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WO2000033821A1 - Preparation a base de billes de pravastatine a enrobage enterique - Google Patents

Preparation a base de billes de pravastatine a enrobage enterique Download PDF

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Publication number
WO2000033821A1
WO2000033821A1 PCT/US1999/028375 US9928375W WO0033821A1 WO 2000033821 A1 WO2000033821 A1 WO 2000033821A1 US 9928375 W US9928375 W US 9928375W WO 0033821 A1 WO0033821 A1 WO 0033821A1
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WO
WIPO (PCT)
Prior art keywords
pravastatin
beads
formulation
enteric coating
enteric
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1999/028375
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English (en)
Inventor
Yacoub S. Habib
Ismat Ullah
Nemichand B. Jain
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Filing date
Publication date
Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Priority to AU21610/00A priority Critical patent/AU2161000A/en
Publication of WO2000033821A1 publication Critical patent/WO2000033821A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds

Definitions

  • the present invention relates to an enteric coated pravastatin formulation, which is in the form of beads, which includes pravastatin, which is sensitive to a low pH environment of less than 3; optionally a basifying agent ,- and an enteric coating, and optionally an antiadherent coating, such formulation being resistant to acid degradation of pravastatin in the stomach but releases pravastatin at pH's greater than 4 as found in the small intestine.
  • Enteric coatings have long been used to inhibit release of drug from tablets and beads and/or prevent the leakage of acid to the inside of the bead or tablet containing acid labile drug.
  • the enteric coatings are resistant to stomach acid and depending on the composition and/or thickness thereof, they begin to dissolve and allow for the release of drug in the intestines.
  • Some examples of coatings previously employed are beeswax and glyceryl onostearate; beeswax, shellac and cellulose; and cetyl alcohol, mastic and shellac as well as shellac and stearic acid (U.S. Patent No. 2,809,918); polyvinylacetate and ethyl cellulose (U.S. Patent No .
  • HPMCP Hydroxypropylmethyl cellulose phthalate
  • HPMCP as its totally neutralized form (treated with sodium hydroxide) as an enteric coating applied from aqueous systems.
  • Aqueous systems are preferred due to environmental concerns and flammability/explosion concerns with solvents.
  • compositions which include a medicament which is unstable in an acidic environment such as the stomach will require an enteric protective coating to prevent release of such medicament prior to reaching the intestines .
  • Pravastatin an HMG CoA reductase inhibitor disclosed in U.S. Patent No. 4,346,227 to Terahara et al and having the formula
  • pravastatin is sensitive to a low pH environment and is very unstable at pH 3 or less as found in the stomach.
  • the primary degradation product of pravastatin is the inactive isomer 3- ⁇ -hydroxy-isopravastatin as disclosed by J. Triscari et al, "Gastrointestinal Absorption of Pravastatin in Healthy Subjects", J. Clin. Pharmacol., 1995; 35:142-144.
  • the acid instability of pravastatin reduces its bioavailability and results in degradation of pravastatin and formation of significant levels of the inactive isomer 3- ⁇ -hydroxy- isopravastatin in the serum following oral administration of pravastatin. It has also been found that pravastatin is absorbed rapidly from immediate release dosage forms with the major absorption site being the upper intestines, that is the duodenum.
  • U.S. Patent No. 4,661,162 to Kurihara et al discloses an enteric soluble pharmaceutical dosage form which includes an active ingredient surrounded by a membrane which is formed of a mixture of an enteric-soluble polymer and a polyanionic polymer which is soluble in or permeable to a liquid having a pH greater than or equal to 2.
  • the active ingredient may be "the sodium salt of M-4 carboxylic acid, an anti-hyperlipidemic agent described in U.S. Patent No. 4,346,227.”
  • the polyanionic polymer may be alginic acid, polypectinic acid or carboxymethyl cellulose.
  • the enteric- soluble polymer may be among others methyl acrylate/methacrylic acid copolymers and methyl methacrylate/methacrylic acid copolymers.
  • Japanese Patent Application (Kokai) No. 62-263124 discloses a pravastatin formulation which includes one or more (1) low molecular weight acids, (2) polyanionic polymers, and (3) enteric macromolecules, but not containing both a polyanionic polymer and an enteric macromolecule .
  • the low molecular weight acid may be phosphoric acid, fumaric acid, tartaric acid, citric acid, malic acid, succinic acid, phthalic acid and vitamin C.
  • the enteric macromolecule may be among others methyl acrylate/methacrylic acid copolymers and methyl methacrylate/methacylic acid copolymers.
  • pravastatin compositions which have good stability in an acidic environment and thus enhanced storage stability.
  • the pravastatin compositions include a basifying agent (such as magnesium oxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide) to ensure acceptable storage stability, and may include a coating layer which includes one or more film-formers or binders such as hydroxypropylmethyl cellulose, ethyl cellulose, cellulose acetate and the like, and one or more plasticizers such as diethyl phthalate.
  • a basifying agent such as magnesium oxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide
  • a coating layer which includes one or more film-formers or binders such as hydroxypropylmethyl cellulose, ethyl cellulose, cellulose acetate and the like, and one or more plasticizers such as diethyl phthalate.
  • U.S. Patent No. 5,225,202 to Hodges et al discloses an enteric coated pharmaceutical composition which is formed of a core which includes a medicament which is sensitive to a low pH environment of less than 3 (such as pravastatin) , a disintegrant or swelling agent, a buffering agent (such as magnesium oxide, calcium or magnesium hydroxide, as well as others) and an enteric coating surrounding the core which coating includes a neutralized form of hydroxypropylmethyl cellulose phthalate and plasticizers (such as diethyl phthalate, polyethylene glycol as well as others) and an anti-adherent (in the case of coating of pellets) such as talc.
  • a medicament which is sensitive to a low pH environment of less than 3
  • a disintegrant or swelling agent such as magnesium oxide, calcium or magnesium hydroxide, as well as others
  • a buffering agent such as magnesium oxide, calcium or magnesium hydroxide, as well as others
  • enteric coating surrounding the core which coating includes a neutralized form
  • the Kabadi et al HMG CoA reductase inhibitor is preferably fluvastatin and does not include pravastatin.
