Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• • 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1611—Inorganic compounds
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • 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
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2009—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
• • 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
  • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
• • 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
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

• the present invention relates to compositions, particularly, pharmaceutical compositions in particulate form such as granulate or in solid dosage forms comprising a combination of a fibrate and atorvastatin (also known as an HMG CoA reductase inhibitor). More specifically, the invention relates to a solid pharmaceutical composition comprising atorvastatin and a low dose, i.e. a reduced amount, of fenofibrate having improved bioavailability and/or improved pharmacological response, i.e. improved effect.
• the composition may be in the form of an immediate release formulation, a controlled release formulation or a combination thereof.
• the invention also relates to methods for making the compositions in particulate form, i.e. as particles, and in solid dosage forms. Background art
• Fibrates are drug substances that generally are poorly and variably absorbed after oral administration. Normally they are prescribed to be taken with food in order to increase the bioavailability. There has been a number of improvements in dosage form of the currently most used fibrate, fenofibrate, in an effort to increase the bioavailability of the drug and hence its efficacy. Furthermore, clinical guidelines indicate that not only fibrate therapy but also a combination therapy with e.g. fenofibrate and a statin should be the most effective means of cholesterol and lipid management. In fact, treatment with fenofibrate is often prescribed together with a statin as clinicians seem to prefer the use of e.g.
• Fenofibrate due to its triglyceride-lowering and HDL-C increasing effects while a statin is used for its positive effects on lowering LDL-C and raising HDL-C.
• a statin is used for its positive effects on lowering LDL-C and raising HDL-C.
• such a combination therapy can only be achieved by the use of two separate products, i.e. the patient needs to take e.g. one fenofibrate tablet together with another tablet or capsule containing a statin.
• Fenofibrate is chemically named 2-[4-(4-chlorobenzoyl]-2-methyl-propanoic acid, 1 -methylethyl ester and has the following structural formula: [0004]
• Fenofibrate is a white solid. The compound is insoluble in water. The melting point is 79-82 0 C. Fenofibrate is metabolised to the active substance fenofibric acid. Fenofibric acid has an elimination half-life of about 20 hours. Measurement of the detected amount of fenofibric acid in the blood of a patient can reflect the efficacy of fenofibrate uptake. Fenofibric acid produces reductions in total cholesterol (total-C), LDL-C, apo-lipoprotein B, total triglycerides, and triglyceride rich lipoprotein (VLDL) in treated patients.
• total-C total cholesterol
• LDL-C LDL-C
• apo-lipoprotein B total triglycerides
• VLDL triglyceride rich lipoprotein
• Fenofibrate acts as a potent lipid regulating agent offering unique and clinical advantages over existing products in the fibrate family of drug substances.
• Fenofibrate produces substantial reduction in plasma triglyceride levels in hypertriglyceridemic patients and in plasma cholesterol and LDL-C in hypercholesterolemic and mixed dyslipidemic patients.
• Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal subjects by increasing the urinary excretion of uric acid.
• LDL-C low density lipoprotein cholesterol
• apo B apo-lipoprotein B
• HDL-C high density lipoprotein cholesterol
• apolipoprotein A apo Al and apo All
• Fenofibrate is also effective in the treatment of Diabetes Type Il and metabolic syndrome.
• lipid improvements seen with fenofibrate therapy are associated with reduced progression to microalbuminuria in patients with Diabetes Type II.
• a recent study shows that fenofibrate treatment for at least 3 years is effective in reducing the progression of renal disease in patients with Diabetes Type Il without diabetic nephropathy (Am. J. Kidney Dis. 2005, vol. 45, p. 485- 493).
• Fenofibrate is also indicated as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV and V hyperlipedemia).
• Fibrates are drug substances known to be are poorly and variably absorbed after oral administration. Normally they are prescribed to be taken with food in order to increase the bioavailability.
• the absorption and bioavailability of a therapeutically active substance can be affected by a variety of factors when administered orally. Such factors include the presence of food in the gastrointestinal tract and, in general, the gastric residence time of a drug substance is significantly longer in the presence of food than in the fasted state. If the bioavailability of a drug substance is affected beyond a certain point due to the presence of food in the gastrointestinal tract, the drug substance is said to exhibit a food effect. Food effects are important because there is a risk associated with administering the drug substance to a patient who has eaten recently. The risk derives from the potential that absorption into the bloodstream may be adversely affected to the point that the patient risks insufficient absorption to remedy the condition for which the drug was administered.
• fenofibrate drug products are: From Abbott Laboratories: TriCor ® tablets 160 mg, 145 mg, 54 mg, 48 mg, Lipanthyl ® capsules; from Reliant Pharmaceuticals Inc., NJ, U.S.A.: Antara ® capsules 130 mg, 43 mg.
• the fenofibrate present in these commercial products is in micronized form, i.e. crystalline fenofibrate in the form of fenofibrate particles as such, prepared by subjecting crystalline fenofibrate to a mechanical milling in order to reduce the particle size.
• WO 04/041250 relates to nanoparticulate compositions of fenofibrate, i.e. fenofibrate particles having an effective average particle size of less than about 2000 nm.
• Atorvastatin is a synthetic reversible inhibitor of the microsomal enzyme HMG-CoA reductase. Atorvastatin is usually administered orally as the calcium salt of the active hydroxy acid in a dosage range of 10-80 mg/day. Atorvastatin acid is converted to its lactone in vivo in humans, and these two forms appear to have approximately the same AUC.
• Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5- [0017] (1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 -heptanoic acid, calcium salt (2:1) trihydrate.
• the empirical formula of atorvastatin calcium is (C33H34FN 2 O5)2Ca3H 2 O and its molecular weight is 1209.42.
• the molecular weight of atorvastatin as such is 546, pKa 4.46.
• Atorvastatin calcium is a white to off-white crystalline or amorphous powder that is insoluble in aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile, slightly soluble in ethanol, and freely soluble in methanol.
• the solubility of the calcium salt of atorvastatin is 1.23 mg/mL at pH 6.0; accordingly, it is believed that solubility in the intestinal lumen is not a limiting factor in vivo.
• the calcium salt has the following structural formula: [0019]
• Atorvastatin magnesium is a crystalline or amorphous powder.
• LipitorTM tablets for oral administration contain 10, 20, 40 or 80 mg atorvastatin and the following inactive ingredients: calcium carbonate,
• Atorvastatin is a synthetic lipid-lowering agent. Atorvastatin is a selective, competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.
• This enzyme catalyzes the conversion of HMG-CoA to mevalonate, a precursor of sterols, including cholesterol.
• Cholesterol and triglycerides circulate in the bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL (high-density lipoprotein), IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions.
• Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral tissues.
• LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor.
• Atorvastatin acid is highly soluble and permeable, and the drug is completely and rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to the atorvastatin dose (for a dose below 40 mg).
• atorvastatin acid is subject to extensive first-pass metabolism in the gut wall and in the liver, and the absolute bioavailability of atorvastatin acid (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%.
• the low systemic availability is attributed to pre- systemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism (oxidation, lactonization and glucuronidation; the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine).
• LDL-C reduction is said to be similar whether atorvastatin is given with or without food.
• Plasma atorvastatin concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning.
• LDL-C reduction is said to be the same regardless of the time of day of drug administration
• WO 03013608 describes semi-solid pharmaceutical compositions containing a fibrate and a statin prepared by melting the inactive substances, adding the active substances and filling the melt into pharmaceutically acceptable capsules.
• WO 03103640 discloses nanoparticulate compositions comprising statin particles having an effective average particle size of less than about 2000 nm, optionally in combination with other cholesterol lowering agents.
• US-A-2003-0162827 discloses an atorvastatin composition with improved bioavailability allegedly due to the presence of atorvastatin in a rapidly dissolvable and more solubilized state.
• a pharmaceutical composition that in a single formulation, preferably in a single solid dosage form, contains a fibrate and atorvastatin as active substances, which composition is stable and provides suitable and desirable biopharmaceutical properties of the active substances (e.g. for each of the active substances a suitable bioavailability, a suitable pharmacological response, less dependency on food intake etc), and which composition can be easily manufactured in large scale.
• a fibrate and atorvastatin which formulations can be further processed into pharmaceutical dosage forms with a high degree of flexibility of choosing the particular kind of dosage form. Within the pharmaceutical field such flexibility can be obtained when the formulation is in the form of a solid product such as powder or particles.
• compositions that have a suitable or even improved bioavailability, that can substantially reduce or overcome the differential between the bioavailability of the drug in patients who are fasted versus the bioavailability of the drug (in particular relevant for fenofibrate) in patients who are fed, and/or than can substantially reduce or overcome the intra- and/or inter- individual variations observed with the current treatment. Furthermore, there is also a need for a composition that enables reduction in observed side effects and minimizes any possible drug-drug interactions. Disclosure of the invention Summary of the invention
• fenofibrate a solid pharmaceutical composition in particulate form comprising a combination of two active substances, namely fenofibrate and atorvastatin or a pharmaceutically active salt thereof such as the calcium salt or the magnesium salt, where the fenofibrate is at least bioequivalent to the commercially available drug at present containing the lowest dose of fenofibrate (that is 130 mg, full dose).
• the inventors have found that the bioavailability of the combination drug can be significantly enhanced by dissolving the active substance fenofibrate in a suitable vehicle and using the resulting composition for preparing a solid dosage form, i.e. a dosage form excluding material in liquid form.
• Fenofibrate is known to be insoluble in water and the present invention includes pharmaceutical composi ⁇ tions and formulations exhibiting release profiles which have significantly increased in vivo bioavailability in patients in need thereof, especially eliminating the food effect of fenofibrate known from commercially available fenofibrate tablets (Tricor/Lipanthyl tablets or other drug products containing micronized fenofibrate).
• the inventors have succeeded in preparing a solid dosage form, such as a tablet, which ensures suitable bioavailability of the active substances upon oral administration.
• the advantages of a solid and stable dosage form useful for oral administration are well-known.
• a fenofibrate-atorvastatin combination composition comprising a controlled release formulation of atorvastatin, preferably a delayed release formulation, even a formulation with a reduced amount of atorvastatin is contemplated, including a time-controlled coating or an enzyme controlled coating or a pressure controlled coating.
• compositions i.e. the particulate composition and the solid dosage forms, are manufactured without any need of addition of water or an aqueous medium.
• the compositions of the invention have a very low content of moisture, i.e. less than about 2.5% w/w water, or less than about 2% w/w water, or less than about 1 % w/w water are obtained, thereby ensuring suitable storage stability, since both fenofibrate as well as atorvastatin is degradable by water.
• the solid pharmaceutical compositions in the form of particles and solid dosage forms of the present invention are useful for treatment of conditions that respond to fibrate and atorvastatin treatment, including hypercholesterolemia and hyperlipidemia.
• the present invention provides a solid pharmaceutical composition in particulate form, which composition comprises a vehicle, an effective amount of atorvastatin or a pharmaceutically acceptable salt thereof, and an effective amount of fenofibrate exhibiting a bioavailability which is at least bioequivalent to a 130 mg Antara ® capsule.
• the composition of the invention provides a combination drug product with a low dose of fenofibrate, i.e. a reduced amount of this active substance, while at the same time providing a pharmaceutical composition being bioequivalent to commercially available fenofibrate-containing medicaments or, alternatively, being even more efficient by exhibiting an increased bioavailability such as an AUCo-24 value for fenofibrate relative to the AUC 0-24 value for a 130 mg Antara ® tablet of at least about 1.3.
• the amount of fenofibrate is less than 130 mg. That is a low dosage, i.e. a reduced amount, as compared to the commercially available medicaments providing various dosage forms typically containing 160 mg, 145 mg or 130 mg of fenofibrate, usually micronized fenofibrate.
• the composition of the invention comprises about 120 mg of fenofibrate. It is contemplated that the minimum effective amount of fenofibrate is about 30 mg.
