and all results were expressed as nanogram equivalent per milliliter. The standard curves for total and active inhibitors were over the concentration range of 0.5-
- the bioavailability of Lovastatin XL relative to MEVACOR in terms of AUC 0.24hr or AUC 0 . 4ghr ratio of lovastatin, is greater than 100% after single-dose administration. The same is true at steady state. However, the relative bioavailability of Lovastatin XL to MEVACOR at steady state, in terms of AUC 0.24hr ratio of lovastatin acid or active or total inhibitors of HMG-CoA reductase, is close to or less than 100%.
- Lovastatin XL indicates that the systemic exposure of patients to active drug and metabolites of lovastatin as well as total inhibitors of HMG-CoA reductase after administration of Lovastatin XL is not higher than that after administration of MEVACOR.
- Lovastatin XL following a high- fat breakfast decreases the bioavailability of lovastatin acid. 4. As the dose of Lovastatin XL increases from 10 to 40mg, the plasma profiles (including the AUC 0 . 48hr and C max values) of lovastatin appear to increase linearly.
- controlled release oral lovastatin formulations of the invention may be characterized by other pharmacokinetic values which are set forth in the data provided in the appended examples, which data can be readily gleaned by one of ordinary skill in the art reviewing the appended Tables and Figures.
- Such pharmacokinetic values may be derived in part based on parameters such as Cmax (ng/mL); Cmin (ng/mL); Tmax (hr); fluctuation (%o)(expressed as the difference between Cmax and Cmin expressed as a percentage of Cmin); the area under the curve (AUC); and any combination thereof.
- Cmax ng/mL
- Cmin ng/mL
- Tmax hr
- fluctuation %o
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Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
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IL14952400A IL149524A0 (en) | 1999-11-08 | 2000-11-03 | HMG-CoA REDUCTASE INHIBITOR EXTENDED RELEASE FORMULATIONS |
CA002390301A CA2390301A1 (en) | 1999-11-08 | 2000-11-03 | Hmg-coa reductase inhibitor extended release formulation |
AU13607/01A AU768950B2 (en) | 1999-11-08 | 2000-11-03 | HMG-COA reductase inhibitor extended release formulation |
GB0210619A GB2371748B (en) | 1999-11-08 | 2000-11-03 | HMG-COA reductase inhibitor extended release formulation |
DE10085183T DE10085183T1 (en) | 1999-11-08 | 2000-11-03 | Preparation of an HMG-COA reductase inhibitor with prolonged release |
NZ518770A NZ518770A (en) | 1999-11-08 | 2000-11-03 | HMG-COA reductase inhibitor extended release formulation |
HK03100941A HK1050134A1 (en) | 1999-11-08 | 2003-02-07 | Hmg-coa reductase inhibitor extended release formulation. |
AU2004201520A AU2004201520B2 (en) | 1999-11-08 | 2004-04-08 | HMG-COA reductase inhibitor extended release formulations |
Applications Claiming Priority (2)
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US43557699A | 1999-11-08 | 1999-11-08 | |
US09/435,576 | 1999-11-08 |
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PCT/US2000/030415 WO2001034123A1 (en) | 1999-11-08 | 2000-11-03 | Hmg-coa reductase inhibitor extended release formulation |
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CA (1) | CA2390301A1 (en) |
DE (1) | DE10085183T1 (en) |
GB (1) | GB2371748B (en) |
HK (1) | HK1050134A1 (en) |
IL (1) | IL149524A0 (en) |
NZ (1) | NZ518770A (en) |
WO (1) | WO2001034123A1 (en) |
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EP1490029A1 (en) * | 2002-03-22 | 2004-12-29 | Ranbaxy Laboratories, Ltd. | Controlled release drug delivery system of pravastatin |
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EP1817010A2 (en) * | 2004-11-22 | 2007-08-15 | Dexcel Pharma Technologies Ltd. | Controlled absorption of statins in the intestine |
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US9845511B2 (en) | 2013-03-15 | 2017-12-19 | Cedars-Sinai Medical Center | Methods of diagnosis, selection, and treatment of diseases and conditions caused by or associated with methanogens |
US9956292B2 (en) | 2014-08-13 | 2018-05-01 | Cedars-Sinai Medical Center | Anti-methanogenic compositions and uses thereof |
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US10668159B2 (en) | 2014-08-13 | 2020-06-02 | Cedars-Sinai Medical Center | Anti-methanogenic compositions and uses thereof |
US11344501B2 (en) | 2014-08-13 | 2022-05-31 | Cedars-Sinai Medical Center | Anti-methanogenic compositions and uses thereof |
US10736871B2 (en) | 2015-04-01 | 2020-08-11 | Cedars-Sinai Medical Center | Anti-methanogenic lovastatin analogs or derivatives and uses thereof |
US11590102B2 (en) | 2015-04-01 | 2023-02-28 | Cedars-Sinai Medical Center | Anti-methanogenic lovastatin analogs or derivatives and uses thereof |
Also Published As
Publication number | Publication date |
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AU1360701A (en) | 2001-06-06 |
IL149524A0 (en) | 2002-11-10 |
GB2371748B (en) | 2004-12-01 |
NZ518770A (en) | 2004-02-27 |
DE10085183T1 (en) | 2002-10-24 |
CA2390301A1 (en) | 2001-05-17 |
AU768950B2 (en) | 2004-01-08 |
GB2371748A (en) | 2002-08-07 |
HK1050134A1 (en) | 2003-06-13 |
GB0210619D0 (en) | 2002-06-19 |
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