  • the Kabadi et al composition contains an alkaline stabilizing medium capable of imparting a pH of at least 8 which include alkali metal hydroxides such as NaOH, KOH or LiOH, inorganic carbonate salts such as Na 2 C ⁇ 3 , K 2 CO 3 , NaHC ⁇ 3 as well as others .
  • alkali metal hydroxides such as NaOH, KOH or LiOH
  • inorganic carbonate salts such as Na 2 C ⁇ 3 , K 2 CO 3 , NaHC ⁇ 3 as well as others .
  • the Kabadi et al composition may optionally include an enteric film coating such as "hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, polyvinyl acetate phthalate, methyl cellulose phthalate, copolymerized methacrylic acid/methylacrylic acid methyl esters (e.g. Eudragit ® Rohm America Incorporated) .” (Column 5, lines 9 to 18) . Kabadi et al teach that "the enteric coating is preferably applied to result in about a 5 to 12%, preferably 8 to 10%, weight increase of the capsule, pellet or tablet core.”
  • U.S. Patent No. 4,997,658 to Alberts et al discloses a method for enhancing the lowering of plasma cholesterol level by the time-controlled administration of an HMG CoA reductase inhibitor (which can include pravastatin) over a period of 6 to 24 hours employing diffusion controlled systems, osmotic devices, dissolution controlled matrices and erodible/degradable matrices. Alberts et al do not disclose any specific examples or formulations containing pravastatin.
  • HMG CoA reductase inhibitor which can include pravastatin
  • a pravastatin formulation which decreases pravastatin exposure to the deleterious acidic environment of the stomach while enabling pravastatin to be absorbed in the small intestine to increase bioavailability and blood levels while enhancing LDl-C and triglyceride reduction would indeed fulfill a long felt want and would be a significant advance in treatment of cholesterol related diseases .
  • an enteric coated pravastatin formulation which includes a medicament which may degrade in a low pH environment but which is protected by the enteric coating from doing so.
  • the pravastatin formulation of the invention which is preferably in the form of beads or pellets, each bead of which includes a core which includes a medicament which is sensitive to a low pH environment, such as pravastatin, an optional buffering or basifying agent, and an enteric coating surrounding the core which coating will comprise at least about 17.5 grams of coating per m 2 surface area of the core beads (which is equivalent to about 5% w/w or more enteric coating for an average diameter core bead of 1.0 mm and an average weight of 0.78 mg) , and preferably from about 20 to about 210 grams of coating per m 2 surface area of the core beads which is equivalent to about 5 to about 60% w/w enteric coating for an average diameter core bead of 1.0 mm and an average weight of 0.78 mg.
  • the enteric coating will comprise from about 35 to about 150 grams per m 2 surface area of the core beads which is equivalent to from about 10 to about 50% w/w enteric coating for an average diameter core bead of 1.0 mm and an average weight of 0.78 mg.
  • enteric coated pravastatin formulation will be free of polyanionic polymers, namely, alginic acid, polypectinic acid or carboxymethyl cellulose and salts thereof and low molecular weight acids, namely, phosphonic acid, fumaric acid, tartaric acid, citric acid, malic acid, succinic acid, phthalic acid and vitamin C.
  • polyanionic polymers namely, alginic acid, polypectinic acid or carboxymethyl cellulose and salts thereof
  • low molecular weight acids namely, phosphonic acid, fumaric acid, tartaric acid, citric acid, malic acid, succinic acid, phthalic acid and vitamin C.
  • the formulation of the invention may be formed of beads contained in a single capsule or in two or more different capsules each containing beads of a different level of enteric coating and/or a different amount of pravastatin. It will also be understood where two or more capsules are required, the beads in each capsule may be the same or different insofar as enteric coating levels and/or amounts of pravastatin employed and/or size of beads.
  • a prolonged release enteric coated pravastatin formulation which is in the form of a plurality of beads each of which includes an enteric coating which protects against pravastatin degradation in an acid environment as in the stomach while enabling release of pravastatin in the small intestine to be absorbed therein.
  • the pravastatin is absorbed throughout the small intestine, namely, in the duodenum, jejunum and ileum.
  • the resulting prolonged release composition provides for improved bioavailability, increased blood levels and enhanced reduction in LDL-C cholesterol and triglycerides as compared to immediate release compositions which have the duodenum as the major absorption site.
  • the prolonged release enteric coated pravastatin formulation of the invention which is in the form of a plurality of beads, particles, beadlets, granules or pellets, includes beads having a core which includes pravastatin which is sensitive to a low pH environment, optionally a buffering or basifying agent, and an enteric coating surrounding the core which coating will comprise at least about 17.5 grams of coating per m 2 surface area of the composition, (which is equivalent to 5% w/w or more enteric coating for an average diameter core bead of 1.0 mm and an average weight of 0.78 mg) .
  • the prolonged release enteric coated pravastatin formulation of the invention will preferably comprise a plurality of enteric coated beads (in the same capsule or in two or more capsules) , the beads containing varying and different levels or amounts of enteric coating (that is a mixture of beads of the same or different bead size and containing different enteric coating levels or amounts) , the mixture of beads being contained in the same capsule or divided up into two more capsules, to enable the beads to pass through the stomach while providing adequate protection against acid degradation, and pass into the small intestine wherein it allows for release of pravastatin throughout the small intestine, that is into the duodenum, jejunum and ileum from which the pravastatin is absorbed into the bloodstream.
  • the prolonged release enteric coated pravastatin formulation of the invention may comprise beads of different size containing the same level (%) of enteric coating to achieve release of pravastatin throughout the small intestine.
  • the enteric coating will include a methacrylic acid copolymer, preferably a copolymer of methacrylic acid and methacrylic acid methyl ester or a methylmethacrylate/ methacrylic acid copolymer.
  • the enteric polymer may be partially neutralized.
  • the formulation will include a hydrophobic plasticizer for the enteric coating material, such as diethyl phthalate, and an optional overcoating of an anti-adherent .
  • novel enteric coated pravastatin formulation of the invention will provide for protection of pravastatin, at pH's less than 3 (such as found in the stomach) but will allow for prolonged slow drug release at a pH 4 or higher (such as found in the small intestine) over a period of less than 6 hours, and preferably over a period from about 1 to about 5 hours .