• the amount of atorvastatin in the composition may vary from about 5 mg to about 80 mg. Conventionally the amount of fenofibrate present in the combination composition is higher that the amount of atorvastatin. However, effective co-formulations comprising a higher amount of atorvastatin than of fenofibrate is contemplated.
• the relative amount of atorvastatin to fenofibrate is at least 1 :15.
• a suitable vehicle which may be hydrophobic, hydrophilic or water- miscible.
• the invention in a second aspect, relates to a solid oral dosage form comprising the pharmaceutical composition.
• Useful solid dosage forms are in the form of tablets, beads, capsules, grains, pills, granulate, granules, powder, pellets, sachets or troches.
• the invention relates to a solid oral dosage form comprising an immediate release formulation of fibrate, preferably fenofibrate, and a controlled release formulation of atorvastatin.
• the solid dosage form may be tablets prepared by compressing a mixture of fibrate granulate and entero-coated atorvastatin granulate.
• the solid dosage form may be fibrate granulate, fibrate granules, fibrate grains, fibrate beads and/or fibrate pellets filled into capsules or sachets together with entero-coated atorvastatin granules, atorvastatin grains, atorvastatin beads and/or atorvastatin pellets.
• the invention relates to a method of manufacturing the pharmaceutical compositions and the solid oral dosage forms of the invention.
• the invention relates to a method of treating hyperlipid- emia or hypercholesterolemia comprising administering to a human in need of such treatment the pharmaceutical composition of this invention, and to use of the pharmaceutical composition or a solid dosage form of this invention for manufac ⁇ turing a medicament for treatment of hyperlipidemia or hypercholesterolemia in mammals.
• the pharmaceutical composition of the invention is advantageous by being in the form of particles, for example granulate, which can easily be further processed into solid dosage forms, especially tablets or filled into capsules. That is, the pharmaceutical composition of the invention exhibits suitable properties such as for example being free-flowing, non-adherent and compressible. [0045] Further aspects of the invention are evident from the following description. [0046] Comparison in vivo tests in dogs have shown, cf. the examples herein, that solid dosage forms and compositions of the invention exhibit significantly enhanced bioavailability of fenofibrate compared to commercially available solid dosage forms containing the same active ingredient, i.e.
• compositions and dosage forms according to the invention provide for a significant reduced food effect, i.e. the absorption is relatively independent on whether the patient takes the composition or dosage form together with or without any meal. It is contemplated that a modified release formulation may reduce the number of gastro-intestinal related side effects.
• fenofibrate-atorvastatin significantly reduces any negative effects of possible drug-drug interactions (i.e. fenofibrate-atorvastatin).
• the present invention fulfils the need for pharmaceutical compositions containing a combination of fenofibrate and atorvastatin or a pharmaceutically acceptable salt thereof for oral use that lead to an improved treatment of conditions requiring lipid management (e.g., atherosclerosis, coronary heart diseases, diabetes management, obesity, overweight, metabolic syndrome etc).
• lipid management e.g., atherosclerosis, coronary heart diseases, diabetes management, obesity, overweight, metabolic syndrome etc.
• the invention provides improved bioavailability, especially of the fenofibrate component, and an improved pharmacological response (LDL-cholesterol lowering and HDL-cholesterol increase) of atorvastatin.
• Fenofibrate has a very poor solubility in water, which property is regarded as one of the major reasons for the poor bioavailability of fenofibrate.
• Improved bioavailability results in improved treatment.
• Another way of obtaining an improved treatment of conditions where fenofibrate is indicated is by balancing the release of fenofibrate to the gastro-intestinal tract in such a manner that an enhanced plasma concentration of fenofibrate is obtained initially or delayed with respect to the time of administration, i.e. by administering modified or delayed release compositions containing fenofibrate.
• Figure 1 shows the mean plasma concentration data of Lipanthyl 160 mg fed state and Lipanthyl 160 mg fasted state (0-96 hours).
• Figure 2 shows the mean plasma concentration data of invention fenofibrate formulation (LCP-feno) 160 mg fed state and invention fenofibrate formulation (LCP-feno) 160 mg fasted state (0-96 hours).
• Figure 3 shows mean (average) AUCo-24 and mean (average) AUCo-inf for each of Lipanthyl fasted state, Lipanthyl fed state, invention fenofibrate formulation
• active substance As used herein, the terms “active substance”, “active pharmaceutical substance”, “active ingredient” and “active pharmaceutical ingredient” (API) denote any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals.
• the term includes those components that may undergo chemical change in the manufacture of the drug product and are present in the drug product in a modified form intended to furnish the specified activity or effect.
• hydrophilic describes that something 'likes water 1 , i.e. a hydrophilic molecule or portion of a molecule is one that typically is electrically polarized and capable of forming hydrogen bonds with water molecules, enabling it dissolve more readily in water than in oil or other "non-polar" solvents.
• amphiphilic describes a molecule (as a surfactant) having a polar water-soluble group attached to a water-insoluble hydrocarbon chain.
• hydrophilic polar
• non-polar hydrophobic
• hydrophobic denotes a compound tending to be electrically neutral and non-polar, and thus preferring other neutral and non- polar solvents or molecular environments.
• water-miscible denotes a compound being fully or partly miscible with water.
• certain polar lipids are partly water- miscible.
• the term "vehicle” means any solvent or carrier in a pharmaceutical product that has no pharmacological role.
• water is the vehicle for xylocaine and propylene glycol is the vehicle for many antibiotics.
• solid dispersion denotes a drug or active ingredient or substance dispersed on a particulate level in an inert vehicle, carrier, diluent or matrix in the solid state, i.e. usually a fine particulate dispersion.
• solid solution denotes a drug or active ingredient or substance dissolved on a molecular level in an inert vehicle, carrier, diluent or matrix in the solid state.
• interstitial crystalline solid solution denotes a drug or active ingredient or substance dissolved on a molecular level in an inert vehicle, carrier, diluent or matrix in the solid state, where the inert vehicle, carrier, diluent or matrix forms a crystal lattice and the dissolved fenofibrate molecules occupy the interstitial spaces between the solvent molecules in the crystal lattice, cf. the review article: Leuner C. and Dressman, J., European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 47-60.
• analog means a chemical compound that is structurally similar to another.
• drug means a compound intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.
• dosage form means the form in which the drug is delivered to the patient. Examples of known dosage forms are parenteral, topical, oral (liquid or dissolved powder, tablet, capsule, sachet), suppository, inhalation, transdermal, etc.
• bioavailability denotes the degree to which a drug or other substance becomes available to the target tissue after administration.
• suitable bioavailability is intended to mean that administration of a composition according to the invention will result in a bioavailability that is improved compared to the bioavailability obtained after administration of the active substance(s) in a plain tablet; or the bioavailability is at least the same or improved compared to the bioavailability obtained after administration of a commercially available product containing the same active substance(s) in the same amounts.
• compositions of the invention may also reduce or negate the need for the dosage form to be taken simultaneously with intake of food (this is in particular relevant fenofibrate) thereby allowing patients more freedom to choose when to administer the drug.
• bioequivalency denotes a scientific basis on which generic and brand name drugs are compared with one another. For example, drugs are bioequivalent if they enter circulation at the same rate when given in similar doses under similar conditions.
• bioequivalency of two compositions is established by a 90% confidence interval of between 0.80 and 1.25 for AUC (either AUCo-infinity or AUCo-24). In addition, a 90% confidence interval of between 0.80 and about 1.40 for Cmax is also required for bioequivalency.
• the combination composition of the invention i.e.
• fenofibrate active ingredient may be compared with standard commercial fenofibrate formulations, for example 160 mg or 145 mg Tricor®/I_ipanthyl® tablets or capsules or 130 mg Antara® capsules or similar, preferably 130 mg Antara® capsules.
• tmax denotes the time to reach the maximal plasma concentration (c ma ⁇ ) after administration
• AUCo-infinity or AUC denotes the area under the plasma concentration versus time curve from time 0 to infinity
• AUCo-t denotes the area under the plasma concentration versus time curve from time 0 to time t, especially, AUCo-24 is the area under the plasma concentration versus time curve from time 0 to time 24 hr at steady state conditions
• W50 denotes the time where the plasma concentration is 50% or more of C ma ⁇
• W75 denotes the time where the plasma concentration is 75% or more of C ma ⁇
• MRT denotes mean residence time for each of the active pharmaceutical ingredients of the compositions of the present invention.
• the term "medicine” or “medicament” means a compound used to treat disease, injury or pain. Medicine is designated “prophylactic,” i.e. the art of preserving health, and “therapeutic”, i.e. the art of restoring health. [0069]
• the terms "controlled release” and “modified release” are intended to be equivalent terms covering any type of release of active ingredient, e.g. fenofibrate or atorvastatin, from a composition of the invention that is appropriate to obtain a specific therapeutic or prophylactic response after administration to a subject. A person skilled in the art knows how controlled release/modified release differs from the release of plain tablets or capsules.
• release in a controlled manner and “release in a modified manner” have the same meaning as stated above.
• the terms include slow release (that results in a lower C ma ⁇ and later t ma ⁇ , but the half-life remains unchanged), extended release (that results in a lower C ma ⁇ , later t ma ⁇ , but apparent half-life is longer); delayed release (that result in an unchanged C max , but lag time and, accordingly, t max is delayed, and the half-life remains unchanged) as well as pulsatile release, burst release, sustained release, prolonged release, chrono-optimized release, fast release (to obtain an enhanced onset of action) etc. Included in the terms is also e.g.
• the term "erosion” or “eroding” means a gradual breakdown of the surface of a material or structure, for example of a tablet or the coating of a tablet.
• the active drug substances are the active drug substances.
• a first drug or active substance of the dosage forms and pharmaceutical compositions of this invention is a fibrate, usually fenofibrate as described above or an analog thereof. It should be understood that this invention includes dosage forms and compositions comprising a mixture of two, three or even four different fibrates and/or fibric acids.
• fibrates examples include bezafibrate, ciprofibrate, clinofibrate, clofibrate, etofylline, clofibrate, gemfibrozil, pirifibrate, simfibrate and tocofibrate; particularly useful are gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate and active metabolites and analogues thereof including any relevant fibric acid such as fenofibric acid.
• a second drug or active substance of the dosage forms and pharmaceutical compositions of this invention is atorvastatin as described above or, typically, a pharmaceutically acceptable salt thereof such as the calcium salt or the magnesium salt in either amorphous or crystalline form.
• the calcium salt exists in a number of crystalline forms (Forms I-XIV).
• any type and physical form of atorvastatin is useful in the compositions and solid dosage forms of the present invention.
• the first and second active substance i.e. fenofibrate and atorvastatin or a pharmaceutically acceptable salt thereof, is present in the composition or the solid dosage form of the invention in effective amounts together with a vehicle and optionally further excipients or additives. It is believed that fenofibrate in combination with atorvastatin may have an added effect; it has been shown that use of the combination results in TG and LDL levels being more decreased while
• HDL level is increased.
• the effective amount of fenofibrate is an amount which is at least bioequivalent to a 130 mg Antara ® capsule.
• the amount of fenofibrate present in the composition of the invention exhibits an increased bioavailability as compared to 130 mg Antara ® capsule by exhibiting a relative AUCo-24 value of 1.3 (AUC of fenofibrate of the invention relative to AUC of the 130 mg Antara ® capsule).
• fenofibrate is present in the composition of the invention in an amount below about 130 mg.
• fenofibrate is present in the composition of the invention in an amount of about 120 mg.
• the fenofibrate of the solid composition or the solid dosage form of this invention provides, after oral administration, an AUCo-24value of fibric acid
• the solid composition or the solid dosage form of this invention at least about 50% w/w, preferably at least about 75%w/w, of the total amount of active substances or essentially all of the fenofibrate is dissolved in vehicle selected from the group consisting of a hydrophobic, a hydrophilic and a water-miscible vehicle.
• fenofibrate is present in the form of a solid solution in the particulate composition.
• the presence of a solid solution can be tested by a DSC test mentioned herein.