  • the ability of the enteric coat to prevent stomach acid migration to the core and/or prevent drug release from the core to the acidic environment of the stomach, and consequently prevent acid degradation of pravastatin, and allow for and enable release of pravastatin for absorption in the small intestine, preferably substantially throughout the small intestine, is critical to achieving maximum improvement in bioavailability and blood levels and maximum improvement in LDL-C and triglyceride reduction. This is dependent upon levels of enteric coating, type of enteric polymer, and plasticizer used.
  • a method for enhancing absorption properties of pravastatin in human patients wherein the pravastatin in the form of a formulation comprising pravastatin, optionally a basifying agent and an enteric coating as described herein, (which preferably includes varying and different levels or amounts of enteric coating) is administered to a human patient in need of treatment, wherein due to the enteric coating, the absorption and/or bioavailability properties of the pravastatin are enhanced, preferably by at least about 75%, and more preferably by about 100%, to achieve enhanced human patient benefit including enhanced LDL- cholesterol lowering and triglyceride lowering and maximum benefits resulting from such cholesterol lowering and triglyceride lowering.
  • a method for lowering serum cholesterol, preventing or inhibiting or treating atherosclerosis, and/or reducing risk of or treating a cardiovascular event or disease including coronary artery disease and cerebrovascular disease, in human patients, wherein a prolonged release pravastatin formulation comprised of a plurality of enteric coated pravastatin beads which preferably include a plurality beads of different levels of enteric coating, is administered to a human patient in need of treatment .
  • the enteric coated beads will be formed of a mixture of beads which include varying and different amounts of enteric coating so as to enable the beads to release pravastatin substantially throughout the small intestine.
  • a 10 to 160 mg pravastatin dose may include one or more portions of beads containing from about 0 to about 50%, preferably from about 10 to about 40% by weight of the total bead formulation containing from about 17.5 to about 87.5 mg of enteric coating per m 2 surface area of bead, and/or one or more portions of beads containing from about 0 to about 60%, preferably from about 20 to about 50% by weight of the total bead formulation containing from about 105 to about 140 mg of enteric coating per m 2 surface area of bead, and/or one or more portions of beads containing from about 0 to about 60%, preferably from about 30 to about 50% by weight of the total bead formulation containing from about 140 to about 210 mg of enteric coating per m 2 surface area of bead.
  • pravastatin bead dosage form for example, average diameter of about 1 mm and weight of about 0.78 mg per bead
  • amount of pravastatin present in the beads may vary from portion to portion of beads making up the formulation.
  • number of different portions of beads making up the formulation may vary from one to seven or more, preferably two to four.
  • present invention includes a mixture of two or more beads of different dimensions each of which may have the same enteric coating level. The beads of varying size, but having the same (or different) enteric coating levels, will achieve prolonged release of pravastatin.
  • a pravastatin formulation is provided in the form of a plurality of beads which includes a pravastatin-containing core in the form of beads which optionally include a basifying agent as described above, and an enteric coating as described above surrounding the core.
  • the core may include a protective coating under the enteric coat and an outer coating of an anti-adherent material. The beads may be loaded into capsules for dosing.
  • enteric coated formulations of the invention may be employed in admixture or combination with known pravastatin formulations including immediate release formulations including the commercially available Pravachol ® formulation.
  • the pharmaceutical composition of the invention which includes a core containing pravastatin and an optional basifying agent, and an enteric overcoat as described herein, is effective in preventing, reducing and/or treating elevated cholesterol levels (such as in hypercholesterolemia) ; atherosclerosis, cardiovascular events and disease including coronary events and cerebrovascular events, and coronary artery disease and/or cerebrovascular disease, and hypertriglyceridemia .
  • elevated cholesterol levels such as in hypercholesterolemia
  • cardiovascular events and disease including coronary events and cerebrovascular events
  • coronary artery disease and/or cerebrovascular disease and hypertriglyceridemia.
  • hypertriglyceridemia hypertriglyceridemia
  • cardiac disease refers to coronary and/or cerebrovascular event (s) and disease including primary myocardial infarction, secondary myocardial infarction, myocardial ischemia, angina pectoris (including unstable angina) , congestive heart failure, sudden cardiac death, cerebral infarction, cerebral thrombosis, cerebral ischemia, transient ischemic attack and the like.
  • CAD coronary artery disease
  • cancer refers to diseases including atherosclerosis of the intracranial and/or extracranial arteries, cerebral infarction, cerebral thrombosis, cerebral ischemia, stroke, and/or transient ischemic attacks.
  • absorbed substantially throughout the small intestine refers to the ability of pravastatin to be absorbed not only in the duodenum but down to the jejunum and the ileum where substantial amounts of pravastatin are absorbed as well .
  • mixture of beads containing different levels of enteric coating refers to the fact that the pravastatin bead formulation of the invention includes a mixture of beads, which may be the same or different sizes, preferably the same size, prescribed portions of which are coated with prescribed levels of enteric coating (preferably different levels of enteric coating) to enable beads to be released and absorbed throughout the small intestine, that is in the duodenum, jejunum and ileum, and not primarily in the duodenum as in the case of immediate release pravastatin formulations .
  • the various portions of beads containing different enteric coating levels may also contain different amounts of pravastatin.
  • pravastatin refers to the ability of the pravastatin to be absorbed into the blood stream of a human patient by delivering it to the desired site, namely the small intestine.
  • particles are used interchangeably, and will preferably have from about 0.1 to about 10 mm diameter.
  • pravastatin as employed herein encompasses pravastatin and all salts such as the sodium salt, and all forms thereof including the lactone.
  • granules or beads of pravastatin can be incorporated into the formulation. In many cases, discrete granules of pravastatin are needed so that these can be coated with a protective coating layer.
  • the process of making pravastatin granules may be common to most of the formulations .
  • the granules or beads may be prepared in different ways and used in any of the above formulations depending on the specific needs and limitations of the formulation. Some of the processes which can be used for preparing granule formulations are described below.
  • the granules or beads of pravastatin cholesterol lowering agent can be formed by dry compacting the pravastatin as is or after blending with a basifying agent (such as magnesium oxide or calcium carbonate) and a lubricant, such as zinc stearate, magnesium stearate, calcium stearate, talc, carnauba wax, or hydrogenated vegetable oils and/or fats, in an amount within the range from about 0.01 to about 4%, and preferably from about 0.1 to about 2%.
  • suitable bulking agents and/or fillers and/or binders can be added, as described hereinafter.
  • the compacts can be prepared by roller compaction or slugging. By this process, granules of almost 100% drug load can be prepared. Lower drug load granules may be prepared by employing additional fillers and excipients in the blend used for compaction.
  • the compacts can be broken into granules with suitable equipment. The resulting granules can be sized and the desired size fraction can be separated and collected with the rest being recycled.
  • Spherical and very high drug load granules or beads of pravastatin can be prepared by simple wet granulation or micro-granulation of pravastatin powder in a high shear granulator using water. Sufficient water is added to enable preparation of small spherical granules (that is, average particles size of less than about 1mm) . The resulting granules can be sized and screened to collect desired size fraction, and dried to desired moisture level. As indicated, basifying agent will be included in the formulation. The under and over sized fractions can be recycled. If less than 100% drug load is desired, fillers and excipients can be included in the powder to be micro granulated.
  • pravastatin granules or beads can be prepared using Moisture Activated Dry Granulation (MADG) process.
  • MADG Moisture Activated Dry Granulation
  • a portion (30-60%) of the pravastatin core can be granulated as above using all of the moisture needed for the whole blend to form agglomerates and then the remaining pravastatin added, and the mixture blended to prepare the granules.
  • the final blend can be sized, screened, and desired size fraction removed with over and under size to be recycled if necessary.
  • minimum quantities of moisture will be used as compared to process (b) . However, for stability reasons, the granules so prepared can still be dried.
  • (b) can be prepared by first making a wet mass using conventional wet massing equipment.
  • the wet mass can be sized wet and dried or dried as is and then broken into granules, which are screened and the desired size fraction is collected.
  • the wet mass prepared in method (d) can be extruded.
  • the extrudate can be dried, broken into granules, and sieved to collect desired size fraction. This process can produce high (>90%) drug load, dense and hard particles .
  • more uniform and spherical particles can be prepared by employing conventional spheronization processes. This will require use of higher level of excipients to allow proper extrusion of the wet mass and trouble free spheronization of the extrudate. Depending on the selection of the excipients and modification of the spheronization process, it may require 5 to 99% excipients.
  • pravastatin is blended with microcrystalline cellulose and with a small amount (0.5-5%) of basifying agent such as magnesium oxide, calcium carbonate or magnesium hydroxide, to insure chemical stability. The blend is then wet massed and extruded.
  • the extrudate is then spheronized to prepare the beads .
  • These beads are dried in a hot air tray oven or fluid bed dryer.
  • the beads can be further sized to remove under and over sized particles. While microcrystalline cellulose is preferred for bead formation, other excipients, for example, starch, lactose, starch 1500, silicified microcrystalline cellulose and the like, or any combination of these may be used as well .
  • a much higher drug concentration bead can be prepared by saving a portion of the drug blend before wet massing and using this dry powder to dust while spheronizing.
  • the pravastatin formulation of the invention in the form of a plurality of enteric coated pravastatin granules, particles, beadlets, beads, or cylindrical particles, may be prepared by first forming pravastatin granules, particles, beads or cylindrical particles (hereinafter "granules") employing any of the granulation processes described above, preferably process (f) for beads or process (e) for granules.
  • granules which will have an average particle size within the range from about 200 ⁇ m to about 2000 ⁇ m, can be coated with an optional protective coat, for example, employing a coating polymer such as a 2- 10% basified solution of polyvinyl pyrrolidone (PVP) , a 2- 20% solution of hydroxypropylmethyl cellulose (HPMC) , or Opadry Clear (HPMC) , or a 10-30% suspension of neutralized Eudragit L-30-D55 (acrylic acid copolymers-Rohm America Incorporated) (about 30% solids) containing 10 to 40% diethyl phthalate (W/W) or Citroflex ® as plasticizer.
  • PVP polyvinyl pyrrolidone
  • HPMC hydroxypropylmethyl cellulose
  • HPMC Opadry Clear
  • a 10-30% suspension of neutralized Eudragit L-30-D55 acrylic acid copolymers-Rohm America Incorporated
  • W/W diethyl
  • 0.5 to 10% protective coating may be applied in a fluid bed particle coating system or a coating pan.
  • the pravastatin beads optionally containing basifying agent with or without the protective coating are enteric coated.
  • the enteric coated beads can be further coated with an anti-adherent coating. These beads can be dosed as granules or beads or in the form of capsules after encapsulation. Upon ingestion, the beads will pass through the stomach as intact beads due to the enteric coat. ⁇ As the beads reach the duodenum, jejunum and ileum, the enteric coat will dissolve followed by dissolution of the pravastatin particles and absorption thereby into the duodenum, jejunum and ileum.
  • the pravastatin formulation of the invention will contain pravastatin in an amount within the range from about 1 to about 90% by weight of the formulation.
  • the amount of pravastatin normally employed will be exemplified in the 53nd edition of the Physician's Desk Reference (PDR) (1999) .
  • PDR Physician's Desk Reference
  • it may be employed in amounts within the range from about 0.1 mg to 2000 mg per day in single or divided doses, and preferably from about 0.2 to about 400 mg per day.
  • Most preferably for pravastatin a daily dosage of 5 to 160 mg may be employed.
  • the basifying agent will optionally be incorporated into the granules prepared by means of processes (a) to (g) employing conventional procedures as described in the working Examples.
  • the basifying agent will be included to aid in minimizing drug degradation in the core due to acid ingress in low pH environments as well as to increase the shelf life of the product.
  • the basifying agent will be present in an amount within the range of from about 0.1 to about 15% by weight and preferably from about 0.5 to about 10% by weight of the composition.
  • basifying agents include, but are not limited to, sodium acetate, sodium citrate, sodium tartrate, sodium fumarate, sodium malate, sodium succinate, calcium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, dihydroxy aluminum sodium carbonate, magnesium oxide, aluminum oxide, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide or an alkaline earth metal hydroxide such as calcium hydroxide or magnesium hydroxide, with magnesium oxide or calcium carbonate being preferred.