• the fenofibrate forms an interstitial crystalline solid solution with the vehicle.
• the atorvastatin component may be co- dissolved or, at least when crystalline or semi-crystalline atorvastatin is used, dispersed homogeneously in the solid solution.
• crystallization of a diminutive amount of any of the active substances (notably fenofibrate) from the solid solution may occur during storage of the solid dosage form of the invention, especially in tablets due to the possibility of formation of cavities in the tablet during manufacturing (tablet compression), which cavities may leave space for crystallization.
• the present invention includes particulate material wherein the active substances, or at least the fenofibrate, are present in the form of a solid solution, but it is within the scope of the present invention that a minor or diminutive amount of the active substance(s) in solid solution may precipitate or crystallize upon storage.
• At least about 80% w/w, preferably 100% w/w, of fenofibrate is dissolved in the vehicle, which is further processed into the particulate form as described herein.
• the solid particles for examples granulate, comprising the dissolved fenofibrate is then mixed or blended with micronized atorvastatin, and the resulting composition is optionally subjected to conventional methods for preparing solid dosage forms, especially tablets.
• the solid fenofibrate particles are mixed with entero-coated atorvastatin particles, for example entero-coated granulate, and subjected to conventional methods for preparing tablets or simply filled into capsules or sachets.
• the solid composition of the invention is free-flowing, i.e. has a suitable flowability as determined according to the method described in the European Pharmacopoeia (Ph. Eur.) measuring the flow rate of the composition out of a funnel with a nozzle diameter of 10.0 mm.
• the concentration of fenofibrate in the vehicle is at least about 10% w/w, based on the total weight of the fibrate, the statin and the vehicle.
• the concentration of fenofibrate in the vehicle is at least about 15% w/w, or at least about 16% w/w, or at least about 17% w/w, or at least about 20% w/w, preferably at least 25% w/w, more preferably at least about 30% w/w, especially at least about 35% w/w, based on the total weight of the fibrate, the statin and the vehicle.
• the concentration of atorvastatin in the vehicle of the solid composition or solid dosage form according to the invention is at least about 1 % w/w, based on the total weight of the fibrate, the statin and the vehicle. More specifically, the concentration of statin in the vehicle is at least about 1.5% w/w, or at least about 2.5% w/w, or at least about 5% w/w, or at least about 7.5% w/w or at least about 10% w/w, based on the total weight of the fibrate, the statin and the vehicle.
• the present invention provides solid compositions and solid dosage forms for improved treatment of conditions that respond to fenofibrate and atorvastatin treatment, for example hyperlipidemia and hypercholesterolemia.
• the fibrate is fenofibrate present in the solid dosage form or the pharmaceutical composition of this invention in an amount selected from the group consisting of 160 mg, 145 mg, 130 mg, 120 mg, 110 mg, 100 mg, 90 mg, 87 mg, 80 mg, 70 mg, 60 mg, 50 mg, 48 mg, 45 mg, 43 mg, 40 mg, 35 mg and 30 mg of fenofibrate.
• the solid dosage form comprises 145 mg of fenofibrate.
• the solid dosage form comprises 130 mg of fenofibrate.
• the solid dosage form comprises 120 mg of fenofibrate.
• the solid dosage form comprises 110 mg of fenofibrate. In yet another preferred embodiment, the solid dosage form comprises 50 mg of fenofibrate. In yet another preferred embodiment, the solid dosage form comprises 48 mg of fenofibrate. In yet another preferred embodiment, the solid dosage form comprises 43 mg of fenofibrate. In yet another preferred embodiment, the solid dosage form comprises 87 mg of fenofibrate.
• Atorvastatin may be present (conveniently as atorvastatin calcium or as atorvastatin magnesium, either in amorphous form, in semi-amorphous form, in semi-crystalline form or in crystalline form) in an amount of from about 5 mg to about 80 mg, for example in an amount of about 5 mg or about 10 mg or about 15 mg or about 20 mg or about 25 mg or about 30 mg or about 35 mg or about 40 mg or about 45 mg or about 50 mg or about 55 mg or about 60 mg or about 65 mg or about 70 mg or about 75 mg or about 80 mg of atorvastatin or a pharmaceutically acceptable salt thereof, for example the calcium salt or the magnesium salt.
• Examples of useful combinations are about 120 mg of fenofibrate and about 10 mg of atorvastatin; about 120 mg of fenofibrate and about 20 mg of atorvastatin; about 120 mg of fenofibrate and about 30 mg of atorvastatin; about 120 mg of fenofibrate and about 40 mg of atorvastatin; about 120 mg of fenofibrate and about 10 mg of atorvastatin; about 110 mg of fenofibrate and about 10 mg of atorvastatin; about 110 mg of fenofibrate and about 20 mg of atorvastatin; about 110 mg of fenofibrate and about 30 mg of atorvastatin; about 110 mg of fenofibrate and about 40 mg of atorvastatin.
• the fenofibrate solid dosage forms and pharmaceutical compositions of the present invention eliminate the food effect, i.e. may be administered in the fed or the fasted state. Accordingly, the present invention provides the patient the choice of taking only one tablet daily at any time over the commercially available fenofibrate-containing medicament which should be taken with food in order to achieve the desired bioavailability of the active ingredient.
• the liver is the primary site of action (first-pass metabolism); accordingly, the pharmacological or therapeutic response is correlated to the actual oral dose administered and not correlated to the plasma exposure. That is, plasma concentrations of atorvastatin acid and its metabolites do not correlate with LDL-cholesterol reduction at a given dose. Thus, the efficacy of atorvastatin may be better predicted by drug dose than by peak concentration (Cmax).
• the best possible total in vivo efficacy of orally administered atorvastation can be obtained by providing the drug in a controlled release formulation or, alternatively, in a delayed release formulation, since atorvastatin is metabolized in vivo by cytochrome P450 (CYP) 3A4 to two active metabolites (2-hydroxy-atorvastatin acid and 4-hydroxy- atorvastatin acid), thus allowing the active substances to be released in areas of the intestine having a reduced CYP3A4 activity and optionally over an extended period of time, resulting in a relatively larger amount of the administered drug actually reaching the liver. Accordingly, it is contemplated that the dose level can be reduced while maintaining the LDL-lowering effect.
• CYP 3A4 cytochrome P450
• the invention relates to a pharmaceutical composition in particulate form or solid dosage form comprising fenofibrate and atorvastatin, wherein the composition upon oral administration to a mammal in need thereof exhibits an AUC/AUCcontroi value for fenofibrate of at least about 1.0, the AUCcontroi being determined using a commercially available product containing fenofibrate, and the AUC values being determined under similar conditions.
• No absolute bioavailability data based on an injectable composition are available e.g., for fenofibrate (most likely due to solubility problems in aqueous media).
• compositions containing fenofibrate include surface-active agents and/or e.g., a lipophilic medium.
• the surface-active agents may impart improved bioavailability and therefore, the bioavailability of such a composition may be sufficient already.
• the AUC/AUCcontroi value for fenofibrate obtained by administering the solid dosage form or pharmaceutical composition of the invention is at least about 1.1 such as, e.g., at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, about 1.75 or more, about 1.8 or more, about 1.9 or more, about 2.0 or more, about 2.5 or more, about 2.75 or more, about 3.0 or more, about 3.25 or more, about 3.5 or more, about 3.75 or more, about 4.0 or more, about 4.25 or more, about 4.5 or more, about 4.75 or more or about 5.0 or more, the AUC values being determined under similar conditions.
• the c ma ⁇ value for fenofibrate obtained by administering the solid dosage form or pharmaceutical composition of the invention relative to the c ma ⁇ value of commercially available Tricor ® (Lipanthyl ®) tablets, or alternatively to commercially available Antara ® capsules is at least about 1.1 , or at least about 1.2, or at least about 1.3, or at least about 1.4, or at least about 1.5, or at least about 1.6 or more, or at least about 2.0, or at least about 2.5, or at least about 3.0, the Cmax values being determined under similar conditions.
• Another object of the invention is to reduce or eliminate the food effect.
• the invention relates to a pharmaceutical composition in particulate form or solid dosage form comprising one or more fibrates, especially fenofibrate, wherein the composition or solid dosage form upon oral administration to a mammal in need thereof does not exhibit a significant adverse food effect as evidenced by a value of (AUCfed/AUCfasted) of at least about 0.85 with a lower 90% confidence limit of at least 0.75.
• the pharmaceutical composition or solid dosage form of the invention has a value of (AUCfed/AUCfasted) that is about 0.9 or more such as, e.g., about 0.95 or more, about 0.97 or more or about 1 or more.
• the difference between a bioequivalence parameter measured after oral administration to a mammal with and without food, respectively, is less than about 25% such as, e.g., less than about 20%, less than about 15%, less than about 10% or less than about 5%.
• the invention relates to a pharmaceutical composition in particulate form or solid dosage form comprising fenofibrate, wherein the composition upon oral administration to a mammal in need thereof is essentially bioequivalent with a commercially available product containing fenofibrate when administered in the same or lower dose as the commercially available product containing fenofibrate.
• the dose is at the most about 98% w/w such as, e.g., at the most about 95% w/w, at the most about 90% w/w, at the most about 85% w/w, at the most about 80% w/w, at the most about 75% w/w, at the most about 70% w/w, at the most about 65% w/w, at the most about 60% w/w, at the most about 55% w/w or at the most about 50% w/w of the dose of fenofibrate administered in the form of a commercially available product containing fenofibrate.
• the invention relates to a pharmaceutical composition in particulate form comprising fenofibrate, wherein the composition upon oral administration to a mammal in need thereof reduces inter- and/or intra-individual variations compared to those of a commercially available product containing fenofibrate under the same conditions and in a dose that provides an equivalent therapeutic effect.
• the commercially available fenofibrate product is Tricor® (Lipanthyl ®) in the form of tablets or, alternatively, Tricor® in the form of capsules, or Antara® capsules.
• a convenient method for determining whether a suitable amount of fenofibrate has been absorbed may be to determine the content of unchanged fibrate excreted via the faeces.
• the invention relates to a solid pharmaceutical composition or solid dosage form, wherein at most about 25% w/w such as, e.g., at the most about 20% w/w, at the most about 15% w/w, at the most about 10% w/w, at the most about 5% w/w of the fenofibrate contained in the composition is excreted in the faeces after oral administration.
• the vehicle e.g., at the most about 20% w/w, at the most about 15% w/w, at the most about 10% w/w, at the most about 5% w/w of the fenofibrate contained in the composition is excreted in the faeces after oral administration.
• Vehicles useful in the present context are vehicles, which are water- miscible, hydrophilic or hydrophobic.
• Useful vehicles are non-aqueous substances which may be hydrophilic, lipophilic, hydrophobic and/or amphiphilic materials.
• the hydrophobic or hydrophilic or water-miscible vehicles will normally be liquid at ambient or elevated temperature.
• a hydrophobic or a hydrophilic or water-miscible vehicle is used in a very broad sense including oils, waxes, semi-solid materials and materials that normally are used as solvents (such as organic solvents) or co-solvents within the pharmaceutical industry, and the term also includes therapeutically and/or prophylactically active substances that are in liquid form at ambient temperature; furthermore the term includes emulsions like e.g., micro-emulsions and nanoemulsions and suspensions.
• the oils or oily materials that are suitable for use in the present context are substances or materials, which have a melting point of at least about 1O 0 C and at the most about 25O 0 C.
• the oily material has a melting point of about 5 0 C or more such as, e.g., about 1O 0 C or more, about 15 0 C or more, about 2O 0 C or more or about 25 0 C or more.
• the oily material has a melting point of at least about 25 0 C such as, e.g., at least about 3O 0 C at least about 35 0 C or at least about 4O 0 C.
• the melting point may normally not be too high, thus the oily material normally has a melting point of at the most about 25O 0 C, at the most about 200°C, at the most about 15O 0 C or at the most about 100°C.