  • the formulation of the invention will also include one or more fillers or excipients in an amount within the range of from about 0 to about 90% by weight and preferably from about 5 to about 80% by weight such as lactose, sugar, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate, calcium phosphate, and/or cellulose derivatives such as wood cellulose, hydroxypropylmethyl cellulose (HPMC) , and microcrystalline cellulose.
  • One or more binders will be present in addition to or in lieu of the fillers in an amount within the range of from about 0 to about 35% and preferably from about 1 to about 30% by weight of the composition.
  • binders which are suitable for use herein include basified polyvinylpyrrolidone (molecular weight ranging from about 5000 to about 80,000 and preferably about 40,000), lactose, HPMC, starches such as corn starch, modified corn starch, sugars, gum acacia and the like as well as a wax binder in finely powdered form (less than 500 microns) such as camauba wax, paraffin, spermaceti, polyethylenes or microcrystalline wax.
  • basified polyvinylpyrrolidone moleukin
  • lactose HPMC
  • starches such as corn starch, modified corn starch, sugars, gum acacia and the like
  • a wax binder in finely powdered form less than 500 microns
  • camauba wax, paraffin, spermaceti polyethylenes or microcrystalline wax.
  • the enteric coating will be present in varying and different levels as described hereinbefore to impart the desired properties to such formulation, namely, improved bioavailability and efficacy (in lowering LDL cholesterol) and triglycerides .
  • the enteric coating will be methacrylic acid copolymer (Eudragit L30D-Rohm America Incorporated) , and preferably a copolymer of methacrylic acid and methacrylic acid ester or a copolymer of methylmethacrylate/methacrylic acid, which will be present in an amount from about 70 to about 95% by weight of the enteric coating.
  • the enteric polymer may be partially neutralized.
  • the enteric coating will include a plasticizer preferably a hydrophobic plasticizer in an amount from about 5 to 30%, preferably from about 0.5 to about 6% by weight of the enteric coating.
  • plasticizers include diethyl phthalate, tributyl citrate, triacetin, dibutyl phthalate, dibutyl sebacate, or Myvacet 940 (acetylated monoglycerides ) and other commonly used plasticizers as may be suitable for the enteric polymer employed herein. It will be appreciated that the enteric polymer with suitable plasticizer can be used in aqueous or non-aqueous system to form an enteric coating on the pravastatin bead or granule.
  • Preferred enteric coating polymer is Eudragit L-30- D55 with diethyl phthalate as a plasticizer. At least 35 grams of the coating solution per m 2 surface area would be sufficient to provide a coat with enteric qualities when applied from an aqueous system.
  • a 10-30% suspension of Eudragit ® L-30-D55, preferably 15 to 20% containing 1 to 5% diethyl phthalate, preferably 1.5-3.0% is prepared in purified water.
  • the uncoated or protective-coated cores or beads are enteric coated with this suspension in a fluid bed coater fitted with a Wurster column or top coating capability or a pan-coater.
  • the above enteric coated granules are further coated with an anti-adherent material.
  • Talc magnesium stearate, calcium stearate, silica gel, titanium dioxide and the like may be used.
  • the anti-adherent material preferably talc, is used at 0.1-5% level and preferably 0.2 to 2.0%. Coated particles and talc may be loaded into a tumbling type blender and blended for 5-30 minutes.
  • the above coated particles can be encapsulated into hard gelatin capsules for the desired potency.
  • a preferred enteric coated pravastatin formulation of the invention in the form of a bead is set out below. Material Possible Preferred Range % Range %
  • Basifying Agent such as MgO or CaC0 3 0.1 to 15 . 0.5 to 10 .
  • Filler such as 10 to 99 20 to 95
  • Film polymer such as Methocel 0 to 35 1.8 to 17.5
  • Dusting Talc 0 to 5 0.1 to 2.0
  • the enteric coat and the optional subcoat are based on the surface area of the core beads .
  • the possible range of the enteric coat is from about 5% to about 60% and the preferred range is from about 15% to about 40% based on the weight of the core and the enteric coat, respectively.
  • the possible range of the subcoat is from about 0% to about 10% and the preferred range is from about 0.5% to about 5.0% based on the weight of the core, the optional subcoat, and the enteric coat, respectively.
  • the enteric coated pharmaceutical composition in the form of pellets or beadlets may also be prepared employing an extrusion-spheronization procedure such as described in U.S. Patent No. 4,808,413 to Joshi et al .
  • the pharmaceutical preferably pravastatin
  • a granulation liquid water
  • the fillers, binders, disintegrants and buffering agent for example, microcrystalline cellulose, lactose, sodium starch glycolate, polyvinylpyrollidone and sodium citrate
  • the dry blend is then granulated using the above granulation solution and continued to the endpoint with water.
  • the wet mass is extruded, for example, employing a Nica, Luwa or other type of extruders to form an extrudate which is then passed through spheronizing equipment, such as Nica, Caleva or other type, which converts the extrudate into beadlets of appropriate particle size range.
  • the beadlets may then be dried by tray drying oven or fluid bed drying.
  • the core is to be a tablet, the tablet may be formed using conventional techniques .
  • the dried beadlets or pellets may then be coated with a subcoat, for example, with a solution of hydroxypropylmethyl cellulose (Pharmacoat 603) and polyethylene glycol 400.
  • a subcoat for example, with a solution of hydroxypropylmethyl cellulose (Pharmacoat 603) and polyethylene glycol 400.
  • These sub-coated beadlets or pellets are then overcoated with the enteric coating composition which is a dispersion of a copolymer of polymethacrylic acid esters and a plasticizer preferably diethyl phthalate .
  • the so-formed pellets or beadlets may be filled into hard gelatin capsules .
  • the pravastatin bead formulation of the invention may be administered to mammalian species, such as monkeys, dogs, cats, rats, humans, etc., and, as described hereinbefore, may be incorporated in a capsule .
  • the above dosage forms may also include antibacterial, anti-oxidants such as Vitamin C and Vitamin E, as well as Vitamin B ⁇ , Vitamin B 12 , folic acid, sodium bisulfite, and the like.
  • the dose administered must be adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.
  • the formulations described above may be administered in the dosage forms as described above in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination.
  • Such dosage forms can be administered to the patient on a regimen of one to four doses per day.
  • pravastatin forms commonly known pharmaceutically acceptable salts such as alkali metal and other common basic salts or acid addition salts, etc. References to the base substances are therefore intended to include those common salts known to be substantially equivalent to the parent compound.
  • the formulations as described above will be administered for a prolonged period, that is, for as long as the potential for atherosclerosis, cardiovascular events and disease including coronary artery disease and/or cerebrovascular disease remains or the symptoms continue. Sustained release forms of such formulations which may provide such amounts daily, biweekly, weekly, monthly and the like may also be employed. A dosing period of at least 10 days are required to achieve minimal benefit.
  • the following Examples represent preferred embodiments of the present invention.
  • Formulations suitable for oral administration are prepared as described below.
  • a pravastatin capsule formulation which includes granules or beads of pravastatin sodium, MgO or CaC ⁇ 3 basifying agent, filler-binder, and Eudragit L-30-D55 enteric coating having the following composition is prepared as described below.
  • Procedure A multi-step process is employed which starts with the preparation of pravastatin sodium granules .
  • the granules can be prepared by any of the methods (a) -(f) described above, but methods (e) and (f) are preferred. These granules (having an average particle size ranging from about 710 ⁇ m to about 1700 ⁇ m) may optionally be coated with a protective coat.
  • the protective coating polymer may be a 2-10% solution of basified PVP, or 2-20% solution of HPMC or Opadry ® Clear with or without a suitable plasticizer such as polyethylene glycol.
  • a 0.5- 10% coating can be applied in a fluid bed particle coating system. Among these, a preferred protective coating will be formed of 1-20% HPMC.
  • the beads or particles are coated to 0.5-10% coat level in fluid bed apparatus with or without a Wurster insert or in a pan coater.
  • the above granules are coated as described above. These are coated with enteric coating polymers as follows .
  • the uncoated or protective coated beads are enteric coated with this suspension in a fluid bed coater fitted with or without a Wurster column or in a pan coater. A 15% to 60% weight gain would be sufficient to provide coat with enteric qualities .
  • enteric coated granules are further coated with anti-adherent material such as talc, magnesium stearate, calcium stearate, silica gel or titanium dioxide.
  • anti-adherent material such as talc, magnesium stearate, calcium stearate, silica gel or titanium dioxide.
  • talc is used as anti-adherent at 0.1 to 4% level, preferably 0.5 to 2%.
  • Enteric coated granules and talc are loaded into a tumbling type blender and blended for 5 to 30 minutes, preferably 10 minutes.
  • the above coated granules are encapsulated into capsule hard shells suitable for the desired potency or compressed into a tablet matrix using a cushioning filler- binder system to provide a dosage form with 5 to 160 mg drug potency.
  • the resulting pravastatin sodium formulation will provide for improved absorption and/or bioavailability in human patients by at least about 75-100% over a similar formulation which does not contain the enteric coating as defined above. When the beads with different coating levels are mixed, these provide a prolonged release formulation.
  • Formulations 1-11 are specific preferred examples of enteric coated pravastatin beads filled in a capsule.
  • Formulations 1-5 and 8 are intended to deliver 40 mg pravastatin sodium.
  • Formulations 6, 7 and 9 are intended to deliver 20 mg.
  • Formulation 10 is intended to deliver 80 mg, and Formulation 11 is intended to deliver 160 mg.
  • the beads of Formulations 1-6 and 8-11 are composed of pravastatin sodium, magnesium oxide as basifying agent, and microcrystalline cellulose coated with different levels of the enteric polymer Eudragit ® L30D plasticized with diethyl phthalate and dusted with talc prior to filling in capsules .
  • the % of pravastatin in the core beads for Formulations 1-4, 6, 7 and 9 is 10%, whereas those of Formulations 5, 10 and 11 are 20%, 40% and 80%, respectively.
  • the coated beads are resistant to the acid degradation in the stomach but release the pravastatin at pH greater than 4.
  • the coating levels presented in these examples are 15%, 20%, 25%, 30% and 40% w/w which for an average diameter core bead of 1.0 mm and an average weight of 0.78 mg, represents a 52.5, 70, 87.5, 105, and 140 gram of enteric coating per m 2 surface area of the core beads .
  • Beads with different coating levels should release the drug at different portions of the gastrointestinal tract. Thus, beads having higher coating levels would release at a later time. Different fractions of beads with different levels of coating can be mixed to achieve desired release rate for optimum bioavailability and efficacy.
  • the difference between Formulations 1,2,3,4,6 and 8 is in the level of the enteric coating applied to the beads as well as the fraction of each enteric coated beads present.
  • Formulation 1 contains 40 mg pravastatin loaded beads coated at 15% level.
  • Formulation 2 contains 20 mg pravastatin coated at 15% coating, 12 mg pravastatin coated at 25% coating and 8 mg pravastatin coated at 40% coating levels.
  • Formulation 3 contains 10 mg immediate release pravastatin in the form of Pravachol ® 10 mg tablet, 10 mg pravastatin coated at 15% coating, 10 mg pravastatin coated at 25% coating and 10 mg pravastatin coated at 40% coating.
  • Formulation 4 contains 10 mg pravastatin coated at 15% coating, 12 mg pravastatin coated at 25% coating and 18 mg pravastatin coated at 40% coating.
  • Formulation 5 contains 40 mg pravastatin coated at 30% coating.
  • Formulation 7 is similar to Formulation 6, except that it contains calcium carbonate as the basifying agent instead of magnesium oxide.
  • Formulation 8 contains 20 mg pravastatin coated at 20% coating and 20 mg pravastatin at 40% coating.
  • Formulation 9 contains a hydroxypropyl methylcellulose subcoat to separate the acid-sensitive drug pravastatin sodium from the acidic enteric coating polymer (Eudragit ® L30D) .
  • Formulation 10 contains 80 mg pravastatin coated at 30% coating.
  • Formulation 11 contains 160 mg pravastatin at 40% coating level.
  • Formulation 12 contains 40 mg pravastatin coated at 40% coating level.