• a suitable hydrophilic oil or oily material is selected from the group consisting of: polyether glycols such as, e.g., polyethylene glycols, polypropylene glycols; polyoxyethylenes; polyoxypropylenes; poloxamers and mixtures thereof, or it may be selected from the group consisting of: xylitol, sorbitol, potassium sodium tartrate, sucrose tribehenate, glucose, rhamnose, lactitol, behenic acid, hydroquinon monomethyl ether, sodium acetate, ethyl fumarate, myristic acid, citric acid, Sucro-ester 7, Sucro-ester 11 , Sucro-ester 15, maltose, mannitol and mixtures thereof.
• polyether glycols such as, e.g., polyethylene glycols, polypropylene glycols; polyoxyethylenes; polyoxypropylenes; poloxamers and mixtures thereof, or it may be selected from the group consisting of: x
• the pharmaceutical composition or a solid dosage form according to the invention may have a concentration of oil or oily material in the composition or the dosage form of about 5% w/w or more such as, e.g., about 10% w/w or more, about 15% w/w or more, about 20% w/w or more, about 25% w/w or more, about 30% w/w or more, about 35% w/w or more, about 40% w/w or more, about 45% w/w or more, about 50 w/w or more, about 55% w/w or more, about 60% w/w or more, about 65% w/w or more, about 70% w/w or more, about 75% w/w or more, about 80% w/w or more, about 85% w/w or more, about 90% w/w or more or about 95% w/w or more.
• 5% w/w or more such as, e.g., about 10% w/w or more, about 15% w/w
• the concentration of the oily material in a composition or solid dosage form of the invention is in a range from about 20% to about 80% w/w such as, e.g., from about 25% to about 75% w/w.
• the hydrophobic or hydrophilic or water-miscible vehicles that are suitable for use in the present context are substances or materials having a melting point of at least about O 0 C and at the most about 25O 0 C.
• hydrophobic or hydrophilic or water-miscible vehicles are generally substances, which are used in the manufacture of pharmaceuticals as so-called melt binders or solid solvents (in the form of solid dosage form), or as co- solvents or ingredients in pharmaceuticals for topical use.
• It may be hydrophilic, hydrophobic and/or have surface-active properties.
• hydrophilic and/or hydrophobic vehicles are suitable for use in the manufacture of a solid pharmaceutical composition in particulate form or a solid dosage form according to the invention. In a specific embodiment they may be used when the release of the active substance from the pharmaceutical composition is designed to be immediate or non-modified or modified.
• Hydrophobic vehicles are normally used in the manufacture of a modified release pharmaceutical composition.
• hydrophobic vehicles useful in the present invention are straight chain saturated hydrocarbons, paraffins; fats and oils such as cacao butter, beef tallow, lard; higher fatty acid such as stearic acid, myristic acid, palmitic acid; hydrogenated tallow, substituted and/or unsubstituted triglycerides, yellow beeswax, white beeswax, carnauba wax, castor wax, Japan wax, and mixtures thereof.
• water-miscible vehicles useful in the present invention are: [0114] water-miscible polar lipids such as sorbitan esters, polyether glycol esters; higher alcohols such as cetanol, stearyl alcohol; glyceryl monooleate, substituted and/or unsubstituted monoglycerides, substituted and/or unsubstituted diglycerides, and mixtures thereof.
• water-miscible polar lipids such as sorbitan esters, polyether glycol esters; higher alcohols such as cetanol, stearyl alcohol; glyceryl monooleate, substituted and/or unsubstituted monoglycerides, substituted and/or unsubstituted diglycerides, and mixtures thereof.
• the vehicle is hydrophilic or water- miscible.
• the vehicle is selected from the group consisting of polyethylene glycols, polyoxyethylene oxides, poloxamers, polyoxyethylene stearates, poly-epsilon caprolactone and mixtures thereof.
• Examples of useful hydrophilic or water-miscible vehicles are polyvinylpyrrolidones, polyvinyl-polyvinylacetate copolymers (PVP-PVA), polyvinyl alcohol (PVA), PVP polymers, acrylic polymers, poly methacry lie polymers (Eudragit RS; Eudragit RL, Eudragit NE, Eudragit E), myristyl alcohol, cellulose derivatives including hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, pectins, cyclodextrins, galactomannans, alginates, carragenates, xanthan gums and mixtures thereof.
• PVP-PVA polyvinyl-polyvinylacetate copolymers
• PVA polyvinyl alcohol
• PVP polymers acrylic polymers
• poly methacry lie polymers Eudragit RS; Eudra
• the vehicle is preferably a mixture of two or more substances.
• the vehicle may also be an oily material as defined and described below.
• the melting point of the vehicle is preferably in the range of 1O 0 C to 25O 0 C, preferably in the range of 3O 0 C to 100 0 C, more preferably in the range of 4O 0 C to 75 0 C, especially in the range of 4O 0 C to 7O 0 C.
• the hydrophobic or hydrophilic or water-miscible vehicles have a melting point of about 5 0 C or more such as, e.g., about 1O 0 C or more, about 15 0 C or more, about 2O 0 C or more or about 25 0 C or more.
• a melting point of about 5 0 C or more such as, e.g., about 1O 0 C or more, about 15 0 C or more, about 2O 0 C or more or about 25 0 C or more.
• vehicles having such a low melting point require addition of an oil-sorption material.
• a person skilled in the art will know when it is necessary to add such an oil-sorption material.
• the vehicle is a polyethylene glycol having an average molecular weight in a range of from about 400 to about 35,000 such as, e.g., from about 800 to about 35,000, from about 1 ,000 to about 35,000 such as, e.g., polyethylene glycol 1 ,000, polyethylene glycol 2,000, polyethylene glycol 3,000, polyethylene glycol 4,000, polyethylene glycol 5,000, polyethylene glycol 6,000, polyethylene glycol 7,000, polyethylene glycol 8,000, polyethylene glycol 9,000 polyethylene glycol 10,000, polyethylene glycol 15,000, polyethylene glycol 20,000, or polyethylene glycol 35,000.
• polyethylene glycol may be employed with a molecular weight from about 35,000 to about 100,000.
• the vehicle is polyethylene oxide having a molecular weight of from about 2,000 to about 7,000,000 such as, e.g. from about 2,000 to about 100,000, from about 5,000 to about 75,000, from about 10,000 to about 60,000, from about 15,000 to about 50,000, from about 20,000 to about 40,000, from about 100,000 to about 7,000,000 such as, e.g., from about 100,000 to about 1 ,000,000, from about 100,000 to about 600,000, from about 100,000 to about 400,000 or from about 100,000 to about 300,000.
• the vehicle is a poloxamer (PEO-PPO-PEO, a polyethylene oxide-polypropylene oxide-polyethylene oxide tri-block polymer), for example Poloxamer 188, Poloxamer 237, Poloxamer 338 or Poloxamer 407 or other block copolymers of ethylene oxide and propylene oxide such as the Pluronic® and/or Tetronic® series from BASF.
• Suitable block copolymers of the Pluronic® series include polymers having a molecular weight of about 3,000 or more such as, e.g.
• Suitable examples include Pluronic® F38, P65, P68LF, P75, F77, P84, P85, F87, F88, F98, P103, P104, P105, F108, P123, F123, F127, 10R8, 17R8, 25R5, 25R8 etc.
• Suitable block copolymers of the Tetronic® series include polymers having a molecular weight of about 8,000 or more such as, e.g., from about 9,000 to about 35,000 and/or a viscosity (Brookfield) of from about 500 to about 45,000 cps such as, e.g., from about 600 to about 40,000.
• the viscosities given above are determined at 6O 0 C for substances that are pastes at room temperature and at 77 0 C for substances that are solids at room temperature.
• a particulate material according to the invention comprises as vehicle a mixture of a polyethylene glycol and a poloxamer in a proportion (weight) of between about 1 :3 and about10:1 , preferably between about 1 :1 and about 5:1 , more preferably between about 3:2and about 4:1 , especially between about 2:1 and about 3:1 , in particular about 7:3.
• the poloxamer is poloxamer 188.
• polyethylene glycol is employed as a vehicle, the PEG having an average molecular weight of about 6000 (PEG 6000).
• the vehicle may also be a sorbitan ester such as, e.g., sorbitan di- isostearate, sorbitan dioleate, sorbitan monolaurate, sorbitan monoisostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesqui-isostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan tri- isostearate, sorbitan trioleate, sorbitan tristearate or mixtures thereof.
• the vehicle may also comprise a mixture of different vehicles, for example a mixture of hydrophilic and/or hydrophobic materials.
• Other suitable vehicles may be solvents or semi-solid excipients, for example propylene glycol, complex fatty materials of plant origin including theobroma oil, carnauba wax, vegetable oils like e.g. almond oil, coconut oil, corn oil, cottonseed oil, sesame oil, soy bean oil, olive oil, castor oil, palm kernels oil, peanut oil, rape oil, grape seed oil etc., hydrogenated vegetable oils such as, e.g.
• One of the advantages is that is it possible to incorporate a relatively large amount of vehicle and still have a material that is solid. Thus, it is possible to prepare solid compositions with a relatively high load of vehicle by use of an oil sorption material as mentioned above.
• a vehicle e.g., with oil or oi Iy-I ike characteristics
• a solid composition especially in those situation where the active substance does not have suitable properties with respect to water solubility (e.g., poor water solubility), stability in aqueous medium (i.e. degradation occurs in aqueous medium), oral bioavailability (e.g.
• a suitable vehicle being pharmaceutical acceptable, capable of dispersing, dissolving or at least partly dissolving the active substances and having a melting point in the desired range using general knowledge and routine experimentation.
• Suitable vehicles are for example disclosed in WO 03/004001 , which is incorporated herein by reference.
• the solid composition of the invention has a suitable flowability. In order to avoid any adherence to the manufacturing and/or filling equipment it is important that the particulate material is free-flowing. This characteristic is also important in those cases where it is desired to process the particulate material further, for example into solid dosage forms.
• the particulate composition of the invention is a free-flowing powder it can be immediately processed into e.g. solid dosage forms such as tablets, capsules or sachets. Normally, the particulate composition has properties so as to allow manufacturing of tablets by direct compression without addition of large amounts of further additives.
• the used vehicle is an oily material which may be present in a relatively high amount.
• the particulate material may contain one or more oil-sorption materials, which - when tested as described herein - i) has an oil threshold value of 10% or more, when tested according to the Threshold Test herein, and at least one of ii) releases at least 30% of an oil, when tested according to the Release Test herein, and iii) in the form of a tablet, has a disintegration time of at the most 1 hour, when tested according to Ph. Eur.
• the tablet containing about 90% w/w or more of the oil-sorption material.
• a sorption material in the composition in order e.g., to enable a high concentration of a vehicle has oil or oily-like character.
• the vehicle has a melting point of at the most about 25 0 C, it may be especially suitable to incorporate a sorption material.
• Suitable examples of materials suitable as vehicles as well as sorption materials are given herein.
• composition or solid dosage form according to the invention may contain one or more pharmaceutically acceptable excipients.
• suitable excipients for use in a composition or solid dosage form according to the invention include fillers, diluents, disintegrants, binders, lubricants etc. or mixtures thereof.
• composition or solid dosage form according to the invention may be used for different purposes, the choice of excipients is normally made taken such different uses into considerations.
• Other pharmaceutically acceptable excipients for suitable use are e.g. acidifying agents, alkalizing agents, preservatives, antioxidants, buffering agents, chelating agents, coloring agents, complexing agents, emulsifying and/or solubilizing agents, flavors and perfumes, humectants, sweetening agents, wetting agents etc.
• suitable fillers, diluents and/or binders include lactose (e.g.
• methylcellulose polymers such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g., basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulfate, calcium
• diluents are e.g., calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pre-gelatinized starch, sucrose, sugar etc.
• disintegrants are e.g., calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pre-gelatinized starch, sucrose, sugar etc.
• disintegrants are e.g.
• alginic acid or alginates microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl starch (e.g. Primogel® and Explotab®) etc.
• binders are e.g., acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropyl methylcellulose, methylcellulose, pectin, PEG, povidone, pregelatinized starch etc.
• Glidants and lubricants may also be included in the second composition.
• Examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearate, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc.
• compositions or solid dosage form of the invention are e.g., flavoring agents, coloring agents, taste-masking agents, pH-adjusting agents, buffering agents, preservatives, stabilizing agents, anti-oxidants, wetting agents, humidity-adjusting agents, surface-active agents, suspending agents, absorption enhancing agents, agents for modified release etc.
• excipients which may be included in a composition or solid dosage form of the invention are e.g., flavoring agents, coloring agents, taste-masking agents, pH-adjusting agents, buffering agents, preservatives, stabilizing agents, anti-oxidants, wetting agents, humidity-adjusting agents, surface-active agents, suspending agents, absorption enhancing agents, agents for modified release etc.
• additives in a composition or a solid dosage form according to the invention may be antioxidants like e.g.
• the carrier composition may also contain e.g., stabilising agents.
• concentration of an antioxidant and/or a stabilizing agent in the carrier composition is normally from about 0.1 % w/w to about 5% w/w.
• a composition or solid dosage form according to the invention may also include one or more surfactants or substances having surface-active properties. It is contemplated that such substances are involved in the wetting of the slightly soluble active substance and thus, contributes to improved solubility characteristics of the active substance.
• Suitable surfactants for use in a composition or a solid dosage form according to the invention are surfactants such as, e.g., hydrophobic and/or hydrophilic surfactants as those disclosed in WO 00/50007 in the name of Lipocine, Inc.
• Suitable surfactants are polyethoxylated fatty acids such as, e.g., fatty acid mono- or diesters of polyethylene glycol or mixtures thereof such as, e.g., mono- or diesters of polyethylene glycol with lauric acid, oleic acid, stearic acid, myristic acid, ricinoleic acid, and the polyethylene glycol may be selected from PEG 4, PEG 5, PEG 6, PEG 7, PEG 8, PEG 9, PEG 10, PEG 12, PEG 15, PEG 20, PEG 25, PEG 30, PEG 32, PEG 40, PEG 45, PEG 50, PEG 55, PEG 100, PEG 200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000, PEG 3000, PEG 4000, PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG 9000, PEG 1000, PEG 10,000, PEG 15,000, PEG 20,000, PEG 35,000, polyethylene glycol
• vegetable oils like e.g., hydrogenated castor oil, almond oil, palm kernel oil, castor oil,
• glyceryl monooleate glyceryl dioleae, glyceryl mono- and/or dioleate, glyceryl caprylate, glyceryl caprate etc.
• sterol and sterol derivatives polyethylene glycol sorbitan fatty acid esters (PEG-sorbitan fatty acid esters) such as esters of PEG with the various molecular weights indicated above, and the various Tween® series (from ICI America, Inc.); polyethylene glycol alkyl ethers such as, e.g., PEG oleyl ether and PEG lauryl ether; sugar esters like e.g.
• sucrose monopalmitate and sucrose monolaurate polyethylene glycol alkyl phenols like e.g. the Triton® X or N series (Union Carbide Chemicals & Plastics Technology Corporation); polyoxyethylene-polyoxypropylene block copolymers such as, e.g., the Pluronic® series from BASF Aktiengesellschaft, the Synperonic® series from ICI America, Inc., Emkalyx , Lutrol® from BASF Aktiengesellschaft, Supronic etc.
• polymers The generic term for these polymers is "poloxamers" and relevant examples in the present context are Poloxamer 105, 108, 122, 123, 124, 181 , 182, 183, 184, 185, 188, 212, 215, 217, 231 , 234, 235, 237, 238, 282, 284, 288, 331 , 333, 334, 335, 338, 401 , 402, 403 and 407; sorbitan fatty acid esters like the Span® series (from ICI) or Arlacel® series (from ICI) such as, e.g., sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate etc.; lower alcohol fatty acid esters like e.g., oleate, isopropyl myristate, isopropyl palmitate etc.; ionic surfactants including cationic, anionic and zwitterionic
• the concentration of the surfactant(s) is normally in a range of from about 0.1 - 80% w/w such as, e.g., from about 0.1 to about 20% w/w, from about 0.1 to about 15% w/w, from about 0.5 to about 10% w/w, or alternatively, from about 0.10 to about 80% w/w such as, e.g. from about 10 to about 70% w/w, from about 20 to about 60% w/w or from about 30 to about 50% w/w.
• the at least one of the one or more pharmaceutically acceptable excipient is selected from the group consisting of silica acid or a derivative or salt thereof including silicates, silicon dioxide and polymers thereof; magnesium aluminosilicate and/or magnesium aluminometasilicate, bentonite, kaolin, magnesium trisilicate, montmorillonite and/or saponite. Sorption materials
• sorption material for oily materials in pharmaceuticals, cosmetics and/or foodstuff.
• the material is used as a sorption material for oily materials in pharmaceuticals.
• the material that has the ability to function as a sorption material for oily materials is also denoted “oil sorption material”.
• sorption is used to denote “absorption” as well as “adsorption”. It should be understood that whenever one of the terms is used it is intended to cover the phenomenon absorption as well as adsorption.
• sorption material and “oil sorption material” is intended to have the same meaning.
• a sorption material suitable for use according to the present invention is a solid pharmaceutically acceptable material, which - when tested as described herein - i) has an oil threshold value of 10% or more, when tested according to the Threshold Test disclosed herein, and which material is used in a composition of the invention further fulfilling one or both of i) and ii): i) the composition releases at least 30% of the hydrophobic or a hydrophilic or water-miscible vehicle, when tested according to the Release Test; ii) the composition contains, in the form of a tablet, at least about 90% w/w of the oil-sorption material, and exhibits a disintegration time of at the most 60 minutes when tested according to the Ph. Eur. Disintegration Test.
• the material is especially useful as a sorption material for oily materials in pharmaceuticals, cosmetics and/or foodstuff, especially in pharmaceuticals.
• the Threshold Test involves the determination of the flowability of the solid material loaded with different amounts of oil.
• the oil threshold value normally must exceed 10% and often the oil sorption material has an oil threshold value of at least about 15%, such as, e.g., at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, or at least about 45%.
• An especially suitable material for use according to the invention, Aeroperl ® 300 has a very high oil threshold value of about 60%. Accordingly, materials that have an oil threshold value of at least about 50%, such as, e.g., at least about 55% or at least about 60% are used in specific embodiments of the present invention.
• an oil sorption material for use according to the invention must fulfil at least one further test, namely a release test and/or a disintegration test.
• the release test gives a measure of the ability of an oil sorption material to release the oil that is absorbed to the material when contacted with water. This ability is very important especially in those situations where an active substance is contained in the oily material. If the oil sorption material is not capable of releasing the oil from the material then there is a major risk that the active substance will only to a minor degree be released from the material. Accordingly, it is envisaged that bioavailability problems relating to e.g., poor absorption etc. will occur in such situations.
• the solid pharmaceutical acceptable material when tested as described herein, releases at least about 30% such as, e.g., at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 60% of an oil.
• a suitable oil sorption material like Aeroperl ® 300 has a much higher release. Therefore, in a specific embodiment of the invention, the solid pharmaceutical acceptable material, when tested as described herein, releases at least about 65% such as, e.g., at least about 70%, at least about 75% or at least about 80% of an oil.
• the disintegration test is not performed on the solid composition in particulate form but on a tablet made of the solid material.
• a requirement with respect to disintegration is important in order to ensure that the solid composition, when included in solid dosage forms, does not impart unwanted properties to the dosage form e.g., leading to unwanted properties with respect to dissolution and bioavailability of the active substance contained in the dosage form.
• excipients normally used in the preparation of compressed tablets up to a concentration of 10% w/w or less.
• suitable pharmaceutically acceptable excipients include fillers, diluents, binders and lubricants.
• excipients, normally classified as disintegrants, should be avoided.
• the solid pharmaceutical acceptable material for use according to invention when tested as described herein, in the form of a tablet should have a disintegration time of at the most 1 hour, when tested according to Ph. Eur. Disintegration test, the tablet containing about 90% w/w or more, such as, e.g., about 92.5% w/w or more, about 95% w/w or more, about 97.5% w/w or more or about 100% of the pharmaceutically acceptable material.
• the solid pharmaceutical acceptable material when tested as described herein, in the form of a tablet has a disintegration time of at the most about 50 min, such as, e.g., at the most about 40 min, at the most about 30 min, at the most about 20 min, at the most about 10 min or at the most about 5 min, when tested according to Ph. Eur. Disintegration test, the tablet containing about 90% w/w or more, such as, e.g., about 92.5% w/w or more, about 95% w/w or more, about 97.5% w/w or more or about 100% of the pharmaceutically acceptable material.
• the solid material used as a sorption material fulfils all three tests.
• the solid pharmaceutical acceptable material when tested as described herein, i) has an oil threshold value of at least about 10%, such as, e.g., at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 60%, ii) releases at least about 30% such as, e.g., at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75% or at least about 80% of an oil, and iii) in the form of a tablet has a disintegration time of at the most 1 hour such as at the most about 50 min, at the most about 40 min, at the most about 30 min, at the most about 20 min, at the most about 10
• the tablet containing about 90% w/w or more, such as, e.g., about 92.5% w/w or more, about 95% w/w or more, about 97.5% w/w or more or about 100% of the pharmaceutically acceptable material.
• solid pharmaceutical material used as a sorption material in a composition of the invention when tested as described herein, i) has an oil threshold value of at least about 55%; the solid pharmaceutical material, when tested as described herein, ii) releases at least about 75% of an oil; and/or the solid pharmaceutical material, when tested as described herein, iii) in the form of a tablet has disintegration time of at the most about 10 min, when tested according to Ph. Eur. Disintegration test, the tablet containing about 97.5% w/w of the pharmaceutically acceptable material.
• the solid pharmaceutically acceptable material used as a sorption material in a composition according to the invention is normally a particulate material in the form of e.g. powders, particles, granules, granulates etc.
• Such particulate material suitable for use as an oil sorption material has normally a bulk density of about 0.15 g/cm 3 or more such as, e.g., at least about 0.20 g/cm 3 or at least about 0.25 g/cm 3 .
• the oil sorption material normally has an oil absorption value of at least about 100 g oil/100 g such as, e.g., at least about 150 g oil/100 g, at least about 200 g oil/100g, at least about 250 g oil/100 g, at least about 300 g oil/100 g or at least about 400 g oil/100 g pharmaceutically acceptable material.
• the oil absorption value is determined as described in the experimental section herein.
• pharmaceutically acceptable material for use as an oil sorption material according to the invention may have a BET surface area of at least 5 m 2 /g such as, e.g., at least about 25 m 2 /g, at least about 50 m 2 /g, at least about 100 m 2 /g, at least about 150 m 2 /g, at least about 200 m 2 /g, at least about 250 m 2 /g or at least about 275 m 2 /g.
• a pharmaceutically acceptable material for use as an oil sorption material according to the invention retains a good flowability even if it has been loaded with oily material.
• the flowability of the pharmaceutically acceptable material loaded with about 25% w/w or more such as, e.g. about 30% w/w or more, about 40% w/w or more, about 45% w/w or more, about 50% w/w or more, about 55% w/w or more, about 60% w/w or more, about 65% w/w or more or about about 70% w/w viscoleo will normally meet the Ph. Eur. requirements.
• the oil sorption material may comprise a silica acid or a derivative or salt thereof such as, e.g., silicon dioxide or a polymer thereof as a pharmaceutically acceptable excipient.
• a silicon dioxide may be a lubricant or it may be an oil sorption material. Qualities fulfilling the latter function seem to be most important.
• a composition or solid dosage form according to invention comprises a pharmaceutically acceptable excipient that is a silicon dioxide product that has properties corresponding to Aeroperl® 300.