  • Pravastatin Sodium 0 . . 100 A g Magnesium Oxide, NF 0 . . 005 g Microcrystalline Cellulose, NF ccaa . 0 . . 895 B g Purified Water, USP q - . s . c Total Weight 1 . . 000 g
  • Purified water is used for processing only and is removed during drying.
  • the preferred amount is 0.890 g.
  • the range is 0.850 g to 0.950 g.
  • Dust the coated beads with talc in a tumbling mixer Dust the coated beads with talc in a tumbling mixer.
  • This amount is based on the amount of pravastatin sodium at 100% potency. The exact amount will vary depending on the chemical purity ("as is" potency) of the pravastatin sodium.
  • microcrystalline cellulose will vary depending on the chemical purity of the pravastatin sodium used.
  • c Purified Water is used for processing only and is removed during drying.
  • the preferred amount is 0.7640 Kg.
  • the range is 0.7500 Kg to 0.7780 Kg.
  • a This amount is based on the amount of pravastatin sodium at 100% potency. The exact amount will vary depending on the chemical purity ("as is" potency) of the pravastatin sodium. B The amount of microcrystalline cellulose will vary depending on the chemical purity of the pravastatin sodium used.
  • C Purified water is used for processing only and is removed during drying.
  • the preferred amount is 0.8900 g.
  • the range is 0.8500 g to 0.9500 g.
  • Dust the coated beads with talc in a tumbling mixer Dust the coated beads with talc in a tumbling mixer.
  • Pravastatin Sodium Modified Release Enteric Coated Beads for Capsules Pravastatin Sodium Modified Release Enteric Coated Beads for Capsules
  • Methocel E3 Hydropropyl Methylcellulose
  • Methylcellulose from Step 1 to the weighed Water for Injection in Step 2 and stir.
  • FORMULATION 10 a Composition of Core Beads Ingredient Amount Per g Pravastatin Sodium 0.4000 KgA Magnesium Oxide, NF 0.0050 Kg Yellow Ferric Oxide, NF 0.0010 Kg
  • This amount is based on the amount of pravastatin sodium at 100% potency. The exact amount will vary depending on the chemical purity ("as is" potency) of the pravastatin sodium.
  • microcrystalline cellulose will vary depending on the chemical purity of the pravastatin sodium used.
  • C. Purified Water is used for processing only and is removed during drying. The preferred amount , is 0.4270 Kg.
  • the range is 0.4200 Kg to 0.4300 Kg.
  • This amount is based on the amount of pravastatin sodium at 100% potency. The exact amount will vary depending on the chemical purity ("as is" potency) of the pravastatin sodium.
  • microcrystalline cellulose will vary depending on the chemical purity of the pravastatin sodium used.
  • Purified Water is used for processing only and is removed during drying.
  • the preferred amount is 0.3000 Kg.
  • the range is 0.2900 Kg to 0.3100 Kg.
  • Dust the coated beads with talc in a tumbling mixer Dust the coated beads with talc in a tumbling mixer.
  • the above formulations of the invention provide a core containing pravastatin and a basifying agent.
  • the enteric coating will be present in an amount sufficient to protect from gastric acidity and yet release the drug at the desired site for absorption.
  • a 35 g/m 2 coating is desired which translates to 10% w/w coating for a 1 mm (average diameter) core bead of 0.78 mg average weight.
  • Bioavailability of pravastatin in the above formulations is enhanced over prior art pravastatin formulations (which do not contain an enteric coating) while a substantially greater LDL-C and TG reduction is achieved.
  • the pravastatin dosage in the formulations of the invention may be decreased by as much as 50% without loss of LDL lowering capability as compared to pravastatin formulations which do not include the enteric coating required in the formulations of the invention.
  • 10 mg, 20 mg, 40 mg, 80 mg and 160 mg pravastatin formulations in accordance with the invention may have an LDL lowering capability equivalent to 20 mg, 40 mg, 80 mg, 160 mg and 320 mg, respectively, pravastatin formulations which do not include the enteric coating employed in the present invention.

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Abstract

L'invention concerne une préparation à base de billes de pravastatine à enrobage entérique qui comprend de la pravastatine, éventuellement un agent basifiant tel que MgO ou CaCO3 et un enrobage entérique formé à partir d'un copolymère d'acide méthacrylique qui peut se présenter comme un copolymère de méthylacrylate/d'acide méthacrylique ou comme un copolymère de méthylméthacrylate/d'acide méthacrylique, ainsi qu'un plastifiant tel que diéthylphtalate et une poudre de talc. La préparation à enrobage entérique possède une bonne résistance à la détérioration lorsque le pH est inférieur à 3 et manifeste de bonnes propriétés de libération de médicaments lorsqu'il est supérieur à 4; en outre, elle assure une plus grande biodisponibilité et une réduction plus sensible de LDL et de TG en comparaison aux préparations à base de pravastatine qui ne comprennent pas d'enrobage entérique et n'assurent pas de libération à travers l'intestin grêle pendant un temps d'absorption prolongé.
PCT/US1999/028375 1998-12-07 1999-12-01 Preparation a base de billes de pravastatine a enrobage enterique Ceased WO2000033821A1 (fr)

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WO2003000177A3 (fr) * 2001-06-21 2003-11-06 Andrx Pharmaceuticals Inc Compositions pharmaceutiques a liberation controlee, stables, contenant de la pravastatine
WO2004021973A3 (fr) * 2002-09-03 2004-05-21 Biovail Lab Inc Formulations pharmaceutiques de pravastatin et leurs modes d'utilisation
EP1490029A4 (fr) * 2002-03-22 2006-02-22 Ranbaxy Lab Ltd Systeme d'administration de medicaments a liberation controlee de pravastatine
WO2006055142A3 (fr) * 2004-11-12 2006-07-20 Eurand Pharmaceuticals Ltd Compositions pharmaceutiques au gout masque preparees par coacervation
WO2007006353A3 (fr) * 2005-07-12 2007-04-12 Roehm Gmbh Utilisation d'un copolymere (meth)acrylique anionique partiellement neutralise comme enrobage dans la production d'une forme medicamenteuse liberant le principe actif a un ph reduit
WO2007048233A1 (fr) * 2005-10-24 2007-05-03 Orbus Pharma Inc. Compositions pharmaceutiques stabilisées et à libération retardée qui comprennent un antagoniste de bêta-adrénorécepteur
US7262218B2 (en) * 1999-12-14 2007-08-28 Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag Forms of pravastatin sodium
EP1545503A4 (fr) * 2002-09-03 2007-12-12 Circ Pharma Res And Dev Ltd Formulations pharmaceutiques et procedes de liberation modifiee de statines
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CN111803462A (zh) * 2020-07-15 2020-10-23 浙江诺得药业有限公司 一种普伐他汀钠肠溶片及其制备方法

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US8071128B2 (en) 1996-06-14 2011-12-06 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US8956650B2 (en) 1996-06-14 2015-02-17 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US8945618B2 (en) 1996-06-14 2015-02-03 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US7262218B2 (en) * 1999-12-14 2007-08-28 Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag Forms of pravastatin sodium
US7642286B2 (en) 2001-06-21 2010-01-05 Andrx Pharmaceuticals, Inc. Stable pharmaceutical compositions containing pravastatin
WO2003000177A3 (fr) * 2001-06-21 2003-11-06 Andrx Pharmaceuticals Inc Compositions pharmaceutiques a liberation controlee, stables, contenant de la pravastatine
US9358214B2 (en) 2001-10-04 2016-06-07 Adare Pharmaceuticals, Inc. Timed, sustained release systems for propranolol
US9040086B2 (en) 2001-10-04 2015-05-26 Aptalis Pharmatech, Inc. Timed, sustained release systems for propranolol
WO2003057195A1 (fr) * 2002-01-11 2003-07-17 Athpharma Limited Preparations pharmaceutiques de pravastatine et procedes d'utilisation associes
US6967218B2 (en) 2002-01-11 2005-11-22 Biovail Laboratories, Inc. Pravastatin pharmaceutical formulations and methods of their use
EP1905431A1 (fr) * 2002-01-11 2008-04-02 Circ Pharma Research and Development Limited Formulations pharmaceutiques de pravastatine et leurs procédés d'utilisation
AU2003201735B2 (en) * 2002-01-11 2008-11-13 Circ Pharma Research And Development Limited Pravastatin pharmaceutical formulations and methods of their use
EP1490029A4 (fr) * 2002-03-22 2006-02-22 Ranbaxy Lab Ltd Systeme d'administration de medicaments a liberation controlee de pravastatine
EP2033631A3 (fr) * 2002-09-03 2009-06-03 Circ Pharma Research and Development Limited Formulations pharmaceutiques de pravastatine et leurs procédés d'utilisation
EP1545503A4 (fr) * 2002-09-03 2007-12-12 Circ Pharma Res And Dev Ltd Formulations pharmaceutiques et procedes de liberation modifiee de statines
WO2004021973A3 (fr) * 2002-09-03 2004-05-21 Biovail Lab Inc Formulations pharmaceutiques de pravastatin et leurs modes d'utilisation
US8367111B2 (en) 2002-12-31 2013-02-05 Aptalis Pharmatech, Inc. Extended release dosage forms of propranolol hydrochloride
US8747895B2 (en) 2004-09-13 2014-06-10 Aptalis Pharmatech, Inc. Orally disintegrating tablets of atomoxetine
US10130580B2 (en) 2004-10-12 2018-11-20 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US11452689B2 (en) 2004-10-12 2022-09-27 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US10568832B2 (en) 2004-10-12 2020-02-25 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US9884014B2 (en) 2004-10-12 2018-02-06 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US10952971B2 (en) 2004-10-21 2021-03-23 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions with gastrosoluble pore-formers
US10471017B2 (en) 2004-10-21 2019-11-12 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions with gastrosoluble pore-formers
WO2006055142A3 (fr) * 2004-11-12 2006-07-20 Eurand Pharmaceuticals Ltd Compositions pharmaceutiques au gout masque preparees par coacervation
EP2319498A1 (fr) * 2004-11-12 2011-05-11 Eurand Pharmaceuticals Ltd Une composition pharmaceutique multiparticulaire pour masquer le gout - contenant un noyau avec un principe actif et une membrane gràce à une coacervation avec un solvant
US10500161B2 (en) 2005-05-02 2019-12-10 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9161919B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9161918B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US11147772B2 (en) 2005-05-02 2021-10-19 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9566249B2 (en) 2005-05-02 2017-02-14 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9579293B2 (en) 2005-05-02 2017-02-28 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US10045946B2 (en) 2005-05-02 2018-08-14 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
WO2007006353A3 (fr) * 2005-07-12 2007-04-12 Roehm Gmbh Utilisation d'un copolymere (meth)acrylique anionique partiellement neutralise comme enrobage dans la production d'une forme medicamenteuse liberant le principe actif a un ph reduit
US7932258B2 (en) 2005-07-12 2011-04-26 Evonik Roehm Gmbh Use of a partially neutralized, anionic (meth) acrylate copolymer as a coating for the production of a medicament pharmaceutical form releasing active substance at reduced pH values
WO2007048233A1 (fr) * 2005-10-24 2007-05-03 Orbus Pharma Inc. Compositions pharmaceutiques stabilisées et à libération retardée qui comprennent un antagoniste de bêta-adrénorécepteur
US8580313B2 (en) 2009-12-02 2013-11-12 Aptalis Pharma Limited Fexofenadine microcapsules and compositions containing them
US10166220B2 (en) 2009-12-02 2019-01-01 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them
US9233105B2 (en) 2009-12-02 2016-01-12 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them
US10729682B2 (en) 2009-12-02 2020-08-04 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them
EP2343054A1 (fr) 2010-01-04 2011-07-13 LEK Pharmaceuticals d.d. Granules et microparticules de sodium de pravastatine et leur procédé de fabrication
WO2011080346A2 (fr) 2010-01-04 2011-07-07 Lek Pharmaceuticals D.D. Pellets et microparticules de pravastatine sodique et leur procédé de fabrication
WO2011080346A3 (fr) * 2010-01-04 2012-04-12 Lek Pharmaceuticals D.D. Pellets et microparticules de pravastatine sodique et leur procédé de fabrication
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US10736871B2 (en) 2015-04-01 2020-08-11 Cedars-Sinai Medical Center Anti-methanogenic lovastatin analogs or derivatives and uses thereof
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