• Use of an oil sorption material in compositions or dosage forms according to the invention is very advantageous for the preparation of pharmaceutical, cosmetic, nutritional and/or food compositions, wherein the composition comprises oily material.
• One of the advantages is that is it possible to incorporate a relatively large amount of and oily material and still have a material that is solid. Thus, it is possible to prepare solid compositions with a relatively high load of oily materials by use of an oil sorption material according to the invention.
• an oil sorption material according to the invention.
• the oil sorption material for use in the processing into solid compositions normally absorbs about 5% w/w or more, such as, e.g., about 10% w/w or more, about 15% w/w or more, about 20% w/w or more, about 25% w/w or more, about 30% w/w or more, about 35% w/w or more, about 40% w/w or more, about 45% w/w or more, about 50 w/w or more, about 55% w/w or more, about 60% w/w or more, about 65% w/w or more, about 70% w/w or more, about 75% w/w or more, about 80% w/w or more, about 85% w/w or more, about 90% w/w or more or about 95% w/w or more of an oil or an oily material and is still a solid material.
• the oils and oily-like materials that can be absorbed are normally liquid at ambient or elevated temperature (for practical reasons the max. temperature is about 25O 0 C). They may be hydrophilic, lipophilic, hydrophobic and/or amphiphilic materials.
• Method of manufacture The particulate composition of the invention may be prepared by any method which is suitable for incorporation of poorly water-soluble active substances.
• the pharmaceutical compositions may be prepared by any convenient method such as, e.g. granulation, mixing, spray drying etc. A particularly useful method is the method disclosed in Applicants' co-pending international application published as WO 03/004001 , which describes a process for preparation of particulate material by a controlled agglomeration method, i.e.
• the method involves spraying a first composition comprising the active substance and a vehicle in liquid form onto a solid carrier.
• the vehicle has a melting point of at least 5 0 C, but the melting point must indeed be below the melting point of the active substance. In the present invention, the melting point of the vehicle and should not exceed 25O 0 C.
• a suitable vehicle being pharmaceutical acceptable, capable of dispersing or fully or at least partly dissolving the active substance and having a melting point in the desired range using general knowledge and routine experimentation.
• Suitable candidate for carriers are described in WO 03/004001 , which is herein incorporated by reference.
• suitable vehicles are e.g., those mentioned as vehicles or as oily materials as well as those disclosed in WO 03/004001.
• An advantage of using the controlled agglomeration method described in WO 03/004001 is that it is possible to apply a relatively large amount of a liquid system to a particulate material without having an undesirable growth in particle size.
• the particulate material of a pharmaceutical composition has a geometric weight mean diameter d gw of > 10 mm such as, e.g. > 20 mm, from about 20 to about 2000, from about 30 to about 2000, from about 50 to about 2000, from about 60 to about 2000, from about 75 to about 2000 such as, e.g.
• compositions and dosage forms of the invention are preferably formed by spray drying techniques, controlled agglomeration, freeze-drying or coating on carrier particles or any other solvent removal process.
• the dried product contains the active substances present preferably in dissolved form either fully dissolved as a solid solution, for example forming an interstitial crystalline solid solution, or partly dissolved as a solid dispersion including a molecular dispersion and a solid solution.
• composition and dosage forms of the invention are preferably manufactured by a method comprising the steps of: i) bringing the vehicle in liquid form, i.e. melting the vehicle if solid at room temperature, ii) maintaining the liquid vehicle at a temperature below the melting point of the fibrate, iii) dissolving the desired amount of fibrate in the vehicle, iv) spraying the resulting solution onto a solid carrier having a temperature below the melting point of the vehicle, v) mechanically working the resulting composition to obtain particles, i.e. a particulate material, and vi) optionally subjecting the particulate material to conventional methods for preparing solid dosage forms.
• the solid oral dosage form of the invention may be prepared by a method comprising the steps of i) Bringing the vehicle in liquid form, if applicable, ii) Maintaining the liquid vehicle at a temperature below the melting point of fenofibrate or a pharmaceutically acceptable salt thereof, iii) Dissolving the desired amount of fibrate in the vehicle, iv) Spraying the resulting solution onto a solid carrier having a temperature below the melting point of the vehicle, v) Mechanically working the resulting composition to obtain particles, i.e.
• a particulate material containing fenofibrate a particulate material containing fenofibrate, and, prior to or simultaneous with or after applying steps i) to v), vi) Bringing the vehicle in liquid form, if applicable, vii) Maintaining the liquid vehicle at a temperature below the melting point of atorvastatin or a pharmaceutically acceptable salt thereof, viii) Dissolving the desired amount of atorvastatin in the vehicle, ix) Spraying the resulting solution onto a solid carrier having a temperature below the melting point of the vehicle, x) Mechanically working the resulting composition to obtain particles, i.e.
• a particulate material containing atorvastatin followed by the steps of xi) Mixing the particulate material containing fenofibrate and the particulate material containing atorvastatin, and xii) Optionally subjecting the particulate material to conventional methods for preparing solid dosage forms.
• the solid oral dosage form of the invention is prepared by a method comprising the steps of: i) bringing the vehicle in liquid form, if applicable, ii) maintaining the liquid vehicle at a temperature below the melting point of fenofibrate or a pharmaceutically acceptable salt thereof, iii) dissolving the desired amount of fenofibrate in the vehicle, iv) spraying the resulting solution onto a solid carrier having a temperature below the melting point of the vehicle, v) Mechanically working the resulting composition to obtain particles, i.e.
• a particulate material containing fenofibrate and, prior to or simultaneous with or after applying steps i) to v), vi) micronizing atorvastatin or a pharmaceutically acceptable salt thereof, if applicable, followed by the steps of vii) mixing the particulate material containing fenofibrate and micronized atorvastatin, and viii) optionally subjecting the particulate material to conventional methods for preparing solid dosage forms.
• the solid oral dosage form of the invention is prepared by a method comprising the steps of: i) Bringing the vehicle for fibrate in liquid form, if applicable, ii) Maintaining the liquid vehicle at a temperature below the melting point of the fibrate or a pharmaceutically acceptable salt thereof, iii) Dissolving the desired amount of fibrate in the vehicle, iv) Spraying the resulting solution onto a solid carrier having a temperature below the melting point of the vehicle, v) Mechanically working the resulting composition to obtain particles, i.e.
• a particulate material containing fibrate containing fibrate, and, prior to or simultaneous with or after applying steps i) to v), vi) Bringing the vehicle for atorvastatin in liquid form, if applicable, vii) dissolving or dispersing the desired amount of atorvastatin in the vehicle, viii) Spraying the resulting solution onto a solid carrier having a temperature below the melting point of the vehicle, ix) Mechanically working the resulting composition to obtain particles, i.e.
• a particulate material containing atorvastatin a particulate material containing atorvastatin
• x) subjecting the particles to enteric coating followed by the steps of xi) Mixing the particulate material containing fibrate and the entero-coated particulate material containing atorvastatin, and xii) Optionally subjecting the particulate material to conventional methods for preparing solid dosage forms, for example compression into tablets of filling into capsules or sachets.
• at least part of the active substances is present in the composition in the form of a solid dispersion including a molecular dispersion and a solid solution and an interstitial crystalline solid solution.
• compositions comprising the active substance at least partly in form of a solid dispersion or solution may in principle be prepared using any suitable procedure for preparing pharmaceutical compositions known within the art.
• a solid dispersion may be obtained in different ways e.g., by employing organic solvents or by dispersing or dissolving the active substance in another suitable medium (e.g. an oily material that is in liquid form at room temperature or at elevated temperatures).
• Solid dispersions are prepared by dissolving a physical mixture of the active substance (e.g. a drug substance) and the carrier in a common organic solvent, followed by evaporation of the solvent.
• the carrier is often a hydrophilic polymer.
• Suitable organic solvents include pharmaceutical acceptable solvent in which the active substance is soluble such as methanol, ethanol, methylene chloride, chloroform, ethylacetate, acetone or mixtures thereof.
• Suitable water-soluble carriers include polymers such as polyethylene glycol, poloxamers, polyoxyethylene stearates, poly-epsilon-caprolactone, polyvinylpyrrolidone (PVP), polyvinyl pyrrol idone-polyvinylacetate copolymer PVP- PVA (Kollidon VA64), poly-methacrylic polymers (Eudragit RS, Eudragit RL, Eudragit NE, Eudragit E) and polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methyl cellulose, and poly(ethylene oxide) (PEO).
• PVP polyvinylpyrrolidone
• PVP- PVA Kerdon VA64
• PVA polyvinyl alcohol
• HPC hydroxypropyl cellulose
• HPMC hydroxypropyl methyl cellulose
• PEO poly(ethylene oxide)
• Polymers containing acidic functional groups may be suitable for solid dispersions, which release the active substance in a preferred pH range providing acceptable absorption in the intestines.
• Such polymers may be one ore more selected from the group comprising hydroxypropyl methylcellulose phtalate (HMPCP), polyvinyl acetate phtalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), alginate, carbomer, carboxymethylcellulose, methacrylic acid copolymer (Eudragit L, Eudragit S), shellac, cellulose acetate phthalate (CAP), starch glycolate, polacrylin, methyl cellulose acetate phtalate, hydroxypropyulcellulose acetate phthalate, cellulose acetate terephtahalate, cellulose acetate isophthalate and cellulose acetate trimellitate.
• HMPCP hydroxypropyl methylcellulose phtalate
• PVAP polyvinyl
• the weight ratio of active substance to polymer may be in a range of from about 3:1 to about 1 :20. However, narrower ranges of from about 3:1 to about 1 :5, such as, e.g., from about 1 :1 to about 1 :3 or about may also be used.
• solid dispersion or solid solutions of one or more fibrates may be also obtained by dispersing and/or dissolving the active compound in the carrier composition used in the controlled agglomeration method. Stabilizing agents etc. may be added in order to ensure the stability of the solid dispersion/solution.
• a fenofibrate granulate is prepared as disclosed in International Application PCT/DK2004/000667 and example 9 herein.
• the fenofibrate granulate may be in the form of an immediate release formulation or in the form of a delayed release or even a controlled release formulation.
• a atorvastatin granulate is prepared in the same manner as the fenofibrate granulate, i.e. by dissolving or dispersing atorvastatin in a suitable vehicle such as the vehicle used for dissolving/dispersing fenofibrate and spraying the dispersion onto a suitable carrier to obtain a granulate.
• the two granulates are mixed and either compressed into tablets or filled into hard gelatine capsules.
• the atorvastatin granulate is optionally subjected to entero-coating prior to mixing, thus providing a controlled release atorvastatin formulation.
• the atorvastatin granulate may also be in the form of a delayed release formulation.
• a single granulate of fenofibrate and atorvastatin is prepared by dissolving fenofibrate together with atorvastatin in a suitable vehicle as described herein, followed by spraying the solution (or dispersion) on a a suitable carrier (as described herein), thereby obtaining a particulate material, i.e. a single granulate, which may be compressed into tablets in a conventional manner or filled into hard gelatine capsules.
• a single granulate of fenofibrate and atorvastatin is prepared by dissolving fenofibrate in a suitable vehicle as described herein, followed by spraying the solution (or dispersion) on a mixture of a suitable carrier (as described herein) and the desired amount of atorvastatin, thereby obtaining a particulate material, i.e. a single granulate, which may be compressed into tablets in a conventional manner or filled into hard gelatine capsules.
• a fenofibrate granulate is prepared as disclosed in International Application PCT/DK2004/000667 and example 9 herein.
• An atorvastatin granulate corresponding to the granulate composition of Lipitor ® tablets is prepared. The two granulates are mixed and either compressed into tablets or filled into hard gelatine capsules.
• a fenofibrate granulate is prepared as disclosed in International Application PCT/DK2004/000667 and example 9 herein. Atorvastatin is micronized and mixed with fenofibrate granulate and optionally conventional excipients and/or additives such as glidants, fillers, binders or disintegrators. The mixture may be compressed into tablets or filled into hard gelatine capsules.
• a fenofibrate granulate is prepared as disclosed in International Application PCT/DK2004/000667 and example 9 herein.
• Granulate is compressed into a tablet, and the tablet is coated with an aqueous suspension comprising a sufficient amount of atorvastatin including a film-forming polymer and stabilizers (antioxidants).
• atorvastatin including a film-forming polymer and stabilizers (antioxidants).
• the tablets might be sub-coated with a film-forming polymer before coating with the statin suspension below.
• film polymers include water soluble agents such as hydroxypropylmethylcellulose, Metolose ® (HPMC), hydroxypropylmethylcellulose, Klucel ® (HPC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) or combinations of PVA and PVP (Kollicoat ® IR) and acid soluble acrylic polymer (Eudragit E, soluble in gastric juice).
• water soluble agents such as hydroxypropylmethylcellulose, Metolose ® (HPMC), hydroxypropylmethylcellulose, Klucel ® (HPC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP) or combinations of PVA and PVP (Kollicoat ® IR) and acid soluble acrylic polymer (Eudragit E, soluble in gastric juice).
• antioxidants examples include butylhydroxyanisol (BHA), ascorbyl palmitate, ascorbic acid or combinations of BHA, ascorbyl palmitate and citric acid.
• Wetting and pH adjusting agent might be included in the coating suspension.
• the amount of atorvastatin in the coating suspension is between about 2% w/w and about 40% w/w, such as for example between about 5% w/w and about 30% w/w. The skilled person will know how to determine the exact amount of atorvastatin in the coating composition, when the desired amount of atorvastatin in the final composition and/or dosage form is known, for example 20 mg atorvastatin and 120 mg fenofibrate.
• Coating of fenofibrate tablets is performed in conventional coating equipment such as drum coater, perforated vessel or fluidized bed (Wurster insert).
• the atorvastatin coated fenofibrate tablets might be further coated with a suitable polymer to protect the atorvastatin from degradation.
• the pharmaceutical composition according to the invention is in solid, particulate form and may be employed as such. However, in many cases it is more convenient to present the composition in the form of granules, pellets, microspheres, nanoparticles and the like or in the form of solid dosage forms including tablets, tablets, beads, capsules, grains, pills, granulates, granules, powder, pellets, sachets, lozenges, troches and the like.
• a solid dosage form according to the invention may be a single unit dosage form or it may in the form of a poly-depot dosage form contain a multiplicity of individual units such as, e.g., pellets, beads and/or granules.
• a pharmaceutical composition or a solid dosage form of the invention is intended for administration via the oral, buccal or sublingual administration route.
• the dosage form of the invention is truly a solid, i.e. the dosage form does not comprise any liquid, semi-liquid or semi-solid material. Neither does the solid dosage form of the invention comprise a suspension, an emulsion or a micro- emulsion.
• a solid dosage form according to the present invention comprises a pharmaceutical composition in particulate form as described above.
• the details and particulars disclosed under this main aspect of the invention apply mutatis mutandis to the other aspects of the invention. Accordingly, the properties with respect to increase in bioavailability, changes in bioavailability parameters, reduction in adverse food effect as well as release of one or more fibrates etc. described and/or claimed herein for pharmaceutical compositions in particulate form are analogues for a solid dosage form according to the present invention.
• the solid dosage form of the invention i.e. in unit dosage form, comprises comprises from about 30 to about 170 mg of fenofibrate and from about 5 to about 80 mg of atorvastatin or a pharmaceutically acceptable salt thereof.
• the unit dosage form comprises about 160 mg of fenofibrate, or about 145 mg of fenofibrate, or about 130 mg, or about 120 mg of fenofibrate, or about 110 mg of fenofibrate, and about 10 mg of atorvastatin, or about 15 mg of atorvastatin, or about 20 mg of atorvastatin, or about 25 mg of atorvastatin, or about 30 mg of atorvastatin, or about 40 mg of atorvastatin, or of a pharmaceutically acceptable salt of atorvastatin.
• the unit dosage form comprises fenofibrate and atorvastatin or pharmaceutically acceptable salt thereof in the (relative) weight ratio between fenofibrate and atorvastatin or a pharmaceutically acceptable salt thereof from about 1 :1 to about 40:1.
• the concentration of the pharmaceutical composition in particulate form is in a range of from about 5 to 100% w/w such as, e.g., from about 10% to about 90% w/w, from about 15% to about 85% w/w, from about 20% to about 80% w/w, from about 25% to about 80% w/w, from about 30% to about 80% w/w, from about 35% to about 80% w/w, from about 40% to about 75% w/w, from about 45% to about 75% w/w or from about 50% to about 70% w/w of the dosage form.
• the concentration of the pharmaceutical composition in particulate form is 50% w/w or more of the dosage form.
• the solid dosage forms of the invention are stable.
• the fenofibrate is present in an amount of at least about 90%, or at least about 95%, or at least about 99.3%, or at least about 100%, relative to the amount prior to storage, when assayed after 3 months of storage at a temperature of about 4O 0 C and a relative humidity of about 75%.
• the physical stability is high as can be seen from the Examples below.
• the solid dosage form according to the invention is obtained by processing the particulate material according to the invention by means of techniques well- known to a person skilled in the art. Usually, this involves further addition of one or more of the pharmaceutically acceptable excipients mentioned herein.
• the composition or solid dosage form according to the invention may be designed to release fenofibrate and/or atorvastatin in any suitable manner provided that the increase in bioavailability is maintained.
• the active substance(s) may be released relatively fast in order to obtain an enhanced on-set of action, it may be released so as to follow zero or first order kinetics or it may be released in a controlled or modified manner in order to obtain a predetermined pattern of release. Plain formulations are also within the scope of the present invention.
• composition or solid dosage form according to the invention may also be coated with a film coating, an enteric coating, a modified release coating, a protective coating, an anti-adhesive coating etc.
• a controlled release profile of atorvastatin is obtained by means of applying a time-controlled coating or en enzyme controlled coating or a pressure controlled coating.
• a solid dosage form according to the invention may also be coated in order to obtain suitable properties e.g. with respect to release of the active substance.
• the coating may be applied on single unit dosage forms (e.g. tablets, capsules) or it may be applied on a poly-depot dosage form or on its individual units.
• Suitable coating materials are e.g.
• compositions i.e. particulate material or the solid dosage form
• the active substances may be released relatively fast in order to obtain an enhanced on-set of action, it may be released so as to follow zero or first order kinetics or it may be released in a controlled or modified manner in order to obtain a predetermined pattern of release. Plain formulations are also within the scope of the present invention.
• a solid dosage form of the invention results in an increased bioavailability of fenofibrate and/or atorvastatin relative to existing commercial fenofibrate and/or atorvastatin dosage forms when administered to a mammal in need thereof.
• a solid dosage form according to the invention may provide an AUCo-24 value of fibric acid relative to that of commercially available Tricor ® (Lipanthyl ®) tablets, or alternatively of commercially available Antara ® capsules, of at least about 1.1 , or at least about 1.2, or at least about 1.3, or at least about 1.4, or at least about 1.5, or at least about 1.75 or more, or at least about 2.0, or at least about 2.5, or at least about 3.0, the AUCo-24 values being determined under similar conditions.
• a solid dosage form may provide a c ma ⁇ value relative to that of commercially available Tricor ® (Lipanthyl ®) tablets, or alternatively of commercially available Antara ® capsules, of at least about 1.1 , or at least about 1.2, or at least about 1.3, or at least about 1.4, or at least about 1.5, or at least about 1.6 or more, or at least about 2.0, or at least about 2.5, or at least about 3.0, the c ma ⁇ values being determined under similar conditions.
• a solid dosage form according to the invention may provide an AUCo-24 value relative to that of commercially available Lipitor ® tablets of at least about 1.0, or at least about 1.1 , or at least about 1.23, or at least about 1.3, or at least about 1.4, or at least about 1.75 or more, or at least about 2.0, or at least about 2.5, or at least about 3.0, the AUCo-24 values being determined under similar conditions.
• a solid dosage form may provide a Cmax value relative to that of commercially available Lipitor ® tablets of at least about 1.0, or at least about 1.1 , or at least about 123, or at least about 1.3, or at least about 1.4, or at least about 1.5 or more, or at least about 2.0, or at least about 2.5, or at least about 3.0, the c ma ⁇ values being determined under similar conditions.
• the AUCo-24 of fenofibrate resulting from the administration of 160 mg fenofibrate tablets are about 118,300 ng h/mL.
• wide individual variations in bioavailability are usually observed.
• a pharmaceutical composition or a solid dosage form according to the invention is designed to release the fenofibrate in a suitable manner. Specific release patterns as well as specific absorption patterns are mentioned below. [0215] In specific embodiments, the fenofibrate and/or the atorvastatin is released from the composition within about 2 hours such as, e.g., within about 1.5 hours or within about 1 hour after oral administration, and/or about 50% w/w or more of the fibrate and/or the statin is released from the composition within about 30 min after oral administration, and/or about 50% w/w or more of the fibrate and/or the statin is released from the composition within about 20 min after oral administration, and/or about 60% w/w or more of the fibrate is released from the composition within about 1.5 hours after oral administration, and/or about 60% w/w or more of the fibrate and/or the statin is released from the composition within about 1 hour after oral administration, and/or about 70% w/w or more of the fibrate and/or the
• about 50% w/w or more of the fenofibrate and/or the atorvastatin is released from the composition within about 20 min, 15 min or 10min, and/or about 60% w/w or more of the fibrate and/or the statin is released from the composition within about 20 min or 15 min, and/or about 70% w/w or more of the fibrate and/or the statin is released from the composition within about
• about 50% w/w or more of the fenofibrate and/or the atorvastatin contained in the composition is absorbed within about 8 hours, 7 hours, 6 hours or 5 hours, and/or about 60% w/w or more of the fibrate and/or statin contained in the composition is absorbed within about 8 hours or 7 hours after oral administration, and/or about 60% w/w or more of the fibrate contained in the composition is absorbed within about 7 hours after oral administration, and/or about 70% w/w or more of the fibrate contained in the composition is absorbed within about 8 hours or 7 hours after oral administration.
• Lactose monohydrate 200 mesh (from DMV)
• Tablets, capsules or granules might be enteric coated with different types of polymers such as hydroxypropylmethylcellulose acetate succinate
• TRICOR ® (Lipanthyl ®) tablets from Abbott Laboratories are fenofibrate-containing tablets available for oral administration, either containing 48 mg or 54 mg or 145 mg or 160 mg of fenofibrate per tablet.
• the tablets contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide, xanthan gum, colorant.
• the melt feed unit is a prototype composed of separate units for heating of air supplies for the atomizer, pressure tank and feeding tube. Granulate was sieved manually and mixed with extragranular excipients in a Turbula mixer.
• the fenofibrate drug was dissolved into the liquefied vehicle(s) and applied on the particulate carrier(s) as follows:
• the vehicle(s) was melted in a beaker placed in a microwave oven.
• the beaker was transferred to a temperature controlled heating plate supplied with magnetic stirring.
• Fenofibrate was dissolved slowly in the liquefied vehicle at a temperature of 75 0 C under magnetic stirring.
• the hot solution was transferred to the pressure tank for melt spray application onto the carrier in the fluid bed.
• the granulate product was discharged from the fluid bed and sieved through sieve 0.7 mm or 1.0 mm manually.
• the sieved product was blended with magnesium stearate for 0.5 min in a Turbula mixer. If an extragranular phase has to be incorporated, the extragranular phase was premixed with granulate in 3 minutes in a Turbula mixer.
• the test involves determination of flowability according to the method described in Ph. Eur. by measuring the flow rate of the material out of a funnel with a nozzle diameter of 10.0 mm.
• Viscoleo medium chain triglycerides MCT; Miglyol 812 N from Condea
• MCT medium chain triglycerides
• Miglyol 812 N from Condea
• the material to be tested has a high bulk volume (e.g. like that of Aeroperl 300) only 50 g of the mixture is used when testing these blends.
• the maximal concentration of oil where flow of material could be obtained is called the
• Threshold Value (given as % w/w).
• Dissolution test [0242] The test was performed in accordance with Ph. Eur 2.9.3 using the paddle apparatus. The quantification was performed using HPLC with UV-detection.
• the bulk density was measured by pouring 100 g of the powder in question in a 250 ml graduated cylinder. The bulk density is given as the tapped bulk density in g/ml. The determination was performed according to Ph. Eur. (apparent volume).
• the oil absorption value is determined by adding well-defined amounts (a 10 g) of viscoleo to a well-defined amount of the pharmaceutically acceptable material (100 g) to be tested.
• the oil absorption value (expressed as g viscoleo/100 g material) is reached when a further addition of 10 g oil results in a material that does not have suitable properties with respect to flowability, i.e. the material does not meet the meet the requirements when tested according to
• the apparatus applied was a Micromertics Gemini 2375.
• the method applied was according to USP volumetric methods based on multiple point determination.
• the fenofibrate is dissolved in a vehicle.
• test involving differential scanning calometry is performed.
• the test is performed on the particulate composition, solid dosage form or mixture of vehicle and fibrate (after the solid solution is supposed to form).
• Heating rate 5 0 C /min from 27 0 C to 110 0 C
• the geometric weight mean diameter was determined by employment of a method of laser diffraction dispersing the particulate material obtained (or the starting material) in air. The measurements were performed at 1 bar dispersive pressure in Sympatec Helos equipment, which records the distribution of the equivalent spherical diameter. This distribution is fitted to a log normal volume-size distribution.
• geometric weight mean diameter means the mean diameter of the log normal volume-size distribution.
• Pre-dose 1 , 1.5, 2, 3, 4, 6, 8, 12 and 24 hours after dosing. 4 ml of blood were collected, mixed with EDTA, and the samples were frozen (-8O 0 C). The blood samples were analyzed using on-line extraction LC/MS and results were given in mg/mL.
• Fenofibrate and atorvastatin are mainly dissolved/dispersed in polyethylene glycol 6000 and poloxamer 188 (70:30 w/w ratio) at 7O 0 C.
• the dispersion is sprayed on 250 g lactose in a fluid bed Phast FB-100 with a Phast FS-1.7 melt- spray unit.
• the particular material obtained is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
• the powder mixture is compressed into 13 mm tablets with strength of 130 mg fenofibrate and 10 mg atorvastatin in to a 637 mg tablet with compound cup shaped.
• Fenofibrate and atorvastatin are mainly dissolved/dispersed in polyethylene glycol 6000 and poloxamer 188 (70:30 w/w ratio) at 7O 0 C.
• the dispersion is sprayed on 261 g lactose in a fluid bed Phast FB-100 with a Phast FS-1.7 melt- spray unit.
• the particular material obtained is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
• the powder mixture is compressed into 13 mm tablets with strength of 120 mg fenofibrate and 20 mg atorvastatin into a 648 mg tablet with compound cup shaped.
• Mean disintegration time 25 min, Hardness: 47 N
• Fenofibrate and atorvastatin are mainly dissolved/dispersed in polyethylene glycol 6000 and poloxamer 188 (70:30 w/w ratio) at 7O 0 C.
• the dispersion is sprayed on 250 g lactose in a fluid bed Phast FB-100 with a Phast FS-1.7 melt- spray unit.
• the particulate material obtained is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
• the powder mixture is compressed into 12 mm tablets with strength of 120 mg fenofibrate and 10 mg atorvastatin into a 618 mg tablet with compound cup shaped.
• Mean disintegration time 22 min, Hardness: 41 N
• Fenofibrate and atorvastatin are mainly dissolved/dispersed in polyethylene glycol 6000 and poloxamer 188 (70:30 w/w ratio) at 7O 0 C.
• the dispersion is sprayed on 266 g lactose in a fluid bed Phast FB-100 with a Phast FS-1.7 melt- spray unit.
• the particulate material is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
• the powder mixture is compressed into 13 mm tablets with strength of 120 mg fenofibrate and 30 mg atorvastatin into a 673 mg tablet with compound cup shaped.
• Fenofibrate and atorvastatin are mainly dissolved/dispersed in glyceryl monostearate at 70 0 C.
• the solution is sprayed on 200 g lactose in a fluid bed Phast FB-100 with a Phast FS-1.7 melt-spray unit.
• the particulate material is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
• the powder mixture is compressed into 11 mm tablets with 532 mg tablet with compound cup shape.
• Modified release poly-depot capsule based on swelling hydrocolloid matrix of hydroxypropylcellulose
• Substance Ingredient mg Drug Fenofibrate 120.00 Drug Atorvastatin calcium 20.00 Carrier HPMC 2910 3 cp 150.00 Carrier Lactose 200 mesh 50.00 Vehicle Glyceryl monostearate 300.00 Total 640.00
• Fenofibrate and atorvastatin are mainly dissolved/dispersed in glycerylmonostearate at 7O 0 C.
• the solution is sprayed on a mixture of 50 g lactose and 150 g HPMC in a fluid bed Phast FB-100 with a Phast FS-1.7 melt-spray unit.
• the particulate material is sieved through sieve 0.7 mm and filled into hard gelatine capsules (640 mg)
• Fenofibrate and atorvastatin are mainly dissolved/dispersed in polyethylene glycol 3000 at 70 0 C.
• the dispersion is sprayed on 95 g Aeroperl in a fluid bed Phast FB-100 with a Phast FS-1.7 melt-spray unit.
• the particulate material is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
• the powder mixture is compressed into 11 mm tablets with strength of 120 mg fenofibrate and 40 mg atorvastatin into a 463 mg tablet with compound cup shaped.
• compositions were prepared according to the method described in Example 1 above.
• All granulates listed herein can either be filled into hard gelatin capsules or compressed into tablets.
• the fenofibrate granulate is mixed with another granulate containing atorvastatin.
• This statin granulate is as follows:
• the granulate obtained is sieved through sieve 0.7 mm and blended with the fenofibrate granulate and magnesium stearate for 0.5 min in a Turbula mixer.
• the final granulate is compressed into 13.5 mm tablets with strength of 160 mg fenofibrate and 10 mg atorvastatin into a 970 mg tablet with compound cup shaped.
• Fenofibrate granulate was prepared as described in PCT/DK2004/000667.
• Atorvastatin granulate was prepared in a conventional manner using wet granulation, i.e. mixing atorvastatin, lactose and calcium carbonate, adding the appropriate amount of Klucel and Ac-di-sol, adding sterile water to the mixture, mixing and drying off the water, sifting the dried mixture and adding magnesium stearate and Avicel.
• the resulting tablets were oblong, white to slightly pale yellow tablets (7.0 mm x 18 mm).
• a single granulate comprising fenofibrate and atorvastatin is made as follows:
• Fenofibrate and atorvastatin are mainly dissolved/dispersed in polyethylene glycol 6000 and Poloxamer 188 (70:30 w/w ratios) at 70 0 C.
• the dispersion is sprayed on 329 g lactose in a fluid bed Phast FB-100 with a Phast FS-1.7 melt- spray unit.
• the particulate material obtained is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
• the granulate is compressed into 13.5 mm tablets with strength of 120 mg fenofibrate and 30 mg atorvastatin into a 752 mg tablet with compound cup shaped.
• a single granulate comprising fenofibrate and atorvastatin is made as follows:
• Fenofibrate is dissolved in polyethylene glycol 6000 and Poloxamer 188 (70:30 w/w ratios) at 7O 0 C.
• the dispersion is sprayed on a mixture of 349 g lactose and 10 g of atorvastatin in a fluid bed Phast FB-100 with a Phast FS-1.7 melt- spray unit.
• the particulate material obtained is sieved through sieve 0.7 mm and blended with magnesium stearate for 0.5 min in a Turbula mixer.
• the granulate is compressed into 13.5 mm tablets with strength of 120 mg fenofibrate and 10 mg atorvastatin into a 780 mg tablet with compound cup shaped.
• the fenofibrate granulate is mixed with a granulate similar to the granulate composition of LipitorTM tablets of either 10, 20 or 40 mg of atorvastatin in order to obtain the same plasma profiles as those of LipitorTM .
• LipitorTM based granulates may have the following composition(s):
• the fenofibrate granulate and the "Lipitor" granulate are mixed in a turbula mixer and the final granulate is then either filled into hard gelatin capsules or compressed into tablet with a suitable crushing strengths around 40-50 N.
• a fenofibrate granulate B of table 9 was manufactured.
• the fenofibrate granulate is mixed with micronized atorvastatin, optionally added conventional excipients or additives for tablet production like a glidant, filler, binder, or disintegrator.
• the granulate is either filled into hard gelatin capsules or compressed into tablet with a suitable crushing strength.
• Example 9F The granulate is either filled into hard gelatin capsules or compressed into tablet with a suitable crushing strength.
• a fenofibrate granulate B of table 9 was manufactured.
• the fenofibrate granulate were compressed into oblong tablets 19.9 x 8 mm with a mean tablet hardness of 80 N.
• the combination product of fenofibrate and atorvastatin is prepared by coating the fenofibrate tablets with a coating comprising atorvastatin, i.e. an aqueous suspension of atorvastatin including a film-forming polymer and stabilizers (antioxidants).
• atorvastatin i.e. an aqueous suspension of atorvastatin including a film-forming polymer and stabilizers (antioxidants).
• the fenofibrate tablets may optionally be sub-coated with a film-forming polymer prior to coating with the atorvastatin suspension.
• the aqueous suspension of atorvastatin has the following composition:
• Each tablet is coated with approx 171 g coating suspension corresponding to 10 mg atorvastatin per tablet.
• the atorvastatin-coated fenofibrate tablets may additionally be coated with a suitable polymer to protect atorvastatin from degradation.
• compositions of the invention were investigated in in vivo studies in dog. As fenofibrate is a drug substance that has major bioavailability problems, the study was primarily to investigate whether an improved bioavailability could be obtained. Accordingly, no data with respect to the statin component is available. [0362] Tablets of 50 mg and 160 mg strength with respect to fenofibrate, respectively and having the following compositions were prepared as described in Example 1 : [0363]
• a clinical trial study was carried out in order to determine the pharmacokinetic profile of the fenofibrate formulation used in the combination composition of this invention, 160 mg tablets taken with food and without food in comparison with Lipanthyl ® (Tricor ®) 160 mg tablets taken with and without food.
• the study was conducted in Switzerland as a randomized, four-way cross ⁇ over study including 24 healthy volunteers (aged 27-55 years; 21 males and 3 females; body weight > 65 kg); 23 subjects concluded the study, 1 subject dropped out after period 3 for personal reasons (missing period: Lipanthyl fasted).
• the study was carried out as a combined PK and food-effect study according to FDA guidelines.
• the objective was to demonstrate that the fenofibrate formulation used in the combination composition of the present invention (administered in fed state) and Lipanthyl (administered in fed state) are bioequivalent and, further that the present fenofibrate formulation, when administered in fed state, is bioequivalent to the identical formulation administered in fasted state.
• Conditions (fed state) were according to Guidance for Industry: Food-effect Bioavailability and Fed Bioequivalence Studies; CDER December 2002: An overnight fast of the subjects of at least 10 hours; high-fat, high-calorie breakfast within 30 minutes or less; 800-1000 calories in total (150 from protein; 250 from carbohydrate; 500-600 from fat); 240 ml plain water at study drug administration.
• Conditions (fasted state) were according to Guidance for Industry: Food- effect Bioavailability and Fed Bioequivalence Studies; CDER December 2002: An overnight fast of the subjects of at least 10 hours; no breakfast and no food intake 4 hours after drug administration; 240 ml plain water at study drug administration.
• a product is considered bioequivalent with a reference product, when AUCo- t, AUCo-inf, Cmax is within 80-125% of the reference product, including the 90% Confidence Intervals (Cl).

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